A Basis for the Theory of Medicine

Citation preview

А

Basis for

the Theory of Medicine А.

D. Speransky

WHAT IS ТН Е ROLE of the nervous system in disease? То what extant is it а factor in regulating metabolic changes involved in the growth and functioning of the tissues? This book includes 46 illustrations оп the results of his scientific investigations of the effects of disease in causing changes in the nervous system. Не estaЫishes the nature of the participation of the nervous system in the development of pathological processes.

А

BASIS FOR

ТНЕ

THEORY OF MEDICINE

А

BASIS FOR ТНЕ THEORY OF MEDICINE в,

А.

D. SPERA.NSKY

Director of tl.e Dettll't11Unt of Patho-Pl.ytiology of tlu All-Unio11 lnstitute of Experinuntal Medicine

Transloted and Edited hy с. Р. DUТТ, В.А. (CANTAB.)

With the Col/.ahoratwn of

A.A.SUBKOV Senior Re1111rcJ, Workl'r of the TimiryBiological lnstituu

INTERNATIONAL PUBLISHERS NEW YORK

COPYRIGHT 1

1943,

._у

INTl!J.NATIONAL PUBLJSHl!J.S

со.,

PJ.INTl!D IN THI! U.S.A.

This printing 2013

INC.

CONTENTS РАС!!

Author's Preface to the English Edition

13

Preface to the Russiэ.n Edition .............. . . . ... . .. . ... . .

15

ТНЕ

NERVOUS MECHANISM OF COMPLEX CONVULSIVE STATES

СНАРТЕR.

I.

Consequences of Freezing Portions of the Cerebral Cortex in Dogs П. Subcortical Phenomena in the Co;istitнtion of the Epileptic Attack .. . .. III. The Cortex IV. The ThresholJ of Excitability in Convulsive Processes . ТНЕ

21

29 39

55

ROLE OF ТНЕ CEREBRO-SPINAL FLUШ IN ТНЕ GENESIS OF SOME FORMS OF ENCEPHЛLITIS

V. Enceph:ilitis as One of the Conscquences of Freezing а Portion of the Cercbral Cortex in Dogs . ........ VI. The Role of Cerebro-Spinal Fluid in the Proce~5 of Disintegration of Brain Substance . . . . . . . ....... ......... VII. The Toxicity of Cerebro-Spinal Fluid . . . . . . . . . . . . . . . . . . ТНЕ

CIRCULATION OF CEREBRO-SPINAL FLUID IN BRAIN, ТНЕ SUBMEMBRANOUS SPACES AND ТНЕ NERVES

67 7I 77

ТНЕ

VIII. The Connection of the Submembranous Spaces of the Brain with the Lymphatic Systcm IX. Our Invesrigations on the Connection of the Submembranous Spaces with the Lymphatic System . . . . . . . . . . . . . . . . . . . . . Х. The Movement of Cerebro-Spinal Fluid Within the Medulla and Submembranous Spaces XI. On the Penetration ufVarious SuЬstances into the Nerve Trunk and their Movement Along lt. . . . . . . . . . . . . . . . . . . . . . . . . 7

89 94 109

I 17

CONTENTS

8 ТНЕ

ROLE OF ТНЕ NERVOUS SYSTEM IN ТНЕ PATHOGENESIS OF CERTAIN INFECТIOUS DISEASES РАСЕ

СНЛРТЕ~

ХП. The Role of the Nervous System in the Pathogenesis of Certain Infectious Discases . . . . . . . . . . . . . . . . . . . . . . . . Rabies . . . ... : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diphtheria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tetanus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dysentery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scarlatina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

XIII. General Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I

3r

134I 39 140 140 I 41 145

147

AND FORМS OF DEVELOPMENT OF DYSТROPHIC PROCESSES WITHIN ТНЕ NERVOUS SYSTEM

ТНЕ CONDIТIONS

XIV. The Mechanism of Segmentary Affections of the Nervous System Through the Nerve Trunk . . . . . . . . . . . . . . . . . XV. The Extension of the Dyщophic Process Beyond the Limits of the Segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XVI. Standard Forms of Nervous Dystrophy and Their Quantitative Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . QUALITATIVE VARIATIONS OF NERVOUS

163 I

76

I

97

DYSТROPHY

XVII. Acute Irritation (Infiammation) . . . . . . . . . . . . . . . . . . . . XVIII. Chronic Irritation (Inflammation) . . . . . . . . . . . . . . . . . . XIX. Specific Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ХХ. General Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 33

254

278 3I о

CONCLUSION

XXI. XXII. XXIII. XXIV. XXV. XXVI. XXVII.

Basic Propositions Parkinson's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................. Rheumatism Typhus Exanthematicus. . . . . . . . . . . . . . . . . . . . . . . . . . ........... ........................ Malaria Persian (Recurrent.) Typhus . . . . . . . . . . . . . . . . . . . . . . An:r:sthesia as an Irritation . . .......... .. ..... . .. · .

331 351 355 362 366 373 377

CONTENTS CНAPn:Jt.

XXVIП.

~ РАСЕ

Affections of the Digestive Organs . . . . . . . . . . . . . . . . .

382

XXIX. Affections of the Cavities of the Mouth, Nose and Middle Ear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Affections of the Еуе (Ceratitis) . . . . . . . . . . . . . . . . . . . XXXI. Septic Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ХХХП. Other Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XXXIII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BiЬliog1·aphy . .. . . . . . .. .. . .. . .. . .. . .. . .. . ... . . . .. . .. . .. Plates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ХХХ.

384 387 391 395 398 409 411

LIST OF PLATES l'LAП

РАСЕ

NO.

Brain of а dog after freezing the cerebral cortex . . . . . . . . . . . .... . ... . :а. Injection of lymphatica of nual mucous membrane from the auЬarach~oid space 3. Injection of pharyngeal lymphatic glanda aod veuela from the 1uЬarachnoid •расе .......... ... ....................................... . 4. GaogrenoUI ulcer with aeque.tration of phalange. and metatanal Ьоnеа, after injection of рш into the 1eiatic nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5· Symmetric;il ulcen оп Ьoth hind extremities, after injection of рш into the left 1eiatic nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. X-ray photograph of extremity 1hown in Plate 4, and contralateral extremity 7. Experi1nent;Ll group. Sciatic nerve in region of suture (aftcr 6 weeks) . . . . . 8. Control group. Sciatic nen·e io region of suture (after 6 weeka) . . . . . . . . . . . . 9. Effect of trypan Ыuе in dyeing the spinal cord, arachnoidea and pia mater. . . . 10. Infiltration of perineurium in 1-egion of lower lumЬar inter-vertebral ganglion, 14 days after chemical trauma of the sciatic nerve . . . . . . . . . . . . 1 1. lnter-vertebral ganglion of cervical region after chemical trauma of "· nudianus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 а. Inflammatory infiltrate in а nerve root sheath after chemical trauma of the eciatic nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 з . Alteration of nerve cella in lumbar inter-vertebral ganglion after chemical trauma of the sciatic nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. PolyЬlast infiltrates in cervical reJfion of apinal cord after chemical trauma of "· medianus . . .. . . ... . . .. . ........ .. ............. . ...... . . . . . 15. Infiammatory fосш in cervical region of spinal rord after chemical trauma of the sciatic nerve . . . . . . . . . . . . . . . . . . . . . . . . . ..... . . . .. .. ... .. . 16." Motor cells of lumЬar region of spinal cord after chemical trauma of the aciatic nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J 7· Nerve cells of anterior horn in lumЬar region of spinal cord, after chemical trauma Ьу formalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . t 1. Infection Ьу tetanUI ahortly after removal of sympathetic chain . . . . . . . . . . . . 19. Infection Ьу tetanus somc time after removal of sympathetic chain . . . . . . . . . . 20. Brain of а dog after placing а glass ring around the infundibulum . . . . . . . . . . :11. Non1a after the "glass sphere operation". ..................... . ..... . . :12. Noma after the "glaas aphere operation" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Dental decay after the "glass aphere operation" .. . ...... . .... . ..... . .. . 14. Loss of hair round the cycs and opacity of the cornea after the "glass aphere operation" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.

IJ

4:11 423 424424 415 426 4:16 427 4z8 421

4z9 429 430 430 4з 1 43 1

43 2 4 за 4зз 434

435 436 437

LIST OF PLATES

12 l'LAТE

:а5.

NO.

H2morrhagea in the lunga after the "glua iphere operation" ....... . .. ... . 26. llzmonhagea in the vilceral organa after the "glaa арЬеrе operation". ... . . . 37. Hzmorrbages in the valvula Bauhinii, czcum and lar~ intestine after tbe "gla88 sphere operation'' ........... . ..... ·.· . . . . . . . . . . . . . . . . . . . 21. Diagranunatic repraentation of diatribution of luemorrhagea in the gaatrointeatinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . а9. Degt'neration of cells of upper cervical ganglion after the "glua iphere operat1on11 • • • • • • • . . . • • • • • • • • • • • • • • . • • . • • • • • • • • . . • . • . 30. Rectum and 8IDal1 inteatine of dog poiaoned Ьу mercuric chloride . . . . . . . . . . . . 31 . H;e.rnorrhages in the atomach of а rabblt after injury to. the IК:iatic nerve . . . . . 32. H:miorrhagea in the atomach of а raЬЬit dying from rablea .. . . . . . . . . . . . . . . 3 3. Papillomata on the mucoua membrane of the mouth of а dog . . . . . . . . . . . . . . 34. Stomach of control raЬЬit after inoculation of gastric wall with tuЬerculoais culture . ... ... ... .. . ............ . .... . ...... . . .... · · . . . . . . . 35. Stomach of experimental raЬЬit in which Ьoth "· flagi were eevered Ьefore infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36. Stoп1ach of experimental raЬЬit, in which Ьoth "· wgi were eevered after infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37. Fint atage of tuЬeтculoua infection of testicles and their mesenteries . . . . . . . . 311. Severe tuЬerculoua infection of teaticle and meaentery . . . . . . . . . . . . . . . . . . . . 39. Viaceral organs of а cat infected Ьу tuЬerculosi1 . . . . . . . . . . . . . . . . . . . . . . . . . 40. Mortification of the 8kin of the ICJ'Otum after applying lewilite to the dietal end . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41. Ditto, after applying lewiaite to the root of the acrotum near the inguinal canal 41. Mortification of .ltin of the Ьelly after applying lewiaite to the lower portion . . 43. А case of red lupus of 10 yeara' duration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44. The same, 1 % montha aftcr Ыocltade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45. D6bring'1 dermatitia Ьefore Ьlockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46. The ame patient after Ыockade ........... . ... . ... . . . .... . . . .. ... ..

l'ЛGE

431 438 439 440 44 1 44а

443

443 44+ 44 S

445 446 447 447' 441 449

449 450

451

4S 1 457.

451

PREF АСЕ ТО ТНЕ ENGLISH EDITION recent years it has often Ьееn remarlted that the science of medicine is patsing through а crisis. On а superficial view there would seem to Ье little ba.'iis for such а judgment. Ea.ch year sees the addition of tens of thousands of researches directly or indirectly affecting medicine; new methods of technique are continually arising, new fields of work are Ьeing opened up. In size of output and intensity of study there are few branches of science w hich сап compare with medicine. What is wrong then? An effort to answer this question leads inevitably to the conclusion that medicine has gradually and almost imperceptiЬly ceased to treat its subject matter in а synthetic form, suЬstituting instead а. comprehensive and often profound analysis of details. Specialisation, carried to an extreme degree, has almort Ьесоmе the hallmark of contemporary theoretical ~nd practical medicine. As а result, medical science ha.s Ьееn broken up into separate pa.rts, Ьoth as regards subject matter and method. Already, from time to time, many physicians have proclaimed the need for а. return to а synthetic form of worlt. Such a.ppeals, however, have not yielded any real results for they left undecided the questioa how exactly this was to Ье realised. А formal union of the isolated parts can Ье easily achieved Ьу any method of worlt. But it has not led, and cannot lead, to the desired goal, and is even сараЫе of introducing still more confusion into the subject Ьу deliЬerately directing it along а wrong path. Непсе, the question remains опе of the search for the essential principles for umon. This demands а method сараЫе of unifying not merely diverse but eyen contradictory phenomena. А consistent analysis must reveal the general laws underlying а mass of particular data. Then, at last, the investigator will Ье in possession of the "leading linlt," а grasp of which enaЬles one, as Lenin remarked, to manipulate the whole chain. For а numЬer of years past, together with my collaЪorators, I have been engaged in research on the participation of the nervous system in the genesis of various pathological processes. The originally limited, special proЬlem grзdually assumed larger and larger dimensions, research widened out, en1braced new fields and yielded new data of а varied nature. The appraisal of these data led so often to а conflict with many existing views that very soon we perceived the necessity of giving up the study of isolated questions. Ву the force DuaiNG

13

PREFАСЕ

ТО ТНЕ

ENGI"ISH EDITION

of circumstances, we were compelled to pass to а revision of the conceptions of the basic processes of general physiology, from the point of view of the nervous component in their origin and history. As а result, а system came into Ьeing сараЫе not only of unifying around а common centre а11 the diverse data provided Ъу pathology and the clinic, but also of advancing these branches of science along а characteristic and as yet almost untrodden path. The time has come when the matter сап по Jonger Ье left in the exclusive possession of а limited circle of persons but imperatively demands the wide participation of scientific circles for testing what has been achieved, for judging the propositions that have been enunciated and, аЬоvе all, for ensuring further progress. This has impelled me to embark on the puЫication of our views in the Soviet and foreign press. I ат very glad to welcщne the appearance of an English translation of my Ьооk, since this will make it more widely accessiЫe Ьoth to European and American readers. А.

Leningrad, July 14, 1935

D.

SPER.ANSKY

PREFACE

ТО ТНЕ

RUSSIAN EDITION

WнEN

the material of а book is finally arranged and the Ьооk written, the order of exposition of the material appears to Ье the same as that of its colltction. As а matter of fact, many years of work may elapse Ьetween two experiments which occupy adjacent places in the description, and Ьetween which there appears to Ье an uninterrupted internal connection. As the material accuп1ulates, parts of it, arranged according to old systems, may Ье set out in а new order. ln this process, the original starting point may lose its value and Ье done away with; the facts acquired earlier receive then а new significance and take up а new place in the logical order of the book. The exposition of material obtained as the result of а long course of work could turn out to сопи iп advance of the cause which gave rise to the whoJe sequence. Thus the historical order of succession in the production of the material does not coincide with the logical order of succession in the exposition of it. This holds good not only for Ьiology but also for the so-called exact sciences. lt is, of course, particularly evident in biology, which operates with highly complex processes. Five years ago the author wrote а Ьооk entitled The Nervous System iп Pathology. Very shortly aft~rwards it becamc clear that the Ьооk could not Ье repuЬlished in its previous form. The advance of research not only added something new to the data already availaЬle Ьut necessitated а reaпange­ ment of the entire material. ln part, this occurred because particular questions were repeatedly made the subject of experiment and then set aside. Such processes as tetanus, rabies, epilepsy, tuЬerculosis алd othcrs, used Ьу us as indicators in the study of various physiological mechanisms, were repeatedlymade the subject of fresh experiments depending on the acquisition of new facts in other spheres. Since the basic idea of this work wa::; to grasp the common elements in pathological processes that are externally dissimilar, each fact came under а cross-fire of criticism from other facts, frequently taken from very remote spheres. This made possiЬle the noting of details that had previously escaped oЬservation, but which now altered not only the genera.1 appearance of the phenomenon itself, but also its place in the series of other phenomena. ln the above-mentioned book, it was still possiЬle for me to set out the material in the order of the experiments; this has now become impracticaЬle_ 15

16

PREF АСЕ

ТО ТНЕ

R USSIAN EDITION

Вeginnings and ends have so frequently changed places and have Ьесоmе so intricately entangled that а description of the material in historical sequence would make the line of thought appear disjointed, which in actual fact is not the case. It was necessary either to renounce the possibility of seeing the material as а whole and to restrict oneself to the puЬlication of separate facts or to pass to а systematic exposition of th11 subject. The latter depends on two factors: on the quantity of new facts and on their co-ordination with already existing scientific systems. For the solution of the first task, the volume of research was consideraЫy increased and the work encroached upon all the basic departments of general pathology. The second taslc proved to Ье much more difficult, and in certain respects simply impossiЬle to fulfil since the new material could not Ье inserted in the framework of the old ideas. The original intention of giving merely а systematic exposition of the' subject gave place to the n~cessity of constructing а new system and the question was shifted to the plane of methodological relations. Not only facts and general propositions had to Ье revalued, but also the methods and manner of the research itself. It can Ье understood that such а work could not Ье brought to а conclusion in а few years; nevertheless its fundamental features have Ьееn adequately defined. lt may Ье mentioned in passing that even now а numЬer of difficulties in the way of systematic exposition still remain; the conclusions arrived at ha~ proved to Ье so far from those generally accepted that to set out the subject directly, without any introduction depicting the work in its evolutionary course, would have involved the risk of Ьeing not understood or understood wrongly. Consequently it was necessary to keep to а mixed form: at the out&et to demonstrate the course of the experiments, and only afterwards to pass to the systematic arrangement of the conceptions. One of the defects of this form of exposition lies in а certain lack of correspoпdeпce in the treatment of the separate questions that are aпalysed in the Ьeginning and at the епd of the Ьооk, but this provides а striking example of the evolutioп of views in dependence оп the evolution of the work. As regards characterisation of the concrete forms and directions of ex~rimeпtal activity, it is пecessary to say the following: Although we carried out experimeпts with various chemical suЬstances, toxins and viruses, we did поt wume the special task of studying iпdividually each process brought aЬout Ьу these ageпts. We merely had recourse to them at particular points in the course of research, as indicators for throwing light оп those parts of the geпeral question in which we were interested.

PREFАСЕ

ТО ТНЕ

RUSSIAN EDITION

Hence, in this Ьооk also, which represents а summary of our work, I do not unite togethe.r the separate oЬservations made at various times and with various purposes. In the reactions evoked Ьу various agents we frequently saw so much similarity that it was impossiЪle to distinguish them, and we turned our attention to the study of the mechanisms lying at the basis of this unity. The usual form of work Ьoth in the laЬoratory and in the clinic does not ensure an exhaustive treatment of the subject. Тhе clinic, Ьу the nature of its position, is deprived of the right of extensive, a11d particularly of unhampered, experiment, while the J.aЬoratory investigates each pathological process separately as а special and independent entity. This, of course, is also nec~ and has its advantages. But in that case, everything taking place in the organism has to Ье looked at from the very Ьe­ ginning and is inevitaЫy connected with the properties of the "causal agent." In actual fact, however, it may happen that а certain phenomenon in raЬies can Ье more easily understood Ьу the study of epilepsy, and in scarlatina Ьу oЬservation of tetanus. If each pathological process in each appropriate case is approached as an indicator of а definite physiological process and is included in the arsenal of other methodological means which contemporary science has at its disposal, then it will Ье seen that the virus of raЬies сап play the same role in the solution of one particular proЫem as the string galvanometer in the solution of another. In spite of the fact that the questions touched upon in this Ьооk have already а history of many years Ьehind them, it must Ье admitted that at the present time they are still in their infancy. Only too frequently it is still necessary to Ье content here with compiling а series of indirect data, seeking out unexpected occasions for experiment and conducting the research itself in circumstances as complicated as the solution of an equarion with а number of unknown quantities. It will Ье evident from the materials presented that only simultaneous work on а numЬer of a~iated questions, often very dis&milar in externals, has enaЬled us to discover the requisite conditions and, at least in part, to advance the subject over the dead point. This work hаз Ьееn carried out during ten years in the laЬoratories and clinics under ту guidance in the Institute of Experimental Medicine and the Institute of Surgical Neuro-Pathology in Leningrad, with the participation of а large numЬer of specialists in different subjects who have collaЬorated with me in the provision of the necessary material. Each of them, Ьesides giving his laЬour, has also introduced much that is individual, thereЬy making possiЫe the gradual extension of the limits of the research. In the shaping of this Ьооk, much assistance has Ьееn given me Ьу ту

i8

PREFACE

ТО ТНЕ

RUSSIAN EDITION

co11.aЬorators Dr. I. А. Piga1cv, and Dr. С. I. Lebedinskaya, and also Ьу Dr. N. Е. LeЬedev and my wife. I take this opportunity ot acknowledging my deeply felt thanks. А.

Leningrad, SeptemЬer 1934

D.

SPERANSК.Y

ТНЕ

NERVOUS MECHANISM OF COMPLEX CONVULSIVE STATES

CHAPTERI CONSEQUENCES OF FREEZING PORTIONS OF CEREBRAL CORTEX IN DOGS ТнЕ

ТНЕ

origin of these researches was as follows. In 1923-24, while working in the physiological laЬoratory of I. Р. Pavlov at the Institute of Experimental Medicine, I participated, among other things, in the surgical activities of thc laЬoratory, preparing animals for future special investigations. Naturally, likc others, I encountered the unpleasant fact that many of the animals ( dogs), after removal of diff erent portions of the cerebral cortex, not infrequently died from epilepsy. It is true that one can counteract this phenor:.enon, but Ьу no means in all cases. In addition, а new trcpanning, with e:rrcision of the cicatrice, gives what is physiologically а new dog that cannot serve for the continuation of old experiments Ьegun on it. Hence I set myself the task of working out а method of disconnecting limited portioпs of the cortex in such а way as to leave intact Ьoth the dura mater and the soft membranes. I took as my starting point the instability of nerve tissue in the face of sharp chaпges of temperature. Experimental worlc in this direction had already Ьееn carried out in the period of physiology when the theory of the localisatioп of functioпs iп the cerebral cortex was still new and alluring. Thus, in 1883, in Goltz's laЬoratory, Openchowski carried out research оп the local effect of oold applied to the cerebral cortex. The results of this work were puЬlished Ьу him in а short commuпicatioп printed iп Cpt. "e,,J. Soc. Biol., Vol. 2. То obtaiп а restricted or extensive effect of cold he applied to the cortex а glim apparatus cooled Ьу means of ether vapour. Тhе work was carried онt оп raЬ­ bits and dogs. In the latter, the development of coпvulsive attacks was oЬ­ served in two cases. In rabblts, symptoms of amesthesia were oЬserved, and certain pathological forms of movement on the opposite side of the Ьоdу. Openchowski also obtained convulsive phenomena Ьу the cooling and partial freezing not опlу of the motor, but also of the occipital areas of the cortex. Hence, he came to the conclusion that there are no special epileptogenous zones or centres in the cortex of the hemispheres. As regards the solution of the Ьasic task of his investigatio~he application of cold for the purpose of studying the localisation of cortical processes-he remained dissati$Ded, since hc considered the effect of cold to Ье superficial. Later, other invest).

21

BASIS FOR ТНЕ THEORY OF МEDICINE

gators also studied the infiuence of cold оп nerve elements. Thus, Trendelenburg estaЬlished а numЬer of data providing evidence that even simple cooling of the cortex results in prolonged disorganisation of its functions. It was estaЬlished that sufficiently intense freezing of а portion of the cortex kills the nerve elements in it. At the same time, other more staЫe structures can withstand such destruction of their normal state. W е must expect that if freezing of the cortex is carried out through the dura mater without damaging ·the latter but only exposing it over а limited area, then Ьoth the dura mater and the soft membranes will suffer less than the cortex.

Fig. а) Тhick-walled

Apparatus for Freezing the Cerebral Cortex metal chamЬer. Ь) ТuЬе for incoming vapour. с) Openings for exit of vapour from the chamЬer

1.

It was not diffic\dt to realise this in practice. The cerebral cortex of the dog has а relatively elementary character. The sulci and convolutions throughout almost their whole extent have the form of arcs, Ьeginning at the frontal pole and ending at the temporal. The variations are also simple. This renders possiЫe sufficiently accurate reference of definite parts of the cortex to corresponding places of the skull of the dog. It is convenient to protect ad jacent parts of the brain Ьу trepanning over а restricted area, strictly within the limits of that area of the cortex which it is proposed to exclude. Having constructed ъоmе pieces of apparatus Ьased on the principle of the freezing microtome, of various sizes and forms, and having provided them with openings for the exit of carbon dioxide in such а way that neighЬouring parts (muscles, skin) would not suffer, I proceeded to carry out the experiments.1 The first dog which was subjected to the operation of freezing а small portion of the cortex in the visual zone died in Jhe course of 24 hours, with "· 1 А. D. Speransky. Zhurn. Ехр. Biol. i M~J., No. 7, 19z61 Апп. ае l'lnst. Pasteur,

"'

Vol. 40, 1926.

CONSEQUENCES OF FREEZING

ТНЕ

CORTEX

23

the exhiЬition of severe epileptic convu1sions during more than 12 hours. Repetition of this experiment 'in а second, third and fourth case had the same results. In all cases the general character of the illness developed not immediately but after а definite interval of time-from one to five hours. The dog emerges from narcosis without any special phenщnena as regards the nervous system. Very soon, tonic spasms develop in various groups of muscles, after which comes clonic twitching, also in various groups of muscles з. nd separate mнscles. Following on this, or simultaneously, rhytl1mic convulsions and other complex movements take place and, finally, а typical epileptic seizure in its classical form sets in. These attacks are repeated at various, often rernarkaЬly accurate, intervals of time; they Ьесоmе more and more frequent and lead to а condition which can Ье defined as status epilepticus. Then coma supervenes. In this state the animals die, some I 2-50 hours after the operation. The post-mortem examiпation reveals that the external part of the dura mater is ha:morrhagic, but entire and firm; its internal surface is smooth and shining. There is no growth of connective tissue either on it or between it and the surface of the brain. The pia mater is pe1·meated \\'ith Ыооd throughout thc whole extent of the hemisphere. At the point where freezing has taken place, the suЬstance of the brain is visiЪly changed, appea1·ing as а sharply demarcated patch of а dark cherry colour. The vessels in this portion undergo thrombosis. The size and shape of the dark portion corresponds almost exactly to the size and shape of the apparatus. In cross-section it is found that the alteration of the Ъrain suЪstance extends to а depth of 2-4 mm. In this region, the cortex is converted into а pulpy mass of а cherry colour which can Ье abradcd from the surface of the section like the pulp of the spleen in cases of acute swelling. ( Plate I.) SuЪsequently, а numЪer of such experim.ents were perforшed, and it \vas possiЪle to estaЬlish the following results: 1. The location of the portion of cortex subjected to freezing does not play ач essential role in the developmerit of the resulting picture of the illness. Freezing different points of the cortex ( excluding motor points) i11 the accessiЬle parts of the occipital and temporal areas yields approximately the same picture. 2. If freezing is carried out on any portion of the cortex of the dog, :ind this portion is afterwards removed, then no convulsive or otl1er phenomena of motor agitation develop afterwards. The animal quickly recovers w ithout complications. 3. On the other hand, if one waits for the appearance of pronounced symptoms after freezing ( such as usu:illy occur after some hours) and then

BASIS FOR ТНЕ THEORY OF MEDICINE the corresponding porrion of the cortex is removed, tbls does not save the animal from the further development of the illness, although the latter changes its course and general character• .f.. Freezing а portion of the cortex in а dog which had Ьееn subjected а month previously to the operation of section of the corpus callcsum cau5es the development of epileptic seizures and other convulsive phenomena оп Ьoth sides of the Ьоdу simultaneously and equally. 5. More detailed oЬservation has demonstrated that the first symptoms to appear after freezing, and the last to vanish, in the general picture of the illness are not corrical but suЬcortical. For purposes of illustration 1 will give an extract from the records. :RECORD No. 5 Dog. МtШ. W1ig!U 18 ltg. On August 12., 1925, trepanning was carried out, and а1ао frcezing of а portioD of the cortex through the undamaged dura mater Ьу the application to the latter of the freezing apparatш, cooled to а very low temperature. Тhе operation wu concluded (and the wound .ewn up) at 11.05 a.m. 12.15 p.m. Tonic apum of the extenюn of the fore extremities. Twitching of mUlclea of the face and tongue. 12.35 p.m. Movement of all the extremities u in running; the dog lies оп its aide with head and Ьоdу rating on the rround and in thia position "runs," coordinating tbe movements of its extremitiea aЬюlutely correctly and consiatently-right foreleg and left hind leg, then left foreleg and right hind leg. These movementa are carried out uninterruptedly, increasing in speed or 1lowing down. 1.10 p.m. The fint epileptic attack. Tonic-clonic convulaions affecting the whole mшculature of the Ьоdу, head and extremitiea. Heavy attack. Foam at the mouth. Defecation and arination. Duration of the attack-1 1/1 minutea. Immediately after the conclusion of the attack, 11atationary running" ia reaumed. 1.20 p.m. Тhе attackt are renewed after 3-5 minutes. "Running'' during the intervals. Вetween the attacЬ (and of coune during them) there is no reaction to external (even painful) 1timuli. Лt timea, tonic apum of the fiexors of the hind extremities occun. Лt 1ucb timea the movement of "running" is carricd out only Ьу the fore extremities, the hind ones are preaed to the Ьоdу and in this po1ition twitcb awkwardly. 1.30 p.m. Status itUт. 2.15 p.m. Тhе Ьeginning of an attack either with tonic spasm of tbe hind extremities or with tonic 1pasm of the lower jaw (with forced opening of the mouth}. Тhia i1 followed Ьу rapid maaticatory movementa and further Ьу general tonic-clonic convul1ion1. М uch frothy muc111. 3.30 p.m. Interval1 of 5-6 minutes Ьet\veen the attacb. The mucoid froth is --:creted in auch qaantity that tЬе whole fioor of the chamЬer ia covered Ьу it. Durin_g the intervals, the dog lies immovaЫe. 11Statio11&ry running'' hu ceated. 4.30 p.m. The int.erval1 Ьetween tbe attacks Ьесоmе longer, the attacb tbem telves shorter and less pronounced. 7.15 p.m. Since 4.48 p.m. there wu only оае con\•ul1i\"e attack. Сота. In tЬе Ьeginning-laЬoured breathing of the expiratory tJpe, afterwards the breathing 8 regular and deep, but 1low.

CONSEQUENCES OF FREEZING ТНЕ CORTEX

25

7.а8 p.m. Heavy attack of epileptic convulaions luting al/1 minute1. Convulli~ panting at the outlet. 7. 3s p.m. А new attack lasting а minutet. 8.05 p.m. Epileptic .eizure, followed Ьу а 1eeond after а .Ьort interval of timeo (3 minutet) then а third and 80 оп. 8.55 p.m. Status •Piиplicш. 1 о. 4 о p.m. Stillus •tiuptkш. Тhе convulliona affm all m111Cular group1 but are more fееЫу expre.ed. 11.15 p.m. Coma. Breathing very dow, regular and deep. Auglllt 13, 1,35 a.m. Death. Breathing gradually Ьесоmее dower Ьut remai111 regular and deep to the end. Тhе dog lived 14. houn 30 minutet after the operation. Weight at death 15.7 kg.

