Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study.

BACKGROUND: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). METHODS: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. RESULTS: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. CONCLUSIONS: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

Continued safety and long-term effectiveness of onasemnogene abeparvovec in Ohio.

5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023. In our cohort, onasemnogene abeparvovec treatment remained safe and no child experienced any significant adverse events, including thrombotic microangiopathy, liver failure or death. All children experienced benefit, although the benefit in those with 2 copies of SMN2 was variable. 79 % of the children treated when symptomatic had a SMN2 modifying therapy added on. With careful screening and post treatment monitoring, onasemnogene abeparvovec is safe and effective for children with SMA in the state of Ohio, but more work needs to be done to ensure optimal outcomes for all children with 2 copies of SMN2.

Powassan Virus Infection Detected by Metagenomic Next-Generation Sequencing, Ohio, USA.

We describe a 4-year-old male patient in Ohio, USA, who had encephalitis caused by Powassan virus lineage 2. Virus was detected by using metagenomic next-generation sequencing and confirmed with IgM and plaque reduction neutralization assays. Clinicians should recognize changing epidemiology of tickborne viruses to enhance encephalitis diagnosis and management.

Causes of HyperCKemia in Children: A Retrospective Cohort Study.

Background and Objectives: Creatine kinase (CK) is a commonly used screening test for neuromuscular disorders (NMDs). However, hyperCKemia can result from several pathologic and physiologic causes. We analyzed neuromuscular disorders in noninfant children with hyperCKemia including those with no weakness and mild CK elevations (<5 times the upper limit of normal). We hypothesized that children with mild CK elevation and no weakness would be unlikely to have neuromuscular disorders and require additional evaluation. Methods: We retrospectively evaluated patients between 1 and 18 years of age seen at a single children's hospital over a 3-calendar-year period with initial total CK values greater than the upper limit of normal with at least 2 years of follow-up data. Final diagnoses were analyzed and associations with possible risk factors assessed. Receiver operating characteristic curves were generated to assess altering CK cutoff values. Results: Of 260 subjects with hyperCKemia, 18 had a neuromuscular disorder (6.9%, 95% confidence interval [CI] 4.2%-10.9%). Of 166 subjects with CK <5 times the upper limit of normal and no weakness, 8 had a neuromuscular disorder (4.8%, 95% CI 2.3%-9.6%). Weakness (odds ratio [OR] 32.5, 95% CI 4-385, P = .0002), and family history of neuromuscular disorders (OR not calculable, P = .0003) were associated with neuromuscular disorders. An optimal CK threshold of 777 was identified on receiver operating characteristic curve analysis (sensitivity of 72% and specificity of 64%). The most commonly identified neuromuscular disorders were muscular dystrophies, inflammatory myopathies, and metabolic myopathies. Conclusion: Most children with hyperCKemia will not be diagnosed with a neuromuscular disorder, but a significant minority even with mild hyperCKemia and without weakness may warrant additional evaluation.

Evidence-based guideline: Neuromuscular ultrasound for the diagnosis of ulnar neuropathy at the elbow.

INTRODUCTION/AIMS: The purpose of this literature review is to develop an evidence-based guideline for the use of neuromuscular ultrasound in the diagnosis of ulnar neuropathy at the elbow (UNE). The proposed research question was: "In patients with suspected UNE, does ulnar nerve enlargement as measured with ultrasound accurately identify those patients with UNE?" METHODS: A systematic review and meta-analysis was performed, and studies were classified according to American Academy of Neurology criteria for rating articles for diagnostic accuracy. RESULTS: Based on Class I evidence in four studies, it is probable that neuromuscular ultrasound measurement of the ulnar nerve at the elbow, either of diameter or cross-sectional area (CSA), is accurate for the diagnosis of UNE. RECOMMENDATION: For patients with symptoms and signs suggestive of ulnar neuropathy, clinicians should offer ultrasonographic measurement of ulnar nerve cross-sectional area or diameter to confirm the diagnosis and localize the site of compression (Level B).

Using and interpreting electrodiagnostic tests.

Electrodiagnostic testing, consisting of nerve conduction studies and needle electrode examination, serves as an extension of a neurologic examination for evaluating a variety of focal and generalized neuromuscular conditions. By providing important clues on location, chronicity, severity, and pathophysiology, it can help to establish a diagnosis, evaluate the need for surgery, and assess patients who do not improve as expected after surgery.

Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes.

BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

Utility of electrodiagnostic studies in patients referred with a diagnosis of polyneuropathy.

BACKGROUND: Peripheral polyneuropathies (PN) are common neuromuscular conditions. The role of electrodiagnostic study (EDX) in diagnosis of PN is not well-defined. METHODS: We performed a retrospective chart review of patients referred for EDX evaluation of PN. RESULTS: Of 162 patients analyzed, 23 had pure peripheral neuropathy (pPN; 14.2%), 29 had peripheral neuropathy and another diagnosis (PN+; 17.9%), 51 had an alternative diagnosis (nonPN; 31.5%), and 59 had normal studies (36.4%). In univariable analysis, age (P < .001) and gender (P = .004) were weakly associated with final diagnosis. In multinomial logistic regression analysis, significant predictors included age (odds ratio [OR] for nonPN/PN+:1.07 per year; 95% confidence interval [CI], 1.03-1.11), gender (OR for PN+:0.2, 95% CI, 0.07-0.61), and diabetes/prediabetes (OR for pPN:3.29; 95% CI, 1.17-9.27). CONCLUSIONS: These data suggest that EDX commonly yields additional or nonPNs in patients referred with a diagnosis of PN, and although some variables predict electrodiagnosis, none have a large enough effect to suggest poor utility in any subpopulation.

Pediatric-Onset Multiple Sclerosis: A Single Center Study.

Pediatric-onset multiple sclerosis (POMS), once thought to be rare, is now being diagnosed in increasing numbers in children. Despite improvements to diagnostic criteria, the diagnosis and management of POMS remains challenging. The aim of this study is to retrospectively describe a growing POMS patient population seen at a single center over a 13 year period. Epidemiologic, clinical, neuroimaging, laboratory features and therapeutic management and outcome data were collected and analyzed. These data support associations between MS and environmental triggers such as obesity and vitamin D deficiency. Presenting symptoms, magnetic resonance imaging and laboratory findings were consistent with the existing literature; however, the prevalence of cortical lesions and abnormal saccadic pursuit is higher than other reports. Data also demonstrate a shift in practice from first- to second-line therapies over the observed period.

Patterning of regional gene expression in autism: new complexity.

Autism is a common and often severe neurodevelopmental disorder for which diverse pathophysiological processes have been proposed. Recent gene expression data comparing autistic and control brains suggest that the normal differential gene expression between frontal and temporal cortex is attenuated in autistic brains. It is unknown if regional de-differentiation occurs elsewhere in autistic brain. Using high resolution, genome-wide RNA expression microarrays and brain specimens meeting stringent selection criteria we evaluated gene expression data of two other regions: Brodmann area 19 (occipital cortex) and cerebellar cortex. In contrast to frontal/temporal cortical data, our data do not indicate an attenuation of regional specialization between occipital and cerebellar cortical regions in autistic brains.

Long-term effects of deep brain stimulation for essential tremor with subjective and objective quantification via mailed-in questionnaires.

BACKGROUND: Deep brain stimulation (DBS) is a standard treatment for patients with disabling essential tremor. The short-term efficacy rate is well established. OBJECTIVES: To assess the long-term effects of DBS in our series and evaluate the durability of the effects over time. METHODS: Eighty-four patients implanted with unilateral or bilateral DBS for essential tremor were asked to complete three mailed-in questionnaires to assess DBS efficacy objectively and subjectively. RESULTS: Twenty-six patients responded, with a median follow-up of 41 months. Approximately half of the patients had more than 48 months of follow-up. At the time of follow-up, the Tremor Rating Scale was reduced from a mean score of 7 (5-8) to 3 (2-3) with DBS OFF and ON, respectively. Quality of life, measured with a subset of items of the ADL Taxonomy, improved from a mean of 26 (23-33) to 12 (12-14), comparing DBS OFF and ON. No significant differences were seen when comparing efficacy at short- (<12 months), middle- (12-48 months) or long-term (>48 months) follow-ups. CONCLUSION: DBS has long-term efficacy for tremor control. This is associated with sustained benefits in quality of life. The duration of the follow-up was not associated with any significant difference in efficacy.

Brain transcriptional and epigenetic associations with autism.

BACKGROUND: Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic. METHODOLOGY/PRINCIPAL FINDINGS: To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and whole genome DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling. CONCLUSIONS/SIGNIFICANCE: This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes.