Pure Motor Demyelinating Neuropathy: Deterioration After Steroid Treatment and Improvement with Intravenous Immunoglobulin

77878ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:778-783

PAPERS J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.7.778 on 1 July 1994. Downloaded from

Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin

Michael Donaghy, K R Mills, S J Boniface, J Simmons, I Wright, Norman Gregson, Jean Jacobs

Abstract In recent years, various subtypes of MFMN Within one month of starting oral pred- have been characterised and associated with nisolone treatment weakness unexpect- high titres of antiganglioside antibodies in edly increased in four patients aged 34 to 1 1% to 84% of cases depending on the clini- 75 years with purely motor forms of cal subtype.9 10 This motor neuropathy is most acquired chronic demyelinating neuro- commonly multifocal and associated with pathy. By contrast, steroids produced the motor nerve conduction block. Less often expected improvement in 11 other patients show symmetric weakness with dif- patients with symmetric sensorimotor fusely slowed motor conduction velocities. chronic inflammatory demyelinating These pure motor neuropathies have usually polyneuropathy. Two of the patients with failed to respond to treatment with pred- purely motor demyelinating neuropathy nisolone. Indeed, progression of weakness were subsequently treated with high dose seems to be common despite the use of high IVIg (0.4 glkglday for five days) with dose steroid treatment in MFMN.91 In one prompt improvements in strength mea- report, eight of nine patients improved with surements and motor nerve conduction. cyclophosphamide treatment" but the pros- Thus IVIg seems to be the treatment of pect of serious side effects makes this an unat- choice and steroids should be used with tractive long term treatment for such a extreme caution, if at all, in patients with chronic disease. Improved strength has been purely motor forms of acquired demyeli- reported recently after high dose IVIg treat- nating polyneuropathy. ment.12-'5 In some cases IVIg or cyclophosphamide treatment had been started while the ( Neurol Neurosurg Psychiatry 1994;57:778-783) patient was already taking or had recently taken prednisolone and these reports of beneficial treatments must be seen in the light of http://jnnp.bmj.com/ This communication highlights unpredicted the unexpected steroid induced weakness we Department of differences in the response to steroid treat- report here. Clinical Neurology, ment of different types of acquired chronic Radcliffe Infirmary, demyelinating neuropathy. These differences Woodstock Road, Oxford OX2 6HE, UK have important practical implications con- Methods M Donaghy cerning the choice of appropriate treatment PATIENT POPULATION

K R Mills for patients with chronic inflammatory The study is based on retrospective analysis of on September 24, 2021 by guest. Protected copyright. S J Boniface J Simmons demyelinating sensorimotor neuropathy 12 patients with CIDP and four with MFMN I Wright (CIDP), by contrast with those with purely referred consecutively over a three year period Department of motor demyelinating neuropathy or multifo- to a peripheral neuropathy clinic run by one Anatomy, Guy's cal motor neuropathy (MFMN). physician (MD). Diagnosis, decisions to treat, Hospital, St Thomas CIDP was first recognised as a treatable and monitoring of treatment were all under- Street, London SE1 9RT, UK cause of neurological disability over 20 years taken by MD. Because the need for formal N Gregson ago after reports of steroid responsiveness, study of different neuropathy subgroups was Department of subsequently confirmed by a controlled trial.5 not anticipated, there were no standard proto- Neuropathology, Azathioprine is often added to prednisolone, cols for assessing the degree of weakness, the Institute ofNeurology, causes nature of the studies Queen Square, and occasionally improvement in electrophysiological (per- London WClN 3BG, patients who failed to respond to prednisolone formed by three different neurophysiologists), UK alone.67 Plasma exchange is effective in CIDP the necessity for sural nerve biopsy, or the J Jacobs and is often used to initiate improvement in estimation of serum ganglioside antibodies. Correspondence to: to steroids.8 Routine serum was Dr Michael Donaghy, patients initially unresponsive protein electrophoresis Department of Clinical Two follow up studies of a total of 152 undertaken on all patients and no parapro- Neurology, Radcliffe with that between 85% was detected. Patients were Infirmary, Woodstock Road, patients CIDP suggest teinaemia diag- Oxford OX2 6HE, UK. and 95% of patients respond favourably to nosed as having CIDP according to standard Received 5 July 1993 and varying regimens of immunosuppressive treat- guidelines'6; all had symmetric distributions of in final revised form ment on absence or reduced 18 October 1993. based prednisolone, azathioprine, weakness, tendon Accepted 27 October 1993 and plasma exchange.67 reflexes, large fibre modality sensory loss, and Treatment ofpure motor neuropathy 779

