We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

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OBJECTIVE -The purpose of this study was to evaluate intraepidermal nerve fiber density (IENFD) as a sensitive measure of neuropathy change in patients with neuropathy associated with impaired glucose tolerance (IGT) receiving lifestyle intervention based on that used in the Diabetes Prevention Program.RESEARCH DESIGN AND METHODS -We performed 3-mm skin biopsies with measurement of IENFD at the distal leg and proximal thigh at baseline and after 1 year in 32 subjects with IGT. Each received individualized diet and exercise counseling as a standard of care. Nerve conduction studies, quantitative sensory testing, quantitative sudomotor axon reflex testing, and the Michigan Diabetic Neuropathy score were performed, and a visual analog pain scale was completed. Two-hour oral glucose tolerance tests (OGTTs) following the American Diabetes Association guidelines were performed, and serum lipid levels were measured at baseline and 1 year later.RESULTS -Baseline distal IENFD was 0.9 Ϯ 1.2 fibers/mm and proximal IENFD was 4.8 Ϯ 2.3 fibers/mm. Baseline distal IENFD correlated with fasting glucose (P Ͻ 0.001) and OGTT (P Ͻ 0.01). After 1 year of treatment, there was a 0.3 Ϯ 1.1-fiber/mm improvement in distal IENFD and a 1.4 Ϯ 2.3-fiber/mm improvement in proximal IENFD (P Ͻ 0.004). The change in proximal IENFD correlated with decreased neuropathic pain (P Ͻ 0.05) and a change in sural sensory amplitude (P Ͻ 0.03).CONCLUSIONS -These findings indicate that diet and exercise counseling for IGT results in cutaneous reinnervation and improved pain. Skin biopsy was the most sensitive measure of neuropathy change over 1 year. IENFD should be included as an end point in future neuropathy trials. Diabetes Care 29:1294 -1299, 2006I diopathic peripheral neuropathy is common. Population studies indicate that 5-14% of individuals Ͼ40 years old have neuropathy (1,2). Several groups have demonstrated a 40% prevalence of impaired glucose tolerance (IGT) among subjects with otherwise idiopathic neuropathy (3-5), compared with Ͻ15% in the age-matched general population (6). This observation supports the hypothesis that IGT-related neuropathy may represent the earliest stage of diabetic neuropathy. One practical test of this hypothesis is to determine whether treatment of IGT results in slowed progression of neuropathy. The Diabetes Prevention Program (DPP) demonstrated that intensive diet and exercise counseling slows progression of IGT to diabetes compared with placebo or metformin (7). We are studying patients with IGT and neuropathy in the Impaired Glucose Tolerance Neuropathy (IGTN) study, a National Institutes of Health-funded Clinical Pilot Project investigating the clinical features and progression of IGTN. As a standard of care, all IGTN study subjects receive diet and exercise intervention modeled on that used in the DPP.The neuropathy associated with IGT and early diabetes is sensory predominant and painful and is characterized by prominent small-fiber injury. The most sensitive diagnostic measure is skin biopsy with measurement of...

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

We performed a retrospective chart review on 53 muscle-specific kinase antibody (MuSK-Ab)-positive myasthenia gravis (MG) patients at nine university-based centers in the U.S. Of these, 66% were Caucasian, 85% were women, and age of onset was 9-79 years. Twenty-seven patients were nonresponsive to anticholinesterase therapy. Myasthenia Gravis Foundation of America improvement status was achieved in 53% patients on corticosteroids, 51% with plasma exchange, and in 20% on intravenous immunoglobulin (IVIG). Thymectomy was beneficial in 7/18 patients at 3 years. Long-term (> or =3 years) outcome was very favorable in 58% of patients who achieved remission and/or minimal manifestation status. Overall, 73% improved. There was one MG-related death. This survey reinforces several cardinal features of MuSK-Ab-positive MG, including prominent bulbar involvement and anticholinesterase nonresponsiveness. Facial or tongue atrophy was rare. Most patients respond favorably to immunotherapy. The best clinical response was to corticosteroids and plasma exchange, and the poorest response was to IVIG. Long-term outcome is favorable in about 60% of cases.

Early neuropathy is often sensory predominant and prominently involves small-diameter nerve fibers. Established neuropathy examination scales such as the Michigan Diabetic Neuropathy Scale (MDNS) and the Neuropathy Impairment Score-Lower Leg (NIS-LL) focus primarily on large-fiber sensory and motor function. Here, we validate the Utah Early Neuropathy Scale (UENS), a physical examination scale specific to early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. UENS, MDNS, and NIS-LL were compared in 215 diabetic or prediabetic subjects, with (129) or without neuropathy (86), and repeated in 114 neuropathy subjects after 1 year of follow-up. Neuropathy severity was also evaluated with nerve conduction studies, quantitative sensory testing, quantitative sudomotor axonal reflex testing, and intraepidermal nerve fiber density determination. The UENS had a high degree of interrater reliability (interclass correlation of 94%). UENS correlated significantly to MDNS and NIS-LL (p < 0.01), and more significantly than MDNS or NIS-LL to confirmatory tests. In this cohort, UENS had a superior profile to receiver operating characteristic analysis across a range of scores, with a sensitivity (92%) higher than MDNS (67%) or NIS-LL (81%), without sacrificing specificity. UENS more closely correlated with change in ancillary and small-fiber neuropathy measures over 1 year follow-up than did MDNS or NIS-LL. UENS is a sensitive and reproducible clinical measure of sensory and small-fiber nerve injury and may be useful in trials of early neuropathy.

The aim of the study was to determine the frequency of undiagnosed abnormal glucose metabolism in patients with idiopathic sensory neuropathy. Patients were separated into two groups depending on presence or absence of painful symptoms, and an oral glucose tolerance test was performed. Of the 48 patients studied, those with painful symptoms had a higher frequency of abnormal glucose metabolism than literature-based controls, whereas patients without painful symptoms showed no difference. Comparison of patients with and without painful symptoms had a P-value of 0.02. The results indicate the need to consider undiagnosed abnormal glucose metabolism in patients with idiopathic sensory neuropathy.

Our results support the hypothesis that rituximab is beneficial and well tolerated in managing refractory myasthenia gravis and nearly doubles published cases. We propose that B-cell-directed therapies may become an attractive option and suggest pursuit of a prospective trial.