52ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:352-358

Chronic demyelinating polyneuropathy associatedwith eosinophilia-myalgia syndrome

Miriam L Freimer, Jonathan D Glass, Vinay Chaudhry, William R Tyor,David R Cornblath, JohnW Griffin, RalphW Kuncl

AbstractEosinophilia-myalgia syndrome (EMS) isa newly described syndrome associatedwith use of L-tryptophan. A neuropathywith features of axonal degeneration hasalso been described in conjunction withEMS. Demyelinating polyneuropathy isnot a well recognised association of thesyndrome. The two patients with EMSreported presented with profound weak-ness and sensory loss and were found tohave clinical, electrophysiological andpathological evidence ofa chronic demye-linating polyneuropathy. The concurrenceof this neuropathy with EMS, as well asseveral other features of their illness, issuggestive of an immune mediated mech-anism in the pathophysiology of EMS.

Johns HopkinsUniversity School ofMedicine, Baltimore,MD, USADepartment ofNeurologyM L FreinerV ChaudhryW RTXrorD R CornblathRW KunclDepartments ofNeurology andPathologyJ D GlassDepartments ofNeurology andNeuroscienceJW GriffinCorrespondence to:Dr Freimer, Department ofNeurology, Johns HopkinsUniversity School ofMedicine, Meyer 5-119,600 N Wolfe Street,Baltimore, MD 21205, USAReceived 20 November 1990and in final revision13 August 1991.Accepted 21 August 1991

In the autumn of 1989 the eosinophilia-myalgia syndrome (EMS) was recognised to beassociated with the use of L-tryptophan. Thekey features of this syndrome are a raisedperipheral blood eosinophil count (usually> 1000 cells/mm3); severe generalised myalgia;and absence of any infection or neoplasm thatcould account for the first two.' Numerousother features may accompany these signs andsymptoms, including sclerodermatous skinchanges, dyspnea, cough, and inflammatoryinfiltrates in skin, muscle, and other tissue.More than 1200 cases of EMS associated

with L-tryptophan have been reported.2 Themost frequently reported neurological mani-festations of EMS are weakness and pain.These symptoms have usually been attributedto myopathy and fasciitis. Several brief state-ments have suggested that neuropathy may beseen in EMS.' 3 There are two detailedreports of associated peripheral neuropathy:one suggests a disorder predominantly due toaxonal degeneration,' and the other presentselectrophysiological data consistent withdemyelination but pathological data showingsevere axonal degeneration.6 We reported twopatients with L-tryptophan associated EMSand chronic demyelinating motor and sensorypolyneuropathy. The syndrome may easily bemistaken for myopathy associated with EMS.Several clinical and pathological features ofEMS associated demyelinating neuropathysuggest an immunopathogenesis.

Case ReportsCase 1

In May 1988 a 45 year old woman was given

L-tryptophan, 3 g nightly, for insomnia andpersistent lower back pain. Sixteen monthslater she developed a macular rash on herforearms, thickening of the skin, and persistentlow grade fever associated with increasingfatigue and weakness. In addition, she devel-oped severe lancinating pains in her hands andfeet. The peripheral blood eosinophil countwas > 4000 cells/mm3. A full thickness skinbiopsy showed fasciitis with lymphocytic infil-trates. A diagnosis oftryptophan induced EMSwas made, L-tryptophan was discontinued,and prednisone 25 mg daily was started. Therash and fevers abated and the peripheraleosinophilia disappeared; however, the painpersisted, and the weakness progressed suchthat by December 1989, she was bed bound.Her history revealed hypothyroidism and aremote episode of "fever of unknown origin".The family history was negative for any neuro-muscular disease. She was admitted to theJohns Hopkins Hospital in February 1990. Onadmission she was an ill appearing woman withthickened, leathery skin. Her hands and facewere swollen, and her feet and legs wereoedematous and discolored. There were flex-ion contractures at the elbows and knees, andthe "groove" sign (branching pattern of col-lapsed veins, reflecting the absence of dermalfibrosis at venous sites, next to otherwisesclerodermatous skin7) was present on herarms. Her lungs were clear to auscultation butbreath sounds were diminished. She had mildfacial diplegia and ptosis but full extraocularmovement. Proximal and distal limb muscleswere weak: MRC grade 3 in the arms andproximal muscles of the legs and MRC grade 2in distal leg muscles. She was unable to walk orsit up independently. Deep tendon reflexeswere absent. Plantar responses were flexor. Allsensory modalities were diminished in a stock-ing-glove pattern.

