INVITED REVIEW

ABSTRACT: Evaluation of peripheral neuropathy is a common reason for referral to a neurologist. Recent advances in immunology have identied an inammatory component in many neuropathies and have led to treatment trials using agents that attenuate this response. This article reviews the clinical presentation and treatment of the most common subacute inammatory neuropathies, GuillainBarre syndrome (GBS) and Fisher syndrome, and describes the lack of response to corticosteroids and the efcacy of treatment with plasma exchange and intravenous immunoglobulin (IVIG). Chronic inammatory demyelinating polyneuropathy, although sharing some clinical, electrodiagnostic, and pathologic similarities to GBS, improves after treatment with plasma exchange and IVIG and numerous immunomodulatory agents. Controlled trials in multifocal motor neuropathy have shown benet after treatment with IVIG and cyclophosphamide. Also discussed is the treatment of less common inammatory neuropathies whose pathophysiology involves monoclonal proteins or antibodies directed against myelinassociated glycoprotein or sulfatide. Little treatment data exist to direct the clinician to proper management of rare inammatory neuropathies resulting from osteosclerotic myeloma; POEMS syndrome; vasculitis; Sjo grens syndrome; and neoplasia (paraneoplastic neuropathy).
Muscle Nerve 28: 273292, 2003

IMMUNOTHERAPY OF IDIOPATHIC INFLAMMATORY NEUROPATHIES

PETER D. DONOFRIO, MD Department of Neurology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1078, USA Accepted 26 March 2003

The inammatory neuropathies are a diverse group

of disorders in which inammation of the peripheral nerve is the primary pathologic substrate. Many of the inammatory neuropathies are autoimmune in nature, and the pathophysiologic process is directed either at the Schwann cell, myelin, or axon, or some combination of these structures. Other inammatory neuropathies are granulomatous in nature, such

Abbreviations: ACTH, adrenocorticotropic hormone; AIDP, acute inammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor sensory axonal neuropathy; CIDP, chronic inammatory demyelinating polyneuropathy; CMAP, compound muscle action potential; CNS, central nervous system; CSF, cerebrospinal uid; EMG, electromyogram; GALOP, gait ataxia and late-onset polyneuropathy; GBS, GuillainBarre syndrome; GCA, giant cell arteritis; HIV, human immunodeciency virus; IVIG, intravenous immunoglobulin; MADSAM, multifocal acquired demyelinating sensory and motor; MAG, myelin-associated glycoprotein; MGUS, monoclonal gammopathy of undetermined signicance; MMN, multifocal motor neuropathy; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; SIDP, subacute inammatory demyelinating polyneuropathy Key words: chronic inammatory demyelinating polyneuropathy; Fisher syndrome; Guillain-Barre syndrome; idiopathic neuropathy; immunotherapy; inammatory neuropathy; intravenous immunoglobulin; multifocal motor neuropathy; plasma exchange Correspondence to: P. D. Donofrio; donofrio@wfubmc.edu 2003 Wiley Periodicals, Inc.

as sarcoidosis, leprosy, and lymphomatoid granulomatosis. Infectious causes of inammatory neuropathies include leprosy, human immunodeciency virus (HIV) infection, Lyme disease, cytomegalovirus infection, and Chagas disease. The paraneoplastic and paraproteinemic-mediated neuropathies sometimes have inammation as their primary mechanism of nerve damage. This review focuses on the autoimmune or presumed autoimmune inammatory neuropathies (Table 1). Because of their high prevalence in a busy neuromuscular practice, emphasis is placed on the treatment of acute and chronic autoimmune inammatory neuropathies (Table 2).
SYNDROME GUILLAINBARRE

In 1916, Guillain, Barre , and Strohl described an illness characterized by rapidly ascending paralysis, hyporeexia or areexia, and dissociation between the albumin level and cells (cytoalbuminologic dissociation) in the cerebrospinal uid (CSF). For decades, GuillainBarre syndrome (GBS) was categorized as an acute demyelinating neuropathy, fortied by the identication by Asbury and col-

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Table 1. Classication of inammatory neuropathies. GuillainBarre syndrome Acute inammatory demyelinating polyneuropathy (AIDP) Acute motor axonal neuropathy (AMAN) Acute motor sensory axonal neuropathy (AMSAN) Fisher syndrome Subacute inammatory demyelinating polyneuropathy (SIDP) Chronic immune neuropathy Chronic inammatory demyelinating polyneuropathy (CIDP) Multifocal motor neuropathy (MMN) Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy Antimyelin-associated glycoprotein (MAG) neuropathy Anti-sulfatide neuropathy Anti-GM2 and GalNac-GD1a neuropathy Gait ataxia late-onset polyneuropathy (GALOP) syndrome CIDP with monoclonal gammopathy of undetermined signicance (MGUS) Osteosclerotic myeloma POEMS syndrome Vasculitic neuropathy Sjo grens syndrome Paraneoplastic sensory neuronopathy

leagues of demyelination and mononuclear inltration in the nerves and nerve roots of autopsy cases of GBS.2 Over the past decade, based upon the careful analysis of pathologic specimens and electrophysiologic data, several illnesses have been discovered that mimic the illness as originally described. These disorders primarily show axon loss rather than demyelination. They include acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN).3 GBS is now considered a constellation of conditions that present with rapidly ascending paralysis, reex abnormalities, and characteristic CSF changes. Under the rubric of GBS are included acute inammatory demyelinating polyneuropathy (AIDP), AMAN, AMSAN, and Fisher variant.3 AIDP is the most common presentation of GBS in western countries, whereas AMAN is common in Chinese children particularly during the summer.46 The clinical presentation of the illnesses that constitute GBS is often characteristic, but not all cases of GBS t into the classic description of a predominantly motor neuropathy that evolves over several days to weeks. Ropper and colleagues have proposed criteria for several types of GBS including typical GBS, a pure motor form, a pure sensory presentation, pure pandysautonomia, Fishers syndrome, and regional variants of GBS.114 The diagnostic criteria for typical GBS require: (1) weakness that is symmetric in all limbs, (2) paresthesias in the hands and feet, (3) hyporeexia or areexia in all

limbs by the end of the rst week, and (4) progression of the weakness, paresthesias, and reex abnormalities over several days to 1 month.114 In approximately 70% of patients with typical GBS, the illness is preceded, often by 12 weeks, by a febrile illness that is frequently mild in acuity. The paralysis may begin distally or proximally and is typically symmetrical in nature. Patients rapidly become paretic over days to weeks. Approximately 50% of patients have cranial nerve involvement, with bifacial weakness serving as the most common disability; 30% of patients develop diaphragmatic weakness from phrenic nerve involvement and require mechanical ventilation. Sensory symptoms and signs are frequent, but are not as severe as muscle weakness. Because of inammation in the posterior rami of the thoracic and lumbar roots, pain in the back or posterior thighs occurs in 40% of patients. Autonomic dysfunction can be documented in over half of patients with GBS, and may include hypotension, hypertension, cardiac arrhythmias, gastroparesis, constipation, and urinary retention. The mortality rate in GBS is approximately 1.5% and is more likely to arise from autonomic dysfunction than respiratory failure. Treatment of AIDP should begin with best medical management focusing on prevention of contractures and deep venous thrombosis, management of pain and autonomic dysfunction, airway protection, and mechanical ventilation. Corticosteroids, although prescribed widely in many inammatory and autoimmune disorders, are not effective in treating GBS. In 1991, Hughes reported results from using methylprednisolone to manage 242 adult patients with GBS.60 Half received placebo and the other half were treated with methylprednisolone (500 mg) for 5 days. No signicant difference was observed between the two groups with regard to the principal outcome measure, a change in disability grade after 4 weeks. In a recent report, Hughes and Van der Meche, culling data from the Cochrane Neuromuscular Disease Group register, compiled the results of six randomized trials that assessed the efcacy of corticosteroids or adrenocorticotropic hormone (ACTH) in the treatment of GBS.62 The authors analyzed data from 195 corticosteroid-treated patients and 187 control patients. The results demonstrated no benet of steroid therapy for any disability-related outcome. A surprising result was the development of hypertension in fewer patients in the steroid-treated group than the control group. In 1985, the GBS Study Group reported their results comparing plasma exchange to conventional

