MOTOR NEURONE DISEASE · ticity is the presenting feature, and atrophy of muscle may be delayed and be minimal, or even absent, throughout the course of the disease. These uncommon

POSTGRAD. MED. J. (I962), 38, 383

MOTOR NEURONE DISEASETHOMAS PARTINGTON, M.D., F.R.C.P.

Physician, Kettering and Northampton General Hospitals

THE story of motor neurone disease goes backmore than a hundred years, to the latter half ofthe igth century, and the days of the great clinicalneurologists of France. Of the many famousnames linked to this story three are pre-eminent:Charcot-physician and neuropathologist, andgreat teacher, who became even more renownedfor his studies of hysteria (Fig. i); Duchenne, theone from Boulogne, who came from a family offishermen and seafarers (Fig. 2); and Dejerine,great clinical neurologist, and pioneer in the studyof localization of function in the brain (Fig. 3).

Progressive degenerative lesions affecting bothupper and lower motor neurones of the spinalcord and brain stem were described as separatediseases, distinct one from another, under thetitles of progressive muscular atrophy, a spinaldisease of lower motor neurones (Aran, I850;Duchenne, I858); progressive bulbar palsy, adisease of bulbar lower motor neurones (Wach-smuth, I864); and amyotrophic lateral sclerosis(Charcot and Jqffroy, I869), a disease of bothlower and upper motor neurones. Progressiveophthalmoplegia (Hutchinson, I879; Gowers,I879; Brissaud, I895) was formerly considered tobe a nuclear disease analogous to the cases ofprogressive bulbar palsy originally described byDuchenne (i858) as 'primary labio-glosso-laryn-geal paralysis'. The nuclear origin of progressivebulbar palsy was demonstrated by Charcot, andthe association with amyotrophic lateral sclerosisby Dejerine (I883). Chronic poliomyelitis,nuclear amyotrophy and progressive spinal mus-cular atrophy are other synonyms which havebeen used to describe the diseases now groupedby many authorities under the name of motorneurone disease. The Werdnig-Hoffmann paralysisof infantile progressive spinal muscular atrophy isusually added to this grouping, the original casesbeing described in I89I and I893. The unity ofthese several conditions has been criticized byWilson (1954), who considers the term motorneurone disease 'etiologically vague and patho-logically unspecific'. The clinical picture andprogress of these diseases often remain distinctthroughout life, and there is a tendency for thisclarity of outline to become blurred by nosological

fusion into a single disease entity. Despite theprobable pathological unity there is much to besaid for retaining within the overall heading ofmotor neurone disease, the original individualnames for diseases which have many clinicaldifferences and differing prognoses.

General AEtiologyThough cases of motor neurone disease may

occur in childhood and adolescence (van Bogaert,1925), it is a disease mainly of early middle life,from about the age of 30 to 50 years. Cases ofbulbar palsy occur twice as commonly in womenas in men, but progressive muscular atrophy andCharcot's disease affect men far more often than

U..UU..

FIG. i.-Jean Martin Charcot (I825-I893)(Reprinted with permission from Webb Haymaker: 'The Founders

of Neurology', Ed. Ig. Courtesy of Charles C Thomas, PublisherSpringfield, Illinois.)

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384 POSTGRADUATE MEDICAL JOURNAL July I962

..: ..... ...

FIG. 2.-Guillaume Benjamin Amand Duchenne(i8o6-i87r)

(Reprinted with permission from Webb Haymaker: 'The Foundersof Neurology', Ed. I9. Courtesy of Charles C Thomas, Publisher,Springfield, Illinois.)

women, in the proportion 2 to i and 3 or 4 to Irespectively. Occasional familial cases are re-ported (Osler, i88o; Hammond, I88I; Holmes,1905), but are uncommon in western countries.On the island of Guam, and others of the MarianasIslands in the Pacific, Koerner (I952), Arnold,Edgren and Palladino (I953), Kurland andMulder (1954, 1955) and Kurland (I957) havereported a remarkable incidence of the disease,with a frequency ioo times more than normal,I% of the adults being affected and io% of alldeaths being due to motor neurone disease.Familial cases here, with a high incidence inyoung people, are very common. These reportshave brought into prominence possible racial andheredo-familial factors, which were previouslyconsidered unrelated in this disease.

Cases occurring after acute poliomyelitis, andat varying times after syringomyelia and epidemicencephalitis, have been frequently reported (Carr,1926; Ornsteen, 1930; Greenfield and Matthews,1954). The possibility of a deficiency factor hasbeen pointed out by Ask-Upmark and Meurling(1955). Neurosyphilis and lead poisoning occa-

sionally produce spastic paralysis and wasting,which may imitate motor neurone disease, butdistinguishing features can usually be found.Fatigue and trauma (Jelliffe, 1935), whether fromdirect injury or concussion (Alpers and Farmer,I949), or past injection therapy, seem to have abearing in precipitating the onset of motor neuronedisease at a particular site, e.g. injections into thebuttocks or upper arms in lumbar and shoulder-girdle types of progressive muscular atrophyrespectively. In most cases preceding incidentsare probably coincidental, occurring by chanceonly, the majority of cases occurring idiopathicallyand belonging to the class of 'primary endogenoussystematized degeneration' (Wilson, 1954).

Progressive Muscular Atrophy-Varietiesand Clinical FeaturesThe progressive muscular atrophy of Aran and

Duchenne, with its distinctive features of nuclearamyotrophy and without clinical evidence ofpyramidal disease, continues to be seen frequently.The classical variety of symmetrical wasting andweakness of the small muscles of the hands isfound in many of these cases (up to 50%-accord-ing to Wilson),' involving interosseous and lum-brical, thenar and hypothenar muscles, with pro-gression proximally to the forearm and later theupper arm muscles. Not infrequently weakness andwasting start first in the muscles of the shouldergirdle (Vulpian-Bernhardt's proximal type)-thesupraspinati, infraspinati and latissimus dorsibeing affected-with extension to deltoid andpectoral muscles later. The presence of fascicu-lation distinguishes this variety from the proximalmyopathies. The brachio-radialis muscles, theupper third of the trapezii, and the sterno-mastoidmuscles often remain unaffected until the laterstages of the disease. This proximal or scapulo-humeral type often pursues a relatively mildcourse (Swank and Putnam, 1943).A pelvic girdle onset is also not uncommon,

with extension both to the lumbar muscles andmuscles of the thighs. Wasting of gluteus mediusand minimus muscles produces characteristichollowing of the outer portions of the buttocks,with resulting prominence of the greater tro-chanters; atrophy of the erector spinx musclesemphasizes the vertebral spines and the diamond-shaped outline of the sacrum. Wasting of thequadriceps muscles brings out the anatomicalfeatures of individual muscles, with the longstrap of the sartorius muscle standing out stronglyon knee flexion and emphasizing also the hollow-ing above the patella from the wasted vastusmedialis portions of the quadriceps muscles. Bothgait and posture are affected early in this variety,the patients adopting an unsteady forward-bending

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July I962 PARTINGTON: Motor Neurone Disease 385

'I

FIG. 3.-Joseph Jules Dejerine (I849-I9I7)(Reprinted with permission from Webb Haymaker: 'The Founders

of Neurology', Ed. ig. Courtesy of Charles C Thomas, Publisher,Springfield, Illinois.)

attitude to maintain balance with weakeningmuscles.

