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JULY 17, 1926.

Victor Horsley Memorial LectureON THE

INSULATION OF THE NERVOUSSYSTEM.

Delivered at the House of the British MedicalAssociation on July 9th, 1926,

BY WILFRED TROTTER, M.S. LOND.,F.R.C.S. ENG.,

SURGEON, UNIVERSITY COLLEGE HOSPITAL.

WITHIN a few days it will be exactly ten years sinceVictor Horsley died. The circumstances of his death,however lamentable they may seem to us who losthim, were not, perhaps, very different from what hehimself might have wished. He was at work in thedirect service of his country ; he was using his wholestrength in the relief of suffering, while his mind andbody kept unabated their astonishing and characteristicvigour. In commemorating this great man our

attention is attracted to three separate aspects ofhis life. We think of him as a physiologist and asa surgical pioneer, and we think of the personalitywhich lay behind and informed these and all theactivities of his crowded years.

His work for science and for surgery has long beenincorporated with the general body of knowledge andhas its lasting place. For his personality there isno such lodgment and those in whose memory itlives so vividly are already, after the passage of eventen years, a heavily reduced company. I thereforegratefully accept this chance to make my small recordof a man who, in my knowledge of men, was unique ein this, that he combined an inflexible belief in hisown standards and a truly apostolic zeal in all publicaffairs, with a disposition that was in its essenceboyish and simple and in every private relation easyand mild and kind.

METHODS OF INVESTIGATION IN NEUROLOGY.The pioneer work of Horsley in the surgery of the

central nervous system has had, and must continueto have, remote and secondary effects upon thedevelopment of neurology. Whenever a region ofthe body has been made accessible to surgery, a newinsight into its pathology has resulted from the freshexperience that has been acquired of morbid processesin the living and especially of the earlier stages ofdisease. This has been abundantly shown in thecase of the abdomen and in the case of the thorax.In that of the central nervous system it is, perhaps, asyet less obvious, but it is already unmistakable andwill become increasingly so as experience accumulates.While most of us would no doubt agree that import-

ant practical knowledge is to be acquired in this way,there are probably few who look to it with much hopefor the discovery of principles of general scope andfundamental significance. As a possible source ofany wide expansion of neurological theory it is justand natural to look to laboratory methods and thestudy of animals, rather than to methods of the bed-side and to the study of man himself in his reactionsto injury and disease. In the familiar and not alwaysphilosophically made comparison between the experi-mental and clinical methods, it is usually, however,overlooked that the latter has of necessity a virtuewhich is in some degree its special possession. Thestudent whose material is man is drastically handi-capped by the limited extent to which experimentis open to him. He must take his problems as hefinds them and deny himself the help of almost allthe preliminary simplifications which are the essenceof the laboratory worker’s advantage. At the sametime, however, the conditions of his work impose uponhim a knowledge of his material at once so intimateand so wide as to constitute a situation probablyunique in the whole field of science .When we con-

sider the intensity of watchfulness which the quite,ordinary practice of neural surgery calls for and obtainsit must be obvious that the behaviour of the human-brain in the various circumstances of injury and diseaseis far better known than that of any other animal.Indeed, one of the characteristic difficulties of theclinician comes from this very abundance of the stuffof observation, and he is likely to be overwhelmed byits bulk and rendered inattentive by its familiarity.-losing amongst details his sense for larger groupings.and amidst the everyday his eye for the significant.Nevertheless, the history of science shows that oneimportant source of general ideas has been just thisvery circumstance of a close intimacy with a largerange of observed facts.The familiarity with the behaviour of the central

nervous system that has been possible since it has beenaccessible to surgical exploration and treatment, ÍrÎ>

capable of reacting in an important way on our attitudto neurologica,l theory.

THE ABSTRACT METHOD IN NEUROLOGY.There are few departments in biological science in

which what we may call abstract methods of thoughtare more naturally and inevitably used than they arclin neurology. By abstract methods I mean method?in which the single or grouped items of experience arefor convenience of thought represented by abstractedsummaries of themselves or symbols, which have ahandiness for working on in the mind that the rawundigested facts cannot possess. The discovery ofthe uses of abstraction was an event of fundamentalimportance in the evolution of science, and in theearly Greek natural philosophers we can see with whatexultation was welcomed the extension it gave tothe powers of the mind. Perfectly legitimate andindeed indispensable as the method is, it is obviouslynot applicable to all material of inquiry with equalease and safety. With what certainty and precisionthe qualities of number, space, and motion allow ofabstraction is seen in the noble achievements ofmathematics, physics, and astronomy, achievementswhich through their most recent extensions in atomicand in stellar physics have finally established theoverwhelming prestige of the method and its effectiveleadership in science.When, however, we make living matter and

