Motor neuron disease

Journal of the neurological Sciences Elsevier Publishing Company, Amsterdam - Printed in The Netherlands

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Motor Neuron Disease A Clinical Study A. VEJJAJIVA*, J. B. FOSTER AND H. M I L L E R Department of Neurology, University of Newcastle upon Tyne (Great Britain) (Received 16 August, 1965)

INTRODUCTION

Metropolitan in location and to a considerable degree literally consultative in function, British neurology has been traditionally clinical and descriptive. Its special contributions have comprised clinicopathological correlations and the meticulous study of individual patients with neurological injury or disease to unravel the physiology and pathophysiology of the human nervous sytem. A usually episodic relation between the neurologist and his patient has meant that studies of prognosis or of the natural history of neurological illnesses in length have been few and far between. Often indeed such observations have been stimulated only by the introduction of some new and controversial form of treatment. The early excesses of intervertebral disc surgery, improbable claims of successful therapeutic intervention in multiple sclerosis, and bold statements as to the efficacy of anticoagulant treatment in cerebrovascular disease spring to mind as errors which owed at least as much to basic ignorance about the natural course of untreated disease as to the uncritical enthusiasm of their progenitors. In the United States neurology developed later, and in general rather than in special hospitals. Perhaps partly for this reason it has been more ready to exploit the newer techniques of internal medicine as well as to employ those of experimental pathology, epidemiology and genetics. Investigation has been concerned as much with aetiology as with pathophysiology. The influence of this approach on British neurology is now evident in the active multi-discipline research directed for example to the muscular and demyelinating diseases. Little recent attention has however been paid to motor neuron disease. Indeed except for a Symposium at the Royal Society o f Medicine (SPILLANE 1962) there have been few significant contributions to the literature for more than a decade. The reasons for this relative neglect are not far to seek. Motor neuron disease is at least as enigmatic a disorder as multiple sclerosis or muscular dystrophy. It is how* Present address: Department of Medicine, Chulalongkorn Hospital, Bangkok (Thailand). J. neurol. Sci. (1967) 4:299-314

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ever a rare disease and since the mean expectation of life in authenticated cases is no more than three years the patients do not survive their tragic illness long enough to become a reproach to medicine. The brevity of the disease in itself leads to an underestimate of its frequency. A recent intensive investigation of neurological morbidity in an English city (BREWIS et al. 1965) yields a prevalence rate of about 80 per 100,000 for multiple sclerosis and of somewhere between 7 and 11 per 100,000 for motor neuron disease. In other words there are at least eight times as many established cases of multiple sclerosis in the community as of the disorder under consideration. However if annual incidence figures are considered the position is rather different. The annual incidence rate of multiple sclerosis is 4 per 100,000 but that of motor neuron disease is rather more than 1 per 100,000 - - in other words the disease is onequarter as frequent as the commonest structural nervous disease encountered in Great Britain. The purpose of the present study is to review the clinical features and natural history of motor neuron disease, to search for possible clues to its aetiology and to collect case-material for a variety of further investigations.

HISTORICAL NOTE

In 1850 ARANN described progressive muscular atrophy and in 1860 DUCHENNEgave a detailed account of progressive bulbar palsy. A few years later CHARCOT (1869) drew attention to an association between spinal muscular atrophy and corticospinal tract degeneration. Recognition of the relation between chronic bulbar palsy and the spinal disorder is usually attributed to DI~J~RINE, but writing more contemporaneously GOWERS (1893) unhesitatingly gave KUSSMAUL credit for the observation. In 1902 GOWERS included the condition amongst those attributable to 'abiotrophy' or degeneration arising from an inherent loss of stamina in the neuron, and despite its vague and unsatisfactory nature this hypothesis has yet to be replaced by anything more convincing. The occasional pathological finding of degenerative changes in other parts of the spinal cord such as the spinocerebellar tracts (GREENFIELD 1958) has provoked some objection to the term 'motor neuron disease' but this remains the best clinical description. MATERIAL AND METHODS

It is often said in neurological circles that motor neuron disease is more often wrongly diagnosed than any other chronic neurological disorder, and there is certainly an appreciable minority of cases in which the diagnosis can remain no more than a suspicion even over a period of years. Furthermore there are cases in which a similar syndrome is found in association with other diseases such as Parkinsonism, cerebral arteriosclerosis or severe cervical spondylosis. All these present serious difficulties of assessment and for the purpose of the present study we have limited ourselves to the disorder as it occurs in its classical and unequivocal forms. This has no doubt led to the omission of material that would have been valuable for this study but has on the J. neurol. Sci, (1967) 4:299-314

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other hand the advantage that cases included in the series are more likely to be accepted as undisputed instances of the disease under consideration. The definition of motor neuron disease presents obvious difficulties, but for practical purposes we have regarded it as a progressive neurological disorder of adult life characterized by clinical evidence of wide-spread progressive damage to motor neurons in the form of wasting, weakness and extensive fasciculation; either bilateral spastic weakness of the lower limbs due to corticospinal tract involvement or flaccid bulbar palsy or both are almost invariably present or develop at some stage of the illness. All patients in whom examination revealed impairment of sensation have been excluded, as have those whose signs could possibly be accounted for by coincidental cervical spondylosis, all in whom E M G had yielded anomalous results or in whom serological tests for syphilis were positive. The medical records of the two major Newcastle hospitals during the past decade furnish the notes of 215 patients in whom this condition had been diagnosed. Of these 45 were discarded on initial scrutiny because the diagnosis was probably incorrect. Of the remaining 170 patients, 10 were untraced, 6 were uncooperative and 84 had died. All 70 surviving cases were personally examined and in 45 of these the stringent criteria mentioned above were satisfied. Analysis of this material falls into two parts: a brief account of the findings in 51 of the 84 fatal cases where information was adequate and the clinical syndrome classical, and an account based on re-examination of the 45 surviving patients.