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Table 2. Treatment of inammatory neuropathies.* Disorder GBS Fisher syndrome SIDP CIDP Accepted pharmacological treatment Plasma exchange39,43,47,61,63,113,133 IVIG61,63,64,68,125,133 Plasma exchange92,141 IVIG1,142 Unproven Corticosteroids25,59,82 Plasma exchange20,27,31,50 IVIG20,31,49,59,84,134,136 Cyclophosphamide12,40 Azathioprine26,88 Cyclosporin-A7,79 Methotrexate117 Mycophenolate94 IVIG46,18,36,38,74,86,96,128,130,132,135 Cyclophosphamide5,6,37,86,109 Prednisone119 IVIG119 Plasma exchange11,43 IVIG32,43 Cyclophosphamide11,43,95 Unproven IVIG78 Plasma exchange110 IVIG110 Prednisone110 Cyclophosphamide110 Plasma exchange29,42,101 IVIG22,42,80 Prednisone42,98 Cyclophosphamide98 Interferon-alpha80 Chlorambucil101 Fludarabine138 Radiation therapy116 Prednisone melphalan24,103 Radiation therapy116 Prednisone melphalan24 IVIG dexamethasone53 Corticosteroids28,52,67,118 Cyclophosphamide52,67,90 Plasma exchange52 Plasma exchange19 IVIG89,105 Chemotherapy (Hodgkins)13,56,124 IVIG10,93 Cyclophosphamide93,99

MMN MADSAM neuropathy Anti-MAG neuropathy

Anti-sulfatide neuropathy Anti-GM2 and GalNACGD1a neuropathy GALOP syndrome

CIDP with MGUS

Osteosclerotic myeloma POEMS syndrome

Vasculitic neuropathy

Sjo grens syndrome Paraneoplastic sensory neuronopathy

*The listed therapies have shown benet in one or more patients with the corresponding disorder. Only those treatments indicated by a dagger () are supported by Class I evidence (one or more well-designed, randomized, controlled clinical trials). The listing of a treatment does not imply that it is FDA-approved for that disorder.

therapy in 245 patients with GBS.47 Statistically signicant differences were found between the two groups in the degree of improvement at 4 weeks, time to improve one clinical grade, time to indepen-

dent walking, and outcome at 6 months, all favoring the plasma exchange group. Plasma exchange was most effective in those patients who were treated within 7 days of disease onset and in those patients who required mechanical ventilation. There were no statistically signicant differences in the number of complications reported between the two groups. The French Cooperative Group published similar impressive results in 1987 in 220 patients.39 Statistically signicant improvement, favoring the plasma exchange group, was observed in the number of days to walk with assistance and the number of days to improvement. No difference was recorded between patients who received albumin or fresh frozen plasma as the replacement uid in the plasma exchange arm of the study. At 1 year follow-up, full recovery was observed in 71% of the patients who underwent plasma exchange compared to 52% who received best medical management. In a subsequent study, the French Cooperative Group on Plasma Exchange in GBS showed that plasma exchange is benecial in patients with mild disease (Hughes grade 2, able to walk unaided or walk but not run) and reported that two plasma exchanges are sufcient in mild cases of GBS, but four exchanges are preferable in patients with moderate (walking impossible) or severe disease (mechanically ventilated).34 Six plasma exchanges were no more benecial than four. The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology has strongly recommended plasma exchange as an established treatment for GBS based upon Class I evidence (one or more well-designed, randomized, controlled clinical trials).113 The optimum number of exchanges and volume of plasma removed has not been established in clinical trials. Many neurologists use the protocol advocated in the North American Trial where a total of 200 250 ml/kg were exchanged over 710 days.47 Van der Meche and colleagues described the rst controlled trial comparing intravenous immunoglobulin to plasma exchange in GBS.133 In the study, 73 patients were randomized to receive plasma exchange and 74 to infusions of intravenous immunoglobulin (IVIG). Patients received either ve plasma exchanges or ve infusions of intravenous immunoglobulin at a dosage of 0.4 gm/kg per day. Among patients treated with intravenous immunoglobulin, 53% improved by one grade at 4 weeks after treatment initiation compared to 34% of those who underwent plasma exchange (P 0.024). The median time to improvement of one grade was 27 days in the patients receiving immunoglobulin therapy compared to 41 days in the plasma exchange group (P

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0.05). Although a clear trend in producing more rapid improvement appeared to be present favoring the IVIG group, the main outcome measure did not achieve statistical signicance as measured by 95% condence intervals. The results of this study have been criticized because of the unusually large number of patients in the plasma exchange group who did not respond as well as those in the previous North American Study of plasma exchange in patients with GBS.47 A recent study of 383 patients with GBS showed that IVIG and plasma exchange were of equal efcacy.63 A third group that received plasma exchange followed by IVIG did not improve more than the groups that received plasma exchange or IVIG. At the present time, no solid evidence favors IVIG or plasma exchange as the best treatment for GBS.61 Many physicians prefer IVIG because of the simplicity of administering it. Only peripheral venous access is necessary compared to an indwelling central line for plasma exchange, and IVIG can be infused at any time and does not require special apparatus. Some data exist supporting a preferential response to IVIG therapy in patients with serum antibodies against specic gangliosides. Kuwabara and his group studied whether a difference in response to IVIG or plasma exchange exists in patients with IgG antibodies directed against the GM1 antigen.68 In a group of 24 patients with anti-GM1 antibodies, 10 of whom were treated with IVIG and 14 by plasma exchange, the IVIG group achieved signicantly lower Hughes grade scores at 1, 2, and 6 months after onset of GBS, a greater change in independent locomotion at 6 months, and a lessened chance for a delayed recovery. Summed scores of amplitudes of compound muscle action potentials (CMAPs) were higher at 6 months in the IVIG group. In a recently published search of the Cochrane Neuromuscular Disease Group, Hughes and colleagues attempted to determine the efcacy of IVIG compared to other treatments or no treatment in GBS, and whether plasma exchange followed by IVIG infusion was superior to plasma exchange alone.64 The authors combined the data from the two largest trials of IVIG compared to plasma exchange into a meta-analysis of 398 patients. They concluded that no adequate controlled studies existed to show that IVIG is better than supportive therapy (it would be unethical to conduct such a trial today) and that plasma exchange and IVIG are similar in their propensity to effect recovery. The combined use of plasma exchange followed by IVIG is no better than plasma exchange alone. The authors found no convincing data regarding the optimum

dose of IVIG to be prescribed for patients with GBS. They commented on the need for randomized trials to determine the need for IVIG in mild cases of GBS and in patients who had not been treated within the rst 2 weeks of disease presentation. A small uncontrolled study of 25 patients showed more rapid recovery in patients with GBS treated with a combination of IVIG (0.4 gm/kg per day) and high-dose methylprednisolone (500 mg per day) than a control group of patients culled from a previous publication that had been treated only with IVIG.125 The Plasma Exchange/Sandoglobulin Guillain Barre Syndrome Trial Group demonstrated that the incidence of relapse after initial treatment was similar for the groups receiving IVIG and plasma exchange.63 This discovery claried previously held misperceptions that a larger percentage of patients with GBS relapsed after the rst course of IVIG than plasma exchange. Unclear is the efcacy of plasma exchange or intravenous immunoglobulin treatment in the 10% of patients with GBS who relapse after the rst course of IVIG. Relapses tend to occur in patients treated early in the illness. Many neurologists recommend re-treatment with the same therapy for those patients who relapse.3 They prescribe either IVIG at one half of the total dosage infused initially or two plasma exchanges. Switching from IVIG to plasma exchange or plasma exchange to IVIG is not supported by the neurologic literature. Wollinsky and his group recently published their data from a prospective controlled trial of CSF ltration compared to plasma exchange in 37 patients with GBS.140 The primary outcome variable, improvement at 28 days after randomization, was almost identical for the two groups of patients. Utilizing the 6-point grading scale of the GBS Study Group, the mean grade improvement was 0.82 in the CSF ltration group and 0.80 in the plasma exchange group (P 0.0014, test for equivalence). At 6 months, the probability to reach grade 2 was approximately 80% in both groups. Relapses or lack of improvement were observed in 9 patients in the CSF ltration group and 10 patients in the plasma exchange group within the rst 28 days of treatment. The authors had originally intended to recruit 40 patients into the study, but the protocol was terminated before the full number could be achieved because of difculty in recruiting patients.
Acute Motor Axonal Neuropathy.

