A CASE OF AMYOTROPHIC LATERAL SCLEROSIS COMPLICATED BY PROGRESSIVE LIPODYSTROPHY)

By J. (rOSTOWSKI, Consultant Neurologist to the Royal Edinburgh Hospital for Mental and Nervous Disorders

and JAMES F.[McHARG^M.B., M.R.C.P.E., D.P.M. Assistant Physician to the Royal Edinburgh Hospital for Mental and Nervous Disorders

Introduction Since the classical description of amyotrophic lateral sclerosis by ^arcot (1865) various atypical cases have been described. Special j^tention has been drawn to additional signs and symptoms indicating S1?ns other than those of the upper and lower motor neurone, which

. ake it necessary to consider disseminated sclerosis or syringomyelia the differential diagnosis. In some instances the peripheral nerves ave been affected?as in the so-called pseudopolyneuritic form of j^yotrophic lateral sclerosis. In many of the cases cited the pathology ^as been consistent with the clinical picture. It has shown that the . ^enerative process has not been restricted to the motor tracts but has lny?lved also other tracts (sensory and cerebellar pathways of the sP1nal cord) and that it has even affected wide areas of the brain stem and hemispheres as well. Moreover, the literature shows that very rarely involvement of sensory nerves has been observed. No special has been paid to these conditions, however, so that we think ^tentione Publication of such a case, distinct from even the most atypical ases, may be justified.

Case History

M. M. P., aged 24 years. Admitted 26/11/48. ?1n^aints-?At the time of admission to the 0f d hospital patient complained the hands which caused her to thi ea^ness> Poor eyesight and weakness of drop nSs. In some an to addition, she described difficulty with speech, inability rinkle her forehead and a general weakness and tiredness with feelings of ^fort across the chest, in the neck and in the lumbar region. was entirely negative. The father S history.?The family history as a alty chauffeur. Apart from nephrectomy following an injury he has enj?yed g??d health. The mother also has enjoyed excellent health exce^S ^0r a certain amount of nervous trouble at the time of the menopause. beetl^a^ent has three adult brothers who are in good health and who have in A1 in the services. There was no history of any nervous disease theCate?oryPatlent's or relatives. Y0l forebears other LX. no. 6 281 s 282 J. ROSTOWSKI AND JAMES F. McHARG