Arterial blood gas analysis showed hypoxiaand a partially compensated respiratory acid-osis (Pao2 71 mm Hg, Paco2 74 mm Hg, andpH 7 31). Vital capacity was 1 0 litre. A searchfor autoantibodies showed that the anti-acetylcholine receptor antibody titre was1-66 x 10-9 M (normal < 0 13 x 10-9 M),and the IgG anti-GM1 ganglioside titre was2216 by ELISA (normal < 60; levels > 60commonly associated with autoimmune dis-orders8 9). Normal laboratory results includedthe following: complete blood count, routineserum chemistries, complement, antinuclearantibodies, rheumatoid factor, creatine kinase,vitamin B,2, folate, hepatitis B and HIVserologies, and cerebrospinal fluid analysis.

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The absolute eosinophil count was 53 cells/mm3. A diagnosis of EMS and demyelinatingmotor and sensory polyneuropathy was madebased on data presented below.The patient was given prednisone 80 mg

daily. Over the following month her skinbecame softer, less indurated and discolored,and less wooden, but her strength continued todeteriorate, particularly in the hands, and hersensory loss progressed to include the fore-arms. After she had received high dose steroidsfor two months her vital capacity was 0 5 litres.Nerve conduction studies showed furtherreduction in both distal and proximal com-

pound muscle action potential amplitudes. Shewas readmitted to the hospital and givenintravenous gammaglobulin 0-4 g/kg/day forfive days while being maintained on high dosesteroids. After this treatment was completedher vital capacity improved to 1 1 litres, andher strength improved to the point that she wasable to sit up independently and walk shortdistances with help. Over the ensuing year thepatient was maintained on prednisone,30-50 mg/day, with little functional improve-ment but no apparent progression of herdisease.

Case 2A 68 year old woman with a history of vitiligoand hypothyroidism had been taking L-trypto-phan for insomnia, 1 g nightly, for more thantwo years. In August 1989 she stopped themedication when she was notified by themanufacturer of potential dangerous sideeffects. One month later she developed parotidswelling and a dry mouth. An antinuclearantibody titre was 1:160, and a lip biopsyshowed sialoadenitis. In October 1989 shenoticed dysphagia, limb weakness, and footpain. She became unable to eat solid foods. InDecember she was admitted to a local hospital,severely dehydrated and profoundly hypothy-roid. She was rehydrated, placed on thyroidreplacement, and discharged. She was

readmitted in January 1990 because of severe

dehydration and a recent 18 kg weight loss.She was able to swallow only clear liquids.Normal laboratory results were obtained forrheumatoid factor, antibodies to double stran-ded DNA, erythrocyte sedimentation rate, andconcentrations of creatine kinase, vitamin B,2,and aldolase. Pulmonary function tests showeda restrictive pattern.

In February 1990 she was admitted to theJohns Hopkins Hospital. Examination showeda cachectic, ill appearing woman with patchesof hypopigmented skin. Her legs were mildlyoedematous and the skin had a leathery qual-ity. Neurological examination showed a distalto proximal gradient of weakness, MRC grade4 distally and 4+ proximally. Deep tendonreflexes were reduced in the right arm and bothlegs and absent in the left arm. Plantarresponses were flexor. There was a mildsensory loss in a stocking-and-glove distribu-tion.The following laboratory values were abnor-

mal: antinuclear antibodies, 1:640; absoluteeosinophil count, 480 cells/mm3; T4 cells,

26 ,ug/dl (normal, 5-0-130 ,ug/dl); and thyroidstimulating hormone, 32-9 mIu/ml (normal,0 5-45 mIu/ml). IgM anti-GM1 gangliosidetitre was 241 (normal, < 50; levels 50-350commonly associated with autoimmune dis-orders), and IgG anti-GM1 ganglioside titrewas 1612 (normal < 60; levels > 60 commonlyassociated with autoimmune disorders89).Normal results were obtained for analysiscerebrospinal fluid, electrolytes, transamina-ses, erythrocyte sedimentation rate, creatinekinase, hepatitis B and HIV serology, andantibodies to Ro and thyroglobulin.A lip biopsy showed severe sclerosing

inflammation of the minor salivary glands.There was squamous cell metaplasia of theremaining ducts, and most of the acini weredestroyed. In the context of dry mouth, thispathology substantiated a diagnosis of Sjog-ren's disease.10 On the basis of electrophysio-logical and pathological data (presentedbelow), a diagnosis of EMS and chronicdemyelinating motor and sensory polyneuro-pathy was made.The patient was given prednisone 50 mg