Acute motor axonal neuropathy (AMAN) was rst described in the early 1990s by a group of neurologists from the United States and China who studied patients from

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China who had clinical features of GBS.46 The Chinese cohort differed from most cases of AIDP in that most of the patients were children or young adults, and most cases occurred during the summer. When studied electrophysiologically, the results were more in keeping with a motor axon-loss process than multifocal acquired demyelination. Of the cases, 80% were associated with a recent Campylobacter infection and approximately one-half were found to have antibodies directed against GM1/GD1a gangliosides. Similar to AIDP was the attainment of peak disability within 7 weeks of disease onset and rapid recovery. It is estimated that approximately 65% of patients with GBS in China have AMAN. The disease is also common in Latin America. The electrophysiologic features of AMAN differentiate this illness from the more common AIDP and consist of reduced CMAPs, relatively preserved motor conduction velocities, normal or slightly prolonged distal motor and F-wave latencies, absence or paucity of temporal dispersion, and normal sensory studies. Sural nerve biopsy specimens in patients with AMAN have been normal or minimally affected, implying that the disease only affects motor axons. Initially, investigators tried to explain the pathophysiology of AMAN using a model of axon loss and Wallerian degeneration. In keeping with this concept, any recovery would have to occur through axon regeneration. Studying the clinical pattern of recovery of patients with AMAN and those with AIDP, Ho et al. found that the time to regain the ability to walk 5 meters with assistance was the same in both groups.54 This rapid improvement is inconsistent with the model of axon loss and Wallerian degeneration of motor roots and peripheral nerve. The authors proposed that a better hypothesis would be reversible immune-mediated changes at the nodes of Ranvier of motor bers, degeneration and regeneration of intramuscular motor nerve terminals, or both mechanisms. Therapy for this disorder is the same as for GBS. Early on in the illness, it is not possible to differentiate AMAN reliably from other types of AIDP. Approximately 15 years ago, Feasby and colleagues from Canada reported patients with fulminant GBS who experienced slow and usually incomplete recovery.35 Electrodiagnostic ndings suggested severe motor and sensory axon loss. Autopsy cases conrmed the presence of prominent axon degeneration without segmental demyelination. Little inammation was observed on pathologic study of the nerve. This disease has been labeled acute motor sensory axonal
Acute Motor Sensory Axonal Neuropathy.

neuropathy (AMSAN). In the rst few weeks of the illness, distinguishing AMAN and AMSAN from AIDP using clinical and electrophysiologic criteria can be difcult, as the expected electrophysiologic features of AIDP, i.e., slowing of conduction, prolongation of distal motor and F-wave latencies, and temporal dispersion, may not yet have evolved. Many neurologists consider AMSAN to be a more severe and extensive form of AMAN with the addition of sensory involvement. Recovery is typically slow and incomplete. Treatment of this disorder is the same as for GBS. Miller Fisher in 1956 described a syndrome of acute onset characterized by ophthalmoplegia, areexia, and ataxia. Because of similarities to GBS, it is often classied with the acute inammatory neuropathies. Patients have cytoalbuminologic dissociation and nerve conduction abnormalities, although the latter tend to affect primarily sensory bers. Motor conduction velocities are minimally slowed. Recently, Mori and colleagues proposed expanding the clinical triad to include pupillary abnormalities, blepharoptosis, and facial palsy.91 The observation of high signal abnormalities on MRI in the brainstem of patients with Fisher syndrome has clouded our understanding of the principal area of pathology in this condition.3 All of the clinical ndings, including ataxia and areexia, can be explained either by a peripheral nerve or neuronal process or by encephalitis of the brainstem. The latter would be in keeping with the hypothesis of Bickerstaff and Cloake, who described 3 patients with ophthalmoplegia in 1951.9,139 The authors attributed the clinical features of the disease to cerebral edema arising from a viral infection or hypersensitivity of the midbrain (Bickerstaffs encephalitis).9,139 Further confusion has arisen over the identication of anti-GQ1b antibodies in approximately 95% of patients with Fisher syndrome.3 The antigen for GQ1b has been identied in sensory, oculomotor, and cerebellar neurons as well as in the organism, Campylobacter jejuni. Anti-GQ1b antibodies have also been found in patients with Bickerstaffs encephalitis. For this reason, the presentation of Fisher syndrome can best be understood as a disease that can affect either the central or peripheral nervous system and can give rise to similar if not identical clinical ndings. Fortunately, Fisher syndrome is usually a relatively benign illness and resolves without treatment. Both plasma exchange and IVIG have been used with success, but no controlled trials exist of either therapy in Fisher syndrome.1,141,142 Recently, PfauFisher Syndrome.

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sler and colleagues reported improvement using CSF pheresis in a 47-year-old man who had previously not responded to IVIG or plasma exchange.111 In a retrospective review of 50 consecutive patients with Miller Fisher syndrome, Mori and his group reported a good recovery, free of residual decits, in all of their patients 6 months after disease onset.91 In another study, treatment with immunotherapy did not improve chances for a good recovery. In particular, the 22 patients who were treated with a course of plasmapheresis (every other day, two to six treatments) did not improve more quickly than the control group with regard to resolution of ataxia or ophthalmoplegia.92
SUBACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Approximately 90% of patients with GBS reach their nadir of weakness within 4 weeks of disease onset. Patients who were thought to have GBS but progressed beyond 4 weeks were often categorized as early cases of chronic inammatory demyelinating polyneuropathy. Hughes and colleagues have coined the term subacute inammatory demyelinating polyneuropathy (SIDP) for those patients whose illness progresses beyond 4 weeks but arrests within 8 weeks.58 Treatment of this disorder is the same as for AIDP.
CHRONIC IMMUNE NEUROPATHY

This broad group of neuropathies includes idiopathic chronic inammatory demyelinating polyneuropathy (CIDP), chronic neuropathies associated with connective tissue disorders and chronic infections, CIDP associated with paraproteinemias, multifocal motor neuropathy, multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome), and the chronic ataxic neuropathies with predominantly sensory demyelination (anti-MAG syndrome, anti-GM2 and GalNacGD1a neuropathy, anti-sulfatide neuropathy, and GALOP syndrome).
Chronic Inammatory Demyelinating Polyneuropathy.

In many patients, CIDP resembles a slowly progressive form of GBS. Examination reveals both proximal and distal weakness which is relatively symmetric, hypo- or areexia, and distal sensory loss of vibration and joint position perception more than small-ber functions.8 The degree of sensory loss is usually greater than in most patients with GBS. Facial weakness is less common than in GBS. Very few patients progress to respiratory failure. In addition

to the chronic progressive form, CIDP may also present as a monophasic, relapsing and remitting, or step-wise progressive disorder. Dyck and colleagues have proposed diagnostic criteria for CIDP and diagnostic categories for denite, probable, and possible disease.30 Mandatory are features of progressive weakness for 2 months or longer, symmetric proximal and distal weakness in the upper and lower extremities, and hyporeexia or areexia. As in GBS, CSF analysis shows cytoalbuminologic dissociation. Few patients can remember an upper respiratory tract or gastrointestinal infection immediately before the onset of symptoms. Electrodiagnostic testing usually reveals slowed motor conduction velocities, prolonged distal motor and F-wave latencies, partial conduction block or abnormal temporal dispersion, and sensory abnormalities. CIDP responds to a greater array of treatments than GBS (Table 2). Patients have beneted after treatment with corticosteroids, plasma exchange, IVIG, and various other immunosuppressants. In a recently conducted Cochrane Database System Review of corticosteroid use in CIDP, Mehndiratta and Hughes identied only one controlled trial in which specic primary and secondary outcome measures, nerve conduction study parameters, and side effects were published.82 In this study, Dyck and colleagues reported that prednisone treatment, beginning at a daily dosage of 120 mg and slowly tapered over 13 weeks, led to a small but statistically signicant improvement in patients with CIDP compared to those receiving no drug treatment.25 Patients began to improve after 2 weeks and had a maximum response after 6 months.25 Dyck et al. also reported improvement in a small group of patients with CIDP who underwent twice weekly plasma exchange for 3 weeks.27 Hahn and colleagues demonstrated similar improvement in patients with progressive or relapsing forms of CIDP in a double-blind, sham-controlled, cross-over study of plasma exchange compared to sham plasma exchange.50 The rst large report of the use of IVIG in CIDP was published by van Doorn and colleagues in 1991. They treated 52 patients meeting a strict criterion for CIDP,134 and 17% achieved complete remission after receiving IVIG; 40% required continued intermittent treatment with IVIG in order to maintain improvement. Another 38% did not improve after IVIG infusion, and 4% experienced only brief improvements. Patients with a disease duration of less than 1 year, progression of weakness prior to treatment, areexia, and slowed median nerve conduction velocity were most likely to improve. Hahn and col-