Personal History and Previous Illnesses.?The patient was born in 1924 and the birth was normal. She was a happy, contented child and a satisfactory scholar. By nature she was always even-tempered, helpful at home and popular with her workmates. In childhood she suffered from measles and mumps, but these were not followed by any complications. In fact before puberty she was a normal healthy child. Present Illness.?At the time of the menarche in 1937, when she was 13> eve11 she began to lack energy and was always wanting to lie down. She was she off school for a period because of her tiredness. It was at that time that the began to complain of deafness which to begin with was more marked in ^'aS right ear. Her mother states that at the start of the illness her hearing impaired and remained impaired, but not markedly so, for several years- Sometimes she would hear certain voices?especially high pitched voices^ better than others. Her hearing was changeable, being better at certain time? ^aS than at others. Sometimes she said she could hear the birds singing. It also thought that she could hear better against a background of noise. She was referred, at the beginning of the illness, to the E.N.T. Department011 of the Royal Infirmary, Edinburgh, and was seen there for the first time ^ 16th November 1937. She attended regularly over a period of months. first little in the way of objective findings could be made out and it was suspecte^ ' that her complaints were functional. Nevertheless, on 5th February i9<3 was a reduction in the U.T.L. observed. _ ^ Simultaneously with the onset of her deafness, or after it, she shortly notic^ ' her eyesight failing. On 13th April 1939 she was referred by the E.N- e) specialist to the Eye Department. Her vision at that time was 6/24 in each but on examination there was no objective abnormality in the fundus and agal11 the impression was of a functional disorder. After that time, however, her vision deteriorated to a certain extent and . " Tifl mother remembers that one day she came home and said Oh, mummy? going blind." t She became rather shy of company by reason of her deafness, but ap^ from that she was not at the of i7 greatly troubled by symptoms and age ^ able to run the house single-handed for a year. She started work threa> dressmaker in 1944 at the age of 20. Having to work with needle and she was to notice that her was unsatisfac compelled quite definitely eyesight ^ and she went once more to the Eye Department. According to the was that that she a of in eachre^.e it found by time had visual acuity 6/36 ^ riot associated with a degree of optic atrophy, the origin of which could determined. The W.R. was negative. In she underwent a examination but , 1945 complete general apart ^ e% signs, which had already been noted, no additional features were elicited for a transitory renal glycosuria. jte de In she was seen Dr Simson who made the February 1947 by Hall, ^ diagnosis of a nerve deafness and recommended a hearing aid. An audi?? indicated that the question of a fenestration operation did not arise. From 1944 until 1948 she continued at her work as a dressmaker t0^ satisfaction of her employers. Apart from the condition of her hearing her eyesight, which remained the same, she was fairly well. It was in May 1948 that the present phase of her illness began. Her noticed that she was generally weak, easily tired and exhausted and AMYOTROPHIC LATERAL SCLEROSIS 283 able to walk. Also she was going down in weight and losing fat mostly on the trunk but not on the arms. Later, she became thin all over the body. Her voice also seemed to become high-pitched at times and she had difficulty in the use ?f her . She complained spontaneously to her mother that she could wrinkle her brow. During her work she started to drop articles from her hands. Her writing became very bad. She developed increasing lassitude and transient numbness of the left leg when it was tired by walking. Her hearing was deteriorating rapidly. Before admission to this hospital she was e*amined on several occasions and apart from the nerve deafness, her other symptoms were still regarded as being essentially hysterical. For this reason, ?n 3ist August 1948, she was seen by Professor Sir David Henderson, who Suggested her admission to hospital for full investigation. a . While waiting for admission there was worsening of her symptoms with lncreased giddiness, transitory loss of power, and loss of weight. Because of this her admission to Jordanburn Nerve Hospital was expedited.

Physical Findings On Admission.?The general appearance is of a thin, pallid and almost Satiated girl. J he cardiovascular, respiratory, alimentary, haematopoietic and urinary systerns all show no abnormality. The urine itself is normal.

. ^ is striking that except for the breasts there is no fat deposit on the trunk, iri the upper limbs and on the buttocks and hips whereas the thighs and calves aPpear normal. The skin itself shows no change. It can easily be pinched UP and one feels there is no subcutaneous fatty tissue. ^he facial appearance is lean and drawn. The pupils are regular and j^ual. Occasionally, however, one is bigger than the other. Both pupils ,act Well to light and accommodation. Inspection of the fundi of the eyes Qf0Ws bilateral temporal atrophy and this is associated with central vision 6/24 on both sides. There is no reduction of the visual fields taken by hand ?vements. The third, fourth and sixth are all normal; no or , PioPia. There is slight nystagmus to the right and left (three four jerks) en the eyes are in the extreme positions to the right and to the left. ^ere *s no sensory disturbance in the distribution of the trigeminal nerve. Th e corneal are normal. There is an atrophy of both masseter muscles, : the can chew The , ^eir power is preserved and patient properly. jaw 1S not increased. The lips seem to be thinner than normal. The patient i^11 Purse the lips and blow out the cheeks. On the other hand, she has difficulty her forehead and she still complains of the tightness there, which Wa^nkling?nG initial in Orbicularis oculi and oris muscles are symptoms 1948. ^0rmal and there is no twitching of the facial muscles. confirms that both ear (jr Xamination by the E.N.T. specialist (13/12/48) test on left and Sjj appear healthy and normal. Rinne negative right, lin aPPears to have a severe degree of bilateral nerve deafness and is a good p~reader. " test (Dr A. Brownlie Smith) shows : An almost complete dejLUdiometry66 low nerve deafness with retention of only a few of the high notes. The Hery^01"68 are completely lost and this is not typical of the common type of J; deafness where the high notes are lost before the lower ones." e caloric no from either Hyst tests show response ear?there is neither agnius nor deviation of the trunk and extremities. 284 J- ROSTOWSKI AND JAMES F. McHARG