Rarely, onset with peripheral leg wasting imi-tates peroneal muscular atrophy. Lack of sym-metry of wasting is found only in the early stagesof the disease, but for a time a hemiplegic picturemay be found. A generalized tetraplegic variety,purely atrophic, affecting all four limbs withspread later to the trunk and bulbar.muscles, isperhaps more common than is realized. Occa-sionally, this tetraplegic variety is associated withsevere limb pains imitating a polyneuritis, butwith preservation of reflexes until a late stage.

In clinically pure cases of progressive muscularatrophy, weakness and severe lack of tone withflaccidity of muscle groups, and progressive re-duction of reflexes are usual, especially wheremuscle wasting is severe. Tonic wasting withactive reflexes suggests the later development ofCharcot's disease. All varieties show active fatatrophy as well, and this sometimes appears toprecede the muscle wasting. In the later stagesof atrophy, whether regional or generalized, themuscles of respiration become involved, withwasting and weakness of intercostal muscles anddiaphragm, and of the oblique abdominal muscles.

The recti abdominis muscles seem rarely to beaffected. Muscle wasting and weakness are in-variably accompanied by fasciculat on-the spon-taneous flicker of groups of muscle fibres suppliedby a degenerating motor unit-muscle twitchingwhich can be demonstrated or increased by pre-liminary limb contraction against mild resistance.Fasciculation undoubtedly increases after exer-tion, and despite some statements to the contrary(Wechsler, 1958) seems to be more frequent andgeneralized in rapidly progressive cases, and hastherefore definite prognostic as well as diagnosticvalue.

Atrophic spread to the bulbar muscles iscommon and occurs in up to 5o% of casesclinically (Swank and Putnam, I943). Somecases present initially with Duchenne's labio-glosso-laryngeal paralysis. Post-mortem manycases show anatomical spread of degeneration,without having produced associated symptomsduring life. In these bulbar cases the tonguebecomes flabby, shrunken and wrinkled, lying inthe floor of the mouth and showing prominentfasciculation. There is difficulty in putting outthe tongue, or moving it from side to side.Eating, as well as speaking, becomes difficult.The lips and chin are involved, together with thepalate and extrinsic muscles of the pharynx andlarynx. Dysarthria results from defective articu-lation, pronunciation of dentals (d, t), labials(b, f, m, p, v), linguals (1, n. r) and palatals (g, k)is lost, and slurred speech gives way to unin-telligible noises. The voice becomes' monotoned'or monotonous, swallowing becomes increasinglydifficult, and inhalation of food and nasal regurgi-tation are further symptoms which develop lateras the dysphagia becomes more severe (Wilson,1954). The progression of primary atrophicbulbar cases is rapid and death is usual within ayear of onset. Secondary cases may deterioraterather more slowly over a period of two to threeyears. Involvement of the upper brain stem withresulting nuclear ophthalmoplegia is rare. Hereptosis and gradual paralysis of external ocularmuscles may complicate bulbar palsy, or veryrarely be a primary manifestation of the disease.Progressive ophthalmoplegia has been reported iryounger cases with a distinct familial incidence.Most of these, however, are now considered to beof myopathic origin (Kiloh and Nevin, 195I).As previously noted, familial cases of pro-

gressive muscular atrophy occurring in childhoodare recognized under the title of Werdnig-Hoff-mann paralysis or progressive spinal muscularatrophy of infancy, and must be included in thegeneral grouping of cases, showing chronic de-generative atrophy of lower motor neurones (seeCase No. 4). Normal at birth, weakness and

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POSTGRADUATE MEDICAL JOURNAL

wasting commence at about six months in themuscles of the back and shoulder and pelvicgirdles, spreading later to the intercostal musclesand peripheral muscles of the limbs. Fascicula-tion of muscle occurs and tendon reflexes diminish.The muscles are flaccid. Recently, identity withOppenheim's amyotonia congenita has been sug-gested (Brandt, I950), particularly on patho-logical grounds, though profound lack of toneand lack of fasciculation is characteristic of thesefloppy babies.

General Symptoms and Signs ofAmyotrophicLateral SclerosisThe advent of spasticity of the limbs in motor

neurone disease profoundly affects the progressand prognosis of the case. Whereas in the earlieststages the presence of upper limb weakness andwasting of small muscles suggests the morerestricted anatomical diagnosis of progressivemuscular atrophy, with usually its more pro-longed clinical course, the recognition of spasticityof muscle indicates the development of Charcot'sdisease with the classical picture of amyotrophiclateral sclerosis. Stiffness of muscles and increasedreflexes are then found with varying degrees ofclonus. The muscle spasticity is found pre-dominantly in the lower limbs, accompanyingand usually following small muscle weakness andatrophy of the upper limbs. Occasionally spas-ticity is the presenting feature, and atrophy ofmuscle may be delayed and be minimal, or evenabsent, throughout the course of the disease.These uncommon cases are often referred to ascases of primary lateral sclerosis, described byErb as 'spastic spinal paralysis', and may indeedbe a different disease entity. Wasting of spasticmuscles in classical Charcot's disease occurs inonly slight degree after one or two years, and isdue to spread of cord cell involvement from lateralto anterior horns. Variations of this picture ofupper limb wasting and lower limb spasticity are,however, commonly found. Tendon reflexes maybe exaggerated in the arms, wrists and fingers,with muscle spasticity, and 'tonic wasting' of but-tocks, thighs and lower limbs, with prominentfasciculation of muscle, may occur in the presenceof very brisk reflexes.

Bulbar spread is invariable, occurring usuallyin the later stages of the disease, but may beearly and predominate (Alpers, I958). Occa-sionally it is of spastic type, and instead of thewasted lower facial, tongue and laryngeal musclesof progressive bulbar atrophy a condition ofspastic weakness of these muscles is found fromsupranuclear neurone involvement. A brisk jawjerk, small spastic tongue and stiff lower facial

muscles are found. The emotional picture ofpseudo-bulbar palsy, with its inappropriate anduncontrolled paroxysmal laughing and crying,sometimes accompanies these findings (Davisonand Kelman, I939; Wechsler, Sapirstein andStein, I944). Perhaps most commonly a com-bined upper and lower motor neurone bulbar.lesion is found, with dysphagia and dysarthria ofboth spastic and atrophic type. Ocular involve-ment of spastic type is difficult to assess, for eventhe atrophic variety of nuclear ophthalmoplegiais now felt, as previously noted, to be allied tothe familial muscular dystrophies. Ptosis, enoph-thalmos, and small pupils of oculo-sympatheticHorner's paralysis have been reported (Wechsler,1958) from spread of the degeneration to thelateral horns of grey matter in the thoracic cord,involving sympathetic ganglion cells there, butmust be very rare.