living organisms the subject of study, we find,though we can by no means dispense with theuse of abstraction, it is far less effective in appli-cation and has disadvantages which it does notseem to possess in the inorganic world. In biologicalinquiry an abstract conception, though professedly nomore than a convenient summary of experience andconstantly subject to the censorship of facts, is aptto acquire a quasi-vitality of its own through whichit loses its immediate dependence on experience andcomes to dominate instead of serving. The dangerarises not so much from the extreme cases of concep-tions which easily show as flagrantly inconsistent withfacts, but from ideas primarily good and sound whichhave been endowed with a prestige that in their verynature they could not deserve. That an over-valuationof the abstract conception as an implement of researchcan deceive even the very elect could be shown bymany eminent examples. The biological writings ofHerbert Spencer are, perhaps, as good an instance ascomes readily to mind, and it is easy to trace in themhow this very weakness has led within a few yearsto their greatly diminished influence. To find so dis-tinguished a man in a state of reprobation may wellmake humble people look anxiously to their owndoctrines. and indeed which of us, for example, can askhimself without a qualm what is the exact. meaning heattaches to the abstract conception of evolution which. has dominated the biological world for half a century.! When we turn to neurology. we find the’ currency and influence of abstract conceptions verygreat, as, for example, in the theory of aphasia,. in Hughlings Jackson’s interpretation of cerebral, functions, in Monakow’s doctrine of diaschisis and so. forth. All these are doubtless, in their essence and

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originally, good and valuable conceptions. It isanother matter, however, how far their function asprofessed summaries of experience is kept distinctfrom their charm as mere intellectual patterns. It isthus peculiarly necessary for neurology to submit itselfto the discipline of frequent returns to thecomparatively primitive and clumsy method ofdirect and concrete thinking. Such efforts should, Ithink, be guided by’two principles. The first is theobvious one that a constant and docile reference toexperience is indispensable. The second is, perhaps,less obvious and is less simple to state ; it accepts thefree use of hypothesis as essential to neurologicalprogress, but it enjoins, that in drawing up our

necessarily more or less abstract conceptions of thenature and working of the nervous system, we shouldincline to the use of ideas of a definitely_ biologicaltype and should, as far as possible, avoid concepts thatin their very nature can have no direct resemblanceto what actually happens in the body. In giving toour neurological ideas this concrete and realistic tonewe shall always depend to a great extent on anintimate familiarity with the appearances and. behaviour of the actual nervous tissues. The. knowledge of this kind we possess to-day may well beregarded as having in great part grown out of Horsley’swork.The surgical neurologist is perhaps fortunately

placed for considering the nervous system in anattitude of mind at once general and concrete ; whilehe lacks the special knowledge of the anatomist, the

physiologist, and the pathologist, he is also free fromtheir special preoccupations ; while the behaviour ofthe nervous tissues in injury and disease is a matter offamiliar knowledge it is prevented from becomingcommonplace by the narrow margin of safety withinwhich he works and the serious consequences thatfollow when it is exceeded. Thus is almost forced onhim the development of views which, whatever theymay lack in the way of abstruse detail will, at any rate,always tend to be strictly realistic.

’

INJURIES TO THE LIMITING STRUCTURES OFTHE NERVOUS SYSTEM.

In illustration of this general point of view I

propose to call attention to a small group of factswhich, while they are of more or less common know-ledge, are perhaps more especially within the observa-tion of the surgeon. They are concerned with theresponses of the nervous system to certain injuries.

Division of a Nerve.-It is a very old observationthat when a mixed peripheral nerve is cut its centralend becomes swollen into a bulbous mass of densefibrous tissue. It seems sometimes to be thoughtthat this is only an occasional result of a nerve section,and is especially to be looked for when persistentpain has followed the injury. This is, of course, notthe fact. The bulbous end is the invariable and inevit-able result of a nerve section to which it is the necessaryand, so to say, physiological response. When weinquire into the exact nature of this so-called amputa-tion neuroma we find that in immediate consequenceof the section the nerve-fibres ramify and grow outfrom the cut end so that there issues from this averitable spray of fine naked axis cylinders. Theresult of this invasion is to call forth an energeticresponse from the adjacent non-neural tissue leadingto the formation of a peculiarly dense fibrous materialthat resists the spread of the nerve-fibrils and finallyencloses them in an impenetrable capsule. Withinthis limiting substance the growth of axis cylinderscontinues, but since there is no exit it can resultonly in the formation of an intricate and aimlesslyconvoluted network.

Breaches of the Spiyactt Theca.-It occasionallyhappens, usually, perhaps, in connexion with theavulsion of a spinal nerve, that a subcutaneous lacera-tion of the spinal dura occurs. More commonly thesurgeon has an opportunity of studying the effect ofbreaches of the theca in cases where a laminectomywith incision of the membranes has to be followedby a second similar operation after some weeks or

months. We find then that wherever the cerebro-spinal fluid has been able to escape into the tissues ithas been everywhere walled off by a dense imperviousmembrane so that, according to the extent to whichthe fluid has made its way, there will be a more orless complicated series of cyst-like spaces communicat-ing with the intrathecal cavity. It is the wall ofthese cystic extensions of the theca that is of interest,for it shows all the characters of the normal dura. Itis of a dense fibrous substance, its inner surface issmooth and glistening, and its outer surface, insteadof merging with the surrounding tissues like a scar,is easily separable from them along a well-markedline of cleavage.

