multiple sclerosis associated with defects in neuromuscular

Journal of Neurology, Neurosurgery, and Psychiatry, 1972, 35, 385-394

Multiple sclerosis associated with defects inneuromuscular transmission

BERNARD M. PATTEN, AVERY HART, AND ROBERT LOVELACE'

From The Neurological Clinical Research Center, Department ofNeurology, College ofPhysicians and Surgeons,Columbia University, New York City, U.S.A.

SUMMARY Three patients with multiple sclerosis characterized by exacerbations and remissions ofnervous system signs and symptoms disseminated in time and space also had the kind of easy fatigu-ability seen in myasthenia gravis. In each case abnormal decrements to repetitive stimulation were

electromyographically demonstrated and treatment with ephedrine or anticholinesterase drugsincreased the patient's functional capacity while improving the electromyographic abnormality.The suggestion is that these patients represent an overlap syndrome, analogous to the overlapsyndrome existing between systemic lupus erythematosus and rheumatoid arthritis where clinicaland laboratory features of two diseases coexist in the same patient at the same time. Presumablysome patients with multiple sclerosis have deficient production of acetylcholine, just like patientswith myasthenia, and treatment with agents useful in myasthenia is able partially to correct thesymptoms caused by the deficiency. The cases illustrate how in neurology greater attention to themore immediate cause of clinical symptoms, in the absence of a known aetiology, may result inbenefit to the patients.

Multiple sclerosis continues to be a disease ofenigmas. Not only are we ignorant of its causeor cure, but also we can not adequately explainthe exacerbations and remissions, or the lackof correlation between the patient's functionalcapacity and the number and severity of thedemyelinated plaques (Namerow and Thompson,1969). The significance of the peculiar epidemi-ology of the condition escapes us, as do thereasons for the reported association of multiplesclerosis with migraine (Watkins and Espir,1969) and narcolepsy (Ekbom, 1966).The existence of so much unexplained data

has led some to postulate that multiple sclerosisis not a disease entity, but is merely a clinicalsyndrome which includes many disorders ofdifferent causation (Ekbom, 1966; Connor,1970). An alternative explanation is that somediseases may use similar mechanisms of expres-sion. To support this idea, we wish to report aclass of multiple sclerosis patients who havesigns and symptoms of both multiple sclerosisand myasthenia gravis analogous to the overlapsyndrome existing between systemic lupuserythematosus and rheumatoid arthritis in whichclinical and laboratory features of the two dis-

1 Reprint requests: Dr. Robert Lovelace, Neurological Institute, 710West 168th Street, New York, New York 10032, U.S.A.

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eases coexist in the same patient. The recognitionof the multiple sclerosis-myasthenia gravis over-lap syndrome has both fundamental and practicalsignificance in view of our ignorance of the causeof both conditions, as well as the possible diag-nostic and therapeutic benefit that may be ob-tained for multiple sclerosis patients by druginduced improvement of neuromuscular trans-mission. In the absence of a known aetiology,our cases illustrate how an approach to therapymight be found in a better understanding of thecauses of symptom formation.

CASE 1

O.R., a 26 year old Negro woman, was well untilJanuary 1968 when she noted episodes of markedweakness and easy fatiguability. By May 1968 shewould wake up feeling normal but became quitefatigued on dressing, and at times was so weakshe could not comb her hair. On lying down for10 minutes the weakness remitted. She said she hadoccasional double vision and decreased vision whichcleared spontaneously. Because of her fatiguability,she was unable to work at her job as a maid. InJune of 1968, she presented to the PresbyterianHospital complaining of double vision. On examina-tion, she had mild weakness of both deltoid muscles.She could not walk on her toes or heels. No objectiveevidence for extraocular movement dysfunction was

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Bernard M. Patten, Avery Hart, and Robert Lovelace

found. Intravenous saline gave no response but 10mg edrophonium (Tensilon) made the patient feelstrong, relieved the diplopia, and increased strengthin the deltoid muscles. For the duration of theeffect of Tensilon, she was able to walk on her toesand heels. She was admitted to the NeurologicalInstitute for evaluation of possible myastheniagravis.WBC was 4150/cu mm with 47°/ lymphocytes.