Objective sensory changes are uncommon, buthave been reported (Wechsler, Brock and Weil,I929; Davison and Wechler, 1936; Friedman andFreedman, I950; Lawyer and Netsky, 1953).Early, severe and long-persisting cramp-like painsin the muscles of the back and shoulders, as wellas of buttocks and legs, are however not uncom-mon, and transitory neuritic 'lightning' pains alsooccur as in pure progressive muscular atrophy.Both are often reported by patients as due to'rheumatism'. They can be very disabling inthemselves. Numbness and 'pins and needles' inthe feet and fingers are also complained of in theearlier stages of the disease. The hands and feetof atrophied spastic limbs are often cold andcyanotic. Involvement of sphincters is very rareand late in appearance, and presents with eitherretention or incontinence. Rarely also urgencyof micturition occurs, and in cases showingfasciculation suggests pyramidal tract involvement(Swank and Putnam, 1943). Impotence maydevelop. Mental changes occur, but are rare(Davison and Wechsler, 1936).The syndrome of Jakob (1923), with the unsatis-

factory title of 'spastic pseudosclerosis', describedalso by Creutzfeldt (1920) and later by Davison(I932), Worster-Drought, Hill and McMenemey(I933) and others, shows a clinical picture ofmuscular atrophy with fasciculation and spasticparalysis of either bulbar or spinal type, givingrise to dysarthria and weak stiff limbs. Extra-pyramidal symptoms of tremor, Parkinsonianrigidity and poverty of movement, and mentalsymptoms with gradual loss of intellect, pro-gressing to dementia, are also found. Thepresence or development of these latter featuresdistinguish this special syndrome from theaccepted grouping of motor neurone disease, andjustify separation from it.

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PARTINGTON: Motor Neurone Disease

Illustrative Case Record of Jakob-CreutzfeldtDisease

0. D., female, aged 54 years. She first attended on15.I2.6i with a history of increasing forgetfulness forthe previous 12 months, dragging of the feet for aboutnine months, and progressive weakness of all her limbsfor the last six months. On examination she showedsevere dysarthria, increased jaw jerk, and severe spasticweakness of all limbs, with mild wasting of the forearmsand hands without sensory loss. No fasciculation ofmuscle. B.P. I45/80 mm. Hg. X-rays of skull andspine normal. CSF normal. EEG abnormal, withbilateral theta activity in occipital areas supportingclinical diagnosis of basilar artery insufficiency. On9.3.62 air encephalograms at Churchill Hospital,Oxford, showed widespread atrophy of cerebrum, mid-brain and cerebellum. Dr. Spalding considered thatdespite a speech 'resembling that characteristicallyheard in severe motor neurone disease', the above find-ings and mild dementia indicated a diagnosis of Jakob-Creutzfeldt disease.

In the following summarized case reports adiagnosis of motor neurone disease has beenmade on clinical grounds, supported by routineX-rays and CSF examinations, with EMG recordsin several cases, but without autopsy confirmation.These patients usually die at home, where consentfor post-mortem examination is either not ob-tained or not given.

Case No. i.-W. A., male, aged 52 years. Symptomswere present for six months before he was first seenon I7.1.58. Weight I3 st. 8 lb. He complained of painsin the limbs at night, with flushing of feet and twitchingof legs. On examination he showed auricular fibrilla-tion, B.P. 130/90 mm. Hg, no neurological signs,haemoglobin I09%, ESR 3 mm./hr. X-ray of chestnormal. On 25.4.58, with a weight of ii st. io lb.,anxiety state was present, and possibly fasciculation ofleg muscles. By 23.7.58 he complained of weakness ofthe legs and showed generalized fasciculation of musclesof the legs, arms and shoulders, increased after exercise.There was partial left foot drop, and both arms wereweak. CSF-protein 70 mg./ioo ml., globulin negative,no cells. On I8.8.58 wasting of small muscles of bothhands and of quadriceps muscles was noted. Seen byDr. Ritchie Russell on 8.9.58, who confirmed diagnosisof MND. Eleven months later, on 30.7.59, there wasmarked wasting of trapezii, pectorals, forearm andinterossei muscles, and of thigh and leg muscles.Bilateral foot drop and wrist drop were present, withgeneralized fasciculation. Knee and ankle reflexesabsent and plantars flexor. He died several days later.Post-mortem examination not obtained.

Diagnosis: Progressive muscular atrophy.

Case No. 2.-J. B., male, aged 69 years. He attendedon i8.io.6I complaining that I8 months previously hehad noticed 'flopping' of the left foot. A limp graduallydeveloped, and later weakness of the left leg and leftarm. On examination there was weakness of dorsi-flexion of the left foot, wasting and weakness of bothquadriceps muscles, especially of the vastus medialisportions, with prominent fasciculation. Reflexes werenormal, but the right plantar response was extensor.Wasting and weakness of all shoulder girdle muscles,including deltoid and pectoral muscle groups, withgross fasciculation, was also noted. Heart and lungs

normal. Seen again on 5.3.62 he showed severe weak-ness of arms and shoulder girdle muscles; walking wasdifficult.

Diagnosis: Amyotrophic lateral sclerosis.Here the rapid progress of the disease over a period

of two years, with positive Babinski response, despitenormal reflexes and absence of spasticity, indicate themore serious diagnosis of amyotrophic lateral sclerosis.The family doctor has since noted that this patientsaw an E.N.T. specialist two years ago because of anunexplained difficulty in swallowing, which later seemedto clear. This suggests mild bulbar palsy at the onsetof the disease, which is uncommon.

Case No. 3.-L. B., female, aged 48 years. Shecomplained of progressive loss of power of the righthand and 'jumping' of the upper arm muscles for theprevious eight months. No pain or sensory symptoms.On examination, 10I.0.58, there was wasting of rightsupraspinatus, infraspinatus, trapezius, and deltoidmuscles, with active fasciculation and wasting of thenarand hypothenar muscles and both quadriceps muscles.Sensory loss right hand of ulnar distribution, possiblyan associated ulnar nerve lesion. Knee and anklereflexes were exaggerated, with clonus. Plantar re-sponses flexor. On 25.5.59 there was obvious spasticparaplegia and extensor plantar responses. By I3.5.60spastic tetraplegia was evident, the legs were paralyzedand very little movement was left in the arms andhands. Swallowing was difficult, with some choking oneating, speech slow and cough defective. There wasmild euphoria. She died in January I96I. No autopsy.

Diagnosis: Amyotrophic lateral sclerosis; bulbar palsy.

Case No. 4.-K. C., male, aged 5 years. He is underthe care of Dr. Wigglesworth and was admitted tothe Hospital for Sick Children, Great Ormond Street,at I8 months, in August 1958. Birth weight 8i lb.,movements always weak, sitting up at 5j months, noattempt to stand; general hypotonia, reflexes all absent.Plantars equivocal. Muscle biopsy right quadriceps-appearances of progressive muscular atrophy. Electro-myogram, September I96I, showed fibrillation andfasciculation potentials, and a gapped action pattern,with giant polyphasic potentials supporting a diagnosisof motor neurone disease.

Diagnosis: Infantile progressive spinal muscularatrophy (Werdnig-Hoffmann).The original differential diagnosis in this case lay

between muscular dystrophy, amyotonia congenita, andprogressive muscular atrophy. This boy's mother'suncle is R. T., Case No. i i, who has amyotrophiclateral sclerosis.

