Neurologic Aspects of Systemic Disease Part I [1st Edition] 9780702044328, 9780702040863

Table of contents :
Content:
Series PagePage ii
CopyrightPage iv
Handbook of Clinical Neurology 3rd SeriesPage v
ForewordPage viiMichael J. Aminoff, François Boller, Dick F. Swaab
PrefacePage ixJosé Biller, José M. Ferro
ContributorsPages xi-xiv
Chapter 1 - Cardiovascular manifestations of neurologic diseasePages 3-17Keith Dombrowski, Daniel Laskowitz
Chapter 2 - Sudden cardiac deathPages 19-24Alejandro A. Rabinstein
Chapter 3 - Neurologic complications of cardiac arrestPages 25-39Matthew McCoyd, Thomas McKiernan
Chapter 4 - Neurologic complications of cardiac tests and proceduresPages 41-47Cathy Sila
Chapter 5 - Neurologic complications of congenital heart disease and its treatmentPages 49-59Emily de los Reyes, E. Steve Roach
Chapter 6 - Neurologic complications of valvular heart diseasePages 61-73Salvador Cruz-Flores
Chapter 7 - Infective endocarditisPages 75-91José M. Ferro, Ana Catarina Fonseca
Chapter 8 - Neurologic complications of myocardial infarctionPages 93-110Moneera N. Haque, Robert S. Dieter
Chapter 9 - Neurologic complications of cardiomyopathies and other myocardial disordersPages 111-128John F. Moran
Chapter 10 - Neurologic complications of arrhythmia treatmentPages 129-150Megan C. Leary, Jeffrey S. Veluz, Louis R. Caplan
Chapter 11 - Neurologic complications of catheter ablation/defibrillators/pacemakersPages 151-160Smit C. Vasaiwala, David J. Wilber
Chapter 12 - Hypertension and hypertensive encephalopathyPages 161-167Raymond S. Price, Scott E. Kasner
Chapter 13 - Transient loss of consciousness and syncopePages 169-191Claudio L. Bassetti
Chapter 14 - Neurologic complications of cardiac surgery and interventional cardiologyPages 193-208Sara Hocker, Eelco F.M. Wijdicks, Jose Biller
Chapter 15 - Neurologic complications of cardiac tumorsPages 209-222David Roeltgen, Chelsea S. Kidwell
Chapter 16 - Neurologic complications of aortic diseases and aortic surgeryPages 223-238Richard Hershberger, Jae S. Cho
Chapter 17 - Breathing and the nervous systemPages 241-250Mian Zain Urfy, Jose I. Suarez
Chapter 18 - Obstructive sleep apnea and other sleep-related syndromesPages 251-271Teresa Paiva, Hrayr Attarian
Chapter 19 - Acute and chronic respiratory failurePages 273-288Sabin Oana, Jayanta Mukherji
Chapter 20 - Venous thromboembolism in neurologic diseasePages 289-304Michael J. Schneck
Chapter 21 - Neurologic manifestations of sarcoidosisPages 305-333Allan Krumholz, Barney J. Stern
Chapter 22 - Neurologic complications of lung cancerPages 335-361Edward J. Dropcho
Chapter 23 - Neurologic complications of electrolyte disturbances and acid–base balancePages 365-382Alberto J. Espay
Chapter 24 - Neurologic complications of acute and chronic renal diseasePages 383-393Martin W. Baumgaertel, Markus Kraemer, Peter Berlit
Chapter 25 - Nervous system disorders in dialysis patientsPages 395-404Vinod K. Bansal, Seema Bansal
Chapter 26 - Nephrotic syndromePages 405-415David S. Liebeskind
Chapter 27 - Use of antiepileptic drugs in hepatic and renal diseasePages 417-432Jorge J. Asconapé
Chapter 28 - Neurologic complications of craniovertebral dislocationPages 435-448Mamede de Carvalho, Michael Swash
Chapter 29 - Rheumatoid arthritis, spondyloarthropathies, and relapsing polychondritisPages 449-461Rochella A. Ostrowski, Troy Takagishi, John Robinson
Chapter 30 - Connective tissue disorders: systemic lupus erythematosus, Sjögren’s syndrome, and sclerodermaPages 463-473Jonathan Y. Streifler, Yair Molad
Chapter 31 - Cerebral vasculitisPages 475-494Harold P. Adams Jr.
Chapter 32 - Idiopathic inflammatory myopathiesPages 495-512A.J. van der Kooi, M. de Visser
Chapter 33 - FibromyalgiaPages 513-527Janice E. Sumpton, Dwight E. Moulin
Chapter 34 - Paget’s disease of bonePages 529-540Gregory Gruener, Pauline Camacho
Chapter 35 - Spinal stenosisPages 541-549João Levy Melancia, António Fernandes Francisco, João Lobo Antunes
Chapter 36 - Neurologic manifestations of achondroplasiaPages 551-563Jacqueline T. Hecht, John B. Bodensteiner, Ian J. Butler
Chapter 37 - Neurologic manifestations of inherited disorders of connective tissuePages 565-576Stéphanie Debette, Dominique P. Germain
Chapter 38 - Nonsteroidal anti-inflammatory drugs exposure and the central nervous systemPages 577-584Eitan Auriel, Keren Regev, Amos D. Korczyn
IndexPages I1-I46

Citation preview

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 119

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2014

ELSEVIER B.V. Radarweg 29, 1043 NX, Amsterdam, The Netherlands © 2014, Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (þ1) 215 239 3804 (US) or (þ44) 1865 843830 (UK); fax: (þ44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). ISBN: 9780702040863 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the contributors or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. The Publisher

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Handbook of Clinical Neurology 3rd Series Available titles Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 9780444513571 Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 9780444514905 Vol. 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016 Vol. 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941 Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009 Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933 Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104 Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996 Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965 Vol. 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972 Vol. 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989 Vol. 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958 Vol. 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081 Vol. 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036 Vol. 93, Stroke – Part II: clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043 Vol. 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050 Vol. 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081 Vol. 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159 Vol. 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392 Vol. 98, Sleep disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067 Vol. 99, Sleep disorders Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074 Vol. 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142 Vol. 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315 Vol. 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039 Vol. 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927 Vol. 104, Neuro-oncology Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385 Vol. 105, Neuro-oncology Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023 Vol. 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029 Vol. 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988 Vol. 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995 Vol. 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378 Vol. 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015 Vol. 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919 Vol. 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107 Vol. 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652 Vol. 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds. ISBN 9780444534903 Vol. 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022 Vol. 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972 Vol. 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910 Vol. 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016

Foreword

Although neurology and psychiatry are closely linked specialties, many neurologists see their specialty as part of internal medicine. Indeed, neurology departments in the United States often began as divisions within departments of internal medicine, attesting to their special relationship. With the evolution of neurology as an independent discipline, it has become particularly important for its practitioners to remain familiar with the neurologic aspects of systemic diseases as well as with the systemic aspects of neurologic disorders. This has been recognized since the Handbook of Clinical Neurology was founded by Pierre Vinken and George Bruyn, with volume 1 appearing in December 1968. That first series concluded in 1982 and was followed by a second series, edited by them, that concluded—in turn—in 2002. We then took over as editors of the current third series, with volume 79 appearing in late 2003 and several volumes appearing annually since then. Two volumes (38 and 39) were published in the first series of the Handbook, focusing on the neurologic manifestations of systemic diseases. The second series included a further three volumes (63, 70, and 71) on the same topic, published in 1993 and 1998, with one of us (MJA) serving as an editor of those volumes. Advances in the field, but especially in immunology, genetics, imaging, pharmacotherapeutics, and intensive care, since that time have necessitated a reappraisal of the field and the publication of three new volumes on the topic. We are therefore particularly delighted at the publication of this scholarly contribution to the medical and neurologic literature and welcome it as part of the Handbook. We believe that it will appeal not only to neurologists but to physicians in all specialties, helping in their interactions with each other and with their patients. Professors Jose´ Biller and Jose´ M. Ferro have together produced an authoritative, comprehensive, and up to date account of the topic and have assembled a truly international group of authors with acknowledged expertise to contribute to these important multifaceted volumes. We are grateful to them and to all the contributors for their efforts in creating such an invaluable resource. We are confident that clinicians in many different disciplines will find much in these volumes to appeal to them. It is a pleasure, also, to thank Elsevier, our publishers – and in particular Tom Stone, Michael Parkinson, and Kristi Anderson – for unfailing and expert assistance in the development and production of these volumes. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

Preface

Medicine has always been in a state of evolution and today, more than ever, with the accelerated growth of scientific knowledge, patients are evaluated and treated by teams of physicians. The extensive body of knowledge and the major scientific and clinical advances in neurology and internal medicine are again drawing both specialties closer together. Whatever the subspecialty area of interest, the nature of modern clinical medicine calls for multidisciplinary collaborative efforts to better meet the needs of individual patients. The aim of these three volumes of the third series of the Handbook of Clinical Neurology is to integrate and provide a thorough framework of the core neurologic manifestations of a wide array of systemic disorders. Each chapter provides a critical appraisal and extensive background information regarding the variety of presentations of each disorder, the characteristic clinical course, the typical neurologic manifestations of each disease, and current therapeutic strategies. Comprehensive and updated references also bring forth valuable resources for further topical reading and research. Our intended audience includes experienced practitioners and residents in neurology, neurosurgery, and internal medicine, as well as other health care professionals in different subspecialties caring for these challenging patients. We have purposely divided these three volumes into chapters uniformly organized by organ system, which are further divided by specific conditions and disease categories. Volume I is dedicated to the neurologic aspects of cardiopulmonary diseases, renal disorders, and selective rheumatologic and musculoskeletal disorders. Volume II encompasses core neurologic aspects of gastrointestinal and hepatobiliary disorders, endocrinologic diseases, and a gamut of metabolic, nutritional and environmental conditions. Volume III concentrates on the neurologic aspects of hematologic and oncologic disorders, organ transplantation, infectious diseases, and tropical neurology. It also includes a miscellaneous group of disorders including neurodermatology, neurological complications of pregnancy, iatrogenic neurology, neuromuscular disorders in the intensive care setting, posterior reversible leukoencephalopathy and reversible cerebral vasoconstriction syndromes, neuro-Behcet’s, complications of neuroimaging, neurotraumatology, and observations pertaining to neurology in the developing world. These volumes go beyond the scope of classic neurology and examine the neurologic manifestations of a wide range of medical conditions, spanning most areas of medicine, that neurologists, neurosurgeons, internists, and other specialists must diagnose and treat in everyday practice. We are hopeful that these three volumes will contribute to the best possible care of patients with these disorders, and that the readership will find the material informative, authoritative, reliable, and stimulating We are extremely grateful to all the contributors from across the globe, who by sharing their knowledge and expertise made these volumes possible. To bring to fruition a work of this magnitude requires a highly professional editorial effort, and for this we thank Linda Turner for her wonderful organizational skills and administrative expertise, and Mike Parkinson and the editorial staff at Elsevier for their unfailing dedication, professionalism, and expert assistance in the development and production of these three volumes. Jose´ Biller, MD Jose´ M. Ferro, MD

Contributors

H.P. Adams Jr. Division of Cerebrovascular Diseases, Department of Neurology, Carver College of Medicine, University of Iowa Health Care Stroke Center, University of Iowa, Iowa City, IA, USA J.L. Antunes Department of Neurosurgery, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal J.J. Asconape´ Department of Neurology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA H. Attarian Circadian Rhythms and Sleep Research Laboratory, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA E. Auriel Department of Neurology, Tel-Aviv University, Ramat-Aviv, Israel S. Bansal Pediatric Neurology, National Children’s Medical Center, Washington, DC, USA V.K. Bansal Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA C.L. Bassetti Department of Neurology, University Hospital of Bern (Inselspital), Bern, Switzerland

M.W. Baumgaertel St. Franziskus Hospital Muenster, Department of Nephrology, M€ unster, Germany J.B. Bodensteiner Department of Neurology, Mayo Clinic, Rochester, MN, USA I.J. Butler Division of Child and Adolescent Neurology, Department of Pediatrics, University of Texas Medical School, Houston, TX, USA P. Camacho Loyola University Osteoporosis and Metabolic Bone Disease Center, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA L.R. Caplan Division of Stroke and Cerebrovascular Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA J.S. Cho Division of Vascular Surgery and Endovascular Therapy, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA S. Cruz-Flores Department of Neurology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

P. Berlit Department of Neurology and Clinical Neurophysiology, Alfried-Krupp-Hospital, Essen, Germany

M. de Carvalho Department of Neurosciences, St Maria Hospital, and Institute of Molecular Medicine, Lisbon, Portugal

J. Biller Department of Neurology, Loyola University Medical Center, Maywood, IL, USA

E. de los Reyes Division of Child Neurology, Ohio State University, Columbus, OH, USA

xii CONTRIBUTORS M. de Visser M.N. Haque Department of Neurology, Academic Medical Centre, Division of Cardiology, Department of Medicine, Amsterdam, The Netherlands Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA S. Debette Department of Epidemiology and Public Health, J.T. Hecht Raymond Poincare´ Hospital, Garches; INSERM Unit Department of Pediatrics and Pediatric Research U708, Pitie´-Salpeˆtrie`re Hospital, Paris and University of Center, University of Texas Medical School, Houston, Versailles – St Quentin en Yvelines, Versailles, France TX, USA R.S. Dieter Division of Cardiology, Department of Medicine, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA

R. Hershberger Division of Vascular Surgery and Endovascular Therapy, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

K. Dombrowski Department of Medicine (Neurology), Duke University Medical Center, Durham, NC, USA

S. Hocker Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA

E.J. Dropcho Department of Neurology, Indiana University Medical Center, Indianapolis, IN, USA

S.E. Kasner Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

A.J. Espay James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, UC Neuroscience Institute, University of Cincinnati, Cincinnati, OH, USA

C.S. Kidwell Department of Neurology, Georgetown University Medical Center, Washington, DC, USA

J.M. Ferro Department of Neurosciences, Servic¸o de Neurologia, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal A.C. Fonseca Department of Neurosciences, Servic¸o de Neurologia, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal A.F. Francisco Department of Neurosurgery, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal D.P. Germain Division of Medical Genetics, National Referral Center for Fabry disease and Inherited Disorders of Connective Tissue, CHU Raymond Poincare´, Garches and University of Versailles – St Quentin en Yvelines, Versailles, France G. Gruener Leischner Institute of Medical Education and Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

A.D. Korczyn Department of Neurology, Tel-Aviv University, Ramat-Aviv, Israel M. Kraemer Department of Neurology and Clinical Neurophysiology, Alfried-Krupp-Hospital, Essen, Germany A. Krumholz Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA D. Laskowitz Departments of Medicine (Neurology), and Anesthesiology, Duke University Medical Center, Durham, NC, USA M.C. Leary Department of Neurology, Harvard Clinical Research Institute, Boston, MA, USA D.S. Liebeskind UCLA Stroke Center, Los Angeles, CA, USA M. McCoyd Department of Neurology, Loyola University Healthcare Center, Maywood, IL, USA

CONTRIBUTORS xiii T. McKiernan E.S. Roach Center for Heart and Vascular Medicine, Loyola Division of Child Neurology, Ohio State University, University Healthcare Center, Maywood, IL, USA Columbus, OH, USA J.L. Melancia Department of Neurosurgery, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal

D. Roeltgen Cape Physicians Associates, Cape May Court House, NJ, USA

Y. Molad Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Rheumatology Unit, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel

M.J. Schneck Departments of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

J.F. Moran Division of Cardiology, Loyola University Medical Center, Maywood, IL, USA

C. Sila Department of Neurology, Case Western Reserve University School of Medicine and Stroke and Cerebrovascular Center, University Hospitals–Case Medical Center, Cleveland, OH, USA

D.E. Moulin Departments of Clinical Neurological Sciences and Oncology, University of Western Ontario, London, Ontario J. Mukherji Department of Anesthesiology, Loyola University Medical Center, Maywood, IL, USA

B.J. Stern Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

S. Oana Department of Anesthesiology, Loyola University Medical Center, Maywood, IL, USA

J.Y. Streifler Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and Neurology Unit, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel

R.A. Ostrowski Division of Rheumatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA

J.I. Suarez Department of Neurology, Baylor College of Medicine, Houston, TX, USA

T. Paiva Sleep Medicine Centre, Medical Faculty of Lisbon, Lisbon, Portugal

J.E. Sumpton Department of Pharmacy, Victoria Hospital, London Health Sciences Centre, London, Ontario, Canada

R.S. Price Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

M. Swash Department of Neurology, Royal London Hospital, Queen Mary School of Medicine, University of London, London, UK

A.A. Rabinstein Department of Neurology, Mayo Clinic, Rochester, MN, USA K. Regev Department of Neurology, Tel-Aviv University, Ramat-Aviv, Israel J. Robinson Division of Rheumatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA

T. Takagishi Division of Rheumatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA M.Z. Urfy Department of Neurology, Baylor College of Medicine, Houston, TX, USA A.J. van der Kooi Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands

xiv

CONTRIBUTORS

S.C. Vasaiwala Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

E.F.M. Wijdicks Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA

J.S. Veluz Cardiothoracic Surgery, St. Luke’s Hospital and Health Network, Bethlehem, PA, USA

D.J. Wilber Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 1

Cardiovascular manifestations of neurologic disease 1

KEITH DOMBROWSKI1* AND DANIEL LASKOWITZ1,2 Department of Medicine (Neurology), Duke University Medical Center, Durham, NC, USA 2

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA

CARDIOLOGY IN VASCULAR AND INTENSIVE CARE NEUROLOGY The relationship between the nervous and cardiovascular systems has been well recognized since the mid-19th century (Coote, 2007), and cardiac complications are common during the care of hospitalized neurology patients. In recent years, an increasing body of experimental work has further defined the role of neurologic disease in mediating arrhythmias, subendocardial injury, neurogenic cardiomyopathy, and neurogenic shock (Oppenheimer, 1993; Cheung et al., 1997; Coote, 2007).

Pathophysiology Although the relationship between the heart and the brain has been explored for the better part of a century, more recent work has localized discrete neuroanatomic sites that influence heart rhythm and rate, myocardial function, and vascular tone (Oppenheimer, 1993; Tokgozoglu et al., 1999; Coote, 2007). These locations include the insular cortex, amygdala, paraventricular and caudal hypothalamus, and various sites in the brainstem and spinal cord including rostral ventrolateral medulla, solitary tract nucleus, and intermediolateral cell column (Fig. 1.1). (Aminoff, 1995; Coote, 2007). The insular cortex can influence the generation of arrhythmias and release of cardiac enzymes when irritated by vascular disease or epileptic phenomena, and several preclinical and clinical studies have demonstrated laterality of insular responses. The right insula is associated with tachyarrhythmias and a pressor response, while stimulation of the left insular cortex is more commonly associated with bradycardia and a depressor response (Oppenheimer et al., 1992; Oppenheimer, 1993; Tokgozoglu et al., 1999; Ay et al.,

2006). Decreased heart rate variability, suggestive of impaired autonomic regulation, is seen in stroke patients with right insular cortex involvement, and is associated with arrhythmias and an elevated risk of sudden cardiac death (Tokgozoglu et al., 1999; Colivicchi et al., 2004). Outflow from the insular cortex feeds back to subcortical and diencephalic structures such as the amygdala and hypothalamus. The amygdala is believed to play an important role in mediating cardiovascular responses to emotional stimuli, particularly negative stress responses. In a rat model of right middle cerebral artery stroke, increased concentrations of adrenergic precursors have been observed in the amygdala (Cheung et al., 1997). Extreme stress responses have been associated with the rare occurrence of neurogenic stunned cardiomyopathy (takotsubo disease). The hypothalamus, particularly dorsomedial and paraventricular nuclei, integrates input from higher neural centers and transmits autonomic information to sites within the brainstem and spinal cord (Furlan and Fehlings, 2008). There is a known correlation between damage to the hypothalamus and necrosis of myocardial tissue in subarachnoid hemorrhage (Doshi and Neil-Dwyer, 1977). The brainstem also plays an important role in mediating autonomic tone, and preclinical studies have implicated lower brainstem structures such as the rostral ventrolateral medulla and solitary tract nucleus (Coote, 2007). Clinically, the importance of brainstem structures in mediating cardiovascular responses is evident during neurosurgical procedures of the skull base and rostrocaudal herniation in the setting of intracranial hypertension. Changes in vascular tone may also be clinically important in the setting of trauma. Cases of spinal cord injury, particularly above the level of T6, may result in vasomotor paralysis

*Correspondence to: Keith Dombrowski, M.D., Fellow, Neurocritical Care, Department of Medicine (Neurology), Duke University Medical Center, Box 2905, Durham, NC 27710, USA. Tel: þ1-919-684-5650, Fax: þ1-919-684-6514, E-mail: keith.dombrowski@ duke.edu

4

K. DOMBROWSKI AND D. LASKOWITZ

Fig. 1.1. Sympathetic and parasympathetic outflow tracts of the central nervous system.

CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE and neurogenic shock. Thus, cervical and high thoracic spinal cord injury may impair sympathetic outflow with resultant autonomic dysreflexia, arrhythmias, and orthostatic hypotension (Furlan and Fehlings, 2008).

Acute ischemic stroke Cardiac complications from ischemic stroke are extremely common and may complicate clinical management. Such complications may be the result of concurrent cardiovascular disease or be caused by focal cerebral injury (Touze et al., 2005; Dhamoon et al., 2007; Lee et al., 2008). For example, the incidence of comorbid coronary artery disease in patients with ischemic cerebrovascular disease may be as high as 65% (Rokey et al., 1984). In the acute setting, it may be difficult to differentiate the influence of pre-existing coronary disease from cardiac dysfunction mediated by acute neurologic injury. Electrocardiographic changes are extremely prevalent in the setting of acute ischemic stroke, with some studies reporting EEG changes in up to 90% of patients. T wave inversion, ST-T changes, and premature ventricular beats are the most common (Dimant and Grob, 1977; Goldstein, 1979). In many circumstances, these ECG changes are transient and of little clinical consequence. However, more malignant arrhythmias, including third-degree atrioventricular block and asystole, may also occur (Christensen et al., 2005), and ventricular ectopy and QTc prolongation directly correlate with mortality. This may be related to elevated rates of ischemic cardiac disease in the ischemic stroke population (Stead et al., 2009). Arrhythmias are also common with stroke and include atrial fibrillation and sinus bradycardia. Although it is often difficult to discern whether newly documented atrial fibrillation is the cause or the consequence of stroke, ECG and cardiac monitoring of all acute ischemic stroke patients is recommended (Adams et al., 2007). Ischemic changes on ECG and elevation of serum cardiac enzymes (CK-MB and troponin I) are also commonly observed in the setting of acute ischemic stroke. Because ischemic stroke and myocardial infarction (MI) share similar risk factors, the occurrence of acute MI in the setting of large-artery cerebral atherothrombosis is not surprising. However, myocardial damage is frequently seen in the absence of cardiac symptomatology such as chest pain or echocardiographic change (Chalela et al., 2004; Lee et al., 2008). In circumstances such as this, myocardial injury is likely the result of dysautonomia with excess sympathetic tone. This may be produced by an increase in circulating catecholamines or norepinephrine release at endocardial nerve terminals. Stroke severity and localization to the

5

insular cortex and parietal lobe appear to correlate with the presence of myocardial damage and poor cardiac outcome (Ay et al., 2006; Rincon et al., 2008). The phenomenon of neurogenic stunned cardiomyopathy is less frequent in acute ischemic stroke, but is well described (Yoshimura et al., 2008).

Intraparenchymal hemorrhage ECG changes following intraparenchymal hemorrhage are similar to those of ischemic stroke and subarachnoid hemorrhage. Retrospective studies of patients with lobar and basal ganglia hemorrhages demonstrate ECG changes in 64–95% of cases (Goldstein, 1979; Hays and Diringer, 2006; Maramattom et al., 2006; van Bree et al., 2010). Repolarization changes are most characteristic and include QTc prolongation, nonspecific STT changes, and deeply inverted T waves. Prolonged QTc is frequently associated with hydrocephalus and insular cortex involvement (van Bree et al., 2010). Sinus bradycardia is a common arrhythmia found in patients with supratentorial intracerebral hemorrhage (ICH), while atrial fibrillation has been associated with brainstem hemorrhage (Talman, 1985). Although a common finding after ICH, ECG changes also do not consistently indicate that myocardial injury has taken place, and there is no clear association between mortality and the appearance or severity of ECG changes (Maramattom et al., 2006). Myocardial injury is observed in a small proportion of patients with intracerebral hemorrhage, likely as a result of an increase in sympathetic tone. The finding of troponin elevations may serve as an independent predictor of in-hospital mortality (Hays and Diringer, 2006; Sandhu et al., 2008; Chung et al., 2009).

Subarachnoid hemorrhage ECG changes in subarachnoid hemorrhage (SAH) were first described by Byer in 1947 (Byer et al., 1947), and may occur in up to 90% of patients, especially those of poor clinical grade (Andreoli et al., 1987). ECG changes in SAH are similar to those in intraparenchymal hemorrhage. T wave changes (22%) are the most frequent ECG abnormality reported, followed by U waves, presence of left ventricular hypertrophy (LVH), and prolonged QT (Di Pasquale et al., 1987; Kawahara et al., 2003; van der Bilt et al., 2009). The most common rhythm changes are sinus arrhythmias and atrial fibrillation, which typically occur in the first 24–48 hours after ictus. More ominous arrhythmias such as ventricular tachycardia, torsades de pointes, ventricular fibrillation, and asystole have also been described, and are more likely to occur in the setting of prolonged QT and hypokalemia (Di Pasquale et al., 1987, 1988).

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Myocardial injury is a common event in SAH and is probably of greater clinical significance than in intraparenchymal or ischemic stroke. The presence of ECG abnormalities, particularly repolarization changes and sinus arrhythmias, is significantly associated with an increase in poor outcome and death (van der Bilt et al., 2009). The frequency of cardiac biomarker elevation in SAH is approximately 33% (van der Bilt et al., 2009), with a direct correlation between clinical severity of the subarachnoid hemorrhage and the presence of myocardial injury (Tung et al., 2004; Kothavale et al., 2006). Elevations of serum brain natriuretic peptide may be secondary to direct brain injury or neurogenic cardiac injury, and may be correlated with delayed cerebral ischemia (Wijdicks et al., 1997; McGirt et al., 2004). Histologic evidence of myocardial injury changes consists of contraction band necrosis and myofibrillar degeneration with an inflammatory infiltrate (Doshi and Neil-Dwyer, 1977). In addition to cardiac enzyme elevations, transient wall motion abnormalities (WMA) on echocardiography have been reported in 22–31% of patients (van der Bilt et al., 2009). Myocardial WMAs are outside of normal coronary vascular distribution and can vary from segmental changes to global hypokinesis. It is likely that the changes correspond to the localization of cardiac sympathetic nerve terminals. In recent years, severe left ventricular systolic function (neurogenic stunned cardiomyopathy) (Fig. 1.2) has

been documented with increasing frequency in SAH. Left ventricular apical ballooning similar in appearance to stress cardiomyopathy (takotsubo disease) and severe global hypokinesis has been documented (Jain et al., 2004; Lee et al., 2006). Neurogenic stunned cardiomyopathy appears to be most common in young women who use sympathomimetic drugs (Kothavale et al., 2006). Although such phenomena are typically transient, these cardiac abnormalities are associated with a poor prognosis in SAH as well as increased frequency of vasospasm and delayed cerebral ischemia (Kothavale et al., 2006; van der Bilt et al., 2009). The clinical significance of impaired systolic or diastolic dysfunction is most evident during the treatment of vasospasm and delayed cerebral ischemia where augmentation of blood pressure with inotropic agents may be initiated to optimize cerebral perfusion.

Head trauma Cardiac abnormalities in traumatic brain injury (TBI) are likely common, although less well characterized than in other neurologic diseases (Hersch, 1961; Wittebole et al., 2005). In the largest series of 164 TBI patients, QT prolongation, increased P wave amplitudes, and T-wave inversions were found (Hersch, 1961; Wittebole et al., 2005). Additional reports have shown ischemic ECG changes in patients with TBI with no evidence of

Fig. 1.2. Diagnostic images in a single patient with neurogenic stunned myocardium. (A) Coronary angiogram without significant disease (left coronary artery). (B) Transthoracic echocardiogram showing systole with left apical ballooning (solid arrow) and hypercontractile base (dashed arrow). (C) Left ventriculogram in diastole showing apex (solid arrow) and base (dashed arrow). (D) Left ventriculogram in systole showing left apical ballooning (solid arrow) and hypercontractile base (dashed arrow). (Illustration graciously provided by David Adams, M.D., Duke University Medical Center Echocardiography Laboratory.)

CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE coronary vascular disease (Syverud, 1991). There are rare reports of myocardial injury and regional wall motion abnormalities (RWMA), as well (Riera et al., 2010). Studies of dysautonomia in TBI have demonstrated a correlation between decreased heart rate variability and poor prognosis in this patient population (Lowensohn et al., 1977).

Management of neurogenic cardiac events Although it is important to identify and monitor patients at risk for neurogenic cardiac injury, the optimal management of cardiac changes associated with acute brain injury has not been studied rigorously. This is particularly important, as ECG and echocardiographic findings consistent with ischemia or infarction may occur in patients without coronary artery disease, and these abnormalities are often self-limited and may be associated with focal wall motion abnormalities. An appropriate history and diagnostic workup should be performed, as the consequences of inappropriate thrombolytic, antithrombotic, and anticoagulant therapy in the setting of acute brain injury may be deleterious. For many patients, especially those with large intraparenchymal and subarachnoid hemorrhage, intensive care monitoring is required, though prospective data demonstrating the effect of dedicated neurointensive care units on patient outcomes remains an active area of research. The treatment of arrhythmias for patients with neurogenic cardiac abnormalities should include standard pharmacologic therapy and pacing. As overstimulation of the sympathetic nervous system is implicated in many forms of cardiac dysfunction following catastrophic brain injury, adrenergic blockade has been studied as a means of preventing myocardial injury and possibly improving survival in acute brain injury (Neil-Dwyer et al., 1978). In patients with decreased heart rate variability (cardiac uncoupling) and severe TBI, b-blockers may be associated with a survival benefit (Riordan et al., 2007). However, at the present time, there is no recommendation for the use of adrenergic blockade following TBI in the US (Carney and Ghajar, 2007). Several randomized clinical trials of atenolol, propranolol, and phentolamine have also suggested a reduction of myocardial necrosis and improved outcome in patients with subarachnoid hemorrhage (Neil-Dwyer et al., 1985, 1986). Although several observational studies have explored the use of b-blockade in patients with ischemic stroke and suggested benefit (Dziedzic et al., 2007), its use was not as promising when explored prospectively. The current recommendations by the American Heart Association do not recommend the use of antihypertensives in most cases of acute stroke (Barer et al., 1988; Adams et al., 2007).

7

In the care of patients with intracranial hypertension, optimizing cerebral perfusion pressure (CPP) may require augmentation of blood pressure with intravenous inotropic agents as well as peripheral vasoconstrictors. Mean arterial pressure goals are often maintained at supraphysiologic levels in order to obtain a desired CPP. However, the use of pressors to induce hypertension must be carefully considered in patients with neurogenic cardiac injury, as this may exacerbate sympathetic-mediated cardiac injury. One study has found a univariate association of increasing phenylephrine dose and regional wall motion abnormalities in subarachnoid hemorrhage, although this may have been related either to the adrenergic effect of phenylephrine or the poor neurologic condition of the patient (Tung et al., 2004). Induced hypertension may also be associated with acute lung injury in those with acute brain injury (Contant et al., 2001). Thus, the development of optimal strategies for the treatment of cardiac dysfunction in the setting of neurologic catastrophe has not been fully defined and remains an active area of research.

CARDIOLOGY OF PAROXYSMAL NEUROLOGIC EVENTS Migraine Migraine headaches are a common cause of neurologic referral and may be associated with prominent autonomic symptoms such as flushing, piloerection, diaphoresis, and lacrimation. In migraine variants such as cluster headaches, focal sympathetic dysfunction can take the form of a Horner’s syndrome (ipsilateral ptosis, meiosis, and anhidrosis). Cardiovascular dysfunction has been studied extensively in migraine headache. Abnormalities that occur in migraineurs include mild orthostasis, arrhythmias, and repolarization changes on ECG (Aygun et al., 2003; Thijs et al., 2006). Cardiovascular changes are noted during, as well as in between, attacks. During headaches, benign, transient sinus arrhythmias, premature ventricular contractions, and repolarization changes may occur on ECG (Aygun et al., 2003). Reversible disturbances of autonomic regulation with sympathetic hyperfunction or hypofunction are likely responsible for these cardiovascular changes (Duru et al., 2006). Migraineurs also appear to have a unique pattern of cardiac structural changes. Mitral valve prolapse, patent foramen ovale (PFO), atrial septal defect (ASD), and right-to-left shunting are more common in patients with migraine headache than in the general population (Schwedt, 2009). Although PFO is prevalent in the general population (25–30%), as many as 50% of patients with migraine with aura may have this defect (Schwedt, 2009). The degree of right-to-left shunting appears to correlate with the presence of migraine headaches (Post and Budts, 2006; Woods et al., 2010). Intracardiac or

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intrapulmonary shunting may allow paradoxical emboli to reach the cerebral microcirculation and produce cortical spreading depression with subsequent aura or migraine headache. PFO closure has been explored as a possible therapy for intractable migraines. Small noncontrolled studies have reported significant benefit but larger trials such as the Migraine Intervention with STARflex Technology (MIST-1) study using a percutaneous inserted device found only minimal benefits (Anzola et al., 2006; Carroll, 2008; Jesurum et al., 2008). “Triptan” medicines, which target the serotonin 5-HT1D receptor, are increasingly used to treat migraine headaches in migraineurs with and without aura. Although the use of triptans has evolved as a first-line abortive therapy for many migraineurs, triptans may induce peripheral vasoconstriction associated with hypertension, chest pain syndromes, and, rarely, coronary vasospasm (Sumatriptan, 2010). Thus, triptans should be used with caution in patients with suspected coronary artery disease, angina, or significant cerebrovascular disease, although in those without known cardiovascular disease, there does not appear to be a significantly elevated risk of cardiac complications (Hall et al., 2004).

Epilepsy Heart rate and rhythm alterations are common in patients with epilepsy (Opherk et al., 2002; Mayer et al., 2004), and this is often the most recognizable non-neurologic symptom associated with seizures. The prevalence of ictal tachycardia (IT) is as high as 80–100% (Zijlmans et al., 2002). In rare cases, sinus tachycardia will degenerate to a more concerning rhythm such as atrial fibrillation or flutter (Nei et al., 2004). It is important to recognize that tachycardia is not always a response to increased physiologic demand as it may occur in partial seizures without secondary generalization (Mayer et al., 2004; Surges et al., 2010). Ictal bradycardia (IB) is also a common pattern, and has been reported in as many as 20% of epileptic patients (Rugg-Gunn et al., 2004). Typically, the decrease in heart rate is asymptomatic but bradycardia can progress to asystole. Ischemic ECG changes and conduction block are also common findings during epileptic seizures (Opherk et al., 2002; Zijlmans et al., 2002; Nei et al., 2004). Dysautonomia

causing cardiovascular dysregulation is the likely cause for these changes in children and adults with a possible predominance in symptomatic mesial temporal lobe epilepsy (Opherk et al., 2002; Mayer et al., 2004). Although malignant ventricular arrhythmia due to autonomic dysfunction is relatively rare, it is postulated that neurogenic cardiac events are responsible for an increased risk of sudden death in epileptics. At present, the mechanisms for sudden death in epilepsy (SUDEP) have not been fully defined, although there is a strong association with medically refractory epilepsy in young adults. It has been proposed that fatal arrhythmias are the immediate cause of death with bradycardia and ictal asystole as one possible mechanism (Fig. 1.3) (So, 2008). As neurogenic cardiac events may result from an imbalance in the tone of the autonomic nervous system, victims of SUDEP have been demonstrated to exhibit increased autonomic activity with seizures. This increased activity was noted particularly during sleep–wake transitions This is consistent with the observation that SUDEP victims are frequently found in bed (Nei et al., 2004). The occurrence of cardiac changes in cases of convulsive status epilepticus (SE) is also common, and may be exacerbated by extreme metabolic demands. Ischemic changes on ECG are most common followed by bundle branch block and axis changes. Although the majority of arrhythmias are not symptomatic, potentially lifethreatening arrhythmias, including ventricular fibrillation, may occur. As with neurovascular events, ECG abnormalities and myocardial injury in SE may portend a poor prognosis, and the presence of ECG changes other than sinus tachycardia more than doubled the mortality of patients in SE (Boggs et al., 1993).

CARDIOLOGY OF MOVEMENT DISORDERS AND NEURODEGENERATIVE DISEASES Parkinson disease and parkinsonian disorders Autonomic disturbances and cardiovascular changes are common in patients with Parkinson disease and related syndromes including multiple system atrophy (MSA)

Fig. 1.3. Electroencephalogram showing a sinus pause (line with arrow) during a seizure. (Reproduced from Nei et al., 2000, with permission.)

CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE

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and dementia with Lewy bodies. Orthostatic hypotension is the most frequent symptomatic cardiovascular abnormality, and may be extremely challenging to manage. In Parkinson disease (PD), orthostasis is caused by baroreflex failure and postganglionic cardiac sympathetic denervation, which has been demonstrated using 123 iodine-metaiodobenzylguanidine (MIBG) scintigraphy. In MSA, symptoms of autonomic failure are more severe and appear earlier than in PD. Autonomic function tests and MIBG studies can help diagnose MSA (Courbon et al., 2003; Goldstein et al., 2003). Prolongation of the QT is known to occur in patients with Parkinson disease and multiple system atrophy (MSA) and may be related to the increased incidence of sudden cardiac death in this population (Deguchi et al., 2002). In 2007, ergotaminebased dopamine agonists such as cabergoline and pergolide received national attention and were removed from the market due to an increased rate of fibrotic valvulopathies associated with clinically significant valvular insufficiency (Zanettini et al., 2007).

upper motor neuron findings. FA is caused by an abnormal expansion of GAA trinucleotide repeats in the frataxin gene with resultant mitochondrial respiratory chain dysfunction. ECG and echocardiographic abnormalities are common in this disorder and may include repolarization changes and hypertrophic cardiomyopathy. In unusual circumstances, asymmetric septal hypertrophy and dilated cardiomyopathy may also occur. Arrhythmias, including atrial flutter, are common and become clinically apparent as the disease progresses (Alboliras et al., 1986). The cause of death of most patients with FA is congestive heart failure as a result of cardiomyopathy. Therapies aimed at reducing oxidative stress such as idebenone, a synthetic analog of coenzyme Q10, have achieved marginal success in preventing the progression of structural cardiac disease and neurologic dysfunction (Trujillo-Martin et al., 2009).

Dementia

Disorders of peripheral nerves

Selective impairment of parasympathetic and sympathetic nervous systems resulting orthostatic hypotension have been described in vascular (VaD) and Alzheimer’s dementia (AD) (Allan et al., 2007). Decreased heart rate variability, increased QT dispersion, and other autonomic nervous system involvement in patients with dementia may correlate with the degree of cognitive impairment as well as mortality, particularly in those with low blood pressure (Guo et al., 1998; Zulli et al., 2005; Royall et al., 2006). VaD and AD are difficult to differentiate clinically and share many similar risk factors with cardiovascular disease, including hypertension, diabetes, and presence of the APOE4 polymorphism. Risk factor modification for atherosclerosis may play a role in the prevention of dementia and has garnered significant interest in recent years. Trials of antihypertensive agents, including calcium channelblockers, ACE inhibitors, and diuretics, have found a reduced incidence of dementia with treatment (Forette et al., 2002; Tzourio et al., 2003). Cholesterol-lowering agents, including statins, have used similar endpoints in studies and found potentially protective effect (Jick et al., 2000). However, a recent prospective trial failed to demonstrate a significant difference in cognitive testing in patients with established dementia taking atorvastatin after 72 weeks (Feldman et al., 2010).

Acquired disorders of peripheral nerves, such as Guillain-Barre´ syndrome and diabetes mellitus, are frequently associated with an autonomic neuropathy that produces sinus arrhythmias and orthostatic hypotension. Sympathetic nerve axons traverse the spinal cord and exit through white rami at the level of T1 and L2–L4. These fibers synapse in paravertebral ganglia and merge with anterior spinal roots before traveling to innervate organs. Preganglionic parasympathetic fibers travel in cranial nerves III, VII, IX, and X and S2–S4 spinal roots. These myelinated axons synapse within small ganglia near their target organ. Dysautonomia results from demyelination or degeneration of these small myelinated and unmyelinated sympathetic and parasympathetic nerve fibers. Most frequently, involvement of the carotid sinus, glossopharyngeal, and vagus nerves results in dysautonomia.

Degenerative ataxias: Friedreich’s ataxia Friedreich’s ataxia (FA) is an autosomal recessive spinocerebellar neurodegenerative disease characterized by progressive ataxia, areflexia, proprioceptive loss, and

NEUROMUSCULAR DISORDERS WITH CARDIAC MANIFESTATIONS

GUILLAIN–BARRE´ SYNDROME Cardiovascular abnormalities are common and may be life-threatening in Guillain–Barre´ syndrome (GBS), an inflammatory disease that results in demyelination of peripheral nerves. Although most often sporadic, GBS occurs with increased frequency after upper respiratory and Campylobacter jejuni infections, as well as some vaccinations. Autonomic dysregulation is often clinically significant and the presence of cardiovascular complications is a predictor of mortality in GBS (Alshekhlee et al., 2008). The most common cardiovascular changes include labile blood pressure, arrhythmias, ECG changes, and, less frequently, myocardial dysfunction

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(Durocher et al., 1980; Pfeiffer et al., 1999; Yoshii et al., 2000). Cardiovascular changes tend to be more prominent in those with significant motor involvement requiring mechanical ventilation (Winer and Hughes, 1988). Likewise, the resolution of dysautonomia parallels neurologic improvement (Lyu et al., 2002). Pathologically, autonomic neuropathy is likely the result of inflammatory demyelination of the vagus, glossopharyngeal nerves, and preganglionic sympathetic fibers (Matsuyama and Haymaker, 1967; Tuck and McLeod, 1981). Fluctuations of greater than 85 mmHg systolic blood pressure are an important indicator of dysautonomia and may correlate with the occurrence of significant arrhythmias (Winer and Hughes, 1988; Pfeiffer et al., 1999). Although sinus tachycardia is the most frequent arrhythmia observed in GBS, sinus bradycardia may occur in a third of patients and is more clinically significant (Flachenecker et al., 2000). When bradycardia is severe or occurs with periods of asystole, implantation of a pacemaker may be necessary. Autonomic neuropathy in GBS may result in a profound increase in sympathetic tone and the occurrence of neurogenic stunned cardiomyopathy, hypertensive encephalopathy, and posterior reversible encephalopathy syndrome (PRES) (Durocher et al., 1980; Elahi et al., 2004). ECG repolarization changes and cardiac enzyme elevations should prompt echocardiographic investigation (Bernstein et al., 2000). I-MIBG scintigraphy may show defects similar to those patients with neurogenic stunned cardiomyopathy following subarachnoid hemorrhage (Yoshii et al., 2000). Because of the potential for significant dysautonomia, most GBS patients with severe motor deficits should be monitored in an intensive care setting with continuous heart rate and blood pressure monitoring. As a practical consideration, vigilance is required when turning the patient and during tracheal suctioning, as vagal stimulation may precipitate profound bradycardia and asystolic episodes. When treating the hypertension associated with GBS, b-blockers should be avoided, and short-acting agents should be utilized in case of an exaggerated response to vasoactive drugs.

by the duration and severity of diabetes. CAN is diagnosed after demonstrating a decrease in heart rate variability and resting tachycardia, likely as a result of vagal neuropathy (Pop-Busui, 2010). I-MIBG scintigraphy is also helpful in the diagnosis of CAN and may be more sensitive than HRV studies (Scholte et al., 2010) Although there is no specific intervention for CAN, treatment focuses on improving glycemic control (Pop-Busui et al., 2010).

DIABETIC CARDIAC AUTONOMIC NEUROPATHY

DYSTROPHINOPATHIES

Peripheral and cardiac autonomic neuropathy (CAN) is common in diabetic patients and is associated with an increase in mortality. Recent glucose control trials have found an independent association between all-cause mortality and CAN, regardless of the duration of diabetes and presence of other cardiovascular risk factors (Gerritsen et al., 2001; Pop-Busui et al., 2010). CAN is also associated with silent myocardial ischemia and sudden death (Maser et al., 2003; Young et al., 2009). The development of CAN is multifactorial and is influenced

Dystrophinopathies, including Duchenne and Becker muscular dystrophy (MD), are X-linked recessive inherited diseases that result from mutations on the dystrophin gene. Symptoms are characterized by progressive weakness of skeletal muscle, beginning in the pelvic girdle with eventual involvement of appendicular and respiratory musculature. Duchenne MD (DMD) results from severely reduced or absent normal dystrophin. It results in an earlier and more severe phenotype than Becker MD (BMD). Cardiac involvement is prominent

Disorders of neuromuscular junction Cardiovascular changes may also be associated with disorders of the neuromuscular junction including myasthenia gravis (MG) and Lambert–Eaton myasthenic syndrome (LEMS). Giant cell myocarditis has been seen in association with MG in a significant number of patients (58%), particularly those with thymomas (Gibson, 1975). One study found that antistriational autoantibodies may be directed against myocardial tissue in some patients with MG-associated myocarditis (Suzuki et al., 2009). ECG changes are also noted in a earlier studies, including ischemic-appearing ST-T changes and prolonged QT (Gibson, 1975; Chiavistelli et al., 2009). Interestingly, ECG changes and myocardial dysfunction occurring with MG may be pyridostigmine-responsive in some patients (Gibson, 1975; Furlund Owe et al., 2008). Lambert–Eaton myasthenic syndrome is a paraneoplastic neuromuscular junction disorder that affects presynaptic voltage-gated Caþ channel and produces subacute, progressive muscle weakness that improves with exercise. In LEMS, cardiovagal abnormalities are common and may occur in 75% of patients. Cardiovascular and other autonomic signs may occur as the result of deficient presynaptic neurotransmitter release as symptoms respond to treatment with 3,4-diaminopyridine (McEvoy et al., 1989; O’Suilleabhain et al., 1998).

Disorders of muscle (Table 1.1)

CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE

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Table 1.1 Cardiac manifestations of muscle disorders: myopathies with significant cardiac involvement with respective abnormal genetic or gene product abnormality

Disease

Mode of inheritance

Genetic/protein abnormality

Dystrophinopathies Duchenne Becker Emery–Dreyfus disease Myotonic dystrophy

Xr

Dystrophin

Xr

Emerin

AD

Abnormal CTG repeats

Laminopathies

AR

Lamin A/C

Limb girdle muscular dystrophies Congenital myopathies Nemaline rod myopathy Desmin myopathy

AD or AR

Sarcoglycans

AD or AR

a-Actin

Myocardial dilatation and heart failure

AD, AR, or sporadic AD

Desmin

ECG – AV block and ventricular tachycardia Systolic and diastolic heart failure Myocardial dilatation and heart failure

Central core myopathy Myofibrillar myopathy Glycogenoses Andersen–Tawil disease Mitochondrial cytopathies (MELAS, MERFF, LHON) Kearns–Sayre syndrome Barth syndrome

AD and unknown X-linked and AR AD periodic paralysis Mitochondrial

Xr

Cardiac manifestations ECG – large R waves in lead 1, AV block, atrial fibrillation, and ventricular arrhythmias Dilated cardiomyopathy and heart failure ECG – bradycardia, AV block, and sudden death ECG – AV block, prolonged QT and torsades de pointes Dilated cardiomyopathy and heart failure ECG – supraventricular arrythmias and AV block Cardiac dilatation and dilated cardiomypathy ECG – conduction abnormalities and ST elevation Dilated cardiomyopathy

Ryanodine receptor gene Various Z-disk proteins Various enzyme deficiencies Kþ channelopathy Mitochondrial DNA point mutations

Taffazine

Dilated cardiomyopathy and LVHT Myocardial thickening, heart failure, and sudden cardiac death Prolonged QT and bidirectional ventricular tachycardia ECG – ventricular ectopy and WPW Dilated and hypertrophic cardiomyopathy ECG – atrivoventricular block and BBB

ECG — ventricular arrhythmias Endocardial fibroelastosis and cardiomyopathy

MELAS, metabolic encephalopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; LHON, Leber’s hereditary optic neuropathy; Xr, X-linked recessive; AD, autosomal dominant; AR, autosomal recessive; CTG, cytosine-thymineguaninenucleotide sequence; AV, atrioventricular; LVHT, left ventricular hypertrabeculation; WPW, Wolf–Parkinson–White syndrome; BBB, bundle branch block.

in dystrophinopathies and significantly contributes to the morbidity and mortality of these conditions. Cardiac conduction abnormalities have been found in 48% of DMD patients with pathologic evidence of multifocal fibrosis in the cardiac conduction system (Sanyal and Johnson, 1982). Rhythm abnormalities are common and include sinus tachycardia, atrial fibrillation, and atrial flutter (Perloff et al., 1967; Finsterer and Stollberger, 2008b). Ventricular arrhythmias are also common and are an important cause of death for those with

DMD (Connuck et al., 2008). Typical ECG changes in these muscular dystrophies include atrioventricular conduction block, a marked increase in the R wave of lead V1, and deep Q waves in the precordial leads (Perloff et al., 1967). Fibrotic change and fatty infiltration of the myocardium result in dilated cardiomyopathy with systolic and diastolic dysfunction in most DMD patients (Brockmeier et al., 1998). Although, historically, death typically occurred by the third decade in patients with DMD as a result of respiratory failure, advances in the

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supportive treatment of DMD patients have led to a longer life expectancy and a resulting increase in cardiac symptoms (Cripe, 2005; Bushby et al., 2010). Thus, cardiac dysfunction represents a serious source of morbidity in this patient population, with approximately two-thirds of DMD patients dying as a result of congestive heart failure (Connuck et al., 2008). In BMD, the incidence of cardiac abnormalities may approach 90%, although symptoms rarely present early in the disease course (Finsterer and Stollberger, 2008a; Yilmaz et al., 2008). Cardiac involvement typically becomes clinically apparent in the third decade of life, and is associated with ECG abnormalities, arrhythmias, and myocardial abnormalities that are similar to, but less severe than, those seen with DMD (Yilmaz et al., 2008). In a rare subset of patients, cardiac disease may be more severe than skeletal muscle weakness, or even the presenting symptom of BMD (Finsterer et al., 1999; Yokota et al., 2004). In pediatric patients, the occurrence of cardiomyopathy is less frequent than those with DMD but may be more severe. Cardiac transplantation for cardiomyopathy in BMD is a viable option due to a favorable neurologic prognosis (Finsterer et al., 1999; Yokota et al., 2004; Connuck et al., 2008). The cardiac management of patients with muscular dystrophy is multifaceted and includes early evaluation and involvement of a cardiologist in the care of the patient. Cardiac symptoms may be masked my musculoskeletal limitations, and guidelines devised by the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery recommend a baseline exam, ECG, and echocardiography at the time of diagnosis or by age 6 for DMD (Cripe, 2005). Cardiac MRI may also be considered as it may be more sensitive than echocardiography in evaluating myocardial disease in DMD (Yilmaz et al., 2008). Pharmacologic intervention should begin when ventricular function abnormalities are first noted. The management of heart failure in patients with DMD involves b-blockers, diuretics, and ACE inhibitors. ACE inhibitors have beneficial effects on cardiac remodeling, endothelial function, and when in combination with b-blockers may delay progression of LV systolic dysfunction in DMD (Duboc et al., 2005; Ogata et al., 2009). For patients with BMD, screening cardiologic evaluations should begin at age 10 or at the onset of symptoms, and be continued every 2 years. Treatments for the cardiac manifestations are similar to those of DMD. Carriers for DMD and BMD are susceptible to cardiac disease and should be referred to a cardiologist (Cripe, 2005).

EMERY–DREYFUS MUSCULAR DYSTROPHY Emery–Dreyfus muscular dystrophy (EDMD) is an X-linked muscular dystrophy caused by an abnormality in the nuclear membrane protein emerin. The disorder is

manifest with progressive proximal weakness in the pelvic girdle and early onset contractures at the elbows. Xlinked EDMD is more frequently associated with conduction abnormalities than structural heart disease. Supraventricular and His–Purkinje conduction system disease is evident with numerous and dangerous arrhythmias including atrial fibrillation and flutter, atrial standstill, and ventricular tachycardia. Ventricular arrhythmias may be responsible for the occurrence of sudden death in patients with EDMD. Permanent pacemaker implantation is indicated in many patients with Emery–Dreyfus disease. An autosomal dominant variant of EDMD that results from a defect in lamin A/C manifests with cardiomyopathy in addition to conduction defects (Finsterer and Stollberger, 2000, 2008b).

Myotonic dystrophy Myotonic muscular dystrophy type 1 (MMD) is the most common inherited muscular dystrophy presenting in adulthood. This disease is caused by an expansion of CTG repeats at the 30 -UTR of the serine/threonine myotonic dystrophy protein kinase (DMPK). Multiple organ systems are involved in MMD, including vision, endocrine, and cardiovascular. Cardiac involvement is very common in MMD and includes conduction abnormalities and structural heart disease as a result of interstitial myocardial fibrosis and myofibrillar degeneration (Motta et al., 1979). Electrocardiographic abnormalities are reported in 65–80% of patients, who most commonly experience PVCs, QRS prolongation, PR interval prolongation with atrioventricular block, and left fascicular block (Perloff et al., 1984; Groh et al., 2002). Atrial fibrillation and flutter are also commonly reported (Finsterer and Stollberger, 2008a). The presence of ECG abnormalities correlates with skeletal muscle disability, age, and, possibly, CTG repeat length (Groh et al., 2002). Significant cardiomyopathy can occur but it is less common than conduction abnormalities. Management of patients with MMD should include an annual ECG from the time of diagnosis, Holter monitoring if PR interval increases or bradycardia is noted, and pacemaker implantation with evidence of a progressing arrhythmia or atrioventricular block (Gregoratos et al., 1998).

MITOCHONDRIAL CYTOPATHIES The mitochondrial cytopathies include a large number of disorders with diverse clinical presentations that occur as a result of abnormalities within the respiratory chain and lipid b-oxidation. Disorders of the respiratory chain typically result from point mutations in the mitochondrial DNA. Mutant DNA is present in variable proportions in muscle and cardiac tissues, accounting for significant phenotypic heterogeneity. The more common signs and symptoms include lactic acidosis, myopathy, external

CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE ophthalmoplegia, and central and peripheral nervous system disease, such as encephalopathy, dementia, seizures, and neuropathy. Cardiac involvement is common in mitochondrial respiratory chain disorders and includes conduction disturbances, myocardial thickening, hypertrophic and dilated cardiomyopathy. In mitochondrial disorders of b-oxidation of long chain fatty acids, hypertrophic cardiomyopathy with lipid deposition is often present. Some of these disorders are the result of primary carnitine deficiency and respond well to supplementation (Finsterer and Stollberger, 2008a). Kearns–Sayre syndrome (KSS) is a sporadic mitochrondrial cytopathy that exists along a spectrum of diseases, although external opthalmoplegia is an invariant feature. In addition to ocular muscle weakness, the most prominent features of the syndrome include cardiac arrhythmias, retinopathy, and proximal muscle weakness. Prolonged intraventricular conduction time, atrioventricular block, and bundle branch block are the most frequent cardiac findings (Berenberg et al., 1977; Anan et al., 1995). Fibrous and adipose tissue deposition in the bundle of His and distal bundle branches are found on pathologic analysis (Clark et al., 1975). Prior studies have shown a high prevalence of serious cardiac events in those with KSS, necessitating close cardiac follow-up and permanent pacemaker implantation in many patients (Berenberg et al., 1977; Gregoratos et al., 1998). Cardiomyopathy is much less common but it has been reported in pediatric patients with KSS.

CONCLUSION Cardiac manifestations of neurologic disorders are common, and there is a growing understanding of the important interaction between the heart and brain. This has become increasingly evident in the setting of vascular disease, in which cardiovascular and cerebrovascular pathology is often comorbid. The increased sympathetic tone that occurs in the setting of acute neurologic disease may also exacerbate cardiac dysfunction. Characteristic patterns of cardiac dysfunction have been identified in neuromuscular disease, neurodegenerative disease, and in the setting of paroxysmal neurologic events, such as epilepsy. Thus, a thorough understanding of the cardiac complications associated with neurologic disease will facilitate the prompt recognition and management of cardiac dysfunction, and will play an increasingly important role in optimizing clinical management.

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Young LH, Wackers FJ, Chyun DA et al. (2009). Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 301: 1547–1555. Zanettini R, Antonini A, Gatto G et al. (2007). Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med 356: 39–46. Zijlmans M, Flanagan D, Gotman J (2002). Heart rate changes and ECG abnormalities during epileptic seizures: prevalence and definition of an objective clinical sign. Epilepsia 43: 847–854. Zulli R, Nicosia F, Borroni B et al. (2005). QT dispersion and heart rate variability abnormalities in Alzheimer’s disease and in mild cognitive impairment. J Am Geriatr Soc 53: 2135–2139.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 2

Sudden cardiac death ALEJANDRO A. RABINSTEIN* Department of Neurology, Mayo Clinic, Rochester, MN, USA

INTRODUCTION That people can die of a “broken heart,” be “scared to death,” or be killed by an attack of anger have probably been common notions for centuries. However, it is only within the last few decades that medicine has recognized the conceptual truth behind these popular sayings. Sudden death can occur as a consequence of neurocardiogenic injury related to extreme emotional stress, and a similar phenomenon may cause fatalities after acute, severe brain insults. This chapter will summarize current knowledge about the history, definition, histopathology, presumed pathophysiology, precipitants, clinical manifestations, and potential preventive treatments of neurocardiogenic injury and sudden cardiac death (SCD).

HISTORY Walter B. Cannon was the first to bring the topic of sudden death to the forum of scientific medical literature, in 1942, in a publication entitled “‘Voodoo’ Death” (Cannon, 1942). In this piece, Cannon compiled examples from anthropology research into fatal events induced by an absolute belief that a powerful external force (such as sorcery or black magic) completely beyond the control of the victim would cause irrevocably the victim’s death. Cannon postulated that the death was due to the “lasting and intense action of the sympathico-adrenal system” and thus opened a line of research that continues even today. Less visionary was his conviction that these phenomena were confined to human groups plagued by ignorance and dominated by primitive superstition. In fact, there are much older written accounts of emperors, kings, and popes said to have died after a sudden emotion, and the idea that sudden death could be provoked by psychological stress was accepted by prominent physicians until the 19th century (Engel, 1971). Subsequent

research would confirm that reason and intelligence do not make people immune to sudden cardiac death. George L. Engel further moved the concept of sudden death from the realm of folk wisdom to that of scientific medicine in a remarkable paper published in 1971 in which he described 170 cases and classified them into eight categories according to the “life settings” (i.e., precipitants) in which death occurred (Engel, 1971): collapse or death of someone close, acute grief (within 16 days of the loss), threat of loss of someone close, during mourning or anniversary, loss of status or self-esteem, real or symbolic personal danger or threat of injury, after danger is over, and at the time of a happy ending. Settings of loss accounted for nearly two-thirds of cases and danger for another third, while happy settings were much more rarely the trigger (10 cases, 6%). People of all ages and social extractions formed this series. The clinical detail presented in this paper remains unsurpassed. The following 40 years brought us much useful information leading to our current understanding that acute cardiac injury produced by catecholamine toxicity is probably responsible for at least some cases of unexplained sudden death. We have also learned that cardiac arrest related to acute, severe brain insults may share a common mechanism with the cases of sudden death after emotional stress. Less severe forms of neurocardiogenic injury, such as apical ballooning syndrome, have been identified. Yet, the precise pathophysiology underlying these events remains incompletely elucidated.

DEFINITION Research on SCD has been hampered by the lack of a uniformly accepted definition. Perhaps the most used is an unexpected natural death due to cardiac cause and heralded by abrupt loss of consciousness within 1 hour of onset of acute symptoms (Priori et al., 2002).

*Correspondence to: Professor Alejandro A. Rabinstein, 200 First Street SW, Mayo W8B, Rochester, MN 55905, USA. E-mail: [email protected]

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By stating that the event should be natural, the aim is to exclude death by violent or traumatic causes. The time criterion attempts to focus on arrhythmic deaths, as this is the mechanism considered most often causative. Yet, it is important to be mindful that instantaneous death can follow various acute diseases which neither necessarily induce fatal arrhythmias nor share the mechanisms and characteristics of SCD to be discussed in this chapter. Examples include ruptured aortic aneurysm, massive pulmonary embolism, and cardiac tamponade, to mention just a few. Furthermore, the most common cause of SCD is myocardial infarction from coronary disease. Cardiomyopathy, with or without left ventricular dysfunction, and various arrhythmogenic disorders (prominently including the Wolff–Parkinson–White syndrome and inherited channelopathies, such as congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome) are also relatively common primary cardiac causes of SCD (Priori et al., 2002; Camm et al., 2006). In fact, it is estimated that only 5–10% of cases of SCD occur in subjects without coronary disease or heart failure (Priori et al., 2002). It is these cases that are the focus of the following sections.

PATHOPHYSIOLOGY AND HISTOPATHOLOGY The prevailing concept is that neurocardiogenic injury is caused by catecholamine toxicity, mainly related to sympathetic hyperactivity (Samuels, 2007). It has been known for decades that electrocardiographic changes and myocardial fiber damage can be induced by hypothalamic stimulation in experimental models (Melville et al., 1963). Similar abnormalities have been reported in patients succumbing to strokes that involve the insular cortex (Oppenheimer et al., 1992), another brain structure that participates in the control of central autonomic responses. It is also known that direct stimulation of the heart by catecholamines released by the nerves reaching the myocardium is more toxic than high levels of circulating catecholamines. This notion is supported by experiments demonstrating that the toxicity can be blocked by direct intramyocardial catecholamine depletion with drugs such as reserpine, but less effectively by adrenalectomy (Samuels, 2007). A potential contributing role from simultaneous parasympathetic (vagal) activation has been discussed (Corr et al., 1987), but remains more speculative. The pathologic hallmark of neurocardiogenic injury found in necropsies of patients who suffered sudden cardiac death without pre-existing heart disease (coronary artery disease, cardiomyopathy, or myocarditis) is the myofibrillary degeneration (also known by the more

descriptive terms coagulative myocytolysis or contraction band necrosis) (Reichenbach and Benditt, 1969; Karch and Billingham, 1986; Fineschi et al., 2010). The dead myocardial fibers are widely distributed and they are characterized by a hypercontracted state with abnormal, irregular cross-band structures and associated mononuclear infiltrates. The predominant subendocardial localization (i.e., in close proximity to the electrical conduction system) may contribute to the higher propensity to induce serious cardiac arrhythmias. Calcifications are common. In fact, excessive calcium entry into the myocardial fiber has been postulated to be a key factor in the sequence of molecular changes leading to sudden muscle fiber contraction before cell death (Samuels, 2007). Toxicity mediated by reactive oxygen species may also play a major role. Catecholamines might generate these reactive intermediaries from their auto-oxidation, which in turn could cause loss of intracellular potassium and high-energy phosphates, calcium overload, and local activation of cytokines (Fineschi et al., 2010). Vasospasm and reperfusion injury have also been proposed as alternative mechanisms for the occurrence of neurocardiogenic injury and neurogenic SCD. These mechanisms could be a component of the catecholamine toxicity rather than a separate process. Coronary (macrovascular) vasospasm of epicardial arteries has been conspicuously absent in most series of patients with apical ballooning syndrome (Wittstein et al., 2005; Prasad et al., 2008) and there is no solid documentation of epicardial vasospasm in cases of SCD. Indirect evidence of microvascular spasm in patients with apical ballooning syndrome does exist, but the clinical significance of these findings remains uncertain (Prasad et al., 2008).

PRECIPITANTS Neurogenic triggers of SCD include intense psychological stress and severe acute brain disease (Table 2.1). The role of intense emotions in the generation of neurocardiogenic injury has been pointed out in the historical Table 2.1 Main precipitants of neurocardiogenic injury Emotional stress Fear Anger Acute grief Acute brain disease Aneurysmal subarachnoid hemorrhage Ischemic stroke (insular involvement) Epilepsy with poorly controlled seizures Exposure to extrinsic adrenergic agents

SUDDEN CARDIAC DEATH section of this chapter. More recent literature has confirmed the association between anger, fear, or sudden personal loss with the occurrence of ventricular arrhythmias and myocardial stunning, even in persons without coronary artery disease (Lampert et al., 2002; Wittstein et al., 2005). Extreme versions of these phenomena could produce SCD, which would explain the spikes in SCD observed after natural disasters or in the midst or the aftermath of terrorist attacks (Meisel et al., 1991; Leor et al., 1996; Steinberg et al., 2004). Examples of brain disease that can result in SCD include aneurysmal subarachnoid hemorrhage, acute ischemic stroke (especially when involving the insula), intracerebral hemorrhage, and epilepsy (Ozdemir and Hachinski, 2008; Baranchuk et al., 2009; Schuele, 2009). As emotional stressors, these conditions can also produce nonfatal manifestations of neurogenic heart syndrome, such as repolarization changes, ventricular arrhythmias, and apical ballooning syndrome (Khechinashvili and Asplund, 2002; Prasad et al., 2008).

CLINICAL MANIFESTATIONS Little is known of the events immediately preceding cardiac arrest in patients with neurogenic SCD. It is often assumed that a ventricular arrhythmia would be the final event. Yet, the histopathology of muscle fibers in contraction is not seen in usual cases of death from fatal arrhythmia. Therefore, direct myocardial damage is the primary mechanism of neurogenic SCD. The typical semiology of cardiac failure is not observed before the arrest because of the suddenness of the event. Many more data exist on nonfatal cases of neurocardiogenic injury. The main manifestations are electrical conduction abnormalities and left ventricular stunning (stress cardiomyopathy).

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Electrical conduction abnormalities Electrocardiographic changes are very prevalent after various forms of acute stroke. In a systematic review, it was concluded that electrical conduction abnormalities can be observed in three-quarters of patients with subarachnoid hemorrhage regardless of whether they had pre-existent heart disease. They were present in one-third to nearly one-half of patients with acute ischemic stroke and intracerebral hemorrhage without known heart disease and over 90% of those with this antecedent (Khechinashvili and Asplund, 2002). The incidence of electrocardiographic changes in general and ventricular arrhythmias in particular is much higher when cerebral infarctions affect the insular cortex (Cheung and Hachinski, 2000; Abboud et al., 2006; Ay et al., 2006; Laowattana et al., 2006). The most common abnormalities are repolarization changes, and they may mimic myocardial ischemia. While QT prolongation and ST segment depression or elevation are most frequently noted, diffuse T-wave inversion throughout the precordial leads (often referred to as “cerebral T waves”) are the most characteristic (Fig. 2.1). Q waves may also appear, especially in V1 to V3 leads (Wittstein et al., 2005). When in doubt about the possibility of acute myocardial ischemia, cardiac enzymes and echocardiography should be obtained to determine whether coronary angiography is necessary. Electrophysiologic studies have shown that mental stress can increase the T-wave alternans, a validated measure of heterogeneity of repolarization, in patients with known ventricular arrhythmias treated with implantable cardioverter-defibrillators (Lampert et al., 2009). Polymorphic ventricular arrhythmias can be triggered by emotional stress and acute brain disease, especially (but not exclusively) in patients known to be prone to arrhythmogenesis (Lampert, 2010).

Fig. 2.1. Electrocardiographic changes in a patient with aneurysmal subarachnoid hemorrhage on an electrocardiogram obtained 36 hours after symptom onset. Notice the deep negative T waves in the anterolateral precordial leads and the prolongation of the QT interval.

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Neurogenic electrocardiographic changes are typically transient. Resolution may start within 1–2 days of their appearance, but full normalization may take days or even weeks and occasionally minor repolarization changes may become permanent (Wittstein et al., 2005).

Stress cardiomyopathy Stress cardiomyopathy is a reversible form of primary, acquired cardiomyopathy due to neurogenic myocardial stunning (Prasad et al., 2008). It is also known as takotsubo cardiomyopathy (after the similarity of the left ventriculogram during systole in patients with this condition to an octopus-trapping pot (tako tsubo) used in Japan) or apical ballooning syndrome (for its preferential involvement of the left ventricular apex). It usually occurs in postmenopausal women and it is very rare in patients younger than 50 years (Bybee et al., 2004; Wittstein et al., 2005; Lee et al., 2006). In addition to acute emotional stress, documented precipitants include acute intracranial events (e.g., subarachnoid hemorrhage, ischemic stroke), physical stress, and exposure to exogenous catecholaminergic agents (e.g., high-dose inhaled b-agonists, epinephrine, dobutamine, cocaine) (Arora et al., 2006; Abraham et al., 2009). It has also been exceptionally reported as a complication of acute severe medical illness and after noncardiac surgery (Prasad et al., 2008). Its presentation may mimic an acute coronary event. Angina-like chest pain and acute dyspnea are the most common symptoms. Electrocardiographic changes may include ST elevation in the precordial leads, most often followed by deep, diffuse T-wave inversion; prolongation of the PR and especially the QTc intervals is characteristically present (Wittstein et al., 2005; Prasad et al., 2008). These changes are often associated with modest elevation of troponin levels. Normal R-wave progression gets restored within days. The diagnosis is established by the echocardiographic findings. The typical pattern features preserved or hypercontractile basal function, moderate or severe midventricular dysfunction, and apical akinesis or severe dyskinesis. These wall motion abnormalities extend beyond the distribution of any single coronary artery. Left ventricular ejection fraction is acutely diminished (often to 20–30%), but recovers within 2–4 weeks as all segments regain normal contractility. Rarely, variants of the syndrome with atypical echocardiographic presentations can be encountered. These include concurrent right ventricular involvement (in which signs of congestive heart failure can be pronounced), the apical sparing variant (i.e., wall motion abnormalities limited to the midventricular segments), and the inverted takotsubo (i.e., basal hypokinesis with normal apical function) (Wittstein et al., 2005; Prasad et al., 2008). These four patterns – apical,

Table 2.2 Criteria for the diagnosis of apical ballooning syndrome (adapted from Prasad et al., 2008) Transient akinesis, hypokinesis, or dyskinesis of the left ventricular mid-segments, with or without apical dysfunction, extending beyond the territory of any single coronary distribution Presence of a recognized trigger (not indispensable) No evidence of coronary plaque rupture on angiography New transient electrographic changes and modest elevation of serum cardiac troponin concentration Absence of pheochromocytoma or myocarditis

biventricular, midventricular, and basal – can also be documented by cardiovascular magnetic resonance imaging, which also shows myocardial edema, some myocardial inflammation, and no significant necrosis/fibrosis (Eitel et al., 2011). Pericardial effusion is not infrequent, but usually not severe (Eitel et al., 2011). If performed, coronary angiography shows normal or only mildly atherosclerotic coronary arteries. The absence of delayed gadolinium hyperenhancement on cardiac magnetic resonance imaging may be useful to differentiate stress cardiomyopathy from myocardial ischemia and myocarditis. Criteria for the diagnosis of stress cardiomyopathy are presented in Table 2.2. It is thought that this condition is caused by the effects of excessive sympathetic stimulation of the myocardium. Markers of increased sympathoneural and adrenomedullary activity have been identified in patients with stress cardiomyopathy and endomyocardial biopsies have often shown typical changes of myofibrillary degeneration (Wittstein et al., 2005). Experiments in animal models indicate that high concentrations of epinephrine could change b2-receptor agonism from cardiostimulant (mediated by Gs protein and seen with low concentrations of epinephrine) to cardioinhibitory (mediated by Gi protein) (Paur et al., 2012). Direct myocardial injury would be the main cause of the stunning, but microvascular spasm could play a contributory role. Although the density of sympathetic nerves is greater at the base of the ventricle, the apex may be more responsive to adrenergic stimulation (Mori et al., 1993) and consequently more vulnerable to the detrimental effects of sympathetic surges. It has been proposed that the vulnerability of postmenopausal women to this syndrome could be related to the loss of protective estrogen actions (Prasad et al., 2008).

SPECIFIC CLINICAL SCENARIOS Sudden unexplained death in epilepsy The pathophysiology of sudden unexplained death in epilepsy (SUDEP) remains speculative (So et al., 2009).

SUDDEN CARDIAC DEATH Potential mechanisms include cardiac, respiratory, and autonomic abnormalities. Seizures have various effects on cardiac function which are primarily mediated by ictal activation and postictal suppression of the autonomic nervous system (Schuele, 2009; Sevcencu and Struijk, 2010). Ictal sympathetic activation could lead to myocardial ischemia in patients with coronary disease and fatal arrhythmias. Meanwhile, ictal vagal activation could produce severe bradycardia or asystole, which has been occasionally documented in patients undergoing electroencephalographic monitoring, and this mechanism could explain some cases of SUDEP (So, 2008). Alternatively, postictal suppression of cerebral and brainstem function could provoke a rapid sequence of events mediated by extreme autonomic dysfunction and culminating in respiratory arrest (So, 2008; Schuele, 2009). Reduction in heart rate variability has been documented in patients with refractory epilepsy (Ansakorpi et al., 2002); however, it is not known whether this sign of autonomic dysfunction could represent a marker of patients at high risk for SUDEP. Stress cardiomyopathy can occur after seizures and it has been implicated as a potential mechanism of SUDEP (Dupuis et al., 2012). Numerous risk factors for the occurrence of SUDEP have been identified. Principal among these are frequent generalized tonic-clonic seizures, subtherapeutic anticonvulsant levels, young age, early epilepsy onset, long epilepsy duration, combination of multiple antiepileptic drugs, and low intelligence quotient (So, 2008; Hughes, 2009; Hesdorffer et al., 2011). Currently recommended preventive strategies focus on correcting modifiable risk factors: optimize seizure control (especially reducing the number of generalized tonic-clonic seizures), evaluate for epilepsy surgery immediately after two antiepileptics have failed to control the seizures, emphasize the importance of compliance with medications, and use the lowest possible number of drugs (So et al., 2009; Hesdorffer et al., 2011).

Sudden death after stroke A higher risk of cardiac arrhythmias and sudden death has been observed in patients with infarction involving the insular cortex (Cheung and Hachinski, 2000). It is less clear whether the side of infarction makes a major difference in this risk. While some investigators have found a greater risk in patients with right insular strokes (Abboud et al., 2006; Ay et al., 2006), others have reported a higher risk with left insular infarctions, especially among patients with coronary artery disease (Laowattana et al., 2006). Hence, the validity of the concept of cerebral lateralization of autonomic function and differential risk of cardiac depending on the side of brain damage remain unproven.

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The significance of the finding in a large populationbased study of an association between parietal lobe infarction (but not insular infarction) and higher risk of cardiac events and death over a median follow-up of 4 years cannot presently be elucidated (Rincon et al., 2008).

POTENTIAL PREVENTIVE STRATEGIES Given the unexpected nature of the problem, there are no known strategies to prevent neurogenic SCD. However, it is conceivable that certain pharmacologic interventions could alter the sequence of events responsible for acute neurocardiogenic injury. For instance, b-blockers could diminish the myocardial damage induced by excessive adrenergic stimulation, calcium channel blockers could reduce calcium entry into the cells, and antioxidants and free radical scavengers could minimize the toxicity mediated by reactive oxygen species (Samuels, 2007). Studies evaluating these alternatives could be conducted in selected high-risk populations, such as patients with severe aneurysmal subarachnoid hemorrhage.

REFERENCES Abboud H, Berroir S, Labreuche J et al. (2006). Insular involvement in brain infarction increases the risk for cardiac arrhythmia and death. Ann Neurol 59: 691–699. Abraham J, Mudd JO, Kapur N et al. (2009). Stress cardiomyopathy after intravenous administration of caecholamines and beta receptor agonists. J Am Coll Cardiol 53: 1320–1325. Ansakorpi H, Korpelainen JT, Huikuri HV et al. (2002). Heart rate dynamics in refractory and well controlled temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 72: 26–30. Arora S, Alfayoumi F, Srinivasan V et al. (2006). Transient left ventricular apical ballooning after cocaine use: is catecholamine toxicity the pathologic link? Mayo Clinic Proc 81: 829–832. Ay H, Koroshetz WJ, Benner T et al. (2006). Neuroanatomic correlates of stroke-related myocardial injury. Neurology 66: 1325–1329. Baranchuk A, Nault MA, Morillo CA (2009). The central nervous system and sudden cardiac death: what should we know? Cardiol J 16: 105–112. Bybee KA, Kara T, Prasad A et al. (2004). Transient left ventricular apical ballooning: a syndrome that mimics STsegment elevation myocardial infarction. Ann Intern Med 141: 858–865. Camm AJ, Pakrashi T, Savelieva I (2006). Sudden cardiac death: risk factors, treatment, and prevention. Dialogues Cardiovasc Med 11: 175–201. Cannon WB (1942). “Voodoo” death. Am Antrhopologist 44: 169–181. Cheung RTF, Hachinski V (2000). The insula and cerebrogenic sudden death. Arch Neurol 57: 1685–1688.

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Corr PB, Pitt B, Natelson BH et al. (1987). Sudden cardiac death: neural-chemical interaction. Circulation 76: I208–I214. Dupuis M, van Rijckevorsel K, Evrard F et al. (2012). Takotsubo syndrome (TKS): a possible mechanism of sudden unexplained death in epilepsy (SUDEP). Seizure 21: 51–54. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P et al. (2011). Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 306: 277–286. Engel GL (1971). Sudden and rapid death during psychological stress: folklore or folk wisdom? Ann Intern Med 74: 771–782. Fineschi V, Michalodimitrakis M, D’Errico S et al. (2010). Insight into stress-induced cardiomyopathy and sudden cardiac death due to stress. A forensic cardio-pathologist point of view. Forensic Sci Int 194: 1–8. Hesdorffer DC, Tomson T, Benn E et al. (2011). ILAE Commission on Epidemiology, Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia 52: 1150–1159. Hughes JR (2009). A review of sudden unexplained death in epilepsy: prediction of patients at risk. Epilepsy Behav 14: 280–287. Karch SB, Billingham ME (1986). Myocardial contraction bands revisited. Hum Pathol 17: 9–13. Khechinashvili G, Asplund K (2002). Electrocardiographic changes in patients with acute stroke: a systematic review. Cerebrovasc Dis 14: 67–76. Lampert R (2010). Anger and ventricular arrhythmias. Curr Opin Cardiol 25: 46–52. Lampert R, Joska T, Burg M et al. (2002). Emotional and physical precipitants of ventricular arrhtyhmia. Circulation 106: 1800–1805. Lampert R, Shusterman V, Burg M et al. (2009). Angerinduced T-wave alternans predicts future ventricular arrhythmias in patients with implantable cardioverterdefibrillators. J Am Coll Cardiol 53: 774–778. Laowattana S, Zeger SL, Lima JA et al. (2006). Left insular stroke is associated with adverse cardiac outcome. Neurology 66: 477–483. Lee VH, Connolly HM, Fulgham JR et al. (2006). Tako-tsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: an underappreciated ventricular dysfunction. J Neurosurg 105: 264–270. Leor J, Poole WK, Kloner RA (1996). Sudden cardiac death triggered by an earthquake. N Engl J Med 334: 413–419. Meisel SR, Kutz I, Dayan KI et al. (1991). Effect of Iraqi missile war on incidence of acute myocardial infarction

and sudden death in Israeli civilians. Lancet 338: 660–661. Melville KI, Blum B, Shister HE et al. (1963). Cardiac ischemic changes and arrhythmias induced by hypothalamic stimulation. Am J Cardiol 12: 782–791. Mori H, Ishikawa S, Kojima S et al. (1993). Increased responsiveness of ventricular apical myocardium to adrenergic stimuli. Cardiovasc Res 27: 192–198. Oppenheimer SM, Gleb A, Girvin JP et al. (1992). Cardiovascular effects of human insular cortex stimulation. Neurology 42: 1727–1732. Ozdemir O, Hachinski V (2008). Brain lateralization and sudden death: its role in the neurogenic heart syndrome. J Neurol Sci 268: 6–11. Paur H, Wright PT, Tranter MH et al. (2012). High levels of circulating epinephrine trigger apical cardiodepression in a b2-adrenergic receptor/gi-dependent manner: a new model of takotsubo cardiomyopathy. Circulation 126: 697–706. Prasad A, Lerman A, Rihal CS (2008). Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 155: 408–417. Priori SG, Aliot E, Blomstrom-Lundqvist C et al. (2002). Task Force on Sudden Cardiac Death, European Society of Cardiology. Europace 4: 3–18. Reichenbach D, Benditt EP (1969). Myofibrillar degeneration: a common form of cardiac muscle injury. Ann N Y Acad Sci 156: 164–176. Rincon F, Dhamoon M, Moon Y et al. (2008). Stroke location and association with fatal outcomes: Northern Manhattan Study (NOMAS). Stroke 39: 2425–2431. Samuels MA (2007). The brain-heart connection. Circulation 116: 77–84. Schuele SU (2009). Effects of seizures on cardiac function. J Clin Neurophysiol 26: 302–308. Sevcencu C, Struijk JJ (2010). Autonomic alterations and cardiac changes in epilepsy. Epilepsia 51: 725–737. So EL (2008). What is known about the mechanism underlying SUDEP? Epilepsia 49 (Suppl 9): 93–98. So EL, Bainbridge J, Buchhalter JR et al. (2009). Report of the American Epilepsy Society and the Epilepsy Foundation Joint Task Force on Sudden Unexplained Death in Epilepsy. Epilepsia 50: 917–922. Steinberg JS, Arshad A, Kowalski M et al. (2004). Increased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack. J Am Coll Cardiol 44: 1261–1264. Wittstein IS, Thiemann DR, Lima JAC et al. (2005). Neurohormonal features of myocardial stunning due to sudden emotional stress. N Engl J Med 352: 539–548.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 3

Neurologic complications of cardiac arrest MATTHEW McCOYD1* AND THOMAS McKIERNAN2 Department of Neurology, Loyola University Healthcare Center, Maywood, IL, USA

1 2

Center for Heart and Vascular Medicine, Loyola University Healthcare Center, Maywood, IL, USA

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST In the US, about 350 000–450 000 lives per year will suffer cardiac arrest (Callans, 2004). Cardiac arrest is defined as cessation of cardiac mechanical activity and is confirmed by the absence of signs of circulation (Thom et al., 2006). Approximately 80% of cardiac arrests occur at home (Callans, 2004; Young, 2009). Many will receive cardiopulmonary resuscitation (CPR) by well-trained emergency medical service providers (60%) (Thom et al., 2006; Hess and White, 2010). The disappointment is that 69% of patients who have cardiac arrest will not receive bystander assistance (Thom et al., 2006). If a patient does not receive bystander CPR then the chances of survival fall approximately 7% for every minute until defibrillation (Callans, 2004). The survival to hospital discharge for out-of-hospital cardiac arrest is 6.4% and for in-hospital cardiac arrest is a little better at 17.6% (Peberdy et al., 2003; Cooper et al., 2006; Thom et al., 2006; Sandroni et al., 2007). For those who suffered an in-hospital arrest, 95% were monitored or witnessed events and if in ventricular fibrillation (VF), 78% received a defibrillation attempt within 3 minutes. More discouragingly, the survivors of cardiac arrest often suffer severe anoxic-hypoxic brain injury related to prolonged anoxia and the inability of rescuers to restore spontaneous circulation in an acceptable amount of time. Cardiac arrest presents global ischemic insult to the brain. The neurologic complications of cardiac arrest are closely related to anoxic-hypoxic time. Brain anoxic injury is a complex process that begins early after cardiopulmonary arrest and includes transient global hyperemia with delayed prolonged global and multifocal hypoperfusion and reoxygenation injuries that can lead to primary necrosis and triggering of apoptosis

(Holzer et al., 2005). The brain depends on uninterrupted oxidative metabolism to uphold neuronal function, for cellular detoxification and for the maintenance of membrane integrity (Bouch et al., 2008). Cerebral perfusion accounts for approximately 20% of total cardiac output (Bouch et al., 2008). During circulatory arrest, both cerebral blood flow and oxygen delivery rapidly cease, and neither can help compensate for the other (Bass, 1985). Brain damage and subsequent neuronal degeneration is due to both immediate cytotoxicity producing necrosis for up to 72 hours after cardiac arrest and delayed apoptosis leading to neuronal death up to 21 days after the arrest (Bouch et al., 2008; Horstmann et al., 2010). Reperfusion injury causes delayed neuronal death by apoptosis and autophagocytosis (Bouch et al., 2008). The extent of cerebral damage is influenced by the duration of interrupted cerebral blood flow. There are virtually no cerebral stores of oxygen (Bouch et al., 2008). Cerebral oxygen stores and consciousness are lost within 20 seconds of the onset of cardiac arrest. Glucose and adenosine stores are lost within 5 minutes (Booth et al., 2004). Irreversible brain damage occurs within 5–10 minutes of complete circulatory arrest (Bass, 1985). The halt of cerebral activity that occurs within seconds after arrest indicates cessation of synaptic transmission, which may possibly occur as a protective measure employed by the brain to preserve energy and maintain cell survival (Bass, 1985). Without restoration of perfusion/oxygenation, cell injury begins to occur as calcium and lactate levels rise within cells (Bass, 1985). The most vulnerable areas are the large projection neurons of the cerebral cortex, cerebellar Purkinje cells, and the CA-1 area of the hippocampus. Subcortical areas including the brainstem, thalamus, and hypothalamus are more resistant to injury (Geocadin et al., 2008).

*Correspondence to: Matthew McCoyd, M.D., Loyola University Healthcare Center, Building 105, Room 2700, 2160 S. First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-2127, Fax: þ1-708-216-5617, E-mail: [email protected]

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Prolonged cardiac arrest can also be followed by fixed or dynamic failure of cerebral microcirculatory reperfusion despite adequate cerebral perfusion pressure. Impaired reflow can cause persistent ischemia and microinfarcts in some brain regions (Nolan et al., 2008). A generalized inflammatory response also occurs following arrest, which has been referred to as the postcardiac arrest syndrome (Busto et al., 1989). The brain–heart connection remains a poorly understood but real physiological phenomenon that has long been recognized by neurologists and neurosurgeons and is now acknowledged by cardiologists with the description of the takotsubo syndrome. This syndrome presents as a severe cardiomyopathy that is associated with catastrophic life events or stress, such as the death of a loved one, or being “scared to death.” Despite significantly elevated troponin levels, the patients demonstrate normal coronary arteries at coronary angiography and complete recovery of left ventricular function in approximately 1–2 weeks (Kawai et al., 2000). A similar event occurs in the heart when severe cerebral damage occurs, particularly following subarachnoid hemorrhage. This cardiac dysfunction is probably related to excess catecholamine stimulation or some other cerebral–cardiac relation and is not as yet well delineated (Wittstein et al., 2005). Over 50 years ago, Kouvenhouven and Safar reported their work on, respectively, chest compression and mouthto-mouth pulmonary resuscitation, and modern CPR was born. Kouvenhoven et al. reported the results of chest compression on 20 hospitalized patients, of whom 14 were successfully resuscitated (Kouwenhoven et al., 1960; Eisenberg and Psaty, 2010). At the same time, Safar reported his data on the benefit of mouth-to-mouth ventilation (Eisenberg and Psaty, 2010). In 1947, Claude Beck performed the first successful open human defibrillation with recovery of the patient (Beck et al., 1947; Cooper et al., 2006). Paul Zoll recorded the first successful closed chest defibrillation in 1955 (Zoll et al., 1956; Cooper et al., 2006). Many lives since have been saved by CPR due to training in the use of this technique under the support and guidance of the American Heart Association. Currently, specific guidelines are published every 5 years to advise rescuers on the best practices for CPR. There is a current paradigm shift, however, in CPR technique that is expected to be outlined in the next set of CPR guidelines. This shift is toward cardiocerebral resuscitation (CCR) and away from cardiopulmonary resuscitation and has been spearheaded by Gordon Ewy and his colleagues at the Sarver Institute at the University of Arizona. Ewy and colleagues designed a study to compare 24 hour neurologically normal survival between continuous chest compressions (CCC) without assisted ventilations and 30 compressions to 2 breaths (CPR) as recommended in the 2005 American Heart Association guidelines in a

swine model of witnessed out-of-hospital cardiac arrest. They showed that continuous compression resuscitation was better at producing neurologically normal survivors than classic CPR (Ewy, 2005; Ewy et al., 2007). In a human retrospective observational cohort study by Garza et al., they found improved survival to discharge when a protocol that optimized chest compressions was used for outof-hospital ventricular fibrillation/ventricular tachycardia cardiac arrest (Garza et al., 2009). Subsequently, papers simultaneously published by Svensson and Rea reported opposite results, with Svensson concluding no benefit or advantage to CCC and Rea favoring the technique by showing a trend toward benefit in certain subgroups for CCC. However, these important papers viewed in context support the hypothesis that compression only resuscitation (CCC), which is easier to learn and perform, should be the preferred and instructed method of CPR (Rea et al., 2010; Svensson et al., 2010). Likewise, the increasing use of hypothermia for cerebral function preservation as established by the work of Bernard, the Hypothermia After Cardiac Arrest (HACA) group in Europe, and others has finally helped to improve neurologic outcomes in cardiac arrest patients (Hachimi-Idrissi et al., 2002; Bernard et al., 2003; Hypothermia After Cardiac Arrest Study Group, 2003). In discussing neurologic complications of cardiac arrest, the focus will be on preventing anoxic-hypoxic complications and will include the epidemiology of cardiac arrest, the neuropathology and physiology of anoxic-hypoxic brain damage, neurologic clinical syndromes after cardiac arrest, diagnosis and prognostic indicators, and finally, treatment of the post-cardiac arrest patient. In the 1970s, Negovsky described the effects of resuscitation and anoxia-hypoxia and labeled it “postresuscitation disease” (Negovsky, 1972). Now, Neumar et al. have described a “post-cardiac arrest syndrome” and its treatment, and how we can limit neurologic damage after cardiac arrest by aggressive treatment including therapeutic hypothermia (Neumar et al., 2008).

EPIDEMIOLOGY OF CARDIAC ARREST In-hospital cardiac arrest The incidence of in-hospital cardiac arrest has been well tracked since 2000 with the advent of the National CPR (NCPR) registry sponsored by the American Heart Association (Peberdy et al., 2003). This registry uses Utstein outcome criteria to follow in-hospital arrest at over 500 institutions (Cummins et al., 1997). As far back as 1987, McGrath and colleagues looked at in-hospital cardiac arrest in 13 000 patients and noted an overall survival to discharge of 14%. While this overall survival rate is low, neurologic recovery in survivors was

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST 27 approximately 60% (McGrath et al., 1987; Weil and Fries, outcome included sepsis, malignancy, renal failure, 2005). The NCPR initial data in 2003 on resuscitation of homebound status, and age, which was felt to be a boradults and children in the hospital had 14 720 cardiac derline predictor. Predictors of good outcome included arrests that were evaluated with an overall survival to early resuscitation, early defibrillation, mild hypotherdischarge of 17%. If the initial rhythm was VF, survival mia, and out-of-hospital arrests from VT/VF (Sandroni to discharge was 34% (Peberdy et al., 2003). This same et al., 2007). registry reported again in 2006 and at that time included These data give a much clearer picture of in-hospital 253 centers and 36 902 adults and 880 children with pulcardiac arrest outcomes, especially with the inception of seless cardiac arrest. They excluded peripartum, neonathe National Registry of Cardiopulmonary Resuscitation tal, and out-of-hospital arrests. The endpoint was (NRCPR) database. The sad fact is that for overall sursurvival to hospital discharge. Overall survival was vival we have not improved significantly. 27% in children and 18% in adults. VT/VF was the initial rhythm in 14% of children and 23% of adults. Survival to Out-of-hospital cardiac arrest discharge was 29% in children and 36% in adults, and good neurologic outcome occurred in 62.9% of children The outcomes of out-of-hospital cardiac arrest are worse than the in-hospital data, and the reporting and collection and 75.3% of adults. Asystole was the initial rhythm in of outcome data is particularly problematic. There is 40% of children and 35% of adults. Survival to discharge was 22.3% in children and 10.6% in adults and good wide variation in the reported incidence of out-ofneurologic outcome occurred in 55% of children and hospital cardiac arrest. Death certificate reporting in 61% of adults. PEA was the initial rhythm in 24% of chilmany US states will not allow for “cardiac arrest” or dren and 32% of adults. Survival to discharge was 26.6% “sudden cardiac arrest” as a diagnosis, and therefore in children and 11.2% in adults and good neurologic outsurrogate diagnoses are used, thus decreasing the accucome was 63.2% in children and 62.2% in adults. They racy of epidemiologic data. These surrogate data often include death due to coronary artery disease that concluded that asystole and PEA were the most common occurred within 1 hour of symptom onset and without initial rhythms and that children had better outcomes (Nadkarni et al., 2006). Patient characteristics included other probable cause of death (Thom et al., 2006). a mean age of 65, male sex predominance (57% versus In 1994, Lombardi published the New York City out43%); only 11% of in-hospital codes occurred in the emercomes for out-of-hospital arrest as part of the PHASE gency room (ER); illness categories included cardiac in study. This observational cohort study interviewed para38% and medical noncardiac in 41%, surgical cardiac medics about postarrest therapy. The endpoint for this in 7% and surgical noncardiac in 11%. The event was wittrial was discharge to home. They studied 3243 patients of whom 72% suffered primary cardiac events. The nessed and/or monitored in 88% of cases. In adult caroverall survival rate was 1.4%. Witnessed arrest survival diac arrest the mean interval to initiation of CPR was 0.5 minutes, mean interval to first attempted defibrillawas 5.3%. They noted 32% received bystander CPR, of tion was 2.1 minutes, mean duration of CPR was 22.3 whom 2.9% survived; among those without bystander minutes, and mean duration of CPR in survivors to hosCPR, 0.8% survived (Lombardi et al., 1994). Comparipital discharge was 16 minutes (Nadkarni et al., 2006). sons with other large urban areas were similar but midWhat is also apparent is that there is little improvement size towns and rural areas did better, particularly the in survival to discharge overall since McGrath’s data in highly organized King County, Washington (Eisenberg and Mengert, 2001). 1987. In a study from the Netherlands in 1999 that looked In Scotland, a 1996 study of initially resuscitated outat in-hospital CPR and tried to find predictors of survival of cardiac arrest, 553 patients were studied. Overall surof-hospital cardiac arrests in 1476 patients showed that vival to hospital discharge was 21.7%. Independent pre46% were discharged alive. In this group, 89% had good dictors of poor outcome included age > 70, stroke, renal neurologic function (Cobbe et al., 1996). In 2004, the failure, and congestive heart failure. Independent preOntario Prehospital Advanced Life Support Study studdictors of good outcome included angina pectoris and ied the rate of survival to discharge in 5638 cardiac VT/VF (de Vos et al., 1999). Saklayen et al. reported a arrests. The investigators noted survival to discharge in patients with rapid defibrillation of 5%, with advanced worldwide survival to discharge of 15.2% in 1995. This life support 5.1%, after a witnessed arrest by a bystander included survival by world regions as follows: US 15%, Canada 16%, UK 17%, and Europe 14% (Saklayen 4.4%, after CPR by a bystander 3.7%, and after rapid et al., 1995). In 2007, Sandroni et al., from Italy, reported defibrillation by a bystander 3.4% (Stiell et al., 2004). an overall survival to discharge from 0 to 42% in a Valenzuela noted a 74% survival to hospital discharge literature search and review of cardiac arrest. They also in out-of-hospital cardiac arrest when on-site lay listed predictors of outcome. Predictors of poor responders provided defibrillation in < 3 minutes, and

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Caffrey et al. reported overall survival rates of 66% in VT/VF arrest in the Chicago Airport System (Valenzuela et al., 2000; Caffrey et al., 2002). Bunch and his colleagues at Mayo Clinic studied long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation. In Olmstead County, Minnesota, they studied 200 patients with VF and noted excellent long-term survival in these patients. Some 72% survived to hospital admission and 40% were neurologically intact at discharge. The long-term 5 year survival was 79% and as good as age and sex matched controls with a similar disease processes. Bystander CPR was performed in 48% of this group (Bunch et al., 2003). In 2008, Sasson et al. reviewed 142 740 patients with out-of-hospital cardiac arrest and noted an overall survival to discharge of 7.6%. Bystander CPR occurred in 32%. If the patient’s arrest was witnessed by emergency medical services (EMS) the survival was 4.9– 18.2%. If the arrest was VT/VF, the survival was 14.8– 23%. If the arrest had return of spontaneous circulation (ROSC), then survival was best (15–33%). Overall, the conclusion of the authors was that survival in out-ofhospital cardiac arrest has been stable and little improved for almost 30 years (Sasson et al., 2010). In 2010, Svensson and his colleagues, in a lead New England Journal of Medicine article, studied 1226 cardiac arrests that took place outside hospital and reported a 30 day survival of 7.0–8.7%. Rea and colleagues, in the same issue, reported survival to discharge of 11.0–12.5% (Rea et al., 2010; Svensson et al., 2010). The lack of improvement in survival, especially for out-of-hospital cardiac arrest, carries significant implications for the neurologist. Almost all of these patients’ survival relates to the anoxic-hypoxic damage occurring during cardiac arrest.

TREATMENT OF CARDIAC ARREST The initial resuscitation of cardiac arrest is well outlined in the 2005 AHA Guidelines and includes specific algorithms for pulseless VF/VT, PEA, and asystole (Committee, Subcommittees and Task Forces of the American Heart Association, 2005). These measures are beyond the scope of this chapter and can be reviewed in detail in the 2010 AHA Guidelines (Field et al., 2010). The purpose of our review is to focus on the postresuscitative care of these patients, specifically a brain-oriented therapeutic approach. Neumar et al., in the 2008 International Liaison Committee on Resuscitation (ILCOR) consensus statement on post-cardiac arrest syndrome, have described five stages of postresuscitative care. These include immediate (the first 20 minutes after return of spontaneous circulation)

stabilization; early (the first 20 minutes to 12 hours after ROSC) interventions; intermediate (12–72 hours after ROSC) paths of treatment; recovery (72 hours plus) and prognostic indicators; rehabilitation-disposition and long-term care and rehabilitation (Neumar et al., 2008). It is during these first three phases that the focus is primarily on brain preservation. It is this period that we wish to focus on in terms of treatment post-cardiac arrest. Our goal is preservation of neurologic function. This is commonly measured in the hypothermia literature using the cerebral performance categories (CPC). These categories are as follows: CPC 1: good: the patient is alert and can live independently and has normal cerebral function; CPC 2: moderate disability: the patient is alert and can live independently and work part-time; such patients may have seizures and ataxia, etc.; CPC 3: severe disability: the patient is conscious but dependent on others for daily support (impaired cerebral function); CPC 4: vegetative state (Jennett and Bond, 1975; Cummins et al., 1997). Best outcomes for the cardiac arrest patient will be CPC 1 or 2. This section will review postresuscitative care basic measures, early diagnosis and treatment of the cause of cardiac arrest, temperature regulation therapy (hypothermia), seizure management, and long-term neurologic and cardiac management.

Basic measures The postarrest patient should be cared for in the critical care setting whether it be the medical intensive care unit (MICU) or cardiac care unit (CCU). The 2005 American Heart Association guidelines emphasize optimization of hemodynamic, ventilatory, and neurologic support. It is equally important to correct the underlying cause of the arrest, which is coronary artery disease in approximately 80% of cases (Chugh et al., 2008). Acute myocardial infarction (AMI) caused cardiac arrest in 68% in a study by Herlitz et al. (1995). Adequate airway and breathing, ventilator support, arterial line, ABG, pulse oximetry, CVP, MVO2, lactate levels, frequent vital signs, telemetry, central lines, Foley catheter, and general critical care measures are needed (Neumar et al., 2008). Echocardiography and EKG are necessary to evaluate the heart, and emergent cardiac catheterization and coronary angiography should be undertaken if ST elevation myocardial infarction is present. Knafelj et al. have shown the safety and potential benefit to neurologic survival in combining mild induced hypothermia with percutaneous intervention (PCI) to comatose survivors of cardiac arrest (Knafelj et al., 2007). Likewise, Wolfrum et al. studied 33 consecutive patients after VF cardiac arrest who remained comatose after ROSC and had acute myocardial infarction. Some 16 patients received immediate

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST induced hypothermia and it was continued during PCI. This group was compared to a similar group not receiving induced hypothermia. They found that initiation of hypothermia did not delay door-to-balloon times and that patients receiving induced hypothermia had a lower mortality (25% versus 35%) and an improved neurologic outcome (Wolfrum et al., 2008). An organized approach to the cardiac arrest patient’s postresuscitation treatment is recommended. Sunde and colleagues reported on a standardized treatment protocol for postresuscitation care after out-of-hospital cardiac arrest and compared a protocol using early reperfusion treatment (PCI), therapeutic hypothermia, a standardized treatment protocol (particular goals for seizure control, temperature regulation, glucose control and PaCO2), maintenance of an adequate arterial blood pressure, and prehospital CPR, and compared their results to a time before these standards were implemented. They found a survival-to-hospital discharge with a good neurologic outcome of 26% in the control period and 56% with the current plan including PCI and hypothermia (Sunde et al., 2006). The approach to the postcardiac arrest patient is really dependent on aggressive interventions in this early time period postarrest. Laurent et al. (2002) noted that most postresuscitation deaths occur in the first 24 hours. Perhaps the most important therapeutic intervention since Gorelick and Kelly reviewed this topic in 1993 has been the use of therapeutic hypothermia (Gorelick and Kelly, 1993).

