Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis.

Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4+ and CD8+ T cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8+ T cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4+ T cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4+ T cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in CD39 expression or Treg number.

Is the decremental pattern in Lambert-Eaton syndrome different from that in myasthenia gravis?

OBJECTIVE: We reviewed our experience to determine if the decremental pattern during low frequency repetitive nerve stimulation (LF-RNS) distinguishes between the Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG). METHODS: LF-RNS studies were reviewed from 34 LEMS and 44 MG patients, 4 of whom had antibodies to muscle specific kinase (MuSK). In each train we calculated the ratio between the early and the later decrement. Receiver-operator characteristic curves were calculated to determine the ratio that best distinguished between LEMS and MG. RESULTS: The late decrement was more often greater in LEMS and the converse was true in MG, but with some overlap in values in individual patients. A late decrement more than 102% of the early decrement discriminated between LEMS and MG in 90% of studies. The decremental pattern in MG patients with MuSK antibodies resembled that in LEMS. CONCLUSION: When the decrement becomes progressively greater during low frequency RNS, the patient is more likely to have LEMS than MG, and in MG, is more likely to have MuSK antibodies. SIGNIFICANCE: A progressive decrement in patients otherwise felt to have MG should prompt further clinical, serological and electrodiagnostic tests. Further studies are needed to assess the decremental pattern in MuSK MG.

Trends in American Board of Psychiatry and Neurology specialties and neurologic subspecialties.

OBJECTIVE: To review the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) specialties and neurologic subspecialties and discuss the implications of those trends for subspecialty viability. METHODS: Data on numbers of residency and fellowship programs and graduates and ABPN certification candidates and diplomates were drawn from several sources, including ABPN records, Web sites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of the Journal of the American Medical Association. RESULTS: About four-fifths of neurology graduates pursue fellowship training. While most recent neurology and child neurology graduates attempt to become certified by the ABPN, many clinical neurophysiologists elect not to do so. There appears to have been little interest in establishing fellowships in neurodevelopmental disabilities. The pass rate for fellowship graduates is equivalent to that for the "grandfathers" in clinical neurophysiology. Lower percentages of clinical neurophysiologists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high. CONCLUSION: The initial enthusiastic interest in training and certification in some of the ABPN neurologic subspecialties appears to have slowed, and the long-term viability of those subspecialties will depend upon the answers to a number of complicated social, economic, and political questions in the new health care era.

MuSK-antibody positive myasthenia gravis: clinical and electrodiagnostic patterns.

OBJECTIVE: To examine the clinical manifestations and patterns of electromyographic abnormalities in MuSK-Ab positive myasthenia gravis. METHODS: The clinical evaluations and electrodiagnostic testing results of 20 MuSK-Ab positive myasthenia gravis patients were retrospectively reviewed and compared with matched AChR-Ab positive (N = 72) and MuSK-Ab negative/AChR-Ab negative (N = 24) patients. RESULTS: MuSK-Ab positive patients were younger and more frequently female and African-American, and compared to the AChR-Ab positive patients, were more likely to present with respiratory symptoms or neck extension weakness. MuSK-Ab positive patients were less likely to have abnormal jitter in a limb muscle: only 59% had abnormal jitter in the extensor digitorum communis muscle, compared to 80% of the AChR-Ab negative/MuSK-negative patients and 91% of the AChR-Ab positive patients. CONCLUSIONS: Our MuSK-Ab positive patients not only differ demographically from our MuSK-Ab negative cohort, but they also appear to have a more limited distribution of SFEMG abnormalities. SIGNIFICANCE: The possibility that electrophysiologic abnormalities may not be widely distributed should be considered during electrodiagnostic evaluation of suspected MuSK-Ab positive MG and in selecting muscles for molecular, morphologic, or microphysiologic studies in this condition.

Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability.

The authors report a retrospective analysis of the use of mycophenolate mofetil (MyM) in 85 patients with autoimmune myasthenia gravis. The Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) was used to characterize the treatment response in each patient. Sixty-two patients (73%) achieved a PIS status indicating improvement. Quantitative strength testing performed on the majority of patients before and after treatment also improved. Side effects to MyM were observed in 27% of patients but required discontinuation in only 6%.

Clinical aspects of MuSK antibody positive seronegative MG.

Serum antibodies to muscle-specific receptor tyrosine kinase were detected in 12 of 32 patients with generalized seronegative MG. All were women, with onset between ages 21 and 59 years. Seven had prominent neck, shoulder, or respiratory muscle weakness and little or delayed ocular muscle involvement. The response to cholinesterase inhibitors was variable, and electromyographic findings suggested myopathy in several. None improved after thymectomy. All patients improved after plasma exchange, and most had a good response to selected immunotherapy. MuSK antibody status should help diagnose MG with atypical presentations and ensure appropriate patient treatment.

Mycophenolate mofetil for myasthenia gravis: an open-label pilot study.

In an open-label study, 12 patients with refractory MG or who were taking only corticosteroids and required additional immunosuppression received mycophenolate mofetil 1 g twice daily for 6 months. A reduction of three points in a quantified MG score and two points in a manual muscle test or a reduction of 50% in corticosteroid dose defined efficacy. Eight patients improved, beginning after 2 weeks to 2 months. No major side effects were observed.

Retrospective analysis of the use of cyclosporine in myasthenia gravis.

