Todd Levine

IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using Rituximab

Article abstract Current treatments for anti-GM1 ganglioside or antimyelin-associated glycoprotein (anti-MAG) antibody-associated polyneuropathies are toxic or very costly. In this preliminary study the authors treated five patients with neuropathy and immunoglobulin M antibodies to GM1 ganglioside or MAG by depleting B cells using Rituximab—a monoclonal antibody directed against the B-cell surface membrane marker CD20. Within 3 to 6 months after treatment, all five patients had improved function, significantly increased quantitative strength measurements, and reduced titers of serum autoantibodies.

Treatment of IgM antibody associated polyneuropathies using rituximab

Objectives: Polyneuropathies with associated serum IgM antibodies are often difficult to treat. Rituximab is a monoclonal antibody directed against the B cell surface membrane marker CD20. Rituximab eliminates B cells from the circulation, and, over time, could reduce cells producing autoantibodies. This study tested the ability of rituximab to produce changes in serum antibody titres, and improvement in strength, in patients with neuromuscular disorders and IgM autoantibodies. Methods: Over a period of two years, the authors evaluated changes in strength, measured by quantitative dynamometry, and concentrations of several types of serum antibodies in patients with polyneuropathies and serum IgM autoantibodies. Twenty one patients treated with rituximab were compared with 13 untreated controls. Results: Treatment with rituximab was followed by improved strength (an increase of mean (SEM) 23% (2%)of normal levels of strength), a reduction in serum IgM autoantibodies (to 43% (4%) of initial values), and a reduction in total levels of IgM (to 55% (4%) of initial values). There was no change in levels of serum IgG antibodies. There were no major side effects, even though B cells were virtually eliminated from the circulation for periods up to two years. Conclusions: In patients with IgM autoantibody associated peripheral neuropathies, rituximab treatment is followed by reduced serum concentrations of IgM, but not IgG, antibodies, and by improvement in strength. Additional studies, with placebo controls and blinded outcome measures, are warranted to further test the efficacy of rituximab treatment of IgM associated polyneuropathies.

Sensory exam with a quantitative tuning fork Rapid, sensitive and predictive of SNAP amplitude

Background: In the standard neurologic examination, outcome measures of sensation testing are typically qualitative and subjective. The authors compared the outcome of vibratory sense evaluation using a quantitative Rydel-Seiffer 64 Hz tuning fork with qualitative vibration testing, and two other features of the neurologic evaluation, deep tendon reflexes and sensory nerve conduction studies. Methods: The authors studied 184 subjects, including 126 with Waldenström’s macroglobulinemia and 58 controls, over the course of a weekend. Standard neurologic examinations and quantitative vibratory testing were performed. Sensory nerve action potentials (SNAP) were tested as a measure of sensory nerve function. Tests were carried out by different examiners who were blinded to the results of other testing and to clinical information other than the diagnosis of Waldenström’s macroglobulinemia. Results: Quantitative vibration measurements in all body regions correlated with sural SNAP amplitudes. Quantitative vibration outcomes were more strongly related to sural SNAP results than qualitative evaluations of vibration. Quantitative vibration testing also detected a loss of sensation with increased age in all body regions tested. Conclusions: Quantitative vibratory evaluation with Rydel-Seiffer tuning fork is rapid, has high inter- and intrarater reliability, and provides measures for evaluating changes in sensory function over time. Examinations with the quantitative tuning fork are also more sensitive and specific than qualitative vibration testing for detecting changes in sensory nerve function. Use of the quantitative tuning fork takes no more time, provides more objective information, and should replace the qualitative vibratory testing method that is now commonly used in the standard neurologic examination.

A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.

Peripheral neuropathies in Waldenström’s macroglobulinaemia

Objective: We sought to determine the prevalence, clinical features, and laboratory characteristics of polyneuropathies in Waldenström’s macroglobulinaemia (WM), a malignant bone marrow disorder with lymphocytes that produce monoclonal IgM. Methods: We prospectively studied 119 patients with WM and 58 controls. Medical history was taken, and neurological examinations, electrodiagnostic tests, and serum studies were performed by different examiners who were blinded to results except the diagnosis of WM. Results: Polyneuropathy symptoms, including discomfort and sensory loss in the legs, occurred more frequently (p<0.001) in patients with WM (47%) than in controls (9%). Patients with WM had 35% lower quantitative vibration scores, and more frequent pin loss (3.4 times) and gait disorders (5.5 times) than controls (all p<0.001). Patients with IgM binding to sulphatide (5% of WM) had sensory axon loss; those with IgM binding to myelin associated glycoprotein (MAG) (4% of WM) had sensorimotor axon loss and demyelination. Patients with WM with IgM binding to sulphatide (p<0.005) or MAG (p<0.001) had more severe sensory axon loss than other patients with WM. Demyelination occurred in 4% of patients with WM with no IgM binding to MAG. Age related reductions in vibration sense and sural SNAP amplitudes were similar (∼30%) in WM and controls. Conclusions: Peripheral nerve symptoms and signs occur more frequently in patients with WM than controls, involve sensory modalities, and are often associated with gait disorders. IgM binding to MAG or sulphatide is associated with a further increase in the frequency and severity of peripheral nerve involvement. Age related changes, similar to those in controls, add to the degree of reduced nerve function in patients with WM.