absent or reduced sensory nerve action poten- flow was used in with CIDP patients taking J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.7.778 on 1 July 1994. Downloaded from tials (SAPs). more than two months to improve, and in the Pure MFMN was diagnosed on the follow- four patients with MFMN whose weakness ing grounds: seemed to increase after initiation of steroid (a) Purely motor features with normal treatment. sensation. Patients 1 and 2 with MFMN were given (b) Arm(s) affected at onset. IVIg (0 4 g/kg/day for five days) 33 months (c) Progression over more than two and 26 months respectively after they had last months. received any other immunomodulatory (d) (Multi-) focal onset. treatment (for example, steroids, plasma (e) Relative preservation of tendon exchange, or cyclophosphamide). Before and reflexes even in affected limbs. after treatment, these two patients were (f) Motor nerve conduction block assessed by myometry, a timed walk over a (defined as a proximal/distal CMAP ampli- fixed distance, stamina tests of upper and tude ratio of 60% or less), absent or pro- lower limbs, and by electrophysiology. longed F waves, or motor conduction velocities (MCVs) reduced to 38 m/s in the upper limb and 30 m/s in the lower limb. Results (g) Preserved SAPs or lack of demyelina- PATIENTS WITH SENSORIMOTOR CIDP tion or remyelination on the sural nerve biopsy. Patient profile The 12 patients were aged 10 to 75 years. All SURAL NERVE BIOPSY had a mixed sensorimotor polyneuropathy; Subtotal sural nerve biopsy was undertaken at sensory ataxia was the predominant feature in the ankle in the four patients with MFMN one patient who also had mild weakness and (1-4) to seek evidence of demyelination or electrophysiological evidence of motor nerve remyelination. Plastic embedded semithin demyelination. Immunosuppressive treatment sections and teased fibre preparations were was started in 11 patients; one was not treated analysed morphometrically."7 because of a combination of mild disability, diabetes mellitus, and low intelligence. GANGLIOSIDE ANTIBODIES Frozen stored serum samples from the Response to steroids patients with MFMN (1-4) were analysed. After steroid treatment in the eight patients GM1 and sialo GM1 antibodies were with CIDP aged 10 to 50 years, six regained detected by enzyme linked immunosorbent normal or near normal limb muscle power assay (ELISA).'5 This protocol has been vali- within six months. One had mild pretreat- dated in an international comparative study ment symptoms, barely sufficient to alter gait, organised by Dr Zielasek (Wurzburg). and he improved only slightly. The patient Further ganglioside antibody reactivity was with prominent sensory ataxia regained the detected by thin layer chromatography over- ability to walk briskly without a stick, layer with a total ganglioside extract from although some residual ataxia remained. human brain and cauda equina.'8 Three older patients, aged 66 to 75 years,