Therapeutic hypothermia for cardiac arrest Hypothermia for brain preservation is not a new idea. In the November 1950 Annals of Surgery, Bigelow described the possible role of hypothermia in future cardiac surgery on the basis of experiments he performed on dogs. He described a state in which the body temperature is lowered and the oxygen requirements of the tissues are reduced. He foresaw this allowing exclusion of the organs from the circulation for prolonged periods and thus allowing surgeons to operate on the bloodless heart (Bigelow, 1950). In 1997, Marion et al. reported on the treatment of traumatic brain injury with moderate hypothermia. They randomized 82 patients with severe closed head injuries (Glasgow Coma Score (GCS) 3–7) to hypothermia at 33 C for 24 hours against normothermia. The patients were reevaluated using the Glasgow scale at 3, 6, and 12 months. At 12 months 62% of the patients in the hypothermia group and 38% in the normothermia group had good outcomes (moderate, mild, or no disabilities). The authors concluded that treatment with moderate hypothermia for 24 hours in patients with severe traumatic brain injury and with coma scores of 5–7 on admission may have improved neurologic

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outcome (Marion et al., 1997). Conflicting data were published by Clifton and colleagues in 2001 when they investigated the induction of hypothermia after brain injury. They studied 392 patients with coma after closed head injury and compared hypothermia to normothermia. Their study concluded that hypothermia is not effective in improving neurologic outcomes or mortality (Clifton et al., 2001). Despite this controversy, the interest in this treatment continued and has as its basis fundamental physiologic mechanisms that give it appeal for neurologic injury. Hypothermia may preserve brain function in several ways. In the normal brain, hypothermia reduces the cerebral metabolic rate for oxygen by 6% for every 1 C reduction in brain temperature. Cooling also reduces electrical activity and may increase the seizure threshold. Hypothermia has been reported to suppress reperfusion injury (free radical production, excitatory amino acids release, calcium shifts that lead to mitochondrial destruction and apoptosis). It also reduces tissue lactate and may decrease blood–brain barrier disruption and lead to less cerebral edema (Nolan et al., 2003; Holzer et al., 2005; Greer, 2006). Although the protective mechanism of hypothermia remains to be clearly defined, the above mechanisms should have merit and consideration. Several studies in laboratory animals show that hypothermia induced shortly after cardiac arrest may improve neurologic outcome (Greer, 2006). The breakthrough for the current practice of hypothermic therapy came through two key human randomized controlled studies published in the February 21, 2002 issue of the New England Journal of Medicine. The Hypothermia After Cardiac Arrest (HACA) Study Group in Europe published a paper entitled “Mild therapeutic hypothermia to improve neurologic outcome after cardiac arrest.” In this multicenter trial they studied comatose patients who had been resuscitated after cardiac arrest due to ventricular fibrillation. Patients were randomized to undergo therapeutic hypothermia (32–34 C) over 24 hours or normothermia. The primary endpoint was favorable neurologic outcome at 6 months after cardiac arrest. The study found 55% favorable outcome in the hypothermia group and 39% favorable outcome in the normothermia group. Suprisingly, mortality at 6 months was 41% in the hypothermia group and 55% in the normothermia group. The complication rate was the same for the two groups (Hypothermia After Cardiac Arrest Study Group, 2002). A second study was published from Australia by Bernard et al. and assessed treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. They randomized 77 patients who remained unconscious after cardiac arrest to treatment with hypothermia (core temperature reduced to 33 C within 2 hours after ROSC and maintained

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for 12 hours) or normothermia. They had a good neurologic outcome in 49% of the hypothermia group and in 26% of the normothermia group. The Australian investigators did not show a difference in mortality had been shown in Europe, but they concluded that treatment with moderate hypothermia appears to improve neurologic outcomes in patients with coma after cardiac arrest. There were no differences in complications in this study between the two groups (Bernard et al., 2002). Hachimi-Idrissi and his group studied 33 patients with coma after cardiac arrest and a primary electrocardiographic rhythm of asystole or pulseless electrical activity. Systemic cooling was achieved using a helmet device with a cooling solution. The patients were cooled to 34 C for 4 hours. It was found that 19% of the patients in the hypothermia group were alive at hospital discharge with a favorable neurologic outcome while none of the normothermia group had a favorable outcome. This was the only study to feature asystole and PEA treated with hypothermia (Hachimi-Idrissi et al., 2001). Potential complications of hypothermia involve all organ systems. Cardiovascular complications include sinus bradycardia, prolonged electrocardiographic intervals (QTc especially), atrial fibrillation, and ventricular dysrhythmias. Hematologic complications involve prolonged PT and PTT, thrombocytopenia and platelet dysfunction, impaired granulocyte function, and impaired granulocyte release. Metabolic effects include hypokalemia and hyperkalemia with rewarming, hyperglycemia, and shivering. Gastrointestinal effects are pancreatitis and ileus. Infections are increased, especially pneumonitis and bacteremia (Bernard et al., 2002; Hypothermia After Cardiac Arrest Study Group, 2002; Holzer et al., 2005; Greer, 2006; Seder and Jarrah, 2008). Skin care is crucial and cold-induced skin changes can occur. Following these human randomized controlled studies, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation made strong recommendations regarding the use of hypothermia. They recommended that unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32–34 C for 12–24 hours when the initial rhythm was ventricular fibrillation. Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest (Nolan et al., 2003). This statement was in 2003 and subsequently, in 2005, the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Care made hypothermia for these two categories in the ILCOR statement a Class IIa and Class IIb recommendation, respectively (Guidelines, 2005a, b, c). Despite these strong recommendations by authoritative bodies, the treatment of hypothermia was not

universally adopted. In a survey of physicians’ utilization of hypothermia in published, Abella et al found that use of hypothermia had yet to be broadly incorporated into physician practice. Reasons for nonuse included that it was too difficult, that there was not enough support in the literature, and that they did not know about it (Abella et al., 2005). Slowly these trends are changing and more and more medical centers have active hypothermia protocols. Many questions still remain as areas of future research regarding hypothermia for cardiac arrest. We still need to determine who are the best candidates for this treatment and who should be excluded. What is the target temperature, and for how long should we cool? Many of the studies have variable time periods of cooling. The HACA group cooled for 24 hours, Bernard in Australia for 12 hours, and Hachimi for 4 hours. What is the best way to cool, internal or external, and by what technology? Current cooling techniques vary from iced saline bags around the head to topical cooling blankets to sophisticated chaps and vests systems, and even a cooling helmet. Internal cooling can be accomplished with intravenous iced saline or internal catheters that will cool the body core. When is it best to use neuromuscular blockade for shivering? How soon should cooling take place after cardiac arrest? When is it too late to cool? Abella et al., in a study of a murine arrest model, found that the timing of hypothermia was a crucial element of survival. They demonstrated that early intra-arrest cooling appears to be significantly better than delayed post-ROSC cooling or normothermic resuscitation (Abella et al., 2004). This would dictate in-the-field cooling, as was done in Bernard’s study in Australia (Bernard et al., 2002). How do we determine neurologic prognosis in the presence of hypothermia and sedation and often neuromuscular blockade (Young, 2009)? All these questions need answers before we can optimize this promising treatment for anoxic brain injury.

Sedation and neuromuscular blockade After cardiac arrest, the intubated comatose patient will require sedation and often neuromuscular blockade. Neuromuscular blockade may facilitate induction of hypothermia by blocking shivering and depth of blockade can be assessed by using train-of-four muscle twitch assessment in the intensive care unit (ICU). Deep sedation alone may suppress shivering and there is a movement in hypothermia protocols to use bolus neuromuscular blockade only rather than mandatory blockade in each case (Neumar et al., 2008). Sedation and neuromuscular blockade both affect prognostic neurologic assessment of the patient, as does hypothermia itself

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST (Young, 2009). Because of the relatively high incidence of seizures after cardiac arrest, continuous EEG recording is recommended when neuromuscular blockade is in place (Neumar et al., 2008).

Seizure control and prevention Seizures, myoclonus, or both occur in 10–40% of adults who remain comatose after cardiac arrest (Neumar et al., 2008). No studies have directly addressed the use of prophylactic anticonvulsant drugs after cardiac arrest in adults. Myoclonus can be difficult to treat and clonazepam remains the most effective antimyoclonic drug. Prolonged seizures can cause cerebral injury and should be treated promptly by standard drugs such as benzodiazepines or phenytoin. Prospective studies to determine the benefit of prophylactic seizure treatment and the benefit of continuous EEG monitoring remain to be done. A recent prospective observational study by Rundgren studied comatose cardiac arrest survivors using a continuous amplitude integrated EEG during hypothermia until the patient regained consciousness or 120 hours had elapsed. The study looked at 34 patients and at normothermia the EEG pattern was discriminative for outcome. They found that a continuous EEG pattern at normothermia was predictive of regaining consciousness whereas a pathologic pattern (flat, burstsuppression, or status epilepticus) was not. Seven patients (21%) developed clinical seizures and electrographic status epilepticus during hypothermia. None of these patients regained consciousness and all died in the hospital (Rundgren et al., 2006).

Neuroprotective pharmacology A number of trials have investigated neuroprotective mechanisms in the immediate postarrest period (Geocadin et al., 2008). With the exception of therapeutic hypothermia, few have proven successful. Treatment strategies that have shown promise in experimental studies, but whose success could not replicated in larger or controlled trials, have included barbiturates such as thiopental (Brain Resuscitation Clinical Trial I Study Group, 1986), glucorticoids (Jastremski et al., 1989), calcium channel blockers such as lidoflazine (Brain Resuscitation Clinical Trial II Study Group, 1991), nimodipine (Roine et al., 1990; Safar, 1993), resuscitation with 0.45% NaCl versus 5% glucose (Longstreth et al., 1986), intravenous magnesium alone (Thel et al., 1997) or with diazepam (Longstreth et al., 2002). The use of tenecteplase in the Thrombolyisis in Cardiac Arrest (TROICA) trial for patients with out-of-hospital cardiac arrest of presumed cardiac etiology did not increase 30 day survival compared with placebo (Bottiger et al., 2008). A recent retrospective, nonrandomized study of 227

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patients following cardiac arrest suggested that the early administration of intravenous selenium for 5 days following arrest was a significant predictor of regaining consciousness. Overall survival at 6 months was not significantly influenced (Reisinger, 2009). Coenzyme Q10, whose potential benefit has been speculated on in diseases ranging from congestive heart failure to amyotrophic lateral sclerosis, has also been studied as a therapy for cardiac arrest. Coenzyme Q10 combined with mild hypothermia in a small study of 49 patients appeared to improve survival at 3 months (68% versus 29%) and was associated with a lower mean serum S100 protein level (Damian et al., 2004). Several protective measures have demonstrated some benefit in the postarrest patient, including management of intracranial pressure, fever, and seizures. Maintenance of an adequate mean arterial pressure (MAP) between 80 and 100 mmHg has been suggested to ensure adequate cerebral blood flow (Bell et al., 2005). In one retrospective study of 136 patients, good neurologic recovery was independently and directly related to a MAP > 100 mmHg during the first 2 hours after the return of spontaneous circulation, but not associated with hypertensive reperfusion within the first 5 minutes after the return of spontaneous circulation (Mullner et al., 1996).

PROGNOSIS In addition to attempting to minimize brain injury in the immediate postarrest period, one of the most common questions for neurologists is to predict the longterm prognosis for these patients. Approximately 18% of patients who have an inpatient cardiac arrest survive to discharge while only 2–9% of those who experience an out-of-hospital arrest survive to discharge (Geocadin et al., 2008). In those that survive cardiac arrest, only 3–7% are able to return to their previous level of functioning (Geocadin et al., 2008). In those that survive cardiac arrest, brain injury is common. In one study of patients who survived to ICU admission but subsequently died in the hospital, brain injury was the cause of death in 68% after out-of-hospital cardiac arrest and 23% after in-hospital arrest (Laver et al., 2004; Nolan et al., 2008). In 1985, Levy et al. published a report on predicting outcome from hypoxic-ischemic coma (Levy et al., 1985). Poor prognostic signs included absent pupillary light reflexes, motor responses at 24 hours that were absent, extensor, or flexor, and by spontaneous eye movements that were neither orienting nor roving conjugate. The ensuing two and half decades of clinical experience and research data have largely validated their findings. Awakening generally occurs within 3 days in

32 M. McCOYD AND T. McKIERNAN patients who are comatose due to anoxic-ischemic epilepticus, characterized by bilaterally synchronous encephalopathy following resuscitation, if patients twitches of limb, trunk, or facial muscles, occurring awaken at all. Neurologic impairment is expected in within the first 24 hours in patients with primary circulathose that fail to do so (Wijdicks et al., 2006). Most studtory arrest is invariably associated with in-hospital death ies that assess predictors of poor outcome in patients or poor outcome, even in patients with intact brainstem with anoxic-ischemic encephalopathy have as their prime reflexes or some motor responses (Wijdicks et al., 2006; objective the reliable prediction of an outcome no better Young, 2009). In a prospective study of 407 patients, than a vegetative state or severe disability with total myoclonic status epilepticus at 24 hours after arrest dependency at 3–6 months after arrest (Young, 2009). was associated with no false-positive predictors of poor The circumstances of the arrest, including time between outcome (Zandbergen et al., 2006a; Young, 2009). collapse and initiation of CPR, duration of CPR, cause Information derived from electroencephalograms of the arrest (cardiac versus noncardiac), and type of (EEG) has been difficult to apply broadly owing to difarrhythmia are related to poor outcome but cannot disferences in interpretation and categorization. It is genercriminate accurately between patients with poor and ally accepted that generalized suppression to 20 mV, favorable outcomes (Wijdicks et al., 2006). The presence burst-suppression pattern with generalized epileptiform or absence of any single specific clinical sign observed activity, or generalized periodic complexes on a flat immediately after cardiac arrest has not been shown background are strongly but not invariably associated accurately to predict outcome either. However, patients with poor outcome (Wijdicks et al., 2006). Burst suppreswho lack pupillary and corneal reflexes at 24 hours and sion on isoelectric pattern on EEG within the first week have no motor response at 72 hours have an extremely had a 100% specificity for poor outcome in most studies small chance of meaningful recovery (Booth et al., (Zandbergen et al., 1998). In one older study, only two of 2004). Absent pupillary light reflexes 24–72 hours after 18 patients with a seriously impaired EEG had a relatively CPR and absent corneal reflexes after 3 days has consisgood outcome (Cloche et al., 1968). A recent study by tently shown a 0% false-positive prediction rate for poor Thenayan et al. looked at EEG reactivity as an indicator outcome in multiple studies (Wijdicks et al., 2006). In of recovery (Thenayan et al., 2010). The study found a several prospective studies, 108 patients identified with strong association between the presence of reactivity absent pupillary light responses 3 days after cardiac on EEG and the comatose patient regaining awareness. arrest all had poor outcomes (Young, 2009). FalseTen of 11 patients with EEG reactivity regained conpositive predictions of poor outcome based on motor sciousness; the one that did not had life support withresponse may occur with a GCS motor score of < 2 drawn on day 5 after cardiac arrest in part due to (i.e., extensor or absent motor responses) 24–48 hours absent somatosensory evoked potential (SSEP) response after CPR, but no false predictions have occurred after and poor prognostic clinical features. Seventeen of 18 72 hours other than in patients who have undergone therpatients with no reactivity on EEG did not regain conapeutic hypothermia (Wijdicks et al., 2006). sciousness (Thenayan et al., 2010). Clinical predictors should be treated with some Short-latency SSEPs have proven to be the most degree of caution in patients who undergo therapeutic robust predictor of poor outcome following cardiac hypothermia. One study by Al Thenayan et al. of 37 arrest (Bleck, 2006). Early cortical responses are generpatients showed recovery of awareness on day 6 in ated in the somatosensory cortex and can help identify two of 14 patients who had motor responses no better patients with severe brain damage (Allison et al., 1991). than extensor posturing on day 3. However, none of SSEPs are less influenced by drugs and metabolic the patients without pupillary reactivity on day 3 and derangements than EEG and are therefore more accunone with absent corneal reflexes recovered awareness rate than EEG in prognostication (Wijdicks et al., (Al Thenayan et al., 2008; Young, 2009). These findings 2006). The bilateral absence of the N20 of the SSEP were confirmed in a second study by Rossetti et al. of 111 in patients with postanoxic coma of at least 24 hours patients that also showed that motor response to pain duration is invariably associated with poor outcome was a less reliable predictor of poor outcome in coma(Zandbergen et al., 2006b). Loss of the cortical response tose cardiac arrest survivors after therapeutic hypotherto median nerve stimulation (the N20 potential) when the mia, with a false-positive mortality prediction of 24% earlier potentials (those recorded over the brachial (Rosetti et al., 2010). plexus and the dorsal root entry zone near C7) are intact Though seizures are often considered to portend a carries an almost certain prognosis of death or poor poor outcome, no individual studies or summary meafunctional recovery (Bleck, 2006). Of 187 patients with sures have established that single seizures or sporadic absent N20 responses, 179 died and the remaining eight myoclonus accurately predict outcome (Booth et al., were in a vegetative state. The chance of recovery of con2004; Wijdicks et al., 2006). However, myoclonic status sciousness in patients with absent N20 responses in the

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST 33 first week who are in a vegetative state after 1 month is occurring potentials are generated by thalamocortical virtually nil, indicating irreversible brain damage severe interactions and are modulated by the reticular activatenough to justify its combination with death as an outing system (Pfurtscheller et al., 1985). Smaller studies come measure (Zandbergen et al., 1998). Bilateral were supportive of the use of long-term latencies to absence of the N20 component of the SSEP with median improve the sensitivity of SSEPs in predicting poor outnerve stimulation had good predictive value for poor come. In one study by Madl et al., the preservation of the outcome with almost all studies showing false-positive N70 SSEP had a sensitivity of 94% and a specificity of rates of 0% (Wijdicks et al., 2006). Absent SSEP has 97% for predicting good outcome in patients with prebeen found more often than any other neurophysiologic served N20 potentials (Madl et al., 2000). In another or clinical predictor with 100% predictive value small study, by Young et al., all five patients with pre(Zandbergen et al., 2006b). served N70 responses recovered awareness out of 33 The presence of N20 potentials does not select a comatose cardiac arrest survivors (Young et al., 2005). group who will do well, however. The prevalence of A larger study by Prohl et al. found that the long-latency absent short-latency SSEP is rather low. Its sensitivity N70 on day 4 correlated more strongly with the outcome as a test for poor outcome is only moderate (Zandbergen groups than short-latency SSEPs. If SSEP N70 could be et al., 2006b). Many patients who fail to recover will have recorded (which it was in 30 out of 47 examinations), the preserved N20 responses (Wijdicks et al., 2006). In one prediction of a favorable outcome was successful in 87% study, 40% (13/32) of the patients with preserved early of patients (n ¼ 26) (Prohl et al., 2007). However, in a cortical responses achieved a good recovery (Daubin multicenter study by Zandbergen et al., the presence et al., 2008). or absence of the N70 in patients with postanoxic coma It has generally been accepted that once lost, N20 was not found to be precise enough to base treatment responses are not regained, especially if absent 72 hours decisions solely on its absence (Zandbergen et al., after arrest (Young, 2009). Absent SSEPs have rarely 2006b). In the study of 407 patients, poor outcome been associated with recovery of consciousness and in occurred more often when N70 was absent 72 hours after those cases, SSEPs were typically performed in the first CPR compared with earlier recordings. However, there 24 hours, possibly representing a “shock phase” early was a substantial increase of false-positive predictions after the insult from which the brain can recover (4–15%). The presence of the N70 response resulted in (Guerit et al., 1993; Zandbergen et al., 1998). Studies have an outcome better than death in only 28% of patients. suggested that hypothermia, even cooling to 30 C, may There was also a high percentage of failures to classify influence the latencies of the cortical responses but not the N70 response, caused by equivocal readings or techthe responses themselves (Stecker et al., 2001; nically insufficient recordings. The authors concluded Kottenberg-Assenmacher et al., 2003). However, more that the false prediction of poor outcome occurs in a recent data suggest that hypothermia treatment may number of patients when N70 is used (Zandbergen affect the predictive value of clinical findings and N20 et al., 2006b). responses. In a study by Leithner et al., one patient At least one study looked at brainstem auditory had absent N20 3 days after arrest, good outcome, and evoked potentials for predictive value in postanoxic recovery of N20 responses on follow-up, and one patient encephalopathy. The middle latency auditory evoked with barely detectable N20 on day 3 who also had good response was absent in all 13 patients who died or outcome and recovery of N20 on follow-up. Both remained in a persistent vegetative state (with a sensitivpatients’ SSEP recordings were performed 3 days after ity of 34%) (Young, 2009). However, there is only a limcardiac arrest and 2 days after the beginning of rewarmited amount of data to support its routine use. ing at core body temperatures of 36 C and 37 C. These The use of serum biochemical markers has been of findings suggest that the prediction of poor outcome by interest, in part due to the possibility of simplifying the bilateral absent N20 might not be 100% certain and that acquisition of prognostic information, but their poor relevant recovery of N20 might occur beyond 24 hours in sensitivity has limited their use (Bunch et al., 2007). cardiac arrest patients treated with hypothermia Neuron-specific enolase (NSE) is localized primarily in (Leithner et al., 2010). The other 35 patients who had the neuronal cytoplasm and is released into the cerebrospibilateral absent N20 recordings had poor outcomes nal fluid and serum with neural tissue injury (Bunch et al., (Leithner et al., 2010). However, in the study by Rossetti 2007). NSE serum concentration level of > 33 mg/L samet al., no patients with absent N20 responses had favorpled between 1 and 3 days after cardiac arrest was strongly able outcomes despite therapeutic hypothermia (Rosetti predictive of poor outcome with no false positives. Some et al., 2010). 60% of 231 patients in a study by Zandbergen et al. had There has been interest in the use of long-term latenNSE > 33 mg/L at day 1–3 after CPR and all had a poor cies (N70) as well, with mixed results. These later outcome (Zandbergen et al., 2006b). Similar findings

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were reported by Prohl et al., who found that the median values of NSE on days 2–4 were higher among patients with a poor neurologic outcome as compared to those with a favorable outcome. Those who died or remained in a persistent vegetative state had a median NSE of 28.60 on day 4. Those who regained consciousness had a median NSE of 9.75 on day 4. NSE values tended to rise from day 2 to day 4 in those who did poorly and decreased in those who regained consciousness. The authors concluded that NSE can reliably distinguish between patients with favorable and unfavorable neurologic outcomes at an early stage, though biomarkers alone cannot replace a systematic neurologic examination (Prohl et al., 2007). Previous studies have not been as convincing for the validity of timing and cutoff values for biomarkers such as NSE (Schoerkhuber et al., 1999; Rech et al., 2006; Young, 2009). Some patients with NSE values > 33 mg/L have been reported who survived (Zandbergen et al., 2006b). NSE values were found to be significantly lower in patients who underwent therapeutic hypothermia versus those who did not in one study (Tiainen et al., 2003). A limiting factor may be the availability of the assay in North America (Young, 2009). The greatest predictive value of biomarkers such as NSE may be in combination with other variables such as the clinical examination and electrophysiologic testing (Bunch et al., 2007; Prohl et al., 2007). Protein S100B has also been a serum biochemical marker of interest in postarrest patients. Protein S100B is a calcium-binding astroglial protein that is released after stroke and cardiac arrest. Elevated levels of S100B might cause neuronal apoptosis, suggesting that S100B may play a role as a cytokine in brain inflammatory responses (Van Eldik et al., 2003; Bianchi et al., 2007; Shinozaki et al., 2009). The available data seem to indicate that protein S100B is not superior to NSE for predicting poor outcome, in part due to its low sensitivity. A study by Grubb et al. found that a S100B cutoff of > 1.2 mgL1 drawn between 24 and 48 hours after return of spontaneous circulation was required to achieve a false-positive rate of 0% with a sensitivity of 45% (Grubb et al., 1996). Zandbergen et al. found the sensitivity of NSE to be “clearly superior” to that of S100B testing (Zandbergen et al., 2006b). Mild therapeutic hypothermia was not found to significantly influence serum levels of S100B in patients surviving non-traumatic out-of-hospital cardiac arrest (Derwall et al., 2009). The predictive quality of S100B levels was best on admission but not on later time points. S100B levels at baseline were significantly lower in patients with good neurologic outcome at 14 days (Derwall et al., 2009). In a systematic review of the available literature, Shinozaki et al. also found that serum levels of S100B may be the most clinically useful within 24 hours of cardiac arrest in predicting neurologic outcomes such as regaining consciousness and returning to

independent daily life (Shinozaki et al., 2009). In the 2006 American Academy of Neurology Practice Parameter, S100B was felt to be a poor prognostic indicator with inadequate data to support or refute its value (Wijdicks et al., 2006). Imaging studies, particularly CT, in the immediate postarrest period are typically normal. Diffuse brain swelling may occur as early as 3 days after CPR (Wijdicks et al., 2006). There are two CT signs associated with ischemic brain damage: loss of boundary (LOB) between gray matter and white matter, and cortical sulcal effacement. An inversed gray/white matter ratio in Hounsfield units on CT was found in patients who failed to awaken after CPR in at least one study (Torbey et al., 2000; Wijdicks et al., 2006). A recent study by Inamasu et al. found that when the cardiac arrest–return of spontaneous circulation interval exceeded 20 minutes, patients developed a positive LOB sign, and those with an interval of > 30 minutes did so invariably. The signs were recognizable on CT as early as 1 hour after cardiac arrest. Sulcal effacement was not found to be as timedependent or predictable as the LOB sign, but was a more specific sign of fatal brain injury when present (Inamasu et al., 2010). MRI data as a tool for prognostication have been limited (Wijdicks et al., 2006). Diffusion-weighted imaging abnormalities have correlated with poor outcome in several smaller studies of no more than 12 patients (Wijdicks et al., 2001). A larger, more recent retrospective study of 80 patients found that whole brain median ADC was a significant predictor of poor outcome with lower ADCs for patients with poor outcomes. Severe ADC depression within the first few days of global anoxia was highly specific for permanent brain injury (Wu et al., 2009). The ideal time window for prognostication appears to be between 49 and 108 hours after the arrest, when ADC reductions are the most apparent. No patients with > 10% of brain tissue with an ADC value < 650  106 mm2/s to 700  106 mm2/s during this time window regained consciousness. ADC changes due to global ischemic brain injury are delayed compared to changes caused by focal ischemia. Changes in postarrest patients with poor prognosis are the most severe in cortical gray regions and the most prominent between days 3 and 5 after the arrest (Mlynash et al., 2010).

LONG-TERM COMPLICATIONS OF CARDIAC ARREST Approximately 18% of patients who have an inpatient cardiac arrest survive to discharge and only 2–9% of those who experience an out-of-hospital arrest survive to discharge (Geocadin et al., 2008). In those that survive cardiac arrest, only 3–7% are able to return to their

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST previous level of functioning (Geocadin et al., 2008). In those that survive cardiac arrest, brain injury is common. In one study of patients who survived to ICU admission but subsequently died in the hospital, brain injury was the cause of death in 68% after out-of-hospital cardiac arrest and 23% after in-hospital arrest (Laver et al., 2004; Nolan et al., 2008). There are several common immediate and delayed neurologic syndromes associated with cardiac arrest. An amnestic syndrome is common after brief periods of arrest, including both retrograde and anterograde amnesia, which may include a component of confabulation (Bass, 1985). Cortical blindness – an inability to see despite intact anterior visual pathways – has been described. In such cases, pupillary reflexes will remain intact but patients will not blink to threat and will not track. Denial of blindness (Anton syndrome) may occur (Bass, 1985). Bibrachial weakness may occur due to bilateral watershed infarctions related to the close junction of the anterior and middle cerebral arterial zones (Bass, 1985). Bilateral flaccid leg weakness may occur due to hypoperfusion of the poorly vascularized watershed regions of the spinal cord. Delayed postanoxic leukoencephalopathy may occur 2–3 weeks after arrest in patients who appear to be recovering well (Bass, 1985). Movement disorders may arise from metabolic disturbances from hypoxic-ischemic injury to the liver and/or kidney, medications, or brain ischemia (Venkatesan et al., 2006). Posthypoxic myoclonus (PHM) is perhaps the most common, and can occur acutely or begin after a period of delay (the Lance–Adams syndrome) (Venkatesan et al., 2006). Acute PHM occurs in 30– 40% of comatose arrest survivors within 24 hours of the arrest and is characterized by violent flexion movements, usually of the face and limb muscles. Acute PHM lasting > 30 minutes or occurring for most of the first postresuscitation day is termed myoclonic status epilepticus, though the movement may not represent true “epileptic” activity, and is associated with an extremely poor prognosis (Venkatesan et al., 2006). Autopsied patients have evidence of neuronal ischemia and cell death in the cerebral cortex, deep gray nuclei (basal ganglia and thalamus), hippocampus, and cerebellum that is more severe than those who did not have myoclonus (Venkatesan et al., 2006). Chronic PHM occurs within days to weeks of the arrest, and typically while the patient is still in coma. Patients are noted to have action myoclonus involving the limbs and occur on attempting to move or position a limb. Clonazepam and valproate have demonstrated an efficacy in 50% of patients with chronic PHM (Venkatesan et al., 2006). At least half of those who survive cardiac arrest have evidence of neuropsychological impairments, including memory difficulties and problems with planning,

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perception, and language, as well as personality changes (Caine et al., 2000; Lim et al., 2004; Horstmann et al., 2010). Perhaps as many as a third of patients who survive to discharge have cognitive deficits which are severe enough to hinder daily activities (Grubb et al., 1996, 2007). “Isolated amnesia” in the absence of other cognitive or motor deficits is reported but rare. Recovery of memory and visuospatial deficits likely occurs only in the first 3 months after arrest with little recovery beyond that time. Executive disturbances may improve over 3–10 months (Lim et al., 2004). Reductions in gray matter volumes have been noted in the anterior, medial, and posterior cingulated cortex, the precuneus, the insular cortex, the posterior hippocampus, and the dorsomedial thalamus on MRI, correlating with neuropsychological impairments such as amnestic deficits and apathy (Horstmann et al., 2010). Mild therapeutic hypothermia has not been noted to have a negative impact on cognition (Tiainen et al., 2007). In a study of 70 patients randomized to therapeutic hypothermia or normothermia, 67% of the survivors in the hypothermia group and 44% in the normothermia group were cognitively intact or had only subtle cognitive deficits 3 months after the arrest (the difference was not statistically significant) (Tiainen et al., 2007). Protein S100, an astroglial protein that is released after stroke and cardiac arrest, may be associated with cognitive deficits. A study by Grubb et al. found that S100 estimation at 24–48 hours may provide useful prognostic information, correlating with memory indices. S100 concentrations > 0.29 mg/L identified a subgroup of patients with significant impairment in working memory at time of discharge from the hospital (Grubb et al., 2007).

CONCLUSION The management and complications of cardiac arrest pose a significant challenge for the medical community in general and neurologists specifically. Despite intense efforts to optimize care for these patients, prognosis has remained poor for the majority of individuals. Therapeutic hypothermia has emerged as the most promising neuroprotective therapy, validated in multiple studies in appropriately selected patients. The implementation of hypothermia protocols in many centers has established a trend toward better outcomes. The two and a half decades of clinical experience have served to confirm the published work of Levy et al. (1985) in regards to prognosis following cardiac arrest. However, in addition to clinical findings, data have consistently shown that prognosis can also be guided by ancillary studies such as somatosensory evoked potentials, electroencephalography, and brain imaging. The use of serum and CSF biomarkers as an aid to prognosis continues to evolve.

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The hope remains that progress will continue toward effective therapies to reduce the likelihood of death or disability following cardiac arrest, as well as diagnostic modalities to aid the clinician in identifying patients expected to recover.

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Wolfrum S, Perau C, Radke PW et al. (2008). Mild therapeutic hypothermia in patients after out-of hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention. Crit Care Med 36: 1780–1786. Wu O, Sorensen AG, Benner T et al. (2009). Comatose patients with cardiac arrest: predicting clinical outcome with diffusion-weighted MR imaging. Radiology 252: 173–181. Young GB (2009). Neurologic prognosis after cardiac arrest. N Engl J Med 361: 605–611. Young GB, Doig G, Ragazzoni A (2005). Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome. Neurocrit Care 2: 159–164. Zandbergen EGJ, Hijdra A, Koelman JHTM et al. (2006a). Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 66: 62–68. Zandbergen EGJ, Koelman JHTM, de Haan RJ et al. (2006b). SSEPs and prognosis in postanoxic coma: only short or also long latency responses. Neurology 67: 583–586. Zanderbergen EGJ, de Haan RJ, Stoutenbeek CP et al. (1998). Systemic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 352: 1808–1812. Zoll PM, Linenthal AJ, Gibson G et al. (1956). Termination of ventricular fibrillation in man by externally applied electric countershock. N Engl J Med 254: 727–732.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 4

Neurologic complications of cardiac tests and procedures CATHY SILA* Department of Neurology, Case Western Reserve University School of Medicine and Stroke and Cerebrovascular Center, University Hospitals—Case Medical Center, Cleveland, OH, USA

HISTORY Vascular access is the cornerstone of invasive cardiac monitoring and cardiac procedures. Crude methods of arterial blood pressure measurement were available by the late 1700s and by 1828, Jean-Louis Poiseuille had invented the mercury-filled manometer. This technology led to key experiments that were the foundation of Poiseuille’s Law, one of the most famous equations in hemodynamics (Poiseuille, 1828). By the end of World War II, catheters made of plastic and modern capacitance manometers enabled the first clinical use of a peripheral arterial line for continuous measurement of mean arterial pressure (Peterson et al., 1949). The first report of catheter access in the heart was performed in 1929 in a small hospital in Eberswald, Germany, by Werner Forssmann. During his surgical training, Forssmann advanced a percutaneous catheter into his own right atrium. Although his personal career was devastated by his selfexperimentation, he was awarded the 1956 Nobel Prize along with Cournand and Richards, for their application of his technique to image the cardiac chambers and valves. The first contrast visualization of the coronary arteries was performed by F. Mason Sones in 1958 via direct arterial exposure of the brachial artery, which became known as “the Sones technique” (Sones et al., 1959). Subsequent contributions in percutaneous arterial access by Sven-Ivar Seldinger, “the Seldinger technique,” introduction of the percutaneous femoral approach and development of specialized catheters by Melvin Judkins, and the introduction of coronary artery bypass graft surgery by Rene´ Favaloro, led to the development of coronary angiography which became the reference standard for assessing patients for coronary artery disease (Seldinger, 1953; Judkins, 1967; Favaloro, 1968). Many

contemporary cardiac tests and procedures require arterial or central venous access for diagnosis, monitoring, or therapeutics and although their safety has significantly improved due to protocols perfected over decades of use, their widespread use renders even the uncommon neurologic complication clinically relevant.

CLINICAL MANIFESTATIONS OF NEUROLOGIC COMPLICATIONS OF CARDIAC TESTS AND PROCEDURES Peripheral nervous system (PNS) complications Peripheral arterial catheters, or “A-lines,” are commonly used in critically ill patients for mean arterial pressure monitoring. In the setting of arterial pressure gradients resulting from local atherosclerotic stenosis or generalized vasoconstriction with shock, these central measurements are more accurate than peripheral blood pressure cuff monitoring. Arterial lines are typically placed in the radial or femoral artery but the brachial, axillary, and dorsalis pedis arteries can also be used. Arterial vascular access for diagnostic coronary angiography was initially performed by surgical exploration, or “cut down” of the brachial artery and insertion of catheters under direct visualization followed by surgical closure of the arteriotomy and skin. Although institutions and operators vary in their preference for accessing the left heart by the upper extremity brachial, radial, or axillary artery versus lower extremity femoral artery, direct surgical access has been largely replaced by percutaneous arterial access approaches. In addition, catheterization of the right heart is accomplished by percutaneous access of the femoral, internal jugular, or subclavian veins. The choice of

*Correspondence to: Cathy Sila, M.D., George M. Humphrey II, Professor of Neurology, 11100 Euclid Avenue HAN/5040, University Hospitals-Case Medical Center, Cleveland, OH, 44040, USA. Tel: þ1-216-844-8934, Fax: þ1-216-844-4785, E-mail: [email protected]

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vascular site access varies by operator experience and preference but is also driven by the arterial size and anatomy required by the anticipated procedure. For diagnostic and therapeutic procedures requiring multiple changes of catheters, a vascular sheath is used which permits continuous vascular access. These range from 4–6 French for diagnostic catheterization procedures to as large as 24 French for interventional procedures, such as transcatheter valve replacement. The anatomic relationship of the peripheral nerves to their companion arteries and veins renders them vulnerable to injury. Adjacent peripheral nerves can be injured directly during line placement or indirectly from compression when swelling or hemorrhage produces a compartment syndrome.

PNS COMPLICATIONS OF RADIAL ARTERY CATHETERIZATION

The radial artery is the most frequently accessed site for the placement of an arterial pressure monitoring catheter in critically ill patients. The transradial approach for cardiac catheterization varies widely among operators, institutions, and countries and is used more frequently in Europe than the US. Technical expertise is required to overcome the difficulties in accessing and manipulating catheters through this smaller vessel; at 2 millimeters, the largest vascular sheath size is typically 6 French, which limits this technique primarily to diagnostic angiography. The risk of serious complications with radial artery access is less than 0.1%; this includes direct nerve injury or indirect nerve injury from compression due to hematoma or compartment syndrome (Wallach, 2004). The risk of a volar forearm compartment syndrome is increased with concomitant anticoagulation. When the pressure within the carpal tunnel is increased above 20–30 mmHg, the perfusion to the median nerve is impaired, presenting as acute pain and paresthesias followed by sensorimotor deficit. Prevention of nerve infarction requires prompt recognition and the performance of a fasciotomy and surgical release (Kokosis et al., 2010). A pre-existing carpal tunnel syndrome is a risk factor for symptomatic median nerve dysfunction following radial artery catheter placement and may be more common than typically recognized. In one prospective study of 151 patients undergoing radial artery catheter placement, symptoms of median nerve dysfunction were reported by 8/12 (67%) of those with prior carpal tunnel syndrome versus only 1/139 (0.7%) of those without prior symptoms (Martin et al., 1993).

PNS COMPLICATIONS OF BRACHIAL ARTERY CATHETERIZATION

The brachial artery is accessed for cardiac catheterization, particularly in patients with significant lower

extremity vascular disease or prior vascular surgery, and is also an alternate site for the placement of an arterial pressure monitoring catheter. The classic technique developed by Sones required surgical exposure which was complicated by a 1–2% risk of brachial artery thrombosis. Modern percutaneous access techniques have reduced the risk of serious complications with brachial artery access to 0.2–1.4%; this includes vascular complications, direct nerve injury and indirect nerve injury from compression due to hematoma and nerve infarction (Macon and Futrell, 1973). Concomitant anticoagulation therapy increases the risk of hematoma formation, particularly if the puncture was distal to the antecubital fossa and blood collects underneath the lacertus fibrosus (bicipital aponeurosis). The manifestations of median nerve involvement vary with the location of the nerve injury as the course of the median nerve varies with respect to the brachial artery. The median nerve runs lateral to the brachial artery within the upper arm and crosses anteriorly to the brachial artery within the antecubital fossa giving off the anterior interosseus branch and runs medial to the brachial artery within the forearm. Injuries to the median nerve in this region are often distinguished by concomitant involvement of the flexor pollicis longus. Although most nerve injuries improve with time, appreciable long-term disability with high median nerve injuries has been described (Kennedy et al., 1997).

PNS COMPLICATIONS OF AXILLARY ARTERY CATHETERIZATION

The axillary artery approach carries a higher complication rate so it is less frequently used than in prior decades. This approach remains essential when access with larger vascular sheaths is required in patients with severe lower extremity vascular disease. In one series of 320 axillary arteriograms, 9 (2.8%) sustained compression injuries of the median and ulnar nerves due to hematoma formation (Smith et al., 1989). The diagnosis may be difficult as the visual or palpable size of the hematoma may not correlate with the severity of the neurologic deficit and it may evolve up to 2 days postprocedure. Compartment syndrome within the medial brachial fascial compartment at the anterior axillary fold causes injury to the proximal median and ulnar nerves and spares the radial and musculocutaneous nerves due to their proximal exit.

PNS COMPLICATIONS OF FEMORAL ARTERY CATHETERIZATION

The femoral artery remains the primary access technique for interventional procedures requiring large vascular sheath access, cerebrovascular and peripheral vascular angiographic procedures, although in many

NEUROLOGIC COMPLICATIONS OF CARDIAC TESTS AND PROCEDURES institutions it has been replaced by other techniques for coronary angiography. The risk of injury to the femoral nerve or lumbar plexus ranges from 0.5% to 5.0% and is primarily due to retroperitoneal hemorrhage, but it can also be a complication of a femoral pseudoaneurysm or prolonged digital pressure for hemostasis. Risk factors for retroperitoneal hematoma following femoral catheterization from retrospective case series include the use of large-caliber vascular sheaths, multiple procedures, high femoral puncture, female gender, low body surface area, obesity, advanced age, peripheral vascular disease, chronic renal insufficiency, thrombocytopenia, and excessive anticoagulation (Kent et al., 1994). The retroperitoneal hematoma may result from the puncture site, laceration of an arterial branch, or a coagulopathy which may be independent of the procedure itself. Diagnosis requires a high index of suspicion as the clinical presentation may be subtle, without cutaneous ecchymosis or expanding mass, and herald as hypotension, tachycardia, diaphoresis, and worsening discomfort in the lower abdomen, groin, or back (Farouque et al., 2005). Injury to the femoral nerve typically occurs when the hematoma is within or near the iliopsoas muscle or when the hematoma tracks into the femoral canal and is further compressed by the inguinal ligament. Early symptoms include pain in the groin or hip with radiation into the anterior thigh, and compensatory hip flexion with increased pain upon attempts to extend the hip. Progressive focal deficits include paresthesias and sensory loss along the anterior thigh and medial leg, and weakness in the quadriceps, resulting in a lack of knee stabilization upon attempts to ambulate (Parmer et al., 2006). Early recognition of the symptoms, medical stabilization, and prompt reversal of coagulopathy is key in limiting neurologic morbidity. Patients who fail this approach should undergo angiography and assessment for possible endovascular treatment; persistent hemodynamic instability warrants urgent surgical intervention (Chan et al., 2008).

PNS COMPLICATIONS OF CENTRAL VENOUS CATHETERIZATION

Central venous line insertion into the subclavian or internal jugular veins can cause injuries to the vagus, recurrent laryngeal, or phrenic nerves (Martin-Hirsch and Newbegin, 1995). Injuries to the brachial plexus occur in 1–2%; the upper trunk is more often affected with internal jugular vein and lower trunk with subclavian vein catheterizations. Case reports cite multiple attempts at cannulation as a possible risk factor for nerve injury and ultrasound guidance has been recommended as a way to reduce the number of attempts.

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PNS COMPLICATIONS OF TRANSESOPHAGEAL ECHOCARDIOGRAPHY

The most common complication of transesophageal echocardiography (TEE) is local trauma during placement, with serious perforation occurring in 0.1–0.2%. However, rare case reports of cerebral embolism, including two cases (0.0047%) from an aggregate database of 42 355 patients, resulted from periprocedural dislodgement of an intracardiac thrombus (Coˆte´ and Denault, 2008). Traumatic injury to the recurrent laryngeal nerve is a rare complication of TEE placement but a known complication of cardiac surgery with intraoperative TEE occurring in 4% of patients (Zwetsch et al., 2001). The causative role of the TEE is complicated by the fact that thermal injury to the recurrent laryngeal and phrenic nerves can also result from myocardial cooling techniques employing pericardial ice slush or cold saline (Hogue et al., 1995).

Central nervous system (CNS) complications CNS COMPLICATIONS OF CARDIAC CATHETERIZATION Cerebral embolism and ischemic stroke Ischemic stroke is the most common neurologic complication of diagnostic and therapeutic cardiac catheterization. The presumed mechanism is embolization of atherosclerotic plaque or thrombus dislodged during guiding catheter manipulation, platelet–fibrin thrombus that forms on the catheters, or air that arises during catheter flushing (Segal et al., 2001). Risk factors for stroke include advanced coronary artery disease or prior coronary revascularization, reduced ejection fraction, female gender, hypertension, diabetes, renal insufficiency, and prior stroke. Ischemic stroke complicates 0.08–0.17% of cardiac catheterization and catheterbased coronary interventions, 1–10% of endovascular balloon valvuloplasties, and 1–2% of atrial septal closures (Davis et al., 1979; Fuchs et al., 2002). In some series, 60% of events affecting the vertebrobasilar territory manifest as combinations of cortical blindness, hemianoptic visual field defects, intrinsic brainstem signs, confusion, and amnesia. Encephalopathy or seizures with temporal lobe ischemia are commonly misdiagnosed as a complication of sedative and analgesic medications, systemic hypotension, or large volumes of contrast material (Dawson and Fischer, 1977). The posterior circulation predominance of events has been postulated to be due to inadvertent catheterization of the vertebral artery, particularly when a retrograde radial or brachial artery approach is used (Kosmorsky et al., 1988). The carotid circulation accounts for 30–40% of focal deficits, consisting of combinations

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of hemiparesis, hemisensory deficits, retinal ischemia, and dysphasia. Every catheterization laboratory should have a protocol for management of a periprocedural acute neurologic event. Although the outcome is good in about half the patients with resolution of deficits in 48 hours, disabling and fatal stroke can also occur. As the time of stroke symptom onset is known and baseline laboratories and clinical status are readily available, excellent results have been reported both with intravenous tissue plasminogen activator (tPA) or endovascular revascularization when utilizing the hospital’s acute stroke management team (Oezbek et al., 1995, Khatri et al., 2008). Transient cortical blindness following cardiac catheterization Another rare complication of cardiac catheterization is the syndrome of transient cortical blindness, reported in 0.01–0.05% (Zwicker and Sila, 2002). Transient cortical blindness also complicates other intra-arterial contrast procedures such as cerebral angiography and is attributed to a temporary disruption of the blood–brain barrier and cerebral dysautoregulation. The clinical manifestations include an acute, thunderclap, or subacute vascular headache with nausea and vomiting, and hypertension, in addition to the focal neurologic features of cortical blindness sometimes accompanied by amnesia, aphasia, and neglect. Neuroimaging features are similar to those seen in hypertensive encephalopathy, eclampsia, and the reversible cerebral vasoconstriction syndrome, with patchy enhancement involving the posterior cortex and white matter edema (see Fig. 4.1). The treatment is supportive with aggressive control of hypertension and calcium channel blocker therapy.

CNS COMPLICATIONS OF CENTRAL VENOUS ACCESS CATHETERS

Central venous access catheters, employed in critically ill patients to monitor central venous pressure and fluid balance and for the administration of cardioactive drugs, are more often complicated by venous air embolism, but in the presence of intracardiac or intrapulmonary shunting can rarely lead to cerebral air embolism. A literature review from 1975 to 1998 revealed 26 cases, 55% during unintentional catheter disconnection, 30% during removal, and 15% during insertion. An intracardiac or intrapulmonary shunt was identified in 60% of patients and overall mortality was 23% (Heckmann et al., 2000). The treatment of cerebral air embolism includes placing the patient immediately in the left lateral Trendelenberg position, aspirating the air, and administering 100% oxygen with transport to a facility where hyperbaric oxygen therapy can be performed,

Fig. 4.1. Following diagnostic cardiac catheterization, a 58year-old woman with a history of migraine developed a sudden throbbing headache, nausea, and vomiting with a left hemianopsia and left spatial inattention. She was treated with oral calcium channel blockers and her symptoms resolved over 2 days.

ideally within 6 hours of symptom onset, if there is not rapid improvement (Blanc et al., 2002). In addition, systemic anticoagulation has been recommended to prevent the intravascular thrombosis that results from the occlusive process (see Fig. 4.2). Placement of a central venous catheter in the internal jugular vein is complicated by inadvertant cannulation of the internal carotid artery in 6% of cases and 40% of these result in a hematoma. Causes of transient ischemic attack (TIA) and stroke include catheter-related embolization, vessel dissection, and hypoperfusion from compression by the hematoma or digital pressure to promote hemostasis.

CNS COMPLICATIONS OF THROMBOLYSIS FOR ACUTE MYOCARDIAL INFARCTION

Ischemic stroke complicates 1% of patients with acute myocardial infarction, especially those with advanced age, congestive heart failure, atrial fibrillation, and cardiac catheterization but the overall risk is cut in half if an intervention achieved successful reperfusion. The most feared risk of thrombolytic therapy for acute myocardial infarction is intracranial hemorrhage with its attendant morbidity and mortality. The risk of intracranial bleeding varies from 0.3% to 1% in recent trials with risk related to more aggressive dosing and combination antithrombotic therapies as well as advanced age and hypertension (Vaitkus et al., 1992). Multiple risk–benefit analyses indicate that the benefits for myocardial

NEUROLOGIC COMPLICATIONS OF CARDIAC TESTS AND PROCEDURES

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Fig. 4.2. (A) and (B) Before and after windowing. During placement of an internal jugular venous catheter, a 42-year-old woman with a dilated cardiomyopathy unexpectedly started hyperventilating and the catheter tubing became briefly disconnected. Her speech suddenly became incomprehensible and then she developed a right hemiplegia and gaze deviation. Urgent noncontrast CT was unremarkable but adjustment of the window settings revealed air emboli in multiple left middle cerebral artery branches.

salvage and reduction in thromboembolic stroke still outweigh the risk for hemorrhagic stroke. In a systematic review of 244 intracranial hemorrhages complicating the GUSTO-1 trial, the patterns were diverse; although 46% were solitary and lobar in location, 30% also involved either the subdural or intraventricular space and many were bizarre with mottled appearances and blood–fluid levels suggesting multiple etiologic mechanisms (Gebel et al., 1998) (see Fig. 4.3). Most were recognized within 24 hours of thrombolytic therapy, many during the infusion. Neuropathologic studies have invariably demonstrated amyloid angiopathy, which is consistent with the increased risk with advanced age. Mortality was approximately 50% within the first week and was associated with earlier onset of symptoms, hemorrhage volume, and Glasgow Coma Scale score (Sloan et al., 1998).

LABORATORY INVESTIGATIONS Peripheral nervous complications are best addressed by electromyography including nerve conductions studies and needle electrode examination. Definitive studies require a delay of several weeks to allow for wallerian degeneration to be reflected in the needle examination but a baseline study can be useful in documenting preexisting nerve deficits to enhance interpretation of a subsequent study or if litigation is imminent. Although generally to be considered a low risk procedure, there are some important considerations pertinent to the cardiac or critically ill patient (Al-Shekhlee et al., 2003). Nerve conduction studies can result in electrical injuries in the intensive care unit setting or in patients with pacemakers or similar cardiac devices and the needle

Fig. 4.3. Within 2 hours of intravenous thrombolytic therapy for an acute myocardial infarction, an 81-year-old man became agitated and hypertensive then unresponsive with agonal respirations requiring intubation. Urgent CT imaging demonstrates a large multifocal hemorrhage with a blood–fluid level.

examination is invasive and can be associated with bleeding in the setting of antithrombotic therapies.

MANAGEMENT OFACUTE STROKE IN THE CARDIAC INTENSIVE CARE UNIT The diagnosis and management of an acute stroke in the setting of a cardiac procedure follows the same paradigm for acute stroke in other settings, although in the setting of the cardiac catheterization laboratory, stroke is almost exclusively ischemic in nature, and after

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thrombolysis for acute myocardial infarction, intracranial bleeding should be the first consideration. A protocol should be in place in the cardiac catheterization laboratory in the event a complication should occur. In hospitals without neurointerventional services, the mainstay of treatment is intravenous tPA. Although heparin infusions can be reversed with protamine, glycoprotein IIb/IIIa inhibitors cannot, and the safety of tPA in their presence is unknown. In hospitals with neurointerventional capability and multipurpose catheterization laboratories, urgent neuroimaging to exclude an unlikely intracranial hemorrhage may not be necessary if one can proceed directly to angiographic documentation of an acute arterial occlusion relevant to the presenting neurologic deficit. Acute neurologic deterioration after thrombolysis for acute myocardial infarction should be presumed to be an intracranial hemorrhage until proven otherwise. All thrombolytic, antithrombotic, and antiplatelet therapies should be stopped immediately while the patient is stabilized and blood is drawn for coagulation studies including platelet count, prothrombin time (PT), and activated clotting time (ACT) or activated partial thromboplastin time (aPTT). Reversal of the coagulopathy should not be delayed by awaiting confirmation with urgent neuroimaging as the hemorrhage can expand rapidly within several hours.

CONCLUSIONS, FUTURE DIRECTIONS Although peripheral neurologic complications of catheter access procedures are uncommon, they can result in considerable neurologic disability. Proceduralists should be aware of the relevant anatomy and early signs of nerve injury so that prompt diagnosis and treatment can ensue. The diagnosis and management of acute stroke complicating cardiac tests and procedures follows the paradigm for acute stroke in other settings but antithrombotic therapies may limit appropriateness for intravenous tPA therapy but still be amenable to mechanical neurointerventional revascularization options. The ideal angiography suite of the future is patientcentric and multipurpose, coordinating diagnostic and therapeutic strategies for multivascular disease, allowing for multispecialty collaboration, and, in the event of a neurologic complication of a cardiac procedure, facilitating the various treating physicians to converge efficiently upon the patient.

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NEUROLOGIC COMPLICATIONS OF CARDIAC TESTS AND PROCEDURES Martin SD, Sharrock NE, Mineo R et al. (1993). Acute exacerbation of carpal tunnel syndrome after radial artery cannulation. J Hand Surg Am 18: 455–458. Martin-Hirsch DP, Newbegin CJ (1995). Right vocal cord paralysis as a result of central venous catheterization. J Laryngol Otol 109: 1107–1108. Oezbek C, Heisel A, Voelk M et al. (1995). Management of stroke complicating cardiac catheterization with recombinant tissuetype plasminogen activator. Am J Cardiol 76: 733–735. Parmer SS, Carpenter JP, Fairman RM et al. (2006). Femoral neuropathy following retroperitoneal hemorrhage: case series and review of the literature. Ann Vasc Surg 20: 536–540. Peterson LH, Dripps RD, Risman G (1949). A method for recording the arterial pressure pulse and blood pressure in man. Am Heart J 37: 771–782. Poiseuille JLM (1828). Recherches sur la Force du Coeur Aortique. The`se no.166. Didot, Paris. Segal AZ, Abernethy WB, Palacios IF et al. (2001). Stroke as a complication of cardiac catheterization: risk factors and clinical features. Neurology 56: 975–977. Seldinger SI (1953). Catheter replacement of the needle in percutaneous arteriography – a new technique. Acta Radiol 39: 368–376.

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Sloan MA, Sila CA, Mahaffey KW et al. (1998). Prediction of 30-day mortality among patients with thrombolysis-related intracranial hemorrhage. Circulation 98: 1376–1382. Smith DC, Mitchell DA, Peterson GW et al. (1989). Medial brachial fascial compartment syndrome: anatomic basis of neuropathy after transaxillary arteriography. Radiology 173: 149–154. Sones MF, Shirey EK, Proudfit WL et al. (1959). Cine coronary angiography. Circulation 20: 773. Vaitkus PT, Berlin JA, Schwartz JS et al. (1992). Stroke complicating acute myocardial infarction – a meta-analysis of risk modification by anticoagulation and thrombolytic therapy. Arch Intern Med 152: 2020–2024. Wallach SG (2004). Cannulation injury of the radial artery: diagnosis and treatment algorithm. Am J Crit Care 13: 315–319. Zwetsch G, Filipovic M, Skarvan K et al. (2001). Transient recurrent laryngeal nerve palsy after failed placement of a transesophageal echocardiographic probe in an anesthetized patient. Anesth Analg 92: 1422–1423. Zwicker JC, Sila CA (2002). MRI findings in transient cortical blindness after cardiac catheterization. Catheter Cardiovasc Interv 57: 47–49.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 5

Neurologic complications of congenital heart disease and its treatment EMILY DE LOS REYES* AND E. STEVE ROACH Division of Child Neurology, Ohio State University, Columbus, OH, USA

HISTORY OF CONGENITAL HEART DISEASE The occurrence of congenital heart disease has been recognized for centuries, but our ability to diagnose and treat congenital heart disease has improved tremendously during the last several decades. Recognition of specific congenital cardiac syndromes (Table 5.1) was facilitated by advances in echocardiography and cardiac catheterization, and a variety of corrective and palliative surgical procedures were developed to aid children with congenital heart anomalies (Mahle et al., 2009). Prenatal diagnosis is now possible in some instances (Mahle et al., 2001). Numerous palliative and corrective surgical procedures (Table 5.2) have been devised to treat congenital heart defects. Robert Grosse successfully ligated a patent ductus arteriosus in 1938 (Kaemmerer et al., 2004). In 1944 Blalock and Taussig developed the first subclavian to pulmonary artery shunt operation for the palliation of infants with tetralogy of Fallot. In 1954, William W. L. Glenn performed a superior vena cava to right pulmonary artery anastomosis to partially bypass the right heart. A modified version of this procedure remains the treatment of choice in total right heart bypass (Waldhausen, 1997). In 1981, Norwood and colleagues described their staged procedure to improve systemic circulation in babies with hypoplastic left heart syndrome (Norwood et al., 1981). Artificial and porcine valve replacement allows correction of cardiac valvular defects. Adaptations of cardiopulmonary bypass techniques and hypothermic circulatory arrest for children allow longer and more complicated procedures to be performed.

These efforts to treat congenital heart disease may have increased the number of children known to have neurologic dysfunction, because, prior to these procedures, most children with severe cardiac anomalies quickly perished. However, continued improvements in medical and surgical therapy and the ability to perform corrective surgery at younger ages may have reduced the frequency of neurologic complications (Mahle et al., 2001).

INCIDENCE OF CONGENITAL HEART DISEASE The estimated incidence of congenital heart anomalies varies in different reports and also depends on the definition used and the method of ascertainment. In developed countries, moderate to severe lesions occur in about 6 of every 1000 individuals. When small septal defects and other less severe lesions are included, the incidence balloons to 75 of every 1000 individuals (Hoffman and Kaplan, 2002). The prevalence of congenital heart lesions varies with age, because many small septal defects close spontaneously and some individuals with more severe lesions do not survive. Because of the diagnostic and therapeutic advances, most individuals with congenital heart disease live well into adulthood with varying degrees of residual dysfunction. Paradoxically, the improved management may facilitate the occurrence of neurologic complications in some instances by allowing individuals to survive who would have quickly perished before such therapy was available. This chapter summarizes the clinical manifestations and neurologic complications resulting from congenital heart disease and its management.

*Correspondence to: Emily de los Reyes, M.D., Professor of Child Neurology, Nationwide Children’s Hospital, Ohio State University, 700 Children’s Drive, Columbus, OH 43205, USA. Tel: þ1-614-722-4625, Fax: þ1-614-722-4633, E-mail: emily.delosreyes@ nationwidechildrens.org

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Table 5.1 Clinical features of selected congenital cardiac anomalies

Atrial septal defect

Patent foramen ovale Ventricular septal defect

Ebstein anomaly

Coarctation of the aorta

Transposition of the great arteries

Tetralogy of Fallot

Cardiac anomalies

Neurologic complications

Ostium secundum defect Ostium primum defect Sinus venosus Persistence of fetal communication between right and left atria Interventricular septum fails to close

Thromboembolism Paradoxical embolism Paradoxical embolus Migraine exacerbation? Thromboembolism Bacterial endocarditis Ischemic stroke Thromboembolism

Apical displacement of tricuspid valve Atrialization of right ventricle Supraventricular arrhythmias Variable atrial septal defect Fibrotic stenosis of aorta Left ventricular dysfunction Associated bicuspid aortic valve Abnormal ventriculoarterial connections

Altered consciousness (hypoxia) Syncope from arrhythmia Intracranial arterial aneurysm Arterial hypertension Thromboembolism Seizures Cognitive delay Thromboembolism Cognitive impairment Congenital brain anomalies

Hypoplastic left heart

Overriding aorta Right ventricular obstruction Ventricular septal defect Right ventricular hypertrophy Underdevelopment of the left heart

Atrioventricular septal defect

Incomplete septation of atrioventricular canal

Thromboembolism Cerebral anomalies Cognitive impairment Mental retardation if related to Down syndrome

Table 5.2 Selected surgical procedures for congenital heart disease Procedure

Purpose

Heart lesion

Percutaneous device closure

Septal defect closure

Norwood procedure

Atrial septectomy Right ventricle to pulmonary artery conduit Graft or aortic reconstruction Subclavian artery to pulmonary artery to increase pulmonary flow Cavopulmonary shunt Redirects SVC to right pulmonary artery Inferior vena cava flow to pulmonary arteries

Patent foramen ovale Atrial septal defect First stage procedure for single ventricle

Blalock–Taussig procedure Bidirectional Glenn procedure Fontan procedure Arterial switch

Transection of aorta and pulmonary artery followed by their translocation to the opposite root (aorta to left ventricle, and pulmonary artery to right ventricle)

RA, right atrium; RV, right ventricle; SVC, superior vena cava.

Tetralogy of Fallot Second stage procedure for hypoplastic left heart Third stage procedure for single ventricle physiology Transposition of the great arteries

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SIGNS AND SYMPTOMS OF CONGENITAL HEART DISEASE Any portion of the circulatory system is subject to anomalous development, and the array of anomalies determine the clinical signs and symptoms that develop in a given individual. Neurologic dysfunction is far more likely to occur in individuals with complex congenital heart anomalies than in those with isolated septal defects or other less severe anomalies. Table 5.1 summarizes the more common congenital cardiac anomalies. Cardiac anomalies that result in substantial mixing of the venous and arterial circulations, such as transposition of the great arteries or tetralogy of Fallot, are typically discovered soon after birth because of cyanosis and the early occurrence of cardiac dysfunction. Neonates with more severe forms of congenital heart disease tend to have nonspecific signs such as hypotonia, lethargy, irritability, poor feeding, and temperature instability (Limperopoulos et al., 2000). Acyanotic lesions such as atrial or ventricular septal defects and patent ductus arteriosus may cause few initial symptoms, and smaller lesions sometimes go undiagnosed until later in childhood or adult life. Older children with cardiac dysfunction may exhibit exercise intolerance, poor school performance, or respiratory symptoms. Small septal defects often close or become hemodynamically insignificant over time.

CEREBROVASCULAR COMPLICATIONS OF CONGENITAL HEART DISEASE Congenital heart lesions collectively constitute the most common cause of cerebral embolism (Fig. 5.1) in children and typically account for about a fifth of the ischemic brain infarctions in children (Dowling and Ikemba, 2011). The likelihood of stroke is greatest in individuals with severe structural defects such as tetralogy of Fallot, transposition of the great arteries, or hypoplastic left heart syndrome (Terplan, 1973). Isolated septal defects or valvular anomalies pose a lower stroke risk, although stroke has been documented in individuals with most types of congenital cardiac anomaly. Most ischemic infarctions in children with congenital heart disease result from thromboembolism. Paradoxical embolism and cardiac arrhythmias may be responsible for embolism in some individuals. Polycythemia secondary to cyanotic congenital heart disease may increase the risk of thrombosis, particularly venous thrombosis (Cottrill and Kaplan, 1973; Phornphutkul et al., 1973). Conversely, iron deficiency anemia in children with congenital heart disease may increase the risk for an arterial stroke (Stolz et al., 2007; Munot et al., 2011). In one report, eight of 15 (53%) children (12–38 months of age) with otherwise unexplained stroke

Fig. 5.1. Magnetic resonance scan shows multiple cerebral infarctions in an infant with cardiac emboli. (Reproduced from Roach et al., 2011.)

had iron deficiency anemia, while only 14 of 143 (9%) of their age-matched control group were anemic (Maguire et al., 2007). It is likely that the occurrence of iron deficiency in an individual with congenital heart disease increases the risk of both venous and arterial occlusion. Venous emboli are normally prevented from entering the arterial circulation by the pulmonary vascular bed. A venous to arterial (“paradoxical”) embolism can result from any cardiac defect that allows a venous clot to bypass the pulmonary vascular bed and enter the systemic circulation. In practice, however, a diagnosis of paradoxical embolism is usually reserved for individuals with septal defects or other lesions without a high intrinsic stroke risk. Small septal defects usually produce arterial to venous shunting of blood, but the direction of flow may reverse in individuals with pulmonary hypertension or during Valsalva maneuver. In the fetus, oxygenated blood from the umbilical veins is shunted directly from the right atrium to the left atrium via the foramen ovale, bypassing the pulmonary circulation. A patent foramen ovale (PFO) persists in about a quarter of the general population and can be demonstrated by echocardiography with intravenous injection of agitated saline during a Valsalva maneuver. The extent to which a PFO constitutes an avenue for paradoxical embolism is a topic of debate. Endovascular closure offered no benefit over medical therapy (with aspirin or warfarin) in

52 E. DE LOS REYES AND E. STEVE ROACH the reduction of the risk of recurrent stroke or transient among them associated congenital brain anomalies, ischemic attack (Furlan et al., 2012). coexisting genetic disorders that result in brain dysfuncAtrial septal aneurysms are documented in 6–15% of tion, cerebrovascular complications, and complications patients with suspected embolic stroke who undergo of therapy. Prematurity and low birthweight contribute transesophageal echocardiography (TEE) and in 1% of to long-term cognitive impairment in some children with autopsies (Silver and Dorsey, 1978; Pearson et al., 1991; congenital heart disease. Agmon et al., 1999). These lesions consist of redundant The likelihood of an underlying genetic disorder is hypermobile septal tissue that results in turbulent flow substantial even in the absence of a well-recognized that may predispose to arterial embolization. Atrial septal genetic syndrome. In one study, for example, 18.3% of aneurysm can occur in isolation, but it is more commonly the patients with tetralogy of Fallot had a genetic abnorassociated with a PFO or atrial septal defect (Mugge et al., mality (Zeltser et al., 2008). Many genetic disorders 1995). The occurrence of an atrial septal aneurysm (Table 5.3) that cause congenital heart disease also lead together with a PFO increases the risk of recurrent strokes to cognitive impairment independent of cardiac disease. in individuals younger than 55 years of age (Mas et al., Down syndrome, velocardiofacial syndrome, and 2001). The occurrence of atrial fibrillation in an individual CHARGE (Coloboma, Heart disease, choanal Atresia, with an atrial septal aneurysm increases the likelihood of Retarded growth and central nervous system anomalies, thromboembolism (Krumsdorf et al., 2004). An American Genital anomalies or hypogonadism and Ear anomalies) Academy of Neurology evidence-based practice parasyndrome are commonly associated with neurodevelopmeter concluded that an isolated PFO is not associated mental dysfunction even in the absence of congenital with a significant risk of recurrent stroke in individuals heart disease. Deletions on chromosome 22q12 are docuwith an unexplained stroke but that a PFO plus an atrial mented in over 50% of children with conotrucal defects septal aneurysm conveyed an increased stroke risk and in 16% of those with tetralogy of Fallot (Goldmuntz (Messe et al., 2004). et al., 1998). Cardiac lesions that are associated with severe hypINFECTIVE EMBOLISM FROM oxia and hypoperfusion carry a greater risk of long-term CONGENITAL HEART DISEASE cognitive dysfunction. Children with transposition of the great arteries or hypoplastic left heart syndrome, for Infective endocarditis with secondary embolism occurs example, are profoundly hypoxemic until mixing of oxywith increased frequency in children with various forms genated and deoxygenated blood can be increased. The of congenital heart disease (Niwa et al., 2005). In a large duration and severity of hypoxemia no doubt contributes series of Japanese children and adults with infective to the eventual cognitive deficits in these individuals, and endocarditis and congenital heart disease, the most comearlier corrective of palliative surgery should theoretimon bacterial organisms were streptococci species (50%) cally improve long-term function. and staphylococci species (37%) (Niwa et al., 2005). Some Improved survival of children with congenital heart reports suggest brain complications are more likely to defects has resulted in greater emphasis on long-term occur with endocarditis due to Staphylococcus aureus cognitive function. Severe neurologic disability occurs than from enterococcus or other pathogens (Saiman in about 5% of children undergoing surgery for congenet al., 1993; McDonald et al., 2005). ital heart disease, but at least 28% of children with varIn one cohort of 115 children with infective endocarious congenital cardiac lesions have some type of ditis, seven individuals had stroke and four of these had residual neurologic dysfunction (Majnemer et al., congenital heart disease (Venkatesan and Wainwright, 2006). Children selected for more severe cardiac lesions 2008). In contrast, approximately half of the children tend to have even more difficulty. The most common with infective endocarditis have a congenital heart lesion residual neurologic impairments are hypotonia, fine (Saiman et al., 1993). Infarction can occur in any portion and gross motor incoordination, and developmental of the brain but is most likely to occur in the distribution delay (Majnemer et al., 2006). of the internal carotid artery. Infective endocarditis can McGrath and colleagues (2004) evaluated children also result in infective cerebral aneurysms as well as who underwent surgery for transposition of the great bacterial meningitis and cerebral abscess formation arteries at 1, 4, and 8 years. At 1 year, Bayley scores (Dziuban et al., 2008). were lower in children who underwent circulatory arrest and in those who had electrographic seizures. COGNITIVE DISTURBANCES WITH After 4 years, the circulatory arrest group continued CONGENITAL CARDIAC DISEASE to score lower on tests of fine and gross motor function Cognitive impairment in individuals with congenital carand language function. Deficits of visual-spatial and diac disease probably has multiple contributing factors, visual-motor integration were also common. By 8 years

NEUROLOGIC COMPLICATIONS OF CONGENITAL HEART DISEASE AND ITS TREATMENT

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Table 5.3 Selected genetic causes of congenital heart disease Syndrome

Genetic abnormality

Cardiac anomaly

Velocardiofacial syndrome/ DiGeorge syndrome

Chromosome 22 microdeletion

Down syndrome

Trisomy 21

Alagille syndrome

JAG1 or NOTCH2 mutation

Holt–Oram syndrome Williams syndrome

TBX5 gene 7q11 deletion

Noonan syndrome

PTPN11, SOS1, and perhaps other genes

Turner syndrome

Monosomy X

VACTERL* association

Unknown

CHARGE{ syndrome

Unknown

Conotruncal defects Tetralogy of Fallot Interrupted aortic arch Truncus arteriosus Endocardial cushion defect Ventricular septal defect Atrial septal defect Tetralogy of Fallot Pulmonary valve stenosis Pulmonary hypoplasia Atrial septal defect Supravalvular aortic stenosis Large vessel vasculopathy Pulmonary valvular stenosis Atrial septal defect Pulmonary artery stenosis Hypertrophic cardiomyopathy Bicuspid aortic valve Coarctation of the aorta Ventricular septal defect Atrial septal defect Tetralogy of Fallot Transposition of great arteries Truncus arteriosus Tetralogy of Fallot Patent ductus arteriosus Ventricular septal defect Atrial septal defect

*VACTERL, Vertebral anomalies, imperforate Anus, Cardiac anomalies, TracheoEsophageal fistula, Renal anomalies, and Limb anomalies. { CHARGE, Coloboma of the eye, Heart disease, choanal Atresia, Retardation of growth, Genital/urinary abnormalities, Ear anomalies and deafness.

after surgery, more than half of the children had normal intelligence quotients (McGrath et al., 2004). Another study concluded that the neurodevelopmental outcome was better in children with transposition of the great arteries than those with tetralogy of Fallot, probably because more of the individuals with tetralogy of Fallot had underlying genetic abnormalities (Bellinger et al., 2001). Continued improvements in medical and surgical management have improved the cognitive outcome in children with hypoplastic left heart syndrome and other severe cardiac anomalies (Atallah et al., 2008). The long-term outcomes in hypoplastic left heart syndrome indicate that children with this lesion are at high risk for mental retardations and attention deficit hyperactivity disorder. The association of seizures presents as a significant risk factor for the development of learning problems. Infants who underwent cardiac transplantation did not fare better (Mahle et al., 2006).

Children with treated congenital heart disease have a quality of life that approaches that of normal individuals. However, children with corrected congenital cyanotic disease tend to have a lower exercise tolerance than others and tend to be more withdrawn and engage in fewer activities (Casey et al., 1994). About a fifth of children with normal intelligence following cardiac surgery have behavioral and psychosocial dysfunction or abnormal attention (Bellinger et al., 2009). Socioeconomic status and parental intelligence also influences the neurocognitive outcome of children with congenital heart disease (Forbess et al., 2002).

BRAIN ANOMALIES WITH CONGENITAL HEART DISEASE Individuals with congenital heart disease frequently have structural brain anomalies as well. These brain lesions probably occur because of the same underlying genetic

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and environmental factors that caused the heart lesion, although in most individuals these factors are not well known. In some individuals, associated brain anomalies impaired neurodevelopmental function far more than the associated cardiac anomaly. The most common associated brain anomaly is focal cortical dysplasia and other migrational abnormalities. Migrational abnormalities, holoprosencephaly, agenesis of the corpus callosum, and dysmorphic features were found at autopsy in 41 patients (Glauser et al., 1990). In general, brain anomalies are more likely to occur in individuals with more severe cardiac lesions. Routine autopsy studies of children with congenital heart disease also identified anomalies of the brain. Gyral malformations affecting the frontal and parietal lobes were the most common lesions. Other abnormalities also include alterations of the shape of the lobes and anomalies of the sylvian or rolandic fissures (Jones, 1991). The advent of magnetic resonance imaging has also allowed clinicians to investigate risk factors that may impact the child’s future neurodevelopmental sequelae. Neuroimaging abnormalities were found in a series of patients who underwent neuroimaging prior to their cardiac procedures. White matter injury was observed at higher frequency in newborns with congenital heart disease. It has been hypothesized that these abnormalities are secondary to impaired brain development in utero which may be related to impaired cerebral oxygenation delivery (Miller et al., 2007).

A

CEREBRAL ANEURYSM AND AORTIC COARCTATION The association of intracranial aneurysm (Fig. 5.2) and congenital coarctation of the aorta is well recognized. The signs and symptoms of a cerebral aneurysm in an individual with aortic coarctation are identical to those in other aneurysm patients aside from the arterial hypertension that typically accompanies coarctation of the aorta. Despite the congenital nature of aortic coarctation, individuals with an associated intracranial aneurysm seldom become symptomatic until after adolescence or adulthood. On occasion, coarctation of the aorta is diagnosed only after an aneurysm ruptures (LeBlanc et al., 1968; Mercado et al., 2002). Estimates of the incidence of intracranial aneurysm among individuals with aortic coarctation vary with the method of diagnosis but range from 2.5% to 10% (Tyler and Clark, 1958; Connolly et al., 2003). In one cohort of 100 people with coarctation of the aorta who underwent magnetic residence angiography, 10 individuals with an intracranial aneurysm were identified, a fivefold increase above the expected rate in the general population (Connolly et al., 2003).

COMPLICATIONS OF MANAGEMENT Stroke occurs with increased frequency during surgery for congenital heart disease and during cardiac catheterization (Treacy et al., 1991; Oski et al., 1996; Liu et al.,

B

Fig. 5.2. Lateral (A) and anterior-posterior (B) views of a catheter angiogram shows an aneurysm (arrow) of the proximal left middle cerebral artery in an adolescent with coarctation of the aorta. (Reproduced from Roach et al., 2011.)

NEUROLOGIC COMPLICATIONS OF CONGENITAL HEART DISEASE AND ITS TREATMENT 55 2001). However, it can be difficult to determine in these only eight children with evidence of right-sided brain individuals whether the infarction resulted from the prolesions among 59 surviving patients who underwent cedure or from the cardiac defect itself. Neuroimaging ECMO as infants (Schumacher et al., 1988). In another abnormalities are common among individuals who cohort, none of 22 consecutive surviving ECMO patients undergo surgery for congenital cardiac lesions. In one had evidence of cerebral infarction by cranial ultrasound study, 62 near-term neonates with congenital heart or magnetic resonance imaging (Griffin et al., 1992). Some disease underwent presurgical magnetic resonance patients develop intracerebral hemorrhage (Taylor et al., imaging and 53 babies underwent postoperative scans 1989a). Despite the ligation of the right internal carotid (McQuillen et al., 2007). It was found that 56% of these artery required by ECMO, there is little difference in patients had some type of brain injury, but 39% had evithe frequency of infarctions between the two hemispheres dence of brain injury even before surgery. In the preop(Mendoza et al., 1991; Taylor et al., 1989b). This suggests erative scans, 11 (18%) babies had evidence of white that hypoxia probably plays at least as great a role as matter injury, 13 (21%) had an ischemic stroke, and five carotid ligation in causing infarction. (8%) had intraventricular hemorrhage. Postoperative Deep hypothermic circulatory arrest (DHCA) was brain injury in this cohort was more likely to consist of developed by Kirlin and associates in the mid-twentieth white matter injury than stroke and occurred more often century and subsequently applied to children with conin association with surgery for single-ventricle syngenital heart disease (Barratt-Boyes et al., 1971). DHCA dromes and aortic arch obstruction. New postoperative facilitates a bloodless operative field during intracardiac white matter injury was more likely to occur in individsurgery, but some studies suggest that the risk of neurouals who had low mean blood pressure during the first logic dysfunction increases when the duration of circupostoperative day (McQuillen et al., 2007). Not surprislatory arrest exceeds 45–50 minutes. The Boston ingly, the frequency of brain injury is higher among Circulatory Arrest Trial documented lower IQ, higher babies with clinical or electrographic seizure activity rate of acute clinical seizures, and abnormal EEG in chil(Gaynor et al., 2005). dren undergoing circulatory arrest than in those who Stroke can occur in conjunction with any of the surwere managed with low flow cardiopulmonary bypass. gical procedures (Table 5.2) used to treat congenital Longer DHCA times were associated with lower IQ heart disease. Focal infarctions during surgery typically scores (Wypij et al., 2003), but 8 years later, the only preresult from thromboemboli, although stroke due to air or dictor of significant cognitive dysfunction was a longer gas embolism has been recorded (Buompadre and circulatory arrest time (McGrath et al., 2004). Arroyo, 2008). Although the procedure-related stroke Seizures following cardiac surgery often signal brain risk is substantial, in many instances the infarction ischemia or thromboembolism. Neonates are more likely clearly occurs prior to the surgery (McQuillen et al., to develop seizures after cardiac surgery than infants or 2007; Chen et al., 2009). Depending on their size and older children. Gaynor and colleagues documented elecnumber, emboli can cause either large artery ischemic troencephalographic seizures in 15 (14%) of 110 neonates strokes or diffuse neurologic dysfunction from multiple and five (7%) of 68 older infants (Gaynor et al., 2005). small artery occlusions. Microemboli can be detected in Although seizures are clinically obvious in many individsome individuals by transcranial Doppler during cardiouals, electroencephalographic changes in the absence of pulmonary bypass, but the extent to which microemboli obvious clinical seizures are common, especially among correlate with an increased risk of stroke is uncertain neonates. One report documented 21 (11.5%) neonates (Rodriguez and Belway, 2006). Exposure of circulating with electroencephalographic seizures among 183 indiblood in the bypass circuit materials may increase the viduals undergoing cardiac surgery, and none of the stroke risk by activating coagulation responses. babies had clinically obvious seizures (Clancy et al., Extracorporeal membrane oxygenation (ECMO) is 2005). Patients with clinical or electrographic seizures sometimes utilized in cardiac surgery in children who have following cardiac surgery are more likely to exhibit difficulty separating from the cardiopulmonary bypass or long-term neurologic dysfunction and more apt to have other issues (Aharon et al., 2001; Ravishankar et al., 2006). abnormal findings on brain magnetic resonance imaging Given the very severe illnesses that necessitate the use of (Rappaport et al., 1998). Individuals who require longer ECMO, these individuals have a predictably high mortality bypass times or longer periods of hypothermia are and morbidity rate (Huang et al., 2005). The mortality rate more likely to develop seizures (Gaynor et al., 2005), for individuals requiring prolonged ECMO is even higher so the occurrence of postoperative seizures may only (Ravishankar et al., 2006). Despite the sacrifice of the right indicate the occurrence of ischemic or other complicacarotid artery in an individual who is typically very hyptions. Nevertheless, frequent or prolonged seizures oxic, ischemic stroke is relatively uncommon in patients could exacerbate the effects of an earlier ischemic undergoing ECMO. In one report, for example, there were injury.

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Choreoathetosis and other movement disorders have been documented in children with congenital heart disease. The abnormal movements most often affect the limbs, orofacial musculature, or the tongue (Gherpelli et al., 1998). Choreoathetosis typically occurs during the postsurgical period. Most postoperative movement disorders are transient, but symptoms persist in some individuals (Wong et al., 1992).

LABORATORY INVESTIGATIONS A complete discussion of the diagnosis of congenital heart anomalies is beyond the scope of this chapter. Congenital heart lesions are usually suspected on the basis of characteristic signs and symptoms, although some heart lesions are discovered in an individual without cardiac symptoms who has had a stroke. Increasingly, genetic testing allows confirmation of underlying syndromes that feature congenital cardiac anomalies (Table 5.3). Congenital heart defects are often confirmed by echocardiography, and this study may be sufficient for children with relatively straightforward lesions. Echocardiography also helps to pinpoint structural cardiac defects, intraluminal thrombus, vegetations, and cardiac tumors. Individuals with more complex cardiac anomalies usually require cardiac catheterization. Transesophageal echocardiography is more sensitive than transthoracic echocardiography for the detection of structural cardiac lesions in adults (de Bruijn et al., 2006). In children, however, transesophageal echocardiography can be technically more difficult and less useful, particularly in small children with thin chest walls (Hubail et al., 2011). In one study, transthoracic and transesophageal echocardiography were compared in the assessment of patent foramen ovale among 50 children less than 1 year of age. Transthoracic echocardiography was conclusive in 43 of 50 (83%) children, and the two techniques differed in only one of the 43 children with conclusive results (Hubail et al., 2011). Transthoracic studies are less sensitive for valvular vegetations. Saiman and colleagues (1993) found vegetations by echocardiography in only 25 of 49 children with confirmed endocarditis. Echocardiography with either technique has a low yield in children with a normal cardiac examination, an unremarkable chest X-ray, and a normal electrocardiogram. Nevertheless, echocardiography is reasonable when there is a strong suspicion of a cardiac lesion. Neurologic abnormalities in patients with cardiac anomalies are identified in the same fashion as they are in other individuals, and these studies are reviewed in more detail in other chapters. Magnetic resonance imaging can identify cerebral embolic infarctions,

migrational anomalies, and periventricular leukomalacia (Galli et al., 2004). Psychological testing helps to document the extent of cognitive impairment. Catheter angiography and computed tomographic angiography may be necessary to demonstrate infectious aneurysms.

MANAGEMENT Management of acidosis, hypoglycemia, hypoxemia, and volume depletion is essential. Appropriate medical therapy of arrhythmias and congestive heart failure is also recommended (Roach et al., 2008). Administration of prostaglandin E is a useful means of maintaining patency of the ductus arteriosus in individuals whose cardiac anomaly requires it. Most complex congenital heart disease requires immediate corrective or palliative surgical intervention, and the trend in recent years has been to perform surgery as early as is feasible. Optimal correction probably reduces the child’s risk of thromboembolism and may improve the eventual development and cognitive function in some individuals. Palliative surgery is associated with a higher degree of adverse neurodevelopmental outcome compared to corrective surgery (Dittrich et al., 2003). Anticoagulation is recommended for individuals with congenital cardiac disease who are at substantial risk for recurrent embolic stroke. Low molecular weight heparin or warfarin is recommended for 1 year or until the lesion responsible for the risk has been corrected (Roach et al., 2008). For children with a suspected cardiac embolism with a lower or unknown risk for recurrent stroke, it is reasonable to consider aspirin (Roach et al., 2008). Treatment of infective endocarditis with appropriate antimicrobial agents is essential. Anticoagulation is not advised because of the risk of hemorrhage in these individuals (Roach et al., 2008). The American Heart Association guidelines for the prevention of infective endocarditis recommend antibiotic prophylaxis for individuals with high risk congenital cardiac lesions who are undergoing dental procedures that involve gingival manipulation or perforation but not for those undergoing genitourinary or gastrointestinal tract procedures (Wilson et al., 2007).

CONCLUSION The progress of medical and surgical interventions has dramatically improved survival and reduced morbidity and mortality in individuals with congenital heart disease. Palliative and corrective surgical procedures allow most of these individuals to survive into adult life. Neurologic complications from congenital heart anomalies include embolic stroke and infectious aneurysm.

NEUROLOGIC COMPLICATIONS OF CONGENITAL HEART DISEASE AND ITS TREATMENT Neurodevelopmental impairment occurs in some individuals. Identification of genetic abnormalities that promote complex congenital cardiac disease facilitates genetic counseling and the identification of other anomalies. An interdisciplinary team that cares for these children into adulthood is ideal.

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transthoracic and transesophageal echocardiography. Circulation 91: 2785–2792. Munot P, De VC, Hemingway C et al. (2011). Severe iron deficiency anaemia and ischaemic stroke in children. Arch Dis Child 96: 276–279. Niwa K, Nakazawa M, Tateno S et al. (2005). Infective endocarditis in congenital heart disease: Japanese national collaboration study. Heart 91: 795–800. Norwood WI, Lang P, Casteneda AR et al. (1981). Experience with operations for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 82: 511–519. Oski JA, Canter CE, Spray TL et al. (1996). Embolic stroke after ligation of the pulmonary artery in patients with functional single ventricle. Am Heart J 132: 836–840. Pearson AC, Nagelhout D, Castello R et al. (1991). Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 18: 1223–1229. Phornphutkul C, Rosenthal A, Nadas A et al. (1973). Cerebrovascular accidents in infants and children with cyanotic congenital heart disease. Am J Cardiol 32: 329–334. Rappaport LA, Wypij D, Bellinger DC et al. (1998). Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Boston Circulatory Arrest Study Group. Circulation 97: 773–779. Ravishankar C, Dominguez TE, Kreutzer J et al. (2006). Extracorporeal membrane oxygenation after stage I reconstruction for hypoplastic left heart syndrome. Pediatr Crit Care Med 7: 319–323. Roach ES, Golomb MR, Adams RJ et al. (2008). Management of stroke in infants and children. A scientific statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 39: 2644–2691. Roach ES, Lo WD, Heyer GL (2011). Pediatric Stroke and Cerebrovascular Disorders. 3rd edn Demos Medical Publishers, New York. Rodriguez RA, Belway D (2006). Comparison of two different extracorporeal circuits on cerebral embolization during cardiopulmonary bypass in children. Perfusion 21: 247–253. Saiman L, Prince A, Gersony WM (1993). Pediatric infective endocarditis in the modern era. J Pediatr 122: 847–853. Schumacher RE, Barks JDE, Johnson MV et al. (1988). Rightsided brain lesions in infants following extracorporeal membrane oxygenation. Pediatrics 82: 155–161. Silver MD, Dorsey JS (1978). Aneurysms of the septum primum in adults. Arch Pathol Lab Med 102: 62–65. Stolz E, Valdueza JM, Grebe M et al. (2007). Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study. J Neurol 254: 729–734. Taylor GA, Fitz CR, Glass P et al. (1989a). CT of cerebrovascular injury after neonatal extracorporeal membrane oxygenation: implications for neurodevelopmental outcome. AJR Am J Roentgenol 153: 121–126. Taylor GA, Short BL, Fitz CR (1989b). Imaging of cerebrovascular injury in infants treated with extracorporeal membrane oxygenation. J Pediatr 114: 635–639. Terplan KL (1973). Patterns of brain damage in infants and children with congenital heart disease. Am J Dis Child 125: 175–185.

NEUROLOGIC COMPLICATIONS OF CONGENITAL HEART DISEASE AND ITS TREATMENT Treacy EP, Duncan WJ, Tyrrell MJ et al. (1991). Neurological complications of balloon angioplasty in children. Pediatr Cardiol 12: 98–101. Tyler HR, Clark DB (1958). Neurologic complications in patients with coarctation of aorta. Neurology 8: 712–718. Venkatesan C, Wainwright MS (2008). Pediatric endocarditis and stroke: a single-center retrospective review of seven cases. Pediatr Neurol 38: 243–247. Waldhausen JA (1997). The early history of congenital heart surgery: closed heart operations. Ann Thorac Surg 64: 1533–1539. Wilson W, Taubert KA, Gewitz M et al. (2007). Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,

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Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 116: 1736–1754. Wong PC, Barlow CF, Hickey PR et al. (1992). Factors associated with choreoathetosis after cardiopulmonary bypass in children with congenital heart disease. Circulation 86 (5 Suppl): II118–II126. Wypij D, Newburger JW, Rappaport LA et al. (2003). The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 126: 1397–1403. Zeltser I, Jarvik GP, Bernbaum J et al. (2008). Genetic factors are important determinants of neurodevelopmental outcome after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 135: 91–97.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 6

Neurologic complications of valvular heart disease SALVADOR CRUZ-FLORES* Department of Neurology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

INTRODUCTION Cerebral embolism is the main neurologic complication related to valvular heart disease. In fact, as many as 10% of all patients with valvular heart disease have cardioembolic strokes (Cerebral Embolism Task Force, 1986). Platelet thrombi and red thrombi that result from the abnormalities in the valvular surfaces or from the anatomic and physiologic changes that follow valve dysfunction, including atrial or ventricular enlargement, intracardiac thrombi, and cardiac dysrhythmias in addition to prosthetic heart valves, explain the high frequency of embolism in valvular heart disease. Other neurologic complications arise from infection of the valvular system and from complications of anticoagulation used to decrease the risk of embolism. The prevention and management of these complications requires an understanding of their natural history in order to balance the risks posed by valvular disease itself against the risks and benefits associated with its treatment.

RHEUMATIC VALVULAR HEART DISEASE Valvular damage in rheumatic heart disease is the result of an abnormal immune response to Group A streptococcal infection. Rheumatic valvular heart disease (RVHD) is now fairly uncommon in developed countries but it continues to be a burden in developing nations given its association with social factors such as poverty, nutrition and access to medical care. RVHD is responsible for between 200 000 and 250 000 deaths every year (Carapetis et al., 2005) and is a major cause of cardiovascular death in children and young adults in developing countries. Furthermore, in 2004, RVHD was responsible for 5.2 million disability-adjusted life years worldwide

(Marijon et al., 2012). It is estimated that 15.6–19.6 million people worldwide have rheumatic heart disease, with the highest prevalence among adults aged 20–50 years (Carapetis et al., 2005). While the distribution of RVHD varies, the highest prevalence is among subSaharan Africans and indigenous Australians, in whom it can be as high as 20 per 1000 adults aged 35–44 years (Tibazarwa et al., 2008; Marijon et al., 2012). The use of echocardiography for screening has increased the detection of this disorder and therefore has challenged earlier epidemiologic data (Tubridy-Clark and Carapetis, 2007; Tibazarwa et al., 2008; Marijon et al., 2012; Remenyi et al., 2012). Clinical diagnosis of RVHD is primarily based on the identification of a heart murmur. The mitral valve is the most common cardiac valve involved followed by the combined involvement of the mitral and aortic valves. Mitral regurgitation is the most common valvular abnormality and may remain asymptomatic for as long as 10 years; mitral stenosis is the second most common valvular lesion and develops later in the disease course. RVHD often presents with symptoms of heart dysfunction. However, it may present as cerebral or systemic embolism with or without atrial fibrillation (AF), or infective endocarditis (Marijon et al., 2012). Rheumatic mitral valve disease conveys the highest risk of systemic embolization compared to other acquired valvular diseases. Mitral stenosis is not only the predominant lesion but also the lesion with higher risk for embolism(Carabello and Crawford, 1997; Carapetis et al., 2005). In a series of 500 patients, 66% had mitral stenosis and 21% had mitral regurgitation, with the rest having combined lesions. In this population, 125 patients suffered from systemic embolization (60% of which was to the brain); in 116, the predominant lesion was mitral

*Correspondence to: Salvador Cruz-Flores, Department of Neurology, Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA. Tel: þ1-915-545-6703, x273, Fax: þ1-915-545-6705, E-mail: [email protected]

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stenosis; while only 10 patients had mitral regurgitation (Fleming and Bailey, 1971).The incidence of embolism is 1.5–4.7% per year prior to surgery in some reports (Fleming and Bailey, 1971; Adams et al., 1974). The prevalence of embolism is reported to be as high as 20%, with half to three-quarters of embolic events involving the brain. Embolic events occur in patients with mitral stenosis and normal sinus rhythm but AF greatly increases the risk. In fact, the incidence of embolism is seven times higher in patients with atrial fibrillation as compared to those in sinus rhythm (Szekely, 1964; Dewar and Weightman, 1983). Besides AF, other factors are associated with an increased risk of embolism and include older age, the presence of left atrial thrombus, left atrial enlargement, left atrial spontaneous contrast, and aortic regurgitation (Caplan et al., 1986; Stroke Prevention in Atrial Fibrillation Investigators, 1992a, b; Vigna et al., 1993; Atrial Fibrillation Investigators, 1998; Chiang et al., 1998; Goswami et al., 2000). Systemic or cerebral embolism explains 20–30% of deaths due to mitral stenosis (Szekely, 1964; Selzer and Cohn, 1972). AF and atrial flutter occur in 30–40% of patients with mitral stenosis (Szekely, 1964; Selzer and Cohn, 1972; Abernathy and Willis, 1973; Adams et al., 1974; Dewar and Weightman, 1983; Chiang et al., 1998). Atrial fibrillation tends to occur in older patients and is associated with worse prognosis. After AF develops, 30% of the embolic events occur within a month of the onset and 60% within a year. The recurrence rate of embolic events among patients with mitral stenosis and AF is reported at 15–40 events per 100 patient-months (Dewar and Weightman, 1983). Furthermore, recent evidence indicates that in patients with ischemic stroke classified as cryptogenic, the incidence of paroxysmal AF is 10–25% (Wallmann et al., 2007; Flint et al., 2012). Although patients in these studies did not have RVHD, it could be inferred that the incidence of paroxysmal AF may be even higher among patients with rheumatic valvular disease given the frequent occurrence of left atrial enlargement in this population. There are no randomized clinical trials assessing the efficacy of anticoagulation in preventing embolism in patients with rheumatic heart disease. However, retrospective observational studies show that anticoagulation reduces embolic events four- to 15-fold in patients with rheumatic valvular disease (Szekely, 1964). Szekely found a rate of embolism of 3.4% per year among patients on anticoagulation as compared with 9.6% per year among those not anticoagulated. Several randomized clinical trials and meta-analyses have conclusively shown that first and recurrent ischemic stroke and systemic embolization are lower in patients with nonvalvular atrial fibrillation (NVAF) treated with anticoagulation (Salem et al., 2004; Whitlock et al., 2012).

Warfarin anticoagulation has also resulted in the clearance of a left atrial thrombus in 62% of patients after of 34 months of treatment (Silaruks et al., 2002, 2004). More importantly, the disappearance of the thrombus was documented in 25% of patients treated for 6 months but the probability of thrombus clearance increased to 94% when the following factors were present: thrombus size < 1.6 cm2, New York Heart Association class < 2 (mild dyspnea or angina or mild limitation during ordinary activity), left atrial spontaneous contrast grade 1 (defined as dynamic clouds of echoes curling up slowly in a circular shape), and INR at least 2.5 (Silaruks et al., 2004). Therefore, it could be inferred that patients with RVHD and AF and/or left atrial thrombus may benefit from long-term anticoagulation. Most recently, long-term anticoagulation with warfarin has been recommended for patients with rheumatic mitral valvular disease when there is: 1. 2. 3.

normal sinus but the left atrial diameter is > 55 mm a left atrial thrombus AF or the presence of cerebral or systemic embolism.

CALCIFIC VALVE DISEASE Aortic stenosis Calcific aortic stenosis of a normal or a congenitally bicuspid valve is the most common cause of aortic valve disease in developed countries. The disease process resembles the natural course of atherosclerosis with lipid accumulation, inflammatory response, and calcification (Rajamannan et al., 2007; Bonow et al., 2008). Valve calcification is developed by the fourth or fifth decade in patients with bicuspid aortic valves, while calcific aortic stenosis in normal tricuspid valves usually occurs in the sixth through eighth decades (Carabello and Crawford, 1997). Clinical pathologic studies show that embolism from calcific aortic valve disease is not uncommon. In a series of 81 subjects with calcific aortic stenosis, 33% had emboli (Soulie et al., 1969). In another autopsy study of 165 subjects with calcific valve disease, 22% had emboli, 32 individuals had emboli in the coronary arteries, while emboli were found in the renal arteries in 11, the central retinal artery in one, and in the middle cerebral artery in another (Holley et al., 1963a, b). Calcium emboli have frequently been found in the retinal vessels where their appearance is as small white densities. Retinal calcium embolism is uncommon but is often associated with calcific aortic valve disease. In a small series of 24 patients with retinal calcium emboli, nine (38%) had calcific aortic valve stenosis (Ramakrishna et al., 2005). In another series of 103 patients with retinal artery

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE occlusions, 11 patients had aortic stenosis (Wilson et al., 1979). Aortic valve surgery, in particular percutaneous endovascular intervention, is associated with an incidence of embolism as high as 61% (Holley et al., 1963a). Despite the frequency of calcific emboli in the brain and retina found in autopsy studies, the frequency of symptomatic cerebral ischemia resulting from this type of emboli is rather low; the reason for this discrepancy is unclear, although some authors have hypothesized that the small size of the embolic particles is responsible. Therefore, in the absence of other indications such as AF or prosthetic heart valves, antithrombotic therapy is not recommended for stroke prevention in patients with calcified aortic valve disease. Antiplatelet agents should be used for secondary stroke prevention, as recommended for patients with noncardiogenc ischemic stroke (Whitlock et al., 2012).

Mitral annulus calcification Mitral annulus calcification (MAC) occurs most commonly among the elderly and is a degenerative disorder with calcification of the support system and mitral valve annulus. MAC was found in 27% of 100 elderly patients in an autopsy series (MsKeown, 1975; Lausier, 1987). MAC is associated with an increased risk of ischemic stroke. In a case control study of 151 patients with brain and retinal ischemia, eight had MAC compared with none of the age- and gender-matched controls (de Bono and Warlow, 1979). In the cohort of 1159 individuals in the Framingham study, 160 subjects had MAC; the incidence of ischemic stroke was 13.8% among those with MAC compared with 5.1% among those without MAC for a relative risk of 2.10 (CI 95% 1.24, 3.57) (Benjamin et al., 1992). Moreover, the frequency of stroke increased in correlation with the severity of MAC with each millimeter of thickness by echocardiogram, increasing the relative risk of stroke by 1.24. The embolic material causing stroke in MAC can be composed by calcium or by thrombus. The current recommendations for stroke prevention are to treat patients with MAC and embolism with antiplatelet agents. Long-term anticoagulation does not have a role in the secondary prevention of stroke in this condition. Mitral valve replacement should be considered in patients with recurrent embolism despite antiplatelet therapy (Fulkerson et al., 1979; Nestico et al., 1984; Kizer et al., 2005; Lansberg et al., 2012).

MITRAL VALVE PROLAPSE Mitral valve prolapse (MVP) is a condition that is defined by echocardiography as classic MVP when there is a superior displacement of the mitral leaflets of more than 2 mm during systole and a maximal leaflet thickness of at least 5 mm during diastasis; in comparison, nonclassic MVP is defined by a leaflet thickness < 5 mm. In the Framingham

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study, which included 1845 women and 1646 men followed for over 10 years, the overall prevalence of MVP was 2.4% (1.3% classic and 1.1% nonclassic) (Freed et al., 1999). Patients with MVP often seek consultation for a variety of symptoms that occur as part of this syndrome; they include: atypical chest pain, dyspnea and or fatigue, and neuropsychiatric complaints that include panic attacks (Fontana et al., 1991; Bonow et al., 2008). Although early series suggested a causal association between MVP and stroke, more recently that association has not been supported. In a study of 213 patients 45 years or younger with cerebral ischemia and 263 matched controls, MVP was present in 1.9% of patients compared to 2.7% of controls, OR 0.70 (CI 95% 0.12, 2.5) (Gilon et al., 1999). Nevertheless, the Framingham study showed that MVP confers an excess risk of cerebral embolism with ischemia, which is 7% at 10 years compared with the expected rate of 3.2% (Avierinos et al., 2003). Thus, it is still unclear what the causal role of MVP is among patients with ischemic stroke. Considering this uncertainty and the lack of evidence of benefit of anticoagulation for the prevention of embolic events among patients with MVP, antiplatelet agents are the only recommended therapy for secondary stroke prevention (Whitlock et al., 2012).

PROSTHETIC HEART VALVES Cardiac valve prostheses were developed in the early 1960s. There are many different designs but they can be divided in two groups: bioprosthetic valves and mechanical valves. Bioprosthetic heart valves are usually heterografts from pig or cow pericardial or heart valve tissue which are then mounted on a mechanical frame; they have low thrombogenesis and therefore they have the advantage that they do not require anticoagulation with warfarin, but they tend to develop time-related structural failure. In contrast, mechanical heart valves are made of metal and carbon alloy which provide structural stability but they are particularly thrombogenic and require long-term anticoagulation with warfarin (Vongpatanasin et al., 1996; Chikwe et al., 2011). Prosthetic heart valves are associated with complications, some of which are considered of critical importance; they include: structural valve deterioration, nonstructural dysfunction, valve thrombosis, embolism, bleeding events, infection (endocarditis) (Chikwe et al., 2011). Although many of these complications may have an impact on the nervous system, the most common neurologic complications are thrombosis with cerebral embolism, hemorrhage related to anticoagulation, and infective endocarditis. Prosthetic heart valves can develop thrombosis leading to valve dysfunction but more importantly to systemic or cerebral thromboembolism. Thrombosis is more common in mechanical heart valves than in bioprosthetic heart

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valves, and more common in the mitral than the aortic valve. The estimated risk of valve thrombosis has been previously reported as as high as 5.7% per year (Metzdorff et al., 1984). However, more recent estimates are 0.2% per year for mechanical heart valves and less than 0.1% for bioprosthetic heart valves (Hammermeister et al., 2000; Chikwe et al., 2011). In a study of 575 patients undergoing aortic and mitral valve replacement in which patients were randomized to receive a mechanical heart valve (Bjork–Shiley) or a porcine heart valve (Hancock), they noted a valve thrombosis rate of 1–2%; more importantly, they did not find differences in the rate between valve type or location. No difference has been found in the rate of thrombosis between bileaflet and tilting disc valves (Bonow et al., 2008; Chikwe et al., 2011). The average risk of thromboembolism resulting from mechanical heart valves is estimated at 4% a year in the absence of anticoagulation treatment. The risk is decreased to 2% a year by antiplatelet agents and to 1% by warfarin anticoagulation (Cannegieter et al., 1994; Chikwe et al., 2011). Thromboembolism rates are associated to anticoagulation practices. In a study of 541 patients with a followup of 20 years, there were 158 embolic events in 121 patients (23%); the mean occurrence of embolism at 20 years was 24% for mechanical heart valves as compared to 39.2% for bioprosthetic heart valves in the aortic position; in contrast, the rate was 53.4% for mechanical versus 32% for bioprosthetic heart valves in the mitral position (Oxenham et al., 2003). In the Veterans Affairs Cooperative Study on Valvular Heart Disease, the embolism rates were comparable at 18% for either type of valve in the aortic position as compared to 18% for mechanical and 22% for bioprosthetic valves in the mitral position (Hammermeister et al., 2000). However, the thromboembolism rate in patients fully anticoagulated is in the range of 0.5% to 1% per year (Cannegieter et al., 1994; Grunkemeier et al., 2000).

AORTIC BIOPROSTHETIC VALVES Evidence to date suggests that anticoagulation does not decrease the risk of embolism and increases nonsignificantly the risk of hemorrhage. In a retrospective study of 185 patients (109 on anticoagulation and 76 with no anticoagulation) and followed for the first 3 months post valve implant, the risk of stroke was 7.4% among those anticoagulated compared to 6.5% among those not anticoagulated (RR 1.1 CI 95% 03.8, 3.28). The bleeding complication rate was the same in both groups (Moinuddeen et al., 1998). In another retrospective study of patients with aortic bioprosthetic heart valve implant, 103 patients were treated with warfarin, 509 were treated with aspirin, and 136 received no antithrombotic therapy; the rates of hemorrhage were 16.7%, 3.4%, and 3.1%, respectively. The risk of thromboembolism was 0.8% among those treated with aspirin compared to 2.9% and 1.5% in those treated with warfarin and on no antithrombotics, respectively (Blair et al., 1994). Two clinical trials compared antiplatelet therapy versus warfarin anticoagulation and showed no therapeutic effect of warfarin over trifusal in one, RR 1.98 (CI 95% 0.51, 7.68) (Aramendi et al., 2005), and over aspirin, RR 1.52 (CI 95% 0.28, 2.76), in the other (Aramendi et al., 1998; Colli et al., 2007). Although the quality of these studies is low, the current recommendation for patients with an aortic bioprosthetic heart valve replacement who have no other indication for anticoagulation is aspirin during the first 3 months postreplacement (Whitlock et al., 2012). With regards to endovascular aortic valve replacement with a bioprosthesis, the evidence is very limited; however, since this procedure is considered an extension of coronary artery stenting, the current antithrombotic prophylaxis for embolism is a combination of aspirin and clopidogrel (Whitlock et al., 2012).

MITRAL BIOPROSTHETIC VALVES

Bioprosthetic heart valves The risk of thromboembolism in patients with bioprosthetic heart valves and normal sinus rhythm is on average 0.7% per year. The risk is greater in patients with a valve in the mitral position than in the aortic position. The risk is generally greater early in the course after the implantation (first 3 months) before the valve is fully endothelialized (Bonow et al., 2008). Because of the high early risk, anticoagulation with unfractionated heparin is often used in the first few days, overlapping with warfarin until the INR is within therapeutic range. After the first 3 months, warfarin can be discontinued in as many as 60% of patients; the remainder often have to stay on warfarin owing to high risk factors such as AF or previous thromboembolism (Bonow et al., 2008).

The risk of thromboembolism after mitral valve bioprosthetic replacement is very high in the early postoperative period. The overall risk is 55% between days 1 and 10; 10% between days 11 and 90; and 2.4% per year thereafter. The risk is significantly decreased by anticoagulation. In fact, the risk of on and off anticoagulation is 50% versus 60% within the first 10 days, 10% versus 13% between days 11 and 90; and 2.5% versus 3.9% > 90 days (Heras et al., 1995). There is no randomized controlled trial supporting the use of anticoagulation in the first 3 months after mitral valve replacement. Despite the poor quality of the evidence, the current recommendation is for patients with bioprosthetic mitral valve replacement to be anticoagulated during the first 3 months post valve replacement (Whitlock et al., 2012).

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE The long-term risk of thromboembolism and stroke in patients with bioprosthetic valves is 0.2–2.6% per year, with the lowest risk among patients with aortic valve replacement; thus the current recommendation is to administer aspirin for patients with a bioprosthetic valve replacement (Cohn et al., 1981; Whitlock et al., 2012). It is important to note that when AF coexists with the valve replacement, the risk of embolism is as high as 16% at 36 months, and, therefore, anticoagulation with warfarin is indicated when atrial fibrillation coexists. Other associated factors potentially increasing the risk of thromboembolism include a low ejection fraction, an enlarged atrium, a hypercoagulable state, and a history of thromboembolism. Patients with any of these conditions, even in the absence of AF, should receive warfarin in addition to aspirin therapy (Cohn et al., 1981; Gonzalez-Lavin et al., 1984; Nunez et al., 1984; Goldsmith et al., 1998; Whitlock et al., 2012).