Case No. 5.-A. D., female, aged 63 years. She wasfirst seen on I6.9.59 after complaining of weakness ofthe left arm and twitching of both arms for the previousthree months. On examination weakness and wasting,and hypotonia of all muscles of left arm. No sensoryloss. On 21.I0.59 fasciculation and wasting of leftshoulder girdle muscles was quite severe, with lesserwasting of right shoulder girdle and considerablefasciculation of right biceps. ESR 15 mm./hr., WRand Kahn negative. X-ray of cervical spine showedsevere cervical spondylosis. Seen by Dr. Spalding on12.i.6o, who confirmed diagnosis of MND. By I6.3.60there was wasting of muscles of buttocks and thighsand weakness of the left leg. Some bowel frequency,perhaps autonomic diarrhea. On 5. Io.6o marked

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fasciculation of lips and tongue neck and shouldergirdle muscles was noted, and there was difficulty withswallowing. Admitted to Salvation Army Home inJanuary 196I. Died later.

Diagnosis: Progressive muscular atrophy; bulbarpalsy.Case No. 6.-J. I., male, aged 57 years. First seen on

7.9.53, complaining of tremors, numbness and heavinessof the legs for previous three months. On examinationhe showed brisk leg reflexes and right ankle clonus,plantars flexor, no wasting, no sensory loss, and CSFnormal. X-rays of cervical, thoracic and lumbar spinenormal. Not seen again until 54 years later, when onI6.2.59 he complained of pains in the right arm, achingand shaking of the legs, especially at night, and ofdifficulty in walking for the previous three years. Onexamination buttocks and thighs were wasted andshowing fasciculation, the right leg was spastic, withincreased reflexes bilaterally, partial right foot drop,and right extensor plantar response. By 19.12.60 theright arm was weak but spastic, and the right shoulderpainful. On i 8.12.6I fasciculation was noted in theright calf: he walked with difficulty.

Diagnosis: Amyotrophic lateral sclerosis.This case illustrates the difficulty in determining the

total duration of the disease, and the importance ofnoting the date of the earliest symptoms complained ofby the patient which can be certainly related to thedisease.

Case No. 7.-H. L., male, aged 73 years, plumber.-First seen on 13.3.59 complaining of leg weakness andmuscle pains for the previous six weeks. On examina-tion there was considerable wasting of leg muscles, leftquadriceps and right adductors, with fasciculation.Eversion of right foot was weak, increased leg reflexesand left extensor plantar response were noted. Nosensory loss. Interosseous muscles of hands and flexorsof forearms wasted. Arm reflexes brisk. CSF normal;X-ray of chest clear; lumbar spine lipping. Re-examined on 23.6.6I. Marked quadriceps wasting withfasciculation, and brisk reflexes noted. On 9.2.62:tires easily; uses walking stick.

Diagnosis: Amyotrophic lateral sclerosis.

Case No. 8.-J. N., male, aged 57 years. He wasexamined on I8.9.58, after a complaint of weakness andaching in the knees for the previous two years. Con-siderable wasting of right quadriceps and anterior tibialmuscle groups of both legs noted, with active fascicula-tion of left calf, brisk leg reflexes, and bilateral extensorplantar responses. There was wasting also of bothglutei and shoulder girdle muscles, right more than left.Bilateral dorsal interosseous muscle wasting. Sensationnormal. Investigations: X-rays of skull, chest, cervicaland lumbar spine normal. CSF normal, chest clear,electromyogram records inconclusive. On 8.2.62 rightfoot cold and cyanotic, with foot drop, hand grips poor.

Diagnosis: Amyotrophic lateral sclerosis.

Case No. 9.-A. H., female, aged 66 years. Sheattended on 4.7.57, complaining of backache, weaknessof the right leg, and of difficulty in walking for theprevious 12 months. On examination she showedbilateral claw hands, which were cold and cyanosed,and wasting of small muscles of hands and forearmswith fasciculation. The arm reflexes were brisk, andthere was partial right foot drop. On 7.9.57 CSFnormal, X-ray of cervical spine showed degenerative

changes, dorsal and lumbar spine and pelvis werenormal, and chest clear. Re-examined at patient'shome on 5.3.58, when there was complete paralysis ofthe right leg, with foot drop, weakness of the left legand diminution of reflexes, flexor plantar responses,dysphagia, weak voice and ineffective cough, and con-gestive changes in the chest. Patient died some dayslater. Her daughter is A. O., Case No. io.

Diagnosis: Progressive muscular atrophy; bulbarpalsy.The degenerative changes of cervical spondylosis are

common, and spinal cord compression may occur withmyelopathy and brachial neuritis. An amyotrophiclateral sclerosis syndrome may be simulated, butobjective sensory changes are usually found.

Case No. Io.-A. O., female, aged 41 years. Firstseen on 22.6.6I. Weight 8 st. 71 lb., usually io st.She complained of weakness of arms, shoulders andlegs, with twitching movements, for past six months.On examination, wasting of shoulder girdles and smallmuscles of hands, with extensive fasciculation, increasedjaw jerk, brisk leg reflexes, right ankle clonus, andbilateral extensor plantar responses were noted. Electro-myograms characteristic of anterior horn cell degenera-tion. Glucose tolerance curve and CSF normnal. OnI8.I.62, weak voice, swallowing difficult, arms and legsvery weak. Attended in wheel-chair.

Diagnosis: Amyotrophic lateral sclerosis; bulbarpalsy.

This case illustrates the occasional familial historyfound in the disease. The patient's mother also diedfrom motor neurone disease at the age of 63 years(Case No. 9, A. H.).

Case No. xI.-R. T., male, aged 39 years. Firstseen on I1.4.60, this patient complained of weakness ofthe legs for the previous six months, together withshooting pains in the thighs, weakness of the arms, andaching in the wrists and elbows. One year previouslyhe was kicked in the back whilst playing football, andthis was followed by pain for several weeks. Onexamination, sensation was normal, there was wastingand weakness of both quadriceps muscles, with increasedknee and ankle reflexes. Plantar responses equivocal.On 25.4.60 ankle clonus, bilateral extensor plantarresponses, fasciculation of quadriceps and deltoidmuscles noted. Arm reflexes brisk. X-rays of spineand CSF normal. On 12.6.6i weakness of legs andfasciculation left thigh noted. On 8. I.62 condition fair.

Diagnosis: Amyotrophic lateral sclerosis.This patient's joint and muscle pains had suggested

to his doctor a rheumatic polyarthritis. His brother'sdaughter has a boy who suffers from progressive spinalmuscular atrophy (Case No. 4, K. C.), and furtherillustrates the familial history occasionally found. Theapparent association with trauma is worth noting.

