Publications by authors named "Anthony Amato"

196 Publications

Identification of Caveolae-Associated Protein 4 Autoantibodies as a Biomarker of Immune-Mediated Rippling Muscle Disease in Adults.

JAMA Neurol 2022 Aug;79(8):808-816

Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Importance: Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking.

Objective: To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics.

Design, Setting, And Participants: This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months.

Exposures: Diagnosis of iRMD.

Main Outcomes And Measures: Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features.

Results: Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change.

Conclusions And Relevance: The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.
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http://dx.doi.org/10.1001/jamaneurol.2022.1357DOI Listing
August 2022

Safety and outcomes of eculizumab for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

Muscle Nerve 2022 Jun 9. Epub 2022 Jun 9.

Harvard Medical School, Boston, Massachusetts, USA.

Introduction/aims: Safety and outcomes data on eculizumab for generalized myasthenia gravis (gMG) in clinical practice remain limited. Outcomes and concomitant medication use may differ in practice compared with clinical trials. We analyzed the clinical and safety outcomes of patients who received eculizumab at our institutions.

Methods: Patients with acetylcholine receptor antibody positive (AChR+) gMG, who received ≥1 dose of eculizumab and had ≥1 follow-up before December 10, 2021, were identified. Data were abstracted by chart review. Outcomes included MG Foundation of America Post Intervention Status (MGFA-PIS), Clinical Classification (MGFA-CC), MG-Activities of Daily Living (MG-ADL), concurrent immunomodulatory therapy use, and adverse events.

Results: Twelve patients were included. Mean age at eculizumab initiation was 57.4 y (range, 21-77). Eight had refractory MG. Four had history of thymoma and thymectomy. A mean of 3.2 (range, 2-5) immunomodulatory therapies were previously tried. Mean follow-up duration was 18 mo (range, 2-21.6). Clinical improvement occurred rapidly; MGFA-PIS was improved in 80%, and MGFA-CC improved in 83% at 1 mo. Mean MG-ADL decreased from 8.7 to 2.8 at 1 mo, and remained .5 over 1.5 y. Mean daily prednisone dose decreased from 22.5 mg to 7.2 mg at 1.5 y. Five of 7 patients discontinued maintenance IVIG or PLEX. No patients had meningococcal infections and adverse events were mild.

Discussion: Clinical improvement occurred in most patients after eculizumab initiation, beginning as quickly as 1 mo. Steroids were tapered and maintenance IVIG and PLEX were discontinued in most. Eculizumab had a favorable safety profile even when combined with other immunosuppressants.
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http://dx.doi.org/10.1002/mus.27656DOI Listing
June 2022

Carbon conundrums: Do United States' current carbon market baselines represent an undesirable ecological threshold?

Glob Chang Biol 2022 07 10;28(13):3991-3994. Epub 2022 May 10.

USDA Forest Service, Inventory, Monitoring, and Assessment Research, Washington, District of Columbia, USA.

Relative frequency distribution of observed annual mortality expressed in aboveground (AG) carbon (C) (Mg CO e ha year ) summarized across supersections by forest type [Hardwood (HW) vs. Softwood (SW)] and site class (Low vs. High) based on approximately 130,000 remeasured USDA Forest Service Forest Inventory and Analysis plots across the US. Top panel summarizes conditions in plots that do and do not meet the California Air Resources Board standards based on total basal area, whereas bottom panel summarizes conditions in plots falling inside and outside of optimum relative density levels. The latter represents a biophysically-informed approach accounting for changes in tree (and carbon) packing over forest development.
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http://dx.doi.org/10.1111/gcb.16215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322682PMC
July 2022

2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders.

Heart Rhythm 2022 Apr 29. Epub 2022 Apr 29.

Mayo Clinic College of Medicine, Phoenix, Arizona.

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.
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http://dx.doi.org/10.1016/j.hrthm.2022.04.022DOI Listing
April 2022

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2022 07 9;66(1):50-62. Epub 2022 May 9.

Acceleron Pharma, Cambridge, Massachusetts, USA.

Introduction/aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD.

Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated.

Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions.

Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
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http://dx.doi.org/10.1002/mus.27558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321022PMC
July 2022

Cold-air pools as microrefugia for ecosystem functions in the face of climate change.

Ecology 2022 Aug 28;103(8):e3717. Epub 2022 May 28.

Rubenstein School of Environment and Natural Resources, University of Vermont, Burlington, Vermont, USA.

Cold-air pooling is a global phenomenon that frequently sustains low temperatures in sheltered, low-lying depressions and valleys and drives other key environmental conditions, such as soil temperature, soil moisture, vapor pressure deficit, frost frequency, and winter dynamics. Local climate patterns in areas prone to cold-air pooling are partly decoupled from regional climates and thus may be buffered from macroscale climate change. There is compelling evidence from studies across the globe that cold-air pooling impacts plant communities and species distributions, making these decoupled microclimate areas potentially important microrefugia for species under climate warming. Despite interest in the potential for cold-air pools to enable species persistence under warming, studies investigating the effects of cold-air pooling on ecosystem processes are scarce. Because local temperatures and vegetation composition are critical drivers of ecosystem processes like carbon cycling and storage, cold-air pooling may also act to preserve ecosystem functions. We review research exploring the ecological impacts of cold-air pooling with a focus on vegetation, and then present a new conceptual framework in which cold-air pooling creates feedbacks between species and ecosystem properties that generate unique hotspots for carbon accrual in some systems relative to areas more vulnerable to regional climate change impacts. Finally, we describe key steps to motivate future research investigating the potential for cold-air pools to serve as microrefugia for ecosystem functions under climate change.
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http://dx.doi.org/10.1002/ecy.3717DOI Listing
August 2022

Removal of invasive Scotch broom increases its negative effects on soil chemistry and plant communities.

