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Show J. elilf, N"'I/"I.",,!lIItIl/lIl'11. 5: 71>- KO, 19K:; © 1985 Raven Press, New York Myasthenia Gravis Complicating Charcot-Marje-Tooth Disease: Report of a Case JOSEPH R. BERGER, M.D. D. RAM AYYAR, M.D. ITARU KIMURA, M.D. A DREW KOVACS, M.D. Abstract Generalized myasthenia gravis developed in a 61 year old man with the hypertrophic form of Charcot-Marie-Tooth disease (CMT). While ocular abnormalities mimicking myasthenia gravis have been reported in CMT, and two patients with atypical CMT have had features consistent with ocular myasthenia, this is the first report of generalized myasthenia gravis complicating CMT. The estimated prevalence for the concurrence of these two disorders suggests that it is an extremely rare event. Eyelid ptosisl- 4 and motility disord ers J.2,4 consistent with ocular mysathenia have been observed in patients with Charcot-Marie-Tooth disease (CMT). In 1974, Brust and associates5 described a patient with ocular myasthenia and "complicated" CMT that was associated with spasticity of the lower extremities. A dramatic improvement in ptosis and extraocular motility was noted following prostigmine and edrophonium administration, but there was no response in limb weakness. We describe a patient in whom generalized myasthenia gravis was superimposed on classic CMT. The coexistence of these two relatively rare disorders in the same individual has not been previously reported. Case Report A 68-year-old, right-handed man recalled weakness dating to childhood. He commented on difficulty roller-skating, an inability to ice- From the Department uf eurology, Univl'rsitv of Miami School of Medicine, Miami, Flurid,l. Wrilt' for reprillis I,,: J. R, Bergl'r, M,D., Departmt>nt "f Neurology (04-5), University pi Miami School (,f M..dicint>, 1501 N.W, 9th Avenue, Miami. FL :13101, USA, 76 skate because of ankle weakness, and frequent falling while playing soccer. As a young man he pursued a short professional boxing career. In the army, he was unable to march as well as the other troops and dropped out of line frequently due to leg weakness. Over the course of ~he next 15 years, he experienced a heavy sensahon in the lower extremities associated with progressive weakness in the hands and legs. Within ten years, he was unable to walk without assistance. At age 36, he was forced to cease working as a barber and was subsequently confined to a wheelchair. At age 42, he was diagnosed as having Charcot-Marie-Tooth disease. Examination at that time revealed marked distal extremity wasting and weakness, areflexia, impaired distal extremity vibratory sensation, and palpably enlarged peripheral nerves. Cerebrospinal fluid was normal. His family history was negative for any neurological disorders. In 1975, he developed progressive left-gaze palsy that t~'pically worsened late in the day. Examination revealed weakness of the left lateral rectus and right medial rectus muscles. No other cranial nerve abnormalities were detected. The distal extremities were weak and atrophic. Loss of distal vibratory sensation and hypertrophic peripheral nerves were also noted. A diagnosis of ocular myasthenia was entertained, and after the administration of 10 mg intravenous edrophonium hydrochloride (Tensilon) he regained full extraocular motility. erve conduction studies revealed no detectable motor and/or sensory response on stimulation of the median, ulnar, peroneal, tibial, or sural nerves. On electromyography, positive waves and fibrillations were seen in the distal muscles of all extremities in the absence of motor unit potentials. The number of motor units was decreased in the proximal muscles. On routine study there J was no evidence of a superi~lr mediastin"l mOlSS and thyroid function was normal. Subsequently, the patit'nt W.1S pIOl(('d on daily pyridostigmint' (Mt'stilwn), with ,1 pt'rsistt'nt .1Ild profound impnwt'mt'nt in extr.l~x·lll.lr llH1tility until 