In order to complete the picture I shall ~ve some notes from other records and summaries compiled in regard to various symptoms. 1. Practically all the records report consideraЬle flow of saJiva. Sometimes it assumes enormous proportions ( forming pools on the floor around the muzzle of the dog; at times the whole floor is covered Ьу frothy mucus), In some cases the saliva is liquid like water, in other cases it is thick: and mucilaginous. On turning our attention to this phenomenon, we found that the mucilaginous mass was secreted from the oral cavity while the w.atery liquid, devoid of mucus, came from the nostrils. In some cases this flow was very abundant. Further investigation showed that we have here an admixture of cerebrospinal tluid, which during the seizures flows abundandy into the lymphatic system of the nasal cavity and is excreted through the stomata onto the surface of the mucous membrane. Further details of this phenomenon will Ье given Ьelow. 2. In the intervals Ьetween the separate attacks no comatose condition was oЬserved but "stationary running" or very strong motor agitation usually occurred. During the latter the dogs incessantly run aЬout the room, stumЫing against objects, not reacting to pain or to the impossiЬility of overcoming the oЬstacles encountered. During this time they frequently exhiЬit "proud appearance," with widely distended eyes, head held very erect, the ears laid Ьасk and а dancing gait ( "Spanish trot"). As а rule, in а11 serious cases the comatose state is oЬserved Ьetween groups of epileptic seizures. Usually 2-3 such groups occur during the course of the illness. The longer the epileptic state, the more protracted is the comatose period. Coma invariaЬly 5upervenes Ьefore death, sometimes for а short period, sometimes for several hours (5-6). Breathing until the end is regular and deep, gradually slowing down. In some cases Cheyne-Stokes breathing was oЬservcd. 3. In regard to the order of development of the symptoms, the бrst to appear is usually tonic spasm of the .flexors of the hind extremities. It is interest-

BASIS FOR ТНЕ THEORY OF MEDICINE ing to note that this symptom is the most constant, and persists, with interruptions, throughout the course of the illness; and in cases which terminate in recovery of health, it is the last to disappear ( it may Ье retained more than two weeks). Sometimes the first symptom of the illness is а clonic convulsion of one particular muscle or group of muscles, rhythmic convulsions (nictation, nystagmus, twitching of the tongue, ear and one or all of the toes of the fore r hind paws). F ollowing on this, irregular tonic and clonic convulsions develop in various groups of muscles; at th~ same time the rhythmic convulsions are continued and even intensified. SuЬsequently, either the aЬove-descriЬed strong motor agitation or "stationary running" takes place. Finally, the epileptic seizure begins. Sometimes one or two such seizures occur at the Ьegin­ ning of the illness, after which there is а pause of 2-3 houn during which therc are no seizures but other convulsive phenomena develop and intensify. Then the epileptic period is resumed. 4. The latent period, before the appearance of thc first symptoms of thc illness, varies. It depends in part on the size of the portion frozen and on the duration of action of the cold, and in part, apparently, on the individual properties of the animal. The period Ьefore the first symptoms appear \'aries from 30 minutes to 5 hours, and Ьeforc epilepsy-2-13 hours. 5. "Stationary running," descriЬed аЬоvс, is usually oЬserved shortly Ьe­ fore the Ьeginning of the epileptic state and in the intervals Ьetween attacks. It may also Ье the chief symptom in cases where epileptic attacks do not dcvelop. Thus, dog No. I I "ran" for 14 hours without interruption, with fastcr or slower tempo of movement but without any essential alteration, right up to the time of death. 6. Reaction to external stimuli depends on the phase of the illness. During the period when only irregular tonic or local clonic contractions are to Ье oЬserved, reaction to stimuli is usually retarded but correct. At the outset there is reaction to contact, change of position, etc., afterwards to noise and calls. Frequently а consideraЫe time (several seconds) elapses between the stimu1us and the response to it. Sometimes the stimulus has to Ье repeated several times for the reaction to Ье obtained, but the latter remains correct, i.e., it corresponds to the character and strength of the stimulus. Later on, it can Ье­ соmе not only lively but also excessive. During the periods of cpileptic seizures, "stationary running" and coma, there is no reaction to any kind of stimulus, even destructive ones. 7. In cases which last for а long time and end in death or recovery, disorganisation of mastication and swallowing, and of the functions of the tongue, was observed. The external manifestation of this is that the act of eating is disorganised in such animals. Sometimes the dog required I 2 minutes to lap

CONSEQUENCES OF FREEZING ТНЕ CORTEX

27

up 150 с.с. of millc, without stopping once during the whole time. Attention was attracted to the awkward movements of the tongue and ja\vs and the "loud" swallowing. 8. During the illness, the animal oftcn t~kes up awkward postures in the form of а cross, spiral or circle, etc. ; these postures are retained Ьу the animals for а consideraЫe period. 9. W е repeatedly observed also that the illncss exl1ibited а form absolutely typical of Jackson's or Kozhevnikov's local epilepsy. Sometimes the whole illness proceeded in this fashion and ended in recovery. More frequeritly, however, the forms of local epilepsy characterised only а certain period of the illness, and were followed Ьу general epilepsy and the death of the animal. 10. The weight of the animals rapidly 1:ei:-reased. Thus, dog No. 5 lost 2.3 kg. in 14 hours, dog No. 9 lost 2 kg. after 13 hours, and dog No. 10 lost 2.75 kg. after 50 hours, and so on. This is explained Ьу tl1e large loss of saliva, and partly of urine and exhaled water vapour. 1 1. In а number of cases the stomach of tl1e dog was found after death to contain а consideraЬle quantity of turbid fluid, of acid reaction, almost devoid of mucus. During the comatose period intensified peristalsis was frequently oЬserved. 12. Sometimes peculiar forms of illness wcre met ""'ith, suci1 as those dcscribed Ьу ту collaЬorator Dr. L. N. Fedorov. 1 We diagnoscd this case as laryngo-epilepsia. The following is the history of the illn ess in this dog.

Dog No.

21.

Male, rufous.

И1 eight

10

kg.

SeptemЬer 11, 19:i.6 . Operation of free7.ing performed in visual zone of the 1eft hemiaphere. Area of freezinJ:" са. :i. 1/1 S'G · .:m. Duration of freezing 1 uo seconds. 9 .40 a.m. Operation concluded. 12..00 noon. Fint epileptic ~izure. Pre vious to it the phenomcna of ge11eral motor agitat ion and tonic convulsions in various parts of the Ьоdу were oЬserved. SeptemЬer 1 :i., 9.:1.0 a.m. During the past 24 hours there were several groupe of epileptic attacks, dying down during the n ight and occurring only rarely towards morning (after 1-:i. hours). FееЬ\е tonic-cl onic convulsions iп various groups of muscles proceed without interruption. The usual motor agitation is absent. 11.30 a.m. А convulsive attack of а type not previously observed Ьeg-an to develop. This starts suddenly iп the form of а short yelp. The whole Ьоdу is held tensely rigid. Loud, short yelps follow one a r mth ~ r. Then the gene ral t o nu~ " ·eakent and at the same time the short barking comes to an end, but the marked diffi culty in breathing pers istз for aЬout 1-:i. minutes longer. Inspiration is prolonged, п oisy, with whining as in croup. Expiration is much less ] з Ьo u red and therefore qu ickcr, but also n.oisy. Tl1e difficulty of breath ing- gradually grows lf ~~. After зоmе time · (5-10 rninutes) the dog breathes normally. Following this therc is aпoth e r sudden development of ton ic convulsions of the whole body, short barking in the form of yelps, and on its cessatior1 difficulty in breathing in the form d~scriЬed аЬоvе. Thia 1

L. N. Fedorov. Zeitschr.

f. d. ges.

ехр. Med., Vol. 72, No. 1-:i., 1930.

BASIS FOR ТНЕ THEORY OF MEDICINE 1tate peniated for aЬout 3 Ьoun, after which there were no attac:Ь of epileptic convullions · in any fonn. SeptemЬer 13. Durinr the whole day only tonic convulaioas of aeparate muac:ular rroupa and general weakne11 wu oЬeerved. Тhе dog reac:ta fееЫу aad alowly, Ьut correctly, to external atimuli. It attempt1 to driak milk, perfonning aWltwud movemeau witЬ tЬе tonp and jawa. Тhе ac:t of awallowing ia very difficult. Swallowing ia aoiay and tЬе greater part of tЬе millt 1'Wll Ьасk into tЬе Ьowl. , During the followiag с18). tЬе phenomena of in:neral weakne11 are intenaified. Тhе dog ia artificially fed. On SeptemЬer 1 1, а paralytic rondition of the muaclea of the neclt wu oЬeerved 1 when placed on ita feet the dog could atand for 10me time, Ьut tbe neclt hung down fееЫу aad tЬе Ьеаd retaioecl whatever poeition happened to Ье adopted on placing the dor on ita feet. Тhе doir died on SeptemЬer 19.

СНАРТЕR

II

SUBCORTICAL PHENOMENA IN OF ТНЕ EPILEPTIC

ТНЕ

CONSTITU110N

АТТАСК

Iк

weighing up the data regarding the external symptoms of disease in our the following characterisation has to Ье given: freezing separate portions of the cerebral cortex gives rise to а definite sequence of phenomena proceeding in the manner of а progressively developing illness. Тhе latter expresses itself in а gradually increasing excitation of the nervous system Ьoth in the motor and in the secretary and receptor spheres. The most pronounced changes are oЬserved in the motor sphere. These changes are manifold and clearly marked. They include all forms of hyperkinetic disturЬances met with in the clinic. Even the most superficial examination shows that we are confronted here with something more than phenomena which could Ье ascriЬed to isolated damage to the cortex. The general tonus, constituting the fundamental Ьackground of the disease, "frantic running," "Spanish trot," "stationary running," disorganisation of swallowing and other bulЬar phenomena, forced attitudes, special forms of convulsions as descn"Ьed аЬоvе, such as laryngo-epilepsia--ail th1s clearly indicates that cereЬral regions lying below the cortex hfl'Ve Ьееп drawn into the process. The frozen portion itself, or its immediate periphery, is the source from which the process arises. This cannot Ье doubted, Ьecause its extirpation Ьefore the manifestation of the illness prevents the appearance of the ]atter. However, although it has its origin here, the process quickly passes Ьeyond the limits of the cortex. Motor disturbances, tht: origin of which is connected with various nerve structures, arise at the same time, becoming superposed on one another and passing into that highest form of motor excitation which is termed an epileptic seizure. From this moment it is difficult to oЬserve any plan or order in the motor syndrome. Careful oЬservation, however, has shown 11s that in the majority of cases the epileptic state is preceded Ьу а preparatory period which develops а regular fashion. This aroused the desire to analyse the whole picture of the epileptic attack into its constituent elements. Attempts of this nature were also made previously; but so far clarity оп this question has not Ьееn reached. dogз,

m

29

30

BASIS FOR ТНЕ THEORY OF MEDICINE

The method employed Ьу us has the foliowing specific features. I. The iUness does not develop immediately. Various parts of the brain are included gradually, making it possiЬle to oЬserve the development of separate symptoms which in the clinic may exist independently. 2. Owing to this, the whole process follows the type of а progressive illness, concentrating into hours what the clinic obscrves during months and years. ln addition, the freezing method makes it possiЬle to alter the relations Ьetween the cortex апd the uпderlying regions of the brain Ьу the use of various means. The matter сап Ье summarised as follows. The starting point from which the whole process develops is the cortex in the immediate neighЬourhood of the frozen portion. It is natural to supposc that the greatest effect is exercised on the parts of the brain immediately connected with the cortex of the particular hemisphere selected for freezing. Ву combining the extirpation of various areas with altering the position of the frozen portion of the cortex of Ьoth hemispheres, we secure that the freezing exercises the desire!e period of the attack, from start to finish, the participatioн of the cortex will Ье passive, which, however, does not bring about any change in the external picture. This is evidence, once again, that the elements entering into the composition of the epileptic seizure are not derived from the cortex. Freezing а limited portion of the cortex damages to some extent the state of its other regions. Hence, as we have seen, in а certain percentage of cases, freezing alone can result in the development of convulsive phenomena, but in the majority of cases it is not sufficient, and then morphine comes to the assistance, depriving the subcortical cerebral regions of the remaining means for their natural defence. F oerster studied in man symptoms of the first phases of epileptic seizures, the starting point of which was some alteration iп the cortex of the Ьig. hemispheres. Не noticed that with а given localisation of the disease, the initial symptoms were very constant. But the focus from which the irritation spreads exerts its influence on the general picture of the convulsions only at the beginning, during the period when the process proceeds within definite morphological and functional limits. As the irritation increases, or, what is the same thing, as the general excitability is heightened, the local convulsions pass into general convulsions. Generalising, one may say that the process draws in а large numЬer of other automatic mechanisms. The specific picture

THECORTEX

51

characteristic of the first brief stage is now lost and the seizure paues into the standard f orm. If irritation remains localised, then the process is limited to local con• vulsive action in the form of nictation, twitching of the eзrs, tongue, toes. etc. In such cases we have the manifold symptoms of local epilep5y. Under appropriate conditions they can pass into an epileptic attack. The clinic is well acquainted with phenomena of this nature. Recently my collaЬorator S. I. Lebedinsky succeeded in reproducing them experimentally. The experiment was made as follows. U nder light ether narcosis, зn injection of 2 mg. of atropine in а 1 per cent solution was made in а rabЬit Ъу means of а suboccipital puncture. Shortly afterwards it was possiЫe to oЬserve а specific convulsive symptom in the form of periodical shaking of the ears and head. The movement is very easily provoked Ьу touching the ear. If the tactile stimulation is repeated several times with short pauses of less than а second, it ceases to evoke the above-mentioned motor eff ect. But the process is only inhibited, for on waiting for а few seconds and then again touching thc. ear of the rabbit, one obtains the phenomeлon of induction, i.e., not а local convulsive effect but а genuine, even if comparatively short-lived, cpileptic seizure. This phenomenon can Ье repeated several times in the course of the following 30-60 minutes. Interesting data can Ье obtained Ьу comparing the general picture of complex convulsive states with the general picture of raЬies at various stages of Ьoth these processes. 1 Rabies, produced Ьу fixed virus, usually Ьegins with phenomena due to disorganisation of co-ordination. The gait is altered, Ьecoming :;taggering, drunken. During the whole initial period of the illness, however, the behaviour of the animals, at least in dogs, remaiлs practically normal. They respond to calling, approach tottering on their legs, wag their tails, caress, and distinguish Ьetween attractive food ( sausage) and unattractive food ( Ыасk bread), etc. Later the illness passes into the stage of spastic paralysis, and frequently even during the first 8- I 2 hours we find the dog in а characteristic attitude on its side, with extremities stretched out like sticks, the head thrown back and rigid extension of the spinal column ( opisthotonus). These phenomena are intensified reflexly on any external stimulation--sharp sounds, touching or sudden ilJumination. Simultaneously there is nearly always consideraЫe flow of saliva, sometimes squinting, and in rabЬits, grinding of the teeth ( convulsions of the jaw muscles). The stage of spastic phenomena is followed Ьу 1

А. D. Sper:1nsky. Апп.

Je l'lnst. Pasteur, Vol. 41, 1917.

BASIS FOR ТНЕ THEORY OF MEDICINE

52

fееЫе paralysis and then the animal dies. А11 thesr: symptoms do not present anything characteristic or specific and can Ье oЬserved in varying degrees in many diseases of the nervous system: in tetanus, in strychnine and other poisoning, and at particular moments of that characteristlc process which we oЬserve in dogs on partial freezing of the cortex. At the Ьeginning of our work on the infection of dog& Ьу "mrus fixe', we regarded the stereotyped character of all the phenomena as а specific syndrome of raЬies. Later, we had to change this view. It was found that the stereotyped character of the picture was connected with the mode of infection, or more correctly with the place at which the process began. The usual method is to introduce the virus directly in the cerebral region of dogs; introduction of the virus 1 into the Ыооd and other tissues, even into nerve trunks, only rarely results in illness. At the present time, however, we have been аЫе to oЬ­ tain а constant means of infecting dogs Ьу Leningrad and other stocks of virщ fixe through nerve trunks. The number of dogs developing raЬies when infected in this way is about the same as when they are infected through the brain ( the appropriate method is descriЬed in another chapter). On oЬserving such dogs, it was found that the initial symptoms of the disease vary, depending on the place where the virus penetrated from the periphery (п. fJagus, п. hypoglossus, п. ischiadU:us, etc.). Thus the order of inclusion of separate nerve parts into the process is reflected also in the external fcatures of the disease. But this holds good only for its fiпt stages. Very quickly the aЬove-mcntioned diff erence is wiped out and t•fixcd" raЬies develops in its standard form. The external manifestations of disease in "street" rabies are consideraЫy more complicated and manifold; on the other hand the impairment of the cerebral regions lying Ьelow the cortex is here still more pronounced. The dirtinguishing feature of the external picture of ccstreet" raЬies consists in the exhiЬition of an additional period which is entirely, or almost entirely, absent in c'laboratory" raЬies. It is characterised Ьу excitation of the nerve atparatuses of сотроипd automatic movements, such as mastication, swallowing, locomotor actions ( which sometimes compel the dog to run consideraЬle distances), aggressive reactions, etc. The disturbance of co-ordination Ьegins much later, and from this time the picture of the disease in street rabies is in no way different from that of raЬies produced Ьу infection with virus fixe. In our experiments, we were also аЫе to oЬserve directly the correspondence in the external picture of street and laboratory raЬies. This was in the case of dogs in which, 18 hours after subdural inoculation with virus fixe, there was further introduced also subduraHy, а small quantity (aЬout 3.0 1

Leningrad stoclc of "virus fixe."

THECORTEX

5'3

с.с.) of antirabic serum. The same dose of serum was repeated after two days. On the sixth day (the normal incubational period for dogs) the animal had not become ill, nor on the seventh or following days. It Ьесаmе ill on the twelfth day after inoculation, i.e" after an incubational period twice the normal.The disease Ьegan with gcneral agitation. At the slightest noise (knocking, opening the door, entering the room) the dog jumped up, glanced around and attempted to run away. In doing so, the animal fell down, as а result of incipient disorganisation of co-ordination, but after falling continued to run while lying on its side. Very quickly, this is supplemented Ьу clonic convulsioпs, abundant salivation and, finally, ап uninterrupted cont•ulsive state, reminiscent of status epilepticus, broken sometimes Ьу the abovedescribed "statwnary running." This state lasted 12 hours and only then passed into а picture of spastic ;ind afterwards fееЫе paralysis, such as is characteristic of the laboratory form of raЬies ( virus ftxe). F ollowing this the animal died. What happened here? Afte: the measures taken, there was а prolongation of the incubational period. It approached that which is usual for street raЬies on direct infection through t/1e brain. As а result, the process assumed the character of an intermediate disease, uniting together features characteristic of Ьoth forms of raЬies. If we compare these data with those obtained frorn the analysis of the constituent parts of the epileptic attack, it is not difficult to note the great resemЬlance. OЬservations throughout many years have shown that it is sometimes very difficult to distinguish them from one anotlier. This appears especially clearly at particular moments of observation. О11е involuntarily comes to the conclusion that the nervous mechanism of Ьоt!! processes is identical, that rahies is ап epileptic sei:шre extended in time. In spite of the fact that analysis of the processes ent~гirщ into the picture of the epileptic seizure itself, and also of its preliminary а:нi suЬsequent stagcs, inevitaЬly leads us to actio11s of complex automatic n1uve1f!ents--the view of the leading role of the cortex in the origin of clonic conv~1lsions is still maintained very stubЬornly (Gordon Holmes, D. Collier). Rcceпt!y, N. I. Propper carried out а series of experiments on dogs in order to prove the same thesis. The author produced the convulsive process Ьу applying the electric current of the lighting supply to the head of the animal for se•1eral seconds (one electrode Ьeing on the lower jaw, the other on the protui:cratztia oc&ipitalis). Having est;,.olished the usual picture of the convulsive attack brought aЬotit Ьу this means, the author proceeded to an additional extirp:ition of various parts of the nervous system with the object of observing the changes which would thereby Ье produced in the complex conv-ulsive syndrome. А5 а

54

BASIS FOR ТНЕ THEORY OF MEDICINE

result, it was found that the

pictuтe

of the epileptic attack can

Ье

destroyed

Ьу .

flery dwerse means. The greatest effect in altering the clonic phase of the at-

tack is obtained in the period immediately following extirpation of the motor cortex. After that the difference gradually disappears. Injury to the cereЬel­ lum and excision of parts of the peripheral trunk acted in almost the same v;ay. However, the author draws the conclusion from this of the "predominant role of the cortex in the construction of the clonic phase of the epileptic attack.tt Не reduces the role rtebra oЬliquely and subsequently gradually removing the lateral wall of the vertebral canal Ьу means of Lewer forceps.

Fig.

Fig.

i

Fig. 6 F1g1. ~ 1 51 6. Three Moments in t~ Operation of Inserting Around the Spinal Cord.

а

s

Ring of Muscle Tissllt'

The second complication is the insertion of the ring around the spinal cord. This point does 11ot present any technical difficulties. Nevertheless, owing to violence or haste, the animal suddenly dies after making two or three "terminal" breathing movements, -: hich jn the first appearance of the paralytic symptoms, we introduced the serum into the experimental rab\,it Ьoth through the Ыооd and subarachnoidally, while in the control rabЬit it was introduced only throнgh the Ыооd. In а number of cases we obtained а good curatroe effect in the experimental animals. In foнr cases we obtained recovery in animals in а state of prostration, without even strength еnощф to stand on their feet. With the same doses of anti-toxin, we did not succeed in saving diseased animals if the serum was introduced only into the Ыооd. ScARLATINA

Many infectional processes cannot Ье reproduced in animals. Consequently we had to turn to clinkJil material. At the present time, treatment with anti-toxin serum is freqt1ently employed in scarlatina. When we Ьegan our work ( 1926), there was almost по conccntrated anti-scarlatina serum, and the normal dosc for severe cases in adults was 100.0-200.0 c.c--therwise no effect was obtained. The data given Ьу us аЬоvе provide reason for thinking that Ьу the use of so large а volume of serum а certain proportion of the anti-Ьodies penetrate from the Ыооd into the medullary region, and that it is this that forms the indispensaЫe condition for any curative effect. But in that case we ought to Ье аЫе to obtain the effect Ьу subarachnoid injection even with very small doses of the serum. I made this proposal to Professor G. А. Ivashentsov, the head of the Botkin Infectious Diseases Hospital in Leningrad. А number of such experiments were performed t1nder his control, in this hospital, Ьу Drs. Н. G. Kotov 1

А. V. Ponomarev.

Loc. cit., р. 139.

BASIS FOR ТНЕ THEORY OF MEDICINE

142

and В. N. Kotlyarenko.1 Unconcentrated anti-toxin serum to an amount of 4.0-10.0 с.с. was injected into scarlatina patients only subarachnoidally Ьу means of а lumЬar puncture. In а11 these cases the serum was not introduced into the Ыооd or muscles. Ву the summer of 1927, 57 observatioпs had Ьееn m assured . \V е took eigl1t rabbits and introduced а small quantity of 5 per cent form-

184

BASIS FOR

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THEORY OF MEDICINE

гlin solution into the left sciatic nerve. After ten days, the rabЬits were inoculated in the left п. cruraШ, followed Ьу section of the latter. Eight control rabЬits were inoculated along with the experimental group Ьу the same metbod. Of the eight control rahhits, se'Ven hecame i/J. and died. Of the equal пит­ Ьеr of experimental animals, two hecame i/J. and six remained healthy. The data brought forward here show that the reaction which we have oЬserved can Ье regarded to а certain extent as а ccdefensive" one. At the same time confirmation was once more obtained of the view that in regard to infection of tbe nerve system tbrough the nerve trunk, the асtЮп of the irritating agent itself undouhtedly plays а role. W е pos.sess а numЬer of other facts relating to the same subject, but treating it from а somewhat different aspect. These oЬservations were Ъegun Ьу experiments of my collaЬorator Е. Р. Zakaraya. 1 In part, the data obtained Ьу him have already Ьееn used аЬоvе. ТЬе animals experimented оп were rabЬits. The object of the work wa to study the changes iп the nervous system outside the limits of the immediate nerve trauma and during the teriod immediately following the traumo. The method consisted in sectioning one of the Ьig spinal nerves, poisoning the centripetal end with croton oil, and suЬsequent intravenous injection of а I per cent solution of trypan Ыuе. ТЬе diНerence in the degree of coloration of the separate parts served as an indicator of the changes that had Ьegun and gave а certain representation of the development of the process itself. The control animals were normal rabЬits in which corresponding quantities of trypan Ыuе solution were introduced into the Ыооd at the same time as in the others. After а definite interval (2-3 days}, Ьoth animals were killed with chloroform. If the experimental rabЬit died earlier, the control animal was killed at the same time. Dissection provided а numЬer of facts for judging the course of the process under investigation, both 8п the cmtral tur11ou1 system and the sy1111pathetic chain. When croton oil was injected into the nerve on the left side, the gang. mteruertehralia of the lumЬar region were intensely coloured, but consideraЫy more so on the left side than on the right. The dye in the same ganglia of thecervical and thoracic tracts was comparatively weak, but on the left side (i.e., the side of the operation) it was also somewhat more pronounced. The ganglia of the sympathetic cham exhiЬitetl ap;roximotely the SfJm4 changes. The left lumЬar ganglia (L., L 5 , L 8 , L 1 , ) , corresponding to the

m

1 Е. Р. Zakaraya. Arlt!J. Biol. Nault, Vol. 31, No. 2-31 Vol. 80, Noa. 5, 6, 1931.

Zntscм.

f.

а.

ges. ехр. Med.,

EXTENSION OF

ТНЕ

DYSTROPHIC PROCESS

185

nerve traumatised on that side, exceeded iп dimcnsions the corresponding gaпglia оп the right side, sometimes Ьу as much as two or three times. These ganglia were obviously a:dematous. On rare occasions we ohserved here acute hremorrhage. Their colouring was more intense on the left side than on the right. The extent and degree of colouring of the right and left ganglia in other parts of the sympathetic chain were usually similar. When the aЬove-descriЬed trauma was inflicted on one or two nerves of the plexus Ьrachia/.is, the same changes were transferred to the corresponding nerve tracts. W е ohserved here, for example, that as а result of a:dema the gaпglion stellatum on the side of the operation attained а size of 7 mm. in length and 3.5 mm. in breadth. The corresponding dimensions on the right side were 4 mm. and 2.5 mm. The dimensions and colouring of the intervertebral and sympathetic ganglia in the control animals were entirely symmetrical in all cases. Twice we ohserved that the alteratioп оп the side of the iпjury had affected all the ganglia of the sympathetic chain, from the sacrum to the cranium. At the same time, оп the otposite, "hetdthy," side only the sympathetic gaпglia connected with the segmeпts of the sciatic nerve were cedematous. Hence, the proce$ under consideration, starting from а single nerve point ~t the periphery, had spread over the central and sympathetic nervous system, both iп the frontal and iп the sagittal plane, giving rise to Ьoth а symmetrical and non-symmetrical form of affection. Hence, the above-descriЬed method seemed to show that after trauma of the Jpinal nerfJe with crotoп oil the morphologictd changes iп the ceпtrtl/ пervous system of the rabhit could Ье efJeп less inteпse thaп those iп the ganglia of the sympathetic chain. These changes were exhiЬited in the form of a:demata and hremorrhage. At the same time, the elements of the spinal cord do not exhiЬit any morphological departures from the normal st~te. Here the matter is limited to а certain increase in permeability of the "barrier," which can Ье judged Ьу the occurrence of trypan Ыuе in the medullary memЬranes and adventitious spaces of the Ыооd ve~ls of the segments affected. More рrопоипсеd changes in the spiпal cord usually set iп later оп. lt is worth while dwelling on this fact. lt is beyond question that the origin of the phenomena descriЬed is not connected with the movement of the irritating agent itself along the nervous system and its direct action on еасЬ of the affected elements; indeed, after chemical trauma of the spinal nerve, the sympathetic ganglia suffered destruction not only on the side of the trauma, but also on the opposite, "healthy," side. Moreover, in these ganglia the changes developed in general even more rapidly than in the elements of the spinal cord. But the path for the penetration of the hannful influence to

186

BASIS FOR

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THEORY OF MEDICINE

the latter lies open through the nerve spaces; as regards the gonglia, howetJer, we know neither the poths of transmis.rion nor the forces controllinc the motJement olong them. How can one conceive the way in which the sympathetic ganglia are drawn into the process? First of all, an admixture of sympathetic fibres is present in the composition of the spinal nerves, especially of some of them. The irritating agent can, of course, соте into direct contact with these fibres. But this Ьу itself is little enough, for the irritating agent enters also into direct connection with the axis cylinders of the elements of thc central nervous system. actuFurther, it is imposвiЫc to assume that the substance used Ьу us ally selective, i.e., that it was an adequate irritating agent precisely for the sympathetic elements, and indiНerent to the central ones. 1 have already descriЬed, in one of the chapters of the first part of this book, the results of our experiments with injections of bile, croton oil, mustard gas solutions, etc., into the cerebral hemispheres. For instance, placinь drops of bile on any part of the central nervous system was sufficient to kill the animal ( cats, dogs) within а iew hours, after а rather long series of convulsive attacks. The same holds good of mustard gas and croton oil. Even а iшperficial histological analysis of these cases reveals changes of the nerve cells in practically all parts of the central nervous system. Consequet1.tly, the fact that the affection ()f the sympathetic elements outstripped that of the central elements in Zakaraya's experiments could not Ье due to а lesser oction of the irritoting agent ироп the centrol nen;ous system. То understand this phenomenon, it is necessary to recognise the presence of some additional cause. The following series of experiments was undertaken in the attempt to solve this proЬlem. According to the generally accepted view, tetanus phenomena depend .directly on the toxin, which spreads from the place of formation or introduction along the axis cylinders and nerve spaces to the cells of the spinal cord, and affects these. As far as I am aware, the question whether any, and if so, what, role is played here Ьу the sympathetic system has not even Ьееn raised. SuitaЬle experiments were carried out Ьу ту collaЬorator Dr. S. D. Kaminsky. 1 Each experiment involved two dogs. The total number of animals was twenty-eight. The method was the following. The lumbar and sacral part of the left sympathetic chain was removed extra-peritoneally, under narcosis. Within а tew hours, the animals recover completely and do not show any d..:fects in

was

ехр.

1 S. D. Kaminsky. Arkh. Bioi. No ·1k, Vol. 33, No. 1-z, 193:1; Zeitschr. Med" Vol. 88, Nos. 51 61 1933.

f. d. ges.

EXTENSION OF

ТНЕ

DYSTROPHIC PROCESS

187

the motor sphere. After some time (from 30 minutes to 1-2 days) tetanus toxin is injected into the muscles of the left knee of the animal. The dose of toxin variee1, but :t always exceeded the lethal dose, and the difference in the general features of the process was expressed only in the length of the incubation period. Simultaneously with the experimental animal, а normal control animal, specially selected to match the other in weight and growth, w:is given the same dose of toxin and in the same place in the left knee. RECORD OF EXPERIMENT

Control

Expmment Dog No. 161. Weight 16 kg. Dec. :z, 1930. 3 p.m. Extra-peritoneal removal of the lumЬar tract of the aympathetic chain.

