J. Neurol. Neurosurg. Psychiat., 1966, 29, 29

Proximal spinal muscular atrophyMAURICE GROSS

From the Department of Neurology, St. Thomas's Hospital, London

It has been known for some time that cases ofmuscular atrophy can occur in young people whichclinically resemble limb girdle muscular dystrophybut which electromyographically and histologicallycan be shown to be due to damage to the spinalmotor neurone. Investigation of the family fre-quently reveals further cases, and the course andprognosis is often benign and relatively non-pro-gressive and similar in many ways to the course oflimb-girdle muscular dystrophy. Similar casesoccurring in a slightly older age group are likely to beconfused with motor neurone disease, and thus givenan unnecessarily poor prognosis. It is not until theyare seen to survive much longer than would beexpected and their disorder remain confined to thelower motor neurone, that it becomes evident thatone may be dealing with a different condition.Three cases are recorded here which have manysimilarities clinically, electromyographically, andhistologically; the first two started in late adolescenceand were initially thought to have the clinical featuresof muscular dystrophy, and the third case started inmiddle age and was for many years thought to bemotor neurone disease.

REPORT OF CASES

CASE 1 A 15-year-old apprentice printer was admittedto St. Thomas's Hospital in 1960 for investigation ofdifficulty in rising from the lying position for the pre-vious three years. He had always been well and was theonly child of healthy parents; no known relatives had anymuscular or locomotor disorder, nor was there anyknown consanguinity. At the age of 12 years he began tonotice difficulty in running when his legs would give outafter short distances. This slowly got worse, but he wasable to play football until he was 14. At this age he fellover one day and had difficulty in getting up, and thisdisability had persisted ever since; he had to get up byrolling over on to his abdomen and pushing himself upwith his hands. He had not noticed any weakness in hisupper limbs, but for the previous few months he had ex-perienced occasional cramps in his hands and feet.

Examination revealed an overweight boy with proxi-mal weakness of all the muscles round the shoulder andpelvic girdles, most marked in the hip flexors, glutei,'Present address: The National Hospital, Queen Square, London,W.C.1.

and quadriceps. There was no obvious wasting, nofasciculation, and sensation was normal. Biceps andsupinator reflexes were just obtainable but triceps jerkswere absent. In the lower limbs knee jerks were un-obtainable but ankle jerks were present; plantar re-sponses were flexor. No abnormality was found ongeneral examination.

Special investigations Electromyographic studiesshowed reduced motor unit activity in the affectedmuscles, and what activity there was comprised largepotentials of the type encountered in myelopathy(Fig. la).

FIG. 1a. Electromyographic tracing from the It. extensordigitorum communis in case 1, showing large amplitudepotentials.

Muscle biopsy from the left deltoid (Dr. V. Mac-Dermot) showed marked variation in muscle fibrecalibre, both hypertrophic and atrophic fibres beingsees. There was a considerable increase in perimysialfibrous and fatty tissue, and several intramuscular nervebundles showed loss of myelinated fibres. Methylene-blue-stained sections showed complex distal nerve fibrebranching and frequently the innervation of a number ofmuscle fibres by branches of a single nerve. The motorend-plates varied in size and were often large and com-plex. The appearances were considered to be those oflongstanding neurogenic muscular atrophy (Fig. 2a).

Cerebrospinal fluid showed a normal protein contentand negative Wassermann and Lange reactions. Sub-sequently he has been followed up as an out-patient andhas become but little weaker. For four months in 1961he was given oral prednisone, initially 30 mg., later

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FIG. 2a. Lt. deltoid muscle biopsy section from case 1,showing variation in calibre ofgroups of muscle fibres con-sistent with longstanding neurogenic atrophy.

reduced to 20 mg. daily, which did not appear materiallyto benefit him or alter the course of the disease. When lastseen in December 1964 he was working in a clerical job,although for the last few months he was no longer ableto walk to his office a mile away. His main disabilitywas still in rising from the recumbent or sitting positiondue to a weakness of the flexors and extensors of the hips.There was at this time moderate weakness of proximallimb muscles with some wasting, and depression of allreflexes except the ankle jerks. Estimations were made ofthe serum enzymes: creatine phosphokinase was 3-3 units(normal 0-2 to 1 5 units) and aldolase 15-4 units (normal3 to 10 units). The creatine level was 0-60 mg%.Electromyography has been repeated yearly since he

was first seen and remains unchanged. At the last examina-tion in July 1965, nerve conduction studies were madealong the right ulnar nerve, and the responses showednormal latencies and durations. The nerve conductionvelocity over the elbow-to-wrist and axilla-to-elbowsegments of the nerve was 40 m./second which is withinthe normal range.

