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Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Objectives: To determine the prognosis in patients with Lambert-Eaton myasthenic syndrome (LEMS) without small cell lung cancer (SCLC), and to analyse longitudinal clinical, electrophysiological, and immunological data on each patient to establish prognostic factors for long term outcome., Methods: The retrospective and part prospective study of 47 patients with LEMS was undertaken from data recorded during visits to a specialist neuromuscular clinic. Serial measurements of muscle strength score in shoulder abduction, elbow extension and hip flexion, compound muscle action potential (CMAP) amplitude, and postcontraction increment in abductor digiti minimi (ADM), and anti-P/Q-type voltage gated calcium channel (VGCC) antibody titre were made at each visit., Results: Muscle strength scores were improved in 88% of patients after a median duration of immunosuppressive treatment of 6 years (range 1.3 to 17 years); anti-VGCC antibody titres fell in 52% after treatment; and mean resting CMAP amplitude improved from 2.7 mV initially to 8.8 mV after 2 years of treatment p<0.001). Initial pretreatment anti-VGCC antibody titre did not correlate significantly with either CMAP amplitude, CMAP increment, or clinical score: from serial measurements made during follow up, significant correlation between antibody titre and CMAP amplitude was seen in only two patients. Sustained clinical remission was achieved by 20 (43%) of whom only four remained in remission without the need for immunosuppression. Using a Cox proportional hazards model, the only independent predictor of sustained clinical remission was initial pretreatment clinical score (p=0.03). Lymphoma presented in three patients during the study., Conclusions: The prognosis in patients with LEMS without SCLC is favourable, although patients often need significant doses of immunosuppressive treatment to remain clinically stable. Only initial clinical muscle strength measurements and not anti-VGCC antibody titres or electrophysiological recordings are predictive of long term outcome.

Objective: To assess the distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome (LEMS) to identify the most sensitive muscle to use in routine examination., Methods: Surface recorded compound muscle action potential (CMAP) amplitudes were made from abductor digiti minimi, abductor pollicis brevis, anconeus, biceps brachii, and trapezius in 10 patients with LEMS. The effect of 3,4-diaminopyridine (3,4-DAP) was recorded in each muscle in nine patients. CMAP amplitudes were measured at rest and immediately after 10 seconds maximal voluntary contraction in each muscle. Values were compared with results obtained from 12 healthy controls., Results: Resting CMAP amplitudes were reduced in at least one muscle in all patients compared with controls, most markedly in abductor digiti minimi and anconeus. The administration of 3,4-DAP resulted in significantly improved resting CMAP amplitudes in trapezius only. After maximal voluntary muscle contraction, characteristic increments in CMAP amplitude of over 100% above resting values were seen in abductor digiti minimi and abductor pollicis brevis in seven patients, anconeus and biceps brachii in five patients. No patient had this level of increment in trapezius., Conclusion: Despite predominantly proximal limb weakness seen clinically in patients with LEMS, the most sensitive muscles for detecting characteristic electrophysiological abnormalities of low resting CMAP amplitude and increment of over 100% after 10 seconds maximal voluntary contraction are abductor digiti minimi, abductor pollicis brevis, and anconeus.

A new immunoprecipitation assay has been established for detecting antibodies to voltage-gated calcium channels (VGCCs) in Lambert-Eaton myasthenic syndrome (LEMS), using 125I-omega-conotoxin MVIIC, which binds to P-type VGCCs, to label extracts of human cerebellum. Fifty six of 66 serum samples (85%) from patients with clinically and electrophysiologically definite LEMS were positive for the presence of VGCC antibodies, defined as a titre > 3 SD above the mean for the healthy controls (n = 10). All disease controls (n = 40) were negative. This sensitive immunoassay should prove valuable in the diagnosis of LEMS.