ANALYSIS OF CLINICAL

FEATURES

F a t a l cases

The 51 fatal cases can be divided into four main clinical groups according to their presenting symptoms: flaccid bulbar palsy, progressive (spinal) muscular atrophy, amyotrophic lateral sclerosis, and mixed types. Fifteen patients presented with amyotrophic lateral sclerosis, 14 with progressive muscular atrophy, 12 with mixed syndromes, and 10 with pure bulbar palsy. The group comprised 33 male and 18 female patients (1.8 :l). This male preponderance was evident in the cases of progressive muscular atrophy (8:6), in those of amytrophic lateral sclerosis (10: 5) and in the mixed cases (10:2). In the 10 cases of bulbar palsy however the sex distribution was equal. The age of onset ranged from 26 to 71 years, with a mean of 52.7 (54.0 for men and 50.3 for women). The age distribution is set out in Table 1. TABLE

1

AGE OF ONSET IN YEARS

Sex

Number o f cases

Age group (years) 25-34

35-44

45-54

55--64

65-74

Male

33

1

1

16

9

6

Female

18 51

2 3

4 5

6 22

5 14

1 7

Total

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A. VEJJAJIVA, J. B. FOSTER, H. MILLER

The duration of symptoms at the time of the patient's first attendance at hospital varied from 6 weeks to 3 years, with a mean of I 1.7 months. Patients with bulbar palsy presented at hospital earlier than those in the other groups (after 2-18 months, with a mean of 6.4). The figures for progressive muscular atrophy (4 months to 2 years, with a mean of 1.3 years), amyotrophic lateral sclerosis (2 months to 2 years, with a mean of 1.2 years) and mixed syndromes (6 weeks to 3 years, with a mean of 10 months) are probably comparable (Table 2).

TABLE 2 DURATION OF SYMPTOMS WHEN FIRST SEEN

Number o f cases

Duration (years) 0-3/12

3/12-6/12

6/12-I

1-2

2 3

Male Female

33 18

9 1

7 3

8 6

8 8

1

Total

51

10

10

14

16

Bulbar palsy

10

3

3

3

1

--

Progressive muscular atrophy

14

1

2

3

8

--

A m y o t r o p h i c lateral sclerosis

15

1

2

6

6

--

"Mixed"

12

3

4

2

2

1

1

The duration of the illness from onset to death ranged from 6 months to 9 years, with a mean of 3 years. The duration of bulbar palsy was from 6 months to 5 years, with a mean of 22 months (12 for men and 33 for women). The duration in progressive muscular atrophy was from 21 months to 9 years, with a mean of 3.5 years, for amyotrophic lateral sclerosis from 1 to 8 years, with a mean of 3.7 years and for the mixed group from 9 months to 5.5 years, with a mean of 2.4 years (Table 3).

Surviving patients Twenty-nine of 45 surviving patients were males (1.8 : 1). The age of onset ranged from 23 to 70 years, with a mean of 47 years in both sexes. The onset of symptoms was invariably insidious. Muscular weakness and wasting was the commonest presenting symptom and often affected the small muscles of one hand resulting in clumsiness of fine movements and weakness of grip. In half the cases in which symptoms first affected the hand they were bilateral, and in unilateral cases the opposite hand nearly always became involved within weeks or months. The usual sequence of events was successive involvement of the proximal shoulder girdle muscles, the biceps and the flexors of the forearm, followed by involvement of the opposite limb. There were however 2 patients in whom the opposite limb remained normal for 3 and 5 years respectively. There was no significant predilection for either side, J. neurol. Sci. (1967) 4 : 2 9 9 - 3 1 4

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MOTOR NEURON DISEASE. A CLINICAL STUDY TABLE 3 D U R A T I O N OF I L L N E S S I N 5 1 F A T A L CASES

Number

Duration (years)

of cases

½-1

1-2

2-3

3-4

4-5

5--6

6-7

7-8

8-9

All types Male female total

33 18 51

7 2 9

11 3 14

6 7 13

3 2 5

1 3 4

1 -1

2 -2

2 -2

-1 1

Bulbar palsy male female total

5 5 10

2 -2

2 2 4

1 1 2

.

Progressive muscular atrophy male female total

8 6 14

----

4 -4

2 3 5

1 -l

Amyotrophic lateral sclerosis male female total

10 5 15

1 -1

4 2 6

1 1 2

.

"Mixed" male female total

10 2 12

3 1 4

2 -2

2 1 3

.

.

1 1

1

l

.

. --

l --

. --

l .

. .

4

.

1 .

. .

. .

.

. --

1

. . --

.

.

. .

. 3 3

.

.

. .

.

2 2

.

.

1 1

.

