Multifocal motor neuropathy. Serum IgM anti-GM1 ganglioside antibodies in most patients detected using covalent linkage of GM1 to ELISA plates

IgM anti-GM1 antibodies occur with increased frequency in the serum of patients with multifocal motor neuropathy (MMN). We tested the ability of serum IgM from patients with MMN to bind to GM1 ganglioside covalently bound to secondary amino groups on ELISA plates (Co-GM1). The Co-GM1 technique detected high titer (> 1,800), selective, serum IgM binding to GM1 ganglioside in 85% of our MMN patients (23/27), a significantly greater frequency compared with figures of 37% and 52% found using our previous testing methods. Selective IgM anti-GM1 antibodies showed disease specificity. The only other patients with selective, high-titer IgM anti-GM1 antibodies had either chronic motor neuropathy without conduction block or acute immune neuropathy in China. No patient from the amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré, or systemic immune disorder control groups had selective IgM anti-GM1 antibodies at titers greater than 1,800 detected using Co-GM1 ganglioside as ELISA antigen. Titers of IgM anti-GM1 antibodies in MMN (averaging 31,000 +/- 15,000) were more than fourfold higher with Co-GM1 than with previous anti-GM1 assay methods, using conventional ELISA plates with GM-1 antigen alone (7,200 +/- 4,400) or in a lipid environment (3,600 +/- 1,300). We conclude that using ELISA testing with Co-GM1 antigen, serum anti-GM1 autoantibodies are a useful marker for MMN, because they are present in 85% of MMN patients and, at titers greater than 1,800, have strong specificity for immune-mediated motor neuropathies.     

Motor nerve terminal degeneration provides a potential mechanism for rapid recovery in acute motor axonal neuropathy after Campylobacter infection

We investigated the possible mechanisms of paralysis and recovery in a patient with the acute motor axonal neuropathy (AMAN) pattern of the Guillain-Barré syndrome. The AMAN pattern of GBS is characterized clinically by acute paralysis without sensory involvement and electrodiagnostically by low compound motor action potential amplitudes, suggesting axonal damage, without evidence of demyelination. Many AMAN patients have serologic or culture evidence of recent Campylobacter jejuni infection. Pathologically, the most severe cases are characterized by wallerian-like degeneration of motor axons affecting the ventral roots as well as peripheral nerves, but some fatal cases have only minor changes in the roots and peripheral nerves, and some paralyzed patients with the characteristic electrodiagnostic findings of AMAN recover rapidly. The mechanism of paralysis and recovery in such cases has been uncertain. A 64-year-old woman with culture-proven Campylobacter upsaliensis diarrhea developed typical features of AMAN. She improved quickly following plasmapheresis. Her serum contained IgG anti-GM1 antibodies. The lipopolysaccharide of the organism bound peanut agglutinin. This binding was blocked by cholera toxin, suggesting that the organism contained the Gal(beta1-3)GalNAc epitope of GM1 in its lipopolysaccharide. Motor-point biopsy showed denervated neuromuscular junctions and reduced fiber numbers in intramuscular nerves. In contrast, the sural nerve biopsy was normal and skin biopsy showed normal dermal and epidermal innervation. In AMAN the paralysis may reflect degeneration of motor nerve terminals and intramuscular axons. In addition, the anti-GM1 antibodies, which can bind at nodes of Ranvier, might produce failure of conduction. These processes are potentially reversible and likely to underlie the capacity for rapid recovery that characterizes some cases of AMAN.     