Head movements are normal; no wasting of the sterno-mastoid muscles or of the trapezius. The tongue is atrophic and shows many fissures and slight tremor. It is normally protruded and movements to the right and left are normal. The palate is in the normal position and on phonation it moves normally. The pharyngeal is diminished. The voice is monotonous and usually whispered. When the patient does " break into phonation, however, she always speaks shrilly and with a dea* voice." There is a partial double abductor paresis and the cords do not move lS out beyond the midposition. She has slight difficulty in and her always careful to sip her tea because drinking in the normal way makes cough. On the other hand, fluids are never regurgitated through the nose. Upper Limbs.?There is very marked wasting of the thenar, hypothenar> interossei and lumbricales muscles of both hands and in the muscles of forearms. The spaces between the thumbs and forefingers are hollowed the interosseal spaces are deep and the palms flattened out, so that the tendons of the long flexors are visible (Fig. i).

Fig. i.

Both flexion and extension, as well as radial and ulnar deviation 01 wea wrists, are performed with normal power, extension being slightly than flexion on the left side. Abduction and adduction are weak flexion of the thumbs very ; ^ proximal phalanges and opposition of the thumbs are absent. Extension flexion the distal of the is of phalanx thumb normal. e. m Between the and left hand there are certain differences in the right ^ ments the rest of the : the third of fingers. Right hand and fourth finger? ^. constantly bent at the metacarpo-phalangeal joints and cannot be exten 0 ^ at also extension the interphalangeal joints is impossible. Extension t0 index and fifth finger is preserved. Flexion of all fingers, from the seconfllld fifth, normal, with good power. Opposition of the fifth finger, abduction ^ adduction of all fingers almost nil. Left hand : the third, fourth and no ^ are bent and cannot be extended. Flexion fingers constantly they ^ with quite good power. Abduction and adduction of the fingers nil. 0 tion and pronation on both sides normal. The muscles of the shoulder ^ the biceps and triceps, show good motor power. It is difficult to judge they are reduced in size or not as the patient is slightly built. The peC AMYOTROPHIC LATERAL SCLEROSIS 285

Muscles are partly atrophic as can be seen only when motor power is tested and the patient is contracting the muscles ; motor power is still well preserved. There is no fibrillary twitching in the upper limbs even in the atrophic muscles. The periosteal and tendon reflexes are brisk. No ataxia. No intention tremor. Report of Electrical Reactions from the Physiotherapy Department of the Royal Infirmary, Edinburgh Left Upper Limb.?No response?Extensor indicis. Complete reaction of denervation?The interossei, abductor digiti minimi and lateral two lumbricales. Weak normal reaction to Faradism and Galvanism?Flexor sublimis digitorum, opponens pollicis, abductor pollicis, medial two lumbricales, braehioradialis, extensor carpi ulnaris, extensor digitorum, extensor pollicis longus, abductor pollicis, extensor carpi radialis longus. Normal response?In the rest of the muscles of the upper limb. Right Upper Limb.?No response?Abductor and flexor pollicis brevis. Complete reaction of denervation?Lumbricales, opponens and adductor pollicis. Partial reaction of denervation?Extensor indicis, interossei. Weak normal reaction?Supinator, braehioradialis, extensor digitorum, extensor carpi ulnaris, extensor pollicis longus, abductor pollicis longus, flexor carpi ulnaris, flexor pollicis longus, flexor carpi radialis longus, flexor digitorum profundus, flexor digitorum sublimis, abductor minimi digiti. Normal reaction?In the rest of the muscles of the upper limb. -Abdominal reflexes normal and equal on both sides. Lower Limbs.?There is a very marked loss of fat on the buttocks and hips, he appearance of the lower extremities is that of a delicate, thin person, ut there is no muscular wasting and the fat deposit is better than in the other Parts of the body. Motor power is good. There is no change of tonus. Knee ankle jerks brisk. No clonus. Babinski, Oppenheim, Rossolimo negative. 0 ataxia of the lower limbs. 'Sensory System.?There is no sensory disturbance over the entire body. eriPheral nerves are not tender on pressure. The gait is normal, but while walking with the eyes shut slight unsteadiness ^PPears. The patient states that sometimes when she turns rapidly she feels .steady. Otherwise she does not complain of loss of balance. Romberg's Slgn is negative. ?^lood Wassermann is negative. - C.S.F. normal pressure. Clear colourless fluid. Cytological and chemical lngs normal. W.R. negative. A blood sugar curve was normal, ?^-ray (skull, limbs, chest) negative. r?gress hi Hospital.?During observation in hospital the loss of power in the was and of the muscles of fXtensor muscles of fingers progressive atrophy ^stal half ?f t^e forearms At the of % "i appeared. beginning April 1949 were in f0 1, ary twitchings noticed for the first time the perioral muscles, muscles of the hands. The tv tongue and in the small intensity of the ,ng is changeable but it can be easily provoked at any time by mechanical ?r ^ Passive or active movements. No fibrillary twitching was to be Seeti lri the rest of of the and lower ^ the musculature upper limbs. Visual Lx. no. 6 s 2 286 J. ROSTOWSKI AND JAMES F. McHARG

