Peripheral neuropathy was found in 12 (46%) of 26 patients with macroglobulinemia. The neuropathy was subclinical in two. Anti-myelin-associated glycoprotein (MAG) activity was found in six (50%) patients with neuropathy. Sural nerve biopsies showed demyelination and IgM deposits on the myelin sheath. In one patient who had no anti-MAG activity, the serum IgM bound to peripheral myelin by indirect immunofluorescence and to several protein bands in peripheral nerve and other tissues by immunoblot. In the other five patients with neuropathy, we found no binding of M proteins to nerve components, but in three patients there were endoneurial IgM deposits in nerve biopsy. Peripheral neuropathy may be related to the antigen-specificity of M proteins.

Many data point to a pathogenetic role for IgM antibodies to the myelin-associated glycoprotein (MAG) in the neuropathy associated with IgM monoclonal gammopathy, supporting the use of immune therapies in affected patients. Almost 50% of patients have been reported to improve with these therapies, but the effect of treatment on the long-term prognosis of the neuropathy remains unclear. We analysed the outcome of 25 of the 26 patients (mean age at entry 65 years, range 45-85 years) with neuropathy and high anti-MAG IgM, first examined by us between 1984 and 1994. By January 1999, after a mean follow-up of 8.5 years (range 2-13 years) and a mean duration of neuropathy symptoms of 11.8 years (range 3-18, >10 years in 16), 17 patients (68%) (aged 58-84 years, mean 73.4) were alive, while eight (32%) (aged 69-78 years, mean 73.1) had died 3-15 years (mean 10.6) after neuropathy onset; in none of them was death caused by the neuropathy, although in three it was possibly related to the therapy for the neuropathy. By the time of last follow-up or patients' death, 11 patients (44%) were disabled by severe hand tremor, gait ataxia or both. The disability rates at 5, 10 and 15 years from neuropathy onset were 16, 24 and 50%, respectively. Of the 19 patients treated during the follow-up for 0.5-11 years (mean 4 years) with various immune therapies, five reported a consistent and four a slight improvement in the neuropathy (total 47%) after one treatment or more, but in only one patient was improvement persistent throughout, to the end of follow-up. In 10 patients (53%), severe adverse events, possibly related to therapy, occurred during treatment and were considered responsible for the patient's death in three. The neurological impairment did not differ between treated and untreated patients at the end of a similar follow-up. Our findings indicate that (i) the majority of patients with neuropathy and anti-MAG IgM have a favourable prognosis even after several years, and (ii) current immune therapies, though temporarily effective in half of the patients, are associated with considerable side effects which limit their prolonged use and efficacy, suggesting that until more effective or safer therapies become available, they should probably be reserved for patients impaired in their daily life or in a progressive phase of the disease.

Article abstract-Background: Miller Fisher syndrome (MFS), a variant of the Guillain-Barré syndrome, is associated with the presence of neuromuscular blocking antibodies, some of which may be directed at the ganglioside GQ1b. Materials and Methods:The authors investigated the in vitro effects of serum and purified immunoglobulin (Ig) G in a total of 11 patients with typical MFS during active disease, and in three of those patients after recovery. From one patient's serum, we prepared an IgG fraction enriched in anti-GQ1b antibodies by affinity chromatography. For combined pre-and postsynaptic analysis, endplate currents were recorded by a perfused macro-patch clamp electrode. Postsynaptic nicotinic acetylcholine receptor channels were investigated by an outside-out patch clamp technique in cultured mouse myotubes. Results: All MFS-sera depressed evoked quantal release and reduced the amplitude of postsynaptic currents. Five of the 11 sera were additionally examined by outside-out patch clamp analysis and caused a concentration-dependent and reversible decrease in acetylcholine-induced currents. The time course of activation and desensitization of nicotinic acetylcholine receptor channels was not altered by MFS-IgG. Nine patients (82 %) were positive for anti-GQ1b antibodies in ELISA and dot-blot. The enriched anti-GQ1b antibody fraction had a similar effect as whole serum. After recovery from MFS, blocking activity was lost and sera originally positive for anti-GQ1b antibodies became negative. Conclusion: Circulating IgG antibodies induce both pre-and postsynaptic blockade and may play a pathogenic role in acute MFS. NEUROLOGY 2001;56:67-74 Miller Fisher syndrome (MFS) is characterized by the triad of gait ataxia, external ophthalmoplegia, and areflexia.1 As a variant of the Guillain-Barré syndrome (GBS), MFS is thought to be an immunopathologic disorder of the peripheral nervous system. Immunoglobulin (Ig) G autoantibodies directed at the ganglioside GQ1b are found in the acute phase sera of more than 90% of patients with MFS.2-4 Gangliosides are present in high concentrations in peripheral nerve axons and myelin, and several studies indicated that different gangliosides (e.g., GM1) are present at nodes of Ranvier and at neuromuscular junctions. 5 The distal motor nerve terminal lacks the blood-nerve barrier, making it accessible for circulating antibodies and a suitable site to investigate the functional effects of serum-antibodies experimentally.There is evidence that MFS sera block neuromuscular transmission in the mouse hemidiaphragm. [6][7][8][9] Using intracellular microelectrode techniques, a marked increase in spontaneous release (i.e., miniature endplate potential frequency) after application of MFS sera, followed by inexcitability of the muscle upon phrenic nerve stimulation has been demonstrated. 6,9 In that study, the effects depended entirely on the presence of complement, 9 and miniature endplate potential (MEPP) amplitudes appeared unchanged. 6,9 With a perfused macro-patch clamp electrode, we...

