Henry J. Kaminski

Myasthenia gravis Recommendations for clinical research standards

The need for universally accepted classifications, grading systems, and methods of analysis for patients undergoing therapy for MG is widely recognized and is particularly needed for therapeutic research trials. The Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) formed a Task Force in May 1997 to address these issues. Initially, the Task Force planned to develop classifications and outcome measures pertaining only to standardizing thymectomy trials. However, it quickly became apparent that their efforts should apply to all therapeutic trials for MG, and thus the scope of the mission was expanded. During the development of these recommendations, the Task Force faced numerous dilemmas for which no universally satisfactory solution was available. Dilemmas were defined as “situations that require one to choose between two equally balanced alternatives or predicaments that seemingly defy satisfactory solutions.” The Task Force members agreed at the outset, however, that their primary goal was to develop a uniform set of classifications to be used in the comparative analysis of the various therapeutic interventions for MG. With this as the primary goal, a consensus was gradually developed. In developing a consensus, at least two meetings were held each year during a 3-year period. Between meetings there was exchange of all proposals by electronic and surface mail, consultation with national and international experts in the field, critical analysis of all proposals, and many revisions. All conflicts (both minor and major) were resolved by vote. Virtually all issues were eventually approved unanimously; a few received a plurality of six. This report presents the work of the Task Force and proposes classification systems and definitions of response to therapy designed to achieve more uniformity in recording and reporting clinical trials and outcomes research. Although designed primarily for research purposes, we think physicians may find some of …

Myasthenia gravis: past, present, and future

Myasthenia gravis (MG) is an autoimmune syndrome caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signaling at the neuromuscular junction (NMJ). These proteins include the nicotinic AChR or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering. Much is known about the mechanisms that maintain self tolerance and modulate anti-AChR Ab synthesis, AChR clustering, and AChR function as well as those that cause neuromuscular transmission failure upon Ab binding. This insight has led to the development of improved diagnostic methods and to the design of specific immunosuppressive or immunomodulatory treatments.

Spinal epidural abscess: a ten-year perspective.

A retrospective study of spinal epidural abscess spanning 10 years and encompassing 40 patients was done. Epidemiology, clinical features, laboratory findings, radiographic imaging, therapy, and outcome were examined and compared with previous series. An increasing incidence of the disease (up to 1.96 patients per 10,000 admissions per year) and an older, more debilitated population (67% having factors predisposing them to infection) were discovered. Over half of the population was studied with magnetic resonance imaging, which was found to be equally as sensitive (91%) as myelography with computed tomography (92%). Magnetic resonance imaging offers the advantages of being noninvasive and able to delineate other entities, which makes it the imaging modality of choice. Preoperative paralysis and neurological deterioration from normal were identified as poor prognostic features. Of 7 patients with preoperative paralysis, 5 died, and the rest failed to recover neurological function. Eleven patients with initially normal neurological exams deteriorated in the hospital before surgical intervention. Eight of these patients were being treated with appropriate antibiotics; 2 became paralyzed despite more than 3 weeks of antibiotic therapy. Only 3 of these 11 patients recovered fully. Immediate surgical decompression combined with antibiotics remains the treatment of choice.

Extraocular muscle is defined by a fundamentally distinct gene expression profile.

Skeletal muscle fibers are defined by patterned covariation of key traits that determine contractile and metabolic characteristics. Although the functional properties of most skeletal muscles result from their proportional content of a few conserved muscle fiber types, some, typically craniofacial, muscles exhibit fiber types that appear to lie outside the common phenotypic range. We analyzed gene expression profiles of three putative muscle classes, limb, masticatory, and extraocular muscle (EOM), in adult mice by high-density oligonucleotide arrays. Pairwise comparisons using conservative acceptance criteria identified expression differences in 287 genes between EOM and limb and/or masticatory muscles. Use of significance analysis of microarrays methodology identified up to 400 genes as having an EOM-specific expression pattern. Genes differentially expressed in EOM reflect key aspects of muscle biology, including transcriptional regulation, sarcomeric organization, excitation-contraction coupling, intermediary metabolism, and immune response. These patterned differences in gene expression define EOM as a distinct muscle class and may explain the unique response of these muscles in neuromuscular diseases.

