Acta Medica Scandinavica. Vol. CXXI, fasc. I, 1945.

From the Medical Clinic (Director: Professor Sven Ingvar) of the Royal University a t Lund (Sweden).

Contribution to the knowledge of the pathogenesis of amyotrophic lateral sclerosis.

BY

ERIK ASK-UPMARK, M. D. (Submitted for publication January 16, 1945).

Amyotrophic lateral sclerosis is, although a rather rare disease, of particular interest with regard to the nosography, since i t repre- sents a syndrom involving the upper as well as the lower motor neuron. The symptomatology is hence extremely characteristic; the connection of atrophy of the muscles of the hand, particularly so the thenar and hypothenar eminences, with pyraniidal symptoms, not least so with regard to the reflexes of the arm, and the absence of any sensory disturbances, is resembled by no other organic dis- order of the nervous system. The disease thus represents a well- defined entity with regard to the clinical diagnosis, corresponding to a most typical pathological anatomy, affecting the motor cortex, the pjTamida1 tracts, the bulbar nuclei and the anterior horn cells. Whilst our knowledge about the clinical pathology hence is fairly complete, the problems about etiology and pathogenesis have remained almost a8 obscure as the therapeutical achievements have been poor. Briefly summarized, the following factors have been accused as causative agents.

1. ,Exposure to cold, privation, fright, irijuries such as fall on the back, virus and bacterial infections and toxic processes includ- ing lead poisoning - - - syphilis, chronic encephalitis - - - %

4 - Acta med. scandinav. Vol. CXXZ.

50 ERIK ASK-UPMARK.

(Davison in his chapter on amyotrophic lateral sclerosis inTices Medicine).

2. An abiotrophy of the motor system, which is considered to have certain potentialities but when, towards the middle age, the strain on the system becomes too great degeneration is liable to start (Spiller and others).

3. An avitaminosis, represented possibly by the deficiency of vitamin E. This theory is based mainly on certain experiments in animals, which have been deprived of vitamin E and eventually developed a motor syndrom, somewhat resembling the disorder in question (Einarson et al.).

The present paper will attempt to furnish a contribution to our knowledge about these questions. I t is based upon three cases, in whom amyotrophic lateral sclerosis has developed as a compli- cation to ohter disorders of the nervous system. The observations run briefly as follows.

Material.

Case 1. Woman, aged. 63, unmarried. Applied to m y office Dee. 12th 1949. Invalidity since the age of 11, when she had poliomyelitis, with paresis of both legs. With the assistance of orthopedic boots and one stick she has been able to carry on to some degree indoors, busying herself with nursery and educational work but also with knitting and such works, her arms and hands being unaffected by the poliomyelitis. When outdoors she has been driving a tricycle by means of her arms. Last 5 years her hands, most so the right one, have been impaired, she has been unable to do small movements such as pulling a watch, knitting, writing. These sym- ptoms have been particularly pronounced during the last year. - General condition good. Blood pressure lSO/lOO. Both legs severely paretic, atrop- hied, cyanotic. Babinski negative. The thenar and to some degree the hypothenar eminences of the hands, most so the right, are atrophied, whilst the sensibility is entirely unimpaired and the reflexes of the arm are markedly increased.

There could be no reasonable doubt with regaro to the diagno- sis: amyotrophic lateral sclerosis in a woman, previously disabled by poliomyelitis of her legs. Subsequent examinations on repeated occasions have confirmed this impression.

Case 2. Woman, aged 46, unmarriad. (Med. Clin. 2104 and 284811939; admitted Aug. Zlth, died Oct. 19th 1989). When 18 years of age poliomyelitis, causing remaining paralysis of both legs and paresis of lower half of the

C O N T R I B U T I O N TO THE K N O W L E D G E OF THE PATHOGENESIS OF ETC. 51

trunc but leaving the arms unaffected. By means of crutches and ortho- pedic bandages she has been able to carry on and was during the last 18 years teacher in a department for disabled. Nov. 8th 1937, i. e. not quite two years ago, she had an accident when one of the crutches gave away: she fell towards the wall with the right side of her head whilst the right shoulder was forced downwards, and the head thus bent over to the left side. She felt pains in the left half of her neck and her left shoulder but it was not until about 3 weeks later that a certain weakness of the left shoulder and the left arm did appear, connected with severe tremor. The pains and the tremor disappeared but the paresis of the arm eventually progressed so that in Sept. 1938 she was unable to use this arm. Examinations in other hospitals revealed a certain atrophy of the left arm and considerably increased reflexes of both arms, even clonus was obtained and Tromner was positive. Jan. 1939: the right arm began to be paretic, at first in the shoulder, later on also in its distal parts. During this year (1939) the speech has been im- paired and slurred and a t times dysphagia has been present as well.- The examination in the hospital on admittance did reveal a fair general condition, a moderately increased blood pressure (190/110), normal blood morphology and temperature, tachycardia. Neurologically she had without doubt a poor facial motility (masque), a complete, flaccid paralysis of both legs and abdominal wall, paralysis of the left arm and hand and paresis of the right shoulder and arm; the reflexes of the arms were extremely spastic, even so as to produce clonus. Her speech was difficult and slurred. Whilst in the clinic her general condition went downhills, urinary infection appear- ed, drowsiness became pronounced, the difficulties to speak and to swallow increased and she died Oct. 19th.