Mechanical heart valves The risk of thrombosis and embolism increases from the time of valve implantation. Prosthetic materials and injured perivalvular tissue lead to platelet aggregation. Dacron sewing rings are prime material for platelet activation. In a large systematic review including 46 studies between 1970 and 1992, looking at 13 088 patients with a total 53 647 patient-years of follow-up, the incidence of major embolism including stroke was 4 per 100 patientyears among patients not receiving antithrombotic therapy compared to 2.2 per 100 patient-years among those receiving antiplatelet therapy and 1 per 100 patient-years in patients receiving anticoagulation with coumarin (Cannegieter et al., 1994). In the same study, the risk was twice as high among patients with mitral valve prosthesis as compared to aortic valve prosthesis. In addition, bileaflet and disc tilting valves have a lower incidence than caged ball valves. Generally, all patients with mechanical heart valves require warfarin anticoagulation. Aspirin in addition to warfarin is recommended in all patients with mechanical prosthetic heart valves. For heart valves in the aortic position, the target INR is 2–3, although for disc valves and Starr–Edwards valves the recommended INR is 2.5–3.5. A target INR of 2.5–3.5 is also recommended for patients with mechanical heart valves in the aortic position and at high risk defined by the presence of AF, low ejection fraction, hypercoagulable state, and history of thromboembolism (Bonow et al., 2008; Whitlock et al., 2012). For mechanical prostheses in the mitral position, the recommended target INR is 2.5–3.5 for all valve types given the higher risk of thromboembolism (Bonow et al., 2008; Whitlock et al., 2012). The use of bridging therapy with either unfractionated heparin or low molecular weight heparin is rather controversial and based on observational studies.

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Although the thromboembolic risk is certainly increased early after the implantation of the prosthetic heart valve, the reported risk of thromboembolism with bridging therapy with either agent is about 0.6–1.1% with a bleeding risk of 3.3–7.2%. Therefore, bridging therapy is recommended after valve implantation until the INR becomes therapeutic (Whitlock et al., 2012). Recently, a phase 2 dose-validation randomized clinical trial testing several doses of dabigatran vs warfarin in patients with mechanical valves in the aortic or mitral position or both was stopped prematurely after the enrollment of 252 patients due to the excess thromboembolic (5% vs 0%) and bleeding (27% vs 12%) events among patients receiving dabigatran (Eikelboom et al., 2013). For the long-term prevention of thrombosis and thromboembolic events it is recommended to treat patients with warfarin anticoagulation in addition to aspirin. For individuals allergic to aspirin, the addition of clopidogrel is appropriate (Bonow et al., 2008; Whitlock et al., 2012).

ANTICOAGULATION AND ITS COMPLICATIONS Since valvular thrombosis with systemic or cerebral embolism are important complications of valvular heart disease, antithrombotic therapy is an important aspect of the treatment. The current recommendations for antithrombotic therapy can be summarized as follows (Whitlock et al., 2012): 1.

Warfarin anticoagulation a. rheumatic mitral valve disease with normal sinus rhythm and a left atrial diameter > 55 mm. Target INR 2–3 b. rheumatic mitral valve disease associated with left atrial thrombus. Target INR 2–3 c. rheumatic valve disease associated with AF d. bioprosthetic mitral valve in the first 3 months from implantation e. mechanical heart valves. 2. Unfractionated heparin full dose or subcutaneous low molecular weight heparin a. nonbacterial thrombotic endocarditis and systemic or cerebral emboli b. mechanical valves and normal sinus rhythm until INR is therapeutic with warfarin therapy. 3. Antiplatelet agents a. rheumatic mitral valve disease and normal sinus rhythm with normal sized left atrium ( 5, the risk of hemorrhage is 2009). Prevention of early recurrent stroke was considgreatly increased. However, to avoid wide fluctuation in ered the primary indication for emergent anticoagulation INR from excessive anticoagulation to normalization, it as the risk of early recurrence was initially estimated to be 1% per day and as high as 14% in the first 2 weeks after a is possible to use small doses of vitamin K of 1–2.5 mg stroke (Cerebral Embolism Task Force, 1986). However, orally in addition to withholding warfarin and closely monitoring the INR (Weibert et al., 1997; Yiu et al., randomized clinical trials with anticoagulation showed 2006; Bonow et al., 2008). In an emergency situation that the risk of stroke early recurrence is much lower, fresh frozen plasma is used for correction. at 1.1% to 4.9%, among not anticoagulated patients with Interruption of warfarin therapy for invasive proa cardiac source of embolism (Adams, 2002). cedures. A frequent clinical scenario is the need for An important issue on the emergent use of anticoaguinvasive procedures among patients on long-term anticlation during ischemic stroke refers to its safety. Hemorrhagic transformation of an ischemic infarct is a oagulation, from dental procedures to noncardiac surknown potential complication, and all antithrombotics gery. The risks of bleeding during the procedure and the immediate perioperative period have to be weighed may be associated with it. Clinical trials testing unfracagainst the risk of thromboembolism. tionated heparin and a variety of low molecular weigh In general, antithrombotic therapy should not be heparin have shown that the risk of hemorrhagic transstopped for procedures during which the risk of bleeding formation ranges from 0.6% to 6.1%. Furthermore, the is negligible, such as skin surgery, dental cleaning, or a risk of symptomatic hemorrhagic transformation of simple caries procedure. For procedures with potential ischemic stroke is associated with stroke severity (National Institutes of Health Stroke Scale (NIHSS) for significant bleeding complications, the antithrombotic > 15) and high doses of anticoagulation. Although there treatment will have to be modified (Bonow et al., 2008). Since the risk of thromboembolic events in patients with is general agreement that large strokes are associated mechanical heart valves not taking warfarin is 10–20% with a higher risk of bleeding, there are no studies annually, the inference is that the risk for stopping anticlooking specifically at CT findings as predictive of oagulation for 3 days is about 0.08–0.16% (Bonow et al., hemorrhagic complications (Adams, 2002). Patients 2008). In patients with mechanical aortic valves and no with mechanical heart valves do have a higher risk of added risk factors for thromboembolism (AF, low ejecembolic events and therefore, early anticoagulation after an ischemic stroke may be necessary. In these cirtion fraction, history of thromboembolism) it is possible cumstances, it is recommended to repeat a CT scan in to stop warfarin for 2 or 3 days and restarted 24 hours after the procedure (Kearon and Hirsh, 1997; Chikwe the first 2–3 days and start anticoagulation provided et al., 2011). In contrast, patients at high risk of thrombothere is no evidence of hemorrhagic transformation. embolic events, such as those with mechanical heart valves After intracranial hemorrhage, anticoagulation may in the mitral position or with aortic valve prosthesis and need to be withheld for as long as 2 weeks (Adams, risk factors such as AF, low ejection fraction, history of 2002; Ferro, 2003).

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE

INFECTIVE ENDOCARDITIS Endocarditis is the inflammation of the endocardial surface of the heart and its valves. There are infective and noninfective causes of endocarditis. In infective endocarditis, bacteria continue to be the predominant microorganism, although fungi have rarely been reported. The noninfective variety occurs in conditions such as cancer and systemic lupus erythematosus (SLE). Endocarditis continues to have significant morbidity and mortality although there have been changes in its frequency and distribution since it was first described. There are a variety of neurologic complications in infective endocarditis, of which cerebral embolization with stroke is the most common. Other complications described include intracerebral and subarachnoid hemorrhage, mycotic aneurysm, abscess, meningoencephalitis, and encephalopathy. In contrast, the main neurologic complication in noninfective endocarditis is ischemic stroke (Hoen and Duval, 2013). Despite the changes in the distribution and epidemiology of infective endocarditis, the frequency of its neurologic complications has remained relatively stable. The frequency of neurologic complications ranges from 25% to 45% in most series before and after the introduction of antibiotics (Ziment, 1969; Jones and Siekert, 1989). In more recent international registries, stroke and systemic embolization occurred in 17% and 22% among patients with native valve endocarditis, while the rate was 18% and 15%, respectively, in prosthetic valve endocarditis (Wang et al., 2007; Murdoch et al., 2009). The presence of neurologic complications has remained a factor associated with an increased mortality (Pruitt et al., 1978; Jones and Siekert, 1989). In fact, the rupture of a mycotic aneurysm portends a mortality of about 80% if untreated (Bayer et al., 1998). Besides the impact in outcome, the presence of neurologic complications affects medical decision making as they may pose limits or restrictions on valve replacement surgery and the use of anticoagulation, and their timing. Infective endocarditis can also occur in patients with prosthetic heart valves. Mechanical valves have a slighter higher incidence than bioprosthetic heart valves at 1% overall. Prosthetic valve endocarditis can occur early after implantation ( < 60 days) or late. Early endocarditis usually results from seeding occurring intra- or perioperatively due to concurrent infections. The most common organisms include Staphylococcus aureus, S. epidermidis and Gram-negative bacteria. The overall risk of late endocarditis is in the range of 0.2–0.4% per patient year. Late endocarditis usually results from seeding from noncardiac sepsis or after invasive procedures; common bacteria include S. aureus and Streptococcus spp. Unfortunately, valve replacement is often needed

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and common indications include perivalvular leak, partial dehiscence, new conduction deficits, abscess, and infection with organisms with high virulence such as S. aureus. (Hammermeister et al., 2000; Oxenham et al., 2003; Chikwe et al., 2011).

Cerebrovascular complications ISCHEMIC STROKE Brain embolism is the main mechanism of injury. Stroke in fact is the presenting symptom in 15–19% of all cases (Davenport and Hart, 1990; Hart et al., 1990; Thuny et al., 2007). It is estimated that strokes occurs in 21–39% of cases of infective endocarditis (Jones and Siekert, 1989; Salgado et al., 1989; Hart et al., 1990; Hoen and Duval, 2013). However, with the Duke criteria, the actual prevalence of stroke is lower at 9–22%. Most strokes are ischemic (Heiro et al., 2000; Anderson et al., 2003; Heiro et al., 2006; Thuny et al., 2007). As many as three-quarters of all ischemic strokes in patients with infective endocarditis occur at presentation (Hart et al., 1990; Anderson et al., 2003). About 8–10% of all embolic events present as transient ischemic attacks (TIA) (Jones and Siekert, 1989; Hart et al., 1990). While any cerebral vascular territory can be affected, most emboli involve the middle cerebral artery (MCA) distribution. However, more than 50% of patients have multiple vascular territories affected (Singhal et al., 2002; Anderson et al., 2003). Importantly, about 4% of patients may have asymptomatic brain infarctions (Thuny et al., 2007). Risk factors for embolism Factors increasing the risk of embolism include the time period, the virulence of the microorganism, which cardiac valve is affected, and the characteristics of the vegetation. The period of highest risk for neurologic complications is the time prior to diagnosis to the end of the first week of treatment. Neurologic complications usually occur at presentation or within a week from symptom onset and their rate declines very quickly to less than 10% after the first week of antibiotic treatment (Jones and Siekert, 1989; Davenport and Hart, 1990; Kanter and Hart, 1991; Heiro et al., 2000, 2006; Corral et al., 2007). The virulence of the causal organism is an important predictor. As many as 60% of cases of S. aureus endocarditis develop neurologic complications (Kanter and Hart, 1991; Corral et al., 2007). Fungal endocarditis also portends a high risk for neurologic complications. Candida and Aspergillus species endocarditis have rates of neurologic complications as high as 60%. Importantly, the size of embolic particles is larger in fungal

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endocarditis, which results in embolism in larger arteries (Jones and Siekert, 1989; Ellis et al., 2001). Anatomically, left-sided endocarditis carries a higher risk of brain embolism than right-sided endocarditis, although there are reports of paradoxical embolism (Jones and Siekert, 1989; Kanter and Hart, 1991). Mitral involvement carries a higher risk than aortic valve involvement (Pruitt et al., 1978; Vilacosta et al., 2002; Anderson et al., 2003). Native valve endocarditis conveys a higher risk of embolism than prosthetic heart valve endocarditis, and although the reasons are not completely understood, the larger vegetation size in native valve endocarditis and the frequent use of anticoagulation in prosthetic valve endocarditis may influence this distribution (Davenport and Hart, 1990). Some characteristics of the vegetation may impact the risk of embolism. Interestingly, the identification of a vegetation by echocardiography is not a factor increasing the embolic risk (Vilacosta et al., 2002). However, its size and mobility of the vegetation do increase it. Specifically, vegetations larger than 10 mm and mobile have the greatest embolic risk (Rohmann et al., 1992; Di Salvo et al., 2001). In summary, the factors associated with greater embolic risk are: 1. 2.

3. 4.

pretreatment period and the first week of antibiotic treatment virulence of the organism, such as S. aureus, Enterococcus spp., Aspergillus spp., Candida spp., coagulase-negative Staphylococcus spp. left-sided valves; mitral valve greater than aortic valve. Multiple valve involvement vegetations > 10 mm and mobile, or vegetations increasing in size during treatment

INTRACRANIAL HEMORRHAGE Intracranial hemorrhage occurs in 2–8%; however, it carries the highest mortality rate (Hart et al., 1990, Heiro et al., 2000). Most commonly, intracranial hemorrhage, either intracerebral or subarachnoid, results from septic endarteritis with erosion and vascular rupture or the hemorrhagic transformation of an infarction (Hart et al., 1987). Importantly, mycotic aneurysms are found in less than 3% of cases of intracranial hemorrhage.

MYCOTIC ANEURYSM Mycotic aneurysms result from septic microembolism to the vasa vasorum; they predominantly affect the MCA and are multiple in about 25% of patients (Peters et al., 2006). Their prevalence in patients with infective endocarditis is about 3% but is responsible for only 1% of all cerebrovascular complications. These aneurysms are

rarely responsible for intracerebral hemorrhage ( 3400 patients with cancer, about 15% had evidence of cerebral infarction, and NBTE was found in nearly 20% (Graus et al., 1985). In a clinical series of patients with stroke and cancer, cardioembolism explained 54% of cases of ischemic stroke, though NBTE was present in only 3% (Cestari et al., 2004). However, the prevalence of NTBE was 18% in case series of patients with stroke and cancer using transesophageal echocardiogram (TEE) as the diagnostic modality (Dutta et al., 2006). NBTE may present as a focal neurologic deficit characteristic of cerebral ischemia; however, multiple small embolic simultaneous events may lead to a picture of encephalopathy (Biller et al., 1982; Rogers et al., 1987; Singhal et al., 2002).

Libman–Sacks endocarditis The prevalence of this condition is as high as 75% among patients with systemic lupus erythematous (Roldan et al., 1992, 1996). It predominantly affects the valves in the left side. Macroscopically, the vegetations are small (usually < 4 mm) and nonmobile, and heterogeneous in quality, often with a verrucous appearance; they adhere to the base of the valve (Roldan et al., 1992, 1996, 2005). Arteritis, microangiopathy, and hypercoagulability are coexisting mechanisms of stroke in patients with NBTE; however, valvular disease independently predicts the presence of cerebral embolism (Roldan et al., 2007). Although there is a paucity of information and no randomized clinical trials, anticoagulation with unfractionated heparin or with low molecular weight heparinoids is recommended (Rogers et al., 1987; Mocchegiani and Nataloni, 2009; Whitlock et al., 2012). Patients with antiphospholipid antibody syndrome and evidence of systemic or cerebral embolism may also be treated with warfarin to a target INR of 2–3.

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Hart RG, Kagan-Hallet K, Joerns SE (1987). Mechanisms of intracranial hemorrhage in infective endocarditis. Stroke 18: 1048–1056. Hart RG, Foster JW, Luther MF et al. (1990). Stroke in infective endocarditis. Stroke 21: 695–700. Heiro M, Nikoskelainen J, Engblom E et al. (2000). Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med 160: 2781–2787. Heiro M, Helenius H, Makila S et al. (2006). Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980–2004. Heart 92: 1457–1462. Heras M, Chesebro JH, Fuster V et al. (1995). High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol 25: 1111–1119. Hoen B, Duval X (2013). Clinical practice. Infective endocarditis. N Engl J Med 368: 1425–1433. Holley KE, Bahn RC, McGoon DC et al. (1963a). Calcific embolization associated with valvotomy for calcific aortic stenosis. Circulation 28: 175–181. Holley KE, Bahn RC, McGoon DC et al. (1963b). Spontaneous calcific embolization associated with calcific aortic stenosis. Circulation 27: 197–202. Jones HR Jr, Siekert RG (1989). Neurological manifestations of infective endocarditis. Review of clinical and therapeutic challenges. Brain 112: 1295–1315. Kanter MC, Hart RG (1991). Neurologic complications of infective endocarditis. Neurology 41: 1015–1020. Kearon C, Hirsh J (1997). Management of anticoagulation before and after elective surgery. N Engl J Med 336: 1506–1511. Kizer JR, Wiebers DO, Whisnant JP et al. (2005). Mitral annular calcification aortic valve sclerosis and incident stroke in adults free of clinical cardiovascular disease: the Strong Heart Study. Stroke 36: 2533–2537. Kovacs MJ, Kearon C, Rodger M et al. (2004). Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation 110: 1658–1663. Lansberg MG, O’Donnell MJ, Khatri P et al. (2012). Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141: e601S–e636S. Lausier S, B HJA (1987). Cerebral ischemia with mitral valve prolapse and mitral annular calcification. Springer Verlag, London. Lopez JA, Ross RS, Fishbein MC et al. (1987). Nonbacterial thrombotic endocarditis: a review. Am Heart J 113: 773–784. Marijon E, Mirabel M, Celermajer DS et al. (2012). Rheumatic heart disease. Lancet 379: 953–964. MsKeown EF (1975). De Senectute. The F. E. Williams lecture. J R Coll Physicians Lond 10: 79–99. No abstract available. PMID: 1202219. Metzdorff MT, Grunkemeier GL, Pinson CW et al. (1984). Thrombosis of mechanical cardiac valves: a qualitative

comparison of the silastic ball valve and the tilting disc valve. J Am Coll Cardiol 4: 50–53. Mocchegiani R, Nataloni M (2009). Complications of infective endocarditis. Cardiovasc Hematol Disord Drug Targets 9: 240–248. Moinuddeen K, Quin J, Shaw R et al. (1998). Anticoagulation is unnecessary after biological aortic valve replacement. Circulation 98: II95–II98, discussion II98–II99. Murdoch DR, Corey GR, Hoen B et al. (2009). Clinical presentation etiology and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med 169: 463–473. Nestico PF, Depace NL, Morganroth J et al. (1984). Mitral annular calcification: clinical pathophysiology and echocardiographic review. Am Heart J 107: 989–996. Nunez L, Gil Aguado M, Larrea JL et al. (1984). Prevention of thromboembolism using aspirin after mitral valve replacement with porcine bioprosthesis. Ann Thorac Surg 37: 84–87. Oxenham H, Bloomfield P, Wheatley DJ et al. (2003). Twenty year comparison of a Bjork–Shiley mechanical heart valve with porcine bioprostheses. Heart 89: 715–721. Paciaroni M, Agnelli G, Micheli S et al. (2007). Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 38: 423–430. Peters PJ, Harrison T, Lennox JL (2006). A dangerous dilemma: management of infectious intracranial aneurysms complicating endocarditis. Lancet Infect Dis 6: 742–748. Pruitt AA, Rubin RH, Karchmer AW et al. (1978). Neurologic complications of bacterial endocarditis. Medicine (Baltimore) 57: 329–343. Rajamannan NM, Bonow RO, Rahimtoola SH (2007). Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med 4: 254–262. Ramakrishna G, Malouf JF, Younge BR et al. (2005). Calcific retinal embolism as an indicator of severe unrecognised cardiovascular disease. Heart 91: 1154–1157. Remenyi B, Wilson N, Steer A et al. (2012). World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease – an evidence-based guideline. Nat Rev Cardiol 9: 297–309. Roder BL, Wandall DA, Espersen F et al. (1997). Neurologic manifestations in Staphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med 102: 379–386. Rogers LR, Cho ES, Kempin S et al. (1987). Cerebral infarction from non-bacterial thrombotic endocarditis. Clinical and pathological study including the effects of anticoagulation. Am J Med 83: 746–756. Rohmann S, Erbel R, Gorge G et al. (1992). Clinical relevance of vegetation localization by transoesophageal echocardiography in infective endocarditis. Eur Heart J 13: 446–452. Roldan CA, Shively BK, Lau CC et al. (1992). Systemic lupus erythematosus valve disease by transesophageal

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE echocardiography and the role of antiphospholipid antibodies. J Am Coll Cardiol 20: 1127–1134. Roldan CA, Shively BK, Crawford MH (1996). An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med 335: 1424–1430. Roldan CA, Gelgand EA, Qualls CR et al. (2005). Valvular heart disease as a cause of cerebrovascular disease in patients with systemic lupus erythematosus. Am J Cardiol 95: 1441–1447. Roldan CA, Gelgand EA, Qualls CR et al. (2007). Valvular heart disease by transthoracic echocardiography is associated with focal brain injury and central neuropsychiatric systemic lupus erythematosus. Cardiology 108: 331–337. Salem DN, Stein PD, Al-Ahmad A et al. (2004). Antithrombotic therapy in valvular heart disease – native and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 457S–482S. Salgado AV, Furlan AJ, Keys TF (1987). Mycotic aneurysm subarachnoid hemorrhage and indications for cerebral angiography in infective endocarditis. Stroke 18: 1057–1060. Salgado AV, Furlan AJ, Keys TF et al. (1989). Neurologic complications of endocarditis: a 12-year experience. Neurology 39: 173–178. Sandercock PA, Gibson LM, Liu M (2009). Anticoagulants for preventing recurrence following presumed noncardioembolic ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev CD000248. Selzer A, Cohn KE (1972). Natural history of mitral stenosis: a review. Circulation 45: 878–890. Silaruks S, Thinkhamrop B, Tantikosum W et al. (2002). A prognostic model for predicting the disappearance of left atrial thrombi among candidates for percutaneous transvenous mitral commissurotomy. J Am Coll Cardiol 39: 886–891. Silaruks S, Thinkhamrop B, Kiatchoosakun S et al. (2004). Resolution of left atrial thrombus after 6 months of anticoagulation in candidates for percutaneous transvenous mitral commissurotomy. Ann Intern Med 140: 101–105. Singhal AB, Topcuoglu MA, Buonanno FS (2002). Acute ischemic stroke patterns in infective and nonbacterial thrombotic endocarditis: a diffusion-weighted magnetic resonance imaging study. Stroke 33: 1267–1273. Soulie P, Caramanian M, Soulie J (1969). Calcified aortic stenosis; pathological anatomy. Arch Mal Coeur Vaiss 62: 1096–1118. Stroke Prevention in Atrial Fibrillation Investigators (1992a). Predictors of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk. Ann Intern Med 116: 1–5. Stroke Prevention in Atrial Fibrillation Investigators (1992b). Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. Ann Intern Med 116: 6–12. Szekely P (1964). Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 1: 1209–1212.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 7

Infective endocarditis JOSE´ M. FERRO* AND ANA CATARINA FONSECA Department of Neurosciences, Servio de Neurologia, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal

DEFINITION Infective endocarditis is a disease of the inner lining of the heart and cardiac valves, the endocardium, caused by a variety of infectious agents, ranging from streptococci to antibiotic-resistant bacteria, including fungi and rickettsia. Endocarditis causes constitutional, cardiac, and multiorgan symptoms and signs. The central nervous system can be affected in the form of meningitis, cerebritis, encephalopathy, seizures, brain abscess, ischemic embolic stroke, mycotic aneurysm, and subarachnoid or intracerebral hemorrhage (Salgado, 1991; Autret et al., 1993; Sila, 2010). The subject of noninfective endocarditis, also called noninfective or nonbacterial thrombotic endocarditis, which is associated with lupus, antiphospholipid syndrome, hypereosinophilic syndrome, and cancer, is not addressed in this chapter.

CLASSIFICATION Infective endocarditis is traditionally divided into acute and subacute-chronic types, according to the temporal profile of onset. Classically, acute endocarditis usually occurs in previously normal valves and is associated with more aggressive agents and nosocomial infections, while the subacute-chronic form occurs in abnormal valves and is due to more common and “benign” bacteria. Infective endocarditis constitutes a group of clinical situations, whose cause and location can vary. The Task Force on the Prevention, Diagnosis and Treatment of Infective Endocarditis of the European Society of Cardiology (Habib et al., 2009) proposed a classification of infective endocarditis into different categories relating to: ● ●

site of infection: left side; right side the presence or absence of intracardiac foreign material: native valve; prosthetic valve; device-related

●

●

mode of acquisition: community-acquired; health care associated – nosocomial or non-nosocomial; intravenous drug abuse-associated microbiologic findings: with positive blood cultures (streptococci, enterococci, staphylococci); with negative blood cultures because of prior antibiotic treatment; frequently associated with negative blood cultures (variant streptococci, fastidious Gramnegative bacilli of the HACEK group (Haemophilus species – Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus — Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species), Brucella and fungi); infective endocarditis associated with constantly negative blood cultures (Coxiella Burnetti, Bartonella, Chlamydia, Tropheryma whipplei).

HISTORICAL ASPECTS Although several physicians had described valvular vegetations, and a few had studied endocarditis, including Laennec, Bouillaud, and Kirkes (Levy, 1985), the three Gulstonian Lectures on “malignant endocarditis” delivered by William Osler to the Royal College of Physicians in 1885, and published in the same year in the British Medical Journal, are considered the hallmark of modern medical thought in infective endocarditis (Osler, 1885). Mostly based on personal observations, Osler described the symptoms and signs of endocarditis, including its cerebral manifestations (cerebral group) (Osler, 1885), its diagnostic problems, and caveats. He elaborated on an attempted classification (simple and malignant endocarditis) and called attention to the prolonged forms of endocarditis. He also pointed to “persons debilitated,” “addicted to drink,” those with a previous attack of rheumatism, and those affected by the prevalent infectious

*Correspondence to: Professor Jose´ M Ferro, Servic¸o de Neurologia, 6th floor, Hospital de Santa Maria, 1649-028 Lisbon, Portugal. Fax: þ351-21-7957474, E-mail: [email protected]

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disorders of the time, such as scarlet fever, pneumonia, and rheumatic fever, as individuals particularly liable to be attacked by “malignant” endocarditis. Later important contributions include those of Libman, who intensively studied the bacteriology and morbid anatomy of endocarditis. He examined the Austrian composer Gustave Mahler, who died of endocarditis at the age of 51. Libman identified “attenuated Streptococcus” in his blood cultures (Levy, 1986).

EPIDEMIOLOGY Fortunately, infective endocarditis is not very frequent. The estimated incidence is 1.7–6.2/100 000/year (Mylonakis and Calderwood, 2001). A survey in France detected 30 cases per million inhabitants in 1 year (Hoen et al., 2002). The incidence has been stable for several decades. The disease is more common in men (2:1) and in the middle aged, although in recent times an increasing number of the elderly have been affected, due to increased survival and more aggressive diagnostic and therapeutic approaches in this age group. In recent years, the proportion of cases associated with rheumatic valvulopathy and dental surgery has decreased, while several other associated diseases and risk factors have emerged. These include intravenous drug abuse, typically associated with acute right-sided endocarditis, prosthetic valves, degenerative valve disease, implanted cardiac devices (Baddour et al., 2010; Zahr et al., 2010), and iatrogenic or nosocomial infections. About half of the patients in whom the diagnosis is made nowadays do not have a known history of an underlying cardiac disease or intervention. In the International Collaboration on Endocarditis-Prospective Cohort Study, infective endocarditis was most often an acute disease, frequently caused by Staphylococcus aureus infection (Murdoch et al., 2009).

PATHOPHYSIOLOGY As a rule, the valve endothelium and the endocardium are resistant to colonization and infection by circulating bacteria. In the absence of valve lesion, it is necessary to have either mechanical disruption of the endothelium or endothelial inflammation in order for valves to become colonized and infected (Que et al., 2005; Beynon et al., 2006; Prendergast, 2006; Habib et al., 2009). Following mechanical disruption of endothelium, there is an exposure of the underlying extracellular matrix proteins and stromal cells which trigger the deposition of fibrin and platelets as part of a physiologic healing process. A small clot of fibrin and platelets is formed over the damaged endothelium. During transient bacteremia, circulating pathogens bind to the formed coagulum. This process attracts and activates monocytes to

produce cytokines and tissue factor. These mediators activate the coagulation cascade, attract and activate more platelets, and induce the production of cytokines, integrin, and tissue factor from endothelial cells, resulting in progressive enlargement of the infected vegetation. Mechanical damage of endothelium can be caused by turbulent blood flow, electrodes, catheters, or other intracardiac devices, inflammation, or degenerative changes. Local valve inflammation triggers the expression of integrins of the b1 family by the endothelial cells. b1 integrins bind circulating fibronectin to the endothelial surface. Some pathogens, such as Staphylococcus aureus, carry fibronectin-binding proteins on their surface. Therefore, when the activated endothelial cells connect with fibronectin, they are providing an adhesive surface to circulating pathogens. Once adhered, the pathogens can activate their internalization into valve endothelial cells where they can persist, multiply, and spread. In response to invasion, endothelial cells produce cytokines and tissue factor activity, resulting in the formation of the vegetation (Moreillon and Que, 2004; Que et al., 2005). Transient bacteremia can occur during invasive procedures, but also after tooth brushing and chewing. The high incidence of these low-grade and short-lived bacteremias can explain cases of infective endocarditis unrelated to invasive procedures (Strom et al., 2000). Valve colonization and infection can cause valvular dysfunction, continuous bacteremia, embolic phenomena, and immune-mediated disease. The neurologic complications result mainly from systemic embolization of septic emboli from the valvular vegetations, causing an ischemic cerebral infarction, which can eventually undergo hemorrhagic transformation. Septic emboli obstructing the lumen or the vasa vasorum also cause a focal vasculitis, leading to a focal cerebritis, which ultimately can develop into a brain abscess or meningoencephalitis. Mycotic aneurysms occur when the inflammation process from the septic emboli penetrates the vessel wall through the muscularis media to the lamina elastica interna. The rupture of infected vessel wall or of mycotic aneurysms can cause subarachnoid or intracerebral hemorrhage.

CLINICAL ASPECTS Systemic, cardiac and multiorgan manifestations Systemic manifestations of infective endocarditis include fever> 38 C (96% of the patients) (Murdoch et al., 2009), often associated with chills, poor appetite, and weight loss. Fever can be absent in patients with previous use of antibiotics and in endocarditis due to less virulent

INFECTIVE ENDOCARDITIS agents. A new regurgitant heart murmur can be found in half (48%) of the subjects and worsening of old murmur in 20%. Other classic clinical manifestations include active vasculitic phenomena such as splinter hemorrhages (red to brownish, linear, and located under the fingernails or toenails) (8%), Roth spots (retinal hemorrhage with a fibrin-white center) (2%), conjunctival hemorrhages (5%) and glomerulonephritis, emboli to the brain (see below), lung or spleen and splenomegaly (11%). Osler’s nodes (tender, subcutaneous, situated on the pulp of the digits or thenar eminence) (3%), Janeway’s lesions (nontender, erythematous, hemorrhagic or pustular lesions, on the palms or soles) (5%), and digital clubbing are less common nowadays (Mylonakis and Calderwood, 2001; Beynon et al., 2006; Murdoch et al., 2009). Clinical presentation varies with the mode of onset and the involved side of the heart. Acute endocarditis typically has high fever, signs of systemic toxicity, systemic emboli, sudden cardiac failure or valvular incompetence. In right-sided endocarditis, pulmonary emboli are common. In subacute endocarditis, a syndrome of fever of unknown cause, enlarged spleen and the classic vasculitic and cutaneous findings described above are more likely to be seen. Atypical presentations are particularly common in elderly, immunocompromised patients (Pe´rez de Isla et al., 2007) and right-sided infective endocarditis.

Neurologic manifestations Between 20% and 40% of patients with infective endocarditis have neurologic complications. Neurologic complications are more frequent in patients with large size valvular vegetations, mitral valve infective endocarditis, and infection due to Staphylococcus aureus (Nadji et al., 2005) or Streptococcus bovis. The risk of embolism is particularly high within the first 2 weeks after diagnosis and decreases in frequency after the beginning of antibiotic therapy (Thuny et al., 2007; Snygg-Martin et al., 2008). A large single-center study showed a trend for increasing frequency of neurologic complications in infective endocarditis, probably associated with an increase in more aggressive nosocomial acquired and Staphylococcus aureus endocarditis (Corral et al., 2007). Patients with infective endocarditis associated with neurologic complications tend to have higher morbidity and mortality than patients without neurologic complications (Heiro et al., 2000). Neurologic manifestations can be the first sign of infective endocarditis. In one study, 46% of patients first presented with a neurologic manifestation (Heiro et al., 2000). The neurologic complications of infective endocarditis can be divided in two main groups: cerebrovascular and infectious. Cerebrovascular complications are the most

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frequent and include ischemic stroke, transient ischemic attack, hemorrhagic stroke and mycotic aneurysms. Infectious complications include meningitis, cerebritis, brain abscesses and discitis. Acute encephalopathy can also occur. There are reports of isolated neurologic symptoms, such as headache, seizures, or trigeminal neuralgia. Less frequent are reports of peripheral neurologic involvement including peripheral neuropathies and spondylodiscitis. Although the majority of the cerebrovascular complications of infective endocarditis are symptomatic, there has been an increase in the report of “silent lesions,” mainly due to the more frequent use of neuroimaging (Snygg-Martin et al., 2008; Cooper et al., 2009). In a prospective study, “silent lesions” were documented in DWI-MRI in 70% of patients with left-sided heart valvular endocarditis (Cooper et al., 2009). There is no information at present on the impact of these lesions on the long-term outcome. One study reported a high frequency of cerebral microbleeds in patients with infective endocarditis: 57% of patients with infectious endocarditis versus 15% in control subjects (Klein et al., 2009). In T2* sequences, these microbleeds were qualitatively and anatomically different from those found in conditions such as cerebral amyloid angiopathy or hypertensive vasculopathy. They were mostly homogeneous, 50%).

MYCOTIC ANEURYSMS When the infective emboli lodge in small distal cerebral arteries and in the vasa vasorum, they begin an intensive inflammation in the media and adventitia, diminishing the integrity of the vessel wall and weakening it, leading to the formation of a pseudoaneurysm. This process can be as short as a day, but may last more than 1 week under antibiotic treatment (Kannoth and Thomas, 2009).

Fig. 7.2. Multiple brain infarcts of different size in a patient with endocarditis.

Mycotic aneurysms are reported as a complication of infective endocarditis in 2–4% of patients (Peters et al., 2006). However, most mycotic aneurysms are clinically silent and the true prevalence of this complication may be underreported. These aneurysms are more commonly found in the anterior circulation, in the middle cerebral artery territory, mainly on its distal branches, in up to 70% of cases (Fig. 7.3). They have a fusiform and irregular morphology, no neck (Chapot et al., 2002; Kannoth et al., 2007), and are multiple in up to 25% of patients (Chun et al., 2001).

INFECTIVE ENDOCARDITIS

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Spondylodiscitis (vertebral osteomyelitis) can result from septic emboli of vertebral arteries, vertebral septic necrosis or immunocomplex deposition. It was reported in 2.6% of patients in a pooled analysis of six retrospective reviews (Cone et al., 2008). Presentation ranges from low back pain or myalgia to frank septic arthritis. The lumbar region is more frequently involved, followed by the thoracic and cervical regions. More than one vertebra is involved in 10% of cases. Vertebral osteomyelitis caused by streptococci or enterococci should raise the suspicion of an infectious endocarditis. In a retrospective analysis of 136 cases of endocarditis, 26% of patients with streptococcal or enterecoccocal spondylodiscitis had an infective endocarditis (Mulleman et al., 2006). Fig. 7.3. Intra-arterial cerebral angiography: mycotic aneurysm in distal branch of the middle cerebral artery. Notice also the “string of beads” pattern in the distal cortical arteries, typical of associated septic and autoimmune vasculitis.

In a retrospective study, mycotic aneurysms tended to present predominantly with focal signs or intracerebral hemorrhages, in contrast to berry aneurysms, which tended to present as subarachnoid hemorrhage (Kannoth et al., 2007). There are some case reports of mycotic aneurysms presenting as subdural hematomas. Patients with mycotic aneurysms are usually younger than patients with nonmycotic aneurysms and present more frequently with fever (Kannoth et al., 2007). Mycotic aneurysms may disappear, enlarge, or develop de novo during antibiotic therapy (Ahmadi et al., 1993). The mortality rate in patients with infective endocarditis and ruptured intracranial aneurysm is high, and varies between 40% and 80% (Wajnberg et al., 2008).

Central nervous system infection The dissemination of infected embolic material into cerebral or meningeal vessels may lead to meningitis or brain abscesses. Meningitis is reported as a complication of infective endocarditis in up to 3.5% of patients. The most common agent is Staphylococcus aureus. Typically an aseptic pattern in the cerebrospinal fluid with a slight mononuclear pleocytosis can be found. This aseptic pattern can be due to parameningeal inflammation, antibiotic pretreatment, or low cerebrospinal fluid bacterial burden. Brain abscesses are relatively rare, accounting for 1–4% of neurologic complications (Salgado, 1991). These abscesses are usually multiple with no, or limited, meningeal enhancement (Azuma et al., 2009). Pyogenic ventriculitis (Yavasoglu et al., 2005; Kiyan et al., 2007) and intramedullary abscess of the spinal cord (Ferna´ndezRuiz et al., 2009) were also reported.

Other neurologic manifestations ACUTE ENCEPHALOPATHY Acute encephalopathy is thought to result from multifocal brain ischemia related to multiple small emboli. Corral et al., (2007) found, in a retrospective review of infective endocarditis patients, that most of the cases of diffuse encephalopathy were associated with toxic or metabolic changes. A thorough search for metabolic or toxic causes in infective endocarditis patients with diffuse encephalopathy should be carried out before establishing that infective endocarditis is the direct cause of acute encephalopathy (Corral et al., 2007).

MONONEUROPATHY AND POLYNEUROPATHY Seven cases of embolic mononeuropathy in infective endocarditis were reported. The nerves involved were ulnar, peroneal, facial, median, sciatic, and maxillary (Tsai et al., 2008). The peripheral nerve lesion is thought to be caused by embolic occlusion of the vasa nervorum with ischemic changes in the nerve (Jones et al., 1969). Bacterial endocarditis has been associated with Guillain–Barre´ syndrome. These cases were due to infection with Coxiella burnetii, Streptococcus viridans and Staphylococcus aureus (Baravelli et al., 2007).

DIAGNOSIS The diagnosis of infective endocarditis requires a high suspicion rate and pattern recognition in an appropriate clinical context. It also requires the judicious integration of clinical symptoms and signs, including those of central nervous system (CNS) involvement, with the results of ancillary procedures, namely laboratory, echocardiography and neuroimaging studies.

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Laboratory Anemia, leukocytosis, high erythrocyte sedimentation rate (61%), high C-reactive protein level (62%), elevated rheumatoid factor (5%), and abnormal urinalysis, including hematuria (26%), are present in most, but not all, patients. However, these laboratory changes are not specific.

Electrocardiography Electrocardiography should be performed on admission and repeated during the course of the disease, as it may show new conduction defects, namely atrioventricular, fascicular, and bundle-branch block, which suggest perivalvular aortic invasion. These patients may need cardiac monitoring until they are stable.

Echocardiography Echocardiography has an important role in the demonstration of heart involvement in infective endocarditis. Echocardiography should be performed as early as possible. Three echocardiographic findings can be considered typical for the diagnosis of endocarditis: mobile, echodense masses attached to valvular leaflets (Fig. 7.4) or mural endocardium, or on implanted material; periannular abscesses or new dehiscence of a valvular prosthesis; new valvular regurgitation (Baddour et al., 2005). The sensitivity of transthoracic echocardiography (40–63%) is lower than that of transesophageal echocardiography (90–100%). On the other hand, transesophageal echocardiography is less often immediately available and may be difficult to perform in unstable patients.

Fig. 7.4. A 46-year-old woman with bitemporal headache of sudden onset and a right parietal and a left occipital hematoma on brain CT. Transesophageal echocardiogram: 3 mm mobile vegetation adherent to the aortic valve.

The European Society of Cardiology Guidelines recommend the use of transthoracic echocardiography as the first-line imaging modality in suspected infective endocarditis (Habib et al., 2009). Transesophageal echocardiography is recommended in patients with high clinical suspicion of infective endocarditis and normal transthoracic echocardiography. Echocardiography (one or both modalities) should be repeated within 7–10 days if the initial examination was negative but the clinical suspicion of infective endocarditis remains high. Echocardiography is also recommended for the follow-up under medical therapy, intraoperatively if surgery is performed, and following completion of therapy (Habib et al., 2009). North American guidelines prefer transesophageal echocardiography as the early modality, transthoracic echocardiography being used when transesophageal echocardiography is not immediately available (Baddour et al., 2005). With increasing demand for echocardiography to exclude endocarditis in low-risk patients, it is important to fine-tune the selection of suspected patients who most benefit from this diagnostic technique. In one study, the absence of: (1) a history of valve replacement or intravenous drug use; (2) signs of embolic phenomena; (3) central venous access; (4) positive blood cultures indicates a near zero possibility of endocarditis (Greaves et al., 2003).

Identification of the pathogenic agent The identification of the microorganism causing the endocarditis is crucial for planning a rational treatment. Before starting antibiotics, three sets of blood samples of 10 mL should be collected aseptically from a peripheral vein for both aerobic and anaerobic cultures (for anaerobic species such as Bacteroides and Clostridium). Cultures are positive in 85–90% of the patients. If cultures are negative after 5 days, cultures in chocolate agar plates may allow the identification of fastidious agents. Negative blood cultures are particularly likely in patients who were on, or started antibiotics before the diagnosis and in endocarditis caused by agents such as Coxiella burnetti, Brucella, Chlamydia, Legionella, Bartonella, Mycoplasma, Tropheryma whipplei, the HACEK group, and fungi. These organisms are particularly common in patients with prosthetic valves, intracardiac or intravenous devices, and in immunocompromised subjects. In cases with negative cultures, the agent may be identified using prolonged incubation, special culture techniques, serologic tests, and molecular biology techniques. Polymerase chain reaction (PCR) is a reliable and sensitive technique to identify fastidious and nonculturable agents. It must, however, be kept in mind that PCR has been validated in tissue from valve surgery and its application to whole blood samples may not be reliable. Positive PCR may persist for months after successful

INFECTIVE ENDOCARDITIS treatment of the infection. Accessible emboli (e.g., cutaneous) and resected valvular tissue should also be examined pathologically and cultured (Prendergast, 2004; Habib et al., 2009; Parize and Mainardi, 2011). In the International Collaboration on EndocarditisProspective Cohort Study (Murdoch et al., 2009), Staphylococcus aureus was the most frequent pathogen (31%), followed by Streptococcus viridans (17%), coagulasenegative staphylococcus (11%), enterococcus (10%), Streptococcus bovis (6%), other streptococcus (6%), HACEK group (2%), fungus (2%), and other agents in 4%. Cultures were negative in 10% of the patients.

Diagnostic criteria An attempt to define diagnostic criteria which could be simultaneously sensitive and specific for the diagnosis of infective endocarditis led to the establishment of the Duke criteria in 1994 (Durack et al., 1994). These criteria were originally developed to define cases of infective endocarditis for clinical trials and epidemiologic studies. The modified Duke criteria use clinical, microbiologic, echocardiography, and pathologic criteria to establish the diagnosis of infective endocarditis according to three categories: definitive, possible, and rejected (Table 7.1) (Li et al., 2000). The diagnosis of infective endocarditis, according to the criteria, relies on the presence of bacteremia and the demonstration of heart involvement. The specificity of the original Duke criteria is high (0.99), with a negative predictive value of 0.92. The sensitivity of the new criteria is lowered in culture-negative patients and in centers with limited access to echocardiography and polymerase chain reaction. Taking into account the heterogeneous presentation of this disease, both the European Society of Cardiology and the American Heart Association Guidelines suggest that although the Duke criteria are useful for the diagnosis of infective endocarditis and should be used as a primary diagnostic schema, they should not replace clinical judgment (Baddour et al., 2005; Habib et al., 2009).

Diagnosis of the neurologic complications In the presence of neurologic symptoms, early brain imaging with computed tomography (CT) can identify hemorrhagic strokes, early ischemic changes, and established infarcts, and rounded annular, single or multiple hypodense lesions, with variable, asymmetric contrast enhancement suggestive of brain abscess (Fig. 7.5). Magnetic resonance imaging (MRI) is more sensitive than CT, for the identification of small and asymptomatic emboli, microbleeds, for the early detection of acute infarcts (using DWI sequences), and for the diagnosis of brain abscess, cerebritis, and other intracranial infections. Characteristic are bull’s-eye-like lesions, which are

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hyperintense lesions with a central hypointense area on T2 or T2* sequences, representing inflammatory areas surrounding bleeding/aneurysm (Bertonini et al., 1989). MRI can also show reversible T2 prolongation and restricted diffusion in the corpus callosum (Takanashi et al., 2006). In a recent single center study of 130 patients, MRI performed within 7 days after admission identified cerebral lesions in 82% of patients with endocarditis, including many without neurologic manifestations. MRI findings influenced management in 28%, often leading to modifications of the therapeutic plans (18%), including surgical plan modification (14%) (Duval et al., 2010). Lumbar puncture is often performed in the diagnostic work-up of patients with fever and neurologic symptoms, before the diagnosis of endocarditis is established. After endocarditis is identified, lumbar puncture is recommended only in patients with suspected meningitis, or if headache and signs of meningeal irritation persist after fever and bacteremia remit with antibiotics (Salgado et al., 1989). Cerebrospinal blood cultures are positive in only 15–25% of the patients (Sila, 2010). Intra-arterial digital angiography remains the gold standard for the diagnosis of mycotic aneurysm (Fig. 7.3). CT and MR angiography are being increasingly used to screen for mycotic aneurysms, to perform noninvasive follow-up, and to access cure and recurrence of mycotic aneurysms after antibiotic, endovascular, or surgical treatment. At present, CT and MR angiography should be considered screening techniques. They have a comparable sensitivity and specificity (90–95%), but they are much less accurate in the detection of aneurysms smaller than 5 mm (Huston et al., 1994; White et al., 2001). CT angiography can be performed more rapidly than MR angiography, but it has the risk of a substantial volume load, which may produce acute heart failure. Both the American (Baddour et al., 2005) and the European guidelines (Habib et al., 2009) recommend MR or CT angiography to identify and monitor mycotic aneurysms. Intra-arterial angiography is reserved for cases where the suspicion of mycotic aneurysm remains, despite negative MR or CT angiography. Transcranial Doppler can be a promising tool for the prediction of the risk of neurologic complications in patients with infective endocarditis. In one study, neurologic complications occurred in 83% of patients with positive cerebral microembolic signs and in 33% of patients lacking such microembolic signs (Lepur and Barsic, 2009).

PROGNOSIS In-hospital mortality of patients with infective endocarditis ranges between 10% and 25% (Mansur et al., 1996;

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Table 7.1 Modified Duke criteria for the diagnosis of infective endocarditis Definition of terms used in the proposed modified Duke criteria for the diagnosis of infective endocarditis (IE) Definite infective endocarditis Pathologic criteria (1) Microorganisms demonstrated by culture or histologic examination of vegetation, vegetation that has embolized, or an intracardiac abscess specimen; or (2) Pathologic lesions; vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis Clinical criteria (1) 2 major criteria; or (2) 1 major criterion and 3 minor criteria; or (3) 5 minor criteria Possible infective endocarditis (1) 1 major criterion and 1 minor criterion; or (2) 3 minor criteria Rejected (1) Firm alternate diagnosis explaining evidence of infective endocarditis; or (2) Resolution of infective endocarditis syndrome with antibiotic therapy for < 4 days; or (3) No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for 4 separate cultures of blood (with first and last sample drawn at least 1 h apart) Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer 11:800 ● Evidence of endocardial involvement ● Echocardiogram positive for IE (TEE recommended in patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE (paravalvular abscess); TTE as first test in other patients), defined as follows: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or abscess; or new partial dehiscence of prosthetic valve ● New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor criteria

● Predisposition, predisposing heart condition or injection drug use ● Fever, temperature > 37 C ● Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival

hemorrhages, and Janeway’s lesions ● Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factora ● Microbiologic evidence: positive blood culture but does not meet a major criterion as noted above or serologic evidence of active

infection with organism consistent with IE TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. a Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis (Li et al., 2000).

Netzer et al., 2002; Wallace et al., 2002; Hasbun et al., 2003; Chu et al., 2004; Delahaye et al., 2007; San Roman et al., 2007; Thuny et al., 2005; Murdoch et al., 2009). Acute prognosis is influenced by: (1) patient characteristics: older age, prosthetic valve, insulin-dependent diabetes, comorbidities; (2) cardiac complications: heart failure, periannular complications;

(3) noncardiac complications: renal failure, septic shock; (4) stroke; (5) microorganisms: Staphylococcus aureus, fungi, Gram-negative bacilli; (6) echocardiographic features: perianullar complications, severe left-sided regurgitation, low left ventricular ejection fraction, pulmonary hypertension, large vegetations, severe prosthetic dysfunction, premature mitral valve closure, or

INFECTIVE ENDOCARDITIS

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Fig. 7.5. A 74-year-old hypertensive woman found unconscious at home. Coma and tetraparesis. Aortic valve vegetation on transesophageal echocardiography. Brain CT: left temporo-occipito-parietal hematoma (left) and ischemic infarct in the distal territory of the right anterior cerebral artery (right).

other signs of elevated diastolic pressure (Habib et al., 2009). Patients with heart failure, periannular complications, and Staphylococcus aureus infections have the highest risk of death, which reaches 79% when all these three risk factors are present simultaneously (San Roman et al., 2007). In the International Collaboration on Endocarditis-Prospective Cohort Study of 2781 patients, the predictors of in-hospital mortality (17.7%) were prosthetic valve involvement, increasing age, pulmonary edema, Staphylococcus aureus infection, coagulasenegative staphylococcal infection, mitral valve vegetation, and paravalvular complications (Murdoch et al., 2009).

PREVENTION Until recently, there was consensus that infective endocarditis was preventable by using antibiotics in patients with cardiac diseases at risk of endocarditis during procedures associated with transient bacteraemia, such as dental, gastrointestinal, urogenital, and obstetrics procedures. This dominant view has been challenged by the lack of randomized controlled trials demonstrating the efficacy of antibiotic treatment (Oliver et al., 2008) and by the observation that comparable transient bacteremia also occurs during everyday life, e.g., during tooth brushing. Currently no antibiotic prophylaxis is recommended by the National Institute for Health and Clinical Excellence Guidelines (National Institute for Health and Clinical Excellence, Short Clinical Guidelines Technical Team, 2008). The ACC/AHA (American College of Cardiology/American Heart Association) downgraded from class I to class IIa (reasonable practice) their recommendation to use prophylactic antibiotics in high-risk patients undergoing dental procedures (Nishimura et al., 2008). The guidelines of the European Society of

Cardiology (Habib et al., 2009) only recommend antibiotic prophylaxis for dental procedures and for patients at highest risk of infective endocarditis (prosthetic valve, previous endocarditis, and some patients with congenital heart disease). Maintaining good oral hygiene and avoiding piercing and tattoos is advised.

TREATMENT The treatment of endocarditis includes general measures, antimicrobial therapy and treatment of complications, namely systemic, cardiac, and neurologic. The essential aspect of the treatment of infective endocarditis is the eradication of the systemic and cardiac infection by the application of appropriate antimicrobial therapy and, if necessary, by cardiac surgery, which removes infected tissue and material, and drains abscesses.

Antimicrobial therapy A full presentation of the antimicrobial treatments more appropriate for each specific agent is beyond the scope of this chapter. The interested reader is referred to the American Heart Association (Baddour et al., 2005) and the European Society of Cardiology (Habib et al., 2009) Guidelines. Antimicrobial treatment should last longer (minimum 6 weeks) for prosthetic than for native valve endocarditis (2–6 weeks). Otherwise, the antimicrobial regimens are rather similar. Table 7.2 summarizes the antimicrobial treatment of infective endocarditis following the 2009 European Society of Cardiology Guidelines. The reader is advised to check for periodic updates of these treatment regimens. The proposed antibiotic regimen for initial empiric treatment of infective endocarditis, while waiting for

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Table 7.2 Summary of antimicrobial regimens for infective endocarditis, following the European Society of Cardiology guidelines (Habib et al., 2009) Drug Oral and D group streptococci, sensitive to penicillin Penicillin G, or Amoxicillin, or Ceftriaxone Oral and D group streptococci, relatively resistant to penicillin Penicillin G, or Amoxicillin, plus Gentamicin Staphyloccocci, native valves Flucloxacillin, plus Gentamicin Staphyloccocci, native valves, methicillin-resistant Vancomycin, plus Gentamicin Staphyloccocci, prosthetic valves Flucloxacillin, plus Gentamicin, plus Rifampin Staphyloccocci, prosthetic valves, methicillin-resistant Vancomycin, plus Gentamicin, plus Rifampin Enteroccocci Amoxicillin, plus Gentamicin Gram-negative bacteria, HACEK species Ceftriaxone Brucella Doxycycline, plus Cotrimoxazole, plus Rifampin Coxiella burnetii Doxycycline, plus Ofloxacin Bartonella Ceftriaxone, plus Gentamicin Legionella Erythromycin, plus Rifampin

Dosage

Duration (weeks)

12–18 million U/day, IV, every 4 hours 100–200 mg/kg/day, IV, every 4 or 6 hours 2 g/day IV or IM, 1 dose

4 4 4

24 million U/day, IV, every 4 hours 200 mg/kg/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 1 dose

4 4 2

12 g/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 2 or 3 doses

4–6 3–5 days

30 mg/kg/day, IV, every 12 hours 3 mg/kg/day, IV or IM, 2 or 3 doses

4–6 3–5 days

12 g/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 2 or 3 doses 1200 mg/day, IV or orally, 2 doses

6 2 6

30 mg/kg/day, IV, every 12 hours 3 mg/kg/day, IV or IM, 2 or 3 doses 1200 mg/day, IV or orally, 2 doses

6 2 6

200 mg/kg/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 2 or 3 doses

4–6 4–6

2 g/day IV or IM, 1 dose

4

200 mg, orally, every 24 hours 960 mg, orally, every 12 hours 300–600 mg, orally, 2 doses

 12  12  12

200 mg, orally, every 24 hours 400 mg, oral, every 24 hours

 18 months  18 months

2 g/day IV or IM, 1 dose 3 mg/kg/day, IV or IM, 2 or 3 doses

6 3

3 g/24 hours, IV, followed by orally 300–1200 mg, orally, every 24 hours

2þ4 6

IV, intravenous; IM, intramuscular; HACEK, Haemophilus species (Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species.

the identification of the agent or when the pathogen cannot be identified, in patients with native and prosthetic valves, more than 12 months after surgery, consists of amoxicillin þ clavulanate, 12 g/day, intravenously, every 6 hours, plus gentamicin, 3 mg/kg/day, intravenously or intramuscularly, in 2 or 3 doses, for 4–6 weeks.

Role of cardiac surgery In most tertiary centers, half of the patients with infective endocarditis undergo cardiac surgery for the treatment of complications (Tornos et al., 2005). In recent years there has been a trend toward a more aggressive attitude, i.e., toward early surgery in the management

INFECTIVE ENDOCARDITIS of heart failure, abscess, and uncontrolled infection in the context of infective endocarditis (Habib, 2009; Shang et al., 2009). However, the subject is still a matter of intense debate, in particular the indication for cardiac surgery for the prevention of embolism and the timing of surgery after cerebral embolism (Habib, 2009; Prendergast and Tornos, 2010; Thuny and Habib, 2010). The 2009 European Society of Cardiology Guidelines (Habib et al., 2009) and the American Heart Association Guidelines (Baddour et al., 2005) provide recommendations for surgery and their timing. Briefly, in the 2009 European Society of Cardiology Guidelines, surgery should be performed as an emergency when in aortic or mitral endocarditis there is acute heart failure with severe acute regurgitation or valve obstruction, or with fistula in a cardiac chamber or pericardium, manifesting as refractory pulmonary edema or cardiogenic shock, due to aortic or mitral endocarditis. Urgent indications include: (1) persisting heart failure, due to severe acute regurgitation or valve obstruction; (2) uncontrolled infection, owing to local complications such as abscess, fistula, false aneurysm or enlarging vegetation, to persistent (>7 days) fever or positive cultures, or to infection caused by fungi or multiresistant organisms; (3) prevention of embolism. Preventing systemic embolization, which goes mainly to the brain and spleen, is difficult, because most of the emboli occur before admission or are the cause of hospitalization (Di Salvo et al., 2001). The risk of embolization is highest in the first 2 weeks of antibiotic treatment. Size and mobility of vegetations are the most important predictors of a new embolic event. Variables associated with an increased risk of embolism are listed in Table 7.3 (Rohmann et al., 1991; Sanfilippo et al., 1991; Rohmann et al., 1992; Erbel et al., 1995; Tischler and Vaitkus, 1997; Cabell et al., 2001; Di Salvo et al., 2001; Pergola et al., 2001; Vilacosta et al., 2002; Durante Mangoni et al., 2003; Mugge et al., 2003; Thuny et al., 2005; Fabri et al., 2006; Dickerman et al., 2007; Hsu and Lin, 2007; Tleyjeh et al., 2007). For the prevention of embolism, surgery is recommended on an urgent basis in the following scenarios: (1) aortic or mitral infective endocarditis with large (>10 mm) vegetations (i) following one or more embolic episodes despite appropriate antibiotic therapy, (ii) and with other predictors of complicated course (heart failure, persistent infection, abscess); (2) isolated large (>15 mm) vegetation. The American guidelines consider as possible indications for surgery: anterior mitral leaflet vegetation, in particular if larger than 10 mm (Fig. 7.6), persisting vegetation after systemic embolization, and increase in vegetation size, despite appropriate antimicrobial therapy. However, the authors of the guidelines stress that decision making regarding the role of surgical

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Table 7.3 Risk factors for embolism in infective endocarditis Initial phase: first days up to 2 weeks Older age Previous embolism Vegetation Location: mitral valve, anterior leaflet Mobile Size: large (>10 mm) and very large (>15 mm) Increasing size despite antibiotic treatment Microorganism Staphylococci Streptococcus bovis Candida Biologic markers C-reactive protein

Fig. 7.6. A 48-year-old man with fever, acute onset of leftsided weakness and a right middle cerebral artery infarct on CT. Transesophageal echocardiogram: large (15  9 mm), mobile vegetation in the anterior leaflet of the mitral valve. The patient underwent heart surgery.

intervention is difficult and complex and must be individualized. The benefit of surgery appears to be greatest in the first week of antibiotic therapy, when the risk of embolism peaks (Habib et al., 2009). A recent small (76 patients) randomized controlled trial compared early surgery versus conventional treatment in patients with left-sided infective endocarditis, severe valve disease, and large vegetations, and concluded that early surgery significantly reduced the risk of death and embolic events (Kang et al., 2012).

Treatment of endocarditis associated with cardiovascular implantable electronic devices A comprehensive presentation of endocarditis associated with cardiovascular implantable electronic devices is

86 J.M. FERRO AND A.C. FONSECA beyond the scope of this chapter. The interested reader is demonstrated a benefit of intravenous aspirin in experreferred to the recent American Heart Association imental endocarditis (Kupferwasser et al., 1999, 2003). scientific statement (Baddour et al., 2010) on this topic. Several observational studies indicated that patients on Briefly, if there is valve vegetation, treatment should folchronic antiplatelet treatment at the time of endocardilow the current recommendations for the treatment of tis diagnosis had reduced complications, valve replaceendocarditis. If there is lead vegetation the patients should ment surgery, and mortality (Eisen et al., 2009). be treated with antibiotics for 2–6 weeks, depending on Chronic antiplatelet treatment decreased the risk of the presence of complications (4–6 weeks) and on the embolism in one study (Anavekar et al., 2007), but agent (4 weeks if the agent is Staphylococcus aureus). not in others (Chan et al., 2008; Pepin et al., 2009) Complete device and lead removal is recommended for and increased the risk of bleeding (Chan et al., 2008). all patients with definite endocarditis associated with carUnfortunately, a randomized clinical trail comparing diovascular implantable electronic devices. aspirin 325 mg with placebo in 115 endocarditis patients failed to show any benefit of aspirin in the prevention of cerebral embolism: 28% of the patients on aspirin Treatment of the neurologic complications suffered an event comparing with 20% on placebo Neurologic complications should be managed according (OR 1.62; 95% CI 0.68–3.86). There was a trend toward to their respective treatment guidelines or consensus more bleeding in the aspirin group (OR 1.92; 95% CI 0.76–4.86). Aspirin had no effect on vegetation size. (e.g., antibiotic and neurosurgery for brain abscess). In this trial, aspirin was initiated 34 days after symptom However, such guidelines were in general written without considering the context of particular conditions, onset (Chan et al., 2003). Based on the available evisuch as endocarditis. Notoriously, some aspects of dence, routine antiplatelet therapy is not indicated in management of cerebrovascular complications are cominfective endocarditis (Baddour et al., 2005; Salem plex and controversial and deserve some discussion. et al., 2008; Habib et al., 2009). Nevertheless the European guidelines recommend that, if there is a previous indication and the patient is on antiplatelet therapy, Thrombolysis in acute stroke associated interruption of this therapy is only recommended in with endocarditis the presence of major bleeding (Habib et al., 2009). Endocarditis is listed among the contraindications for Concerning anticoagulants, the evidence is based only treatment with intravenous rtPA in acute ischemic stroke on observational studies. There is no indication to (European Agency for the Evaluation of Medicinal start anticoagulants after the diagnosis of infective Products, 2002). In practice, the majority of patients with endocarditis, even if a cardioembolic ischemic stroke the diagnosis of endocarditis and a hyperacute ischemic has occurred. In fact there is no support for the use of stroke will have other contraindications for rtPA. A few anticoagulants in this indication since they do not cases have been reported where intravenous rtPA was prevent embolization from the vegetations (Paschalis given within 3 hours of stroke onset in patients who were et al., 1990) and they increase the risk of intracerebral found later to harbor cardiac vegetation and were then bleeding. Bleeding can be due to hemorrhagic diagnosed with endocarditis. Outcomes were contradictransformation of ischemic infarcts, rupture of vessels tory. Two patients, including a 12-year-old child, were with walls damaged by septic or immune-mediated successfully treated without hemorrhagic complications vasculitis or rupture of a mycotic aneurysm. Anticoagu(Junna et al., 2007; Tan et al., 2009). In contrast, a case lant therapy is associated with increased mortality in series of three patients treated with rtPA reported that particular in Staphyloccocus aureus endocarditis all developed multifocal intracranial hemorrhages. (Roder et al., 1997; Tornos et al., 1999; Heiro et al., None had mycotic aneurysms (Bhuva et al., 2010). This 2000; Baddour et al., 2005), although this was not conlimited evidence suggests that thrombolysis in ischemic firmed in a recent series (Rasmussen et al., 2009). On stroke associated with infective endocarditis carries a the other hand, patients with mechanical valves will have high risk of intracranial bleeding. We found no cases the highest risk of cerebral embolism if anticoagulation reporting on the use of intra-arterial thrombolysis in this is stopped. indication. Current recommendations concerning the use of anticoagulation in infective endocarditis are therefore based on low quality and controversial information. Antithrombotic treatment The European Society of Cardiology Guidelines indicate A mechanistic approach would suggest that antiplatelet that: (1) there is no indication to start antithrombotic drugs and anticoagulants could decrease the risk of drugs; (2) in previously anticoagulated patients: (i) in embolism in endocarditis. An animal study also ischemic stroke without intracerebral hemorrhage, oral

INFECTIVE ENDOCARDITIS 87 anticoagulants should be replaced by unfractionated The timing for cardiac surgery after a central neuroheparin for 2 weeks, with close monitoring of activated logic complication is controversial, and the evidence suppartial thromboplastin time (APTT); (ii) in intracranial porting the recommendations is of limited quality and hemorrhage, all anticoagulation should be interrupted; based on observational studies (Eishi et al., 1995; (iii) in intracranial hemorrhage and a mechanical valve, Gillinov et al., 1996; Jault et al., 1997; Piper et al., 2001; unfractionated heparin, with close monitoring of APTT, Angswurm et al., 2004; Ruttman et al., 2006). When should be reinitiated as soon as possible; (iv) in the needed, cardiac surgery can be performed without delay absence of stroke, in Staphyloccocus aureus endoafter a silent cerebral embolism or TIA lesion. Conversely, carditis oral anticoagulants may be replaced by unfracsurgery must be postponed for at least 1 month following tionated heparin for 2 weeks, with close monitoring intracranial hemorrhage. After ischemic stroke, unless the of APTT (Habib et al., 2009). The American College clinical deficit is very severe, surgery should not be delayed of Chest Physicians Guidelines (Salem et al., 2008) (Habib et al., 2009). If a patient harbors a ruptured mycotic are more conservative regarding the indication for aneurysm, the aneurysm should be treated before cardiac continuing antithrombotic drugs in previously surgery. If unruptured, the aneurysm should not preclude anticoagulated patients. They state that if a patient is or delay cardiac surgery (Kannoth and Thomas, 2009). on vitamin K antagonists at the time of the diagnosis of endocarditis, they should be discontinued at the time Treatment of mycotic aneurysms of the initial presentation and unfractionated heparin substituted, until it is clear that invasive procedures will Unruptured mycotic aneurysms up to 10 mm may be not be required and the patient has stabilized without cured and disappear after antibiotic treatment signs of CNS involvement. It is suggested that the vita(Ahmadi et al., 1993). The risk of rupture and death is min K antagonist be reinstated only when the patient is lower in unruptured (30%) than in ruptured aneurysm deemed stable without contraindications or neurologic (80%) (Bohmfalk et al., 1978; Wilson et al., 1982). In one study (Bingham, 1977), aneurysms resolved in complications. 52% of patients, decreased in size in 29%, but enlarged in 19%. In 10% a new aneurysm was found in follow-up angiography. From the analysis of published case series, Cardiac surgery after a neurologic it is evident that the mortality in more recent series is low complication in both medically and surgical/endovascular treated Patients with infective endocarditis who suffer a neuropatients (Peters et al., 2006). The majority of patients logic event may still need cardiac surgery (Thuny et al., with unruptured aneurysms never required surgery or 2007). In fact, the neurologic complication itself can be endovascular treatment, while the majority of patients an indication for surgery (e.g., recurrent embolism with ruptured mycotic aneurysms needed neurosurgery despite appropriate antimicrobial treatment). Neuroor endovascular treatment (Corr et al., 1995). Contrary to logic complications are not a contraindication for the noninfectious aneurysms, it is difficult to predict which surgical treatment of heart failure, paravalvular infecmycotic aneurysms have the highest risk of rupture. The tious complications, uncontrolled systemic infection, morphologic features, size, and location of mycotic and persistent high-risk embolic vegetation (see above), aneurysms are poor predictors of rupture. The recomunless an intracranial hemorrhage is shown on brain mendation for the management of unruptured mycotic imaging or the CNS damage is clinically very severe aneurysms is antibiotic treatment and noninvasive (e.g., coma, devastating neurologic deficit). follow-up by CT or MR angiography. It is not known Cardiac surgery requiring cardiopulmonary bypass how frequently the imaging follow-up should be percan cause or aggravate cerebral damage by a variety of formed (Kannoth and Thomas, 2009). Our own “edumechanisms, including macro- and microembolization cated guess” is to do the angiographic follow-up on a and hypoperfusion. Cardiopulmonary bypass requires weekly basis, if the neurologic condition is stable. If heparinization, which can induce de novo cerebral bleedthe aneurysm is large (>10 mm), enlarges, does not ing or hemorrhagic transformation of a pre-existent resolve, or ruptures, surgical or endovascular treatment ischemic infarct or infectious lesion. Cardiopulmonary should be performed, as for ruptured aneurysms bypass also induces a systemic inflammatory response, (Baddour et al., 2005; Peters et al., 2006; Habib et al., which may aggravate cerebral edema (Sila, 2010). The 2009; Kannoth and Thomas, 2009; Ducruet et al., 2010). operative risk is increased in patients with neurologic For a ruptured aneurysm, endovascular or neurosurcomplications, except in patients with silent lesions or gical therapy is indicated. Current consensus and recomtransient ischemic attacks (TIAs), whose surgical risk mendations are again based only on case series and case is low (Thuny et al., 2007). control studies. Neurosurgical intervention is emergent

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if there is intracerebral bleeding causing mass effect or hydrocephalus. Endovascular occlusion of the aneurysm with cyanocrylate or coils is an effective and safe alternative to surgery (Chapot et al., 2002; Dhomne et al., 2008). Management algorithms based on expert opinion suggest that neurosurgery (often using microvascular techniques) should be the first option if there is mass effect from the aneurysm or the surrounding hematoma, for aneurysms located in arteries supplying eloquent neural territories, and in distal aneurysms, if they are located in an accessible location. The remaining mycotic aneurysms can be treated by endovascular intervention, if such expertise is available. Any of the treatment modalities can be used as a rescue alternative if the other fails to exclude the aneurysm (Baddour et al., 2005; Peters et al., 2006; Habib et al., 2009; Kannoth and Thomas, 2009; Ducruet et al., 2010). Although new aneurysms can develop after appropriate antimicrobial treatment, there were no instances of subarachnoid hemorrhage among 121 patients discharged after a full course of antibiotics (Salgado et al., 1987).

Treatment of intracranial infections Antimicrobial treatment of meningitis and cerebritis should be that of the endocarditis, depending on the type of agent identified. For brain abscess, ceftriaxone plus metronidazole is the usual empiric combination. Neurosurgery is rarely indicated because brain abscesses are usually small and multiple (Salgado, 1991) and can be cured by antibiotic treatment. Neurosurgery can be indicated in enlarging abscesses and in abscesses associated with a deteriorating neurologic condition, despite antimicrobial treatment.

CONCLUSIONS Despite important improvements in the diagnostic technologies for heart and brain imaging, infective endocarditis remains a formidable diagnostic and therapeutic challenge. Its contemporary management requires the cooperation of cardiologists, cardiac surgeons, neurologists, neurosurgeons, neuroradiologists, intensivists, and specialists in infectious diseases. Most of the current recommendation and guidelines are based on low-quality evidence. The lack of robust information in such a serious and potentially lethal disease stresses the need for large, multidisciplinary registries and randomized controlled trials.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 8

Neurologic complications of myocardial infarction MONEERA N. HAQUE AND ROBERT S. DIETER* Division of Cardiology, Department of Medicine, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA

HISTORY Strokes are a devastating neurologic complication of acute myocardial infarction (Woods and Barnes, 1941; Vaitkus et al., 1992). Acute myocardial infarction (AMI) is characterized by the development of myocardial ischemia leading to myocardial injury or necrosis (Alpert et al., 2000; Thygesen et al., 2007). The term acute coronary syndrome (ACS) applies to patients in whom there is concern of acute myocardial ischemia. Three types of ACS are recognized: ST elevation MI (STEMI), non-ST elevation MI (NSTEMI), and unstable angina (UA). The first two are characterized by a typical rise and/or fall in biomarkers of myocyte injury (Anderson et al., 2007). Survivors of a myocardial infarction are at substantial risk for further complicating events, including the occurrence of mural thrombi contributing to embolic strokes. In 1856, Rudolf Virchow proposed three interrelated factors contributing to thrombosis: (1) injury of the blood vessel wall, (2) stasis of blood flow, and (3) generalized alterations in blood coagulation (Virchow, 1856). Furthermore, he reported brain arteries occluded by thrombi, seemingly originating in the heart; he termed this entity “embolism.” Gordinier suggested that sudden arterial plugging of the vessels of the brain, viscera, or extremities indicated involvement of a branch of the left coronary artery, whereas signs of pulmonary infarct suggested involvement of the right coronary artery or its branches (Gordinier, 1924). Blumer, recognizing the importance of embolism as a complication of cardiac infarction, stated that mural thrombi were frequent following cardiac infarction, and that remains may detach, generating embolic phenomena (Blumer, 1937).

EPIDEMIOLOGY The 2010 Heart Disease and Stroke Statistics update of the American Heart Association estimated that 17.6

million persons in the US have coronary heart disease (CHD), including 8.5 million with AMI (Lloyd-Jones et al., 2009). CHD is a major cause of death and disability in developed countries. Although CHD mortality rates have declined over the past four decades in the US, CHD accounts for about one-third of all deaths in individuals over age 35. Prevalence increases with age for both women and men (Rosamond et al., 2008). Atherosclerotic cardiovascular disease is a diffuse process. Stroke rate among patients with ACS can be extrapolated from the Framingham study. For those patients who had an initial MI, about 10% had previous intermittent claudication, and 5–8% had a stroke (Cupples et al., 1993). Among the cohort of 18 000 patients with non-ST elevation acute coronary syndrome enrolled in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) program, stroke was an infrequent but severe event, associated with considerable mortality. Overall, 238 patients (1.3%) had a stroke over a 6 month follow-up. A Cox multivariate regression analysis identified CABG surgery as the most important predictor of stroke (HR, 4.6), followed by history of stroke (HR, 2.3) (Cronin et al., 2001). Predicting stroke risk factors among hypertensive, clinically stable coronary artery disease patients was evaluated in the International VErapamil SR-trandolapril STudy (INVEST). African American ethnicity, US residency, circumstances associated with increased vascular disease severity, and arrhythmia predicted higher stroke risk; achieving a BP < 140/90 mmHg forecast a reduced stroke risk (Coca et al., 2008). Stroke remains the principal cause of neurologic death and a leading cause of disability among adults in the US. Ischemic stroke accounts for 85% of all strokes. Ischemic stroke subtypes include: (1) largeartery atherosclerosis, (2) cardioembolism, (3) smallvessel occlusion, (4) stroke of other determined

*Correspondence to: Robert S. Dieter, M.D., R.V.T., Associate Professor, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-4466, Fax: þ1-708-327-2770, E-mail: [email protected]

94 M.N. HAQUE AND R.S. DIETER etiology, and (5) stroke of undetermined etiology failure (HF) and/or left ventricular systolic dysfunction (Adams et al., 1993). (LVSD) following myocardial infarction (MI). Left venRisk of ischemic stroke among patients presenting tricular systolic dysfunction, diastolic blood pressure with AMI has declined from 2.4–3.5% to about >90 mmHg, prior stroke, and atrial fibrillation were 0.6–1.8%, probably reflecting a more aggressive the most influential predictors of stroke. Left ventricular approach to coronary revascularization as well as adminejection fraction and gender did not predict stroke risk in istration of thrombolytic or anticoagulant therapy in the this cohort (Sampson et al., 2007). In the Worcester acute phase (Komrad et al., 1984; Mahaffey et al., 1998; Heart Attack Study, a population-based investigation, Hurlen et al., 2002). However, despite the rare occuradvanced age, female gender, previous myocardial rence of ischemic strokes following AMI, their outcome infarction, and occurrence of atrial fibrillation during is often associated with high mortality (17%), and disabilhospitalization were associated with higher stroke risk. ity (80%) (Mahaffey et al., 1998). The association of Conversely, having a percutaneous coronary intervenischemic strokes and AMI is most likely multifactorial, tion during hospitalization was associated with a lower including older age, prior stroke, diabetes mellitus, risk of stroke (Saczynski et al., 2008). hypertension, and the presence of large akinetic segAmong the elderly, a large percentage of myocardial ments of myocardium with or without left ventricular infarctions remain unidentified and are often only thrombus (Vaitkus and Barnathan, 1993; Loh et al., recognized by electrocardiography. The relationship 1997; Hurlen et al., 2002). between unidentified “silent” myocardial infarction and stroke has been observed only among men. Most were cortical ischemic strokes. Thus, screening RISK FACTORS elderly patients for previously unidentified myocardial Risk factors for carotid artery atherosclerosis are similar infarction with electrocardiography may enhance the to those with coronary atherosclerosis. Patients with clinrecognition of a higher risk for stroke cohort (Ikram ically evident or silent myocardial ischemia frequently et al., 2006). have concurrent cerebrovascular disease. Conversely, Stroke is rare following non-ST-segment elevation many patients with cerebrovascular disease have differACS. Data from six trials of NSTE-ACS patients found ent stages of coronary artery disease. Moreover, cardiac older age, prior stroke, and elevated heart rate as the disturbances are common following strokes (Hachinski, strongest predictors of stroke within 30 days of the cor1993; Korpelainen et al., 1997). Among 111 023 Medicare onary event. Predictors were similar for nonhemorrhagic patients discharged with a principal diagnosis of AMI and hemorrhagic strokes. Interestingly, cigarette smokduring an 8-month period between 1994 and 1995, ing, previous myocardial infarction, diabetes, and hyper2.5% had an ischemic stroke within 6 months of hospital tension were not found to be independent predictors of discharge. Independent predictors of ischemic stroke stroke (Westerhout et al., 2006). included age  75 years, African American ethnicity, Delayed stroke following myocardial infarction is no aspirin at discharge, frailty, prior stroke, atrial fibrilunusual. A Swedish study of 3300 patients with a mean lation, diabetes, hypertension, and history of peripheral follow-up of 5 years (range 1.7–6.7 years) found that vascular disease (Lichtman et al., 2002). Among 15 904 approximately 6% (194) patients had a subsequent stroke stabilized patients with acute coronary syndrome, 113 (4.2% nonhemorrhagic, 0.5% hemorrhagic, and 1.3% (0.71%) had a stroke over a median follow-up of 90 days uncertain type). Risk factors included advanced age, his(Kassem-Moussa et al., 2004). Most strokes were ischetory of diabetes mellitus, prior stroke, arterial hypertenmic and occurred within 30 days of presentation. sion, and cigarette smoking (Herlitz et al., 2005). Patients with strokes were older and had more frequent An additional study evaluated the impact of stroke on comorbidities including arterial hypertension, diabetes, survival and the rate of stroke after myocardial infarcperipheral vascular disease, and atrial fibrillation. tion over time. A total of 2160 patients with myocardial Among the subset of stroke patients that had coronary infarction hospitalized between 1979 and 1998 were folrevascularization (percutaneous coronary intervention lowed for a median of 5.6 years (range 0–22.2 years). or coronary artery bypass grafting), strokes occurred The observed stroke rate was 22.6 per 1000 personprimarily following the procedure. Multivariate analyses months during the first 30 days following myocardial showed advanced age, heart failure, prior stroke, left infarction, representing a 44-fold increased risk for bundle branch block, and systolic blood pressure as prestroke. The risk for stroke remained threefold higher dictive of stroke occurrence. than expected during the first 3 years after myocardial The VALsartan In Acute myocardial iNfarcTion infarction. Diabetes, older age, and previous stroke mag(VALIANT) trial compared outcomes with captopril, nified the risk for stroke and did not dissipate over the valsartan, or both agents, among patients with heart study timeline. Strokes were also linked to a robust

NEUROLOGIC COMPLICATIONS OF MYOCARDIAL INFARCTION 95 increase in the risk of death following myocardial infarcof stroke due to thrombolytic therapy in selected patients tion (Witt et al., 2005). with acute myocardial infarction is relatively low comPatients at increased risk of embolic stroke, such as pared to the favorable risk–benefit assessment of this those with large anterior wall myocardial infarctions, therapy. The frequency of early cerebrovascular events may receive the greatest benefit from thrombolytic theramong unselected patients admitted to coronary care apy. However, the risk of intracerebral hemorrhage units in the prethrombolytic versus thrombolytic eras increases with advanced age, history of hypertension, continues to be alike in the overall profile, although morprior cerebrovascular disease or prior head trauma, high tality from acute myocardial infarction has decreased dose of thrombolytic therapy relative to bodyweight, considerably (Tanne et al., 1997). low bodyweight, female gender, African American In patients with ACS without persistent ST-segment ethnicity, high blood pressure upon presentation, and elevation, the occurrence of stroke is rather small. prolonged aPTT with heparin administration LifeA study involving 18 000 patients examining stroke occurthreatening ventricular arrhythmias and hypofibrinogenrence in relation to cardiac procedures among patients emia may also play a role in some cases (Sloan et al., with non-ST ACS, found those who had early coronary 1995). The higher than anticipated rate of intracranial artery bypass grafting surgery, but not early percutanehemorrhage among patients treated with heparin or hiruous coronary intervention, had a substantially increased din in conjunction with thrombolysis emphasizes the risk of stroke (Cronin et al., 2001). Dacey and colleagues risks associated with anticoagulation in combination studied the survival of 35 733 consecutive patients underwith thrombolysis. going isolated coronary artery bypass graft surgery Thrombolytic therapy decreases mortality following (Dacey et al., 2005). There were 147 931 person-years of acute myocardial infarction, but also has a small but follow-up and 5705 deaths. Survival for patients with noteworthy risk of severe bleeding complications, stroke at 1, 5, and 10 years was 83.0%, 58.7%, and including intracranial hemorrhage. Previous trials 26.9%, respectively. Patients who had strokes had more reported an overall incidence of stroke during hospitalcomorbidities. In patients undergoing coronary artery ization for acute myocardial infarction of 0.9–1.6%. bypass graft surgery, the independent predictors for Intracranial hemorrhage accounted for 0.2–0.9% of stroke, in order of risk, were: age older than 70 years, strokes, depending on the type and dose of thrombolytic poor preoperative neurologic status, and previous caragent used (ISIS-3 Collaborative Group, 1992; Maggioni diac surgery (Woods et al., 2004). The use of a stroke risk et al., 1992). Since recording and evaluation of strokes index to predict neurologic complications following corwere not standardized, and variable numbers of strokes onary revascularization on cardiopulmonary bypass was were not codified, the interpretation of these reports retrospectively among 6846 patients. A total of 217 must be approached cautiously. Moreover, in the thrompatients (3.2%), mean age of 65.9  11.7 years, had bolytic trials, high-risk patients (advanced age, prior hisadverse neurologic events following surgery. High-risk tory of stroke, or uncontrolled hypertension) were often variables included cardiac surgery, myocardial infarcexcluded, and as such, the reported rates may underestion, left ventricular ejection fraction < 30%, and timate the degree of this serious complication. Certainly, absence of sinus rhythm (Elahi et al., 2005). in clinical practice, more elderly patients with acute Cardiac catheterization-related stroke has been myocardial infarction have had adverse sequelae of reported in 0.03–0.3% of cases (Brown and Topol, intracranial hemorrhage (Gurwitz et al., 1998; Brass 1993; Lazar et al., 1995; Segal et al., 2001), and in et al., 2000). A registry of acute coronary syndromes 0.3–0.4% of percutaneous coronary interventions involving 111 Canadian hospitals evaluated 12 739 patients (PCI) (Fuchs et al., 2002; Dukkipati et al., 2004). The utiwho received fibrinolytic therapy for acute myocardial lization of guidewires and catheters may possibly cause infarction from 1998 to 2000. Of these, 146 patients fragmentation of atherosclerotic plaques with conse(1.15%) had strokes; 82 of these patients (0.65%) had quent CNS embolization (Lazar et al., 1995; Karalis an intracerebral hemorrhage. Female gender, advanced et al., 1996; Tunick and Kronzon, 2000). Among age, systolic hypertension on arrival (systolic blood pres20 679 patients who had percutaneous coronary intervensure > 160 mmHg) and history of prior stroke were identions, cerebrovascular events occurred in 92 patients tified as independent risk factors for intracerebral (0.3% of procedures); 13 patients had transient ischemic hemorrhage. Patients receiving streptokinase had a attacks (0.04%) and 79 patients (0.25%) had strokes lower risk of intracerebral hemorrhage, particularly (Dukkipati et al., 2004). Another study of 76 903 patients those of advanced age. Patients with myocardial infarcwho had coronary angioplasty found that 140 (0.18%) tion also had fewer systemic hemorrhages when treated had a stroke. Multivariate regression analyses demonwith tenecteplase versus recombinant tissue-type plasstrate that acute myocardial infarction or congestive minogen activator (Huynh et al., 2004). Overall, the risk heart failure on admission, advanced age, use of

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glycoprotein IIb/IIIa inhibitors, history of carotid artery disease, placement of an intraaortic balloon pump, and chronic renal disease were independent predictors for stroke-complicating PCI (Wong et al., 2005).

ETIOLOGY Strokes following ACS have numerous possible pathogenetic mechanisms. The connection between coronary artery disease and ischemic stroke is attributed to a common pathophysiologic process, atherothrombosis. Mural thrombi in areas of ventricular hypokinesis after myocardial damage are also a possible cause. New-onset atrial fibrillation following acute myocardial infarction has been associated with long-term risk for stroke (Milika et al., 2009). Reduced cardiac output may also be a contributory factor to hemodynamic-related strokes. Strokes occurring several weeks after myocardial infarction may be due to embolization from left ventricular thrombi, left ventricular dysfunction, or akinetic left ventricular segments. Cerebral microembolism is often detected by transcranial Doppler among patients with a history of acute myocardial infarction and reduced left ventricular function, akinetic segments, or left ventricular thrombi (Nadareishvili et al., 1999). For every decrease of 5% in the left ventricular ejection fraction, an 18% increase in the risk of stroke has been documented (Loh et al., 1997). Left ventricular thrombi (LVT) are associated with an increased embolic risk (Chiarella et al., 1998). The likelihood of developing a left ventricular thrombus following an acute myocardial infarction depends on infarct location and size, reduced left ventricular ejection fraction, new wall motion abnormalities, and LV aneurysm formation (Asinger et al., 1981; Chiarella et al., 1998). Left ventricular thrombi develop in one third of patients with anterior wall myocardial infarction, and in 5% of patients with inferior wall myocardial infarctions. The highest rate of LVT formation is found among patients with anterior infarcts and low ejection fraction or congestive heart failure (Chiarella et al., 1998). In a series of 30 patients evaluated in the prethrombolytic/prerevascularization era after an acute anterior MI, LV thrombus was identified in 27% at 24 hours, 57% at 48–72 hours, 75% at 1 week, and 96% at 2 weeks (Weinreich et al., 1984). Most thrombi develop within the first 2 weeks after myocardial infarction (Asinger et al., 1981; Nihoyannopoulos et al., 1989). However, some patients develop a new LVT after hospital discharge, often in association with worsening LV systolic function (Keren et al., 1990). In the GISSI-3 database of 8326 patients, where prior to discharge, a transthoracic echocardiogram was performed, LVT was present in 5.1% of patients; 11.5% had an anterior wall myocardial

infarction, and 2.3% had myocardial infarctions at other sites. Furthermore, a LVEF 40% is associated with an increase frequency of LVT with both anterior MI (17.8 versus 9.6% with a higher LVEF) and infarctions at other sites (5.4 versus 1.8%). These data must be interpreted with caution, as patients at high risk for LVT formation (severe heart failure and systolic blood pressure below 100 mmHg) were excluded (Chiarella et al., 1998). In addition, mobile or protruding LVT into the left ventricular cavity on echocardiography were also associated with an increased risk of thromboembolism.

CLINICAL FINDINGS, CLINICAL PRESENTATION, AND DIAGNOSTIC CRITERIA Myocardial infarction (MI) is characterized by the development of acute myocardial ischemia leading to myocardial injury or necrosis (Alpert et al., 2000; Thygesen et al., 2007). Criteria are fulfilled when there is a rise of cardiac biomarkers, along with supportive clinical evidence corresponding electrocardiogram changes, or imaging confirmation of new loss of viable myocardium or acute regional wall motion abnormality. Strokes may obscure the clinical course of patients presenting with acute myocardial infarction. Ischemic strokes are the main type of strokes observed in patients with non-ST-segment elevation ACS. Intracerebral hemorrhages comprise a considerable fraction of strokes after thrombolysis for acute ST-segment elevation myocardial infarction (Kassem-Moussa et al., 2004). Nearly all ischemic strokes after acute myocardial infarction involve the carotid circulation, and are nonlacunar (Mooe et al., 1999). About a third of strokes occur within 24 hours after admission, while two-thirds occur with in the first week after a myocardial infarction (Behar et al., 1991; Sloan et al., 1997). Intracerebral hemorrhage, the most alarming complication of thrombolytic therapy, typically occurs during the first 2 days after administration of thrombolysis (Gore et al., 1995; Gurwitz et al., 1998).

LABORATORY INVESTIGATIONS In patients presenting with a suspected acute MI, electrocardiogram (ECG), an abbreviated history, and physical examination should be obtained within 10 minutes of patient arrival (Diercks et al., 2006). Evaluation requires distinguishing ACS from nonischemic chest pain including potentially life-threatening conditions such as aortic dissection, pulmonary embolism, or esophageal rupture. Diagnosis of acute coronary ischemia depends on the characteristics of the chest pain, specific associated symptoms, ECG abnormalities, and laboratory investigation of serum markers reflecting cardiac injury.

NEUROLOGIC COMPLICATIONS OF MYOCARDIAL INFARCTION Table 8.1 Cardiac serum markers timeline in acute myocardial infarction Laboratory test

Onset (hours) Peak (hours) Duration

Creatine kinase (total and MB) Troponin Myoglobin Lactate dehydrogenase

3–12

18–24

36–48 hours

3–12 1–4 6–12

18–24 6–7 24–48

Up to 10 days 24 hours 6–8 days

Below are biomarkers used to evaluate patients with suspected acute MI (Table 8.1): An elevation in the concentration of troponin or CKMB is required for the diagnosis of acute MI. Troponin is the preferred biomarker for the diagnosis of myocardial injury because of better specificity and sensitivity compared to CK-MB (Alpert et al., 2000; Thygesen et al., 2007). The use of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) for AMI diagnosis has been recommended by the 2007 joint ESC/ACCF/AHA/ WHF Task Force for the definition of myocardial infarction (Goodman et al., 2006). An elevation in cardiac troponins must be interpreted within the proper clinical and ECG framework since troponin elevation can be seen in a variety of clinical settings and is therefore not specific for an acute coronary syndrome. ECG is imperative for identifying simultaneous acute cardiac ischemia and particularly important in the setting of stroke, as patients with ischemic stroke commonly harbor coronary artery disease but may not be able to report angina. Stroke can also be linked with ECG changes. In large strokes, especially in cases of subarachnoid hemorrhage, there are centrally (neurogenic) mediated changes in the ECG. The ECG and cardiac monitoring should be used during the first 24 hours after onset of ischemic stroke as they are vital for the detection of arrhythmias predisposing to embolic events and for providing indirect evidence of atrial/ventricular enlargement that may ultimately predispose to thrombus formation and other potentially serious cardiac arrhythmias (Adams et al., 2007). The utility of this approach is illustrated by a systematic review of five prospective studies including a total of 588 hospitalized patients with ischemic stroke who had Holter monitoring (Liao et al., 2009). Holter monitoring for 24–72 hours detected new-onset atrial fibrillation or atrial flutter in 4.6% of patients (95% CI 0–12.7%). Transthoracic and transesophageal echocardiography are also important as they adequately detect potential cardiac and aortic sources for cerebral embolism. Their use can be postponed until after the acute

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treatment phase, when patients are in a more stable clinical condition. Exceptions may include patients suspected of having strokes due to paradoxical embolism or aortic dissection.

NEUROIMAGING INVESTIGATIONS Neuroimaging is critical for distinguishing between ischemia and hemorrhage, estimating tissue at risk for infarction, and finally identifying the vascular lesion responsible for the ischemic deficit (Adams et al., 2007; Latchaw et al., 2009). Neuroimaging must assess the extracranial and intracranial circulation. Noninvasive methods are favored unless urgent endovascular therapy is planned. Catheter cerebral angiography is usually reserved for acute administration of intra-arterial thrombolysis and for follow-up when noninvasive studies are inconclusive. Magnetic resonance (MR) imaging is an important tool (Bittner and Felix, 1998). Few contraindications to MR imaging exist. Most contraindications are relative precautions; these can be divided into four groups: implanted devices and foreign bodies, unstable patients, pregnancy, and other (Kanal et al., 2004; Marcu et al., 2006). The American Society for Testing and Materials International developed the following terminology for labeling of implanted devices (American Society for Testing and Materials, 2005) (Table 8.2): ● ●

●

MR safe: an item that poses no known hazards in any MR environment MR conditional: an item that has been demonstrated to pose no known hazards in a specified MR imaging environment with specified conditions of use MR unsafe: an item that is known to pose hazards in all MR environments.

Currently, no guideline completely covers all devices. Referring to dedicated websites that list the safety or potential risk of particular devices is suggested (Levine et al., 2007; MRI Safety, 2008). A notable complication is nephrogenic systemic fibrosis (NSF), a fibrosing disorder seen in patients with moderate to severe kidney failure, mainly among patients on dialysis (Grobner, 2006; Sadowski et al., 2007). Increasing evidence has implicated gadoliniumcontaining contrast agents. More than 95% of patients have had recent exposure to gadolinium. The best estimate of risk of NSF following gadolinium exposure is approximately 2.5–5% among patients with severely impaired renal function (LeBoit, 2003). The inciting event is most likely the tissue deposition of gadolinium. Diagnosis is based upon histopathologic examination of a biopsy of an involved site. The US Food and Drug

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Table 8.2 Precautions in MR imaging Parameter for MRI precaution

ASTM designation*

● Coronary artery and peripheral vascular stents

Most labeled as MR safe Remainder MR conditional

– non-ferromagnetic – can be safely scanned at 3 T any time after implantation – weakly ferromagnetic – timing of imaging at < 3 T should be determined on an individual basis ● Aortic stent grafts

● Mechanical cardiac valves

The presence of a prosthetic heart valve or annuloplasty ring that has been formally evaluated for MR safety should not be considered a contraindication to MR examination at 3 T any time after implantation ● Sternal wires ● Cardiac closure and occluder devices – non-ferromagnetic – can be safely scanned at 3 T any time after implantation – weakly ferromagnetic – timing of imaging at < 3 T should be determined on an individual basis ● Inferior vena cava filters Most have been studied at 1.5 T although many have been studied at 3 T – non-ferromagnetic – can be safely scanned at 3 T any time after implantation – weakly ferromagnetic (e.g., Gianturco bird nest IVC filter (Cook), stainless steel Greenfield vena cava filter (Boston Scientific) wait at least 6 weeks ● Embolization coils – non-ferromagnetic – can be safely scanned at 3 T any time after implantation – weakly ferromagnetic – timing of imaging at < 3 T should be determined on an individual basis ● Loop recorder The patient should be warned that he/she may feel the device move since it contains ferromagnetic components ● Hemodynamic monitoring and temporary pacing devices – pulmonary artery hemodynamic monitoring/thermodilution catheters (e.g., the Swan–Ganz catheter) – temporary epicardial pacing wires – temporary pacemaker external pulse generators ● Permanent pacemakers and implantable cardioverter-defibrillators – risks include possible movement of the device, programming changes, asynchronous pacing, activation of tachyarrhythmia therapies, inhibition of pacing output, and induced currents in lead wires leading to heating and/or cardiac stimulation ● Hemodynamic support devices ● Other implanted electronic devices Nerve stimulators Cochlear implants ● Aneurysm clips – non-ferromagnetic – can be safely scanned at 3 T any time after implantation – weakly ferromagnetic – ferromagnetic ● Transdermal patches – cutaneously applied drug-eluting adhesive patches that contain aluminum or other metals in their nonadhesive backing – examples of metal-containing transdermal patches include certain patches containing clonidine, nicotine, scopolamine, testosterone, or fentanyl

Most labeled as MR safe MR unsafe – Zenith AAA endovascular graft (Cook) stent Most labeled as MR safe Remainder MR conditional

MR safe Most labeled as MR safe Remainder MR conditional

Most labeled as MR safe Remainder MR conditional

Most labeled as MR safe Remainder MR conditional

MR conditional – Reveal Plus ILR

MR unsafe MR safe MR unsafe MR conditional

MR unsafe MR unsafe

MR safe MR safe MR unsafe MR unsafe

*American Society for Testing and Materials (ASTM) International. ASTM F2503-05: Standard Practice for Marking Medical Devices and Other Items for Safety in the Magnetic Resonance Environment. ASTM International, West Conshohocken, PA. 2005.

NEUROLOGIC COMPLICATIONS OF MYOCARDIAL INFARCTION Administration (FDA) recommends that gadoliniumcontaining contrast agents, especially at high doses, be used only if clearly necessary and be avoided in patients with a diagnosis or clinical suspicion of NSF.

MRI issues at 3 tesla and coronary artery stents Revascularization in ACS by percutaneous intervention (PCI) may require either the development of a bare metal or a drug-eluting stent. MRI safety information for patients undergoing MR procedures at 3 tesla or less are shown in Table 8.3.

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The potential early and late effects of MRI on stent thrombosis and major adverse coronary events following coronary artery stent (CAS) implantation were investigated in 43 patients who had CAS implantation before MRI examination. An average of 1.3 stents per patient were implanted (1–4 stents); mean follow-up of this study, 36  15 months. In this pilot study, MRI was not associated with increased risk of major adverse clinical cardiac events on long-term follow-up (Kaya et al., 2009).

PATHOLOGY The inflammatory response plays an important role in the genesis and progression of atherosclerotic lesions

Table 8.3 MRI issues at 3 Tesla with coronary artery stents

Type of stent Endeavor Drug Eluting Coronary Artery Stent (Medtronic Vascular) TAXUS Express Paclitaxel-Eluting Coronary Stent (Boston Scientific Corporation) Liberte Coronary Artery Stent (bare metal coronary artery stent, Boston Scientific Corporation) TAXUS Liberte PaclitaxelEluting Coronary Stent (Boston Scientific Corporation) CYPHER Sirolimuseluting Coronary Stent (Cordis Corporation/ Johnson and Johnson)

MULTI-LINK VISION Coronary Stent

MRI safe field strength with no reported migration 3 T 3 T

Maximum whole body averaged specific absorption rate (SAR)

Timeframe MRI may safely be performed after stent implantation

Maximum temperature rise produced by stent

2.0 W/kg for 15 minutes of MR imaging 2.0 W/kg for 15 minutes of MR imaging

Immediately

0.5 C

Immediately

0.65 C

3 T

2.0 W/kg for 15 minutes of MR imaging

Immediately

0.65 C

3 T

2.0 W/kg for 15 minutes of MR imaging

Immediately

0.65 C

Single and two overlapping CYPHER stents have been shown to be MRI safe at field strengths of 3 T or less

4.0 W/kg for 15 minutes of MR imaging

Immediately

Static magnetic field strength of 3 T with a maximum spatial gradient magnetic field of 3.3 T/meter

2.0 W/kg for 15 minutes of MR imaging

Immediately

Single CYPHER stents up to 33 mm in length produced a temperature rise of less than 1 C Two overlapped 33 mm length CYPHER stents produced a temperature rise of less than 2 C 0.60 C

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(Pasceri et al., 2000; Buffon et al., 2002; Lombardo et al., 2004). Inflammation of vulnerable atherosclerotic plaques may contribute to the development of ACS. Plaque instability may extend to other vascular beds such as the extracranial and intracranial circulation. High levels of serum C-reactive protein are frequently observed in cases of unstable angina and AMI. This is mostly regulated by proinflammatory cytokines and is largely unaltered by the administration of anti-inflammatory medications (Pasceri et al., 2000). Such an inflammatory response induces a thrombogenic state that may be responsible for the increased risk of early ischemic strokes in patients with AMI (Van de Graaff et al., 2006). Additionally, sympathetic overactivity may have a possible role in promoting thrombosis via upregulation of platelet activation and factor VIII, and downregulation of the fibrinolytic system and inflammation via upregulation of T-helper cytokines (Yun et al., 2005). This evidence suggests that sympathetic activity along with inflammation can induce, and be further stimulated by, thrombotic events such as AMI and ischemic strokes. We find further support for this concept in the fact that increased heart rate, presumably a surrogate marker for sympathetic activity, is an independent predictor of ischemic stroke in patients with AMI (Mahaffey et al., 1998). Strokes complicating acute myocardial infarctions among the subset of patients not receiving thrombolysis are likely cardioembolic. This notion is further substantiated by their association with large anterior myocardial infarcts and left ventricular thrombi. LV thrombus is most often seen in patients with large anterior ST elevation myocardial infarctions with anteroapical aneurysm formation and akinesis or dyskinesis, expanding the apical zone of intraventricular stasis. Additionally, there is enhanced thrombogenicity in the setting of inflammatory changes at the endocardial surface (Visser et al., 1985; Nayak et al., 2004). A systemic hypercoagulable state may promote thromboembolism early after a coronary event, in comparison to a residual fresh thrombus, which may enhance coagulation during the first 3 months. Several predictors of embolization have been defined in patients who have left ventricular thrombi, in particular mobile and pendulous thrombi. However, the frequency of embolization in patients with thrombus protrusion into the left ventricle (22–100%), or thrombus mobility (35–100%) has varied widely (Haugland, 1984; Meltzer, 1984). Embolization risk from left ventricular thrombi is reflective of thrombogenicity within the left ventricle. This includes activation of the intrinsic coagulation system, endocardial injury, and regional circulatory stasis as well as the dynamic forces potentially propelling thrombotic material into the systemic circulation. Primary prevention studies of myocardial infarction show an increased risk for hemorrhagic stroke with aspirin

use, estimated at 0.2 events per 1000 patient-years. This is similar to the risk associated with aspirin use in secondary stroke prevention (Gorelick and Weisman, 2005). Glycoprotein IIb/IIIa inhibitors have also been implicated in increased bleeding risk. This member of the integrin family of receptors (Hynes, 1987) is of particular interest because of its central role in platelet aggregation. A meta-analysis compared pooled data of 14 randomized trials involving approximately 28 000 patients treated with one of these agents or placebo. The occurrence of intracerebral hemorrhage with heparin plus any GP IIb/IIIa inhibitor was comparable with heparin plus placebo (0.12 versus 0.09%, OR 1.3). There were no differences with a GP IIb/ IIIa inhibitor alone compared to heparin alone (0.07 versus 0.06%) (Memon et al., 2000). Then, the GUSTO V trial examined the risk of intracranial hemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. This trial randomized 16 588 patients to half-dose reteplase plus abciximab or standard dose reteplase (Topol, 2001). The rates of intracranial hemorrhage and nonfatal strokes were similar overall in the two treatment groups. However, combination therapy was linked with a noteworthy increase in intracranial hemorrhage among patients over the age of 75 (2.1 versus 1.1%). The risk of intracranial hemorrhage in GUSTO V was also age-dependent (Savonitto et al., 2003). The dislodgement of an atherosclerotic plaque from the aortic arch serves as a potential source of emboli during invasive procedures such as cardiac catheterization, percutaneous coronary intervention, intra-aortic balloon pumping, and coronary artery bypass surgery (Kassem-Moussa et al., 2004). It has been suggested that the presence of heart failure on admission for an acute myocardial infarction increases in-hospital stroke risk. Using the VALsartan In Acute myocardial iNfarcTion (VALIANT) registry, Szummer and colleagues investigated the contribution of heart failure on admission for an acute myocardial infarction to the subsequent in-hospital stroke risk. HF was present on admission in 38% of patients who subsequently had a stroke. Older age, Killip class III or IV, history of hypertension, and history of stroke, were more common in patients who had in-hospital stroke. The study additionally suggested that heart failure treatments may modify the risk of stroke (Szummer et al., 2005).

MANAGEMENT The patient with myocardial infarction and concomitant cardioembolic stroke is at high risk for recurrent early embolic events. Moreover, the sympathetic response to stroke can lead to demand-induced myocardial ischemia and requires urgent supportive care and treatment. Treatment strategies in CABG, PCI, the use of anticoagulation and thombolytics will be discussed.

NEUROLOGIC COMPLICATIONS OF MYOCARDIAL INFARCTION

Antiplatelet therapy and acute coronary syndrome Atherosclerotic plaque rupture is often the inciting event in ACS, leading to ensuing thrombus formation. Platelets play a significant role in this process, with platelet adhesion, activation, and aggregation all stimulated during an ACS, and antiplatelet agents have been shown to improve clinical outcomes.

CLASSIFICATION OF ANTIPLATELET AGENTS Antiplatelet agents can impede a number of platelet functions and may be categorized according to their mechanism of action (Table 8.4). Data strongly suggest the early initiation of dual antiplatelet therapy with aspirin and either clopidogrel or GP IIb/IIIa inhibitor in all patients with non-ST elevation ACS, regardless of whether they are managed by a conservative or early invasive strategy (Mehta et al., 2001; Steinhubl et al., 2006). Meta-analysis performed by the Antithrombotic Trialists’ Collaboration revealed no significant variations in risk of extracranial bleeding at higher doses of aspirin from 75 to 325 mg/day (Antithrombotic Trialists’ Collaboration, 2002). In nonrandomized post hoc subgroup analyses from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) and the Blockade of the IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trials, bleeding risk was higher at larger doses within the low-dose range (Peters et al., 2003; Topol et al., 2003). In a 2006 systematic review of 22 randomized trials of low-dose aspirin (75–325 mg/day) and clopidogrel for adverse effects, low-dose aspirin increased the risk of any major bleeding, major GI bleeding, and intracranial bleeding 1.7 to 2.1 times compared to placebo. The absolute annual increase in risk was 1.3 per 1000 patients for all major bleeding episodes and 3 per 10 000 for intracranial bleeding (McQuaid and Laine, 2006). The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial shows additional data from post hoc subgroup analysis in which patients with either established cardiovascular disease (about 12 000) or at high risk (about 4000) were randomly assigned to clopidogrel 75 mg daily or placebo (Bhatt et al., 2006; Steinhubl et al., 2009). The incidence of severe or lifethreatening bleeding (primary safety end point) was examined at a median of 28 months in relation to the dose of aspirin ( 100 mg daily) and whether or not the patient received clopidogrel. When examining the adjusted hazard ratio for the incidence of severe or life-threatening bleeding, there were no noteworthy differences between the aspirin dose groups and no effect modification by clopidogrel.