. --

4

--

--

--

--

1

m

i

. l

n o r was t h e side o f o n s e t r e l a t e d to h a n d e d n e s s . Less f r e q u e n t l y the s h o u l d e r girdle m u s c l e s w e r e first affected. T h e d e g r e e o f w e a k n e s s was u s u a l l y p r o p o r t i o n a t e to t h e a m o u n t o f w a s t i n g , b u t o n s o m e o c c a s i o n s p r o f o u n d m u s c u l a r w e a k n e s s was p r e s e n t at a t i m e w h e n w a s t i n g was m i n i m a l . C l i n i c a l p r e s e n t a t i o n w i t h w e a k n e s s a n d w a s t i n g o f t h e l o w e r l i m b was less c o m m o n , b u t m o r e f r e q u e n t in this series t h a n the l i t e r a t u r e w o u l d l e a d o n e to expect. I n 10 o f t h e s e 45 p a t i e n t s a l o w e r m o t o r n e u r o n l e s i o n i n v o l v i n g o n e o r b o t h l o w e r l i m b s was a p r e s e n t i n g f e a t u r e , in 9 w e a k n e s s a n d w a s t i n g a c c o m p a n i e d by flaccid f o o t d r o p w e r e u n i l a t e r a l . T h i s l o c a l i z a t i o n u s u a l l y p e r s i s t e d f o r o n l y a few m o n t h s , b u t in t w o i n s t a n c e s it was t h r e e y e a r s b e f o r e t h e u p p e r l i m b s w e r e i n v o l v e d . B i l a t e r a l flaccid f o o t d r o p was f o u n d in o n l y o n e case. T h e n o r m a l m a l e p r e p o n d e r a n c e seen in the series as a w h o l e was n o t p r e s e n t a m o n g t h o s e p r e s e n t i n g w i t h l o w e r l i m b i n v o l v e m e n t . W e a k ness a n d w a s t i n g o f t h e q u a d r i c e p s o r h a m s t r i n g s w e r e r a r e as p r e s e n t i n g s y m p t o m s t h o u g h t h e y w e r e o f t e n o b s e r v e d l a t e r in t h e c o u r s e o f t h e disease, especially in t h o s e p a t i e n t s w h o h a d p r e s e n t e d w i t h e a r l i e r i n v o l v e m e n t o f a n t e r i o r tibial o r c a l f m u s c l e s . N o case in this series p r e s e n t e d w i t h w e a k n e s s a n d w a s t i n g o f t h e m u s c l e s o f the p e l v i c girdle. I n v o l v e m e n t o f e x t e n s o r m u s c l e s o f t h e n e c k was e n c o u n t e r e d in 3 cases b u t n e v e r until t h e l a t e r stages o f t h e disease. J. neurol. Sci. (1967) 4:299-314

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Fasciculation was seen in most patients with muscular wasting and weakness and had previously been observed in those in whom it was found on re-examination. It was most often observed in weakened muscles but also frequently in muscle groups as yet clinically normal. In one case fasciculation was the presenting symptom. Case 1. A 54-year-old motor engineer reported to hospital complaining of twitching in arms, legs and trunk which interfered with his sleep. Fasciculation involved practically all the muscles of the limbs and trunk including those of the abdomen, but the only other finding was minimal weakness and wasting of the deltoids, and general hyperreflexia without increase in tone and with flexor plantar responses. Twelve months later the patient presented a classical picture of advanced amyotrophic lateral sclerosis.

Spasticity due to corticospinal tract involvement was not uncommon on initial examination, though it was rarely a presenting symptom and was usually an asymptomatic finding in a patient with wasting and weakness from a coincidental lesion of the lower motor neurones. However in 5 patients stiffness of the legs was the most important presenting symptom, and in another with featureless and insidiously progressive spastic quadriparesis of eight years' duration wide-spread wasting and fasciculation developed rapidly. In most patients with involvement of the upper motor neuron spasticity was inconspicuous. Where there was marked evidence of coincidental lower motor neuron involvement hypotonia was frequent especially in the upper limbs. Corticospinal tract implication was often evident in an increased jaw jerk, absent abdominal reflexes and extensor plantar responses, but there was an appreciable minority of patients in whom the abdominal reflexes were brisk and the plantar responses flexor despite the presence of marked spasticity and hyperreflexia. Such a finding is uncommon in any other bilateral corticospinal tract lesion though it is also encountered in long-standing cases of spastic diplegia. Three of the surviving cases presented with flaccid bulbar palsy and all were female. Dysarthria and dysphagia were found singly or in combination, and wasting and fasciculation of the tongue were observed, though in a fourth patient bulbar palsy was spastic. This is an uncommon occurrence in motor neuron disease, but in this case the diagnosis was authenticated by the subsequent development of wasting, fasciculation and hypertonia in all four limbs. The patient in question showed profound emotional lability which was also encountered in 3 other patients with motor neuron disease in whom bulbar palsy developed late in the course of the disease. Flaccid bulbar palsy often affects speech earlier than swallowing and dysphagia is sometimes virtually absent when anarthria is already complete. Flaccid bulbar palsy was a later development in 10 patients, whose symptoms initially involved the limbs. Weakness and wasting of facial muscles were not found as presenting symptoms, though a few patients with bulbar palsy developed weakness of the orbicularis oris. The muscles supplied by the trigeminal and accessory nerves were affected late in the course of the disease and the external ocular muscles escaped entirely even in cases where the symptoms had existed for many years. No patient presented with sphincter disturbance, and even in the late stages of the disease frequency of micturition, hesitancy and incontinence were rare. The lastmentioned disorder was in fact only observed once in a patient who had been ill for J. neurol. Sci. (1967) 4 : 2 9 9 314