responded notably less promptly and com- http://jnnp.bmj.com/ IMMUNOSUPPRESSANT REGIMEN pletely to steroid treatment. The two patients All patients with CIDP or MFMN were in their eighth decade were initially unable to treated with oral prednisolone (60 mg/daily) bear weight or walk but, after a combination for the first two to four weeks, then with 45 of steroids, azathioprine, and plasma mg/day until their neuropathic symptoms sta- exchange, both made sustained improvements bilised or improved. Treatment was then after four and eight months respectively, and gradually converted to 25-45 mg on alternate eventually walked with walking frames. days for maintenance treatment. Azathioprine None of the patients with CIDP deterio- on September 24, 2021 by guest. Protected copyright. (2-5 mg/kg/day) was added in 10 of the 11 rated while taking steroids. treated patients with CIDP, and in all four patients with purely motor neuropathy. PURE MOTOR DEMYELINATING NEUROPATHY Plasma exchange (5 x 4 litres) by continuous (TABLE) Patient profile The duration of symptoms in four male MFMNpatients: summary ofinvestigations patients with MFMN ranged from five months to six years. Three patients (1, 3, and Sural nerve biopsy Electrophysiology Ganglioside 4) had a noticeably asymmetric pattern of MF antibodies muscle weakness. The weakness in patient 2 MCV CB density (normal Patient (mis) (%o) F(ms) (/mm2) range) GMI GDlb GM2 had started asymmetrically, but had later become symmetric. In three patients the arms 1 15,32 (arm) ND 102 (arm) 6100 (7500-1000) + + - 25 (leg) were weaker than the legs, in two the weak- 2 18,34 (arm) 21 Absent (arm) 6729 (7500-8500) - ness had commenced in one arm before 29 (leg) 3 42,46 (arm) 59 Absent (arm) 4038 (4000-7000) + + + spreading to predominate in the legs. None of 36 (leg) 24 64 (leg) the patients had sensory symptoms or signs. 4 15,16,30 ND 47 (arm) 5901 (4000-7000) - - - (arm) Patient 4 had undergone right ulnar nerve 28,32 (leg) ND 75,76 (leg) transposition four years earlier because of MCV = Motor conduction velocity; CB = degree of conduction block (see methods) F = F paraesthesia in the little finger; electrophysio- wave latency; ND = not done. logical studies at that time had shown right 780 Donaghy, Mills, Boniface, Simmons, Wright, Gregson, 3'acobs

median and ulnar motor conduction velocities months and cyclophosphamide (100 mg J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.7.778 on 1 July 1994. Downloaded from of 15 and 16 m/s although the patient did not daily) was started for six months. Strength recollect weakness. was then maintained after cyclosphosphamide The table summarises neurophysiological, was stopped. nerve biopsy, and ganglioside antibody Patient 3 became unable to walk, stand, results. Neurophysiological studies showed shave, or feed himself within four weeks of that at least three nerves in each patient had starting prednisolone. Deterioration pro- one or more of the following features: motor gressed, with temporary improvement after conduction velocity less than 35 m/s (arms) or the first two of three courses of plasma 29 m/s (legs), conduction block of more than exchange. He regained the ability to walk 60%, or prolonged F wave latencies. The when cyclophosphamide (100 mg daily) was SAPs were normal in the two younger patients started, but this drug was stopped after (1 aged 34 years; 2 aged 56 years). Neither Listeria meningitis and he subsequently died the median nor the sural SAP were recordable of overwhelming abdominal sepsis. in patient 4 (aged 75 years) despite a normal Patient 4 had slowly progressing asymmet- routine sensory examination. In patient 3 ric weakness of the arms, slight dysphagia, (aged 72 years), the radial SAP was 6 mV, the and leg unsteadiness. Within two weeks of median 2 mV, and sensory examination was starting prednisolone (60 mg/daily) he was normal. Myelinated fibre densities in the sural unable to stand, sit unsupported, or feed nerve were within the normal range in himself, and required nasogastric tube nutri- patients 3 and 4, and were marginally below tion. Plasma exchange produced a slight tem- normal in the two younger patients (1 and 2). porary improvement in arm power. Six Teased fibres were examined in patients 1, 2, months after stopping steroids he had and 3, and remyelinated segments were found regained the ability to feed and swallow, and in less than 1 % of fibres; no segmental walk with a frame. demyelination was observed. Two patients (1 and 3) had IgM GM1 antibody titres of Response to treatment with IVIg 1/1000 and 1/3000 (90% confidence interval Patients 1 and 2 were treated with IVIg, and for controls 1-180). On overlay both patients both showed an improvement in strength. also showed IgM reactivity with GDIb, and Patient 1 was treated with IVIg 33 months one had weak reactivity with GM2. When run after stopping steroids at a time when he was against human cauda equina gangliosides, able to walk 200 m wearing foot calipers, his three of the serum samples showed some hand and shoulders were weak, he was unable reactivity with sulphated glucuronylpara- to write, and he had difficulty using cutlery globoside.19 and lifting a cup. For nearly three years he had needed help dressing and he had stopped Response to steroids driving because he was unable to hold the All four patients showed significant motor steering wheel. These deficits had been stable deterioration within four weeks of starting before declining slightly over six months. In treatment with prednisolone (60 mg/daily). It December 1992 he was treated with IVIg. By was the striking nature of the deterioration the third day of IVIg treatment he considered