acuity diminished during hospital treatment, so that on 6th May 1949 central vision was reduced from 6/24 to 6/60 in each eye. While in hospital she developed amenorrhoea for the first time. On two or three occasions the patient wet the bed during the night but was never incontinent during the day. Her mother stated that the patient had never had bladder disturbance or nocturnal enuresis as a child. Even just prior to admission to hospital she had not noticed any difficulty in mictu- rition. An urological examination by Mr Band revealed slight cystitis to which the nocturnal incontinence was attributed. Cystometrography showed no abnormality. There has been no bowel disturbance. Her weight on admission was 6 st. 8 lb. and fell to 6 st. 6 lb. in spite of the fact that she had a good appetite and ate well?indeed sometimes excessively. The fat deposit remained more or less the same, but we formed the impression that in the last few weeks the loss of fat was also involving the breasts. She was discharged in June 1949 and has attended the out-patient depart- ment since. Her general health has improved but the atrophies of the small n1 muscles of the hand are progressive and there are visible fibrillary twitches the sterno-cleido-mastoid-muscles, pectorales, and in the small muscles the hands. She is putting on weight and the atrophy of fat on the trunk is much less marked than before. Both breasts are enlarged in comparison with the first examination, but there is a difference between the right and left breast, the right one being definitely smaller than the left one.

