No abstract

; and the Zilucoplan MG Study Group IMPORTANCE Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. OBJECTIVE To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. INTERVENTIONS Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. MAIN OUTCOMES AND MEASURES The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. RESULTS The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change,-2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change,-2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. CONCLUSIONS AND RELEVANCE Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab...

No abstract

No abstract

We report varicella-zoster virus (VZV) meningitis in a healthy adult woman with no antecedent rash and with hypoglycorrhachia. Cerebrospinal fluid (CSF) examination revealed the presence of VZV DNA, anti-VZV immunoglobulin G (IgG) antibody, and intrathecal production of anti-VZV IgG antibody.Keywords varicella zoster; meningitis; hypoglycorrhachia; PCR; immunocompetent Case reportA 26-year-old healthy Bhutanese woman developed increasing throbbing bitemporal headache with photophobia, severe nausea, and vomiting over 2 days. She had been afebrile and denied neck stiffness. There was no past history of headache, skin rash, recent insect bite, or contact with individuals with infections. She had chickenpox at age 5 years. She had emigrated from Bhutan 7 years earlier, but had not traveled abroad recently. Her sister had been treated for tuberculosis. She worked currently as a nanny; the children under her care were healthy and had received Varivax months earlier. On examination, the patient was afebrile and had no rash, nuchal rigidity, or abnormal neurological signs.On day 6 after becoming ill, white blood cell (WBC) count and routine blood chemistries, liver enzymes, erythrocyte sedimentation rate (ESR), anti-nuclear antibody, rapid plasma reagin, and human immunodeficiency virus testing were negative. Brain magnetic resonance imaging (MRI) revealed an ill-defined T2 hyperintensity in the right frontal lobe, extending from the cortical surface to the frontal horn of the lateral ventricle without mass effect, consistent with a hamartoma or cortical dysplasia. The cerebrospinal fluid (CSF) contained 331 WBCs, 99%

The search for effective drug therapy faces important challenges in the areas of basic science and animal research, translation of these results into human clinical trials, inherent bias in human studies and issues related to delays in clinical diagnosis. How these issues may be addressed and why ALS research constitutes fertile grounds for drug development not only for this devastating disease, but also for other more prevalent neurodegenerative diseases, is discussed in this review.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD

Diabetes is the leading cause of peripheral neuropathy globally. Duration of diabetes, glycemic control, and preexisting cardiovascular risk factors independently correlate with the development and progression of diabetic peripheral neuropathy as well as cardiovascular autonomic neuropathy. The pathogenesis of diabetic neuropathy remains unclear, although insulin resistance, oxidative stress, mitochondrial dysfunction, abnormal glucose metabolism, advanced glycation end products, neurotrophic factors, and protein kinase C activation all may play a role. Strict glycemic control remains the only available treatment option, although other treatments are in development. Multiple options are available for symptom management. In this article, we review factors associated with development and progression of diabetic neuropathy and discuss available treatment options.