1977. In 1977, bil"tt'r.ll ptosis. Iwarsl'llt'SS, d)'sphagia and pro~rt'ssi\'t' d)'Splll'., dt'vl'lnpl'd. Physical examination rt'\'e,lll'd ,l thin. ddlilitated man in mild reSpir.ltl1r)' distrt'SS. Bil.1!t'r,11 ptosis was grt'ater 1m thl' right thall llll till' Idt. and there W,l$ pM.,I~·sis llj gaZt' ill all dirl'dillllS. Fadal diplt'gi.1 was apr.1rl'llt .tnd d~·sphI11li.,.md d~'sph,'gid wt're .llYl1mp,mied by .m abSt'nt g.lg rt'ilt'x. Motor t"....lmin.ltillll n've.lled bil,ltt'r,ll wrist and illllt dfllps. HI.' had ,1 nwdt>ratdy SL'\ ·t'rt' distal and nllldt'ratl' pnn.inl<ll weakllt'ss in\' tll\'ing the upper and II1Wt'T t':...trtO'mities bilaterally. Bilateral fllcker ioot dnd "~arter" type atroph~' of lht:' lower t'Jo.trt:'milies were seen (Fig. 1). ThertO' was alSI) diffustO' atrophy of the distal musculature oi tht' uppl'r extrt'mities. The disilppearanctO' llj the thenM and the hypothenar eminences WilS noted, exposing the interosseous spaces in a "main de singe" fashion. The muscle tone ilppeared to be diffusely decreased and no muscle stretch rt'ilexes were elicited. The ""ibratorv sense was decrt'ased symmetri- Figure 1. Mark~ "garler" type ..trophy of lho.' low." l'~' tremilies and bilateral rocker fool characleristic of ChMc"t· Marie-Tooth disease. June 1985 Bt'r~('f ('I al. l'ally in the distal lower extremities. Hypertrophy llf thl' grl'att'r auricular (Fig. 2), ulnar, slIpt'rfkial radiill, sapht'nous, infrapatellar, and supt'riicial pt'ronl'al nerVl'S was noted bilater· "ily. Thl' h'nsilon !t'st was, again, dramatically p\lsitive. with markt'd improvement in the strl'ngth of tht' faciaL extraocular (Fig. 3). and pr~lximaJ limb muscles. Repetitive supra maxim. ll stimulation oi the accessory nerve at the rate of two per second resultt'd in a dt'crt'mental rl'sp\lnse of 15'1.· in the trape<':ius muscle. The ddl'ct was partially corrected by Tcnsilon and aiter milximal voluntary contractions (MVCl for 30 S. F(lur minutt's after MVC a decrement of 30'1.· was noted. No sensory nerve action potentials could be elicited from the median, ulnar. radial, sural, or saphenous nerves. No motor rt'sponse was obtained on stimulating the median, ulnar, peront'al. or tibial nerv('s. Stimulation of the accessory nerve produced a normal compound muscle action potential from the trapezius muscle. However, the latency was twice the normal value al 10.0 ms. The diagnosis of myasthenia was reconfirmed by repeat Tensilon test. Anticholinesterase an~ tibodies were present in high titer, although no thymoma was detected by radiographic means or by gallium scan. HLA typing revealed the following phenotype: AI, Aw24, Bw35, BolO, Cw3, Cw4, DR2, and DR4. Discussion Ocular findings such as ptosis and abnormal extraocular motility,I.~A.l>.; as well as facial di~ Figure 2. tlypt"t'ophy 1'1 lht' lo\r~al.'r iluriculdT n..rv.. (armw), 77 Myaslhenio Cr,wis in Charcot-Maril'-T')\llh Disl'ase Figure J. Bilateral ptosis (left) is dramatically improved Immedi3tefy lo/fowmg thc 30'mmlStranOn vI T~n:;il"'i1 (li&~l;. plegia,U dysarthria,4 and bulbar weakness with dysphagia,S have been reported to occur in CMT. The nature of these findings may suggest myasthenia gravis, but no response to anticholinergic medication is expected and repetitive nelVe stimulation will not reveal a decremental response. Our patient had typical eMT with progressive lower extremity weakness dating back to age 19. Ocular myasthenia supervened at age 60 with the initial disturbance of a leftgaze palsy. Subsequently, the patient developed myasthenic weakness of the bulbar and extremity muscles, superimposed on the weakness attributable to the CMT. A marked improvement in ocular motility and proximal limb weakness following Tensilon administration, a decremental response to repetitive nerve stimulation, and a positive test result for anticholinergic receptor antibodies established the diagnosis of myasthenia gravis. Although neurogenic muscle atrophy has been