These ii cases briefly reported form part of agroup of 17 cases of clinical MND who havebeen under observation in the Kettering areaduring the past five to six years. The remainingsix cases have been excluded on grounds ofinsufficient evidence because the supporting in-vestigations were incomplete. All were con-sidered to be cases of clinical PMA, with cramp-like pains, weakness and wasting of upper or

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PARTINGTON * Motor Neurone Disease

lower limbs, shoulder or pelvic girdles, showingprominent fasciculation, variable reflexes, flexorplantar responses and objectively normal sensa-tion. X-rays of skull, chest and spine and CSFand blood tests were normal. Muscle biopsy andEMG records, glucose tolerance curve, creatininestudies, and perhaps 131I thyroid up-take tests arenecessary in these cases, which probably alsorequire autopsy proof of the extent of the cordcell damage. Clinically pure PMA is moredifficult to substantiate than the combined lesionof ALS.

In my experience subjective sensory symptomsof cramps, neuritic-type pains, aching and heavi-ness of the limbs and parnsthesiae are prominentin motor neurone disease, especially in the PMAvariety, and may be present for several monthsbefore as well as after the onset of muscle weaknessand wasting. This feature has perhaps lackedemphasis because the specific pathological changeinvolves predominantly motor pathways.

Anatomy and Pathology of Motor NeuroneDisease

Pathologically as well as clinically, motorneurone disease shows many variations from theclassical picture of an upper and lower motorneurone degeneration extending from the Betzcells of the cerebral cortex, through the internalcapsule, pons and medulla, to the spinal cord.This cortico-spinal involvement is often onlypartial, frequently patchy, and is far from beingas systematized as originally thought (Wilson,1954).

In the cerebral hemispheres the agranular cortexof the frontal and precentral areas often showssome atrophy, most marked in the 3rd and 5thcortical layers, the latter containing the largepyramidal Betz cells. The middle third of thecorpus callosum, containing crossed associationfibres, shows degenerative changes, together withthe pyramidal fibres in the posterior limb of theinternal capsule. This degeneration may be onlypartial, and not extend outwards beyond the mid-brain. Occasionally lesions have been found inthe extra-pyramidal system (cf. Jakob's syndrome)with involvement of the corpus striatum. In themedulla the cranial nerve nuclei show cellularchanges similar to those of the Betz cells andperipheral anterior horn cells, the 12th, ioth, 7thand 5th nerve nuclei showing most damage.Degeneration has also been described in Deiter'snucleus and in the vesticulo-spinal, rubro-spinaland tecto-spinal tracts, as well as in certain ascend-ing tracts, particularly the spino-cerebellar tract.Involvement of cells of Clarke's column is foundless frequently. In the spinal cord the predominantdegenerative changes are found in the antero-

lateral columns, and in the cells of the anteriorhorns especially of the cervical and lumbar en-largements,

Severe involvement of root fibres passing fromthe anterior horn cells, sometimes, however, onlyas far as the cord margin, has been stressed byHolmes (I909) and by Wilson (I954). In otherwords, the intra-spinal portion of the nerve roots,those parts bare of neurilemma, may degenerateheavily-beyond the cord margins the myelinmay show little degeneration. The dorsal columns,though only rarely involved (Davison and Wech-sler, 1936), do show occasional demyelination inamyotrophic lateral sclerosis, and this was em-phasized at the Paris Symposium during theCharcot Centenary in I925. It may, however, becoincidental. The degree of atrophy of cells andfibres often does not correspond one with theother: in some cases muscle wasting and anteriorhorn-cell degeneration may both be severe, andthe peripheral nerve show only mild changes.Many of these findings suggest a far fromsystematized purely motor degeneration. As arule peripheral nerves show varying amounts ofmyelin sheath degeneration, depending upon theacuteness of the disease, and in relation to thedegree of muscular atrophy the number of largenerve fibres present may be markedly reduced.At least one-third of the motor nerve fibres maybe destroyed before the muscle shows any clinicalsigns of atrophy. Wohlfart and Swank (I94I)have shown the presence of regenerating nervefibres, a condition known as 'sprouting', occur-ring in fibres adjacent to other degeneratingfibres. It has been suggested that this collateralregeneration and nerve-sprouting of knobs may bestimulated by release of some substance from theadjacent degenerating fibres. The more scatteredthe degenerating nerve cells, the better seem tobe the conditions for collateral sprouting. Wohl-fart (I957) feels that sprouting of nerve fibresmust be an important factor in delaying thewasting and weakness of muscle in diseases show-ing progressive degeneration of lower motorneurones. The muscles show disseminated neuro-genic atrophy, with groups of normal fibres inter-mingled with atrophic shrunken fibres arrangedin small bundles. The latter become fragmented,with increase of sarcolemmal nuclei, which latershow clumping and pyknosis. The motor end-plates disappear early. Striation of the musclefibres persists until the late stages. There is arelative lack of fibrosis and fattiness.

Differential Diagnosis of Motor NeuroneDiseaseFrom the foregoing account of the different

ways in which motor neurone disease may present

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it is seen that muscle wasting, spasticity ofmuscle and varieties of bulbar palsy are pre-eminent in the clinical picture. Muscle wasting,localized to a particular group of muscles, mayusher in any one of the three varieties of motorneurone disease. In progressive muscular atrophy,as has been seen, this wasting may affect anymuscle grouping, but especially may it be noticedfirst in the small muscles of the hands, the shoulderor pelvic girdles, the bulbar muscles, or uncom-monly the leg muscles.

In the differential diagnosis of these many waysof presentation, it is immediately apparent that adetailed knowledge of applied anatomy of thenervous system is required. In the earliest stages,before the pattern of wasting has fully developed,clear-cut diagnosis may be difficult. Especially isthis so in wasting confined to the small musclesof the hands, where recognition of individuallesions of ulnar and median nerves, with theircharacteristic wasting and sensory loss, is vital inexcluding them from general spinal cord diseases.Similar diagnostic difficulties may arise in wastingof lower limb muscles, though here not so muchin wasting of the small muscles of the feet as ofthe leg and thigh muscles.Acute lesions of the cervical spinal cord include

poliomyelitis, which occurs usually before middleage, is rapid in onset, non-progressive, and causesasymmetrical paralysis of large as well as smallmuscle groups. In cervical cord compression fromtumours, or as a result of osteophytosis or severedisc lesions, cerebro-spinal fluid changes may befound. Root pains are common in syphiliticmeningo-myelitis, and with this and cervical ribpressure, and in syringomyelia, objective sensorychanges are found. Cervical rib compression ofthe inner cord of the brachial plexus causesmuscle wasting, limited to partial rather than wholemuscle atrophy, corresponding to C.8 and Th.isegmental areas. Th. i lesions may be accom-panied by cervical sympathetic paralysis irre-spective of the underlying disease. Segmentalwasting from localized degenerative anterior horncell changes may follow motor neuritis from injec-tions of various kinds, often involving shoulderor pelvic girdle muscles. With the residual, oftensymmetrical, wasting of peripheral neuritis objec-tive sensory changes are also found.

Carcinomatous neuropathies may cause peripheralsensory and motor lesions, which require recog-nition (Denny-Brown, I948), and may be illus-trated by the following two cases, which wereconsidered originally to be cases of motor neuronedisease.