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leagues49 randomized 30 patients with CIDP to receive either IVIG or placebo on 5 consecutive days in a double-blind cross-over trial. Statistically signicant differences favoring IVIG were noted in the neurologic disability score, clinical grade, and grip strength. Scores in the placebo group either worsened or were unchanged. In 10 patients with relapsing CIDP who responded to IVIG, the median duration of improvement was 6 weeks (range, 322 weeks). Improvement was not observed in patients with predominantly sensory symptoms or signs. Recently, Mendell and his group reported improvement by day 10 in a controlled study of IVIG compared to placebo in previously untreated patients with CIDP.84 Among patients receiving IVIG, 76% improved; one third of responders improved by a full functional grade. Patients continued to improve through day 42.84 The efcacy of plasma exchange has been compared to IVIG in a small group of patients with progressive or static CIDP.31 Both treatments led to statistically signicant improvement in the neurologic disability score, the weakness subset score, and summated CMAPs compared to pretreatment scores. Statistically signicant differences between the two therapies were not found in any end-point. The benet was large but brief, thus necessitating repeated treatments for sustained improvement. In another study of a small number of patients, a randomized, double-blind, crossover design was used to compare oral prednisolone to IVIG in a 6-week study.59 Subjects were prescribed either a tapering dose of prednisolone beginning with 60 mg daily or IVIG 2.0 g/kg given over 1 or 2 days. Both treatments led to signicant improvements in the primary outcome measure, a change in an 11-point disability scale 2 weeks after randomization. No signicant differences between the two groups occurred with regard to primary or secondary measures. In a retrospective review of the change in clinical status of 105 patients with CIDP who were treated with plasma exchange or IVIG,20 improvement occurred in 70% of the patients receiving plasma exchange and 64% of those treated with IVIG. Most patients needed only one course of treatment. Good responders tended to be young patients, women, and those with a short duration of disease. Van Schaik and colleagues reviewed the use of IVIG treatment for patients with CIDP by searching the Cochrane Neuromuscular Disease Review Group for randomized controlled trials.136 They found six controlled trials which included a total of 170 patients. Their results led to the conclusion that IVIG improves disability for at least 2 to 6 weeks compared

to placebo and has similar efcacy to plasma exchange and oral prednisolone. The authors were unable to determine which of the three therapies should be rst choice in the management of patients with CIDP. Many authors have described the efcacy of other immunosuppressant agents in patients with CIDP, usually in single case reports or in publications of small uncontrolled series. Treatments prescribed include azathioprine, cyclosporine, methotrexate, cyclophosphamide, and pulse methylprednisolone.117 Mitchell and colleagues reported substantial improvement in two patients with CIDP and hereditary motor and sensory neuropathy (HMSN) type I who were treated with prednisone and azathioprine.88 Neither had been treated with a single immunosuppressant agent before combination therapy was prescribed. Other authors have reported a positive response to azathioprine alone in single case reports or retrospective studies. In a small controlled study of prednisone alone compared to prednisone plus azathioprine, Dyck et al. identied no signicant differences between the two treatment groups when followed for 9 months.26 Monthly pulse cyclophosphamide has shown benet in 11 of 15 patients with CIDP.40 All patients had previously experienced a suboptimal response to various combinations of IVIG, plasma exchange, and prednisone. High-dose cyclophosphamide (200 mg/kg divided over 4 days) without stem-cell rescue has been used successfully by Brannagan and his group to improve strength and function is four patients with CIDP.12 Patients had responded only partially to previous treatments with immunotherapy including prednisone, IVIG, plasma exchange, azathioprine, oral and intravenous cyclophosphamide, and udarabine. Mahattanakul and colleagues described their experience using cyclosporine (35 mg/kg daily) in eight patients with CIDP,79 who had failed to respond or were responding no longer to other treatments. Three patients improved on cyclosporine and were able to withdraw from prednisone. In a retrospective study of 19 patients with resistant CIDP who had failed treatment with corticosteroids, plasma exchange, IVIG, and other immunosuppressant agents, Barnett et al. observed a statistically signicant reduction in mean disability scores in patients with progressive and relapsing-remitting CIDP treated with cyclosporine.7 Most recently, two patients with CIDP have been reported who responded to treatment with mycophenolate.94 One had previously required IVIG for 5 days every 3 months, and the other had failed treatment with prednisone and IVIG.

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Two separate reports describe the benets of interferon-alpha 2a in a single patient with CIDP who had been refractory to other therapies.85,126 One controlled study has been conducted in CIDP using interferon.48 Hadden et al. performed a double-blind, cross-over study of interferon beta-1a in 10 patients with CIDP who were resistant to previous treatments.48 Improvement occurred in one patient during interferon treatment and in two patients receiving placebo. No signicant difference was recorded between the two groups in any of the individual clinical or electrophysiologic measures. Rosenberg and colleagues reported their results using total lymphoid irradiation (total dose, 2000 rads) to treat four patients with CIDP who were refractory to previous conventional and unconventional treatments.115 Three patients noted improved strength in distal muscles, and two experienced improvement in function. None reported a change in sensory function. Side effects were those expected following radiation therapy and included fatigue, anorexia, nausea, dysphagia, xerostomia, herpes zoster, and neutropenia. Vermeulen and Van Oers described the remarkable improvement of a patient with CIDP after undergoing an autologous stem-cell transplant.137 The patient had had CIDP for 10 years and required at least 20 mg of prednisone daily and addition infusions of IVIG to maintain disease stability. The patient had previously failed to respond to azathioprine and methotrexate. Two years after stem-cell transplantation, he no longer required IVIG infusions and needed only 5 mg of prednisone daily to remain in remission. Figure 1 depicts a treatment algorithm for managing CIDP based upon the authors experience and literature review. Occasionally, patients with longstanding diabetes develop an illness that more resembles CIDP than a typical distal symmetric polyneuropathy. This presentation raises the question of CIDP in a diabetic patient or a more advanced and rapidly progressive form of diabetic polyneuropathy. Sharma and colleagues recently published their experience in an open-label pilot study treating 26 patients with neuropathy and type II diabetes with IVIG.120 The neuropathy met the electrophysiologic criteria for CIDP, and more than 80% of the patients achieved clinically signicant improvement after IVIG infusion.120 Three of the patients experienced reversible renal dysfunction as a complication of the IVIG treatment. Multifocal motor neuropathy (MMN) is an acquired inammatory demyMultifocal Motor Neuropathy.