Randomized Trial of Thymectomy in Myasthenia Gravis

BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Molecular architecture of the neuromuscular junction

The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined. Muscle Nerve, 2005

Supply and demand analysis of the current and future US neurology workforce

Objective: This study estimates current and projects future neurologist supply and demand under alternative scenarios nationally and by state from 2012 through 2025. Methods: A microsimulation supply model simulates likely career choices of individual neurologists, taking into account the number of new neurologists trained each year and changing demographics of the neurology workforce. A microsimulation demand model simulates utilization of neurology services for each individual in a representative sample of the population in each state and for the United States as a whole. Demand projections reflect increased prevalence of neurologic conditions associated with population growth and aging, and expanded coverage under health care reform. Results: The estimated active supply of 16,366 neurologists in 2012 is projected to increase to 18,060 by 2025. Long wait times for patients to see a neurologist, difficulty hiring new neurologists, and large numbers of neurologists who do not accept new Medicaid patients are consistent with a current national shortfall of neurologists. Demand for neurologists is projected to increase from ∼18,180 in 2012 (11% shortfall) to 21,440 by 2025 (19% shortfall). This includes an increased demand of 520 full-time equivalent neurologists starting in 2014 from expanded medical insurance coverage associated with the Patient Protection and Affordable Care Act. Conclusions: In the absence of efforts to increase the number of neurology professionals and retain the existing workforce, current national and geographic shortfalls of neurologists are likely to worsen, exacerbating long wait times and reducing access to care for Medicaid beneficiaries. Current geographic differences in adequacy of supply likely will persist into the future.

Neuromuscular disorders in clinical practice

Neuromuscular disorders in clinical practice / , Neuromuscular disorders in clinical practice / , کتابخانه دیجیتال جندی شاپور اهواز

Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals

Objective: To determine the incidence and mortality rates and predictors of death in myasthenia gravis (MG) and MG crisis in a large US cohort. Methods: Our cohort was identified from the Nationwide Inpatient Sample database for the years 2000 through 2005 using ICD-9-CM codes. MG crisis was identified by the principal diagnosis code or by the presence of respiratory failure. The incidence of MG was stratified by age, ethnicity, and gender. Multivariate logistic regression analysis was used to identify predictors of mortality in MG. For trend analyses of immune intervention, we used the Cochrane-Armitage test. Results: After data cleansing, 5,502 patients with MG were included. In women, the incidence of admission was two to three times higher during the first 5 decades. In men, the incidence of admission was higher during the sixth, seventh, and eighth decades. The annual incidence rate of MG was higher in black women (0.01 per 1,000 persons/year) compared to white women and white and black men (0.009, 0.008, and 0.007 per 1,000 persons/year). The overall in-hospital mortality rate was 2.2%, being higher in MG crisis (4.47%). Older age and respiratory failure were the predictors of death, with adjusted odds ratios of 9.28 (95% confidence interval [CI], 3.31, 26.0) and 3.58 (95% CI, 2.01, 6.38). The trend of IV immunoglobulin utilization has increased compared to plasma exchange and thymectomy (p < 0.0001). Conclusion: Myasthenia gravis (MG) is still a disease of young women and old men, as reflected by the hospital admission rates. In-hospital mortality of MG is low. Hospital utilization of IV immunoglobulin has significantly increased compared to plasma exchange and thymectomy.

A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1).

Protein O-mannose beta1,2-N-acetyglucosaminyltransferase 1 (POMGnT1) is an enzyme involved in the synthesis of O-mannosyl glycans. Mutations of POMGnT1 in humans result in the muscle-eye-brain (MEB) disease. In this study, we have characterized a null mutation generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus. Expression of POMGnT1 mRNA was abolished in mutant mice. Glycosylation of alpha-dystroglycan was also reduced. POMGnT1 mutant mice were viable with multiple developmental defects in muscle, eye, and brain, similar to the phenotypes observed in human MEB disease. The present study provides the first genetic animal model to further dissect the roles of POMGnT1 in MEB disease.