Peripheral neuropathy in an outpatient cohort of patients with Sjögren's syndrome

Peripheral neuropathy is common in patients with Sjögrens syndrome (SS), but its precise prevalence is unknown. Most prior studies were conducted at neurology or rheumatology specialty clinics and likely selected for a more severely affected population. We evaluated 22 SS patients and 10 controls for evidence of neuropathy in an outpatient setting at a regional meeting of the Sjögrens Syndrome Foundation. We performed neurological examinations and nerve conduction studies (NCSs) and measured serum antinuclear antibody (ANA) and SS‐A and SS‐B antibody levels. Participants filled out a questionnaire pertaining to symptoms, diagnosis, and treatment. We found that signs and symptoms related to small axons were more common in patients with SS than in controls. Complaints of painful distal paresthesias in the feet were noted in 59% of patients but in only 10% of controls, and of abnormal sweating in 41% and 0%, respectively. Examination revealed decreased pinprick sensation in 64% of patients with SS, but in only 30% of controls. Overall, 45% of the patients but none of the controls were thought to have an isolated small‐fiber neuropathy. Large‐fiber dysfunction (as measured by testing vibration, deep tendon reflexes, and NCSs) was similar between the two groups. We conclude that small‐fiber neuropathy is common in patients with SS. Muscle Nerve 2006

A pilot trial of memantine and riluzole in ALS: Correlation to CSF biomarkers

Abstract The objective of this trial was to determine the safety and tolerability of memantine in patients with sporadic ALS and to examine changes in CSF biomarkers during drug therapy. Twenty patients on stable doses of riluzole were enrolled. Patients received memantine, 10 mg b.i.d., for 18 months. Lumbar punctures were performed at baseline, six and twelve months. The ALSFRS was measured at six weeks, 3, 6, 9, 12 and 18 months. Results showed that patients treated with memantine and riluzole had an average rate of decline on the ALSFRS of −0.73 points per month. Patients who progressed faster than −0.5 ALSFRS points per month had an average baseline CSF tau concentration of 574 pg/ml, while those who progressed slower than −0.5 ALSFRS points per month had CSF tau levels that averaged 298 pg/ml (p = 0.006). After therapy with memantine, patients had a 27% decline in CSF tau levels (p = 0.04) and four patients whose CSF tau dropped to healthy control levels lost only −0.42 ALSFRS points per month. In conclusion, memantine was well tolerated in patients with ALS. Patients receiving memantine and riluzole lost on average −0.73 ALSFRS points per month. Furthermore, levels of CSF tau at baseline could be correlated with how rapidly a patients disease progressed.

Phase I clinical trial of safety of L-serine for ALS patients

Abstract We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18–85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Usefulness of Skin Biopsies in the Evaluation and Management of Patients with Suspected Small Fiber Neuropathy

ABSTRACT Objective: To assess the usefulness of skin biopsy in the assessment of patients with suspeted small fiber neuropathy (SFN). Methods: Retrospective chart review of patients with sensory symptoms or findings restricted to small nerve fibers and normal nerve conduction studies (NCS) seen in a subspecialty neuromuscular private practice. Results: Assessments were made on 145 patients. Skin biopsy was abnormal in at least one site in 86 patients (59%). There was no significant difference between patients with normal or abnormal skin biopsies with respect to age, gender, or duration of symptoms. Compared to patients with normal skin biopsies, patients with confirmed SFN were significantly more likely to have pain and were more than twice as likely to respond to standard neuropathic pain medications. Conclusions: Skin biopsy is useful in the diagnosis and management of patients with otherwise unexplained sensory symptoms or findings.

Inflammatory myopathy with cytochrome oxidase negative muscle fibers: Methotrexate treatment

Inflammatory myopathy with cytochrome oxidase negative muscle fibers (IM/COX−) is characterized by slowly progressive weakness, most prominent in the quadriceps, muscle fibers with reduced COX staining and mitochondrial DNA mutations, and a poor response to corticosteroid treatment. We reviewed records of quantitative measurements of muscle strength in 7 IM/COX− patients to evaluate the outcomes after treatment with oral, once weekly, methotrexate for an average of 15 months. We compared the results to 6 patients with IM/COX− who received no long‐term immunosuppression, and to 4 with inclusion body myositis (IBM) who received methotrexate during the same period. Methotrexate treatment of IM/COX− was followed by improved muscle strength in 5 of 7 patients, averaging 17 ± 5%. In contrast, there was no improvement in the strength of 6 untreated IM/COX− patients (−6 ± 4%; P = 0.003), or 4 methotrexate‐treated IBM patients (1 ± 2%; P = 0.03). We conclude that, despite clinical similarities to inclusion body myositis, which is usually refractory to immunosuppressive therapy, strength in IM/COX− appears to improve with methotrexate treatment. Biopsy studies of inflammatory myopathies with evaluation of muscle for mitochondrial changes and vacuoles can help to direct the choice of appropriate immunomodulating treatments.