Dog No.

162.

Weight

16

ltg.

Dec. i. 6 p.m. 3 с.с. of tetanus toxin injected into mшcles of the ]eft knee.

3 с.с. of tetanus toxin mшcles of the left kn.ee.

Dec. 5. 9 a.m. Local tetanus. Left hind extremity 1uetched out Ьehind and rigid like а stick. The dog wa!ks on three lega.

Local tetanus. Left bind extremity atretched out Ьehind and rigid like а stick. Тhе dog walЬ on three lega.

Dec. 7. 11 a.rn. Local tetanus. Dog walЬ freely оп tbree lega.

General tetanus. ТЬе dog lies, unaЫe to rile. Marked rigidity of all extremitie. HeaJ thrown Ьасk {opiRhotonш) . High rеВ.ех ~xcitaЬility. The dog responds to touching Ьу refiex convulaiont of all muscle groupa.

Dec. 8. 9 a.m. Local tetanus. Dog walka freely оп three lega. Eats and drinka normally.

Phenomena of general tetanus continue to· inteosify. Convulaive Ьaring of the fanga. Extremities stretched out like пicka, aud tenee. Opilthotonua.

Dec. 9. 9 a.m. As Ьefore, only local tetanus. Dec. 11. 9 a.m. First symptoma of general tetanus. Rigidity of hind extremities. The dog moves about the room independently, tottering at times. Slight rigidity of the neck musrles. Eats and arinks normally. Dec. н. 9 a.m. The dog п1oves aЬout the rоош аз Ьеfо;е. Eat.1 and drinka. Rigidity of thc occipital muscle3 has increased. Heighteлed tonus in fore extremities also. Dec. 1 3. 12 a.m. The dog is unaЫe to ltand up, it raises itself only on the fore

Final tymptoma. At

1о

injected into

p.m. death.

188

BASIS FOR

ТНЕ

THEORY OF MEDJCINE

pawa. Increued tonus of the mшclea of all extremitiea. The dog reacu readily to calling, trying to rile but falling. Dec. 14" ia noon. Dog lying down. On a.lling, it turna ita head, it attemptl to eat from the hand. Dec. 15. 9 a.m. Opiathoton111. At night, death. RECOaD OF ExPEIJMENТ

в~

Dog No. 185. W1ig/J1

Conwol 11

Dog No. 186. W11g/J1

leg.

11

leg.

J a.n. 16, 19 3 1. Extra-peritoneal removal of the lumЬar tra.ct of the aympa.thetic chain. Jan. 17. 4 p.m. 3 с.с. of tetanua toxin injected into mшclea of the left knee.

3 с.с. of tetanua toxin mшclea of the left knee.

Jan. а3. 12 noon. Initia.l aymptoms of loca.l teta.nus. Heightened tonua of left hind extremity. The latter i1 not used in walking.

Initial aymptoma of local tetanua. Heightened tonus of left hind extremity. The latter ia not шеd in walking.

Ja.n.

а5. 9

a..m. Local tetanua.

Jan.

а6. 9

a.m. Local tetanua.

Ja.n.

а7. 9

a.m. Local tetanua.

Jan. 28. 9 a.m. lnitial phenomena of general tetanua. Staggering in walking. MU8Cles of the hind extremitiea te111e. Eau, drinb and reacta readily to calling. Ja.n. 29. 10:30 a.m. Dog lying down, only able to raiee itself on the fore paw1. Eata and drinb normally. React1 readily to calling. Rigidity of hind extremities further increaaed. Jan. 30. 9 a.m. Rigidity of all four extremitiea. Dog lying down. On Ьeing placed on its feet, it fall1 down. Reacu to calling. Rigidity of the occipital muscles hu increaeed, but tbe dog crawl1 aЬout the room, moving it.elf Ьу the fore extremities. Dog killed Ьу chlorofonn.

injected into•

General tetanua. The dog ataggera in walking. Rigidity of the epine and of neck mueclea. Symptom1 of general teta.nus increaae. Dog lies; unaЫe to riae. Rigidity of the whole Ьоdу and extremitiea. Opisthotonua. Convulaive

Ьaring

of the

fanp.

Dog lying down, with hea.d thrown Ьасk. Does not rea.ct to ca.lling• .All four

extremitiea stretched out tenee.

Шее

Fina.l aymptoms. Dog killed form.

aticka, and

Ьу

chlorc:»-

EXTENSION OF

ТНЕ

189

DYSTROPHIC PROCESS

There are eight such records in our possession. In а11 cases the initial symptoms of tetanus either coincided in the experimental and control animals or the control became ill only а few hours in advance. But in the general picture of the further development of the process а consideraЬle retardation was oЬ­ served in those dogs which had undergone preiiminary removal of the sympathetic chain. Moreover, the tetanus symptoms in them did not attain the same degree of intensity as in the controls. The whole process proceeded fееЫу, as if the dose of toxin taken in their case had Ьееn much less. Two forms of interpretation of the results obtained suggest themselves: either the aЬsence of the sympathetic ganglia make the elements of the central nervous system less receptive to irritation Ьу tetanus toxin, or the tetanus toxin itself has to draw the sympathetic part of the nervous system into the specific reaction, for the development of the full picture of the disease. Both these sutpositions were tested, but neither was conftrmed. I have already mentioned that in Dr. Кaminsky's first series cf experiments we in jected the toxin not immediately after the removal of the sympathetic chain Ьut after the lapse of а certain period lasting from thirty minutes to four days. lt was noticed in these experiments that the difference Ьe­ tween the control and the experiment stood out the more sharply the shorter the interval Ьetween the operation mentioned and the injection of toxin. Being interested in the part played Ьу the time factor in the process under investigation, we decided to perform а new series of experiments, separating the time of injection of toxin from that of excision of the sympathetic chain Ьу several days or even weeks. The results poved to Ье directJ.y contrary to those observed earlier. The experimental animals developed the disease more rapidly than their carcfully selected controls, the process was more sharply marked and death ensued within а much shorter period. RECORD OF EXPERIMENТ

Ехр'"1мпt

Dog No.

51.

Weight

ll.2

lrg.

Control Dog No. 64. Weight

11

lrg.

Мау н, 19 31. з p.m. Extra-peritonea 1 removal of the lumЬar trac:t of the left

ll}'IDpathetic chain. Ma:r 19. 7 с.с. of tetanш toxin (а weaker preparation than in the experimentl of the fint series) injected into the mшclea of the left knee. Мау :н. 3.z5 a.m. Heightened tonua of the left hind extremity. Dog moves aЬout on three lega.

7 с.с. of toxin injected u in the experimental dog.

Healthy.

BASIS FOR

190

ТНЕ

THEORY OF MEDICINE

Ма.у :i:i.. 1 о a..m. Appea.rance of local tetanu1, a.nd a.1most immediately afterwa.rd1 (aftп з houn) general tetanua. Rigidity of the Ьind extremities. Ten1eneu of the occipita.l mшcles. Refl.ex convulaiona. Th.e dog moves a.Ьout 'vith difficulty, frequently falling down. Reacts to calling. Ма.у :i3. 9 a.m. Dog lying down, una.Ыe to riae. Head thrown Ьасk. Ma.rked opiathotonus. Refiex convul1ion1 of all mшcle groups. Лll extremitie1 tenae and atretcbed out like lltick:a. Convulaive Ьaring of the fangs. Death.

Fint ligu1 of loal tetanua. Slight in-

creue of tonu1 of left hind leg. 1n walking, the dog юmetimes avoid1 u1ing iu left hind extremity.

Local щa.nua. Muкlea of the left extremity tenae. Runa aЬout the room on three lega only. Eata and drinb norma.lly.

Мау 24. 10

a.m. Fint 1igD1 of general Rigidity of hind extremitiea. Takea food normally. Movea aЬout the room, not using the left hind extremity. At 6 p.m" occipital rigidity.

tetanua.

Мау

:i5.

10

a.m. Full picture of generaJ

tetanua. Мау

26. Death.

RECOll.D OF EXP!:ll.IMENT

Expп-iwunt

Dog No .

180.

Weignt

Comrol ll

ltg.

Dog No.

181. Weigм 11

lig.

Nov. 13. 1931. з p.m. Extra-peritoneal removal of lumbar tract of the left aympathetic chain. Dec. 2. 4 p.m. з с.с. of tetanus toxin injected into the musclet of the left knee. Dec. 4. 1 о a.m. Local tetanus of the left hind extremity, which is st.retched out like а atick. Dcc. 5. 10 a.m. Initial aymptoms of general tetanus. Rigidity of the occipital muscles. Refiex excitability increa.sed. Refiex convulsions of Ьoth hind extremitiea. Dog lying down 1 put on its feet, it fall1 down, but i1 takes food from the ha.nd. Dec. 6. tetanua.

1о

a.m. Full picture of general

3 с.с. of toxin injected imental dog.

а.

in the exper-

Healthy.

Slight increa.1e of tonus of the musclea of the left hind extremity.

Loca.l tetanus of the left hind extremity. The dog walb freely on three lep. Eats normally.

EXTENSION OF Dec. 7. 9 a.m. Death.

ТНЕ

DYSTROPHIC PROCESS

19t

Initial symptoms of general tetanus. Rigidity of hind extremitiea and occipital muscles. The dog take~ food and move•' aЬout the room, but often staggcrs and falla. Dec. 8. 9 a.m. Refiex convulsiom of muscle groups. Dog lying down, head thrown Ьасk. Oµisthotonus. Оп touching" thc refiex convulsiona increue. Dec. 9. (Moming) Death.

The remaining experiments of this series gave in general the same rcsult. It may Ьс considered as estaЬlished, therefore, that the absence of the· ga.nglia of the sympathetic chain does not Ьу itself render the elements of the amrol nervous system less receptive to irritation Ьу tetanus toxin. Moreover, it was found that the development of the disease does not require direct contact of the toxin with the eleme11ts of the sympathetic ganglia .. In а new series of experiments, tetanus symptoms developed in our dogs tothe full extent in spite of the akence of the corresponding sympathetic chaiп. It is also impossiЪle to suppose that during the interval between the operaticns of removing the left sympathetic chain and in jecting the toxin, а replace-· ment of the missing functions takes place Ьу me.1ns of the Ьrmation of new connections with the ganglia of the right-hand side, which have been preserved in their entirety. Experiments specially performed demonstrated that remo'Ual. of the abdominal sympothetic chain оп both sides had the some effect оп the development of tetanus os removal оп otu1 side, and also that tl1e basic factor" determining the character of the reaction, is time. А remote possibility that might occur to one is an immediate i11fluence of the removal of the sympathetic ganglia on the tonus of the striated muscles. ( de Boer, Orbeli, etc.). But, as we have just scen, this would only help in explaining the experiments of the first series. The results of the second series would Ьс in direct contradiction to such ал interpretarion. One explanation remains: viz., that on injection of tetanus toxin at the periphery, the elements of the central neryous system experience not only а special form of irritation, but also an ordinary trauma. This is а second proccss, developing side Ъу side with the first one. The irritation of the spinal elements is handed on from here to the sympathetic parts, drawing them, not into the complex of tetanus phenomena, but into а pathological -рrоищ of the noture of nervous dystrophy. But the sympathetic elements also, Ъecoming ::iltered under the infiuence of the central elements, put the latter iп their turn into aЬnormal conditions of lif е and functioning. When we remove the cor-

192

BASIS FOR

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THEORY OF MEDICINE

responding sympathetic chain shortly Ьefore injecting the toxin, then, in the first place, the cells of the central nervous sy.stem undergo а certain Jeind of shocJe, and, in the second place, they Ql'e depmed of the sutpl.ementlll'y tation, the counter-shock, which under normal conditions they could receive from the sympathetic elements. On the other hand, if а longer period elapses Ьetween our two acts of interference, the result will Ье the opposite, since the

mw

operation of ex&ising the sym~hetie chain is itself а nerve trauma, iп other u.iords, is а stimШus for the detlelopment о/ а dystrophi& 'frocess other nerfJe ,·egions. W е have already seen more than once that this process does not occur

m

immediately but grows gradually, and inevitaЫy adds something to all the other processes taking place in those regions. As а result, the tetanus takes а more serious course. It is interesting to note that this state of things also is not constant. In some recent experiments of ту other collaЬorators, I. Р. Bobkov and А. L. Fenelonov, the following oЬservation was made; they injected tetanus toxin into the neck muscles of two dogs on whom тапу months pretliously the operation of removal of the aЬdominal chain of the sympathetic ganglia had Ьееn carried out on one side. When symptoms of general tetanus developed, the tetanus was very weakly expressed in the muscles of the hind extremities on the side of the operation. The process was almost limited to а certain increase of re8ex excitability. It js evident that the intensity of the dystrophic process produced Ьу nerve ttauma can only rarely Ье altered. For tetanus, conditions are temporarily created afresh resemЬling those during the first hours following removal of the sympathetic chain. The curve of all other processes taking place in the same nerve regions will vary, depending on the course of the curve of the d~ ttophic process. lt is 'fre&isely this that malus it posrihle to understanJ. the signi~ance of time tJS rz f actor in the change. Whatever the properties possessed Ьу the irritating agent and however -isolated the place of its application тау appear to Ые, the consequences express -themselves in а numЬer of nerve structures whieh Juroe never Ьееп in direct contact with it. There is no strict localisation of this process within the limits -of а particular part of the nervous system, since the irritation passes from the elements of the central nervous system to the sympathetic system and Ьасk again. In this way, our conception of segmentary affections of the nervous sysw -tem Ьecomes more precise. It is not а question of formally delimited segments of the spinal cord. We saw that, :ifter trauma of the spinal nerve, alteratior.s are to Ье discovered almost from the very start in the ganglia of the sympathe-tic chain, not only on the side of the injury, but also on the opposite, "healthy,"

EXTENSION OF ТНЕ DYSTROPHIC PROCESS

193

side. Thus, the conception of the segment inclшJes aJso its sympathetic toniott. The subsequent data demonstrate that nerve parts within the organs а1ао have а definite order in which they are included in the process, and that this order is connected with the point of primary irritation. It must Ье stressed that when segmentary nerve changes were found v;ithin the limits of, for instance, the sympathetic nervous system, it wаз often possiЬle to oЬserve also corresponding alterations outside the limits of this segment, the process developing simultaneously in Ьoth the frontal and sagitul planes. The same thing holds good also for the central nervous system. If, nevertheless, we do not give up the term "segmentary aff ections," it is only Ьecause this term defines the initial stage of the process, а ~ge undoubtedly playing а part in its further course. In addition, the extent of functional and morphological changes in the segment that has initially suffered is always small at the Ьeginning. Summing up these results, we have to recognise that, as regards the development of nervous dystrophy, the distortion of normaJ relations omong the nenJe el6ments themselfJes is not of ksser signiftcame tмп the imnudiste nction оп them of the f oreigп agent. During the course of our work we frequently oЬserved that the initial changes of а morphological character in the nerve group primarily suffering were inconsideraЬle. Nevertheless, in definite places at the periphery, the process takes the form of serious destruction of the integrity of the tissues. The immediate irritation Ьу the foreign agent, in spite of its unusual character, did not kШ the nen1e cells. It merely altered their function. The alteration of the normal nerve function, however, resulted in the d~ase and even death of tissue elements at the -periphery. Thus, the nerve trauma Ьу itself does not constitute the direct cause of nervous dystrophy from start to finish. lt merely grues the impul.se to the mel(Jpm'ent of а process which subsequmtly froceeds cumulotively. Hence, changes arising secondarily in the sympathetic system can later prove to Ье Ьoth more dangerous and more severe. The facts brought forward have, in addition, а significance from the point of view of method. In investigating nervous functions, the method of irritation and exclusion plays а fundamental role. The disappeafance of а particular reaction, on the one hand, or the exhibition of it, on the other, is considered as а positive proof that this reaction is connected with the definite group of nerve elements which were the object of immediate interference. For elementary reactions and short periods of oЬservation, such an attitude is permiзsiЬle, although with reservations. If, however, we are dealing with. а complex process, the external manifestations of which Ьegin only after а certain, often

194

BASIS FOR

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rather prolonged, period, then it is impossiЬle to. judge of its localisation merely Ьу data relating to the place of primary iлterference. А much greater role may Ье played here, not Ьу the part which has Ьееn subjected to irritation, but Ьу the act of iпterference itself, which becomes the onginator of а whole group of new processes. If, in the experiments just analysed, we were to leave the act of interference out of account, we would have to ascriЬe its consequences ( the retardation, intensification and new retardation of the tetanus symptoms) to one and the same object, viz., the sympathetic ganglia themselves. The result would Ье the f alse notwn that they are included iп the specific part о/ the reaction, which is actually not the cose. One cannot help recalling here our experiments on epilepsy, descriЬed earlier in the Ьооlс. Externally similar procedures produced different consequences, while, оп the other hand, different forms of interference yielded one and the same result. ln the clinic, for example, this is illustrated Ьу cases of traumatic epilepsy, where Ьoth repeated closure of the Ьоnе defect and repeated removal of the transplanted Ьones in one and the same patient has а curative effect on each occasion, but the effect is always temporary. Consequently, on chemical or infectional nerve trauma, а numЬer of different processes of а physiological and pathological character develop in the nervous system. The former are beneficial, the latter find expression in dystrophic symptoms, Ьoth within the nervous system and in the peripheral tissues. The dystrophic processes take а cyclic course and may end in the complete restoration of norrnal conditions. But m11 number о/ cases they dcvelop progressively. Commencing in the region of а particular nerve segment, they soon разs outside its limits, embrace other portions of the complex nerve network and culminate in general dystrophy and the death of the animal • .J chorocteristic property is thw mcиbotional or latent period. However, in the process of the work it was estaЫished sufficiently clearly that in actual fact there is no latent period. The idea of а latent period is due to the imperf ection о/ the indicators used Ьу us. W е regard the moment of appearance of local dystrophy in the tissues as the Ьeginning of the process, although it is frequently its final result, and in any case not the first stage. Independently of whether the irritating agent itself spreads through the nervous system, or whether its action is limited to а single nerve point, there can arise within the nervous system а numЬer of points of unusual irritation, mиtuo/Jy reinforcmg опе another 11nd creating new ones. ln the genesi!\ of dystrophic processes, it is this, and not the irritating agent Ьу itself, that plays the fundamental role. This explains why chemical and infectional irritating agents a1though of diverse nature can produce the same consequences in the final result.

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special nerve "tropisш" plays no part here. We have seen that any can reach the central nervous &ystem along the nerve trunk. But опе substance тау re11юin imEjferent even after htroing reached there, while another, without even moving from the spot, destroys the nervous syste1n. Recently, from Levaditi's laboratory, two works have appeared Ьу Nicolau, Cruveillier and Kopciowska, dealing with the morpholcgical corisequences of virus ftxe vaccination. Describing а number of changes caused in this way in the central nervous system, the authors estil· ate them as special reactions e'reactions speciales'') to neurotropic virus, as the morphological expression of the "direct struggle'' h1tween th~ virus and the receptive tissue. It is true that this reaction may have а certain defensive significance. But there is nothing special about it. One сап easily convince oneself of this Ьу infecting such rabbits intra-cerebrally; they develop disease and die like normal ones. Vaccination for raЬies makes the animals resistant only ;" respect to infection coming from the pertphery. But it was demonstrated above ( Suslov' s experiments) that it is possiЬle, without any "struggle" of special elements, to obtain the same results Ьу the aid of а single injection of а few drops of formalin solution into the nerve. ln its effect, the reaction here also proved to Ье "defensive," but опе couJ.d hardly regard it as а speciлl aml Ьепе ficial reaction. The same thing holds good in regard to the morphological consequences. If, instead of vaccinaring the rabbits with an emulsion of rabised brain, а small quantity of mustard gas is applied to the skiл, or а solution of formaliп, carЬolic acid or other suЬstances is injected into the tissu~ it will Ье impossiЫe to distinguish the morphological comeqt''"nces in the nervcus system from one another. I can venture to assert this, since I have thc necessary material in ту possession. In our laЬoratory, В. S. Domikov and V. G. Usl1akov also performed experiments on the vaccination qf rabЪits with virus ftxe, and also with the object of studying the morphological changes in thc nervous system. The result was in exact accord.ince with what we oЬserved earlier when we used other irritating agents. Vaccination with emulsion of normal brain produced the same ( only slightly weakt"r) morphological consequences as vaccination with emulsion of rabised brain. This is comprehensiЬle, for the presence of the virus constitutes оп additional irritant. It is enough to prolong the irritation with normal brain or to increase the dose, and the dimensions of the morphological effect are the same in Ьoth cases. This, аЬоvе, all, makes it possiЫe to explain the popularity which has been won in many places Ьу Fermi's method of vaccination for rables. The fact suЬstance

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that here а small quantity of carЪolic acid is added to the emulsion produces an additional irritation strengthening the specific immunity Ьу а non-specifie addition. The latter is а reaction to irritation in general, and not specially to the given irritating agent.

CHAPTER XVI STANDARD FORMS OF NERVOUS DYSTROPHY AND THEIR QUANTITATIVE VARIATIONS ТнЕ

propositions laid down in the preceding chapter were further developed in the course of suЬsequent work. In setting out this new material, I shall begin with the experiments of ту collaborators I. А. Pigalev and Z. G. Kuznetsova. 1 The work was carr1ed out on rabbits and dogs. The irritation was applied to the second and third branches of п. trigeminus, t1iz., п. infraorhitalis and п. mentalis. As has already been mentioned, it was the irritation of intra-cranial parts, and in particular of the trigeminus nerve of the rabbit, which provided the early investigators with the first materials for the foundation of the theory of the trophic function of the nervous system ( Magendie, Samuel). Since then, many scientists have repeated these experiments in the original form or with variations ( Meissner, Longet, Berthold, Kirchner, Schiif, Nasse, etc.). As an indicator of trophic disturbances at the periphery, the majority of these writers employed еуе diseases in the form of conjunctivitis or ceratitis, which after а longer or shorter period developed in the rabbits оп the side of the irritation. W е made it our aim to obtain changes of the еуе in one form or another, not merely on the side of the injured nerve, but also оп the otposite, healthy, Jide. Moreover, we aimed at obtaining them not from the Gasserian ganglion or the intra-cranial parts of the trigeminus nerve, but from its peripheraJ branches having no direct relation to the еуе. А numЬer of substances ( mustard oil, croton oil, bile, lactic acid, etc.) were tested as irritants. Finally, we adopted croton oil. Following its injection into the suЬstance of the nerve, the latter was severed through the middle of the trunk where it was swollen after the injection. For the experiments, we used the peripheral parts of the second and third branches of п. trigeminusn; iпfraorhitalis or п. mentalis. After making а small cut аЬоvе the place of exit of the nerve from the Ьоnе and exposing the nerve, 2-3 drops of croton oil were injected and the nervc severed. lf the wound is sewn up, extensive 1

1.

А.

Pigalev and Z. G. Kuznetsova. ArltlJ. Biol. Nault, Vol. 30, No. 1хр. Med., Vol. 67, Nos. 1, 2, 1929.

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suppuration usually develops. With an open wound, there is only so1ne slight redematic swelling which quickly disappears. In dogs which underwent extraction of the cerebro-spinal fiuid after the injection of croton oil into the nerve, the swelling was always much larger, not only on the side of the operation, Ьиt olso i1J о symmetricolly situoted spot оп the other side. In all cases, the irritating substance was introduced into the nerve on one occasion only. lndiYidual details of the tcchnique were varied and in this way the experiments were divided into series. Since the results of the separate series differ from one another only in а quantitative respect, I shall permit myself to include them all in а general review. The injection of crotoп oil in п. infraorbitalis without sectiori of the latter produced in rabbits, even in the first few days, the development of photophobia and conjunctivitis on the operated side. In rare cases conjunctivitis developed on both sides. In these anin1als, а Ьluish spot followed Ьу an ulcer appeared within 2-4 days close to the mitidle of the line where the skin passes into the mucous membrane of tl1e upper lip. The ulcer slowly increased in size and then, in the course of 2-3 weeks, gradually healed. When we Ьegan to sever the nerve after injection of croton oil, the e.ffect was consideraЬly enhanced. In the~e rabbits, con junctivitis as а rule developed on Ьoth sides, while ceratitis and sometimes ulcer of the cornea frequently developed on the side of the operation. The ulcer on the lip now made its appearance even within one or two days. It rapidly increased in size and did not heal for 5-·6 weeks. Very soon an exactly similar ulcer appeared in the symmetrical place of the other, healthy lip, followed Ьу symmetrical ulcers on the tongue. On two occasions we obtained purulent inflammation of the middle ear on botll sides, as а result of which the animals died. In the majority of the rabbits, all these phenomena gradually suЬsided, which, howev··r, was not а sign of complete recovery from the destruction occasioncd in the nerYe cells. In а number of cases, at the end of 4-8 week!;, animals which seemed healthy Ьegan to exhiЬit olterotion of the teeth, at first оп the side of the injury and afterwards on the opposite side as well. This was most clearly expressed in the incisors. The change Ьegins with the ap~arance of discoloured whitish portions which gradually enlarge and fuse, and sometirr1es occupy the whole tooth. The tooth becomes friaЪle and crumЪles. Th~ alteration of the teeth begins earlier on the side of the nerve in jury and is usually more pronounced than on the "healthy" side. These changes also are of а temporary nature, since the incisors of the rabЪit w-ow continuously during life. The growing portion proves to Ье normal, though this is not always so. W е observed rabЪits in which the incisors remained friaЬle during many months.

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Exactly the same thing results if п. mentalis is taken for the experiment, except that the еуе changes begin soшewhat later, the symmetrical ulcers develop оп the lower lip and the alteration of the teeth in the lower incisors. On one occasion, Ьesides the alteration of the lower incisors, we oЬserved after some v1eeks the formation of whitish, and later, carious, portions in an upp~ r incisor, but only on the side of the nerve injury. Ulcers of the t(Jngue were also obtained from this nerve and were also symmetrical. ln two cases of this series, we again obtained Ьilat.eral purulent inflammation of the middlc ear, ending in the death of the animals. То study in greater detail the nature of the changes observed in the oral cavity and to compare them with corresponding data from the human clinic, the same experiments were once more performed Ьу my collaЬorator Р. А. Gl11shkov.1 In 8 rabЬits, out of 14 experimented оп, it was possiЫe to oЬserve hyperremia of the gнm of the sockets during the days immediately following trauma of the nervc trunk. The hyperremia was nf а stagnant character. lt was most pronounced at the лес: of thc incisors. Very soon the somewhat infl.ated mucous membrane began to separate slightly from the teeth, forming at the necks of the latter small pockets with the surface of the lip. These pockets subsequently became decper and crumЬs and hairs accumulated in thcm. On pressure on the gum, pus exuded from these pockets. ln two cases, these neck pockets were present as early as the second day after trauma of the ncrve; in two other cases on the fifth day, in one on the twelfth day, in оле on the thirteenth day and in two on the fiftieth day. The two last cases are interesting ол account of the weak dcvelopment of the dystrophic i-'rocess. Only on the fiftieth day was it possiЬle to oЬserve а slight separation of the gum from the necks of the corresponding incisors. In both animals а second nerve trat1m:i was inflicted on the eighty-third day after the first trauma; in the first a!1imal, the sciatic nerve was severed and its centripetal end was subjected to chemical irritation; in the second animal, the left t1pper cervical ganglion v;as pricked \Vith а necdle moistened with tincture of iodine. Witl1in а day after this, the separation of the gums from the necks of the incisors markedly increared and pockets were formed with secretion of pus. Compar·ing this general picture with that observed in the human clinic in cases of alveolar pyorrhcea, Glushkov came to the conclusion that there was а close res!lmhlance het7{ ,:еп the two processes. An analysis of the bacterial flora of the pus secreted from the above-descriLed pockets revealed the ordinary micro-flora of the oral cavity (Gram-positive and Gram-negative diplococci ::nd diplobacilli). In al veolar pyorrhcea in human beings the pockets of the 1 ,Р. А.

Glushkov. Arkh. Biol. Nauk, Vol.

н,

No. 4, 1933.