Case No. x.-E. C., male, aged 64 years, was firstseen on 27.II.6I, complaining of weakness of the left

leg, twitching of the left thigh, occasional cramps, andpins and needles in the legs, present for the past year.On examination there was slight muscle wasting ofboth thighs, with occasional fasciculation, and- absentknee and ankle reflexes. The plantar responses wereflexor. There was no objective sensory loss. Earlyclubbing of the fingers was noted. EMGs (Dr. Birk-beck) showed 'moderately gapped action pattems: nofibrillation'. On 29. II.6i CSF and EEG normal,ESR 9 mm./hr., and there was no anemia. On 1.12.6IX-ray of chest showed an opacity at the left hilum,and on II.I.62 left upper lobectomy was carried out(Mr. Grimshaw). Path. report: 'Poorly differentiatedcarcinoma'.

Case No. 2.-A. H., male, aged 62 years, firstattended on 23.3.59 with a complaint of paresthesix ofthe legs with weakness, and weight loss, noticed overthe previous six months. On examination no abnormalphysical signs were noted, and blood tests, X-rays ofchest, thoracic and lumbar spine were normal. On29.4.59 CSF was normal and fasciculation was notedin both legs, and on 12.8.59 he was re-admitted tohospital because of obstructive jaundice, with palpablegall-bladder. Fasciculation of muscles of arms andthighs and obvious wasting of quadriceps muscles wasalso noted. Serum bilirubin 8.5 mg./ioo ml., alkalinephosphatase 67 units. At laparotomy on 22.8.59 (Mr.Phillips) carcinoma of head of pancreas was found, withhepatic secondaries. Cholecyst-jejunostomy was carriedout; the patient died shortly afterwards.

In both these cases the possibility of carcinomaarising coincidentally in patients with progressivemuscular atrophy might be considered, but thetime of onset and progress of the two diseasessuggest an etiological relationship in each case.

Chronic lead poisoning can present a neuro-logical picture not unlike that of motor neuronedisease of both atrophic and combined amyo-trophic-spastic varieties-with small muscle wast-ing, fasciculation, and sometimes increased re-flexes and spasticity. The general clinical featuresof lead poisoning and the occupational historyserve to indicate the atiology.

Distinct from diabetic polyneuritis of sensorytype, with pain, loss of tendon reflexes, ataxia,sensory loss and trophic changes in the feet, asyndrome of diabetic amyotrophy has been reportedon several occasions during the past ten years.Pain, with weakness and wasting in the limbmuscles and sometimes in the pelvic and shouldergirdle muscles, occurs over a period of severalmonths. Depression of reflexes is usual, andobjective sensory loss is not found. Fasciculationhas been reported. The syndrome appears to becompletely reversible (Garland, I957) and maynot be entirely related to good diabetic control.Wasting occurring in the familial muscular

dystrophies is usually proximal in its distribution,but the rare distal type of muscular dystrophy ofGowers and the later age-group type of Nevin,may both resemble progessive muscular atrophy

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PARTINGTON: Motor Neurone Disease

and cause difficulty for some years in differentialdiagnosis. Muscle fasciculation is, however, neverfound in the myopathies. Dystrophia myotonicamay show peripheral weakness and wasting, butthe characteristic delay in muscle relaxation andthe associated features of genital atrophy, bald-ness, cataract and sterno-mastoid weakness clearlydistinguish it from motor neurone disease. Inperoneal muscular atrophy the muscle wasting in-volving the feet and legs affects later the handsand forearms, but here is accompanied by sensorychanges. Werdnig-Hoffmann's progressive spinalmuscular atrophy, including the so-called amyo-tonia congenita of Oppenheim, are now groupedtogether as cases of motor neurone diseaseoccurring in infancy and childhood (Brandt, 1950).The local muscle wasting of chronic joint diseases

such as rheumatoid arthritis rarely causes diffi-culty in differential diagnosis, and the pain andparasthesixe and partial muscle wasting of thecarpal tunnel syndrome, often previously mis-diagnosed as due to cervical rib or thoracic inletsyndrome, is rarely confused with the weaknessand wasting, without sensory loss, of progressivemuscular atrophy.

Apart from clinical assessment in the differentialdiagnosis of motor neurone disease help may beobtained from muscle biopsy and from electricaltests, including electromyographic records. Themuscle changes in neurogenic atrophy have beenbriefly noted above and are to be distinguishedfrom those of the myopathies, including poly-myositis. In the muscular dystrophies somemuscle fibres are shrunken, others are large andswollen with loss of striation; the sarcolemmalnuclei migrate into the substance of the frag-mented fibres, and fatty infiltration and connectivetissue replacement are other changes which differfrom those of denervated muscle. In poly-myositis evidence of inflammatory changes isfound, with cellular infiltration and phagocytosis.Necrosis and fragmentation of swollen musclefibres may be severe, and alongside this evidenceof concurrent muscle regeneration may also beseen.

Electrical tests of value in assessing muscledenervation include faradic-galvanic tests, thedetermination of rheobase and chronaxie, plottingof strength/duration curves, the muscle responseto slowly rising currents, and the motor conduc-tion velocity of nerves. The assistance whichmay be given by electromyogram records isreferred to below.

Recent TrendsThe present-day picture of motor neurone

disease may be viewed from clinical, histo-pathological, electrophysiological and biochemical

aspects. In summary, the clinical features of thedisease in its various forms have been thoroughlydescribed during these past I00 years. As em-phasized by Swank and Putnam (I943), thedifferent types of motor neurone disease varyconsiderably in the speed of progress of thedisease, though all cases are uniformly fatal.Familial cases have been reported. Cases pre-senting during life as clinically pure examples ofprogressive muscular atrophy, often generalizedor tetraplegic, affect men three times as often aswomen, and tend to progress slowly with aduration of 5 to i5 years or more (Muller, I952;Wechsler, 1958; Alpers, 1958; Magee, I960). Inthem subjective sensory symptoms are common,often early and severe and troublesome. A lum-bar type of amyotrophy, distinct from myopathy,is not uncommon. In amyotrophic lateral sclerosisor classical Charcot's disease the stiffness andspasms of spasticity and the subjective sensorysymptoms of trophic changes are predominant.The disease is unremitting and progresses rapidly,with a fatal outcome within three years. Un-common cases occur in which the disease presentsduring life with lateral sclerosis only. Thesecases of spastic paraplegia progress more slowly,over a period of 5 to I0 years, before deathoccurs. Progressive bulbar palsy is found twice ascommonly in women as in men. Three-quartersof the cases occur as an extension of pre-existingmotor neurone disease, either progressive muscularatrophy or amyotrophic lateral sclerosis, one-third of these as a terminal event; 25% occur asthe presenting feature of motor neurone disease,and in them the disease is rapidly progressive,death occurring within 12 months from the onsetof symptoms.

Pathologically, the degenerative changes in theanterior and lateral columns of the spinal cordbecome progressively less severe as the conditionascends to the brain stem and brain (Davison,I941). The disease is not confined to the motorneurones, for other tracts, afferent as well asefferent, are involved in some cases. The spino-cerebellar tracts and cells of Clarke's column,and occasionally the extra-pyramidal tracts, mayall show irregular changes of demyelination. Thehistological picture of degeneration and the later'sprouting' of regenerating nerve fibres have beendescribed above.