daily, which resulted in mild improvement inher skin and her ability to walk. She continuedto have difficulty swallowing and felt that hermanual dexterity had worsened due to painand stiffness. A four week course of plasmaexchange (40-50 cc/kg twice weekly) was givenbut there was no measurable improvement.The course was complicated by multiple com-pression fractures and continued pain. Afterone year of high dose prednisone, the dose wastapered and azathioprine (2-5 mg/kg) wasinstituted. After four months her deep tendonreflexes returned, dramatic improvement wasnoted on quantitative testing of all muscles(particularly in pinch and grip, with gripstrength increasing from five to 30 pounds),and all sensory modalities improved.

MethodsMotor and sensory nerve conduction studies,including late responses and electromyographywere performed using standard techniques inour laboratory.

Sural nerve and an adjacent piece of gastro-cnemius were biopsied from the midcalf underlocal anesthesia. Muscle cryosections wereprepared routinely. A portion of the nerve wasfixed in 5% glutaraldehyde in 0 1 M phosphatebuffer (pH 7-2), post-fixed in osmium tetrox-ide and embedded in Epon. Sections 1 ,umthick were stained with toluidine blue for lightmicroscopy. Thin sections were stained withuranyl acetate and lead citrate for electronmicroscopy.Another portion of the nerve was snap

frozen in isopentane and cryosectioned forimmunocytochemistry. Staining of sectionswas accomplished by using the avidin-biotin-peroxidase method, as previously descri-bed.1' 12 A third portion of nerve was immer-sion fixed in 4% paraformaldehyde in 0-1 Mphosphate buffer (pH 7 2) for nerve fibreteasing. Using the avidin-biotin-peroxidasecomplex, nerve bundles were immunostained

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Table 1 Motor nerve conduction sudies

Distal latency Conduction velocity Baseline to negative peak Baseline to negative peak Minimum F wave(ms) (m/s) distal amplitude (yV) proximal amplitude (pl)9 latency (ms)

Peroneal nerve:Case 1 5-5 34 1200 900 50 5Case 2 4-6 33 3500 1000 63-4Normal 5-5 40 )2000 2000 (55-0

Ulnar nerve:Case 1 6-5 18 1200 250 53-7Case 2 2-8 34 8500 4110 36-6Normal 3-4 50 4000 4000 (32-0

Median nerve:Case 1 4-5 38 5000 5000 29-0Case 2 4-7 32 3500 1100 38-6Normal (4-2 50 4000 >O4000 (31 -0

for macrophages with EBM/ 1, " infiltratedwith glycerol, and teased with fine needles.

ResultsELECTROPHYSIOLOGICAL STUDIESCase 1Electrophysiological studies showed a demyeli-nating motor and sensory polyneuropathy(tables 1 and 2). Distal latencies were pro-longed in five of six motor nerves, as were Fwave latencies in two of six nerves. In the leftulnar nerve the forearm conduction velocitywas severely reduced (18 m/s). The results ofsurface recording and stimulation suggestedpartial motor conduction block in the rightulnar and tibial nerves.'4 In addition, abnor-mal temporal dispersion was present in theright ulnar and peroneal nerves. Compoundmuscle action potential amplitudes werereduced in five of six motor nerves.

Electromyography showed myopathic volun-tary motor unit potentials without abnormalspontaneous activity in the proximal and distalmuscles.A follow up study was performed five weeks

later. In all motor nerves the distal evokedamplitudes were reduced further than in theprevious study. Distal latencies were furtherprolonged in the tibial and ulnar nerves, andconduction velocities were further reduced inall motor nerves. The F wave latency wasprolonged in the tibial nerve and absent in theperoneal nerve. The results of surface record-ings and stimulation in the left ulnar nervesuggested partial motor conduction block.