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6 years and who was bed-ridden with profound generalized muscular wasting and paralysis. Constipation, on the other hand, was c o m m o n and may be related to weakness of the abdominal wall. Motor neuron d i s e a s e - - as its name s u g g e s t s - - is a system-degeneration of the m o t o r cells and fibres. Nevertheless sensory complaints were not infrequent. A mild, dull ache was often encountered in weak and wasted muscles after use, although muscletenderness was not a feature. Muscle-cramps often occurred early in the disease and nearly always in the lower limbs and in the presence of corticospinal tract involvement They were worse at night and did not correlate with fasciculation. Vague peripheral feelings of numbness and tingling were often admitted in reply to leading questions. In a small proportion of cases these occurred early in the illness though they were never included in the patient's spontaneous complaints nor had they led to a request for medical attention. In more advanced cases peripheral sensations of deadness and numbness were frequently mentioned, but in neither group of cases were there any abnormal findings on meticulous sensory examination. In many instances marked wasting of the limb musculature was accompanied by collapse of the superficial veins which made venesection unusually difficult. In all these patients the condition was progressive. In a few there was a phase of apparent arrest after slow deterioration for a year or two. Occasionally some patients claimed that there had been fluctuations in the severity of their disability early in the disease, but evidence of genuine remission with true recovery of function was never found. Misdiagnoses The 25 cases originally diagnosed as m o t o r neuron disease which were rejected after re-examination illustrate the commoner problems encountered in this connection. The diagnosis is especially important, since the disease is untreatable and invariably fatal. The final diagnosis in the rejected cases was: cervical spondylosis (6), multiple sclerosis (5), spastic tetraparesis, carcinomatosis and bilateral carotid artery disease (2 of each). There were also single cases subsequently recognized to be suffering from familial spastic paraplegia, cerebellar ataxia with associated muscle wasting, lateral popliteal nerve palsy, vertebro-basilar atherosclerosis, Parkinsonism with spastic tetraparesis, syringomyelia, and neurosyphilis. Re-examination of one patient several years after motor neuron disease had been diagnosed on the basis of apparent wasting of the small muscles of one hand revealed no abnormal physical findings whatsoever. Cases o f long duration In about 10% of otherwise unremarkable cases motor neuron disease runs an unusually prolonged course. Case 2 A 58-year-old retired miner sought advice because of progressive failure of voice for 5 years and weakness of both legs for 1 year. Examination revealed poor palatal movement, bilateral wasting and fasciculation of the tongue, slight wasting and weakness of all the small muscles of both hands and marked reduction of all deep reflexes. During the subsequent 12 years there has been a slow deterioration. Wasting and fasciculation of the bulbar muscles and both masseters had been accompanied by the development of lower facial weakness and palatal palsy and by progressive flaccid weakness of J. neurol. Sci. (1967) 4:299-314

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the muscles of the limbs with extensive fasciculation. All deep reflexes were absent and there was no evidence of corticospinal tract involvement, the picture being essentially that of a wide-spread degeneration of the lower motor neurones. Case 3

A previously healthy woman of 34 years fell downstairs and bruised her left arm. Immediately afterwards she noticed that it was weak. The weakness was very slowly progressive and when she first reported eight years later it was because her right hand had become similarly affected. Eight years later - - 16 years after the onset of symptoms - - she developed insidious difficulty in speaking and swallowing, with weakness of the legs. Examination showed a thin wasted woman with nasal speech, weakness of orbicularis oris and palatal muscles and marked symmetrical wasting and fasciculation of the tongue. Wasting and fasciculation also involved all the muscle groups of both upper limbs, where the reflexes were absent. The jaw jerk was increased, knee and ankle jerks exaggerated and plantar responses extensor. Case 4

A 47-year-old gardener developed weakness of grip on both sides which slowly progressed to involve the whole of both upper limbs. On examination 8 years later there was extensive wasting and fasciculation in both upper limbs with disappearance of deep reflexes in upper and lower limbs. Seven years later a similar picture of progressive wide-spread lower motor neuron degeneration began to affect the lower limbs and the patient was incapacitated by extensive flaccid weakness and wasting of all skeletal muscles with wide-spread fasciculation. There was no evidence of bulbar or corticospinal tract involvement. This case does not strictly comply with the criteria which applied elsewhere in this series. The case is unusual but all ancillary investigations are negative and it is difficult to conceive of any alternative diagnosis. Case 5

A 34-year-old engine driver presented with a 7-year history of progressive weakness and wasting of the right arm and leg. Examination revealed moderate wasting in the trapezius, serratus anterior, biceps, triceps and finger extensors in the right upper limb and wasting and weakness of the right anterior tibial and quadriceps muscles. Fasciculation was present in the muscles of the right arm. The jaw-jerk was pathologically brisk, abdominal reflexes were retained but knee and ankle jerks exaggerated and the plantar responses extensor. Five years later the signs were more marked but there had been no extension of lower motor neuron features to the opposite side. Case 6

A 55-year-old professional musician first noticed deterioration in his organ-playing because of clumsiness of the hands. Within a few months this was followed by slurring of speech and later by choking spells. Ten years later he was virtually anarthric with profound wasting and fasciculation of the tongue. Both sternomastoids and trapezii and all the muscles of both upper limbs were markedly wasted as were the quadriceps. Fasciculation was wide-spread. The jaw-jerk was present, but all upper limb reflexes were diminished.