Experimentally, the important distinction be-tween fibrillation and fasciculation, so admirablymade by Denny-Brown and Pennybacker (1938),has helped considerably in understanding furtherthe mechanisms involved at the neuro-muscularjunction. Several days after the nerve fibre diesindividual muscle fibres show twitching or fibrilla-tion, which is thought to occur from the local

Yuly I962 391

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392 POSTGRADUATE MEDICAL JOURNAL July i962

:-;~~.B:..-.'....:..

C.-D.-j l-

E-.! 1FIG. 4.-A. Electromyogram of normal resting muscle, showing absence of electrical

activity.B. Electromyogram of normal actively contracting muscle, showing crowded

interference pattern.C. Electromyogram of resting muscle in motor neurone disease, showing

fibrillation potentials.D. Electromyogram of resting muscle in motor neurone disease, showing

fasciculation potentials.E. Electromyogram of actively contracting mus;le in motor ne:irone diseas3,

showing poor frequency response of abnormal motor units(cf. Fig. 4, B).

action of persisting acetylcholine (Adams, Denny-Brown and Pearson, 1953). It is, however,fasciculation, or coarse contraction of a group orbundle or fasciculi of muscle fibres from a singledegenerating motor nerve and its cell, that isusually noted on examination or sometimes com-plained of by the patient suffering from motorneurone disease. When the nerve fibre has com-pletely degenerated, fasciculation no longer occurs.The site of origin of these fasciculations is, how-ever, probably in the region of the myoneuraljunction, and not at the anterior horn cell (Forsterand Alpers, I944). The clinical and electro-myographic differences between this ominousfasciculation in motor neurone disease and thebenign fasciculation of myokymia were pointedout by Denny-Brown and Pennybacker, and havebeen emphasized by Schwab, Stafford-Clark andPrichard (I95I).. In myokymia the fasciculationsare gross, coarse and slow, and involve most orall the motor units in a fasciculus. Occurring in

voluntary muscle, the syndrome includes crampsand emotional tension, and there is no weaknessor wasting of the affected muscles. In motorneurone disease the larger nerve fibres and cellsdegenerate much earlier than the smaller fibres(Wohlfart and Swank, i94I; Wohlfart, 1949).'Sprouting', or regenerating fibres, delay progres-sion of muscle wasting for some time. Fig. 4illustrates electromyograms which show thesefeatures of fibrillation and fasciculation, both inthe resting muscle and during active contraction.Stimulated by the work of Buchthal and Clem-mesen (1943), the study of electromyographyduring the past 20 years has played an increasinglyimportant role, both experimentally and clinicallyin the differentiation of neuromuscular dis-orders.A diagnosis of motor neurone disease cannot

be made from electromyogram records alone.However, anterior horn cell degeneration is sug-gested by spontaneous fasciculation and by the

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July I962 PARTINGTON: Motor Neurone Disease 393

loss of whole motor units on voluntary contrac-tion, the surviving motor units being either normalin size or synchronized to give high voltagepolyphasic potentials. Fibrillation potentials maybe found in chronic spinal atrophy, but are moreoften seen in partial or complete peripheral nervelesions. In the myopathies on voluntary effortrelatively normal interference patterns can stillbe obtained, but the individual motor unitpotentials are reduced both in size and duration;some are very rapid, and the polyphasic potentialsare proportionately increased in number (Kugel-berg, I947). In polymyositis, where electricaltests show no slowing of conduction velocity orabnormalities of excitability of the peripheralnerves as in the neuropathies, automatic fre-quency analysis of the electromyogram againshows marked increase in high frequency or shortduration action potentials of small polyphasiccharacter (Lambert, Sayre and Eaton, 1954)Though clearer recognition of the varieties of

the disease and better understanding of theclinical and neuro-pathological features haveoccurred in recent years, the underlying cause ofmotor neurone disease remains unknown. In-flammatory and toxic causes seem unlikely. Theconcept of premature ageing of the nervoussystem, Gower's 'abiotrophy'-like the label'idiopathic epilepsy-was a negative idea, lackingstimulus to further research. Present-day opinioninclines to the view that motor neurone disease isdue to a biochemical abnormality in the nutritionof nerve cells and fibres, whereby a disturbanceis caused in the enzyme systems concerned withtheir metabolism.From the biochemical aspect of the many enzyme

systems involved in the metabolism of nervoustissue, acid phosphatase activity is considerable inboth nerve cells and axons of nerve fibres, anddisappears rapidly on division of the cell from itsfibre. It is present in non-medullated as well asmedullated nerve fibres. Adenosine triphosphatase(ATP) is directly involved in the energy produc-tion of muscular contraction. Cholinesterase isthe enzyme responsible for the breakdown ofacetyl-choline, both at the neuromuscular junc-tion and along the surface of the nerve fibres, asdepolarization occurs during nerve conduction.Pseudocholinesterases are found -mainly in thewalls of blood vessels and in relation to glial cells.Anti-cholinesterases are found (choline acetylaseand others) which allow persistence of action ofacetyl-choline as required. There is some sug-gestion that the enzyme acetyl-cholinesterase mayplay a part in demyelination (Lumsden,I957).Work done with the electron microscopc has

shown that acetyl-choline, manufactured by the

.......

FIG. 5.-Electron micrograph of part of nerve endingin neurohypophysis of the toad, showing synapticvesicles (SV) and mitochondria (mi). psm -- pre-synaptic membrane.

(From de Robertis, E. (I96i): Histophysiological Aspects ofSignal Transmission in the Nervous System. The Role of theSynaptic Vesicles, Triangle, 5, 76. Reprinted with permission ofthe author and the Editorial Board of Triangle, the Sandoz Journalof Medical Science.)

mitochondria which collect at the nerve endings,is stored in synaptic vesicles, which flow from thepre- to the post-synaptic membrane on receiptof the nervous impulse (de Robertis and Bennett,1955). Release of acetyl-choline by cholinesteraseis promoted by calcium ion, and retarded bymagnesium ion. Fig. 5 illustrates an electronmicroscope photograph of part of a nerve ending,showing some of these features. Whittaker (I962),in a fascinating account of the structure andfunction of the synapse, has described the newtechniques which have been developed in separat-ing and studying the constituents and biochemicalmake-up of nerve endings. This increasing know-ledge of the anatomy and metabolism of nervecell, nerve fibre and synapse, as revealed by theelectron microscope and by studies of the enzymesystems involved, may later advance our know-ledge of motor neurone disease.Of trace metals, no less than I4 have been

found constantly in the brain and shown to play

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394 POSTGRADUATE MEDICAL JOURNAL July I962

a part in cell metabolism and myelin formation.They may act as both enzyme activators andinhibitors. Copper, for instance, may play acatalytic role in the synthesis of the phospho-lipids of cell membrane, and therefore in myelinproduction (cf. 'swayback', a demyelinating diseaseof lambs in Australia, which results from copperdeficiency in the diet). Inhibition of cytochromeoxidase, an important enzyme concerned withcellular respiration, also occurs in copper defi-ciency, and this, too, may affect phospho-lipidsyntheses (Lumsden, 1957). Cholesterol forms anessential part of the lipo-protein complex of themyelin sheath, which has a lamellar structure,with lipid and protein layers alternating. This isthought to be responsible for the high electricalresistance and insulating capacity of the myelinsheath, allowing high conduction velocity. This

function is lost in demyelinating nerve fibres.Somewhere in the complex metabolism of myelin,with its multiple enzyme activity, catalytic tracemetals and lipo-protein structure, lies a defectivelink responsible for the demyelination whichforms one of the important features of motorneurone disease and of other nervous diseases.As we have seen, this neuro-biochemical abnor-mality appears capable of transmission on afamilial basis. It seems likely that the discoveryof the ultimate cause of motor neurone diseasenow lies in the hands of the neuro-biochemists.