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Thienopyridine therapy reduces the long-term occurrence of adverse cardiovascular outcomes in patients with non-ST elevation ACS, including patients treated with both conservative and invasive strategies. Clopidogrel is the best studied (Yusuf et al., 2001). The most significant frequent adverse effect related with thienopyridine therapy is bleeding. The combination of clopidogrel plus aspirin in CURE was associated with a significant increase in major (3.7 versus 2.7% with aspirin alone), minor (5.1 versus 2.4%), and gastrointestinal bleeding (1.3 versus 0.7%), but not life-threatening bleeding events (Yusuf et al., 2001). For very high-risk patients (e.g., markedly elevated troponin, recurrent ischemic discomfort, dynamic electrocardiographic changes, or hemodynamic instability) undergoing an invasive approach, GP IIb/IIIa inhibitors are recommended. This strategy may also be appropriate for high-risk patients managed with medical therapy. In stable patients managed with invasive strategy who have not received a GP IIb/IIIa inhibitor, the addition of one at the time of percutaneous coronary intervention is suitable in most cases. Evidence from TRITON-TIMI 38 and PLATO demonstrates evidence that the level of platelet inhibition is correlated with both efficacy and bleeding outcomes (Wiviott, 2005; Antman et al., 2008). Agents with increased levels of platelet inhibition, such as prasugrel have lower cardiovascular event rates but higher rates of bleeding. Prasugrel has an earlier onset of action and attains increased degrees of platelet inhibition than clopidogrel, while having a similar rate of bleeding (Wiviott et al., 2005). Based on the results of TRITON-TIMI 38, prasugrel should be considered in patients with STEMI and those with NSTEMI, where thienopyridine therapy will be held until after diagnostic coronary angiography, who are not at high risk of bleeding (age < 75 years, weight  60 kilograms, or those without prior transient ischemic attack or stroke), and favored in patients instead of clopidogrel in patients deemed to be at high risk for stent thrombosis. While there are no data on the efficacy or safety of pre-PCI loading with prasugrel, consideration must be given to weighing the increased efficacy and increased bleeding risk, and certainly if the patient is found to need CABG. The role of ticagrelor has yet to be determined as it has only been studied in one outcome trial and is not yet approved for in non-ST elevation ACS patients (Schomig, 2009).

Anticoagulation and acute coronary syndrome Anticoagulation is indicated in the treatment of NSTEMI and unstable angina. Several risk stratification systems to

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Table 8.4 Classification of antiplatelet agents Antiplatelet agents

Mechanism of action

Initial therapy and dose

Long-term therapy and dose

Aspirin Nonsteroidal antiinflammatory drugs Sulfinpyrazone

Inhibits cyclooxygenase (prostaglandin H synthase), the enzyme that mediates the first step in the biosynthesis of prostaglandins and thromboxanes (including TXA2) from arachidonic acid

The first aspirin tablet should contain 162–325 mg and should be chewed

Aspirin indefinitely No stent: aspirin 75–162 mg/day Bare metal stent (BMS): aspirin (162–325 mg daily) for 1 month Drug eluting stent (DES): sirolimus-eluting stent for 3 months paclitaxel-eluting stent for 6 months Indefinite therapy{ For those patients unable to tolerate aspirin: clopidogrel 75 mg daily or ticlopidine 250 mg twice daily

Dipyridamole

Blocks phosphodiesterasemediated breakdown of cyclic AMP, which prevents platelet activation by multiple mechanisms Inhibits the binding of ADP to a specific platelet receptor P2Y12, thereby inhibiting activation of the GP IIb/IIIa complex and platelet aggregation

Loading dose of clopidogrel is 300 mg and 600 mg if patient going to catheterization the same day Loading dose for prasugrel 60 mg

Clopidogrel 75 mg/day indefinitely or prasugrel for 15 months 10 mg for patients  60 kg or 5 mg for patients 160 mmHg, and diastolic pressure > 90 mmHg. sisted until the end of an average follow-up of Autopsy data demonstrate that cerebral amyloid angio8 months and was seen in both stented and nonstented pathy also predisposes to ICH with administration of thrombolytics. Life-threatening ventricular arrhythmias patients. There was no significant difference in major are also a risk factor for ICH. It is hypothesized that a bleeding episodes between the two groups. Large observational cohort studies have demonstrated period of hemodynamic instability alters cerebral perfuthat use of aspirin and clopidogrel does not increase stroke sion, and the wide variation in blood pressure experirisk above baseline, but the combination of aspirin and enced during CPR combined with thrombolytic therapy warfarin increases the risk of stroke to 0.9% per year commay incite ICH (Sloan et al., 1995). pared to 0.2% per year for aspirin alone (Buresly et al., In a clinical setting where the optimal treatment stra2005). Triple therapy with aspirin, clopidogrel, and warfategy is still contemplative for central nervous system bleeding, an early multidisciplinary effort involving rin places the patient at three to five times the risk of major input from neurologists, neurosurgeons, hematologists, bleeding, which includes an increased stroke risk (Patti and Di Sciascio, 2010). A major predictor of bleeding risk with and cardiologists is ideal. Neurosurgical intervention oral anticoagulation is increasing patient’s age. The incimay be needed to alleviate raised intracranial pressure dence of major hemorrhage in orally anticoagulated or to evacuate hematomas (Sloan et al., 1995). Mahaffey patients younger than 60 years is 1.5% per year, but this et al. examined neurosurgical evacuation of intracranial risk increases to 4.2% in patients older than 80 years hemorrhage after thrombolytic therapy for acute myo(Torn et al., 2005). Risk of major bleeding on oral anticoacardial infarction from the Global Utilization of Streptokinase and Tissue-Plasminogen Activator (tPA) for gulation increases by 3% per year in patients over the age Occluded Coronary Arteries (GUSTO-1) trial where they of 75 years (Patti and Di Sciascio, 2010). randomly assigned 41 021 patients with acute myocardial infarction to one of four thrombolytic strategies in Thrombolytic agents 1081 hospitals in 15 countries and found that rapid neuDespite the focus on catheter-based revascularization rosurgical intervention may be beneficial in selected strategies as treatment for ST elevation MI, fibrinolytic cases (Mahaffey et al., 1999a), but evidence from

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Table 8.5 Thrombolytic agents in acute coronary syndrome

Drug

Dose*

Advantage

Risks and limitations

Salient clinical trial associated with thrombolytic agent

Streptokinase

1.5 million units over 30–60 minutes

Less efficacious than alteplase

GISSI-1 ISIS-2

Alteplase

(1) 15 mg bolus (2) Then 0.75 mg/kg (maximum 50 mg) over 30 minutes (3) Then 0.5 mg/kg (maximum 35 mg) over the next 60 minutes

Most widely used agent worldwide as less costly Reasonable efficacy to safety ratio Lower risk of intracranial hemorrhage than alteplase Better outcomes than streptokinase in GUSTO-1 (30 day mortality 6.3% versus 7.3%)

More expensive than streptokinase Difficult to administer because of short half-life GUSTO-I found a 1.4% incidence of stroke (ICH in 0.7% and nonhemorrhagic stroke in the remaining patients)

GUSTO-1 COBALT

Tenecteplase (TNK-tPA)

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 9

Neurologic complications of cardiomyopathies and other myocardial disorders JOHN F. MORAN* Division of Cardiology, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION An appreciation of neurologic complications of cardiomyopathy starts with an understanding of what cardiomyopathy is. The definition of cardiomyopathy requires continuous and evolvingappreciationofdifferentetiologic diseases that can damage the myocardium (Maron et al., 2006). These diseases cause a myocardial dysfunction leading to arrhythmogenesis as well as contractility failures, either systolic or diastolic. An understandingof theetiology of different myocardial dysfunction continues to expand. In 2006, the American Heart Association presented a scientific statement that included the Expert Consensus Panel’s definition of cardiomyopathy: Cardiomyopathies are heterogenous group of diseases of the myocardium associated with mechanic and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failurerelated disability. The panel did not include etiologies of myocardial dysfunction caused by coronary artery disease, hypertension, valvular or congenital heart disease. They concentrated on myocardial diseases that could result in subsequent failure of myocardial performance. There was discussion regarding this classification. Any classification will be difficult and likely be incomplete because of the heterogenous etiology of cardiomyopathy (Elliott, 2008). This is especially true of genetic considerations. However,

the significance of a classification is its usefulness in medical practice. Our chapter focuses on cardiomyopathies associated with neurologic diseases, most often stroke (see Table 9.1). A recent study of 274 patients with nondisabling stroke were shown to have an 18% incidence of asymptomatic coronary artery disease (Calvet et al., 2010). Patients with a high Framingham risk score of greater than 20% ought to have further evaluation for asymptomatic coronary artery disease. An earlier review and meta-analysis to determine the risk of myocardial infarction, transient ischemic attacks (TIA), and ischemic strokes after a stroke or TIA was performed after selecting 65 996 patients in 25 randomized clinical trials, eight population-based cohorts and six single center cohorts (Tonze et al., 2005). The main finding of the metaanalysis was that after a stroke or TIA, the risk of a myocardial infarction or nonstroke vascular death was about 2% per year, or 20% in 10 years. However, there was heterogeneity among the studies. In some studies baseline characteristics including age, diabetes, gender, hypertension, old myocardial infarction, and peripheral arterial disease did correlate with absolute risk of myocardial infarction or nonstroke vascular death. In these studies, left ventricular dysfunction wall motion abnormalities on echo and clinical congestive heart failure were not evaluated. Two-dimensional echocardiography has allowed assessment of mural thrombi in acute myocardial infarction, left ventricular aneurysm, post myocardial infarction, and dilated cardiomyopathy (Meltzer et al., 1986). In these patients, mural thrombi may develop often, but thromboembolic phenomena occur far less often. Thrombus seems to be associated with severe left ventricular dysfunction, dilated left ventricles, and perhaps

*Correspondence to: John F. Moran, M.D., Professor of Medicine, Division of Cardiology, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-327-2784, Fax: þ1-708-327-2770, E-mail: [email protected]

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Table 9.1

PATENT FORAMEN OVALE

Cardiomyopathy diseases Coronary artery disease

Genetics

Cardiomyopathy

Duchennene muscular dystrophy Emery–Dreifuss muscular dystrophy Friedreich’s ataxia Myotonic dystrophy

Left ventricular dysfunction Ischemic Nonischemic Patent foramen ovale

female gender (Diet and Erdman, 2000). These observations were taken from a retrospective analysis of the SOLVED trial, which enrolled 6378 patients. Patients with left ventricular ejection fraction of less than 35% were enrolled to test the hypothesis that enalapril could reduce heart failure mortality (Dries et al., 1997). There were 4228 patients with asymptomatic left ventricular dysfunction and 2569 patients with symptomatic heart failure. Patients with atrial fibrillation were excluded. The women in the study were older than the men with an increased prevalence of diabetes, and more had a history of hypertension. There were 62 thromboembolic events in women, or 2.42 events per 100 patient-years, and 278 thromboemblic events in men, or 1.82 events per 100 patient-years, in the asymptomatic left dysfunction group. Most of these thromboembolic events were nonfatal cerebrovascular events. There were more pulmonary emboli in women (24%) than in men (14%). Only the incidence of pulmonary emboli in women was statistically significantly different. The SOLVED study was the first large database used to evaluate the association of left ventricular dysfunction and the incidence of thromboembolic events in patients with normal sinus rhythm. The incidence of thromboembolic events was low: 2.4% in men and 1.8% in women. An unexpected finding was a higher incidence of pulmonary emboli in women (24%) compared to men (14%). The explanation for this difference was unclear but could be related to older age, and more diabetes and hypertension in the female group compared to men. Most of the events in this trial were cerebrovascular. The SOLVED trial enrolled patients with left ventricular ejection fractions of less than 35%. Cardioembolic strokes can be related to left ventricular dysfunction or dilated cardiomyopathy but also to atrial fibrillation/ flutter or noncompaction (Finsterer and Stollberger, 2010). In addition, cryptogenic strokes are associated with patent foramen ovale.

Patent foramen ovale (PFO) has been associated with stroke, especially cryptogenic stroke, when other causes have been undefined, such as atherosclerosis of the carotid arteries or vertebral arteries, aortic plaques, atrial fibrillation, cardiac thrombus, or coagulation disorders. A PFO is a remnant of the fetal circulation and may be associated with an atrial septal aneurysm. The atrial septal aneurysm is defined on transesophageal echocardiography as a redundant and hypermobile portion of the interatrial septum that has 10 mm or more excursion from the centerline during the cardiac cycle. The Warfarin-Aspirin Recurrent Stroke Study (WARSS), in a 2 year follow-up, found no difference in stroke prevention or in the rate of hemorrhage between aspirin and warfarin (Mohr et al., 2001). In that trial, transesophageal echocardiography was performed in 630 patients; 312 were randomized to warfarin and 318 were randomized to aspirin. Of the 630 patients with transesophageal echocardiography, 601 had adequate images to analyze for PFO (Homma et al., 2002). In that group, 39.2% of patients with a cryptogenic stroke compared to 29.9% of patients with a known cause of stroke. Large PFO were found in 20% of cryptogenic stroke patients compared to 9.7% of patients with a known cause of stroke ( p < 0.001). But there was no significant difference in time to recurrent stroke or death between patients with and without a PFO. There was also no significant difference in time to recurrent stroke or death in those patients with no, small, or large PFO in the 2 year follow-up. Even though autopsy studies show a prevalence of 29% of PFOs and a large PFO with a large shunt present, no difference in time to recurrent stroke was found in these medically managed patients. Paradoxical embolus in patients with PFO is a potential mechanism for stroke. This is in keeping with the presence of a large PFO, cryptogenic stroke, deep vein thrombosis, as well as reports of a trapped thrombus in a PFO. Of the estimated 780 000 strokes that occur in the US, 180 000 are recurrent events. Of these recurrent strokes, 25–40% have no identifiable cause and are labeled cryptogenic (O’Gara et al., 2009). A recent study utilizing cardiovascular magnetic resonance imaging (MRI) in selected patients with PFO after cryptogenic cerebral ischemic events suggested that PFO may allow an embolus to get into the coronary arteries as well as the cerebral arteries. Late gadolinium enhancement is the most sensitive imaging technique to detect small myocardial infarctions. These authors found 74 consecutive patients with a first cryptogenic cerebral event and a PFO defined by transesophageal echocardiography but no history of myocardial infarction (Wohrle et al., 2010). Late gadolinium enhancement was found by

NEUROLOGIC COMPLICATIONS OF CARDIOMYOPATHIES cardiovascular MRI in eight of these 74 patients (10.8%). Signs of a myocardial infarction in the electrocardiogram were present in three of the eight. Coronary angiography ruled out coronary artery disease in seven of the eight patients with late gadolinium enhancement. These authors suggested that a small thrombotic mass can result in a subclinical myocardial infarction as well as a cerebral event. They note that late gadolinium enhancement is not pathognomonic for myocardial infarction because it has been seen in other types of cardiomyopathy, myocarditis, and takotsubo disease. Small studies have suggested that device closure of PFO compared to medical therapy with chronic anticoagulation reduces recurrent strokes from 12% to as little as 4.9% with transcatheter closure compared to medical therapy (O’Gara et al., 2009). Cryptogenic strokes related to a PFO could obscure the diagnosis of myocardial infarction, later discovered by gadolinium enhancement. PFO is more often found in patients with a cryptogenic stroke than in the general population. Closure of the PFO has been recommended. Furlan et al. (2012) published an open label, randomized, open multicenter trial to compare a PFO closure device with medical therapy alone. Eligible patients were 18–60 years old, and had had an ischemic stroke or TIA in the previous 6 months. All patients had a transesophageal echocardiography documenting the PFO with a bubble study showing left to right shunting during a Valsalva maneuver. Exclusion criteria were any identified possible cause of stroke or TIA including atrial fibrillation and carotid artery stenosis. Of the total 909 patients enrolled, 447 patients were randomly assigned to PFO closure, and 462 were assigned to medical therapy. Implementation of the STARFlex closure device was successful in 362 of the 405 patients in whom it was attempted (89.4%). At 6 months, transesophageal echocardiography confirmed effective PFO closure in 366 patients (86.1%). Clopidogrel 75 mg and Aspirin either 81 mg or 325 mg were admistered for six months, and then Aspirin alone for two years of follow-up. Medical patients received warfarin with an International Normalized Ratio (INR) maintained between 2.0 and 3.0, while aspirin 325 mg or both were given at the discretion of the principal investigator at each site. At 2 years there was no significant differences between the two groups in terms of the rate of recurrent stroke or TIA (Furlan et al., 2012). The 2 year stroke rate was low at 3% and nearly identical in the PFO closure group and the medical therapy group. Furlan et al. (2012) noted an increased rate of atrial fibrillation in the closure group, with 23 patients affected (5.7%), compared to the medical treatment group, with three patients affected (0.7%, p < 0.09). In addition, major procedural complications occurred in 13 patients (3.2%) of the

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device group (p < 0.001). None of the patients in the closure group who developed stroke or TIA had a device leak on transesophageal echocardiography at 6 months. The authors still suggested there may be a role for device closure in certain clinical scenarios. Moreover, clinically silent cerebral infarctions may occur in patients with dilated cardiomyopathies (Kozdag et al., 2008). MRI of the brain was performed in 72 patients with dilated cardiomyopathies studied with coronary angiography in all of this group. Of these 72 patients, 46 had idiopathic dilated cardiomyopathy and 26 had nonischemic dilated cardiomyopathy. There were 56 agedmatched control patients. The prevalence of silent cerebral infarctions was 39% in the ischemic cardiomyopathies, 27% in nonischemic cardiomyopathies, and 36% in the control group. The left ventricular ejection fraction in the dilated cardiomyopathy group was less than 45% at enrollment compared to a left ventricular ejection fraction of less than 35% in the SAVE trial (Dries et al., 1997). Multidetector computed tomography (CT) was used in the evaluation of possible stroke patients (Hoey et al., 2009). Multidetector CT provides high resolution images of all possible sources of embolic phenomena as well as definition of intracardiac thrombus. These could include left ventricular noncompaction, PFO, and atrial myxomas. Although multidetector CT and MRI scans can demonstrate structural abnormalities, two-dimensional echocardiogram can show left ventricular noncompaction as well at the bedside (Oechslin, 2000). Cardiomyopathy patients may have mural thrombi that can be demonstrated as well as spongy morphologic appearance of left ventricular noncompaction. This may be most evident at the apical portion of the myocardium. However, the inferior mid and lateral mid-left ventricular walls can be involved with left ventricular noncompaction as well.

LEFT VENTRICULAR DYSFUNCTION Isolated left ventricular noncompaction or left ventricular hypertrabeculation is spongy morphologic appearance, described as an altered structure of the myocardium as a result of intrauterine failure of compacting myocardial fibers (Stollberger et al., 2002). There is usually no associated congenital heart disease. There is a continuity of the left ventricular cavity and the intratrabecular spaces, which fill with blood. There is no connection with the epicardial coronary arteries. Left ventricular noncompaction can also be subdivided into dilated, hypertrophic, and combination hypertrophic and dilated cardiomyopathy. Two-dimensional echocardiography can help diagnose left ventricular compaction and can also show mural thrombi. The diagnosis of left ventricular noncompaction is confirmed by showing a two-layered structure. One is a thin epicardial compacted zone and

114 J.F. MORAN the second is the presence of a thickened noncompacted these spontaneous echo densities. More commonly these zone with deep recesses which fill with blood from the patients died of terminal heart failure or sudden cardiac left ventricular cavity. Left ventricular noncompaction death. has a spongy morphologic appearance. Both layers of Whether two-dimensional echocardiograms, MRI, or the myocardium are perfused with blood from the epimultidetector CT are utilized to identify intracardiac cardial coronary arteries not the left ventricular cavity. thrombi, the incidence of clinical thromboembolic events Long-term major morbidity can be the result of congesseems low. Considering this low clinical event rate and the tive heart failure, arrhythmias, or thromboembolic problems of bleeding with chronic anticoagulation, we events. The risk of thromboembolic events appears to should ask whether these patients with left ventricular be low but some authors have recommended chronic dysfunction should all be anticoagulated. Cardiomyopaanticoagulation in these patients, who are mainly sympthy patients are at risk of thromboembolic events. The fretomatic heart failure patients. In one series of 34 adults, quency of thromboembolic events is unclear, with an there were six TIAs (18%) and one stroke (3%). These increased incidence of 37–50% in autopsied patients with authors also recommended an early consideration of dilated cardiomyopathy and heart failure. This incidence automatic implantable cardiac defibrillators as well as contrasts with clinical events. In a review in 2000, anticanticoagulation (Oechslin et al., 2000). oagulation was recommended for all patients with left In addition to a risk of stroke or TIA, these patients ventricular ejection fractions less than 40% in the absence with left ventricular compaction may have a neuromusof contraindications (Rho et al., 2000). cular disorder. In a series of 49 patients with echocardioHowever, a subsequent review showed the prevalence graphically proven left ventricular noncompaction, of events to vary from 3% to 50%, or 1.5–3.5 events per neurologic examination showed 29 had a neuromuscular 100 patient-years. (Abdo et al., 2010). The SOLVE trial disorder (Stollberger et al., 2002). These authors found studied heart failure patients in a retrospective analysis. 13 patients had a metabolic myopathy, 12 had a myopathy The SAVE investigators studied the incidence of stroke of unknown cause, 2 had Leber’s hereditary optic neufollowing a myocardial infarction. In the SAVE trial the ropathy (LHON), one had Becker muscular dystrophy, overall stroke risk in 5 years was 8%. The size of the myoand one had myotonic dystrophy. Some 18% were neurocardial infarction and left ventricular ejection fraction of logically normal. less than 28% were predictors of a stroke (Loh et al., These 49 patients were part of a series of 62 patients 1997). The SOLVE trial studied heart failure patients with left ventricular noncompaction. The series of and left ventricular dysfunction. These may be different patients had other cardiac issues that included arrhythmorbidities above the factor of severe left ventricular mias, atrial fibrillation, atrial tachycardia, and complex dysfunction alone. ventricular ectopy including nonsustained ventricular An analysis of the sudden cardiac death in heart tachycardia. Moreover, the incidence of congestive heart failure trial (SCD-HeFT) was performed in 2116 heart failure in this group was 73%. Twenty-four-hour ambufailure patients with no history of atrial fibrillation/ latory electrographic monitoring demonstrated signififlutter at the baseline (Akashi et al., 2008). The 4 year cant arrhythmias in 65% of the group. No strokes Kaplan–Meier event rate for thromboembolic phenomwere described in this series of left ventricular noncomena was 4%, or 1% per year. It differed among the three paction. This compares to a smaller study where left vengroups of patients that were randomized in the study: tricular noncompaction with symptomatic heart failure amiodarone arm 2.6%, automatic implantable defibrillapatients was associated with an 18% incidence of TIAs tor arm 3.2%, and placebo arm 6%. The respective analand stroke (Oechslin et al., 2000). ysis annual rates of thromboembolism were amiodarone Left ventricular systolic dysfunction with normal 0.7%, automatic implantable defibrillator 0.8%, and plasinus rhythm seems to predispose some patients to cebo 1.5%. Although these rates of thromboembolism thrombus formation and subsequent thromboembolic are low, postrandomization occurrence of atrial fibrillaevents. Patients with dilated cardiomyopathy and left tion could have had an effect. A subgroup analysis of the ventricular dysfunction can show spontaneous echo conSCD-HeFT trial showed that lower thromboembolic trast (Kozdag et al., 2010). These swirling echo densities rates were predicted by treatment for hypertension, in the left ventricle at echocardiography have been assoamiodarone, the implantable cardiac defibrillator, and ciated with thromboembolic phenomena. In a study of 92 left ventricular ejection fractions greater than 20%. patients with dilated cardiomyopathy and left ventricuSCD-HeFT enrolled patients with ischemic and lar ejection fractions less than 30%, echocardiography non-ischemic etiologies with an average left ventricular demonstrated spontaneous echo contrast. Follow-up of ejection fraction of 25%. In addition to ischemic and these patients was 30  10 months. Nonfatal cerebrovasnonischemic etiology, other causes of left ventricular cular embolic events occurred in eight patients (9%) with dysfunction have been associated with stroke.

NEUROLOGIC COMPLICATIONS OF CARDIOMYOPATHIES Other authors investigated a correlation between cerebral and myocardial ischemic lesions in community living 75-year-old subjects taken from the perspective investigation of the Vasculature in Uppsala Seniors (PIVUS) study (Barbier et al., 2011). The study involved magnetic resonance imaging of the brain and the heart. All subjects lived Uppsala, Sweden, and 2025 were invited to participate in the study. Of the people invited, 1016 agreed to participate. Some 5 years later, 52 subjects had died. After further review, 394 subjects underwent MRI of the brain and the heart. The authors then divided the subjects into three groups on the basis of the cardiac MRI: those in group 1 had no myocardial infarction scars; group 2 had unrecognized myocardial infarction scars, with no clinical myocardial infarction, and group 3 had a clinically recognized myocardial infarction (MI), with an MI scar on the cardiac scan. Myocardial infarction scars were seen in 141 of the 394 subjects. Critical brain infarctions were found in 23 of the 394 subjects (6%) and 87 of the 394 (22%) also showed lacunar infarcts (Barbier et al., 2011). These were subjects who had systolic hypertension, hypercholesterolemia, and diabetes who were followed for 2 1/2 years. This study demonstrated a high prevalence of MRIdetected scars of unrecognized myocardial infarctions. The prevalence of MRI-detected but clinically unrecognized myocardial scars seems to increase with age, likely related to atherosclerosis. These scars were found more frequently in men than in women. These authors thought that MRI-unrecognized myocardial infarction associated with cortical brain scars are more likely to have atherosclerosis as an etiology. But unrecognized myocardial infarctions that are associated with lacunar infarcts may not be on the basis of atherosclerosis (Barbier et al., 2011). There were more lacunar infarcts in women (see Fig. 9.1). More study is needed here. These observations could help explain cognitive and neurologic adverse outcomes that

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occur after coronary artery bypass graft surgery even though the incidence is low. They occur 2–3% of the time and incidence is slightly higher with high-risk cardiovascular surgical patients. The predictors of high risk postoperatively include older age, history of stroke, history of hypertension, and diabetes (Selnes et al., 2012).

TAKOTSUBO STRESS CARDIOMYOPATHY “Takotsubo” refers to a Japanese octopus fishing pot. The shape of the pot resembles the left ventricular angiogram seen in these patients (Akashi et al., 2008). The anteroapex shows akinesia and the basal segments of the left ventricle are hypercontractile. This is called transient left ventricular apical ballooning or stress cardiomyopathy. The presentation is seen usually in postmenopausal women soon after a sudden emotional or physical stress. These patients can present as apparent acute myocardial infarction and may represent 1% or 2% of all cases of acute myocardial infarction seen by emergency services. Although the left ventricle can be significantly depressed, recovery usually occurs in a few weeks. There is often a stressful trigger that sets this off and the coronary angiogram is normal or at least nonobstructive. The left ventricular ballooning can be outside of a single coronary artery distribution. The etiology of this cardiomyopathy is unclear. Multivessel coronary spasm and catecholamine cardiotoxicity have been suggested. Cardiac b-adrenergic systems have been known to cause myocardial dysfunction. Acute myocardial dysfunction has been described in 10 explanted donor hearts (White et al., 1995). b-Receptor densities were similar in donor hearts and age-matched nonfailing hearts. However, the donor hearts exhibited a 30% decrease in maximum isoprenaline (isoproterenol)stimulated adenylyl cyclase activity as well as a decrease

Fig. 9.1. Sex-specific prevalence of lacunar infarcts (see text for discussion). The prevalence of lacunar cerebral infarctions on magnetic resonance imaging displayed separately for female (A) and male (B) NoMI, UMI, and RMI subjects. p values are displayed where there are statistically significant differences. (Adapted from Barbier et al., 2011, with permission.)

116 J.F. MORAN in maximal stimulation with forskolin. There was no survived or died during the hospitalization. These decrease in adenylyl cyclase with manganese, an activator authors used cardiovascular magnetic resonance imagof adenylyl cyclase. Right ventricular trabeculi removed ing and observed a diversity of contraction patterns in from donor hearts showed a decreased contractility the acute phase of stress cardiomyopathy in both the response to isoprenaline as well as reduced calcium right ventricle and the left ventricle. responses. This was interpreted as acute myocardial dysLeft ventricular dysfunction has been associated function secondary to brain injury. This could mean myowith subarachnoid hemorrhage. A recent report of 42 cardial dysfunction was a result of an intense short nontraumatic subarachnoid hemorrhage patients without sympathetic discharge. known cardiac disease were evaluated with serial A more recent study was of stress cardiomyopathy in enzymes, electrocardiograms, and echocardiographic eight female patients where six had chest pain and dysstudies (Vannemreddy et al., 2010). The average age of pnea and a historical trigger while two had epigastric pain these patients was 53 years; 58% were females. The Glasand no trigger event (Uchida et al., 2010). Epinephrine gow Coma Scale upon admission was 13.1. The mean left and norepinephrine levels on admission in these patients ventricular ejection fraction was 55% but 10 patients had were elevated in six of the eight patients. Left ventricular wall motion abnormalities (20%), mostly global hypokineangiography showed the apical ballooning of the left sia (63%, 5 of 8). The mean troponin level was 0.262 and ventricle and hypercontractility of the base. Coronary was significantly higher than patients without wall motion angiography failed to show significant obstructions. abnormalities. Poor neurologic status correlated with myoAfter left ventricular angiography a 6 French bioptome cardial dysfunction. Abnormalities in the electrocardiowas used to take three specimens in each patient from gram as well as the echocardiogram correlated with the the apical ballooning area of the left ventricle. severity of subarachnoid hemorrhage. These authors specIntracoronary injections of acetylcholine caused left ulated that hypothalamic ischemia could cause intense anterior descending coronary spasm in three patients vasospasm and an intense sympathetic discharge. and spasm in the diagonal artery in three other patients. An earlier study of 147 patients with subarachnoid Myocardial perfusion grade changed in all patients after hemorrhage showed that 28% developed global or acetylcholine. No spasm or perfusion grade change was regional wall motion abnormalities in the acute hospitaldemonstrated a month later with acetylcholine. The myoization period (Zaroff and Rordorf, 2000). The average cardial biopsies in the ballooning area of the left ventricage of these patients was 53 years and 77% were women. ular area all showed focal necrosis of the myocardium Many of the wall motion abnormalities did not match and inflammatory cell infiltration at the initial biopsy. coronary artery anatomy distributions. In more than half One month later the biopsy showed focal myocardial of these patients, systolic function of the left ventricular fibrosis and apoptotic cardiomyocytes. These authors apex was preserved relative to the base. Coronary artery proposed that the stress-induced increase in catecholdisease did not seem to be the etiology of the wall motion amine caused apoptosis of endothelial cells of coronary abnormalities. Although the left ventricular ejection microvessels with resultant spasm. The release of the fraction was less than 50% in some of these patients, spasm caused a myocardial stunning with a ballooning there was a tendency to normalization within 30 days of the left ventricular apex. All could then recover in a in follow-up echocardiograms. The authors took these few weeks (Uchida et al., 2010). observations as suggestive of excessive local catecholAlthough strokes, cardiogenic shock, and subarachamine stimulation from myocardial sympathetic nerve noid hemorrhage have been described in stress cardioterminals. myopathy, these are relatively uncommon. In a recent The left ventricular sparing of the apex in these patients series of 136 patients admitted with stress cardiomyopacontrasts with the left ventricular apical ballooning seen in thy, 13 patients developed a cardiomyopathy with casual takotsubo patients. It may well be that b-adrenergic or catdoses of albuterol, subcutaneous epinephrine or dopaecholamine burst stimulation can cause a variety of left mine or dobutamine with stress echocardiography and ventricular wall motion abnormalities depending on the phenylephrine for hypotension for spine surgery severity of the subarachnoid hemorrhage. (Sharkey and Windenburg, 2010). Some 89% of all Most of the data associating stroke with cardiomyoppatients had significant stressful events preceding their athy come from small studies or case reports. A few presentation with cardiomyopathy, but relatively few recent case reports have included the takotsubo synhad severe cardiovascular complications. Five of these drome, celiac disease, Duchenne muscular dystrophy, patients had intraventricular thrombi and two had thromand Loeys–Dietz syndrome (Eckman et al., 2009; boemboli, one cerebral and one had cerebral and a pulDogan et al., 2010; Gimenez-Mun˜oz et al., 2010; Jabiri monary embolus. Half of those nine patients with et al., 2010). The Duchenne muscular dystrophy patient cardiovascular complications had cardiac arrest and showed a mural thrombus by echocardiography but all

NEUROLOGIC COMPLICATIONS OF CARDIOMYOPATHIES 117 four patients had the dilated cardiomyopathy. In the atrial fibrillation/flutter was documented at least once Loeys–Dietz patient the initial presentation was for a (Finsterer and Stollberger, 2008b). Of 139 patients with Stanford Type A aortic dissection followed by a dilated primary myopathy, atrial fibrillation and embolic stroke cardiomyopathy and eventually a cardiac transplant were reported in nine patients (6.5%). The prevalence of within 6 months. atrial fibrillation/flutter was 14.5%. Patients with myoAs these reports demonstrate, most data about strokes tonic dystrophy type 1, Emery–Dreifuss muscular dystrocome from case reports and case series. This seems true phy, Duchenne muscular dystrophy, and Becker muscular even though cardioembolic stroke is the second most comdystrophy had atrial fibrillation most frequently. mon cause of stroke in cardiomyopathy patients (Finsterer As many as half of all cardioembolic strokes are and Stollberger, 2010). Finsterer and Stollberger have related to atrial fibrillation. The left atrial appendage listed the various gene abnormalities where dilated cardiois the source of the thrombus in the majority of these myopathy has been reported. Stroke can result in patients patients (Sila, 2006). Nonvalvular atrial fibrillation can with dilated cardiomyopathy where mural thrombus is preincrease the risk of embolic stroke four to seven times sent or perhaps from hemodynamic deterioration. Despite compared to normal sinus rhythm. This arrhythmia is these and other studies relating stroke with dilated cardiothe most common in the US, affecting 2 million people. myopathy, the actual incidence appears low. In a summary Atrial fibrillation is an independent risk for stroke review of available studies in the absence of atrial fibrillaand is associated with approximately 75 000 strokes tion, the incidence of stroke with dilated cardiomyopathy per year (Chugh et al., 2001). Atrial fibrillation can also could be as low as 2.2 embolic events per 100 patient-years be considered a marker for other conditions associated regardless of treatment (Abdo et al., 2010). Based on this, with stroke. These include aortic atherosclerosis, cerechronic anticoagulation with coumadin could not be bral vascular disease, and mitral annular calcifications. recommended by these authors. In addition to a low thromIf atrial fibrillation increases stroke risk, the risk of boembolic event rate, the heterogeneity of etiologies, atrial fibrillation increases 4.5–5.9-fold in the presence degree of left ventricular dysfunction, prospective versus of heart failure. Heart failure or left ventricular dysretrospective studies, subgroup analyses, duration of function can cause left atrial dilatation, atrial remodelfollow-up, gender differences, presence of inflammation, ing with atrial fibrosis, and ionic atrial remodeling and symptomatic versus asymptomatic strokes are all (Seiler and Stevenson, 2010). The development of atrial complicating factors. Separating these would require a fibrillation can cause further deterioration of left large randomized trial of patients with normal sinus ventricular function with loss of atrial mechanical funcrhythm at baseline. tion and atrial ventricular synchrony with a rapid heart Inherited neuromuscular diseases have been associrate. Left ventricular filling in diastole can be reduced ated with cardiac abnormalities. In a series of 131 patients, by loss of atrial function and a shortened cardiac cycle cerebral infarction developed in two (1.5%). Both of these due to a rapid ventricular heart rate. Cardiac output patients had symptomatic cardiomyopathy and atrial falls. Further deterioration of left ventricular function fibrillation or atrial flutter (Biller et al., 1987). One patient can occur if the heart rate remains above 100 beats had myotonic dystrophy and the other had Friedreich’s per minute (bpm). Tachycardia-mediated cardiomyopaataxia. In Brazil, where trypanosomiasis is epidemic, thy can cause further dilatation. The development of chronic Chagas disease-associated stroke may be more atrial fibrillation with heart failure is at least a marker common than stroke from acute coronary syndromes of increased mortality risk in these patients. This is (Carod-Artal, 2010). In Brazil, 40% of Chagas patients important if the overall stroke risk in patients with nonare diagnosed after their first stroke. Still the annual incirheumatic atrial fibrillation is 4.4% per year without dence of stroke with cardiomyopathy from Chagas diswarfarin therapy. Anticoagulant therapy is useful in ease is low, at 1.2% in 1 year follow-up. However, the preventing the development of left atrial or left atrial autopsy incidence of mural thrombus varies from 35% appendage thrombus. to 46%. Chagas disease is associated with a high incidence There is information that clinically silent cerebral of congestive heart failure, cardiomyopathy, bundle infarctions occur in patients with cardiomyopathies branch block, and arrhythmias such as atrial fibrillation. and left ventricular dysfunction (Kozdag et al., 2008). Cognitive dysfunction is common in patients with atrial fibrillation and may be related to less effective oral ATRIAL FIBRILLATION anticoagulation (Flaker et al., 2010). Most guidelines do Atrial fibrillation has often been associated with strokes. not include cognitive dysfunction in the list of risks for A Medline search taken from 1966 to 2007 using the patients with atrial fibrillation. Moreover, the common terms myopathy, neuromuscular disease, muscular dysrisk factors of hypertension, hypercholesterolemia, diatrophy, and atrial fibrillation yielded 71 studies where betes, and atrial fibrillation apply to both cardiovascular

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and dementia patients. In a review of clinical practice guidelines, only four of 20 discussed cognitive function as a risk factor (Rockwood et al., 2009). Chronic anticoagulation can reduce the incidence of strokes with a small risk of cerebral hemorrhage in patients with atrial fibrillation. Atrial fibrillation can often be subclinical or asymptomatic. A recent study evaluated the incidence of silent atrial fibrillation in patients who had recently had a pacemaker or intracardiac defibrillator unit placed (Healey et al., 2012). The authors felt interrogation of these pacemaker or defibrillator units could identify silent or asymptomatic atrial fibrillation. These patients were over the age of 65, with hypertension, and had AV sequential pacemakers placed for sinus node dysfunction or AV nodal disease. The intracardiac defibrillators were placed for many indications. The authors felt subclinical atrial fibrillation can be suspected in 25% of patients with cryptogenic strokes or where no etiology can be found. In this study of 2451 patients with newly implanted pacemakers or defibrillators, one atrial tachyarrhythmia was discovered in 3 months of follow-up in 10.1% of the group. The median heart rate of the atrial tachyarrhythmia was 480 bpm with a range of 366– 549 bpm. Over the 2.5 years of follow-up, 47 patients, as well as 633 additional patients, had atrial tachyarrhythmias (34.7%). The presumption is the atrial tachyarrhythmias represent atrial fibrillation. Episodes of atrial tachyarrhythmias were eight times more common than clinical atrial fibrillation. Overall, clinical atrial fibrillation was seen in 15.7% of the patients with some subclinical atrial tachyarrhythmias. The second finding of the study was the independent risk of ischemic strokes was two and a half times more common in patients with subclinical tachyarrhythmias. In these patients, if the CHAD score of greater than or equal to 2 or more was found in a patient who had associated atrial tachyarrhythmias on their unit, the risk of stroke or cerebral embolism increased to 4% per year. More than half of these patients were taking aspirin at the baseline, and 18% were taking vitamin K antagonists in the follow-up. The authors felt that aspirin or vitamin K antagonists should have reduced the stroke risk. They suggested that subclinical atrial tachyarrhythmias in these patients may not receive the same benefit as others on vitamin K antagonists (Healey et al., 2012). In this group of patients with atrial-ventricular pacemakers and intracardiac defibrillators plus a history of hypertension and heart block, subclinical atrial tachyarrhythmias were often seen. They also suggested subclinical atrial tachyarrhythmias may precede a diagnosis of clinical atrial fibrillation (Healey et al., 2012). During the entire study period of a mean of 2.5 years, 194 patients received vitamin K antagonists including

47 patients with atrial tachyarrhythmias discovered on their devices. In addition, follow-up studies identified an additional 633 patients (24.5%) with atrial tachyarrhythmias. The risk of ischemic stroke or systemic embolus in patients with atrial tachyarrhythmias was 13% overall (Healey et al., 2012). More data are needed to determine the importance of these pacemaker observations to clinical practice. A recent search of OVID, Medline databases, and the Cochrane Stroke Group Trials yielded 29 published randomized trials that included 28 044 patients with nonvalvular atrial fibrillation (Hart and Pearce, 2007). The mean age of the group was 71 years and 35% of the patients were women. Most of these trials used warfarin or aspirin in varying dosages and intensities. Other anticoagulants were also used. Adjusted dose warfarin was associated with a 64% reduction in stroke. The absolute risk reduction of stroke for 1 year in primary prevention was 2.7%. The number of patients needed to be treated for a year was 37. The reduction for secondary prevention was 8.4% per year and the number needed to treat was 12. When all-cause treated patients were compared to no warfarin patients, stroke was reduced by 60% and death by 25%. The risk for intracranial hemorrhages doubled with the use of adjusted dose warfarin and INR adjusted to 2.0–2.6, but the absolute risk for intracranial hemorrhage increase was small, at 0.2% per year. Highrisk patients seemed to benefit more than low-risk patients.

RISK STRATIFICATION SCHEMES Risk stratification schemes have been developed to distinguish high-risk from low-risk patients with nonvalvular atrial fibrillation (Fang et al., 2008). Since there are associated bleeding risks with warfarin, anticoagulation might not be beneficial in certain low-risk patients (Hart and Pearce, 2007). CHADS2 score was developed from a multivaried analysis of randomized trial participants with nonvalvular atrial fibrillation. The CHADS2 score included congestive heart failure, hypertension, age greater than 75 years, diabetes, and prior stroke or TIA. The CHADS score gives 1 point for each parameter and 2 points for a TIA or stroke history for a total of 3–6 points for high-risk score (Gage et al., 2001). The Framingham Heart Study followed community people who were offspring of the original cohort started in 1948 (Wang and Massaro, 2003). This cohort consisted of 705 patients, ages 55–94 years, with new-onset atrial fibrillation not treated with warfarin at the baseline. These patients were used to derive the risk score for stroke alone or stroke and death (Gage et al., 2004; Walker and Bennett, 2008). There is also a guideline from the 7th American College of Chest Physicians

NEUROLOGIC COMPLICATIONS OF CARDIOMYOPATHIES Table 9.2 ATRIA Cohort 3 risk stratification schemes used to predict atrial fibrillation-related thromboembolism Risk of thromboembolism (%)

CHADS Score FRAMINGHAM Score 7th ACEP AGE

Low

Intermediate

High

18.8 0 37.1 0–7 11.7 Age up to 65

61.2 1–2 46.6 8–15 7.9 Age 65–75

20.1 3–6 16.4 16–31 80.4 Age > 75 HTN, DM, CHF

HTN, hypertension; DM, diabetes mellitus, CHF, congestive heart failure.

Conference on Antithrombotic and Thrombolytic Therapy (see Table 9.2). A study of 2580 participants with data from clinical trial cohorts allows a comparison of similar sets of comorbid conditions where strokes could be identified prospectively and confirmed by CT scans (Gage et al., 2004). The absolute stroke rate is a rate in a group of patients already taking 325 mg ASA/day. The CHADS score identified patients at increased risk. Primary prevention participants with 3 or 4 points had a range of 3.3–8.4 strokes per 100 patient-years. Patients with a prior TIA or stroke averaged 10.8 strokes per 100 patient-years despite aspirin therapy (Gage et al., 2004). For the nonvalvular atrial fibrillation patients, all guidelines for consideration or indication of warfarin anticoagulation included advanced age, hypertension, diabetes, and prior stroke. The ATRIA investigators analyzed 10 392 patient records from the Northern California Kaiser Permanente healthcare system with nonvalvular atrial fibrillation (Fang et al., 2008). These were patients who appeared to have periods of time when they were off warfarin therapy. They examined the specific risk factors of age, gender, history of ischemic stroke, heart failure, hypertension, and diabetes. This amounted to 32 721 personyears of follow-up in a group with a mean age of 72 years. Almost 79% (78 7/10%) of these patients had one clinical risk factor for stroke and 40% acquired an additional clinical risk factor over the follow-up period. These authors validated 685 thromboembolic events (643 ischemic strokes, 42 peripheral emboli) that occurred off warfarin. The rate was 2.1 per 100 patient-years. These patients were evaluated for thromboembolic risk in the above schemes. All risk schemes have a fair ability to

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separate patients into low, intermediate or high risk for thromboembolism (see Table 9.2) (Fang et al., 2008). No risk score was better than any of the others. All schemes had only a fair discriminating ability when applied to the Kaiser cohort of patients. As in the SOLVE analysis, women appeared to have a higher risk for thromboembolsim (Dries et al., 1997; Fang et al., 2008). Anticoagulant therapy is highly effective in reducing all causes of thromboembolic events by 60%. Since warfarin anticoagulation is associated with some life-threatening complications, treatment thresholds could be reduced. More recently, an evaluation of other risk factors was performed. These included female sex, myocardial infarction, peripheral arterial disease, and completx aortic plaque, and older patients with age greater than 75 years (Lip, 2010). Age could be considered on a spectrum, since stroke risk increases beyond age greater than 65 years. The study looked at 1084 patients with nonvalvular atrial fibrillation who were not anticoagulated at baseline and had a year of follow-up regarding thromboembolic events. These patients were relatively high risk for thromboembolic events because 67.3% had hypertension and 38.4% had coronary artery disease (CAD). The average age was 66 years and 40.8% of the group were women. Antiplatelet medications were taken by 74.0% of the study group and ACE inhibitors or angiotensin receptor blockers (ARB) were taken by 56% of the group. On a multivariate analysis, female sex was the most significant associated factor ( p < 0.029). The CHADS2 score categorized 61.9% of these patients as intermediate risk (Lip, 2010). This European Heart Survey considered patients with prior stroke or TIA or patients older than 75 years as high risk and candidates for anticoagulation with warfarin. Moreover, a combination of two of these risk factors: hypertension (HTN), congestive heart failure (CHF), diabetes mellitus, age 65–75 years, female sex, and vascular disease, was also high risk (see Table 9.3, CHA2 DS2VASc score) (Lip, 2010). Each risk factor was counted as 1 point, with 2 points for age > 75 years. (see Table 9.3). In the CHA2DS2 VASc, a low risk score was 0, an intermediate risk score was 1, and a high risk score was > 1 (Lip, 2010). The higher the score, the greater the thromboembolic event rate during 1 year; this varied from 0.6% with a score of 1 to 11.1% at a score of 9. A subgroup analysis of the RE-LY trial showed higher CHADS2 scores were associated with a risk of stroke but also intracranial bleeding and death in patients on anticoagulation (Oldgren et al., 2011). The RE-LY trial compared two doses of dabigatran to warfarin treatment for atrial fibrillation. The increased rate of stroke and thromboembolic events in this study where patients were

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Table 9.3 Scores

CHF HTN Age > 75 Diabetes Stroke /TIA TOTAL

CHADS2

CHA2DS2VASc

1 1 1 1 2 6 High risk 3–6

1 1 2 1 2 Vascular disease MI, PAD 1 Age 65–74 1 Sex – Female 1 Total 10 High risk >1

CHF, congestive heart failure; HTN, hypertension; TIA, transient ischemic attack.

receiving anticoagulation was similar to the 1.5-fold increase at each CHADS score point in the original studies when patients were not receiving anticoagulation. The CHADS score can identify patients with an increased risk for bleeding as well as death (Oldgren et al., 2011). The CHA2DS2VASc score expanded this relationship in anticoagulated patients. In this trial, rates of stroke or intracranial bleeding were lower with dabigatran compared to warfarin. Reluctance to prescribe anticoagulation is related to problems of monitoring warfarin, as well as concern about bleeding risk and food and medicine interactions. This score expands the CHADS2 score. Patients that are high risk for thromboembolic events are also those who potentially would gain the greatest benefit but also a high risk for bleeding episodes or drug-to-drug interactions (Fang et al., 2008). Another retrospective analysis examined the records of 116 969 health insurance plan members with age over 40 years with atrial fibrillation who were followed for 4.5 years (Walker and Bennett, 2008). Some 35% of the patients were incident cases of atrial fibrillation and 65% were prevalent. Slightly more than half of the patients received warfarin (52%). Patients who did not receive warfarin (no INRs recorded) fell into the youngest age group (40–59 years). The prevalence of hypertension was 34% and age greater than 75 years was 36%. Stroke was observed and was 10 times more common than intracranial hemorrhage. Overall, there were 151 strokes, 62 intracranial hemorrhages, and 21 arterial thrombotic events in 13 200 person-years of INR monitoring. The mean INR was 2.2 with an acceptable range of 2.0–3.0. Subtherapeutic INRs were associated

with a doubling of incidence of stroke, and supertherapeutic INRs had a doubling incidence of intercranial hemorrhage. Nearly half of this insurance cohort had atrial fibrillation patients who did not receive warfarin although it was indicated (Massie and Collins, 2009). Another insurance database that included 171 393 patients with atrial fibrillation/flutter used the CHADS2 score to estimate stroke risk (Zimetbaum et al., 2010). These patients were mostly men (54.8%) and had an average age of 73.5 years. They were enrolled from 2003 to 2007. Some 30.3% of these patients had newly diagnosed atrial fibrillation/flutter and 69.75% had pre-existing atrial fibrillation/flutter. With the CHADS2 score to estimate stroke risk, 20% of the patients had low risk, 61.6% had intermediate risk, and 18.4% had high risk for stroke. Fewer than half of the patients in each CHADS2 score received warfarin. These health insurance claims databases suggest warfarin anticoagulation is underused in patients with atrial fibrillation/flutter despite guideline recommendations (Zimetbaum et al., 2010). The reasons warfarin anticoagulation was underused are not clear from these insurance studies but bleeding and fall risk were probably considered. A randomized trial of interventions to improve warfarin adherence (WIN 3) is now enrolling patients with a completion date of April 2013 (ClinicalTrials.gov). Will other anticoagulants besides warfarin improve compliance, especially in patients with heart failure? The WATCH trial (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) was designed to show optimal anticoagulation agents in patients with chronic heart failure. The left ventricular ejection fraction was 24% in these patients (Massie and Collins, 2009). Unfortunately the trial was terminated early because of low enrollment. With early termination 1587 patients rather than the proposed 4500 patients were enrolled. Power to detect a 20% difference dropped from 90% to 40%. Of the 1587 patients randomized, 523 received aspirin, 524 received clopidogrel, and 540 patients received warfarin. Atrial fibrillation occurred in each group, 9.3–10.3%, with no differences between groups. Even though this trial terminated early, the trial did not suggest the hypothesis that warfarin was superior to aspirin or that clopidogrel was superior to aspirin in preventing major cardiovascular outcomes. There was a low incidence of stroke. If hospitalizations for worsening heart failure and nonfatal stroke are examined, warfarin may be superior to aspirin. The authors suggested this result be interpreted with caution. The use of warfarin may have resulted in fewer strokes in this group but the benefit could be offset by increased bleeding risk. Anticoagulation for prevention of strokes with warfarin seems established (Rockson and Albers, 2004).

NEUROLOGIC COMPLICATIONS OF CARDIOMYOPATHIES Nevertheless, there are patients who cannot tolerate warfarin or for whom it is otherwise unsuitable. Connolly et al. (2011b) reviewed data from two ACTIVE trials. These trials compared the combination of clopidogrel 75 mg/day and aspirin 75–100 mg/day with vitamin K antagonists, notably warfarin. The ACTIVE W trial had 7554 patients with atrial fibrillation where warfarin was unsuitable (Connolly et al., 2009b). The mean CHADS2 score in this group was 2. All patients received aspirin 75–100 mg/day and were then randomized to clopidogrel 75 mg/day (3772 patients) or placebo (3782 patients) at a median follow-up of 3.6 years. Major thromboembolic events occurred in 832 patients receiving clopidogrel and aspirin, compared to 924 patients on aspirin alone ( p < 0.01). Thromboembolic events were considered to be myocardial infarction, stroke, and other noncardiac thromboembolic events. The difference here was primarily due to a reduction in stroke rate in patients taking clopidogrel and aspirin. Strokes occurred in 296 patients taking clopidogrel compared to 408 patients in the placebo group or aspirin alone ( p < 0.001). However, more bleeding was seen with clopidogrel and aspirin: 251 patients compared to 162 patients on aspirin alone (Connolly, the ACTIVE Investigators, 2009b). While major vascular events were reduced from 7.6% to 6.8%, major hemorrhage increased from 1.3% to 2.0%. Nevertheless, these authors emphasized that oral anticoagulation with warfarin was the preferred and recommended therapy for stroke patients with atrial fibrillation (Connolly et al., 2009b). A modest benefit for stroke prevention was seen with clopidogrel and aspirin in those patients who could not tolerate warfarin (Connolly et al., 2011a). Still, warfarin is only prescribed to 65% of patients who are appropriate candidates. Inconvenience of multiple laboratory tests, dietary interactions, risk of hemorrhage, and real world effectiveness are all important for warfarin use. In this trial of 1587 patients with atrial fibrillation and heart failure, there was no mortality difference between rate control and maintenance of normal sinus rhythm. All cause mortality was 8%; 182 patients (27%) in the rhythm control group died of cardiovascular causes and 175 patients (25%) died in the rate control group. These patients had an average age of 69 years, were mostly men (82%), and had a left ventricular ejection fraction of 27%. Oral anticoagulation was used in 88% of the rhythm control group and 92% of the rate control group. During the 37  19 months of follow-up, period stroke occurred in 3% of the rhythm control group and 4% of the rate control group. In congestive heart failure patients with left ventricular systolic dysfunction, normal sinus rhythm did not protect against stroke, although the incidence was low with oral anticoagulation (Roy et al., 2008).

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A more recent trial evaluated the technique of radiofrequency ablation in patients with atrial fibrillation. The CHADS2 and the CHA2DS2VASc schemes were developed using patients with nonvalvular atrial fibrilation. Chao et al. (2011) investigated the CHADS2 and the CHA2DS2VASc schemes in 565 patients who were treated with radiofrequency ablation in current atrial fibrillation. Prior to radiofrequency ablation, warfarin anticoagulation in these patients was based on the CHADS2 scores. After radiofrequency ablation, warfarin was continued in patients with CHADS2 score  2. Discontinuation of warfarin was considered after 3 months if the CHADS2 score 1 providing there was no recurrence of atrial fibrillation, no symptoms, and a normal Holter or 7 day event monitor ECG recording. In this study, 27 patients (4.8%) experienced adverse events in the 39.2  22.6 months of follow-up (Chao et al., 2011). Nine patients died; nine patients had a stroke, six patients had a TIA, two had a pulmonary embolus, and one had a peripheral embolus. Recurrence of atrial fibrillation was a significant predictor in these adverse events. Event rates were higher with recurrent atrial fibrillation: no recurrences 2.8%, recurrences of atrial fibrillation 9.6% ( p < 0.01). The CHADS2 and the the CHA2DS2VASc scores remained significant predictors and the higher the score, the greater the event rate (see Fig. 9.2). In this study, the exact technique of radiofrequency ablation was not described, and the techniques for pulmonary vein isolation and radiofrequency ablation are still evolving. More data will be needed here. Based on the RE-LY Trial, dabigatran 150 mg twice a day was approved by the US Food and Drug Administration (FDA) in October 2010 (Oldgren et al., 2011). When compared to dose-adjusted warfarin, dabigatran reduced stroke, thromboembolic event, and death by 0.5% per year. Major bleeding episodes did not differ but intracranial bleeding was less frequent with dabigatran (Connolly et al., 2009). Newer antithrombotic agents may provide an alternative medication. Stroke or systemic embolism was compared in patients with atrial fibrillation taking warfarin or dabigatran. The trial was a noninferiority trial where two doses of dabigatran, 110 mg and 150 mg, were compared to warfarin (INR 2.0–3.0) (Connolly et al., 2009). Stroke or systemic embolism was seen in 182 patients on the 110 mg dabigatran dose, 134 patients had a thromboembolic event on the 150 mg dabigatran dose, and 199 patients receiving warfarin had an embolic event. Rates of death were not significantly different. Rates of lifethreatening bleeding, intercranial hemorrhage, and major or minor bleeding were higher with warfarin than with higher dose of dabigatran ( p < 0.05). But there was more gastrointestinal tract bleeding with 150 mg dabigatran than with warfarin. There was a trend toward more

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J.F. MORAN centers in 36 countries to compare apixaban 5 mg/twice a day with aspirin 81–324 mg/day. The Data Safety and Monitoring Committee terminated the study after 104 events occurred. There was a treatment benefit in favor of apixaban exceeding 4 standard deviations. The mean duration of follow-up was 1.1 years. There were 51 primary outcome events in the apixaban arm (1.6%/year) and 113 in the aspirin arm of the study (3.7%/year). Where warfarin was considered unsuitable, apixaban reduced the risk of stroke or systemic embolus by more than 50% without a significant risk of major bleeding (Connolly et al., 2011). Several other factor Xa inhibitors, as well as thrombin inhibitors, are in development and under investigation.

BLEEDING RISK: WARFARIN USAGE IN PATIENTS WITH ATRIAL FIBRILLATION

Fig. 9.2. Event rates and scores. The adverse event rates continuously increased when the CHADS2 (A) and the CHA2 DS2-VASc (B) scores became higher (see text for discussion). (Adapted from Chao et al., 2011, with permission.)

bleeding with dabigatran 110 mg dose. The rate of myocardial infarction was higher with dabigatran. Whereas warfarin doubles the risk of intercranial hemorrhage, dabigatran in both doses has a rate of this complication less than 1/3 the rate of warfarin. Both doses of dabigatran were noninferior to warfarin with respect to stroke or systemic embolism. Overall, the 110 mg dose of dabigatran had similar rates of stroke and thromboembolism and lower rates of bleeding. The 150 mg dose had comparable rates of stroke and thromboembolism and a similar rate of hemorrhage when compared to warfarin. More data are clearly needed here. The FDA subsequently approved dabigatran 150 mg twice a day on the basis of the RE-LY trial (Oldgren et al., 2011). Another factor Xa inhibitor, apixaban, has shown effectiveness in the prevention of strokes in patients with atrial fibrillation not taking warfarin (Connolly et al., 2011). These authors enrolled 5599 patients from 522

There is much evidence in favor of the use of warfarin anticoagulation to reduce the risk of mortality, thromboembolic events, and stroke in patients with atrial fibrillation. Stroke rate is reduced by two-thirds with warfarin and perhaps 22% with antiplatelet therapy. Concerns about bleeding could be ameliorated with a score that estimated bleeding risk. Table 9.4 shows two scoring schemes that can be used to estimate bleeding risk. In an individual patient, the risk of stroke could be estimated as well as the risk of bleeding. The benefit or harm might be better understood. In the HEMORR2HAGES scheme, severe bleeding risk estimates were obtained from the National Registry of Atrial Fibrillation that included 3791 patients enrolled with Medicare (Gage et al., 2006). The mean age of this group was 80.2 years and 57% of the group were women. In 3138 patient-years of follow-up, 162 admissions for bleeding occurred, or 5.2 bleeds per 100 patient-years. Gastrointestinal tract bleeding accounted for 67.3% while 15.4% were intracranial bleeding. Any bleeding in any location resulted in a 30 day mortality of 21.6% (Gage et al., 2006). Hospitalization rates for bleeding in the patients taking the oral anticoagulation agent warfarin was 4.9 per 100 patient-years. Comorbid conditions were important. High-risk patients had a greater bleeding rate than lowrisk patients. All schemes are affected by different patient populations. Elderly patients and patients new to warfarin therapy may be at greater risk. Stroke risk and bleeding risk from warfarin therapy are clearly related. In Table 9.4, the HEMORR2HAGES risk score is complex, while the HAS-BLED score may be easier to use. In the Euro Heart Survey of Atrial Fibrillation, 3456 patients with nonvalvular atrial fibrillation were followed for 1 year. These patients were younger at mean age of 66.8 years and 59% were men

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Table 9.4 Scores HEMORR2HAGES

HAS-BLED H HTN systolic BP > 160 A AB renal/liver function 1 point each S Stroke B Bleeding tendency predisposition L Labile INRs E Elderly age > 65 years D Drugs/alcohol 1 point each

-1 -2

H Hepatic / renal disease E Ethanol abuse

-1 -1

-1 -1

M Malignancy O Age > 75 years

-1 -1

R Low platelet count/function R Rebleeding risk H HTN uncontrolled

-1 -1 -1

-1 -1 -1 or -2 TOTAL 9

A G E S

Anemia Genetics Fall risk Stroke

-1 -1 -1 -1 TOTAL 11

HTN, hypertension; AB, abnormal; INR, International Normalized Ratio.

(Pisters et al., 2010). Of these 3456 patients, 2242 took warfarin (64.8%) and 286 (12.8%) were also given aspirin and or clopidogrel. Antiplatelet therapy alone was taken by 24% of the group and 10.2% received no antithrombotic therapy. Thirty-three patients received anticoagulation because of a CHADS2 score  1, and four of these had a HAS-BLED risk that outweighed their individual stroke risk (Pisters et al., 2010). The European Heart survey on atrial fibrillation identified three independent risk factors of major bleeding: age > 65 years, clopidogrel use, and renal failure. There are fewer risk factors that are readily available in HAS-BLED so it could be more user-friendly. HAS-BLED also identified dual therapy warfarin plus clopidogrel as a risk factor (Pisters et al., 2010). Interestingly there were 34 patients (2.2%) with a CHADS2 score > 2 who did not have a major bleeding episode but would have been denied warfarin on the basis of a HAS-BLED risk that outweighed their stroke risk. Risk factors for stroke are also risk factors for bleeding. Since the HAS-BLED score may be easier to apply, it may be more useful.

GENETICS Modifiable risk factors for stroke do not account for as much risk as coronary risk factors. Clinically it is difficult to distinguish ischemic from hemorrhagic stroke. Family history of stroke as well as some single nucleotide polymorphisms are associated with an increased stroke risk. Monogenic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and

leukoencephalopathy (CADASIL) is an example (Baird, 2010). A number of genetic factors appear to overlap between stroke and heart. The vasculopathy of CADASIL has been associated with an increased risk of myocardial infarctions. Another monogenetic disorder is Fabry disease. Fabry disease is an X-linked disorder causing a deficiency of agalactosidase, which leads to an accumulation of glycosphingolipids in vascular endothelial cells. Ischemic stroke under age 55 in patients with Fabry disease has been associated with cryptogenic stroke (Flossman, 2006). The contribution to genetic factors in stroke is small at present. Guidelines for evaluation of genetic abnormalities are organized by phenotype (Hershberger et al., 2009b). Clinicians recognize these various entities by phenotype since clinical management decisions are made this way. The quality of genetic data on various cardiomyopathies varies and is evolving, and randomized clinical trials involving available specific genetic tests are not currently readily available. Evidence supporting clinical genetic testing also varies greatly. The guidelines recognize that there may be overlap among phenotypes and mutations can be associated with more than one phenotype. Table 9.5 shows a guideline for evaluating patients with cardiomyopathy (Hershberger et al., 2009a). Hypertrophic cardiomyopathy is thought to develop from mutations in genes encoding sarcomeric contractile proteins and other genetic causes of the hypertrophic phenotype. It is characterized by left ventricular hypertrophy, predominantly of the interventricular septum, myosite disarray, and fibrosis (Hershberger et al., 2009b).

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Table 9.5 Genetic evaluation A. Careful family history over three generations B. Clinical screening for cardiomyopathy in asymptomatic first-degree relatives C. Evaluation, genetic counseling, and testing of cardiomyopathy patients – a referral center (Adapted from Hershberger et al., 2009a.)

Annual mortality is low but atrial fibrillation and stroke are seen. The importance of outflow tract obstruction and resulting increased mortality risk has recently been reviewed (Maron et al., 2009). Removal of the outflow tract gradient provides symptomatic benefit and favorable long-term survival. Left ventricular noncompaction is classified as a primary cardiomyopathy. The genetic inheritance is unclear but there are spontaneous as well as familial patients. Heterozygous mutations in left ventricular noncompaction were found in three genes: b-myosin heavy chain (MYH7), a-cardiac actin, and cardiac troponin T. The mutations in MYH7 as well as others have been found in both hypertrophic cardiomyopathy and dilated cardiomyopathy (Klassen et al., 2008). These authors studied 63 unrelated subjects with echo evidence of left ventricular noncompaction and without hypertrophic cardiomyopathy or dilated cardiomyopathy. This cohort was screened for six sarcomere genes with mutations found in three different sarcomere genes. In 11 people with sarcomere gene mutations, eight were in b-myosin heavy chain, MYH7 (Klassen et al., 2008). Sarcomere mutations in left ventricular noncompaction, hypertrophic cardiomyopathy, and dilated cardiomyopathy can produce cardiomyopathy with decreased left ventricular function and possible mural thrombi and thromboembolic strokes (Dellefave et al., 2009). These actions suggested a shared molecular etiology of different cardiomyopathy phenotypes (Klassen et al., 2008). Hypertrophic cardiomyopathy differs from left ventricular noncompaction because of the spongy nature of the myocardium. Doppler echocardiograms can visualize the blood flow going into the trabecular recesses. In a large series of 1299 patients with hypertrophic cardiomyopathy, 28 (2%) were identified with left ventricular apical aneurysms (Maron et al., 2008). These aneurysms were identified by two-dimensional echocardiography or cardiovascular magnetic resonance images. One-half of these left ventricular aneurysm patients had a confirmed family history of hypertrophic cardiomyopathy and one or more of the sarcomere protein mutations. Ten patients with left ventricular aneurysms (36%) had an intracavitary pressure gradient. Two of the 28 patients developed disabling thromboembolic stroke events and two others

had a mural thrombus in the aneurysm. Hypertrophic cardiomyopathy has a familial variety of clinical presentations, from sudden death in the young to heart failure in older patients. It is a common disease occurring in 1 in 500 in the general population. Mutations in sarcomere proteins affect all myocardial cells but it is unclear how regional myocardial hypertrophy develops. Sixteen hypertrophic cardiomyopathy mutation carriers were identified with mutations in cardiac myosin binding protein or a missense mutation at the gene encoding a-tropomyosin (Germans et al., 2006). There was no left ventricular hypertrophy and normal global left ventricular function. Cardiovascular magnetic resonance plus two-dimensional echocardiography studies were performed and a control group was also studied. Thirteen of 16 hypertrophic cardiomyopathy carriers had abnormal structure of the myocardium (81%). The abnormal structures consisted of profound crypts in the basal and mid-segment of the left ventricular inferoseptal myocardium, only visible at end diastole. The crypts could be visualized in the inferoseptal wall up to the epicardium when the left ventricular wall was less than 9 mm thick. Three female mutation carriers had no crypts. These crypts could be confused with left ventricular noncompaction except that left ventricular noncompaction generally involves the apical and lateral segments of the left ventricle and not the basal interventricular septum. The differential between these two entities, hypertrophic cardiomyopathy and left ventricular noncompaction, is important because hypertrophic cardiomyopathy carriers may be asymptomatic for decades and left ventricular noncompaction patients are at increased risk for thromboembolism (Germans et al., 2007). All of these cardiomyopathies are caused by various mutations on the sarcomere gene and suggest a spectrum of disease. These cardiac disorders affect the brain through the development of mural thrombi and cardioembolic strokes. In some neurologic disorders the cardiovascular manifestations can cause a greater degree of morbidity and mortality than the neurologic diseases themselves. The muscular dystrophies are a group of inherited disorders with variable cardiovascular involvement. The dystrophinopathies are a result of mutations in the dystrophin gene on chromosome Xp21.1. These dystrophinopathy patients comprise the diseases Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilatative cardiomyopathy (XLDCM). Phenotypic differences in these diseases are thought to be the result of different types of mutations in the dystrophin gene (Finsterer and Stollberger, 2003). Clinically the degree of cardiac dysfunction varies from severe arrhythmias, dilated cardiomyopathy and heart failure, to cardiac death. The pathology in the

NEUROLOGIC COMPLICATIONS OF CARDIOMYOPATHIES 125 dystrophinopathies is caused by a progressive replaceThere is a broader availability of clinical genetic testment of cardiomyocytes and the Purkinje fiber system ing for specific cardiomyopathies. Sarcomeric mutaby connective tissue or fat. tions may be different and may be associated with Duchenne muscular dystrophy is the most common different phenotypes. Rhythm control and rate control dystrophinopathy accounting for 80–85% of total cases for atrial fibrillation are important. and occurring in approximately 1 in 3500 live-born males. It is characterized by proximal muscle wasting MITOCHONDRIAL DYSFUNCTION and weakness that can lead to immobility by the teenage Since mitochondria are a major site of energy production years. The mutation is inherited by an X-linked trait in two-thirds of the patients. Cardioembolic events may in the cell, it should not be surprising that energyappear as the left ventricular ejection fraction is reduced dependent tissue such as the myocardium would be in 30% of patients, and some hypokinesia is present in affected by mitochondrial dysfunction. Cardiomyopathy another 50%. Congestive heart failure is present in can be an important complication of mitochrondrial dis10–20% of terminal patients. The electrographic abnorease. In patients with mitochrondrial encephalopathy carmalities of DMD and BMD show tall R waves in lead V-1 diomyopathy, especially hypertrophic cardiomyopathy, can occur as well as lactic acidosis and stroke-like epiand Q waves in the lateral and inferior EKG leads. These sodes (MELAS) (Okajima et al., 1998). In this small series electrocardiographic changes are thought to represent selective atrophy and fibrosis of the posterobasal and latof 11 patients averaging age 11.3 years (range 4–16 years), eral walls of the left ventricle. six patients were followed for more than 5 years. Initially Becker muscular dystrophy is allelic to DMD and left ventricular hypertrophy was seen but then a decreasoccurs at one tenth of the frequency. The onset of the ing left ventricular ejection fraction developed. One disease is often in the third decade of life. Approxipatient died from congestive heart failure and one from mately a third of the patients develop congestive heart encephalopathy. Overall, sudden cardiac arrhythmia seems to be a major cause of death. Between 10% and failure. BMD has a milder course than DMD. A gait 15% of these patients progress from left ventricular abnormality may develop by the time patients reach 10–15 years of age (Finisterer and Stollberger, 2008). hypertrophy to a dilated cardiomyopathy. BMD is due to deletion, duplication, or mutations in More recently, mitochrondrial disorders suggest disthe dystrophin gene. BMD manifests in skeletal muscle ease arising from defects in the mitochrondrial respiraand the myocardium but also in the brain. Intelligence tory chain (MRC). This MRC consists of five subunit may be below average and rarely epilepsy is diagnosed. complexes embedded in the inner mitochrondrial memAtrial fibrillation has been observed resulting in a stroke. brane (Bindoff, 2003). Their purpose is to generate adenosine triphosphate (ATP) oxidative phosphorylation. Rare patients may show left ventricular hypretrabeculaDefects here can affect the heart and skeletal muscle. tion on the echocardiogram or MRI as well as mural thrombi. In these patients with atrial fibrillation and Biopsy material of skeletal muscle showed abnormal mural thrombi, anticoagulation is indicated. Congestive mitochondria as well as ragged red fibers. Mitochronheart failure is treated in the usual fashion. drial disorders are a heterogeneous group of diseases Emery–Dreifuss muscular dystrophy is a disease where mitochrondrial DNA is inherited maternally to inherited in an X-linked recessive fashion. There is a hetchildren of both sexes (Holmgren et al., 2003). In this erogeneity in families that fit an X-link autosomal domreport of 301 children referred for neuromuscular diseases, 101 had mitochrondrial disease, found over a inant and autosomal recessive pattern. The gene period from 1984 to 1999. Seventeen of these patients responsible codes for a membrane protein termed “emerin.” Nuclear membrane proteins such as emerin with mitochrondrial myopathy had cardiomyopathy and lamins A and C provide structural support for the (17%). Diagnosis of the cardiomyopathy was based on nucleus. Arrhythmia such as atrial fibrillation, atrial echo Doppler studies. Hypertrophic cardiomyopathy arrest, or atrial standstill with junctional rhythm are was diagnosed when the left ventricular thickness was reported (Finsterer and Stollberger, 2003). An X-linked greater than two times the standard deviation scores. dilated cardiomyopathy can present as a rapidly progresSimilarly the left ventricular cavity was considered dilated when the left ventricular inner diameter was sive myocardial disorder with rapidly developing congreater than or equal to two standard deviation scores. gestive heart failure. This XLDCM myopathy has dystrophin selectively absent from the myocardium. The diagnosis of cardiomyopathy was made about the There is no treatment for these patients with muscular same time in 10 of these 17 patients. In 7 of these 10 dystrophy. Arrhythmias such as atrial fibrillation are patients, the diagnosis was made at ages 1 to 27 years. treated in the usual fashion; automatic implantable defiEleven of the 17 patients with cardiomyopathy died in brillators have been used in selected patients. the study and 1 had a cardiac transplant (71%). During

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the same study period, 22 of the remaining 84 patients without cardiomyopathy died (26%). On the basis of their experience these authors speculated the incidence of mitochrondrial cardiomyopathy in children and young adults was around 1 in 50 000 with a male to female ratio of 2.5:1. Mitochondrial cardiomyopathy had a poor prognosis overall with a mortality rate around 70%.

SUMMARY The left ventricular dysfunction seen with cardiomyopathy patients is a complex heterogeneous entity. Genetic evaluations are important here, for example, the sarcomeric mutations seen in hypertrophic cardiomyopathy, left ventricular noncompaction, and dilated cardiomyopathy. The connection between cardiomyopathies and neurologic disease is stroke development. Left ventricular dysfunction can present with a range of left ventricular ejection fractions and anatomic abnormalities. Poor contractility is associated with swirling echo-densities in the left ventricular chamber seen in echocardiography. Mural thrombi can be seen in cardiomyopathy regardless of etiology. There seems to be no consistent decrease in left ventricular ejection fraction, whether less than 27% or less than 35%, where mural thrombus always develops. Entities such as left ventricular noncompaction seem to be at risk regardless of the left ventricular ejection fraction. The percentage of thromboembolic events seems relatively low when compared to the incidents of mural thrombi, no matter how they are identified; echocardiography, MRI or multidetector CT. There are no randomized clinical trials here to guide therapy. Nevertheless, the guidelines would recommend chronic anticoagulation when a mural thrombus is found. Studies involving cryptogenic stroke and patent foramen ovale are apparently searching for suitable patients for device closure trials. Trials in patients with atrial fibrillation have shown efficacy in reducing stroke and mortality with oral anticoagulation. This is a standard of care. However, oral anticoagulation seems underutilized in patients with atrial fibrillation, possibly because of bleeding risk. This is especially important in elderly patients, in whom the frequency of atrial fibrillation is higher. Starting anticoagulation can sometimes be difficult, especially in the elderly patient (Wyse, 2007). Risk stratification schemes are good at identifying the high-risk patients for whom oral coagulation gives the greatest benefit. The risk schemes do not include dementia as a risk, despite the relationship with atrial fibrillation. This area and the observation of silent cerebral infarcts with cardiomyopathy need more study. In the absence of randomized clinical trials, tailoring of treatment to the individual by an experienced clinician will generate the greatest benefit.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 10

Neurologic complications of arrhythmia treatment MEGAN C. LEARY1, JEFFREY S. VELUZ2, AND LOUIS R. CAPLAN3* Department of Neurology, Harvard Clinical Research Institute, Boston, MA, USA

1 2

Cardiothoracic Surgery, St. Luke’s Hospital and Health Network, Bethlehem, PA, USA

3

Division of Stroke and Cerebrovascular Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA

DIRECT NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA An arrhythmia is defined as an abnormal heart rhythm. Certain arrhythmias have much higher rates of neurologic complications, including stroke, cognitive impairment, and dementia. According to the Stroke Data Bank, which divided potential causes of cardioembolic brain embolism into strong and weak sources, both atrial fibrillation and sick sinus syndrome are considered to be strong sources of cardiogenic stroke (Kittner et al., 1992; Leary and Caplan, 2009).

Stroke and cerebrovascular disease ATRIAL FIBRILLATION Persistent and paroxysmal atrial fibrillation is a potent predictor of first and recurrent stroke, with > 75 000 attributed cases annually. Cardiogenic cerebral embolism is responsible for approximately 20% of ischemic strokes, and there is a history of nonvalvular atrial fibrillation in roughly half of these patients (Wolf et al., 1987; Bogousslavsky et al., 1988; Cerebral Embolism Task Force, 1989; Fuster and Halperin, 1989; Bogousslavsky et al., 1991; Sacco et al., 2006). Risk of embolism due to atrial fibrillation varies depending on many factors. For example, associated heart disease, age, duration, chronic versus intermittent fibrillation, and atrial size all influence the embolic risk in patients with atrial fibrillation. In general, atrial fibrillation has an annual estimated stroke rate of 4.5% (Wozakowska-Kaplon et al., 2009). In individuals over 80 years atrial fibrillation is

the single leading cause of major stroke. Moreover, about 25% of patients with atrial fibrillation in the absence of neurologic deficits have computed tomography (CT) signs of one or more silent brain infarcts (Wozakowska-Kaplon et al., 2009). Restoration of sinus rhythm in patients with atrial fibrillation is a logical strategy to prevent the neurologic complications of this dysrhythmia. The most common means of restoring sinus rhythm is pharmacologic antiarrhythmic therapy with or without electrical cardioversion. Five randomized clinical trials compared rhythm to rate-control strategies in patients with atrial fibrillation. These trials examined mortality, thromboembolic complications, exercise tolerance, quality of life, hospital admissions, and drug-related adverse reactions. Hospital admissions and drug-related adverse events were increased in the rhythm-control subjects. Stroke and systemic emboli occurred more often in the rhythm-control subjects, many of whom had been withdrawn from anticoagulation. Rhythm control offered no advantage compared with rate control for patients with atrial fibrillation at increased risk for stroke. One explanation for this finding is that those patients thought to have been successfully converted to sinus rhythm in fact had asymptomatic paroxysmal episodes of atrial fibrillation increasing their risk of stroke because they were unprotected by anticoagulation. Pharmacologic attempts to restore atrial fibrillation to sinus rhythm do not improve mortality or reduce stroke. All patients with atrial fibrillation at increased risk for stroke should be continued on long-term anticoagulation even if they appear to have been successfully restored to sinus rhythm (Sherman, 2007).

*Correspondence to: Louis R. Caplan, M.D., Division of Stroke and Cerebrovascular Disease, Palmer 125, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel: þ1-617-632-8910, Fax: þ1-617-632-8920, E-mail: [email protected]

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SICK SINUS SYNDROME Sick sinus syndrome is the name given to several conditions in which the sinus node does not function normally. It affects about three out of every 10 000 persons, and it becomes more common with advancing age. Drugs used for other cardiac conditions often may worsen or cause the development of sick sinus syndrome. In addition, patients with sick sinus syndrome are at high risk for cardioembolic stroke (Fairfax et al., 1976; Bathen et al., 1978). The annual stroke incidence rate in nonpaced sick sinus syndrome patients might approach 8–10% (Radford and Julian, 1974; Abdon and Johnsson, 1979).

MULTIFOCAL PREMATURE VENTRICULAR CONTRACTIONS

Premature ventricular complexes (PVCs) on a 2 minute electrocardiogram are a common, largely asymptomatic finding associated with increased risk of coronary heart disease and death. They may reflect atherosclerosis or other pathogenic pathways that predispose to arrhythmias and stroke. Agarwal et al. (2010) conducted a prospective evaluation of the Atherosclerosis Risk In Communities (ARIC) study cohort (n ¼ 14 783) of middle-aged men and women to assess whether the presence of PVCs at study baseline influenced the risk of incident stroke over several years. PVCs were seen in 6.1% of the participants at baseline, and 4.9% had incident stroke. The unadjusted cumulative proportion of incident stroke in individuals with any PVC was 6.6% compared with 4.1% in those without PVC. Among individuals without hypertension and diabetes at baseline, PVCs were independently associated with incident stroke. Surprisingly, when participants had hypertension or diabetes at baseline, the presence of PVCs did not increase the hazard ratio for stroke compared with participants without PVCs. The association was stronger for noncarotid embolic stroke than for thrombotic stroke, and there was a marked increase in stroke risk in those participants with  4 PVCs in a 2 minute recording. The increased stroke risk was observed irrespective of gender and race (Agarwal et al., 2010). It is unclear how PVCs influence stroke risk (Worthington et al., 2010). PVCs could represent a “culprit arrhythmia” (Bhushan and Asirvatham, 2009) or an early sign of accumulating end organ damage as a result of identified or unidentified risk factors shared with stroke. The ARIC investigators posit that PVCs may be intimately related to the development of new-onset atrial fibrillation, a major risk factor for stroke (Agarwal et al., 2010; Worthington et al., 2010). During follow-up, new-onset atrial fibrillation was identified in 15% of people with PVCs, accounting for 34% of stroke

cases in this group. Atrial fibrillation diagnosis can be elusive, and the reported atrial fibrillation prevalence may be an underestimate. An association between PVCs and atrial fibrillation may explain the preponderance of “embolic stroke of noncarotid origin” in those with PVCs (Agarwal et al., 2010; Worthington et al., 2010). A 2 minute rhythm strip is not a routine test but is simple and feasible in a wide range of clinical settings. PVCs detected on a rhythm strip appear to be a newly identified marker, if not risk factor, for stroke. Most importantly, PVCs may identify stroke risk in middle-aged men and women without hypertension, diabetes, and other established risk factors. If the ARIC findings are replicated with further research, a rhythm strip may be a useful tool in identifying those most likely to benefit from close surveillance as well as lifestyle and pharmacologic interventions (Worthington et al., 2010).

SUPRAVENTRICULAR TACHYCARDIA Unlike adults, a cardiac illness causing stroke is unusual in an otherwise healthy child. However, supraventricular tachycardia has been reported as a cause of stroke in children (Atluru et al., 1985; Zapson et al., 1995). Interestingly, there is no reported link between supraventricular tachycardia and risk of stroke in adults (Aronow et al., 1996).

WOLFF–PARKINSON—WHITE SYNDROME The prevalence of Wolff–Parkinson–White (WPW) syndrome among patients with MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and the A3243G mutation is much higher than in the normal population. While strokes and other neurologic issues associated with MELAS are probably not caused by the arrhythmia, it is important to note that WPW may manifest much earlier than neurologic symptoms. Patients with WPW syndrome should be monitored over time for the development of neurologic abnormalities consistent with MELAS, including seizures, deafness, short stature, and stroke. If neurologic symptoms occur, patients should be screened for the A3243G mutation (Sproule et al., 2007).

Disorders of cognition COGNITIVE IMPAIRMENT Wozakowska-Kapon et al. (2009) investigated whether cognitive function in patients with permanent atrial fibrillation was worse than in patients with sinus rhythm. Subjects were aged > 65 years, without previous stroke or dementia, with permanent arrhythmia lasting > 12 months. Of their 51 patients, 51% had hypertension, 37% coronary artery disease, 12% with concomitant sick

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 131 sinus syndrome or atrioventricular advanced block with irreversibly damaged by ischemic-anoxic damage a VVI pacemaker implanted. Patients in the normal sinus (Caplan, 1999a). Cardiologists must become very rhythm control group had a lower-risk profile and familiar with the pathology, signs, and prognosis of received antithrombotic therapy less often than the atrial brain dysfunction after periods of circulatory failure fibrillation group. However, a significant proportion of (Leary and Caplan, 2009). patients, particularly in the atrial fibrillation group, Different brain regions have selective vulnerability to received less than optimal prophylactic treatment with hypoxic-ischemic damage. Regions that are remote and anticoagulants. Cognitive status was found to be signifat the edges of major vascular supply are more liable to icantly worse in the atrial fibrillation group, compared hypoperfusion injury. Hypoperfusion injuries in these with the sinus rhythm group (p < 0.05), with cognitive areas are usually referred to as border zone or watershed impairment diagnosed in 43% of patients in the atrial cerebral infarction. In the cerebral cortex, these border fibrillation group and 14% in the sinus rhythm group. zone regions are between the anterior cerebral artery Permanent atrial fibrillation in patients older than 65 (ACA) and middle cerebral artery (MCA), and between years is clearly associated with lower Mini Mental State the MCA and posterior cerebral artery (PCA) (Leary and Examination (MMSE) scores compared with individuals Caplan, 2009). When hypoxia and ischemia are especially with sinus rhythm (Puccio et al., 2009; Wozakowskasevere, the spinal cord may also be damaged (Silver and Kapon et al., 2009) Interestingly, studies have shown Buxton, 1974; Caronna and Finklestein 1978). If cortical that patients with paroxysmal atrial fibrillation have damage is severe, cytotoxic edema causes massive brain worsened cognitive performance than patients with perswelling, cessation of blood flow, and brain death manent atrial fibrillation, suggesting a possible micro(Leary and Caplan, 2009). embolic pathogenesis. Anticoagulation therapy could The initial neurologic findings and their course are helpplay a protective role; however, more evidence is needed. ful in predicting neurologic outcome. Among patients who have meaningful responses to pain at 1 hour after resusciDEMENTIA tation, almost all survivors have preserved intellectual function. Patients who do not respond to pain by 24 hours Ettorre et al. (2009) studied the relationship between typically either die or remain in a vegetative state (Bell and atrial fibrillation and various types of dementia, includHodgson, 1974; Levy et al., 1985). In one study of out-ofing vascular dementia, Alzheimer’s disease, and mixed hospital cardiac arrests, patients who did not awaken died dementia. In women – but not men – a statistically sigon average 3.5 days after arrest. Of 459 patients, 40% nificant association was found between the triad of never awakened. Among those who did awaken, 33% MMSE score, clinical dementia rating score, and atrial had persistent neurologic deficits. Prognosis could be fibrillation occurrence. Unexpectedly, atrial fibrillation made by analysis of pupillary light reflexes, eye movewas associated with Alzheimer’s disease more often than ments, and motor responses (Longstreth et al., 1983a, b). with vascular dementia, becoming a possible risk factor Myoclonus also occurs after resuscitation and is a sign for this neurodegenerative disease. The authors note that of poor prognosis as well (Leary and Caplan, 2009). their results are supported by many studies that posit that With severe hypoperfusion ACA-MCA border-zone brain hypoperfusion has a pathogenetic role in causing cerebral infarction, there is weakness of the arms and sporadic Alzheimer’s disease, and they argue that proximal lower extremities with preservation of face, impaired cerebral perfusion may be the primary trigger leg, and foot movement (also referred to as the “man in developing this disease. Moreover, the mildly favorin a barrel” syndrome). With MCA-PCA ischemia, the able treatment response in patients with Alzheimer’s dissymptoms and signs are predominantly visual, and can ease to therapy that improves cerebral blood flow is also include difficulty seeing and integrating the features a consistent finding (Ettorre et al., 2009). In addition to of large objects or scenes despite retained capacity to the higher prevalence of atrial fibrillation observed in see small objects in some parts of their visual fields. patients with dementia ( p ¼ 0.0131), ventricular tachyReading may be impossible (Hecaen and Ajuriaguerra, cardia ( p ¼ 0.0156) and gaps ( p ¼ 0.0347) have also been 1954; Caplan, 1999a; Leary and Caplan, 2009). Formation reported (De Pedis et al., 1987). of new memories is difficult and patchy; retrograde amnesia can also be present. The amnesia may not be NEUROLOGIC COMPLICATIONS reversible, can be accompanied by visual abnormalities, OFARRHYTHMIA TREATMENT: apathy, and confusion, or may be isolated (Leary and CARDIOPULMONARY RESUSCITATION Caplan, 2009). It has been suggested that half of the Unfortunately, patients with arrhythmia can require long-term survivors of aborted sudden cardiac death cardiopulmonary resuscitation (CPR). After CPR, the are cognitively intact 6 months after resuscitation but heart often recovers in individuals whose brains are that 25% have moderate to severe impairment in

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memory, which could hamper and/or preclude the resumption of prearrest roles (Sauve´ et al., 1996). Aphasia, dyskinesias, abnormal motor function, and praxis have also been observed in survivors of arrhythmic cardiac arrest (Maryniak et al., 2008).

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT: DRUGS Antiarrhythmics Many antiarrhythmic drugs that are given to patients with cardiac disease have possible neurologic side-effects

(Caplan, 1999b). It is important to remember that virtually all of these neurologic complications are reversible with the discontinuation of the offending agent (Meschia and Biller, 1998). Potential neurologic side-effects from antiarrhythmic medications are listed in Table 10.1. Dizziness and headache, in particular, are common. Adenosine In patients with known migraines, intravenous adenosine has been reported to precipitate severe headaches (Brown and Waterer, 1995; Guieu et al., 1998; Meschia and Biller, 1998). Adenosine has also been associated with headaches in healthy subjects. While regional cerebral blood flow and middle cerebral artery flow

Table 10.1 Neurologic complications from antiarrhythmic medication Side-effect

Medications

Ataxia Anticholinergic effects Autonomic neuropathy Carpal tunnel Confusion/delirium

Amiodarone, mexiletine, propafenone, tocainide Disopyramide, quinidine Amiodarone Metoprolol Amiodarone, digoxin, diltiazem, disopyramide, esmolol, lidocaine, metoprolol, propafenone, quinidine, sotalol, tocainide, verapamil Diltiazem, dofetilide, dronedarone, encainide, esmolol, flecainide, ibutilide, isoprenaline (isoproterenol), metoprolol, propafenone, quinidine, sotalol, tocainide, verapamil Encainide, flecainide, mexiletine, propafenone, tocainide Amiodarone Flecainide Encainide, flecainide, propranolol, sotalol, verapamil Adenosine, dofetilide, dronedarone, encainide, esmolol, flecainide, ibutilide, isoprenaline (isoproterenol), metoprolol, propafenone, quinidine, sotalol, tocainide, verapamil Amiodarone Metoprolol, propafenone Encainide, metoprolol, mexiletine, tocainide Encainide Diltiazem (Eaton–Lambert), procainamide, propranolol, propafenone, quinidine Amiodarone, diltiazem, propafenone, verapamil Amiodarone, diltiazem, procainamide, propranolol Propranolol Amiodarone, tocaininde Amiodarone Amiodarone, disopyramide, esmolol, flecainide, propranolol, propafenone, sotalol, verapamil Amiodarone, diltiazem, verapamil Amiodarone, disopyramide, flecainide, procainamide, propafenone Amiodarone Diltiazem, esmolol, flecainide, lidocaine, propranolol, propafenone, quinidine, tocainide, verapamil Diltiazem, propafenone Amiodarone, metoprolol Propafenone, quinidine Propafenone Amiodarone, encainide, flecainide, isoprenaline (isoproterenol), mexiletine, propafenone, tocainide Amiodarone, digoxin, flecainide, metoprolol, mexiletine, quinidine Amiodarone, isoprenaline (isoproterenol), propranolol, propafenone, quinidine

Dizziness Dysarthria Dyskinesia Dystonia Fatigue Headache Hemiballism Language disturbance Memory impairment Myalgia Myasthenic syndrome Myoclonus Myopathy Myotonia Nystagmus Optic neuropathy Paresthesias Parkinsonism Peripheral neuropathy Pseudotumor cerebri Seizure Sensory loss Stroke Tinnitus Transient global amnesia Tremor Visual symptoms Weakness

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT velocities remain unchanged in this group of patients, a significant dilation of the superficial temporal artery occurs and is associated with a “pressing sensation” headache (Birk et al., 2005). Amiodarone A variety of neurologic symptoms have been attributed to amiodarone use. Some combination of tremor, ataxia, and peripheral neuropathy typically occurs in 10–50% of all patients on this medication (Fogoros et al., 1983; Charness et al., 1984; Palakurthy et al., 1987; Coulter et al., 1990; Meschia and Biller, 1998). These side-effects may be disabling and result in decreasing or ceasing amiodarone treatment in an estimated 5% of patients. Nystagmus has been reported. Amiodarone can also cause weakness, paresthesias, a distal generalized sensorimotor polyneuropathy, autonomic neuropathy, visual symptoms due to ischemic optic neuropathy and pseudotumor cerebri, myopathy with or without neuropathy, and occasionally delirium. Lastly, amiodarone has been associated with causing abnormal movements including: ataxia, a parkinsonianlike syndrome, myoclonus, hemiballism, and dyskinesias. Thromboembolic stroke (in a nonanticoagulated patient) due to chemical cardioversion with amiodarone has also been reported. Monitoring of amiodarone therapy should include assessment of the central and peripheral nervous system, especially in older patients (Fogoros et al., 1983; Charness et al., 1984; Pellissier et al., 1984; Anderson et al., 1985; Jacobs and Costa-Jussa`, 1985; Grogan and Narkun, 1987; Manolis et al., 1987; Palakurthy et al., 1987; Werner and Olanow, 1989; Coulter et al., 1990; Fernando Roth et al., 1990; Yapa and Green, 1990; Borruat and Regli 1993; Collaborative Group for the Study of Polyneuropathy, 1994; Dotti and Federico, 1995; Meschia and Biller, 1998; Krauser et al., 2005; Kashyap et al., 2006; Purvin et al., 2006; Wei et al., 2007; Younge, 2007; Hindle et al., 2008; Mindel, 2008; Leary and Caplan, 2009; Mahitchi et al., 2009; Ishida et al., 2010). Digoxin Digoxin can cause visual hallucinations, including Charles Bonnet syndrome, and general confusion (Volpe and Soave, 1979; Closson, 1983; G€ odeckeKoch et al., 2002). It has also been identified as a distorter of color vision: causing both blue and yellow vision (Durakovic´ et al., 1992; Leary and Caplan, 2009). People receiving large and repeated doses of this drug often see the world with a yellow-green tint. Interestingly, Vincent van Gogh, the Dutch PostImpressionist painter with a complex medical history (automutilation, depression, insanity, and suicide), characterized many of his paintings with halos and the color yellow during the last few years of his life. Critics have ascribed these aberrations to innumerable causes, one of which may be digitalis intoxication side-effects. Individuals with digitalis intoxication often complain of seeing yellow spots surrounded by coronas, much like those in The Starry Night. The artist’s physician, Paul-Ferdinand

133

Fig. 10.1. Portrait of Dr. Gachet, by Vincent van Gogh, 1890.

Gachet, may have treated van Gogh’s mania or epilepsy with digitalis, a common practice at that time. In one of van Gogh’s three portraits of Gachet, the physician holds a stem of Digitalis purpurea, the purple foxglove from which the drug is extracted (Fig. 10.1). It has been suggested that the toxic effects of digitalis may have, in part, dictated van Gogh’s technique in his later years (Lee, 1981; Wolf, 2001). Interestingly, the digitalis level does not need to be excessively elevated to cause these neurologic issues, and the symptoms disappear with drug cessation. In the setting of toxic doses of digoxin, a digoxin-specific Fab fragment antidote may be potentially useful (Meschia and Biller, 1998; Wijdicks, 2009). Diltiazem There are rare case reports of significant neurological complications with diltiazem. Myoclonus, myopathy, Lambert–Eaton syndrome, and parkinsonism have been associated with diltiazem use (Dick and Barold, 1989; Ueno and Hara, 1992; Ahmad, 1993; Graham and Stewart-Wynne, 1994; Pathirana and Hidelaratchi, 2004). Sensory loss associated with skin thickening of both feet has also been reported (Ilia et al., 1992). CNS depression secondary to hemodynamic instability can occur following a significant overdose. Effects observed during overdose include drowsiness, confusion, lethargy, and lightheadedness (Verbrugge and van Wezel, 2007). Seizures resulted from a 10.8 g ingestion of diltiazem in a 58-year-old man with a history

134 M.C. LEARY ET AL. of idiopathic epilepsy (Malcolm et al., 1986). A second Esmolol Generalized tonic-clonic seizure activity case report described generalized tonic-clonic seizures was described in an 89-year-old man while receiving in a 51-year-old man approximately 18 hours after ingestintravenous esmolol for the treatment of atrial tachycaring 1.8–3.6 g of slow-release diltiazem, as well as paradia. Termination of the infusion resulted in seizures. cetamol, aspirin, isosorbide nitrate, and alcohol The patient was rechallenged with esmolol infusion (Meschia and Biller, 1998; Isbister, 2002). 5 minutes later, again resulting in drowsiness and hyporDisopyramide A slowly reversible peripheral neuesponsiveness. The infusion was again discontinued and ropathy characterized by dysesthesias has been reported seizures did not recur. This patient had no previous seiwith this drug (Dawkins and Gibson, 1978; Briani et al., zure activity and esmolol was given in therapeutic doses. 2002). Additionally, anticholinergic effects, painful Careful monitoring for sedation or other neurologic dysesthesias, paresthesias, psychosis, hallucinations, signs should be routine in esmolol-treated patients, parand delusions are described with disopyramide use ticularly the elderly (Das and Ferris, 1988). Other, more (Teichman et al., 1987). common neurologic symptoms with esmolol infusion Dofetilide About 11% of patients develop headache include: dizziness and somnolence in 3% of patients, after oral dofetilide administration, and dizziness occurs headache, confusion, and agitation in 2% of patients, in some 8% of patients receiving oral dofetilide (Prod and paresthesia, asthenia, depression, anxiety, and seiInfo TIKOSYN(R) oral capsules, 2004). Headache assozures have occurred in less than 1% of patients receiving ciated with syncope and vasodilatation has also been esmolol (Prod Info Brevibloc(R), 2004). reported following a high oral dose of dofetilide Flecainide A common neurologic adverse effect (Allen et al., 2000). of flecainide is dizziness, occurring in about 30% of Dronedarone In the ATHENA trial (a placebopatients treated both chronically and in short-term studcontrolled, double-blind, parallel arm trial to assess the ies. Dizziness results in drug withdrawal in 5.7% of efficacy of dronedarone 400 mg twice daily for the prepatients receiving the drug short term and in 3.7% of vention of cardiovascular hospitalization or death from patients receiving the drug over long periods. Dizziness any cause in patients with atrial fibrillation/atrial flutis most likely related to the effect of the drug on the CNS ter), neurologic events reported in association with dro(Gentzkow and Sullivan, 1984). Neurologic effects of nedarone use included dizziness and headache. However, chronic flecainide dosing are headache (10%), asthenia these neurologic adverse events did not occur signifi(6%), fatigue (6%), tremor (4%), paresthesia (1%), and cantly more often in the dronedarone group compared hypoesthesia (3%). These effects resulted in drug withto the placebo group (Hohnloser et al., 2009). In a pooled drawal in less than 1% of patients treated (Gentzkow analysis of five controlled studies in patients with atrial and Sullivan, 1984). Less commonly, flecainide has been fibrillation or atrial flutter, asthenic conditions were associated with peripheral neuropathy (Palace et al., reported in 7% of patients who received dronedarone 1992), dystonia (Kennerdy et al., 1989; Linazasoro et al., hydrochloride 400 mg twice daily (n ¼ 3282) compared 1991; Miller and Jankovic, 1992; Meschia and Biller, with 5% of patients who received placebo (n ¼ 2875) over 1998), and seizures (Kennerdy et al., 1989; Meschia and a mean duration of 12 months (Prod Info MULTAQ oral Biller, 1998). Dysarthria in association with visual hallucitablets, 2009). nation has also been reported (Ramhamadany et al., 1986). Encainide A 10% incidence of neurologic adverse Ibutilide Headache has been observed occasionally effects was found in 140 patients evaluated with oral after intravenous ibutilide (3.6% of patients) (Prod Info encainide therapy. These symptoms of fatigue, memory Corvert(R), 2002). Stroke was reported in 0.9% of impairment, tremors, and dysarthria were considered patients who received up to two 10 minute intravenous mild in severity and improved with dose reduction. infusions of ibutilide 1 mg for atrial fibrillation or atrial Headache was also reported. The average drug dose flutter (Abi-Mansour et al., 1998). Ibutilide has also been and blood level of encainide in patients experiencing associated with dizziness (Li et al., 2007). adverse effects were not significantly different from Isoprenaline/isoproterenol Isoprenaline/isoproterenol those in patients who did not report neurologic sympuse may worsen a physiologic tremor (Perucca et al., toms (Tordjman et al., 1986). Dizziness was the most fre1981; Pickles et al., 1981; Tera¨va¨inen, 1984). Dizziness, headquent adverse reaction during therapeutic use of ache, nervousness, tremor, and weakness have also encainide, and this symptom appeared to be dose-related occurred during isoprenaline/isoproterenol therapy (Berchtold-Kanz et al., 1984). In one report, dizziness (Dukes, 1975). occurred in 26% of patients (Soyka, 1986). A patient with Lidocaine Patients may become acutely comatose myalgia associated with fever and chills has also been while being treated with intravenous lidocaine. This reported, and symptoms resolved with drug cessation effect has been associated with the accidental adminis(Goli-Bijanki et al., 1989; Meschia and Biller, 1998). tration of very large lidocaine doses, while the more

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 135 common CNS effects of a less extreme toxicity can Procainamide can also rarely cause a myopathy (Sayler include sedation, delirium, irritability, and twitching and DeJong, 1991; Venkayya et al., 1993; Agius et al., (Leary and Caplan, 2009). As part of their delirium, 1998). The creatine phosphokinase (CPK) levels in patients can show “doom anxiety,” an apprehension of procainamide-induced myopathy can be normal or death that can reach delusional proportions (Marke greater than 10 000 IU per liter (Meschia and Biller, et al., 1987; Meschia and Biller, 1998). Twitching can pro1998). Lastly, procainamide can aggravate myasthenic gress to partial or generalized seizures accompanied by symptoms in myasthenia gravis patients (Drachman respiratory depression (Meschia and Biller, 1998; Leary and Skom, 1965; Godley et al., 1990; Meschia and and Caplan, 2009). Seizures precipitated by lidocaine Biller, 1998) and even cause myasthenic-like symptoms usually occur when plasma levels exceed 9 mg per mL such as severe bulbar, limb, and respiratory weakness (Meschia and Biller, 1998) and have been reported with in nonmyasthenic patients in high doses (Niakan et al., topical, subcutaneous, and intravenous administration 1981; Oh et al., 1986; Miller et al., 1993; Meschia and (Boston Collaborative Drug Surveillance Program, Biller, 1998). 1972; Pelter et al., 1989; Meschia and Biller, 1998; Dorf Propanolol Common neurologic adverse effects et al., 2006; Brown et al., 2009). The Boston Collaboraassociated with propranolol therapy include paresthesia, tive Drug Surveillance Program found a convulsion rate fatigue, and insomnia. Propranolol-induced parestheof 5.7 per 1000 patients treated with intravenous lidosia has been reported to occur with an incidence of caine for arrhythmias (Boston Collaborative Drug 0.13–1.5%. Most patients with propranolol-induced paresSurveillance Program, 1972; Meschia and Biller, 1998). thesia tend to respond to a reduction in dose or discontinMetoprolol Dizziness has been reported in about uation of therapy (Prod Info propranolol hcl injection, 10% of patients receiving metoprolol. Metoprolol has 2006). Tonic-clonic seizures have also been reported also been reported to cause delirium, confusion, disoriin a patient with acute propranolol intoxication who entation, agitation, aggression, paranoid delusions, vivid had an acute psychotic episode that preceded the seizure dreams, headache, insomnia, short-term memory loss, as activity by several hours (Love and Handler, 1995). A well as complex visual and auditory hallucinations (Prod small number of case reports have associated propranolol Info Lopressor(R) 1999; Prod Info Toprol XL(R) 2001; with aggravation of myasthenia gravis or development of Fisher et al., 2002; van der Vleuten et al., 2005). Lana reversible myasthenic syndrome. Propranolol should guage disturbance has been reported as well (Fisher be used with caution in patients with known myasthenia et al., 2002). All symptoms resolved with termination gravis (Herishanu and Rosenberg, 1975). Rare cases of metoprolol therapy. Metoprolol has also been of myotonia and muscle weakness in both arms and reported to increase the risk of stroke after noncardiac legs have been reported following several months to years surgery (Roberts, 2008). Lastly, cases of carpal tunnel of propranolol therapy (Blessing and Walsh, 1977; Satyasyndrome associated with long-term (8–11 years) metoMurti et al., 1977; Turkewitz et al., 1984). prolol therapy have been reported. Symptoms typically Propafenone Some of the adverse effects of proresolved over 8–10 weeks following discontinuation of pafenone are neurologic in nature, including dizziness treatment (Emara and Saadah, 1988). (12.5%), ataxia (1.6%), tremor (1.4%), vertigo, and headMexiletine Commonly reported side-effects ache (4.5%) (Prod Info Rythmol(R), 2004). Severe bilatinclude tremor, ataxia, dysarthria, visual blurring, memeral symmetric ataxia occurred in three elderly patients ory impairment, and diplopia (Meschia and Biller, 1998). receiving propafenone. Their symptoms included Visual hallucinations can occur 2–3 days after initiation unclear speech, altered hand coordination, gait impairof therapy and resolve 8–12 hours after drug discontinment, and tremor with movement. Symptoms completely uation. Patients typically remain fully oriented during resolved in all within 3–6 days after discontinuation or a these hallucinations (Campbell et al., 1973; Holt, 1988; dose reduction of propafenone (Odeh et al., 2000). Coma, Meschia and Biller, 1998). Roughly 5% of patients need numbness, paresthesias, vertigo, seizures, and tinnitus to discontinue mexiletine use due to neurologic sidehave been reported in less than 1% of patients receiving effects (Nygaard et al., 1986; Campbell, 1987; Meschia propafenone (Siddoway et al., 1984; Ravid et al., 1987; and Biller, 1998). Prod Info Rythmol(R), 2004). Propafenone has also been Procainamide Neurologic side-effects due to associated with reversible generalized myoclonus (Chua procainamide can be localized to the nerve, muscle, or et al., 1994), myasthenia exacerbation (Lecky et al., neuromuscular junction. Patients with a procainamide1991), peripheral neuropathy (Galasso et al., 1995), and induced, lupus-like reaction can develop a distal sensotransient global amnesia (Jones et al., 1995; Meschia rimotor polyneuropathy. This neuropathy improves and Biller, 1998). In a large multicenter study of 774 with both drug discontinuation and steroids (Sahenk patients on long-term therapy, 21% had a central nervous et al., 1977; Ahmad 1982; Meschia and Biller, 1998). system side-effect (Ravid et al., 1987).