T h e age o f o n s e t in t h e s e 5 u n u s u a l p a t i e n t s r a n g e d f r o m 25 to 59 years a n d was s i m i l a r to t h a t seen in classical cases. H o w e v e r , t h e d u r a t i o n o f s y m p t o m s o n first p r e s e n t a t i o n was l o n g e r a n d r a n g e d f r o m 5 to 8 years, n o d o u b t d u e to the i n s i d i o u s o n s e t a n d s l o w p r o g r e s s i o n o f t h e illness. D e t a i l e d clinical analysis r e v e a l e d n o significant f a c t o r s w h i c h d i s t i n g u i s h e d t h e s e p a t i e n t s f r o m t h e m o r e t y p i c a l ones. O f these 5, 2 w o u l d initially be classified as suffering f r o m p r o g r e s s i v e m u s c u l a r a t r o p h y , o n e f r o m a m y o t r o p h i c l a t e r a l sclerosis a n d t w o f r o m c o m b i n a t i o n s o f b u l b a r p a l s y a n d a m y o t r o p h i c l a t e r a l sclerosis. T h e single p a t i e n t w i t h o u t s p o k e n e v i d e n c e o f a c o m b i n e d l e s i o n o f u p p e r a n d l o w e r m o t o r n e u r o n s was a t y p i c a l in t h a t wasting, w e a k n e s s a n d f a s c i c u l a t i o n w e r e c o n f i n e d to o n e side, t h o u g h it s h o u l d be n o t e d t h a t J. neurol. Sci. (1967) 4:299-314

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involvement of the corticospinal tracts was bilateral. One patient (Case 3) developed bulbar palsy 16 years after the onset of progressive muscular atrophy. The clinical signs in these 5 cases were not significantly different from those encountered in the more typical examples, except that in two instances wide-spread diminution or absence of the deep reflexes was observed early in the course of the disease and at a time when muscular wasting was minimal or absent.

POSSIBLEAETIOLOGICALFACTORS Family history In classical motor neuron disease a positive family history is usually regarded as unusual. KURLAND AND MULDER (1955) encountered it in the case-notes of 5 of 58 patients with motor neuron disease reviewed retrospectively, whilst HABERLANDT (1959) obtained a positive family history in 13.5 °/o of his 251 patients. In RoE's recent report on familial motor neuron disease (1964) it was stated that apart from the Chamorros and those recorded merely as showing 'a positive family history' at least 63 families in which more than one member developed the classical features of motor neuron disease had so far been recorded. Two of the 45 surviving cases reported here had positive family histories of motor neuron disease (4.4%). The first was a miner of 28 years of age whose father died of progressive paralysis of both legs and whose sister died a year before the onset of the patient's illness with classical motor neuron disease of three years' duration. The second was a 61-year-old woman who developed flaccid bulbar palsy followed within a year by progressive muscular atrophy and spastic paraplegia. Her brother had died of typical progressive muscular atrophy and amyotrophic lateral sclerosis 10 years earlier. No patient gave a positive history of parental consanguinity. LEvY (1962) reported a high incidence of cancer of the gastro-intestinal tract in the parents of patients with motor neuron disease. In the present series carcinoma of the stomach was the cause of death in the fathers of 3 patients, and the mother of one of them also succumbed to this disease. Malignant disease of the pancreas and of the lung were the causes of death in the fathers of 2 patients and cancer of the bladder in the mother of another. A further patient had one brother with cancer of the stomach and another a brother with pancreatic carcinoma. Thus 4 fathers and one mother (5.5~o of all parents) succumbed to gastrointestinal cancer. A similar enquiry in 50 consecutive medical admissions in the same age group and sex distribution yielded a figure of 6 ~o for parental deaths from this disease. Two of these 45 patients had a positive family history of diabetes mellitus. In no case had paralytic poliomyelitis affected siblings or parents. The mother of one patient suffered from multiple sclerosis and the sibling of another from Parkinson's disease. Peptic ulcer Four of these 45 patients had suffered from chronic peptic ulcer prior to the onset of the neurological disorder and a further patient had undergone gastro-enterostomy for duodenal ulcer 20 years previously. In an earlier survey of the case-records of 95 J. neurol. Sci. (1967) 4:299-314

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patients with motor neuron disease drawn from the same pool of clinical material (STERN AND VEJJAJ[VA 1964) the symptoms in 4 patients strongly suggested chronic peptic ulcer, gastro-enterostomy had been performed in 2 further cases 9 and 13 years respectively before the onset of motor neuron disease, one patient had coexisting cirrhosis of the liver and another had been treated for several years for pernicious anaemia. In view of the findings of DOLL et al. (1951) that the incidence of peptic ulcer in the male population may be as high as 10"..,,, neither figure suggests a causal relationship. Poliomyelitis

'Chronic anterior poliomyelitis' was an old term for motor neuron disease and an occasional relationship between antecedent paralytic poliomyelitis and the chronic disorder has often been mentioned in the literature. However the nature of any connection between the two diseases remains controversial. The most striking instances have been those in which motor neuron disease began in a limb already the site of atrophy as a result of previous poliomyelitis. SPILLANE(1962) is one of the many workers who have cast doubt on this relationship, but the ingenious epidemiological observations of ZILKHAAND PAYLING WRIGHT (1962) strongly suggest that motor neuron disease occurs in patients previously affected by paralytic poliomyelitis very much more often than could possibly be accounted for by chance, and that the connection is unlikely to be fortuitous. These workers pointed out that from 1925 onwards the relative incidence of paralytic poliomyelitis and motor neuron disease in the age-groups most affected was such that a chance association would be expected once every 39 years in the whole of England and Wales, whereas 11 such cases drawn from this population were seen during a 13-year period at the National Hospital. A previous history of paralytic poliomyelitis was present in one of this series of 45 patients. Case 7. A woman of 60 presented in early 1964 with difficulty in walking of 3 months' duration. At the age of 15 she had suffered a severe attack of paralytic poliomyelitiswhich left her with moderate weakness and wasting of the left arm and right leg. On examination 3 months after the onset of her recent symptoms she was found to have moderate wasting of the left deltoid and supraspinatus and of the right anterior tibial muscles. There was slight wasting of the right deltoid, trapezius and spinati with fasciculation. The deep reflexes in the right arm and left leg were pathologically brisk, spasticity was present in both legs but more marked on the left, the abdominal responses were retained but the plantar responses extensor. Findings on sensory examination, and X-rays of the cervical spine were normal. Twelve months later she had progressive spastic quadriparesis with wide-spread fasciculation. Social incidence In the counties of Northumberland and Durham multiple sclerosis shows a predilection for the upper social classes (MILLER et al. 1960) and subsequent observations have shown a similar social distribution amongst the parents of multiple sclerotic patients (JOHNSON AND MILLER, 1963). Reliable information on occupation was obtained in 90 patients with motor neuron disease, 59 males and 31 females. Social classification of male patients was based on their occupation at the time of onset of symptoms. In the case of female patients the woman's occupation at the date of onset J. neurol. Sci. (1967) 4:299-314