Clinical factors relating to the presence of serum anti-GM1 and GD1b antibodies in demyelinating neuropathy--study using a multivariate analysis

We studied clinical factors relating to the presence of serum anti-GM1 and GD1b antibodies in patients with demyelinating neuropathy using a multivariate analysis. Sera were obtained from 46 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 33 with Guillain-Barré syndrome (GBS) and kept frozen at -20 degrees C until use. Anti-GM1 and GD1b IgM and IgG antibodies were measured by ELISA at serum dilution of 1:100 and considered to be positive when those values were more than the cut off values determined by means and standard deviations in 35 normal controls. Age, sex, duration, prodromal disease, neurological findings, concentration of CSF protein, nerve conduction, treatment, and outcome were investigated in all patients retrospectively. Multivariate logistic models using all those characteristics were used to clarify the clinical factors relating to the presence of anti-GM1 and GD1b antibodies. In CIDP, anti-GM1 antibodies associated with or without anti-GD1b antibodies were frequently seen in patients with motor dominant neuropathy than those with sensory dominant neuropathy (P = 0.007, odds ratio = 11.6). There was significant difference in anti-GM1 IgM antibodies (P = 0.003, odds ratio = 22.2), but no difference in IgG antibodies. Anti-GM1 antibodies were observed 5 (IgM, 5; IgG, 2) of 7 patients with pure motor neuropathy, 9 (IgM, 8; IgG, 4) of 17 with motor dominant neuropathy, 5 (IgM, 2; IgG, 3) of 16 with sensori-motor neuropathy, and none of 6 with sensory dominant neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mapping immunoreactive epitopes in the human peripheral nervous system using human monoclonal anti-GM1 ganglioside antibodies

A series of monoclonal IgM anti-GM1 ganglioside antibodies has been cloned from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain-Barré syndrome. In solid-phase immunoassay, the antibodies react with GMI, and also in differing degrees to the structurally related glycolipids asialo-GM1 (GA1) and GD1b. Here we describe the binding patterns of six human anti-GM I antibodies to epitopes within the human nervous system. Antibodies were observed to bind to motor neurons and spinal grey matter, dorsal and ventral spinal roots, dorsal root ganglion neurons, nodes of Ranvier, neuromuscular junctions and skeletal muscle. The distribution of immunoreactive epitopes, which included sensory structures, extended beyond those sites conventionally regarded as pathologically affected in anti-GM1 antibody-associated motor nerve syndromes. This undermines a model of disease pathogenesis based solely on antigen distribution. Factors other than the presence or absence of antigen, such as the local ganglioside topography, antibody penetration into, and pathophysiological vulnerability of a particular site may also influence the clinicopathological outcome of anti-GM1 antibody-mediated autoimmune attack.     

Anti-GM1 ganglioside antibodies cloned from autoimmune neuropathy patients show diverse binding patterns in the rodent nervous system

We have recently cloned a panel os monoclonal IgM anti-GM1 ganglioside antibodies from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain Barré syndrome. In solid-phase immunoassay, the antibodies all reacted with GM1 and also reacted to different degrees with the structurally related glycolipids asialo-GM1 and GD1b. These antibodies are being used to study the pathogenesis of the anti-GM1 antibody-medicated neuropathy in different experimental systems. In the present immunofluorescence study we report the binding patterns of 5 of these antibodies in the rodent nervous system. The antibodies demonstrated highly diverse binding patterns on tissue sections and teased fibers when compared to one another and between species. The antibodies bound many central and peripheral nervous system structures, including neurons and myelin, motor end plate regions, and muscle spindles. The diversity of binding shown by these antibodies provide evidence that may account for the differing clinical phenotypes, including normality, associated with elevated titers of anti-GM1 antibodies.     

Treatment of immune deficient neuropathies with intravenous polyvalent immunoglobulins. An open study of 16 cases

Between June 1989 and February 1992, in an open controlled study 16 patients with various types of polyneuropathy were treated with high-dose intravenous immunoglobulins (IgIV). Every month during 3 months, each patient received three courses of IgIV in doses of 0.4 g/kg/day during 5 successive days. The trial was discontinued in case of no response or if the neuropathy was considered as being in remission. In the other cases, at most one course of IgIV was given once a month if there was significant improvement (assessed by previously published clinical functional scales, electrophysiological examinations and titers of specific antibodies), or spaced at intervals which varied according to each patient, and sometimes in low doses. Results: 1) A first group of 6 patients had chronic demyelinating polyneuropathy with severe motor disability. The first infusions of IgIV resulted, in 4/6 cases, in a dramatic improvement which lasted under regularly spaced courses in lower doses. 2) Four patients had chronic neuropathy associated with monoclonal IgM gammopathy of undetermined significance (3 had anti-MAG and anti-SPG antibodies, and 1 had anti-GD1a and GD1b antibodies) and had not been improved by the usual immunosuppressive treatments. In 1 case the IgIV treatment had to be discontinued because of skin allergy. In the remaining 3 patients the clinical disorders (mainly the sensory ones) were reduced, but no significant improvement of neurophysiological or immunological data was observed. 3) Three patients had a purely multifocal motor neuropathy with persistent conduction blocks at EMG and high titers of anti-GM1 antibodies in 2/3 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral neuropathies associated with monoclonal proteins