In this case the diagnosis was difficult. I t was perfectly obvious that she had an old poliomyelitis, it was probable that she had achieved a certain Parkinsonism but the increased reflexes and the obvious pareses of the a r m called for additional explanation. On account of the accident she had remained, during lifetime, a problem to the Accident Board. No injuries to the bones in her neck were brought about and as for a plexus injury this possibility was ruled out already by the fact that the paresis did not appear until 3 weeks after the accident, let alone that it was of spastic charac- ter. The possibility of amyotrophic lateral sclerosis was considered since the sensibility was entirely unaffected but the obvious Par- kinsonism made it a bit uneasy to add a third disorder of the nerv- ous system. The necropsy, however, which was performed by pro- fessor E. Sjovall, revealed besides of the old poliomyelitis not only a chroniciting process in corpus striatum and the unpigmented part of substantia nigra but also a most typical amyotrophic lateral sclerosis (fig. 1).

52 E R I K A S K - I l ' h l . \ l l K

Fig. 1 a. Transection of spinal cord in case 2, stained ad modum Spielmeyer. The involvement of the pyramidal tracts is easily to be recognized.

fig. 1. b. Transection of spinal cord in case 2, stained ad modum Mallory. The sclerosis of the anterior horns by means of gliosis is to be seen.

Case 3. Man, aged 39 ( M e d . Clin. 3027!1944; previously examined in rhe clinic 1936, 1939 and 1940). Congenital spina bifida of L 3, L 4, L 5 and sacrum + Meningocele in the lumbar region + Hypertrichosis of the same region. Previously essentially in good health. 1933, i. e. 11 years ago dyspeptic disturbances, causing him to use diet; radiography of the stomach and the duodenum failed to disclose anything abnormal. During the last 10 years increasing weakness and rigidity of the legs, most so the

CONTRIBUTION 1'0 THE K N O W L E D G E OF T E E PATHOGENESIS OF ETC. 53

Fig. 2. The hands of case 3. l h e marked atrophy of the muscles of the right hand is to be recognlzed. No disturbances of the sensibility Pronounced spastlc

reflexes.

right one. Observed on several occasions in the clinic, presenting rigidity and spasticity of the legs (particularly the right), positive Babinski and po- sitive Oppmheim. The meningocele was operated in 1936 with no improve- ment with regard to the legs. Various orthopedic interventions have been performed (tenotomy in the inguinal regions in 1942, orthopedic boots in 1943). During the last 5 years the symptoms have made it impossiblefor him to walk except by the help of a stick; he had also to give up carpenting, gardening etc. by means of which he had busied himself since the onset of the symptoms, previously doing engineering and driving. About 5 years ago a weakness was felt in the right hand and this weakness has conti- nuously increased so that he, by now, is unable to use the hand for writing, dressing, eating and so on; the paresis has engaged also the right arm 80 that he has difficulties to put the right hand to the mouth. His general condi- tion was at first fairly good but eventually the nutrition has suffered: his appetite has been very poor, disappearing already when he saw the food, he has had certain abdominal discomfort (dyspeptic disturbances from fat food) and his ability of eating has been impaired also by the con- dition of his right hand and arm and by his very poor dental state. His bowels have become sluggish and for the last 5 years he has had a feeling of anesthesia in the rectum, so that he is unable to feel when the defeca- tion has been completely performed. The left eye has had a cataract for at least 9 years, more so during recent years. - The examination in the clinic revealed a somewhat reduced nutrition, a normal blood pressure and normal conditions from lungs, heart and abdomen, as observed by the physical examination. Dental condition poor. Mental abilities normal. al- though he for obvious reasons is somewhat depressed. He is able to walk by means of a stick but the gait is very much impaired, the right leg being al- most completely paralytic. Babinski was positive, ankle jerks not to be eli-

54 E R I K A S K - U P M A R K

cited. The left arm and hand does not present any paresis but he is unable to put his right hand in the neck. The right hand presents a most pro- nounced muscular atrophy and he is unable to extend the fingers; as a mat- ter of fact it is a typical claw hand (main en griffe). The reflexes of both arms are considerably increased, Hoffman positive in both hands. The sensibility is entirely unimpaired. On previous occasions Wassermann has been examined repeatedly in blood and liquor and always been found negative. Myelography by means of air was performed some year ago and failed to disclose'any expansive lesion nhatsoever in the spinal canal, which was on the contrary rather wide in its distal parts, owing probably to the vertebral malformations present.

In this case the character of the lesion of the legs is difficult to ascertain but it seems probable that i t is connected with the mal- formational conditions, demonstrated hy the presence of a spina bifida + meningocele. The fact that the symptoms did not appear until the age of 20 does by no means rule out this possibility. With regard to the lesion of the arms, the connection of pronounced atrophy of the muscles of the hand with the intensely increased reflexes of the arms, the positive Hoffman and the unimpaired sen- sibility makes i t probable that it deals with amyotrophic Iateral sclerosis. I t should be observed that the disorder of the legs did precede that of the hand by 5 years.