Regeneration of the Cerebral Dura.-It is not un-common for a second cerebral operation to be necessaryin a case in which the dura mater has already beenopened or removed. If the second operation is doneafter an interval of about six weeks or more it will befound that the gap, however large, that was left inthe dura at the first operation has been closed by theformation of a new membrane having all the charactersof normal dura as above described. Among suchcharacters the most striking, and perhaps the mostconclusive of the nature of the new membrane, is itsdifferentiation from the overlying scalp, so that thelatter can be stripped away from it with ease andwithout bleeding. It is interesting to note that atone time a great deal of surgical ingenuity was expendedon evolving a plastic surgery of the dura in which gapswere closed by the insertion of fascial grafts. Suchgrafts were always remarkably successful because anew dura would have formed quite naturally andequally well without them.Here we have a group of three well-defined facts

established by countless observations and capableof confirmation at any time. They bring evidence fromdifferent parts of the nervous system disclosing even tosuperficial consideration a clear common tendency.The conclusion to which all point is that breaches ofthe normal coverings of the nervous tissues allowingcontact between the latter and other tissues of thebody result of necessity in energetic local reactions.The obvious function of such reactive processes is tore-establish the normal discontinuity between neuraland somatic tissues and to break the contact thathas caused the disturbance.We have met then, with a mechanism of a definitely

physiological type which may well prove to be con-cerned with the very nature of the nervous system.Our next inquiry will naturally be what is theimmediate agent of the reaction we are concerned with.In the case of the divided nerve it seems clear thatthe escaping naked axis cylinder is the actual irritantsubstance ; in the case of the spinal theca it is evidentthat the cerebro-spinal fluid is the effective agent;in the case of the cerebral dura it is probable that inordinary conditions with an intact arachnoid, fluidexuding through this is the excitant, though thecontact of the brain itself is doubtless also effective.It is seen then, that there is a common propertypossessed by naked nerve-fibres, by cerebro-spinalfluid, and almost certainly by the brain substanceitself, which enables these to set up in the somatictissues an energetic reaction the tendency of which isto insulate the one from the other. There is evidencethat the neural side of the contact, while effective eas an irritant, does not contribute to the newly-formedtissue which, whether in the form of the fibromatousmaterial of the bulbous nerve or in that of theextemporised dura is of purely non-neural originthough obviously a highly specialised material andno mere scar.

FUNCTIONAL EFFECTS OF ]3pE-kcREs ININSULATION.

When we see such well-defined mechanisms forthe sealing of breaches in neural insulation we naturallyshould expect to find such breaches to be of greatfunctional importance and capable of causing seriousdisturbance in the tissues unnaturally brought intocontact. There is, in fact, evidence that some effect

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on function is produced, but it is not to the mere

prevention of this that we can look to explain theactual existence of these mechanisms themselves ; thatseems to depend, as we shall see, on some far morefundamental causation. The chief evidence of dis-turbed function is seen in the case of the divided nerve.Here there are symptoms suggesting persistentexcitation of the cut end. These are always presentfrom the first, but they vary greatly in intensity.The sensation of the presence of the limb after an

amputation is universal, and it always lasts for severalweeks. Not uncommonly it is painful, and then ittends to be more persistent and may last for years.The facts suggest that the exposed nerve-fibres ofthe stump are excited by contact with the tissuesand that in the bulbous end the stimulation effectgradually dies down until a state of equilibrium isestablished in which the new tissue sealing off thenerve end is practically as inert towards the nerve asis its normal sheath.

It is natural to suppose that, after a wound of thebrain which allowed a scar of non-neural origin tocome into close contact with the brain substance astate of excitation might be set up. The frequencyof traumatic epilepsy in cases of direct scarring of thebrain is perhaps suggestive, but I know of no evidencethat allows us to take the case beyond a mere suspicion.On the somatic side of a breach of neural insulation

there is no disturbance of function beyond the merereaction already described. It is indeed characteristicof this that it is always and only strictly local. Thereis nothing in the way even of a diffuse or spreadingfibrosis, the new tissue whether it be an amputationneuroma or a new segment of dura, and although itis of somatic origin, becomes sharply differentiated fromthe tissues it is derived from and can be separated fromthem easily without cutting. We see therefore thatalthough breaches of neural insulation are immediatelydealt with by energetic, effective, and highly specialisedmechanisms, the actual disturbances of functionproduced by such breaches do not seem to be veryimportant.INSULATORY ARRA1 GEiVIENTS IN THE 1’;" OR;.BIAL

NERVOUS SYSTEM.If the evidence I have cited bears the meaning I

have given it and we can regard as of high importanceto the body the maintenance of neural insulation,then we can look for confirmation in normal structureand expect to find dispositions in relation to the nervoussystem which are insulatory in function. From thenature of the reaction we have seen to be set up bybreaches of insulation we may infer that the influenceagainst which insulatory mechanisms are provided ischemical in kind, and this inference may serve as aguiding principle in the search.