CASE 2 A 22-year-old unmarried dental technician wasadmitted to St. Thomas's Hospital in September 1964for investigation of muscular weakness for the previousfive years. Six years before admission he had had anillness diagnosed as glandular fever, but had otherwisealways been healthy and athletic. He was one of threesiblings, an older brother and sister being healthy andwithout any muscle disorders; there was no known historyof consanguinity or muscular weakness in the family.

At the age of 17 years he began to notice some difficultyin climbing stairs because of weakness in his thighs. Hislegs had always been thin and he did not think that theyhad become thinner nor had he experienced any muscularcramps. His arms had always been thin, but he had noticedno weakness in them. He claimed that his disability atthe time of admission was no greater than it had been atthe time of onset of the condition five years previously.On examination he was a thin, bearded man of normal

intelligence. There was gross wasting and moderateweakness of the muscles around the shoulder girdle andthe proximal arm muscles, but the distal musculatureretained almost normal bulk and power. There was nodetectable trunk weakness, but in the lower limbs therewas considerable wasting of quadriceps and glutei withcommensurate weakness. Bursts of fasciculation wereseen in shoulder and thigh muscles. Sensation wasnormal, all tendon reflexes were obtainable only withdifficulty, and the abdominal reflexes were absent.Plantar responses were flexor. General medical examina-tion was normal.

Special investigations Electromyographic studies ofthe affected muscles revealed definite fibrillation at rest;in addition fasciculation potentials were recorded andoccasional high frequency discharges. The volitionalmotor unit pattern was reduced and some of the potentialswere of longer duration than normal and polyphasic.Nerve conduction studies in the ulnar nerve were normal.The appearances were those of a myelopathy (Fig. lb).

FIG. lb. Electromyographic tracing from the rt. extensordigitorum communis in case 2, showing large potentialsofmore than 5 m V. amplitude.

A muscle biopsy showed groups of small muscle fibreswhich had lost their striation and showed granulationand sarcolemmal proliferation. The appearances suggestedneurogenic atrophy (Fig. 2b).The cerebrospinal fluid was of normal composition

and the Wassermann and Lange reactions were negative.The serum creatine level was 1-3 mg.% (normal less

than 0-6 mg. %), creatine phosphokinase 3-0 units(normal 0-2 to 1 5units), and aldolase 20-8 units (normal3 to 10 units).

Subsequently the patient has been followed-up in theOut-patient Department, and when last seen in May 1965

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Proximal spinal muscular atrophy

reflexes were reduced in the right arm and both legs, andplantar responses were unobtainable. There was nosensory disturbance. He was diagnosed as having anunusual type of motor neurone disease. Electromyo-graphy at that time revealed fibrillation in both upperand lower limb muscles and large amplitude potentialson minimal volition (Fig. ic). Intravenous injection of10 mg. edrophonium chloride increased the fascicula-tion and provoked it in other parts of the body where ithad not until then occurred.

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* :~~~~~~~~~~~~~.FIG. 2b. Muscle biopsy from case 2 showing variation insize of muscle fibres in longitudinal section; the smallerfibres have no striations and show granular degeneration.

remained unchanged. He was able to walk for two or threemiles on the level and climb 50 stairs slowly, but founddifficulty in getting up from a chair without using hishands because of weakness of the hip muscles.

CASE 3 A 49-year-old motor tester was first seen at St.Thomas's Hospital in November 1953 by the late Dr.J. St. C. Elkington. The first symptoms of muscularweakness had started 11 years previously when at theage of 38 years he had been discharged from the HomeGuard because his legs were not strong enough for himto keep up with the other men during training marches.This weakness remained very slight for several years. Atthe age of 46 he had to give up playing the violin becausehis right wrist had become too weak for bow movements.He had noticed that his hands had become thinner andthat his muscles were twitching frequently. His voicetended to fatigue easily and on one occasion he had hadslight difficulty in swallowingf for a short time. Pre-viously he had had no significant illnesses and he was theonly child of healthy and unrelated parents who were notaffected by any muscular wasting or weakness; there wasno known history of any familial muscular disorder.On examination he was seen to be thin with mild

bilateral wasting and fasciculation in the facial muscles,and his speech was nasal, defective in the production oflabial sounds, and easily fatigued. His tongue was smalland symmetrically wasted, and there was wasting of theneck, shoulder-girdle, arm and leg muscles, mainlyproximally, with hypotonia and fasciculation. Tendon

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FIG. lc. Electromyographic tracing from extensor digi-torum communis in case 3, showing extremely high ampli-tude potentials.