that provoked this comparison with CIDP. In that his arms were stronger. Over the next six http://jnnp.bmj.com/ all four patients the rate of deterioration weeks this improvement was maintained; he increased sharply and could not be regarded went swimming for the first time in two years simply as an extension of the rather indolent and drove his car for the first time in three rate of progression shown by each before years; he was able to use a knife and fork and treatment. lift a cup; and shaved his chin for the first time Patient 1 had previously had stable weak- in two years. He still had difficulty with fine ness of all four limbs. Within two weeks of finger movements including writing and prednisolone treatment he was unable to grip manipulating buttons. His walking speed on September 24, 2021 by guest. Protected copyright. his car controls, bath taps or eating imple- increased. There were large increases in the ments, and his signature deteriorated. He time he could abduct his shoulders against completely regained his presteroid motor gravity and lift his heels off the bed against function within four weeks of stopping gravity (figure; A). steroids; no improvement had occurred with In patient 1 the most pronounced change plasma exchange. in serial measurements in nerve conduction Patient 2 had previously had slowly pro- made by a single observer was an increase in gressive weakness of all four limbs. He rapidly dispersion of the compound muscle action lost the ability to walk within a month of start- potential of the abductor digiti after stimula- ing steriods; within three months he could no tion at the elbow. Before treatment the com- longer roll over in bed or raise his legs or pound muscle action potential from elbow arms. Over five months the (right) ulnar nerve stimulation had a duration of 23 ms with eight MCV fell from 34 to 12-5 ms, the distal motor phases; after treatment the compound muscle latency rose from 8-4 to 12 ms. The median action potential had a duration of >80 ms nerve MCV remained unchanged, but the dis- with >20 phases. Ulnar motor conduction tal motor latency extended from 10 to 19-5 velocity from Erb's point to the elbow ms. Courses of plasma exchange produced increased marginally from 24 m/s to 31 ii/s partial motor recovery lasting about two but there was no consistent change in the weeks. He slowly regained his presteroid velocity through the forearm. There was per- strength when steroids were stopped after 10 sistent EMG evidence of chronic denervation Treatment ofpure motor neuropathy 781