FIGURE 1. Treatment algorithm for chronic inammatory demyelinating polyneuropathy. Those patients in whom prednisone is medically contraindicated should receive IVIG as initial therapy.

elinating neuropathy with unusual and distinctive clinical features. Patients commonly present with chronic weakness, usually more marked in the upper than lower extremities. The weakness is asymmetric and predominantly distal. Patients commonly manifest a wrist drop, grip weakness, or foot drop. Fasciculations are common and their presence often raises the suspicion of motor neuron disease. Sensory symptoms and signs are absent. Reexes are usually absent or reduced in the upper extremities and may be normal in the lower extremities. Even though the clinical examination may suggest MMN, the diagnosis is usually made in the EMG laboratory. Motor nerve conduction studies of upper-extremity nerves show well localized, partial conduction block in the forearm or arm segments. Sensory conduction studies are normal despite the motor conduction blocks. High titers of IgM antibodies directed against the ganglioside GM1 have been detected in 50 80% of patients with MMN.107 Because of its rarity, large controlled studies of therapies in MMN do not exist. At present, IVIG and intravenous cyclophosphamide are considered the treatments of choice.135 Various authors have shown the lack of response to high-dose dexamethasone.129 Feldman and colleagues reported their results using

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various immunosuppressive treatments in 13 patients with MMN.37 Oral prednisone was ineffective in all patients. None of the four patients treated with plasma exchange responded. Eight of nine patients who received intravenous cyclophosphamide improved clinically, corresponding to a fall in GM1 antibody titer. Three of the eight patients worsened when the intravenous cyclophosphamide was discontinued. Nobile-Orazio and colleagues described the rst use of high-dose IVIG in MMN,96 reporting improvement in four of ve consecutive patients. Patients received 0.4 g/kg of IVIG for 5 consecutive days at 2-month intervals. All patients with high titers of anti-GM1 antibodies improved clinically, often as early as 3 days after the rst IVIG infusion. Similar improvement was experienced after the second course of IVIG. No clinical or electrophysiologic change was observed in patients without anti-GM1 antibodies. Chaudhry et al. reported similar results in an open, uncontrolled trial of nine patients.18 Improvement was noted to peak at 2 weeks, and the average duration of benet was 2 months. Electrophysiologic testing showed partial resolution of the conduction block in seven of eight patients. Serum anti-GM1 antibody titers did not change despite clinical and electrophysiologic improvement. In the rst controlled trial, Van den Berg et al. demonstrated improvement in ve of six patients treated with IVIG in a single patient, double-blind, placebo-controlled study.128 All six patients had previously beneted from treatment with IVIG in a dosage of 0.4 g/kg for 5 days. In a larger double-blind, placebo-controlled, cross-over trial, IVIG treatment led to improvement in muscle strength only in patients with conduction blocks identied by nerve conduction studies.4 Meucci et al. studied the longterm effect of combined treatment with high-dose IVIG and oral cyclophosphamide in six patients with MMN.86 All patients initially responded to IVIG, 0.4 g/kg daily for 5 consecutive days. The same patients were subsequently treated at the time of clinical worsening with IVIG for 2 days and oral cyclophosphamide (13 mg/kg daily). All six patients required periodic infusions of IVIG in order to maintain improvement. After 3 to 7 months of oral cyclophosphamide therapy, the interval between IVIG infusions could be lengthened progressively. In three patients, IVIG infusions could be stopped for up to 2 years before clinical worsening ensued. Azulay et al. followed 18 patients with MMN for 9 48 months to determine the response to initial IVIG infusion and the need for re-infusion.5 Median time between onset of the disease and treatment was

almost 6 years. The dose of IVIG was 0.4 g/kg daily for 35 days. Clinical improvement after IVIG infusion was noted in 12 patients (67%). Particularly impressive was the change in isometric strength. There were no clear predictive factors for response to IVIG other than the presence of high titers of anti-GM1 antibodies. The average duration of effect of IVIG was 53 days. Most patients required repeated courses of IVIG to sustain improvement. Two patients were able to tolerate discontinuation of the IVIG infusion without relapsing. Only one of ve patients who did not respond to IVIG infusions improved after a change of therapy to cyclophosphamide. In 2000, Federico and his colleagues reported their results after treating 16 patients with MMN using a randomized, cross-over design under doubleblind conditions. Subjects received either IVIG at a dosage of 0.4 g/kg daily for 5 days or placebo, and were subsequently crossed over to the other treatment.36 They were assessed after 28 days using subjective scores, objective strength testing, and changes in CMAP amplitude and conduction block. Nine patients described their improvement after IVIG as dramatic or very good. Five patients experienced no change in strength. Statistically signicant improvement in neurologic disability score, grip strength, and conduction block occurred after IVIG. In another double-blind, placebo-controlled study including naive and previously treated patients, 12 of 18 patients completing the trial improved after receiving IVIG.74 Several patients did not respond until 7 months after initiation of the IVIG therapy. Of interest, two patients reported improvement after receiving placebo and four patients did not experience improvement after treatment with placebo or IVIG. Felice and Goldstein recently described improvement in three patients who were treated with IVIG for monofocal motor neuropathy, a variation of MMN producing weakness and partial conduction block restricted to a single nerve.38 Little is known about the long-term benet of treatment with immunotherapeutic agents in MMN. Van den Berg-Vos et al. reported a 4 8-year follow-up study of 11 patients who were initially treated with IVIG 0.4 g/kg for 5 days, then 0.4 g/kg every week, followed by a taper in the interval frequency and dosage.132 During the follow-up period, muscle strength was better at the time of the last examination compared to pretreatment measurements, yet overall strength decreased steadily despite regular infusions of IVIG. Electrophysiologically, conduction block disappeared in 6 nerve segments and new conduction blocks appeared in 8 segments.

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Van den Berg-Vos and colleagues also studied the response rate of patients with MMN to IVIG using clinical and laboratory features and an arbitrary criterion for denite and probable conduction block and other features of demyelination.130 Patients with denite MMN were more likely to improve after IVIG infusion (17 of 21 patients) than those with probable MMN (5 of 7 responders) or possible MMN (1 of 9 responders). The same authors described the effect of interferon-beta 1A in nine patients with MMN who had previously shown favorable responses to IVIG.131 Only three patients improved after interferon treatment, yet their amelioration was greater than that achieved during prior IVIG treatment. Four of the six patients who deteriorated after receiving the course of interferon-beta 1A required reinstitution of IVIG.131 In a recently conducted Cochrane Database Search, the authors did not nd any randomized controlled or quasi-randomized trials of immunomodulatory agents for the treatment of MMN.127 On occasion, patients with an illness that mimics MMN clinically and who have IgM anti-GM1 antibodies do not have conduction block on motor nerve conduction studies. Pestronk et al. described four such patients who had high serum titers of IgM anti-GM1 antibodies.109 All patients were treated with 57 monthly regimens of plasma exchange followed on the third day by intravenous cyclophosphamide (1 g/m2). They improved in strength over the subsequent 6 24 months and the improvement was maintained for 1 to 2 years. Azulay and colleagues described a larger study (22 patients) of similar clinical presentation, i.e., patients with ndings consistent with adult-onset lower motor neuron disease.6 All patients had either anti-GM1 antibodies or monoclonal proteins. Twelve patients were tested for, but did not have, the surviving motor neuron (SMN) gene deletion. None had motor conduction block on nerve conduction studies. Five of the 16 patients treated with IVIG improved, but in 2 the improvement was transient and lasted less than 6 months. Three of 6 patients improved after treatment with intravenous cyclophosphamide.
Multifocal Acquired Demyelinating Sensory and Motor Neuropathy. A neuropathy which has many similar

tor nerves in the pattern of a mononeuropathy multiplex. A few patients have central involvement either clinically (optic neuritis) or by laboratory testing (somatosensory and visual evoked potentials).106 Magnetic resonance imaging has identied focal swelling of the nerve at sites of conduction block.65 The presence of sensory symptoms and signs, neuropathic pain, a painful Tinels sign at the sites of conduction block, and sensory nerve conduction abnormalities separate this illness from MMN.75 Sural nerve biopsies in patients with MADSAM neuropathy show variable degrees of subperineurial and endoneurial edema, a decrease of myelinated and unmyelinated bers, and thin myelin sheaths, the latter a feature of remyelination.104 Saperstein and colleagues reported the clinical, laboratory, and histologic characteristics of 11 patients with MADSAM neuropathy.119 Anti-GM1 antibodies were not detected. The CSF protein was elevated in 82% of patients, a nding rarely present in MMN. Patients tended to respond to treatments similar to those used in CIDP; three of six patients improved after treatment with prednisone.119 The response rate to IVIG was described as similar. It is unclear whether Lewis-Sumner syndrome is a separate entity or represents a variant of CIDP. Myelin-associated glycoprotein (MAG) is a structural protein found in noncompact myelin.72,73 Anti-MAG neuropathy is typically observed in patients above the age of 65 who present with a predominantly sensory distal symmetric polyneuropathy, a prominent gait disorder, frequent falls, and a tremor. Joint position sense is often impaired at the toes. Motor abnormalities are minimal. The condition is slowly progressive. The diagnosis is often not suspected until the results of the nerve conduction studies are reviewed. Distal latencies are markedly prolonged and are disproportionately delayed compared to the lesser slowing recorded proximally. Conduction blocks are not seen. Needle examination shows secondary axon loss. A monoclonal protein is detected in approximately 85% of patients with anti-MAG neuropathy and often the antibody is detected in high levels (1:10,000). The anti-MAG antibody is of the IgM type and is directed against myelin-associated glycoprotein. No controlled trials of treatment exist for antiMAG neuropathy. Ellie et al. reported their experience with patients having anti-MAG antibodies and peripheral neuropathy.32 Most patients were men. The average age at onset was 67 years. A sensory presentation was most common. Nerve conduction
Anti-MAG Neuropathy.