I am indebted to Dr. Ritchie Russell for advice, andto him and to Dr. Spalding for their help with the casesindicated. Dr. Wigglesworth kindly allowed me tosummarize his records of Case No. 4. Dr. Birkbeckcarried out the electromyograms, and Miss Elkingtongave invaluable secretarial help.

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BRANDT, S. (I950): 'Werdnig-Hoffmann's Infantile Progressive Muscular Atrophy'. Copenhagen: Munksgaard.BRISSAUD, F. (I895): 'Lesons sur les Maladies Nerveuses'. Paris: Masson.BUCHTHAL, F., and CLEMMESEN, S. (1943): Electromyograms of Atrophic Muscles in Cases of Intramedullary Affections,

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WHITTAKER, V. P. (I962): The Synapse, Discovery, 23, 7.WILSON, S. A. K. (I954): 'Neurology'. Second edition. Edited by A. Ninian Bruce, vol. 2, p. I141, II44. London:

Butterworth.WOHLFART, G. (1949): Muscular Atrophy in Diseases of the Lower Motor Neuron, Arch. Neurol. Psychiat. (Chicago),

6i, 599.(1957): Collateral Regeneration from Residual Motor Nerve Fibres in Amyotrophic Lateral Sclerosis, Neurology,7, 124., and SWANK, R. L. (1941): Pathology of Amyotrophic Lateral Sclerosis, Arch. Neurol. Psychiat. (Chicago),-46, 783-799.

WORSTER-DROUGHT, C., HILL, R. T., and MCMENEMEY, W. H. (1933): Familial Presenile Dementia with SpasticParalysis, J. Neurol. Psychopath., 14, 27.

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BOOK REVIEWSBiological Effects of Freezing and Supercooling

AUDREY U. SMITH, D.+C., M.B., B.S. A Monographof the Physiological Society. Pp. x + 462. London:Edward Arnold. I96I. 55S.

Although Mantegazza in i866 had prophesied thatspermatozoa would one day be preserved by freezing,the idea of suspended anima, on in a frozen state wasused mainly by writers of science fiction, until the teamworking at the National Institute for Medical Researchdiscovered, only ii years ago, the protective effect ofglycerol on frozen spermatozoa, since when progress hasbeen rapid. Artificial insemination of hens and cowswith frozen and thawed spermatozoa was soon accom-plished, and the preservation and distribution of bullsemen in a frozen state has become an important aid tocattle breeding. During the same period a similartechnique has been applied to the preservation of bloodcells, so that it is now possible to store for referencesamples which have rare combinations of antigens;while even more recently a naval hospital in the UnitedStates has transfused its patients with frozen and re-constituted blood for more than a year, without mis-adventure and with complete abolition of transfusionhepatitis. Nowadays similar procedures are beingapplied to yeasts, protozoa, and cells from mammalianorgans. The most astonishing accomplishment has beenfreezing and revival by thawing of small animals; manyhave made an apparently complete recovery.

This book is a review by one of the leaders in thisfield. Not only has she considered the technical prob-lems of the laboratory, but she has extended her reviewto include many matters of importance to clinicians andpathologists, such as the mechanism of frostbite, thepreservation of comeal tissue, of bone marrow andspleen cells, the prevention of gastric heemorrhageduring cooling, and the revival of exsanguinated dogs;it is due largely to the work of the Mill Hill team thatoccasional frozen drunks are being revived and restoredto this unhappy life. Perhaps the science-fiction writersare right in picturing the human passengers on inter-stellar voyages as being permeated. with preservative andfrozen in tanks, to be revived, perhaps centuries later,and light-years elsewhere, by some automatic machine.This story of discovery, accident, and experiment is asfascinating and thrilling as any science fiction.

ArteriographyDAVID SUTTON, M.D., M.R.C.P., F.F.R., D.M.R.D.PP. viii + 322, illustrated. Edinburgh and London:.E. & S. Livingstone. I962. 70s.

This is an excellent book, reflecting as it does thevast personal experience of one of the foremost authori-ties in this field of radiology. The work is a generalsurvey of arteriographv, excluding pulmonary arterio-graphy. Obviously it would be outside the scope of oneauthor in a single volume to cover the whole field ofarteriography in a completely comprehensive manner.What is to be appreciated is that so much usefulinformation and so many beautifully illustrated caseshave been brought together in a volume of moderatesize and price. Radiology being an essentially pictorialsubject, not enough praise can be given to the excellenceof the reproductions in this book.The first part of the book deals with technique,

instruments, and complications. Techniques mavvary, but the text provides a sound basis for arterio-graphy. Nevertheless, two points may be worthy ofcomment. First, many would consider the maximumdosages of contrast media somewhat conservative, andparticularly with large injections, dosage based on bodyweight, bearing in mind renal function, may be moreuseful. Also, in the technique of catheterisation, theoperators are shown ungowned. It is generally acceptedthat sterile gowns are essential to avoid contaminationof the catheters and guide wires by contact with unsterileclothing.The second part of the book, apart from the chapter

on intracranial lesions, which has presumably beencondensed for reasons of space, covers the radiographicappearances of most of the lesions likely to be encoun-tered and includes many of the rarer conditions. Thereis much useful clinical information.

It is safe to say that no one should embark onarteriography without either having read this book, orbeing conversant with its content. Even the experiencedcan learn a good deal from it. Clinicians too will findmuch to interest and instruct them, and this will helptheir radiological colleagues by assisting in the selectionof cases for arteriographv.

This work does great credit to the author, the St.Mary's School, the Institute for Nervous Diseases, andnot least to British radiology.

ERRATA

x. 'Postgraduate Medical Education in New England '-J. A. Curran, Vol. 39 no. 441 (July i962) page 377.The town marked i6 (lower right hand of map between 7 and 3 and to the N.E. of 7) should be marked i9.

2. 'Motor Neurone Disease '-T. Partington, Vol. 38 no. 44I (July I962) page 392.The caption should read as follows:

FIG. 4.-A. Electromyogram of normal resting muscle, showing absence of electricalactivity.

B. Electromyogram of resting muscle in motor neurone disease, showingfibrillation potentials.

C. Electromyogram of resting muscle in motor neurone disease, showingfasciculation potentials.

D. Electromyogram of normal actively contracting muscle, showing crowdedinterference pattern.

E. Electromyogram of actively contracting muscle in motor neurone disease,showing poor frequency response of abnormal motor units(cf. Fig. 4, D).

Documents

MOTOR NEURONE DISEASE · ticity is the presenting feature, and atrophy of muscle may be delayed and be minimal, or even absent, throughout the course of the disease. These uncommon