Insulation of the Peripheral Ner1!es.-Beginning oursurvey with the peripheral nerves, we may at oncedismiss from consideration the medullarv sheathwhich, whatever its physical insulatory function maybe, is clearly not in question as a chemical insulant,since non-medullated nerves lie as peacefully and asinert in the tissues as the medullated. The case isdifferent, however, with the neurilemma. Here wehave a sheath common to all nerves outside the centralaxis, and continuous without a break from spinalcord or brain to end-organ. The motor nerve-fibreis clothed from within the central nervous system tothe muscle-fibre, where the neurilemma completes thesealing off of unnatural contacts by becomingcontinuous with the sarcolemma itself. The sensoryfibres are similarly clothed throughout their length :at their peripheral termination they enter end-organs,all of which throughout a great variety of structurEshow-with one suggestive exception-so marked arencapsulatory arrangement that one cannot but thintthat here the need for insulation must be especiallyvital. The one sensory nerve-fibre which is knowrto terminate in an end-organ which is not of a strongl)capsular type is the fibre that serves the sense o:

pain. This fibre ends in a free arborisation in th<tissue to which it is distributed and this terminal part

is uncovered by neurilemma. It cannot but strike usas significant, though I shall not take up the pointfurther at the moment, that this anomaly of a sensoryfibre making naked contact with the somatic tissues,should be a character of the fibre concerned with pain,a form of sensibility that in itself is so profoundlyanomalous.The view that the neurilemma is the chemically

insulating structure we are looking for is confirmedby the fact that within the central nervous systemwhere insulation is otherwise provided it is defectiveor altogether absent. A point further suggestive ofthe importance of insulation in the peripheral nervesis the evidence we have that there is an upwarddrainage along their trunks, so that the products oftheir metabolism are probably kept from contactwith surrounding tissues and are conveyed into thecentral theca.

I nsuZation of the Centrccl Nervous Sysfem.- ’Yhen weturn to the central nervous system we find that themethod of individual insulation no longer prevails,but that the whole mass of the central axis is protectedas one unit. Plainly, of course, it is the meningeswhich are chiefly concerned. Of these we have =

already seen that the dura has so important a functionthat accidental defects in it are repaired withvery remarkable rapidity and completeness. Themechanically protective function of the dura whichdoubtless has its importance can scarcely be regardedas explaining its peculiarly impervious texture, itsdouble endothelial surface, and the marked line ofcleavage that separates it even when newly formedfrom the surrounding tissues. All these, however,acquire meaning when they are regarded as evidenceof its chemically ;Psttl.,tioiy capacitv. Effective as thedura doubtless is in its way, it deals only with onerelatively small part of the problem of insulation. Ifwe are right in supposing that all neuro-somaticcontacts are inadmissible, and that the blood andblood-vessels belong to the somatic side of the frontier,the nutrition of so large a bulk of nervous tissue asthe central nervous system must involve dispositionsaltogether unique in the. body, and we should expectin regarding the circulatory mechanisms of the partfrom this point of view to meet with features ofa very special kind.The cerebro-spinal fluid and its circulation, the

existence and disposition of the multiple membranesof the brain, and the absence of a recognisable

lymphatic system in the ordinary sense of the term,, constitute a picture which is unique and has admittedly

defied thorough explanation. Let us consider it in

, relation to the avoidance of undue contact between

i neural and non-neural elements.

THE CEREP.RO-SPIXAL FLUID.. Let me briefly review the strange facts of the physiology of the cerebro-spinal fluid as they are nowknown. The cerebro-spinal fluid is an extremely, dilute secretion profusely poured out by the choroid, plexuses of the cerebral ventricles. It flows through3the central cavities of the brain and issues therefrom9 through the roof of the fourth ventricle into the sub- arachnoid space. Through this so-called space, which1 has rather the structure of a cellular spongework, it1 courses, partly into the spinal canal but chiefly upwards and forwards over the brain to escape into) the venous circulation through the arachnoid villi that project into the various lateral extensions of the superior longitudinal sinus. As is well known, anyr obstruction to the flow in any part of this intricate; course downwards within the brain and upwards, outside of it inevitably leads to an accumulation ofe the fluid and to hydrocephalus. Such obstructionsz are easily produced and common. The cerebro-spinal.: fluid with its circulation, whatever function it mayy be there to perform, shows itself thus to constitutez a weak spot in the cerebral organisation that, as ity were, invites pathological attack. That the cerebralf apparatus should contain an arrangement in somee ways so seriously disadvantageous suggests thatt the mechanism must have some deep functional

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<signiticance that is indispensable to the physiology ofthe body.