Discussion

The case is that of a 24-years'-old single woman who began to develop progressive deafness and failing vision at the age of 13. Ten yeafs later she noticed loss of power and wasting of the muscles of the hands> atrophy of the tongue, loss of weight with rapid reduction of body fat' difficulty in speaking and occasional difficulty in swallowing. On physical examination the signs fall into the following three groups :? (1) The most outstanding feature is the wasting of the small muscjeS of the hands and of the distal parts of the forearms, ^ fibrillary twitching and brisk reflexes ; wasting of the tongue' some difficulty in swallowing, change of voice, myopa^^ facies, twitching in the perioral muscles ; slight nystag1^5 and slight loss of balance. (2) Bilateral nerve deafness and bilateral optic atrophy. (3) Loss of fat deposit. The muscular wasting, the fibrillary twitching and the brisk re^ef with the bulbar the of together symptoms justify diagnosis amyotrop ^ lateral sclerosis. The absence of in the lower limbs Is spastic signs ^ argument against this diagnosis as it is known that such signs maY absent even in cases, or completely typical they may only appeal* ^ in the course of the disease. It is also known that spastic phenofl1^ in the lower limbs in young individuals suffering from amyotr?P lateral sclerosis are as a rule less pronounced than in adults. Sinma AMYOTROPHIC LATERAL SCLEROSIS 287 although nystagmus and disturbances of co-ordination are not common amyotrophic lateral sclerosis they have been observed by many authors. Buscher (1922), Haenel (1903), Boisseau and Brissaud (1933), Sarbo (1898), Spiller (1936) noticed nystagmus in otherwise typical cases. It is noteworthy that Helfland (1933) found degeneration of cells ln Deiter's nucleus in amyotrophic lateral sclerosis. Unsteadiness in Walking with the eyes shut and a positive Romberg's sign may occa- Slonally occur in amyotrophic lateral sclerosis, and can be explained by the fact that the spino-cerebellar tracts may undergo degeneration (Dagnelie and Cambier, 1933 ; Gozzano, 1937 ; Ugurgieri, 1937 ; and others). So far these symptoms are consistent with the diagnosis of amyo- trophic lateral sclerosis. However, the bilateral optic atrophy, the bilateral affection of the auditory nerve, the loss of fat deposit, the onset ?f the illness at an early age and the course of the disease are so incon- Slstent with typical amyotrophic lateral sclerosis and are so exceptional as to justify the publication of this rare case. Reviewing the literature on amyotrophic lateral sclerosis we could find mention of atrophy of the optic nerves in 3 cases only (Miinzer, ^92 ; Lannois and Lemoine, 1894 I Maspes and Piolti, 1934). These "-ases had been confirmed by autopsy. Other changes of the optic nerve such as pallor of the discs (Buscher, 1922 ; Bing, 1936), neuro- kinins (Spiller, 1936), venous hyperemia and blurred margins of the discs (Wenderovic and Nikitin, 1913) are occasionally mentioned. Changes of the eighth nerves in amyotrophic lateral sclerosis are even more rare than changes in the optic nerves. In the literature could find only 2 cases of amyotrophic lateral sclerosis with deaf- ness (Lelong, Lereboulet and Merklen, 1932 ; van Bogaert and van Broeck, 1929). The case of van Bogaert and van den Broeck is ne only one in which, as in our case, both the auditory and optic nerves ^ere involved. A young individual (the age is not mentioned), Sloped three years before examination progressive nerve deafness, U?Wed three months later by progressive failure of vision. One year er general fatigue, weakness of all four extremities and unsteady appeared ; after the patient had walked for a few minutes the Uscles became rapidly fatigued ; repeated movements such as repeated ?Slng of the eyes provoked weakness in the muscles concerned. These !ymPtoms had been considered as myasthenic. On examination the ?wing findings were noticed : incipient optic nerve atrophy of the halves of the discs, visual field normal, no central scotoma. -j^Porale Pupils were different in size ; bilateral ptosis of the eyelids, lagoph- ^rnus, bilateral nerve deafness, labyrinth intact, paresis of the masseter Pterygoid muscles, hypaesthesia of the palate and posterior wall , paresis of the palate ; aphonia, atrophy of the tongue n widespread fibrillary twitching, twitching also visible in the Scles innervated by fifth, seventh, ninth and eleventh nerves ; eral atrophy of the musculature of the whole body, especially of 288 J. ROSTOWSKI AND JAMES F. McHARG the face, shoulder girdle and peroneal groups ; marked mechanical hyperexcitibility of the muscles. R.D. in the deltoid, peroneal and calf muscles but no myasthenic reaction of Erb. Exaggerated tendon reflexes, ankle clonus, Babinski positive on the right side. Discussing the diagnosis the authors came to the conclusion that in view of the prevalance of signs of both upper and lower motor of neurone involvement and the presence of bulbar signs it was a case amyotrophic lateral sclerosis. They stressed, however, the fact that the onset of the illness with nerve deafness and optic atrophy predominantly of the temporal parts of the discs were exceptional both in amyotrophic lateral sclerosis and in myasthenia. This case is similar to our case in the respect that the amyotrophy lateral sclerotic symptoms were preceded by nerve deafness, followed three months later by visual disturbances, although in our case both deafness and failure of vision appeared almost concurrently. As in our case the muscular atrophies did not develop at the same time, but later than the deafness and the visual defects ; in the authors' case one year a and in our case ten years later. The optic atrophy was in both cases partial one and affected the temporal halves of the optic discs. There is only one, not essential, difference between our case and the authors case : in the latter it was only the cochlear and not the vestibule branch involved, whereas in our case both branches were affected > ?r caloric stimulation of the labyrinths did not produce nystagmus past-pointing. In the literature on the pathology of amyotrophic lateral sclerose very little is mentioned about changes in the eighth nerve nuclel> the Burnazjan (1933) saw in one case karyolysis and neuronophagia at point of emergence of the eighth nerve ; having only a short summary nn in German of this Russian paper at our disposal we could not out whether or not deafness existed during life. Helfland (1933) stated n that the degenerative process in amyotrophic lateral sclerosis is confined to the motor cells of the cranial nerves and Marburg (*93 adds that occasionally cells of sensory nerves may also underg0 degeneration. The most exceptional sign in our case, never mentioned in l?sS literature in connection with amyotrophic lateral sclerosis, is the p of fat deposit which was to be seen on the trunk (except the breas to a certain extent on the face, on the upper limbs and the buttocksj, the legs were normal. On admission, and during the first months observation in the this was so that the consult hospital, striking ^ physician to the hospital, Dr Fergus Hewat, and one of us (R)> amining the patient independently, formed at the first glance impression that the patient was suffering from progressive lipodystrop 2 In spite of a good appetite and of taking food well the patient lost was that while in hospital. Whereas in the beginning it evident ^ ane breasts were not involved in the loss of fat they later became as well. AMYOTROPHIC LATERAL SCLEROSIS 289