Case 2The nerve conduction studies were interpretedas a demyelinating motor and sensory poly-

Table 2 Sensory nerve conduction studies

Conduction Peak to peakvelocity (mis) amplitude (,V)

Sural nerve:Case 1 NRCase 2 46 8Normal >40 >10

Median nerve:Case 1 38 6Case 2 48 9Normal >50 M0o

Ulnar nerve:Case 1 NRCase 2 48 4Normal 50 >OI

NR = no response.

neuropathy, (tables 1 and 2). Conductionvelocities were reduced and F wave latencieswere prolonged in all motor nerves. Distalmotor latencies were prolonged in two of threenerves. Partial motor conduction block wassuggested by the results of surface recordingand stimulation in the right median and ulnarnerves. 4 Abnormal temporal dispersion waspresent in the right peroneal nerve.Needle electromyography revealed short

duration, low amplitude, polyphasic motorunits in proximal muscles. Abnormal sponta-neous activity was observed only in distalmuscles, where voluntary motor unit potentialswere normal. The electromyography findingswere consistent with a proximal myopathy anda distal neuropathy.A follow up study was performed four

months later. Further reduction in all motorconduction velocities was seen. F wave laten-cies were further prolonged or absent. Motorevoked amplitudes were further reduced, withone nerve being 5% of the lower limit ofnormal.

NEUROPATHOLOGYCase 1A biopsy of sural nerve showed enlargement ofthe nerve with extensive epineurial thickeningas a result of collagen deposition (fig 1). Bothepineurium and endoneurium had scatteredinflammation, and there was rimming of theperineurium with mononuclear cells. The den-sity of large and small myelinated fibres wasnoticeably reduced. Many thinly myelinatedfibres were seen, suggesting remyelination.One fascicle (fig 1B) was extensively demyeli-nated, illustrating the inhomogeneous patternof these changes. The epineurial and endo-neurial blood vessel walls were thickened.Electron microscopy (fig 1C, D) showed evi-dence of prior and active demyelination; somefibres had intratubal macrophages splittingmyelin lamellae.

Examination of teased fibres confirmedextensive demyelination and remyelination; inone fascicle, 38% of fibres had demyelinated ordemyelinating internodes; in a second fascicle,8% of fibres were affected. By immunostainingfor macrophage markers, the demyelinatingfibres had adherent and intratubal macro-phages (fig IE). Remyelinated fibres and fibresundergoing active Wallerian-like degenerationwere also identified. Immunostaining of frozen

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Figure 1 Sural nervefrom patient 1. (A) Lightphotomicrograph showsextensive thickening of bothepineurium andperineurium (bar =200pum). (B) One fascice(box in A) shows featuresof active denyelinatingneuropathy, indudingnaked axons (arrowheads)and large thinly myelinatedfibres that implyremyelination (arrows)(bar = 40 pm). (C)Electron micrographshowing completelydenyelinated axon(asterisk) (bar = 5pum).(D) Macrophage (M) isactively stripping myelinfrom axon. Note tongue ofmacrophage cytoplasminterdigitating betweenmyelin lamellae (arrow)(bar = 5pm). (E) Teasedfibre immunostained withEBMII I, an antibody tomacrophages, showingadherence of macrophagesto nerve fibre (arrows)(bar = 20 pm).

A

C

sections with aT cell marker showed scatteredT cells throughout the perineurium.A biopsy of gastrocnemius muscle (fig 2)

showed widespread fibrosis of the overlyingfascia and endomysial connective tissue. Closeto the fascial plane the muscle fibres wereatrophic and basophilic, often distorted andembedded in collagen. Split fibres and fibreswith abnormal internal architectural changesalso occurred. In a gradient farther from thefascial plane these changes became milder.Throughout the biopsy, focal grouped atrophy,fibre type grouping, and pyknotic nuclearclumps were seen. The intramuscular capillarywalls were thickened and fibrotic. No inflam-matory infiltrates were seen. These findingswere interpreted as consistent with denerva-tion and coexisting fasciopathy, which was alikely residue of severe fasciitis.

Case 2A biopsy of the sural nerve showed thickening

of both the epineurium and perineurium, withparticularly dramatic rimming with mono-nuclear cells, indicating active perineuritis (figs3A, B). Ongoing demyelination as well asWallerian-like degeneration were apparent.The density of large and small myelinatedfibres was slightly reduced. Electron micro-scopy showed scattered demyelinated fibresand some remyelinating fibres, along withfrequent endoneurial inflammatory cells (fig3C). Immunostaining of frozen sections withLeu4 and Dako antibodies showed prominentrimmiing of the perineurium with T cell lym-phocytes (figs 3D, E) and macrophages.The gastrocnemius muscle biopsy showed

diffuse thickening of the fascial plane andendomysial connective tissue. There werechanges consistent with a neuropathic process,including fibre type grouping and small angu-lar fibres. In addition, a gradient of myopathicchanges, including rounded atrophic fibres,central nuclei, and split fibres, extended from

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Figure 2 Gastrocnemius muscle from patient 1. Markedfibrosis of overlying fascia and all layers of investingconnective tissue occurs in gradient from surface inward.Muscle fibres close to fascial plane are distorted; fartherfrom fascial plane, these changes are less severe. Pyknoticnuclear clumps (thin arrow) and grouped atrophy seen inthe deeper areas indicate coexistant denervation atrophy(H&E) (bar = 100 pm).

the muscle fibres adjacent to the fasciainward.