symptoms and signs to MMN is multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome, a disorder rst described in ve patients in 1982.76 Patients typically show evidence for multifocal demyelination, manifested by conduction block in upper-extremity mo-

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ndings consistent with demyelination were detected in 90% of patients and electron microscopy of nerve showed widening of the myelin lamellae in more than 95% of cases. Most patients did not respond to treatment with steroids or chemotherapy and less than 25% improved after treatment with IVIG. In 1988, Nobile-Orazio et al. reported their experience in treating ve patients with cytotoxic agents for 10 20 months. Two patients showed improvement in the neuropathy coinciding with a drop in the anti-MAG IgM levels.95 The remaining three patients did not improve, and a decrease of the IgM titer was not observed. In a much larger study, Nobile-Orazio and colleagues described the long-term prognosis of 25 patients with anti-MAG monoclonal protein and neuropathy.97 After a mean follow-up of 8.5 years, 68% were alive. Only 5 of 25 patients reported consistent improvement after immunotherapy. At the end of the follow-up period, half of the patients were disabled by tremor or gait ataxia. The neuropathy was not the cause of death in any patient. Adverse effects were common and contributed to the cause of death in three patients. Gorson and associates reviewed their treatment experience using plasma exchange, IVIG, and cyclophosphamide in 24 patients with neuropathy and anti-MAG antibodies.43 The response rates respectively to each therapy were: plasma exchange, 40%; IVIG, 16%; and cyclophosphamide, 36%. None of the treatments were considered superior to the other. Only one third of the patients experienced a sustained response and most relapsed after a median period of 7 months. Blume et al. observed improvement in strength and sensation in all four of their patients who were treated with a combination of plasma exchange and cyclophosphamide.11 The regimen consisted of two consecutive days of plasma exchange followed by intravenous cyclophosphamide at a dose of 1 g/m2. Patients were treated for 57 months. Improvement persisted in some patients for up to 2 years. This relatively rare neuropathy is similar to anti-MAG neuropathy except for the absence of tremor and gait disorder. Approximately 30% of patients with anti-sulfatide antibodies will also have a monoclonal gammopathy, usually of the IgM type. Dabby and colleagues studied 25 patients with anti-sulfatide antibodies, using clinical, electrophysiologic, pathologic, and laboratory data to classify them into four groups.21 Eight patients (32%) had a predominantly small-ber sensory neuropathy, ve (20%) a mixed large- and small-ber sensory neuropathy, seven (28%) an axonal sensory
Anti-Sulfatide Neuropathy.

and motor neuropathy, and three (12%) a demyelinating motor and sensory neuropathy. Of the two remaining patients, one had a mononeuritis multiplex and the other had amyotrophic lateral sclerosis. Their results supported the distinctions reported by Pestronk and colleagues between patients with antisulfatide and anti-MAG antibodies.108 Neither group commented on the types of therapies used and the clinical response in patients with anti-sultide antibodies.21 Carpo et al. found elevated titers of anti-sulfatide antibodies in 115 patients with a variety of neurologic disorders and correlated the titers of those patients who had neuropathies with their electrophysiologic features.14 Patients with high titers of anti-sulfatide antibodies (1:8,000) were more likely to have a demyelinating neuropathy with secondary axon loss. Titers of 1:8,000 or less did not correlate with the type of neuropathy, and lower titers could be seen in unrelated neurologic disorders without peripheral neuropathy. Other authors have reported similar ndings, i.e., that patients with high titers of anti-sulfatide antibodies (4,500) and monoclonal proteins (typically IgM) have a predominantly motor demyelinating polyneuropathy without pain or dysesthesias.33 Conversely, patients with anti-sulfatide antibodies and no monoclonal antibodies typically have painful sensory neuropathies without motor involvement and with electrophysiologic features of axon loss.77 Treatments tried for patients with antisulfatide neuropathy include intravenous immunoglobulin, plasma exchange, and cyclophosphamide. GALOP is an acronym for gait ataxia and lateonset polyneuropathy.110 GALOP syndrome presents in patients above the age of 50 who have a predominantly sensory neuropathy, tremor, prominent gait disorder, and frequent falls. Electrophysiologic studies show prolonged distal motor and sensory latencies and slowed conduction velocities, but no features to suggest multifocal segmental demyelination. Almost all patients have an IgM antibody directed against a CNS myelin antigen that co-puries with MAG. In the sentinel article by Pestronk et al. describing eight patients with GALOP syndrome, two patients treated with IVIG clearly improved and three others responded to treatment with plasma exchange alone or in combination with prednisone or cyclophosphamide.110 This syndrome may be more of historical than practical importance as the initially unknown antigen that co-puried with MAG was subsequently determined to be sulfatide.
Anti-GM2 and GalNac-GD1a Neuropathy. Patients with antibodies against GM2 and GalNAc-GD1a may

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also manifest a severe predominantly sensory neuropathy with prominent limb and gait ataxia.78 The onset is in adult life and the neuropathy is slowly progressive in course. A monoclonal protein of the IgM type is detected, directed against gangliosides GM2 and GalNAc-GD1a that contain the terminal trisaccharide moiety GalNAc (beta 1-4)Gal(alpha 2-3)NeuAc. Electrophysiologic studies show demyelinating features. In the two patients reported by Lopate and colleagues, improvement was observed after treatment with intravenous immunoglobulin.78 In one patient, previous treatment with intravenous cyclophosphamide and plasma exchange failed to reverse disease progression. In an earlier study, OHanlon et al. reported a similar neuropathy in patients with IgM antibody directed against the GM2 antigen and showed in several patients that the degree of cell lysis correlated with the titer of anti-GM2 antibodies.100 Serum from patients with this antibody induces complement-mediated cytotoxicity in neuroblastoma cells.15
CIDP Associated with Monoclonal Gammopathy of Undetermined Signicance. A monoclonal gammopa-

thy will be found in approximately 10% of patients with a neuropathy for whom routine blood and urine studies have failed to disclose an etiology.71 The origin of the monoclonal protein may be amyloidosis, multiple myeloma, osteosclerotic myeloma, Waldenstroms macroglobulinemia, cryoglobulinemia, lymphoma, leukemia, Castlemans disease, and heavy gamma disease. In many cases, however, no denite cause is found for the monoclonal protein and the illness is classied by default as monoclonal gammopathy of undetermined signicance (MGUS). In patients with a monoclonal gammopathy and neuropathy, MGUS is the most common association. Approximately 25% of patients with plasma cell dyscrasia eventually evolve into typical multiple myeloma. In MGUS, the monoclonal protein can be of the IgG, IgA, or IgM type. Four patterns of peripheral neuropathic presentation have been identied in patients with monoclonal gammopathy and IgM protein: (1) predominantly sensory, (2) pure sensory, (3) mixed sensory and motor, and (4) mononeuropathy multiplex.17, 41 Sensory symptoms and signs tend to predominate over motor abnormalities.41 Simovic et al. contrasted the clinical and electrophysiologic features and treatment responses of patients with neuropathy and IgM-MGUS and IgG-MGUS.123 No clinical features differentiated the two groups. On nerve conduction studies, IgM-MGUS patients tended to have more