reported in myasthenia gravis,9.lo it is generally mild in degree.9Consistent with these observations, evidence of a neuropathic process would not be anticipated prior to the dear-cut development of the myasthenia, as occurred in our patient. Carcin and colleagues l1 described a man in whom progressive amyotrophic weakness of the extremities followed by 20 years the onset of ptosis and extraocular motility disturbance. A positive response to neostigmine was noted in the eyes and limbs, and electrophysiological studies revealed a decremental response to repetitive stimulation. Despite their 78 case report, clinically Significant neurogenic muscular atrophy in myasthenia gravis is decidedly rare. The prevalence of CMT varies with the population studied. Estimates of between 1.6 and 24 per 100,000 population have been reported,12 and a population study in North Carolina concluded that the prevalence was at least 5.4 per 100,000. 13 The prevalence of myasthenia gravis ranges from 5 to 64 per million, with 40 per million being a conservative estimate. U Assuming that the association of CMT and myasthenia gravis occurs randomly. their concurrence in the same individual would be seen with an approximate incidence of one in every 2 billion people. Two individuals with hereditary neuropathies categorized as CMP·5 have had ocular weakness responsive to cholinergic medication (Table). In both individuals, previously described, the CMT was atypical in nature. Although the patient described by Brust and col1eagues5displayed characteristics of ocular myasthenia, his CMT was unusual in that it was associated with a spastic paraparesis. Stevens3 described a patient with neostigmine-responsive ptosis. In addition to neuropathy with pes cavus. that patient exhibited periodic paralysis and myotonia. There was no comment mentioned of tests performed to confirm the existence of <l neuromuscular transmission defect, and caution must be exerdsed in the presumption that neostigmine-responsive ptosis is sufficient for the diagnosis of ocular myasthenia, Journal of Clinical Neuro-ophthalmology Berger et al. TABLE 1. Case Reports of Myasthenia Gravis Complicating Charcot-Marje-Tooth Disease Ill. I,ll,' II M,ll,' l1blributhln "I r-...1~'\bl'WI1"1 l{t·~J't'I1"4..· tll l."lh1IU\l'q.';'K I\tl'l"ti".III\11l LM(, NH d"l'r,'nll'nt,ll r,'spllns,' fr"m f.J'i<l1 nl'rVl' only lkl'rl'm,'nlill rtlSpon:--l' l\'riodi," pMdly~i~; myoloni.J ~pil~tir parilp.lrl'~is Rl'l ) 5 in as much as positive responses tLl chLllinergic drug administration hCl\'t' been recorded in other dis~rdt?rs14 such as amYLltrophic ICltt?ral sclerosis, I, pol~'myositis,I'" and botulism. 17 The s~'ndrome of peroneal muscular atrophy associated with involvement oi primary sensory neurons has been designated hereditary motor and sensor~' neuropathy (HMSN).I~.I'I In patients with severel\' decreased nerve conduction velocity, nerve biopsy shows extensive segmental demyelination and axonal loss. Hypertrophic changes may also be present. This type of peroneal muscular atrophy is referred to as the hypertrophic iorm of Charcot-Marie-Tooth disease20 or HMS type I (HMSN 1).19 Our patient's symptoms satisfied the criteria for the diagnosis of HMSN I. It is usually dominantly inherited, but autosomal recessive inheritance and a sporadic variety have been described. To the best of our knowledge, there has been no previous description of a patient with classical CMT and well-documented generalized myasthenia gravis. Cholinergic drug administration and electrophysiological studies to look for evidence of a neuromuscular transmission defect characteristic of myasthenia gravis and assays of cholinergic receptor antibody would certainly be warranted in any patient with CMT presenting with ptosis, ocular palsies, facial diplegia, bulbar weakness, or fluctuating levels of extremity strength. The coexistence of myasthenia gravis and CMT in other individuals would suggest a more than chance association. HLA phenotyping in individuals with CMT may reveal an overlap with the phenotypes commonly observed in myasthenia gravis, namely, AI, 68, and Dw2.21 References 1. Spector, R. H., Smith, J. L., and Chavis, P. S.: Charcot-Marie-Tooth disease mimicking ocular June 1985 myasthenia gravis. All//. Ophillaill/oi. 10: 10331036, 1978. 