There is no lymphatic system in the ordinarysense in the brain or spinal cord and no flow outwardsthrough the cerebro-spinal envelopes of anythingcorresponding with lymph occurs anywhere. Itseems clear that products of nervous metabolism findtheir way into the cerebro-spinal fluid in the sub-arachnoid space ; there is, in fact, strong clinicalevidence that this fluid has a definite toxicity for therest of the body, for when it is liberated into the tissueshigh fever is apt to occur during the short periodbefore absorption is arrested by the inevitable reactionin the tissues that produces encystment. It is thoughtthat metabolic products reach the cerebro-spinal fluidalong the so-called perivascular lymphatics. Theseremarkable structures are tubular extensions of thesubarachnoid space which accompany and enclosethe vessels that penetrate the brain to their finestramifications. The interpretation of their meaninghas long been regarded as a great difficulty, but if weaccept the view that somatic structures like the blood-vessels cannot be admitted to direct contact withthe nervous tissues it is natural to regard the peri-vascular lymphatics as mechanisms to insulate theblood-vessels from this contact. It may be assumedfrom what we know of the nourishment of tissuesin general that there is some kind of leakage from thecerebral tissues comparable with lymph as foundeverywhere else and presumably of a not dissimilarconcentration. This fluid will find its way to thesubarachnoid space presumably by the perivascularchannels. The disposal of such a material may wellbe regarded as an exacting task. It is impregnatedwith products of nerve metabolism and is an eminently" neural "fluid capable of producing energetic reactionsin any somatic tissue it meets. Thus there can beno question of its entering the blood stream in therelatively high concentrations that are satisfactory:for lymph, and Nature meets the case by providingfor it being heavily diluted before it is allowed tojoin the somatic blood in the cranial sinuses.The most characteristic feature of the cerebro-spinal

fluid as it exudes from the choroid plexuses is its remark-ably low solid content. It is by far the most waterysecretion produced by the normal body, and one mightalmost say it is an attempt by Nature to secrete purewater. It contains a small amount of the diffusible ’isubstances of the blood, but practically nothing else. ’,So strong is the tendency to keep the fluid waterythat the choroid plexuses have a truly astonishingimpenetrability to drugs and other foreign substances ’,circulating in the blood. Even the bile-pigments incases of jaundice fail to find a passage. Thisfluid, practically amounting to nothing but water,is secreted in large quantities ; on rare occasions Ihave had the experience of seeing as the result ofaccident what was, perhaps, a large fraction of thetotal secretion of cerebro-spinal fluid discharged onthe surface. The amount of fluid escaping has beenvery large and the consequent inanition correspondinglyprofound. The normal function of this great flow ofwater we may suppose with some confidence to be toflush through the whole subarachnoid space and todilute the products of cerebral metabolism to sucha degree that the resulting fluid can be safely admittedto the general blood stream. This view gets someconfirmation from the evidence we have that the fluidin the subarachnoid space has a larger solid contentthan the fluid in the ventricles.

It, is interesting to reflect that the source of thismysterious secretion which has given so much difficultyto the chemical physiologist may turn out to be nomore abstruse a thing than Nature’s nearest approachin the animal body to a spring of plain water ; if thisshould be so it may also remind us of the small andamusing coincidence that one part at any rate of thetortuous channel through which the fluid runs-theaqueduct of SylI’&Icirc;u.’J-has since the very early days ofanatomy borne a singularly exact and appropriate name.

In our review of certain aspects of the nervoussystem we have found reason to regard as of funda-

mental importance the preservation of an impenetrablebarrier between the whole of the nervous system andthe rest of the body. This barrier we have seen tobe made up of a number of highly special structuresand mechanisms. Its function is, on the whole, toprevent contact between the neural and the non-neural, but is also in certain places to permit it. Theseplaces are only two : first, where the motor nerve-end comes into contact with the muscle-fibre, andsecondly, where the naked arborisation of the painnerve meets the tissue in which it is distributed.The nervous system is thus kept apart from the body,as we may say, in order that when the two are per-mitted to meet the reaction shall be the more energetic.It is in fact, then, of the very essence of nervous tissuethat it should be different from the other tissuesso that it can irritate and be irritated by them.This necessity for a certain " strangeness " of thenervous system may possibly throw some light onits curious embryology. The origin of the nervoussystem as an epiblastic tube originating on the surfaceof the body and then sinking into its substance hasbeen investigated chiefly from the morphologicalpoint of view, and great ingenuity and research havebeen expended on it. It may be worth suggesting,however, that the problem has also a functional side,and that the epiblastic origin of an organ that isultimately to be deeply embedded in mesoblastictissues possibly has the function of contributing itsstrangeness and, therefore, its effectiveness to thenervous system as a whole. This quasi-hostilitybetween neural and somatic, between brain and body,is a suggestive and perhaps a disturbing thought,but we shall not attempt here to follow it out.