demyelinating features. Approximately 50% of patients in both groups improved after plasma exchange and other immune therapies. Dyck and colleagues reported a controlled study of 39 patients with neuropathy and MGUS who were randomized to receive either plasma exchange for 3 weeks or shamplasma exchange.29 Patients who received plasma exchange improved by more points in the neuropathy disability score, the weakness score, and in summed CMAP amplitudes. No improvement was recorded in sensory modalities. Patients with IgG and IgA gammopathies improved more than those with IgM gammopathy. Dalakas and colleagues described a poor response rate to IVIG infusions in 11 patients with a demyelinating neuropathy and IgM gammopathy.22 Using a double-blind cross-over study design, patients were treated with either IVIG or placebo for 3 months, followed by a washout period and treatment with the other therapy. Only two patients improved in strength and one experienced subtle improvement in his sensory score. Gorson et al. reviewed the clinical, electrodiagnostic, and treatment response patterns in 67 consecutive patients with either idiopathic CIDP or CIDP associated with MGUS over a 4-year period.42 Patients with CIDP-MGUS were less weak than the group with idiopathic CIDP, yet displayed greater imbalance, leg ataxia, and sensory loss. The response rate to plasma exchange, IVIG, and corticosteroids was similar in the two groups, but the greatest functional improvement was recorded in patients who underwent plasma exchange. Among patients with idiopathic CIDP, 39% responded to initial therapy. Among those who failed initial treatment, 35% beneted from an alternative therapy; 27% of patients who did not respond to treatment with the rst or second modality improved after treatment with the third modality. Overall, 66% of the patients with CIDP improved after treatment with steroids, plasma exchange, or IVIG. Although a higher percentage of patients with CIDP-MGUS experienced benet from plasma exchange compared to the idiopathic CIDP group, the difference did not attain statistical significance. Notermans and colleagues treated 16 patients with MGUS-associated polyneuropathy with a combination of cyclophosphamide (300 mg/m2 body surface daily for 4 days) and prednisone 40 mg/m2 surface daily for 5 days every 4 weeks over 6 months.98 When reevaluated 3 years later, the authors observed improvement in eight patients and stabilization in six patients who had neuropathies with demyelinating and axon-loss features. The pa-

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tient with a purely axon-loss neuropathy worsened despite treatment, and the remaining patient developed severe leukopenia necessitating withdrawal from the study. No difference was observed in response to therapy between the patients with IgM and IgG monoclonal proteins.98 In a controlled study of patients with IgM-associated polyneuropathy, Mariette and colleagues compared treatment with IVIG (2 g/kg and then 1 g/kg every 3 weeks) to recombinant interferon-alpha (3 MU/m2 subcutaneously three times weekly).80 After 6 months of treatment, only 1 of 10 patients who received IVIG improved more than 20% in the clinical neuropathy disability score. Most patients who received IVIG worsened. Eight of the 10 patients who received interferon-alpha improved by more than 20%. Improvement lasted for 1 year and was attributed primarily to augmentation of sensory function. A decrease of the IgM level was recorded in 2 of 10 patients who were treated with interferonalpha. Patients with neuropathy and MGUS have been reported who improved after treatment with plasma exchange and chlorambucil101 or udarabine.138 A severe motor and sensory polyneuropathy is observed in 50% of patients with osteosclerotic myeloma and is commonly the presenting feature of the illness.24 Osteosclerosis is a rare manifestation of myeloma, detected in only 12% of patients with typical myeloma. The disorder differs from typical multiple myeloma by its younger age of onset (average, 49 years), lower frequency of serum and urine immunoglobulin abnormalities, and lack of hypercalcemia, renal impairment, and anemia. In many cases, patients do not appear to be systemically ill. The disorder is characterized by the presence of single or multiple osteosclerotic lesions that are commonly located in the long bones of the arms and legs, the spine, and pelvis. The lesions are not usually found in the skull, where osteolytic lesions commonly occur in typical myeloma. In addition to the neuropathy and osteosclerotic lesions, patients often have enlargement of abdominal organs (liver, spleen), lymphadenopathy, peripheral edema, skins changes, and multiple endocrine complications such as gynecomastia, hypothyroidism, diabetes, hirsutism, impotence, and amenorrhea. Neurophysiologic studies show evidence for a multifocal, segmental demyelinating polyneuropathy affecting motor and sensory bers.24 Patients with solitary lesions may improve after radiation treatment. Osteosclerotic myeloma arising from multiple lesions may respond to treatment with
Osteosclerotic Myeloma.

prednisone and melphalan24,103 and combination therapy with surgical excision, radiation therapy, and chemotherapy using chlorambucil, danazol, and hydrocortisone.116 POEMS is an acronym for a disorder with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes.81,122 Despite the implications of the acronym, not all ve features are observed in every patient or occur at the same time in each patient. The disorder has been described under the terms of Crow-Fukase syndrome, PEP syndrome (pigmentation, edema, and plasma cell dyscrasia), and Takatsukis syndrome. It is twice as common in men as women and often presents between the ages of 40 and 50, a similar age spectrum to osteosclerotic myeloma. Many but not all patients have either single or multiple osteosclerotic bone lesions. Pareyson and colleagues reported six patients with POEMS syndrome, only two of whom had osteosclerotic myeloma.102 The others had either MGUS or Castlemans disease.102 A review of 38 patients with complete or incomplete forms of POEMS syndrome87 revealed that 82% had osteosclerotic bone lesions, 58% had skin abnormalities, 24% had hepatomegaly, and 21% had splenomegaly. Only 5 of the 38 patients fullled all of the criteria for POEMS syndrome. IgG or IgM lambda monoclonal proteins were detected in the serum or urine of 87% of patients. In addition to the abnormalities described above, the general physical examination may disclose lymphadenopathy, testicular atrophy, gynecomastia, impotence, amenorrhea, and edema. Diabetes and hypothyroidism are present more often in patients with POEMS syndrome than in the general public. The electrophysiologic features of POEMS syndrome resemble those of severe CIDP. Nerve conduction studies show evidence of a multifocal demyelinating polyneuropathy. Cytoalbuminologic dissociation is present in the CSF. Treatment is directed towards management of solitary or multiple bone lesions. Solitary bone lesions can be treated by radiation therapy or resection. Multifocal disease is treated with melphalan and prednisone. Two case reports have described a lack of response to plasma exchange.121 In one of the patients who did not improve, the authors measured the quantity of IgG removed after 6 plasma exchanges and found the efciency of the removal process to be much less than predicted. They hypothesized that increased vascular permeability and compartment shifts accounted for the inefciency of plasma exchange in their patient. The response to IVIG has been equally poor.16,57 The one exception is the report by Henze
POEMS Syndrome.

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and Krieger of a patient with POEMS syndrome who regained the ability to walk after combination therapy with IVIG (0.4 g/kg) daily for 4 days, repeated 2 weeks later, and followed by dexamethasone 40 mg daily for 5 days and repeated every 3 4 weeks.53 Half of the patients with POEMS syndrome become bedridden. Death is usually from complications of inactivity (decubitus ulcers, thromboses) or organomegaly and endocrinopathy rather than the aggressiveness of the monoclonal protein. In their review, Miralles and colleagues observed a 60% 5-year survival in their patients with POEMS syndrome, a percentage much superior to the 20% 5-year survival in a comparable group of patients with multiple myeloma.87
VASCULITIC NEUROPATHY

Clinical decits in vasculitic neuropathies arise from nerve ischemia or infarction. Vasculitic neuropathies can be divided into those with systemic and nonsystemic causes. Systemic causes of vasculitic neuropathy include Behc ets disease, giant cell arteritis (GCA), Takayasus arteritis, Wegeners granulomatosis, Churg-Strauss syndrome, Cogans syndrome, Kawasakis disease, Henoch-Schonlein purpura in children, and necrotizing vasculitic neuropathy associated with autoimmune diseases such as polyarteritis nodosa, systemic lupus erythematosus, and rheumatoid arthritis.55 In nonsystemic vasculitis, only the peripheral nervous system is involved, and constitutional symptoms and serologic abnormalities are either absent or unimpressive. Unfortunately, no prospective, randomized, controlled trials have been published on treatments for vasculitic neuropathy. In 1987, Dyck et al. reported 65 patients with necrotizing vasculitis. Twenty were found to have nonsystemic involvement of the peripheral nervous system.28 The clinical presentation was a mononeuropathy multiplex in 13 patients, an asymmetric neuropathy in 4, a distal polyneuropathy in 3, and a pure sensory neuropathy in 1. Nerve pathology showed vasculitis of the epineurial arterioles, focal or multifocal ber loss, and areas of segmental demyelination and remyelination. The spinal uid revealed a mild elevation of protein concentration but no increase in cells. Most patients died from nonneurologic causes. In the cases in this series, treatment was not adequately controlled to allow specic recommendations for therapy.28 In several patients, prednisone therapy prevented the development of new lesions. Moore and Fauci in a retrospective and prospective study of 25 patients with systemic vasculitis iden-