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mucous membrane, formed Ьу the separation of the latter from the necks of the teeth, also contain, as is well known, а quite non-specific micro-fiora. In general features, the same process was also observed in experiments on dogs (Pig'alev and Kuznetsova). In these, besides cases of ceratitis and ulcers of the corneal membrane, which were sometimes symmetrical, we observed а series of symmetrical ulcerous developments on the hard palate, toпgue, teeth апd other parts of the mucous membraпe of the oral cavity. The skin aff ections of the surface of the lips more than once included typical herpes, i.e., the formation of Ыisters on the reddeпed and eroded skin at the corner of the mouth. Several times purulent inflammatioп of the middle ear and accessory sinuses of the пasal cavity оп Ьoth sides was also oЬserved. These symptoms developed Ьoth оп iпjury to the п. infraorbitalis and оп iпjury to the "1. mentalis. One must also mention the constant discovery, on dissectioп, of

m

htnno"hag1s the lung tissue anJ iп the mucous тетЬrапе of flarious of the gastro-intestiмl tract.

parn

lп dogs that lived for а comparatively long time after the aЬove-descriЬed operation to the branches of п. trigeminus, the followiпg phenomeпa were noticed. ln а certain percentage, trophic changes did not develop at aU or were transient. In other cases, all the disturbances, even if severe, in the region of the corresponding nerve segment passed off and suЬsequently the dogs were hardly to Ье tlistinguished from normal animals apart from scars f and spots at the place of the former injuries. Finally, some of the dogs after а certain period of apparent health again exhibited trophic chaпges in the tissues at the places jJreviously affected. This was followed Ьу the development of parti.al baldness and ulcers iп other regions of the body, which apparently did not have any relation to the segment of the trigeminus nerve. From the time of the single injection of croton oil into one or otht:r branch of this nerve, no other actions were carried out. Extraction of cerebro-spinal fiuid also ceased long Ьеfore the appearance of the signs of geпeraJised dystrophic phenomena. Nevertheless, the dogs grew thin, the hair fell out, the gait was altered, feeЬleness and general exhaustion developed. All this ended in death. On dissection, it was possiЬle to discover changes in the brain, in various parenchymatous organs, and also in the Ьones, which sometimes Ьесаmе very thin and brittle, sometimes, on the contrary, so soft that thc riЬs, for instance, could Ье cut with а knife. The whole picture of the disease including the anatomical changes had much in common with what I. Р. Pavlov sometimes oЬserved in dogs thзt had Ьееn kept in а damp place after various operations in the region of the digestive tract. These and similar observations caused us to endeavour to widen the scope

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of the work, operating поt only оп the пerve trunks but also оп other parts of the пervous system. Our atteпtioп was naturally first giveп to that part of the braiп which is поw denoted Ьу the term hypothalamш. This region is considered to Ье the higher centre of vegetative nerve functions. Here are to Ье found the regulatory centres of water, salt, protein, fat and carbohydrate metaЬolism, of the circulatory system of the organs of iпterпal secretion, etc. Disease or iпjury of the hypothalamus may result also iп disorgaпisation iп the motor sphere, including even epileptic attacks (Cushing). This region is regarded Ьу some as that of the localisatioп of the "sleep ceпtre." Еvеп the earliest investigators, Schiff and Browп-Sequard, in cases of injury to the iпtermediate and middle braiп oЬserved the resulting developmeпt of ha:morrhages iп the respiratory and digestive organs. The same thing is descriЬed Ьу many writers who studied the effect of so-called heat puncture. N. N. Burdenko and В. N. Mogilnitsky observed the development of ha:morthages and ulcerations in the stomach of dogs in which the part of the hypothalamus behind the infundibulum had Ьееn destroyed. There is по doubt, therefore, that these regioпs of the brain are coпnected \l\'ith тапу functions of the organism which could Ье comЬiпed in the word "trophic." 1 shall not give the whole history of the subject. Questions relating to it are in the forefront of attention at the present time, апd the basic facts are widely knowп. Moreover, we are not iпterested for the momeпt in isolated facts coпcerniпg the physiology апd pathology of thi~ particular area· of the пervous system, the more so because formal data concerпiпg localisatioп сап hardly Ье of use to us in obtaiпiпg а сопсерtiоп of the course of the dystrophic process withiп the nervous system. The task was to elucidate the form of developtnent of the dystrophic process when the regioп of the hypothalamш, iп particular the tuber cinereum and suЬstantia perforata posterior formed the point of primary irтitation. The chief difficulty of the task consisted in oЬtaining а really isolated апd, moreover, chronic irritation of the tuber cinereum. lts deep situatioп iп the middle of the base of the craпium and its close connection with the hypophysis greatly complicated the technique of the operation, in the first place on account of Ьleeding. lt was necessary to change the usual technique in order to avoid апу Ьleediпg into the craпial cavity. ln consequence of the Ыооd accumulating at its base, the irritation takes on а diffuse character, embracing ·the whole mid- and hind-brain , and even the upper segments of the spinal cord. This defect is inherent in all the methods. It is primarily on this account that so far we have no exact data allowing us to analyse the complex effect into functions of the hypophysis and functions of the tuber cinereum. Thus the first phase of our work was the questioп of techпique. Ву alter-

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ing а numЬer of diff erent technical devices and introducing new ones, we succeeded on the whole in achieving the desired results. W е evolved finally а technique comЬining the following features: I) all suges of the operation could Ье carried out in full view; 2) Ьleeding, Ьoth before and after the operation, was aЬsent; 3) injury to the brain was confined exactly within the limits intended and was prolonged chronically; 4) incidental trauma of other cerebral regions was excluded; 5) the dura ~ter was sewn up without any tension. Details of this technique have Ьееn puЬlished in articles Ьу my collaЬor­ ators М. S. SkoЬlo 1 and I. А. Pigalev.1 I shall permit myself to give .а description of it here for the Ьenefit of those who might desire to employ it in their work. It is Ьest to select а small-sized dog for the experiment, since the operation wound is le$ deep in this case. Young dogs are also to Ье preferred to old ones; the base of the cranium in them is wider and the middle cranial fossa is flatter. The operation itself is performed as follows. U nder general narcosis а cut is made in the skin and underlying ~ues along the medial line of the head from the root of the nose to the second cervical vertebra. On one side of the head ( most conveniently the left side) the skin and platysma were separated up to the level of the cheek-Ьone. This is followed Ьу ligature of the Ыооd vessels supplying the т. tempQf"alis, the removal of this muscle along the edge of the cheek-Ьone and careful stopping of Ьleeding. It is possiЬle to avoid cutting the muscle, Ьу skirting it with а curving cut along the edge of its attachment to the bone, separating it with а spatula from the Ьottom of the temporal and suЬ­ temporal fossre, and pulling it outwards with а hook. The cranial cavity is opened with а gouge or cutter, th.e opening is slightly enlarged Ьу the aid of forceps, and the dura mater is separated Ьу а Ьlunt instrument for some disstance from the inner surface of the Ьones. Following this, the cerebro-spinal fluid is extracted, а procedure which plays а very essential role in the further course of the operation. The immediate result is cessation or consideraЬle decrease of Ьleeding from the Ьones. In addition the resulting evacuation of the ventricular fluid produces а perceptiЫe decrease iп the volume of the cereЬral hemispheres. In the following extensive opening up of the cranium, the hemispheres not only do not protrude from the edge of the Ьоnе opening, but are separated from the Ьones like the kernel of а nut from its shell. Thanks to this the raising up of the 1 М. S. SkoЫo, Naiк/111cye Slo'l. 0 No. 4, 1930; Zeitschr. f. tl, ges. ехр. Meti" 1 Vol. 73, No. 1-2 1 1930. t I. А. Pigalcv. Arkh. Biol. Nauk, Vol, 3:1, No. 1, 193:1; Zeitschr. f. tl. ges. 1zt. 0

Metl., Vol. 82, No. 5-6, 193:1.

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temporal portion from the Ьottom of the cranial cavity is greatly facilit:atcd, and а good suture of the dura mater is always assured. Finally, the extraction of the tluid renders unnecessary special removal of it from the region of the middle cranial cayjty Ьу gauze tampons, а fact which is also of importance since it is precisely at this momeпt that there can easily Ье Ьleeding from the vessels at the base of the brain, rendering the suЬsequent results unclear. After the extraction of the cerebro-spinal tluid, the removal of the dura mater from the Ьones is continued in all directions, especially Ьelow, towards the base. Here it is necessary to Ьeware of injury to the venous sinuses. Following this, the covering cranial Ьones are removed with forceps Ьelow thc line joining externally the upper corner of the еуе socket to the middle of the liмo писм ( cristo occipitolis in the dog) . After remoyjng the Ьones to the level of the cheek-Ьones. it is necessary to ореп widely the 11I0иth of the dog. Ву so doing the processus coronarim of the lower jaw is moved downwards and draws with it а11 the muscl~ vessels and nerves running from the lateral surface of the cranium to the lower jaw. It suffices now to pass the handle of а scalpel along the Ьоnе for the whole lateral surface and part of the base of the cranium to Ье exposed. The deep-lying part of the covering Ьones which have Ьееn exposed in this way are removed as closely as possiЬle to the medial line. lt is necessary to take care that the Ьоnе forceps should not grasp the muscles at the Ьottom of the subtemporal fossa for in the immediate neighЬourhood there are the large Ыооd vessels accompanying the second and third branches of the п. trigeminщ. When the Ьones have Ьееn removed, а T-shaped cut is made in the dura mater. lts horizontal part runs back froпi the angle of the еуе socket. Its vertical part Ьegins from tl1e middle of the horizontal part and runs Ьc:low to the edge of the opening in the Ьоnе. Now the operator passes to the opposite ( right) side of the operating tаЫе. The anzsthetist turns the head of the animal round the longitudinal axis of the vertebral column so that the left side of the operation area passes over to the right. Ву the force of gravity, the cerebrum separates somewhat from t.he base of the cranium. At this moment, without further action there will Ье found to Ье exposed not only the entire temporal tract but also the 1yru1 tynformis and even the edge of the tractus olfactorius. А slight pressure with а smooth instrument is sufficient to expose the region of the hypophysis in the space between the carotid artery and п. oculomotorius. Immediately after exposing the hypophysis, а previously prepared, small glass sphere, of the size of а реа, is cautiously pushed into the space Ьetween the carotid artery and the п. oculomotorius and placed immediately Ьehind the Ьасk of the sella turci&o. The head of the dog is replaced in its former

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position, the hypophysis returns to its place, the brain is let down on the base of the skull and the operation concludes with successive stitching of the wound. The dura mater is always sewn up. It is not at а11 necessary to stretch it, since the hemispheres during the operation do not return to their former size. lt is, however, necessary to sew it as otherwise the brain suЬstance is Ьound to protrude through the орепiпg, and thereby damage would Ье infiicted оп parts of the cortex lyiпg close to the base of the brain. It i& desiraЫe also that the wound secretion of the exterпal parts of the wouпd should not penetrate under the dura mater and on to the Ьаsе of the cranium. Ву the method descriЬed, we had neither Ьleeding, nor suЬsequent penetration of the Ыооd from outside parts of the wouпd. There werc no changes in the region of the cerebral hemispheres or at their base, except for restricted tender fusions in the region of the suture of the dura mater. If, while exposiпg the hypophysis or at апу other moment of the operation, intra-cranial Ьleeding commenced, we did not finish the operation, but, after waiting for the cessation of Ьleeding, simply sewed up the wound апd cxcluded the aпimal from the experimcnt. Dissectioп demoпstrated that the glass sphere hardly produces any signs of reaction on the part of the cerebrum or its membraпes. Being situated оп the middle liпe Ьetween the aпterior ends of the peelunculi cerehri, the glass sphere presses оп the posterior part of thc tuber &iner,eum, corpora mamilUirill and substantia perforata posterior. Here, а sore is f ormerJ. оп the lwain, iп the form of а circular pit correspoпding iп dimeпsions and form to the sphere used. U nder the infiuence of the pressure, the cerebral tissue is atrophied to such an extent that the cavity of the third ventricle is often revealed, remaining covered Ьelow merely Ьу the transparent laycr of soft and arachnoid membranes. The Ыооd vessels are pushed to опе side, as а result of which the Ьottom of the pit is pale. Instead of а glass sphere, we sometimes used а wax ball or еvеп an ordiпary реа, which had Ьееn soaked iп alcohol for some days before the operation. Iп these cases, the reactioп on the part of the surrounding tissues was coпsideraЪly greater, апd the sphere Ьесаmе enclosed iп а capsule of soft scar tissue. Curiously eпough, оп usiпg an ordiпary реа the dogs iп some cases lived for а long while, 1-2 moпths or longer. Owiпg to the swelling of the реа, the contact sore оп the cerebrum attaiпed consideraЬle dimensioпs. This, however, did поt preveпt the aпimal from walkiпg, eating апd еvеп playing, in spite of the preseпce of various symptoms of а dystrophic nature, such as will Ье descnЪed Ьelow. Iп geпeral such animals sооп die. Frequeпtly, еvеп in the hours immediately followiпg the operatioп, they develop typical epileptic

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attacks which follow in succe~ion and lead to the animal's death after the lapse of 1-2 days. Apparencly, the associated chemical trauma, i.e., not the р~а itself, but the alcohol with which it has been moistened, plays а part herc. An argument for this view is that the convulsions sometimes begin within 1 5-20 minutes after the operation, when the dry реа has not yet begun to increase in size. In the ma jority of cases, there were no alterations of the hypophysis which could have developed as а direct result of the press11re of the glass sphere. The sphere is situated behind the hypophysis and cannot Ье displaced forwards, being kept in place Ьу the posterior edge of the sella turcica which is slighcly raised аЬоуе the base of the cerebrum. All the same, in order to avoid the possiЬility of such injuries, we suЬsequently altered the technique and began to use, instead of the sphere, а glass ring from which а piece had Ьееn removed on one side.The size of the ring corresponds to the dimensions of the pit of the sella turcica. Its thickness is 2-3 mm. At the moment when the cerebrum is lifted up, the infundibulum is introduced within the ring, through the break in its circumference, and the rings is turned so that the free ends are directed anteriorly. (Plate 20.) The ring lics at the edge of the pit of the sella turcica, leaving the hypophysis in place, without touching it anywhere or putting it under any constraint. When the cerebrum is allowed to fall back again, the ring presses against the posterior and lateral parts of the tuber cinereum, producing here а St'mi-circular sore. The sole drawback to this form of the operation lies in stagnant phenomena in the hypophysis, which sometimes occur as а result of the pressure of the veSSt'ls around the tuber cinereum. U sing both of these methods, i.e., the sphere and the ring, we have carried out operations on many scores of animals. Here I !\hall give а general review of the data obtained. The first two series of experiments were performed Ьу my coll~borators М. S. SkoЬlo1 and I. А. Pigalev. 1 In the first series the glass sphere was used, in the second the semi-circular ring. The consequences, both as regards the animal's life and the general picture of the dystrophic process, were approximately alike in Ьoth series. In the first place, it must Ье mentioned that the duration of life of the dogs after the operation varies within very wide limits. Some of the ;:i"!imals die even within the first 10-20 hours, others live some days, while in « third group life persists for weeks and even months ( up to а year or more). In 1

!

М. S. SkoЫo . 1. А. Piga!ev.

Loc. cit. Loc. cit.

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spite of these variations, the dystrophic phenomena which develop among them are very much alike, differing only in degree. The first symptom, usually noticed even dщ·ing the first two ho11rs, is htzmorrhage of the gum iп thc region of the parodont. Swelling, loosening and а dark border of acute hremorrhages usually make their appearance around the molars of both jaws. The general picture is very similar to that seen in man in the case of scurvy. The process gradually progresses, the border of hremorrhages around the teeth extends into а continuous strip, tl1e gum separates from the nccks of the teeth, revealing the alveolar edge of the Ьоnе. In severe cases the ulcerations around the separate teeth fuse and then the whole gt1m comes away, laying bare tl1e Ьопе for а considerahle distance. \,Ус oЬ­ scrved several cases where the mucous membrane of the gum disintegrated ichorously outside the limits of the processш alveolarius of the upper and Jower jaws. This occurred without signs of reaction on the part of the surrou11ding tissues, leaving the impression of putrefaction or maceratioп. Apparently, also, it is not accompanied Ъу any marked painful sensation. TJ1c dogs readily permit examination and touching of the altered parts, and they eat and drink without noticeaЬlc difficulty. Such severe cases are met with comparatively rarely. Usually, the phenomenon is limited to swelling, loosening, hremorrhage and ulceration of thc jaws around the necks of the teeth. Тhе process can go оп for many days and even weeks, gradually suЬsiding and breaking out afresh. Other regions of the mucous membrane of the oral cavity are affected at the same time as the gums. Неге also erosions and ulcers make their appearance, especially on the lips, tongue and under the tongue, soinetimes on the cheeks, and on the hard and soft palate, more rarely in the pharynx. Here also signs of reaction are often absent. The tissues are flaccid and dirty or, on the contrary, they may have an unnaturally fresh appearance as if the defect had occurred as the result not of ulceration, but of cutting with а knife. In the majority of cases, these changes are superficial; more than once, however, we observed that they Ьеgап to progress irresistiЫy, destroying tм тисот, muscular and cutaneous portions of the cheek. This resulted in an extensive penetrating defect, with the aЬsolutely typical appearance of what pathology and the clinic terms noma or "watery cancer." (Plates 21, 22.) W е were not interested in the question a.s to what precise microЬes were concerned in these processes and what role they played. It was clear that there is only а quantitative diff erence between the general features of noma and of those ulcers that do not penetrate right through all the tissues. Ulcerations in the oial cavities of our dogs were an invariaЫe consequence of the аЬоvе• descriЬed operations. If any microbe'> also took part in this process, it can only

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mean that they were previously present in the organism of the animal as saprophytes, and the conditions for their activity were the rerult of а diff erent росеи. Moreo·ver, their activity or pathogenic character was strictly loиu. Thus, it was frequently observed that particular ulcers in the oral cavity, when they had react1ed а definite size, came to а stop and, as it were, halted, neitl1er advancing 11or showing any tendency to disappear. lf une speaks of the transition of microbes from а saprophytic to а pathogenic state, then it Ьecomes nece~ry to deliпUt the exact area where this has taken place ! Thi:; area, however, has evidently Ьесn formed Ьу the action of other forces. Thc microЬes are unaЬle to cross its bou11da1·ies. But in that case is their pathogenic character an active property1 It is obvious that in the case before us this conception cannot explain anything and therefore is of по interest to us. The next, very characteristic, form of affection is t:1e development of papillomata. These typic:.il growths, in external appearance resemЪling а caulifiower, сап Ье sin gJ~ or multiple. They arc disposed on the mucous membrane of the lips and che1:ks, and sometimes оп the tongue. Their dimensions vary. Somc do not exceed а piл's head in size; others attain the size of а walnut. Thc time of their appearance reckoned from the moment of the operation is also not нniform, varying from 2-3 weeks up to 5-7 months. After existing for а short time, they become atrophied or fall off, and are replaced Ьу new ones. Оп disappearing, they leave behind а white spot which is especially visiЫc in those cases where the mucous membrane of thc mouth is strongly pigmented. The development of papillomata in f7 char"ur. Their disposition at the periphery can Ье pedicud Ьу us iп adfJanee, and their Ьoundaries remain umhanged, often throughout long periods. It is considered that the basic cause of infiammation is some external "iajurious infiuence." It is clear from our cases that the injurious infiuence waa only such for particular points of the organism and Ьесаmе impotent even in neighЬouring portions. Such а state of things would Ье inconceivaЬle if the "injurious inlluence" was actually brought in from outside. Consequently, other causes are concerned, lying concealed in the primary change of the tissues themselves at particular points. 4 loclll chlmge of tЬ. st.U of tм tur!Joиs system is, аЬоw all,, а loclll change of tм enwonmeпt, а destruction of the normal physico-chemical state of the given region. However this destruction comes aЬout-whether Ьу а f oreign agent or processes of an internal nature-the character of the reactions exhibited will Ье one and the same, for now the damaged elements of the organism themself.Jes bect:»'l'W а foreign agent for it. Consequendy, the nervous system is itself сараЫе of Ьeing the. organiser of inflammation, of creating the "injurious infiuence" wblch produces the infiammation. It seems to me that the aЬove-descл"Ьed oЬservations categorically decide the question of the participation of the nervous system, поt оп/.у m the course Ьиt т tм genesis of tм mftammatory рост, and that as far as pinciple is crmcerned, the matter сап Ье regardetl as settled. An infectional or toxic focus, exactly like an irritating agent of а physical nature, produces changes in the organism Ьoth locally and at а distance. These changes may pass away without leaving traces, but this is not always so. Where the nervous system is drawn into the process, the fate of the primary focus and the generalisation of the process cease to Ье dependent on local causes alone. А new additional cause makes its appearance, as а result of which the original cause easily Ьecomes obscured, and finally loses its importance. This is especially pronounced in processes of infectional origin, where the immediate irritating agent may Ье Ьoth annihilated and neutralised Ьу а series of specific and non-specific reactions. We have seen that if microЬes are present chronically ( often for а numЬer of years) in the pathologically altered tissues, this is far from Ьeing proof that the organism is incapaЬle of coping with them. On the contrary; the microbe is neutralised, it does not itself irritate the tissues any longer, and peclsely for that reason its physical destruction hecomes impossihle. At the same time, such destruction is useless, since, after the microhe has ceased to Ье the cause of the disease, the destruction of the microbe does not aЬolish the disease. If, in our analysis of the genera] complex of conditIOns of acute inBam-

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mation, lasting Ьours or days, we. were compelled to put the nervous system in tbe forefront, its role in c;bronic inflammation must Ье still more marlced. Indeed, in chronic inflammation both the maintenanee of the primary f ocus 11nd the f ormatum of secondary f oci h•come nothing less than а new patholJo gical function of the nervous system. It is no wonder tЬat up to now we have not had any theory of chronic infiammation. W е have Ьееn brought up to Ьelieve tЬat the nervous system does not play any essential role in tЬis phencmenon. Нow coulJ we guess that iп the final analysis it is just the ftenJous system that is its fundament.J c11Us•'

CHAPTER XIX SPECIFIC REACTIONS We have still to analyse one question which we have hitherto deliЬerately omitted from consideration. This question concerns the quality of the irritating agent, in other words, the property of the foreign agent to evoke in the organism а reaction which is distinguished Ьу special features typical of this particular agent. This is а very complicated question. At the same time it is :а fundamental one, siпce it i.1 precisely the proЫem of quality which f orms the object of study of special pathology, as distinct from general pathology. The difficulties that arise in its solution depend not so much even on the complexity of the subject, as оп the absence of correct basic propositions. We have already had to point out more than once that, in judgirig the consequences of irritation, the whole chain of subseqнent reactions is often considered as the result of the direct action of the irritating agent оп each of the reacting elements and that tltis conception is erroneous. W е reached the conviction that the agent commencing the reaction very soon transfers its property of irritatiлg agent to parts of the organism itself. In this way, а whole mass of reactions arise from а single point. Not all of them are specific. For the investigator to Ье аЫе to filter out j~st those processes which are actually connected with а definite and special action, it is necessary to begin Ъу excludiпg everything accideпtal апd subsidiary; in other words the field of work has to Ье cleared. This naturally restrained us from proceeding directly to the study of specific reactions, and for а number of years caused our attention to Ье concentrated оп the study о/ their nonspecific features. We saw that raЪies, а sore on the tuber cinereum produced Ъу а glass sphere, irritation of any branch of the n. trigeminus Ьу croton oil, in jection of formalin into the pulp cavity of. а tooth or of bile into the upper cervical ganglion, introduction of foreign protein or various vaccines into the Ыооd, poisoning Ьу salts of the heavy metals, e.g., corrosive suЬlimate, etc.-all these are сараЪlе of producing in а number of organs changes that are absolutely constant and so much alike that it is impossiЫe to distiпguish tlir.m from опе another. It is clear that we cannot connect the production of these changes with special qualities of the irritant used, otherwise we should have to compare a7S

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а glass sphere with corrosive suЬlimate and the latter with rabies virus. It is clear that the presence of the irritant, e.g., C('lrrosive suЬlimate, in the foci о{ acute local affections cannot alter our point of view on this subject, since we obtain exactly the same foci, in the same form, and at the same places, without using any poisonous substances. Nor is importance to Ье attached to the fact that in cases of chronic poisoning ( mercury, lead), particles of the heavy metals are dcposited in chronic infiammatory foci. It is interesting to note that these places are very constant. The chief proof of the theory of "tropism" is derived from this fact. But, as we have already shown, this topographical сошtапсу &asts suspicion оп the whole interpretation. W е saw in our experiments that а glass sphere placed on the seUa turcica "selects" for local peripheral foci exactly the same places as lead or corrosive suЫimate. Are we not then justified in thinking that these places have been prepared Ъу another process and that their origj.n is only historically connected with the immediate irritati·n g agent? This is the reason why it is necessary at the outset to become acquainted with the constant features which do not depend on the properties of the irritating agent and are exhibited equally in all cases of irritation. In analysing this aspect of the matter we found that the time factor is prominent а Ьоvе all, for without taking it into account all other data lose their value. Additional irritations on the part of the nervous system soon convert the reaction into а complex of direct and r efiected actions. It then becomcs impossiЫe to speak of special properties of the irritating agent, since even its complete removal is often powerless to arrest the process. N evertheless, this process iп some strange fashion is сараЫе of preserving its qualitative peculiarities throughout тапу months and years! The explanotion of this contradiction is simultaneously also the key to the problem of quality iп patholo gy. Concrete work in this direction сап Ье reduced to the analysis of two propositions. The first is connected with estimation of the time factor. If qualitative characteristics are inherent in а pathological process, then ( as was shown Ьу examples taken from the sphere of chronic inflammation) they must Ье communicated to it in the first stages of the action of the irritating agent. The second proposition is of much greater theoretical importance. W е Ьаvе seen thэ.t the irritating agent can Ье withdrawn from the organism or neutralised, and yet the process preserves its specific featur~s. Consequently, for а certain time, changes produced in the organism Ьу the irritating agent сап remain in it, not simply iп the f orm of ordinary irritation, but iп а speci.al -quditatively distinct--f orm of this irritotion.

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It is generally Ьelieved that this peculiar form of irritation is preserved Ьу the elements that havc alrcady comc into immediate contact with the irritating agent. W cighty considerations in support of this vicw arc dcrived from thc study of cxperimental malignant ncoplasms. At thc prcsent timc, methods exist for converting normal tissue cultures into cultures producing malignant tumours under the infiuence of chemical irritation (Fischer, Carrel, Laser). As а result of а number of consecutive transfers, а culture of normal cells Ьecomes "cancerous," with а11 the inherent characteristics thereby involved, and retains its new properties even when the irritant is no longer applied. All this takes place iп vitro; no nerve influcnces are required. The experiments mcntioned give а negative answer to the question of the role of the nervoys system in this process, and any attempt to prove that it does play а part here is condemned to failure in advance. Howcver, this is the situation only on а hasty view. In experiments on tuЬerculosis in tissue cultures iп vitro, wc cncountcred an essentially similar phenomenon. This did not put а stop to our study of the rolc of the nervous system in tuberculosis and, as was shown, led to ап affirmative answer to this question. The Ъasic premise consists in the inadmissibility of analogies Ьetween processes taking place in а complex organism and in tissue cultures. Even if an epithelial cell is converted into а cancer cell in conscquence of immediate contact with the irritant, it is still necessary to discover whether there is anything the organism whi&h is capable of facilitating or preventing such а transformation. The first experimental data on the question of the connection of neoplasms with а definite functional state of the nervous system were provided Ьу Spiess. In the case of cancer in mice or cancer of the throat in man, hc succeeded in showing that repeated local an~sthesia resuJt~ in inhiЬiting the growth of neoplasms and sometim~s even causes them to d1sappear altogether. That the ilervous system must ~ss at least some infiuence on tl1e development of neoplasms can Ье considered experimentally estaЫished Ьу the experiments on so-called tar cancer. First Ischikawa and Kotzareff, and afterwards Tsunoda and others, Ьу severing various nerves of the ear in raЬ­ Ьits, sometimes obtained а consideraЫe increase in growth of tar papillщnata, and at other times, on the contrary, inhiЬition of their development. Even before this, А. G. Molotkov had obtained in some cases rapid cures of cancer .o f the cheek and upper lip in man Ьу severing the second branch of the п. trigeminus. Rickcr also put forward а numЬer of data from his oЬservations providing evidence of the connection of neoplasms with changes in the ner-

m

SPECIFIC REAC110NS vous system. The histological researches of Argaut, Ischikawa and others revealed the presence of nerves in cancer tumours. Martynov proved their consideraЫe development in stages preceding the formation of tar cancer in raЬ­ Ьits. The clinic has long known that cancer is frequently accompanied Ьу pathological symptoms of а nervous character. Consequendy, there is no doubt that some connection exists Ьetween neoplasms and the nervous system. However, а formal indication of the participation of the nervous system in this process is not sufficient. The nervous system, Ьeing connected with almost every cell of the organism, must as а matter of course Ье involved in all pathological processes. The рrоЫет is to determine the form and extent of this partietpation. А series of experiments, descriЬed in preceding chapters of this Ьооk, have shown that the nervous system is not only involved in, but organises and ietermines many pathological forms which hitherto have Ьееn regarded as. independent of nervous infl.uences. W е Ьоrе these conceptions in mind when approaching the study of tar cancer. W е carried out operations on various parts of the gastro-intestinal tract of rabbits. The irritant used was coal tar, obtained from the Moscow Gas Works ( experiments of ту collaЬorator I. А. Pigalev 1 ). In the first place, we tested the action of coal tar оп those regions of the tastro-intestinol tract which had previously attracted our attention during the study of other processes. It was not а matter for surprise that in this new form of experiment approximately the same result was obtained. In the course of 3-4 weeks, а drop of tar, introduced once under the mucous membrane of the stomach, caused cauliflower-lilce tumours, sometimes of consideraЬle size, to develop in the immediate vicinity. Microscopical examination demonstrated the presence of adenoma with atypical growth of epithelium, which invaded the muscularis mucosae and had lost its normal morphological structure ( aЬsence of the chief and covering cells, the epithelium passing into а high cylindrical form). The growth of the adenoma sometimes proceeded very rapidly. W е obtained cases where, even within 20-25 days from the moment of injection of tar, the adenoma reached а size of 5-8 sq. cm. with а height up to I cm. In other, rarer cases, the process was limited to а fееЫе ulcer of the mucous membrane at the point of in jcction. ln тапу scores of experiments, оп the introduction of tar under the mucous тетЬrапе of the smвll or large intestine, we never obsen;ed апу but crdinary inflammatory changes. Only on repeated application of tar tam1 1. А. Pigalev. Arlth. Biol. Naui, Vol. 28, No. •• 19281 Zeitschr. Metl., Vol. 63, Not. 5, 6, 1928.

f.