The authors reviewed the records of patients with myasthenia gravis who took cyclosporine for at least 6 months between November 1987 and January 1999. Of 57 patients who took cyclosporine for an average of 3.5 years, 55 (96%) had clinical improvement. The median time to best clinical response was 7 months. Corticosteroids were discontinued or decreased in 95% of 38 patients taking them. Major side effects included elevated serum creatinine (28%) and malignancy (11%). Five percent could not afford or tolerate the drug.

Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment.

The authors reviewed the incidence of cancer, repetitive nerve stimulation findings, and response to treatment in 73 patients with Lambert-Eaton myasthenic syndrome. Thirty-one patients (42%) had lung cancer, 29 small cell. Doubling of the compound motor action potential amplitude in three tested distal muscles was seen in only 41% of patients. Treatment with 3, 4-diaminopyridine produced moderate to marked self-reported functional improvement in 79% of the 53 treated patients.

A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome.

OBJECTIVES: The authors report the results of a prospective, placebo-controlled, randomized study to evaluate the effectiveness of 3,4-diaminopyridine (DAP) in patients with Lambert-Eaton myasthenic syndrome (LEMS) and to determine the acute and long-term side effects of DAP. METHODS: Twenty-six patients with LEMS completed a two-arm parallel treatment protocol in which DAP, 20 mg three times daily, or placebo was given blindly for 6 days, and a quantitative examination of muscle strength (the quantitative myasthenia gravis [QMG] score) was used as the primary measure of efficacy. After the blinded study, patients were given open-label DAP and monitored for side effects as long as there was symptomatic improvement. RESULTS: Twelve patients took DAP, and 14 took placebo. There was no difference in the age of LEMS onset, gender distribution, incidence of lung cancer, or baseline muscle strength between the patients who were randomly assigned to receive placebo and those randomly assigned to DAP. Statistical analysis using the Wilcoxon's rank sum test demonstrated that patients who received DAP had a significantly greater improvement in the QMG score and in the summated amplitude of compound muscle action potentials recorded from three sentinel limb muscles. All but one LEMS patient had significant symptomatic improvement from subsequent open-label DAP. Side effects of DAP were negligible, consisting of perioral and digital paresthesia. Laboratory measurements demonstrated no evidence of toxicity affecting liver, renal, hematologic, endocrinologic, encephalographic, or electrocardiologic function acutely or after 6 months of open-label DAP. CONCLUSIONS: This study corroborates previous studies and many years of clinical experience showing that DAP is an effective and safe treatment for LEMS.

Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy.

The roles that thymus cytokines might play in regulating thymic atrophy are not known. Reversing thymic atrophy is important for immune reconstitution in adults. We have studied cytokine mRNA steady-state levels in 45 normal human (aged 3 days to 78 years) and 34 myasthenia gravis thymuses (aged 4 to 75 years) during aging, and correlated cytokine mRNA levels with thymic signal joint (sj) TCR delta excision circle (TREC) levels, a molecular marker for active thymopoiesis. LIF, oncostatin M (OSM), IL-6, M-CSF, and stem cell factor (SCF) mRNA were elevated in normal and myasthenia gravis-aged thymuses, and correlated with decreased levels of thymopoiesis, as determined by either decreased keratin-positive thymic epithelial space or decreased thymic sjTRECs. IL-7 is a key cytokine required during the early stages of thymocyte development. Interestingly, IL-7 mRNA expression did not fall with aging in either normal or myasthenia gravis thymuses. In vivo administration of LIF, OSM, IL-6, or SCF, but not M-CSF, i.p. to mice over 3 days induced thymic atrophy with loss of CD4+, CD8+ cortical thymocytes. Taken together, these data suggest a role for thymic cytokines in the process of thymic atrophy.

Predictive value of single-fiber electromyography in the extensor digitorum communis muscle of patients with ocular myasthenia gravis: a retrospective study.

PURPOSE: To determine if the jitter in the extensor digitorum communis (EDC) muscle in patients with purely ocular myasthenia gravis (OMG) predicts the subsequent development of generalized myasthenic weakness-Methods: Included in this retrospective study were patients who initially had purely ocular manifestations and had been followed for at least 2 years after onset of myasthenic symptoms. The group consisted of 50 patients with purely ocular weakness, 26 of whom later generalized. All underwent single-fiber electromyography (SFEMG) studies in the EDC muscle at the initial examination RESULTS: : Statistical analysis did not demonstrate that the amount of jitter in the EDC muscle predicted the development of generalized myasthenia gravis (GMG). Also, there was no threshold jitter value that predicted generalized weakness. CONCLUSIONS: : SFEMG measurement of jitter in the EDC muscle demonstrates abnormal neuromuscular transmission in many patients with OMG but is not useful in predicting generalization in these patients.

Changes in thymic function with age and during the treatment of HIV infection.

The thymus represents the major site of the production and generation of T cells expressing alphabeta-type T-cell antigen receptors. Age-related involution may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection; this effect has been seen after chemotherapy and bone-marrow transplantation. Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells. These cells could arise through expansion of existing naive T cells in the periphery or through thymic production of new naive T cells. Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus can contribute to immune reconstitution following HAART.

Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia.

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.

Acquired myasthenia gravis.

Myasthenia gravis, an antibody-mediated disorder of neuromuscular transmission that produces clinical weakness, may be ocular or generalized. Clinical diagnostic evaluation may be supplemented by electrophysiologic studies and antibody testing. Therapeutic options, including anticholinesterase inhibitors, immunosuppressive agents, plasmapheresis and thymectomy, are tailored for the individual patient. This article emphasizes the key aspects of the clinical evaluation, diagnosis, and therapy.