Lumbar puncture showed no RBC or WBC, sugar67 mg and protein 15 mg/100 ml. on two determina-tions, with gamma globulin of 17%. The followingtests were normal: sedimentation rate, fasting bloodsugar, blood urea nitrogen, VDRL, two LE prepara-tions, creatine phosphokinase, lactic dehydrogenase,SGOT, plasma electrophoretic pattern, sodium,potassium, CO2, Cl, Ca"+, Mg ++, latex fixation,urinalysis, electrocardiogram, electroencephalogram,skull, and chest radiography.

Tensilon test in a double blind controlled manneragain produced remarkable improvement, but theeffect lasted over 20 minutes, so she was not con-sidered to have typical myasthenia. The patient wasdischarged without a diagnosis and was furtherobserved in clinic.

ELECTRODIAGNOSTIC STUDIES Standard techniqueswere used as previously described (Lovelace and

Horwitz, 1968). Conduction velocities in median,ulnar, peroneal, and posterior tibial nerves were nor-mal. Repetitive stimulation of the median nerve atthe wrist was performed, with the right arm, hand,and fingers rigidly controlled for movement. Record-ing of evoked potentials in the thenar muscles wasmade by firmly affixed surface electrodes. Repetitivestimulation of the right median/thenar system at2/sec revealed decrements between 20 and 25%Y(Fig. 1); at 5/sec a decrement of 15% and lessmarked changes at 10/sec, with normal potentiationthere and at 20 and 40/sec (Fig. 1). As shown(Fig. 2), well performed exercise of thenar musclesfor one minute produced initial potentiation withdisappearance of the decrement at 2/sec. The decre-ment progressively returned one minute after cessa-tion of exercise. Similar changes were seen on repeti-tive stimulation of the ulnar/hypothenar system.Unipolar needle electromyography of right armmuscles was normal except for some excessivevariation in amplitude of single firing motor unitpotentials.

These findings indicated a defect in neuromusculartransmission suggestive of myasthenia gravis, sincethe greatest change was at 2/sec; but with demonstra-tion of an atypical exercise study.

In July 1968, the patient was depressed over theapparent hopelessness of her condition. She asked

FIG. 1. Repetitive stimulation ofthe right median-thenar system:case 1. Supramaximal stimulationshowing decrements (A and B)and potentiation (C and D). A.2/sec. B. S/sec. C. 10/sec. D.20/sec. Calibration = 1 mV.

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Multiple sclerosis associated with defects in neutromuscular transmission

EXerCise /1m7

Before /O//30"/ /'2 m 3' 4 5

FIG. 2. Exercise study ofright thenar muscles with repetitive stimulation: case 1. Evokedpotentials are recordedat 2/sec stimulation and superimposed: amplitude when varying always decrements. Tracings are obtained before(first tracing) and at intervals after well-performed maximal exercise ofthenar muscles. Readingfrom left to rightintervals after well-performed maximal exercise of thenar muscles are: 10" = 10 sec, 30" = 30 sec, 1'=1 min,2' = 2 min, etc. Calibration= I m V.

if she could take 'that medicine' (Tensilon) again,since she thought it was the only thing that hadhelped.Examination showed nystagmus on vertical gaze.

Repetitive hand gripping produced early fatigue.She had absent abdominal reflexes and a right sidedhyper-reflexia.

Anticholinesterase therapy in the form of pyrido-stigmine (Mestinon) 60 mg three times daily wasprescribed. The patient improved remarkably withthis agent and she was able for the first time in ninemonths to return to work.From September to December 1968, because of

the side-effects of dry eyes and abdominal cramps,she stopped her medicine four times. Each time, heroriginal weakness returned forcing her to restartthe Mestinon in order to continue earning a living.Examination in December revealed only verticaland horizontal gaze nystagmus. The right sidedhyper-reflexia had disappeared. Repeat electricalstudies using the above techniques showed decre-ments at 2/sec (23%) and 5/sec (12%), but noabnormalities at 10 and 20/sec. This was still consist-ent with a defect in neuromuscular transmissionunder therapy.