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Quinidine Quinidine is known to cause a neurologic syndrome known as cinchonism, named after cinchona bark, the original crude preparation of quinidine. Cinchonism occurs in an estimated 1% of patients taking quinidine (Cohen et al., 1977; Meschia and Biller, 1998) with symptoms of headache, flushing, mydriasis, delirium, and a visual change similar to retinal transient ischemia (Fisher, 1981; Meschia and Biller, 1998). If quinidine is taken with digoxin, quinidine can result in delirium even in the setting of normal serum concentrations (Eisenman and McKegney, 1994; Meschia and Biller, 1998). Some have asserted that quinidineassociated delirium is an anticholinergic syndrome that may be reversed with physostigmine (Summers et al., 1981; Meschia and Biller, 1998). Additionally, quinidine has been associated with seizures, coma, vertigo, tinnitus, and visual blurring (Leary and Caplan, 2009). Lastly, quinidine can also exacerbate weakness in myasthenics (Kornfeld et al., 1976; Meschia and Biller, 1998). Sotalol The most frequently reported adverse reactions at any dose level of sotalol include fatigue (20%), dizziness (20%), asthenia (13%), and lightheadedness (12%), leading to discontinuation of therapy in up to 2–4% of patients. Other commonly reported CNS effects of sotalol include headache and sleep disturbances in 8%, excessive perspiration in 6%, with 4% incidence of altered consciousness and paresthesia (Zanetti, 1993; Prod Info Betapace(R), 2001). Hemifacial edema followed by atrophy has also been described in one patient on sotalol after exposure to cold weather (Aho and Haapa, 1982; Meschia and Biller, 1998). Tocainide Neurologic side-effects associated with tocainide include tremor, restlessness, dizziness, paranoid psychosis, dysarthria, giddiness, and delirium (Streib, 1986; Bikadoroff, 1987; Meschia and Biller, 1998; Prod Info Tonocard(R), 2001). These symptoms are dose-related and resolve with stopping the medication (Horn et al., 1980; Meschia and Biller, 1998). Seizures and coma have also been rarely reported, usually in the setting of overdose (Clark and El-Mahdi, 1984; Forrence et al., 1986; Sperry et al., 1987; Meschia and Biller, 1998). One study reported memory loss to be a common side-effect (Maloney et al., 1980), and headaches have been reported in 4.6% of patients receiving tocainide (Prod Info Tonocard(R), 2001). In long-term controlled clinical trials nystagmus was reported in 1% and ataxia was reported in 3% of patients. (Prod Info Tonocard(R), 2001). Observed tremors are useful as clinical indicators that the maximum dose of tocainide is being approached. In long-term controlled studies, tremor was reported in 8% of patients and increased to 22% in patients receiving 1800 mg/day or more (Prod Info Tonocard(R), 2001).

Verapamil Verapamil has been associated with minimal central nervous system toxicity. Infrequent episodes of dizziness, headache, lassitude, drowsiness, and fatigue have been reported following oral administration (Moyer, 1972; Singh et al., 1976; Greif et al., 1977). Pooled results from trials of controlled-onset extended-release verapamil in 1049 patients noted an incidence of dizziness of 5.9% compared to a 2.1% placebo rate (n ¼ 379), while headache was noted in 10.1% compared to an 8.4% placebo rate (White et al., 2001). Additionally, perceptual disorders described as painful coldness and numbness or bursting feelings (especially in the legs) have been reported in association with chronic oral verapamil therapy. In the three patients with this disorder, all were rechallenged and had a return of symptoms (Kumana and Mahon, 1981). Verapamil has also been implicated in unmasking a parkinsonian syndrome (Garcia-Albea et al., 1993). Symptoms of tremor and leg dragging developed in a 55-year-old man 3–4 hours after verapamil was begun for hypertension. These symptoms progressed and worsened to where a diagnosis of Parkinson’s disease was made 4 years later. However, treatment with carbidopa/levodopa, trihexyphenidyl, and propranolol were only minimally effective. Within 3 months after verapamil was withdrawn, the parkinsonism was markedly improved. Lastly, similar to diltiazem, effects observed during verapamil overdose may include drowsiness, confusion, lethargy, and lightheadedness (Candell, 1979). Coma and cerebral infarction have been observed in rare cases of overdose (Moroni et al., 1980; Samniah and Schlaeffer, 1988; Shah and Passalacqua, 1992; Tuka et al., 2009). Both myoclonic and tonic-clonic seizure activity have been reported after ingestion of large verapamil doses (Passal and Crespin, 1984; Vadlamudi and Wijdicks, 2002). In conclusion, a variety of possible neurologic sideeffects, many of which are rare, can occur with antiarrhythmic drug therapy. However, while many of these reactions are uncommon, it is important to recognize if a neurologic condition is potentially drug-related, because virtually all of these complications can resolve with the discontinuation of the offending agent (Meschia and Biller, 1998).

Hematologic agents Anticoagulant and antiplatelet medications are commonly prescribed drugs in cardiac patients, particularly those with arrhythmia. Although the potential benefit of these medicines in reducing the risk of stroke is great, there is an inherent risk of hemorrhagic complication as well (Williams and Biller, 1998). Potential neurologic

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT Table 10.2 Neurologic complications from hematologic medications Side-effect

Medications

Carotid occlusion associated with heparin-induced thrombocytopenia (HIT) Carpal tunnel syndrome Cerebral venous sinus thrombosis (with HIT) Epidural hematoma Femoral neuropathy Hematomyelia Intracerebral hemorrhage

Unfractionated heparin

Neuropathy Spinal hematoma

Subdural hematoma Transient global amnesia (with HIT)

Warfarin Unfractionated heparin Unfractionated heparin Warfarin Warfarin Unfractionated heparin, warfarin, dabigatran Warfarin Unfractionated heparin, low molecular weight heparin, warfarin Unfractionated heparin, warfarin Unfractionated heparin

side-effects from hematologic agents are listed in Table 10.2. Unfractionated heparin Unfractionated heparin is the most commonly used parenteral anticoagulant in the US and is frequently used in ischemic stroke patients with atrial fibrillation. Intracerebral hemorrhage has been often noted in stroke patients anticoagulated with heparin. The interval between stroke onset and intracerebral hemorrhage was less than 72 hours in 80% of the patients, with intracerebral hemorrhage occurring 24 hours or less after heparin was started in 80% of the patients. The APTT closest to the time of hemorrhage was greater than two times control in seven patients. The findings suggest that heparin-related intracerebral hemorrhage occurs early after stroke onset, usually with moderate-sized or large infarcts, and with excessive anticoagulation in some patients. In theory, then, while heparin is generally safe to use in ischemic stroke patients, physicians should be cautious utilizing this drug in patients with moderate to large infarcts (Babikian et al., 1989). Heparin-induced thrombocytopenia (HIT) is a lifethreatening thrombotic disorder caused by antibodies (HITAb) against a complex of heparin and platelet factor 4 (Visentin et al., 1994; Pohl et al., 2000). There are 10 case reports in the English literature of heparin-induced thrombocytopenia-related cerebral venous sinus thrombosis (Fesler et al., 2011). In a series from the Mayo

137

Clinic, 33% of postendarterectomy carotid occlusions occurred in patients with HIT (Atkinson et al., 1988). HIT-induced carotid occlusion has also been reported after endovascular repair of high cervical extracranial internal carotid artery (ICA) aneurysms (van Sambeek et al., 2000). Transient global amnesia has also been reported in two patients who had disorientation, anterograde amnesia, and retrograde amnesia 30 minutes after receiving intravenous heparin 5000 U. Interestingly, both patients also had HIT. Platelet counts normalized after discontinuation of heparin with resolution of amnesia after 24 hours (Warkentin et al., 1995). Although rare, both spinal and epidural hematomas have occurred in patients given neuraxial anesthesia during heparin thromboprophylaxis. In order to reduce this risk, stopping heparin for a minimum of 10–12 hours before neuraxial block and 1–2 hours afterwards has been recommended (Parnass et al., 1990; Schneider et al., 1997). In the case report of epidural hematoma, complete paraplegia developed over 3 hours (Parnass et al., 1990). Surgery to improve the deficit was unsuccessful in one patient who had a normal APTT, PT, and platelet count before the procedure was performed, which suggests that even minimally dosed heparin may carry a risk. Low molecular weight heparins There is a paucity of data regarding indications for, and risk–benefit ratio of, low molecular weight heparin “bridging” for cardioembolic stroke prevention in patients with atrial fibrillation until their INR levels are in therapeutic range (Billett et al., 2010). Although perhaps safer than heparin, low molecular weight heparins have also rarely been associated with central nervous system bleeding complications (Sternlo and Hybbinette, 1995; Williams and Biller, 1998). Warfarin Warfarin is associated with many neurologic complications, including various types of neuropathy. Carpal tunnel syndrome due to hematoma in the carpal canal has been reported. Complete resolution of symptoms occurred following carpal tunnel release surgery (Bonatz and Seabol, 1993). Femoral neuropathy has also been reported in association with the therapeutic use of warfarin, usually caused by retroperitoneal bleeding in and around the psoas muscle. Most patients have had sudden onset severe groin pain, pain in the lower thigh area, inguinal area pain, and hip pain. Numbness or weakness of the thigh and leg follows, as well as paresthesias. The knee jerk is lost as an early diagnostic sign. Recovery has occurred but permanent disability has been reported in several cases. Immediate surgical decompression may be necessary to prevent residual disability (Butterfield et al., 1972; Susens, 1974; Michel and Alevizatos, 1975; Brantigan et al., 1976; King and Bechtold, 1985). Spinal hematomas have been reported with the therapeutic use of warfarin, including epidural hematoma, extradural hematoma, and meningeal hematoma

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(Dabbert et al., 1970; Harik et al., 1971; Lederle et al., 1996). Hematomyelia, an uncommon occurrence, has also been reported following warfarin therapy. Symptoms include paresis, back or neck pain, and urinary incontinence(Murphy and Nye, 1991; Liebeschuetz et al., 1994; Pullarkat et al., 2000). Intracranial hemorrhage is a well-known serious adverse event associated with the use of warfarin (Kase et al., 1985; Hylek and Singer, 1994). Patients with atrial fibrillation, who are at a higher risk of thromboembolism and thus stand to benefit more from anticoagulation, appear also to have a higher risk of intracerebral hemorrhage with warfarin treatment (Table 10.3) (Williams and Biller, 1998). Information from several clinical trials estimated the risk of intracerebral hemorrhage at from 0% to 1.8% per patient-year treated (Williams and Biller, 1998). Headache and altered consciousness were common presenting symptoms in patients with intracerebral hemorrhage (Volans, 1998). An increase in prothrombin time ratio (PTR) above 2.0 increases the risk for an intracranial hemorrhage, as does

increasing age. In one study, the risk for a subdural hemorrhage doubled with each 10 year increase in age. These two risk factors indicate the necessity of careful control of anticoagulation with warfarin, especially among elderly patients (Hylek and Singer, 1994). Additionally, based on multivariate analysis, a study of 68 cases and 204 matched controls identified international normalized ratio (INR) above 4.5, short (1 year or less) duration of oral anticoagulant therapy, hypertension, alcohol abuse, and a history of cerebral vascular disease as independent risk factors for intracranial hemorrhage (Berwaerts and Webster, 2000). Irbesartan The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) evaluated the safety and efficacy of the combination of aspirin plus clopidogrel in atrial fibrillation patients who were unsuitable candidates for vitamin K antagonist therapy. In those patients, the addition of clopidogrel to aspirin did reduce the risk of major vascular events, especially stroke, but also increased the risk of major hemorrhage (ACTIVE Investigators, 2009).

Table 10.3 Risk of intracranial hemorrhage in warfarin-treated atrial fibrillation patients*

Study

Special characteristics

Treatment

SPAF I

Atrial fibrillation (AF)

SPAF II

AF Age  75 AF Age > 75 AF and one thromboembolic risk factor

1. 2. 3. 1. 2. 1. 2. 1.

SPAF II SPAF III

EAFT

AF and TIA or minor stroke

VA

AF, males only

Pooled data{

AF

Warfarin Aspirin 325 mg Placebo Warfarin Aspirin 325 mg Warfarin Aspirin 325 mg Warfarin (fixed) and aspirin 325 mg 2. Warfarin (adjusted)

1. 2. 3. 1. 2. 1. 2. 3. 4.

Warfarin Aspirin 300 mg Placebo Warfarin Placebo Warfarin Placebo Aspirin 75–300 mg Placebo

Target/mean INR or PTR for warfarin Target PTR 1.3–1.8 Mean PTR 1.45 Target INR 2.0–4.5 Mean INR 2.7 Target INR 2.0–4.5 Mean INR 2.6 1.Target INR 1.2–1.5 Mean INR 1.3 2.Target INR 2.0–3.0 Mean INR 2.4 Target INR 2.5–4.0

Target PTR 1.2–1.5 Target INR 2.0–4.2 Target PTR 1.2–1.5

% Intracranial hemorrhages per patient-year 1. 2. 3. 1. 2. 1. 2. 1.

0.8 0.3 0.3 0.6 0.2 1.8 0.8 0.9

2. 0.5 1. 2. 3. 1. 2. 1. 2. 3. 4.

0 0.2 0.1 0.2 0 0.5 0.1 – –

*Adapted from Biller. { Data from: Atrial Fibrillation, Aspirin, Anticoagulation Study (AFASAK); Boston Area Trial For Atrial Fibrillation Study; Canadian Atrial Fibrillation Anticoagulation Study; SPAF, and VA. (Adapted from Atrial Fibrillation Investigators, 1994.) INR, international normalized ratio; PTR, prothrombin time ratio.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 139 recently, intracardiac direct-current electrical shock of Direct thrombin inhibitors variable energies is delivered. Elective direct-current car1. Ximelagatran was voluntarily withdrawn from the dioversion can now be carried out externally with chest European market and further development was terelectrodes (transthoracic) or endocardially using elecminated because of liver toxicity in clinical trials trode catheters or leads. (Lazo-Langner et al., 2009). EXTERNAL CARDIOVERSION 2. Dabigatran is a different oral direct thrombin inhibitor that has been compared to warfarin in a The initial shock energy may be as low as 50 J depending noninferiority trial. In this trial, 18 113 patients with on the type of arrhythmia and the hemodynamic stability atrial fibrillation were assigned to either 110 mg of the patient. After shock delivery, the rhythm is noted, dabigatran twice daily, 150 mg dabigatran twice and if conversion is unsuccessful, repeat direct-current daily, or adjusted-dose warfarin. Dabigatran was cardioversion is attempted with higher energy. This found, at the 110 mg dose, to have similar rates of can be repeated until the arrhythmia terminates or a decistroke and systemic embolism as well as lower rates sion is made to abandon direct-current cardioversion of major hemorrhage when compared to warfarin. (Tracy et al., 2000). The 150 mg dose had lower rates of stroke and The most common arrhythmia subjected to elective embolism, but similar rates of major hemorrhage. direct-current cardioversion is atrial fibrillation (Tracy However, the rate of MI was slightly higher in both et al., 2000). Electrical cardioversion of atrial fibrillation dabigatran groups. Theoretically, if dabigatran is associated with an increased risk of stroke, and its were FDA approved, potentially the dose could be appropriate prevention is still debated. Besides dislodgetailored to specific patient risk factors (Connolly ment of pre-existing intra-atrial thrombi, the “stunned” et al., 2009). atrium after cardioversion is an important cause of thrombus formation and subsequent embolism (Nabavi Orally available antagonists of factor Xa New et al., 2001). Stroke as a direct result of cardioversion medications for the prevention of stroke in atrial fibrilhas been estimated to occur in 1.3% of patients lation patients are also being tested. Seven compounds (Arnold et al., 1992). The patients with the highest risk including rivaroxaban, apixaban, betrixaban, and eribaxof embolism are those who are older than 55 years of aban are orally available direct inhibitors of activated age, those who have coronary artery disease, and those factor X now in development for thromboprophylaxis who have a pre-existing cardiomyopathy (Weinberg in patients with atrial fibrillation or following an acute and Mancini, 1989; Adams, 1998). Embolism is not precoronary syndrome. Trials comparing the efficacy of dicted by a history of prior stroke, an enlarged left rivaroxaban or apixaban to standard therapy for stroke atrium, diabetes mellitus, or hypertension (Arnold prophylaxis in patients with atrial fibrillation are in proet al., 1992). Anticoagulation before and after cardiovercess. Rivaroxaban, the sentinel compound in this class, is sion lowers the risk of embolism (Arnold et al., 1992; already approved in the European Union and Canada. It Ewy, 1992; Manning et al., 1993; Adams, 1998). is likely to be approved for use in the US in 2010. The The following protocol has been advocated by the neurologic complications from these agents are not well American College of Cardiology for stroke prevention known at present (Morell et al., 2010). and is considered standard of care (Tracy et al., 2000):

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT: CARDIOLOGY PROCEDURES Patients with arrhythmias are diagnosed, treated, and sometimes cured with a variety of cardiac procedures. Although the implicit goal with any cardiac intervention is to improve a patient’s quality of life, these procedures carry a risk as well as a possible benefit.

Electrical cardioversion Since the introduction of direct current transthoracic electrical shock, its use has become fairly routine for the termination of tachycardias (Lown et al., 1962; Tracy et al., 2000). A variety of clinical scenarios are now encountered in which transthoracic and, more

1.

2.

3.

Individuals with atrial fibrillation of > 48 hours’ duration should receive warfarin therapy for  3 weeks before cardioversion. In patients in whom earlier cardioversion is desired, anticoagulation with heparin can be initiated and transesophageal echocardiography can be performed (use of transesophageal echocardiography has been advocated to identify small atrial thrombi that are not visible on transthoracic echocardiography). If no clots are seen, cardioversion can be undertaken. Routine anticoagulation must still be maintained after cardioversion (Silverman and Manning, 1998; Tracy et al., 2000).

While postponing cardioversion if there is transesophageal evidence of a thrombus is recommended

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(Ewy, 1992; Manning et al., 1993; Klein et al., 1997; Adams, 1998), the value of transesophageal echocardiography (TEE) to prevent cardioversion-related stroke in patients with atrial fibrillation and left atrial thrombus is unclear (Saeed et al., 2006). In patients with atrial fibrillation, left atrial thrombus, and effective anticoagulation, Saeed et al. found no difference in the risk of clinical thromboembolism between direct-current cardioversion with or without follow-up TEE. The absence of atrial thrombi at TEE does not exclude the possibility of thromboembolic complications of cardioversion conducted without anticoagulant therapy (Missault et al., 1994; Preobrazhenskiı˘ et al., 2005). Consistent with the American College of Cardiology/American Heart Association Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion, many physicians prefer to delay cardioversion until the patient has received anticoagulants for at least 4 weeks (Prystowsky, 1997; Adams, 1998). An INR goal of 2.5 (range 2.0–3.0) is recommended for most patients undergoing external cardioversion. For high-risk patients such as those with mechanical heart valves, an INR goal of 3 (range 2.5–3.5) is recommended to prevent brain embolism. The routine use of warfarin therapy in arrhythmias other than atrial fibrillation is still controversial (Tracy et al., 2000). The benefits of warfarin are thought to be related to thrombus resolution and prevention of new thrombus formation (Saeed et al., 2006). This appears to be confirmed by the findings of Nabavi et al. (2001), who investigated whether cardioversion of atrial fibrillation was associated with occurrence of circulating microemboli. A total of 29 patients with valvular or nonvalvular atrial fibrillation were studied. All but one had been prescribed oral anticoagulation (with an INR > 2.0) for at least 3 weeks before and 4 weeks after successful cardioversion. In all patients, exclusion of internal carotid artery stenosis and atrial thrombus was performed before cardioversion. Five unilateral 1 hour transcranial Doppler monitorings for microemboli over the middle cerebral artery were performed: (1) before cardioversion, and (2) immediately, (3) 4–6 h, (4) 24 h, and (5) 2–4 weeks after cardioversion. A complete absence of circulating microemboli was found before cardioversion as well as during a cumulative monitoring time of 115 h after successful cardioversion, showing that cardioversion of atrial fibrillation after at least 3 weeks of effective anticoagulation is not associated with occurrence of cerebral circulating microemboli (Nabavi et al., 2001).

INTERNAL CARDIOVERSION In those patients for whom external direct-current cardioversion is unsuccessful, an internal shock using

electrode catheters can be effective (Schmitt et al., 1996; Levy et al., 1997). The primary indication for internal cardioversion is atrial fibrillation when external shock fails or to assess the feasibility of an implantable atrial defibrillator (Levy et al., 1992; Schmitt et al., 1996; Sra et al., 1996; Levy et al., 1997). Because of the potential risk of bleeding, warfarin therapy is usually withheld and resumed after the procedure. Temporary anticoagulation before and after the procedure can be accomplished with heparin. Preprocedural and postprocedural antiarrhythmic therapy considerations are similar to those for external cardioversion. The possible risks of right heart catheterization with electrode catheters and the fact that direct-current shock is delivered within the myocardial structures adds to specific complications. However, recent studies suggest that stroke, and transient ischemic attack complication rates are similar for both external and internal cardioversion procedures (Ozdemir et al., 2006).

Pacemakers BRADYCARDIA Ventricular single chamber permanent cardiac pacing undoubtedly eliminates symptoms related to the extremely low cardiac rate in bradycardic patients. However, it also contributes to neurologic morbidity as it results in the onset of permanent atrial fibrillation. Many studies have shown the superiority of atrial and dual chamber cardiac pacing in reducing atrial fibrillation risk and in preventing the related embolic complications. Saccomanno et al.’s analysis of 690 chronically paced patients found that the total incidence of permanent atrial fibrillation was 51.4% in the ventricular pacemaker group and 11.4% in the dual chamber pacemaker group (p < 0.05). After 7 years from implant, permanent atrial fibrillation was present in 90% of ventricular-paced patients and 20% of dual chamber pacemaker patients (p < 0.001). A significantly higher occurrence of stroke and transient ischemic attack occurred in the ventricular pacemaker group (p < 0.05) (Saccomanno et al., 1999).

SINUS NODE DYSFUNCTION Greenspon et al. (2004) investigated the effects of dualchamber versus single-chamber ventricular pacing on subsequent stroke in patients with sinus node dysfunction. A total of 2010 patients with sinus node dysfunction were randomized to ventricular or dual-chamber pacing and followed for a median of 33.1 months. During 5664 patient-years of follow-up, 90 strokes (11 hemorrhagic) occurred. The rate of stroke was 2.2% at 1 year and 5.8% at 4 years. The incidence of stroke was not significantly different in dual-chamber (4%) compared

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 141 with ventricular-paced patients (4.9%). Multivariable ventricular-demand pacemaker might represent highanalysis showed that significant predictors of stroke risk groups for stroke. However, patients who have sick after pacemaker insertion included prior stroke or transinus syndrome even without atrial fibrillation still have sient ischemic attack, Caucasian race, hypertension, a significant risk of stroke after pacemaker insertion. prior systemic embolism, and New York Heart AssociaMattioli et al. (1999) analyzed 100 consecutive patients tion functional class III or IV (p < 0.05); pacing mode with sick sinus syndrome without atrial fibrillation remained nonsignificant after adjustment for these facwho received either dual chamber or ventricular pacetors ( p ¼ 0.37). Similar to bradycardic patients with makers. Cerebral ischemia occurred in 18 of the 100 pacemakers, developing atrial fibrillation after impatients. Univariate predictors for cerebral embolism plantation is a significant risk factor for stroke in this were age > 65 years ( p < 0.001), low atrial ejection force cohort after adjustment for other predictors of stroke ( p < 0.01) and a dilated left atrium with spontaneous (Greenspon et al., 2004). echo contrast ( p < 0.05) (Mattioli et al., 1999). The role of antithrombotic medications for the prevention of stroke still needs further clarification. Clinical SICK SINUS SYNDROME trials to assess the efficacy of antithrombotic medicaSick sinus syndrome (SSS), a common cardiac rhythm tions, perhaps including a subgroup treated with aspirin, disorder in the elderly, is now the most common inin reducing stroke risk might be necessary in paced sick dication for permanent cardiac pacemaker insertion sinus syndrome patients (Fisher et al., 1988). (Kaplan, 1978). The stroke risk in sick sinus syndrome before cardiac pacemaker insertion is substantial and probably remains so after pacemaker insertion (Fisher Implantable defibrillators et al., 1988). The first implantable defibrillation device used was the The precise stroke risk after cardiac pacemaker inserMetrix system, a stand-alone atrial defibrillator (without tion remains uncertain, but strokes have been observed ventricular defibrillation) which was found to be safe in 4.5–23% of paced sick sinus syndrome patients who and effective in selected groups of patients. Unfortuare followed for 2–3 years (Stone et al., 1982; nately, this device is no longer marketed. Only doubleRosenqvist et al., 1986; Fisher et al., 1988). Data from chamber defibrillators with pacing capabilities are now long-term follow-up of paced sick sinus syndrome available: the Medtronic GEM III AT, an updated verpatients indicates that the incidence of stroke is 3% at sion of the Jewel AF, and the Guidant PRIZM AVT. 1 year, 5% at 5 years, and 13% at 10 years (Sgarbossa These devices can be patient activated or programmed et al., 1993). The development of chronic atrial to deliver automatically, once atrial tachyarrhythmias fibrillation and stroke in paced patients with sick sinus are detected, therapies including pacing or/and shocks. syndrome is strongly determined by clinical variables Attempts to define the group of patients who might benand secondarily by the pacing modality. Independent efit from these devices are described; however, the predictors for stroke were history of cerebrovascular respective roles of atrial defibrillators versus other nondisease, ventricular pacing mode, and history of paroxpharmacologic therapies for atrial fibrillation, such as ysmal atrial fibrillation. Stroke has been reported in surgery and radiofrequency catheter ablation, remain paced sick sinus syndrome patients with ventricularto be determined (Le´vy, 2005). demand, dual-chamber, and atrial-inhibited pacemaker. Cardioversion of atrial fibrillation carries a risk of Ventricular pacing mode does predict chronic atrial thromboembolic complications and stroke (Przybylski fibrillation in patients with preimplant paroxysmal et al., 2002). As a result, anticoagulation therapy is rouatrial fibrillation but not in those without it (Sgarbossa tinely given before and after this procedure. In patients et al., 1993). with permanent atrial fibrillation who undergo implantaAtrial pacing or atrial-ventricular sequential pacing tion of cardioverter-defibrillator (ICD), anticoagulants has been posited to be better than ventricular-demand are usually withdrawn during the perioperative period. pacing in reducing the risk of subsequent embolic epiHowever, in some patients sinus rhythm may be restored sodes (Rosenqvist et al., 1986; Sgarbossa et al., 1993). during defibrillation threshold testing which potentially The role of anticoagulants in reducing stroke risk has may increase the risk of thromboembolic complications not been assessed, but Radford and Julian (1974) recomand stroke. Przybylski et al. noted that sinus rhythm was mend their use after pacemaker insertion in sick sinus restored in 21.7% of patients with permanent atrial fibrilsyndrome patients. Stroke in sick sinus syndrome after lation who underwent ICD implantation. Temporary pacemaker insertion is not rare, and pacing does not withdrawal of anticoagulation therapy did not increase appear to be protective. Sick sinus syndrome patients the risk of stroke (Przybylski et al., 2002). who convert to atrial fibrillation or who have a

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Electrophysiologic procedures STROKE Thromboembolic stroke can be a complication of cardiac electrophysiologic procedures, including radiofrequency catheter ablation of arrhythmia. Multicenter data are limited; however, the stroke risk appears to be < 2%, with a range from 1% to 5% (DiMarco et al., 1982; Tanel et al., 1997; Adams, 1998; Alvarez and Merino 2002; Borger van der Burg et al., 2002; Di Biase et al., 2010). The thromboembolic risk during and after cardioversion and ablation of atrial flutter is higher than previously recognized and anticoagulation therapy decreases this risk (Reithmann et al., 2007). Di Biase et al. (2010) developed a prospective database to evaluate the prevalence of stroke over time in patients undergoing ablation of atrial fibrillation. Patients were divided into three groups: ablation with an 8 mm catheter off warfarin (group 1), ablation with an open irrigated catheter off warfarin (group 2), and ablation with an open irrigated catheter on warfarin (group 3). Outcome data on stroke/transient ischemic attack and bleeding complications during and early after the procedures were collected. Among 6454 consecutive patients, periprocedural stroke/transient ischemic attack occurred in 1.1% in group 1 and 0.9% in group 2. Despite a higher prevalence of nonparoxysmal atrial fibrillation and more patients with CHADS2 (congestive heart failure, hypertension, age > 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score > 2, no stroke/transient ischemic attack was reported in group 3. The authors concluded that a combination of an open irrigation ablation catheter and periprocedural therapeutic anticoagulation with warfarin reduces the risk of periprocedural stroke without increasing the risk of pericardial effusion or other bleeding complications (Di Biase et al., 2010). Because periprocedural stokes can occur several hours postprocedure, overnight in-hospital observation is warranted for patients who undergo radiofrequency ablation of a left-sided accessory pathway or an accessory pathway in a patient with the ability to shunt right to left. If an ischemic stroke is detected, case studies have reported that tPA was an effective and safe drug to use following a cerebral thromboembolic event occurring after a cardiac catheterization procedure (Cannon et al., 2001).

PHRENIC NERVE INJURY While epicardial catheter ablation can cure arrhythmia resistant to endocardial ablation (Sosa et al., 1996), the risk of collateral damage to adjacent structures is increased with the epicardial approach. From a neurologic standpoint, this risk of complications includes left phrenic nerve injury, given its close contact to the left

lateral ventricular wall (Rumbak et al., 1996). Studies suggest that during electrophysiologic interventions, the left phrenic nerve is particularly at risk when cardiac ablation procedures are performed in the vicinity of the left atrial appendage, the high left ventricular wall, the right superior pulmonary vein, and the superior vena cava (Sacher et al., 2006; Sa´nchez-Quintana et al., 2009). Sacher et al. (2006) reported that of the 3755 consecutive patients undergoing ablation to treat atrial fibrillation, phrenic nerve injury was noted as a rare complication (0.48%) of the procedure. Symptoms in patients with phrenic nerve injury vary broadly from asymptomatic to dyspnea, and even to respiratory insufficiency requiring temporary mechanical ventilation support (Bai et al., 2006). Coughing, hiccupping, and/ or sudden diaphragmatic elevation have also been reported (Sacher et al., 2006). Dyspnea is often noted after exertion. Some patients with transient phrenic nerve injury resolve quickly after the procedure and others within months. Some studies suggest that phrenic nerve injury caused by catheter ablation functionally recovers over time regardless of the energy sources used for the procedure (Bai et al., 2006). Other studies note that complete (66%) or partial (17%) recovery is observed in the majority of patients; however, some patients do continue to have permanent sequelae (Sacher et al., 2006).

Percutaneous closure of the left atrial appendage In patients with nonvalvular atrial fibrillation, ischemic stroke is often attributed to left atrial appendage clot formation and subsequent embolization. The difficulties of using anticoagulants, as well as the increased risk of hemorrhage, have resulted in the exploration of alternative stroke prevention treatment options. Some investigators have assessed whether occlusion of the left atrial appendage could potentially become an alternative to warfarin. One multicenter, randomized noninferiority trial found that percutaneous closure of the left atrial appendage was noninferior to warfarin treatment. In the future, closure of the left atrial appendage might provide an alternative to chronic warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (Holmes et al., 2009). A second study, by Block et al., assessed percutaneous closure of the left atrial appendage in patients who were nonwarfarin candidates (Block et al., 2009). They reported the first long-term results after transcatheter left atrial appendage occlusion with the PLAATO device in 64 patients enrolled in the former PLAATO multicenter study. Their findings are encouraging: only one major adverse event (tamponade) was related to the procedure. The annualized stroke/TIA rate in this study was 3.8%, which was almost half of the

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT actual expected stroke/TIA rate based on CHADS (2) scores of 6.6% per year (Block et al., 2009). No major adverse neurologic complications directly due to percutaneous closure of the left atrial appendage have been reported to date. The PROTECT AF study compared the efficacy and safety of the WATCHMAN device, an umbrella-like left atrial appendage closure device, to warfarin treatment in patients with nonvalvular atrial fibrillation (Holmes et al., 2009). A total of 707 eligible patients with atrial fibrillation at risk for cerebral embolism were randomly assigned to receive warfarin with a target INR of 2–3 or percutaneous WATCHMAN implantation and subsequent discontinuation of coumadin. The WATCHMAN percutaneous closure device was not inferior to anticoagulation for the primary efficacy endpoints of ischemic stroke, hemorrhagic stroke, cardiovascular or unexplained death, and systemic embolization. There was a slightly higher risk of ischemic stroke in the device group, with a total of five ischemic strokes (three from air embolism) that occurred at the time of the implantation procedure. Device closure of the left atrial appendage was associated with a significant reduction in the hemorrhagic stroke risk compared to warfarin, meeting superiority criteria. All-cause stroke outcomes in the group undergoing WATCHMAN implantation were noninferior to the warfarin group. Death occurred at similar proportions. The WATCHMAN device had a higher rate of adverse safety events, mainly from periprocedural complication (7.4 per 100 patient-years versus 4.4 per 100 patient safety-years). The teofold increase in safety events in the device group was mainly due to non-neurologic causes such as pericardial effusion. Additionally, these safety events decreased over time with procedural modifications. The probability of WATCHMAN device noninferiority was greater than 99.9%. The authors suggest that closure of the left atrial appendage may provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with nonvalvular atrial fibrillation (Holmes et al., 2009). The most important impact of the PROTECT AF trial may actually be on the subgroup of atrial fibrillation patients who have contraindications to long-term anticoagulation, especially in those individuals with contraindications due to bleeding complication or noncompliance.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT: CARDIOVASCULAR SURGERY THE MAZE PROCEDURE In the “Maze” operation introduced by Cox, several small incisions are made in the atria to interrupt atrial fibrillation re-entry pathways (Cox et al., 1991). The Cox-Maze III operation, “cut and sew Maze,” or simply

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Maze procedure is now the gold standard for surgical treatment of atrial fibrillation. The operation may be performed alone or in conjunction with other cardiac surgical procedures, such as mitral valve repair or coronary artery bypass grafting (Gillinov, 2007). In a report of 197 patients who underwent the Maze procedure, the mean rate of freedom from atrial fibrillation was 89% after 10 years of follow-up (Gaynor et al., 2005). Despite these good results, the Maze procedure is seldom used because it is complicated and time-consuming. Operations that were modified from the original Maze procedure were shown to be less effective than the original procedure (Barnett and Ad, 2006). Complications of the Maze operation include different types of atrial arrhythmias as a possible consequence of partial denervation of the sympathetic and parasympathetic systems of the heart. Most importantly, it does not reduce the risk of embolic events, including stroke, so patients must continue with anticoagulation therapy. As with other cardiac surgical procedures, abnormalities of intellectual function and behavior can occur (Barbut and Caplan, 1997; Wolman et al., 1999). Although it carries a low risk of stroke, perioperative stroke has been reported in conjunction with the Maze procedure (Gammie et al., 2009). A particular patient’s risk of perioperative stroke may be estimated using the Society of Thoracic Surgeons 2008 cardiac surgery risk models, which include outcomes for stroke as well as other morbidities. Several variables were forced into each model to ensure face validity (for example, the permanent stroke model includes atrial fibrillation as a variable) (O’Brien et al., 2009; Shahian et al., 2009a, b).

EPICARDIAL RADIOFREQUENCY ATRIAL AND/OR PULMONARY VEIN ISOLATION AND GANGLIONATED PLEXUS ABLATION

Several new procedures have been developed that attempt to mimic the Maze procedure using a variety of energy sources to create conduction block rather than cardiac incisions. These procedures appear to provide effective treatment for atrial fibrillation, with 75% subjects overall and 87.5% subjects with paroxysmal or persistent atrial fibrillation having a successful procedure (defined as freedom from atrial fibrillation and antiarrhythmic agents throughout 1 year of follow-up) (McClelland et al., 2007). A second study with 6 months of follow-up showed freedom from atrial fibrillation in 93% of patients (Mehall et al., 2007). Specific neurologic complications from this procedure have not yet been reported. Ganglionated ablation directs an energy source onto the cardiac plexi usually located on the epicardial surface of the main pulmonary veins. Specific risks from these procedures are yet to be determined; however, a

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postprocedure requirement for permanent pacemaker is not insignificant, with the pacemaker-neurologic risk as previously mentioned.

OTHER CARDIAC SURGICAL PROCEDURES Preoperative arrhythmia has been shown to affect neurologic outcome after cardiac surgery. Preoperative atrial fibrillation increases the risk of cardiac surgical postoperative complications, including delirium, stroke, and death. The pilot study of the CODACS trial (COnsciousness Disorders After Cardiac Surgery) prospectively assessed 260 patients admitted for open-heart surgery. Preoperative atrial fibrillation was diagnosed on the basis of multiple electrocardiograms and confirmed by 24 hour Holter monitoring. Diagnosis of delirium following surgical intervention was based on DSM-IV criteria. Preoperative atrial fibrillation was an independent predictor of postoperative delirium (p < 0.001), increasing its risk of occurrence over sevenfold. Atrial fibrillation also increased the risk of other postoperative neurologic complications including stroke (8.7% versus 1.3%, p < 0.001). These results and data from available studies suggest that preoperative atrial fibrillation should be considered an important predictor of postoperative neurologic outcome (Banach et al., 2008).

CONCLUSION There are many causes of neurologic complications in arrhythmia patients. Certain arrhythmias have direct complications, such as stroke, cognitive impairment, and dementia. Other individuals with arrhythmia develop neurologic problems as an indirect result of their diagnosis or treatment. It is important to recognize these patients, because some of these neurologic complications can be prevented and others can be reversed with the discontinuation of the offending agent.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 11

Neurologic complications of catheter ablation/ defibrillators/pacemakers SMIT C. VASAIWALA* AND DAVID J. WILBER Cardiovascular Institute, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION

CLINICAL HISTORY

Approaches to the management of patients with cardiac arrhythmias have significantly evolved over the last decade, with advancement in catheter ablation and device implantation techniques. As the techniques and tools evolve, so does our understanding of the possible complications from these procedures. The focus of this chapter is to discuss the neurologic complications involved with catheter ablation, pacemaker and defibrillation implantation, with the focus on timely diagnosis, and management strategies.

Neurologic insult during cardiac procedures may be related to hypotension, hypoxia, use of contrast agents, use of antithrombotic medications, or embolization of air, debris, or pieces of atherosclerotic plaque during cardiac procedures (Duffis et al., 2007). This may result in global brain ischemia resulting in coma or encephalopathy, localized brain ischemia resulting in visual loss or cognitive defects, intracranial hemorrhage, or acute ischemic stroke (Adams, 2010). Patients may also experience long-term neuropsychological sequelae including memory loss or impaired executive functioning. Brain imaging performed following procedures may also detect silent or subtle ischemic strokes (Duffis et al., 2007). What follows is a discussion of specific neurologic complications associated with ablation procedures. Thromboembolic complications associated with ablation of atrial fibrillation are well described and discussed separately.

HISTORY Over the last few decades, catheter ablation has become a widely utilized clinical tool in the management of patients with cardiac arrhythmia. Also, the use of implantable pacemakers and cardiac defibrillators has increased for treatment of certain arrhythmias and prevention of sudden cardiac death. As the prevalence of these procedures has increased, there has been an increased understanding of associated complications. Although these complications are uncommon (Fuchs et al., 2002), they may be related to significant neurologic morbidity and even death (Adams, 2010). The purpose of this chapter is to discuss the neurologic complications associated with procedures involving cardiac ablation and device implantation, and to discuss strategies geared toward prevention, detection, and treatment of the complications. The majority of the chapter is geared toward discussion of neurologic complications with ablation including thromboembolic events, cerebral air embolism, and phrenic nerve injury. Neurologic complications associated with pacemaker and defibrillator placement are discussed separately.

Thromboembolism associated with ablation of atrial fibrillation The demographic of patients referred for ablation of atrial fibrillation (AF) is becoming increasingly complex, as the percentage of patients undergoing ablation for persistent AF with associated risk factors such as diabetes, hypertension, structural heart disease, and older age has increased (Cha et al., 2009). Thus there is an increased urgency for minimizing the risk of thromboembolic complications associated with AF ablation. Most studies have reported a 0.5% to 2.0% risk of stroke and transient ischemic episodes following radiofrequency ablation of AF (Chen et al., 1999; Zhou et al., 1999; Haissaguerre et al., 2000; Kok et al., 2002; Marrouche

*Correspondence to: Smit C. Vasaiwala, M.D., Loyola University Medical Center, 2160 South 1st Avenue, Building 110, Room 6232, Maywood, IL 60153, USA. Tel: þ1-708-216-9449, Fax: þ1-708-327-2377, E-mail: [email protected]

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et al., 2002; Oral et al., 2002, 2004; Pappone et al., 2003; Cauchemez et al., 2004; Ren et al., 2004; Cappato et al., 2005). This risk is generally reported to be higher in the earlier studies prior to maintenance of higher activated clotting time (ACT) in the more recent experience. The risk of fatal cerebrovascular accident is low, and occurs in about 1/10 000 cases (Cappato et al., 2009). The risk of thromboembolic complications associated with AF ablation is variable and influenced by the presence of various comorbid conditions. Oral et al. (2006) evaluated the risk of thromboembolism following percutaneous radiofrequency ablation of AF in 755 patients who underwent 929 AF ablation procedures. Thromboembolism occurred in 7/755 (0.9%) within 30 days of the ablation procedure. The authors concluded that the risk of postablation thromboembolism was 1.2%, with the highest risk being in the initial 1–2 weeks when the INR is still subtherapeutic. The risk of late thromboembolism was low (0.3%), with events occurring despite maintenance of therapeutic INR. The results indicated that ablation of AF was associated with early postprocedure thromboembolic events regardless of the presence or absence of sinus rhythm or risk factors for thromboembolism. The likely cause was char and/or thrombus formation at the sites of left endocardial ablation. One patient suffered a thromboembolic event in the setting of therapeutic anticoagulation, suggesting an inherent thromboembolic risk from the ablation procedure independent of anticoagulation status. The authors added that all patients underwent ablation with a nonirrigated-tip catheter that may be more prone to thrombus formation; this risk may be minimized with ablation performed with an irrigated-tip catheter. In a similar study, Bertaglia and colleagues (2007) collected clinical and procedural data from 1011 consecutive patients undergoing ablation for AF. In this study, 905 cases (89.5%) were performed with an open irrigated-tip catheter. They reported cerebral embolism in five (0.4%) patients (four major strokes, one transient

ischemic attack; four procedures performed with irrigated-tip catheter). Four events occurred on the day following the procedure while transitioning from intravenous unfractionated heparin to oral warfarin and one event occurred during the procedure. A single patient also experienced phrenic nerve paralysis during isolation of the right pulmonary veins. Due to a low number of events there were no clinical variables that significantly identified the patients that suffered the embolic events. The authors concluded that the lower embolic rates they observed in their study might have been a result of more aggressive procedural and periprocedural anticoagulation regimen and the use of irrigated-tip catheter. Other studies have tried to identify predictors of thromboembolic complications. In a study by Kok et al. (2002), 56 patients underwent catheter ablation for AF. Cerebrovascular accident occurred in three patients. All patients were more than 60 years old; however, age was not a statistically significant predictor in this study. Two out of three patients had history of previous transient ischemic attacks that proved to be a statistically significant clinical predictor for predicting thromboembolic risk in the setting of catheter ablation for AF. Silent infarction in the setting of atrial fibrillation is not uncommon. In the European Atrial Fibrillation Trial (EAFT Study Group, 1996), 14% of 985 patients had evidence of cerebral infarction on commuted tomography. Schrickel and colleagues (2010) investigated the incidence and predictors of silent cerebral embolism in 53 consecutive patients with low risk for thromboembolism undergoing catheter ablation for AF. All patients underwent a postprocedural cerebral diffusion-weighted MRI (DW-MRI) 1 day following the ablation procedure. In six patients (11%), DW-MRI depicted new clinically silent microembolism (Fig. 11.1). The study showed a high incidence of clinically asymptomatic cerebral microembolism following ablation. Patients with

Fig. 11.1. Two white matter lesions (arrows) seen on diffusion weighted image (DWI) (A) and apparent diffusion coefficient (ADC) map (B) consistent with acute embolic cerebral infarctions. Patient had no clinical sequelae. Fluid attenuated inversion recovery (FLAIR) (C) with extensive white matter lesion due to microangiopathy. (Reproduced from Schrickel et al., 2010, with permission.)

NEUROLOGIC COMPLICATIONS OF CATHETER ABLATION/DEFIBRILLATORS/PACEMAKERS 153 cerebral microembolism were more likely to have evidence of coronary artery disease, larger left ventricular volume and septal thickness, and were more likely to have failed treatment with multiple antiarrhythmic agents prior to ablation. The amount of radiofrequency energy applied was equal in both groups, substantiating the fact that further protective measures (i.e. standardization of the use of irrigated-tip catheters, activated clotting time screening, high flush sheaths, minimizing procedure times and manipulation in the left atrium) are important in preventing the possible devastating complication of cerebral embolism (Cauchemez et al., 2004; Schrickel et al., 2010). Scherr and colleagues (2009) reported their findings on 721 cases involving catheter ablation for AF. Despite implementation of commonly used procedures to minimize risk of thromboembolism, such as preprocedural transesophageal echocardiography, preprocedural anticoagulation, intraprocedural use of heparin, continuous flushing of transseptal sheaths, and use of irrigated-tip catheters, 10/721 patients (1.4%) suffered from periprocedural thromboembolic complications. In two separate multivariable analyses, having at least two risk factors for thromboembolism in the setting of AF (hypertension, age > 75, diabetes, or congestive heart failure) and history of cerebrovascular accident were found to be independent predictors of periprocedural cerebrovascular thromboembolism. The risk of thromboembolism was low (0.3%) in patients with no risk factors for thromboembolism. In the most recent study, Di Biase et al. (2010) investigated the role of periprocedural therapeutic international normalized ratio (INR) on the role of periprocedural stroke. This was a multicenter prospective study that categorized patients into three groups: those undergoing ablation with an 8 mm tip catheter without periprocedural warfarin (group 1), those undergoing ablation with an open-irrigated-tip catheter without periprocedural warfarin (group 2), and those with open-irrigated-tip catheters on warfarin (group 3). Periprocedural stroke/transient ischemic attacks occurred in 27 patients (1.1%) in group 1, and 12 patients (0.9%) in group 2. Despite greater risk factors for stroke and greater prevalence of nonparoxysmal AF, patients in group 3 incurred no strokes/transient ischemic attacks. Performing ablation with a therapeutic INR with an irrigated-tip catheter may be a potential strategy for stroke prevention in the setting of catheter ablation for AF. The risk of thromboembolism may be significantly reduced with the use of irrigated-tip catheters. In the recently reported Thermacool Study (Wilber et al., 2010), none of the 106 patients that underwent catheter ablation with irrigated-tip catheter incurred thromboembolic events.

Thromboembolism associated with catheter ablation of other supraventricular and ventricular arrhythmias The risk of thromboembolic complications during ablation of various supraventricular and ventricular arrhythmias has been reported to be between 0% and 1.3% (Hindricks, 1993; Greene et al., 1994; Kugler et al., 1994; Thakur et al., 1994; Chen et al., 1996; Epstein et al., 1996). In the study by Hindricks (1993), thromboembolic events occurred in 33/4398 (0.8% overall incidence) patients, including cerebral embolism in 0.4%. Procedure related thromboembolic complications in relation to the type of ablation varied from 0.2% for atrioventricular nodal ablation to 2.8% for ventricular tachycardia ablation (Scheinman and Huang, 2000; Delacretaz and Stevenson, 2001). Possible explanation for a higher incidence of thromboembolic complications with ablation of ventricular tachycardia include longer procedure duration, more ablation, and possibility of pre-existing thrombus not previously identified on echocardiography. In the study by Thakur et al. (1994), 3/153 patients undergoing catheter ablation on the left side of the heart experienced stroke; 2/3 patients that experienced stroke presented 3 months following the ablation. Only one patient had a history of AF. Also, the total amount of ablation performed in the patients with stroke was less than the patients that did not experience stroke. The authors concluded that the embolic events occurred despite anticoagulant therapy, and were not predicted by the amount of endocardial damage due to ablation, and that embolic complications may occur at a remote time following the ablation procedure.

Cerebral air embolism complicating catheter ablation procedures Cerebral air embolism is a rare complication of catheter ablation procedures and is usually a result of introduction of air into the arterial system at the time of sheath placement or catheter exchange. It is critical to establish the diagnosis of cerebral air embolism early, as management strategies can significantly alter the clinical course. Information regarding the course and prognosis of cerebral air embolism is mostly derived from a few case series (Aikawa et al., 1995; Wijman et al., 1998; Heckmann et al., 2000; Akhtar et al., 2001; Hinkle et al., 2001; Inamasu et al., 2001; Yang and Yang, 2005). The initial presentation may be more severe than that seen secondary to a cerebrovascular event from a thrombus. Patients may present with confusion, agitation, aphasia, and hemiparesis. There may be initial resolution of neurologic symptoms which may be transient (Hinkle et al., 2001). This is thought to be due to initial infarction

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from arterial occlusion, followed later by a thromboinflammatory response in the injured endothelium. Neuroimaging with either computed tomography or magnetic resonance imaging is generally unremarkable and diagnosis is established by clinical suspicion. Another manner by which air may enter the arterial system is via an atrioesophageal fistula. This devastating complication of catheter ablation of AF is fortunately rare, although incidence as high as 1% has been reported in some series, with mortality rates approaching 50% (Gillinov et al., 2001; Doll et al., 2003; Sonmez et al., 2003; Scanavacca et al., 2004). The relative anatomy of the posterior left atrium lying adjacent to the esophagus and the typical sites of ablation lesion makes the esophagus susceptible to thermal injury. Patients typically present with symptoms 3–28 days following the ablation (Stollberger et al., 2009). Mortality arises from widespread esophagoatrial air and septic embolization to the coronary and cerebral circulation along with morbidity associated with embolization to other organ systems. Neurologic symptoms include confusion, meningitis, grand mal seizures, focal cortical signs, and postprandial transient ischemic attacks associated with fever. Neuroimaging is consistent with various different findings including intravascular air, ischemic lesions, and evidence of cerebral emboli. Application of barium swallow is contraindicated due to the risk of barium entering systemic circulation. Also, transesophageal echocardiography or insertion of nasogastric tubes must be avoided due to the risk of food or air embolism from inflation of air during the procedure. Diagnosis is established by thoracic contrast computed tomography, which may show air within the cardiac cavities or contrast entering the left atrium from the esophagus (Schley et al., 2006). The strategies for management of cerebral air embolus as a result of either venous sheath placement or exchange, or as a result of atrioesophageal fistula are discussed later in the chapter.

Phrenic nerve injury during catheter ablation The right phrenic nerve courses anterior to the right superior pulmonary vein and posterior to the superior vena cava and courses down adjacent to the free wall of the right atrium (Bunch et al., 2005). This places it at risk of injury during radiofrequency ablation for AF (during isolation of right superior pulmonary vein) and atrial tachycardias originating from free wall of the right atrium (Durante-Mangoni et al., 2003). The left phrenic nerve can also be compromised with ablation for Wolf– Parkinson–White syndrome in the left atrium (Rumbak et al., 1996). The potential damage to the nerve is thought to be due to direct thermal energy with secondary

inflammation and edema (Haines and Watson, 1989). Clinical manifestations can range broadly from asymptomatic to severe respiratory dysfunction requiring prolonged mechanical ventilation, and mortality; however, most patients tend to be either asymptomatic or present with dyspnea. Complete or partial recovery occurs in most patients (Sacher et al., 2006). Phrenic nerve injury can be prevented by pacing at a high output to assess phrenic nerve capture in areas at risk for phrenic nerve damage prior to ablation. Ablation should be avoided in areas where there is phrenic nerve capture. Another approach involves placement of an epicardial balloon catheter to move the phrenic nerve away from the epicardial surface prior to ablation in an area where potential for damaging the phrenic nerve is high (Lee et al., 2009).

NATURAL HISTORY Thromboembolism during catheter ablation The natural history after thromboembolic event following catheter ablation is variable. In the Kok et al. study (2002), 3/56 patients had a cerebrovascular event. The first patient presented with right hemiparesthesia, followed with left hemiparesis and dysarthria. This patient had completely recovered at 18 month follow-up. The second patient developed dysarthria, hemiparesis, and diplopia, along with hemorrhagic infarct in the left cerebellum requiring emergent evacuation of clot for posterior fossa syndrome. This patient ultimately developed normal pressure hydrocephalus and required treatment with a ventriculoperitoneal shunt. At 1 year follow-up, the patient continued to require assistance with activities of daily living and a walking frame to ambulate. The third patient presented with left sided hemiparesis. At 14 month followup, she had regained full neurologic function. In the study by Oral et al. (2006), three out of nine patients had residual symptoms at 2 year follow-up. Scherr et al. (2009) reported periprocedural cerebrovascular accident in 10/ 721 (1.4%) cases undergoing catheter ablation of AF. The symptoms ranged from right or left hemiparesis (three patients and one patient, respectively), aphasia (two patients), visual field change (three patients), and left leg weakness. In three patients, neurologic symptoms resolved completely within 24 hours. In two patients, the symptoms resolved in the following weeks. In the remaining five patients, mild-moderate neurologic deficits persisted beyond 30 days.

Cerebral air embolism Cerebral air embolism is a rare complication of catheter ablation procedure. The majority of information regarding the natural history of cerebral air embolism in the setting of catheter ablation procedures comes from case

NEUROLOGIC COMPLICATIONS OF CATHETER ABLATION/DEFIBRILLATORS/PACEMAKERS 155 reports. Hinkle et al. (2001) describe two patients who suffered severe neurologic illness as a result of cerebral air embolism while undergoing catheter ablation for AF. The first patient suffered from a left homonymous hemianopsia with left facial droop, hemiparesis, and hemineglect. One month later, the patient exhibited only mild residual left arm weakness. The second patient suffered from global aphasia and right side hemiparesis. All neurologic deficits improved over 4 days and the patient was discharged with only mild residual language impairment, which also improved to baseline over the next several weeks. In another patient undergoing catheter ablation for AF, at the time of sheath exchange fluoroscopic contrast changes consistent with intracardiac air were observed (Mofrad et al., 2006). The patient subsequently went on to develop inferior ST-segment elevation on ECG associated with bradycardia and hypotension. He also developed a left hemiparesis. The patient was placed in a hyperbaric chamber, following which he regained control of both left sided extremities and ultimately gained fine motor control. At 4 days following ablation, the patient had attained full neurologic recovery. If cerebral air embolism is recognized and promptly treated, the outcomes can be favorable. Although the formation of atrioesophageal fistula complicating atrial fibrillation ablation is rare, the consequences are usually devastating (Sonmez et al., 2003; Pappone et al., 2004; Schley et al., 2006; Malamis et al., 2007). In the five patients presented in the above case series, only one patient survived. To have any chance at survival the diagnosis needs to be made promptly, with immediate surgical repair following the diagnosis. Even with early diagnosis and treatment, the mortality following atrioesophageal fistula remains high.

LABORATORY INVESTIGATIONS Catheter ablation of atrial fibrillation There are no specific laboratory tests that are routinely recommended to aid in prevention, evaluation, or treatment of neurologic complications associated with catheter ablation of AF. There may be increased thrombogenicity with insertion and presence of catheters in the heart as measured by levels of thrombin-antithrombin III, D-dimer and prothrombin fragment 1 þ 2 with and without application of radiofrequency ablation lesions (Manolis et al., 1996; Michelucci et al., 1999; Lee et al., 2001) A greater degree of D-dimer level elevation may be seen in patients that had ablation, indicating a greater degree of thrombus production as compared to those patients undergoing only electrophysiology studies. Although this finding has not been consistently validated by all studies (Dorbala et al., 1998), it does provide a stimulus for

exploring the utilization of intravascular catheters coated with heparin.

Cerebral air embolism Laboratory evaluation in the setting of cerebral air embolism as a result of atrioesophageal fistula is likely to reveal leukocytosis, elevation of markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate, and thrombocytopenia. Blood cultures are frequently positive for bacteria (Stollberger et al., 2009).

NEUROIMAGING INVESTIGATIONS Thromboembolism during catheter ablation When assessing an acute stroke both the location of neurologic insult and potential for recovery need to be assessed. Often a noncontrast head coronary tomography (CT) is usually utilized as the initial imaging modality since it allows for rapid acquisition and provides information regarding the location and extent of ischemia. CT or magnetic resonance perfusion imaging allow for assessment of not only the location, but also the extent of cerebral blood flow and volume (Shetty and Lev, 2005; Lickfett et al., 2006). This in turn allows for accurate assessment of the extent of ischemic territory, vascular reserve, and reversibility. Transcranial Doppler (TCD) monitoring has been utilized for monitoring microemboli during ablation (Sauren et al., 2009). Increasing numbers of microembolic signals (MES) have been detected with increasing power, duration, and temperature of ablation, and with the use of radiofrequency ablation as compared to cryoablation. Since there is a correlation between cerebral microemboli and brain damage (Kilicaslan et al., 2006; Lickfett et al., 2006), lower incidence of cerebral complications may be expected with reducing duration of each ablation, using irrigated-tip catheters, and using cryoablation rather than radiofrequency (Khairy et al., 2003; Sauren et al., 2009).

GENETICS Genetic polymorphisms that increase propensity to systemic hypercoagulability and thrombosis, such as prothrombin gene mutation, factor V Leiden, and protein C and S mutations, are well characterized (Monsuez et al., 2003). Although there are no specific genes implicated in increasing the propensity to thrombus formation with catheter ablation, it is likely that there are genetic differences between individuals, such as the ones described for systemic hypercoagulable states, that determine how much thrombus is generated and how readily it is dissolved by the endogenous fibrinolytic system (Zhou et al., 1999).

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PATHOLOGY

Cerebral air embolus

Endothelial cells are highly sensitive to injury, to the degree that even selective ablation with radiofrequency energy results in damage or loss of endothelium. The lining of the atrial and ventricular endocardium mediates natural anticoagulant properties by release of nitric oxide, prostacyclin, tissue plasminogen activator, and thrombomodulin. These mediators aid in clearance of newly formed fibrin and prevent thrombus formation. With the disruption of the endocardium with radiofrequency ablation, these properties are affected (Bombeli et al., 1997; Zhou et al., 1999), leading to a propensity toward thrombus formation. The gross examination reveals charring and endocardial disruption. The histology reveals endocardial disruption with loss of subendocardial architecture (Kongsgaard et al., 1994; Tanno et al., 1994). A better understanding of the pathophysiology of scar formation from catheter ablation should lead to improved methods of energy delivery to the endocardial and epicardial surface.

Recognition of cerebral air embolus is crucial as appropriate treatment can have favorable results. Following recognition of this complication, the most important initial step is to maximize cerebral perfusion. This is done with administration of intravenous fluids, supplemental oxygen, and placement of patient in a supine position with the head of the bed flat. Trendelenberg positioning is contraindicated as it may exacerbate cerebral edema. It is important to rule out intracerebral hemorrhage following these initial steps. Once that is ruled out, the patient is placed in a hyperbaric oxygen chamber, which is pressurized according to the US Navy Treatment Table 6 protocol (Mofrad et al., 2006). To our knowledge, there are five cases of cerebral air embolism reported in the literature that were treated with hyperbaric oxygen therapy (Hinkle et al., 2001; Mofrad et al., 2006). Although this is considered the treatment of choice for suspected air embolus by most, some have questioned its role in this setting (Heckmann et al., 2000). It is thought to promote absorption of nitrogen from the air bubble into the blood and to reduce endothelial injury from air embolism, potentially improving neurologic outcome (Muth and Shank, 2000). An absolute contraindication to hyperbaric oxygen therapy is untreated pneumothorax. Relative contraindications include upper respiratory infections, high fevers, seizure disorders, emphysema with carbon dioxide retention, uncontrolled hypertension, asthma, hypoglycemia, and pregnancy. Recent treatment with doxorubicin, disulfiram, cisplatinum, and mafenide acetate are also relative contraindications to hyperbaric oxygen. A directory of hyperbaric centers in the US is available on the website of the Undersea and Hyperbaric Medical Society (Weaver, 2010). It is imperative that clinicians involved in management of patients undergoing such catheter ablation procedures know about hyperbaric centers in the area of their practice. Lidocaine therapy may also play a role in managing cerebral air embolism. It has been shown to have protective effects from ischemia and to reduce intracranial pressure in animal studies (Mofrad et al., 2006). Administration of lidocaine in a bolus dose of 1.5 mg/kg with maintenance infusion thereafter has been shown to be helpful in treating patients with significant cerebral artery air embolus burden (Muth and Shank, 2000). Despite early recognition and therapy, the mortality associated with atrioesophageal fistula is significantly high. Besides supportive treatment including intravenous fluids and supplemental oxygen, definitive treatment comprises surgical resection of parts of the esophagus and closure of the left atrium (Borchert et al., 2008). Bunch and colleagues report a case where a patient underwent esophageal stenting following an ablation-induced atrioesophageal fistula, with complete defect resolution 3 weeks following stenting (Bunch et al., 2006).

MANAGEMENT Thromboembolism during catheter ablation Early heparinization prior to transseptal puncture (Bruce et al., 2008), higher intensity of anticoagulation with heparin and intracardiac echocardiographic imaging during the procedure (Ren et al., 2005; Wazni et al., 2005), the use of high-flow perfusion sheaths (Cauchemez et al., 2004), and ablation of patients with therapeutic INR may minimize the risk of thromboembolic complications. Although the risk may be low, the cost to the patient is enormous, making very early recognition and management of this complication imperative. There are minimal published data on the management of embolic complications in the setting of catheter ablation. Most cerebrovascular events likely have to do with placement of intravascular catheters in the left atrium or coagulum formation as a result of tissue heating. The management of this complication requires a multidisciplinary approach with close collaboration with the electrophysiologist and the neurologist or neurointerventionalist. The choice of perfusion therapy depends on the length of symptoms prior to presentation with stroke, NIH Stroke Scale, and coronary tomography perfusion data showing salvageable ischemic tissue (Ghanbari et al., 2009). Intravenous thrombolysis with recombinant tissue plasminogen activator (tPA) is currently FDA-approved for treatment of acute stroke with symptoms of less than 3 hours duration. Other techniques such as intra-arterial tPA or mechanical embolectomy may also be considered (Furlan et al., 1999; Smith et al., 2008).

NEUROLOGIC COMPLICATIONS OF CATHETER ABLATION/DEFIBRILLATORS/PACEMAKERS 157 echocardiography or monitoring with continuous tranNEUROLOGIC COMPLICATIONS scranial Doppler may have a role in ablation procedures ASSOCIATED WITH PACEMAKERS AND (Zhou et al., 1999). Biochemical measures of thrombin DEFIBRILLATORS activity such as thrombin-antithrombin complex, platelet Neurologic complications associated with placement of activity such as P-selectin, and fibrin formationpacemakers and defibrillators are rare. Most of the degradation such as D-dimer may also serve as surrogate knowledge regarding these complications comes from measures of thromboembolism in patients undergoing case reports. One of the well-recognized complications catheter ablation. with device implantation is capture of the phrenic nerve At this time there is no specific evidence for prevenand diaphragmatic stimulation. Although this complition of thromboembolism with anticoagulant therapies. cation can be avoided with high output pacing to The role for newer anticoagulants targeting indirect or assess phrenic capture at the time of implantation, it direct thrombin inhibition and newer antiplatelet agents is difficult to exclude phrenic nerve capture that may to prevent thromboembolism in the setting of catheter result from changes in body position once the patient ablation needs further study. In the meantime, unfractiobecomes ambulatory. Management of this complicanated heparin, low molecular weight heparin, and warfation requires repositioning of the lead (Hamid et al., rin remain the standard anticoagulant agents for patients 2008). undergoing catheter ablation. Since the implantation of these devices requires Alternate sources of energy to radiofrequency, such placement of venous sheaths, there is a potential for as cryothermal energy, microwave, and laser, are availair embolism; however, cerebral air embolism would able. Of these, cryothermal energy is widely accepted in theory require a right to left shunt across the cardiac and utilized for ablation of several different arrhythchambers. To the best of our knowledge, there have mias, including atrial fibrillation (Chierchia et al., been no case reports of cerebral air embolism during 2009). Cryothermy has the advantage of leaving the placement of pacemakers or defibrillators. endothelium intact, and has been shown to have a Pacemaker lead thrombus and vegetation have been reduced risk of stroke in patients undergoing ablation reported to cause thromboembolic events in patients for Wolf–Parkinson–White syndrome (Gallagher with patent foramen ovale (PFO). Transesophageal echoet al., 1977). Definitive data on whether this advantage cardiography may be able to visualize the presence of is present with ablation of AF is lacking and there are thrombus or vegetation. Lead thrombus may be an some reports that suggest significant risk for phrenic unrecognized source of thrombus in patients with crypnerve damage with this technology (Saliba et al., togenic stroke. In patients presenting with neurologic 2002). This risk was also seen in the Sustained Treatsequelae who are found to have a PFO and lead thromment of Paroxysmal-AF trial that was recently prebus, closure of PFO may be considered (Michaels and sented at the American College of Cardiology 2010 Burlew, 2009). meeting, where 29/245 patients undergoing catheter ablation had phrenic nerve injury (O’Riordan, 2010). Laser and microwave energy do lead to endothelial disCONCLUSION ruption, like radiofrequency ablation. It remains Cerebral embolism is an infrequent complication associunclear whether shorter procedure times associated ated with catheter ablation procedures and rare with with these technologies will lead to fewer thromboemdevice implantation. Early recognition of this problem bolic complications. could have a significant impact in the overall prognosis. Percutaneous strategies to exclude left atrial appendClose collaboration with the neurologist or neurointerage from the circulation via either an endocardial or epiventionalist is important in guiding management of cardial approach seem promising; however, definitive these patients. The timing of the events could be acute data toward stroke prevention are lacking (Onalan and in the setting of the procedure or could be delayed Crystal, 2007; Singh et al., 2010). (Oral et al., 2006). Postprocedure thromboembolic comDespite appropriate measures, cerebral embolism plications can occur despite maintenance of sinus remains a potential complication of cardiac procedures rhythm or the presence of risk factors for involving catheter ablation and device implantation. thromboembolism, thereby stressing the need for Early recognition and treatment of these problems is aggressive anticoagulation in the early postprocedure imperative as it may have a significant impact on progperiod. nosis for the patient. With advent of newer imaging Neuroimaging techniques and laboratory evaluation modalities, ablation techniques and medical therafor recognition of cerebral thromboembolism in the pies, one may expect to see fewer neurologic comsetting of catheter ablation are evolving. Real time plications and improved survival following these imaging of thrombus formation with transesophageal complications.

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NEUROLOGIC COMPLICATIONS OF CATHETER ABLATION/DEFIBRILLATORS/PACEMAKERS 159 Haines DE, Watson DD (1989). Tissue heating during radiofrequency catheter ablation: a thermodynamic model and observations in isolated perfused and superfused canine right ventricular free wall. Pacing Clin Electrophysiol 12: 962–976. Haissaguerre M, Shah DC, Jais P et al. (2000). Electrophysiological breakthroughs from the left atrium to the pulmonary veins. Circulation 102: 2463–2465. Hamid S, Arujuna A, Rinaldi CA (2008). A case of diaphragmatic pacing with cardiac resynchronization therapy. Europace 10: 1229–1231. Heckmann JG, Lang CJ, Kindler K et al. (2000). Neurologic manifestations of cerebral air embolism as a complication of central venous catheterization. Crit Care Med 28: 1621–1625. Hindricks G (1993). The Multicentre European Radiofrequency Survey (MERFS): complications of radiofrequency catheter ablation of arrhythmias. The Multicentre European Radiofrequency Survey (MERFS) investigators of the Working Group on Arrhythmias of the European Society of Cardiology. Eur Heart J 14: 1644–1653. Hinkle DA, Raizen DM, McGarvey ML et al. (2001). Cerebral air embolism complicating cardiac ablation procedures. Neurology 56: 792–794. Inamasu J, Nakamura Y, Saito R et al. (2001). Cerebral air embolism after central venous catheterization. Am J Emerg Med 19: 520–521. Khairy P, Chauvet P, Lehmann J et al. (2003). Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation 107: 2045–2050. Kilicaslan F, Verma A, Saad E et al. (2006). Transcranial Doppler detection of microembolic signals during pulmonary vein antrum isolation: implications for titration of radiofrequency energy. J Cardiovasc Electrophysiol 17: 495–501. Kok LC, Mangrum JM, Haines DE et al. (2002). Cerebrovascular complication associated with pulmonary vein ablation. J Cardiovasc Electrophysiol 13: 764–767. Kongsgaard E, Foerster A, Aass H et al. (1994). Power and temperature guided radiofrequency catheter ablation of the right atrium in pigs. Pacing Clin Electrophysiol 17: 1610–1620. Kugler JD, Danford DA, Deal BJ et al. (1994). Radiofrequency catheter ablation for tachyarrhythmias in children and adolescents. The Pediatric Electrophysiology Society. N Engl J Med 330: 1481–1487. Lee DS, Dorian P, Downar E et al. (2001). Thrombogenicity of radiofrequency ablation procedures: what factors influence thrombin generation? Europace 3: 195–200. Lee JC, Steven D, Roberts-Thomson KC et al. (2009). Atrial tachycardias adjacent to the phrenic nerve: recognition, potential problems, and solutions. Heart Rhythm 6: 1186–1191. Lickfett L, Hackenbroch M, Lewalter T et al. (2006). Cerebral diffusion-weighted magnetic resonance imaging: a tool to monitor the thrombogenicity of left atrial catheter ablation. J Cardiovasc Electrophysiol 17: 1–7.

Malamis AP, Kirshenbaum KJ, Nadimpalli S (2007). CT radiographic findings: atrio-esophageal fistula after transcatheter percutaneous ablation of atrial fibrillation. J Thorac Imaging 22: 188–191. Manolis AS, Melita-Manolis H, Vassilikos V et al. (1996). Thrombogenicity of radiofrequency lesions: results with serial D-dimer determinations. J Am Coll Cardiol 28: 1257–1261. Marrouche NF, Dresing T, Cole C et al. (2002). Circular mapping and ablation of the pulmonary vein for treatment of atrial fibrillation: impact of different catheter technologies. J Am Coll Cardiol 40: 464–474. Michaels AD, Burlew BS (2009). Pacemaker lead thrombus causing cryptogenic stroke in a patient referred for percutaneous patent foramen ovale closure. J Invasive Cardiol 21: E224–E225. Michelucci A, Antonucci E, Conti AA et al. (1999). Electrophysiologic procedures and activation of the hemostatic system. Am Heart J 138: 128–132. Mofrad P, Choucair W, Hulme P et al. (2006). Case report. Cerebral air embolization in the electrophysiology laboratory during transseptal catheterization: curative treatment of acute left hemiparesis with prompt hyperbaric oxygen therapy. J Interv Card Electrophysiol 16: 105–109. Monsuez JJ, Bouali H, Serve E et al. (2003). Deep venous thrombosis associated with factor V Leiden, G20210A mutation, and protein S deficiency. Am J Med 114: 421–422. Muth CM, Shank ES (2000). Gas embolism. N Engl J Med 342: 476–482. O’Riordan M (2010). STOP-AF and CABANA: Trials show effectiveness of ablation over drugs in AF. theheart.org. [Clinical Conditions > Arrhythmia/EP > Arrhythmia/ EP]; Mar 15, 2010. Accessed at, on Jul 18, 2010. http:// www.theheart.org/article/1057265.do. Onalan O, Crystal E (2007). Left atrial appendage exclusion for stroke prevention in patients with nonrheumatic atrial fibrillation. Stroke 38: 624–630. Oral H, Knight BP, Ozaydin M et al. (2002). Segmental ostial ablation to isolate the pulmonary veins during atrial fibrillation: feasibility and mechanistic insights. Circulation 106: 1256–1262. Oral H, Chugh A, Scharf C et al. (2004). Incremental value of isolating the right inferior pulmonary vein during pulmonary vein isolation procedures in patients with paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 27: 480–484. Oral H, Chugh A, Ozaydin M et al. (2006). Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 114: 759–765. Pappone C, Rosanio S, Augello G et al. (2003). Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 42: 185–197. Pappone C, Oral H, Santinelli V et al. (2004). Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation 109: 2724–2726.

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Ren JF, Marchlinski FE, Callans DJ (2004). Left atrial thrombus associated with ablation for atrial fibrillation: identification with intracardiac echocardiography. J Am Coll Cardiol 43: 1861–1867. Ren JF, Marchlinski FE, Callans DJ et al. (2005). Increased intensity of anticoagulation may reduce risk of thrombus during atrial fibrillation ablation procedures in patients with spontaneous echo contrast. J Cardiovasc Electrophysiol 16: 474–477. Rumbak MJ, Chokshi SK, Abel N et al. (1996). Left phrenic nerve paresis complicating catheter radiofrequency ablation for Wolff–Parkinson–White syndrome. Am Heart J 132: 1281–1285. Sacher F, Monahan KH, Thomas SP et al. (2006). Phrenic nerve injury after atrial fibrillation catheter ablation: characterization and outcome in a multicenter study. J Am Coll Cardiol 47: 2498–2503. Saliba W, Wilber D, Packer D et al. (2002). Circumferential ultrasound ablation for pulmonary vein isolation: analysis of acute and chronic failures. J Cardiovasc Electrophysiol 13: 957–961. Sauren LD, Van Belle Y, De Roy L et al. (2009). Transcranial measurement of cerebral microembolic signals during endocardial pulmonary vein isolation: comparison of three different ablation techniques. J Cardiovasc Electrophysiol 20: 1102–1107. Scanavacca MI, D’Avila A, Parga J et al. (2004). Left atrialesophageal fistula following radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 15: 960–962. Scheinman MM, Huang S (2000). The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 23: 1020–1028. Scherr D, Sharma K, Dalal D et al. (2009). Incidence and predictors of periprocedural cerebrovascular accident in patients undergoing catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 20: 1357–1363. Schley P, Gulker H, Horlitz M (2006). Atrio-oesophageal fistula following circumferential pulmonary vein ablation: verification of diagnosis with multislice computed tomography. Europace 8: 189–190. Schrickel JW, Lickfett L, Lewalter T et al. (2010). Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 12: 52–57.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 12

Hypertension and hypertensive encephalopathy RAYMOND S. PRICE AND SCOTT E. KASNER* Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

HISTORY AND TERMINOLOGY The sphygmomanometer, or inflatable blood pressure cuff, was invented by Scipione Riva-Rocci in 1896 to measure systolic blood pressure (Riva-Rocci, 1896). The modern method of determining the diastolic blood pressure by auscultation was developed by Nicolai Korotkov 8 years later (Berend and Levi, 2008). Over the next 50 years, the morbidity and mortality associated with asymptomatic elevated blood pressure was generally unrecognized. Only patients with evidence of end organ dysfunction received treatment for elevated blood pressure. Moreover, treatment options were limited. A low salt diet to reduce elevated blood pressure was proposed by Allen and Sherrill in 1922 (Allen and Sherrill, 1922). Pharmacologic treatments were limited to barbiturates, bromides, and thiocyanates, all of which had severe side-effect profiles (Moser, 2006). More effective and tolerable pharmacologic treatments for hypertension with thiazide diuretics were developed in 1957. About 5 years later, the b-blocker propranolol became available. In the late 1960s, the association between hypertension and vascular disease, including coronary artery disease, congestive heart failure, ischemic and hemorrhagic strokes, and chronic renal insufficiency, was clearly demonstrated by the Veterans Administration Study (Veterans Administration Cooperative Study Group on Antihypertensive Agents, 1967) and the Framingham Heart Study (Kannel et al., 1969). Over the last 40 years, the risks associated with elevated blood pressure have been further delineated and the optimal systolic and diastolic blood pressures have been redefined. Optimal blood pressure is currently defined as less than 120/80 mmHg (Chobanian et al., 2003).

Worldwide, 54% of strokes, 47% of ischemic heart disease, and 13.5% of all deaths are attributed to blood pressure elevations above this optimal threshold (Lawes et al., 2008). Additionally, the mortality associated with either stroke or heart disease doubles for every 20/10 mmHg elevation above optimal blood pressure in patients 40– 69 years of age (Vasan et al., 2001). Hypertension is currently defined as a blood pressure greater than 140/90 mmHg. The estimated prevalence of hypertension in the US is 24% of the adult population (Burt et al., 1996). Hypertension is by far the most common risk factor identified in stroke patients, occurring in 52% of patients (Bornstein et al., 1996). Hypertensive emergency is currently defined as a blood pressure greater than 180/120 mmHg associated with end organ dysfunction, including diffuse encephalopathy, intracerebral hemorrhage, subarachnoid hemorrhage, acute coronary syndrome, acute congestive heart failure, and aortic dissection (Chobanian et al., 2003). Hypertensive encephalopathy is the most common cause of reversible posterior leukoencephalopathy syndrome (RPLS), which is also known as posterior reversible encephalopathy syndrome (PRES), accounting for 61% of cases (Fugate et al., 2010). Often RPLS/PRES may be synonymous with hypertensive encephalopathy in many cases, though other reported causes of RPLS include medication toxicity, sepsis, and eclampsia. Hypertensive urgency is currently defined as a blood pressure greater than 180/120 mmHg without evidence of end organ dysfunction. The prevalence of hypertensive emergency or urgency is unknown. Hypertensive emergency or urgency has been estimated to account for approximately 3% of emergency department visits (Zampaglione et al., 1996).

*Correspondence to: Scott E. Kasner, M.D., Professor of Neurology, Department of Neurology, 3W Gates Bldg., University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Tel: þ1-215-662-3564, Fax: þ1-215-614-1927, E-mail: kasner@ mail.med.upenn.edu

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CLINICAL FINDINGS Hypertension is classically asymptomatic. Signs of chronic hypertension can often be detected by a thorough funduscopic and cardiac examination. Funduscopic findings in chronic hypertension include narrowed arterioles, arteriovenous nicking, retinal hemorrhages, and retinal exudates. Cardiac findings in chronic hypertension include a sustained apical impulse, increased volume of the first component of the second heart sound (S2), and an atrial gallop (S4). Hypertension is diagnosed after two separate clinical visits demonstrate a blood pressure greater than 140/80 mmHg using proper sphygmomanometric technique (measured with an appropriate-sized cuff applied to a bare arm supported at heart level with the patient at rest for at least 5 minutes). Patients with hypertensive urgency present with headache, epistaxis, light-headedness, shortness of breath, or agitation and a blood pressure greater than 180/ 120 mmHg. Patients with hypertensive emergency present with chest pain, shortness of breath, encephalopathy, or focal neurologic deficits. Hypertensive encephalopathy commonly presents with seizures (generalized or focal), altered mental status, visual field loss, and/or headache (Lee et al., 2008). There are more than 40 case reports of hypertensive encephalopathy with brainstem involvement, usually manifesting as ataxia and less frequently diplopia (Ogaki et al., 2009). Focal neurologic deficits may also result from intracerebral or subarachnoid hemorrhages. The type of focal neurologic deficits depends upon the location of hemorrhage. Hypertensive encephalopathy may progress to coma and death if not effectively treated.

NATURAL HISTORY Hypertension can develop throughout a person’s lifetime and becomes more likely to develop with advancing age. Some 90% of people over the age of 55 without hypertension will develop hypertension if they live to be 80 years of age (Vasan et al., 2002). As a result, the prevalence of hypertension increases with age, affecting 50% of people over the age of 60 and 75% of people over the age of 70.

LABORATORY INVESTIGATIONS The diagnosis of hypertension does not require any confirmatory laboratory testing. Serum creatinine is often assessed to determine if there is evidence of hypertensive renal injury. A 12-lead ECG is also performed to evaluate for evidence of left ventricular hypertrophy or ischemic changes.

Secondary causes of hypertension are rare but should be considered if hypertension develops suddenly or responds poorly to antihypertensive therapies. Laboratory evaluation for secondary causes of hypertension usually includes a thyroid-stimulating hormone level for hyperthyroidism, a parathyroid hormone level for hyperparathyroidism, a dexamethasone suppression test for hypercortisolemia, urine metanephrine and normetanephrine for pheochromocytoma, and a 24 hour urinary aldosterone level for hyperaldosteronism. A renal ultrasound or magnetic resonance angiogram (MRA) may be performed to exclude renal artery stenosis. A polysomnogram may be performed to evaluate for obstructive sleep apnea. In patients with hypertensive urgency or emergency, a urine toxicology screen is recommended to evaluate for illicit drug use, such as cocaine or amphetamines, which can acutely elevate blood pressure.

NEUROIMAGING INVESTIGATIONS Neuroimaging is not routinely recommended for patients with hypertension without neurologic symptoms. In patients with hypertension, a CT of the head may incidentally demonstrate focal hypodensities, typically smaller than 1.5 cm in diameter, consistent with remote lacunar infarctions, and diffuse hypodensities in the subcortical white matter or brainstem (leukoaraiosis), believed to correlate with small vessel ischemic disease. The sensitivity for detecting both small vessel ischemic disease and lacunar infarctions is markedly higher with magnetic resonance imaging (MRI) (George et al., 1986). On MRI of the brain, small vessel ischemic disease and lacunar infarctions appear hyperintense on T2-weighted and FLAIR imaging (Fig. 12.1). Additionally, gradient-echo (GRE) MRI techniques may demonstrate subcortical microhemorrhages (Fig. 12.2) which are less than 5 mm in diameter and have been associated with hypertension in both asymptomatic patients and patients with either ischemic or hemorrhagic strokes (Viswanathan and Chabriat, 2006). The classic MRI findings in hypertensive encephalopathy are symmetric subcortical parieto-occipital hyperintense lesions on T2 and FLAIR imaging (Fig. 12.3). However, approximately two-thirds of patients will also have hyperintense lesions on T2 and FLAIR imaging in the frontal and temporal lobes and a third will have brainstem, cerebellum, or basal ganglia involvement (Fugate et al., 2010). Additionally, 40% of patients have asymmetric lesions. Restricted diffusion and contrast enhancement are seen in 25% and 15% of patients, respectively (Fugate et al., 2010). Improvement or resolution of radiographic findings after treatment often lags behind clinical improvement. The neuroimaging findings in either subarachnoid hemorrhage or

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intracerebral hemorrhage secondary to hypertensive emergency are typical for those disease processes with hyperdense lesions on head CT in the sulci and cisterns or the parenchyma.

GENETICS

Fig. 12.1. Chronic ischemic cerebrovascular disease due to hypertension. Axial FLAIR MRI scan of an 81-year-old woman with chronic hypertension demonstrating innumerable subcortical hyperintensities typical of small vessel ischemic disease (leukoaraiosis).

Hypertension is a complex disease influenced by both environmental and genetic factors. The genetics of hypertension are quite complex since it involves multiple genes with only mild effects on phenotype, gene–gene interactions (epistasis), and genes that manifest as multiple traits (pleiotropy) (Shih and O’Connor, 2008). Despite advances in molecular biology and medical genetics utilizing both association studies of candidate genes and genome-wide association studies, an understanding of the genetics of hypertension remains elusive. A genome-wide association study of 2000 patients with hypertension compared to 3000 controls failed to demonstrate a significant association between hypertension and any of the single nucleotide polymorphisms tested, which included polymorphisms previously associated with hypertension (Wellcome Trust Case Control Consortium, 2007). Similarly, a genome-wide analysis of 1200 patients from the Framingham Heart Study also failed to demonstrate a significant association between hypertension and any of the single nucleotide polymorphisms tested (Levy et al., 2007). Even less is known about the underlying genetic factors potentially predisposing to hypertensive urgency or emergency.

PATHOLOGY

Fig. 12.2. Chronic hemorrhagic cerebrovascular disease due to hypertension. Axial GRE MRI scan of a 52-year-old woman with chronic hypertension demonstrating numerous subcortical microhemorrhages and a symptomatic hemorrhage in the right thalamus. A subsequent brain biopsy showed lipohyalinosis without evidence of vasculitis or amyloidosis.

Hypertension causes pathologic changes in the walls of small (diameter < 300 microns) arteries and arterioles of both the cerebrovascular and systemic circulations. The most common finding is the loss of the normal structure of the arterial wall. Instead, the arterial wall appears uniformly eosinophilic. This process is known as hyalinization. Hypertension can also cause the extravasation of plasma proteins, including fibrin, into segments of the arterial wall, resulting in decreased elasticity (Andrade and Pitelle, 2009). This also appears eosinophilic, but can be differentiated from hyalinization by immunohistochemical stains for fibrin. This process is known as fibrinoid necrosis in the systemic circulation and lipohyalinosis in the cerebrovascular circulation (Fig. 12.4). Lipohyalinosis usually occurs at short branches of major arteries such as the lenticulostriate arteries and the pontine penetrating arteries, which are the common locations for leukoaraiosis, lacunar infarctions, and hypertensive hemorrhages. Lipohyalinosis, and not hylanization, is believed to be the underlying pathologic mechanism for both lacunar infarction and intracerebral hemorrhage in hypertensive patients (Rosenblum, 2008).

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A

B

Fig. 12.3. Acute hypertensive encephalopathy. (A) Axial FLAIR MRI scan demonstrating the classic findings of hypertensive encephalopathy with symmetric subcortical parieto-occipital hyperintense lesions. (B) Axial FLAIR MRI scan of the same patient demonstrating pontine hyperintense lesions, which occur in 33% of patients with hypertensive encephalopathy. These lesions resolved after appropriate blood pressure management.

edema. The molecular cascade that regulates the blood–brain barrier has been partially elucidated. Protein kinase C (PKC) activation increases blood vessel permeability via nitric oxide release (Ramirez et al., 1996). There are 10 different isoenzymes of protein kinase C of which the d-isoenzyme appears to regulate intracerebral blood vessel permeability (Qi et al., 2008). In a rat model of hypertensive encephalopathy, selective inhibition of d-PKC resulted in decreased neurologic symptoms and mortality despite persistently elevated blood pressure (Qi et al., 2008).

MANAGEMENT Fig. 12.4. Hypertensive small artery pathology. Hematoxylin and eosin stain of a subcortical arteriole demonstrating a diffusely eosinophilic arterial wall. Immunohistochemical staining of this arteriole demonstrated fibrin deposition consistent with lipohyalinosis.

Hypertensive encephalopathy is believed to be caused by acute failure of cerebrovascular autoregulation resulting in inappropriate dilation of small arteries and arterioles and disruption of the blood–brain barrier (MacKenzie et al., 1976). This in turn results in extravasation of plasma constituents and subsequent brain

Standardized guidelines have been published for the routine management of blood pressure in the general population (Chobanian et al., 2003). Patients with optimal blood pressure (30 beats per minute) while blood pressure regulation was within limits. The patient was diagnosed as having postural orthostatic tachycardia syndrome (PoTS).

environments, inadequate fluid intake, volume depletion due to hemorrhage, diarrhea, or Addison’s disease. Postural tachycardia syndrome (PoTS; Fig. 13.1). PoTS is an important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. It mainly affects young women, and is characterized by a marked rise in heart rate while standing without OH (Mathias et al., 2011). PoTS is usually defined as a heart rate increase of > 30 beats per minute (bpm) occurring within 10 minutes of standing (> 40 bpm for individuals aged 12–19 years), or a heart rate while upright of > 120 bpm without a fall in blood pressure (Freeman et al., 2011). Patients often complain of dizziness, palpitations, tremulousness, exercise intolerance, hyperventilation, leg weakness, or fatigue, and some experience occasional syncope. Symptoms can be exacerbated by exertion, food and alcohol ingestion, and heat. In some patients, onset is linked to a previous infection/viral illness, Guillain–Barre´ syndrome (GBS), trauma, or surgery. The pathophysiology of PoTS is not fully understood and probably heterogeneous. Possible mechanisms include: ● ●

alterations in neural control due to sympathetic denervation in the lower limbs (“neuropathic PoTS”) increased central sympathetic drive (leading to a hyperadrenergic state)

Etiologically such factors as autoimmune mechanisms (with circulating antibodies), functional gastrointestinal disorders (with altered water intake), psychological factors (including anxiety), and genetic predisposition have been suggested (Shannon et al., 2000; Benarroch, 2012). Autonomic failure. Orthostatic hypotension (OH) may also result from autonomic diseases where adaptation to the upright posture is inadequate. This is found in central nervous system (CNS) disorders such as multiple system atrophies (MSAs) or Parkinson disease (PD), in peripheral nervous system (PNS) disorders such as pure autonomic failure, sequelae from GBS, or postganglionic autonomic polyneuropathies (ganglionopathies). Although the classification into primary and secondary autonomic failure is somewhat arbitrary, in primary autonomic failure there is primarily a structural autonomic failure typically found in neurodegenerative diseases (MSAs, PD, pure autonomic failure) (Figs 13.2 and 13.3), while secondary autonomic failure occurs in the context of systemic diseases, such as diabetes mellitus, chronic renal failure, long-standing alcohol abuse, autosomal dominant familial amyloid polyneuropathy, and GBS with autonomic involvement. An autonomic neuropathy may rarely develop acutely or subacutely. In such instances of acute pandysautonomia, there is widespread sympathetic and parasympathetic autonomic disintegration leading to severe orthostatic hypotension, anhydrosis, unreactive pupils, impaired lacrimation and salivation, gastrointestinal paresis, and impaired genitourinary function. The clinical spectrum ranges from purely autonomic dysautonomia to autonomic neuropathy with sensory or sensorimotor involvement (GBS with dysautonomia). The presence of ganglionic acetylcholine receptor antibodies in patients with acute or subacute autonomic neuropathy have led to the concept of a treatable autoimmune autonomic neuropathy or ganglionopathy (Vernino et al., 2000). Chronic and inherited pandysautonomia is rare. The rare familial dysautonomia (Riley– Day syndrome) has an autosomal recessive inheritance. Symptoms of autonomic dysfunction such as peripheral hypohidrosis, compensatory hyperhidrosis (abnormally increased truncal sweating), dry eyes or mouth, and GI dysfunction must be inquired after. In diabetic and amyloid polyneuropathies, the autonomic involvement with GI dysfunction and dry palms and soles typically occurs early in the course of the disease. In contrast,

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Fig. 13.3. Skin laceration after a fall in a 43-year-old patient with orthostatic hypotension in the context of a multisystem atrophy.

Clinical features

Fig. 13.2. A 59-year-old woman had a 9 month history of gait unsteadiness. She experienced recurrent syncope early in the morning and after food intake or exercise. There was no past medical or family history of neurologic illness. Neurologic examination showed dysarthria, predominantly right-sided bradykinesia and rigidity, gait and limb ataxia, and bilateral Babinki signs. Head-up tilt table testing: the upper panel shows beat-to-beat recording of blood pressure (reBAP) and the middle panel of heart rate (HR) during head-up tilt table testing (tilt angle 60
). The lower panel indicates tilt table position. There is an immediate fall of blood pressure with almost no increase of heart rate whilst the patient is standing, fulfilling the criteria for orthostatic hypotension (fall in blood pressure of 20 mmHg systolic and 10 mmHg diastolic). The examination had to be interrupted after 2.5 minutes because of presyncope. The patient was diagnosed as having multiple-system atrophy.

NMS typically presents with a prodrome preceding the loss of consciousness by approximately 30–60 seconds; this is seldom reported by elderly subjects, probably because of less autonomic activation and greater propensity for amnesia (Wieling, 2009). Facial pallor is often the first manifestation, followed by cold sweating, yawning, salivation, palpitations, pupillary dilatation, and increased peristalsis (Alboni et al., 2001). Eventually, this is followed by symptoms of cerebral or retinal hypoperfusion such as mental changes, lightheadedness, fatigue, visual and hearing changes, hallucinations, and even near death experiences (Lempert et al., 1994a). Typically, the duration of unconsciousness varies from 10–20 seconds to 5 minutes. This is influenced by body position (Wieling, 2009). Diagnosis of NMS is further suggested by the following features (Brignole et al., 2004): ●

in alcohol abuse, wet palms and soles are found during the early stages, and then replaced by hypohidrosis only during later stages of the disease.

NEURALLY MEDIATED (REFLEX) SYNCOPE Different terms have been used for this type of syncope. The term vasovagal syncope was introduced by Lewis (1932). The terms neurally mediated syncope (NMS) and reflex syncope are currently preferred. NMS is observed more commonly among women and the young (Colman et al., 2004a). Caucasians are more often affected than African Americans (Colman et al., 2004a). NMS is subdivided into vasovagal syncope (induced by standing), and situational syncope (triggered by different stimuli/situations).

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spells following sudden unexpected sight, sound, smell or pain spells after pressure on the carotid sinus (head rotation, shaving, tight collar) spells during prolonged standing in crowded and/or hot places spells after eating and alcohol intake spells following exertion.

The last three are also often seen in the context of syncope due to orthostatic hypotension (see above). Pathophysiology Physiologically, standing leads to baroreflex mediated vasoconstriction and increased cardiac output due to sympathetic activation and parasympathetic inhibition.

TRANSIENT LOSS OF CONSCIOUSNESS AND SYNCOPE The vasoconstrictive response is more important than the increase in heart rate in maintaning CBF (Hainsworth, 2004). In NMS, this physiologic reflex is abnormally activated and eventually reversed. The exact mechanisms involved remain controversial and may include hypothalamic and neurohormonal factors, that may also be genetically determined (Hainsworth, 2004; Klein et al., 2013; van Dijk and Wieling, 2013). The afferent pathways of the vasovagal reflex, which appears to be present only in humans, may be initiated by several triggers such as standing, carotid sinus massage, pain, and emotional triggers such as fear. However, the teleologic purpose of this reflex remains unclear (van Dijk and Wieling, 2013). According to measurable cardiovascular parameters, NMS is subdivided into hypotensive, asystolic, and mixed forms. Efferent pathways lead always to a decrease in blood pressure (vasodepressor) and in some cases also asystole (cardioinhibitor). A decrease in blood pressure can lead to syncope even in the absence of changes in heart rate (Wieling, 2009). This explains why cardiac pacing may be ineffective in the treatment of some cases NMS. Several activities and emotional factors have been identified as predisposing or precipitating factors of NMS (Colman et al., 2004b).

Etiologies While the classification of NMS remains controversial, we have followed the modified version recently suggested by the Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology. 1. Vasovagal syncope (Fig. 13.4). Usually affecting young subjects, this type of syncope is associated with sudden orthostatic stress or emotions. Familial cases related have been reported (Klein et al., 2013). 2. Situational syncope. This type of syncope is associated with specific circumstances, including: ● ● ● ● ● ● ●

exercise (Krediet et al., 2004) urogenital triggers: micturition, prostatic massage, vaginal examination gastrointestinal triggers: swallowing, defecation, rectal examination respiratory triggers: airway instrumentation pain: venipuncture, trigeminal or glossopharyngeal neuralgia fear: sight of blood, needle phobia, blood-injury phobia, dental phobia increased intrathoracic pressure: sneezing, coughing, wind instrument playing, weight lifting, stretching, breath holding spells, “fainting lark”.

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Fig. 13.4. An 18-year-old woman was referred because recurrent syncope during prolonged standing or venous puncture but never during exercise. Syncope was typically preceded by nausea, vertigo and sweating with only a short loss of consciousness. Neurologic examination was normal. Head-up tilt table testing: the upper panel shows beat-to-beat recording of blood pressure (reBAP) and the middle panel of heart rate (HR) during head-up tilt table testing (tilt angle 60
). The lower panel indicates tilt table position. After 14 minutes, there was a marked fall in systolic and diastolic blood pressure. The patient experienced a typical prodrome followed by a short loss of consciousness. The patient was diagnosed as having vasodepressor vasovagal syncope.

Several pathophysiologic mechanisms may be involved in individual cases, such as in micturition syncope where syncope may occur before, during or after voiding, and may be associated with factors predisposing to orthostatic stress such as arousal from sleep, alcohol consumption, bladder distention, or Valsalva maneuver (Fagius and Karhuvaara, 1989). Cough syncope involving impaired cerebral venous outflow is discussed below. 3. Carotid sinus syndrome (CSS; Fig. 13.5). CSS was reported as a cause of syncope by Weiss and Baker in 1933 (Weiss and Baker, 1933). The CSS is considered to represent an exaggeration of the normal carotid sinus reflex which regulates blood pressure. A ventricular pause lasting 3 seconds and a fall in systolic blood pressure of > 50 mmHg or more define carotid sinus hypersensitivity (Brignole et al., 2004). CSS is observed more commonly among elderly men and classically presents with syncope, or other symptoms such as drop attacks or dizziness, and is typically induced by head rotation or shaving (Healey et al., 2004). What accounts for the changes in baroreceptor sensitivity is often unclear. Patients usually have atherosclerosis risk factors, and rarely head and neck malignancies (Healey et al., 2004). 4. Others. ●

Breath holding spells. Observed in children, “white” or “pallid” and “blue” or “cyanotic” forms have been differentiated. Hyperventilation and Valsalva maneuver are involved in the pathophysiology of cyanotic breath holding spells (Breningstall, 1996).

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Fig. 13.5. A 78-year-old man with dyslipidemia had a 6 month history of recurrent unexplained falls. One syncope occurred during shaving. Neurologic examination was normal. Autonomic testing: the upper panel shows beat-to-beat recording of blood pressure (reBAP) and the middle panel of heart rate (HR). There was an exaggerated fall in blood pressure and heart rate in response to carotid sinus massage for 10 seconds at the level of the cricoid cartilage in the supine position. The patient was diagnosed as having carotid sinus syndrome.

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Breath holding spells are often triggered by sudden distressing stimuli. Loss of consciousness is followed by stiffening and brief clonic movements of the limbs (“convulsive syncope”). An asystole lasting 4 seconds or more is observed in approximately 50% of cases (Stephenson, 1978). A compulsive Valsalva maneuver leading to frequent syncope can be observed at times in children with autistic spectrum disorder. Rarely, the syncope may be complicated by seizures and even status epilepticus (anoxic-epileptic seizures) (Horrocks et al., 2005). Fainting larks. This entity is typically used by children, students, or military recruits for either amusement purposes or for some secondary gain. This type of syncope results from different mechanisms including hyperventilation, orthostatism and Valsalva). The clinical features have been videographically analyzed by Lempert et al. in 59 young subjects (Lempert et al., 1994b).

NEUROLOGIC CAUSES OF SYNCOPE Most TLOC due to neurologic disorders are not due to cerebral hypoperfusion and are discussed in the next section. However, the following few exceptions exist:

Except for very unusual circumstances, transient ischemic attacks (TIAs) typically do not cause TLOC (Davidson et al., 1991). TLOC can be very rarely observed in patients with diffuse atherosclerosis and vertebrobasilar ischemia or unilateral/bilateral carotid artery stenosis in the presence of fluctuations of blood pressure due to low cardiac output or hypotensive drugs (orthostatic TIA) (Kimura et al., 1999). Subclavian steal syndrome (SSS) (Hennerici et al., 1988; Smith et al., 1994). The classic presentation of SSS is that of claudication of the ipsilateral arm induced by arm exercise, often accompanied by vertigo, syncope, and blood pressure differential between both arms. Patients often have advanced concomitant atherosclerotic carotid artery disease. Takayasu arteritis, an unusual cause of SSS, can rarely lead to convulsive syncope (Menon and Himabindu, 2010). Arturo Toscanini is thought to have presented an episode of syncope due to SSS while vigorously directing an NBC symphony concert (Klawans, 1988). Epilepsy leading to cardiac asystole and other cardiac arrhythmias has been known for decades (Constantin et al., 1990). In a series of 1244 patients with epilepsy undergoing long-term video EEG monitoring, this was observed in four patients. The events lasted 4–60 seconds (Rocamora et al., 2003). All seizures had a left frontal lobe or temporal lobe origin. Two patients had simultaneous central apnea during asystole. The reversed situation, epilepsy arising from syncope, is rare, but has been reported in adults following a prolonged orthostatic syncope, and in some children with breath holding spells (Horrocks et al., 2005; Wieling, 2009). Cough syncope was first described in 1876 by Jean Martin Charcot as “laryngeal vertigo” (Charcot, 1876). A detailed description of 26 patients was given in 1953 (Kerr and Derbes, 1953). Patients are typically middleaged obese men with history of COPD (Figs 13.6 and 13.7) or signs of right ventricular heart failure or constrictive pericardial disease. Syncope follows a prolonged bout of coughing. Typically, patients become cyanotic and exhibit convulsions. Blood pressure, pulse, and blood oxygen saturation are within normal range (Kerr and Derbes, 1953). TLOC is due to a cerebral circulatory arrest (“arreˆt circulatoire ”) related to impaired venous outflow, caused by the marked elevation on intrathoracic pressure (Mattle et al., 1995).

Nonsyncopal transient loss of consciousness (unrelated to cerebral hypoperfusion) In a recent large multicenter study, a nonsyncopal cause of TLOC accounted for 16% of patients evaluated at an

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Fig. 13.7. Transcranial Doppler (TCD) in a patient with cough syncope shows (upper panel) a normal middle cerebral artery flow signal before coughing, and loss of signal during coughing (with the typical cough artifacts and with “Pendelfluss” (oscillatory flow) (lower panel).

emergency department (Baron-Esquivias et al., 2010). The TLOC was unrelated to cerebral hypoperfusion. The most frequent cause of a nonsyncopal TLOC is epilepsy.

EPILEPTIC TRANSIENT LOSS OF CONSCIOUSNESS Disturbances of consciousness are a typical feature of different types of epilepsy (Gloor, 1986). Clinical features Epileptic TLOC is one of the most important differential diagnostic considerations in patients with either syncope or TLOC of unknown origin. Epileptic TLOC typically follows an aura. An epileptic etiology of TLOC is suggested by the following features (Benke et al., 1997; Sheldon et al., 2002; McKean et al., 2006): ●

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Fig. 13.6. A 54-year old man (A) and a 55-year-old man (B) with cough syncope. The second patient had recurrent episodes

unusual tastes, smells, de´ja` vu or jamais vu sensations (though not specific for epilepsy; see section on Psychiatric disorders, below), preceding the spell lateral tongue biting (Fig. 13.8) (though biting at the tip of the tongue can occur during syncope) head turning during the spell amnesia for the spell

of syncope for the previous 5 years, with cyanotic discoloration of the face, generalized “jerking,” without tongue biting or bladder incontinence, lasting about 30 seconds. Recovery after the episodes was complete.

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Fig. 13.8. Lateral tongue biting in three patients with epileptic transient sudden loss of consciousness.