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o f the disease if she was single a n d working, the h u s b a n d ' s o c c u p a t i o n if she was married, a n d the father's o c c u p a t i o n in the cases of single w o m e n never employed were used in this classification, which was arranged according to the Registrar G e n e r a l ' s five social classes. The d i s t r i b u t i o n of these 95 patients a m o n g s t social classes I - V is shown in Table 4, together with that of the male p o p u l a t i o n o f N o r t h u m b e r l a n d a n d D u r h a m aged 15 years a n d over. It will be observed that there is n o evidence of any differential social incidence of m o t o r n e u r o n disease, n o r is any differential incidence observed if the patients are divided a m o n g s t the various clinical syndromes concerned.

TABLE 4 DISTRIBUTION OF MOTOR NEURON DISEASE AND OF THE MALE POPULATION AT RISK BY SOCIAL CLASS

Social class I

H

III

IV

V

59 male patients 31 female patients Total: 90 patients Expressed in ~

2 2 4 4

7 4 11 11

16 14 30 33

26 7 33 37

8 4 12 14

Percentage distribution of male population of Northumberland and Durham over 15 years

2

10

53

21

13

Trauma

The medical records m e n t i o n e d a history of t r a u m a preceding the onset of n e u r o logical s y m p t o m s in 17 out of the 45 surviving patients. I n five it was so slight as to be discounted. I n two other instances its remoteness in time-relationship a n d site rendered it unlikely to be significant, a n d in five further patients the site of injury was distant from that of initial neurological signs even t h o u g h the time-relationship was close a n d the injury material. There were however 5 patients, four of w h o m were male, in w h o m the relationship was suggestive, a n d 3 deserve m e n t i o n . Case 8. At the age of 49 a miner sustained a fracture of the right forearm which was immobilized in piaster for three months. Three years later he was struck by a large stone on the left knee and was unable to walk because of severe pain. Two weeks later a foreign body was removed from the knee. Postoperative recovery of function was good but by the end of the year he began to limp and drag the left leg. Neurological examination 12 months later revealed flaccid left foot drop with marked wasting and fasciculation of the anterior tibial and calf muscles on this side, marked wasting of the muscles of the right shoulder girdle and of the upper arm where fasciculation was prominent, an exaggerated jaw jerk and an extensor plantar response on the right, that on the left being absent. There was no sensory change and progression of the disease to a symmetrical generalized lesion of upper and lower motor neurons has been unremitting. Case 9. A woman of 52 sustained severe bruising of the left foot which was struck by a heavy wooden bar. Radiological examination revealed no bone injury, but the left lower leg was immobilized in plaster for 4 weeks. On removal of the plaster weakness of this leg was noticed which progressed and J. neurol. Sci. (1967) 4:299-314

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spread within six months to involvethe opposite lower limb. Examination at this time showedbilateral flaccid foot drop, moderate wasting of arms and shoulder girdles with fasciculation and generalized increase of deep reflexes, an increased jaw jerk and bilateral extensor plantar responses. Three months later the patient died of bronchopneumonia and the diagnosis of motor neuron disease was confirmed at autopsy. Case 10. A 48-year-old miner sustained a fracture of the pelvis and of the right humerus in a coalmining accident. Both fractures were immobilized in plaster for 6 weeks. Two weeks after the removal of the plaster he noticed wasting and weakness of the right arm which ~ ere progressive. Within a few months both hands became weak and clumsy and he had difficulty in feeding himself. Exarnirmtion 10 months later revealed wasting and fasciculation of the right deltoid, biceps and triceps. There were no convincing signs on the left and the diagnosis was obscure, but re-examination three years later showed a florid picture of motor neuron disease with flaccid weakness and fasciculation in all four limbs, dysarthria associated with wasting and fasciculation of the tongue and bilateral extensor plantar responses. Miscellaneous observations