Thereafter electromyography has continued to show thesame changes twice yearly. In 1957 he was admitted forexamination of the spinal fluid which was found to benormal in all respects; the protein content was 25 mg. %and the Wassermann and Lange reactions were negative.Over the next four years he was seen regularly as an out-patient and there appeared to be only a very slight in-crease in weakness. In 1958 he was again admitted formuscle biopsy by Dr. Violet MacDermot. The biopsy wasreported on as follows:Muscle biopsy (It. peroneus longus) The general

picture was of well-marked focal atrophy of musclefibres. The atrophic fibres were markedly reduced incalibre. A considerable number of fibres were, however,of normal calibre; among these were scattered fibresshowing basophilic staining, central emigration of nuclei,and degenerative changes in the cytoplasm. Nerve bundlesshowed considerable loss of myelinated fibres. Methylene-blue-stained sections showed variation in calibre of intra-muscular nerve fibres and nerve bundles appeared poorlyinnervated. Motor end-plates were degenerate and someterminal branching was seen. The picture was that of afocal neurogenic muscle atrophy with unusual degenera-tive changes occurring in the muscle (Fig. 2c).

Also at that time the serum creatine level was 0 99mg. % (normal less than 0-6 mg. %) and serum creatinephosphokinase 2-79 units (normal 0-2 to 1-5 units).

Since that time his condition has hardly deteriorated.He was last seen in August 1965, some 23 years after hisinitial symptoms, not greatly incapacitated, able to walk

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FIG. 2c. Part of section of muscle biopsy (left peroneuslongus) from case 3, under high power ( x 500), showingarea offloccular degeneration of muscle.

and to enjoy his retirement. Examination showed that hismuscles had wasted a little more, both proximally anddistally, fasciculation was prominent and widespread andincluded the tongue, and the tendon reflexes were un-obtainable. There were no upper motor neurone signsand sensory examination was entirely normal.

REVIEW OF THE LITERATURE

It is relevant at this point to discuss the previousliterature describing muscular atrophy of spinalorigin not only in the age groups covered by thethree cases presented above, but also as it occurs ininfancy and childhood. Just before the turn ofthe century Werdnig (1891 and 1894) and Hoffmann(1893 and 1897) in four articles described severalcases of a rapidly progressive, familial muscularwasting and weakness occurring in infancy. Thesecases were summarized by Hoffmann in 1897; mostof them had died in the first year of life, althoughWerdnig's cases showed some variation in severity,one child surviving to over 6 years of age. The patho-logical basis for the disease was found to be spinalatrophy.

In 1950 Brandt reviewed over 100 cases of infantile

muscular atrophy. The majority had started theirdisease in the first year of life and died before theage of 4 years, but several survived until lateadolescence. Of those who were still living, the twooldest were aged 18 and 20 years but were completelydisabled by extreme weakness and wasting.

Wohlfart, Fex, and Eliasson described threefamilies in 1955, containing seven cases of a relativelynon-progressive proximal muscular atrophy withan onset in childhood or adolescence. Most of thesecases were already in their teens or twenties whendescribed. Four cases were studied electromyo-graphically, which indicated a spinal origin to thewasting, and there was further confirmation of theneurogenic nature of the disorder from musclebiopsy in one of these cases.A year later in 1956, Kugelberg and Welander de-

scribed 12 patients with an hereditary type of juve-nile muscular atrophy all of whom had been con-sidered initially to have muscular dystrophy. Thedisease started at ages which varied between earlychildhood and adolescence, and progressed onlyvery slowly over the course of many years. Most ofthe cases belonged to families in which another one ormore members could be found with a similar disorder,and there appeared to be a recessive inheritancewithout sex linkage. The lower limbs were usuallyaffected first, mainly proximally, and the upperlimbs were not affected for many years. The weak-ness was accompanied by wasting of muscle, particu-larly around the limb girdles, and fasciculation wasoften seen or could be provoked by neostigmine.Tendon reflexes gradually disappeared, although theankle jerks were frequently retained until late in thedisease. Plantar responses were normal, and thecranial innervated muscles remained intact. Electro-myography showed characteristic changes of lowermotor neurone damage and muscle biopsy showedneurogenic atrophy.