Peripheral neuropathies associated with monoclonal proteins have received considerable attention as a clinically important group of chronic late-onset neuropathies. When a monoclonal protein is found in patients with peripheral neuropathy of unknown cause, as occurs in 10% of such cases, usually no associated disease is discovered; hence MGUS. Less often, disorders such as multiple myeloma, AL amyloidosis, Waldenstr?m's macroglobulinemia, osteosclerotic myeloma, and lymphoma are found. Demyelinating neuropathies associated with MGUS of all classes, but particularly IgM, Waldenstr?m's macroglobulinemia, and osteosclerotic myeloma typically follow an indolently progressive course, and frequently respond to treatments aimed at interfering with putative underlying immune mechanisms. By contrast, axonal neuropathies associated with MGUS, multiple myeloma, and AL amyloidosis have generally shown no response to therapy. Recently, IgM monoclonal and polyclonal antibodies directed against human peripheral nerve antigens including MAG and various glycolipids such as GM1 ganglioside have been found in patients with specific neuropathy syndromes. Anti-MAG antibodies occur in predominantly sensory demyelinating neuropathies, whereas elevated titers of anti-GM1 ganglioside antibodies are associated with lower motor neuron syndromes with multifocal motor conduction block. Although the evidence for autoimmune mechanisms in some monoclonal protein-associated neuropathies is mounting, a causal connection between monoclonal proteins and these neurologic syndromes has yet to be established.     

Hypertrophied cauda equina presenting as intradural mass: case report and review of literature

BACKGROUND: Hereditary motor and sensory neuropathy types I and III usually lead to enlargement of peripheral nerves. Rarely, spinal nerve roots may also be involved, leading to radiculopathy and/or myelopathy. METHODS: This 44-year-old man with back and lower extremity radicular pain and distal lower extremity weakness and numbness was found to have a nonenhancing intradural mass that caused a nearly complete myelographic block from L1-L4. He underwent a decompressive laminectomy with intradural exploration. RESULTS: Hypertrophic but otherwise normal-looking nerve roots were observed. Subsequent electrodiagnostic testing and sural nerve biopsy confirmed that this patient had a previously unsuspected hereditary motor and sensory neuropathy (HMSN). His pain resolved, but at latest follow-up his weakness and numbness persisted. CONCLUSIONS: Nonenhancing spinal intradural mass lesions may represent enlarged nerve roots, which have a number of potential etiologies. Electrodiagnostic studies and peripheral nerve biopsy are instrumental in establishing the diagnosis of HMSN.     

Acute and chronic neuropathies: new aspects of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, an overview and an update