maintained. Myometry at one week showed J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.7.778 on 1 July 1994. Downloaded from * Right shoulder abduction improvement in the muscle groups tested * Left shoulder abduction except the first dorsal interosseous, although o Left heel off bed o Right heel off bed only three groups remained improved at six A * Walking time weeks. His walking speed was faster at one and six weeks and he could raise his legs Five days IV Ig Two days IV Ig against gravity for longer (figure; B). In patient 2 the most pronounced early change in nerve conduction was an increase in the amplitude of the distal compound muscle action potentials. This rose from 0-8 mV to 2-7 mV for the right median nerve by the second day after treatment, retaining the normal E biphasic waveform. The proximal compound muscle action potentials became more dis- persed and polyphasic but F waves were 1I detectable in the right ulnar nerve at a mini- 0 10 mum latency of 38 ms. Motor conduction B velocity was more variable, showing no con- Five days IV Ig Two days IV Ig sistent change in two out of three upper limb 500 -; nerves and increasing from 18 m/s to 42 m/s 400 -A after nine weeks in the right median nerve. Sensory conduction remained normal and unchanged. ,,i 200 From six to 12 weeks after treatment, a)E 100 _ . patient 2 noticed a gradual return of his weakness. He could no longer confidently climb steps. He remained able to drive his car, and was still stronger than he was before treatment 25 with IVIg. His walking time increased and the 0 10 time he could keep his heels off the bed fell to Time (weeks) pretreatment values (figure; B). A second, shorter course of IVIg (0 4 g/kg for two days) Walking time over a fixed distance and ability to hold limbs outstretched in relation to IVIg treatment produced rapid improvement in strength and (0-4gIkg/day). (A) Patient 1; (B) patient 2. ability to walk up an incline or climb steps. The tests of his leg stamina improved, though not to as great an extent as with the initial but sensory conduction remained normal and treatment. This improvement was maintained unchanged. for only five weeks, by which time his strength By 10 weeks after treatment with IVIg his had declined; he was using two walking sticks strength had declined. He was once again and the times for lifting his heels off the bed finding difficulty in using eating implements, had fallen to below the pretreatment values. http://jnnp.bmj.com/ and shaving. His walking speed had slowed and the times for abducting his shoulders and raising his heels had declined, although these Discussion were still better than before treatment with This series of patients draws attention to the IVIg. Patient 1 was then treated again, with a rapid deterioration in motor function that can smaller dose of IVIg (0 4 g/kg for two days). be precipitated by high dose oral prednisolone As before he experienced a rapid increase in (60 mg/day) in a motor, and often (multi-) on September 24, 2021 by guest. Protected copyright. his strength, regained the ability to shave him- focal, subgroup of chronic acquired demyeli- self, and outstretched limb times improved nating neuropathy. Such steroid induced once more (figure; A). This smaller dose was deterioration only occurred in the four less beneficial and the patient reported a patients with purely motor symptomatology. decline in strength within six weeks. A further It never followed steroid treatment in the 11 small dose of IVIg (0 4 g/kg for one day) pro- patients with symmetric sensorimotor CIDP. duced slight improvement lasting only two to The prompt deterioration within four weeks three weeks. of commencing prednisolone treatment, and Patient 2 received IVIg 26 months after the rapid improvement with plasma exchange stopping cyclophosphamide. From October or on stopping steroids, are all incompatible 1992 he noticed increased difficulty in walk- with the notion of steroid myopathy, which ing, could not climb steps, and had to stop generally occurs after long term dosage with driving his car. In January 1993 he was admit- fluorinated steroids. As expected6720 patients ted for IVIg treatment (0 4 g/kg day for five with sensorimotor CIDP improved with days). Seven days later his legs were stronger. steroids; it was noteworthy that the younger Within two weeks his walking distance had patients improved more promptly and to a improved and he required only one walking more satisfactory extent than the older stick rather than two on inclines. He could patients. We regard the deterioration in climb steps again and restarted driving. His MFMN as being due to steroid accelerated arms were stronger. Six weeks after treatment worsening of the underlying neuropathy. We he considered that this improvement had been did not undertake detailed neurophysiological 782 Donaghy, Mills, Boniface, Simmons, Wright, Gregson, 3'acobs

monitoring of this unanticipated phenome- genic antibody that has already bound to J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.7.778 on 1 July 1994. Downloaded from non. Its brisk responsiveness to plasma nerve fibres and caused conduction block. exchange, however, in patient 2 suggests that One cannot exclude the possibility that the it reflects a promptly reversible deterioration IVIg solution, or steroids, alter the levels of in motor nerve function, such as increased other factors such as cytokines, which may conduction block. mediate conduction block. The four patients with steroid induced Given that steroids may induce deteriora- motor deterioration all fitted the diagnostic tion in purely motor demyelinating neuro- category of demyelinating motor neuropathy, pathy, how should we treat this condition? often associated with conduction block.9 Such Although cyclophosphamide seems to be patients are predominantly male, have slowly effective" most physicians would baulk at evolving multifocal muscle weakness usually long term use of such a toxic drug except in worse in the arms, and normal sensation. seriously disabled patients. Currently IVIg Bulbar involvement has been recorded'4 as in seems to be the most effective and least toxic our patient 4. As in two of our patients, GM1 treatment. It should be recognised, however, ganglioside antibodies occur in 11% to 84% that many patients with pure motor demyeli- of such patients, depending on the clinical nating neuropathy are inconvenienced rather subgroup.'9 Such antibodies, however, are not than profoundly disabled by their disease, specific markers for pure motor demyelinating particularly early on. Thus conservative treat- neuropathy as they also occur although less ment may be realistic in the early years of a often in sensorimotor demyelinating neu- patient's disease, before introducing regular ropathies.10 None of these four patients had IVIg infusions once significant disability has the paraesthesiae or demonstrable sensory accrued. We recommend that each patient's loss so common in conventional CIDP.6720 response is monitored closely when IVIg is Unlike the patients with CIDP, the SAPs initially introduced, firstly to be sure of its were preserved in the patients with MFMN, effectiveness in that particular patient and sec- except in the 75 year old (patient 4). Sural ondly to identify suitable dosages and treat- nerve biopsy revealed no evidence of active ment intervals. It may prove misleading to try sensory nerve fibre demyelination in the four and assess the response to IVIg in patients patients with MFMN, unlike the findings who are already taking prednisolone or often reported in sensorimotor CIDP."3 6 cyclophosphamide, and who may have a Clear improvement in strength and motor changing background of weakness. nerve conduction occurred in our two patients Until the specific biological mechanisms with MFMN (1 and 2) who were treated with underlying the various syndromes of acquired IVIg. Symptomatic improvement started at demyelinating neuropathy are defined, the three and seven days respectively after the validity of differentiating them on clinical and start of IVIg (five days at 0 4 g/kg/day), and electrophysiological grounds will be debated. lasted up to 10 weeks; lower doses were less For instance, how do patients with sensorimo- effective. Other recent reports have shown tor multifocal conduction block2l relate to similar improvement in MFMN after treat- those with conventional symmetric sensori- ment with IVIg.12-5 Blinded, controlled trials motor CIDP on one hand, and MFMN on