In April 1969, in spite of her medicine, the patientdeveloped ataxia, positive Romberg test, left inter-nuclear ophthalmoplegia with failure to adduct theleft eye, and coarse nystagmus in right eye (converg-ence was normal). The right hyper-reflexia had re-

turned. By July 1969, her examination was normalexcept for downward drift of the right arm and someweakness of the left psoas muscle. In October 1969,she developed a numb sensation in the whole rightlower extremity with decreased pain perception.In addition there was a Babinski sign on the right.By January 1970, the patient felt entirely normal.Her neurological examination revealed no evidenceof cord or brain-stem pathology and she continuedon Mestinon for relief of fatigue. She continuedto work, but found the need for the medicine wasgradually declining. By July 1970, she was able todo her job while taking only one tablet of Mestinondaily. Examination at that time showed nystagmuson left lateral gaze, bilateral Babinski signs, absentright knee and ankle jerks, and ptosis of the lefteyelid. The Tensilon test was repeated in January1971, after cessation of Mestinon therapy for 12hours. Before injection, repetitive stimulation at 1and 2/sec (Fig. 3) showed some decrement by ap-proximately 15% which improved with continuedstimulation. This was less marked at 5/sec with clearlater potentiation. Ten milligrams of Tensilon wasgiven intravenously, which produced complete clear-ing of the decrement.

COMMENT This woman had a clinical syndromecharacterized by a myasthenic defect in neuro-muscular transmission associated with signs of

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FIG. 3. Successive thenar potentials are recordedfrom left to right directly on afibre optic recorder (F. 0. 100,Teca Corp.). A= Ilsec, B = 2/sec, and C=5/sec. Repetitive median nerve stimulation with thenar recording isexhibited both before and at 2 min after the intravenous injection of10 mg edrophonium (Tensilon).

CNS dysfunction that spontaneously exacerbatedand remitted. Her complete remission in January1970 was remarkable, but not unknown eitherin multiple sclerosis or myasthenia gravis.

According to Norris (1963), decrements in thesupramaximally evoked potential at stimulusrates 10/second or below, as were seen in thispatient, are diagnostic of myasthenia. Othercriteria considered essential for the diagnosis ofmyasthenia gravis in our laboratories and bySimpson (1966a), such as an increment atstimulation rates of 10/sec and higher, togetherwith the retention of post-tetanic facilitationwere seen (Fig. 1). The elevated percentage ofgamma globulin in the cerebrospinal fluid in theface of normal globulins in the peripheral bloodis highly significant and characteristic of multiplesclerosis (Schneck and Claman, 1969). We there-fore believe that the laboratory and clinicalfeatures of both myasthenia gravis and multiplesclerosis were present in this case, and that shehas an overlap syndrome in which features ofboth conditions coexist in the same patient atthe same time.The remaining illustrative cases will be pre-

sented in less detail.

ness of both legs lasting several weeks and improvingspontaneously. He also complained of day-long epi-sodes of numbness and tingling of the legs. At age41 years, the weakness became rapidly worse and hedeveloped diplopia and numbness of the left sideof his face and tongue. On examination there washypalgesia of the left side of the face, nystagmus onhorizontal gaze, bilateral Babinski signs, and cere-bellar ataxia of the left arm. Routine laboratoryevaluation similar to case 1 was normal. Lumbarpuncture with CSF examination was normalexcept for a colloidal gold curve of 0013211000.Gamma globulin was not estimated. He wasdiagnosed as having multiple sclerosis and over theensuing two weeks, spontaneous dramatic improve-ment occurred. He was then well except for mildepisodic leg weakness until age 46 years when hedeveloped numbness of the right leg, paraparesis,bilateral Babinski signs, and nystagmus. Thesegradually cleared, leaving only a mild paraparesis.At age 50 years, he had an episode of blurred visionwhich cleared spontaneously. After the attack, visualacuities were 20/30, but optic disks were pale andvisual fields constricted to red test objects. His dis-ease then stopped progressing, and he has remainedwith fixed neurological deficits. Because he com-plained of easy fatiguability and had decreasedstrength with successive hand grips, electrical studieswere performed.