A 13 year old Greek girl with myasthenia gravis developed widespread muscle paralysis and atrophy after large parenteral doses of corticosteroids (5.48 g methylprednisolone). An electromyogram showed myopathy, creatine kinase concentration below normal, and a muscle biopsy showed severe myopathy with selective loss of the thick filaments (myosin). Previous reports of myopathy associated with large steroid doses have mostly been in patients who were also receiving non-depolarising neuromuscular blocking drugs. This patient is unique in that severe myopathy was associated with neuromuscular blockade caused by antibodies to acetylcholine receptors. The findings in this case suggest that high doses of parenteral corticosteroids in patients with myasthenia gravis may be dangerous and that blocking the neuromuscular junction with drugs or antibodies predisposes skeletal muscles to the injurious effects of corticosteroids.

Congenital or hereditary myasthenia describes a heterogeneous group of disorders in which the immune system is not implicated. Treatment has previously depended on anticholinesterase medication. The effectiveness of 3,4-diaminopyridine (3,4-DAP), a preparation that enhances acetylcholine release from motor nerve terminals, has been evaluated using a series of standardised strength measures. Sixteen patients (aged seven to 47 years) were studied in an open prospective trial, and four of them in a double blind crossover trial; existing anticholinesterase medication was continued. For the group as a whole, there was a highly significant increase in muscle strength (p less than 0.001; n = 16). In individual paired comparisons, 13 out of 16 showed significant improvement in the open trial and four out of four in the blind crossover trial. In conclusion, 3,4-DAP, either alone or combined with anticholinesterase medication, may be a useful additional treatment in congenital myasthenia.

One hundred and fifty patients presenting with small cell lung cancer (SCLC) to chest physicians, were assessed neurologically. Neuromuscular or autonomic deficits were common and occurred in up to 44% of cases. Weakness, dry mouth, and weight loss were not mutually independent and may represent the syndrome formerly described as carcinomatous neuromyopathy. By contrast, undoubted paraneoplastic syndromes were much less commonly detected. Two patients had the Lambert-Eaton myasthenic syndrome (LEMS) and one had subacute sensory neuropathy (SSN). In these patients, neurological symptoms antedated other manifestations of cancer, by between six and 17 months. The 95% confidence interval for the prevalence of LEMS or SSN among SCLC patients was 0-4%, consistent with the results of previous retrospective or smaller studies: summing these, the overall prevalence of LEMS among SCLC patients is close to 3%, which implies about 250 new cases per annum in England and Wales. If LEMS and SSN are the least uncommon neurological paraneoplastic syndromes in SCLC patients, this may reflect the accessibility of motor nerve terminals and dorsal root ganglia to cross-reactive anti-tumour cell antibodies.

Two patients are described in whom a clinical and electromyographic diagnosis of the Lambert-Eaton myasthenic syndrome (LEMS) was made. Serum antibodies to voltage-gated calcium channels (VGCCs), the antigenic target in LEMS and to acetylcholine receptors (AChRs), the antigen in myasthenia gravis, were detected at raised titres in both cases, using radioimmunoassays based on 125I-omega-Conotoxin labelled VGCCs and 125I-alpha-Bungarotoxin labelled AChRs. These data provide immunological evidence for the coexistence of the two disorders in these patients.

We have investigated whether plasma exchange in myasthenia gravis synergises with additional immunosuppressive drug therapy (azathioprine, cyclophosphamide or cytosine arabinoside). Serum anti-acetylcholine receptor (AChR) antibody titres were followed over 28 days after a course of PE in 20 patients, of whom 17 were taking 20-80 mg prednisone on alternate days. No significant difference was observed in mean anti-AChR antibody recovery following plasma exchange with and without additional immunosuppressive therapy. In paired studies where patients served as their own controls, mean anti-AChR recovery with and without azathioprine or cytosine arabinoside showed no significant differences. Anti-AChR recovery rates after large and small plasma exchange courses also did not differ significantly. Prolonged administration of azathioprine reduced antibody titres independently of plasma exchange. These results fail to demonstrate significant synergy between plasma exchange and the additional immunosuppressive drugs used, and suggest that the effects of plasma exchange were transient.