tied a peripheral neuropathy in 60% and central nervous system involvement in 40% of patients.90 The neuropathies could be categorized into four types: mononeuritis multiplex, extensive mononeuritis, cutaneous neuropathy, and polyneuropathy. Nine of the 13 patients with peripheral neuropathy improved, the degree of response ranging from mild to excellent. Only a small number of patients responded to corticosteroids alone, and most required combination therapy of cyclophosphamide, 2 mg/kg daily, typically prescribed in concert with an alternate-day regimen of corticosteroids. Harati and Niakan treated 33 patients with an inammatory-angiopathic neuropathy.51 Most presented with a symmetric sensory and motor polyneuropathy. Only eight patients were found to have an identiable etiology for the vasculitic neuropathy ve patients had a collagen vascular disorder and three patients had a malignant tumor. Half of the patients were treated with prednisone, and 75% of them improved as a result of therapy. Hawke and associates described 34 patients with peripheral neuropathy arising from a necrotizing vasculitis.52 All patients were treated with prednisone alone (15 patients) or prednisone plus other immunosuppressants or plasma exchange. Patients were treated for more than 2 years. The group was followed for a mean of 36 months, and over that period 50% died. In six instances, death could be related to the vasculitis causing multiorgan failure, and all of those deaths occurred within 6 months of disease onset. Cyclophosphamide was the most effective drug in prolonging survival. The only statistically signicant prognostic factor was age; survival was not related to the type of neuropathy, i.e., mononeuritis multiplex, asymmetric or symmetric.52 Said recommends treatment of vasculitic neuropathy with prednisone, 1 mg/kg daily.118 He states that simultaneous treatment with oral cyclophosphamide, 2 mg/kg daily, or bimonthly IV cyclophosphamide (1 g), may help to reduce the dose of corticosteroids. Intravenous prednisolone may be used in the place of oral steroids. He recommends full-dose corticosteroids for 6 8 weeks and thereafter a slow taper over 6 10 months or longer. If abnormal prior to treatment, serial monitoring of the erythrocyte sedimentation rate and C-reactive protein should be used to adjust the dose of corticosteroids. Approximately half of his patients relapsed during the tapering of prednisone. Kissel and Mendell recommend a similar approach.67 They initiate therapy with prednisone 1.5 mg/kg daily and oral cyclophosphamide 2mg/kg daily. After 2 4 weeks of treatment, prednisone is

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changed to alternate-day therapy at the same dosage. Both prednisone and cyclophosphamide are prescribed until improvement ensues and the disease is stabilized. Thereafter, prednisone is tapered by 5 mg every 2 weeks and cyclophosphamide is continued for approximately 1 year after the prednisone is discontinued. They recommend azathioprine for patients who are unable to tolerate cyclophosphamide. In fulminant cases of vasculitic neuropathy, treatment is initiated with intravenous pulse methylprednisolone therapy, 1 g every other day for 6 doses, and thereafter alternate-day oral prednisone as described above.67
GRENS SYNDROME SJO

neuropathy secondary to Sjo grens syndrome after 59 sessions of plasma exchange.19 In the other two patients, no detectable benet was observed. The authors advised early treatment with plasma exchange. Improvement of foot pain has been reported in a patient with a sensory polyneuropathy and Sjo grens syndrome after treatment with a 5-day course of IVIG and prednisone,105 and a good clinical response to serial treatments with IVIG has been described in a man with Sjo grens syndrome, a distal sensory neuronopathy, and bilateral trigeminal neuropathy.89
PARANEOPLASTIC SENSORY NEURONOPATHY

Sjo grens syndrome most commonly presents as a chronic and slowly progressive sensorimotor neuropathy or a sensory neuropathy or neuronopathy.83 Motor involvement is either minimal or absent. A superimposed unilateral or bilateral trigeminal neuropathy, a mononeuropathy, or an autonomic neuropathy is observed in approximately 25 40% of patients with a diffuse and symmetric neuropathy.66 Other types of neuropathy associated with Sjo grens syndrome include mononeuritis multiplex, multiple recurrent cranial neuropathies,112 and a subacute demyelinating polyradiculopathy.70 The neuropathy may be extensive to the point of causing a tremor or choreoathetotic movements. Single and multiple lesions of the brain and spinal cord may be identied, but are rare.69 Nerve conduction studies in the diffuse neuropathy or neuronopathy associated with Sjo grens syndrome are characteristic and highly suggestive of the disorder. Patients have either small or absent sensory nerve action potentials in the upper and lower extremities in the setting of normal motor studies. Absent blink reexes conrm trigeminal nerve involvement. In approximately 50% of patients, an IgG antibody can be detected directed against SS-A and SS-B antigens. Nerve biopsy typically shows a necrotizing vasculitis, perivascular inammation, and axon loss.45 Response to treatment has been disappointing in most patients.69 In rare instances, patients improve without specic therapy or respond partially to prednisone. A good response to corticosteroid therapy has been described in two patients with Sjo grens syndrome, one with mononeuritis multiplex and the other with recurrent cranial polyneuropathy.112 Most patients do not improve after immunosuppression and some may develop the neuropathy during treatment. Chen and associates reported dramatic and sustained improvement in two of four patients with an ataxic sensory

Denny-Brown rst described the paraneoplastic sensory neuropathy associated with small cell carcinoma of the lung in 1948.23 On clinical examination, patients have normal strength, diffuse areexia, and sensory loss often of large-diameter bers. They are frequently disabled by pronounced sensory ataxia, gait instability, or hyperalgesia. Some patients have dysautonomia to the point that gut dysmotility produces a pseudoobstruction. Most patients with paraneoplastic neuronopathy are found to have small cell carcinoma of the lung. Much less commonly, patients can have anaplastic, bronchial, or squamous cell carcinomas of the lung, or reticuloendothelial neoplasms such as Hodgkins disease or reticulum cell sarcoma. It is most common for the neuropathy to precede detection of the tumor, often by several months. Electrophysiologic studies typically show markedly reduced or absent sensory nerve action potentials and normal motor studies. Neuropathology usually demonstrates degeneration of the dorsal root ganglia, posterior roots, peripheral sensory nerves, and posterior column, in combination with inammation and phagocytosis of dorsal root ganglion cells. The mean survival for patients with paraneoplastic sensory neuronopathy is 10 months. In rare cases, survival can be extended by chemotherapy of the underlying tumor.56 Brunet and colleagues reported impressive improvement in the neurologic decits in two patients with paraneoplastic sensory neuronopathy and Hodgkins disease after treatment with multiple-drug chemotherapy.13 A man with a hilar mass, metastatic lymph node, anti-Hu antibodies, and a biopsy-proven sensory neuropathy improved after receiving chemotherapy with carboplatin and etoposide, and subsequent radiation therapy.124 Oh and colleagues reported improvement after treatment with oral cyclophosphamide in a woman with metastatic endometrial carcinoma and a neuropathy.99

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Unfortunately, the response to immunotherapy has been recorded only in a few single case reports. Graus and colleagues reported the effect of plasma exchange in four patients with subacute sensory neuronopathy associated with small cell carcinoma of the lung.44 In addition to plasma exchange, three patients were treated with prednisone and one patient with prednisone plus cyclophosphamide. Two of the four patients had anti-Hu antibodies. None of the four patients improved after plasma exchange. Of note, all were severely disabled at the time the plasma exchange was initiated. One of three patients with paraneoplastic sensory neuropathy reported by Blaes et al. showed rapid clinical improvement after receiving IVIG treatment and complete remission of the neuropathy following radiotherapy to the lung carcinoma.10 A decline in the intrathecal synthesis of antineuronal antibody corresponded to the initial improvement from IVIG treatment.10 Mowzoon and Bradley reported a dramatic clinical response to treatment in a woman with severe subacute cerebellar degeneration and peripheral sensory neuropathy.93 Although suspected to be harboring an underlying cancer, none was found despite repeated investigations. She was treated with IVIG, oral cyclophosphamide, and prednisone. She regained the ability to write, cook, walk, and speak clearly.
SUMMARY

This review was presented in part at the annual meeting of the American Association of Electrodiagnostic Medicine, October 2001, Albuquerque, New Mexico.

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