In 1961 Byers and Banker reviewed 52 cases ofinfantile muscular atrophy and lay stress on thevariability in clinical and pathological severity. Ingeneral they found that the earlier the age of onset,the more severe and rapidly progressive the diseasewas likely to be; the least severely affected cases hadall started after the first year of life, and manysurvived into early and late childhood.Dubowitz in 1964 described a further 12 cases of

spinal muscular atrophy which had started beforethe age of 18 months and appeared to have anautosomal recessive inheritance. Most of thechildren presented had already reached late child-hood, and again there seemed to be a great variationin severity. The disease seemed to progress rapidlyat first and thereafter to decline in severity so as tobecome almost stationary, leaving the patients with

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varying degrees of disability from residual weaknessand contractures. There was neither intellectualdeterioration nor upper motor neurone involvement.The diagnosis in nearly all the cases was confirmedelectromyographically and histologically from musclebiopsy specimens. In one case the levels of the serumenzymes creatine phosphokinase and S.G.O.T. wereslightly raised. In those cases that were familial,there was such variation in the severity of the diseasethat both Werdnig-Hoffmann and Kugelberg-Welander types of atrophy seemed to occur withinthe confines of a single family.The most recent significant paper by Tsukagoshi,

Nakanishi, Kondo, and Tsubaki (1965) describesfive cases of a slowly progressive, hereditary proxi-mal muscular atrophy, with symptoms beginningusually in the third or fourth decade. Clinically itclosely resembled Kugelberg and Welander's con-dition except that in three of the cases there wasbulbar palsy. Electromyographically there wasevidence of a disorder of the spinal neurone. Musclebiopsy showed changes implying anterior horn celldamage, but also certain architectural abnormalitiesin some muscle fibres, such as central nuclei andisolated fibre necrosis, which suggested a myo-pathic element. These last changes could probably becorrelated with the grossly elevated creatine phos-phokinase levels which were found to occur in fourof the cases.

DISCUSSION

The first two cases in this paper are very similar tothose of Kugelberg and Welander, but are notobviously familial. However, an entirely accuratefamily history cannot be relied upon and in view ofthe limited sibships there could still be an under-lying inherited basis. Clinically from the age ofonset, distribution of weakness, and the rate ofevolution it seems indistinguishable from a limb-girdle type of muscular dystrophy, but electro-myographically and histologically differs completely.There is still the paradox that, although neurogenicin origin, these two cases have both shown abnor-malities in serum enzymes which are normallyassociated with myopathic conditions rather thanneurogenic atrophies. In a survey of enzyme valuesin a collection of mixed cases of neurogenic atrophyand muscular dystrophy patients, Okinaka,Kumagai, Ebashi, Sugita, Momoi, Toyokura, andFujie (1961) showed that a rise in creatine phos-phokinase was limited to patients with musculardystrophy, their relatives, or occasionally patientswith polymyositis or Charcot-Marie-Tooth disease.Case 3 differs in that for many years it has

simulated not muscular dystrophy but motor neuronedisease. At first sight this patient appears to havethe Aran-Duchenne type of motor neurone disease,in which muscular atrophy is the main feature, butthis hardly seems a tenable diagnosis in a patientwhose disease has progressed only mildly in over twoscore years and who still has no evidence of uppermotor neurone damage. This case is in nearly allrespects identical to the cases described by Tsuka-goshi et al. (1965), even to the unusual muscle biopsyappearance which seemed to combine the features ofneurogenic atrophy with some evidence of a myo-pathic process. The level of serum creatine phospho-kinase was raised, although not to the same extent asin the cases of Tsukagoshi et al. (1965). The absenceof a positive family history does not necessarily ruleout a hereditary basis in view of the limited sibshipand incomplete family data.