Comment and discussion. Among the three cases liere described the diagnosis seems to

be established with reasonable certainty by clinical nieans in the first and the last case, in the second case, which was perhaps the most complicated one, the diagnosis was suspected in vivo and eventually confirmed by the necropsy. All three cases have in common the developnient of amyotropldc lateral sclerosis in indi- viduals previously disabled by other diseases with regard to the motility of their legs, in case (1) and (2) by poliomyelitis, in case (3) by a malformational condition of the spinal cord. 1 In all three

A fourth simllar case may or may not be represented by an old woman in the seventies who applied for assistance at my office because of a very severe arthrosis deformans of the hip joints, which had forced her to use crutches for several years. The muscles of her hands were wfthout doubt atrophied as in amyotrophic lateral scIemsis, a mrrespondng weakness of the hands was experienced as well and no sensory disturbances suggesting any neuritls or syringompelia were to be elicited. The reflexes of the arm8 were obviously vivid but if they were increased I could not tell with certainty, because of which this case has been excluded from the material, although it was felt to represent an amyotrophic lateral sclerosis as well.

CONTRIBUTION TO THE KNOWLEDGE O F T H E P.4THOGENESIS OF ETC. 55

instances the patients had to rely upon their arms and hands not only for the daily work but more or less also for the locomotion. I t seems entirely possible that the heavy strain hence exerted upon the system of available motor neurons is liable to favour the appearance of the disorder in question. If such be the case one has obviously to reckon with the possibility of the development of amyotrophic lateral sclerosis in individuals accordingly disabled. The objections may be raised on the one side that not all indi- viduals with more or less immobilized legs do present the syndrom here discussed, on the other hand that several instances of amyo- trophic lateral sclerosis are liable to appear unheralded by another disorder of the legs. It is however obvious that the factor here stressed as responsible - the undue surmenage or exertion of the motor system in order to compensate the immobility otherwise experienced -. should only be looked upon as a contributory cause. l h e aspect here marshalled is, however, entirely compatible with the idea of an abiotrophy of the motor system: in individuals ac- cordingly disposed this abiotrophy is liable to be facilitated by the strain on the motor neurons still available for use. It is by no means impossible to harmonize this apprehension with the Observations suggesting a deficiency disease due to the lack of necessary sub- stances such as perhaps vitamin E. It is perfectly obvious that the nervous system and not least so the motor neurons are apt to suffer from a malnutrition and it may be remembered that in an otherwise entirely different condition, polioencephalitis hemorrha- gica superior Wernicke, conclusive evidence has been brought forward, suggesting the character of a deficiency syndrom (cfr Neu- burger’s observations in man, Pu tnam-Alexander’s in pigeons); the same goes, of course, for the affection of the spinal cord in per- nicious anemia. With regard to the nutrition in the present mate- rial it may be said that case (2) and case (3) represented poor people, where the nutrition with certainty was not too good and whilst case (1) was fairly well-off her manual disability had advanced rapidly in connection with the restrictions necessitated by the war condi- tions. It seems important that in the future due regard is given to the nutritional conditions when analyzing a case of amyotrophic lateral sclerosis; the presence of a severe gastritis may mean some- thing. The matter is another evidence for the importance of a close connetcion between general medicine and neurology.

56 ERIK ASK-UPMARK.

Briefly summarizing the discussion i t may be said that the following factors are liable to be of importance for the development of amyotrophic lateral sclerosis: --

1. An individual dispositioii towards abiotrophy of the motor system, as supposed by Spiller and others.

2. An undue strain exerted upon the niotor system available, as demonstrated by the present material.

3. A nialnutritional factor, possibly represented by vitamin E, as suggested by Einarson and Ringstell (1939).

With regard to the other causes, occasionally accused, the ma- terial did not yield any conrtibutions. I t is true that incase(2)a traumatic injury did precede the development of the syndrom but although a connection with trauma is suggested by some authors it is difficult to see how such a correlation may be brought about; in cases (1) and (3) no injuries were present. Case (2) was remark- able also with regard to the presence of an extrapyramidal syndrome but since the amyotrophic lateral sclerosis represents an affection of the pyramidal system it is difficult to untangle any correlations, although it may be admitted that a common cause (exertion'! defi- ciency?) may be responsible for both affections (Wimmer has sug- gested a #chronic encephalitis, as a possible causative agent in amyotrophic lateral sclerosis).

Summary and Conclusions.

1. Three cases of amyotrophic lateral sclerosis are described, in whom the disease appeared as a complication to a previous long- standing disability of the legs, caused hy other disorders (polio- myelitis, malformations).

2. It is suggested that the heavy strain, exerted on the motor system available for use, in order to compensate the immobility otherwise present, may favour the development of amyotrophic lateral sclerosis. This aspect is compatible not only with the appre- hension of an abiotrophy hut also with the probable importance of a malnutritional factor.