CASE 2

J. F., a 57 year old white man, was well until the ELECTRODIAGNOSIS Nerve conduction velocities wereage of 37 years when he developed attacks of weak- slightly slow with right median and ulnar motor

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Multiple sclerosis associated with defects in neuromuscular transmission

A B

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FIG. 4. Results of treatment in case 2. A. Untreated supramaximal stimulation of the median-thenar system atthe rate of 10/sec for 15 sec produced a 20% decrease in the amplitude of the evoked muscle actioni potential.B. Ephedrine treated: after one week of ephedrine 25 mg t.i.d., stimulation in the same cirumstances produced nodecrement. C. Mestinon treated: after one week ofMestinon 60 mg b.i.d., stimulation in the same circumstancesproduced no decrement. Time line (0J1 sec) forms lower quarter of tracings B and C.

conduction velocity being 44 and 42 m/sec respective-ly. Median motor and sensory distal latencies wereprolonged at 6-1 and 4 5 msec respectively. Onneedle electromyography, there were occasionalspontaneous positive waves, but otherwise noabnormalities were seen. Repetitive stimulationshowed decrements at 5, 10, 20, 30, and 50/sec.These decrements were less marked when the patientwas treated by ephedrine and pyridostigmine (Fig.4). Serial studies each week over the course of twomonths indicated unequivocal electrophysiologicaland clinical improvement while under therapy andthere was a rapid relapse to the original state ofdisability when medicines were temporarily stopped.

COMMENT Whereas case 1 presented primarilywith excessive fatiguability suggestive of myas-thenia and only subsequently was found to havefeatures of multiple sclerosis, case 2 presentedin the reverse fashion: initially a picture ofmultiple sclerosis followed by the laboratoryfindings of myasthenia gravis. The use of ephe-drine and Mestinon in this latter patient hasenabled him to work again as a carpenter,something he had not been able to do for severalyears.

CASE 3

This 41 year old Negro woman was well until oneyear ago, when she noted episodic burning of thehands, and difficulty in buttoning her clothes. Shealso had attacks of unsteadiness with frequent falls.One episode of diplopia cleared spontaneously over

the course of two weeks. Her main complaint wasweakness of her hands, but questioning revealedthat she suffered from easy fatiguability. Indeed,while doing housework she became so fatigued thatshe had to rest every few minutes to recover herstrength. On examination, there were bilateralBabinski signs, decreased vibration and positionsense in hands, nystagmus on lateral gaze, ataxictandem gait, and bilaterally absent abdominal andtriceps reflexes.Lumbar puncture and CSF examination was nor-

mal except for a protein of 38 mg/100 ml., 21% ofwhich was gamma globulin. Colloidal gold curvewas 2223300000. ESR was 40 mm in the first hourand EEG was mildly and non-specifically abnormaldue to bilateral slow waves. The rest of the routinelaboratory tests were normal.

ELECTRODIAGNOSIS Conduction velocities and needleelectromyography were normal. Repetitive sti-mulation showed decrements especially at 10, 20,and 50/sec (Fig. 5). During the two minutes afterintravenous edrophonium (Tensilon), there wasclear improvement in the weakness and fatiguabilitytogether with a less marked decrement on repetitivestimulation.One month later, she had an ataxic gait, a right

medial longitudinal fasciculus lesion with failureto adduct the right eye and coarse nystagmus in theleft eye on attempted left lateral gaze. In addition,there was rotatory nystagmus on upward gaze withthe quick component clockwise. Decreased positionsense in the right hand was still present, but positionsense in the leftwas normal. Babinski's sign, previously

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Bernard M. Patteni, Avery Hart, anid Robert Lovelace