NEURAL INSULATION IN PATHOLOGY.It is more convenient at the moment to consider

certain pathological evidence that has some bearingon the conclusions we have already reached. Thatthe central nervous system differs from other organsin having a certain inaccessibility has long beenrecognised in connexion with syphilis. The differencebetween the strictly extraneural mesoblastic infectionof the meningeal gumma on the one hand, and theintraneural parenchymatous infection of generalparalysis on the other, shows that the frontier betweenthe two regions is as sharply marked pathologicallyas it is physiologically. Moreover, the relativeinefficacy of antisyphilitic treatment in the paren-chymatous infection reminds us that the frontier isalso impassable for many drugs.The dura and arachnoid are in some sense

intermediate tissues for they show a certain tolerancefor both neural and non-neural contacts, the arachnoidhaving slightly greater affinities for the former, andthe dura perhaps for the latter. That they are,however, fundamentally non-neural in their behaviour,and probably also in their nature, is suggested stronglyby their relations to certain tumours. The gliomais probably the one truly neural tumour that affectsthe central nervous system. Although it behaveswithin the brain as a malignant infiltrating growth,its spread is restrained by the neuro-somatic barrier,so that while in exceptional cases it may affect themeninges and skull by pressure atrophy it can neverinvade them or extend to the tissues of the body. Onthe other hand, the so-called " dural endothelioma "which is relatively so common as a growth involvingarachnoid and dura, frequently shows the power toinfiltrate the skull and overlying parts as a malignantneoplasm ; but although it may press deeply intothe brain it never invades it, being restrained as

effectively in the one direction as is the neural gliomain the other. The behaviour of these two tumours haslong been familiar, but seems always to have beenaccepted as very much a matter of course. It isperhaps more reasonable to regard it as one of themost significant anomalies in the whole of pathology.Our final pathological illustration takes us back to

the peripheral nerve. We have already seen that thisis the only part of the nervous system where a breachof insulation produces immediate and definite

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disturbance of function. The neurilemma seems

fortunately, however, to be an exceedingly effectivebarrier between neural and somatic tissues. There isclinical evidence that a relatively slight subcutaneousinjury can lead to the formation of a neuro-fibromapresumably through damage to the neurilemma ; butthis is a rare event of little practical importance, andfailing gross injury the insulatory mechanism iswholly satisfactory. That this is the result of effectiverestraint rather than inertia on the side of the nervoussystem is perhaps shown by that fortunately rare

complaint multiple neuro-fibromatosis or Reckling-hausen’s disease. In this condition it has beenshown that every fibromatous formation, localised ordiffuse, contains nerve-fibrils which presumably bytheir irritant qualities have given rise to the fibrosismuch as might a foreign body or a micro-organism ofhighly attenuated virulence. It seems clear that itis the presence on a large scale of nerve-fibrils outsidetheir normal insulating sheath which is the proximatecause of the morbid state. It may be doubted whetherthe neural leakage is a primary manifestation or isdue to an essential weakness or collapse of the insulat-ing function of the neurilemma. Whether the failureof this sheath is primary or secondary, absolute’ orrelative, no one who has seen a severe case of thedisease can doubt that any general collapse of theperipheral insulatory mechanism makes the life of itsunfortunate subject almost insupportable.

INSULATION AND THE PHYSIOLOGY OF PAIN.I have already called attention to the remarkable

fact that there is one kind of sensory fibre which endsin a free arborisation in naked contact with the tissues.Our last task in dealing with the insulation of thenervous system is to examine a little more in detailthe striking anomaly that in their end-organs thepain fibres make this unique exception to the rulethat sensory fibres are insulated up to and includingtheir end-organs.

This anatomical uniqueness of the pain fibre inits end-organ is matched by the uniqueness of thephysiological characters of pain sensibility, and it isvery natural that we should desire to correlate thesetwo anomalies. Pain sensibility is remarkable inthree respects, first in the quality of the sensationitself, secondly in its threshold of sensitiveness, andthirdly in the nature of its appropriate stimuli. (a)The sensation of pain is peculiar in that it has asudden and as it were explosive way of bursting intoconsciousness, in that it calls urgently and oftenirresistibly for some kind of motor response, and inthat it is in its very nature distracting so as to beincompatible with quiet contemplation or steadyjudgment. (b) The threshold for pain stimuli isremarkably high, so that in comparison with otherforms of common sensibility the stimulus has to berelatively energetic to call forth the characteristicsensation. (c) The stimuli that call forth painsensations are remarkable for being very miscellaneous.In every other kind of sensibility but pain, the normalresponse is to a single well-defined physical change-pressure is evoked by weight, touch by movement,cold by loss of heat, warmth by access of heat. Theordinary stimulants of pain, on the other hand, such aspressure, pin-pricks, cold, heat, and the electric currentmake up a thoroughly odd class, the members of whichshow no common character. They are all capable ofproducing the characteristic sensation before, andusually long before, an intensity of stimulation isreached that can be shown to be harmful. Thatmany of the stimuli would be harmful in greaterintensities can scarcely therefore be regarded as

forming a common physical basis, but must ratherbe explained as merely a consequence of the normallyhigh threshold.When we consider these peculiarities we can hardly