During the last 15 years new information about clinical, electrophysiological, immunological and histopathological features of acute and chronic inflammatory neuropathies have emerged. Thus, the Guillain-Barré syndrome (GBS) is no longer considered a simple entity. Subtypes of the disorder besides the typical predominant motor manifestation, are recognized, i.e. a cranial nerve variant with ophthalmoplegia, ataxia and areflexia, an immune-mediated primary motor axonal neuropathy (AMAN), and a motor-sensory syndrome (AMSAN). Also, the clinical pattern of GBS is related to preceding viral or bacterial infections. Two types of acute motor paralysis have been described, one with slow and incomplete recovery, another with recovery times identical with acute inflammatory demyelinating polyneuropathy (AIDP). Histologically, the first is characterized by Wallerian degeneration of motor roots and peripheral motor nerve fibres. In the latter anti-GM antibodies bind to the nodes of Ranvier producing a failure of impulse transmission. Motor-point biopsies have shown denervated neuromuscular junctions and a reduced number of intramuscular nerve fibres. Molecular mimicry has been postulated as a possible mechanism triggering GBS. Thus, in the cranial variant antibodies to ganglioside GQ1b recognizes similar epitopes on Campylobacter jejuni strains and similar observations apply to anti-GM1 antibodies. Chronic inflammatory demyelinating polyneuropathy (CIDP) also has several different clinical presentations such as a pure motor syndrome, a sensory ataxic variant, a mononeuritis multiplex pattern, relapsing GBS, and a paraparetic subtype. Each of the acute and the subtypes have different, more or less distinct, electrophysiologic and pathological findings. Instructive patient stories are presented together with there electrophysiologic and biopsy findings.     

Peripheral motor and sensory nerve conduction studies in haemodialysis patients. A study of 54 patients

Peripheral motor and sensory nerve conduction velocities were studied prospectively in 54 chronic haemodialysis patients. The most sensitive parameters for the detection of polyneuropathy were the deep peroneal nerve motor conduction velocity, the sural nerve sensory conduction velocity and the H-reflex latency and H-index of the S1 roots. All patients examined were found to present at least one abnormal nerve conduction parameter. In the present study the side of the arteriovenous shunt had no statistically significant effect on the sensory and motor nerve conduction velocities in the upper extremities. There was a significant correlation between H-reflex latency and H-reflex index, and between H-reflex latency and sural nerve sensory conduction velocity.     

Granulomatous orchitis. A case report and review of the literature

We developed a method for determination of motor conduction along the mandibular and sensory conduction along the lingual and inferior alveolar nerves in 10 controls and 6 patients with lingual neuropathy following lower wisdom tooth extraction. Patients with lingual neuropathy had reduced/absent or delayed compound sensory action potentials and normal conduction along the fibers of the inferior alveolar nerve and mandibular nerve. The method provides a useful electrophysiological means of evaluating lingual nerve lesions.     

Subacute multifocal painful neuropathy with spontaneous remission

We present the cases of two patients with subacute onset of multifocal painful neuropathy with spontaneous remission and no relapse. The distribution of pain in patient 1 was hands (median > ulnar nerve region) and feet (peroneal and terminal tibial nerve regions), and in patient 2, hands (ulnar nerve region) and feet, left worse than in right. Both patients experienced facial numbness. Deep tendon reflexes were intact except for absent ankle jerks in patient 2. Motor nerve conduction studies demonstrated a marked prolongation of the distal motor latencies with normal proximal segment conduction velocities, suggesting distal demyelination. Cerebrospinal fluid protein concentration was elevated in patient 2, but no definite abnormality was found on sural nerve biopsy. A demyelinating neuropathy with a monophasic self-limited course may be consistent with Guillain-Barre syndrome (GBS). However, the multifocal painful sensory symptoms with facial numbness and the marked distal nerve conduction slowing in our cases are not consistent with GBS.     

Peripheral nervous system involvement in human and experimental chronic American trypanosomiasis