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FIG. 5. Decrements in patient 3. A. Supramaximal stimulation of median-thenar system at 10/sec for 15 secproduceda 20% decrease in the amplitude ofthe evokedmuscle actionpotentiaL B. At the rate of20/secfor 15 secthe decrement was again 20%. C. At 50/sec for 15 sec the decrement was 35%. Tensilon test in patient 3: D.Control trace: in spite ofrecovery of the amplitude of the single action potential, supramaximal stimulation at10/secfor 15 sec shows 40%. decrease in amplitude. This decrement is greater than previously seen in this patientatthisrate(seeAabove)andprobably indicated residualfatiguefrom the 50/sec stimulation which hadtaken place,10min before. E. Tensilon trace: one minute after the injection ofTensilon intravenously a repeat tracing wasmadefor 15 sec. The amplitude ofthe first potential is the same as in the control (D). However, subsequent potentials inthe Tensilon trace are 10% greater than the controlfor thefirst 10 sec. However, the ultimate decrement at 15 secis the same as in D (40%). Time line (0 1 sec) is seen in all tracings below lower horizontal line; at lower edge ofpotentials in A, B, and C, but superimposed on D and E.

bilateral, was now present only on the right. Onemonth after that, she felt less fatigued and had notrouble in buttoning her clothes. Her Romberg testwas negative, the medial longitudinal fasciculuslesion had disappeared, and sensation was normal.The Babinski sign was also gone. Repetitive handgrips produced no decrements in strength.

COMMENT The clinical presentation of thispatient's disease was puzzling. Her initial dis-ability could have been explained by a cervicalsyrinx, but the elevated gamma globulin andabnormal colloidal gold curve of the CSFsuggested multiple sclerosis. The subsequentcarefully documented exacerbation and remis-sions of CNS signs support the diagnosis of

demyelinating disease. Myasthenia gravis wasnot considered at all. Yet without invoking thatdiagnosis the decrements to repetitive hand grip,electrical findings, and positive Tensilon testcannot be explained. In retrospect, her easyfatiguability takes on a greater meaning and wasthe first clue to the presence of a defect inneuromuscular transmission.

DISCUSSION

Stimulation for 15 seconds of the median-thenarsystem in normal controls in our laboratoryat frequencies including 50/sec produces a slightpotentiation but no decrements in the amplitudeof the evoked muscle action potential (Fig. 6).

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FIG. 6. Comparison ofnormal, myasthenic, and multiple sclerosis neuromuscular response to repetitive stimula-tion. A. Normal (BP): supramaximal stimulation ofmedian-thenar system at SO/sec for 15 sec produces a slightincrease in the amplitude of the evoked muscle action potential. B. Myasthenic: stimulation under the same con-ditions produces an initial decrement, followed by potentiation, followed by decrement. C. Multiple sclerosis:stimulation ofcase 2 under same conditionsproduces a 70% decrease in the amplitude ofthe evokedactionpotential.The potenltiation seen in niormals and in myasthenics is not present. A and C include lower time line as in Figs 4and 5.

We, therefore, believe that normal human muscleaction potential evoked by supramaximal stimu-lation in these circumstances maintains itsamplitude and does not decrement. By contrast,the fatiguability demonstrated electrically andclinically in our cases occurred within one totwo seconds at low stimulus frequencies andresembles the fatigue seen in myasthenia gravis.Harvey and Masland, in their original studies

of repetitive stimulation, noted that patients withmyasthenia gravis showed initial fatigue, thensome recovery, and finally more fatigue (Harveyand Masland, 1941). The cause of the temporaryrecovery is unknown, but initial decrement,followed by potentiation, followed by decrementwas not characteristic of our patients withmultiple sclerosis (Fig. 6). Harvey and Maslandthought that some apparently normal individualshad unusually rapid fatigue, but they did notidentify these controls or specify how many werestudied, and what stimulus frequencies producedwhat degrees of decrement. They did say thatnone of these allegedly normal people had anysignificant change in either strength or evokedpotential during Tensilon testing, and, therefore,concluded that the favourable response toTensilon was a more reliable sign of myasthenia

gravis than repetitive stimulation alone. In thisregard, all of our cases showed definite, and attimes dramatic, improvement in amplitude ofevoked muscle potential with Tensilon confirm-ing that repetitive stimulation studies during themaximal effect of this short-tracing anticholin-esterase drug are quite useful and provide aquantitative, objective assessment of the patient'sresponse.The suggestion is that acetylcholine is deficient