of treatment are unlikely to be feasible for the other? Given our present lack of absolute http://jnnp.bmj.com/ MFMN and these reports of clear cut respon- criteria for differentiating subgroups of siveness provide an empirical basis for estab- acquired demyelinating neuropathy, a clinical lishing IVIg as the most effective, reasonably classification is important so as to choose safe, contemporary treatment mi MFMN. appropriate modes of treatment. It is clearly After IVIg treatment in our patients the pro- important to avoid inducing deterioration nounced early increase in the amplitude of the with steroids in the purely motor subgroup, biphasic distal compound muscle action and yet to offer this valuable mode of treat- potentials combined with the persistence of ment to those with sensorimotor CIDP. on September 24, 2021 by guest. Protected copyright. polyphasic proximal compound muscle action We are grateful to Mrs Anne Richardson for preparing the potentials (some of which became longer in manuscnpt. duration) suggests that the main process affecting distal conduction was a reversal of 1 Dyck PJ, Lais AC, Ohta M, Bastron JA, Okazaki H, conduction block. The subsequent increase in Groover RV. Chronic inflammatory polyradiculopathy. maximal motor conduction velocity in some Mayo Clin Proc 1975;50:621-37. 2 Matthews WB, Howell DA, Hughes RC. Relapsing corti- nerves probably reflects the unblocking of costeroid-dependent polyneuritis. J Neurol Neurosurg faster conducting fibres. Certainly the prompt Psychiatry 1970;33:330-7. 3 Prineas JW, McLeod JG. Chronic relapsing polyneuritis. clinical response to IVIg, and the irreversible JNeurol Sci 1976;27:427-58. deterioration induced by steroids, would be 4 Thomas PK, Lascelles RG, Hallpike JF, Hewer RL. Recurrent and chronic relapsing Guillain-Barre poly- hard to attribute to mechanisms other than neuritis. Brain 1969;92:589-606. changes in the degree of conduction block. 5 Dyck PJ, O'Brien PC, Oviatt K, et al. Prednisone improves chronic inflammatory demyelinating polyradiculoneu- We did not perform serial studies of antigan- ropathy more than no treatment. Ann Neurol 1982; glioside titres during steroid treatment and 11:136-41. 6 Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic cannot comment on whether clinical worsen- inflammatory demyelinating polyradiculopathy: clinical ing correlated with raised antibody titres, pos- characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989;46:878-84. sibly resulting from steroid induced 7 McCombe PA, Pollard JD, McLeod JG. Chronic inflam- lymphocytosis. It is difficult to attribute the matory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases. Brain prompt improvement with IVIg to a putative 1987;110: 1617-30. anti-idiotype antibody neutralising a patho- 8 Dyck PJ, Daube J, O'Brien P, et al. Plasma exchange in Treatment ofpure motor neuropathy 783

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