An electrophysiological and histological study of the muscle and the peripheral nervous system (PNS) was carried out in chronic human American trypanosomiasis (Chagas' disease) and in an experimental Chagas' disease (Chd) mouse model. Altogether 995 patients with chronic Chd and 261 mice, experimentally infected with RA and CA-I parasite strains, were investigated. Results were compared with matched controls. Techniques employed in humans were: clinical assessment, conventional electromyography (EMG), estimated number of motor units, motor and sensory nerve conduction velocities, repetitive nerve stimulation and muscle and sural nerve biopsies. In mice conventional EMG, sciatic nerve conduction time, sciatic nerve action potential amplitude, in vitro miniature end-plate potentials (MEPPs) and end-plate potentials (EPPs) recordings, muscle, nerve and spinal cord histology and identification of cell phenotypes within the inflammatory infiltrates were the employed procedures. Out of 511 patients submitted to clinical examination, 52 disclosed signs and symptoms of mixed peripheral neuropathy. By employing electrophysiological techniques, it could be shown that about 30% of the investigated patients had one or more of the following features: diminished interference pattern, most of the remainder motor unit potentials being (MUPs) polyphasic; reduced number of functional motor units in the thenar, hypothenar, soleus and/or edb muscles; slow sensory and motor nerve conduction velocities; low sensory action potential amplitude and impairement of neuromuscular transmission. In mice, MUPs duration and amplitude were increased at later stages of the infection, nerve conduction was slow, nerve action potentials were of low amplitude, mepps were of low amplitude and double epps were frequently found. Muscle histology in humans with chronic Chd showed type I and type II grouping, atrophic angular fibers and targetoid muscle fibers. In mice perivascular mononuclear cells infiltrates, small round fibers, muscle fibers necrosis, atrophic angular fibers, type II muscle fibers grouping and grouped muscle fibers atrophy were found. Sural nerve samples showed segmental and paranodal demyelination and axonal loss. The same features were observed in mice nerves, also in this model mononuclear cells infiltrates at the nerve, dorsal root ganglia and meninges surrounding the spinal cord were observed. Muscle and nervous tissues infiltrates were mainly composed of T lymphocytes with predominance of CD8 or CD4 subsets according to the parasites strain employed for infecting the animals. These findings suggest that the skeletal muscle and the PNS may be involved in chronic American trypanosomiasis.     

Subclinical thyroid disease in the elderly

The present study investigated the effect of NT-3, a neurotrophin expressed in nerve and skeletal muscle, on myelinated fiber disorders of galactose-fed rats. Adult, female Sprague-Dawley rats were fed diets containing complete micronutrient supplements and either 0% D-galactose (control) or 40% D-galactose. Treated controls received 20 mg/kg NT-3 and treated galactose-fed rats received 1, 5, or 20 mg/kg NT-3 three times per week by subcutaneous injections. After 2 months, sciatic and saphenous sensory nerve conduction velocity (SNCV) and sciatic motor nerve conduction velocity (MNCV) were measured and the sciatic, sural, peroneal and saphenous nerves and dorsal and ventral roots processed for light microscopy. Treatment of control animals with NT-3 had no effect on any functional or structural parameter. Compared to control values, galactose feeding induced a sensory and motor nerve conduction deficit and a reduction in axonal caliber. Treatment with 5 and 20 mg/kg NT-3 ameliorated deficits in sciatic and saphenous SNCV in galactose-fed rats but had no effect on the MNCV deficit. NT-3 treatment also attenuated the decrease in mean axonal caliber in the dorsal root and sural nerve but not in the saphenous nerve, ventral root and peroneal nerve. These observations show that NT-3 can selectively attenuate the sensory conduction deficit of galactose neuropathy in a dose-dependent manner that depends only in part on restoration of axonal caliber of large-fiber sensory neurons.     

Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice

Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.     

Quality assurance in palliative care: some of the problems

Twenty four patients with pure motor neuropathy are reported. The chronic motor involvement associated with fasciculations and cramps, mainly in the arms, led, in most patients, to an initial diagnosis of motor neuron disease. In some patients (nine of 24), there was no appreciable muscle atrophy. Tendon reflexes were often absent or weak. The finding of persistent multifocal conduction block confined to motor nerve fibres raises questions about the nature and the importance of this syndrome. Segmental reduction of motor conduction velocity occurred at the site of the block, but significant slowing of motor nerve conduction was not found outside this site. The response to intravenous IVIg treatment seems to be correlated with the absence of amyotrophy. Patients with little or no amyotrophy had an initial and sustained response to IVIg, and did not develop amyotrophy during the follow up study. They could be considered to have a variant of chronic inflammatory demyelinating polyneuropathy. Patients with pronounced amyotrophy independent of the disease duration did not respond as well to IVIg treatment, suggesting the existence of a distinct entity. Among the patients treated about two thirds who had an initial good response to IVIg had high or significant antiganglioside GM1 (anti-GM1) antibody titres, but there was no correlation between the high titres before treatment and long lasting response to IVIg treatment.     