Motor neuron disease has been described in association with hyperthyroidism and acromegaly (ADAMS et al. 1953), hypoglycaemia (ToM AND RICHARDSOr~ 1951), electrical injuries (CRITCHLEY 1934; PANSE 1955; HAVNALAND REGLI 1964) and repeated trauma by pneumatic drill (ALPERS AND FARMER 1949). Occasionally, the syndrome of 'motor neuron disease' has been found in the course of intoxication by heavy metals such as lead (WILSON 1907), mercury (BRowN 1954; KANTJARJIAN 1961) and after exposure to triorthocresyl phosphate (Scr~EID 1947 ; VO~EL 1947 ; MERTENS 1948). In none of our cases was there any evidence of such associations, nor had the onset of the disease followed infection or vaccination against poliomyelitis. There was no evident relation to dietary habits, smoking, alcohol or drugs. No correlation was found between bulbar localization and preceding tonsillectomy, nor between progressive muscular atrophy and especially laborious occupations or addiction to athleticism or weight-lifting. DISCUSSION Our findings with regard to sex and age incidence accord with previous observations (SWANK AND PUTNAM 1943; FRIEDMANAND FREEDMAN1950), the male preponderance seen in other forms of the disease being absent in bulbar palsy. This also presents earlier to the physician than other forms of the disease, and patients in whom it is the first symptom have a shorter expectation of life. Dysarthria is more conspicuous than dysphagia in these cases and fasciculation of the tongue is invariable except where this is spastic. The onset of motor neuron disease is insidious and its course always progressive. In all 51 fatal cases death was due to the disease, and bronchopneumonia or choking accounted for most. Weakness of the orbicularis oris was seen in several cases where there was no evidence of weakness in any other muscles supplied by the facial nerve, lending support to a suspicion that this muscle may be innervated from the hypoglossal nucleus (MOLL 1913). It is remarkable that the ocular muscles escape even in terminal cases, where virtually every other muscle is affected (MuLDER1957; EARL 1962) and in these circumstances the possibility mentioned by WILSON(1940) that some cases of insidiously progressive total ophthalmoplegia might represent a larval form of motor neuron J. neurol. Sci.(1967) 4:299-314

MOTOR NEURON DISEASE. A CLINICAL STUDY

311

disease carries little conviction. Onset with unilateral flaccid foot drop is less infrequent than the textbooks suggest, and initial localization of weakness and wasting to anterior tibial muscle groups may raise the possibilities of lateral popliteal or cauda equina lesions. Spasticity due to corticospinal tract disease is sometimes mitigated by coincidental lesions of the lower motor neurons, but even where these are lacking and the deep reflexes outstandingly brisk it rarely approaches the intensity commonly encountered in multiple sclerosis. Retention of abdominal reflexes and flexor plantar responses are frequent. Sphincter control is hardly ever affected. Subjective sensory complaints unsupported by abnormal findings on examination sometimes confuse the diagnosis, which may also be long delayed in cases presenting with insidious featureless quadriparesis. Chronic motor polyneuropathy and myelopathy due to cervical spondylosis especially may be simulated. Psychotic or psychoneurotic reactions were no commoner in our cases of motor neuron disease than in a random sample of hospital patients, and there were no instances of dementia. Emotional lability was sometimes a feature of bulbar palsy, but retention of mental clarity until the very end of the illness is one of the most distressing features of motor neuron disease in all its forms. Although familial incidence has occasionally been reported in motor neuron disease ever since the disorder was recognized, interest in the genetic aspects of the disorder has been mainly due to the discovery of the high prevalence of the condition amongst the Chamorros on the island of Guam (KOERNER 1952 ; ARNOLD et al. 1953 ; KURLAND AND MULDER 1954). In a recent review of hereditary amyotrophic lateral sclerosis ESPINOSAet aL (1962) proposed a sub-division of the disease into three forms: sporadic, hereditary, and Chamorro. On present evidence it seems that a minority of cases such as those reported by OSLER (1880) and ESPINOSA et al. (1962) undoubtedly manifest genetic determination. In the Guam cases this is less certain. The fact that there are some differences in clinical and pathological features between the pattern of motor neuron disease commonly encountered in Europe and America and that seen in Guam should not immediately determine the division of the disorder into two forms. The relationship might for example even be comparable with that believed to exist between the chronic remittent multiple sclerosis familiar in Western Europe and North America and the acute monophasic neuromyelitis optica of East Asia, which many neurologists regard as probable variants of a single pathological process. Confirmation of a significant preponderance of blood group B amongst patients with motor neuron disease (VEJJAJIVAe t al. 1965) would lend further support to the concept that motor neuron disease may involve inherited vulnerability to a number of possible exogenous factors. LEvV's (1962) interesting note that the parents of patients with motor neuron disease exhibited a significantly high incidence of cancer of the gastro-intestinal tract has not been supported by our present study. In this connection our survey differed from that of LEVY since we used consecutive admissions to the medical wards of the hospital as a sample of the population at risk, whereas LEvY was able to employ mortality rates drawn from the reports of the Registrar General for Scotland for comparison. LEvY's method of ensuring comparability of the two populations has J. neurol. Sci. (1967) 4 : 2 9 9 - 3 1 4