It is well known that patients suffering from amyotrophic lateral sclerosis become emaciated ; this becomes conspicuous late in the course of the illness when the muscular atrophy is already advanced. In our case, however, loss of fat was one of the first manifestations ?f the second stage of the illness which began in June 1948. Both the Patient and her mother state that at that time the patient felt weak, easily exhausted and she was lapidly reducing and losing fat. On admission there was wasting of the small muscles of the hands but not ?f the shoulder girdle muscles or of the arm muscles; even now, although the atrophy has progressed since admission to hospital, the muscles ?f the shoulder girdle, arms and pectorals are still fairly well preserved and show good motor power. Thus it is mostly the loss of fat deposit ^hich is the cause of the patient's emaciated appearance. We are quite aware that the distribution of the loss of fat in our Case does not correspond with the typical progressive lipodystrophy as described by Barraquer (1906, 1935, 1949) and by Simons (1911), Vlz- : loss of fat deposit in the face, trunk and arms ; in the lower part ?f the body?on the buttocks, hips and thighs?there may be an excess ?f fat deposit, or the fat tissue may be normal. Our case differs from ^ch typical cases in that the loss of fat involves also the buttocks and ls not so marked on the face. However, since the description of lipo- dystrophy by Barraquer and Simons, cases deviating from the typical f?rm have been reported. Tromner (1923) demonstrated a case in ^'hich apart from the trunk, arms and face the loss of fat involved also buttocks. Patton (1945) saw a case with loss of fat of the four ejctremities only. In Bigler's (1939) case the fatty tissue was reduced ?n the legs only ; a similar case was described by Smith (1930). In ?ne of Ziegler's (1928) cases there was loss of fat in the upper part the body, whereas the legs were covered with a normal amount of subcutaneous fat. A similar case has been recently described by Murray (1952). Lamy, Jammet and Amelin (1947) described a case of amyotrophy of Charcot-Marie type combined with atypical progressive Podystrophy and Garciso (1932) has found muscular atrophy in a - PJcal case of lipodystrophy. is difficult to explain the combination of lipodystrophy with amyotrophic lateral sclerosis in our case as the pathogenesis of lipo- is mostly based on clinical observations. Many suppositions dystrophyave been put forward to explain this extraordinary disease. Endocrine |s?rders (excess of folliculin, thyroid dysfunction) disturbances in the gher vegetative centres in the mes- and diencephalon have been Warded as the cause of Boissonnas j lipodystrophy (Pollak, 1930 ; 5 Roger, Alliez and Paillas, 1936). In a recent paper Barraquer p19erre (1949) denies that hyperfolliculinism or hyperthyroidism is the cause of the disease and considers it as well as the disturbance Qflmary as He considers that the cause lie metabolism secondary. primary the disturbance of the central hypothalmic regulation causing ni*?ld vegetative symptoms. The author observed a case of pro- 290 J. R0ST0WSKI AND JAMES F. McHARG gressive lipodystrophy hereditary in three generations and comes to " the conclusion that the disease can best be explained as hypothalamic heredo-degeneration (selective involvement of the nucleus in the posterior hypothalamus ?) with liberation of the cervicothoracic sympathetic. Barraquer assumes a genuine as well as a symptomatic form the first being due to a hypothalamic heredo-degeneration, the symptomatic form being caused by various processes, e.g. nervous, hormone, meta- bolic, or encephalitic processes. In amyotrophic lateral sclerosis we very often meet with symptoms such as seborrhcea, increased salivation, muscular cramps, sympathetic changes in the eyes, hyperhydrosis, shivering, oedema of the hands and feet, vasomotor changes and others pointing to vegetative disorder5 (Orzechowski, 1925 ; Patrikios, 1936; Lejonne and Lhermitte, 1934' van Bogaert, 1925 ; Neri, 1925 ; Maspes and Piolti, 1934, and others)- Orzechowski (1925) refers these disorders to changes of the lateral and posterior horn cells of the spinal cord. The possibility, however) cannot be excluded that they may be due to changes of the higher 111 vegetative centres since we know that the degenerative process amyotrophic lateral sclerosis may involve the brain stem, the hyp0' thalamic region and ihe thalamus opticus (Marburg, 1936 ; Bertran and van Bogaert, 1925 ; Buscher, 1922 ; Matzdorf, 1924 ; Tretiakoft 1936 ; Davidson and Wechsler, 1936). Theoretically it may be assume that in our case pathological changes in the hypothalamic regi?n exist which cause the loss of fat deposit. This assumption is, of course* hypothetical and could be proved by histological examination only- There is another factor which makes our case exceptional : ? 