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prolonged confusion or somnolence following the spell.

Sweating and nausea preceding the spells and their frequent association with prolonged sitting or standing speak against an epileptic cause of TLOC (Hoefnagels et al., 1991; Sheldon et al., 2002). Against common belief, bladder incontinence, trauma and “convulsions” are not discriminative enough between cardiovascular, epileptic, or psychogenic causes of syncope (Hoefnagels et al., 1991). Tonic, tonic-clonic, or other involuntary motor activities can be present (Lempert et al., 1994b). These involuntary motor activities are thought to arise from noncortical, areas resulting from disinhibition of brainstem motor circuits. Eye movements including downbeat nystagmus or forced upward eye deviation are also possible in syncope (Lempert and von Brevem, 1996). Finally, confusion may occasionally be seen in patients with severe or prolonged cardiovascular syncope.

The following forms of epilepsy can lead to TLOC: ● ● ● ●

epilepsy with generalized tonic-clonic seizures epilepsy with absence seizures epilepsy with temporal lobe seizures miscellaneous. Syncopal-like episodes have been described in Panayiotopoulos syndrome (Koutroumanidis et al., 2012).

Pathophysiology The origin of TLOC among patients with epilepsy is due to loss of functional connectivity between cortical areas responsible for the normal state of consciousness and/or their thalamic connections (Lee et al., 2002; Blumenfeld, 2012). As previously mentioned, seizures can be complicated by bradyarrhythmias or asystole (ictal asystole), a mechanism which has been advocated for sudden unexpected death in patients with epilepsy (SUDEP) (Horrocks et al., 2005).

TRANSIENT LOSS OF CONSCIOUSNESS AND SYNCOPE 179 ● Other forms of fluctuating vigilance. The same comNONEPILEPTIC, NEUROLOGIC CAUSES OF TRANSIENT ment applies as for “sleep attacks” (see section LOSS OF CONSCIOUSNESS below on Other forms of fluctuating vigilance and ● Excessive sleepiness/sleep attacks. Occasionally Table 13.2). “sleep attacks,” mainly in patients with narcolepsy, ● Increased ICP. A colloid cyst of the third ventricle may present in association with cataplexy, thus mimcan present with recurrent episodes of TLOC icking a syncopal episode. However, excessive sleepwith or without postural failure. This is typically iness and sleep attacks most commonly present with accompanied by headaches triggered by changes episodes of altered consciousness without associin head position (Lancon et al., 1996; Goldberg ated postural failure (see section below on Sleepiet al., 2011). Other manifestations include visual ness and sleep attacks and Table 13.2). disturbances, nausea, cognitive disturbances, or

Table 13.2 Clinical pitfalls in the recognition of syncopal and nonsyncopal transient loss of consciousness Cardiac syncope Context: known cardiac disorder, history of sudden death in the family, abnormal ECG, initiation or changes in medication Situation: in all body positions; during exercise or strain Preictal: occasionally no prodrome, dizziness or lightheadedness and other autonomic symptoms possible Ictal: flaccid fall, eyes open, convulsions or other abnormal movements possible Postictal: usually rapid recovery, bladder or bowel incontinence and injuries possible, amnesia possible Orthostatic syncope Context: known parkinsonism or autonomic neuropathy, initiation or changes in medications Situation: prolonged sitting, standing; after exercise, after a meal, crowded or heated places Preictal: facial pallor, sweating, dizziness or lightheadedness, occasionally no prodrome Ictal: flaccid fall, eyes open, convulsions or other abnormal movements possible Postictal: usually rapid recovery, bladder or bowel incontinence and injuries possible, amnesia possible Neurally mediated/reflex syncope Situation: venipuncture, micturition, stress, pain, swallowing, head turning, shaving, crowded or heated places Preictal: facial pallor, sweating, nausea, coat-hanger pain, palpitations, dizziness or lightheadedness, rarely no prodrome Ictal: flaccid fall, eyes open, convulsions or other abnormal movements possible Postictal: pallor, sweating, tongue biting possible, bladder incontinence and injuries possible, rapid or slow recovery Epileptic, nonsyncopal transient loss of consciousness Context: known epilepsy, sleep deprivation Situation: in all body positions Preictal: aura (de´ja` vu/de´ja` ve´cu, jamais vu/jamais ve´cu, unusual smells/taste, rising abdominal sensations, movements (head turning, abnormal posturing) Ictal: stiff fall, eyes open, tonic-clonic movements Postictal: lateral tongue biting, bladder/bowel incontinence, injuries possible, slow recovery (rapid recovery possible), headache, muscle ache, amnesia Psychiatric, nonsyncopal transient loss of consciousness Context: known psychiatric disorder, history of childhood trauma or abuse Preictal: emotional stress, suggestive situation, distractibility Ictal: eyes closed, forced eye closure, “convulsions,” coma with normal brainstem reflexes, nystagmus induced by caloric testing Postictal: bladder or bowel incontinence and injuries possible, usually rapid recovery

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C.L. BASSETTI neuroendocrine changes. Sudden death is a complication. Other disorders occasionally presenting with syncope and increased ICP include Chiari malformation, idiopathic intracranial hypertension (pseudotumor cerebri) and cerebral venous sinus thrombosis (Villamayor-Blanco et al., 2004; Garcia et al., 2013). Others. Basilar migraine can cause TLOC. Typically basilar migraine is accompanied by headache and other manifestations of brainstem dysfunction (Bickerstaff, 1961; Sturzenegger and Meienberg, 1985). In children, migraine can present with recurrent episodes of altered levels of alertness (“migrainous stupor”) (Lee and Lance, 1977). Familial forms and psychogenic variants have been described (Feely et al., 1982; Sanchez-Villasenor et al., 1995). In some of these families, genetic mutations have been found linking basilar migraine with hemiplegic migraine. The differential diagnosis with psychogenic states can be extremely challenging (Lotz et al., 1993).

MEDICAL CAUSES OF TRANSIENT LOSS OF CONSCIOUSNESS

In some situations (e.g., pheochromocytoma) TLOC may be due to a syncope, as defined above. In others, history and investigations may not allow the physician to decide wether TLOC was syncopal or not. These difficulties stress the limitations of the current classification (also used in this chapter). ●

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Hypoglycemia. Neuroglycopenic symptoms include hunger, cognitive changes, visual problems, TLOC, or even coma; convulsions, hyperkinesias, hemiparesis or paraparesis may also occur (Pleet, 1995). Nonneurologic manifestations include facial flushing, chest pain, and cardiac arrhythmias. Neuroendocrine disorders. Mast cell activation disorders can present with syncope and syncopal-like episodes, typically accompanied by headache, flushing, and diarrhea (Molderings et al., 2011). Pheochromocytoma typically presents with paroxysmal hypertension, palpitations, sweating, headache, and pallor. Weight loss, chest and abdominal pain, and flushing are also typical. On occasion, patients may also present with hypotension and syncopal TLOC (Ueda et al., 2005). Carcinoid and idiopathic flushing present with flushing and diarrhea. Syncope and near syncope as well as abdominal pain are more frequent, however, in carcinoid syndrome (Aldrich et al., 1988). Medullary thyroid carcinoma is another neuroendocrine syndrome that can present with flushing and syncope/near syncope (Suchard, 1997). Drug intoxications. Intoxications with sedatives, psychotropic or recreational drugs (e.g.,

g-hydroxbutyrate) can lead to TLOC. The duration of unconsciousness is typically longer than in instances of syncopal TLOC (Tancredi and Shannon, 2003; Baron-Esquivias et al., 2010).

PSYCHIATRIC CAUSES OF TRANSIENT LOSS OF CONSCIOUSNESS (“PSYCHOGENIC NONEPILEPTIC SEIZURES”, “PSYCHOGENIC PSEUDOSYNCOPE”) Emotional factors can be involved in instances of cardiovascular syncope. Hyperventilation, while insufficient to trigger syncope in isolation, may precipitate NMS (Wieling, 2009). Similarly, emotional triggers can also lead to NMS. Also, recurrent syncope/TLOC can account for secondary psychological distress and or disorders. Although rare (1–7% of all nonsyncopal causes of TLOC), its frequency has probably been underestimated (Luzza et al., 2004; Baron- Esquivias et al., 2010; van Dijk and Wieling, 2013). Clinical features Psychiatric causes of TLOC may present with challenging clinical syndromes. Most common is “psychogenic nonepileptic seizures” with unresponsiveness and “convulsions” resembling epilepsy. Urinary incontinence and injuries can also occur, whereas lateral tongue biting is unusual. Less common is “psychogenic pseudosyncope.” These patients present with loss of consciousness, associated with motionlessness and eyelid closure, but otherwise normal physical findings. Brainstem reflexes are preserved. Caloric testing induces nystagmus. Passive eyelid opening is followed by forced eyelid closure (Fig. 13.9). TLOC due to psychiatric causes may be spontaneous or triggered by stimuli such as tilt-table testing, saline placebo injection, or emotional stress (Benbadis et al., 2000). Several features suggest a psychiatric cause

Fig. 13.9. Forced eye closure in a patient with psychogenic transient loss of consciousness.

TRANSIENT LOSS OF CONSCIOUSNESS AND SYNCOPE of TLOC (Luzza et al., 2004; Anderson, 2006; McKean et al., 2006; van Dijk and Wieling, 2013): ● ● ● ● ● ●

forced eyelid closure (Fig. 13.9) recurrent or frequent spells prolonged duration of the spells (30 or more minutes) normal EEG during spells suggestibility (Benbadis et al., 2000) or distractibility (Anderson, 2006) marked improvement of TLOC with psychiatric, or nonpharmacologic treatment.

Pathophysiology/etiology Anxiety, depression, somatization and panic disorder have been associated with psychiatric causes of TLOC. Childhood trauma, history of childhood abuse and brain disorders ( epilepsy, narcolepsy) have also been recognized as predisposing factors (Krumholz, 1999).

TRAUMATIC TRANSIENT LOSS OF CONSCIOUSNESS Previous head trauma is not an uncommon cause of TLOC. The presence of TLOC following mild head trauma is a predictor of postconcussive manifestations. The pathophysiology of TLOC following head trauma includes acceleration-deceleration injuries as well as possible intracranial vasospasm (Morioka et al., 1996). Not uncommonly, syncope may lead to head trauma (BaronEsquivias et al., 2010). Albeit rarely, the head trauma can be severe. The term “concussive convulsions” refers to brief episodes of muscle stiffness or jerking lasting for 1–2 seconds following head trauma, followed by rapid postictal recovery. A transient disinhibition of motor brainstem circuits is the likely pathophysiologic explanation (Crompton and Berkovic, 2009).

DIFFERENTIAL DIAGNOSIS OF TRANSIENT LOSS OF CONSCIOUSNESS Table 13.3 summarizes the differential diagnosis of TLOC.

Episodes without (or with only apparent) unconsciousness and altered postural control (“drop attacks”) Presyncopal episodes may present with loss of postural control without loss of consciousness (Meissner et al., 1986). In one study, over 50% of elderly patients referred for “drop attacks” following extensive workup were ultimately diagnosed as having a cardiovascular etiology of syncope (Dey et al., 1997).

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Table 13.3 Differential diagnosis of transient loss of consciousness/syncope 1. Episodes with postural failure without/with only apparent loss of consciousness (“drop attacks”) Presyncope of cardiovascular origin Vertebrobasilar transient ischemic attacks (TIAs) Vestibular “syncope,” drop attacks Hyperekplexia Epilepsy (myoclonic-astatic seizures, Lennox–Gastaut syndrome, temporal lobe syncope) Chalastic attacks Cataplexy, cataplexy-like episodes (Coffin–Lowry syndrome, gelastic seizures) Cryptogenic drop attacks of women Astasia with or without abasia Falls in the context of gait ataxia or extrapryamidal disorders* (e.g., PD, MSA DLB) Falls in the context of muscle weakness (e.g., myopathy, myasthenia gravis) Psychiatric disorders Accidental falls Others 2. Episodes of altered state of consciousness without loss of postural control (“absences”{) Excessive sleepiness/“sleep attacks” Other forms of fluctuating vigilance (dementia with Lewy bodies) Epilepsy (petit mal epilepsy, temporal lobe epilepsy, inhibitory seizures) Metabolic or neuroendocrine disorders Psychiatric disorders Others/unclear (transient unresponsiveness in the elderly, orthostatic TIAs, “blip syndrome”) *Also in the absence of orthostatic hypotension/autonomic failure. { This term is traditionally used to describe a specific form of generalized epilepsy (so-called petit mal); here it is used as a synonym of “absent mindedness.” PD, Parkinson disease; MSA, multisystem atrophy; DLB, dementia with Lewy bodies.

VERTEBROBASILAR TRANSIENT ISCHEMIC ATTACKS Drop attacks have been described in patients with vertebrobasilar ischemia (Williams and Wilson, 1962; Kubala and Millikan, 1964). Pontomedullary junction ischemia has been suggested as the possible underlying mechanism (Brust et al., 1979).

VESTIBULAR SYNCOPE Tumarkin, citing previous authors, related the occurrence of falls in the context of Me´nie`re’s disease (Tumarkin, 1936). The concept of vestibular syncope was then confirmed and expanded by other authors (Kuhl, 1980; Baloh et al., 1990). Usually, patients present with drop attacks, and rarely with true TLOC. Most of

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C.L. BASSETTI these patients suffer from Me´nie`re’s syndrome (Baloh Canadian lumberjack communities, and Latah in Southet al., 1990). An association with migraine has been noted east Asia). by some authors. Typically, these patients report the feeling of being pushed by an external force and an environCATAPLEXY AND CATAPLEXY-LIKE EPISODES mental tilt also during these spells. Syncope can also be ● The term cataplexy describes a sudden and short-lived accompanied by disturbances of eye movements loss of muscle tone triggered by emotions in patients (Lempert and von Brevem, 1996). with narcolepsy (Sturzenegger and Bassetti, 2004; Overeem et al., 2011). Falls in the context of cataFALLS IN THE CONTEXT OF EPILEPSY WITHOUT plexy occur only in a minority of patients (Fig. 13.10) LOSS OF CONSCIOUSNESS (Sturzenegger and Bassetti, 2004). Less commonly Falls in the context of seizures without loss of consciousobserved are spells without associated loss of muscle ness have been reported mainly in temporal lobe epilepsy tone but with inability to move. Occasionally, patients (“temporal lobe syncope”) (Gambardella et al., 1994). may present spells with both loss of muscle tone and Lennox–Gastaut syndrome, myoclonic-astatic epilepsy, decreased vigilance (“sleep attack”). Patients may atypical benign partial epilepsy, and startle epilepsy are also develop “status cataplecticus” (Poryazova et al., also associated with tonic, myoclonic or atonic drop 2005). The diagnosis of narcolepsy with cataplexy is attacks (Meissner et al., 1986; Hirano et al., 2009). In supported by the following: (1) low or absent CSF patients with epilepsy and unclear spells of TLOC, synhypocretin (orexin) levels; (2) rapid response to cope, or drop attacks the possibility of a secondary asysanticataplectic drugs. A characteristic multiple sleep tole or bradyarrhythmia should always be considered latency test, (MSLT) and detection of specific HLA (Kohno et al., 2011). markers further support the diagnosis. ● Cataplexy-like episodes in healthy subjects. In CHALASTIC ATTACKS cataplexy-like episodes in healthy subjects, usually mild, often nonvisible, knee buckling may occur. This term refers to falls associated with loss of muscle This is more common among children and in sleepy tone (chalasis ¼ relaxation), with and without loss of adults (Paskind, 1932; Overeem et al., 1999; consciousness, due to frontal lobe damage, including Sturzenegger et al., 2001). In patients with psychiatthose secondary to hydrocephalus (Ethelberg, 1950; ric disorders, cataplexy-like episodes may occur Botez, 1979). Unexplained falls are also a feature of neuspontaneously or after antidepressant drug withrodegenerative diseases involving the frontal lobes (such drawal (Nissen et al., 2005). Such psychogenic as frontotemporal lobar degeneration), and astasia has attacks can also occur in patients with true cataplexy been reported following frontal lobe strokes. (Plazzi et al., 2010). ● Cataplexy-like episodes in other neurologic disorHYPEREKPLEXIA ders. Cataplexy-like episodes can also occur in cases The term hyperekplexia refers to the appearance of of Coffin–Lowry, Norrie, and Niemann–Pick type C enhanced surprise reactions to sudden and unexpected disease (Nakamura et al., 1998; Parkes, 1999). Falls auditory or tactile stimuli accompanied by falls and associated with laughter are a feature of gelastic seioccasionally limb stiffness (Gastaut and Villeneuve, zures observed in patients with hypothalamic hamar1967; Dreissen and Tijssen, 2012). Etiology includes tomas (Totah and Benbadis, 2002). brainstem lesions, stiff person syndrome, and genetic/ familial conditions (Brown et al., 1991; Meinck, 2002). CRYPTOGENETIC DROP ATTACKS IN WOMEN Mutations in the glycine gene are responsible for familial hyperekplexias (Dreissen and Tijssen, 2012). AntiThis syndrome was described in 1973 by Stevens and bodies against the glycine receptor (GlyR) have been Matthews (Stevens and Matthews, 1973). Women reported in cases of progressive encephalomyelitis with around the menopause or during pregnancy, and less rigidity, myoclonus, and hyperekplexia (Lizuka et al., frequently around the menarche, are affected. The fre2012). Startle epilepsies are often seen in the context quency of falls varies from single episodes to one per of severe perinatal anoxic damage. The term neuropsymonth. Typical findings of this condition include: chiatric startle refers to exaggerated startle responses ● falls occur only during walking, usually outdoors observed in specific cultures and/or ethnic groups (the but also indoors “jumping Frenchmen of Maine” among Franco-

TRANSIENT LOSS OF CONSCIOUSNESS AND SYNCOPE

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Fig. 13.11. Multiple knee scars in a woman with recurrent falls due to cryptogenic drop attacks (“maladie des genoux bleus”) ● ● ●

lack of prodromes falls most commonly occur forwards and may lead to knee (Fig. 13.11), hand, and facial injuries patients are able to rise immediately after the fall.

ASTASIA (WITH AND WITHOUT ABASIA) Astasia-abasia refers to the inability to stand and walk in the presence of normal supine neurologic functions. Astasia-abasia, first described by Paul Blocq in 1888 as a psychogenic disorder (Okun, 2007), can be accompanied by falls. Currently, astasia-abasia is considered as a possible manifestation of: ● ●

● ● ●

orthostatic tremor (Sharott et al., 2003) stroke in the thalamus (Masdeu and Gorelick, 1988); or less commonly, strokes involving the midbrain, pons, medulla, motor supplementary area, posterior cingulum, or frontal lobe (Wada and Nishimura, 2010) normotensive hydrocephalus peripheral nervous system disorders functional/psychogenic disorders.

FALLS IN THE CONTEXT OF GAIT ATAXIA AND EXTRAPYRAMIDAL DISORDERS

Fig. 13.10. Fall in a 30-year-old woman with sporadic narcolepsy with cataplexy after having been tickled by her husband. Intervals between onset of the stimulus (first picture, 16:51:01) and onset of weakness (16:51:08) leading to the fall (16:51:09).

Gait ataxia can lead to falls. Early falls are a typical feature of atypical parkinsonian syndromes such as PSP or MSA (Litvan et al., 1996; Nath et al., 2003). In advanced cases of PD, falls are also common. Falls, syncope, episodes of unexplained TLOC, or transient fluctuations of consciousness are also a frequent feature of dementia with Lewy

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bodies (DLB) (McKeith et al., 1996) and can be observed also in patients with frontotemporal dementia.

FALLS IN THE CONTEXT OF MUSCLE WEAKNESS Myopathies (quadriceps myopathy) and myasthenia gravis involving the proximal muscles may account for falls.

PSYCHIATRIC DISORDERS (“PSYCHOGENIC FALLS”) Syncope-like episodes with falls can be the main presenting symptom of a psychiatric disorder.

ACCIDENTAL FALLS Accidental falls increase with advanced age and may represent the most common cause of “drop attacks” in the elderly (Sheldon, 1960). Sedation, cognitive impairment, lower-extremity disability, foot problems, and gait imbalance represent potential predisposing factors (Tinetti et al., 1988).

Episodes of altered state of consciousness without loss of postural control (“absences”/ “absent mindedness”) The differential diagnosis of TLOC/syncope also includes transient episodes of altered state of consciousness without loss of postural control. These conditions may overlap and in fact be difficult to be differentiated by history from a nonsyncopal TLOC.

SLEEPINESS/“SLEEP ATTACKS” “Sleep attacks,” typical for narcolepsy, can also be observed among patients with excessive daytime sleepiness of other origin, including behavioral induced sleep deprivation (Hishikawa et al., 1968; Sturzenegger and Bassetti, 2004). In patients with parkinsonism or restless legs syndrome (RLS), “sleep attacks” have been observed following initiation or potentiation of levodopa or dopamine agonist treatment (Ferreira et al., 2000; Bassetti et al., 2002).

OTHER FORMS OF FLUCTUATING VIGILANCE In patients with DLB and other neurodegenerative dementias, fluctuations of vigilance can be observed. The term “fluctuations” has been used to describe this state, typically characterized by motionlessness, staring into space, napping, drowsiness, and speech disturbances (Ferman et al., 2004).

EPILEPSY Transient alterations in the level of consciousness without postural failure are not uncommon in epilepsy (Gloor, 1986). Clinical characteristics of the spells,

clinical context, EEG findings, and other ancillary tests are usually diagnostic. Inhibitory seizures in the elderly population are characterized by episodes of speech difficulties, amnesia and abnormal interictal EEG that can be misdiagnosed as TIAs (De Reuck and van Maele, 2009).

METABOLIC/NEUROENDOCRINE DISORDERS Hypoglycemia, hyponatremia, hypothyroidism, Addison’s disease, or the polyglandular syndrome can present with attacks of altered consciousness. Typically, duration of these attacks is longer than those observed among patients with syncope/TLOC.

PSYCHIATRIC DISORDERS Psychiatric disorders can cause transient alterations of consciousness with and without postural failure. Occasionally, they can arise from apparently normal sleep (Thacker et al., 1993). In other instances they may mimic basilar migraine (Sanchez-Villasenor et al., 1995). De´ja` vu episodes or similar experiences can be seen in patients with epilepsy, psychiatric disorders, and even in normal subjects (Devinsky et al., 1989; Wild, 2005). Conversely, epileptic seizures can be mistaken for a primary psychiatric disorder (Tisher et al., 1993).

OTHERS/UNCLEAR The term “transient unresponsiveness in the elderly” was suggested for elderly patients with recurrent episodes of altered state of consciousness of nonobvious cause lasting for minutes to hours, and with normal EEG findings (Haimovic and Beresford, 1992). A cardiogenic and orthostatic presyncope as well as sedative drug effects should always be suspected. Likewise, orthostatic TIAs can present with TLOC or episodes of unresponsiveness without loss of postural control. The term “blip syndrome” was coined to describe momentary sensations of impending loss of consciousness when a person is relaxed; these episodes have a benign prognosis (Lance, 1996).

DIAGNOSTIC WORKUP OF TRANSIENT LOSS OF CONSCIOUSNESS Clinical history, including eyewitness accounts, thorough physical examination, and 12-lead ECG should be obtained in all patients. Additional testing should be obtained when appropriate or when the initial assessment did not lead to a firm diagnosis (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009; Cooper et al., 2011; Brignole and Hamdan, 2012). It has been estimated that approximately 10% of patients presenting to an emergency department with

TRANSIENT LOSS OF CONSCIOUSNESS AND SYNCOPE TLOC have a severe outcome or death in the following month (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009). A few features have been proposed to identify patients at high risk that require immediate hospitalization, including the following: ● ● ●

history or signs of cardiac disease abnormal ECG important comorbidities.

Clinical history

Basic investigations Basic laboratory investigation should include hemoglobin, hematocrit, electrolytes, serum creatinine, and blood glucose. A 12-lead ECG is always necessary and helpful to detect potential forms of cardiac syncope. The following findings are suggestive of an arrhythmic cause of cardiac syncope (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009; Brignole and Hamdan, 2012): ●

History should always assess the following features :

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●

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●

●

●

●

Onset of TLOC (or presumed TLOC) (preictal phase): prodromes/aura (odors, smells, de´ja` vu, visual or auditory hallucinations, sweating, feeling warm or hot, palpitations), facial discoloration, motor features (head turning, jerking, “convulsions,” unusual posturing). Characteristics of the TLOC (ictal phase): duration, face color, type of fall (atonic, tonic), motor features (head turning, jerking, convulsions, unusual posturing), tongue biting, other injuries. End of TLOC (postictal phase): urinary/fecal incontinence, drowsiness/slowness/disorientation, headache, muscle aches. Circumstances of the TLOC: standing/sitting/ supine, changes in position, head turning, pain, fear, activity/exercise, postprandial, before/during/after micturition, coughing, sneezing. Clinical context: age, general status, history/ evidence for cardiac disease, medications, alcohol consumption, family history (sudden death, syncope).

Medications used by the patient should be reviewed carefully because of their potential role in provoking autonomic dysfunction or cardiac arrhythmias. Some of these features may point to specific causes of TLOC (Table 13.2).

Physical examination The physical examination should assess the presence of injuries and check for signs of cardiac, autonomic, neurologic, medical, or psychiatric disorders. Blood pressure and heart rate should be measured after the patient has been supine for 5 minutes, and in the upright position immediately after rising, then serially for another 3–5 minutes or longer, when delayed orthostatic hypotension is suspected (Schellong’s test). Orthostatic hypotension is diagnosed when a sustained reduction of systolic blood pressure of > 20 mmHg or a diastolic blood pressure (BP) of > 10 mmHg are observed.

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● ● ● ● ● ●

sinus bradycardia (< 40 bpm) Mobitz II AV block complete AV block alternating left and right bundle branch block paroxysmal tachycardia ventricular tachycardia pacemaker or implantable cardioverter defibrillator (ICD) malfunction Q waves suggesting myocardial infarction negative T waves in right precordial leads suggesting acute coronary syndrome long or short QT intervals.

Further investigations PROLONGED ECG MONITORING A prolonged ECG should be performed in patients older than 40 years of age and with TLOC of unknown origin (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009). Holter monitoring over 24–48 hours is recommended in patients with frequent episodes. The gold standard for the diagnosis of syncope refines a correlation between symptoms and a documented arrhythmia. Some asymptomatic arrhythmias (prolonged asystole > 3 seconds), rapid supraventricular or ventricular tachycardias have been considered diagnostic by some authors (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009). For patients with rare episodes ( 30 bpm within 10 minutes of standing (> 40 bpm for individuals aged 12–19 years), or an upright heart rate of > 120 bpm without a fall in blood pressure (Freeman et al., 2011). Occasionally a psychogenic pseudosyncope is observed in the course of a tilt test.

CAROTID SINUS MASSAGE The carotid sinus massage (CSM) should be performed in patients aged > 40 years and with TLOC of unknown origin (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009). The examination is generally safe, but should be avoided in patients with carotid stenosis and with TIA or stroke in the last 3 months. CSM should be performed for 5–10 seconds in the supine position first and if negative in the upright position. A pathologic response is diagnosed in the presence of a ventricular pause lasting more than 3 seconds or more and a fall in systolic blood pressure of 50 mmHg (Brignole et al., 2004; Healey et al., 2004).

OTHERS ●

●

Exercise stress testing is recommended for patients with syncope/TLOC during or shortly after exercise (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009). Electrophysiologic studies are rarely indicated and usually done in patients suspected of arrhythmogenic causes of syncope in the context of a known cardiac

●

●

disease and negative noninvasive tests (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009). EEG, brain MRI, Doppler ultrasound of the cervicocranial vessels should be obtained only in patients suspected of having a neurologic etiology of syncope or nonsyncopal TLOC. Injections of saline placebo have been suggested, in analogy to pseudoseizures, as a procedure to induce and diagnose psychiatric pseudosyncope. VideoEEG monitoring and tilt test can also lead to the documentation and eventually diagnosis of a psychiatric TLOC. Open mouth hyperventilation was used until the 1990s, but its sensitivity and specificity are low (Hornsveld et al., 1996).

TREATMENT OF TRANSIENT LOSS OF CONSCIOUSNESS Treatment of TLOC depends on identification of a specific cause. A review of all available treatments is beyond the scope of this chapter. Treatment of TLOC is important for different reasons: (1) risk related to the underlying cause of TLOC; (2) risk of injuries; (3) risk related to TLOC in some situations (e.g., driving, swimming); (4) emotional stress of patients.

Treatment of syncopal transient loss of consciousness CARDIAC SYNCOPE The following interventions have been recently considered class I evidence (Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology, 2009): ● ●

●

●

antiarrhythmic drugs for atrial fibrillation pacing for sinus node disease, Mobitz type II; complete AVB; and bundle branch block with positive electrophysiologic testing implantable cardiovertor defibrillator for ventricular tachycardia and structural cardiac disease; ischemic and nonischemic cardiomyopathy with severely depressed left ventricular ejection fraction/heart failure cathether ablation procedures for supraventricular and ventricular tachycardias without structural heart disease.

ORTHOSTATIC SYNCOPE The following interventions are considered to have a satisfactory evidence from available literature and clinical practice:

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TRANSIENT LOSS OF CONSCIOUSNESS AND SYNCOPE 187 Adequate hydration and salt intake is important, NEURALLY MEDIATED SYNCOPE particularly in warm weather. This class I evidence ● Adequate hydration is important, particularly in recommendation has been proposed in a recent warm weather. review of orthostatic hypotension (Task Force for ● Avoidance of predisposing conditions (whenever the Diagnosis and Management of Syncope of the possible). European Society of Cardiology, 2009). Particularly ● Support stockings. before arising from bed in the morning, a bolus ● Physical counter-maneuvers such as leg crossing, water intake has a substantial pressor effect resultlimb and/or abdominal contractions, squatting, ing in a sustained increase in blood pressure. In bending forward, toe raising and knee flexion may patients with MSAs pure water is preferred over combat orthostatic intolerance (Wieling et al., 2004). soup or the like which does not seem to elicit a pres● Isometric muscle training (counter-pressure maneusor effect and may even worsen OH after rapid vers) of arms and/or legs has been shown to improve ingestion (Z’Graggen et al., 2010). neurally mediated syncope (NMS) (Task Force for Avoidance of predisposing conditions such as severe the Diagnosis and Management of Syncope of the physical exertion, large meals, especially with European Society of Cardiology, 2009). refined carbohydrates, and alcohol. Drugs lowering ● Several agents, including midodrine, fludrocortiblood pressure must be avoided. sone, disopyramide, ephedrine, propranolol (and Support stockings. other b-blockers), serotonin reuptake inhibitors, Moderate exercise (e.g., swimming) can be sugand scopolamine, have been tested in small trials gested based on the fact that patients with orthowith mostly disappointing results (Task Force for static intolerance and PoTS present signs of the Diagnosis and Management of Syncope of the cardiorespiratory deconditioning (Parsaik et al., European Society of Cardiology, 2009). 2012). ● Tilt training may be useful in highly motivated Midodrine (5–20 mg three times daily) and or young patients with NMS. fludrocortisone (0.1–0.3 mg once daily). Other ● The efficacy of pacemaker therapy for NMS drugs occasionally used are pyridostigmine, domremains controversial. After two negative randomperidone, erythropoietin in patients with anemia, ized double-blind studies, a third recent study and desmopressin in patients with nocturnal reported a positive effect (32% absolute reduction polyuria (Mathias and Kimber, 1998; Schoffer in recurrence) in patients > 40 years of age with et al., 2007). asystolic NMS (Brignole et al., 2012). Older patients with autonomic dysregulation suf● Treatment of carotid sinus syndrome is pharmacofering from OH often show a marked supine nocturlogic (e.g., anticholinergic drugs, SSRIs) in patients nal hypertension. This obviously may complicate with the predominant vasodepressor form (Healey treatment, since most measures which stabilize or et al., 2004). In patients with the predominantly carelevate diurnal blood pressure exacerbate nocturnal dioinhibitory form, a dual chamber pacing may be supine hypertension, while nocturnal antihyperteneffective. sive treatments exacerbate OH. As a short-lasting antihypertensive medication, transdermal nitroglycerin during the night is favored over conventional drugs. Treatment of nonsyncopal transient In patients with impaired autonomic function, sleeploss of consciousness ing with the head-up position to diminish nocturnal Treatment of nonsyncopal TLOC is selected according sodium loss is an effective measure. These patients to the identified etiology (Table 13.1) and can be highly should also avoid lying down during the day, and effective. rest in a seated rather than a supine position if taking a nap. Treatment options for PoTS include endurance exerDriving in patients with transient cise training, low-dose propranolol or calcium antagloss of consciousness onists for hyperadrenergic forms, and midodrine and or fludrocortisone in neuropathic forms Driving restrictions are recommended for nonprofes(Arnold et al., 2013). sional drivers with cardiac syncope (before treatment), Plasma exchange has been shown to be effective in frequent or recurrent syncope of unknown origin, TLOC patients with primary autoimmune autonomic failwithout prodrome, epileptic TLOC, and after the occurure (Schroeder et al., 2005). rence of an event during driving (Task Force for the

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Diagnosis and Management of Syncope of the European Society of Cardiology, 2009).

ACKNOWLEDGMENTS I thank Professor Christian W. Hess, Department of Neurology, University Hospital Bern, for his input into the section on orthostatic hypotension and his suggestions on the overall structure of the chapter, and Professor Werner Z’Graggen, Department of Neurology, Autonomic Unit, University Hospital Bern, for providing the materials for Figures 13.1, 13.2, 13.4 and 13.5 and for his review of the final version of this chapter.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 14

Neurologic complications of cardiac surgery and interventional cardiology 1 2

SARA HOCKER1*, EELCO F.M. WIJDICKS2, AND JOSE BILLER3 Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA Division of Critical Care Neurology, Mayo Clinic, Rochester, MN, USA

3

Department of Neurology, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION Most cardiac surgeries and procedures are without major complications, or the neurologic presentation is fleeting and not concerning to the cardiac surgeon. Any data on neurologic complications is therefore biased towards referral to a neurologist. Over the years, a full spectrum of neurologic complications have been described, and they can be summarized as complications due to anesthesia (i.e., nerve injury), invasive procedures (i.e., coronary angiogram and stenting), or open heart surgery. Many systemic factors change during and after surgery and this may include intraoperative and postoperative blood pressure fluctuations and cardiac arrhythmias. This chapter provides a comprehensive overview of all facets of neurologic complications after cardiac surgical procedures. It will highlight the neurologic complications of cardiac procedures including cardiac catheterization and percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), valvular surgery, patent foramen ovale (PFO)/atrial septal aneurysm (ASA) surgery, surgery for cardiac tumors, and mechanical circulatory devices including extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pump (IABP), and ventricular assist devices (VADs). Congenital heart disease surgery, cardiac transplantation, aortic surgery, catheter ablation and device implantation are discussed in other chapters within this volume.

HISTORY Cardiac surgeries are being performed in increasing numbers and with lower mortality than in previous

decades, largely due to technological, anesthetic, and surgical advances in the field of cardiology. The number of surgeries and procedures is staggering. In 2006, an estimated 1 313 000 inpatient percutaneous coronary intervention (PCI) procedures, 448 000 inpatient coronary artery bypass grafting (CABG) procedures, and 1 115 000 inpatient diagnostic cardiac catheterizations were performed in the US alone (Lloyd-Jones, 2010). An estimated 99 000 cardiac valve surgeries are performed annually in the US (American Heart Association, 2008). This experience, however, has also brought to light a host of possible neurologic complications. While neurologic complications of cardiac surgeries and procedures can occur in any age group, higher risk groups include older patients and those with significant comorbidities (Libman et al., 1997; Bando et al., 2003; Cho et al., 2003; Cline et al., 2003; Fleck and Biller, 2003; Ruel et al., 2004; Sankaranarayanan et al., 2007; Aggarwal et al., 2009). Neurologic complications have only been examined in detail in the last three decades. Prior work has included trials to test agents that protect the brain (Nussmeier et al., 1986; Zaidan et al., 1991), studies that identified risk factors for postoperative stroke (McKhann et al., 2006), and, most recently, large prospective studies from Johns Hopkins on cognitive impairment, led by McKahnn (Selnes et al., 2009).

CLINICAL FINDINGS Neurologic complications of cardiac surgery and interventional cardiac procedures are obviously numerous. Moreover the clinical syndromes are extremely variable,

*Correspondence to: Sara Hocker, M.D., Division of Critical Care Neurology, College of Medicine, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA. Fax: þ1-507-266-4419, E-mail: [email protected]

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depending on the localization of the lesion, and can be transient or persistent, depending on the mechanism of injury. The subsections below list the various neurologic complications reported in association with the procedures of interest in this chapter. Further discussion of the natural history, pathology, investigation, and management of these entities will follow this general introduction to the spectrum of neurologic complications that can be encountered.

Cardiac catheterization and percutaneous coronary intervention Patients undergoing cardiac catheterization and percutaneous coronary intervention (PCI) can experience strokes, both ischemic or hemorrhagic, global cerebral hypoxic or anoxic insult, seizures, transient global amnesia, brachial plexopathy, peripheral mononeuropathies, complex regional pain syndrome (CRPS), and cortical blindness (Table 14.1).

Valvular surgery Neurologic complications of cardiac valve surgery are similar to those reported with CABG and include both ischemic and hemorrhagic strokes, seizures, coma, cognitive dysfunction, migraine-like phenomena, brachial plexopathy, and peripheral mononeuropathies (Table 14.3). Neurologic complications of infective endocarditis are discussed in a separate chapter in this volume.

Patent foramen ovale/atrial septal aneurysm surgery Transient ischemic attacks (TIAs) are a rare occurrence following percutaneous patent foramen ovale (PFO) closure (Dorenbeck et al., 2007; Balbi et al., 2008).

Surgery for cardiac tumors Coronary artery bypass grafting After coronary artery bypass grafting (CABG), patients may present with signs and symptoms which can be divided into (1) cerebrovascular events, (2) encephalopathy or coma, (3) early or delayed cognitive impairment, (4) peripheral nervous system injury, and (5) other neurologic events (Table 14.2).

Neurologic complications of surgery for cardiac tumors include intraoperative or perioperative ischemic or hemorrhagic stroke or delayed intracerebral or subarachnoid hemorrhage from tumor recurrence (Price et al., 1970; Roeltgen et al., 1981; McCarthy et al., 1986; Bjessmo and Ivert ,1997; Scrofani et al., 2002; Walker et al., 2003; Kvitting et al., 2008).

Table 14.1 Etiologies and potential mechanisms of neurologic complications following cardiac catheterization and percutaneous coronary intervention Neurologic complication

Etiology/potential mechanism

Ischemic stroke

Thromboembolism, air embolism, atherosclerosis, vasospasm, vessel trauma, hypotension Pharmacotherapy, vessel trauma, catecholamine surge Ischemic infarction, subdural hemorrhage, air embolism, contrast administration Contrast Acute low cardiac output, hypotension, shock, hypoglycemia Mechanism unknown Direct compression, or hematoma or pseudoaneurysm formation with axillary angiography Direct injury, hematoma formation Trauma Direct injury, compression by groin hematoma, arteriovenous fistula or pseudoaneurysm, superficial or common femoral artery occlusion With transradial approach

Hemorrhagic stroke Seizure Cortical blindness Hypoxic-ischemic encephalopathy Transient global amnesia Brachial plexus injury Median nerve injury Lateral femoral cutaneous nerve injury Femoral nerve injury

Complex regional pain syndrome

(Sources: Piatt, 1984; Vik-Mo et al., 1986; Thomas et al., 1989; Brown and Topol, 1993; Rama et al., 1993; Lazar et al., 1995; Sticherling et al., 1998; Wijman et al., 1998; Kuruvilla et al., 1999; Liu et al., 2001; Cho et al., 2003; Cline et al., 2003; Ozcakar et al., 2004; Restrepo et al., 2005; Yazici et al., 2007; Mehta et al., 2008.)

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Table 14.2 Etiologies and potential mechanisms of neurologic complications following coronary artery bypass grafting Neurologic complication

Etiology/potential mechansim

Ischemic infarction of the brain or spinal cord

Thromboembolism, air embolism, atherosclerosis, vasospasm, vessel trauma, hypotension, underlying coagulopathy or factors related to use of IABP Mechanism unknown Proposed mechanisms include: factors related to the extracorporeal bypass apparatus, anticoagulation, low cerebral blood flow, anesthetic agents or presence of subclinical pituitary tumor Medication toxicity, cerebral thromboembolism, cerebral air embolism Acute low cardiac output, hypotension, shock, hypoglycemia Sedatives, analgesics, showers of microemboli Mechanism unknown Optic nerve ischemia, retinal artery embolism Atherosclerotic disease of the proximal subclavian artery Injury to the cervical sympathetic chain Stretching, direct trauma or compression Stretching, direct trauma, ischemia or topical hypothermia Compression Stretching, direct trauma or hypothermia Direct trauma Ischemia due to stretching or compression

Hemorrhagic stroke Pituitary apoplexy

Seizure Hypoxic-ischemic encephalopathy (HIE) Encephalopathy Delayed cognitive dysfunction Visual loss Subclavian steal syndrome Horner syndrome Brachial plexopathy Phrenic nerve injury Ulnar nerve injury Recurrent laryngeal nerve injury Saphenous nerve injury Common peroneal nerve injury

IABP, intra-aortic balloon pump. (Sources: Addonizio et al., 1980; Anderson et al., 1985; Cooper et al., 1986; Kestin et al., 1993; Busch et al., 1998; Dimopoulou et al., 1998; Katz et al., 1998; Sharma et al., 2000; Newman et al., 2001; Nuttall et al., 2001; Geyer et al., 2002; Vasquez-Jimenez et al., 2002; Likosky et al., 2003; Canbaz et al., 2005; Gootjes et al., 2005; McKhann, 2006; Stamou, 2006; Onem et al., 2007; Sadek et al., 2008; Hunter et al., 2011; Yakupoglu et al., 2010.)

Table 14.3 Etiologies and potential mechanisms of neurologic complications following valvular surgery Etiology/potential mechanism Neurologic complication

Intraoperative

Postoperative

Ischemic stroke

Atherosclerotic emboli Hypoperfusion Air embolism Fat embolism Vessel clamping Anticoagulation Cerebral air embolism Cerebral air embolism Possibly due to showers of microemboli to the bilateral subcortical white matter Mechanism unknown Stretching, direct trauma or compression Stretching, direct trauma or compression

Valve thrombosis Left atrial thrombi Septic emboli

Intracranial and spinal hemorrhage Seizure Coma Cognitive dysfunction Migraine-like phenomena Brachial plexopathy Peripheral nerve injury (see section on CABG)

CABG, coronary artery bypass graft. (Sources: Caplan et al., 1976; Armon et al., 1991; Cannegieter et al., 1995; Deklunder et al., 1998; Caswell et al., 2003; Nakajima et al., 2003; Abend and Levine, 2007; Aoyagi et al., 2007; Oka et al., 2008.)

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Table 14.4 Etiologies and potential mechanisms of neurologic complications following implantation of mechanical circulatory devices Device/procedure

Neurological complications

Etiology/potential mechanism

IABP

Ischemic stroke and TIA

Cerebral air embolism due to IABP rupture Thromboembolism Anticoagulation Obstruction to blood flow, or thromboembolism in the femoral artery Thromboembolism

Ventricular assist devices

Hemorrhagic stroke Neurologic deficits in one or both legs ranging from foot drop to complete paralysis Ischemic stroke Seizure Delirium Sciatic nerve injury

Secondary to stroke Multifactorial Compression due to posterior compartment syndrome of the thigh

Ischemic stroke

Thromboembolism, air embolism, ligation of the carotid artery and internal jugular vein Anticoagulation, thrombocytopenia, systolic hypertension Changes in cerebral blood flow and arterial oxygen pressure Mechanism unclear Mechanism unclear Anterior ischemic optic neuropathy Mechanism unclear, probably related to hypoxia

ECMO

Hemorrhagic stroke Hypoxic-ischemic encephalopathy Seizure Sensorineural hearing loss Visual loss Neuropsychological deficits

IABP, intra-aortic balloon pump; TIA, transient ischemic attack; ECMO, extracorporeal membrane oxygenation. (Sources: Honet et al., 1975; Bartlett et al., 1986; Hazelrigg et al., 1992; Jarjour et al., 1994; Glass et al., 1995; Busch et al., 1998; Thomas et al., 2001; Ho et al., 2002; Copeland et al., 2004; Cruz-Flores et al., 2005; Kakkar et al., 2010; Zanatta et al., 2010; Mateen et al., 2011)

Mechanical circulatory devices The use of mechanical circulatory devices has been associated with cerebrovascular events including ischemic stroke, hypoxic-ischemic encephalopathy (HIE), transient ischemic attack (TIA) and intracranial hemorrhage, seizures, delirium, visual loss, hearing loss, and neuropsychological deficits as well as peripheral neurologic deficits (Table 14.4).

PATHOLOGY Cardiac catheterization and percutaneous coronary intervention Cardiac catheterization-related strokes are expectedly embolic in origin (Weissman et al., 1985; Liu et al., 2001). Clinically apparent embolic strokes have been reported to occur during diagnostic cardiac catheterization and PCI in 0.08–0.4% of adult patients (Brown and Topol, 1993; Jackson et al., 2000; Segal et al., 2001; Fuchs et al., 2002; Dukkipati et al., 2004; Mack et al., 2004; Sankaranarayanan et al., 2007). While most are due to thromboembolism, other mechanisms of cerebral

infarction include atherosclerosis, air embolism, vasospasm, vessel trauma, and hypotension (Wijman et al., 1998; Cline et al., 2003; Mehta et al., 2008). Cardiac catheterization is not so innocuous as it may seem because asymptomatic cerebral infarction in patients undergoing diagnostic or interventional cardiac catheterization has been detected by diffusion-weighted MRI in 15–100% of patients (Busing et al., 2005; Lund et al., 2005). There is a suggestion that posterior circulation strokes are more common with the brachial artery approach and anterior circulation events are more common with the femoral artery approach (Lazar et al., 1995); however, overall, the data regarding stroke in association with cardiac catheterization are conflicting as to whether there is an anterior or posterior predominance (Brown and Topol, 1993; Segal et al., 2001; Cho, 2003). A randomized controlled multicenter trial by Burzotta and colleagues prospectively assessing both clinically silent and apparent cerebral embolisms by diffusion-weighted magnetic resonance imaging before and after angiography has been completed but results have not yet been published. The authors of this study randomized patients into radial and femoral access to

NEUROLOGIC COMPLICATIONS OF CARDIAC SURGERY allow assessment of risk of silent brain injury associated with the different vascular access sites (Burzotta et al., 2007). Risk factors predisposing to cerebrovascular complications with cardiac catheterization include patient characteristics such as age, gender, and vascular comorbidities, as well as procedure-related factors such as longer fluoroscopic time, use of large-caliber catheters, and introduction of emboli during catheter advancement, flushing, contrast injection, and ventriculography (Lazar et al., 1995; Cline et al., 2003; Sankaranarayanan et al., 2007; Aggarwal et al., 2009). Cerebral microemboli are predominantly detected during catheter advancement, catheter flushing, contrast injection, and ventriculography. There is also a significant correlation between the number of microemboli and the volume of contrast used (Lund et al., 2005). Hemorrhagic stroke has been reported to occur secondary to vessel pharmacotherapy, vessel trauma, and catecholamine surges (Piatt, 1984; Liu et al., 2001; Cline et al., 2003). Seizures with cardiac catheterization are uncommon but do occur in the adult population (Lazar et al., 1995). In the pediatric population, seizures are more common. While they typically represent a new ischemic stroke, they have been reported to occur in the absence of new lesions and in these cases were tentatively attributed to contrast administration (Frye et al., 2005; Sansone et al., 2007). Seizures due to contrast administration result from nonidiosyncratic and idiosyncratic reactions. Nonidiosyncratic reactions are hypothesized to be related to the hyperosmolar and chemotoxic properties of the contrast media, while idiosyncratic reactions are allergic-like reactions which are not well understood (Sansone et al., 2007). In one 12 year prospective study, 0.24% of children had neurologic events during diagnostic cardiac catheterization and 1% of children undergoing percutaneous coronary intervention had neurologic complications. The majority of these events manifested as seizure; however, stroke was determined to be the cause of neurologic symptoms in 57% of cases (Liu et al., 2001). Another 4 year study involving 1362 cardiac catheterization procedures in children less than 15 years of age revealed that 18 (1.3%) of children, without prior nervous system disease, developed neurologic sequelae including transient neurologic deficits, isolated seizures, and focal seizures associated with ischemic stroke within 24 hours of cardiac catheterization (Weissman et al., 1985). Transient cortical blindness after contrast media exposure is a well described phenomenon during cardiac catheterization and PCI but is less common now that nonionic, low-osmolality radiocontrast agents are being used. It has been thought to be due to a breakdown of the

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blood–brain barrier selective for the occipital cortex with subsequent direct neurotoxicity of the contrast media (Rama et al., 1993; Sticherling et al., 1998). Hypoxic-ischemic encephalopathy is an unfortunate but rare complication of cardiac catheterization and occurs in the context of a severe periprocedural event such as cardiac arrest, arrhythmia resulting in low cardiac output, prolonged hypotension, or hypoglycemia. The outcome can be devastating and similar to that in other conditions associated with cardiopulmonary resuscitation (Liu et al., 2001). Peripheral nervous system complications can be divided into brachial plexopathy, median nerve injury, lumbosacral plexopathy, femoral nerve or lateral femoral cutaneous nerve injury. Brachial plexopathy can occur due to prolonged fixed posture during the procedure. Median neuropathy is a rare complication of brachial artery catheterization and is thought to be due to direct injury in the antecubital region or hematoma formation. Brachial plexopathy has been described after axillary angiography and may be secondary to hematoma, pseudoaneurysm formation, or direct compression (Ozcakar et al., 2004). The femoral nerve can be severed or compressed by a hematoma at the groin puncture site or, rarely, by an arteriovenous fistula or pseudoaneurysm of the femoral profunda artery (Kuruvilla et al., 1999). Groin, flank, or abdominal pain that radiates to the thigh associated with numbness of the anterior thigh and medial calf, with a reduced or absent patellar reflex, should alert the clinician to discontinue any anticoagulation and investigate for retroperitoneal hematoma resulting in a lumbar plexopathy or femoral neuropathy. The lateral femoral cutaneous nerve can be injured from tight compression bandages, resulting in meralgia paresthetica (Karsli et al., 2005).

Coronary artery bypass grafting Clinically apparent strokes occur in approximately 0.8–5% of patients undergoing CABG (Stamou, 2006). They can affect the brain, or rarely, the spinal cord (Geyer et al., 2002). Using highly sensitive diffusionweighted MRI increases the incidence of cerebral infarctions to 18%. However, about two-thirds of these infarcts are asymptomatic (Floyd et al., 2006). Most strokes (61%) occur within the first 2 postoperative days while the remainder (39%) occur by the 9th postoperative day (Libman et al., 1997). Embolic cerebral infarctions are the most common type of stroke occurring in the perioperative period after CABG (Likosky et al., 2003; Stamou, 2006). Watershed cerebral infarctions typically occur in the setting of prolonged hypotension, but they can also occur in patients without documented

198 S. HOCKER ET AL. hemodynamic instability. The mechanism in these cases decline of 53% at discharge, 36% at 6 weeks, 24% at may be showers of microemboli that lodge in terminal 6 months, and 42% at 5 years (Newman et al., 2001). branches resulting in perfusion failure (Hupperts et al., There is a large body of literature on what damages the 1995). In cases of arterial embolism, seizures, status epibrain during cardiopulmonary bypass. The most imporlepticus, and coma may ensue. Other mechanisms of tant factor is embolic load, typically from microbubbles stroke include lacunar, thrombotic, and intracerebral of air, the propagation of which may be influenced by hemorrhage (Likosky et al., 2003). Lacunar infarction in changes in pH. Acid–base management during cardiopulthis population is often due to small emboli that occlude monary bypass can be accomplished with the pH-stat single perforating arteries (Macdonald et al., 1995; technique which maintains a plasma pH of 7.4 regardless Libman et al., 1997). Hemorrhagic stroke may be related of temperature by artificially increasing the carbon dioxto hematologic disturbances resulting from cardiopulmoide component of blood, resulting in hyperemia and posnary bypass. There may be consumption of platelets and sibly cerebral edema. With this technique, there is a coagulation factors, decreased platelet adhesiveness, mismatch in cerebral blood flow and metabolic rate; thus and abnormal activation of the coagulation cascade cerebral blood flow is pressure-passive and changes (Addonizio et al., 1980; Kestin et al., 1993). depending on cerebral perfusion pressure. Alternatively, Atheromatous aorta and carotid artery disease are acid–base management can be accomplished with the known predictors for stroke after CABG. It is likely that “a-stat” technique which permits relative alkalosis when in some way or form, placement of catheters into an aththe patient is cooled, preserving cerebral autoregulation, eromatous arch as part of cardiopulmonary bypass plays resulting in less cerebral blood flow, and probably a major role. decreased embolic load. In a randomized study of pH-stat Intracerebral hemorrhage including pituitary apoversus a-stat management, cognitive dysfunction was plexy is a rare occurrence following CABG (Anderson significantly greater in the pH-stat group when bypass et al., 1985; Cooper et al., 1986; Likosky et al., 2003; time was longer than 90 minutes (Wijdicks, 2002). Onem et al., 2007; Yakupoglu et al., 2010). A recent literature review of 16 papers addressing this Infarction of the spinal cord typically affects the midquestion found that the best technique to follow in patients thoracic spinal cord level, between the circulatory areas undergoing deep hypothermic circulatory arrest during of the descending spinal arteries and the artery of cardiac surgery is dependent upon the age of the patient, Adamkiewicz. Possible etiologies of spinal cord ischewith better results using pH-stat in the pediatric patient mia include use of an intra-aortic balloon pump, aortic and a-stat in the adult patient (Abdul Aziz et al., 2010). trauma secondary to cross-clamping, or insertion of Central retinal artery occlusion or branch retinal intra-aortic balloon pump, aortoiliac occlusive disease, artery occlusion may occur with CABG, most commonly microembolization of atherosclerotic plaques or cholesdue to embolism. Patients are noted to have acute onset terol emboli, hypotension, hypoperfusion, or an underlyof complete visual loss in one eye (with central retinal ing protein C or S deficiency (Geyer et al., 2002). artery occlusion) or acute onset of partial visual loss Seizures may occur as a consequence of thromboemin one eye (with branch retinal artery occlusion). bolic ischemic stroke, cerebral air embolism, or more Ischemic optic neuropathy is an extremely rare event commonly due to medication toxicity related to antibiafter cardiac surgery, with an overall frequency of otics or other perioperative drugs such as tranexamic 0.06% (Nuttall et al., 2001). Anterior ischemic optic neuacid (Hunter et al., 2011). ropathy is characterized by sudden painless visual loss Encephalopathy following CABG is typically cliniinvolving mainly the lower part of the visual field in cally apparent following extubation and is frequently one eye with optic disc swelling. Posterior ischemic optic related to the effects of sedatives and analgesics adminneuropathy is characterized by unilateral or bilateral loss istered during anesthesia or for comfort during mechanof visual acuity, visual fields, or blindness without disc ical ventilation, or to metabolic disturbances. In patients swelling. Factors associated with visual loss after cardiowithout obvious drug-related or metabolic causes, there pulmonary bypass are low hemoglobin concentration may be evidence of showers of microemboli. It has been ( 30 mmHg gradient is present across the coarctation. Options include open surgical repair or equately treated patient. General paresis or tabes dorsalis, endovascular placement of stents. As a general rule, surmeaning “decay of the back,” follows 10–20 years later. gery is the treatment of choice for all native coarctation in Tabes dorsalis, the most common presentation of tertiary children less than a year of age. Balloon angioplasty can syphilis, is a progressive degenerative process involving be considered for recurrent stenosis. Stent placement can demyelination and inflammatory changes of the spinal

NEUROLOGIC COMPLICATIONS OF AORTIC DISEASES AND AORTIC SURGERY cord. It is manifested by a triad of neurologic symptoms: unsteady gait, lightening-type pains, urinary incontinence, and sexual dysfunction. In advanced cases, anterior horn cells may also be involved. Charcot joint, hyporeflexia, Romberg sign, and Argyll Robertson pupil (pupils that accommodate but do not react) are also relatively common findings in late-stage disease (Hook and Marra, 1992; Pandey, 2011).

NEUROLOGIC COMPLICATIONS WITH AORTIC SURGERY Ischemia or embolism to the brain or spinal cord may result in stroke and/or spinal cord ischemia (SCI) following aortic surgery. SCI, paraplegia, or paraparesis, is one of the most feared complications of aortic surgery. It primarily results from ischemic injury to the spinal cord from either direct exclusion of the segmental spinal blood flow or from perioperative hypoperfusion of the spinal column. It is a devastating complication that changes the quality of life of both the afflicted and family members. Furthermore, it also adversely affects the operative mortality rates as well as late outcomes. Risk factors for developing SCI include: total aortic cross-clamp time, extent of aorta repaired, aortic rupture, patient age, proximal aortic aneurysm, and baseline renal dysfunction (Svensson et al., 1993; Cambria et al., 2002). The primary contributing factors to perioperative SCI revolve around permanent exclusion of critical segmental blood supply to the spinal cord following graft replacement. Alternatively, paraplegia and paraparesis can occur due to malperfusion of the spinal cord during

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surgery. The development and degree of malperfusion is dependent upon the length of time the aorta is crossclamped, the extent of repair, and the presence of a collateral circulation. Therefore, the maintenance of spinal cord perfusion pressure (SCPP) is paramount when treating thoracoabdominal/thoracic aortic pathology in order to minimize risk of SCI. Incidence of neurologic complications and its mechanisms differ depending on the nature of disease and extent of aortic repair performed. TAAA is well known for its risk for spinal cord ischemia. In a landmark article by Crawford and colleagues, the incidence rates of SCI following repair of TAAA were reported to range from 4% for type IV TAAAs to 31% for type II TAAAs (Fig. 16.6) (Svensson et al., 1993). Since then, a number of advances in techniques and adjunctive measures have been taken to reduce the incidence of SCI. These include hypothermia, CSF drainage with lumbar drains, maintaining distal arterial perfusion pressure, monitoring of evoked potentials with reimplantation of the intercostal arteries when changes occur, and minimizing aortic cross-clamp time. With selective use of the aforementioned methods, centers of excellence have been able to diminish their paraplegia rates (Fig. 16.7). The experience at Baylor is one such example. After performing 2286 thoracoabdominal aneurysm repairs, they report an astoundingly low paraplegia rate of 3.8% (Coselli et al., 2007). Other centers mimic this experience, where paraplegia rates have been reported to be 5–10% (Estrera et al., 2001; Jacobs et al., 2006; Greenberg et al., 2010; Conrad et al., 2011). Similarly, the incidence rates of SCI with open repair of the descending thoracic aortic

Fig. 16.6. Crawford classification of thoracoabdominal aneurysms. (Reproduced from Conrad et al., 2007.)

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Fig. 16.7. Plot of observed/expected ratios for paraplegia based on 82 clinical series showing a significant (p < 0.001) decrease in paraplegia rates over the last 23 years. (Reproduced from Acher and Wynn, 2009.)

aneurysm (DTAA) range from 2.5% to 3% in centers of excellence (Coselli et al., 2004; Estrera et al., 2005). Although primarily described as a complication of intervention on the thoracic and thoracoabdominal aorta, paraplegia can also occur following infrarenal aortic procedures. The incidence of SCI following infrarenal abdominal aortic aneurysm repair is about 0.25% (Gloviczki et al., 1991). Delayed paraplegia may develop. It is usually associated with transient hypotension in the postoperative period, although extremes as long as 10 months postprocedure have been reported (Cho et al., 2008). Early recognition is critical as prompt restoration of hemodynamic stability with mean arterial pressure (MAP) above 90 mmHg and institution of CSF drainage are crucial for neurologic recovery. Hyperperfusion syndrome is another mechanism of stroke in patients undergoing bypass grafting of great vessels for occlusive diseases of great vessels, whether due to atherosclerosis or vasculitis. Increased blood flow to the brain following revascularization of severely stenotic carotid arteries result in brain edema, seizure, and potentially, intracranial hemorrhage and stroke. Intracerebral hemorrhage due to cerebral hyperperfusion syndrome has been observed in 4.8% (Fields et al., 2006) and 13.3% of patients (Kim et al., 2009). In order to prevent this complication, the need for tight control of blood pressure cannot be overemphasized. Staged, rather than simultaneous, carotid reconstruction in the setting of severe bilateralcarotid occlusive disease will also help reduce the risk of hyperperfusion syndrome.

Stroke following aortic intervention can be the result of either embolic or ischemic process. Ischemic strokes result from brain hypoperfusion from either clamping of the great vessels or perioperative hypotension. Concomitant cerebrovascular disease as well as heavily diseased aorta places patients at risk for perioperative stroke. As such, evaluation of extracranial carotid arteries by duplex scanning and of the aorta by CTA would be important to minimize the risk. Stroke risk has been shown to be directly related to aortic cross-clamp positioning. As the clamp is placed more distally, the stroke risk decreases. With clamp placement adjacent to the left subclavian artery (LSCA), stroke risk is 2.0%. This decreases to 1.5% when clamped near the midthoracic level and 0.4% when clamped near the diaphragm (Schmittling et al., 2000). When the atherosclerotic disease burden is prohibitive for aortic cross-clamping, hypothermic circulatory arrest (HCA) may be used selectively, albeit at an increased morbidity and mortality rate (Coselli et al., 2008; Safi et al., 1998). Although some espouse routine use of HCA (Fehrenbacher et al., 2007; Kulik et al., 2010), it has not been shown to particularly reduce the stroke risk compared with conventional methods (Safi et al., 1998). Embolic strokes can occur secondary to manipulation of atheroma-burdened aorta and consequent embolism. This may occur at the time of manipulation of the aorta either during open surgery or during endovascular intervention. Deployment of the proximal end of the endograft in zone 2 (proximal to the left subclavian artery) has been shown to have a strong association with perioperative stroke; this is most likely secondary to manipulation of the arch with catheters, wires, balloons, and stent-grafts at the origin of great vessels in patients with high disease burden of atheromatous debris (Criado et al., 2005; Cho et al., 2006; Thompson et al., 2007). Thus, the importance of preoperative identification and avoidance of aortic arch with atheroma, minimal manipulation in the arch, meticulous cleansing of guidewires and catheters, and use of balloon molding only inside the grafts cannot be overemphasized (Cho and Makaroun, 2010).

CONCLUSION A subset of patients with adverse neurologic events can attribute their symptoms to aortic disease processes. Diseases of the aorta can both directly and indirectly lead to a variety of neurologic presentations. Although rare at times, they must be kept in mind by the clinician, as neurologic manifestations of aortic disease can be the subtle sign of a more complex, life-threatening process. Surgical techniques continue to evolve in an attempt to improve neurologic outcome both prior to and after intervention.

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NEUROLOGIC COMPLICATIONS OF AORTIC DISEASES AND AORTIC SURGERY Kazui T, Washiyama N, Bashar AH et al. (2002). Surgical outcome of acute type A aortic dissection: analysis of risk factors. Ann Thorac Surg 74: 75–81. Kendall BE, Andrew J (1972). Neurogenic intermittent claudication associated with aortic steal from the anterior spinal artery complicating coarctation of the aorta. J Neurosurg 37: 89–94. Kerr GS, Hallahan CW, Giordano J et al. (1994). Takayasu arteritis. Ann Intern Med 120: 919–929. Khan IA, Nair CK (2002). Clinical diagnostic and management perspectives of aortic dissection. Chest 122: 311–328. Khan IA, Wattanasauwan N, Ansari AW (1999). Painless aortic dissection presenting as hoarseness of voice: cardiovocal syndrome: Ortner’s syndrome. Am J Emerg Med 17: 361–363. Kilian K (2006). Left sided obstructive congenital heart defects. Newborn and Infant Nursing Reviews 6: 128–136. Kim HA, Kim JH, Won JH et al. (2009). An unusual clinical manifestation of Takayasu’s arteritis: spinal cord compression. Joint Bone Spine 76: 209–212. Kim YW, Kim DI, Park YJ et al. (2012). Surgical bypass vs endovascular treatment for patients with supra-aortic arterial occlusive disease due to Takayasu arteritis. J Vasc Surg 55: 693–700. Klein RG, Hunder GG, Stanson AW et al. (1975). Large artery involvement in giant cell (temporal) arteritis. Ann Intern Med 83: 806–812. Koshino T, Murakami G, Morishita K et al. (1999). Does the Adamkiewicz artery originate from the larger segmental arteries? J Thorac Cardiovasc Surg 117: 898–905. Kulik A, Castner CF, Kouchoukos NT (2010). Replacement of the descending thoracic aorta: contemporary outcomes using hypothermic circulatory arrest. J Thorac Cardiovasc Surg 139: 249–255. Lacasa J, Ruiz F, de Escalante B et al. (1994). Lumbosacral plexopathy from aortic aneurysm. An Med Interna 11: 105–106. Lainez JM, Yaya R, Lluch V et al. (1989). Lumbosacral plexopathy caused by aneurysms of the abdominal aorta. Med Clin (Barc) 92: 462–464. Lee MS, Smith SD, Galor A et al. (2006a). Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 54: 3306–3309. Lee SI, Pyun SB, Jang DH (2006b). Dysphagia and hoarseness associated with painless aortic dissection: a rare case of cardiovocal syndrome. Dysphagia 21: 129–132. Lefebvre V, Leduc JJ, Choteau PH (1995). Painless ischaemic lumbosacral plexopathy and aortic dissection. J Neurol Neurosurg Psychiatry 58: 641. Loddenkemper T, Sharma P, Katzan I et al. (2007). Risk factors for early visual deterioration in temporal arteritis. J Neurol Neurosurg Psychiatry 78: 1255–1259. Longo GM, Xiong W, Greiner TC et al. (2002). Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110: 625–632. Maksimowicz-McKinnon K, Clark TM, Hoffman GS (2007). Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum 56: 1000–1009.

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Shelhamer JH, Volkman DJ, Parrillo JE et al. (1985). Takayasu’s arteritis and its therapy. Ann Intern Med 103: 121–126. Shetty AK, Stopa AR, Gedalia A (1998). Low-dose methotrexate as a steroid-sparing agent in a child with Takayasu’s arteritis. Clin Exp Rheumatol 16: 335–336. Sinha I, Bethi S, Cronin P et al. (2006). A biologic basis for asymmetric growth in descending thoracic aortic aneurysms: a role for matrix metalloproteinase 9 and 2. J Vasc Surg 43: 342–348. Stoob K, Alkadhi H, Lachat M et al. (2004). Resolution of hoarseness after endovascular repair of thoracic aortic aneurysm: a case of Ortner’s syndrome. Ann Otol Rhinol Laryngol 113: 43–45. Svensson LG, Crawford ES, Hess KR et al. (1993). Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 17: 357–368. Taketani T, Miyata T, Morota T et al. (2005). Surgical treatment of atypical aortic coarctation complicating Takayasu’s arteritis – experience with 33 cases over 44 years. J Vasc Surg 41: 597–601. Tamarina NA, McMillan WD, Shively VP et al. (1997). Expression of matrix metalloproteinases and their inhibitors in aneurysms and normal aorta. Surgery 122: 264–271. Thompson M, Ivaz S, Cheshire N et al. (2007). Early results of endovascular treatment of the thoracic aorta using the Valiant endograft. Cardiovasc Intervent Radiol 30: 1130–1138. Tsutsumi K, Nagata K, Terashi H et al. (1998). A case of aortic coarctation presenting with Brown–Sequard syndrome due to radicular artery aneurysm. Rinsho Shinkeigaku 38: 625–630. van Zeggeren L, Waasdorp EJ, van de Worp BH et al. (2011). Painless transient paraparesis as the solitary manifestation of aortic dissection. J Vasc Surg 54: 1481–1484. Weyand CM, Fulbright JW, Hunder GG et al. (2000). Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 43: 1041–1048. Wilberger JE Jr (1983). Lumbosacral radiculopathy secondary to abdominal aortic aneurysms. Report of three cases. J Neurosurg 58: 965–967. Wolinsky H (1970). Comparison of medial growth of human thoracic and abdominal aortas. Circ Res 27: 531–538. Wolinsky H, Glagov S (1969). Comparison of abdominal and thoracic aortic medial structure in mammals. Deviation of man from the usual pattern. Circ Res 25: 677–686. Yamada N, Okita Y, Minatoya K et al. (2000). Preoperative demonstration of the Adamkiewicz artery by magnetic resonance angiography in patients with descending or thoracoabdominal aortic aneurysms. Eur J Cardiothorac Surg 18: 104–111. Zehr KJ, Mathur A, Orszulak TA et al. (2005). Surgical treatment of ascending aortic aneurysms in patients with giant cell aortitis. Ann Thorac Surg 79: 1512–1517. Zhao SH, Logan L, Schraedley P et al. (2009). Assessment of the anterior spinal artery and the artery of Adamkiewicz using multi-detector CT angiography. Chin Med J (Engl) 122: 145–149. Zull DN, Cydulka R (1988). Acute paraplegia: a presenting manifestation of aortic dissection. Am J Med 84: 765–770.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 17

Breathing and the nervous system MIAN ZAIN URFY AND JOSE I. SUAREZ* Department of Neurology, Baylor College of Medicine, Houston, TX, USA

INTRODUCTION Breathing is a complex phenomenon requiring the complex interaction of the central and peripheral nervous systems, mechanical and chemical receptors, and respiratory system. The Roman physician Galen (AD 131–201) was the first to note that gladiators injured below the neck continued to breathe, whereas those with injuries above the neck did not (Benditt, 2006). No major further advances took place until almost 2000 years later, when John Mayow, an English physiologist, in 1668, described the lungs with air-filled cavity driven by negative inspiratory force. Subsequently, in the 1800s, Hering and Breuer discovered mechanoreceptors for reflex control of inspiration and expiration. Later on, the discovery of oxygen (O2) and carbon dioxide (CO2), coupled with the works of John Scott Haldane and Joseph Priestley, elucidated their chemical control of breathing by central and peripheral receptors (Haymaker, 1953). It is now evident that the nervous system plays a major role in the control of volitional and involuntary breathing and that various disease states such as stroke, multiple sclerosis, and tumors can result in various respiratory abnormalities. Although it is still incompletely understood, research continues to add to our knowledge regarding the anatomy and physiology of central respiratory control. In this chapter we will present an overview of the underlying anatomic and physiologic principles of breathing and ventilation control as it is currently understood. We will also delve into some of the pathophysiologic mechanisms of abnormal breathing in neurologic disorders.

NEUROANATOMY OF RESPIRATORY CONTROL

postulated that apart from involuntary subcortical control, there exist extensive cortical neural networks to exert voluntary control of breathing. Previous studies using electrical stimulation, mainly in cats, dogs, and monkeys, showed widespread cortical involvement in voluntary control (Bianchi et al., 1995). Recent advances in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have further provided evidence for this postulate. Breathing has been shown to activate widespread bilateral cortical regions involving, but not limited to, the superior motor cortex, the supplementary motor cortex, and the premotor cortex. The extent of bilateral cortical representation remains debatable. Whereas previous transcranial magnetic stimulation and electrical stimulation showed bilateral involvement, fMRI and PET studies conducted recently showed lateralization towards the left hemisphere (Fink et al., 1996; Evans et al., 1999). Apart from motor cortices, there was also activation of the inferolateral sensorimotor cortex. It should be noted that transection of suprapontine respiratory circuitry does not abolish respiratory rhythm; however, it seems to be important in regulating it under various physiologic conditions including hypoxia, exercise, sleep, and arousal (Honda and Tani, 1999). Cortex has extensive connections with caudal hypothalamus as well as basal ganglia. It mainly appears to decrease rate and increase depth of ventilation, as is evident from studies on cat (Horn and Waldrop, 1994). The exact mechanism remains unknown. Further in-depth investigation using breath-to-breath analysis employing physiologic methods would shed more light on our understanding of the volitional control of breathing.

Cortical control of breathing

Subcortical and brainstem control of breathing

Breathing centers in the brain are now believed to be present in the cortex (voluntary) and the brainstem (involuntary) (Bolton et al., 2004) (see Fig. 17.1). It has long been

The brainstem respiratory network consists of three groups of nuclei present in the pons and the medulla: (1) the pontine respiratory group (pneumotaxic center);

*Correspondence to: Jose I. Suarez, M.D., Professor of Neurology, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, NB:320, Houston, TX 77030, USA. Tel: þ1-713-798-8472, Fax: þ1-713-798-3091, E-mail: [email protected]

CEREBRAL CORTEX C

BASAL GANGLIA, HYPOTHALAMUS

O

P

R

A

T

T

I

H

C

W

A

A

SUB CORTICAL L

C O R T I C

Y

O

S

S P I N A L

BRAIN STEM RESPIRATORY NUCLEI (PNUMOTAXIC CENTER, DRG, VRG)

T

RETICULOSPINAL

R A

T

C

R

T

A C T

PETROSAL GANGLION

ANTERIOR HORN CELLS (SPINAL CORD)

NODOSE GANGLION

CN IX

CN

CN

X

V, VII,

CB

AB

IX, X, X1

PERIPHERAL CHEMORECEPTORS

UPPER AIRWAY RECEPTORS NASAL (SNEEZE, DIVING REFLEX) EPIPHARYNGEAL (ASPIRATION REFLEX)

I N T E R C O S T A L

P H R E N I C

N E R V E

N E R V E S

LUNGS

C2 T1-11 C5

PHARYNGEAL (SWALLOWING) LARYNGEAL (COUGH, APNEA)

CN X

C-FIBER ENDINGS, HERING-BREUER INFLATION, DEFLATION REFLEX

Fig. 17.1. Respiratory feedback loop involving cortical (volitional) and subcortical (automatic) connections. Corticospinal tract carries input from cortex, whereas reticulospinal tract (RST) carries input from brainstem nuclei to anterior horn cells in spinal cord. Brainstem nuclei include pneumotaxic center, dorsal respiratory group (DRG), and ventral respiratory group (VRG). Feedback from lungs stretch receptors (Hering–Breuer reflex) as well neural receptors is conveyed through vagal nerve to brainstem. Upper airway receptors as shown also provide extensive input from cranial nerves V, VII, IX, X, XI, and XII. Peripheral chemoreception involves carotid (CB) and aortic bodies (AB), and carries signal through IX and X nerves respectively to nucleus tractus solitarius through relay ganglions. Central chemoreception is mainly serum CO2- and pH-dependent located in brainstem respiratory group of nuclei.

BREATHING AND THE NERVOUS SYSTEM (2) the dorsal respiratory group (DRG); and, (3) the ventral respiratory group (VRG) (Feldman, 1986; Bianchi et al., 1995; Duffin et al., 1995; Blessing, 1997) (see Fig. 17.1). The pontine respiratory group is located in the dorsal lateral pons and contains both inspiratory and expiratory neurons. It includes the nucleus parabranchialis medialis and the K€ olliker-Fuse nucleus. It appears to exert fine modulation of respiration and experimental lesions of this center prolong inspiration (Richter and Spyer, 2001). However, the pontine respiratory group does not seem to be necessary for basic respiratory rhythm generation (McCrimmon et al., 2000). The two groups of neurons present in the medulla, DRG and VRG, are essential for basic respiration generation. DRG is anatomically located in the ventrolateral subnucleus of the nucleus of the tractus solitarius (NTS) and contains inspiratory neurons receiving input from the vagal nerves (Bianchi et al., 1995). VRG neurons are present in the ventrolateral medulla and contain the B€ otzinger and pre-B€ otzinger Complex of neurons necessary for respiratory rhythm generation. Experimental lesions of theses complexes have shown to abolish normal respiratory rhythm generation (McCrimmon et al., 2000; Del Negro et al., 2002; Doi and Ramirez, 2008). Nerve impulses from the cortex and the brainstem reach the spinal cord via the corticospinal and the reticulospinal tracts for voluntary and involuntary control, respectively (Benditt 2006; Bolton et al., 2004). These axons synapse onto anterior horn cells. It also is important to mention that there are extensive interactions between the autonomic cardiovascular and respiratory responses. These involve, but are not limited to, modulations from the NTS and the ventrolateral medulla. The NTS receives inputs from baroreceptors and other arterial receptors and is involved in the integration of both responses. Inhibition of central cardiovagal neurons during inspiration and excitation during expiration provides the basis for sinus arrhythmia (Spyer et al., 1994). The basal ganglia and caudal hypothalamus also play a role in control of respiration. The caudal hypothalamus has reciprocal connections with motor cortex as well as the periaqueductal area and ventrolateral medulla (Yeh et al., 1997; Eric and Tony, 1998). It provides excitatory input on brainstem respiratory centers as evidenced by studies using barbiturates and/or electrical stimulation of the hypothalamus (Keller, 1960; Dean and Boulant, 1989). Furthermore, investigators have found that sectioning of the brain rostral to the diencephalon increases ventilation, while a mid-collicular lesion has no effect on ventilation (Eric and Tony, 1998). Electrical stimulation of the basal ganglia elicits a locus-dependent response in animal models. For instance, in cats, stimulation of the external portion of the globus pallidus results in increased

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respiratory rate, whereas stimulation of the internal segment of the globus pallidus has the opposite effect. These effects were seen to be abolished after neurotoxic damage of the basal ganglia (Angya´n and Angya´n, 2001).

PHYSIOLOGIC CONTROL OF BREATHING AND RHYTHM GENERATION Rhythm generation The central nervous system controls breathing through its effects on lung volumes, and inspiration and expiration duration. Extensive in vivo and in vitro studies conducted in the last few decades have helped to establish the basic respiratory control as rhythm generation (Doi and Ramirez, 2008). It is now widely believed that there is a rhythm-generating group of neurons to maintain the basic control of breathing. They also seem to have cortical control of breathing but mainly act automatically. The B€otzinger and pre-B€otzinger groups of nuclei have been found to have pacemaker activity. It is generally believed that this pattern resulting in rhythm generation consists of three phases: inspiration, early expiration and late expiration, even though respiration is a twophase process consisting of inspiration and expiration (McCrimmon et al., 2000; Ramirez et al., 2002; Bolton et al., 2004). This pacemaker activity is in turn influenced by the sensory integration of chemical and mechanical feedback stemming from peripheral receptors. Several neurotransmitters, including GABA, glycine, GABA and neurokinin-1, appear to play a major role in modulating this response (Murakoshi et al., 1985).

Pacemaker neurons The B€otzinger and pre-B€otzinger neurons located in the VRG appear to generate pacemaker activity through burst neurons. The exact mechanism leading to this pacemaker activity and how these neurons are influenced via multiple stimuli is poorly understood. There is now increasing evidence that these pacemaker cells have differential properties and contain multiple different types of ionic channels (Smith et al., 1991; Nogues et al., 2002). Onimaru et al. (1997) have classified six different types of pacemaker cells in rats labeled as preinspiratory (Pre-1), three inspiratory (Insp I, II, III), and two expiratory neurons (Exp I, II), based on their postsynaptic potentials (see Fig. 17.2). These groups of neurons have different type of channels (calcium, chloride, and sodium) proven through differential pharmacologic blockade. They also appear to have differential response under varying concentrations of blood gases. For example, in experimental models using calciumsensitive fluorescent dye, these groups of neurons have shown periodic increases in intracellular calcium mediated

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Fig. 17.2. Classes of respiratory neurons in the brainstem–spinal cord preparation. (A) Preinspiratory (Pre-I) neurons are characterized by synaptic drive potentials and spike discharge which onset prior to and terminate after cessation of inspiratory spinal (C4) nerve discharge. Cl-mediated IPSPs during the inspiratory phase are a feature of most Pre-I neurons Aa, whereas inhibition is not observed in a subclass of these cells (Ab). Ac and Ad exemplify that the duration of the pre- or postinspiratory activity phase varies between individual cells. (B) Type-I inspiratory (Insp-I) neurons are characterized by spike discharge during C4 burst activity and by subthreshold (Ba) or spike-evoking EPSPs (Bb) within the peri-inspiratory period. Type-III Insp neurons are hyperpolarized by Cl-mediated IPSPs during the peri-inspiratory phase (Bd), whereas peri-inspiratory PSPs are not observed in type-II Insp cells (Bc). (C) Expiratory (Exp) neurons are hyperpolarized by Cl-mediated IPSPs either during the inspiratory (Exp-i, Ca) or the peri-inspiratory (Exp-p-i, Cb) phase. (Reproduced from Onimaru et al., 1997.)

by voltage-sensitive ion channels, as evidenced by regular increase in fluorescence (Onimaru et al., 1996). However, several groups of neurons continue to show burst activity even in the presence of pharmacologic and glutamate blockade (Smith et al., 1995). Further research using various intra- and intercellular physiologic methods is needed to classify this incompletely understood process.

NEUROCHEMICAL CONTROL OF BREATHING The control of breathing involves interaction of both chemical and neural receptors found in the peripheral and central nervous system as well as end organs. The neural receptors are found in upper airway, respiratory

BREATHING AND THE NERVOUS SYSTEM muscles, lungs, and pulmonary vessels (Bolton et al., 2004). These include muscle spindles, and pulmonary stretch receptors responding to changes in lung volumes and thoracic cavity pressure. There have been multiple different types of pulmonary sensory receptors identified including fast and slow adapting (stretch) receptors and C-fiber receptors (J receptors) (Widdicombe, 1982, 2001; Brouns et al., 2012). These receptors detect changes in lung tidal volumes. Slow adapting fibers seem to have a role in inflation reflex and terminate inspiration and prolong expiration (Schelegle, 2003). Fast adapting fibers regulate deflation reflex and mediate deep augmented breaths. C-fiber receptor (J receptors, previously known as juxtapulmonary receptors) stimulation causes reflex increase in breathing rate and is also important in the detection of dyspnea. This J receptor-mediated reflex initially causes apnea followed by rapid, shallow breathing, bradycardia, and hypotension mediated by the vagal nerve. In addition, J receptors also play a role in bronchoconstriction, laryngospasm, airway mucus secretion, and bronchial and nasal vasodilatation (Paintal, 1995; Sant’Ambrogio and Widdicombe, 2001; Widdicombe, 2001). The peripheral chemoreceptors include the carotid and aortic bodies and are primarily sites that respond to changes in PaO2 but they also modulate their activity to PaCO2 and pH changes (Honda and Tani, 1999). Neural firings of these receptors are increased in response to PaO2 decrement and increase in PaCO2 concentration with subsequent decrease in pH. There is evidence to suggest that aortic bodies respond more in infancy whereas carotid bodies respond more in adulthood (Daly and Ungar, 1966; Lahiri et al., 1981; Horn and Waldrop 1994). Impulses through these are carried to the central nervous system respiratory modulators as described in sections of neuroanatomy via cranial nerves IX and X. Carotid bodies and their role in hypoxia-induced hyperventilation have been extensively studied (Gonzalez et al., 1995; Milsom and Burleson, 2007). They are composed of glomus cells (also known as type I) and sustentacular cells (type II). Carotid bodies release multiple neurotransmitters under hypoxic stimulation. Glomus cells are believed to be involved in afferent transduction. In animals, it has been shown experimentally that potassium-related channels contribute to neurotransmitter release and act as oxygen sensors (Prabhakar, 2006). Sustentacular cells act as glial cells. Hypoxic stimulus is then transferred to the brainstem through the vagal nerve. Aortic bodies are less well studied but there is experimental evidence that they respond to changes in oxygen saturation whereas carotid bodies seem to respond to changes in PO2 (Lahiri et al., 1981). These peripheral receptors also mediate exerciserelated ventilator drive and altitude acclimatization (Dempsey and Smith, 1994; Prabhakar et al., 2009). Receptors situated in the central nervous system are more important and crucial in maintaining body pH and

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acid–base balance. They are mostly responsive to CO2 and pH changes. These receptors are present in different areas including the following: the locus ceruleus, the NTS, the midline raphe and ventrolateral quadrant of the medulla (Bianchi et al., 1995; Honda and Tani, 1999; Nattie, 1999; Kara et al., 2003). Increases in CO2 or decreases in pH have been associated with increases in ventilator response by multiple mechanisms even though they are still incompletely understood. These may include increases in conductance of potassium as well as synaptic transmission via several neurotransmitters such as acetylcholine, and glutamate (Nattie, 1999). There is increasing evidence that central respiratory control of breathing is more widespread and may involve suprapontine structures in the hypothalamus, amygdala, and cerebral cortex. Recent fMRI studies have shown that arcuate nucleus firing increases in response to hypercapnia in cats (Honda and Tani, 1999). In addition, it has also been shown that infants who die of sudden infant death syndrome may have depletion of muscarinic receptors in the arcuate nucleus (Kinney, 2009). Studies using PET and fMRI have shown activation of premotor, primary motor, and supplementary motor cortex areas during increased respiratory drive (Horn and Waldrop, 1994). Future studies using physiologic approaches such as PET and fMRI are expected to shed further light on nervous control of breathing.

NEUROLOGIC CONDITIONS AFFECTING BREATHING Various central and peripheral neurologic disorders have been important in elaborating our understanding of breathing. Lesions affecting cerebral cortex, pathways and tracts, nuclei in the hypothalamus, the brainstem, and the spinal cord can lead to various breathing-related issues. Peripheral nervous disorders affecting pre- and postsynaptic receptors and neurotransmitters can also lead to a variety of abnormal breathing patterns (Nogues et al., 2002; Benditt, 2006). Below are some specific examples further elaborating the importance of nervous control and its interaction with the respiratory system at various anatomic levels (Table 17.1).

Diseases affecting the hemispheric cortex, subcortical structures, and brainstem Neurologic insults causing disruption of the pathways from cerebral cortex, corticospinal tracts, or volitional respiratory centers can lead to loss of voluntary control of breathing. These disorders can include ischemic and hemorrhagic strokes, central pontine myelinolysis, head injury, neurodegenerative conditions, and head injury, to name but a few. It is believed that at the brainstem level, the reticulospinal tract conducts information for voluntary control. One particular state where it can be affected

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Table 17.1 Diseases of the central and peripheral nervous systems associated with abnormal breathing Central nervous system diseases associated with abnormal respiration Cerebral cortex Stroke Tumor Dementia Prion disease Epilepsy Infections

Peripheral nervous system conditions associated with abnormal respiration

Brainstem

Basal ganglia

Spinal cord

Motor nerves

Neuromuscular junction

Stroke Neoplasm Multiple system atrophy Encephalitis Multiple sclerosis Central alveolar hypoventilation Infections

Parkinson’s disease Huntington’s chorea Heavy metal poisoning Carbon monooxide poisoning Fahr’s disease

Trauma Demyelinating conditions (multiple sclerosis, Devic’s disease) Syringomyelia Tumor Motor neuron disease Infections

Motor neuron disease Guillian–Barre´ syndrome Diphtheria Critical illness neuropathy Diabetes Acute intermittent porphyria Uremia Iatrogenic Trauma

Myasthenia gravis Lambert-Easton myasthenic syndrome Botulism Neuromuscular blockers Acetylcholinesterase inhibitors Snake venom Shellfish poisoning Scorpion poison

includes the so-called “locked-in syndrome,” where volitional control of breathing is lost and there is complete paralysis except for horizontal or vertical eye muscles due to lesions involving the basis pontis. Diseases affecting the involuntary control of breathing appear more common and can again be affected by all processes resulting in poor volitional control. They may include unilateral or bilateral medullary infarcts, demyelinating conditions such as multiple sclerosis, or even genetic disorders such as central alveolar hypoventilation. One well-known condition is so-called Ondine’s curse, which results from damage to respiratory centers in brainstem. In this disorder, patients do not have symptoms as long as they are awake, but they develop central sleep apnea as soon as they go to sleep from lack of voluntary control of breathing (Moss, 2005). Different breathing patterns have been described associated with various neurologic conditions. Breathing patterns related to coma have been well described in the literature and correlate with nervous system injury at various anatomic levels (Fig. 17.3). Almost all the neurodegenerative diseases at some stage exhibit breathing abnormalities. These include Parkinson’s disease, multiple system atrophy, Huntington’s chorea, and Lewy body dementia among others (Chokroverty et al., 1978; Hardie et al., 1986). Breathing difficulties may represent early features of some of these conditions and can alert a vigilant physician. These patients usually present with sleep-disordered breathing (SDB) (Gaig and Iranzo, 2012). Cell loss of the brainstem nuclei that modulate respiration, and dysfunction of

pharyngeal, laryngeal, and diaphragmatic muscles can increase the risk for SDB in neurodegenerative disorders. Below, we discuss a few commonly encountered neurodegenerative disorders.

PARKINSON’S DISEASE Parkinson’s disease (PD) is a disorder which is characterized by bradykinesia, rigidity, resting tremor, and postural instability. Excessive daytime sleepiness, obstructive sleep apnea (OSA), and upper airway obstruction are more prevalent in PD patients than in the general population (Neu et al., 1967; Shill and Stacy, 2002). Upper airway obstruction is possibly related to chest wall rigidity and hypokinesia. Several factors have been thought to increase risk of OSA in PD patients, including age and central neurodegeneration of respiratory centers (Neu et al., 1967; Apps et al., 1985). Close monitoring of respiratory problems and addressing them can improve PD patients’ quality of life.

MULTISYSTEM ATROPHY Multisystem atrophy (MSA) is another neurodegenerative disorder, presenting as parkinsonism, cerebellar dysfunction, and dysautonomia. Respiratory difficulties can be the presenting feature in this disorder. It can include central and obstructive breathing problems during wakefulness and sleep. Involuntary gasping, irregular breathing, abnormal hypoxic and hypercapnic respiratory responses, respiratory failure and stridor have been observed during wakefulness (Munschauer

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Fig. 17.3. Abnormal breathing patterns encountered in patients with pathologic lesions (shaded areas) of the central nervous system. (A) Cheyne–Stokes breathing is seen in patients with metabolic encephalopathies and in those with lesions in the forebrain or diencephalon. (B) Central neurogenic hyperventilation is seen in patients with metabolic encephalopathy or upper brainstem tumors. (C) Apneustic breathing is seen in patients with bilateral pontine lesions. (D) Cluster breathing is seen in patients with lesions affecting the pontomedullary junction. (E) Apnea is seen in patients with lesions affecting the VRG in the ventrolateral medulla bilaterally. (Reproduced from Saper, 2000, p. 902, with permission from McGraw-Hill.)

et al., 1990; Sadaoka et al., 1996). While asleep, patients may complain of OSA, central sleep apnea, apneustic breathing, or Cheyne–Stokes breathing as well as nocturnal stridor. In some studies, these abnormalities have been attributed to degeneration of ventral arcuate nucleus and pre-B€ otzinger Complex (Benarroch et al., 2001, 2007). Aggressive management of these respiratory abnormalities can not only improve quality of life but can also be life-saving. For instance, continuous positive airway pressure (CPAP) can be instituted for OSA and tracheostomies for stridor.

ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is the most common cause of dementia. OSA is encountered with increasing frequency in AD patients. The frequency and prevalence of nocturnal breathing abnormalities has been estimated to be high, ranging from 40–70% in AD patients (Vitiello and Borson, 2001). OSA is also thought to further contribute to cognitive decline in AD along with exacerbations of behavioral abnormalities (Bliwise, 1996). Elimination of OSA by CPAP devices has been reported to result in significant and sustained improvement in cognitive functioning and remains an important research area (Ancoli-Israel et al., 2008; Cooke et al., 2009).

AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder resulting from degeneration of neurons located in the cortex, brainstem nuclei, and ventral horn of the spinal cord. Nocturnal alveolar hypoventilation, central sleep apnea, OSA and mild periodic oxygen desaturation appear to be more prevalent in ALS patients (Labanowski et al., 1996). Loss of motor neurons in the central nervous system leads to upper and lower respiratory tract muscular weakness and predisposes to respiratory failure and infections. Ventilatory failure is the most common cause of death in ALS, and deterioration in pulmonary function predicts mortality (Fallat et al., 1979). Early detection of respiratory dysfunction and noninvasive ventilation (BIPAP) prolongs survival and quality of life (Aboussouan et al., 1997; Bourke et al., 2003, 2006).

Diseases of the spinal cord Spinal cord injuries can invariably affect breathing and result in devastating complications for the patient. It is important to emphasize that the level of spinal cord injury determines the severity of breathing complications. For those patients with lesions affecting C3

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ventilator support is always required, as the diaphragm, which contributes to 70% of inspiration, takes its nerve supply from C3–C5 (Howard et al., 1998). Various disease processes can result in cord injuries, with trauma being the major one. However, demyelinating lesions (multiple sclerosis, Devic’s disease), tumors, and vascular anomalies can also result in damage to the spinal cord. Patients with injuries below C5 may not require mechanical ventilation, whereas those with lesions between C3 and C5 can require various levels of ventilatory support.

Neuromuscular junction disorders and nerves Various motor nerve disorders and pathologies affecting the neuromuscular junction can result in breathing abnormalities. They can include Guillain–Barre´ syndrome (GBS), myasthenia gravis, botulism, neoplastic and paraneoplastic conditions (Polkey et al., 1999; Benditt, 2006). For example, GBS results in demyelination of nerves innervating respiratory muscles, resulting in ineffective saltatory conduction and decreased muscle strength. Myasthenia gravis mostly results from antibody-mediated autoimmune damage of postsynaptic acetylcholine receptors resulting in loss muscle excitation. This again results in muscle weakness. Phrenic nerve dysfunctions are also seen after surgical manipulation following open thoracotomies and open heart surgeries, resulting in paralysis or weakness of diaphragm. It therefore, can lead to profound respiratory muscle weakness and failure to wean from ventilator.

CLINICAL MANIFESTATIONS OF CENTRAL AND PERIPHERAL NERVOUS SYSTEM CONDITIONS Clinical manifestations of central and peripheral nervous system diseases vary considerably depending on the anatomic location and primary disease process. Affected individuals present with signs of upper motor neuron dysfunction (spasticity, hyperreflexia) for injuries above the anterior horn cells in spinal cord. These conditions may be accompanied by sudden onset weakness (stroke), gradual onset weakness (tumors), behavioral changes and tremors (neurodegenerative conditions). Demyelinating lesions usually present with fluctuating and periodic symptoms and are more common in young females. Whereas conditions below or at anterior horn cells (e.g., polio, GBS) may present with lower motor dysfunction (flaccid paralysis, hyporeflexia), neuromuscular junction disorders present with fluctuating weakness which may be exacerbated or improve with physical activity (myasthenia gravis and Lambert–Eaton syndrome, respectively). These patients may also have signs of involvement of other muscular

groups, e.g., diplopia, leg, or arm weakness (Bolton et al., 2004).

Neurogenic pulmonary edema Neurogenic pulmonary edema (NPE) is a life-threatening complication resulting from severe central nervous system injury. It is characterized by pulmonary vascular congestion causing perivascular edema, intra- and extra-alveolar accumulation of protein-rich edema and intra-alveolar hemorrhage (Brambrink and Dick, 1997; Baumann et al., 2007). It has been attributed to multiple factors but the exact mechanism remains uncertain. It is seen in a variety of neurologic insults including head injury, subarachnoid hemorrhage, status epilepticus, intracerebral hemorrhage, and intracranial tumors, as well as postoperatively. It is more common after cerebral hemorrhage than other neurologic insults (Colice et al., 1984). Two different mechanisms have been believed to contribute to the pathophysiology behind NPE: (1) a sudden increase in intracranial pressure (ICP) and (2) localized ischemic insult to brain trigger zones (vasomotor centers, pulmonary input and output locations, including medulla oblongata, area postrema, caudal medulla, NTS). A sudden increase in sympathetic surge leading to a dramatic increase in a-adrenergic catecholaminergic surge most probably leads to NPE. A diagnosis of NPE should be suspected in any head injury patient who suddenly develops dyspnea. Early and appropriate treatment of the underlying neurologic injury is the fundamental treatment along with standard respiratory support depending on clinical severity. Mortality associated with NPE is high, but recovery can be rapid and full if it is detected early and managed appropriately. NPE in brain death patients is the leading cause of lack of pulmonary grafts and transplantation failure (Trulock, 1997).

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 18

Obstructive sleep apnea and other sleep-related syndromes 1 2

TERESA PAIVA1* AND HRAYR ATTARIAN2 Sleep Medicine Centre, Medical Faculty of Lisbon, Lisbon, Portugal

Circadian Rhythms and Sleep Research Laboratory, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

The International Classification of Sleep Disorders (ICSD2) (AASM, 2005a) divides the sleep-related breathing disorders into three groups: central apnea syndromes, obstructive syndromes, and hypoventilation syndromes. Due to their high prevalence and clinical repercussions, obstructive syndromes are presented here first.

OBSTRUCTIVE SLEEPAPNEA Definition Obstructive sleep apnea is a sleep-related breathing disorder associated with an obstruction in the upper airway that results in an increased breathing effort and inadequate ventilation. The clinical and neurophysiologic expression differs in adults and in children (ICSD2) (AASM, 2005a) and therefore they must be considered separately. Obstructive sleep apnea (OSA) in the adult is characterized by repeated episodes of cessation of breathing (apnea) or partial upper airway obstruction (hypopnea); each episode, whether apnea or hypopnea, should last at least 10 seconds. These events are often associated with reduced blood oxygen saturation. Snoring and sleep disruption are typical and common. Excessive daytime sleepiness or insomnia can result, with the first being more frequent in general and the second being more frequent in females. Five or more respiratory events (apneas, hypopneas, or respiratory effort-related arousals) per hour of sleep are required for diagnosis. Increased respiratory effort occurs during the respiratory event. Upper airway resistance syndrome has been recognized as a manifestation of obstructive sleep apnea syndrome.

Obstructive sleep apnea in children is characterized by features similar to those seen in the adult, but cortical arousals may occur, possibly because of a higher arousal threshold. At least one obstructive event, of at least two respiratory cycles duration, per hour of sleep is required for diagnosis. Hyperactivity or attention deficit manifestations are more common in children. These criteria are applied up to 18 years of age, although some authors consider that after 13 years the adult criteria can be applied; in fact, many neurophysiologic markers of maturation normalize by that age (Grigg-Damberger et al., 2007). The relation between sleep and obstructive sleep apnea syndrome (OSAS) is bidirectional. Sleep interferes with respiration and in susceptible individuals produces obstructive sleep apnea (OSA). Subsequently OSA causes organic diseases which themselves interfere with sleep. OSA interferes with sleep directly, inducing sleep fragmentation and reducing the core sleep stages (slow wave sleep and REM sleep). Indirect interference also occurs due to provocation of events that disturb sleep, such as nocturia, agitation, etc.

Control of breathing during sleep Breathing has a complex regulation, which is influenced by wakefulness and by sleep. It involves mainly the central and autonomic nervous systems, the respiratory muscles, the anatomy of the chest and the upper airways, hormones, and chemical mechanisms related to the blood gases. Respiration is generated in the caudal brainstem by various respiratory neural groups: the dorsal respiratory group, ventral respiratory group and B€otzinger Complex, ventral medullary surface and pontine respiratory group.

*Correspondenc to: Teresa Paiva, Associate Professor of Neurology, Medical Faculty of Lisbon, IMM, CENC – Sleep Medicine Centre, R. Conde Antas, 5, Lisbon, 1070-068, Portugal. Tel: þ351-96-801-1648, Fax: þ351-21-371-5459, E-mail: [email protected]

252 T. PAIVA AND H. ATTARIAN In sleep, two respiratory parameters, the respiratory In addition to the increased pharyngeal collapsibility, frequency and the ventilatory drive, change depending sleep interferes with respiration by reduction of the lung on the sleep stage. They are influenced by the central nervolume in lying positions, especially in obese people, vous system, the autonomic nervous system, hormonal reduced breathing response to CO2 during sleep, and respiratory variability depending on the sleep stage. regulation, and the peripheral structures involved in respiration. In general there is a decrease in the medullary activity in non-REM (NREM) sleep. In REM sleep Pathophysiology of obstructive apneas respiratory neural activity is very variable. There is good Whenever an obstructive sleep apnea occurs there are correspondence between the activity in ventral respiratory group neurons and irregular respiration during direct consequences both during the pharyngeal obstrucREM sleep. In addition to these neuronal changes, tion and at the end of the apnea event. Concomitant with the processing thresholds for afferent stimuli in the the apnea O2 desaturation can be observed, with possible respiratory centre typically change during sleep. hypoxemia and hypercapnia, intrathoracic pressure flucIn brief, during sleep there are marked changes in tuations, recorded by esophageal manometry, which lead breathing regulation due to the different controls in the to strong variations in the blood volume offered to the right and left heart, bradycardia, and persistence of several sleep stages, namely reduced ventilation, reduced respiratory effort. functional residual capacity (FRC), reduced activity in the intercostal muscles during REM sleep with a tendency to At the end of the apneic event changes in the blood paradoxical breathing and hypotonic airway tract muscles gases cause microarousals and/or sleep stage changes during REM. These changes have consequences with which stabilize the muscle tone in the upper airway by regards to blood gas concentrations, namely increased an activation chain aiming to stop the apnea; a gross PaCO2, reduced PaO2, and reduced SatO2. body movement is often present, together with a sympaDuring inspiration the upper airway is mechanically thetic activation, with tachycardia and transient blood relocated by a collapse of the pharyngeal muscles. pressure increase. With a loud snoring noise the airflow During sleep the upper airway resistance doubles with resumes and oxygen saturation returns to normal values. the onset of NREM sleep due to the phasic effect of The patient’s sleep structure pays a price for these reduced muscle tone, reduced tonic activity related to successive bouts of airflow arrest and restoration: sleep sleep onset, and reduction in the FRC. will be fragmented; the quantity of deep sleep and of The oropharynx is the collapsible part of the extraREM sleep will be reduced. Often, however, the affected thoracic respiratory airways. Its mandatory resistance individual does not perceive the transient arousals or against the negative pressure (pull) while breathing in, awakenings, being able to maintain sleep. inspiration, is based on the reinforcement of the pharynAirflow suspension occurs if the obstruction is geal muscles by increase of their muscle tone. The upper complete. This is called obstructive apnea. The obstrucairway patency is maintained if the transmural pressure tion can also be incomplete, known as hypopnea. is positive, that is, the endoluminal pressure exceeds the The breathing difficulty may not be accompanied by closing forces (mainly inspiratory subatmospheric obstructive apneas, but by snoring. This incomplete pressure and tissue pressure). obstruction can cause the same health risks as obstrucDuring sleep the regulation of the muscle tone changes. tive apneas. During inspiration, a dissociation of the muscle activity of If the snoring has no pathologic effects upon the the diaphragmatic respiration and pharyngeal musculablood gases, the sleep process or the cardiovascular ture may be produced. The activation of the pharyngeal system, it is called primary snoring. According to the muscles strongly decreases during sleep, increasing the ICSD definition it belongs to the group of normal varicollapsibility of the upper airways. The activation of the ants. However, histologic studies performed on segdiaphragm is, however, relatively unimpaired. ments have proved the existence of neurologic lesions The respiratory effort of the diaphragm (diaphragin patients with OSA. This is probably the reason for matic respiration) leads to a collapsing force on pharynthe abnormal sensory afferent input from the palatal geal structures during inspiration. The negative pressure mucosa during awake periods, which is independent of which then leads to the collapse is called the pharyngeal the sensory modality used for stimulation. critical pressure (Pcrit) due to its critical obstructive OSA patients have been proven to suffer a decreased pressure. The Pcrit is individually different, depending inspiratory occlusion response. It is now considered that on bodyweight and unfavorable anatomic conditions these neural-histologic alterations in combination with in the pharynx. The Pcrit can also vary intraindividually, the signs of inflammation of the upper airway tissue i.e., depending on body position, sleep stage, or conare due to polyneuropathy caused by the vibration of sumption of alcohol. chronic snoring.

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES

Prevalence The prevalence of the full picture of OSAS is 2–4% in males and 1–2% in females (Young et al., 2002; Al Lawati et al., 2009); these figures from population studies have been found in the USA (Young et al., 1993), Spain (Dura´n et al., 2001), Hong Kong (Ip et al., 2001), and Israel (Lavie, 1983). Some reports indicate a higher prevalence of snoring and sleep-disordered breathing in African Americans and Hispanics when compared to a Caucasian control group and matched for age and BMI (Ancoli-Israel et al., 1995; Redline et al., 1997). What appears more striking is the fact that China and India also report about a 4% prevalence of OSAS in males, although in these countries the average obesity-related factors (BMI, neck circumference, waist/hip ratio) are lower. This implies other causes, especially craniofacial particularities, as a possible reason for the high OSAS prevalence in Asia (Li et al., 1999; Lam et al., 2006). Recently, however, these figures have been challenged, with the finding of very high prevalence rates in the region of Sao Paulo, Brazil, when the community questionnaires were confirmed by laboratory polysomnography (PSG) (Tufik et al., 2010); the prevalence was 32.8%, with, as in other studies, an increased prevalence in males, obese subjects, in the elderly, and in low social class females. Furthermore the prevalence increases in certain populations. It is around 30% in hypertensive patients and it can reach 80% in drug-resistant hypertension (Logan et al., 2001).