Peripheral neuropathy (PN) is a frequent complication during primary macroglobulinemia (PM), whose immunological genesis has been suggested by various authors. This study involved 65 PM patients (44 men and 21 women aged 35-78), diagnostically divided into MGUS (31 cases), and indolent (IWM, 24 cases) or symptomatic (WM, 10 cases) Waldenstrom macroglobulinemia groups. All patients underwent neurological examination, including electrodiagnostic evaluation and the determination of the serum titre of antimyelin-associated glycoprotein (MAG). An evaluation was made of the prevalence of PN and its correlation with a series of hematological variables. The prevalence of PN was 31.6%: of those with PN, 73.1% manifested both clinical and electrophysiological signs of PN, primarily of the demyelinating type. Significant correlations emerged between the presence of PN and sex (M vs. F P = 0.0001), advanced age (P = 0.049), low MC levels (P = 0.025), high anti-MAG titres (P = 0.001) and high Hb levels (P = 0.001). No significant correlation with the diagnostic definition of PM was found, although the majority of cases with (particularly demyelinating) PN were MGUS or IWM. At multivariate analysis, the presence of PN significantly correlated with sex (P = 0.0001), age (P = 0.019), and anti-MAG titre (P = 0.001). Ten of the 26 PN cases showed no MAG reactivity. Significant correlations between PN and low serum MC levels/high MAG reactivity support the hypothesis of the antibody-mediated origin of many PN, and that the presence of PN depends on the characteristics of the proliferating pathological B clone, rather than on the tumor burden of the form of macroglobulinemia. Clinically, our data reconfirm the frequency of PN during PM and indicate simple clinicohematological variables useful for identifying patients at high neuropathic risk.

We examined 52 asymptomatic patients with IgM monoclonal gammopathy and correlated anti–myelin‐associated glycoprotein (anti‐MAG) IgM with the presence of subclinical neuropathy and, in 24 of these patients, with the development of symptomatic neuropathy during a follow‐up interval of 40 to 144 months (mean, 75.3 months). Three of 6 patients (50%) with high (>1/6,400) anti‐MAG IgM had subclinical neuropathy at entry compared with 2 of 46 patients (4.3%) with low or no reactivity. At follow‐up, a symptomatic neuropathy occurred in 3 of 4 patients with high reactivity and in 3 of 21 patients with low or no reactivity. The correlation of high anti‐MAG IgM with the presence of subclinical neuropathy or the development of symptomatic neuropathy supports its pathogenetic role in the neuropathy. Ann Neurol 1999;46:119–122

Seven consecutive patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous immunoglobulins (IVIg; 0.4 g/kg per day for 5 consecutive days followed by monthly 2-day infusions at the same daily dosage) continued with oral cyclophosphamide (1-2 mg/kg per day), for 4-13 months (mean 8.1). Response to treatment was assessed by means of the Medical Research Council (MRC) rating scale for muscle strength on 40 muscles (10 per limb), a clinical scale for bulbar function and a modified Rankin disability scale. All patients continued to deteriorate during treatment on as regards both their MRC score and either their bulbar or Rankin score or both. The progression of the disease during treatment, expressed as the monthly variation in MRC score (mean = -2.71; SD = 1.36), was no slower than that estimated before therapy (mean = -1.81; SD = 0.93). Even if the results of this small, uncontrolled study do not permit the exclusion of an effect of IVIg on the progression of ALS, they also do not provide any evidence that this expensive form of therapy consistently slows the course of the disease.

Anti‐sulfatide IgM antibodies have been recently associated with neuropathy but the clinical and electrophysiological correlations of this reactivity remains unclear. We reviewed the clinical and electrophysiological features of patients with high anti‐sulfatide titers detected in our laboratory from 1991 to 1998. Of the 564 patients with different neurological diagnosis tested by enzyme‐linked immunosorbent assay (ELISA), 11 had high anti‐sulfatide IgM titers (>1/8000), 26 had titers of 1/8000 while 78 had titers of 1/4000. All patients with high anti‐sulfatide IgM titers had a chronic, dysimmune, mostly sensorimotor neuropathy that in seven was associated with IgM monoclonal gammopathy. In most of these patients electrophysiological and morphological studies were consistent with a predominantly demyelinating neuropathy frequently associated with prominent axonal loss. Antibody titers of 1/8000, though always associated with neuropathy, did not correlate with a particular form or cause of neuropathy, while lower titers were equally distributed in patients with different neurological disorders. Our study indicates that high anti‐sulfatide IgM titers (>1/8000) are highly predictive for a chronic, dysimmune, mostly demyelinating neuropathy often associated with IgM monoclonal gammopathy, and may therefore have potential diagnostic relevance.

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