DiscussionThese two patients show the symptoms, signs,laboratory findings, and pathological changeswhich comprise the recently described eosino-philia-myalgia syndrome.' This report callsattention to two striking findings in thesepatients: demyelinating neuropathy and severeperineuritis. Unlike the vast majority ofpatients with EMS, these two patients devel-oped rapidly progressive weakness. The weak-ness occurred with a distal to proximal gra-dient, accompanied by mild wasting andmoderate sensory loss. Reflexes were reducedor absent. Nerve conduction studies showed a

severe demyelinating motor and sensory poly-neuropathy. The nerve biopsies confirmedongoing demyelination and remyelination andactive inflammation. This constellation of find-ings suggests an acquired demyelinating poly-neuropathy. Such neuropathies are postulatedto be immunopathogenic.'5The eosinophilia-myalgia syndrome ap-

peared as an epidemic in 1989.1 2 16-18 Thesyndrome is characterised physically by theacute onset of pain, oedema, and induration ofthe legs, arms, and trunk. Other prominentfeatures may include weakness, cough, anddyspnea. Pathological findings in the skininclude perivascular collections of lympho-cytes, eosinophils, and plasma cells and exces-sive collagen deposition. EMS has been linked

to the chronic use of L-tryptophan, but theexact pathophysiology is unknown. Specula-tion has centred on three hypotheses: (a)L-tryptophan may trigger an autoimmuneresponse in some susceptible individuals;' 16(b) EMS is due to a contaminant of somepreparations of the drug; or (c) EMS may bedue to faulty tryptophan metabolism.The autoimmune hypothesis may be sup-

ported by several notable features of thesecases. Firstly, both patients, before beingexposed to L-tryptophan, had a strong historyof other disorders thought to be autoimmune.Secondly, after exposure to L-tryptophan bothpatients also had high concentrations of severalautoantibodies in their serum samples. Thepresence of anti-acetylcholine receptor anti-bodies in patient 1 and anti-GMl antibodies inboth patients does not necessarily imply thatthese patients had myasthenia gravis or multi-focal motor neuropathy8 9; rather, it suggeststhat regulation of the immune system is dis-turbed. Thirdly, the temporal lag between drugdiscontinuation and the onset of the diseasesuggests an intervening mechanism (forexample, autoimmunity) rather than a directtoxic mechanism. A fourth clinical feature thatsupports the autoimmune hypothesis is theapparent improvement of patient 1 after onecourse of intravenous gammaglobulin'9-22 andthe dramatic improvement of patient 2 afterfour months of azathioprine treatment. Finally,inflammation was a prominent part of theneuropathology in both cases.What is the pathophysiological relation

between a demyelinating polyneuropathy andtryptophan associated EMS? While their coex-istence may be due to chance, several spec-ulative mechanisms may be considered. EMSor L-tryptophan might trigger a widespreadautoimmune response, as suggested above. Or,as the morphological data presented heresuggest, there may be more specific targetingby the immune system of peripheral nervemyelin, resulting in macrophage mediateddemyelination. Perhaps L-tryptophan or acontaminant serves as an antigen or antigenicmodifier (adjuvant), stimulating the immunesystem to recognise self antigens in peripheralnerve myelin. Those patients with EMS whodeveloped demyelinating polyneuropathy mayhave a latent hypersensitivity to nerve antigenthat is activated by the L-tryptophan prepara-tion. Both our patients had a strong history ofimmune dysfunction which may have predis-posed them to develop either demyelinatingneuropathy or EMS. A similar mechanism wasproposed in a patient with procainamideinduced polyradiculopathy who showed lym-phocyte sensitisation to peripheral nerve mye-lin and procainamide.23The similarities between the neuropathy

descibed in this paper and chronic inflamma-tory demyelinating polyradiculopathy (CIDP)should be noted because CIDP is generallyconsidered to be a disorder of the immune

23 2system. 24 Electrophysiologically, ourpatients' neuropathy was indistinguishablefrom CIDP.5 Clinically, both present withpredominantly motor dysfunction and hypore-