11the onset of the illness at the age of 13 years. Though there are in literature reports of cases of amyotrophic lateral sclerosis in y?un^an individuals (Wilson, 1940; Ballif and Briese, 1936 ; Gordon Delicati, 1938 ; Marques, 1930 ; Bogaert, 1925, and others) they ta^e considered as exceptions and Wilson (1940) thinks that although kinship of the juvenile types with the adult forms is undoubted, question whether they are identical must depend in the last resort pathology ; only when the syndrome is typical or pathologic confirmed can these cases be as such. regarded ^ We like to stress the case of MaSP should fact that except for the j and Piolti (1934) all the above-mentioned cases of amyotrophic later^ sclerosis with atrophy and nerve deafness respectively were optic a? young individuals ; Miinzers' (1892) patient was 22, Lanois Lemoine's (1894) patient was 24, Lelong, Lereboulet and Mer^eI^e' (1932) patient was 16, van Bogaert's (1925) patient was a Je " malade when the illness started. that j Finally, the course of the disease in our case differs from ^ typical amyotrophic lateral sclerosis. There have been two stageS the illness one at deal ; the age of 13 when the patient developed ^ and her to were sight began fail, symptoms which preceded by gen ^ was malaise and tiredness which lasted quite a long time so that she AMYOTROPHIC LATERAL SCLEROSIS 291 able to attend school for one year. The second state began at the age 23> again with general symptoms such as weakness and tiredness. At the same time the patient developed muscular wasting of the upper limbs, loss of fat deposit and later amenorrhoea. During the interval ?f nearly ten years there was a slow progressive diminution of hearing "which deteriorated in the second stage since 1945 much more quickly; her vision also became worse in the second phase of the disease. The change for the worse, both of hearing and vision during the second Period entitles us to the assumption that this period is a continuation ?f the first stage, which started at the age of 13. It is noteworthy that in van Bogaert and van den Broeck's (1928) case the deafness and failure of vision preceded the muscular atrophy by one year. In Lelong, Lereboulet and Merklen's case (1932) the filing of hearing was noticed two months after the onset of the illness. Also the optic atrophy was an early sign appearing in Lannois and Lernoine's case (1894) sxx months after the onset of the illness. In ^taspes and Piolti's (1934) case the optic atrophy appeared simul- taneously with other signs of the illness. In Miinzer's (1892) case, however, changes of the optic discs did not develop for two years after the onset of the amyotrophic lateral sclerosis. At present there are too few cases to draw general conclusions, but we think we should stress the fact that in 2 cases?van Bogaert and van den Broeck's and in our case?in which both the second and eighth nerves were involved, these changes preceded the amyotrophic lateral sclerotic symptoms and that there was a long interval in between. In the differential diagnosis in atypical cases of amyotrophic lateral Xerosis it is disseminated sclerosis which may occasionally have to be c?nsidered ; in our case we had to think of it with regard to the temporal atr?phy of the optic nerve, slight nystagmus and some co-ordination disturbance. The presence of the abdominal reflexes, the lack of as tic signs in the lower limbs, no paresis, no hypertonus, absent abinski's, Oppenheim's and Rossolimo's signs, no intention tremor, sPeak against disseminated sclorisis. Deafness is as rare in disseminated s^erosis as in amyotrophic lateral sclerosis and is, therefore, diagnos- tlcally, insignificant for either of these diseases. Muscular atrophy may occur in disseminated sclerosis but the wasting is never so pro- ri?Unced or so symmetrical as in our case and the muscles never show COrnPlete R.D. With these considerations in mind we have, therefore, n? doubt that in our case disseminated sclerosis can be ruled out. Syphilitic amyotrophic lateral sclerosis can be excluded on the of the negative W.R. in the blood and the C.S.F. Syringo- j^?Undsyeha which may come into consideration in atypical cases of amyo- Phic lateral sclerosis could be ruled out in view of the absence of ens?ry disturbances.