regard them as those of a highly differentiatedmechanism, but rather as those of one relativelycrude. All sensibility may well have been of thiskind in organisms to which the distracting explosive qualities of the sensation would be no detriment. If

we look upon the peculiarities of pain as an evidenceof crudity rather than of differentiation it is relativelyeasy to correlate them with the uninsulated end-organof the pain fibre which we must regard as lessdifferentiated and cruder than the complex end-organs of the other fibres. Pain sensibility would thusowe its special character to being the function of a,

nerve-fibre of a peculiar kind, which while relativelyinsensitive responds in an exaggerated way when itsthreshold is reached. Presumably these charactersare to be associated with the uninsulated end-organ,and we may suspect that it is this lack of insulationwhich gives to the fibre its characteristic features ofblunt sensitivity and emphatic response.We possess a possible source of further light on

this problem in the phenomena that accompany therecovery of function in sensory nerves after divisionand immediate suture. It is well known that thisprocess as observed under experimental conditionsin the human subject by at least three independentgroups of investigators, is accompanied by remarkablemodifications in all forms of sensibility. It is impos-sible to refer to these modifications in detail, but itgives them in a broadly approximate way-and Ispeak from actual personal experience of them--tosay that they are generally in the direction of thepeculiarities shown by normal pain ; in other words,the modified sensations compared with the normal aremore explosive and more urgent, they have a higherthreshold, and they call for some kind of motorresponse. The explanation of these and the othermodifications that are to be observed during recovery ofsensory nerves has differed with different investigators.It is far too much a matter of detail to discuss thesediffering hypotheses here, but there is one criticismto be offered of some that is relevant to the generalattitude we have tried to support. This criticismis that there has been a tendency to approach theproblem in too abstract a way. It has been assumedthat the question is one of the mere return of functionsthat are present in the normal and in the form in whichthey are then present, modifications in the characterof sensation being ascribed to such factors as theorder of return and the rate of return of differentfunctions, and the modification in character of oneform of sensibility to the presence or absence ofanother. This is to assume that the processes andincidents of regeneration itself have nothing to sayto the problem ; and that the struggle between theadvancing nerve-fibres and the reaction they arousefrom the line of suture onwards can be ignored. Totake it for granted that the naked growing fibres canpass through this difficult and prolonged ordeal withoutany alteration in their function, and to limit theproblem in this way to strictly and exclusively neuralfactors, seems to me a method less concrete andpractical than the case demands.An alternative hypothesis, which is at any rate more

comprehensive and more simple, can, however, be putforward. The general tendency of all forms of sensa-tion yielded by a regenerating nerve to develop a,

certain resemblance to pain reminds us that regenerat-ing fibres resemble pain fibres in a lack of completeinsulation. It is probable, therefore, that imperfectinsulation tends to render all fibres less sensitive thannormal but more apt when effectually stimulated torespond in an exaggerated explosive way. With theadvance of regeneration the fibres serving touch, heat,and cold become once more connected with end-organs,and then their insulation, by the junction of theneurilemma with the capsule of the end-organ, canbe completed. The completely insulated fibre, havinglost its temporary resemblance to the pain fibre,becomes once more sensitive to the finer stimuli andceases to yield exaggerated responses.The process of regeneration thus seems capable of

causing a regression of function in all kinds of nerve-fibres to a cruder type that in the normal is representedonly by pain. This regression occurs because duringregeneration insulation must necessarily be defective.According to this hypothesis normal pain and thesensibility of regenerating nerves give us an insight

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into the ancestry of common sensation. Primitivesensibility of all kinds we may suppose to have beenlike pain in us ; it had a relatively high threshold, butit was effective because its sensations were urgentand explosive and. of course (also like pain in us),were exactly localised. Among such sensations finediscrimination was plainly impossible. With thedevelopment of the completely insulated nerve andend-organ, the fibres thus equipped became capableof yielding sensation to finer and to specialised stimuli,and of a quality no longer explosive but able to besubmitted to discrimination ; at the same time thelarge number of pain nerves remained in their primi-tive state to warn the body of strong stimuli by urgentsensations, among which there was no power andno need for discrimination because their functionwas to excite immediate response.

The great and manifest difference between the verte-brate and the invertebrate nervous systems is that

,-the former is centralised and the latter is scattered’throughout the body. The facts I have quoted andthe inferences I have drawn suggest the hypothesisthat side by side with centralisation and renderingit possible, insulation also must have proceeded.Insulation, on the one hand, must have been madeincreasingly necessary by the growing differentiationof neural from somatic tissues, and, on the other hand,must have helped to sharpen this very difference.It is not, therefore, surprising that a function so

fundamental is not only recognisable in the structureand behaviour of the normal nervous system, but isalso evidently at work in morbid processes and con-stitutes at once a help and a limitation to the work ofthe surgeon.

FURTHER OBSERVATIONS ON IMMUNITYIN RELATION TO

TRANSPLANTABLE MALIGNANTTUMOURS.

BY THOMAS LUMSDEN, M.D. ABERD.(From the Department of Experimental Pathology,

Lister Institute.)