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Chronic demyelinating polyneuropathy associated with eosinophilia-myalgia syndrome

Figure 3 Sural nervefrom patient 2. (A) Lightphotomicrograph showingthickening of epineuriumand perineurium andactive perineurialinflammation (toluidineblue) (bar = 100 pm).(B) Blood vessel typical ofthose seen throughout thebiopsy shows perivascularmononuclear cells(toluidine blue) (bar =351um). (C)Completely demyelinatedaxon (EM, bar = 1pum).(D) Frozen section ofnerve immunostained withLeu4, an antibody to CD3antigens on T cells, showingextensive rimming of allfascicles with T cells(bar = 200 pm). (E)Boxed area (from D) isshown at higher power andshows intensity ofinflammatory infiltrate(bar = 60 pm).

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flexia. Our patients differed from those withCIDP pathologically because there was pro-nounced fibrosis and perineuritis in ourpatients. In addition, the abnormalities ofmuscle are not found in patients with CIDP.One final analogy that suggests an autoim-

mune mechanism is the remarkable resem-blance of EMS to eosinophilic fasciitis (EF),first described by Shulman in 1975. Patientswith EF develop cutaneous lesions similar tothose described in EMS, as well as fascialinflammation, weakness, and peripheral eosi-nophilia.25 26 The oetiology of EF is unclear,but EF has occurred in association withhypergammaglobulinaemia and in associationwith autoimmune syndromes such as vitiligo,

thyroid disease, and Sjogren's syndrome. Todate, there is no strong evidence to link EFwith L-tryptophan.2

In favour of a toxic substance causing EMSis the presence of an unidentified chemicalfound in some retail lots of L-tryptophanwhich were consumed by patients who devel-oped EMS.27 Perhaps this "toxin" triggers theeosinophilic proliferation in EMS. The sub-sequent nerve damage could then be due toeosinophil derived neurotoxins.5 28-30 Thismight explain why the polyneuropathy mostcommonly seen in EMS is predominantly dueto axonal degeneration; however, this wouldnot account for the inflammation, demyelina-tion, and other features seen in our patients.

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There is little data to support the remaininghypothesis concerning tryptophan and itsmetabolism. Recent reports have suggestedthat levels of kynurenine, a major product ofL-tryptophan metabolism, are increased inpatients with EMS compared with controlpatients.'6 In addition, two patients with EMSand neuropathy had raised concentrations ofthe excitotoxin quinolinic acid, a final productof L-tryptophan metabolism, in cerebrospinalfluid.

Experience in treating EMS is limited. Whilesome patients have responded to corticoste-roids, those patients with the more severeforms of the disease, including the neuro-pathies and pulmonary disease, may not. Oneof our patients improved clinically after receiv-ing gammaglobulin, but she continues to havedebilitating pain and weakness. The otherpatient remained stable on long term, highdose prednisone and has shown considerableimprovement on azathioprine. Other immunetreatments have been tried, including cyclo-sporin, plasmapheresis, hydroxychloroquine,and methotrexate, with variable success.3 32

Perhaps when the pathophysiological mecha-nism of EMS is delineated a more effectivetreatment will be developed.Although L-tryptophan was banned by the

Federal Drug Administration in March 1990,patients with this syndrome may continue topresent to neurologists and rheumatologists forseveral reasons. Firstly, symptoms may notbecome apparent until several months after thediscontinuation of the drug. Secondly,although both our patients had long sincediscontinued the medication, they continuedto show disease progression. Lastly, althoughL-tryptophan is no longer available in stores, itmay remain in medicine cabinets for manyyears.

In conclusion, we draw attention to theimportant association of demyelinating neu-ropathy with the eosinophilia-myalgia syn-drome. Electrophysiological studies are impor-tant in patients with EMS, particularly in thosepatients with a rapidly progressive proximaland distal weakness, in order to identify thoseindividuals with neuropathy. The treatment ofthis subgroup of patients and their diseaseprogression may differ from that in the usualEMS patient.

This work was supported by The Muscular Dystrophy Associa-tion (MLF), The Jay Slotkin Fund for Neuromuscular Research(RWK), and National Institutes of Health grants PO1NS26643 (WRT) and NS 07179 (JDG). We thank Dr RonennRoubenoff and Dr William Ravich for referring their patients;Dr Mohammed Lehar for technical assistance; and Dr ChunYan U for preparation of teased fibres. Rod Graham preparedthe manuscript and offered editorial assistance.

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