J. g1s. ехр .

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pons iп the rectum of rabblts did we obtain in two or three cases the formation of small adenomata in the substance of the mucous membrane and papillomata on the skin around the anus. То clear up the question, it was desiraЬle to put it experimentally in а sharper form. This involved obtaining an answer to the question whether the epitheliu1n actually reacts to the tar only as а result of direct contact with it. The mucous membrane of the stomach is very sensitive to this irritant: within 3-+ weeks we often obtained an adenoma of consideraЬle size. Consequently, the reaction must have Ьegun here from the very beginning. lf it were to Ье shown that etJen iп the first stage the reactioп was governed Ьу changes iп the state of the local inner'l.Jation, then the que;tion wnuld Ье automoticall.y settled.. The experiment was arranged Ьу us in the old form that had previously proved its worth ( experiments of I. А. Pigalev). А series of observations were made on rabbits in which we severed both trunks of the п. vagi at the cesophagus before in jecting tar into the stomach. The animals were killed at various ·periods--from З weeks to I % months. А tyfical growth of efithelшm was поw not obtmned iп а single case. Sometimes а fееЫе, slowly cicatrising ulcer made its appearance. ln the later period~ we succeeded in noting the formation of shagreened portions of the mucous membrane but the development did not go so far as adenoma. W е should lilce to emphasise once again the resemЬlance between these results and those repeatedly obtained Ьу us in other experiments. This resemЫance goes even further. lt was once more confir1ned here that it is not оп account of the denervation of the tissues that vagotomy has an infiuence on the process of development of tar adenomata. lt is а question of nerue trauma, i.e. 1 of temporary change in the state of the nervous system. It was found that after vagotomy the development of the adenoma is only retarded, but not abolished. When we tried killing the rabbits after а long period (2%-3% months), we discovered in many cases atypical growth of epithelium in the locus of the old ulcer with its ca1loused base. The edges of the ulcer were raised, giving а caulifiower-like appearance. Microscopical analysis revealed adenoma with atypical growth of epithelium. lt should Ье remembered that in our experiments during the study of acute and chronic inf!ammation, something very similar was noted. W е were compelled to connect the result with а change in the character of nervous interrelations. Consequently, hoth categories of processes have опе thing iп соттоп, viz.. 1 their nervous component. If there is anything that must Ье demonstrated, it is not the participation of the nervous system in these processes, but, on the contrary, our right to regard local elements ( epithelium, muscles, connective tissue,

SPECIFIC REACTIONS etc.) as independent origiпators of special forшs of response to 1rntation. Experiments on the development of ' 'iaalignant" properties Ьу cells in tissue cultu1·es iп vitro, uлder the influence of chemical actions, cannot in any way contradict this thesis. The effect which is produced in tissue cultures iп vitro, Ьу а chemical agent introduced from outside, is performed iп vivo Ьу а diff erent agent, also foreign and also chemical in nature, but arising in this case as а result of an abnormal state of the nervous system. Everyone is acquainted with cases where, after the ear of the rabЬit has been smeared with tar several times, this operation was for some reason or other discontinued. Inflammatory changes of the skin, in the form of des" quamation rapidly disappear. The rabbit remains healthy for many months. But sometimes, without any yjsiЬle cau5e, tr.r papillomata and genuine chancroids suddenly appear оп the ear. 1'hus, the trace of the former irritation proves to have Ьееп preserved here iп exactly the same form щ originally. The fact that the character of the reaction is determined during the first stages of irritation and that the nervous system plays а decisive role in this process, permits us to answer the question put at the beginning of this chapter: what are the elements in which the traces of the special form of irritation are preserved? Let us assume that under laboratory conditions, when а really foreign agent artificially introduced from outside begins the reaction, the nervous system опlу creates accessory conditions wl1ich are, neverthe!ess, essential for the courst: of the process. This signifies that if the local nerve coлditions at any point of the organism are changed Ьу some othtr cause, but iп the same way as Ъу the action of the foreign agent, the cQnsequences wiil inevitaЫy Ье identical. From this we сап draw two conclu~io ns: I) The quality of an irritating agent is expressed in its capacity to evoke а special form of nerve irritation; 2) The nervous system can retain for some time traces of sucl1 irritation without changing the characteristic features of the latter. It is necessary to test these prcpositions Ьу tl1e investJl_.i if tion of some process where the specific properties of the irritating agent are unqнestioned. The most suitahle procers for this purpose is tetanш. If it had not been for tetanus toxin, the idea of the quality of the irritating agent would never have attained its present form. Iл this regard, tetanus toxin is cven more intf'resting tha11 diphtheriз toxin. In animals, the use of the latter produces а non-typical picture of "general" disease, tnding in death. Tetanus toxin also produces death, Ьнt before this it gives rise to а series of symptoms which are very charactcristic and comprise а definite cycle of pathological symptorm. At the present time, the whole pathogenesis of tet2nus is looked upon as

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the result of the direct contact of each reacting element to the irritant. According to the generally accepted point of view, the toxin advances along the nerve from itз place of formation or introduction to the corresponding cell structures of the spinal cord. Acting directly on them, it sharply increases their reiiex excitability. At the Ьeginning, this is oЬservaЫe within the limits of one or two nerve segments. As new portions of the toxin arrive, the toxin spreads upwards and downwards along the spinal cord, involving the corresponding elements of neighЬouring regions. The process terminates in generalisation of the tetanus symptoms throughout the central nervous system. Hence, the whole thing is reduced to а sirnple and almost mechanical factor; a1l nerve elements drawn into the process are connected directly with the toxin; if the toxin did not move along the nerve and spinal cord, we should not know what tetanus is. In full accordance with this view, it u beli6ved that

the only way to put ап end to the symptoms of tetaпus

uЬу remoW.g or neu-

tralising the toxin. As already noted, this view enjoys g"neral recognition. It is based on aЬ­ solutely direct experiments, the chief of which can Ье divided into two series. The first series comprises experiments demonstrating the progressive accumulation of the toxin at various levels of the nerve trunks connected with the place of in jection. The second estaЬlishes that preliminary section of the corresponding spinal nerves safeguards the animal against the disease, even when active and fatal doses of toxin are injected into the tissues. Other researches have airned only at supplementing these data with further details. The matter seemed settled without leaving any doubts or reasons for new experiments. Such was the state of affairs Ьefore we had arrived at the necessity of dividi.ng the mechanism of movement of various suЬstances along the nerve trunk into two forms, passive and active. If the active form of movement is the result of chemical interaction Ьe­ tween the toxin and the nerve tissue, then irritation hegins from the first stage of the process and not merely from the moment when the toxin reaches the nerue cell and enters into comЬination with it. This circumstance has somehow Ьееn left out of account. W е directed attention to it for the fir5t time in the experiments described аЬоvе, performed on dogs, in which we injected the toxin into the muscles of the knee after unilateral or bilateral removal of the abdominal sympathetk chain. The infiuence on the course of the tetanus process of the new conditions thus created was then obvious. It Ьесаmе clear that, other conditions Ьeing equal, changes even iп remote nerve regions 11re сараЫе of sharply altering the f orm of response of elements iп which the process appears to develop selectively. All this caused us to doubt the correctness of the orthodox conception of the pathogenesis of tetanus.

SPECIFIC REACTIONS Direct grounds for such doubt were furnished Ьу а chance oЬservation described in the work of my collaborator Dr. S. !. LeЬedinskaya, 1 Ьelonging to the period when we were studying the consequences of nerve trauma infticted repeatedly after various intervals of time. As has been shown, the reaction obtained Ьу no means always corresponded to the character of the repeated irritation. Frequently it gave rise to а process which had developed or ought to have developed as а result of the primary irritation. On one occasion we used а dog which had recovered after injection of а small dose of tetanus toxin into the muscles of the left knee. During the illness it had suffered only from tetanus of the left hind extreщity. Thi:> developed seven days after injection of the toxin and gradually increased, but did not pass to the region of other muscles and persisted aЬout twenty days. After that, the animal regained the power of using the affected organ. Five days after the final extinction of the disease symptoms, the dog was accidentally included in another experiment which at the time did not have any relation to the study of tetanus. The animal underwent trepanning, and а glass sphcre was placed in the region behind the sella turcica ( tuber cincreum). The consequences of this operation, as described many times above consists of various forms of dystrophy, generalised throughout certain tissues and organs. In this particular case, the consequence of the operation was the re-estahlishment of the tetanus symptoms wl1ich had disappeared not long before. Within 24 hours, the dog underwent tonic cramps mзinly in the hind extremities, which after 48 hours resulted in the typical syndrome of segmentary tetanus. This was followed Ьу heightened reftex excitability, rigidity of the vertebral column, opisthotonus and death. There сап Ье ло doubt that the tetanus was renewed here without апу participation of the specific toxin. The "glass sphere operation" was carried out more than а month after the injection of toxin, i.e., after а period fully sufficient for the developmcnt of immunity. Moreover, the animal had Ьееn i1l and had recovered, and it is usнally considered that recovery is only possiЬle if the toxin has been removed or neutralised. But the most important feature is that we obtained here something more tl1an а simple relapse. The original character of thr disease consisted only in local tetanus of one of the hind extremities. The relapse not only gave а repetition of the same symptom, but also segmentary, and suЪsequently general, tetanuз.

The inevitaЬle conclusion to Ье drawn is that local tetanus сап pass into general tetanus without the spreading of the toxin from the region of the primary focus throughout the central nervous system. 1

S. 1. LeЬedinskaya. Arkh. Biol. Nauk, Vol . 34, No. ""' 1933.

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ln our case, the local symptom was merely the first stage of а complex nervous process having its own deftnite cycle of developmerit. With an original irritation of small magnitude, the process was сараЫе of coming to а stop halfway. When, however, the strength of the irritation exceeds а certain limit, the process develops to the end. U nderlying it, therefore, is the readyprepared nervous mechanism, where ~ach new part that is set to work determines thereby the functioning of the succeeding part. lf this particular case can Ье explained in this way, it is surely possiЫe to extend the explanation to all other forms of spontaneous and laboratory tetanus. The question thus raised acquires exceptioпal importance not only for the pathogenesis of tetanus but for pathology as а whole. It was natural that we made this the subject of special investigation. First of all, it was necessary to test whether а nerve trauma of accidental origin (а "second Ыоw"), applied shortly after the liquidatioл of tetaлus symptoms, was actually сараЫе of re-estaЬlishing the process in one or another of its forms. The corresponding research was conducted Ьу ту collaborators !. Р. Bobkov and А. L. l' enelonov. 1 Cats were used as the experimental animals, since with dogs it is in general di.fficult to select а dose of toxin which gives only local tetanus without its subsequer.t generalisation. In cats, the process develops more slowly, easily stops at thr stage of local tetanus and quite often ends in recovery. It was estaЬlished Ьу preliminary experiments, that on introducing tetanus toxin into the anterior chamber of the еуе, and especially into the corpus vitreum, cats are easily аЫе to соре with the disease, even if the toxin is injected in more than fatal doses. In addition, the disease is deprived of its characteristic features. The symptoms of local tetanus are lacking or, in some strange fashion, they are transferтed to the opposite end of the central nervous system. Thus, we frequently oЬserve the first ]ocal symptom in the caudal region and muscles of the hind extremities. On stroking the animal, rigidity was increased to the degree of tonic cramps. Subsequently, rigidity of the vertebral column developed, but it rarely reached а high degree. АН these symptoms usually persist for а comparatively short time, 3-7 days and disappear without leaving traces. Of nine cats, only опе died. When the same toxin, but in а dose only one-sixth to one-eighth of the former amount was injected intramuscularly into nine other cats, the consequence was always local, and sometimes general, tetanus. О/ this series, only four cats recovered. Some 3-5 days after the convulsive symptoms had disappeared, ап additional пеМJе trauma was infticted о·п the animal1 of both series: in some cases 1 UnpuЬlished

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SPECIFIC REACTIONS bile was in jected into the right or left sciatic nerve, and the nerve. was then severed, in other cases drops of bile were .ntroduced into the upper cervical ganglion. F or almost all the animals, Ьoth forms of operation proved fatal. Some of them even died in the hours immediately fc.Ilowing the operation, others lived for 2-6 days. ln this exper1ment, it was found that the convulsive phenomena, w!-1ich had disappeared some days previously, sufjered а relapse tl1at took оп ап even more pronounced form than fJriginally. Here also it '"'as noticed that touching produced а pronounced increase of the rigidity of the tail, liind extremities and Yertebral column, tw·itchiпg of the spinal muscles, etc. Normal animals e.lsily tolerate an injection of Ьile into the sciatic nerve. The consequence in their case takes the form of tissue dystrophy developing after а cornparatively long period. W е have perforшed operations of this kiпd so often that there was no necessity of repeating them specially in this case. As far as injection of bile into the upper cervical gaпglion of normal cats is concerned, we made а series of control experiments. Of five cats, three died on the sixth or seventh day, two remained alive. Not опе of the animals exhibited convulsive symptoms. ln all of them, only coughing and general weakness was observed. W eighing up these data, we have to recognise that а nerve trauma, applied to various regions of the nervous system of an animal that has only just recovered from tetanus, is actuaUy сараЫе iп some cases of restoring the previous picture of the disease iп all its details. Thus, we find а repetition here of the phenomenon which we have already repeatedly encountered in investigating the processes comЬined in this Ьооk under the general name of nervous dystrophy. If traces of а previously existing irritation are retained within the nerve network, then а new, even accidental, action may evoke а reaction corresponding in form to the primary irritation. W е cannot, of course, count cn restoring the original picture Ьу means of а second Ыоw in аП experiments without exception. The second Ыоw can evoke tl1e reaction interesting us only as long as the latter has not Ьееп finally extinguished. Consequently, it is necessary here to take into account the basic factor of time, which, ho\vever, is not fully at the disposal of the investigator. We have seen that not only the result of the reaction Ьиt also its whole course тау he re-estaЬlished. This means that the nervous process, developing in time and consisting of an intricate complex of successively deve1oping stages, is contained in the nervous system as such iп the form of а ready-prepared mechanism. The externa1 agent is merely necessary to supply sufficienl force to start the reaction. Subsequently, this agent can Ье completely neutral-

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ised or removed but the process will nevertheless proceed to its natural condusion. In the aЬove-descriЬed data, attention is attracted Ьу the fact of local symptoms Ьeing transferred from the region of the segment immediately irritated to the opposite c:nd of the central nervous system. This fact has not yet Ьееn made the subject of investigation in the pathogenesis of tetanus. U р to now three forrns of the development and course of tetanus have Ьееn ·known. Usually, the discasc Ьegins with the nerve segment corresponding to the place of injection of toxin. From here the process graduaJly spreads to the spinal cord and brain. This form is oЬserved in dogs, cats, rabЬits, guinea-pigs, mice and some other animals. In man and in horses, а second form occurs, in which tetanus Ьegins at once with so-called general phenoinena, omitting the local stage. Finally а third form, descriЬed Ъу Roux, can Ье obtained only under artUicial conditions, when tetanus toxin is introduced directly into the central nervous system. This form is known Ьу the name of cerebral tetanus. The features that we observed on injecting the toxin into the corpus tlitr.um of the cat do not соте under опу of the obove-mentioned cotegories. This caused us to devote more detailed study to the tetanus syndrome in cati on injection of the toxin into various organs of the Ьоdу. The aim in view was to test the infiuence exerted Ъу the ploce of tnml'J mjectioп of the toxin оп the f orm of the disease ond successive de'velopnent of its symptoms. Various types of experiment were performed Ьу my collaЬorators Drs. 1. Р. Bobkov, А. L. Fenelonov, М. О. Ossipov and S. I. LeЬedinskaya. The 1 oЬservations of LeЬedinskaya and Ossipov showed that, on unilateral injection of the toxin into the musdes of the knee the ftrst local symptom wos fr•quently caudol tetoпus. The tail was rigid and sharply Ьent to the side in which the to:Юn had Ьееn injected. Even when the disease involves Ьoth halves of the nerve segment, the tail still remains bent asymmetrically. Оп suboccipital injection о/ toxin, the first local symptoms ore ogain exhiЬited iп the tail ond hind extremities. It might Ье thought that the nervous system of the tail is especially sensitive to the action of tetanus to:Юn. This aroused а natural desire to find out how the tetanus would develop if the tail itself was selected as the place for injection of to:Юn. The result obtained was unexpected. Оп subcutaneous iпjection of toxin in the distal portion of the tail, rigor frequently commenced iп the hind extumities. Only afterwards did the tail become involved in the process. If а 1

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small dose of toxin is taken (Ъut one sufficient for producing the disease on injection into the tissues of other parts of the body), and is injected suЪcutan­ eously in the distal portion of the tail, it is quite possiЫe that no symptoms at all will Ье obtained. lt is interesting to note that in some cases such animals died fairly rapidly, but without developing either local or general tetanus symptoms. In these cases, the toxin apparently evoked some new form of reaction not typical of the disease. 1 should lilce to call to mind here some experiments of ту collaЬorators Doinikov, Suslov and ZhaЬotinsky, which were described аЬоvе in the chapter on the generalisation of dystrophic phenomena. On the application of chemical trauma to the sciatic nerve, the most pronounced morphological changes are oЪserved in the nerve elements of the corresponding segment. From here the affection spreads upwards along the spinal cord, mor6 or le11 uniformly diminishing in intensity. An entirely different picture is obtained if one of the nerves of the brachial plexus is selected for the application of the trauma. U niformity is here replaced Ьу discontinuity. The process suddenly passes from the cervical into the caudal part of the spinal cord, letroing intact its thoracic portion. An analysis of the causes of this lack of correspondence led us to recognise differences in the course of the process of irritation itself. Тhе irritating agent was the initiator of all the phenomena but played no part suЬsequently.

Similar data were also obtained in investigating tetanus symptoms. It is to explain the strange anarchy prevailing here if опе starts out merely from conceptions of the movement of toxin in the nervous system. W е were finally conyjnced of this Ьу the material of my collaЪorators Bobkov and Fenelonov.1 In testing the influence of the place of injection on the general picture of the disease, among other experiments we introduced the toxin into the upper ceryjcal sympathetic ganglion. When this is performed on cats, а remarJeahle picture of sagittal tetanus almost regularly develops. The disease Ьegins with the cervical muscles, as а result of which the head is turned to the side corresponding to the place of injection. This is followed Ьу tetanus of the fore and hind extremities of the same side and also Ьу muscle rigor of the same half of the trunk. lf the toxin is injected on the left side, the body of the animal will also Ье bent towards the left, while the left fore and hind extremities are sometimes stretched out like sticks. At the same time, the right extremitier remain flexihle and retain almost thcir normal moЬility. In some cases, the general picture appears in а pronounced form, in others it is more weakly expressed. Usually, the transition of the process to the орimpoSS!Ъle

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posite side of the nervous system is retarded, and the process itself rarely attains а consideraЬlr. degree on that side, since the animal dies before this can happen. In other experiments with cats, the toxin '>''i.IS injected cither into the т. sterno-cleido-mastoideus or subcutaneously into the lateral part of the neck. In some cases, а sagittal form of tetanus was also observed here, but it was ноt pronounced. Here agai11 we recall our old experiшents, the object of which ·.vas to study the morphologic:tl consequences of cl1emical trauma of various nervc structures. W е oЬserved then that changes in the ganglia of the sympathetic chain in rabbits after unilateral chemical trauma of the sciatic nerve (Ьу croton oil) spread mainly оп the same side as that of the nerve subjected to trauma. The aлalysis of the causes of this process also led us to deny that the irritating agent itself took part in it. If we now compare the various forms of generalisation of the tetanus process, we shall have to divide them into two categories--frontal and sagittal. Both of them can take place in animals of the same species. Thus, on injection of toxin into the mu ~'cles of the hind extremities, cats usually experience the frontal form of the development of the disease. The first symptom here will Ье local tetanus, at the beginning in one, and afterwards in the other, hind extremity, followed Ьу rigor of the vertebral column and fore extremities, opisthotonus, etc. The same cat, if inoculated in the upper cervicaJ ganglion, develops sagittal tetanus. The cause of the difference indicated lies · solely in the choice of the point of priт.ary irritation. During the first period at any rate, it determines the course of the process of irritation within the network of the nervous system. It would Ье а difficult task indeed to attempt an explanation of the phenomena described from the point of view of the movement of the toxin within the central nervous sy~tem, and to define the paths and forces of this movement ! Hence, the process of generalisatioп of tetanus symptoms throughout the central nervo.us system сап Ье independent of the presence of toxin within the reactiпg elements. In that case, what proofs are there that the primary loca] symptoms themselves are necessarily connected with the toxin whir11, Ьу moving along the nerve trunk, reaches the corresponding cells of tl-1e spinal cord and affects them? This conception is based on the well-cstaЬlished fact that tetanus toxin moves along the nerve and penetrates intu the brain-stem. Nevertheless, this fact alone is not sufficie,it. We hav~ seen that absolutely indifferent substa11ces are а1€о сараЫе of entering the nerve trunk and moving along it to the central

SPECIFIC REACTIONS nervous system. There must Ье some additional proofs for attachiлg special significance to this process. Such proofs actually exist. The most important of them are the well known experiments of Meyer and Rзn5om. These authors introduced tetanus toxin subcнtancously into one of the extremities of а rabbit, simultaneously in jecting а small quantity of anti-toxin into the corresponding nerve; in these conditions the tetanus symptoms "'ere either absent or were retarded in comparison with the control. The conclusicн was drawn that tetanus will not result if а barrier is estaЬlished on the path of the movement towards the spinal cord, neutralising only that portion of the toxin which has penetrated into the nerve trunk. W е гepeated the above-described experiments, and fully confirmed them. Ву this time, however, we had already become well acquainted with the sig-nificance of the act of operation itself. ln introduci11g anti-toxin, i.e., а serum, а complcx mixture of foreign proteins, the authors aimed at estaЬlishing а "specific" barrier for the toxin; they did not takc into account that at the same time they subjected the nerve to trauma. Ву so doing, they barred the road to all processes takiлg place along the nerve, and not only to the toxin alone. As а result of the operation, both the morphological and physiological substratum was altered. lt is not surprising that in consequeлce the normal course of the tetanus process is destroyed. As а matter of fact, severing the corresponding лerve, as is well kг.own, quite certainly prevents the development of tetanus. Consequently, we considered it necessary to perform а new series of experiments. From а formal point of view, they were intended to repeat the conditions of the experiment of Meyer and Ransom. But, instead of speciftc serum f or barring the nerve path, we employed normnl semm ( experiments of my collaЬorators V. М. Aristovsky and А. V. Ponomarev 1 ). The observations were made on rabbits. ln various comhinations, in one animal or severa1, with single or douЬle controls, the sciatic nerve was barred Ьу а small quantity of diluted anti-toxin or normal serum. Not only was there no difference iл the res11lt~, but frequently tetanus developed later and w:is less pronounced in these extremities when normal serum formed the barrier than when specific serum was cmployed. In order to settle the question finally, we decided to repeat the experiments in, so to say, а grotesque form, and to bar the path for tetanus toxin Ьу tеtапщ toxin itself. As controls, analogoнs experiments were mad~ with anti-toxin and normal serum. 1

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Тhе toxin used for forming the barrier was diluted several times with physiological solution. The volume and mode of introduc:tion into the ne"e of аП

the

suЬstances

mentioned waa always the aame. Аа was to Ье expected, tJu ctmsepmces of usini wwe 1"6 stmN .s ftW ioU. sw11. In some cases an even more pronounced efi'ect waa oЬtained Ьу using toxin. Consequently, the act itзelf of introducing а foreign suЬstance into the nerve, whatever the nature of the suЬstanc:e, plays а fundamental role in the process under consideration. In another series of experiments, carried out on dogs Ьу my c:ollaЬorator S. I. LeЬedinskaya, the toxin was sometimes injected into the sciatic nerve, at other times jnto the musc.les of the knee. In two cases, this experiment was performed on one and the same animal. Out of six experiments, only once did the process Ьegin simultaneously in the experimental and the control animal. In the remainder, local phenomena were markedly retarded on the side of injection of toxin into the nerve as compared with injection into the muscles. This occurred Ьoth in experiments with different animals and on the same animal. А still greater difference was noted in respect of the time of transition from local to general tetanus and of the duration of the whole disease. After intramuscular injection of toxin, the disease took а more rapid and severe course. It must Ье added that the dose used in Ьoth forms of experiment was almost the same. ln any case, toxin in this quantity is not сараЫе of penetrating into the spaces of the nerve trunk from the peripheral tissues either under laЬoratory or spontaneous conditions. Moreover, а certain amount of it flows Ьасk through the puncture from the portion of the nerve that is swollen after the in jection. Consequendy, the cause of the disease here may Ье not only the toxin inside the nerve trunk, Ьut also that: part of it which enters into contact with the nerve endings inside the tissue. АЬоvе, we reached the conclusion that the presence of toxin within the central nervous system is not indispensaЬle for the generalisation of tetanus symptoms. Now, the same must Ье repeated in regard to local tetanus; in the course of our work, we gradually went further and further from the elements of the centi·al nervous system, until only а few nertJe structures within the tissues remained for us to deal with. W е now concentrated our attention on these. Thus, the question of tetanus was formulated as the question of а specific form of nerve irritation, which arises in the region of the nerve receptors and which is transferred from there to the centre, suЬscquendy Ьecoming manifested in the form of а ready-prepared complex reaction. If this is the case we may expect that Ьу separating the nerve endings

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from the more centrally situated parts of the nervous system, or even Ь, merely making them unexcitaЬle during the time of encounter with the toxin1 we ought to prevent the development of tetanus. The prophylactic value of severing the nerve concerned was known long ago in the pathogenesis of local tetanus. Unfortunately, this form of experiment does not furnish any proof in this case, since at the same time it interrupts the path for the movement of toxin. H6wever, the taslc car1 Ье easily fulfilled Ьу adding an ana:sthetic to the toxin, in particular novocaine. ТЬе cnly drawback was the possibility that novocaine would have а direct effect оп the toxin Ъу neutraliъing it; hence my collaЬorator S. I. LeЬedinskaya Ьegan her experiments Ъу testing this question. Standard doses of the toxin in our possession were estaЬlished and several diff erent mixtures of it with novocaine were prepared. ТЬеу were dialysed at room temperature under conditions which did not allow access of any more water ir1to the prepared mixture. Dialysis was continued until it was impossiЬle to detect evt:n traces of novocaine in the water. F ollowing this, а test was made of the action· of the dialysed toxin on dogs and rabЬits specially selected in pairs, and а comparison made with the same doses of the original preparation. It was found that the toxin had not changed iп the least during its со,._ tact with novocaine. The experimental animals Ьесаmе ill and died more or lcss simultaneously with their controls--sometimes а little earlier, sometimes а little later. W е drew the conclusion that novocaine and tetanus toxin are indifferent to one another and do not enter into any kind of mutual reaction. Then we passed to the basic experiments, also on dogs and rabЬits. One animal of each pair received а suЬcutaneous injection into the knee of а dennite quantity of tetanus toxin, the other-the same dose of toxin mixed with novocaine. The volume of liquid injected was the same in Ъoth cases. Sirice our aim was to study the genesis particularly of local tetanus symptoms, the doses of toxin used were kept within the limits of one MLD or less. The results took the following form. In more than hal.f the cases, tJu 1mimals that were given а mixture of toxin and novocaine did not Ьесоте ill, while all their controls exhibited the full syndrome of local, and often also general, tetanus with the fatal outcome inevitaЬle in such cases. In another part of the experiments, the development of local tetanus symptoms in the experimental group of animals was retarded two or even three times in comparison with the controls. Finally, in а certain number, the difference was inconspicuous, but this occurred either on using an increased dose of toxin or on decreasing the percentage content of novocaine. It is easy to understand the reason why increasing the dose of toxin also results in wiping out the difference between the experiment and the control.

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In studying tetanus under laЬoratory conditions the whole of the required quantity of toxin is injected at once. Within а few minutes, the suЬcutaneous swelling at the place of injection disappears, the toxin Ьeing abюrbed into the drainage system of the organism and passing into the general Ыооd circulation, where, as is well known, its action is consideraЬly weakened. Only а small portion of the toxin remains at the place where it was introduced. If, at this time, the structures subjected to irritation lose their capacity of reacting owing to anresthesia, а further quantity of the toxin will Ье washed away. At the moment whe11 normal nerve conditions are re-estaЬlished, the quantity of to.'!fn оп the spot will Ье less than the minimum necessary, and tеtапщ will поt result. There is по douЬt that it is precisely the threshold dose of the irritating agent that matters here, since not all the tetanus toxin is drained away from the place of introduction. It is easy to convince oneself of this Ьу performing experiments with the same or an even greater percentage of novocaine, but increasing the dose of toxin. In that case, the react.ioп of the experimental animals will only Ье retarded, and even retardation will not always occur. Tetanus toxin is а colloid and is taken up Ъу the local tissue elements more energetically than crystalline substances. The larger the dose introduced, the larger will Ье the remainder. After а short period, the novocaine will Ье washed away and the phenomena of anresthesia will pass off, but the quantity of toxin remaining at the point of introd.uction will Ье sufficient to produce irritation and call forth the corresponding reaction. In а series of further experiments, we replaced novocaine Ъу other anresthetics--cocaine and quinine. The results obtained were fundamentally similar to those already described. One further question remains to Ье examined, viz., whether the addition of novocaine does not prevent the penetratiort of tetanus toxin into the nerve, and whether, perhaps, it may not Ье possiЬle to explain in this way the retardation and even .prevention of tetanus symptoms. This supposition was tested and not confirmed. We introduced а mixture of toxin with 5 per cent solution of novocaine into the leg muscles of а dog or rabbit and killed the animals after variouз periods. An emulsion was prepared from pieces of the corresponding sciatic nerve, taken at various levels, and introduced suЬcutaneously into white mice. AU the mice developed tetanus. Consequently, the toxin did not lose its capacity of entering the nerve and moving along it, owing to the addition of an anresthetic. Since, in spite of this, the disease is averted Ьу anresthetics, it is clear that it does not owe itr origin to that part of the toxin which penetrates into the nerue trunk.

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The logical conclusion is that tetanus toxin does Jfread al.ong the nerve trunk, but that this spreading does not play апу essential role iп the pathogenesis of either local or general tetanus. The complex reaction which we know under the name of tetanus is produced as soon as the toxin encounters the peripheral. nerue endings. It has its cycle of development, which is constant for the given animal, where each succeeding link is determined Ьу the preceding one, and where variations depend on physiological differences in thr nerve structures which ~·ere the starting points of t1'e process. It does not follow from this that the penetration of toxin along the nerve into the central nervous system is to Ье considered as an entirely indifferent action. W е are very well aware how easy it is to produce tetanus Ьу subarachnoid injection of the toкin. But it is а fact that there are а sufficient number of receptor !1erve-endings in the submembranous spaces of the spinal cord and brain, сараЬlе of beginning the reaction under the influence of irritation. Direct rntat;t;n of the nerve cells Ьу the toxin penetrating into them is not at all indispensaЬle iп this cnse. Consequently, the cause of tetanus is tetanus toxin. But this does not mean that the tetanus toxin is directly responsiЬle for all the tetanus phenomenз from Ьeginning to end. This explains, at lзst, а strange fact which has long been а fundamental perplexity in the pathogenesis of tetanus. The iact is this: we have at our disposal very few sera whose specific properties cannot Ье doubted. Among these, two are pre-eminent-anti-diphtheria serum and anti-tetanus serum. Ву various technical devices, the concentration of anti-bodies in them has now been raised to а high figшe. Nevcrtheless, anti-tetanus serum does not exert апу curative ef!ect. Its ernployrnent is of great significance, but only iп prophylaxis, i.c., in conditions which are in no way different from reactions ir. vitro; the specific scrum simply neutralises thc toxin, converting the irritating agent into an indifferent substance. Thereby the very possibility of irritation is prevented. Even if, in the human clinic, it is possiЬle to note from time to time а useful effect from subarachnoid injections, th~re always remains а doubt as to what precisely is the cause--whcthcr the specific .properties of the serum or the act of operation. Under laboratory conditions, however, when the disease fo\1ows the introduction of а definite dose of toxin, the appearance of the first local symptoms of tetanus is, as а rule, а sign of inevitaЬle death, whatever the amount of serum afterwards in jected, and whatever the nianner of its introduction. In exp~rimcnts with "pumping" also, we did not obtain any positive effect.