THE conclusions arrived at and reported in previous Icommunications in THE LANCET 1 have been con-firmed and extended. The further experimentsdescribed below were mostly designed towardssupplying an answer to the following questions :-

(A) What is the nature of the antibodies whichcan be demonstrated to exist in the serum of ananimal (e.g., rabbit, sheep, horse) which has beenrepeatedly inoculated with tumour cells from anotherspecies (e.g., mouse, rat, man) ?

(B) When by treating one of two coexistingtumours both are caused to disappear, may we conclude that products absorbed from the regressingtreated tumour effect the cure of the untreatedtumour by giving rise to antibodies in the host’sblood or tissues ?

. (C) When an animal has been rendered resistantto a particular tumour wherein does its immunityconsist ? The methods employed in these investigations

were (except where detailed below) those describedin the papers above referred to.

’

Antiserum Treatment in Vivo.

, To 50 rats bearing a J.R.2 sarcoma of each hind

foot, varying in size from a green pea to a haricotbean, treatment was applied as follows :-

In 38 rats 0-9 c.cni. of anti J.R.S. serum was injected inthree doses of 0.3 c.cm. each. the circulation in the footbeing coincidentally shut off by constriction at the anklefor 2-3 hours. Tn all of these animals the tumour of. the

1 THE LANCET, July 12th, 1924, and Feb. 21st and Sept. 12th,1925.

2 J.R.S. is an abbreviation for Jensen’s rat sarcoma ; M63for the mouse carcinoma, so named by the Imperial CancerResearch Laboratory.

treated foot disappeared rapidly, while in 37, about 7-10days later, regression began also in the untreated foot andwent on to complete cure. In one rat, probably becausethe treated tumour was too severely constricted, theuntreated tumour grew progressively. The fact that inthese cases the untreated tumour only begins to absorbfrom 7-10 days after the cure of the treated tumour, indicatesthat the regression is not spontaneous but is due to treatment.This view is corroborated by the fact that of the 50 controluntreated animals only in five did the tumours regress.Fig. 1 shows the condition of the tumours in the last24 controls when the experiment ended ; it will be noticedthat in all except two of these, progressive tumours havedeveloped. In 12 rats of this series of 50, cure was effectedwithout constriction by means of repeated inoculations ofantiserum into and around the tumour. Of this dozenanimals, in six the antiserum used was one made againstmouse carcinoma (M63). Even in these 12 rats it is possiblethat part at least of the curative effect was due to inter-ference with the vascular supply, for not infrequentlyhaemorrhages occur into the tumour after the antiserum hasbeen injected.

In a previous paper 3 it was reported that after cureof their feet in the above way rats were found to beabsolutely immune to the tumour concerned. It isnow possible to state that this immunity is of longduration. A test inoculation was given to 50 ratssix months after their recovery. Of these, onlytwo developed progressive tumours, the other 48were still completely resistant to a sarcoma whichgrew rapidly in all of 12 normal animals inoculatedwith identical material at the same time. It musthere be reiterated that striking results can onlybe obtained by using a tumour of great virulenceand in its most active phase, otherwise so many ofthe control tumours might regress as to lessen thecogency of the experiment.

In a large number of animals the attempt wasmade to cause the disappearance of tumoursof each flank in the above way. The resultswere not very satisfactory. The tumours growso rapidly as to cause death in three or at mostfour weeks. Thus the untreated tumour attainsenormous proportions before the regression ofthe treated tumour can influence its growth, bywhich time the defence mechanism of the animalappears to have broken down completely. In thelast 20 animals a second tumour was inoculateda week later than the tumour which it was intendedto treat. Of these animals, in six regression of thetreated tumour was followed by absorption of theuntreated tumour and the animals were thereafterfound to be immune ; in ten the attempt to cure thelarger tumour failed and both tumours grew progres-sively, while in four rats the treated tumour was soseverely constricted that it separated after a day ortwo and no effect was produced on the smalleruntreated tumour. It appears that in order to effectewe and evoke immunity gradual regression of thetreated tumour is essential.

Attentuation.Many attempts were made to attenuate J.R.S.

cells (by heat, by cold, by autolysis, and by treatingthe cells in vitro with antiserum, &c.), so that wheninoculated into a tumour-bearing animal an effectcomparable with that produced by gradual regressionof one of two tumours should be obtained. Theseattempts were unsuccessful. Frequently attenuationwas not carried far enough and a fresh tumour aroseat the spot where the attenuated cells were injected.Even when this did not happen not only was itfound impracticable to cure an animal in this way,but the attempt to produce immunity to a subsequenttest inoculation also failed. The only successfulexperiment, inconclusive on account of the smallnumber of animals used, was one in which J.R.S.fragments coated with agar were injected into threerats bearing a tumour and into three healthy rats.Xo curative effect was noticed but the three healthyrats were found two weeks later to be immune, whilethree control rats of similar breed, given a testinoculation with the same material, all developed

3 THE LANCET, Sept. 12th, 1925.