. lri view of the fact that in our case there are so many exceptional s j additional to those of lateral sclerosis, viz. nerve a amyotrophic ness, optic atrophy, loss of fat deposit, onset at puberty and the 292 J. ROSTOWSKI AND JAMES F. McHARG

appearance of muscular atrophy nearly ten years after the vision and hearing disturbances, the question arises whether this case can still be regarded as an atypical case of amyotrophic lateral sclerosis or whether it should be regarded as a chronic progressive degenerative process with a different pathology from that of amyotrophic lateral sclerosis. This question cannot be answered on the grounds of the clinical observations only. As long as we do not know the pathology of these atypical cases we think ourselves to be right in placing our case under the heading of atypical amyotrophic lateral sclerosis. " Perhaps it may be regarded as what Schaffer (1936) calls a para- " typical form of amyotrophic lateral sclerosis. This author distinguishes two forms of amyotrophic lateral sclerosis, (1) the primary* endogenous idiopathic form (and this is the classical one), (2) the " " secondary, exogenous, the paratypical form which only sympt?' matically imitates the typical Charcot disease. Further clinical and pathological observations will show whether these atypical cases of amyotrophic lateral sclerosis in young individuals in which there is also optic nerve atrophy and nerve deafness, should not be separated from that disease as a distinct entity.

Summary

1. A case of amyotrophic lateral sclerosis combined with bilateral lS optic nerve atrophy, bilateral nerve deafness and lipodystrophy reported. 2. The literature of similar cases is reviewed. 3. The conclusion is drawn that in view of the unknown pathology in these cases it is to say whether they should be regarde impossible a as atypical amyotrophic lateral sclerosis or whether they constitute separate clinical entity. We wish to thank Professor Sir David Henderson for permission to publish case, and also Miss Mann, of the Physiotherapy Department of the Royal Infirm3^' Edinburgh, for her help in testing the electrical reactions.

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