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An inte1·esting series of clinical oЬservations were made Ьу us some time ago in connection with five cases of pronounced spontaneous tetanus in human Ьeings. Intra-lumbar injection of serum was made after preliminary extrac· tion of the maximum quantity of cerebro-spinal fluid. The withdrawal of the iiuid was carried out gradually, the amount withdrawn Ьeing from -4-О to I 10 с.с. The operation was repeated every 1-2 days until the appearance of marked signs of improvement (3-5 times in all). At the same time the serum was introduced into the Ыооd. /п all these cases, the tetanus symptoms gradually duatpeared. In а sixth case, in which cerebro-spinal fiuid was not obtained on puncture (punctio sicca) and the serum was introduced without preliminary emptying of the membranous sac, we did not obtain any effect and the patient succumЬed. Later, these experiments were repeated with success in the clinic of Professor У. У. Janelidze. This seemed quite all right at first; but certain oЬservations made Ьу us in the course of these experiments shook our confidence: in many cases the tetanus symptoms, after Ьecoming weaker some hours after introduction of the serum, were later renewed with the same intensity as Ьefore, suЬsiding again after а second operation. It is impossiЬle to explain this if one starts out from the idea of а reaction Ьetween specific anti-bodies. If the weakening in the intensity of the tetanus was connected with the neutralisation of the toxin, where could the new portion of the latter соте from to produce а renewal of the process? The amount of serum used Ьу us so much excecded the maximum possiЬle content of toxin in the organism, that even if we had introduced an enormous add).. tional dose of toxin, it would not ha ve made itself manifest. U nder the conditions of our action, the anti-toxin was present in excess in both the Ьlood and the brain. This, however, did not prevent the renewal of the process in its original dimensions. lt is clear that the anti-toxin played по part here. The reaction was merely а response to the operational interference, to an extraor counter-irritation. This altered the conditions within the nerve network and created for а time being а new nerve battlefield which hindered the development of the process p1·eviously existing. Lack of faith in tl1e curative properties of anti-tetanus serum has already caused the clinic to return to the methods of symptomatic treatment. Thus, we see again employment of narcosis, which at any rate guarantees the patient а temporary alleviation of suff ering; trial is made of magnesium, intra-lumЬar injections of novocaine and even of solutions of carЬolic acid (Synn Suvansa). It was found that novocaine and carbolic acid have an undoubted curativeeffect. True, this effect is not present in all cases; it is, nevertheless, consillerohly m~re constant than that of specific anti-toxin. Of course, the specifk

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anti-toxin, introduced subarachnoidally, can neutralisc the toxin that has made its way along the nerve trunk from the place of its formation. In this way, the intensity of the additional irritation may Ье, and will Ье, somewhat decreased. However, this does not abolish those tetanus symptoms which have already developed. The sole conclusion to Ье drawn is that serum treatment of tetanus not Jfeciftc since the cause of the di1ease changes with the developnent of the process. On the other hand, infiuences which thc clinic puts in the ~tegory of symptomatic irUlucnces now acquire the right to Ье termed causal. Serum does not exhiЬit any curative action in tetanus Ьecause the process, even during the period of incubation, loses those properties which immunology includes in the sphere of specific reactions. The proЬlcm of the absence of curative properties in the serum is not the sole perplcxity in thc pathogenesis of tetanus. Indeed, such perplexities are rathcr numerous, but I do not consider it necessary to enumerate them all in view of the fact that it is not our task to study tetanus as а special pathological form. I shall only mention certain features which may Ье of use in elucidating questions with which we are more directly concerned. А strange and unexplained fact is the exceptional sensitivenesr of horses to tetanus toxin. It is not only relatively but even absolutely greater than that of the guinea-pig, although the latter is itself accounted one of the most sensitive animals. No assistance can Ье obtained here from consideration of weight relations. This is another proof that tetanus cannot Ье explained as the pure result of the direct contact of each of the reacting elements with the toxin, since if it were so, the effect should depend on weight relations of toxin and substratum. Only the conception of this p1·ocess as а specific and complex form of nerve reaction, where the thresl1old of irritation is detcrmined Ьу the sensitivity of the reacting substratum, is сараЫе of introducing the necessary clarity. Another fact, too, becomes comprehe n si Ыe, one which has Ьеел noted in the clinic more than once and which is evidence that operating tetanus patients is useless: in those c:ises where the indubitaЬle source of the whole proce~s is removed ( e.g., Ьу amputation), the tetanнs symptoms not only do not subside Ьиt are often sharply intensified. If the toxin, after penetrating into the central nervous system through the spaces in the nerve trunk, also participates in the development of the process, it is only as an auxiliary factor; we may, of course, take this factor into account, but in practice it is useless to do so, since the process is not brought to а standstill even when the toxin is removed from the nerve cells. In one of the earlier chaptcrs of this book, devoted to the role of the cerebro-spinal

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fluid in the pathogenesis of tetanus, I brought forward data testifying to the consideraЫe retardation in the development of thc pathological proce$ in animals from which the cerebro-spinal fluid had been periodically extracted. In our description there, we linked it up with questions of circulation, with the fact that removal of the fluid creates а mechanical oЬstacle to the spreading of the toxin. These experimental results сап now Ье gwen another interpretation as well. The extraction of large quantities of cerebro-spinal fluid must Ье regarded also as а direct action on the nervous system, initiating а chain of additional irritations. This results in а temporary alteration of the mutual relations of the various parts of the nervous system. N ow when the state of the nert1ous system is changed, the process sertling as ап indicator wi/J olso develop iп а new way. Here, not for the first time, we encounter а contradiction. Additional irritation in some cases intensifies the existing process, in other cases it weakens or even extinguishes it. However, strange as this fact may appear, it is undeniaЬle; consequently, the only thing to do is to recogni!>e it. The cause lies in thc fact that the suhstratum acted on is the nervous system, all elements of which are connected with one another in labile comЬinations. Only if the irritation arising in this network is weak is it extinguished without spreading far. Unusual forms of irritation, such as pathology has to deal with, spread over consideraЬle nerve areas and produce а temporary transformation of intra-nerve relations far beyond the limits of immediate contact witl1 the irritating agent. The response to irritation is here always complex, t!1e reaction always proceeds not along опе pnth but along several different paths and is thercfore manifested iп various forms and degrees. Depending on the individual conformation of the given nervous network, the strength of the irritation, the time and а number of other factors, one part or another of the reaction acquires preponderant importance and, oЬscuring the other parts, determines the external form of the process. Hence, difference in response is not due to the reaction proceeding from tl1e very beginning in di.fferent and even opposite directions. The degree ~f irritation plays а large part here. As а result of our oЬserva­ tions, we found that the greater it is, the more rapid is its effect in intensifying the process already existing, or which previously existed and hаз still not disappeared. 1 have in my possession the results of а series of experiments which may serve as partial evidence that the toxin, on penetrating into the region of the central nervous system, does not remain indifferent ( experiments of my collaЬorator А. V. Ponomarev 1 ). А.

V. Ponomarev. Arkh. Biol. Nauk, Vol. 28, No. 1, 1928.

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Equal doses of tetanus toxin were introduced at the same time into the muscles of the left leg in two dogs of like weight and growth. Afterwards one of theш was placed in а cell with а low ceiling and for the most part remained there lying down. The other, immediately after the injection of toxin, was harnessed to а cart loaded with stones, which it drew for 2-3 hours. In some of the experiments, we made the dog draw the load again after an interval of 12-15 hours. The result showed that local tetanus developed earlier in the dog that had drawn the cart than iп the control. The differencc was consideraЬle. It often reached 20-26 hours. It is true that even in specially selected animals the time of appearance of the first symptoms does not always coincide. In the above-described experiments, however, it was shown in all cases, and the chief thing is that it proved to Ье proportional to the period during which the dog had been working. А further interesting phcnomenon was noted in these experiments. In the dog which had drawn the cart, general tetanus developed simultaneous1y with or immediately after the local symptoms. Trism, rigor of the vertebral column, etc., appcared almost immediatcly after the exhibition of the first local symptoms. We had cases where at the moment when the control animal Ъесаmе ill, the experimental dog had already perished or was on the point of death. Experiments, described in arюthtr chapter of this Ьооk, have demonstrated that muscular wvrk promotes an accelerated movement of the lymph (and of substances included in it) along the nerve trunk. It would seem th~t the immediate appearance of symptoms of general tetanus in our do~ is to Ье connected with this fact. But here again а doubt arisc:;. W ork performed Ьу the muscles in the region of the nerve segment irritated Ьу the toxin is also supplementary work for tl1e corresponding nerve elements, and we know now the ГС11е of additional irritation in the pathogenesis of tetanus. In any case, this question is only of academic interest. Whether the toxin penctrates into the region of the central nervous system or not, the basic features of the process are not altered. Before the contemporary view of the pathogenesis of tetanus obtained confirmation and general recognition, there were iso1ated expressions of opinion shifting the ce::ntre of gravity of the process to the nerve periphery (Go1dscheider, 1894; Courmont and Doyon, 1899). Few now even remember the existencc of these views, which were crushed under the weight of the so-called "ocular" proofs provided Ьу the new theory. The latter, as we have just seen, has also not been cqual to the demands made on it, and we have returned to the starting point. Of course, this position cannot satisfy us either, since it takes into account 011ly the reflex mechanism of origin of loca1 tetanus and is quite po~·erless to solve the proЬlem of the generalisation of

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tetanus symptoms. The objections raised Ьу Ransom and Meyer ( 1903) were along this line. The authors pointed out that apart from the electric current, contemporary science does not know any means which, originating from one point, could alter the excitability of the whole nerve arc. They regarded this as an additional oЬstacle for recognising "dynamic spreading" through the nervous system of changes produced at the periphery. Such recognition, they said, would mean "coming into contradiction with а11 contemporary experiments.»t Paraphrasing the words of Hegel, we could reply here: "So much the worse for the experiments." Facts, and especially facts taken from the Ьiolog­ ical sphere, do not always have an independent significance outside the system c:reated Ьу them. Transference of the material from one system into another, with the aim of testing the latter, is only possiЬle provided the material has an objective value confirmed in а11 directions. However, in the vast majority of cases each of our facts is only а fragment of а phenomenon. ТЬе reference of various writers to the aЬsence of appropriate data in contemporary science has not signified the actual aЬsence of such data in nature, as indeed is proved Ьу this Ьооk. W е have adduced а sufficiently large amount of varied material putting beyond question precisely the "dynamic spreading" of irritation from the region of the terminal nerve apparatus at the periphery to the whole complex nerve network. With this I shall bring to а close the examination of material dealing with tetanus as а special pathological form. Our work has pursued а different aim. Even in the very Ьeginning of this chapter, in elucidating the role of the nervous component in the origin of tar neoplasms in rabЬits, I formulated two preliminary propositions: 1. The specitic quality of an irritating agent is its capacity to evoke an unusual form of nerve irritation, bringing definite nerve mechanisms into ac:tion. This is expressed at the periphery Ьу а number of functional and structural disturbances, developing successively according to а constant plan. 2. The nervous system has the property, during а certain period of time, which is sometimes quite long, of preserving traces of such irritation witho•tt any alteration of the characteristic features of the latter. We are now аЫе to confirm both these propositions. The speciftc qua/.ity of tetanus toxin is its capacity to evoke а characteristic and constant f orm of complex nerve reaction merely through irritation of the penphera/. пеМJе 11pparatus. 1 It is ltrange that they forgot here the well-known experiment of Tiirck on tbe atimulation Ьу acid of а paw of а decapitated frog, аа а reault of wЬiсЬ а very complex and completely co-ordinated reaction ia obtained, coll8iating of а numЬer of linka.

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Passing to an estimate of the nature of this irritation, we must mention the following points. 1. It cannot Ье referred to one of the known categories, such as tactile, nocuous, thermal, etc. 2. lts characteristic incubational period has а duration which is not met with among other, more or less simple, nerve reactions. 3. Arising at one point and progressively intensifying, the process involves а numЬer of parts of the nervous system in а definite sequence, putting them in а state in which life is impossiЬle. 4. The usual and constant form of this process can Ье altered only in part and only in the first stages, for instance, Ьу the transference of the point of primary irritation from one nerve region to another. 5. Removal of the irritating agent is аЫе to hold up the generalisation of the irritation only at the very beginning. If the process has reached а certain stage-removal of the irritating agent cannot arrest it. 6. Disappearance of the external symptoms of the process is not always evidence of its complete liquidation. Traces of the former special irritation remain in the nervous system for some time. In many cases, if а new action, even an ordinary trauma, is brought to Ьеаr on the nervous system, it can restore the process in its typical form. Еvеп а hasty glance at tl1ese six poiпts enaЬles опе to recognise that they embody all the characteristic f eatures of thnt other group of processes, already aescribed тапу times iп the pages о/ this book. Н owever specific tetaпus та1 seem iп regard to тапу oj its characters, it ht1s а very close resemblance to what we have grouped tog-f!ther under the пате nervous dystrophy.

This difference is that the non-specific influences giving rise to nervous dystrophy can Ье of very diverse nature. The variations here are connected only with the degree of irritation and with the place where the process starts. It was this fact which gave us the very idea of the existence of standard fnrms of nervous dystrophy. lt must not Ье forgotten, however, that this idea is а relative опе. If it was possiЬle to produce tetanus, not only Ьу tetanus toxin, but Ьу а whole series of other substances and methods, we would also include tetanus in the group of standard reactions. Тhе only thing that really appears specific is the course of the process in those cases where the illness, beginning with local symptoms, passes through а sequence of stages. Human beings and horses usually begin at олсе with the symptorns of general tetanus. ln this form, the process сап easily Ье reproduced artificially Ьу employing various inflнences; thi~ has repeatedly Ьееn demonstrated in the first part of this Ьооk, devoted to the study of convulsive states. Hence, а specific reaction is also а group reaction; only the numЬer of

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externзl i11fluences .knov.rn to Ье сараЫе of producing it is comparativcly very small. The same holds for diphtheria also. Nobody will doubt, I think, that diphtheria is а spccific process. Now, why exactly do we call it specific? Two aspects of the matter .must Ье distinguished here: the first is the extcrnal manifestation of the process; the second is the immuno-Ьiological reactions. А description was given above of the experiments of my collaborators Nikitin and Ponomarev,1 who studied the effect of introducing diphtheria toxin into the central nervous system of guinea-pigs. The animals had previously been given intravenous injections of enormous doses of specific antitoxin. This did not save them from death, which usually occurred during the first twenty-four hours. On dissection, characteristic changes of the suprarenal glands and cardiac ganglia were discovered in these animals, although under the conditWns indicated not а single molecule of to:~in could have reached either the supraren4t glands or 1he heart. It is clear that these changes under ordinary circumstances also do not depend on contact between the toxin and the elements of the organs themselves, and that the producing agent consists in processes of а nervous nature. Nevertheless, the aЬove-men­ tioned changes in the cardi.ic ganglia, and especially in the suprarenals, are regarded as typical precisely of diphtheria. In another investigation, also previously mentioned, of my collaЬorator G. F. Ivanov,' who studied the morphological consequence of stimulating the region of the tuber cinereum in dogs Ьу means of the "glass sphere operarion,'' it was noticed that in all cases where there was а violent development о{ dystrophic changes in the tissues, and the animals perished within the first 2-3 days, there were severe changes of the suprarenals, with pronounced lipoidosis. The cells of the cortical layer were almost entirely filled with fat, to the same, or an eve11 much greater, degree than occurs in diphtheria. The following is another series of experiments carried out Ьу ту collaborator I. А. Pigalev.3 The question that was being tested was whether the mechanism of the origin of the diphtheria deposit is related to the mechanism which determines the development of local symptoms in tetanus. It was possiЬle to suspect something of the sort, since we have seen, for instance, that sore throat in scarlatina was а process of а nervous nature, being the reflection of the nervous process in the peripheral tissues. 1 N. N . Nikitin and А. V. Ponomarev. Arkh. Biol. Nauk, Vol. 30, No. 1, 19301 Zeitschr. /. J.. ges. ехр. MeJ" Vol. 70, No. 3-4, 1930. t G. F. Ivanov. Zeitschr. f. d. ges. ехр. Med., Vol. 74, Nos. 5, 6, 1930. 1 I. А. Pig:ilev. Arkh. Biol. Nauk, Vol. 27, No. 4-5, 19:1.7; Zeitschr. f. J.. ges. 1хр. MeJ.., Vol. 6з, Nos. 5, 6, 19:1.8.

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Gibier obtained "diphtherial" inflammation of the tissues in rabbits Ьу introducing the toxin into the rectum Ьу means of а tampon or an enema. This form was inconvenient for our purpose in view of the relative difficulty of operating оп the nerve connections of the rectum. Consequently, we performed our experiments on the ear. ln two rabbits, an artificial ulcer was produced on the back of the ear in its distal half. For this i urpose, an area of about 3-4 sq. cm. of the skin was prepared and cut away. It is necessary to Ье very careful in separating the skin from the underlying tissues since the layer Ьetween the skin and the cartilage is very thin. SuЬsequently ( or previously) in one of the rabbits, the п.п. auricularis, occipitalis and facialis are severed outside the region of the ear-by а single cut in the neck. The vessels and their nervous system are left untouched. In the second rabbit, which served as а control, the nerves were not severed. А tampon, periodically moistened with diphtheria toxin during 24 hours, was sewn on the ulcer thus produced. lt was found that usually in less than 24 hours а whitish, strongly adhering deposit appears on the ear of the normal rabЬits. The Ьottom and tdges of the lesion develop а dirty "greasy" appearance. On rtmoving the gauze of the bandage, the deposit is partially torn away from the surface of the lesion, ас; а result of which slight Ьleeding occurs at these places. On the second day, the above-descnЪed phenomena are intensified. On the third and fourth days, if the rabЬit has not died, heavy suppuration takes place owing to orJinary dirt contamination and this interferes with further comparison. In more than half of the rabbits in which the nerves were severed the wound iп the ear retained its fresh appearance for 24-48 hours, but then also dtveloped suppuration. In some cases, the difference was not pronounced. lt is interesting to note, that to obtain а marked difference it is necessary to sever the nerves ,;юrtl~ ь~forc the application of toxin to the wound. With а Jonger period hetween the two operations, the difference in the effect is gradually effaced. I have already more than once cited facts of this nature and given their explanation in descriЬing other observations of а similar kind. Thus, one and the same preparation of diphtheria toxin had а varying ~ffl"rt оп the tissues, depending оп the integrity or alteration of the nl'rtJe cnnditions iп the corresponding regioti. We see here an undoubted resemЬlance tn tet:inus. The resemЬlance goes further. Thus, rahЬits in which diphtheria toxin had been applied to the denervated wound surface outlived their controls :\!;а rule hy what is for diphtheria а very consideraЫe period-up to 3-5 days. As far as diphtheria in m;in is concerned, here also the ~ndrome in itself doe!I not denoti: anything definite, much Jess rategorical. The final decision

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of the question depends entirely on the bacteriological analysis. А negativ1 answer transfers the di.sease to the group of ordinary processes, iп s-pite of the рrпепсе iп

the throat of deposits characteri.stic of diphtheria.

lt follows from а11 this that in diphtheria also we have no firm grounds for regarding local manifestations of the disease as the result of direct contact of the toxin with each of the elements that have suffered. On the contrary, there is every reason to think that the majority of these manifestations owe their origin to the changes which the toxin evokes within the network of the nervous system. The latter, too, does not change diffusely but in а more or less definite sequence, and this is the reason for the constancy of the order in which the external symptoms of the disease develop. ln this case again, however, the constancy cannot Ье treated as а specificity, since here also the reaction has а group character. W е have, therefore, decided the first question, that of the nature of the external manifestations of the process in diphtheria. The second question concerns the immuno-biologkal reactions in this

clisease. Let us Ьegin with the fact that anti-diphtheria serum exhiblts its properties Ьoth iп vitro and iп vivo. Moreover, it has not only а prophyltuti& but al.so а curative effect, Ьу which it would seem to Ье favouraЬly distinguished from anti-tetanus serum. However, is this distinction actually so very great? Let us take experiments on animals. As was shown аЬоvе (Ponomarev's experiments1 ), it is easy to choose such relations of diphtheria toxin and anti-toxin that the latter does not save the rabЬit in spite of the fact that it is injected only 45 minutes later and in а dose more than а hundred times exceeding that required for neutralising the dose of toxin. When we accompanied this Ьу "pumping," i.e., when we created conditions .for the penetration of the anti-toxin into the region of the central nenJous system, the rabЬits usually survived. lt sufficed, however, to

increase the interval between the in jection of toxin and anti-toxin Ьу а few do:zen minutes for "pumping" to lose its useful effect, so that the animals died. Three years ago we again repeated these experiments, but we varied the time-intervals within much wider limits ( experiments of my collaЬorator N. N. Nikitin). The rabЬits were divided into two groups. The toxin was injected intravenously in а dose of aЬout one MLD, since we were interested in securing the longest possiЬle duration of the process. ln the first group, anti-toxin was 1

А.

V. Ponomarev. Af'kh. /Jiol. Nauk, Vol. 28, No. 4, 1928; Zeitsch". f. а. ges. e:it. Сотрt. R1t1J. Soc. Je Bio 1., Vol. 97, 1927.

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introduced into the blood after I о hours, in the second group after 30-40 hours, all the animals suЬsequently undergoing "pumping." The result fr011ed to Ье the otposite о/ that obsenJed Poпomar.Vs experiments. The duration of life was greater in the rabЬits subjected to "pumping" after а longer interval. The procedure which in Ponomarev's experiments was the indispensaЬle condition for preservation or prolongation of life поw accelerated death. The penetration of the anti-toxin into the region of the central nervous system, whether after 10 or after 40 hours, was Ьelated in Ьoth cases. But the fact that in the second group the familiar trauma caused Ьу "pumping" was considerably delayed gave the rabЬit 1-3 extra days of life. These traumatic consequences of the operarion in Ponomarev's expcriments were entirely concealed Ьу the neutralisation of the toxin within the central nervous system. The trauma was the lesser evil. ln Nikitin's experiments, the neutralisation of the toxin was already unnecessary, and therefore the efject of the oteration proved to Ье due merely to traum11. But the usefulness of the act of "pumping'' itself depended on creating in the ne"ous system conditions сараЫе of hampering the course of the basic pathological process. ln the case considered the result was diff erent; as in many other experiments descriЬed in this Ьооk, the new trauma intensified the pathological process already existing in the · 11ervous system. In the human clinic, we see eS11enrially the same thing. In the first place, 1s it not strange that up to now по ftrm tJiew has Ьееп taken of the serum 01 п reaUy specific agent iп the treatment of diphtheria. Е. FriedЬerger, in one of his articles has collected а consideraЬle numЬer of contradictions of various sorts relating to this subject. Analysing the statistics of mortality from diphtheria, he points·out, for instance, that in the epidemic of 1885-88 in \Vest Prussia, mortality from diphtheria fell to one-third as compared with previou'> years, in spite of the aЬsence of serum treatment, while in 1926-2 7 it increased greatly in spite of widespread application of concentrated sera in large doses. The author also cites Bingel's statistics dealing with 937 cases of diphtheria oЬserved Ьу him in the epidemic of 1913-16, in which anti-diphtheгia and normal serum was employed in an equal degree. The statistics of mortality in Ьoth groups were alike. FriedЬel'ger does not connect the rise and fall of mortality from diphtheria with the general adoption of specific prophylaxis and therapy, explaining them Ьу other laws governing the epidl'mics; nor does he consider it proved that the complex of injurious infiuences in diphtheria infection can Ье identified with diphtheria toxin. Other authors (Cruveiller, Roux, Kraus, etc.) point out that there is no parallelism between the anti-toxin content and the curative

m

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effect of the serum. Gottstein asserts that the theory that immunity to spontaneous diphtheria infection is assured Ьу the presence of anti-toxin in the Ыооd is "an inspiring but still unproved hypothesis" ( cited Ьу Friedberger). Finally, everyone is acquainted with cases of relapse of diphtheria witl1in а short period ajter recovery. Without any more ado, they are regarded simply as cases of reinfection. lf we set aside the facts and conclusions mentioned аЬоvе, and take only those propositions which enjoy general recognition, it will Ье found that in the human clinic the basic criterion oj the curative action of anti-diphtheria serum lies, not iп the quantity of specific anti-bodies, but iп the time fa(tor. Statistics show that the curative effect decreases in proportion to the delay of the moment of injection of the serum. In this matter, therefore, the data of the laЬoratory and the clinic coincide. The curative action of anti-diphtheria serum, exactly as in the case of anti-tetanus serum, must Ье judged throug/1 the prism of time. We may, of course, adhere to the old meaning of the term "specificity," applying it to properties inherent in а given irritating agent. ln that r.ase, however, the process Ьegun Ьу the specific agent will have а right to Ье termed specific only as long as specific anti-bodies are сараЫе of abolishing it. As soon as this neutralisation loses its influence on the course of the process, the latter must Ье included in the category of non-specific processes. However, this cannot Ье done for the reason that even when it has lost its connection with the irritating agent, the process still retains the characteristic features of its development. Consequently, the concept "specificity," тщt Ье define_d along other lines. An analysis of the data obtained during the study of tetanus enaЬled me t() formulate my point of view on this subject. But the pathogenic kinship Ьetween tetanus and diphtheria is obvious. The diff erence depends on the nerve structures which, Ьecause of their sensitivity, are the first to enter into comЬination wth the toxin and thus Ьegin the process. It is well known that, to produce an effect, it is advantageous to inject letanus toxin into tissues ( ceUular tissue, muscles) rather than into the Ыооd, whi/,e with diphtheria toxin the rwerse is the case. At the same time, our experiments with "pumping" showed that, under certain conditions, if the anti-toxin reaches the region of the central nervous system, it ensures the recovery of animals which otherwise are bound to die. It is clear from this that iп expenmental diphtheria the receptors of the special form of irritatioм are to Ье found someu.•here iп the spinal cord or Ьrain. Other nerve mechanisms, not the same as in tetanus, Ьесоmе involved in the pathological process. Whatever the difference in details Ьetween spontaneous human diphtheria

SPECIFIC REACTIONS and the process artificially evoked Ьу the toxin, it does not play any part in deciding the question from the point of view of principle. Diphtheria in man can also Ье divided easily into two periods. They are Ьoth connected with processes of а nervous nature. At the outset, the toxin is the irritating agent. It produces pathological changes in the nervous system, which in the first period have а functional character. This indicates that the pathological process is maintained only from the focus where the nerve elements are directly irritated Ьу the toxin, Ьиt the latter has not yet managed to inftict irreparaЫe damage оп them. The removal of the irritating agent is here removal of the irritation and specific serum will certainly give а positive effect. The second period Ьegins with а change in the causes of the process, i.e., from the moment when the damaged nen;e elements themselves Ьесоте the source of irritation. The time of the transition of diphtheria from one period to the other must not Ье calculated in а formal fashion. Both individual peculiarities and epidemiological factors, in the broad socio-biological interpretation of the word, can shorten or lengthen it. It is highly probaЬle that in many cases the second period begins almost simultaneously with the first, which explains failures in specific treatment, even though applied in good time and in heroic doses. From the beginning of the second period, the course of the diphtheria process depends on the degree of in jury infiicted on the nerve elements. Recovery is possiЬle even here. The process gradually decreases, as we repeatedly observed in other forms of nervous dystrophy descriЬed above. lt сап also suffer а relapse, i.e., suddenly repeat the entire syndrome of disease which had соте to ап end not so long before, thereby giving rise to various perplexities and queries as to the cause of re-infection. Finally, it may take а gradually progressing course and kill the animal within а shorter or longer period. Apparently, thC' nerve apparatus of the heart as а r11le becomes involved during the development of this process within the nerve network, and consequently death ensues Ьefore the process itself passes into one of the standard forms of gen.eralised dystrophy. However, in our animals which perished at later periods, after 20-30 days from in jection of the toxin, it was always possiЬle to oЬserve some of the signs characte'ristic of extensive dystrophyemaciation, loss of hair, infiammatory changes of the mucous inembrane of the mouth and nose, hzmorrhages in internal organs, etc. The production of large-scale derangements Ьу minimal doses of toxin has always seemed puzzling. А special theory was even created to explain it, in whicl1 toxins were included among the enzymes. Whether it is correct or not,

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THEORY OF MEDICINE the fact remains that this theory is not мcessary f or uШrstмuUnt the tro-

cesses m а сот;lех orgaпism. ln concluding this chapter, I wish to reiterate that the employment of вerum in the second period of diphtheria is useless. Here we are confronted Ьу the same phenomenon as in tetanus, since the prophylactic action of specific sera сап Ье separated from the curative action only on the basis of practical considerations. There is по differme1 m frincipU between these two со,.. c'ptions; the characteristic symptoms of disease are already oЬservaЫe in the first period of diphtheria, while the same period in tetanus proceeds without e:xternal symptoms. If in the future some characteristic is found Ьу which the diagnosis of tetanus сап Ье accelerated, even if Ьу only а few hours, there is по doubt that we shaU соте to recognise curatwe froperties a/.so the case о/ anti-tetanus serum. The view put forward Ьу us is new not only in а formal sense, but in essence, since it u not explicaЫe from tм dllU which physЮlogy luzs at its duposal. Nevertheless, 1 consider it necessary to adhere to this view. Essentially, therc is only one oЬstacle to itз recognition-the present stattJ of the question ret•tl.ing the qulllity of excitation. The opinion held Ьу the majority is that the statc of excitation conducted. along the nerve in either direction is always alike, that it does not Ьеаr any individual marks. Wh.at we have oЬscrved in the experiments with tetanus toxin raises very acute douЬts in this reapect. Тhere is no cloubt that here some special kind of irritation was passed on to the centre, serving as the originator of а complcx reaction with а definite cycle of deyelopment. lt was estaЫished that the character of this reaction is deterтffud at tM mom.mt when IM toxm CtmNS WIO C01JUra wit/J tM pmpheraJ tun1e aptaratus. The participation of other nerтe parts is conditioned Ьу this process. Consequently, even from the very Ьeginning some s-p6cial or, figurмtf.vely speaking, ''tetd all sorts of inoculations, and Ьесоmе quite clear as to the reality of their harmlessness; otherwise, the so-called "achievements of science" та'' 6asiJ.y Ье coпverted into опе of the methods of cntpling humanity. This question Ьecomes especially acute owing to the fact that the existing methods of active immunisation of human ЬeЦigs are not unanimously accepted. In this .field, Wt' have more hopes than achievements. Even the interpretation itself of the results of mass inoculations is strangely contradictory and ambiguous. One frequently reads or hears that even if active immunisation does not lower the percentage of cases of diseзse among those inoculated, still it alleviates the form and course of the process. Supposing this to Ье true, where does specific immunity come in? The form of the given pathologiclll P'ocess тоу Ье light or severe, Ьиt, опсе it has begun, tms means there is по immunity. U nder spontaneous conditions of infection, let us say of scarlatina, the organism cannot all at once come under the infiuence of а quantity of virus which neutralises the whole amount of anti-Ьodies present; therefore, the animal cannot Ьесоmе ill. If all the anti-Ьodies were neutralised the organism would lose its immunity, and the alleviation of the form of the pathological process would Ьесоmе incomprehensiЫe. The abdominal typhus clinic, more often than any other, is confronted with relapses beginnint almost immediately after recovery; iп these relapses, the syndrome repeats the whou cycle of the disease ;ust ter,,,Unated. If the recovery was due solely to the development of speci.fic immunity ( as is genera11y accepted), then why such а suddcn loss of this immunity? Two years ago, one of my friends, Professor В., developed abdominal typhus in the classical form which is now comparatively rarely 1net with. From the third week onwards, the Ьladder had to Ье emptied daily Ьу а catheter. Even when the temperature had returned to normal and other symptoms had disappeared this operation had to Ье continued. As а result, the patient developed а slight cystitis, following which the typhus syndrome reappeared in the previous classical form and again lasted exactly three weeks. Тhe disease reproduced iп the most precise f ashion the whou course of the process that had only iust соте to ап end. 1 shall refrain from any categorical judgment as to the causes of the aЬove-descriЬed relapse, but 1 cannot avoid the suspicion that it was caused Ьу the second "Ыоw', to the nervous system, in which the process taking place

GENERAL REVIEW had not yet Ьееn fully extinguished. Careful study of analogous cases, which are not rare in the typhus clinic, would, of course, make it possiЪle to obtain а more exact idea in regard to this subject. At the present moment, however, we are interested in а different matter. If, even in the exceptional conditions of immunisation created Ьу overcoming the disease, there is no guarantee against immediate heavy relapses, then it is clear that the severity of the process is not connected with so-called immunity reactions, and that the effect of moculations mentioned abof)e dces 1fOt depend оп specific anti-bodies alone. The repeated action of the specific agent in small doses trains the nervous system in increasing its resistance to the given form of irritation and perhaps also to а numЬer of other irritations of а similar kind. Simultancously, however, another neuro-dystrophic process can arise and we can never say in advance whether it will disappear without leaving any tracc. Statistics show apparently that Ьу active immunisation to aЬdominal typhus, we actually neutralise this irritating agent, rcndering it indifferent. The subject does not develop typhus, or overcomes it easily. But this effect cannot Ье called aЬsolutely positive if it is obtained Ьу а procedure which creates а focus of pathological excitation сараЫе later of acting as the source of another tathological -process. If this is the case, we must estimate the application of specific antigens for the purpose of obtaining spccific immunity as ап inetlitable Ьиt temporary working stage. In the prophylaxis of infection, our task is to ensure such а state of the macro-organism that at the moment of its encounter with the micro-organism the nervous system should not Ье involved in the process, and hoth ordinary and speciftc irritation should profJe too weak to woke the duease. Up to the present, this goal was attained Ьу decreasing the strength of the irritating agent; bu.t the same task may Ье achieved in another way: increasing the resistive capacity of the macro-organism Ьу training its nervous system ought to give the sarne effect to an even much grcater extent. Hence it Ьecomes the task of the invcstigator to estaЬlish the concrete conditions in which this training is not accompanied Ьу harm in other respects. Тhis chapter cannot Ье concluded without mentioning incubation. This question has Ьееn raised more than once in this Ьооk, and it remains for me merely to summarise the results. The incubational or latent period of а process is а widespread Ьiological phenomenon, but in the theory of infection and immunity it attracts special attention. Up to now many regard it as а period of "concealed struggle" Ьetwcen the micro-organism on the one hand, and the macro-organism on the other. This point of view is unsatisfactory, for it groes по answer to the guestioff

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as to the form of tl1e mutual relations of micro-organism and macro-organism during incubation. The whole conception is а verbal echo of well-known, biological ideas arising from the theory of evolution •. There is, of course, а particle of truth in it, provided that the valuation is made on а historical scale and is evidence merely of tl1e evolutioп of the properties of the complex organism. The complex orgaлism, as is weH known, is сараЫе of elaЬoratiлg various kinds of adaptions to the conditions of its environment. These include reactions to antigen. The diff erentiation of this capacity of the organism is remarkaЬly subtle. It is evident, therefore, that it is ап old, excellently constructed functioп, iп по way iпferior to secretioп of saliva, circulatioп of the Ыооd, etc. The encounter between the micro-organism and macro-organism is the impulse evoking this function, just as bread placed in the mouth evokes secretion of saliva. In Ьoth cases the quality and quantity of the response corresponds to the character of the ;igent evokiлg it. But where does disease come in here? What we have Ьееn speaking of is а normal or ph3•siological fuпction, directed towards activ~ maintenance of the equilibriuш between the organism and its environment. Disease, as we have seen, is somcthing entirely different. lts manifestations go outside the limits of physiolog}', they are not necessary to the organism. Moreover, the first external signs of disease sometimes begin а long time after the foreign agent has been acting. Ву this time tlie reactions to the atitigen тау already Ье preseпt. We know, for instance, that in the climax of abdominal typhus \Viedal's reaction is а trustworthy indication for diagnosis. Coлscquently, Ьу that time the macro-organism already responds actively and specifically to the micro-organism. Nevertheless, it has still to pass through а series of pathological changes during а period of at least two more weeks and, moreover, without any guarantee of а favouraЬle outcome. Вепсе, Jtruggle is not disease, апd disease is поt struggle. We have here two categories of aЬsolutely distinct phenomena. Coinciding in time, they actuall:v intermingle their features but do not fuse them. lncubation occurs in both groups, but it also is а distinct process in each, both in time and in essentials. Pathology can Ье interested only in that one of them which represents the introduction to the disease, i.e., belongs to the pathological symptoms. Three facts estaЫished Ьу i1s serve to decide the question of incubation. In the first place, our experiments have shown that the latent period of action lasting some days, weeks or even months is not а special property of ~ubstances of а protein nature, and still less of definite micro-organisms; this property тау Ье shared Ьу тапу other substances since the cause of the pheлomenon depends only on the organism that undergoes irritation.