2. Sp~ctor, R. H.: Neuro-ophthalmologic manifestations of Charcot-Marie-Tooth disease and related disorders. In Nellro-ophtirall/llJllJX.1I Update. Smith, J. L., Ed. New York, Masson, 1977. 3. Stevens, J. R.: Familial periodic paralysis, myotonia, progressive amyotrophy, and pes cavus in members of a single family. Ardl. Nt!llfIJl. Psychiatrl/ 72: 726-741, 1954. 4. Brusl: J. C. M, List, T. A., Catalano, L. W., and Lovelace, R. E.: Ocular myasthenia gravi mimicking progressive external ophthalmoplegia. Nt'lIrohl~y 24: 755-760, 1974. 5. Brust, J. C. M., Lovelace, R. E., and Devi, S.: Clinical and electrodiagnostic features of Charcot-Marie-Tooth syndrome. Acta. ('111'01. Scalld. 58(suppI68): 1-142, 1978. 6. Dubrovsky, A., Taratuto, A. L., Martino, R.: Distal spinal muscular atrophy and ophthalmoparesis. Arc/I. Nt!lIrtl/. 38: 594-596, 1981. 7. Stephens, J., Hoover, M. L., dnd Denst, J.: On familial ataxia, neural amyotrophy and their association with progreSSive ophthalmoplegia. Braill 81: 556-566, 1958. 8. deRecondo, J.: Hereditary neurogenic muscular atrophies. In Halldll(lilk ,If Clilli'lll N"I/",It'.I;.II. vol. 21, Vinken, r. J., Bruyn, C. W., Ed '. \1rth HoIland, Amsterdam, 1975. pp. 271-317. 9. Brody, I. A., and Engel, W. K.: Denervalion of muscle in myasthenia graviS. Arch. NCII,,'/. 11: 350-354, 1964. 10. Brownell, B., Oppenheim, D. R., and Spalding, J. M. K.: Neurogenic muscle atrophv in myasth~ nia graviS. ,. Nt'II"II. M.'II"I~lIrs. P~y(hialr!! 35: 311-322, 1972. II. Carrin, R., Fardeau, M., ,1I1d Codet-Cuillain, M.: A clink'll and pathol'lgic,ll study of a case of alternating 'll1d recurr\'nt t'xternal 'lphthalmopll'gia with amyotrophy ,If the limbs observed for forty five ye.us: discus -ion of the relationship of this condition with my,lsthenia graviS. Brt/ill 88: 739-752, 1%5. 12. Kurt,kt', J. F., and Kurl'1nd, L. T.: The epidemiologv of neurologic Jist'ase. In C1illical Nellrology. B,1kl'r, A. B., Baker, L. H_, Eds. Harper & Row, Philaddphia, 1973, pp. 1-80. 79 1:\. Herndon, C. N.· I'robll'lll:; and mdhods in hllll1<ln ~l'nl'lil:s: 3 N\lrth Cmllina survl'yS. Alii,.,. I HUII/. Crllcl. &: 05-7-1, 1';154. 1-1. RlIwlalld, l.. P., ,1I1d Lwzl'r, K B.. Musculardystrllphks, ,1lrol'hil'S ,md rl'lakd disl"l.~l'S. In Cliui'- I,I NCUl<l/"S,II, B,lh'r, II B., B.lkl'r, L. fl., Eds. f{,upl'r &. Row, l'hiladdphi.l, 1'177, p. 7.1. 15. Muldl'r. D. W., L.ullpert, E. II.. ,1nd E,ltun, L M.· My,'SIIll'llil' syndwl111' in piltil'nts with ,'I1lVlltrophi.. l.lkral sdl'rllsis. N../lr"JoSY 9: 1'>27(, 31. I'IS,). [0. Rl'l'Sl" H. H., .1I1d H.ullllln, J W.: II hitl",r'" un· d"ssifil'd ll1usclllM disorder. Tn/II:;. Alii. Nl'um/. A:;:;,~·. 79: K!.-!:\7, 1954. 17 Ry,1I1, D. W., and Ch~rrin~tun, M.: Human tn'" A botulism. l-AM.A. 216: SI:\-514, 1971. 18. Th\lm.1S, P. K., C"lnl', D., and Stl'w.ul, G.' "krl'dit. uy mutor .1I1d sl'nsory polynl'urol'.llhy (pl'- 80 roneal muscular atrophy). AIlII. Hum. G~lll't. 38: 111-153,1974, 19. Dyck, P. J.: Inherited neuronal degeneration and atrophy afkcting peripheral motor, sensory, and autonomic neurons. In Peripl/era/ Neuropathy, vol. 2, Dyck, P. J., Thomas, P. K., Lambert, E. H., bh. W.B. Saunders, Philadelphia, 1975, PI'. 1'125-Hh7. 211. Dyck, f' J., and Lambert, E. H.' Lower motor and prim<1fy sensory neuron diseases with peroneill muscular atrophy. I. Neurologic, genetic, and t:koctrophysiologic findings in hereditary polynl'ump.lthies. Arch. Neural. 18: 603-618, 1%1:l. 21. Bl'han, P.O.. Immune disease and HLA associ, llitln~ with myasthl'nia ~ravis. J. Ne/lrvl. Neurosur...:. P~l/dllalr.1/ 43: 011-621, 1980. Journal of Clinical Neuro-ophthalmology |