Genetics The heritability of OSAS is around 30%. The Cleveland Family Study showed an increased risk of OSAS in first-degree relatives of patients and the susceptibility further increased with the number of affected family numbers (Redline et al., 1995). Obesity only explains 40% of the variability, and craniofacial morphology, together with soft tissue characteristics, has an important role in genetic transmission of OSAS (Schwab et al., 2006). Genetic studies elucidating the relevance of the genome and single nucleotide polymorphism (SNP) effects are just beginning. In Caucasians and African Americans a whole genome search showed a linkage of the apnea–hypopnea index (AHI) to chromosome 2p and 19p or 8q respectively, after adjustment for BMI (Palmer et al., 2004). However, obesity remains a major confounding factor and definitive conclusions are still to be established (Casale et al., 2009).

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Pathophysiology of the obstructive sleep apnea syndrome Besides association with hereditability and obesity, OSAS has been significantly linked to insulin resistance and some inflammatory markers. In a cohort of male patients, significant increases of insulin resistance, leptin levels, and C-reactive protein (CRP) were associated with OSAS severity; the waistto-hip ratio was the most significant determinant of insulin resistance; the percentage of total sleep time (TST) with hypoxemia was the best predictor of leptin levels (Kapsimalis et al., 2008). However, among the inflammatory markers usually considered in cardiovascular risk, tumor necrosis factor-a (TNFa), IL6, IL8, and CRP, only TNFa is significantly associated with OSAS, since the others give results which might be confounded by obesity (Ryan et al., 2009). Nitric oxide (NO) changes have also been evaluated as another putative indicator of upper airway inflammation; however, in a controlled study, no differences between OSAS and controls were found in the exhaled NO (Dias et al., 2008).

Clinical presentation Many patients have a longstanding history of snoring which has recently become worse and is, at the time of the medical consultation, associated with excessive daytime sleepiness. There is, in fact, a trend across the lifespan which starts with intermittent snoring; this becomes continuous and is often unbearable to the bed partner, and later is interrupted by silent pauses announcing respiratory arrests. Other patients consider themselves in perfect health, even enjoying their ability to fall asleep, and only attending the medical consultation because of complaints concerning snoring from the husband or wife. The main symptoms reported are loud and irregular snoring, hypersomnia manifested in an inability to tolerate anything monotonous and excessive daytime sleepiness, observed apneas during sleep, dry mouth upon awakening, nocturia, lack of concentration, reduced performance, risk of accidents, unexplained hypertension, and morning headaches. Other possible symptoms are disturbed sleep, unusual movement during sleep, insomnia, enuresis, excessive dreaming, difficulties in maintaining sleep, choking or suffocation, impotence (in 50% of affected men), depression, and nocturnal sweats. Snoring is the main reason for consultation, usually prompted by the bed partner. Patients might have two erroneous notions relative to snoring: that it indicates a “sound sleep,” or that it is so common, since

254 T. PAIVA AND H. ATTARIAN “everybody snores,” that it is of no importance. Snoring Morning headaches are not specific of OSAS (Paiva, is initially intermittent and affected by body position, 2011). The prevalence of chronic morning headaches ceasing whenever the bed partner, via a small kick or (CMH) is 7.6% as determined in a European study push, induces a change in body position. It increases (Ohayon, 2004); CMH are more common in females whenever there is a party or any unusual alcohol drinkand in subjects between 45 and 64 years of age. In heading. Later it will become persistent, independent of body ache clinics, 12–41.7% of patients with severe morning position, and unbearable, inducing separation of beds or and nocturnal headaches have sleep apnea (Neau et al., even the bedroom itself, and becoming a point of friction 2002) and 53% of them had headaches associated with between the couple. Snoring induces bed partner a sleep disorder (Paiva et al., 1997), mainly periodic leg insomnia. movements (PLM), restless legs syndrome (RLS), or Excessive daytime sleepiness is another frequent sleep deprivation (Paiva, 2011). According to the complaint. Patients in the initial stages cannot bear ICHD-II (Olesen, 2005), the headache in sleep apnea is monotony, falling asleep while viewing uninteresting a specific entity; it implies the existence of recurrent TV programs, for instance; however, progressively, headaches, present upon awakening, with confirmed sleepiness will become more severe, causing marked apnea in polysomnography and clinical improvement difficulties in daily life since it will interfere with work, with efficient apnea treatment; furthermore the frepleasure, and performance capacity, which ultimately quency should be higher than 15 days per month, it will have life risks for the subject and others. The should have a pressing quality, without nausea, without increased risk of traffic accidents is among them. photo- or phonophobia, and each headache should In children, excessive sleepiness is socially accepted, a resolve within 30 minutes. factor that might delay diagnosis; furthermore sleepHabitual snoring is more frequent in chronic daily deprived children may have hyperactive behaviors. headaches (24%) than in controls (14%) (Scher et al., 2003). Witnessed apneas are also a common complaint; this Complaints of insomnia, fatigue, and headaches are is, however, unspecific since, especially in mild cases, more frequent in females and they tend to underreport it may reflect excessive attention from the bed compansnoring. Insomnia might be a further difficulty in continion, and furthermore during apneas the respiratory uous positive airway pressure (CPAP) treatment effort persists. adaptation. A dry mouth upon awakening or dried saliva result Sleep may be disturbed and restless, with this nocturfrom mouth breathing during sleep. Mouth breathing nal agitation causing difficulties for the bed companduring daytime is common in children with OSAS. ion’s sleep. Usually agitation is due to the body Nocturia is common and is often confused with prosmovements associated with the termination of the apnea tatic dysfunction. It is a direct result of the increase in event; there may be erratic movements of the arms, thoracic negative pressure, which, extending to the kicks, a rising up of the upper body, or sudden body abdominal cavity, compresses the bladder. Severe cases turns. Differential diagnosis with other causes of nocturoften go to the toilet four or five times, or more, during nal agitation is required. the night. This has a negative impact upon sleep continuExcessive dreaming is usually attributed to sleep ity and might have implications for home accident risk in fragmentation and the consequent ability to remember elderly patients. dreams due to the successive awakenings. The dreams Lack of concentration and reduced performance are usually have no particular character, but sometimes they discussed within the framework of neurocognitive might include situations associated with drowning or deficits of OSAS. suffocation. The risk of accidents is high. In 2000 there were Choking and suffocation are associated with sudden 800 000 drivers suffering from OSAS involved in traffic awakenings, with the feeling of imminent death, tachyaccidents in the US. The corresponding costs were US cardia, and sweating. They are not specific of OSAS, $15.9 billion and 1400 lives. Adequate treatment of these since they can occur in panic attacks and laryngospam. subjects would have cost US$3.18 billion and saved 980 Impotence, poor sexual function, and reduced libido lives (Sassani et al., 2004). In Spain, an AHI score > 10/h are frequent in OSAS. predicts traffic accidents (Masa Jimenez et al., 2003). In Depression might be a confounding symptom, mainly Turkey, in a clinical population of 316 truck drivers, in females; this is further explained below, in the section 29.7% had traffic accidents and 29.8% of those accidents on the neuropsychiatric consequences of OSAS. caused loss of life. Snoring, increased neck circumferNocturnal sweats are usually associated with nocturence, and years of driving were significantly higher in nal agitation; they can occur in adults but they are drivers who had accidents (Fidan et al., 2007). particularly important in children.

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES Furthermore, patients are often obese or carrying excess weight. Whenever the BMI is normal craniofacial abnormalities are common. Hypertension is also common.

Neuropsychiatric symptoms Neurologists tend to forget the important impact of OSAS upon the central nervous system; in fact it is associated with both cognitive problems and with depression. Neurobehavioral and neurocognitive impairments are commonly encountered in both adults and children with untreated OSAS. Clinical trials have clearly demonstrated an increased prevalence of memory and concentration problems, mood disturbances, and fatigue in OSAS patients, and have shown a significant relationship between these deficits and OSAS. What remains unclear, however, is whether the OSAS is directly responsible for these complications. This is primarily because of the multiple comorbidities that OSAS patients themselves contribute to neurologic deficits. Significant improvement with CPAP treatment strongly supports the role of OSAS as a causative factor in these deficits. Full resolution of severe deficits, though, does not usually happen, raising the question whether OSAS can lead to irreversible neurologic damage (Dempsey et al., 2010).

COGNITIVE PROBLEMS The first observations of neurocognitive and neurobehavioral problems in OSAS date from the early 1990s. In 2003, Beebe et al. published a meta-analysis of all the papers that had appeared up to then discussing the neurobehavioral and cognitive effects of OSAS. For statistical analysis they used the random and mixed-effects method (0.2 is indicative of a small effect, 0.5 a medium and 0.8 a large effect size) (Engleman et al., 2000; Beebe et al., 2003). They found that general intelligence (IQ) and verbal ability are unaffected by OSAS but vigilance is markedly affected (effect size of 1.40) and executive functioning is also substantially affected (effect size of 0.53–0.73) (Beebe et al., 2003). Furthermore they found a high variability in OSAS’s impact on visual and motor skills, varying from an effect size of < 0.15 to 1.2; this was primarily test dependant. The effect on short-term memory was also found to be inconsistent (Beebe et al., 2003). Neuropsychological testing has revealed primarily frontal cortex dysfunction and cognitive impairment more similar to mild Alzheimer’s than any other type of dementia (Salorio et al., 2002). Both a higher cognitive reserve (Alchanatis et al., 2005) and a younger age (Alchanatis et al., 2008) are associated with fewer

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deficits and better response to treatment with positive airway pressure (PAP). Concerning treatment, not all studies have shown a total recovery of cognitive impairment with PAP. Performance on driving simulators improves greatly but it is not completely normal even after 12 months of compliant treatment (George et al., 1997). Verbal and visual learning seem to normalize (Feuerstein et al., 1997), but despite significant improvement in attention and executive function, which occurs after a few weeks of use (Ferini-Strambi et al., 2003), cognitive function remains impaired to some degree and no further improvement is demonstrated with longer treatment (Ferini-Strambi et al., 2003). Impact on short-term memory is inconsistent (Naegele et al., 1998). More rigorous placebo controlled testing, however, has not shown any significant improvements with PAP treatment in any of the following measures: speed of information processing, attention and working memory, executive functions, alertness and sustained attention, verbal memory, visuospatial memory, and psychomotor performance (Bardwell et al., 2001; Henke et al., 2001; Lim et al., 2007).

DEPRESSION AND OBSTRUCTIVE SLEEP APNEA SYNDROME

The prevalence of depression is high in patients with OSAS. In the community at large it is about 17% versus a prevalence of 4.3% in subjects without OSAS (Ohayon, 2003). In sleep clinic populations, 21–41% of patients with OSAS have depression versus 9% in nonapneics (Sharafkhaneh et al., 2005). OSAS is not only considered a risk factor for depression but depressed patients with sleep-related breathing disorders tend to report more sleepiness and fatigue (Kjelsberg et al., 2005; Bardwell et al., 2007a), and subsequently lower quality of life (Akashiba et al., 2002) and higher disability (Akashiba et al., 2002; Bardwell et al., 2007a; Sivertsen et al., 2008). Treating the OSAS sometimes, but not always, reverses depression, and treatment of depressive symptoms may increase compliance with PAP treatment (Kjelsberg et al., 2005; Santamaria et al., 2007). The burden of a chronic medical condition such as OSAS could clearly lead to depression (Harris et al., 2009) but its exact pathophysiology remains unclear. Both hypoxemia (Bardwell et al., 2007b) and sleep fragmentation (Yue et al., 2003) seem to play a role although there are contradictory studies which support the role of one while refuting that of the other (Yue et al., 2003; Bardwell et al., 2007b). Another theory involves proinflammatory cytokines such as cytokines IL6 and tumor necrosis factor that

256 T. PAIVA AND H. ATTARIAN have been shown to be elevated both in OSAS (Vgontzas between epidemiologic studies (male:female ratio is et al., 1997, 2000a, 2004) and in major depression (Irwin 2–3: 1) and clinical populations (the ratio is 5–8:1) and Miller, 2007). The studies, however, do not suggest (Guilleminault et al., 1988; Young, 1993; Redline causality nor take into account obesity, also associated et al., 1994; Bixler et al., 2001; Dura´n et al., 2001); in with elevated cytokines, as a confounding variable addition, in clinical populations, the male prevalence (Vgontzas et al., 2000a). becomes extremely high for the more severe cases. Abnormal serotonin transmission could also explain There are several possible explanations for OSAS genthe relationship between the two conditions, as der differences: decreased neurotransmission is associated with both 1. The epidemiologic and the clinical studies evaluate depressive symptoms (Jans et al., 2007) and decreased different disorders or different aspects of the activity of the upper airway dilator muscles (Fenik and disorder. Veasey, 2003). 2. Women, despite seeking medical advice more often, tend to underreport unpleasant symptoms. IMAGING AND NEUROLOGIC DAMAGE IN OBSTRUCTIVE 3. OSAS is underdiagnosed in women because their SLEEP APNEA SYNDROME chief complaints, insomnia, fatigue, depression, and Studies utilizing MRIs of the brain have produced morning headache, lead to other diagnoses. conflicting results. Macey and colleagues not only dem4. Excessive daytime sleepiness is predictive of sleep onstrated gray matter loss in the cingulate gyrus and the apnea in males but not in females (Young et al., hippocampus of subjects with OSAS (Macey et al., 1996). 2002), but the degree of reduction correlated to the 5. The bed partner role, with wives more attentive than severity of OSAS (Morrell et al., 2003). Morrel and husbands, could also play a part in the discrepancy coworkers corroborated these findings (Morrell et al., (Jordan and McEvoy, 2003). 2003) but in a younger cohort, O’Donoghue et al. found 6. Female hormones are protective against apnea, and no difference between patients with severe OSAS and this would explain the increased prevalence after age-, sex- and medical condition-matched healthy menopause (Ware et al., 2000; Hachul et al., controls (O’Donoghue et al., 2005). MRI spectroscopy 2010); however, it is well known that hormonal treathas also shown gliosis and neuronal loss correlating with ment does not improve OSAS. AHI in both adults (Kamba et al., 2001) and children 7. Women have an advantageous craniofacial anat(Halbower et al., 2006) with cognitive dysfunction and omy with larger airways, which would protect them OSAS. from apneas in NREM sleep, but, since they have Positron emission tomography (PET) scans of the stronger atonia and greater respiratory instability brain have shown decreased metabolism in the temporal in REM, they would have more REM-related and frontal cortices of the brain in subjects with OSAS apneas. which does not appear to reverse after CPAP treatment 8. Apneas and hypopneas are shorter in females and (Antczak et al., 2007). Similarly single photon emission therefore they have less desaturation (Ware et al., tomography (SPECT) has shown decreased blood flow 2000); this is so in spite of the fact the hypoxic venin the parahippocampal gyri of OSAS subjects (Joo tilatory response and the respiratory effort et al., 2007). responses to hypercapnia are similar in both genders Lastly, functional MRI studies have correlated (Sin et al., 2000). neurocognitive deficits in severe OSAS to decreased 9. Mortality is, however, higher in women for activation in both the prefrontal and the parietal cortices, equivalent levels of OSAS severity (Young and the latter being more affected in subjects with hypoxFinn, 1998). emia (Thomas et al., 2005). 10. Obesity and fat distribution also play a role: Could this mean permanent damage from OSAS that women with equivalent AHI have higher body is not reversible with PAP treatment (Dempsey et al., mass index then men (Quintana-Gallego et al., 2010)? This may make a case for early detection and diag2004); the fat distribution is different: males have nosis since the mean duration from onset of symptoms to more visceral fat deposition and a central obesity diagnosis is approximately 60–87.5 months (Rahaghi and type. Increased visceral fat correlates with Basner, 1999; Greenberg-Dotan et al., 2007). increased insulin resistance, increased cortisol levels, and abnormal sex hormones in both genders Gender differences (reduced testosterone in males, reduced progesterSymptoms of OSAS differ between the genders one and increased testosterone in females) (Jordan and McEvoy, 2003). The prevalence differs (Bj€orntorp, 1991).

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES

Risks and predisposing factors for obstructive sleep apnea There are several factors which predispose to sleep apnea, namely male gender, ethnicity, increasing age, overweight, truncal obesity with increased abdominal fat, defined as a waist circumference  106 cm in men and 89 cm in women or a waist to hip ratio  1 in men and  0,85 in women, Pickwick morphotype, low soft palate (measured by the Mallampati scale), anatomic narrowing of the upper airway (e.g., short mandible with retrognathia, short cranial base, midface or mandible hypoplasia, macroglossia, hypertrophied tonsils, spacedemanding processes in the pharyngonasal cavity, lipopexia in the tongue base as well as in the cervical and pharyngeal muscles which is present in obesity), nasal obstruction, alcohol consumption, smoking, medication use, short sleep duration, and hereditary syndromes (Down, Pierre Robin, achondroplasia, Crouzon, Treacher Collins, Cornelia de Lange). As already discussed, OSAS prevalence increases with age; furthermore the AHI conventionally considered abnormal in elderly subjects should be higher than 15/h. Overweight and obesity are important contributors and risk factors. It has been shown that a 10% increase in bodyweight has a sixfold increase in apnea risk in the following 4 years, whereas a 10% decrease has 26% decrease in the AHI (Strobel and Rosen, 1996; Peppard et al., 2000). This has two important consequences: overweight and obesity are important risk factors and weight reduction is an important, but often not achieved, therapeutic objective. The Pickwickian morphotype can be associated with OSAS or with the hypoventilation obesity syndrome. The characteristics of the soft palate, namely the big dimensions of the uvula and tongue, the position of the pillars, the enlarged tonsils and adenoids, predispose to OSAS. Tonsil and adenoid enlargement are common in children. It must be noted that mouth-breathing children in fact have the same cephalometric characteristics as children with OSAS (Juliano et al., 2009), having therefore a higher risk of OSAS. The craniofacial anatomy is quite important in subjects with normal BMI; the so-called bird-like face, with retrognathia and a long nose with septal deviation, is very suggestive; however. many subjects have relatively normal facial characteristics with a long and oval face shape and slightly short mandible with backward chin placement; these subjects have a higher risk of upper airway resistance syndrome (Exar and Collop, 1999; Guilleminault and Los Reyes, 2011). Only 33% of the variance in the AHI is explained by cephalometric variables and BMI, since in the sleeping

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apneic patients the collapse of the pharynx commonly occurs at multiple sites (Zucconi et al., 1992; Morrison et al., 1993). Patients with any type of nasal obstruction and allergic seasonal rhinitis have a higher OSAS risk (Al Lawati et al., 2009). Congenital syndromes associated with maxillary hypoplasia and mandibular hypoplasia are significantly associated with OSAS; however, besides the abnormalities in the anatomic features and soft tissue enlargements, impaired neuromuscular control might be at stake (Lee-Chiong, 2008). Alcohol consumption, especially at dinner or during the evening, relaxes dilator muscles, increases upper airway resistance, and decreases respiratory reflexes, and so it increases snoring and sleep apnea duration in susceptible individuals. OSAS prevalence, however, is not increased in those who have been alcohol abusers (Al Lawati et al., 2009). Smoking increases OSAS risk, since current smokers have an odds ratio for OSAS of 4.44 when compared with those who have never smoked, with heavy smokers having the greatest risk (odds ratio of 6.47) (Wetter et al., 1994); current smokers are 2.5 times more likely to have OSAS than nonsmokers or those who have never smoked (Kashyap et al., 2001). Several medications provoke or aggravate OSAS; these include muscle relaxants, sedative hypnotics (benzodiazepines and barbiturates), narcotics, and opioid analgesics. Several mechanisms are in action here: the depression of the respiratory centers and reflexes decreases ventilator drive and increases apnea duration, while the associated respiratory muscle hypotonia tends to further intensify the problem (Lee-Chiong, 2008; Guilleminault et al., 2010). Short sleep duration has a metabolic and increased weight gain risk; therefore it is indirectly considered as a risk factor for OSAS (Al Lawati et al., 2009).

Diseases associated with obstructive sleep apnea syndrome, comorbidities Several sleep-related disorders are often associated with OSAS, such as periodic limb movement disorder (PLMD), restless legs syndrome (RLS), bruxism, and narcolepsy. The prevalence of PLMD in OSAS is around 14% (Iriarte et al., 2009; Monteiro et al., 2010). The association with narcolepsy is mainly due to the increased bodyweight currently observed in narcolepsy. The association with bruxism implies evaluation of the temporomandibular joint, the teeth and dental occlusion. Endocrine disorders. OSAS can appear symptomatically in acromegaly and hypothyroidism. Untreated hypothyroidism can precipitate or exacerbate OSAS;

258 T. PAIVA AND H. ATTARIAN several mechanisms might intervene: macroglossia, saturation seem to stimulate the inflammatory system myopathy, and impairment of ventilator control (Leeleading to endothelial alteration with an increased risk Chiong, 2008). OSAS prevalence in acromegaly is very for atherosclerosis. high, ranging from 75% to 93% of the cases (Grunstein The risk of sudden death due to cardiovascular events et al., 1991; Van Haute et al., 2008); several anatomic is clear in OSAS, death being significantly more frequent and neuroregulatory mechanisms are involved. in OSAS between midnight and 6 a.m. (Gami et al., 2005). Cardiovascular and pulmonary disorders. OSAS OSAS and stroke. The association between OSAS has also been found to be associated with arterial hyperand stroke has been well established. Throughout the tension, heart failure, pulmonary hypertension, cardiac past two decades there have been several case reports arrhythmias, and increased nocturnal death due to (Tikare et al., 1985), case series, and case control studies cardiovascular diseases. all demonstrating a higher prevalence (about 70%) and Arterial hypertension. The relation between arterial severity of OSAS (AHI of over 30/h) among stroke hypertension and OSAS is bidirectional: 40% of unpatients as compared to controls (Hudgel et al., 1993; treated OSAS patients have arterial hypertension and a Bassetti et al., 1996; Dyken et al., 1996). Symptoms of third of essential hypertensive patients (Silverberg and OSAS often precede the occurrence of stroke, suggestOksenberg, 2001) and 87% of refractory hypertension ing a causative relationship (Good et al., 1996). subjects have OSAS (Logan et al., 2001). These facts Large risk ratio studies have shown a strong association have led to specific guidelines in arterial hypertension between snoring and cerebral infarction with a risk ratio of evaluation: in hypertensive patients OSAS should be 10.3 (Partinen and Palomaki, 1985); whenever snoring is considered whenever it is drug-resistant or when there more frequent, the higher the risk of stroke. Snoring is also are witnessed apneas during sleep (Logan et al., 2001). an independent risk factor for cerebrovascular accidents Furthermore it is nowadays good clinical practice to mon(CVA) with a risk ratio of 3.16, especially in subjects having itor blood pressure over 24 hours in OSAS in order to their events during sleep or shortly after awakening evaluate arterial hypertension together with its circadian (Palomaki et al., 1989). This risk more than doubles if, in dipping pattern (Del Colle et al., 2005). In a number of addition to snoring, the subjects are obese and have daystudies therapy with positive pressure devices has been time sleepiness, and it becomes sevenfold higher if they found to reduce OSAS cardiovascular effects. also report witnessed apneas (Palomaki, 1991). Congestive heart failure (CHF). The prevalence of Even when subjects with mild OSA are included in the OSAS is increased in patients with moderate or severe analysis, the relative odds of prevalent stroke is 1.58 CHF. Furthermore CHF can be a result of OSAS: in fact, (Shahar et al., 2001) and the overall hazard ratio is one of the hallmarks of OSAS is the reduction (more 2.89 (Valham et al., 2008). When stratified for severity, negative) of intrathoracic pressure caused by the mild OSAS has 2.44 times the risk of stroke while modimpeded breathing during an OSA; this leads to acute erate or severe OSAS has 3.56 times the risk (Valham changes in pulmonary blood flow and pressure and et al., 2008). increased cardiac afterload. Sympathetic activation In 2005, Arzt and colleagues published one of the during OSAS is another putative mechanism. seminal papers on this topic. In a population of 1475 Pulmonary hypertension. Pulmonary hypertension subjects between 30 and 60 years of age, an AHI of and even cor pulmonale might be present. Two syn20 per hour or higher (determined by PSG) at baseline dromes often occur: the “overlap syndrome,” which was associated with a higher prevalence of stroke OR has both apnea and chronic obstructive pulmonary disof 3.83 after other confounding variables were conease, and the “obesity hypoventilation syndrome,” which trolled for. A subset of 1189 subjects was followed prointegrates OSAS and morbid obesity. spectively for 12 years and the presence of an AHI of 20 Cardiac arrhythmias. Sinus arrhythmia, bradycarper hour or more was associated with increased incidia, sinus pauses, premature ventricular contractions, dence of stroke in the subsequent 4, 8 ,and 12 years, with ventricular tachycardia, and atrioventricular block are an OR of 4.48. This was the first study to show two common. The mechanisms are due to the important important aspects: OSAS was prevalent among stroke impacts suffered by the heart at each obstructive apnea. patients and it also preceded stroke, and so, potentially, OSAS was found to increase morbidity and mortality. it was a risk factor (Arzt et al., 2005). In recent years several studies have investigated the augEven adjusting for age, sex, race, smoking, weight, mented risk of cardiovascular disease in these patients. hypertension, diabetes, atrial fibrillation, and hyperlipidThe sympathetic tone is elevated in OSAS patients due to emia, over a span of 6 years, OSAS is associated with the hypoxemia-induced chemoreflex response and the a significant risk of composite stroke, TIA, or death frequent arousals. Additionally, the dips in oxygen (hazard ratio (HR), 1.97; 95% CI, 1.12–3.48; p ¼ 0.01).

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES Furthermore, the more severe the OSAS, the higher is the risk for stroke, TIA, or death (Yaggi et al., 2005), with severe OSAS (AHI  30) having a HR of 2.52 (Munoz et al., 2006). Treatment does prevent cerebrovascular morbidity, the prevalence of stroke in untreated OSAS (on a weight loss regimen only) over 7 years being almost 4.5 (5.2%/ 1.2%) times that of treated patients (tracheostomized patients, since CPAP was not widely available at the time of these studies) (Partinen et al., 1988; Partinen and Guilleminault, 1990). Despite this robust data in favor of OSAS being a risk factor for stroke, the results are conflicting when one looks for OSAS as a specific risk factor for TIA. A small, 53 subject study showed a significantly higher risk for TIA in OSAS vs controls (Bassetti and Aldrich, 1999), but a similar but larger study with 86 subjects did not duplicate these results (McArdle et al., 2003). OSAS also worsens disability, morbidity, and mortality from stroke (Dyken and Im, 2009). In a number of small studies, hospital stay duration was longer and functional disability higher in the presence of OSAS (Kaneko et al., 2003) and so was mortality 5 and 10 years out (Hardie et al., 2005; Selic et al., 2005; Sahlin et al., 2008). Treatment with CPAP has been shown to reduce mortality (Hardie et al., 2005; Martinez-Garcia et al., 2009) but adherence to CPAP and compliance with it after stroke, although not impossible (Disler et al., 2002), has been fraught with problems (Strollo et al., 1998; Disler et al., 2002; Bassetti et al., 2006). There are no papers defining the exact pathophysiology of OSAS-induced stroke. The most likely reason is elevated sympathetic nerve activity (SNA) due to hypoxia, hypercarbia, and diminished activity of the thoracic stretch receptors (Somers et al., 1995; Dyken and Im, 2009). SNA can increase by up to 246% during a single 10 second apnea event. This also leads to persistent increase in mean blood pressure, especially in REM sleep where SNA is typically high and apneas worse (Somers et al., 1995). There is also a high prevalence of atrial fibrillation due to the same mechanism in OSAS (Gami et al., 2004). Atrial fibrillation in turn increases the risk of stroke (Lloyd-Jones et al., 2009). Worsening of OSAS in REM sleep and the related increased SNA, and increases in catecholamines (Fletcher et al., 1987), in addition to hemodynamic instability, potentiate the early morning hypercoagulable state (Geiser et al., 2002) (a state characterized by increased blood viscosity, low fibrinolytic activity, and high platelet aggregability) (Tofler et al., 1987). There is a link between elevated CD40 ligand and soluble P-selectin (two platelet activation proteins) and silent strokes as well as moderate to severe OSAS. Moreover the

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prevalence of silent strokes was 25% in moderate to severe OSAS subjects and only 6.7% in controls. CPAP therapy significantly reduces the levels of both CD40 ligand and soluble P-selectin (Minoguchi et al., 2007). Lastly, OSAS increases intracranial pressure and may reduce cerebral blood flow, hence further contributing to cerebral ischemia (Jennum and Borgesen, 1989; Klingelhofer et al., 1992). As well as the above, there are rare neurologic complications of OSAS, namely: Neuro-ophthalmologic problems. Nonarteritic optic neuropathy (NAON) has been reported in subjects with OSAS, and in fact the prevalence of OSAS in NAON is 71–89% (Mojon et al., 2002; Palombi et al., 2006) depending on the series. Recently a very small case series showed failure of improvement in NAON after successful OSAS treatment with CPAP (Behbehani et al., 2005). Another neuro-ophthalmologic problem is idiopathic intracranial hypertension (IIH) or pseudotumor cerebri (McNab, 2007). Several studies have shown the presence of papilledema and IIH in patients with OSAS, and CPAP treatment has been shown to reverse disc swelling (Lee et al., 2002). Peripheral neuropathy. Recurrent hypoxemia due to OSAS has been shown be associated with an axonal polyneuropathy (Mayer et al., 1999), with both ischemic and preischemic neuronal damage, and the severity of the former is associated with the severity of the latter (Ludemann et al., 2001). Treatment with CPAP partially reverses the neuropathic damage (Dziewas et al., 2007). Seizure disorder. Although there are no reports of OSAS causing seizures, it can exacerbate pre-existing epilepsy (Oliveira et al., 2000; Chihorek et al., 2007), and treatment with CPAP can improve seizure control (Malow et al., 2008). The association is particularly relevant in children with OSAS, in whom a prevalence of 16% of seizures/and or paroxysmal EEG activity has been described (Miano et al., 2010); this is higher than the prevalence observed in snoring children without OSAS (Miano et al., 2009). Cluster headache has a higher prevalence of sleep apnea (Kudrow et al., 1984; Chervin et al., 2000; Nath Zallek and Chervin, 2000; Paiva, 2011), which varies from 58.3% (Nobre et al., 2003) to 80.6% (GraffRadford and Newman, 2004); patients have 8.4 times more chance of sleep apnea than controls; the risk increases to 24.38 if the body mass index is higher than 25 kg/m2 and patients are male and older than their 40s (Nobre et al., 2003). CPAP treatment of sleep apnea in CH patients reduces CH severity (Nath Zallek and Chervin, 2000). Sleep-disordered breathing probably does not cause CH but may worsen CH attacks. Fibromyalgia may be associated with apnea (Sepici et al., 2007). The association is, however, complex since

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in females the chronic disordered breathing may lead to insomnia, fatigue, and pain, simulating the clinical presentation of fibromyalgia. Gastroesophageal reflux (GER) is also a cause and aggravating factor of OSAS, whereas OSAS due to the changes in abdominal/thoracic pressure increases reflux; but in spite of the relation recognized by some (Lee-Chiong, 2008), other authors deny this relationship (Kim et al., 2005). In fact the recumbent position aggravates both situations and it is common for OSAS patients to complain of heartburn sensations and a bitter taste in the mouth in the morning. GER is also important in children with OSAS, since in them it might contribute to increased psychological disturbance (Noronha et al., 2009). There are more respiratory arousals associated with GER events (Suzuki et al., 2010); furthermore the treatment of GER in mild to moderate OSAS improves the respiratory condition (Orr et al., 2009).

(respiratory effort), pulse oximetry, microphone, ECG, esophageal manometry (optional/standard), optional continuous blood pressure and optional end-tidal PCO2 or transcutaneous PCO2 measurement. Ambulatory recordings can be performed whenever they are requested by a physician expert in sleep medicine and the test is performed and evaluated by accredited specialists in sleep medicine (Collop et al., 2007); however, all patients with comorbidities should perform a standard in-laboratory PSG. In accordance to the findings in the patient’s history and the clinical examination, further investigation might include: evaluation of an anatomic upper airway alterations (cephalometry, CT scan), pulmonary disorders (body plethysmography, chest X-ray, blood gases, and pulmonary function), cardiac diseases (ECG, 24 hour ECG, echocardiography, cardiopulmonary function tests), specific hormonal disorders: hypothyroidism (TSH, FT3, FT4) and acromegaly (IGF1, glucose tolerance test).

Clinical observation

Estimating severity

From what has been said, several aspects are essential in the physical examination in OSAS:

The quantification of the obstructive sleep apnea results from the apnea/hypopnea index (AHI) and the respiratory disturbance index (RDI). Fewer than five apneas per hour of the total sleep time (IAH index < 5/h) is considered to be harmless. A third of all adults have an apnea index > 5/h. In most cases there is no need for treatment. According to the International Classification of Sleep Disorders (ICSD), an apnea index > 5/h with clinical daytime symptomatology constitutes an obstructive apnea syndrome. From 5 to 15 apneas/h the severity is considered mild; it is considered moderate when the AHI ranges from 15 to 30/h and severe in cases where the AHI is higher than 30/h.

1.

2.

3.

4. 5.

bodyweight: (i) measurement of BMI (kg/m2) (ii) waist: values above 102 cm for men and 88 cm for women increase cardiovascular risk, although the maximal values associated with no increased risk are 89 cm and 82 cm, respectively nose and nostrils: observation in order to look for asymmetries and bilateral nasal obstructions, septal deviation, nostril collapse during inspiration, all of them inducing increased nasal resistance upper airways: size and shape, looking for enlarged tonsils and/or adenoids, size of the uvula, tongue size, palate configuration evaluation of a low soft palate (Mallampati class III–IV) craniofacial and cephalometric characteristics, looking for the mandible, the teeth position (overbite, underbite, or superimposed teeth, etc.)

Based on a clear suspicion of sleep apnea, a diagnostic sleep study with polysomnography (PSG), according to standard recommendations should be carried out in the sleep laboratory (Collop et al., 2007). The polysomnographic parameters consist of EEG (at least three derivations), electro-oculogram (EOG), electromyogram (EMG) mentalis, EMG tibialis muscle, nasal and oral airflow (thermistor and nasal cannula for nasal flow and pressure), thoracic and abdominal respiratory signals measured by plethysmography

Assessment of sleepiness in obstructive sleep apnea syndrome Since sleepiness is very frequent, it should be evaluated in all suspected cases, in principle by questionnaires, and in specific cases by neurophysiologic tests. Available questionnaires are: 1. 2.

Stanford Sleepiness Scale (Hoddes et al., 1973): evaluates instantaneous sleepiness Epworth Sleepiness Scale (Johns, 1991): evaluates behavioral sleepiness and correlates with Multiple Sleep Latency Test (MSLT) and with OSAS severity. Scores up to 7 are considered normal; between 8 and 9 is borderline; between 10 and 12 the sleepiness is mild; between 13 and 16 the sleepiness is moderate; and scores higher than 17 indicate a severe degree of sleepiness

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES 3.

4.

Paediatric Sleepiness Scale: also evaluates behavioral situations and has been validated for sleep apnea in children (Drake et al., 2003; Perez-Chada et al., 2007) vigilance and performance tests include the Quatember and Maly Clocktest, driving simulators, and sustained attention tasks: evaluate vigilance and performance.

The neurophysiologic tests are used in specific situations: 1.

2.

Mulitple Sleep Latency Test (MSLT): evaluates the ability to fall asleep and is usually used whenever the suspicion of narcolepsy exists; it is not a routine test in OSAS (AASM, 2005a, b) Maintenance of Wakefulness Test (MWT): evaluates the ability to stay awake and is used whenever there is need to evaluate driving capacity (AASM, 2005a; Littner et al., 2005).

The MSLT is not routinely indicated in the initial evaluation and diagnosis of obstructive sleep apnea syndrome or in assessment of change following treatment with nasal CPAP. In two papers comparing subjects with obstructive sleep apnea with control subjects, there was significant overlap in mean sleep latency values on the MSLT. Nine studies showed statistically significant increases in mean sleep latency values following CPAP therapy (Littner et al., 2005). Pretreatment and post-treatment mean values were within one standard deviation of normal control means, indicating that mean sleep latency values are poor discriminators of response to treatment.

Diagnostic criteria The ICSD2 (AASM, 2005a) has established clear diagnostic criteria. For adults they are as follows: Diagnostic criteria: A, B and D or C and D satisfy the criteria: A. At least one of the following applies: I The patient complains of unintentional sleep episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue, or insomnia. II The patient wakes with breath-holding, gasping, or choking. III The bed partner reports loud snoring, breathing interruptions, or both during sleep. B. Polysomnographic recording shows the following: I Five or more scored respiratory events (i. e., apneas, hypopneas, or RERAs/hour sleep. II Evidence of respiratory effort during all or a portion of each respiratory event.

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OR C. Polysomnographic recording shows the following: I Fifteen or more scoreable respiratory events (i.e., apneas, hypopneas, or RERAs/hour sleep. II Evidence of respiratory effort during all or a portion of each respiratory event. D. The disorder is not better explained by another current sleep disorder, medical or neurologic disorder, medication use or substance use disorder. The PSG diagnostic criteria for children are, as noted above, different: AHI higher than 1/h is considered abnormal; a set of rules both for recording and for scoring sleep apnea in children has been recently defined by the American Association of Sleep Medicine (AASM, 2007).

Treatment Before the 1980s, tracheotomy was considered to be the only reliable therapy for obstructive sleep apnea. Due to the surgical operation the airflow is able to bypass the pharyngeal obstruction. Medical treatment is nowadays a standard (Veasey et al., 2006).

POSITIVE AIRWAY PRESSURE THERAPY Application of noninvasive ventilation with positive airway pressure (PAP) is nowadays the gold standard for treatment. The rationale of PAP therapy is as follows: the positive airway pressure induces splinting the upper airways and prevents them from respiratory collapse and eliminates the apneas. The additional activation of stretch receptors possibly causes an increase of the pharyngeal muscle tone. It is undoubtedly proven by methods of evidencebased medicine that PAP treatment eliminates obstructive apneas, normalizes the sleep profile, and treats hypersomnia appropriately. In addition, PAP increases the pharyngeal volume and reduces the upper airway resistance. Particularly in obese men it causes an enlargement of the residual lung capacity (RC) which is accompanied by an increase in the tidal volume. Associated cardiovascular diseases such as hypertension, arrhythmia, or heart failure are improved by the treatment of obstructive sleep apnea. The indications for PAP therapy are (Gay et al., 2006): 1. 2. 3. 4.

moderate to severe OSAS (AHI  15/h) (standard) mild OSAS (AHI  5 to 14 events/h) (optional) OSAS patients with daytime excessive sleepiness (standard) improvement of quality of life of OSAS patients (optional)

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T. PAIVA AND H. ATTARIAN as an additional therapy in hypertensive OSAS patients and in patients with systemic hypertension (optional).

There are several types of equipment for PAP therapy in OSAS: CPAP – provides a continuous positive airway pressure APAP – the continuous positive airway pressure is provided automatically on demand BPAP – the expiratory and inspiratory pressures are set CFlex – the expiratory and inspiratory pressures change in each respiratory cycle in order to increase patient comfort. Compliance is the most important factor in PAP treatment. Frequent and disagreeable side-effects of the treatment lead to a decreasing compliance. Nevertheless, these can be improved to a great extent with adequate aftercare. Thus dry nasal mucous membranes can be avoided by the application of an additional humidifier. The careful choice of a mask is recommend: some fit the nose (nasal mask), others fit the nose and the mouth (facial mask), while others fit only the nostrils. In less than 10% the nCPAP therapy is not sufficient, and other forms of nasal ventilation must be applied such as bilevel positive airway pressure (n-biPAP). Recently, the American Academy of Sleep Medicine published guidelines concerning the manual titration of positive airway pressure in OSAS patients of all ages (Kushida et al., 2008). The widespread practice of unattended positive pressure titration with automatic positive pressure devices is not generally recommended by this society and should only be performed in patients with moderate to severe OSAS without any comorbidity. Guidelines for titration of APAP devices were also published (Morgenthaler et al., 2008).

SURGICAL PROCEDURES If CPAP therapy is not accepted by the patient despite being adjusted carefully, other less successful options may be considered. A recent meta-analysis provides relevant information in this issue (Caples et al., 2010). In the case of dysmorphia of the jaws, maxillomandibular osteotomy, or maxillomandibular advancement (MMA) may be an option after careful differential diagnosis. MMA has proven to be efficient with long-term benefits and few side-effects. Other surgical options, such as uvulopalatopharyngoplasty (UPPP), have been evaluated in controlled studies and these have been reviewed by the Cochrane

Collaboration for evidence-based medicine (Li, 2005; Elshaug et al., 2007; Elshaug et al., 2008). According to these reviews, this treatment achieves a reduction of only 50% in the apnea–hypopnea index (AHI). In addition, it is only in 50% of patients that a reduction of apneas and hypopneas is achieved at all. Thus this option cannot be considered as a recommended therapy. UPPP is associated with more adverse events (Caples et al., 2010). For Laser assisted uvulopalatoplasty (LAUP) and radiofrequency ablation (RFA) there are not consistent controlled studies evaluating the effect in AHI and adverse events (Caples et al., 2010). Surgical correction of the nasal cavities can be very useful also to improve efficacy of nasal CPAP ventilation therapy.

ORAL APPLIANCES (LOWER JAW PROTRUSION

PROSTHESES)

Oral appliances have recently been studied as a therapy option in the obstructive sleep apnea syndrome. The principle of all dental devices is based on a lower and upper jaw prosthesis, which creates forces on the lower jaw in order to advance it as well as the tongue. These prostheses are individually adapted by dental laboratories. The devices are used to mechanically enlarge the pharyngeal cross-sectional area and thus avoid upper airway obstruction during sleep. Efficacy of this method differs widely from person to person. In general, oral appliances are not as effective as positive pressure devices in the treatment of obstructive sleep apneas. However, the actual guideline of the American Academy of Sleep Medicine recommends oral appliances in (Kushida et al., 2006) primary snoring, in patients with mild to moderate OSAS who prefer oral appliances, in patients who do not respond to CPAP, and in patients who fail treatment attempts with CPAP.

PHARMACOLOGIC TREATMENT Subsequent and concomitant diseases must be treated. There have been successive attempts to implement pharmacologic treatments of OSAS (Veasey et al., 2006); nevertheless, there are as yet no studies fulfilling the requirements of evidence-based medicine regarding the results. A few examples are given: theophylline led to a significant decrease of apneas in some isolated cases; mirtazapine was initially found to reduce the AHI, but two recent studies could not reproduce this effect; furthermore, its frequent adverse effect of increasing weight precludes its use in OSAS.

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES

BEHAVIOR MANAGEMENT The purpose of behavior management is the prevention of apneas as well as therapeutic support in mild cases or as an adjuvant treatment procedure in general reduction of weight, sleep hygiene, physical exercise, avoiding substances affecting vigilance and sleep (such as alcohol, smoking, hypnotics, sedative substances), and as support to CPAP adaptation.

CENTRAL SLEEPAPNEA AND HYPOVENTILATION SYNDROMES Central sleep apnea (CSA) syndromes can be divided in two groups according to the levels of CO2 and the characteristics of CO2 response; namely: Group I – CO2 in sleep decreases and/or CO2 response increased: 1. 2. 3. 4.

primary central sleep apnea Cheyne–Stokes breathing pattern high-altitude periodic breathing primary sleep apnea of infancy.

Group II – CO2 in sleep is increased and/or CO2 response is reduced: 1. 2. 3. 4. 5. 6.

sleep-related nonobstructive alveolar hypoventilation, idiopathic congenital central alveolar hypoventilation syndromes sleep-related hypoventilation/hypoxemia due to pulmonary parenchyma or vascular pathology sleep-related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders sleep-related hypoventilation/hypoxemia due to lower airway obstruction central sleep apnea due to a medical condition not Cheyne–Stokes.

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decreased and close to the apnea threshold and tends to decrease further after a small increase in ventilation. Polysomnographic and other objective findings: as with OA, the duration is at least 10 seconds and an index higher than 5/h is required. Events are less frequent in stable NREM than in REM sleep; desaturations are commonly less severe than in OSAS since the chemoreflex is not blunted. PaCO2 is less than 40 mmHg (AASM, 2005a).

Cheyne–Stokes respiration pattern The Cheyne–Stokes respiration pattern (CSRP) includes both periodic breathing and Cheyne–Stokes respiration (AASM, 2005a). The CSRP is characterized by apneas, hypopneas, or both; these events alternate with prolonged hyperpneas during which the tidal volume gradually waxes and wanes in crescendo/decrescendo style (Fig. 18.2). The hypopneas and apneas are associated with reduced respiratory effort and respiratory drive. This recurrent cessation of breathing leads to repetitive hypoxic dips, to sleep fragmentation, and to frequent sleep stage changes. Pathophysiology: CSRP occurs at the transition of wake to sleep in chronic hyperventilating persons. The hyperventilation is caused by stimulation of pulmonary vagal irritant receptors (pulmonary congestion) and /or increased responsiveness of the peripheral and central chemoreceptors. The crescendo/decrescendo pattern is caused by the blood circulation time. The main clinical associations are congestive heart failure and less often, stroke and renal failure.

Primary central sleep apnea CSA is defined by recurrent cessation of respiration during sleep not associated with ventilatory effort (Fig. 18.1). Therefore there is sleep fragmentation due to respiratory events and associated arousals, but during wakefulness PaCO2 is normal or low, around 40 mmHg. As in OSAS there is a male predominance and daytime sleepiness-related frequent nocturnal awakenings. Insomnia is likely to increase occurrence of CSA. Pathophysiology: CSA is caused by the instability of the respiratory control system at the transition from wakefulness to sleep in individuals with an increased ventilatory responsiveness to CO2; in fact PaCO2 is

Fig. 18.1. Central apnea - There is a cessation of both nasal flow and respiratory effort for at least 10 seconds.

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Fig. 18.2. Cheyne Stokes breathing - There is a wax and waning periodic pattern, in which periods of hyperventilation alternate with respiratory pauses.

The polysomnographic and other objective findings are as follows: 1. 2. 3. 4. 5. 6.

recurrent central apneas/hypopneas alternating with ventilatory crescendo/decrescendo pattern occurrence decreases from WAKE to NREM 1–2 to slow wave sleep and to REM arousals are frequent but not mandatory; they usually follow the initial breaths desaturations are usually modest ( 80%) reduced amount of slow wave sleep PaCO2 is less than 45 mmHg.

At 5000 m periodic breathing might resolve over time, but at 7600 m it persists indefinitely. Again there is a male preponderance due to increased chemoresponsiveness in men (AASM, 2005a).

Central sleep apnea due to medical condition not Cheyne–Stokes This may be caused by neurologic and medical disorders, such as brainstem lesions, cardiac, or renal disorders (AASM, 2005a).

Central sleep apnea due to drug or substance Complex sleep apnea syndrome The complex sleep apnea syndrome (CompSAS) has only been recently defined and it is not included in the definitions of the ICSD2. It corresponds to central sleep apneas that occur following the treatment of obstructive sleep apneas with a positive pressure device (CPAP, BiLevel), usually whenever the pressure is too high. CompSAS may play an important role in the healthcare of sleep disordered breathing since it was observed in about 15% of the patients following CPAP treatment. The recommended treatment includes the more expensive adaptive servoventilation devices.

High-altitude periodic breathing High-altitude periodic breathing is a normal adaptation to altitude and there are no specific criteria regarding the frequency of central apneas that should be considered normal or abnormal. Occurrence depends on rapidity of the ascent, the altitude and individual preposition.

This may occur in patients taking a long-acting opioid regularly for at least 2 weeks. Opioid-induced ventilation disorders may also include Biot breathing and obstructive apneas/hypopneas (AASM, 2005a).

Primary sleep apnea of infancy Infants, especially small, preterm infants, have prolonged central, mixed, or obstructive apneas or hypopneas associated with hypoxemia, bradycardia, and need for intervention (ventilation). This disorder represents a deficit in respiratory control via direct depression of the respiratory center, disturbance of oxygen delivery, or ventilation defects; it may be due to brainstem immaturity or medical conditions. It does not include sudden infant death syndrome (SIDS). There are predisposing factors, namely: low birthweight (25% of infants below 2500 g and 84% of infants below 1000 g develop the disorder) and developmental

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES alterations in the respiratory drive due to chemo- or mechanoreceptor responses and to upper airway reflexes. There are precipitating factors: thermal instability, gastroesophageal reflux, intracranial pathology, drugs, anesthesia, impaired oxygenation. and infection. The condition usually starts on the 2nd to 7th days after birth and at 37 weeks postconception 92% of the babies have no further symptoms (AASM, 2005a). The respiratory events increase during active sleep (REM).

Sleep-related nonobstructive idiopathic alveolar hypoventilation This idiopathic hypoventilation is also called central or primary and is associated with increased CO2. There is a blunted chemoresponsiveness without detectable abnormalities (pulmonary, endocrine, neurologic, ventilatory muscle, cardiac); its is eventually due to subtle medullar abnormalities. The ventilatory output during sleep is reduced, and therefore an initial nocturnal hypoventilation will become both diurnal and nocturnal. The PSG shows hypoventilation, which is increased in REM sleep with severe hypoxemia and hypercapnia and also sleep fragmentation. The main symptoms are: morning headaches, cor pulmonale, peripheral oedema, polycythemia, and sometimes daytime sleepiness (AASM, 2005a).

Congenital central alveolar hypoventilation syndrome Congenital central alveolar hypoventilation syndrome (CCAHS) is a central or primary alveolar hypoventilation syndrome; it was formerly also known as Ondine’s curse, but this term should no longer be used. The condition is due to failure of automatic central control of breathing and the onset of alveolar hypoventilation occurs usually in childhood; the child is otherwise relatively normal, but does not breathe spontaneously. Some patients hypoventilate only when asleep, others also during wakefulness. There are associated disorders: Hirschsprung disease occurs in 16% of the cases and there is an association with neural tumors. There is a familial pattern with an association with siblings and twins and the majority of the cases are PHOX2B gene-positive. There are other mild clinical symptoms, namely swallowing dysfunction, ocular abnormalities, and cognitive dysfunction due to hypoxemic events. Pulmonary function tests show hypoxemia and hypocapnia. Polysomnography shows a diminished arousal response which progresses in the course of sleep; the abnormalities are often more severe in SWS than in REM

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sleep; Cheyne–Stokes respiration may occur (AASM, 2005a).

Sleep-related hypoventilation due to neuromuscular and chest wall disorders This category includes: alveolar hypoventilation, secondary alveolar hypoventilation, and obesity hypoventilation syndrome. These syndromes are due to impairment of the chest wall musculature (AASM, 2005a). The essential features are: 1.

2. 3.

an abnormal ventilatory pump (VP) due to reduced respiratory muscle contractibility (neuromuscular) and/or distortion of chest wall structures (reduced muscular efficiency) the VP is unable to keep PaCO2 at values equal to or below 45 mmHg other factors may coexist, namely OSA, reduced central neural chemoresponsiveness.

Patients complain of daytime sleepiness. Prolonged alveolar hypoventilation may cause increased pulmonary hypertension and/or increased mortality. The predisposing factors are morbid obesity and neuromuscular disorders. The precipitating factors include excessive obesity, REM sleep (due to the respiratory burden on the diaphragm), hypoxemia and hypercapnia during wakefulness; bulbar dysfunction with abnormal swallowing increases the risk of sleep-related hypoventilation and hypoxemia, as in amyotrophic lateral sclerosis, and in myotonic dystrophy and other situations associated with reduced chemosensitivity. The polysomnographic findings are: 1. 2. 3. 4. 5.

frequent arousals (due to the respiratory effort) increased wakefulness hypoventilation with increased desaturations in REM sleep REM sleep reduction OSA and central apneas (not mandatory).

An example of hypoventilation is shown in Figure 18.3.

Sleep-related hypoventilation/hypoxemia due to lower airway obstruction This item includes: nocturnal oxygen desaturation; low oxygen saturation; nocturnal hypoxemia; sleep-related oxygen desaturation; sleep-related hypoxemia; secondary alveolar hypoventilation (AASM, 2005a). The main features are: 1. 2.

obstruction or increased resistance below laryngeal area heterogeneous ventilation

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Fig. 18.3. Hypoventilation – Notice the decreased amplitude of ventilation, the low values of O2 saturation, and the frequent arousals in the EEG and EMG channels.

3. 4.

absolute or relative increase in PaCO2 (>45 mmHg) during sleep prolonged sustained desaturation and hypoventilation without apneas, hypopneas, or airflow limitation.

The associated diseases are: COPD (emphysema, chronic bronchiolitis), asthma, bronchiectasis, cystic fibrosis, and disorders of the immune system.

Sleep-related hypoventilation due to pulmonary parenchymal or vascular pathology This includes: nocturnal oxygen desaturation; low oxygen saturation; nocturnal hypoxemia; sleep-related oxygen desaturation; sleep-related hypoxemia; secondary alveolar hypoventilation; excessive nocturnal hypoxemia. The essential features are: 1.

2. 3.

4.

significant sleep-related hypoxemia associated with lung parenchyma disease; pulmonary vascular pathology; hemoglobinopathies observed hypoxemia is not a function of other sleep disorders gold standard is the identification of sustained desaturation without apneas (central, mixed obstructive), inspiratory flow limitation and snoring PaCO2 does not necessarily reflect absolute alveolar hypoventilation (PaCO2 > 45 mmHg) but, in sleep, it is abnormally increased compared to wakefulness.

The pathophysiology implies reduced lung volume; decreased oxygen reserve; desaturation enhanced;

abnormal ventilation/perfusion; chemosensitivity compensation and increased elastic load; augmented activation of the ventilatory muscles; relative and absolute hypercapnia and low hemoglobin saturation at wakefulness ¼ close to the steep portion of the desaturation curve. The polysomnographic findings are: sustained oxygen desaturation; discrete or absent respiratory events; intermittent arousal associated with hypoxemia (AASM, 2005a).

ACKNOWLEDGEMENTS We would like to thank Dr. Richard Staats for his support and for collaboration in certain aspects of this chapter.

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 19

Acute and chronic respiratory failure SABIN OANA* AND JAYANTA MUKHERJI Department of Anesthesiology, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION Respiratory failure (RF) is defined as failure of oxygenation and/or carbon dioxide (CO2) elimination. Hypoxemia exists if arterial oxygen tension (PaO2) is below 60 millimeters of mercury (mmHg). Hypercapnia is present if arterial CO2 tension (PaCO2) is above 50 mmHg. There are three common mechanisms that could lead to RF: right to left shunt (cardiac or intrapulmonary), ventilation/perfusion mismatch, and hypoventilation. In addition, low partial pressure of inspired oxygen, diffusion impairment, and high partial pressure of inspired CO2 have also been described as rare causes of RF (Bartter et al., 2011). Another way of looking at the pathophysiology is to imagine the respiratory system as consisting of two parts: the lung and the pump that moves the lung (respiratory centers, spinal cord and respiratory peripheral nerves, respiratory muscles, chest wall). Failure of the lung is primarily manifested as hypoxemia (hypoxemic or type I failure; shunt physiology) and failure of the pump results mainly in hypercapnia (hypercarbic or type II failure; hypoventilation is the principal mechanism). Recent literature mentions a type III or perioperative failure, associated mainly with lung atelectasis, and a type IV, related to hypoperfusion of respiratory muscles in shock (Kress and Hall, 2012). The majority of neurologic diseases that progress to RF are therefore type II failures and are characterized by either a reduced drive to breathe or weak respiratory muscles. Depending on the speed of onset, RF can be classified as acute, acute on chronic, or chronic. RF usually supervenes insidiously in chronic progressive neuromuscular diseases (NMDs) such as amyotrophic lateral sclerosis (ALS). There can also be an acute superimposed factor (e.g., respiratory infection) that precipitates their

deterioration. On rare occasions, however, RF may herald disease onset. More commonly, there are acute conditions that are associated with RF (e.g., Guillain–Barre´ syndrome (GBS)). Other entities such as critical illness neuropathy and myopathy are often first diagnosed in the critical care unit. The initial manifestations of RF usually appear during sleep and, as the diseases progress, they are also present during the daytime. In normal individuals, during sleep, especially in the rapid eye movement state, there is hypotonia of respiratory muscles and of the airway as well as decreased chemosensitivity to CO2. These otherwise normal changes produce an abnormal degree of hypoventilation and hypoxemia in individuals affected by NMD (Chokroverty, 2001). Disruption of any segment of the neural pathway of respiration can produce RF. RF may be classified according to the anatomic site of origin into: central nervous system disorders, spinal diseases, peripheral nervous system dysfunction, and muscle diseases. Previous work reviewed the need for primary mechanical ventilation (MV) in patients affected by peripheral nervous system diseases (Cabrera Serrano and Rabinstein, 2010). The most frequent conditions were myasthenia gravis (MG), GBS, myopathies, and ALS, together accounting for 75% of cases. However, 55% of patients did not have a diagnosis on admission and 10% never had a final diagnosis.

GENERAL APPROACH TO DIAGNOSIS Respiratory symptoms in NMDs include dyspnea or shortness of breath with its variants orthopnea (dyspnea when supine) and platypnea (dyspnea when upright). Very commonly, and generally early in the course of diseases, there are various sleep disturbances (restless

*Correspondence to: Sabin Oana, M.D., Assistant Professor of Anesthesiology, Loyola University Medical Center, Department of Anesthesiology, Bldg 103, Rm 3102, 2160 S 1st Ave, Maywood, IL 60153-3328, USA. Tel: þ1-708-216-8866, Fax: þ1-708-216-1249, E-mail: [email protected]

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sleep, frequent awakenings, nightmares, and migraines) and related symptoms of daytime fatigue. Difficulty in speech and swallowing are markers of bulbar symptoms (i.e., of the cranial nerves that originate in the medulla) that predispose the patient to ineffective cough and aspiration pneumonia. Physical examination can reveal tachypnea, shallow breathing, accessory inspiratory and expiratory muscle contraction (parasternal, sternocleidomastoid, scalene, intercostal, and abdominal) and ribcage–abdominal asynchrony. Of note, the reliability and reproducibility of the clinical examination with neurologic focus of a RF patient are greatly reduced, especially in the intensive care setting. In cases with mild hypoxia, one can encounter headaches or inattentiveness, lethargy or delirium, somnolence or anxiety, tremors or seizures that, untreated, progress toward loss of consciousness and unresponsiveness. Hypoxic-ischemic encephalopathy is a complication of prolonged hypoxia during cardiac and respiratory arrest. A special type is that encountered during birth, which can cause long-term damage including intellectual developmental disorder and cerebral palsy. A low percentage of adults can regain consciousness after cardiopulmonary arrest but still suffer long-term neurologic sequelae, including motor, memory, or personality changes (Dreibelbis and Jozefowicz, 2010). A special type of RF occurs when the inspired oxygen is low, as, for example, during climbing at high altitudes. Acute mountain sickness can progress to high altitude cerebral edema and is manifested as dizziness, somnolence, confusion, and decreased consciousness. Arterial blood gas analysis is one the first steps in the characterization and differential diagnosis of RF. It entails measuring pH, PaO2, PaCO2, and bicarbonate.

These should provide enough data to diagnose an acute versus chronic, respiratory versus metabolic acid–base disorder. Once the respiratory component is assessed, there are multiple indices of hypoxemia that can be calculated to aid in the more detailed diagnosis of RF (i.e., differentiating pulmonary versus extrapulmonary causes). Each has its own merits and limitations. Tension-based indices are based on alveolar air equation and content-based indices are based on oxygen content equation (Siggaard-Andersen and Gothgen, 1995; Wandrup, 1995) (see Table 19.1). Electrophysiologic studies consist of nerve conduction studies (motor and sensory) as well as needle electromyography (EMG). More specialized testing includes: neuromuscular junction testing with repetitive nerve stimulation, single-fiber EMG and train of four stimulation, respiratory EMG with percutaneous or needle stimulation of phrenic nerve and diaphragm, and direct muscle stimulation (Dhand, 2006). In axonal disease there is normal conduction but reduced amplitude, whereas in demyelinating disease there is slow conduction with normal potential amplitude. For needle EMG the neurogenic pattern shows spontaneous activity, large potentials with mild contraction and less than complete recruitment and interference with full contraction. The myopathic pattern might demonstrate some spontaneous activity with small potentials during mild contraction but small amplitude and full interference patterns with full stimulation. Pulmonary function testing in NMDs encompasses spirometry, lung volume and capacity, and measurement of respiratory muscle strength (Aboussouan, 2005). The most common clinical picture is that of a restrictive respiratory disorder, albeit with some

Table 19.1 Oxygen parameters* Equation

Formula

Alveolar pressure of oxygen

PaO2 ¼ FiO2  (Patm  PH2O)  PaCO2/RQ or PaO2  700  FiO2  1.2  PaCO2 CaO2 ¼ 1.34  Hgb  SaO2 þ 0.03  PaO2 Qs/Qt ¼ (CcO2  CaO2)  (CcO2  CvO2) or Qs/Qt ¼ (1  SvO2)  (1  SaO2) Vd/Vt ¼ (PaCO2  PeCO2)  PaCO2

Arterial oxygen content equation Shunt equation

Dead space fraction

Normal values

Less than 5% (0.05)

Below 0.33(33%)

*Where: PaO2, alveolar partial pressure of oxygen in mmHg; FiO2, inspired fraction of dry oxygen; Patm, atmospheric pressure (760 mmHg at sea level); PH2O, partial pressure of water vapor (47 mmHg); PaCO2, alveolar partial pressure of CO2 in mmHg; RQ, respiratory quotient or CO2/O2 exchange ratio (approx 0.8); Hgb, hemoglobin concentration; CaO2, CcO2, CvO2 are oxygen content of arterial, capillary, and mixed venous blood; SvO2 and SaO2 are the saturation of hemoglobin in mixed venous blood and, respectively, arterial blood; PeCO2, partial pressure of expired CO2.

ACUTE AND CHRONIC RESPIRATORY FAILURE particularities. Weakness in expiratory muscles generates a decreased expiratory reserve volume but with preserved functional residual capacity. In consequence there is elevated residual volume. Associated weakness in inspiratory muscles decreases the inspiratory reserve volume. The overall result is a marked decrease in vital capacity (VC) with a preserved total lung capacity. Diaphragmatic dysfunction has a characteristic 20–50% decrease in VC when supine. Maximal voluntary ventilation could be reduced. Strength of the respiratory muscles is assessed by measuring the maximum inspiratory and expiratory pressures (MIP and MEP). More recently, sniff inspiratory pressures (nasal (SNIP), esophageal, and gastric) have also been employed to provide data regarding the respiratory muscles. Transdiaphragmatic pressure is the difference between the esophageal and gastric pressures and is sensitive for diaphragmatic dysfunction (Steier et al., 2007). Genetic testing is usually recommended in inherited diseases with specific presentations like familial ALS, spinal and bulbar muscular atrophy, Charcot–Marie–Tooth (CMT) 1A, myotonic dystrophy, Duchenne muscular dystrophy (DMD) (Burgunder et al., 2011), and congenital central hypoventilation syndrome (CCHS).

SPECIFIC DISEASES Stroke RF in stroke occurs in about 2–4% of patients and is an ominous sign, traditionally being associated with high mortality. The treatment of such patients should be performed in acute stroke units, resulting in a decrease in mortality (Gattellari et al., 2009). Younger patients with posterior circulation involvement have better prognosis (Rabinstein and Wijdicks, 2004). Common indications for MV in stroke patients are neurologic reasons (coma, loss of brainstem reflexes, brain edema with impending herniation), general deterioration in clinical condition, cardiopulmonary causes (pneumonia, aspiration, pulmonary embolism), or elective

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for neuroradiologic or neurosurgical procedures (Steiner et al., 1997). There are several patterns of impaired breathing described after stroke that could help in the localization of stroke (Brazis et al., 2011) (see Table 19.2). Upper airway obstruction is common in stroke patients, obstructive sleep apnea (OSA) being considered both a risk and a consequence for stroke. In OSA patients with stroke, continuous positive airway pressure (CPAP) should be offered, as it reduces mortality (Martı´nez-Garcı´a et al., 2009). Dysphagia is very frequent and can be diagnosed early and safe with the help of flexible fiberoptic endoscopy (Warnecke et al., 2009). More recent studies found that aggressive treatments with thrombolysis, decompressive hemicraniectomy, MV, and feeding tubes are achieving functional independence for an unexpectedly high number of patients (Seder and Mayer, 2009).

Amyotrophic lateral sclerosis ALS is being increasingly recognized as a disease of diverse genotype, phenotype, and rate of progression (El Escorial Criteria Revisited) (Brooks et al., 2000). RF is rare at the onset, but is the most frequent cause of death. It signifies degeneration of the center and/or of the neurons of the phrenic nerve (Kiernan et al., 2011). Respiratory symptoms in ALS are dyspnea on exertion, orthopnea, disturbed sleep, daytime somnolence, and vivid nightmares (Wijesekera and Leigh, 2009). Respiratory signs in ALS include tachypnea, use of accessory muscles, and paradoxical movement of the abdomen. As far as respiratory investigations are concerned, forced vital capacity (FVC) is increasingly recognized as being an insensitive marker for early RF. In order to predict the need for noninvasive ventilation (NIV), recent focus has been on measurements such as nocturnal oximetry, nocturnal desaturations less than 90% for more than 1 full minute, MIP, supine FVC, transdiaphragmatic pressure, SNIP. Common indications for NIV are: orthopnea, SNIP 35 cmH2O) leading to volutrauma. Lower TVs of 6–8 mL/kg limit plateau pressures, prevent release of inflammatory mediators, and reduce ventilatorinduced lung injury. Lung protective strategies in ARDS include using lower TV and higher PEEP to avoid alveolar overdistention and derecruitment (Petrucci and Iacovelli, 2007). PEEP prevents alveolar derecruitment by restoring the functional residual volume to the physiologic range. Permissive hypercapnia is a strategy whereby lungs are protected during MV by adoption of deliberate alveolar hypoventilation. Hypercapnic acidosis is a consequence of this strategy and not a goal. Lung protective ventilation impairs CO2 clearance and may lead to right heart dysfunction or increased intracranial pressure. Extracorporeal CO2 removal has the potential to optimize lung protective ventilation by uncoupling oxygenation and CO2 clearance (Cove et al., 2012).

Complications in mechanically ventilated patients Respiratory complications may result from MV itself. A bedside evaluation of patient, airway, and ventilator settings to monitor for ventilator–patient dysynchrony, oxygenation, gas exchange and airway pressures (peak and plateau), and compliance should be undertaken (Tables 19.4 and 19.5). Cardiovascular complications may be secondary to sepsis, or from the effects of positive pressure ventilation. Cardiac output is diminished with decreased venous return from high airway pressures, decreased intravascular volume, fluid sequestration from sepsis, and trauma.

Table 19.4 Differential diagnosis of hypoxemia and/or hypoventilation during mechanical ventilation Patient-related

Airway-related

Ventilator-related

Tension pneumothorax Atelectasis Pneumonia Bronchospasm Pleural effusion Pulmonary edema Laryngospasm Airway trauma

Right mainstem intubation Kinked endotracheal tube, occlusion due to biting Endotracheal tube cuff leak, herniation Inadvertent extubation with neck extension, migration of tube Unrecognized esophageal intubation

Ventilator circuit leak Low FiO2 Inappropriate ventilatory settings Patient–ventilator dysynchrony

ACUTE AND CHRONIC RESPIRATORY FAILURE Table 19.5 Diagnostic approach of hypoxemia and/or hypoventilation during mechanical ventilation Bag ventilate with FiO2 of 1.0 Auscultate and check capnogram to confirm endotracheal tube placement Chest X-ray, CT scan to diagnose lung parenchymal conditions Arterial blood gas to determine hypoxemia, hypoventilation, acidosis Fiberoptic bronchoscope to ascertain endotracheal tube position, bronchoscopy for removal of mucus plugs, bronchoalveolar lavage for pneumonia Echocardiogram to rule out intracardiac shunts Ventilator: check for disconnection, leaks or blockages Ventilator: check difference between exhaled and set TV, airway pressure profile, peak and plateau pressures, check response to lung recruitment and PEEP FiO2, fraction of inspired oxygen; CT, computed tomography; PEEP, positive end-expiratory pressure; TV, tidal volume.

Gastrointestinal complications such as upper GI bleed, gastric stasis, and ileus may be caused by shock, hypoxemia, drugs that inhibit gastrointestinal motility such as narcotics, antipsychotics, or hypokalemia. Sepsis syndrome. The inflammatory response is triggered by infection and is a series of humoral and cellular cascades. The mediators of sepsis, neutrophils, cytokines, coagulation factor, prostaglandins, and nitric oxide, target the endothelium and increase capillary permeability. This is expressed in the lungs as noncardiogenic pulmonary edema.

Noninvasive ventilation NIV is largely utilized in patients with acute hypercapnic RF, acute cardiogenic pulmonary edema, and acute exacerbation of COPD. The level of success is variable in hypoxemic forms of RF and is useful in select populations with no contraindications such as multiple organ failure, loss of consciousness, or hemodynamic instability. NIV can be used either as a primary ventilation mode for acute RF or for weaning patients from MV (Peter et al., 2002). It preserves airway defense mechanisms, lowers sedation requirements, and allows patients to speak, eat, and clear secretions. NIV unloads inspiratory muscles and reduces the work of breathing. The mask interface has to fit well and the patient should be comfortable. Nasal masks may be used but are ineffective in patients likely to mouth breathe. The applied pressure starts at 8–12 cmH2O and is adjusted according to the patient’s tolerance and desired TV. NIV has been associated with reduced infections (pneumonia, sinusitis) and hospital stay, when compared with MV delivered via an endotracheal tube

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(Brochard, 2003). Immunocompromised patients with RF may benefit from a reduced need for intubation and reduction in mortality (Hilbert et al., 2001). In patients with COPD exacerbation, NIV counters the effects of auto-PEEP and diminishes dyspnea and the work of breathing (Keenan et al., 2003). In cardiogenic pulmonary edema, positive pressure breathing restores functional residual capacity (FRC), improves ventilation/perfusion ratios, and reduces afterload (Vital et al., 2008). NIV is contraindicated in patients who are unable to protect airway due to altered mental status, agitation and excessive secretions, or develop hemodynamic instability, respiratory arrest, and myocardial ischemia. In general, younger, cooperative patients with intact dentition, having less severe illness, hypercarbia (PaCO2 > 45 mmHg, 7.10), have a higher rate of success with NIV (Hill et al., 2007). Some centers have reported the use of a pumpless extracorporeal lung-assist device for extracorporeal CO2 removal allowing them to avoid invasive MV in patients with acute hypercapnic RF not responding to NIV (Kluge et al., 2012).

Weaning from mechanical ventilation Weaning usually implies two closely related aspects of care, discontinuation of MV and removal of any artificial airway. The clinician determines when a patient is ready to resume spontaneous ventilation. Once a patient is able to sustain spontaneous breathing, a second decision is made whether the artificial airway can be removed by assessing the patient’s mental status, airway protective mechanisms, and ability to cough and clear secretions (Alia and Esteban, 2000) (see Tables 19.6 and 19.7). Table 19.6 Checklist for weaning and extubation Patient awake and responds appropriately, aspiration risks assessed No agitation, cooperative, adequate pain control Hemodynamically stable, normal acid–base status, no electrolyte disturbance Pulmonary gas exchange with acceptable parameters for oxygenation and ventilation Cardiogenic pulmonary edema (fluid overload, left ventricular dysfunction) resolving Noncardiogenic pulmonary edema (pneumonia, acute lung injury) resolving Respiratory mechanics optimized, abdominal distention Underlying cause for ventilator dependency resolving

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Table 19.7 Causes of failed extubation Upper airway obstruction Obstructive sleep apnea Tracheal stenosis Laryngeal edema Airway compression from neck hematoma Airway trauma Inability to clear secretions Altered mental status Poor VC Muscle fatigue Aspiration Emesis from tube feeds Gastroesophageal reflux

The most effective means of weaning follows a systematic approach that includes a daily assessment of weaning readiness, along with interruption of sedation infusions and spontaneous breathing trials. Evidencebased practice dictates using protocols and checklists as decision support tools. Most studies of weaning protocols applied by nonphysician healthcare providers suggest faster weaning and shorter duration of ventilation and ICU stay (Haas and Loik, 2012). Tracheostomy should be considered in head-injured or critically ill patients as soon as the need for prolonged intubation (longer than 14 days) is identified. Mortality is not worse with tracheotomy and may be improved with earlier provision (Durbin, 2010).

WEANING PARAMETERS Sleep-deprived patients in the ICU manifest signs of agitation and lethargy. Establishing sleep patterns and daily orientation to the day, time, and surroundings are helpful. Daily interruption of sedative infusions is advocated to avoid prolonged sedation and increased duration of MV (Kress et al., 2000). The patient is assessed for respiratory drive, muscle strength, and the imposed workload before attempting weaning. Muscle fatigue results from muscle atrophy or electrolyte imbalance, NMD, increased work of breathing from acute bronchospasm, pulmonary edema, or depleted respiratory drive from excessive sedatives and narcotics. Weaning is considered successful if patients do not require resumption of ventilatory support within 48–72 hours after extubation (MacIntyre, 2004). About 20% of patients may fail their first attempt at weaning and may require prolonged support (Rothaar and Epstein, 2003). A somewhat particular cause of failure is due to postextubation pulmonary edema, either from loss of positive pressure ventilation with increased afterload in left ventricular dysfunction or from negative pressure pulmonary edema. Unplanned extubation requiring reintubation is detrimental as it increases mortality and the chances of prolonged MV, and ICU stay (Seymour et al., 2004). Evidence-based practice supports early attempts at weaning in a protocol-driven fashion (Robertson et al., 2008). Prolonged MV has been associated with pneumonia, gastrointestinal bleeding, and deep venous thrombosis. It is difficult to determine the optimal time for extubating patients with neurologic deficit from brain injury. Impaired airway reflexes and inability to clear secretions creates conditions for aspiration risks. However, delaying extubation of patients breathing spontaneously can carry an increased risk for pneumonia.

No index has proven to be ideal. The work of breathing is more predictive of successful weaning outcome in long-term MV patients. Weaning criteria consist of TV, VC, RR, MIP and rapid shallow breathing index (RSBI). The sensitivity and specificity of the weaning parameters are relatively poor (El-Khatib and BouKhalil, 2008). VC is measured upright rather that supine, because diaphragmatic paralysis may cause a 30% positional reduction. Patients may be too weak to sustain prolonged inspiratory effort or fail to cooperate. It is an unreliable measure of strength and fails to predict weaning outcome (threshold is 10–15 mL/kg for VC) (Yang, 1992). MIP provides a better negative than positive predictive value and may be performed in uncooperative intubated patients. A MIP value exceeding 30 cm of H2O is associated with successful extubation. RSBI is the ratio of RR/TV and is an accurate predictor of weaning outcome when lower than 105. It is not dependent on patient cooperation and effort (Chao and Scheinhorn, 2007).

WEANING MODES AND PROTOCOL-DRIVEN WEANING The optimal mode of weaning from MV remains controversial. Most patients do not require progressive withdrawal of support during weaning. The commonly used techniques of weaning are T-piece, SIMV, or PS. Spontaneous breathing trials using PS or T-piece is commenced if RSBI is less than 107. Daily T-piece trials are equivalent to a PS mode of weaning, and are superior to the SIMV mode (Esteban et al., 1995). PS provides a progressive unloading of inspiratory muscles compared with SIMV. NIV has been used as a method to support ventilation following early extubation (Burns et al., 2010). A successful trial for duration of 30 minutes up to 2 hours assures successful extubation (Epstein, 2009).

ACUTE AND CHRONIC RESPIRATORY FAILURE A protocol-driven weaning is based on best evidence, and is less influenced by personal decisions, allowing a systemic approach to learning and quality monitoring. It leads to a significant reduction in the duration of MV and complications (Blackwood et al., 2010). Protocolized weaning may be computer driven and has reduced MV duration when compared with physiciancontrolled weaning (Lellouche et al., 2006).

Management of patients on prolonged mechanical ventilation Prolonged mechanical ventilation (PMV), according to the Centers for Medicare and Medicaid Services, includes patients who have required more than 6 hours of MV for greater than 21 consecutive days and who are eligible for transfer to long-term acute care (White et al., 2008). In single center studies, about 3–7% of ICU patients meet PMV criteria (MacIntyre et al., 2005). Unlike the 48–72 hour criteria used in acute RF, patients on PMV are considered weaned if liberated from MV for 7 consecutive days. Comorbidities commonly associated with PMV include include malignancy, COPD, immunosuppression, poor nutritional status, polyneuropathy, myopathy, sepsis, recurrent aspiration, sedation, sleep deprivation, and delirium. Diaphragmatic contractile dysfunction is present in PMV with as few as 18 hours of MV, resulting in diaphragmatic atrophy (Powers et al., 2009). Managing patients on PMV involves more than ventilator weaning and has a rehabilitative focus, involving nutritional support, respiratory muscle training, physical and occupational therapy including speech therapy, psychological and social services. Long-term facilities caring for PMV patients have some environmental advantages in that they are relatively quiet, with distinct day–night cycles, and, unlike an acute ICU, they are geared towards receiving family members, encouraging mobility, providing more staff–patient interactions and counseling.

MANAGEMENT OF OROPHARYNGEAL AND TRACHEOBRONCHIAL SECRETIONS NMDs may compromise the effectiveness of the cough by producing weakness of the involved skeletal muscles. A weakened cough leads to inability to clear secretions and places patients at risk for atelectasis, mucus plugging, and pneumonia. A PCEF less than 2.7 L/sec produces an ineffective cough, with retention of airway secretions predisposing to pneumonia. Patients with low VC (less than 1.5 L) and vocal cord dysfunction

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are susceptible to retained secretions (Kang and Bach, 2000). Anticholinergic medications inhibit the saliva production but their use is limited by side-effects related to blurred vision and urinary retention. Injection of botulinum into salivary glands produces local functional denervation and has been successfully used to treat sialorrhea in stroke, parkinsonism, and ALS (Ondo et al., 2004). Patients experience relief within days and the therapeutic effect usually lasts for approximately 3–4 months, when reinjection may be required. The use of anticholinergics and botulinum toxin can produce thick, tenacious secretions, which are difficult to mobilize in the setting of compromised musculature. This can be minimized by maintenance of adequate hydration and by coadministration of medications that thin secretions, such as guaifenesin or N-acetylcysteine (Elman et al., 2005). Physical modalities usually employed in handling secretions include manual suctioning, respiratory physical therapy, postural drainage, and glossopharyngeal breathing (GPB). Postural drainage allows the mobilization of tracheobronchial secretions by gravity-assist positioning, deep breathing with or without chest percussions. When secretions reach the upper airway they are expelled via coughing. Incentive spirometry is commonly used postoperatively to reduce pulmonary complications. While deep breaths taken with an incentive spirometer may help reduce atelectasis, there is no evidence that it helps in reducing pulmonary complications after upper abdominal surgery (Guimara˜es et al., 2009). GPB is useful for airway clearance in patients with low VC, as in NMD. It is accomplished by a series of air gulping actions generated by the lips, pharynx, and palate while the larynx serves as a valve maintaining air in the lungs between gulps. Both GPB and air stacking can increase lung volumes and, thereby, cough flows. GPB helps supplement mechanical insufflations and may be used to decrease daytime ventilator use (Bach et al., 2007). Oscillating devices assist in clearance of airway secretions. They generate intra- or extrathoracic oscillations orally or external to the chest wall. Mechanical vibration of the chest using vests that provide high frequency chest wall oscillations is believed to aid in the mobilization of tracheobronchial secretions by producing shearing forces that thin mucus. Forced expiratory maneuvers with Flutter VRP1® (Scandipharm Inc., Birmingham, AL) creates an oscillatory positive pressure and vibration within the airways which facilitates mucus mobilization and expulsion. There was no clear evidence that oscillation is a more or less effective intervention overall than other forms of physiotherapy (Morrison and Agnew, 2009).

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MANAGEMENT OF RESPIRATORY FAILURE IN PATIENTS WITH NEUROMUSCULAR DISEASE Improving pulmonary gas exchange requires an assortment of maneuvers ranging from providing supplemental oxygen and bronchodilators, to use of pulmonary support to sustain the weak respiratory muscles. The use of CPAP or low span BiPAP (inspiratory–expiratory pressure difference 60 years old Oral contraceptive use Hormone replacement use Malignancies Chemotherapy use Heart disease Ischemic or hemorrhagic stroke Nephrotic syndrome Prior history of venous thromboembolism Family history of venous thromboembolism

et al., 2002; Browd et al., 2004; Lijfering et al., 2010). The leading cause of acquired (as opposed to hereditary) thrombophilias is the antiphospholipid (APL) syndrome. The risk of venous thrombosis is higher with the APL syndrome in the presence of a concomitant lupus anticoagulant. The VTE risk associated with hereditary, acquired, or mixed thrombophilia of is not clear, but factor V Leiden and prothrombin G20210A mutations are among the thrombophilic markers for which there is a very strong association (Rees et al., 1995; Rosendaal et al., 1995, 1998; Lijfering et al., 2010). The factor V Leiden mutation is the most common prothrombotic mutation in Caucasians but is very rare in Asians and African Americans (Rees et al., 1995; Lijfering et al., 2010). The prevalence of factor V Leiden mutation is approximately 5%, and that of the prothrombin G20210A mutation is approximately 2% in white patients. Heterozygous patients with factor V Leiden mutations have a fivefold to sevenfold increased VTE risk, whereas heterozygous prothrombin G20210A carriers have a threefold to fourfold higher VTE risk. Double heterozygous carriers of factor V Leiden and the prothrombin G20210A mutation have a 20-fold increased risk of first-ever VTE, and homozygous factor V Leiden carriers have an 80-fold increased VTE risk. Heterozygous carriers of each mutation alone do not have an increased risk compared to noncarriers (Lijfering et al., 2010). Hospitalized patients are at particular risk for VTE which has been deemed to be one of the most preventable causes of inpatient mortality. The American College of Chest Physicians (ACCP) 2008 guidelines estimate a

hospital prevalence of VTE ranging from 10% to 40% in moderate-risk patients and a prevalence as high as 80% among high-risk patients (Geerts et al., 2008). Neurologic and neurosurgical disease is highly associated with an increased VTE risk in hospitalized patients. Neurologic impairments are present in about 7% of all immobile inpatients at risk for VTE (Gaber, 2007). DVTs may be present in 15–40% of all hospitalized neurosurgical patients, 40–80% of all patients with major head trauma, and 20–40% of all hospitalized stroke patients. Patients with spinal cord injury, not treated with prophylactic anticoagulation, have a particularly high DVT rate of approximately 60–80% (Browd et al., 2004). Patients with head injury have a reported DVT rate as high as 31.6%, though the DVT rate is lower, at 25.5%, among patients with isolated head injuries (Rogers et al., 2002; Sharma et al., 2007). Older age, subarachnoid hemorrhage, associated lower extremity injury, and higher injury severity scores have been associated with increased risk in patients with moderate to severe brain injury (Sharma et al., 2007). These patients with traumatic injuries and a high DVT rate are also at particularly high risk for PE because patients with head trauma also have relative contraindication to pharmacologic prophylactic anticoagulation (Rogers et al., 2002; Sharma et al., 2007). The overall incidence of DVT in neurosurgical patients is highly variable but may be as high as 50% (Auguste et al., 2004; Browd et al., 2004). The incidence of PE ranges from 1.5% to 5%, with a 9–50% related risk of death (Auguste et al., 2004; Browd et al., 2004). In elective neurosurgical and spine procedures, the risk of DVT is much lower, particularly if patients receive pharmacologic prophylaxis (Sansone et al., 2010). In Japan, the risk of symptomatic VTE in neurosurgical patients is only 0.07–0.22%, but in one small 37 patient series, the lower extremity DVT rate was 13.5% with 60% of those five DVT patients having an asymptomatic PE (Taniguchi et al., 2009). Thus, ascertainment bias remains a problem in determining the true rate of VTE in neurosurgical patients. VTE risk factors in neurosurgical patients include concomitant hemorrhagic or ischemic stroke, spinal cord injury, benign or malignant CNS tumors, the duration of the surgical procedure, and the general duration of hospital immobility (Hamilton et al., 1994; Rogers et al., 2002; Browd et al., 2004; Danish et al., 2004; Sharma et al., 2007; Ageno et al., 2009; Carlile et al., 2010; Ekeh et al., 2010). For spine surgery, the type of case may reflect the underlying VTE risk. A large series of 108 419 cases from the Scoliosis Research Society morbidity and mortality database, reported the 2004–2007 complication rates related to clinically evident VTE for lumbar microdiscectomy, anterior cervical discectomy and fusion, and lumbar

VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE 291 spinal stenosis decompression. The rate of the DVT rate histologic grade 4 tumor, and prolonged surgery (longer was 1.18/1000 and the PE rate was 1.38/1000 cases with a than 4 hours). Mortality is also higher for astrocytoma mortality rate of 0.34/100 cases. The rates were lowest patients with VTE, with a 30% increased risk of death for lumbar microdiscectomy, and highest for spine prowithin 2 years (Browd et al., 2004). The risk of VTE is cedures for metastatic tumors (Smith et al., 2010). The lower in other tumor types but is not insignificant. risk of PE may also be higher in patients undergoing VTE has been recognized as one of the more common combined anterior and posterior surgeries as compared complications in patients with meningiomas though the with posterior spine surgery only (Ozturk et al., 2010). rate is relatively low for this tumor type. Sughrue Overall, the VTE rate in neurosurgical patients is not et al. (2011) reported a series of 834 patients who underhigh. A meta-analysis of patients undergoing elective went craniotomy for meningioma in which 57 (6.8%) had neurosurgical procedures noted that the DVT rate was serious medical complications with a reported clinically just 1.09% and the PE rate was 0.06% ( Sansone et al., symptomatic VTE rate of 0.8% (7/834). 2010). For neurosurgical patients with cancer, however, Stroke patients are also at very high risk for VTE. the VTE rates are much higher. In general, cancer conTong et al. (2010) reported that the prevalence rate of veys upon all patients a particularly significant VTE risk, DVT was 0.8% and the rate of PE was 0.3% for all but patients with central nervous system (CNS) tumors patients hospitalized with ischemic stroke as a primary are at particularly high risk (Hamilton et al., 1994; diagnosis. Medical complications were associated with Semrad et al., 2007). Patients with an intracranial tumor, an increased hospital length of stay in this cohort. Over in an Australian series of 2279 patients treated only with the period from 1998 to 2007, the overall length of stay of sequential compression devices (SCDs), had a higher hospitalized stroke patients declined but remained VTE rate than patients with spinal cord tumors. While unchanged for those patients with medical complicathe overall rate in this series was low; there was a roughly tions (including DVT or PE, stroke-related myocardial 3% VTE rate among the patients with intracranial tumors infarction, or pneumonia). Early stroke-related DVT (Smith et al., 2004). Cumulative rates of symptomatic was studied in a series of 278 ischemic and 12 hemorVTE as high as 30% may occur in patients with brain rhagic stroke patients who underwent venous duplex tumors (Perry et al., 2010). It is hypothesized that ultrasonography (VDU) on day 3 and day 9 (Bembenek tumor-induced hypercoaguable states may be present et al., 2011). DVT occurred in 8% of these stroke patients in patients with malignant astrocytoma, especially in with 83% (24/29) of DVTs occurring at day 3. A subsethe context of higher grade tumors. This VTE risk in quent 3% (9/299) had new onset DVT at day 9. These patients with astrocytoma is attributed to specific coagnewly discovered DVTs increased the risk of 3 month ulation abnormalities, including elevated fibrinopeptide mortality with an odds ration (OR) of 12.4 (95% CI A, elevated fibrinogen fragment Bb 15-32, and 1.72–89.4). Adjusted for stroke severity and prestroke decreased activated partial thromboplastin times with disability, an elevated serum C-reactive protein (CRP) resultant increases in procoagulant activity and platelet was associated with increased risk of DVT (OR 8.75; activation (Hamilton et al., 1994). The astrocytoma95% CI 1.61–47.6) (Bembenek et al., 2011). The risk is associated VTE rate depends upon a number of factors related both to immobility and to a greater risk for hyperincluding ascertainment biases related to the diagnosis coagulable states in patients with stroke. Patients with and associated prophylaxis regimens. Among 9489 cases cryptogenic stroke or transient ischemic attack (TIA) of hospitalized patients with malignant glioma hospitalmay also have a greater risk of silent PE. Patients who ized during a 6 year period in California, the cumulative had a patent foramen ovale (PFO) and underwent V/Q 2 year incidence of VTE was 7.5% with 55% being diagscans were identified from a stroke registry. The evalunosed within 2 months of surgery. Risk factors included ation included 151 patients from the 266 patient registry. histology of glioblastoma multiforme (GBM), older age, In 35% of the patients, a silent PE was found (56/151), and three or more chronic associated medical conditions. though a DVT was identified in only 7% (11/151) of the The presence of VTE conveyed a greater risk of death patients. An atrial septal aneurysm was independently within 2 years (HR 1.3 95% CI 1.2–1.4) (Semrad et al., associated with PE. There was also an association with 2007). VTE rates in the 6 weeks after surgery range from oral contraceptive use and PE among the women in this 3% to 60% (Semrad et al., 2007). Beyond this 6 week series of PFO-related stroke (Tanislav et al., 2011). postoperative period, the VTE rate remains high in astroIn stroke patients, clinical prediction models based on cytoma patients, with symptomatic DVT rates of 24% clinical factors alone were unable to identify immobile reported over the 17 months following initial surgery stroke patients at low versus high risk for DVT (Semrad et al., 2007). Patients with astrocytoma and (Dennis et al., 2011). DVT is a clinically significant comthe following risk factors have a higher VTE risk: age plication in these patients, however. Approximately 75% older than 60 years, larger tumor size, chemotherapy, of patients may develop DVT without prophylaxis

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(Kelly et al., 2001; Adams et al., 2007; Sherman et al., 2007; Kase et al., 2009). PE is also a significant cause of mortality in stroke patients, with upward of 25% of early poststroke deaths attributable to PE (Kase et al., 2009). Most fatal PE occurs within 2–4 weeks after an ischemic stroke. The diagnosis of PE can be challenging in stroke patients who have accompanying cognitive deficits, dysphagia, or speech impairments, and concomitant pneumonia or fever. A high index of clinical suspicion is particularly needed in stroke patients (Kumar et al., 2010). Patients with hemorrhagic stroke have a VTE rate that is roughly 65% higher than patients with ischemic stroke (Skaf et al., 2005). In a single center retrospective series of patients treated for aneurysmal subarachnoid hemorrhage (SAH), the incidence of asymptomatic DVT was 24% in patients who had surveillance screening by VDU. Risks for DVT were higher with greater Hunt and Hess aneurysmal SAH scores, length of ICU stay, and total length of hospital stay (Ray et al., 2009). Patients with neuromuscular and neurodegenerative diseases also have a high VTE risk particularly because of immobility but also because patients with autoimmune states have a greater risk for hypercoagulability (Ageno et al., 2009). The actual incidence in many of these neurologic diseases is not well studied (Ageno et al., 2009). VTE risk was elevated in a number of autoimmune diseases (Ramagopalan et al., 2011). Among them were multiple sclerosis, myasthenia gravis, and dermatomyositis or polymyositis. For multiple sclerosis, the rate ratio ranged from 2.14 to 2.52 in the cohorts studied. For myasthenia gravis, the rate ratio ranged from 2.04 to 2.34. For dermatomyositis or polymyositis, the rate ratio ranged from 1.98 to 3.04. By comparison, the highest rates in this study were seen for systemic lupus erythematosus (rate ratios of 3.61–4.60) and polyarteritis nodosa (rate ratios of 2.88–5.36). Multiple sclerosis patients who are at particular risk for DVT are those who are bedridden or wheelchair bound. In one series of 132 patients, the average duration of illness was 18.7 years and only 25 patients were able to walk with even some assistance. A total of 113/132 patients had lower limb edema. All of these 132 patients had VDU and a DVT was found in 58 patients (43.9%). A total of 32 had a prior history of DVT. D-dimer levels were elevated in 45% (26/58) of patients with DVT and 35% (26/ 74) of patients without DVT. Of note, a number of multiple sclerosis patients had elevated D-dimer with VDU negative DVT. The converse was also true. Thus, D-dimer values may be of limited utility in excluding VTE in multiple sclerosis patients (Arpaia et al., 2010) For Parkinson disease, in a study of 81 patients, the asymptomatic DVT rate, determined by VDU, was 4.9 % (Burbridge et al., 1999). In a Mayo Clinic study

of the morbidity associated with 114 Guillain–Barre´ patients admitted to an intensive care unit, the incidence of DVT was 4%, and the incidence of PE was 3%. The exact details are unknown but the authors suggested that most, if not all, of the patients were on some form of pharmacologic prophylaxis. (Henderson et al., 2003). A retrospective study of 73 patients with Guillain–Barre´ syndrome reported an incidence of symptomatic DVT of 7% (five patients with DVT; three of whom also had PE) (Gaber et al., 2002). Fifty of the 73 patients were on pharmacologic prophylaxis. Of the five patients with DVTs, two were not anticoagulated and the other three were on enoxaparin. Finally, patients who receive intravenous immunoglobulin (IVIG) treatment for neurologic diseases are also at increased risk for thromboembolism complications including VTE (Hommes et al., 2004; Vucic et al., 2004)

GENERAL PRINCIPLES Presentation and diagnosis Frequently, patients with VTE will not have apparent clinical symptoms or have symptoms or signs that can be indistinguishable from other disease states. Thus, for example, extremity swelling due to DVT may be attributed to dependent edema due to paralysis, and pain and burning due to DVT may be attributed to neuropathy in some patients. The classic symptom onset of a DVT is that of an acute painful, enlarged, swollen, and erythematous extremity, but some 50–60% of patients will not have clinical symptoms (Danish et al., 2004). Additionally, a Homan’s sign may be present, but the accuracy of the Homan’s sign is very unreliable with both low sensitivity and specificity. Estimates are that this sign is present in only 33% of patients with DVT, with an accuracy ranging from 8% to 50% for patients with DVT (Urbano, 2001). Similar to DVT, almost 50% of patients with PE have no apparent clinical symptoms. In those instances, PE is typically found in the context of an initial DVT diagnosis (Geerts et al., 2008). The classic symptom presentation of PE includes pleuritic chest pain, variable degrees of shortness of breath, and cardiac dysrhythmias or sinus tachycardia. The signs and symptoms may help to assess pretest probability for PE but are not sufficiently accurate for the exclusion of PE. In these circumstances, arterial blood gases and electrocardiogram may be suggestive but are also not sufficiently accurate to exclude PE. Echocardiography may further hint at a possible PE if there are signs of increased pulmonary arterial pressures such as right heart strain (McConnell’s sign) though this is not a specific sign for PE (Torbicki, 2005). Elevated D-dimers are found in most patients with VTE but may also be present in patients with acute

VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE stroke, myocardial infarction, malignancy, or autoimmune states; patients undergoing recent surgery; or patients with recent history of trauma. Thus the utility of a negative D-dimer serum assay is to further exclude patients at low or intermediate probability for VTE in the outpatient setting (Wells et al., 2003; Thachil et al., 2010). While a positive D-dimer is not diagnostic, a negative D-dimer has a negative predictive value of 99% (Wells et al., 2003). The D-dimer assay is much less useful in the diagnosis of VTE in hospitalized patients where false-positive tests are common (Thachil et al., 2010). Ultimately, the diagnosis of DVT or PE is dependent on confirmatory imaging tests. Contrast venography is the nominal gold standard for the diagnosis but is rarely used because of limited availability, cost, patient discomfort, and a significant risk of contrast-induced thrombosis (Browd et al., 2004; Miller and Lee, 2005). Impedance plethysmography is also rarely used as it does not help to identify nonocclusive thrombus and cannot easily find calf-vein thrombosis. Thus, the mainstay for DVT diagnosis and screening is venous duplex ultrasonography (VDU) (Taniguchi et al., 2009). VDU is a readily available tool that is 89–96% sensitive and 96–100% specific in the diagnosis of significant DVT. VDU has a lower sensitivity (75%) for isolated calf DVT (Browd et al., 2004; Giannoukas, et al., 1995; Stein et al., 2010). In addition to widespread availability at most hospitals, VDU is relatively less expensive, portable, and noninvasive. It can therefore be used in a wide variety of settings including the intensive care unit, emergency department, and ambulatory clinics. Limitations of VDU include dependence on operator skill and problems in visualizing the veins in certain patients. VDU also cannot adequately visualize iliac or pelvic veins. The use of VDU, along with clinical prediction rules, improves the DVT likelihood ratio with a specificity of 98–100% to 0.2 among low-risk patients, 1.3 among moderate-risk patients, and 3.3 among highrisk patients (Thachil et al., 2010). In this regard, MR venous imaging has a distinct advantage compared to VDU for imaging the iliac and other pelvic veins and is also more accurate for imaging of below the knee DVT. When compared to conventional venography, MR imaging has an estimated sensitivity of 91.5% and specificity of 94.8% in pooled estimates for detection of lower extremity DVT. The sensitivity is higher for proximal DVT as opposed to distal DVT (Sampson et al., 2007). MR imaging is still superior to CT venography or VDU. Using MR imaging as the reference standard, VDU has a sensitivity of 93.5% and specificity of 98.0%, and CT venography has a sensitivity of 89–100% and specificity of 94–100% (Sampson et al., 2007; Miller and Lee, 2005). The limitations of MR venography are cost and limited availability.

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Pulmonary angiography is the “gold standard” for the diagnosis of PE. Ventilation/perfusion (V/Q) scans and spiral or helical CT angiography are less invasive and so these are the preferred modalities (PIOPED Investigators, 1990; Coche et al., 2001). The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study demonstrated that a normal V/Q scan excluded PE with high sensitivity and specificity. (PIOPED Investigators, 1990) In this study, a high probability V/Q scan had a 95% positive predictive value for those patients where there was a strong clinical suspicion for PE. In 40–70% of patients, however, a low or intermediate probability V/Q scan result occurred and so V/Q scans were nondiagnostic for exclusion of PE in many patients where there was an intermediate or high pretest PE probability (Kearon et al., 2008). In these patients, further testing that includes DVT screening and/or pulmonary angiography is indicated if there is a sufficiently high suspicion for PE. Unfortunately, high probability V/ Q scan results occur in only 41% of patients with angiographically proven PE, and a negative lower extremity ultrasound occurs in 40% of angiographically proven PE. Conversely, a negative D-dimer assay and a negative lower extremity duplex ultrasound are associated with a negative predictive value of greater than 99% in making a negative diagnosis of PE (Coche et al., 2001; Thachil et al., 2010). Spiral CT is probably superior to V/Q scans for detection of PE. V/Q scans, however, have an advantage in patients who do not have reasonable kidney function or who have contrast dye allergy, for whom spiral CT is therefore contraindicated (Coche et al., 2001). On CT, a pulmonary artery occlusion appears as either a partial or complete filling defect (Fig. 20.1). Spiral CT has a sensitivity of 99% and a specificity of 95% compared to the gold standard of pulmonary angiography (Coche et al., 2001). MR angiography (MRA) of the pulmonary vessels is also an option but is not superior to spiral CT (Stein et al., 2010). The Wells criteria are a useful clinical prediction tool for identifying patients at high risk for VTE. Separate prediction tools exist for DVT and PE (Wells et al., 1997, 2001; Thachil et al., 2010). Among the risk factors incorporated into the DVT prediction tool are: active cancer, asymmetric pitting edema, swelling of the entire leg, asymmetric calf swelling, presence of nonvaricose superficial veins, paralysis or leg immobilization, bedridden > 3 days, history of major surgery in the prior 4 weeks, localized tenderness along the deep venous distribution, and presence of nonvaricose collateral superficial veins. Risk factors incorporated in the Wells predictive criteria for PE without diagnostic imaging include: active cancer, clinical signs of DVT, hemoptysis, tachycardia, immobilization including paresis or

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Fig. 20.1. A 73-year-old woman with a longstanding history of tinnitus and right hearing loss of undetermined etiology had a syncopal episode. At an outside hospital a CT scan revealed a large right cerebellopontine angle mass. On admission, she underwent an echocardiogram for evaluation of the syncope. This echocardiogram showed a hypokinetic right ventricle with decreased contractility sparing the apex (McConnell’s sign). A spiral CT of the pulmonary vessels (coronal cut below) was then obtained. This revealed filling defects with the appearance of pulmonary emboli noted bilaterally in both pulmonary arteries branching into several segmental arteries consistent with multiple pulmonary emboli. There was also mild dilatation of the right pulmonary artery.

leg paralysis, bedridden > 3 days, history of major surgery in the prior 4 weeks, prior DVT or PE, and an alternative diagnosis that is less likely than PE. Additional clinical and historical risk factors conveying particular high risk of DVT or PE include: age 75 years or older, acute spinal cord injury with paralysis, elective major lower extremity surgeries, leg, hip or pelvis fractures, prior history of stroke or trauma, and prior history of VTE (Bahl et al., 2010). Increased risk associated with thrombophilia history or markers were: a history of congenital or acquired thrombophilias, a family history of thrombosis, presence of prothrombin G20210A, factor V Leiden mutations, elevated homocysteine levels and acquired thrombophilias including a positive lupus anticoagulant, and elevated anticardiolipin antibodies.

General treatment issues PROPHYLAXIS Mechanical and/or pharmacologic thromboprophylaxis clearly decreases the incidence of VTE, and all-cause mortality, in hospitalized patients. There are defined advantages and disadvantages for both mechanical

and pharmacologic prophylaxis. Additionally, there may be risk/benefit profile differences between the various pharmacologic agents used for VTE prophylaxis, particularly related to the risk of hemorrhagic complications. This risk of hemorrhagic complications is particularly problematic in patients with neurologic or neurosurgical disease, and the guidelines for VTE prophylaxis established in the general medical and surgical population may not be easily extended to the neurologic patient population (Geerts et al., 2008). VTE prophylaxis entails mechanical prophylaxis, pharmacologic prophylaxis or a combination of both modalities. Mechanical prophylaxis that is achieved by early ambulation, intermittent pneumatic compression (IPC), or sequential compression devices (SCD), has been shown to decrease the risk of DVT (Agnelli et al., 1998; Rogers et al., 2002; Geerts et al., 2008; Kearon et al., 2008; Taniguchi et al., 2009; CLOTS II Investigators 2010; Morris and Woodcock, 2010; Sachdeva et al., 2010). The utility of graduated compression stockings has been debated. A Cochrane metaanalysis of 18 studies suggested that the use of graduated elastic compression stockings was of benefit when used with additional prophylactic therapies (Sachdeva et al., 2010). The CLOTS II (Clots in Legs Or sTockings after Stroke) trials (CLOTS Investigators, 2010) suggested that thigh-length stockings were more effective than below-the-knee stockings in patients with stroke screened by VDU at 7–10 days and 15–20 days posthospitalization. The CLOTS II study reported a proximal DVT rate of 6.3% for thigh-length stockings and 8.8% for below-the-knee stockings. However, skin breakdown occurred in 3.9% of those with thigh-length stockings and in only 2.9% of those with below-the-knee stockings. A caveat of the CLOTS II study was that the results of the CLOTS Trial I of thigh-length stockings versus placebo were not associated with a clinically significant reduction in proximal DVT but were associated with significant skin breakdown events (Dennis et al., 2009). Compression devices (either intermittent pneumatic compression (IPC) or sequential compression devices (SCDs)), may be used with or without elastic stockings. These devices are assumed to prevent DVT by promoting hemodynamic flow and fibrinolytic function. These devices are associated with low risk, though there is a concern that thrombus may be dislodged by an SCD in patients with have undetected or pre-existing extremity thrombus. A systematic review suggested that IPC/ SCD may be associated with a decrease in the rate of DVT but the evidence is weak (Agnelli et al., 1998; Rogers et al., 2002; Kearon et al., 2008; Morris and Woodcock, 2010). The main advantage of mechanical prophylaxis is a reduced risk of bleeding. These devices, however, are still associated with a high rate of DVT.

VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE Among neurosurgical patients treated with SCDs, the DVT rate is as high as 32% (Taniguchi et al., 2009). By contrast, the rate of DVT using pharmacologic prophylaxis in a similar population is much lower. Even with the use of pneumatic compression devices, the incidence of DVT is high with reported rates of 32% in neurosurgical patients. Pharmacologic thromboprophylaxis, however, is associated with a reduction of DVT incidence by up to 50% (Agnelli et al., 1998; Geerts et al., 2008). Pharmacologic options for VTE prophylaxis include unfractionated heparin (UFH), low molecular weight heparins (LMWH), warfarin, factor Xa inhibitors, and indirect or direct thrombin inhibitors. UFH may be administered intravenously or subcutaneously and LMWH are typically given subcutaneously. Recently, new oral anticoagulants that directly inhibit thrombin or activated factor Xa have been approved for VTE prophylaxis and for prophylaxis of systemic embolism and stroke in atrial fibrillation (AF) (Eriksson et al., 2011). These agents have a once or twice daily fixed-dose oral regimen and do not require routine anticoagulant monitoring. Dabigatran, rivaroxaban, and apixaban are some of the new anticoagulants that have been studied for DVT prophylaxis in patients undergoing knee or hip surgery but have not been studied in a wide variety of surgical or medical patients. Among the limitations of these agents are cost and ease of reversibility of their anticoagulant effects, especially in the context of trauma or urgent neurosurgical interventions (Cotton et al., 2011). At this time, VTE pharmacologic prophylaxis typically consists of either UFH or LMWH (Geerts et al., 2008; Kearon et al., 2008) (Table 20.2). Enoxaparin and dalteparin are the most commonly used LMWH in the US. Warfarin, at low doses, is often used as an alternative in patients undergoing hip or knee surgery. For pharmacologic VTE prophylaxis, UFH is administered two or three times daily. The higher dose is slightly more effective with a slightly greater bleed risk. LMWH, by comparison with UFH, is superior for VTE prophylaxis because of a relative risk reduction (RRR) of 58% to 68% for VTE, lower risk of recurrent VTE (RRR 53–68%), lower risk of death (RRR 47%), and a decreased risk of bleeding complications. LMWH has a longer half-life compared to UFH and greater bioavailability, longer duration of action, and less variability in activity because LMWH has a greater ratio of antifactor Xa to antifactor IIa and fewer nonspecific binding proteins. While there has been some concern that LMWH may have a greater bleeding risk because of their greater potency and longer duration, there are no data to support that LMWH conveys a greater risk of bleeding, at least in neurosurgical patients, in whom enoxaparin was reviewed (Browd et al., 2004).

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Table 20.2 Selected drugs for venous thromboembolism treatment or pharmacologic prophylaxis and their doses For deep vein thrombosis or pulmonary embolism prophylaxis: 1. Unfractionated heparin 5000 units subcutaneously (SC) two or three times daily 2. Enoxaparin: ● 40 mg SC daily for venous thromboembolism prophylaxis ● For patients with reduced creatinine clearance (75 years old) and patients with low bodyweight ( > various others including SCLC and NSCLC

Anti-Ma1 (Dalmau et al., 2004; Hoffmann et al., 2008) Anti-amphiphysin (Pittock et al., 2005; Graus et al., 2008) Anti-glutamate (AMPA) receptor (Lai et al., 2009) Anti-GABAR (Lancaster et al., 2010; Boronat et al., 2011) Anti-GAD (Boronat et al., 2011)

Various including SCLC and NSCLC SCLC, breast Various including SCLC and NSCLC SCLC (small number of patients) SCLC

Special clinical features* Ataxia, sensory neuronopathy, and/ or other features of multifocal encephalomyelitis Multifocal involvement of extralimbic cerebral cortex and/ or basal ganglia; polyneuropathy Hyponatremia; sleep disorders; faciobrachial dystonic seizures; neuromyotonia; Morvan syndrome Acute psychosis; central hypoventilation; autonomic instability; catatonia/ movement disorder Diencephalic (sleep disorder and/or autonomic dysfunction); brainstem (mainly ocular motor) Ataxia, brainstem involvement Stiff person syndrome

Neurological outcome{ Generally poor

Variable

Very good

Very good after protracted illness

Improvement in onethird of patients

Generally poor Variable Frequent neurologic relapses Good Good

SCLC, small cell lung carcinoma; NSCLC, non-small cell lung cancers. *Additional features variably present in addition to the features of classic limbic encephalitis; in some patients these features may overshadow the limbic component. { After tumor treatment and/or immunotherapy. { In most patients with anti-VGKC antibodies the antibody reactivity is actually against one or more proteins complexed with VGKC.

patients develop symptoms or signs of multifocal encephalomyelitis. Paraneoplastic cerebellar degeneration in patients with SCLC may occur in conjunction with paraneoplastic peripheral neuropathy or Lambert–Eaton myasthenic syndrome (Mason et al., 1997; Graus et al., 2002; Fukuda et al., 2003). The neurologic deficits in

paraneoplastic cerebellar degeneration generally worsen over a period of several weeks to months and then stabilize at a level of severe disability (Shams’ili et al., 2003). Anti-Hu antibodies are the most common onconeural antibodies among patients with paraneoplastic cerebellar degeneration and lung cancer (Mason et al., 1997; Shams’ili et al., 2003) (Table 22.3). The great majority

NEUROLOGIC COMPLICATIONS OF LUNG CANCER of patients have SCLC. Other patients with cerebellar degeneration have anti-CV2 antibodies (Hoffmann et al., 2009), anti-Zic4 antibodies (Bataller et al., 2004), or one of a number of less common autoantibodies. Anti-Yo and anti-Tr antibodies which are strongly associated with breast or ovarian cancer, or with Hodgkin lymphoma (respectively), are rarely associated with lung carcinoma.

OPSOCLONUS-MYOCLONUS Opsoclonus is defined as chaotic, continuous multidirectional rapid eye movements (saccadic oscillations) without an intersaccadic interval. Opsoclonus as a paraneoplastic disorder is less common in adults than in children and most often occurs in association with SCLC or breast carcinoma, occasionally with NSCLC (Bataller et al., 2001; Pittock et al., 2003). The neurologic symptoms and signs which accompany paraneoplastic opsoclonus in adults are heterogeneous and include multifocal limb myoclonus, pancerebellar dysfunction, and signs and symptoms of brainstem dysfunction, including vertigo, vomiting, dysphagia, and gaze palsy. A small number of autopsied cases variably implicate injury to cerebellar neurons and/ or to brainstem ocular motor nuclei in opsoclonus, but the exact pathophysiology remains unclear. Anti-Hu, anti-Ri (ANNA-2), anti-CV2, or antiamphiphysin antibodies are present in some patients with opsoclonusmyoclonus and SCLC or NSCLC (Pittock et al., 2003). Other patients with lung cancer and opsoclonusmyoclonus have no identifiable onconeural antibodies, or have one of several unnamed “atypical” antibodies with heterogeneous patterns of reactivity (Bataller et al., 2003).

EXTRAPYRAMIDAL SYNDROME Chorea, athetosis, dystonia, or parkinsonism are rare manifestations of paraneoplastic encephalitis, occurring most often in association with SCLC and rarely with NSCLC, lymphoma, thymoma, or other tumors (Vigliani et al., 2011). The extrapyramidal features may occur with or without other signs of multifocal encephalomyelitis. In most patients MRI shows focal lesions in the basal ganglia. Anti-Hu and anti-CV2 are the most commonly associated antibodies.

BRAINSTEM ENCEPHALITIS Paraneoplastic brainstem encephalitis manifests as a variety of gaze palsies or other ocular motor disturbance, possibly together with dysarthria, dysphagia, facial weakness, vertigo, central respiratory failure, or other signs and symptoms referable to the brainstem (Saiz et al., 2009). This most commonly occurs in the setting of multifocal encephalomyelitis associated with

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SCLC, or in patients with testicular germ cell tumor who generally have additional limbic and/or hypothalamic involvement. Most patients with SCLC have anti-Hu antibodies. The neurologic outcome is generally poor; in some patients the brainstem dysfunction proves fatal.

OPTIC NEURITIS Optic neuritis is a rare complication of SCLC, breast carcinoma, or other tumors. Patients present with unilateral or bilateral decreased visual acuity, afferent pupillary defects, cecocentral scotomas, and disc edema. Some patients have serum anti-CV2 or other antineuronal antibodies (Cross et al., 2003; Hoffmann et al., 2009).

CARCINOMA-ASSOCIATED RETINOPATHY More than 75% of reported patients with carcinomaassociated paraneoplastic retinopathy have SCLC (Adamus et al., 2004; Ohguro et al., 2004). There are a few reported patients with NSCLC. In nearly all patients the visual symptoms precede discovery of the tumor by intervals ranging from several months up to 2 years or more. The initial symptoms are most often a painless bilateral but asymmetric dimming or blurring of vision. Night blindness is common and may be the sole initial complaint. Many patients report episodic obscurations or positive symptoms described as distortions, “sparkles,” “shimmering,” or bizarre images. Some patients report visual glare or photosensitivity. Examination usually shows severely impaired visual acuity, with relative sparing of color vision. Some patients have a relative afferent pupillary defect. The most common visual field deficits are asymmetric central or ring scotomas and concentric constriction. The electroretinogram in almost all patients is flat or nearly so, reflecting diffuse dysfunction of both rod and cone photoreceptor cells. In most patients the visual symptoms worsen to severe impairment over several weeks to months, either in a steady or stepwise course. The great majority of patients with lung cancer and paraneoplastic retinopathy have circulating autoantibodies against the 23 kd calcium-binding protein recoverin. A minority of patients have antibodies against one of a number of other retinal proteins. Antirecoverin antibodies are occasionally present in patients with retinopathy but no identifiable neoplasm.

MYELOPATHY Patients with paraneoplastic encephalomyelitis associated with SCLC or NSCLC may present with a predominant myelopathy syndrome. Spine MRI in some patients

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shows focal or longitudinally extensive T2-weighted signal abnormality, with or without gadolinium enhancement. Some patients have myelopathy with rigidity, myeloradiculopathy, or myelopathy plus optic neuritis (Devic syndrome) (Cross et al., 2003; Pittock et al., 2005; Flanagan et al., 2011). Associated antibodies include anti-Hu, anti-CV2, and antiamphiphysin. Paraneoplastic necrotizing myelopathy is a rare syndrome which may occur in association with a variety of carcinomas and lymphoid tumors. Patients develop a rapidly ascending level of flaccid paralysis and numbness, often leading to death from respiratory failure or medical complications.

STIFF PERSON SYNDROME A syndrome of muscle rigidity and spasms which clinically resembles the “stiff person syndrome” is associated with a variety of neoplasms, including SCLC. Rigidity is probably caused by multifocal encephalomyelitis affecting the spinal cord and/or brainstem. Patients develop progressive aching and rigidity of the axial and proximal limb musculature, usually asymmetric at onset. There are superimposed painful and sometimes violent spasms, either occurring spontaneously or triggered by voluntary movement, passive movement, or sensory stimuli. Patients may eventually develop fixed flexion of the limbs or even opisthotonos and respiratory difficulty. Some patients with SCLC have antibodies against the synaptic vesicle-associated protein amphiphysin (Dropcho, 1996; Pittock et al., 2005).

MOTOR NEURON DISEASE Paraneoplastic motor neuron dysfunction occurs in a variety of different settings. Lower motor neuron signs and symptoms are among the presenting or predominant manifestations in up to 25% of patients with SCLC and multifocal encephalomyelitis associated with anti-Hu or other antibodies (Graus et al., 2001). Motor neuron involvement in these patients does not usually improve with treatment. There are several well-described patients with a lower motor neuron syndrome or combined upper and lower motor neuron syndrome who had significant neurologic improvement after resection of lung carcinoma.

SUBACUTE SENSORY NEURONOPATHY The most common clinical manifestation of paraneoplastic encephalomyelitis is subacute sensory neuronopathy reflecting involvement of the dorsal root ganglia (Dalmau et al., 1992; Graus et al., 2001; Sillevis Smitt et al., 2002). More than 90% of reported patients have SCLC; a very small percentage have NSCLC. Early

symptoms are patchy or asymmetric numbness and paresthesias, often involving face, trunk, or proximal limbs. The symptoms eventually spread to involve all limbs. Burning dysesthesias and severe aching or lancinating pain are common. Examination reveals severe sensory ataxia, predominant impairment of vibration sense and proprioception, frequent pseudoathetosis, and hypoactive or absent muscle stretch reflexes. Most patients cannot walk unassisted due to pain and profound loss of proprioception. A minority of patients have prominent pain and mechanical hyperalgesia with at least partial preservation of large fiber sensibility and muscle stretch reflexes (Oki et al., 2007). Most patients have additional signs and symptoms that reflect a multifocal encephalomyeloneuritis. The characteristic electrophysiologic profile of paraneoplastic sensory neuronopathy includes severely reduced amplitude or complete absence of sensory nerve potentials, with normal or only slightly reduced sensory nerve conduction velocities if a response is able to be elicited. Most patients do show at least minor abnormalities in motor nerve conduction studies, with or without symptoms of a mixed sensorimotor polyneuropathy (Camdessanche et al., 2002; Oh et al., 2005a). The clinical course of sensory neuronopathy in patients with SCLC is fairly stereotyped. By far the most common pattern is deterioration over a period of weeks to months, and then stabilization at a level of severe neurologic disability, regardless of treatment. Other patients have subsequent stepwise or gradual neurologic deterioration. A few patients have minimal CNS manifestations and a sensory neuronopathy that takes a relatively indolent course independent of any treatment (Graus et al., 1994).

NEUROMYOTONIA Patients with SCLC may develop peripheral nerve hyperexcitability which manifests as the “cramp-fasciculation syndrome” or as a syndrome of diffuse muscle stiffness, cramps, and myokymia similar to neuromyotonia or continuous muscle fiber activity (Isaacs’ syndrome) (Hart et al., 2002). Needle EMG shows repetitive bursts of rapidly firing motor unit discharges (myokymic potentials) and/or very high-frequency trains of discharges. Some patients have serum antibodies against proteins in the voltage-gated potassium channel complex, including contactin-associated protein-2 (Caspr2) (Irani et al., 2010b, 2012). Morvan syndrome (neuromyotonia, neuropsychiatric symptoms, dysautonomia, sleep disturbance, and neuropathic pain) is most often associated with thymoma, but may rarely occur in association with lung carcinoma.

NEUROLOGIC COMPLICATIONS OF LUNG CANCER 353 the relatively minor abnormalities seen on neurologic OTHER NEUROPATHIES examination. Symmetric weakness predominantly Rather than the more common sensory neuronopathy, a affects proximal leg muscles, and to a lesser extent minority of patients with SCLC and anti-Hu antibodies shoulder girdle muscles. Over time the weakness tends have a mixed sensorimotor polyneuropathy with a mixed to progress from proximal to distal muscles. Myalgia axonal-demyelinating electrophysiologic pattern (Oh and/or distal paresthesias are not uncommon. Muscle et al., 2005a). A few patients with anti-Hu antibodies stretch reflexes are characteristically diminished have what appears to be a primary demyelinating polyor absent. Over the course of illness, 90% of patients neuropathy superimposed on sensory neuronopathy. eventually develop symptoms of sympathetic or paraMononeuritis multiplex with biopsy-proven nerve vascusympathetic autonomic dysfunction, including dry litis can occur in association with SCLC or NSCLC, with or mouth, erectile dysfunction, blurred vision, constipawithout anti-Hu antibodies (Oh, 1997). Patients with antition, difficulty with micturition, orthostasis, and hypohiCV2 antibodies (most of whom have SCLC) may develop drosis. About one-third of patients have dysphagia, a sensorimotor polyneuropathy with mixed axonalptosis, or diplopia, which are generally mild and occur demyelinating electrophysiologic features (Antoine in the setting of significant limb weakness. et al., 2001; Hoffmann et al., 2009). Some of these The characteristic electrophysiologic profile of patients have both anti-Hu and anti-CV2 antibodies. LEMS includes reduced amplitude of muscle action potentials, a significant increase in amplitude of comAUTONOMIC INSUFFICIENCY pound muscle action potentials after several seconds of maximal voluntary contraction, a decremental Paraneoplastic autonomic dysfunction most commonly response at low rates of repetitive nerve stimulation, occurs as a part of encephalomyelitis in patients with and an incremental response at high rates of stimulation SCLC, or rarely in patients with NSCLC or other tumors. (Oh et al., 2005b). The electrophysiologic abnormalities In some patients the autonomic symptoms overshadow are often detected in clinically unaffected muscles, other manifestations of encephalomyelitis. These though not all muscles are equally affected. patients may develop severe and progressive gastrointesThe primary pathophysiologic abnormality in LEMS tinal dysmotility, with gastroparesis, chronic intestinal is a reduction of the calcium-dependent quantal release pseudo-obstruction, and severe constipation/obstipaof acetylcholine triggered by a nerve impulse. Ultrastruction, presenting up to several months prior to discovery tural studies of muscle from LEMS patients show a of the tumor (Condom et al., 1993; Lee et al., 2001; marked depletion of presynaptic active zones (the sites McKeon et al., 2009). Patients may also have other feaof synaptic vesicle exocytosis), paucity and disorganizatures of sympathetic dysfunction (e.g., orthostatic hypotion of active zone intramembrane particles, and aggretension or anhidrosis) and/or parasympathetic gation of the active zone particles into clusters. Active dysfunction (e.g., dry mouth, urinary retention, or impozone particles contain P/Q-type voltage-gated calcium tence). Patients generally have a poor neurologic outchannels that mediate the quantal release of acetylchocome and are at risk for sudden unexplained death. line in response to nerve impulses. Several lines of clinical and experimental evidence LAMBERT–EATON MYASTHENIC SYNDROME support an autoimmune etiology for LEMS. Passive Approximately one-half of patients with Lambert–Eaton transfer and in vitro experiments using sera from LEMS myasthenic syndrome (LEMS) have an associated neopatients have shown that autoantibodies against presynplasm, which is SCLC in over 90% of well-documented aptic P/Q-type voltage-gated calcium channels cross-link cases (O’Neill et al., 1988; Chalk et al., 1990; Sanders, and downregulate the channels, thereby blocking the 2003; Titulaer et al., 2011a). Conversely, LEMS is the sinnerve impulse-evoked release of acetylcholine. gle most frequent neurologic paraneoplastic syndrome The autoantibodies also impair neurotransmitter associated with SCLC. LEMS may also occur rarely in release from parasympathetic and sympathetic neurons. patients with NSCLC (Grommes et al., 2008). In at least Serum antibodies against P/Q-type voltage-gated cal75% of patients with paraneoplastic LEMS, the neurocium channels are found in over 90% of paraneoplastic logic symptoms precede discovery of the associated neoor nonparaneoplastic LEMS patients (Motomura et al., plasm; this interval is usually less than 6 months but may 1997). Patients with nonparaneoplastic LEMS cannot be be as long as 5 years. absolutely distinguished from paraneoplastic cases by Most patients with LEMS have an insidious and gradtheir neuromuscular symptoms, electrophysiologic abnorual onset of weakness and fatigue (Titulaer et al., 2011a). malities, or by the presence or titer of anticalcium channel Early in the course there is often a discrepancy between antibodies. A more rapid progression of neurologic symppatients’ subjective weakness and easy fatigability and toms is somewhat more likely among paraneoplastic

354 E.J. DROPCHO LEMS patients (Titulaer et al., 2011a). In patients Most patients with paraneoplastic LEMS improve presenting with LEMS, factors predictive of SCLC neurologically with successful treatment of the associinclude current or prior cigarette smoking, age over ated SCLC (Titulaer et al., 2011a). Pyridostigmine is of 50 years, poor performance status, erectile dysfunction benefit but is generally less effective for LEMS than in men, and early bulbar weakness (Titulaer et al., for myasthenia gravis. The potassium channel antago2011b). Some patients with paraneoplastic LEMS have nist 3,4-diaminopyridine prolongs the action potential concomitant cerebellar degeneration, multifocal encephaat motor nerve terminals and improves strength in nearly litis, or neuropathy. all patients with LEMS (Sanders, 2003). For patients with Antibodies against the SOX1 transcription factor are paraneoplastic LEMS who are receiving or will receive present in nearly two-thirds of patients with LEMS assotumor treatment, it is usually reasonable to use pyridosciated with SCLC but only in 5% of patients with nonpartigmine and/or diaminopyridine, and to defer immunoaneoplastic LEMS (Sabater et al., 2008; Titulaer et al., therapy, since many of these patients will improve 2009). Anti-SOX antibodies are also present in 40% of with successful tumor treatment. If this is not an option patients with SCLC but without neurologic symptoms. or patients still have severe weakness, prednisone and/or Anti-SOX antibodies are not directly involved in the azathioprine are generally effective after a lag period of pathogenesis of LEMS, but this seems to be a valuable several weeks or longer. Ciclosporin may be used for serologic marker for SCLC. patients who do not respond to or tolerate corticosteroids or azathioprine. Plasma exchange or intravenous MYOPATHIES immunoglobulin produce improvement in most patients, usually lasting from 2 to 3 months. There are anecdotal Lung cancer is one of several neoplasms that may occur reports of response to rituximab (Maddison et al., 2011). in association with dermatomyositis (Buchbinder et al., Successful tumor treatment and/or immunosuppres2001; Hill et al., 2001; Fardet et al., 2009). In most sive therapy often results in significant neurologic patients the myositis and the associated neoplasm are improvement for patients with several other syndromes, diagnosed within a short time of each other. There is including neuromyotonia and stiff person syndrome. For nothing distinctive about the neurologic symptoms, these syndromes it is postulated that onconeural antiEMG findings, muscle pathology, clinical course, or bodies cause neuronal or peripheral nerve dysfunction response to immunotherapy in patients with paraneobut not neuronal cell death, allowing for recovery if plastic myositis, though some reports suggest a more the autoimmune response can be suppressed. severe course of dermatomyositis in paraneoplastic Most patients with paraneoplastic retinal degenerapatients. A few published patients with polymyositis or tion and antirecoverin antibodies treated with prednidermatomyositis had significant neurologic improvesone show mild to moderate vision improvement, ment after treatment of the associated tumor, without often prior to discovery of the underlying neoplasm. immunosuppressive therapy. Some patients have a fluctuating steroid-dependent Severe necrotizing myopathy is a rare complication of course or deteriorate after an initial partial response. lung carcinoma or other neoplasms (Levin et al., 1998). There are no definite reports of visual improvement Patients develop severe, rapidly progressive weakness following surgery or chemotherapy of SCLC without with marked elevation of serum creatine kinase. Muscle concomitant corticosteroid therapy. Intravenous immubiopsy or autopsy show diffuse, extensive muscle fiber noglobulin may also be beneficial. degeneration and necrosis with minimal or no inflammaAs a group, adults with paraneoplastic opsoclonustory reaction. A few patients improved after tumor myoclonus have a better neurologic outcome than resection and corticosteroids, while others were severely patients with paraneoplastic cerebellar degeneration or disabled or died of bulbar and respiratory weakness. encephalomyelitis. In some patients the opsoclonus and other neurologic features spontaneously improve Treatment and outcomes prior to any therapy (Pittock et al., 2003). Some patients There is a wide spectrum of neurologic outcomes in show significant neurologic improvement with successpatients with paraneoplastic neurologic disorders folful treatment of the associated tumor (Bataller et al., lowing tumor treatment, with or without immunosup2001), or with corticosteroids, plasma exchange, or intrapressive therapy. For many syndromes there is venous immunoglobulin (Pittock et al., 2003). Other increasing evidence that successful tumor treatment is patients with SCLC show little neurologic response to a major factor in determining neurologic outcome, therapy and are left with severe neurologic disability. and that immunotherapy is more likely to be effective The neurologic course of paraneoplastic limbic when the tumor is also treated successfully (Graus encephalitis is variable and partly related to the type et al., 2001; Sillevis Smitt et al., 2002). of associated onconeural antibody. A few patients with

NEUROLOGIC COMPLICATIONS OF LUNG CANCER clinically “pure” limbic encephalitis show spontaneous neurologic improvement prior to any treatment (Sillevis Smitt et al., 2002). Overall, 30–50% of patients with limbic encephalitis and SCLC improve after tumor treatment, with or without immunotherapy (Dalmau et al., 1992; Alamowitch et al., 1997; Gultekin et al., 2000). Among patients with anti-Hu antibodies in whom limbic encephalitis is a component of multifocal encephalomyelitis, the “limbic” features may improve after tumor treatment, even if the other neurologic features do not improve. The most favorable neurologic outcomes among patients with lung cancer and limbic encephalitis are associated with antibodies against voltage-gated potassium channel-associated proteins (Irani et al., 2010b) or with anti-NMDAR antibodies (Dalmau et al., 2011). Some of these patients recover nearly completely. Some but not all patients with limbic encephalitis and other antibodies (e.g., anti-Ma2, antiAMPA, anti-GABAR) show at least partial neurologic improvement after therapy (Dalmau et al., 2004; Lai et al., 2009; Lancaster et al., 2010). The poorest neurologic outcomes among patients with lung cancer and paraneoplastic disorders are those with cerebellar degeneration (Keime-Guibert et al., 2000; Shams’ili et al., 2003), or with encephalomyelitis or other syndrome associated with anti-Hu antibodies (KeimeGuibert et al., 1999; Graus et al., 2001; Sillevis Smitt et al., 2002; Oh et al., 2005a). Fewer than 10% of these patients show significant neurologic improvement after successful tumor treatment and attempts at aggressive immunosuppressive therapy with corticosteroids, cyclophosphamide, intravenous immunoglobulin, or plasma exchange. Exceptional patients do improve with immunotherapy. For these few responders, the only factors which sometimes correlate with neurologic improvement are successful tumor treatment, and the duration and severity of neurologic deficits prior to diagnosis and initiation of therapy. For patients who have already stabilized at a plateau of severe neurologic disability for more than several weeks, subsequent improvement with any intervention is not impossible but extremely unlikely. The decision whether to try immunosuppressive therapies must therefore be based on the particular syndrome and on the individual patient’s circumstances. There are several potential explanations for the disappointingly poor response to immunotherapy in many patients. As noted above, the continuing presence of even a small tumor burden seems to provide an “antigenic drive” for further neuronal injury. It is also likely that current immunotherapies do not adequately gain access to the central nervous system, and do not effectively abrogate an ongoing autoimmune response which is sequestered in the central nervous system. Unfortunately, for many central syndromes it is likely that

355

patients have already suffered neuronal death or irreversible injury by the time the diagnosis of a paraneoplastic disorder is made. There is theoretical concern that if paraneoplastic disorders arise from an immune response directed against the tumor, attempts to treat the neurologic disorder with immunosuppression may adversely affect the evolution of the tumor. At this time, there is no definite evidence that patients given immunosuppressive treatment have a worse tumor outcome (Keime-Guibert et al., 1999).

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 23

Neurologic complications of electrolyte disturbances and acid–base balance ALBERTO J. ESPAY* James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, UC Neuroscience Institute, University of Cincinnati, Cincinnati, OH, USA

INTRODUCTION The complex interplay between respiratory and renal function is at the center of the electrolytic and acid-based environment in which the central and peripheral nervous systems function. Neurological manifestations are accompaniments of all electrolytic and acid–base disturbances once certain thresholds are reached (Riggs, 2002). This chapter reviews the major changes resulting from alterations in the plasma concentration of sodium, potassium, calcium, magnesium, and phosphorus as well as from acidemia and alkalemia (Table 23.1).

HYPONATREMIA History and terminology Hyponatremia applies to a plasma sodium concentration of less than 135 mmol/L. As sodium is the major osmotically active solute in the extracellular compartment, hyponatremia is of concern to neurologists insofar as it may reduce plasma osmolality below 285 mmol/L. In the setting of hypo-osmolality, water osmotically flows from the plasma and interstitial fluid into the intracellular compartment, with resulting intracellular edema and decreased cellular function (Adrogue and Madias, 2000b). Hence, the main concern with hyponatremia is the potential induction of brain edema and secondary intracranial hypertension (Nathan, 2007). Sodium and osmolality should both be low in the presence of true hyponatremia (hypotonic). Pseudohyponatremia occurs in the setting of hyperlipidemia or hyperproteinemia, when the plasma osmolality is normal (isotonic), or with

hyperglycemia or mannitol intake, when plasma osmolality is high (hypertonic) due to the presence of either of these osmotically active substances (Weisberg, 1989; Lippi and Aloe, 2010). True or hypotonic hyponatremia is always due to a relative excess of water compared to sodium, and can occur in the setting of hypovolemia, euvolemia, and hypervolemia (Table 23.2), invariably reflecting an abnormal relationship between water and sodium, whereby the former is retained at a rate faster than the latter (Milionis et al., 2002). Homeostatic mechanisms protecting against changes in volume and sodium concentration include sympathetic activity, the renin– angiotensin–aldosterone system, which cause resorption of sodium by the kidneys, and the hypothalamic arginine vasopressin, also known as antidiuretic hormone (ADH), which prompts resorption of water (Eiskjaer et al., 1991). The release of ADH from its storage in the neurohypophysis is activated when the plasma volume is low and/or osmolality high, and acts by decreasing the maximum daily urine volume and correspondingly increasing the minimum urinary concentration (Kjaer, 1996). If ADH activity is very low, as much as 12 L of urine may be excreted daily and the minimum urinary concentration can be as little as 50 mmol/L. If ADH activity is at its maximum, only 0.5 L of urine can be excreted daily and the minimum urinary concentration may be as high as 1200 mmol/L (Robertson, 2006). Increased ADH activity, maximally limiting excretion of water, is the most common cause of hyponatremia. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is used to identify excessively released ADH despite normal plasma volume.

*Correspondence to: Alberto J. Espay, M.D., M.Sc., Associate Professor of Neurology, James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, UC Neuroscience Institute, Department of Neurology, University of Cincinnati, 260 Stetson St., Suite 3200, Cincinnati, OH 45267-0525, USA. Tel: þ1-513-558-4035, Fax: þ1-513-558-7015, E-mail: alberto. [email protected]

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Table 23.1 Major electrolyte and acid–base disturbances

Hyponatremia Hypernatremia

Definition

Major neurological manifestation

Sodium < 135 mmol/L Osmolality < 285 mmol/L Sodium > 145 mmol/L Osmolality > 295 mmol/L

Muscle cramps, hyporeflexia, encephalopathy, seizures Weakness, hyperreflexia, rigidity, tremor, chorea, or myoclonus and encephalopathy with seizures Weakness with normal reflexes, ascending weakness with sparing of cranial nerves, paresthesias

Hypokalemia

Potassium < 3.5 mmol/L

Hyperkalemia

Potassium > 5 mmol/L

Hypocalcemia

Hypercalcemia

Calcium < 8.2 mg/dL Ionized calcium 10.5 mg/dL

Hypomagnesemia

Magnesium < 0.6 mmol/L

Hypermagnesemia

Magnesium > 2 mmol/L

Hypophosphatemia

Phosphorus < 0.8 mmol/L

Acidosis

Serum pH < 7.35

Alkalosis

Serum pH > 7.44

Weakness with hyporeflexia, ascending weakness with sparing of cranial nerves, burning paresthesias Tetany, trismus, opisthotonus, encephalopathy, seizures, Chvostek’s sign, Trousseau’s sign Encephalopathy, myoclonus, rigidity, proximal weakness and hyperreflexia Tetany with Chvostek’s and Trousseau’s signs, encephalopathy, seizures, hyperreflexia, tremor, chorea, and myoclonus with startle Acute flaccid areflexic paralysis with respiratory insufficiency (may mimic a midbrain syndrome) Acute areflexic paralysis with diaphragmatic, pharyngeal, facial, and extraocular weakness preceded by perioral paresthesias Encephalopathy, visual impairment, asterixis, increased intracranial pressure (papilledema) Encephalopathy, seizures, tremor, myoclonus, circumoral/limb paresthesias, Chvostek’s sign, tetany, hyperreflexia

Perils of rapid or aggressive treatment Central pontine myelinolysis Brain edema with seizures and coma Cardiac arrhythmias; hypocalcemic tetany with concurrent hypocalcemia Cardiac arrhythmias, especially when failing to coadminister calcium Digitalis toxicity in patients on digoxin Furosemide may worsen hypercalcemia in the presence of heart failure Weakness

Ischemic heart disease, arrhythmias, preeclampsia, asthma Hypocalcemia-related complications

Hypokalemic arrhythmias if potassium is not replaced prior to insulin in diabetic ketoacidosis Failure to correct hypocalcemia first may lead to hypocalcemic tetany

Acute areflexic flaccid paralysis with respiratory insufficiency can occur in hypermagnesemia and hypophosphatemia. Untreated hyperkalemia may cause chronic flaccid quadriplegia. Instead, hypokalemia, hypernatremia, and hypercalcemia lead to hypereflexic weakness. Derangements in potassium and hypermagnesemia do not affect the central nervous system. Sodium disorders, hypocalcemia and hypomagnesemia are common causes of encephalopathy with seizures. Hypercalcemia produces encephalopathy rarely with seizures (Castilla-Guerra et al., 2006).

Clinical findings More than any other electrolytic disturbance, the symptoms and signs of hyponatremia are primarily neurologic due to the resulting cerebral edema (Table 23.3). In acute hyponatremia, occurring within 48 hours, the rapid brain adaptation (see section on pathophysiology) is insufficiently compensatory and patients are more likely to

be symptomatic. Chronic, slow reductions in sodium concentration occurring over days to weeks allow the brain to adapt and patients to remain asymptomatic or have only subtle findings on neurological examination. Consequently, the sodium level is not a good predictor of whether a patient will be symptomatic: relatively mild hyponatremia (e.g., 125 mmol/L) can cause seizures and

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Table 23.2 True (hypotonic) hyponatremia in the three volume states Hypovolemia

Normovolemia

Hypervolemia

Disorders

Renal: diuretic excess, renal tubular acidosis Extrarenal: diarrhea, vomiting, burns

Psychogenic polydipsia Hypothyroidism Adrenal insufficiency SIADH

Urine sodium* low: 20 mmol/L Treatment

Renal: high Extrarenal: low

Polydipsia: high Other disorders: low

Renal failure Nephrotic syndrome Congestive heart failure Liver failure Excessive water intake Renal failure: high Other disorders: low

Plasma volume restoration: isotonic saline (0.9% NaCl)

Chronic: fluid restriction to correct sodium at < 12 mmol/L per day Acute: IV furosemide, hypertonic saline (3% NaCl) to correct sodium at 1–2 mmol/L/hour

Correction of underlying disorder; fluid restriction

*Urine sodium concentration is a not a reliable marker of volume status in patients with renal failure, increased renal fluid loss from diuretics, or metabolic alkalosis. SIADH, syndrome of inappropriate secretion of antidiuretic hormone, IV, intravenous.

Table 23.3 Symptoms and signs of hyponatremia Symptoms

Signs

Nausea, vomiting Anorexia Headaches Lethargy Disorientation Muscle cramps

Seizures Coma Hyporeflexia Cheyne–Stokes respiration Respiratory depression Hypothermia

coma if it develops within 48 hours. Conversely, a patient with more severe hyponatremia (e.g., 118 mmol/L) may be asymptomatic if it has developed it over weeks or months. In order of severity, patients may develop anorexia, nausea, and vomiting, followed by headache, blurred vision, lethargy and disorientation, irritability, and muscle cramps. Abnormal sensorium, seizures, and coma may ultimately develop (Lien and Shapiro, 2007). Left untreated, progressive cerebral edema may lead to brain herniation (Mulloy and Caruana, 1995). Hyporeflexia and muscle cramps are helpful clinical features that are more often present in hypo- than hypernatremia.

Laboratory investigations Plasma osmolality may be normal, that is, between 285 and 295 mmol/L (hyperlipidemia or hyperproteinemia), or high, greater than 295 mmol/L (hyperglycemia or mannitol

administration) in cases of pseudohyponatremia, where the treatment differs radically to what is laid out below. Plasma osmolality can be calculated using the formula: 2  ½sodium mmol=L þ ½BUN  mg=dL=2:8 þ ½glucose mg=dL=18 Plasma osmolality less than 285 mmol/L confirms the presence of true (hypotonic) hyponatremia (Hoorn et al., 2005). Besides plasma osmolality, ascertaining volume status helps to narrow the differential diagnosis. In hypovolemic hyponatremia, urine sodium concentration can be used to distinguish renal from extrarenal fluid loss. Only in renal hypovolemia, such as in renal failure or in the setting of diuretic use, may patients have a urine sodium concentration >20 mmol/L (kidneys are unable to concentrate urine by retaining sodium) (Reddy and Mooradian, 2009). Extrarenal volume losses, when urine sodium concentration is 20 mmol/L and the urine osmolality is >200 mmol/L higher than plasma (Fenske and Allolio, 2010) Confirming inappropriate release of ADH in the absence of hypovolemia or hyperosmolality (the usual stimuli for ADH release) requires investigations for a large number of etiologies, including autoimmune, infectious, vascular, and iatrogenic disorders (Table 23.4) (De and Demanet, 1976; Hannon and Thompson, 2010).

Pathophysiology Hyponatremia causes osmotic shifts of water from the hypotonic extracellular compartment into the relatively hypertonic intracellular compartment, with resulting brain edema, decreased cerebral blood flow, and cerebral compression (Hoorn and Zietse, 2008). The increased pressure from brain edema causes fluid to move from the interstitium into the cerebral spinal fluid (CSF). The shunting of CSF to the systemic circulation relieves some of the intracranial pressure. Also, in hypovolemic hyponatremia, where symptoms are due to hypovolemia rather than hyponatremia, volume depletion stimulates ADH release, which limits the excretion of water (Hoorn and Zietse, 2008). Additional adaptive responses include releasing intracellular potassium (rapid adaptation) and organic solutes or osmolytes such as inositol, glutamine, glutamate, and taurine (slow adaptation, 24–48 hours after onset of hyponatremia), in an effort to decrease the osmotic gradient drawing water into the neurons (Diringer and Zazulia, 2006).

Management Slow correction of hyponatremia (8–10 mmol/L/day) is always preferred with normal saline (0.9%). Too slow a

correction, however, may lead to death from brain edema (Vaidya et al., 2010). Rapid correction of the hypotonic state may lead to brain shrinkage and osmotic demyelination of pontine and/or extrapontine neurons (central pontine or extrapontine myelinolysis (CPM)) that can express as quadriplegia, pseudobulbar palsy, seizures, coma, and death (Mount, 2009). The more severe and chronic the hyponatremia, and the faster the correction rate, the likelier it becomes that CPM may develop (Brunner et al., 1990). This complication of rapid correction of chronic hyponatremia is more common among those with comorbid alcoholism, malnutrition, hypokalemia, liver disease, and malignancy (Dellabarca et al., 2005; Heng et al., 2007). Similar complications may occur during rapid osmotic shifts in plasma (Fig. 23.1). In acute hyponatremia, when brain adaptation has not fully occurred, rapid correction is warranted and risk of central pontine or extrapontine myelinolysis is minimal (Soupart and Decaux, 1996). Treatment is also guided by volume status since the focus of correction varies from restoration of normal plasma volume in hypovolemic hyponatremia to treating the underlying disorder in hypervolemic hyponatremia (Table 23.2). In normovolemic hyponatremia, the primary goal of correcting acute symptomatic (rapidly) and chronic asymptomatic hyponatremia (gradually, no faster than 0.5 mmol/L per hour or 12 mmol/L per 24 hours) is restricting water intake to below the maximum daily urine volume (Soupart and Decaux, 1996). The water excess to be removed by this water restriction strategy in both acute symptomatic and chronic asymptomatic hyponatremic patients can be calculated as follows: Weight ðkgÞ  ½0:6 in men OR 0:5 in women  ð1  ½sodium=125Þ In addition to water restriction, strategies to increase maximum daily urine are employed in patients with

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Fig. 23.1. Brain MRI of a 37-year-old insulin-dependent diabetic man with remote kidney transplant, admitted for diabetic ketoacidosis. His calculated serum osmolarity fluctuated from 304 to 287 over a 6 hour period. Serum glucose reached 528 mg/dL (normal, 70–105 mg/dL). The MRI showed a large area of T2-weighted hyperintensity in the pons, with diffusion restriction (not shown), consistent with osmotic demyelination (A, arrowhead). Despite symptomatic resolution, serial brain MRI studies obtained at 3 months (B) and 1 year after onset (C) continued to demonstrate similar imaging abnormalities. Central pontine myelinolysis can develop from rapid serum glucose changes without necessarily any sodium changes.

normovolemic hyponatremia due to SIADH (Decaux et al., 1982). These strategies consist of increasing the daily solute load, which is accomplished by administering urea tablets or by increasing sodium intake, and inhibiting ADH activity. ADH can be inhibited through demeclocycline, a tetracycline derivative, given a dose of 600–1200 mg/day divided into two to four doses per day (Cherrill et al., 1975). The resulting inhibition of the renal response to ADH increases urine output and lowers its osmolality and is referred to as diabetes insipidus. Of interest, lithium (used in the treatment of bipolar disorder) can also induce a nephrogenic diabetes insipidus and was used for the treatment of SIADH before demeclocycline was found to be safer and more effective. More recently, arginine vasopressin antagonists, conivaptan and tolvaptan, are a new class of drugs indicated to treat hypervolemic and euvolemic hyponatremia (Ferguson-Myrthil, 2010; Khanna and Menon, 2010). Conivaptan is a nonselective antagonist available intravenously (Ghali et al., 2009), and tolvaptan is a V2selective arginine vasopressin antagonist available in oral formulation (Aperis and Alivanis, 2011). These drugs produce aquaresis, that is electrolyte-sparing excretion of water, an ideal approach to correct hypervolemic hyponatremia.

HYPERNATREMIA History and terminology Hypernatremia refers to a plasma sodium concentration greater than 145 mmol/L. Since sodium is the major

contributor to plasma osmolality, hypernatremia is always associated with hyperosmolality (Agrawal et al., 2008). The converse is not true. Hyperosmolality is not always due to hypernatremia but could result from the hyperglycemia of diabetics and the hyperuricemia of renal failure patients. The hypertonic hyperosmolality of hypernatremia causes cellular dehydration due to water shifts following a concentration gradient favoring the extracellular compartment (Ruth and Wassner, 2006).

Clinical findings Hypernatremia may present with weakness, hyperreflexia, tremor, chorea, or myoclonus in the setting of irritability or frank encephalopathy, which ranges from drowsiness to coma, and may include seizures (Morris-Jones et al., 1967; Sparacio et al., 1976). Extreme ages are most vulnerable. Brain shrinkage induced by hypernatremia can cause rupture of cerebral veins, with focal intracerebral and subarachnoid hemorrhages (Adrogue and Madias, 2000a). Hypernatremia is among the causes of the so-called reversible splenial lesion syndrome, a localized cytotoxic edema restricted to the splenium and identified as a nonenhancing T2-weighted and FLAIR hyperintense oval lesion by magnetic resonance imaging (Garcia-Monco et al., 2010). This syndrome has also been reported in association with high-altitude cerebral edema, infectious encephalitis, antiepileptic drug withdrawal, and hypoglycemia (Maeda et al., 2006; Garcia-Monco et al., 2011).

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The typical presentation of diabetes insipidus (see below) is a relatively rapid onset of polyuria, polydipsia, and nocturia (Bichet, 2006). Interestingly, patients with neurogenic diabetes insipidus prefer ice cold water to satisfy their thirst (Jane et al., 2006).

Laboratory investigations Hypernatremia can be caused by either a gain of sodium (typically in the setting of hypervolemia) or a loss of water, hypovolemia (Table 23.5) (Agrawal et al., 2008). In the hypervolemic category, after ruling out the more common iatrogenic etiology, the use of hypertonic solutions, it is important to evaluate for the presence of disorders with excess mineralocorticoid activity, such as primary hyperaldosteronism, hyperreninism (renal artery stenosis), and Cushing syndrome. These disorders are suspected in the setting of hypertension, hypokalemia, and/or metabolic alkalosis. In the hypovolemic category, urine is most informative to help distinguish between renal and extrarenal water loss. Renal loss of water causing hypernatremia is either due to osmotic diuresis, where the urine osmolality is high, or diabetes insipidus (DI), in which the urine osmolality is low (Fig. 23.2). In both cases the urine volume is high

(Agrawal et al., 2008). Lithium is one of the most common causes of nephrogenic DI a few months after initiating therapy in as many as 20% of patients with bipolar disorder (Cox and Singer, 1975). Lithium-induced nephrogenic DI may not be reversible (Guirguis and Taylor, 2000). Other causes of nephrogenic DI, which need to be ruled out in the high-volume diluted-urine scenario, include hypercalcemia, hypokalemia, loop diuretics, and sickle cell disease (Khanna, 2006). Extrarenal water loss allows the kidney to both concentrate and decrease production of urine (high urine osmolality, low urine volume). A rare disorder of childhood, idiopathic hypothalamic adipsia is characterized by a complete inability to experience thirst and frequent episodes of hypernatremia (Hayek and Peake, 1982). These patients have a global hypothalamic dysfunction as recognized by obesity, decreased growth hormone-releasing hormone (GHRH), and decreased thyrotropin-releasing hormone (TRH).

Pathophysiology The symptoms and signs of hypernatremia are due to osmotic shifts of water, whereby water flows out of the intracellular compartment into the relatively hypertonic extracellular compartment. The resulting brain

Table 23.5 Hypernatremia according to volume state Hypovolemia

Hypervolemia

Diabetes insipidus Disorders

Nondiabetes insipidus ● Neurogenic DI Primary and metastatic tumors, tuberculosis, hystiocytosis, sarcoidosis, traumatic brain injury, strokes, encephalitis, Guillain– Barre´ syndrome ● Nephrogenic DI (renal disease or drugs)*

Urine osmolality (Osm), urine volume (UV), and urine sodium (UNa)

Diabetes insipidus: Osmotic diuresis: Osm: low Osm: high UV: high UV: high UNa: low UNa: low Plasma volume restoration: isotonic saline (0.9% NaCl); oral tap water or D5W is given to specifically correct hypernatremia. DDAVP in central DI

Treatment

Gain-of-sodium disorders Vomiting, diarrhea Nasogastric drainage Enterocutaneous fistula Excessive sweating Burns Osmotic diuresis (hyperglycemia, mannitol, uremia) Hypothalamic adipsia

●

Iatrogenic Hypertonic sodium bicarbonate Hypertonic tube feedings/ TPN Hypertonic saline solutions Hypertonic dialysis ● Excess mineralocorticoid Hyperaldosteronism Cushing’s syndrome Hyperreninism Osm, UV, UNa: often normal Excess mineralocorticoid: hypertension, hypokalemia, and/or metabolic alkalosis Diuretics to increase loss of salt and water; D5W can be given to replace urinary water loss

*Nephrogenic diabetes insipidus (DI) can be induced by hypercalcemia, hypokalemia, loop diuretics, lithium, demeclocycline, foscarnet, methoxyflurane, and amphotericin B. TPN, total parenteral nutrition; DDAVP, desmopressin; D5W, 5% dextrose in water.

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Fig. 23.2. Axial FLAIR (left column) and postcontrast T1-weighted sequences (right column) brain MRI of a 44-year-old woman with pulmonary sarcoidosis and newly developed neurosarcoidosis. The chiasmal contrast-enhanced hyperintensity (A) resolved within 1 month after initiating treatment with oral prednisone (B). She presented with blurry vision and generalized weakness in the context of excessive thirst and large urinary volume. These features were consistent with diabetes insipidus.

shrinkage can cause hemorrhagic events (intracerebral hemorrhage, subdural hematoma, or subarachnoid hemorrhage in adults; intraventricular hemorrhage in neonates) (Adrogue and Madias, 2000a). The brain adaptive response, or osmoprotection, includes the accumulation of electrolytes, sodium, potassium, and chloride (rapid adaptation, hours) as well as organic osmolytes, such as myoinositol, taurine, and glutamine (slow adaptation, after 24–48 hours) (Adrogue and Madias, 2000a). These organic osmolytes are protective against damages to proteins or DNA from increased ion strength within cells. DI is a disorder characterized by the inability to concentrate urine due to the inability of the hypothalamus to secrete an adequate amount of ADH (neurogenic DI) (Jane et al., 2006) or from a defect in the kidney response to ADH (nephrogenic DI) (Bichet, 2006) (Table 23.5). In

both cases, there is excretion of large volumes of diluted urine. Mineralocorticoids cause hypernatremia by stimulating the resorption of sodium and the excretion of potassium at the collecting renal tubules. Aldosterone, the most important mineralocorticoid, is excessively produced in hyperaldosteronism and hyperreninism. Although cortisol has lesser mineralocorticoid activity, such activity is enhanced when the levels become high enough in Cushing’s syndrome (Stewart, 1999).

Management Rapid correction of the hypertonic state may lead to cerebral edema (and seizures, coma, and death) as the accumulated electrolytes and solutes cannot be rapidly dissipated (Kang et al., 2002). Slow correction of

372 A.J. ESPAY hypernatremia (0.5 mmol/L/h or 10 mmol/L/day) is the extracellular concentration of potassium have prepreferred (Adrogue and Madias, 2000a). A rate of dominant effects on the function of the cardiovascular 1.5–2.0 mmol/L/h is appropriate in patients with acute and neuromuscular systems. Severe potassium abnorsymptomatic hypernatremia (Kang et al., 2002). The malities may provoke fatal arrhythmias or muscle paralmost important step in the treatment is the calculation ysis before encephalopathy or seizures may appear of the water deficit, the amount of water that must be (Gennari, 1998). administered to return the sodium concentration to normal. The water deficit is the difference between the ideal Clinical findings total (iTBW ¼ [sodium]  weight [kg]  [0.5 in men OR 0.4 in women]/140) and the current total body water Generalized weakness, predominantly proximal, is the (cTBW ¼ weight [kg]  [0.5 in men OR 0.4 in women]), common presentation of hypokalemia. from gastrointesas per the formula, in men: tinal or renal loss, often induced by drugs. Rhabdomyolysis may develop when the potassium level falls below ð½Sodium ½weight ½kg0:5=140Þ ðweight ½kg0:5Þ 3.0 mmol/L. An ascending paralysis with respiratory involvement that spares facial muscles and muscle Hypovolemic hypernatremia is treated with isotonic stretch reflexes occurs when potassium drops under saline until adequate circulation is restored and volume 2.0 mmol/L (Weiss-Guillet et al., 2003). Magnesium is restored (Hoorn et al., 2008). Often plasma osmolality deficiency causes reduced intracellular potassium is concurrently lowered because hypernatremic patients (impaired sodium/potassium-ATPase) and renal potashave a plasma osmolality greater than the concentration sium wasting. Hypokalemia may also exacerbate digoxin of isotonic saline (sodium chloride, 154 mmol/L) (Kang toxicity (Sundar et al., 1983). Non-neurological findings et al., 2002). Diuretics are recommended in cases of may include heart arrhythmias (with classic EKG hypervolemic hypernatremia (Table 23.5). findings of flattened T waves, ST segment depression, In cases of central DI, patients respond to DDAVP, a U waves, and T wave inversion with progressive severity synthetic analog of vasopressin (the human form of of potassium depletion), rhabdomyolysis, and polyuria. ADH), which can be given intranasally (Robinson, The latter is due to the inability to concentrate urine in 1976). The starting dose is 1–4 mg every 12–24 hours, hypokalemia, which is a form of nephrogenic diabetes titrated to reduce urine output to a tolerable level. Overinsipidus. Of importance, hypokalemia in an otherwise use of DDAVP can cause plasma overdilution and healthy young woman should prompt evaluation for hyponatremia (iatrogenic SIADH). In cases of nephrobulimia nervosa. The “compensatory” purging after genic DI, the goal of therapy is to remove offending binge eating in bulimia, aided by self-induced vomiting agents (e.g., lithium, demeclocycline, and loop diuretics) and abusing laxatives, leads to hyperchloremic metabolic and to correct potassium and calcium levels. Lacking alkalosis and the associated alkalosis-generated hypokathese specific targets, a counterintuitive approach in lemia. Finally, tetany is seen during alkalosis, which nephrogenic DI is to administer thiazide diuretics in comdecreases ionized calcium by binding calcium to probination with a potassium-sparing diuretic and a saltteins. Paradoxically, when hypocalcemia is present, restricted diet (Mizuno et al., 2003). The goal is to induce hypokalemia protects against tetany. Correction of a mild hypovolemia, which triggers the ADH-independent hypokalemia can precipitate hypocalcemic tetany. regions of the kidney (mainly the proximal tubule) to Recurrent, transient attacks of muscle weakness may increase water resorption and reduce urine output. be seen in hypokalemic periodic paralysis, a rare cause of familial hypokalemia. Hypokalemic periodic paralysis HYPOKALEMIA type 1, due to a mutation in the calcium channel CACNL1A3 on chromosome 1q, is the most common periTerminology odic paralysis, affecting approximately 1 in 100 000 peoHypokalemia is defined as a plasma potassium concenple. This disorder is recognized by transient flaccid tration below 3.5 mmol/L. Whereas sodium is the cation weakness in voluntary muscles except facial and respiraof the extracellular space whose shifts affect osmotic tory. Attacks may last hours to days and occur upon movement of water across intra- and extracellular comawakening after vigorous exercise or a carbohydrate-rich partments, potassium is 99% intracellular and mostly meal. If onset is beyond the age of 30 years, thyrotoxicoregulates electrical excitability of muscle and nerve cells sis, secondary potassium wasting, or medications should (Gennari, 2002). Small changes in plasma potassium can be suspected (Table 23.6). Symptoms can be induced by have dramatic consequences. Unlike other electrolyte glucose, glucagon, or epinephrine challenges. Permanent alterations, hypokalemia or hyperkalemia rarely causes proximal weakness eventually develops due to vacuolar symptoms in the central nervous system. Changes in myopathy.

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Table 23.6 Mechanisms of hypokalemia Intracellular shift

Increased losses

b2-sympathomimetics (albuterol, terbutaline, metaproterenol, ephedrine, pseudoephedrine, phenylpropanolamine) Xanthines (theophylline, caffeine) Verapamil intoxication Chloroquine intoxication Insulin overdose Hypercatecholaminergic states Hyperthyroidism Hypomagnesemia (potentially caused by cisplatin, aminoglycosides, amphotericin B) Familial hypokalemic periodic paralysis

Diuretics (acetazolamide, thiazides, furosemide) Excess mineralocorticoid activity (primary hyperaldosteronism, pseudo-hyperaldosteronism, Cushing’s syndrome, high-dose fludrocortisone treatment) Nonresorbable anions (diabetic ketoacidosis, vomiting, renal tubular acidosis, toluene, penicillin)

Laboratory investigations

Decreases in plasma hydrogen (which increases pH, induces alkalosis) drive potassium into cells. Thus, the metabolic alkalosis generated from vomiting, hyperaldosteronism, diuretics, and antacid abuse is often associated with hypokalemia (Cely and Contreras, 2001). Renal potassium excretion is primarily regulated by the mineralocorticoid aldosterone, in part by the same mechanism of increasing the sodium/potassium-ATPase pump activity (Krishnan et al., 2005). Pseudohyperaldosteronism, a syndrome of apparent mineralocorticoid excess (White et al., 1997), is a condition of increased mineralocorticoid activity without elevated aldosterone levels that can be induced by consumption of licorice, a sweet flavor extracted from the root of the legume Glycyrrhiza glabra (Fig. 23.3). Licorice contains glycyrrhetinic acid, which inhibits the enzyme that deactivates the mineralocorticoid activity of cortisol by transforming into cortisone (11b-hydroxysteroid dehydrogenase), allowing physiologic levels of cortisol to activate the aldosterone receptors in the collecting tubules of the kidney (Schambelan, 1994).

A variety of conditions related to transcellular shift of potassium or renal/gastrointestinal losses of potassium need to be investigated (Table 23.6). Magnesium and calcium should also be checked as hypomagnesemiainduced hypokalemia and the hypocalcemic hypokalemia of metabolic alkalosis demand correction of magnesium, exclusively, and calcium, preferentially (Siddiqui et al., 1998). Creatine kinase is typically increased when hypokalemia is severe enough to cause rhabdomyolysis (Shintani et al., 1991). Primary hyperaldosteronism is suspected in patients with hypertension, hypokalemia, and a 24 hour urine potassium > 30 mmol/L. Confirmation of the diagnosis requires documenting elevated aldosterone and low renin levels (aldosterone:renin ratio > 30) in the absence of hypovolemia (Vallotton, 1996). Low-dose dexamethasone suppression test is the screening test of choice for patients suspected of having Cushing’s syndrome. Morning cortisol level is high because dexamethasone fails to suppress cortisol production in Cushing’s syndrome.

Management Pathophysiology Potassium regulation is tightly controlled by two systems: intracellular buffering and renal excretion (Gennari, 1998). Cellular redistribution is controlled by the membrane-bound sodium/potassium-ATPase pump, which maintains a high concentration of potassium and a low concentration of sodium inside the cells. Catecholamines, b2-selective agonists (e.g., albuterol), and insulin decrease potassium by increasing the sodium/potassiumATPase activity. Hence, hypercatecholaminergic and hyperinsulinergic states commonly cause the transcellular shifts that lead to hypokalemia (Braaten, 1987).

Potassium chloride (KCl) is the most suitable salt for repletion of the common forms of hypokalemia but potassium bicarbonate (KHCO3) and potassium phosphate (KPO4) are used in the setting of associated acidosis and hypophosphatemia, respectively. Potassium replacement should be given at a rate 20 mEq/h in glucose-free solutions with cardiac monitoring (Gennari, 1998). KPO4 may lead to phosphorus intoxication, which reduces calcium and may lead to hypocalcemic tetany. In hypomagnesemia, magnesium replacement alone should correct hypokalemia. In the hypokalemia associated with alkalotic states, hypocalcemia should be corrected first to avoid the

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HYPERKALEMIA Terminology Hyperkalemia applies to a plasma potassium concentration > 5 mmol/L. Hyperkalemia is a common complication of renal failure. In the absence of renal failure, hyperkalemia is relatively uncommon because the kidneys have the ability to excrete large amounts of potassium.

Clinical findings The muscle weakness associated with hyperkalemia typically begins in the legs and ascends to the trunk, eventually affecting the arms (McCarty et al., 1998). It is associated with a sensation of burning paresthesias. Even when flaccid quadriplegia with respiratory involvement develops, the cranial nerves are often but not always spared (Cheng et al., 2005; Panichpisal et al., 2010). Hyporeflexia is common. Neurologic deficits without cardiac conduction defects only occur when hypercalcemia (antidysrhythmic) is present. Without this protective element, the most feared non-neurological complication of hyperkalemia is altered cardiac conduction leading to ventricular fibrillation or asystole. The EKG changes include peaked T waves, increased P-R interval, widening of the QRS complex, and loss of the P wave due to the impairment of atrial contraction.

Laboratory investigations Fig. 23.3. Glycyrrhiza glabra, taken from Flora von Deutschland, O¨sterreich und der Schweiz, by Prof. Dr. Otto Wilhelm Thome´, 1885, Gera, Germany. (Permission to use this image granted under GFDL by Kurt Stueber. Source: www.biolib.de, public domain image.)

hypocalcemic tetany that may develop when potassium is corrected alone (Goldfinger, 1969). The hypokalemia of patients with bulimia nervosa should first be addressed by normalizing volume status before potassium replacement can be effective. Whenever present, reduction or removal of offending agents (e.g., albuterol, fludrocortisones, thiazides) may be required. Removal of the dietary product licorice in cases of episodic hypertension and hypokalemia of otherwise unknown etiology should revert the hypokalemia and associated metabolic alkalosis, volume expansion, and hypertension of the licoriceinduced pseudohyperaldosteronism (Chatterjee et al., 2010). Patients on treatment with digoxin and diuretics should be monitored for hypokalemia, which causes digitalis toxicity even at low serum digoxin levels (Sundar et al., 1983).

Confirming hyperkalemia requires ruling out hemolysis, leukocytosis, and thrombocytosis, all of which can spuriously elevate the potassium measurement. A small list of conditions related to transcellular shift of potassium or decreased renal losses of potassium need to be investigated (Table 23.7). The major entities to consider are renal failure, metabolic acidosis, insulin deficiency (diabetic ketoacidosis), adrenal insufficiency, crush injuries (rhabdomyolysis), and drugs (potassium-sparing diuretics, NSAIDs, b-blockers, and digoxin intoxication).

Management In mild hyperkalemia, furosemide is used to enhance excretion. Calcium chloride or calcium gluconate are critical to stabilize cell membranes and prevent cardiac arrhythmias. If severe hyperkalemia is present (e.g., EKG changes, plasma potassium greater than 7.0 mmol/L), calcium should be the first medication administered (Iijima et al., 2005). Calcium chloride is preferred because it provides three times as much calcium but can only be given through a central line. Alkalinizing agents such as sodium bicarbonate are used to shift potassium from the extra- to the intracellular

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Table 23.7 Mechanisms of hyperkalemia Intracellular shift

Decreased renal losses

Tumor lysis syndrome Trauma (rhabdomyolysis) Hypothermia Metabolic acidosis Hyperglycemia Hypoinsulinemia b2-blockers Digoxin toxicity Hemolysis (pseudohyperkalemia)

Renal failure (acute and chronic) Hypoaldosteronism (adrenal insufficiency (Addison’s disease), hyporeninemic hypoaldosteronism, ACE inhibitors, angiotensin receptor blockers, ciclosporin, NSAIDs) Aldosterone resistance (spironolactone, amiloride, triamterene) Trimethoprim (high doses) Hypovolemia

compartment (Williams, 1992). Sodium bicarbonate 50 mEq given intravenously over 5 minutes decreases plasma potassium by 0.5–1.5 mmol/L within 30 minutes. A complementary strategy is to exploit the ability of insulin to cause the movement of potassium into cells. Insulin is administered with glucose in this situation (Kim, 1996). Nebulizations with the b2-agonist albuterol can also lower the plasma potassium in a short time frame. However, b2-agonists may lower the threshold for cardiac arrhythmias and therefore are considered in special circumstances only, bearing the risk in mind. Sodium polystyrene sulfonate (Kayexalate, 20 g given with 100 mL of 20% sorbitol to prevent constipation) and other binding resins promote exchange of potassium for sodium in the gastrointestinal system. Loop diuretics can be used to increase excretion of potassium only if renal function is not impaired.

metabolic acid–base disorder is present. Conversely, if a primary carbon dioxide change is not compensated for by a corresponding bicarbonate change, a respiratory acid–base disorder is present. Respiratory acidosis with hypercapnia (elevated PCO2) is largely due to respiratory insufficiency and respiratory alkalosis with hypocapnia (decreased PCO2) to any form of hyperventilation. On the other hand, metabolic acidosis may be due to a loss of bicarbonate or an addition of acid, which accumulate anions in plasma other than the major anions, chloride (Cl) and bicarbonate (HCO3  ). The anion gap, which is calculated by the difference between sodium, the major plasma cation, and the sum of the major plasma anions (Naþ  ½Cl þ HCO3  ), can distinguish a metabolic acidosis due to the loss of bicarbonate (nonanion gap metabolic acidosis or hyperchloremic acidosis; gap 12 mEq) (Kraut and Madias, 2010). The latter can be caused by lactic acidosis, ketoacidosis, uremia, and toxic ingestions (paraldehyde, methanol, ethylene glycol, and salicylate poisoning, among others) (Table 23.8).

ACID^BASE DISORDERS Terminology Acidemia is defined as an increase in plasma hydrogen concentration above normal, measured by a hydrogen concentration >45 nanoEq/L or a pH below 7.35. Alkalemia refers to a decrease in plasma hydrogen concentration below normal, defined by a hydrogen concentration 170 mg/dL Severe acidosis (pH < 7.2, BE < 10) Refractory hypertension Serum sodium > 155 mmol/L or < 120 mmol/L Intoxication with dialysable drugs BE, base excess.

2005). Manifestation of the full picture of uremic encephalopathy has a significantly higher morbidity and mortality (Burn and Bates, 1998; Brouns and De Deyn, 2004).

THERAPY The indication for the initiation of hemodialysis is significantly influenced by the neurologic complications, and thus a knowledge of neurologic disorders in renal diseases is of particular importance. The indications for dialysis in acute renal failure are listed in Table 24.2. Most signs of uremic encephalopathy decline within a few days after the initiation of renal replacement therapy. In addition, both EEG (Battaglia et al., 2005) and acute neuroradiologic changes are reversible with adequate hemodialysis (Schmidt et al., 2001). Dialysis improves, but not always completely ameliorates, CNS symptoms in acute renal failure or CKD (Brouns and De Deyn, 2004). In addition to direct elimination of toxins, protective effects of dialysis on CNS symptoms also include the treatment of frequently therapy-resistant hypertension and hyperhydration, especially caused by the correction of metabolic acidosis. The correction of renal anemia with erythropoiesis-stimulating agents (ESA) is also a significant part of the treatment; the target hemoglobin in dialysis patients is 10–12 g/dL, and should not exceed 13 g/dL (Dr€ ueke et al., 2006).

CENTRAL NERVOUS SYSTEM SYNDROMES ASSOCIATED WITH RENAL REPLACEMENT THERAPY Under renal replacement therapy, clinical symptoms of uremic encephalopathy improve rapidly. With intensive hemodialysis therapy, however, acute metabolic encephalopathies may also be observed, which are referred to as the disequilibrium syndrome. Under renal replacement procedures, including hemodialysis,

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patients have an increased risk of developing Wernicke’s encephalopathy. Chronic dialysis patients also have a higher risk of cognitive deficits compared to the normal population. In earlier decades, a so-called dialysis encephalopathy syndrome – secondary to acute or chronic aluminum intoxication – was occasionally observed. Important differential diagnoses of neurologic symptoms in dialysis patients include subdural and intracerebral hemorrhage.

Dialysis disequilibrium syndrome The first observations of a dialysis disequilibrium syndrome (DDS) date from the early years of the wider use of dialysis procedures. It was first described by Kennedy and colleagues in 1962 (Kennedy et al., 1962). The paradoxical observation that patients with severe uremia may show a deterioration of CNS symptoms during or immediately after a forced dialysis lead to the hypothesis that the DDS osmotic gradient may trigger brain edema (Kennedy et al., 1962).

PATHOGENESIS Urea is able to diffuse freely through cell membranes. In uremia, there is a balance between the urea concentration in blood plasma and brain. Hemodialysis leads to elimination, and in turn, to a relevant decrease in plasma osmolality. Under forced dialysis, there is an osmotic concentration gradient between the urea concentration in the brain and the blood plasma causing a significant water influx into the brain (Silver et al., 1996). This water shift produces cerebral edema which explains the clinical symptoms of DDS. A rapid fall in cerebral pH is also very important for the development of brain edema with paradoxical increase in cerebral pH and a concurrent decrease of plasma pH (Arieff, 1994).

CLINICAL PRESENTATION DDS is an acute hemodialysis complication which typically appears during or immediately after a first hemodialysis treatment. Patients with extreme uremia, usually with urea values above 175 mg/dL, the elderly, and children are at increased risk, as are patients with pre-existing CNS damage (Arieff, 1994; Burn and Bates, 1998). Peritoneal dialysis is not associated with this complication (Arieff, 1994). Mild forms of DDS present with headaches, restlessness, and muscle cramps, which can also occur at the end of the dialysis in continuous dialysis patients and are associated with a high ultrafiltration volume (Arieff, 1994). In severe DDS, increased blood pressure, confusion, seizures, or coma can be part of the symptom spectrum.

Table 24.3 Causes of seizures in dialysis patients Increase of blood pressure, hypertensive encephalopathy, for example, erythropoietin-associated Failure of blood pressure, for example, ultrafiltrationassociated Uremic encephalopathy Intracerebral or subdural hemorrhage Dialysis encephalopathy syndrome Hypo- or hyperglycemia Stroke Electrolyte imbalance Air embolism Alcohol withdrawal seizure Drug-associated, especially in the absence of dose adjustment (e.g., carbapenems and penicillins, acyclovir, lithium, metoclopramide)

THERAPY Milder courses are self-limited. If DDS is suspected, dialysis should be stopped rapidly. Severe cases with seizures can occasionally be stopped by an injection of 5 ml 10–20% NaCl. The differential diagnosis of seizures in dialysis is summarized in Table 24.3. To prevent DDS, the slow and stepwise correction of urea levels is crucial. This may be achieved by using smaller dialyzers with a surface area of 0.9–1.2 m2, due to reduced blood flow and dialysate flow, or by switching to the so-called co-current mode during the use of hemodialysis products. First dialysis should be started with the smallest dialyzer available and a blood flow up to a maximum of 150–200 mL/min. After the first three dialysis sessions, patients should slowly be adapted to the standard conditions. In the case of significant hyperhydration, the change of hemodialysis to pure ultrafiltration provides a safe way to lower extreme urea levels as it only withdraws a small amount of urea. In high-risk patients, hemodialysis should be avoided in favor of peritoneal dialysis.

Wernicke’s encephalopathy Occasionally, patients under hemodialysis or peritoneal dialysis suffer from Wernicke’s encephalopathy (WE). The diagnostic differentiation of WE and other neurologic complications is not easy, especially since the classic triad of ataxia, confusion, and bilateral oculomotor dysfunction is not always fully present. MRI may show hyperintensities in the aqueduct regions of the midbrain and thalamus (Ueda et al., 2006). Decreased blood levels of thiamine support the diagnosis (Hung et al., 2001; Ueda et al., 2006). The loss of this water-soluble vitamin caused by the malnourished state of many dialysis

NEUROLOGIC COMPLICATIONS OF ACUTE AND CHRONIC RENAL DISEASE patients contributes to the pathogenesis of the disease. In case of an early diagnosis, a rapid improvement of symptoms can be achieved by intravenous administration of 500 mg thiamine three times daily in the first 2 days and further 500 mg daily over 5 days. Thereafter, an oral dose of 100 mg thiamine daily should be maintained (Thomson et al., 2002).

Subdural hematoma and intracerebral hemorrhage The incidence of subdural hematoma in hemodialysis patients is increased more than 20-fold compared to the general population (Power et al., 2010). Causative factors are uremic thrombocytopathy and the use of anticoagulant substances during dialysis treatment. The hematomas occur spontaneously and a history of head trauma is rarely found. Patients complain of headaches, nausea, and vomiting. Rapidly increasing intracranial pressure leads to convulsions and coma, with a fatal outcome if treatment is not initiated promptly. Even so, there is a 30 day mortality of 40% in treated patients (Power et al., 2010). Intracerebral hemorrhages are frequently found in dialysis patients. In addition to the above-mentioned factors, the often treatment-resistant renal hypertension plays a major role. Studies on the outcome of hemodialysis after intracerebral hemorrhage, comparing continued treatment with peritoneal dialysis or hemodialysis, have shown no significant differences (Hsieh et al., 2010). However, it is not only dialysis patients who experience this complication, and a mildly decreased GFR may increase the risk of ischemic fatal or non-fatal stroke, and severely decreased GFR the risk of hemorrhagic stroke, in the general population (Holzmann et al., 2012). In regards to ischemic stroke, CKD seems to be an important predictor of poor clinical outcomes after acute ischemic stroke. Proteinuria independently contributes to the increased risks of neurologic deterioration, mortality, and poor functional outcome (Kumai et al., 2012).

Cognitive impairment in chronic dialysis patients CKD is an independent risk factor for cognitive dysfunction and dementia. According to recent studies, cognitive deficits in dialysis patients are more frequent than previously anticipated. With more subtle diagnosis, up to 70% of patients present cognitive deficits. Cognitive impairment in dialysis patients is mainly due to vascular causes (Pereira et al., 2005). Studies show significantly higher MRI structural changes including white matter hyperintensities, microbleeds, and microinfarctions.

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This is also evident in clinically inconspicuous patients (Naganuma et al., 2005). Clinically relevant is the observation that cognitive function varies significantly during the dialysis intervals. It is interesting that the worst test results are observed during the dialysis treatment (Murray et al., 2007). It was recently shown by magnetic resonance spectroscopy (MRS) that in CKD patients, hemodialysis was accompanied by more severe cognitive dysfunction and metabolic alterations than CKD alone, thus a negative impact of hemodialysis on cognitive function must be considered. Elevated serum uric acid has also been associated with mild cognitive dysfunction in subjects with CKD (Afsar et al., 2011). Severe cognitive impairments causing dementia are observed in up to 37% of dialysis patients in comparison to 12% of age-matched controls (Murray et al., 2006). Dementia represents a strong predictor of mortality in dialysis patients (Griva et al., 2010).

Dialysis encephalopathy syndrome In 1972, Alfrey and coworkers first described a neurologic picture associated with long-term dialysis – the so-called dialysis encephalopathy syndrome (Alfrey et al., 1972). As extremely high concentrations of aluminum in the brain and other tissues were found in these patients (Alfrey et al., 1976), aluminum intoxication was suspected. In recent decades, dialysis encephalopathy syndromes have again been reported, caused by the use of aluminum-contaminated dialysate (Parkinson et al., 1981; Berend et al., 2001). Since aluminum is subject to glomerular filtration, anuric dialysis patients suffer from a dialysate aluminum content above 5 mg/L leading to a positive balance of aluminum. Acute intoxication occurs at much higher aluminum dialysate concentrations (>200 mg/L). Nowadays, with the regular use of reverse osmosis and control of dialysates, these outbreaks are rare, and modern water filtration methods ensure that acute aluminum intoxication has become rare. Occasionally, chronic aluminum intoxication is still seen in patients taking aluminum-containing antacids or oral aluminum-containing phosphate binders (Jaffe et al., 2005), although their use in recent years is less common. In preterminal renal failure, the use of citratecontaining drugs may cause aluminum intoxication, as citrate enhances aluminum intake (Russo et al., 1992).

DIAGNOSIS Plasma levels of aluminum should be determined in every dialysis encephalopathy syndrome. In healthy patients, the aluminum plasma level is normally < 5 mg/L, whereas in asymptomatic dialysis patients, higher levels < 50 mg/L are found. An increase to > 100 mg/L is

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usually associated with symptoms of acute or chronic aluminum intoxication (de Wolff, 1985). In case of suspected intoxication, by clinical findings or elevated aluminum levels (>50 mg/L), the low-dose desferrioxamine (DFO) test, which has a high diagnostic sensitivity (D’Haese et al., 1995), can be used for diagnosis. In this test, injection of the chelating agent desferrioxamine (5 mg/kg) leads to the mobilization of aluminum stores followed by a significant increase in plasma aluminum levels 2 days after injection.

CLINICAL SYMPTOMS The clinical spectrum of dialysis encephalopathy syndrome differs from other common neurologic diseases. The disorder typically starts with intermittent alteration of the language, apraxia, and fatigue. Myoclonic jerks and occasional grand mal seizures may be observed. In advanced disease, persistent dysphasia and dysarthria are evident. Later, in the terminal stage of the disease, patients suffer from dementia and ataxia, dysphagia, and myoclonus. Patients with fatal complications due to aluminum-contaminated dialysate had mean plasma aluminum levels of 808 mg/L in comparison to 255 mg/L in survivors of dialysis encephalopathy (Berend et al., 2001). Acute aluminum intoxication may also lead to fatal infections such as pneumonia or sepsis (Parkinson et al., 1981). As well as neurologic symptoms, patients with chronic accumulation of aluminum complain of bone and muscle pain, a condition known as aluminuminduced myopathy. Frequently, there is osteomalacia with hypercalcemia, caused by adynamic bone metabolism and microcytic anemia (Slatopolsky, 1987).

TREATMENT In the case of proven aluminum intoxication, it is important to eliminate underlying causes, which are usually aluminum-containing drugs and adverse comedications (citrated medication). In general, there are three methods of detoxification: intensified renal replacement therapy, kidney transplantation, and the use of the chelating agent desferrioxamine, which is administered intravenously in a low dose (5 mg/kg) in the last hour of a high-flux dialysis (Molitoris et al., 1988) once a week over several months. However, in cases of very high plasma aluminum levels (>200 mg/L) and higher doses of desferrioxamine, an acute worsening of dialysis encephalopathy is possible due to the strong mobilization of aluminum deposition with a correspondingly large increase in plasma levels (Sherrard et al., 1988). In conclusion, the 5 mg/kg DFO treatment is not only a diagnostic tool, but also a safe and adequate therapy for aluminum overload.

Drug-induced disorders in renal failure About half of all drugs are metabolized or excreted by the kidney. Patients suffering from renal disorders therefore have an increased risk of drug-induced neurologic disorders caused by incorrect dosage or adverse interactions of drugs. The dosage of renally eliminated drugs must be adjusted to renal function, since their half-life is inversely related to clearance. Prolonged half-lifes result in accumulation and adverse drug reactions (Aymanns and Keller, 2004). Besides faulty filtration, certain drugs and their metabolites are secreted by tubular filtration. The clearance of drugs may be further reduced by drug interactions. Severe damage of the peripheral nervous system has been observed caused by numerous chemotherapeutic agents, among others, and also by nitrofurantoin. Although nitrofurantoin polyneuropathy may also occur after long-term treatment in normal renal function, patients with renal insufficiency are at a substantially high risk of polyneuropathy. Potentially dangerous antibiotics include penicillins, cephalosporins, fluoroquinolones, and carbapenems. It is crucial to pay attention to dose adjustment of these drugs according to the glomerular filtration rate. Drugs such as metoclopramide, and especially lithium and aciclovir, can potentially cause seizures and other serious neuropsychiatric adverse events. The risk of lithium intoxication causing metabolic encephalopathy is particularly high in patients with acute renal failure and comedication of ACE inhibitors, NSAIDs, or thiazide and high-ceiling diuretics. These drugs reduce the clearance of lithium and thereby increase the lithium level. Regular monitoring of lithium levels should reduce the risk of serious side-effects of lithium therapy. Severe neuropsychiatric complications caused by aciclovir therapy have been repeatedly observed. These can lead to coma, especially if the exact dosage adjustment is not considered. Patients undergoing peritoneal dialysis are at higher risk because under peritoneal dialysis, no significant elimination of aciclovir is possible. In this situation it can be necessary to perform hemodialysis therapy, which improves the clinical symptoms by removing aciclovir in sufficient quantities (Davenport et al., 1992).

PERIPHERAL NERVOUS SYSTEM DISORDERS Uremic polyneuropathy It has long been known that uremia leads to nerve injury. Kussmaul first described uremic polyneuropathy (PNP) as a complication of advanced uremia in 1863. Typically, the PNP occurs in patients with advanced renal failure

NEUROLOGIC COMPLICATIONS OF ACUTE AND CHRONIC RENAL DISEASE only. Uremic polyneuropathy usually occurs with a glomerular filtration rate below 12 mL/min. The PNP affects both sensory and motor nerves and represents an indication to initiate renal replacement therapy. The loss of motor function in uremic PNP is usually a sign of an advanced disease process. PNP is frequent in dialysis patients, and with more accurate diagnostic tools it can be demonstrated in up to 60–100% of patients (Krishnan and Kiernan, 2007). This is explained in part by the fact that every second patient with renal replacement therapy is suffering from a diabetic late syndrome and, consequently, most patients have already presented a diabetic PNP. In the early years of dialysis therapy, the electrophysiologically measured stage of PNP was interpreted as a quality criterion of an adequate or inadequate dialysis therapy. Even today, this can be seen as an indicator of an inadequately controlled metabolic situation. The development of a PNP under renal replacement therapy should be a hint to reconsider the effectiveness of dialysis and to adjust the dialysis dose, particularly by extending the dialysis time.

PATHOGENESIS In advanced uremia, with a glomerular filtration rate of < 12 mL/min, there is a metabolic milieu that leads to the development of uremic PNP. In addition to thiamine, biotin and zinc deficiencies, an accumulation of neurotoxic uremic toxins, especially so-called middle molecules, may be causative (Vanholder et al., 2008). The term middle molecules refers to a variety of uremic toxin molecules with molecular weights above 500 daltons. Due to the greater molecular weight, the dialyzability of these neurotoxins is impaired. The dialyzable amount of middle molecules is greater with continuous peritoneal dialysis than with hemodialysis or hemofiltration. Supporters of the middle molecule hypothesis support their argument with the better course of uremic PNP in peritoneal dialysis as proof of their hypothesis. However, it has to be taken into consideration that the longevity of residual renal function in peritoneal dialysis may also contribute to better outcomes.

CLINICAL PICTURE Uremic PNP presents as a distal symmetric sensorimotor axonal neuropathy. With involvement of the longer axons at the beginning, typically the lower extremity is primarily affected. Men are affected more often than women. Sensory irritations and phenomena such as tingling, burning, and pain are usually followed by motor disturbances. Patients complain about stocking-like furry and numbness and temperature sensations, especially with exposure to cold. In the early stages, examination reveals pallhypesthesia with a diminished

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vibration sense in the great toe and the medial malleolus, which is easily recognized by means of a tuning fork test (Quellhorst et al., 1979). Other clinical findings are low or missing tendon reflexes; later, even the upper extremity reflexes may be diminished. Often there are painful spasms of the lower extremities and in more advanced stages atrophies and paralysis of the distal muscles are found. As an early sign of motor dysfunction, the dorsiflexion of the great toe is restricted. Rarely, uremic PNP presents with acute or subacute tetraparesis resembling the Guillain–Barre´ syndrome (Ropper, 1993).

DIAGNOSIS The diagnosis of uremic PNP is based on the typical clinical signs in patients with advanced renal failure. Differential diagnoses include other diseases that lead to both CKD and peripheral nerve injury. These include diseases such as diabetes mellitus, immune system diseases, amyloidosis, or multiple myeloma. The clinical examination of the tuning fork test for vibration sensation at the great toe or on the inner ankle is an early striking sign. In the advanced stage of the disease, tendon reflexes are reduced or eliminated completely. With neurophysiologic testing, reduced sensory and motor nerve conduction velocities are found. The elicited potentials show reduced amplitudes as a sign of axonal damage. Electromyography indicates acute and chronic damage of motor fibers. Often there is a discrepancy between the electrophysiologic signs and clinical symptoms. The neurophysiologic tests may already be pathologic before the clinical appearance of a PNP, and vice versa, and neurophysiologic findings can persist long after clinical recovery. Nerve conduction measurements at the arteriovenous fistula-arm may be altered by the surgical procedure, and therefore the contralateral arm should be used for electrophysiologic examinations (Brouns and De Deyn, 2004).

THERAPY The evidence of uremic PNP is an indication to initiate renal replacement therapy. Hemodialysis and peritoneal dialysis are considered equally effective in the treatment and prevention of uremic PNP. However, some studies demonstrated a better course of uremic PNP under peritoneal dialysis (Tegner and Lindholm, 1985). Mild forms usually fully recover after the initiation of renal replacement therapy. However, the electrophysiologic tests often remain pathologic (Ogura et al., 2001). Despite initiation of renal replacement therapy, severe manifestations recover very slowly, over months and years, and may even be not reversible (Tegner and Lindholm, 1985). If the symptoms of a PNP begin during renal replacement therapy, the dialysis dose should be increased by

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prolonging the treatment time to a weekly Kt/V > 1.5. Neuropathic pain can be ameliorated with drugs. Physical therapy and muscular training during dialysis treatment should counteract the loss of muscle power. Successful kidney transplantation represents the most effective therapy of uremic PNP (Ho et al., 2012). The recovery of renal function may show successes within days to weeks. However, a full recovery is expected only after several months.

Restless legs syndrome A common problem for patients with end-stage renal failure is a secondary restless legs syndrome (RLS), often in connection with uremic polyneuropathy (Winkelman et al., 1996). Uremic toxins appear to be involved in the pathogenesis of RLS, because an inverse relationship between the glomerular filtration rate and the frequency of RLS is evident (Molnar et al., 2005). The percentage of RLS in dialysis patients is as high as 21.5–30% (Molnar et al., 2005; Merlino et al., 2008; Araujo et al., 2010). Patients with peritoneal dialysis are more often affected. The symptoms typically start in the evening before falling asleep, but may also appear during resting times in the day and even, at an advanced stage, during dialysis treatment. RLS is associated with sleep disorders and leads to increased daytime sleepiness. Iron deficiency and anemia are associated with an increased incidence of RLS (Molnar et al., 2005). In these cases, intravenous iron and erythropoietin substitution is the treatment of choice. Otherwise L-dopa and dopamine agonists are used. Frequently, there is the problem of augmentation, i.e. maintained increase in symptom severity despite appropriate treatment. In addition, gabapentin has proven to be effective in hemodialysis patients. However, because of the high renal elimination, a significant dose reduction is required. The initial dose of gabapentin should be 300–400 mg, followed by a maintenance dose of 200–300 mg three times per week after hemodialysis. Opioids and clonidine are other treatment options for RLS in renal patients.

Mononeuropathies In the context of uremia, several mononeuropathies are observed as a consequence of the uremic intoxication and specific complications of renal replacement therapy. Most commonly, the nerves of the forearm, especially the median nerve, are affected. Patients complain of night pain and prickling sensations in the forearm and hand. The carpal tunnel syndrome (CTS) is characterized by a numbness of the volar first three fingers and hand, with paresis and atrophy of the thenar muscles (Halter et al., 1981). An ulnar nerve syndrome can be detected in half the cases of hemodialysis patients (Nardin et al., 2005).

Of note, the CTS occurs mainly on the side used in vascular access for dialysis. Besides a nerve injury caused by the shunt implantation itself, compression by hematoma after failed puncture or extravasation, as well as an increased venous pressure can lead to compression and damage of the nerves. However, there is not always a connection with shunt implantation, since the contralateral arm may also be affected (Delmez et al., 1982) and peritoneal dialysis patients may also suffer from CTS. After hemodialysis access replacement, occasionally a shunt-associated ischemia or ischemic monomelic neuropathy occurs (Pirzada and Morgenlander, 1997). In contrast to the shunt-associated ischemia, the hand is warm with palpable pulses in most cases of monomelic ischemic neuropathy. In extreme cases, ischemia leads to limb loss. The rapid ligation of the shunt represents the only treatment option. In long-term dialysis patients, CTS is observed in nearly 90% of patients (Otsubo et al., 2009) and pathophysiologically can be explained by b2 microglobulinassociated amyloidosis. The middle molecule b2 microglobulin, which is the precursor of the amyloid structure, is inadequately eliminated by hemodialysis. This amyloid is in turn deposited into the carpal tunnel and tendons. The clinical result of this process is the so-called amyloid hand, with atrophy of hand muscles and limited flexion and extension of the fingers. Other manifestations of dialysis-associated amyloidosis are cystic bone lesions and articular amyloid deposits, which can lead to a destructive arthropathy, especially of smaller joints. Cranial nerve deficits are rarely observed in advanced renal failure. Especially in hearing and balance disorders associated with vestibulocochlear neuropathy, drug toxicity is more likely causative than uremia. High doses of loop diuretics can trigger acute and reversible hearing loss (Heidland and Wigand, 1970). Treatment with aminoglycosides in dialysis patients may cause irreversible damage.

Autonomic disturbances Autonomic neuropathy is a common complication of patients with CKD. More than 50% of patients on renal replacement therapy are affected, and parasympathetic dysfunction is twice as likely as sympathetic disorder (Stamboulis et al., 2010). Interestingly, there is no correlation between the degree of autonomous neuropathy and other PNP symptoms (Stamboulis et al., 2010). There is also no relationship between the extent of autonomic dysfunction and the therapy of renal failure. The prevalence in conservatively treated patients is as high as with hemodialysis or peritoneal dialysis (Malik et al., 1986). Autonomic neuropathy affects numerous organs. A typical manifestation is orthostatic hypotension, often

NEUROLOGIC COMPLICATIONS OF ACUTE AND CHRONIC RENAL DISEASE occurring in diabetic dialysis patients. Due to the autonomous disorder, there is limitation of the baroreflex, which then, under dialysis conditions and ultrafiltration, despite increased catecholamine, leads to a sudden drop in blood pressure and vascular resistance. This so-called dialysis hypotension is a typical and dreaded complication of patients with autonomic dysfunction. However, dialysis hypotension surely underlies other pathogenetic factors as well (Converse et al., 1992). In addition to heart rate rigidity and tachycardia, pupillary disorders and hypohidrosis may be noticed. Occasionally patients show bladder dysfunction or impotence. In the gastrointestinal tract, autonomous disorders manifest by gastroparesis, nocturnal diarrhea, or constipation. For establishing clinical diagnosis, six cardiovascular reflex tests are used. The parasympathetic function is tested by heart rate response to the Valsalva maneuver, to forced breathing, and orthostasis. The sympathetic function can be examined by the blood pressure response to orthostasis and the “cold pressure test” or the sustained hand grip test. Nuclear medicine procedures such as 123I-MIBG scintigraphy can assess cardiac sympathetic innervations deficits. The patient must be informed about strategies in order to avoid syncopes. A significant improvement in autonomic neuropathy has so far been detected only after successful kidney transplant (R€ ockel et al., 1979; Kurata et al., 2004).

Uremic myopathy At an early stage of renal failure, patients often complain of muscle cramps, with painful contractions of the lower limbs. Muscle weakness and rapid muscle fatigue and muscle atrophy are common problems in uremic patients (Johansen et al., 2003) and are observed under long-term dialysis therapy, especially in elderly patients. The etiology is multifactorial. Causative factors include reduced nutritional status with catabolism (Locatelli et al., 2002) and chronic metabolic acidosis, which accelerates the oxidation and degradation of important amino acids. Hormonal disorders such as androgen deficiency, physical inactivity, and vitamin D deficiency also play a significant role (McElroy et al., 1970; Gordon et al., 2007). An accompanying secondary hyperparathyroidism can cause severe neuromuscular damage with proximal myopathy. Uremic polyneuropathy leads to distal motor disorder or generalized muscle weakness, muscle wasting, or paresis. Calciphylaxis (Edelstein et al., 1992) is a rare cause of painful myopathy. It occurs in terminal renal failure with extensive calcifications and intimal proliferation of small and medium-sized arteries and typically manifests

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with necrotic skin lesions. This myopathy is of ischemic origin. Painful muscle weakness also occurs in chronic aluminum intoxication (see above). Moreover, dialysis patients may experience repeated states of acute muscle weakness secondary to severe hyperkalemia; these dissolve completely after adequate treatment. Typically elevated levels of creatine kinase are not detectable in this condition and should prompt the consideration of other muscle diseases as a differential diagnosis. Muscle biopsies demonstrate nonspecific light microscopic changes, among others with atrophy, degeneration, and regeneration of muscle fibers, and necrotic lesions (Diesel et al., 1993). In particular, the evidence of intramuscular lipid accumulation is closely correlated with a poor musculoskeletal performance (Cheema et al., 2010). Muscle wasting is clinically confirmed by functional tests such as the sit-to-stand or the hand grip test. Through strength training, improvements in muscle fiber composition, muscle metabolism and evidence of transcriptional gene regulations and an increase in maximum muscle strength and endurance are observable (Kopple et al., 2007). The hours of dialysis treatment should be used for appropriate training, for example, using a bicycle ergometer (Cheema et al., 2010). Since protein and amino acid loss worsens the catabolic metabolism of hemodialysis and promotes muscle degradation, it is important to pay attention to sufficient protein intake. This should be at least 1–1.2 g daily per kg. Also, secondary hyperparathyroidism has to be treated with appropriate interventions, e.g., by adequate vitamin D substitution.

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NEUROLOGIC COMPLICATIONS OF ACUTE AND CHRONIC RENAL DISEASE Locatelli F, Fouque D, Heimburger O et al. (2002). Nutritional status in dialysis patients: a European consensus. Nephrol Dial Transplant 17: 563–572. Malik S, Winney RJ, Ewing DJ (1986). Chronic renal failure and cardiovascular autonomic function. Nephron 43: 191–195. Massry SG, Smogorzewski M (1994). Mechanisms through which parathyroid hormone mediates its deleterious effects on organ function in uremia. Semin Nephrol 14: 219–231. McElroy A, Silver M, Morrow L et al. (1970). Proximal and distal muscle weakness in patients receiving hemodialysis for chronic uremia. Phys Ther 50: 1467–1481. Mehta RL, Pascual MT, Soroko S et al. (2004). Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 66: 1613–1621. Merlino G, Serafini A, Gigli GL (2008). Response to restless legs syndrome and diabetic neuropathy – commentary by Gemignani et al. Sleep 31: 1069. Meyer TW, Hostetter TH (2007). Uremia. N Engl J Med 357: 1316–1325. Molitoris BA, Alfrey AC, Alfrey PS et al. (1988). Rapid removal of DFO-chelated aluminum during hemodialysis using polysulfone dialyzers. Kidney Int 34: 98–101. Molnar MZ, Novak M, Ambrus C et al. (2005). Restless legs syndrome in patients after renal transplantation. Am J Kidney Dis 45: 388–396. Murray AM, Tupper DE, Knopman DS et al. (2006). Cognitive impairment in hemodialysis patients is common. Neurology 67: 216–223. Murray AM, Pederson SL, Tupper DE et al. (2007). Acute variation in cognitive function in hemodialysis patients: a cohort study with repeated measures. Am J Kidney Dis 50: 270–278. Naganuma T, Uchida J, Tsuchida K et al. (2005). Silent cerebral infarction predicts vascular events in hemodialysis patients. Kidney Int 67: 2434–2439. Nardin R, Chapman KM, Raynor EM (2005). Prevalence of ulnar neuropathy in patients receiving hemodialysis. Arch Neurol 62: 271–275. National Kidney Foundation (2002). K/DOQI clinical practice guidelines for chronic kidney disease: evaluation classification and stratification. Am J Kidney Dis 39: S1–S266. Ogura T, Makinodan A, Kubo T et al. (2001). Electrophysiological course of uraemic neuropathy in haemodialysis patients. Postgrad Med J 77: 451–454. Otsubo S, Kimata N, Okutsu I et al. (2009). Characteristics of dialysis-related amyloidosis in patients on haemodialysis therapy for more than 30 years. Nephrol Dial Transplant 24: 1593–1598. Parkinson IS, Ward MK, Kerr DN (1981). Dialysis encephalopathy bone disease and anaemia: the aluminum intoxication syndrome during regular haemodialysis. J Clin Pathol 34: 1285–1294. Pereira AA, Weiner DE, Scott T et al. (2005). Cognitive function in dialysis patients. Am J Kidney Dis 45: 448–462. Pirzada NA, Morgenlander JC (1997). Peripheral neuropathy in patients with chronic renal failure A treatable source

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Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 25

Nervous system disorders in dialysis patients 1

VINOD K. BANSAL1* AND SEEMA BANSAL2 Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA 2

Pediatric Neurology, National Children’s Medical Center, Washington, DC, USA

INTRODUCTION End-stage renal disease (ESRD) patients require lifelong dialysis unless they receive a kidney transplant. Various neurologic disorders have been reported in such a population, whether receiving hemodialysis or peritoneal dialysis. Currently there are approximately 500 000 patients on dialysis in the US (U.S. Renal Data System, 2010). The neurologic manifestations may be seen in patients with advanced chronic kidney disease who have not yet been started on dialysis or in patients who have been started on dialysis. These disorders, which may be of either the central nervous system (CNS) or the peripheral nervous system (PNS), are given a simple classification in Table 25.1.

CENTRAL NERVOUS SYSTEM COMPLICATIONS Uremic encephalopathy The syndrome of uremic encephalopathy is the cerebral manifestation of the uremia and varies from subtle neuropsychiatric changes such as mild cognitive impairment to coma (Brouns and De Deyn, 2004; Seifter and Samuels, 2011). Severe uremic encephalopathy in early childhood may affect the brain development in children (Gipson et al., 2004). Earliest symptoms include lack of attention, concentration, emotional changes, subtle or advanced cognitive changes, memory deficit, delirium, psychosis, seizures, and coma. Motor symptoms, although less common, include generalized weakness, myoclonus, and asterixis. Seizures are generalized, with partial seizures less common. Depression, anxiety, and action tremors are often seen (Brouns and De Deyn, 2004). Neurologic impairment may develop in about

20% of the patients with acute renal injury (Mehta et al., 2004). In chronic kidney disease the uremic syndrome is more subtle and does not correlate with severity of uremia. Uremia is used in the setting of either acute or chronic kidney failure where generally both serum blood urea nitrogen or serum creatinine are elevated. But the symptom complex of uremic encephalopathy may not correlate to the severity kidney failure or the levels of blood urea nitrogen and creatinine (Tyler, 1970; Brouns and De Deyn, 2004). Uremic encephalopathy is much less commonly seen today because of earlier dialysis intervention and occurs only in circumstance where either the patient refuses to accept dialysis until symptomatic or a decision has been made not to initiate dialysis (Seifter and Samuels, 2011). The circumstances where it occurs are generally in acute renal failure, where there are many other concurrent diseases that may produce similar symptoms. A careful search should be made for any other causes before a decision is reached to initiate dialysis because of neurologic status. Upper motor neuron signs as well as speech and gait disturbances may also be present in late stages of uremic encephalopathy (Burn and Bates, 1998; Smogorzewski, 2001). The diagnosis of uremic encephalopathy is made based on clinical signs and symptoms. The level of blood urea or blood urea nitrogen or serum creatinine is not related to the onset or severity of uremic encephalopathy. Lumbar puncture, EEG, or imaging procedures are nonspecific and are used to exclude other conditions. Cerebrospinal fluid (CSF) in uremic encephalopathy may show pleocytosis (usually less than 25 cells/mm3) and increased protein (usually less than 100 mg/m). The electroencephalogram (EEG) is abnormal with generalized slowing and excess of d and y waves (Balzar et al., 1986). Brain imaging may show cerebral atrophy and

*Correspondence to: Vinod K. Bansal, M.D., Professor of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-3306, Fax: þ1-708-216-4060, E-mail: [email protected]

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V.K. BANSAL AND S. BANSAL

Table 25.1 Simple classification of central and peripheral nervous system complications observed in dialysis patients Central nervous system complications

Peripheral nervous system complications

Uremic encephalopathy Dialysis disequilibrium syndrome Dialysis dementia Wernicke’s encephalopathy Posterior reversible leukoencephalopathy Intracranial hypertension Movement disorders, restless legs syndrome Sleep disorders Cognitive abnormalities

Mononeuropathy Polyneuropathy Myopathy

enlargement of the ventricles. The differential diagnosis of uremic encephalopathy includes hypertensive encephalopathy, ischemic stroke, electrolyte abnormalities, metabolic acidosis, and sepsis. In some ways, it remains a diagnosis of exclusion. The pathogenesis of uremic encephalopathy is not precisely known but it is fairly clear that the level of urea or blood urea nitrogen or serum creatinine do not have significant relationship to the symptoms. Many so-called neurotoxins are hypothesized but no single neurotoxin has been identified that might be linearly related and dialyzable, whose removal would result in improvement, and that experimentally could reproduce symptoms complex of uremia. The many compounds incriminated in uremic pathogenesis are those which accumulate in serum in renal failure. The balance of excitatory and inhibitory neurotransmitters may be disrupted by various organic substances Among the most reported are the various guanidino compounds which are increased in cerebral spinal fluids (De Deyn et al., 2001; Smogorzewski, 2001; Vandolder et al., 2003). These compounds antagonize g-aminobutyric acid (GABA) which leads to cortical excitability (De Deyn et al., 2003). There are disturbances in monoamine metabolism such as depletion of norepinephrine, and suppression of central dopamine has also been described. A number of metabolites, such as myoinositol, carnitine, indoxyl sulfate, and polyamines, may also play some role. One other consideration should be the drugs which are being administered to such patients since in acute renal failure the excretion of various medications is impaired and could lead to cumulative effects. Treatment of uremic encephalopathy is initiation of dialysis. Although either hemodialysis or peritoneal dialysis may be used, in general, hemodialysis is the

preferred modality. The decision to initiate dialysis is made on several factors, such as neurologic status, and metabolic and electrolyte abnormalities. Most nephrologists consider neurologic symptoms to be an indication for dialysis initiation. Dialysis should gradually improve the neurologic status fairly rapidly; if, after dialysis has been started, there is no neurologic improvement, other conditions should be pursued vigorously.

Dialysis disequilibrium syndrome Dialysis disequilibrium syndrome (DDS) is an infrequent complication due to rapid metabolic changes occurring at the initiation of hemodialysis (Arieff, 1994). Patients exhibit signs and symptoms suggestive of cerebral edema. These include acute onset of headache, fatigue, nausea, vomiting, tremors, blurred vision, muscle cramps, disturbed consciousness, convulsions, and coma (Benna et al., 1981; Arieff, 1994). The term disequilibrium is used because, whereas blood biochemistries such as blood urea nitrogen and serum creatinine levels improve, clinical neurologic signs and symptoms deteriorate. DDS usually results from acute changes in osmolality when there is rapid decrease in urea in extracellular fluid but the decrease in brain cells lags, thus favoring water movement into brain cells. Other intracellular osmolytes within brain cells may also be present (Arieff, 1994). The condition spontaneously reverses after a period of dialysis. The osmotic gradient occurs because of delay in urea being removed from brain as compared to plasma. In bilateral nephrectomized rats, hemodialysis reduced brain urea concentration less than plasma, thus setting up a high osmotic gradient and increased brain water (Silver et al., 1992). It was proposed that because urea is so highly diffusible and a small molecule, that the blood–brain barrier is due to development of organic osmolytes or idiogenic osmoles (Arieff, 1994). Subsequent experimental studies convincingly established that DDS was due to reverse urea gradient (Silver, 1995). The presence of cerebral edema is confirmed by either computerized brain scan or by diffusion-weighted magnetic resonance imaging (MRI) (Chen et al., 2007). The reverse urea effect is the result of slow removal of urea from the brain compared to large decreases in plasma concentration. Recent studies have shed light on the molecular mechanism of dialysis disequilibrium syndrome. Water and urea movements across cell membranes are facilitated by water channels, called aquaporin (AQP) and urea transporters (UTs). In brain, among the APQ and UTs cloned so far, AQP1, AQP4 AQP9 and UT-B1 are expressed (TrinhTrang-Tan et al., 2005). AQP4, AQP9 and UT-B1 are believed to facilitate rapid equilibrium of water and urea throughout the brain parenchyma. Trinh-Trang-Tan et al., in an experimental model of chronic kidney disease, showed that in brain, in such a model, there is a decrease

NERVOUS SYSTEM DISORDERS IN DIALYSIS PATIENTS in UT-B1 expression and rise in AQPs. This leads to impaired transport of urea out of the brain cells and facilitates water movement inside the cells, resulting in brain edema (Trinh-Trang-Tan et al., 2005). The mechanism for marked reduction of UT-B1 in chronic renal failure is unclear. The other hypothesis is that there is disparity in CSF pH and blood pH due to rapid dialysis. The systemic metabolic acidosis is quickly corrected by rapid hemodialysis while the CSF acidosis lags. This may lead to secondary hypoventilation and rise of plasma PCO2 which diffuses into CSF, elevating CSF PCO2. The resulting fall in CSF pH may contribute to development of brain edema by unknown mechanisms. (Arieff, 1994). In current practice, DDS has largely disappeared. The initial dialysis is started slowly, with low blood flow of around 150–200 mL/min and a less efficient dialyzer and short duration, all in an effort to slow down the disparity between plasma and brain urea concentration. The dialysis is then gradually increased in time and efficiency. With the use of bicarbonate bath and the slow dialysis, there should be minimal or no rapid changes in CSF and plasma pH.

Dialysis dementia Dialysis encephalopathy or dialysis dementia is a subacute, progressive, and often fatal disease. It is typically observed in prevalent dialysis patients who have been on hemodialysis for a while. Symptoms include personality changes, directional disorientation, seizures, visual and auditory hallucinations, dysarthria, dysphagia, apraxia asterixis, myoclonic jerks, seizures, and dementia (Brouns and De Deyn, 2004). The disease is progressive and may eventually lead to death. EEG findings showed a relatively normal background with very frequent frontal intermittent bursts of d activity, triphasic waves, and paroxysmal bursts of spike and wave activity (Chokroverty and Gandhi, 1982). The etiology of dialysis dementia was determined to be aluminum neurotoxicity. This was demonstrated by markedly increased levels of total body aluminum in patients who died of dialysis dementia as compared to nonuremic patients or uremic patients dying of some other cause. The evidence for aluminum toxicity came from epidemiologic studies. The places where dialysis dementia was seen had a higher water concentration of aluminum as compared to areas where no such cases were being reported. Another source of aluminum was the use of aluminum hydroxide phosphate binders. The resulting absorbed aluminum increased serum levels. The mechanism by which aluminum leads to neurodegenerative changes in the brain is unknown (Bolton and Young, 1990). With water treatment that removes aluminum from water and discontinuation of oral Al(OH)3 the incidence has fallen and the disorder is now rarely seen (Dunea, 2001). Aluminum toxicity also leads to

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osteomalacia and anemia in dialysis patients and, along with neurologic symptoms, helps diagnose this condition. Treatment is the avoidance of aluminum-containing phosphate binders and the maintenance of proper water treatment. In established patients, treatment is use of the chelating agent desferrioxamine (DFO), and has been shown to reverse the symptoms of dementia (Milne et al., 1983). Although this entity is now rarely seen, if suspected, the diagnosis should be made on the blood level of aluminum (normally