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In the second place, it was found from the same experiments that inis а typical feature of neuro-dystrophic processes. Finally, the third fact was cstaЬlished during the study of specific reactions, а numЬer of features compelling us to inclt1de them in а special group of pro-cesses allied in type to nervous dystrophy. Нелсс, we have come to regard incuЬation as the time during which the irritation arising from one or several nervo points draws other parts of the nervous system into the process and brings aЬout temporary or permanent functional changes in them. If that is th~ case, then not оп/.у the initial Ьиt also the second and thtrd sym;.toms of the disease havc the1r incubational period. Incubation lasts from the moment of irritation t1Лti1 death or recovery; the disease itself is consideraЪly shorter since we are accustomed to measure it олlу from the time when external symptoms are found. In essentials, incubation is the disease itself and not а latent state of some other process, for the external symptoms are already а secondary feature. lt follows from this, that if there are elements of mutual interaction in the encounter Ьetween the foreign agent and the reacting organism, then the whole action is in accordance with purely physiological laws. The pathological processes arising simultaneously proceed independently. The task of medicine consists in finding means of actively interfering in their course The first attempts at work iл this direction form the subject of the last ~art of this book.

cuЬation

CONCLUSION

CHAPTER XXI BASIC PROPOSITIONS Тн1s Ьооk

cannot have а conclusion. I have more than once had occasion to mention that although the question of the role of the nervous system in pathological processes was first raised а long time ago, it has not lost its novelty even today. The reason lies in the fact that this questwn has always Ьееп analysed as а special aspect of the study of separate pathological forms. The nervous system was regarded as а supplementary factor, introducing some extra features into the intricate complex of symptoms of а particular disease. Leaving out of account certain attempts (including the old investigations of Samuel and the recent work of Ricker) it can Ье said that · по real atpraisal of the neruous f actor has ever Ьееп matk from the point of view of general pathology. At the beginning our work also had а sporadic character, passing from one subject to another according to the logic of the experiment itself. Subsequently, when the need for systematising thc materials became clearlv defined, we discovered also the inadequacy, or more correctly, the simple aЬsence, of the necess:iry basic principles. From that moment, the conditions of our work took another form: what had previously heen tlie suhject of our work we converted into its method. /nstead of investigating tetanus or tиht'rculosis, we conducted our worle Ьу means of tetanus or hy means of tuherculosis, etc., with the aim of maleing а comparativ e study of the nerve mechanism of processe1 which often externally had 1zothing iп common with опе another. Naturally, under the new conditions many details were elucidated relating also to the processes themselves taken as indicators, but this now became а secondary proЬlem, а byproduct, as it were, of the basic output. In setting to work, we, like everyone else, regarded neuro-trophic disturbances as а special form of reaction of the organism, forming the subject matter of а special chapter of pathology. The further our analysis of the subject advanced, the more necessary it became to enlarge the circle of phenomena where the nervous component is the fundamental part of the process deter1niлiлg the outcome of the disease and the fate of the aлimal. I am not speaking here of various forms of vascular derangeщents, ihe nervous nature 331

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of which is sufficient1y clear at the present time. Our work has shown that various destructive changes, acute and chronic inflammation, neop)asms, and cven trauma, are close)y connected with processes of а nervous character. At the present moment, we are in а position to assert that neuro-dystrophie processes are not co11fined to а umited sphere, that they enter into the composition of all pathological processes without exception, are not separaЫe from them, and, comequently, do not constitute and cannot constitute а separate clul'pter iп patholo gy. In order to make clear the position adopted Ьу us, it is nece!&ry to turn to the history of the subject. The time is still quite recent when the existence of а trophic function of the nervous system was only а matter f or debate. The controversy arose in the middle of the nineteenth century and has persisted to our day. All will rememЬer it; there is now no necessity to resuscitate its whole history, since the emЬittered disputes have gradually died down and we have, at last, the right to speak of the trophic role of the nervous system without fearing to encounter objections at every step. The question at issue was first raised Ьу pathology and the clinic. It is natural that, Ьefore recognising the fact, physiology and morphology demanded proofs. Morphology demanded а definite substratum in the form of п 'ttrophie nerue celJ," while physiology insisted that the process should Ье shown at work iп those conditions of technique in which it had confidence. This was the chief cause why the question was held back for many years. The process was hardly susceptiЫe of appreciation under the usual conditions of physio)ogical investigation; hence, its very existence was doubted. Since, at the same time, it was impossiЬle to deny the existence of а whole series of characteristic phenomena, attempts were made to explain them Ьу the facts of the past. This gave rise to the "vaso-motor theory" of neuro-trophic infiuences; this theory has persisted to our day and explains everything Ьу "the play of the vessels" and Ьу the quantitative variations in tl1e nutrition of the tissues, and the drainage of products of metaЬolism. Other views on the subject were formed along the same lines. The faith of the physicians in the authority of physiology made them share the same opinion. The controversy that flared up within the coлfines of the laЬoratory spread to the clinic. However, pathology and the clinic could not wholly disclaim their own observations and conclusions. Not all co11temporary medicine has its origin in contemporary biology. Medicine is а much older system than scieлtific physiology; trt1e, it has joined the route of physiology, renouncing many of its former theories and constructing new ones in contact

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with the more exact sciences, but it cannot cancel its past altogether, and in this it is right. Contemporary physiology studies fragments of processes under suitaЬle and artificially created conditions--whereas 'medicine is occupied with life in the totality of its simple and complex manifestations, including all those exceptional comЬinations which only nature knows how to produce. Contemporary physiology, is still practically оп analytical science--medicine has 11t ад times Ьееп i11terested оп/.у iп synthesis, defending its right day Ьу day to pursue its propositions to the end and to use them for practical purposes. This is the basic and inevitaЫe feature of medicine; for medicine cannot Ье guided merely Ьу the approbation of laЬoratory research, and it often maintains an independent attitude. Such а rupture took place Ьetween the laЬoratory and the clinic in regard to the question of neuro-trophic processes, and the clinic has continщ:d to collect and systematise the relevant material in its own way. An important part was played here Ьу the experience of the \Vorld War, 1914-18. It Ье­ саmе evident that the consequences of nerve traumata are Ьу no means restricted merely to anresthesia, pain, paralysis or vaso-motor disturbances. А lively interest was once again awakened in neuro-trophic phenomena. This attracted the attention of research laЬoratories, and proofs were at last oЬ­ tained сараЫе of convincing the old physiology of the existence of the direct infiuence of the nervous system on Ьio-chemical processes in the tissues; these proofs were reinforced Ьу the study of the nerve aspect of so-called vegetative processes. The foundations for this were laid even before the World War, but it reached its full development only during recent years. It should Ье noted, Ьу the way, that the proofs now discovered Ьу physiology were necessary for physiology itself. The recognition of the existence of trophic processes Ьу physiology had соте too Jate; as far as the clinic is concerned, the matter was already Ьеуолd dispute. Some years ago, when we Ьegan our systematic work in this field. the data puЬlished Ь}' us still produccd the impression of something unusual, in spite of the fact that the propositions to which these data were related could have been known even for decades. The subject must Ье considered to date from the experiments of Magendie ( 1 824). On in juring intra-cranial portions of the trigeminнs nerve in rabЬits, he noticed the resulting development of еуе disease in the form of ceratitis. These experiinents were repeated Ьу Sarnuel, Meissner, Schiff, Кirchner and others. Their data made it possiЬle to estaЬlish that, as а result of in jury to, or irritation of, the intra-cranial portions of the trigeminus nerve in rabЬits, conjunctivitis and ceratitis, sometimes even penetration of the cornea, is ех-

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hiЬited on the side of the trauma. At the time, а controversy developed around these experiments, and this has only recently Ьegun to die down. The subject of the discussion was not the f act itself, Ьиt its interpretation. Some considered the inflammatory changes in the еуе as the direct consequence of the nerve trauma and saw in them the manifestation of а special "trophic function" of the nervous system. Others sought an explanation simply in the loss of sensitivity of the еуе, resulting in an increased percentage of accidental lesions. In proof, experiments were performed providing evidence that the disease could Ье prevented in the operated rabЬits if the eyes were protected from externa1 influences. Meissner and Schiff showed that this is not quite correct. Ву injuring only part of the Gasserian ganglion they peserved the sensitivity of the еуе and ne'Uertheless obtained tlze development of ceratitis and ulcers of the corneal membrane. Berthold noted that on stimulation of the Ga$erian ganglion in rabЬits, changes took place not only in the cornea, but also in the middle ear, i.e., in а region the alteration of which cannot Ье due to postoperational damage from without. Samuel carried out а large number of experiments of various kinds with the aim of proving the existence of the trophic function of the nervous system. This provided him with material for elaborating а special theory expounded in his book, HDie trophischen N erven" ( 1860) . Не gives а detailcd analysis of the experimental and clinical data in his possession and not only arrives at the conclusion that there exists in the organism а special "trophic nervous system," but he even gives а general plan of its distribution and functioning. This theory did not receive general recognition and for а long time served only as а subject for criticism. However, the author did not remain alone. Very soon, Charcot categorically pronounced in favour of the connection of certain chronic local changes with the disturbance of some sort of special function of the nervous system. The same point of view was put forward Ьу DupJay and Morat ( 187 3), Erb, etc. After the American CiviJ War, the work of W. Mitchell, Morehouse and Keen appeared, devoted to an examination of the pathological consequences of nerve trauma. The development of dystrophic phenomena in the tissues after injury to the nerves was regarded Ьу them as а peculiar form of nerve reaction. F ollowing the discovery of the secretory nerves ( Ludwig, I 8 5 I), Heidenhain undertook а detailed analysis of the nervous aspect of the secretory process. In а series of experiments, he elucidated the significance of variouc; forms of innervation in this process and arrived at the conclusion of the existence here of trophic inftuence1 of the nervoщ system, and even of the presence of trophic ftbres iп the composition of the sympathetic nerves.

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At aЬout the same time the classical experiment of Claude Bernard with "sugar puncture" became widely known. The phenomenon observed Ьу him has up to the present time not received а final appraisal, although it has Ьееn the subject of ardent research for sixty ycars, but there is no doubt that the question of the active participation of the nervous system in the processes of metaЬolic regulation was thereby definitely raised. In 1884, the dissertation of V. I. Razumovsky appeared, dealing with atrophic processcs in bones after severance of the nerves. In 1885, I. Р. Pavlov puЫished his research on the nerves augmenting the Ьeats of the heart. Togethcr with the data of Claude Bernard and Heidenhain this research must Ье regarded as the basic experimental matfrial of physiology in this sphere. The earlier oЬservations were based оп facts belonging to the sphere of pathology. Later, а certain decrease of interest in the subject Ьecomes apparent. Individual researches appear sporadically. The greater part of them are clinical and hardly deal with the theoretical a~ects of the questinn. Among the experimental clinical invcstigations of this period ( I 90 х-06) we must mention the works of Spies.s, who succeeded in showing the influence of an~sthesia upon the course of certain local pathological processes ( acute and chronic infl.ammation, neoplasms). At the time his observations did not attract the attention they deserved. Under the infiuence of Virchow and his school, the opinion was maintained that the nervous system plays no essential part in such processes. It w:is considered that а final negative answer had been given to the question. The pathological consequences of nerve traumata were explained either Ь}' the loss of functions or Ьу local alteration of vascular reactions. Since. the Ьeginning of the present century, the joint efforts of physiology and morphology have laid the foundations for а systematic study of the sympathetic nervous system. The principles of its differentiation and distribution were estaЬlished and it was found that together with certain other nerve structures it enters into the composition of the vegetative nervous system. The starting point in the development of this knowledge was provided Ьу the oЬservations of Gaskell, but the basis of contemporary views here was laid Ьу Langley, Sherrington, and others. The most important feature of these works was the discovery of vegetative centres ( more correctly of vegetative regions) in the spinal cord and brain. The sympatlsctic nervous syrtem was found to Ье included iп the central nen;ous system and fused with it morpholo gically and functionally to such an extent that it became simp]y impossiЫe to speak of any exact Ьoundaries between them. In the last resort, this made it necessary to separate under the name of the vegetative nervous

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system а special functional group, consisting of central portions, the sympathetic chain and the nerve structures within the organs at the periphery. Very soon, the clinic also developed а new department of surgery, viz., the surgery of the vegetative nervous system. Of the works in this sphere, one must mention the researches of Leriche and his collaborators, who successfully employed operation on the sympathetic nervous system in the treatment of chronic ulcers. The abundance and diversity of the materials on nerve trauma, obtained during the last W orld W ar, revived the memory of past experiences and resuscitated ideas which had Ьееn buried since the end of the past century. As а result, four directions of work hecame clearly marked out. One proceeded from the oЬservations of Samuel, Charcot and other clinicians; the second Ьegan with the experiments of Claude Bernard; the third owes its foundation to the researches of Ludwig, Heidenhain and I. Р. Pavlov; while the fourth arose from the experiments of Loewi. Samuel's ideas found а response mainly in the clinic. In various places, simultaneously and independently of one another, physicians once more Ьegan to study the nature of the trophic consequences of nerve injuries. The work of some tended to Ье concerned with operations on the sympathetic ganglia and paths (Leriche, Mathey-Cornat); others concentrated their attention on parts of the central nervouз systeщ. Among the leading workers in the second direction one must mention Molotkov, Shamov, and Briining. А. G. Molotkov collected material which finally determined the part played Ьу the centripetal end of а damaged spinal nerve in the development of trophic disturbances at the periphery. Severing the nerve above or below the place of injury (neuroma), he oЬserved the consequences of each of these operations. lt was found that severing the nerve Ьelow the neuroma \!sually caused no change in the development of chronic ulcers and other trophic aff ections of the lower extremities. The same operation, if carried out аЬоvе the point mentioned, healed these diseases--sometimes in а remarkaЫy short period. Similar oЬservations were made Ьу Briining, Shamov, Polyenov, А. S. Vishnevsky, and later Ьу others as well. Shamov, as а result of his clinical data, comes to the conclusion that the arcs of those reflexes which participate in peripheral trophic disturbances ( trophic ulcers in particular) include Ьoth central and sympathetic nervous elements. Similar conclusions were arrived at Ьу Briining, Hahn and Polyenov. ln his suЬsequent researches, Molotkov consideraЬly enlarges the group of pathological proce$CS in which the nerve factor plays а decisive role. А numЬer of theoretical works in the field of pathology (one must mention here Ricker, and а numЬer of Russian investigators, Davidovsky, Abrikosov, Burdenko,

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Mogilnitsky, Weil, etc.) helped to strengthen the view that the nervous system actively participates in the development of certain pathological processes. The second direction of research Ъegan, as mentioned аЬоvе, with the investigations of Claude Bernard. The purpose of these was to estaЫish the role of the nervous system in general metaЬolism. W е are indebted not only to the laЬoratory but also to the clinic for succe~ in this field. The clinic collected and systematised data concerning the pathology of the suЬcortical cerebral ganglia ( corpus striatum, hypothalamus, nuclei peduncularum cerebri) The oЬservations made in this connection were а direct impulse for а numЬer of laЬoratory experiments in which clinical oЬservation, physiology and morphology mutually supplemented one another. ln this way, the conception of the role of the nervous system in the physinlogy and pathology of carЬohy­ drate, salt, fat and protein metaЬolism was gradually created Ьу the laЬour of many workers including Aschner, Кarplus and Кreidl, Marinesco, Mohlant, Freund, Trendelenburg, MacLeod, Eckhard, Jungmann and Meyer, Levi, Dresel, Ascher, Кraus, and Zondek, Biedl, Cushing, Foerster and many others; among Russian authors-Burdenko, Mogilnitsky, Astanin, Pines, Alpern and their collaЬorators. Many of these works provide ground for thinking that the nervous system has а really direct influence on the course of physico-chemical processes in the organism. The third series of researches, Ьegun Ьу the works of Ludwig, Heidenhain and 1. Р. Pavlov, studied the infiuence of the nervous system оп local tissue metaЬolism Ьу means of physiological technique. Among the works of this group, Babkin's researches must Ье mentioned. Using the method of conditioned reflexes he has succeeded in эhowing that, in spite of severing the sympathetic nerves of the salivary gland, the composition of the saliva continues to vary with various forms of conditioned stimuli, i.e., remains as Ъefore, dependent on the unconditioned reflex for which the gjven conditioned stimulus is the signal. Alpern and his collaЬorators have developed in detail Heidenhain's experiments on the direct influence of nerves on the composition of saliva. In 1922, Magnus-AlsleЬen and Р. Hoffmann puЬlished simultaneously their researches on the influence of the sympathetic nervous system on the vital staining of the striated muscles of frogs. They also came to the conclusion that the sympathetic system has а direct influence on this process. Later ( I 930-3 I), Bykov showed that it is possiЫe to elaЬoratc conditioned refl.exes influenciлg the proces5es of oxidation in the tissues. In I 9 I 3, Boecke puЬlished his observations on the sympathetic innervation of the skeletal muscles--a proЬlem which had Ъееn discussed earlier Ьу Perroncito. Boecke showed the presence in striated muscle of sympathetic elements

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connected with muscle .fibres and not with the Ыооd vessels. Before him (1895), D. А. Timofeyev had followed sympathetic fibres into the interior of the Pacinian corpuscles. Boecke's researches served as the starting point for а large numЬer of works of other morphologists, some of whom confirmed, while others denied, Boecke's data. The same thing occurred among the physiologists. Thus, de Boer (1921) and Orbeli (1922) almost simultaneously came to the conclusion that the sympathetic nervous system exercises direct influence on the tonus of striated muscles. Analogous oЬservations were made in N. А. Mislavsky's laЬoratory. Orbeli succeeded in demonstrating this process under various conditions of experimental physiological tecl1nique (Tonkikh, Ginetsinsky). А series of OrЬeli's subsequent researches were devoted to the infiuence of the sympathetic nervous system on the work of the central nervous system (Streltsov). In spite of the very careful technique and the definite results, both series of experiments were subjected to adverse criticism as regards principle as well as technique ( Beritov). In this criticism, the vaso-motor theory of trophism again appeared on the scene, the question being thus brought back to the starting point from which it had arisen in the past. Physiology, demanding purely "physiological proofs," found itself in а vicious circle. In any case, not all physiologists approached this question from the customary point of view. Thus, I. Р. Pavlov was one of the first physiologists who recognised the scientific validity of indicators taken from the pathological sphere. In 1922, he puЬlished ал article devoted to the description of а nнmЬer of severe pathological changes in various organs of dogs that had undergone operations on the gastro-intestinal tract. Не regards these processes of а dystrophic character as definitely due to the injury of nervous mechanisms. There remains the fourth group of researches, which started with the well-known experiment of О. Loewi (1923). After stimulating various nerves of an isolated heart, he collected the issuing fluid and passed it through another heart. It was found that the fluid taken during the period of irritation of the vagi or the sympathetic nerves had the same effect on а normal heart as the immediate irritation of the same nerves. Consequently, irntation of different nerves iп the tissues of the heart leads to the formation of different шbstances. The properties of each such substance correspond to the functional state of the given nerve (Vagusstojf, Sympathicusstoff) . SuЬsequently, these data were consideraЬly extended Ьу the work of various investigators, including that of I. Р. Razenkov and his collaЬorators, who showed the existence of the same phenomenon dшing the functioning of other organs, for instance the digestive glands. The facts obtained are not only evidence of the

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existence of the neuro-humoral regulation of physiological processes; they опсе more confirm the thesis that the nervous system has а really direct influence оп the chemical processes iп the tissues, Since then, and especially in recent years, а large number of works have appeared dealing with the participation of the nervous system in tissue metabolism. These works relate to various branches of physiology, pathology and medical practice. 1 shall not describe them here, since they do not add anything essentially new to the question, and onJy increase the quantity of material. Moreover, this book does not aim at giving а full list of all the facts relating to this subject. The addition of one more case demonstrating the participation of the nervous system in physiological or pathological processes is of no consequence. A.t the present stage of science, the basic tasks are: I) То estaЫish the f orms of this participation; 2) То obtain а concrete conception of the work of the co"espoпding ncrvous mechanisms. 3) То deterтlne the laws of а general and special character applying to processes of this nature. I have also deliberately avoided citing literature that is of significanct' only from the point of view of discussion. In summarising the results and giving an explanation of the causes that have so long prevented the recognition of the phenomena under consideration, what has to Ье taken into account is not separate factors but the general conditions under which the study of the question proceeded. At the present time, this can and should Ье done. It is noteworthy that during the earliest period, the question of neurotrophic regulation as one of the forms of physico-chemical processes in the tissues was regarded quite calmly as something inevitaЬle and self-evident. Some will remember, for instance, that as far back as 1874 Charcot made the following statement on this subject: "Rien de тiеих etaЫi еп pathologie, que l'existence de ces trouЫes trophiques consecutifs аих lesions de centres nerveux ои d11 nerfs." 1 It would seem that from the theoretical side also, the recognition of these propositions should not encounter any obstacles. Finally, the discovery of secretory nerves decided this same question in an absolutely simple fashion. How is it possiЫe to understand that, under the infl.uence of а nerve stimulus, а gland cell passes from а state of rest into one of secretion, if this act is not looked upon as direct nerve influence on tissue metaЬolism~ The nerve is secretory onJy because it is trophic. The one cannot exist without the t "Nothing in pathology is better estaЫished than the existence of these trophic disturbanccs resulting from lesions of the nerve centres or nerves."

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other. If we deny this, what suffers is Ьу no means the conception of trophic nerves, but that of secretory nerves. Motor, receptor and secretory nerve functions were noted as functions sui generis, and recognised without any struggle, although the essence of the phenomena taking place here still remains unknown. The theory of trophic nerve functions aroused а storm of opposition, although we cannot conceive of апу Ьiological processes without changes iп matter. The cause of the struggle that arose did not lie, therefore, in facts or direct contradictions. The basic cause lay iп the question being raised from the very beginning as а question of а special дпd completely new nervous function, distinct from those pre'Viously Jenown. According to the accepted physiological view, all forms of nervous activity are connected with а definite morphological suЬstratum specially designed for this purpose. The same demand was put forward now also and did not receive any formal satisfaction. The history of the theory of the trophic functions of nerves is therefore divided into two parts: the history of the шbject itself and the history of misunderstandings. As already mentioned, the basic misunderstanding lay in regarding the trophic function as а special function distinct from those previously known. Even considerations of а general character ought to have shown that this was improbaЬle. In а complex organism, the nervous component enters into the composition of every process without exception. The concept of an organ, of its structure and function, takes this into account, since an attempt to change the nerve conditions of an organ may easily lead to the loss of the organ itself. А s long as а given tissue is iп а normal condition, the neuro-trophic proиsses in it remain inwiЫe precisely because they determine the state of normality. Any change Ьeyond the usual limits is а signal of the transition to pathology. This is why pathology and the clinic are so far ahead of physiology in this question. Physiology, claiming to study the no№al state, for а long time had no suitaЬle means of approach to the phenomena mentioned. The inertia resulting from what had been useful in the past prevented а review of the basic propositions of physiology itself, and instead of revising its own methods, the f ai/,ure was ascribed to the subject under investigation. The second misunderstanding in the history of the theory of neuro-trophism is the demand that J:,,.ect nervous inftuences оп metabolism should Ье definitely demonstrated in "restiпg" tissues. А strange term ! It is supposed to separate reactions that are the consequence of the activity itself from those that form part of the complex of causes of the activity. But, surely, every tissue change, at whatever time it is mani-

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fested and however it finds expression, is already evidence that the tissue is not in а state of rest. Nevertheless, much effort was expended in vain in the endeavour to sarisfy the aЬove-mentioned demand. It can hardly Ье said that these efforts added anything essentially new to the sum of knowledge already obtained. It suffices to recall the well-known experiments of Heidenhain on the question of the secretion of salivary glands. They led him to recognise trophic nerves on the basis of precisely those changes that take place in а "resting" gland, outside the period of its secretion, under the influence of nerve stimulation. The convincingness of his data is in no way inferior to that of а11 the results of the further treatment of these data at the hands of late1· investigators. Hence, the question of the direct infiuence of the nervous system on the course of physico-chemical processes in the organism was even at that time decided positively, not merely for tissues the functional state of which was easily distinguishaЬle from the state of rest (glands), but also for others where this diff erence is not pronounced. These include fascia::, tendons, Ьones, etc., the peculiar forms of affection of the Ьones in tabes dorsalis, severe local destruction of various tissues in syringomyelia, and, further, such diseases as myositis ossificans, where Ьоnе develops in the place of muscle tissue, left no doubt of their nervous nature. They could not Ье explained either Ьу simple atrophy from disuse or Ьу vascular derangements. Оп looking for the cause of the demand that the phenomena of neurotrophism should Ье demonstrated iп "resting'' tissue, опе sees that it also is based оп the question of ап indicator. Facts which are convincing within the Ьounds of one science are not considered as proof Ьу another. Hence, the origin of disagreements and an atmosphere of distrust and uneasiness. Finally, there is yet another question. This concerns the direction taken at the present time Ьу the theory of the vegetatroe nervous system. It is interesting that its right to independent existence was recognised without any struggle. The chief oЬstacle confronting the trophic nervous system was easily overcome Ьу the vegetative nervous system, Ьecause from the outset it satisfied morphology Ьу presenting а material suЬstratum. This, Ьу itself, not only strengthened the position of the new theory, but led to 1.т exaggerated conception of the i1olated nature of vegetatrue nerve functions, isolated as they were iп а specioJ system. This was а reftection of tradition, an act of oЬeisance to the old theory of localisation, understood in а narrow and purely formal manner. It is here that criticism ought to begin its work. Numerous researches, for which the works of Gaskell and Langley were the starting point, have enaЫed the sympathetic paths to Ье traced within the central nervous system and separate stages of them, or vegetative centres, to

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Ье estaЬlished. These investigations are closely Ьound up with others, the starting point of which must Ье considered the "sugar puncture" of Claude Bernard. Fundamentally, this work is of а purely analytical character. It consists in excluding from the nervous system particular regions connected with processes regulating metaЬolism. These regions or centres were graded and systematised. However, in order to get а clear idea of the whole combination, it is nece!&ry to assess the actual significance of each component, to deftne exactly what must Ье understood Ьу the term "пerve centre." In the vast majority of cases, we are confronted here Ьу а finally fixed, summary function. It is something like the short formula of а few symlюls which forms the culmination of а mathematical calculation that may have occupied many weeks. The use of the formula is justijied in suitaЫe cases, Ьиt it does not groe апу idea of the proceu that created it. If, in analysing а complex nerve reaction, the whole preliminary path is not taken into account, then the nerve centre which carries out the completing portion is also only а fragment of the process. W е recognise as а nerve centre any group of elements, the direct irritation of w hicl} results in а definite action at the periphery (in general, movement). But with these elements, others are connected, and with these, in their turn, still others. And everywhere, direct iпitation brings in new parts. ln а complex physiological action, each of these links, whether permanent or accidental, is а nerve centre. Thus, а nerve cell of the intestinal canal can Ье а centre for epilepsy. Consequently, the vegetative nervous S}'stem is not more independent than, let us say, the pyramidal system and others. The пате "fJegetatifJe nerfJous systemJ' merely unites а certain пит­ Ьеr of working functions belonging to those lower centres that are called ироп to realise the last stages of the process. It does not follow from this that we deny the theory of localisation altogether. We desire only that the concepts in this field should finally Ье made more precise. The differentiation of the nervous system, and the aggregation of nerve elements of the same designation into ganglia or centres, are facts that cannot Ье doubted. Виt this does not теап at all that а particular ne?"Uoиs function proceeds within special elements from beginning to end. From the very moment of its origiп, the question of neuro-trophism was analysed from the general to the particular. When а series of miщnderstand­ ings assailed the question, the method also suffered. As regards neuro-trophism, this was manifested Ьу fear of synthesis and distrust in it. In place of general laws, special ones were put forward, and these were connected, moreover, with special nerve regions. The fact that vegetative functions were ascnbed to the sympathetic nerfJOUS system сап hafJe useful consequences onJy for analytic work; for synthetic work it is of по use. Along this line it is