Sporadic reports have suggested central involvement in myasthenia gravis, a disorder in which there is an antibody-mediated loss of peripheral nicotinic acetylcholine receptors. Five patients with symptomatic myasthenia gravis performed an auditory vigilance test of ability to direct and sustain attention, presumed to reflect central cholinergic function. No deficits were found, either in comparison with the same subject's performance when muscle strength had improved after plasma exchange, or compared with that of healthy controls. The results thus failed to substantiate reports of functionally significant central cholinergic deficits in myasthenia gravis.

The in vivo synthesis of diaphragm endplate acetylcholine receptors was estimated in mice treated daily with IgG from eight myasthenia gravis patients. Myasthenia gravis IgG preparations which had previously been shown to increase the rate of receptor degradation also increased the rate of receptor synthesis, suggesting the existence of a compensatory mechanism serving to stabilise the number of acetylcholine receptors.

The in vivo degradation of endplate acetylcholine receptors was investigated in mice treated daily with IgG from 10 myasthenia gravis patients. Four preparations increased the rate of degradation. The number of endplate acetylcholine receptors after 7 days of IgG treatment was greater than that predicted on the basis of the increased degradation rate, suggesting a compensatory increase in receptor synthesis.

Peripheral blood T cell subsets were measured using monoclonal antibodies and a fluorescence activated cell sorter in 15 untreated patients with Lambert-Eaton myasthenic syndrome (nine with small cell carcinoma, one undifferentiated epithelial tumour (ca-LEMS], five with no demonstrable tumour (non-ca-LEMS), 10 age-matched healthy controls and 10 patients with small cell carcinoma without neurological disease. OKT8+ (suppressor/cytotoxic) T cells were significantly decreased in ca-LEMS compared with non-ca LEMS (p less than 0.001) ca-controls (p less than 0.01) and healthy controls (p less than 0.001). In one patient depressed OKT8+ T cells antedated clinically evident tumour by five months. OKT3+ (total) and OKT4+ (helper) T cells were similar in ca-LEMS, non-ca LEMS and controls. The mechanism underlying the loss of circulating OKT8+ T cells in ca-LEMS is unknown, but these changes may help to predict the presence of carcinoma in this disease.

The G2m(n) allotype was significantly increased in Chinese female and high autoantibody cases, and in caucasians with pure ocular myasthenia, or undetectable autoantibody. In contrast to the strong Glm(x) association reported in Japanese, no overall Gm haplotype, or Am or Km allotype association was found in 90 (Taiwan) Chinese and 181 caucasian myasthenia gravis patients.

Early suggestions that a humoral factor might be implicated in the disorder of neuromuscular transmission in myasthenia gravis have been confirmed by the detection of anti-AChR antibody in 85-90% of the patients with generalised disease and in 75% of cases with restricted ocular myasthenia. Plasma exchange reveals that serum anti-AChR usually has an inverse relationship to muscle strength and present evidence indicates that patients responding to thymectomy and immunosuppressive drug treatment usually show a consistent decline in serum anti-AChR titres. The antibody is heterogeneous and can lead to a loss of muscle AChR by several mechanisms. Anti-AChR is produced in the thymus in relatively small amounts. Anti-AChR antibody synthesis by thymic lymphocytes and pokeweed stimulated peripheral lymphocytes in culture provides a means of studying the effect of different lymphocyte populations in vitro. Analysis of clinical, immunological and HLA antigen characteristics in MG suggest that more than one mechanism may underlie the breakdown in tolerance to AChR, leading to the production of anti-AChR antibodies.

Anti-acetylcholine receptor (AChR) antibody was undetectable in 26/153 (17%) sera from myasthenia gravis patients assayed by standard RIA using human acetylcholine receptor. Eight of these were found to be positive with a modified protocol using a mixture of normal and denervated AChR, reducing the proportion of "negative" sera to 12%. Many of these were from patients with a short history; two such patients later developed low positive values. Anti-AChR without clinical evidence of myasthenia was found in one of three monozygotic twins of myasthenia gravis patients, and in one of thirty other first degree relatives of a further 17 patients. Anti-AChR is a valuable and highly specific diagnostic test which, with the assay used here, is positive in about 88% of patients with clinical features of myasthenia gravis.