Electrophysiologic findings in multifocal motor neuropathy

We performed detailed electrophysiologic studies on 16 patients with clinically defined multifocal motor neuropathy and found a wide spectrum of demyelinating features. Only five patients (31%) had conduction block in one or more nerves. However, in 15 patients (94%) at least one nerve showed other features of demyelination. We also noted a significant degree of superimposed axonal degeneration in 15 patients. Eight patients (50%) had individual nerves with pure axonal injury, despite the presence of demyelinating features in other nerves. Antiganglioside antibodies were elevated in four of five patients with conduction block and five of 11 patients without conduction block. We conclude that multifocal motor neuropathy is characterized electrophysiologically by a wide spectrum of axonal and demyelinating features. Diagnostic criteria requiring conduction block may lead to underdiagnosis of this potentially treatable neuropathy.     

Abnormal sensory nerve conduction in multifocal demyelinating neuropathy with persistent conduction block

Two patients exhibited chronic, slightly asymmetric weakness and wasting with fasciculations of the upper limb and hand muscles. Motor nerve conduction studies showed features of multifocal conduction block in nerve segments other than those usually involved in entrapment syndromes. The F wave was markedly delayed in the median and ulnar nerves. Transcranial cortical and cervical root magnetic stimulation showed bilaterally delayed thenar responses with normal central conduction time. Needle electromyography demonstrated a chronic denervation pattern with large polyphasic motor units in several muscles of the upper limbs. Sensory symptoms were mild and limited to paresthesias in the fingertips. Sensory nerve conduction velocity and sensory nerve action potential amplitudes were normal in elbow-to-wrist and wrist-to-finger segments of the median and ulnar nerves, but there was a delayed cortical response and unrecognizable Erb's point and cervical responses in the somatosensory evoked potentials to median nerve electrical stimulation. Electrophysiologic examination was normal in most nerves of the lower limbs. These two patients, meeting clinical and electrophysiologic criteria of multifocal neuropathy with conduction block, demonstrate that sensory fibers may also be involved in this syndrome.     

Lipoteichoic acid as a target for antimicrobial action

Fifteen patients with unilateral functioning arteriovenous fistula were assessed clinically and electromyographically to identify local neurologic changes. Ten of the patients were symptomatic (motor and/or sensory) and 5 were asymptomatic. Clinically, 11 patients had signs of a mild polyneuropathy, 2 patients of ulnar neuropathy, and 1 patient had signs of median neuropathy. A decrease of the above-elbow ulnar conduction velocity was noted in the study group on the side of the functional fistula, and in the symptomatic patients only on the side of the nonfunctional/nonexisting fistula. We suggest that ulnar nerve vulnerability should be taken into consideration during construction of the fistula, as well as during dialysis.     

Video-assisted thoracoscopic surgery for pneumothorax

A 28-year-old Japanese woman who suffered from mononeuritis multiplex was admitted to our hospital. Serological study revealed cryoglobulinemia (type III), hypocomplementemia, high titers of rheumatoid factor (RF), and positive antihepatitis C virus (HCV) antibody. Nerve conduction velocities were slower in sensory nerves than in motor nerves. Biopsied sural nerve showed a marked decrease of myelinated fibers but no evidence of angitis. She received plasma exchange and cryoglobulinpheresis over a period of 2 months with approximately 2.0 L (40 ml/kg) of plasma replaced in each procedure. Both plasma exchange and cryoglobulinpheresis alleviated clinical symptoms, and nerve conduction velocities were improved in several nerves. The serum cryoglobulin level was markedly reduced after the treatment together with the recovery of the C4 level. Thus, complements appeared to be consumed in large quantities in the presence of cryoglobulinemia in this patient. Efficacy of cryoglobulinpheresis indicates the possibility that cryoglobulins produced in association with HCV infection played a role in damaging the nerve directly through the activation of the complement system.