in our patients, just as it is in myasthenia gravis(Roberts and Wilson, 1968), and that the decre-ments reflect the easy fatiguability of metabolic-ally deficient neurones. The clinical and electricalimprovement with Tensilon, ephedrine, andMestinon, drugs effective in myasthenia gravis,indicates that the defect in neuromusculartransmission is in part correctable. In thisconnection, it must be remembered that thepatients reported here are a highly selectedgroup in which myasthenic features were easilydetected clinically, and were superimposed on anunderlying substrate of multiple sclerosis. Anti-cholinesterase drug therapy, because of possibletoxic side effects, is not needed in all cases ofmultiple sclerosis. Certainly, only those patientswith unequivocal clinical and electrodiagnostic

391





responses to these agents are suitable candidatesfor long-term treatment.

Milder defects in neuromuscular transmissionthan reported here may be more common thangenerally realized, as studies indicate somefatiguability to repetitive stimulation in amyo-trophic lateral sclerosis (Simpson and Lenman,1959; Mulder, Lambert and Eaton, 1959),chronic polyneuritis (Baginsky, 1968), and polio-myelitis (Hodes, 1948). Of course, myasthenicfeatures have been noted with carcinoma of thelung, botulinus intoxication, magnesium intoxi-cation (Lambert, 1966), thyroid disease (Norris,1966), trimethadione therapy (Peterson, 1966),and with the use of various antibiotics (McQuil-len, Cantor, and O'Rourke, 1968). None of theseknown causes of a myasthenic syndrome waspresent in our cases. One case of multiplesclerosis-myasthenia gravis overlap syndromehas been previously identified (Margolis andGraves, 1945), and Keane's patient (Keane andHoyt, 1970) with tingling in the hands and feet,unsteady gait, blurred vision in the evenings,'dubious' Babinski sign on the right, pale opticdisks, vertical gaze nystagmus with a rotatorycomponent who had a positive Tensilon test,reported as a puzzling case of myasthenia gravis,seems to more closely fit the overlap syndromereported here.The interrelationships between peripheral and

central nervous system are only recently comingto light. Antineuronal antibodies have now beenreported in myasthenia gravis (Kornguth, Han-son, and Chun, 1970) and muscle biopsies inmyasthenia gravis are said to show neurogenicatrophy (Engel and McFarlin, 1966). Sensoryloss, psychosis, epilepsy, face numbness, lossof taste and smell were well recognized in myas-thenia gravis, especially in early studies (Simp-son, 1966b). In fact, Simpson at the Erb MuscleSymposium in Heidelberg in 1966 commented on10 cases of myasthenia gravis with raised proteinin the cerebrospinal fluid, one of which hadincreased gamma globulin level (an abnormalLange curve), probably due to multiple sclerosisassociated with myasthenia gravis (Simpson,1966c). Indeed, some of the older necropsyreports of myasthenia gravis concentrated oncerebral and spinal pathology exclusively withno mention of peripheral disease (McAlpine,1929; Mott and Barrada, 1923). These observa-tions, our own data, and Desmedt's electro-physiological evidence that the presynaptic regionof the neuromuscular junction is the site of

primary involvement in myasthenia gravis(Desmedt, 1966) should lead us to considerwhether myasthenia gravis is a primary neuro-genic disorder. Other muscle conditions such asmuscular dystrophy and myotonic dystrophyhave been associated with intellectual defectsand central nervous system pathology (Wordenand Vignos, 1962; Rosman and Rebeiz, 1967),and Engel has recently reported abnormal muscleenzymes and muscle biopsies in patients withacute psychoses (Engel and Meltzer, 1970). Thecases reported here indicate that multiple sclero-sis is another condition in which association be-tween central and peripheral nervous system maybe found. Even though nerve histopathology(Ward, Cannon, and Lindsay, 1965), conductionvelocity, and needle electromyography are nor-mal in multiple sclerosis (Rinne and Tuovinen,1968), the demonstration of a defect in neuro-muscular transmission in some patients with thiscondition indicates that further study of theperipheral nervous system should be undertaken.