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not been presented in detail. Our own observations must be recorded as tar t¥om definitive, but they might have been expected to reveal any striking relationship between the two disorders. Clinical evidence of infection preceding the onset of motor neuron disease is negligible, nor does the natural history of the condition particularly favour an infective aetiology. However accumulating evidence suggesting a relationship between antecedent paralytic poliomyelitis and the chronic disease raises interesting possibilities, especially at a time when chronic virus diseases and the possibility of prolonged parasitism and symbiosis between virus and host cells are attracting increasing attention. It is noteworthy that motor nerve cells are highly vulnerable to viruses, especially to poliovirus, perhaps because their nuclei are rich in ribose nucleic ~cid which is needed by these organisms for their successful replication (MCMEYEMEV 1962). An alternative and possibly more plausible hypothesis is that wide-spread but clinically silent motor neuron damage sustained during the acute paralytic virus infection may render the cells of the system particularly vulnerable to subsequent damage by some other agent or agents. A possible relation between serious systemic disease and trauma often arouses medical scepticism. In many instances the association is dismissed as coincidental, or alternatively the trauma is thought to be a result rather than a cause of the disability, especially when this is neuromuscular. A early as 1922 COLLIER AND ADIE remarked that injury was an important occasional exciting factor and that typical progressive muscular atrophy not infrequently began in the region of an injury. In an extensive review of the literature on this aspect of the disease JELLIEEE(1935) was able to collect more than 90 such instances. In 5 of our patients the time-relationship between the onset of the disease and injury was so striking that it seems unlikely to be fortuitous. It is also noteworthy that in 3 patients, whose clinical details have been presented, the onset of the disease followed immobilization of the injured limb in plaster and the symptoms were first noticed at this site. The relationship between trauma and motor neuron disease recalls that reported in multiple sclerosis (MILLER 1964). In laboratory animals stimulation of a peripheral nerve often produces vasodilatation and increased blood flow in the appropriate segments of the spinal cord ; in some instances however continued stimulation evoked vasoconstriction (FIELD et al. 1951). TRUEVAAYO HODES (1954) found that immobilization of the hind limbs of experimental animals in plaster resulted in vasodilatation in corresponding segments of the spinal cord. The situation is however rather different from that of a patient with an injured limb. In the animals it is quite likely that increased activity of the limb muscles in the course of struggling for freedom might be responsible for the increased blood flow to the corresponding part of the spinal cord. The combination of immobility and continued painful stimulation in our patients might well produce the opposite effect. In such circumstances a reduction in blood supply to motor neurons might provoke a symptomatic onset by disturbing the metabolism of cells already affected by the disease. In the present study we have observed no significant relation between motor neuron disease and other factors such as malnutrition, peptic ulcer and electrical injury. The failure to demonstrate such findings in this small sample of the disease does not of J. neurol. Sci. (1967) 4 : 2 9 9 - 3 1 4

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313

course preclude the possibility t h a t such factors m a y be as significant as t r a u m a in o c c a s i o n a l l y p r e c i p i t a t i n g the onset o f the disease.

ACKNOWLEDGEMENTS W e t h a n k the physicians o f the R o y a l Victoria Infirmary for allowing us to study p a t i e n t s u n d e r their care a n d Mrs. D. W e i g h t m a n o f the Department o f Biostatistics in the University for her assistance. O n e o f us (A.V.) held a C o l o m b o Plan Travelling F e l l o w s h i p d u r i n g the present study. SUMMARY The clinical features o f m o t o r n e u r o n disease are described in 51 fatal a n d 45 surviving cases. The fatal cases yield figures for sex d i s t r i b u t i o n , age o f onset a n d d u r a t i o n o f the disease. I n surviving patients the clinical features are also p r e s e n t e d in detail. Possible aetiological factors are investigated, a n d cases o f unusually l o n g d u r a t i o n described. I n a few patients there is suggestive evidence o f a significant relation between t r a u m a a n d the onset o f the disease. Its social incidence is similar to t h a t o f the p o p u l a t i o n at risk, a n d no a s s o c i a t i o n was f o u n d in this series with p e p t i c ulceration, gastro-intestinal cancer or o t h e r c o n d i t i o n s i n c r i m i n a t e d by s o m e previous observers. H o w e v e r 4 % o f surviving patients gave positive family histories o f m o t o r n e u r o n disease, a n d one p a t i e n t h a d suffered a previous a t t a c k o f p a r a l y t i c poliomyelitis. Clinical features, d i a g n o s t i c p r o b l e m s a n d possible aetiological factors are discussed. REFERENCES ADAMS,R. D., D. DENNY-BROWNAND C. M. PEARSON(1953) Diseases of Muscle: A Study in Pathology, Harper, New York. ALPERS,B. J., ANDR. A. FARMER(1949) Role of repeated trauma by pneumatic drill in production of amyotrophic lateral sclerosis, Arch. Neurol. Psychiat. (Chic.), 62:178. ARAN, F. A. (1850) Recherches SUEune maladie non encore d6crite du syst6me musculaire (atrophic musculaire progressive), Arch. gdn. Mdd., 24: 5. ARNOLD, A., D. C. EDGRENAND V. S. J. PALLADINO(1953) Amyotrophic lateral sclerosis, fifty cases observed on Guam, J. herE. ment. Dis., 117: 135. BREWIS, M. R., D. C. POSKANZER,C. ROLLANDAND H. MILLER(1966) Neurological disease in an English city, Actapsychiat. neurol, scand., Suppl. 24, p. 66. BROWN, I. A. (1954) Chronic mercurialism; a cause of the clinical syndrome of amyotrophic lateral sclerosis, Arch. Neurol. Psychiat. (Chic.), 72: 674. C~ARCOT, J. M. ANOA. JorraoY (1869) Deux cas d'atrophie musculaire progressive avec 16sions de la substance grise et des faisceaux ant6ro-lateraux de la moelle 6pini6re, Arch. Physiol. norm. Path., 2:354, 629, 744. COLLIER,J. AND W. J. /~IE (1922) Price's System of Medicine, Ist ed., Oxford University Press, London. CRITCHLEY,M. (1934) Neurological effects of lightning and electricity, Lancet, i: 68. DOLL, R., F. AVERYJONESAND M. i . BUCKATZSCH(1951) Occupational factors in the aetiology of gastric and duodenal ulcers, with an estimate of their incidence in the general population, Spec. Rep. Ser. reed. Res. Coun. (Lond.), No. 276: 1. DUCHENNE, G. B. (1860) Paralysie musculaire progressive de la langue, du voile du palais et des 16vres, Arch. gdn. M~d., 2: 283. EARL, C. J. (1962) Discussion on motor neuron disease, Proc. roy. Soc. Ned., 55 : 1033. J. neuroL Sci. (1967) 4:299-314

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