It is difficult to be certain of the precise relation-ship between these various forms of spinal muscularatrophy. Certainly, when one considers the Werdnig-Hoffmann and Kugelberg-Welander types of atrophyand the many documented cases ranging betweenthem, even within the confines of a single family, itseems possible that one is dealing basically with asingle condition which may combine variable agesof onset and rates of progress. The group of caseswhich start at a later age than the infantile andjuvenile groups, such as case 3 above and the casesof Tsukagoshi et al. (1965), are in many wayssimilar and may be related, although there seems tobe less overlap between these cases and those occur-ring at an earlier age. More extensive series are re-quired to see whether infantile and juvenile formsmay occur in the same family setting as the lateradult cases.

Finally, it is worth briefly considering whetherthere could be any relationship between the variousforms of chronic spinal muscular atrophy, here-ditary or otherwise, and motor neurone disease.Motor neurone disease can occasionally occurhereditarily and this topic has been discussed indetail by Kurland and Mulder (1955). However,familial motor neurone disease usually presents as arapidly progressive amyotrophic lateral sclerosis,with dominant inheritance, rather than as pure pro-gressive muscular atrophy. Also in those cases ofmotor neurone disease in which muscular atrophypredominates, the wasting tends initially to be distalrather than proximal as is seen in the chronic spinalmuscular atrophies. There is thus no real evidence tosuggest any close relationship between motorneurone disease and the chronic spinal atrophiesseen in adult life, and indeed, in view of the markeddifference in course and prognosis, it is importantto try and distinguish between them.

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SUMMARY

Three cases were presented of chronic muscularatrophy occurring in adult males with the histologicaland electromyographic characteristics of atrophy dueto damage to the spinal motor neurone.Two of the cases were in most respects similar

to those described by Kugelberg and Welander, butdiffered in the absence of a positive family history.The third case occurring in an older man was

similar in most respects to the cases recently des-cribed by Tsukagoshi et al. (1965), but again differedin the absence of a positive family history.I wish to thank Dr. R. E. Kelly for help and permissionto publish the reports of cases under his care, Dr. R. W.Ross-Russell for advice and guidance, Dr. P. Bauwensand Dr. D. A. H. Yates for electromyographic studies,and Dr. J. R. Tighe for the photomicrographs.

REFERENCES

Brandt, S. (1950). Course and symptoms of progressive infantilemuscular atrophy. Arch. Neurol. Psychiat. (Chic.), 63, 218-228.

Byers, R. K., and Banker, B. Q. (1961). Infantile muscular atrophy.Arch. Neurol. (Chic.), 5, 140-164.

Dubowitz, V. (1964). Infantile muscular atrophy, a prospective studywith particular reference to a slowly progressive variety. Brain,87, 707-718.

Hoffmann, J. (1893). Ueber chronische spinale Muskelatrophie imKindesalter, auf familiarer Basis. Dtsch. Z. Nervenheilk., 3,427-470.

(1897). Weiterer Beitrag zur Lehre von der hereditaren pro-gressiven spinalen Muskelatrophie im Kindesalter nebstBemerkungen uber den fortschreitenden Muskelschwund imAllgemeinen. Ibid., 10, 292-320.

Kugelberg, E., and Welander, L. (1956). Heredofamilial juvenilemuscular atrophy simulating muscular dystrophy. Arch. Neurol.(Chic.), 75, 500-509.

Kurland, L. T., and Mulder, D. W. (1955). Epidemiologic investiga-tions of amyotrophic lateral sclerosis. 2. Familial aggregationsindicative of dominant inheritance. Neurology (Minneap.), 5,182-196, and 249-268.

Okinaka, S., Kumagai, H., Ebashi, S., Sugita, H., Momoi, H.,Toyokura, Y., and Fujie, Y. (1961). Serum creatine phospho-kinase activity in progressive muscular dystrophy and neuro-muscular diseases. Arch. Neurol. (Chic.), 4, 520-525.

Tsukagoshi, H., Nakanishi, T., Kondo, K., and Tsubaki, T. (1965).Hereditary proximal neurogenic muscular atrophy in adult.Ibid., 12, 597-603.

Werdnig, G. (1891). Zwei fruhinfantile hereditare Falle von pro-gressiver Muskelatrophie unter dem Bilde der Dystrophie,aber auf neurotischer Grundlage. Arch. Psychiat. Nerven-kr., 22, 437-480.

- (1894). Die fruhinfantile progressive spinale Amyotrophie.Ibid., 26, 706-744.

Wohlfart, G., Fex, J., and Eliasson, S. (1955). Hereditary proximalspinal muscular atrophy-a clinical entity simulating progres-sive muscular dystrophy. Acta psychiat. scand., 30, 395-406.

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