It is difficult at present to draw any firm con-clusions about the significance of the multiplesclerosis-myasthenia gravis association. Simpsonpoints out that the factors which may be associa-ted with the first attack or later relapses ofmyasthenia gravis are emotional disturbances,infection, and trauma (Simpson 1966b). Inthis respect, and also in sex incidence, age ofonset, and remittent course, there are strik-ing resemblances with the collagen vasculardiseases and multiple sclerosis. The occurrenceof myasthenia gravis with other diseases ofsupposed autoimmune origin including pemphi-gus (Beutner, Chorezelski, Hale, and Hausma-nowa-Petrusewicz, 1968), haemolytic anaemia(Halperin, Minogue, and Komninos, 1966),ulcerative colitis (Engel and Meltzer, 1970),polymyositis (Halperin et al., 1966), and thyroid-itis, systemic lupus, and pernicious anaemia(New England Journal of Medicine, 1966) couldnot have been an accident. Thymic germinalcentres, identical to those seen in myastheniagravis, have been reported in lupus erythematos-us, rheumatoid arthritis, colitis, and thyroiditis(New England Journal of Medicine, 1966), andshould increase our consideration of the possiblerelation of myasthenia gravis to these diseasesand to the autoiminune diseases in general. Inmyasthenia gravis the most significant observa-tion has been the finding of muscle antibodiesdirected against thymic epithelial cells, thatcross-react with the A band of striated muscle

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Multiple sclerosis associated with defects in neuromuscular transmission

(New England Journal of Medicine, 1966). Theseanti-A band antibodies are not useful to explainmyasthenic phenomena when all available infor-mation indicates a disorder of neuromusculartransmission and normal A band function.Nevertheless, the thymic pathology, chroniclymphocytic infiltration of muscles, autoanti-bodies, and the beneficial response to ACTH(Grob and Namba, 1966) and immunosuppres-sive agents (Mertens, Balzereit, and Leipert,1969) indicate that immune mechanisms areplaying an important, if only indirect, role inthe genesis of symptoms.The relationship of multiple sclerosis to auto-

immunity is not clear, but the demonstrationof a multiple sclerosis-myasthenia gravis overlapsyndrome tends to strengthen the association.The discovery of a serological factor in bothexperimental allergic encephalomyelitis, a de-myelinating disease of susceptible animals, andmultiple sclerosis, which actively demyelinatescultures of rat cerebellum, raises the question ofthe role of circulating antibody in the patho-genesis of demyelinating disease (Dowling andCook, 1968). The report of systemic lupuserythematosus and multiple sclerosis in identicaltwins suggests that these two diseases are relatedbut clinically distinct separate manifestationsof a basic disease process (Holmes, Stubbs, andLarsen, 1967). Further study of the inter-rela-tionship of multiple sclerosis, myasthenia gravis,and the autoimmune diseases is clearly needed.The clinician must avoid too rigid thinking aboutclassifying these conditions, so that a funda-mental relationship or a new overlap syndromethat could be quite important is not obscured ormissed. The association of the signs and symp-toms of one disease with another is more thanfortuitous and indicates the possibility of differ-ent diseases using like mechanisms of clinicalexpression. In neurology the attention to thecorrection of the immediate cause of symptomsmay, in the absence of a known aetiology, beof benefit to the patient.

This work was supported in part by the Glorney-Raisbeck Fellowship in the Medical Sciences underthe auspices of the New York Academy of Medicine.The authors gratefully acknowledge the cooperationof Dr. Richard Koenigsberger in helping supplythe equipment for the electromyographic study.Mr. Avery Hart was supported by a summer studentfellowship from the United Cerebral Palsy Researchand Educational Foundation Gift for Dr. RichardKoenigsberger. The potential trains illustrated in

Figs 3 to 6 were recorded on Fiber Optic Recorder(F. 0. 100) from the Teca Corporation, White Plains,New York.

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transmissionwith defects in neuromuscular Multiple sclerosis associated

LovelaceBernard M. Patten, Avery Hart and Robert

doi: 10.1136/jnnp.35.3.3851972 35: 385-394 J Neurol Neurosurg Psychiatry

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