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to enlarge the conception of the special physiology of separate sympathetic structures and of their complexes; but, at the same time, it can strengthen an incorrect conception of the generalisation of trophic nerve functions, enclosing it in the sphere of definite morphological associations. As а result of several years of work, my collaborators and I have become convinced that iп studying processes of this nature the traditional subdivision of the nervous system into central, peripheral, sympathetic, etc., has по just" ification. Many examples in this book have shown that from any nerve point it is easy to bring into action nerve mechanisms, the functioning of which tcrminates at the periphery in changes of а bio-physico-chemical character. Let us suppose that the final part of the process is realised in all cases Ьу а particular portion of the so-called vegetative nervous system. Is that really sufficient cause for isolating ti1e whole process in а special group? Much greater justification exists for the thesis that апу neМJe point, not excluding peripheral пеМJе structures, сап Ьесоте the originator of neuro-dystrophic processes seruing as the temporary or permanent neМJe centre of these processes. The vegetative nervous system is only а special case of those forms of physiological relationships which were previously known under the name of neuro-trophism. No special characteristics were included in this new conception. The clinic ap-proached the question synthetically, while theory approached it analytically. But it is customary to repose more trust in the data of laЬoratory experiments in science than in the observations made in the clinic. An idea of the clinic is recognised as scientific when it is supported Ьу the laЬoratory, and the latter, rather naively, reckons the age of the idea precisely from this point. The circumstance that the physiologist or histologist of the present day is not аЫе to isolate а "trophic nerve cell" has ceased to Ье an objection and has lost its force as а refutation. The form of the decision of this question we сап calтly leave to the future. Numerous clinical oЬservations and absolutely direct experiments have shown that the пеМJе form of regulating physicochemical phenomena iп the complex organism does exist. The process has Ьoth а gtneral significance for the whole organism and а special one for each separate organ. It would seem that this is all that is required. Another reason why research activity in the direction mentioned can Ье c.arried on independently of the recognition of special trophic nerve elements lies in the fact that there are по non-trophic nen;e element; iп the organirm, i.e., elements that have neither direct nor indirect connection with metabolisм. In actual work the question that has to Ье put is not that of the trophic nervous

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system as such) but of the nen;ous cotnponent of processes which are very diverse in external form. It was pointed out аЬоvе that whenever our procedure affected the nervous aspect of any phenomenon, this resulted in changes not only in the nerve portion concerned but in the whole intricate complex. Gradually two basic facts were estaЬlished. The first is that many pathological processes, the cause of which had been regarded as aЬsolutely foreign to nervous infiuences, have Ьееn found to Ье in reality entirely dependent оп the latter for their origin. The second thesis concerns all the processes not Ьelonging to the first group. То whatever chapter of pathology they Ьelong, ho~er complicated their composition and however variaЬle their course, the neNJoиs componetlt remains from beginning to end the fa&tor that detet'mines their general stot~. It, as it were) unites the separate elements into а whole) it forms the cement) any change in which inevitaЬly alters the appearance of the process in а11 its other parts. It is impossiЫe to separate it from the remaining elements of the Complex process • .Jf.part from memory, Wtl do not /&nOW of Q nngle nertJOUS function which сап he realised hy itself, without change iп the state of some other organ. lt is clear from this thot the externaJ. manifestations of nen;ous processes iп а &omplex organism must Ье just as diverse as in general all the manifestations of lif е. U nder the conditions mentioned, an appraisal of the role of the nervous component of pathological processes presents innumeraЬle difficul ties. This is the reason why this boole &annot ha'Ue а &onclusion. The varied material, obtained as the result of а consideraЬle numЬer of experiments, connectcd Ьу unity of aim, allows us, however) to attempt to give some formulations and generalisations. Without mentioning details. I shall formulate some of the propositions which years of research have convinced us are trustworthy. 1. The forms of nervous activity known to us--motor, receptor and secretory-are manifested Ьу changes in the state of various parts of the organism and are inevitaЫy &onnected with changes iп matter. Hence) nervous influences on the course of Ьio-physical and Ьio-chemical processes in the tissues (neuro-trophic infiuences) are not а form of physiological relation new in principle; they are not а characteristic) and still less а unique, nervous function. 2. Direct irritation of definite nerve structures may give rise to biochemical changes in the Ыооd and organs without these Ьeing accompanied a.t the same time Ьу any other easily noticeaЬle reaction. This gives rise to the conception of the independence of the nervous functions of metaЬolism. ln

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point of fact, this is merely а series of preparatory changes indispensaЫe for the suЬsequent development of а chain of reactions. W henever the fuп;;tion under consideration is tиtuolly mamfested independently, out of contact with other physiologicaJ, processes, this means that it has a/,ready Ьесоте pathologicaJ,. 3. In relation to processcs of а neuro-trophic character, the theory of localisation has only а relative application. The grouping of functionally united morphological elements does undoubtedly take place; this, however, determines not .the whole process Ьиt only its separate linles. Taken Ьу them• selves, these links have no independent character and do not constitute а whole. Moreover, they can Ье brought into action Ьу the most diverse energy sources, which in this way are temporarily included in the chain of nervous centres of the given process. Consequently, the trophic nervous function as such has no exact localisation. The morphological groups of elements performing this function are scattered throughout the whole complex nervous system, consisting of central, peripheral and sympathetic parts. 4. Each of these structures is linked Ьу simple and complex connections, not only with other nervous mechanisms, but also with tissue elements at the periphery, and performs its function iп association with them. Hence, there cannot Ье any form of interference in neuro-trophic processes which does not affect other functions at the same time. 5. The alteration of the nervous part of any process at а given pl.ace and time is the sum-total of а series of other proces.ses, one of the links of the continuously changing combinations which are built up within the nervous system. А special comЬination exists in so far as it is connected with the gt:neral combination and is derived from the latter, which itself is the mobile sum of all the special parts. 1t is obvious from this that the irritation of anv point of the crмnplex network of the neruous system сап evoke changer not only in the adjacent parts but also iп remvte regions of the organism. 6. These changes consist in transformations of the internal nerve conditions, gradually developing and later Ьecoming extinguished. Their inftuence upon various forms of nervous activity is Ъу no means uniform. In the general physiological complex, there exist nerve combinatioлs of varying constancy, depending ол the constancy of function and the functioning periods of the separate systems. Since а pathological nerue comhination is al· ways а new comhination, interf erence in its course сап Ье achieved more easily than iп cases where we are confronted Ьу а staЫe physiological process. 7. The stability of combinations of а pathological type is also very diverse and depends оп а number of factors. They owe their origin to the actioл of some irritating agent. Виt the strength of the irritating agent is the degree of irritation. The disturbances occasioned сал Ье transient or permanent. If ir-

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1·f'versiЬle changes ( even at only one point) arise in the nerve network as the result of local irritation, the process is not confined 'merely to loss of а particular function or part of а function. Besides traces of former damage, we shall have here а focus of new pathological excitations, drawing other, healthy parts into the process. А temporary, pathological nerve combination becom~s constant and acquires the same stability in relation to influences acting on it as the nerve comЬinations underlying normal physiological processes. From this time onwards, new irritations, im-pinging оп the tJtered nervous system, wi/.l frequently he reftected iп its damgged areas hy ап intensiftcation of the pathological excitation which i.s already taking place there. 8. This is the reason why, when we attempt to interfere in the pathological re-grouping of the internal nerve comЬinations, we frequently obtain at the outset а certain intensification of existing pathological symptoms. The old comЬination i1 de1troyed Ьу our treatment not directly, Ьиt only Ьесаще new опе1 are created. This naturally requires time. The operation itself, however, is always and under all circumstances an ordinary nerve trauma in а greater or lesser degree. The result of it is rapidly seen, especially in the case of elements which are already irritated at the given moment. 9. In consequence of this, even under precisely equalised experimental conditions, we cannot always obtain an identical effect. То foresee the direction which the process will take, it is necessary to know in advance the history of every individual nervous system, to ha 1

А. А. Babkova and А. А. Ka11arevskaya.

Arkh. Biol. Na11lt, Vol. 34, No. 5-6, 1933.

TYPHUS EXANTHEMATICUS eompare the elfect of speciftc and non-specific influences exerted nerreparations allied to it, which have such decisive action in European recurrent typhus, produce the slightest effect in this case (Martsinovsky, Ruge, Kassirsky, Iren, etc.). Consequently, Professor Alisov decided to employ here the method of "pum-ping" Ьу itself, without апу acccmpanying administration of drugs. Together with his collaborator I. А. Ku373

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sayev,1 he carried out observations oil I 8 patients suffering from Persian typhus. The method of "pumping' was employed in the usual form, as already described Ьу us several times. After it, the patient was kept in bed for some days. After "pumping," headache, а usual symptom of recurrent typhus, Ьесаmе intensified and lasted I-2 days. After that it coir.pletely passed off. ln I 1 cases out of 18, the patients could Ье regarded objectively and subjectively as healthy within 40 hours after "pumping." The temperature returned to normal, the spleen di1ninished in size and the spiroch;ete disappeared from the Ыооd. А daily test for the spirochrete was carried ощ during 2-3 weeks, always with а negative result. АН the patients were under oЬservation Mar. t93~

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for three months. Throughout this period none of them had any new attack f the disease. Of these I I patients, + had Ьееn given "pumping" at the height of the first attack, 4 at the height of the second attack, I at the height of the third attack, 1 at tl1e height of the fou ;·th, and 1 during apyrexia after the second attack. In а second group, consisting of 4 patients, "pumping" had to Ье emp1oyed twice, after which the attacks ceased, the spirochrete disappeared f rom the Ыооd, and the other symptoms were aЬolished. All the patients remained under observation for 3 months and the1·e was no renewal of the attacks. А third group consisted of 2 patients, each of whom had one attack after 1

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"pumping" had been ca.rricd out once. After that, the attacks ceзsed and the spirochrete finally vanished from the Ыооd. These two patients were also under observation during 3 months. Tlie fourth group cnmprised only one patient, ~ged 12 years, who had whooping-cough as well as Persian typhus. А single "pumping" produced no effect.

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8. Persian (Recurr-ent) Typhus. Recovery After "Pumping" Performed Twice. The Small Arrows lndicate Occurrcn~ of Attacks 1

As а result, the investigators come to the conclusion that in Persian ( re ~ :.1rrent) typhus, "pumping" without any administration of drur s represents the simplest and most hopeful treatment, not resultiпg in апу uнfavour­ aЬle suЬsidiary effects. The temperature fails to normal within 40 hours. The spirocha:tes disappear from tl1e Ыооd within the same period. The general state of the patients shows а marked improvement. The material described аЬоvе supplements the data obtained in thc work on malaria. Here also, in the majority of cases our action interrupted the disease without the emµ1oyment of any llt 'ler n1eans to which the immediate effect on the exciting agent of the disease might have been ascribed. lf а temporllry transforrnati1Jn alonc of t.he nerve interrelations suffices for abolishiнg all the symptomr of a"Z infе . tious disease, u•here must опе look for the source of the development of these symptoms? The onset of the att::tcks, the rise of temperature, the enlargement of the spleen, etc., ~·J not occu : berзuse the foreign agrnt penetrates the organism

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from outside or emerges from its refuge in the organism itself and spreads in it. Exactly the reverse is the case. The microЬe makes its appearance Ьecause the organism makes this роsМЫе. А specific exciting agent produces an equally specific form of nerve irritation leading to а perfectly definite process. With this its role comes to an end. The reacting suЬstratum is responsiЬle for everything that follows. Apart from what has been descriЬed above, we do not at present have any therapeutic means against Persian typhus. But if апу such means were to he found iп the near future, of whatetJer nature, it would Ье bound to agree with our system of conceptions as far as the mechanism of its action сопсепшl.

u

CHAPTER XXVII AN.tESTHESIA AS AN IRRITАТION WE employed the method of "pumping," Ьoth Ьу itself and in comЬination with other forms of treatment, in various illnesses. At the present time, I cannot yet give а report of this work, the availaЫe data Ьeing insufficient. There can Ье no doubt that the form of nerve irritation produced Ьу this method must have certain detinite features. As а result, each form of neruour dyrtrophy, agoinst which our action is directed, changer its course iп its own fashion. The effect obtained in the treatment of rheumatism cannot serve as an example for the treatment, let us say, of typhus. Among scattered clinical observations of this kind, we have facts on which Ьoth positive and negative conclusions can Ье based. An estimate of these data will Ье given when it has been possiЫe to systematise them. At present, however, I shall pass on to an account of another series of our clinical experiments, in which our operation took the form of ana:sthetising extensive nerve tracts. At the Ьeginning of the present century, Spiess applied the method of local an2sthesia in inflammatory proce$eS and лoted its therapeutic action, on the basis of which he elaЬorated а special theory. Не considered that the initial factor in iлflammation of the tissues was the "primary pain," the aЬolition of which Ьу means of an~sthesia was favouraЬly reflected on the suЬsequent course of the process. His doctrine did not find any response, owing to fears that injections would cause the basis of the infection to advance into neighЬour­ ing healthy regions and thus produce а further extension of the process per

contmuitatem. The systematic researches of Professor А. V. Vishnevsky and his collaЬor­ ators once more revived the question, not only of the permissibility, but of the advantage of applying local anжsthesia to the region of inf\amшatory foci. Working along these lines for а number of years, А. V. Vishnevsky elaborзted his method of anжsthesia, called Ьу him the method of "creeping infiltration." Не employed it with success not only in inflammation Ьщ also in the treatment of such diseases as trophic ulcers, gangrene of the extremities, psoriosir 'Vиlgaris, and some others. His aim was to cause an interruption of the paths of "pathological reflexes," with less trauma than in the usual forms of opera.tion. Moreover, on the basis of oЬservations on inflammatory proce$eS, ь~ 377

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·regarded novocaine as а means exercising immediate curative action on the a.ffected nerve elements. At that time we estimated the curative effect even of direct interruption of the nerve paths, or of extirpation of tl1e corresponding nerve structures, not only as а consequence of disconnection (i.e., putting а stop to pathological irritation), but also as а factor promoting transformation of nerve interrelations, i.t>., as а factor of additional. irritation. It is easily comprehensiЫe that this poirit of view acquired even greater significance in relation to local anzsthesia. А. V. Vishnevsky found that а temporary "Ыосk" in the paths of the "pathological reflex," although it lasted only а few dozen minutes, nevertheless gave а result that was not only not worse, but frequently even Ьetter than the usual Ыооdу operative 1neans. The therapeutic effect of such anzsthesia employed on а single occasion could sometimes Ье followed up for months and years. In particular cases, its useful effect progressively increased throughout this period. Could there Ье а Ьetter proof than this that we are сог fronted here neither Ьу tl1e ··~ action of novocaine itself as а curative means, nor Ьу simple anzsthetic disconnecс tion, for :i. short period, Qf the periphery from the damaged elements of the centre? In 1932, when I Ьegan the study of anzsthesia as а method of active interference in the course of pathological processes of various kinds, 1 adopted the following diaFig. 19 grammatic scheme as а starting point. The nervous system (А) of а given animal is а completely closed network 111 whic:h all the elements are connected with one another not only structurally Ъut dynamically. Let us suppose that а certain portion (В) i!> tempurarily separated from this labile network. The remaining portion will not simply Ье the system Л minus В, since the elements will unite in new comЬinations. This process, beginning at one spot will progтessively sp1·ead to neighЬouring .a nd тemote nerve parts, before gradually dying out. W е shall Ье faced, not with

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the system А tnin1Js В, but with а new system C-figuratively speaking, а new animal. If we now reconnect the temporarily separated portion В with the rest of the organism, we shall not get А again, because neither the original action of subtraction nor the subsequeлt addition fo!~ JWS the rules of simple arithmetic. Time plays а part. In both cases new combinations, new ronnections are created. On relinking the disconnected elements, the order of their inclusio11 will Ье different from the order of their separation. As а result, instead of the system А we shall get а system А 1 • This, of course, will Ье closely related to А, and will, moreover, have а tendency to approximate to it, but it will not attain this in full measure, at least for some time. ln tl:is respect the onset of antl'sthesia and its cessation act alike. If, during anresthesia, а nerve combination that formed part of the complex of conditions governing а patlюlogical process was broken up, then it тау happen that, even \\'ith the tull restoration of the system А, the pathological process may not Ье renewed, since otl1er elements of tl1e given complex system have по longer the origi1ial f orm of interrelution. This would mean that the temporary curative effect has become permanc:nt. It is possiЬle to count on such an effect in practice mainly in pathological processes nf an acute nature, in which the changes in the nerve c:lc:ments have not yc:t attaiпed the degree of irreparaЬle disturbances. But in chronic processes also, а favouraЬle turn may last as long as the process evoked Ьу us is still going on iн the nerve network, where it slowl) spreads and gradually disappears. Even а prWri there would Ье reason to believe that any form of such temporary disconnection of nerve parts in any part of the organism would have а repercussion on а pathological nerve rombination precisely because the latter is always iп а state of excitation. But it is 011so ckar that the place and forш of operation, the degree of irritation апd а number of other factors wi!l determine the final result. Hence, the samc meam тау result iп а positive effect iп опе group of -processes and iп а negative cjfect iп another. The чuestion here wШ Ье decided Ьу experiшent. Prolonged work in the laboratory has convinced us that, in beginning а ncw series of investigations, it is often advantageous to go from thc complex to the simple, from tl1e strong to the weak. Therefore, in commencing work on anresthesia, we took an intercst in Professor А. V. Vishnevsky's method, since his "creeping infiltration" makes it possiЫe to involve really extensive nerve regio r>. Of the separate procedures, the one inost worthy of attention from our poiнt of view was the method of novocaine "Ыockad c " of the l1Jmbar section of t!1e symp:tthreum of а dog. W е consider that пото, or watery cancer, is а disease of the oral cauity llllied in nature both to alveolar pyorrhcea and to scurvy, though tleveloping more acutely. I should like to recall that we c:iЬserved several aЬsolutely typical cases of noma in our dogs after the "sphere" operation. Sometimes the ulceratioп Ьegan to progress irresistiЬly, resulting in destruction of the epitheliaJ, muscular and cutaneous parts of the cheek, and laying bare the Ьоnу parts of the jaw over а consideraЬle area. Оп this account, I was very interested to receive а letter from Dr. S. Р. Ponomarev at Starominsk in the Azov-Black Sea regioп. Duriпg the summer of I 934 he succeeded in collecting eight cases of noma at different stages of development which were successfully cured Ьу

386

BASIS FOR

ТНЕ

THEURY OF MEDICINE

novocaine lumbar Ыockade. His patients were demonstrated at the session of the Regional Surgical Society in Rostov-on-Don. I hav.: also received letters from physicians informing me of successful employment of lumbar Ьlockade in several cases of disease of the accessory cavities of the nose and middle ear. 111 acute purulent inflammation of the middle ear, complicated Ьу mastoiditis, the treatment somi:times interrupted the process and made surgical operation unnecessary.

CHAPTERXXX AFFECTIONS OF

ТНЕ ЕУЕ

(CERATITIS)

I HAVE pointed out elsewhere that among the special symptoms of generalisation of neuro-dystropЫc processes are included aff ection of the еуе in the form of ceratitis. In our laboratory, my collaborator Professor V. V. Chirkovsky 1 carried out systematic observations and experiments on this question. The results were summmarised in а special article. They can Ье formulated in the following statements. 1. In animals ( dogs and rabbits) Ьу action оп various nerve re gionr we succeeded iп obtaining affections of the cornea in the form of ceratitis of different types--ranging from restricted, superficial to deep-seated, purulent and extensive ceratitis. Among these regions, one must mention above а11 the Gasserian ganglion, the peripheral portions and even comparatively fine branches of the trigeminus nerve, the ganglion ciJiare, tuber cinereum, upper. cervical ganglion, lumbar-sacral region of the sympathetic chain, and in special casc:s-the brachial plexus, sciatic nerve and even places of the cerebral cortex selected at random. 2. The largest percentage of cases of the aЪove-described alteration of the corneal membrane is obtained as а result of injury to nerve parts in the immediate periphery of the еуе, including the upper cervical ganglion and tuber crnereum. 3. Where unilateral. injury to one of the aЪove-mentioned nerve structures resulted in ceratitis, we frequently observed that the latter developed iп both &)'&t. lt is of mter·est that iп а certain percentage of cases, ceratitis developed immediately оп the contralateral side. 4. Work with а comparatively large amount of material showed that whatever the nerve structure selected for injury, the development of ceratitis does not invariaЫy follow. 5. We consider that this circumstance, taken in comЬination with the other facts enumerated аЪоvе, is categorical proof that the ceratitis was not а direct consequence of injury to the given nerve structure, i.e., that попе of these nerve structures спп Ье regarded as а special trophic centre for the corneal membrane of the еуе. 1

V. V. Chirkovtky. Arlth. Biol. Nault, Vol. 14, No. 4, 1933. зs7

BASIS FOR ТНЕ THEORY OF MEDICINE

388

6. It follows from this that all the forms of opcration unucrtaken Ьу us served mercly as impulies f or the commencement of а сотрlек tun1ous process iп which ceratitis WQI опе of the linki. That the proccss actually arises in this way is evident from thc exceptional divcrsity of the incuЬational period; in some cascs we obtained an effect within а few hours after the operation, in other cases only after several months. At the time that the experiments were transferred to clinical conditions, we were already aware that it is Ьу по means always essentIOl to atply our tJCtion to the innervation of the aflected organ. Such а form of action could even Ье of harm, intensifying the irritation already existing in а definite group of nerve structures. It is more advantageous to atply the action to nerve reP,ni not ~1 connected with the aflected organ. Moreover, ourexperiments were of а general character and had the aim of establishing exactly how changes of the relations in remote parts of the nerve networlc would Ье refiected in th~. &ivcn process. Thc work on this subjcct was carricd out in the First Еус Clinic of the Leningrad Medical Institute Ьу Professor V. V. Chirkovsky and his collaЬora­ tors I. Е. BarЬcl, А. А. Vishncvsky, L. А. Dymshits and R. К. Mikhaclyan. 1 Thc chief point on which our interest was concentratcd was to obt.;,, tm e/eet in ceratitis of flarying trtiology Ьу means of ап identieal form of action. F or 0Ьscrvi11g the course of the process, we used the method of bio-microscopy as well as the usual methods of clinical analysis. Changcs in thc sensitivity of the corneal membrane werc also investigated. Тhе usual thcraprutic methods wcre not uaed, and atropine was cmployed only in cases of pronounced byperzmia or inflammation of the iris. In а numЬcr of cases where thc paticnts were transferred to the clinic from the out-patients' department, they had already Ьсеn treated Ьу ordinary thcrapy. Its lack of success was а sptcial incentive for employing our procedure. In all, oЬscrvations were made on 34 cases of various kinds of acute and chronic ceratitis, including 10 caaes of herpetic ceratitis (.c.-kw.tёtlr ~ tiea, 3-ulcш cornerz herpetka, 2-keratitis tlisciformis, tmJ 1-Мrtllitis

superftcialU tutШtJU) • In 7 of these cases, lumЬar Ыockade resulted in rapidly extinguishing the disease. In 3, recovery was delayed. The first consequence was usually а marked improvement in thc gencral ·state of the patient which has to Ьс connected with the cessation of tormenting pains, lachrymation and photophobia. In 2 cases, а bricf intensification of the symptoms was noted immediately after the operation. I. Е. ВаrЬеl, А. А. Vilhnevaky, L. А. Dym.ьiь, R. К. Mikltaclyan, V. V. Cblrltowky. Arltlt. Biol. N1111lt, Vol. 34, No. 4, 1933. 1

AFFECTIONS OF ТНЕ ЕУЕ (CERATITIS)

389

The objective changes in the disease were as follows. In the first place, there was diminution and suЬsequendy dissolution of infiltrates both in the superficial and deeper layers of the cornea. At the same time, the vascular reaction of the conjunctiva was weakened. Hyperzmia and intiammation of the irideal membrane was often aЬolished in the first fe·w days. The pupils, which had shown no reaction to atropine, Ьесаmе dilated. In two cases hypopyon rapidly disappeared. Among these patients were some with ulcerous ceratitis of long standing who had Ьееn unsuccessfully treated Ьу various methods and in whom the disease easily yielded to the aЬove-mentioned form of operation. There were I 7 cases of purulent ceratitis. In 9 of them there was creeping ulcer, in 4 ulcerous ceratitis accompanied Ьу trachoma, and in + peripheral ceratitis of the catarrhal ulcer type. The cases were diverse in ztiology, severity and stage of disease. Out of 9 cases of utcus CONJ8tZ serpens, pneumococcus was found in 5 cases, diplobacillus МА in 1 a11d staphylococcus in 1 case. In 2 cases. no microЬe was discovered. Tlu efficacy of lumbar ЫосЬlе this trou'P of ~ was 6fle" gretlUr tl11m tlu first. However, Ьesides rapid cure of the diseaae, there were three cases in which an intensi.fication of the pathological symptoms was oЬeerved after the operation, and the useful etiect was delayed. In 4 cases of ceratitis, not of typical form, which had developed on the basis of trachoma and had Ьее11 treated for а long time without result, our operation caused а marked turn towards recovery. One case of purulent ceratitis, resemЬling а round aЬscess, was especially convincing. :Гhе disease had involved а consideraЬle portion of the periphery of the cornea and threatened to destroy it. During the days immediately following Ьloclcade, the patient had а restful night for the first time in 2 weeks. The depressed condition gave way to cheerfulness. The purulent globular in.filtrate quickly dissolved and was only maintained а little in the lower part of the cornea. А second in jection of novocaine in the lumbar region on the opposite side of the Ьоdу quiclcly resulted in the aЬolition of the pathological symptoms. One of the 2 cases of keratitu '4renchym4tosa which had Ьееn unsuccessfully treated for а long period was also very significant. Within 14 days after the Ьlockade, the acuity of vision, which on entry of the patient to the clinic had Ьееn equal to the movement of the hand Ьefore the еуе, increa.ced to 0.5. The second case also yielded to the action of blockade, but only on repetition of the latter. Out of 2 cases of rosa&ea keratiti.r, in one а positive effect was oЬserved within 2 days from the operation, and within 9 days the patient was discharged with а healthy еуе. In the other case, rapid reaЬsorption of the infiltrate in the cornea and weakening of all the inflammatory symptoms also Ьegan within 2

m

m

BASIS FOR ТНЕ THEORY OF MEDICINE

390

days. The patient was discharged after 9 days, but returned after а week with relapse of the disease. А second Ьloclcade was required to strengthen the

а

~~

.

The last group contained 5 cases of scrofulous ceratitis, of various ages and intensity. In 3 of them, we observed rapid dissipation of the disease very soon after the Ыockade. In all forms of ceratitis, there were changes of sensitivity, Ьoth decrease and increase; the former, however, occurring more frequently. lt was not possible to estaЫisli апу parallelism between the process of extinction of ceratitis and the restoration of sensitWity. There were cases where the inflammatory process came to an end while the sensitivity still remained unchanged for а long period. Вепсе, there is apparently по direct connection between these tr. No. 4, 1933. Goly&heva, К. Р.: "Experimental Data on the Question of the Genesia of the Toxic Form of Epilt'ptic Seizures," Archifle of Biologiclll Scimces, Vol. 3z, No. 4, 1932. Gontchkow, М. А. und Babkowa, А. А.: "Zur Fr11g1 Jer Pathog1,.,s1 Jes illtutm R.Jиu­ tismш," Zeitschr. f. J. ges. ехр. MeJ" Vol. 67, рр. 278-92 1 19z9. H&lperin, S. J.: "Die Entfaltung des tlystroph;sch111 Proиss bei А ff1lttio111n tl.1r ob1r11t symttJthischen Halsganglitln," Zeitschr. f. tl.. ps. 1хр. Metl.., Vol. 90, рр. н5-19, 1933. 1linaky, V. 1. and Evzerov, У. D.: "The Role of the Nervous System in the Pathogenesia of Rheumatism." (Manuscript.) lwanow, G.: "0bef" die А bflusswege аш Jen 1ubm1пing111/e11 Riiumen tles Riicltt11'm11rlts," Zlitschr. f. d. ges. t:rp. Metl." \'ol. J8 1 рр. 1-:11, 19z7.

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BIBLIOGRAPHY

411

l\\·anow, G .: "0ber tlu Ab/Jшswegc аш den Subarachnoidalraumen J1s G1hirns 1mJ RШ:lunmarks und uber du M1thodik ihrer Untersи

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Stomach of а control 1abbit (normal) killed 4 0 days after inoculating the gastric wall with Vallee

PLATE 34.

tuЬerc ulosis

culture

PL ATE 35. Stomach of an experimental rabbit. Both п. vagi were severed Ьelow the diaphragш 22 days Ьefore infection with Val\ee culture. The rabЬit was killed 40 days after infection

PLATE 36. Stomach of an experimental rabЬit. Both 11. vagi were severed Ьelow the diaphragm z7 days after infection Ьу Vallee culture. The rahЬit was killed 40 days after infection

PLATE 3 7. First stage of tuЬerculous infection of the testicles and their

mesenteries

PLATE 3 8, Severe tuЬerculous affection of the testiclc and its mesentery

447

PLATE 39. Visceral org:шs of а cat infected Ьу tuberculosis intra-peritoneally, and killed after six months twelve days. Pronounced tuberculous affection of the epiploon and serosa of the rectum

РLЛТЕ

40. Mortification of the skin of а rabЬit' s scrotum after applying а loop with

lewisite to its distal end

PLATE 41.

Ditto, after applying

а

loop with lewisite to the root of the scrotum near the inguinal сапа! 449

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PLATE .р.

Mortification of the skin of the Ьelly after applying а loop with lewisite to its lower portion near the inguinal canal

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suffering from red lupus. Duration of the disease ten years

РLЛТЕ 44.

The same patient one and а halt months after Ыockade

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PLATE 45.

Herpes-like Duhring's dermatitis before Ыockade

PLATE 46.

The same patient twelve days after Ыockade

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