Oecologia 2022 Jan 4;198(1):243-254. Epub 2022 Jan 4.

USDA Forest Service, Pacific Northwest Research Station, 3625 93rd Avenue Southwest, Olympia, WA, 98512, USA.

Recovery of ecosystem properties following removal of invasive plants likely varies with characteristics of the plant and the relative soil quality at a given site. These factors may influence the occurrence of soil legacies and secondary invasions, hindering the effectiveness of restoration strategies. We assessed the potential for ecosystem recovery following removal of N-fixing Scotch broom for 4 years at two sites that contrasted strongly in soil quality in western Washington and Oregon, USA. Comparisons were made among plots, where Scotch broom was never present (uninvaded), retained, or removed. Scotch broom removal increased PAR and soil temperature but had limited effects on soil moisture. Concentrations of soil Ca, Mg, K, and P were significantly lower with Scotch broom removal, with the effect being most pronounced at the low-quality site. NMS ordinations indicated that the treatments differed in vegetation composition, with limited recovery following broom removal. Non-native and native species varied inversely in their abundance responses, where non-native species abundance was greatest in the removal treatment, intermediate in the retained treatment, and lowest in the uninvaded treatment, indicating occurrence of a secondary invasion following removal. As with the soil response, effects were more pronounced at the low-quality site. Our findings indicate that Scotch broom removal exacerbates negative effects on soil chemistry and plant communities, with little evidence of recovery over our study period. These findings highlight the importance of controlling Scotch broom invasions immediately after the species establishes, especially on low-quality sites that are more susceptible to Scotch broom invasion.
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http://dx.doi.org/10.1007/s00442-021-05099-zDOI Listing
January 2022

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study.

Neurology 2021 Dec 2. Epub 2021 Dec 2.

Department of Neurology, Kansas University School of Medicine, Kansas City, KS.

Objective: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG).

Methods: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks.

Results: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified.

Conclusions: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG.

Classification Of Evidence: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.

Trial Registration: ClinicalTrials.gov Identifier: NCT02110706.
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http://dx.doi.org/10.1212/WNL.0000000000013121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8793103PMC
December 2021

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A.

Orphanet J Rare Dis 2021 10 16;16(1):433. Epub 2021 Oct 16.

Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A.

Methods: In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set.

Results: High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI [- 0.68 to - 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated.

Conclusion: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.
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http://dx.doi.org/10.1186/s13023-021-02040-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520617PMC
October 2021

Retrospective analysis of safety and outcomes of rituximab for myasthenia gravis in patients ≥65 years old.

Muscle Nerve 2021 12 28;64(6):651-656. Epub 2021 Aug 28.

Harvard Medical School, Boston, Massachusetts, USA.

Introduction/aims: Optimal management of myasthenia gravis (MG) in individuals ≥65 y old is unknown and patient factors may limit therapeutic choices. Safety and efficacy of rituximab in older patients with MG has not been well-studied.

Methods: This retrospective study examined 40 patients (14 patients ≥65 y old) treated with rituximab for MG. The primary efficacy outcome was the proportion of patients reaching "Improved" or better on Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) at 12 mo, compared between younger and older patients.

Results: Ninety-two percent of patients ≥65 y old achieved MGFA PIS Improved or better at 12 mo compared to 69% of those <65 y old (P = .11). Median prednisone dose for the cohort decreased in the year following rituximab initiation (20 mg [interquartile range, 10-35] to 10 mg [0-13], P = .01). Non-refractory MG was predictive of favorable outcome, whereas age was not. Serious adverse events (SAEs) were similar between older and younger patients (21.4% vs. 30.8%, P = .715). No patients ≥65 y old required discontinuation of rituximab due to SAE. One death occurred in a patient <65 y old due to systemic inflammatory response syndrome.

Discussion: At 12 mo following initiation of rituximab for MG, patients ≥65 y old experienced similarly high rates of improvement in their myasthenic symptoms as younger patients, without an increased risk of experiencing SAEs. Rituximab should be considered in the treatment paradigm in older patients and in non-refractory MG patients of any age.
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http://dx.doi.org/10.1002/mus.27393DOI Listing
December 2021

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

J Immunother Cancer 2021 07;9(7)

Harvard Medical School, Boston, Massachusetts, USA.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
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http://dx.doi.org/10.1136/jitc-2021-002890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291304PMC
July 2021

Neuromuscular complications of coronavirus disease-19.

Curr Opin Neurol 2021 10;34(5):669-674

Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Purpose Of Review: Since its outbreak in Wuhan, China in late 2019, coronavirus disease-19 (COVID-19) has become a global pandemic. The number of affected cases and deaths continues to rise. Primarily a respiratory illness, COVID-19 is now known to affect various organ systems including peripheral nerve and skeletal muscle. The purpose of this review is to discuss the scope of neuromuscular manifestations and complications of COVID-19.

Recent Findings: Several neuromuscular conditions, including Guillain-Barré syndrome, rhabdomyolysis, and myositis, have been reported in patients infected with COVID-19, but even with a temporal association, a causal relationship remains unproven. Direct invasion of neurons or myocytes by the virus, and immune-mediated injury have been speculated but not consistently demonstrated. In addition to potentially causing the above conditions, COVID-19 can trigger exacerbations of preexisting neuromuscular conditions such as myasthenia gravis, and severe infections can lead to critical illness myopathy/polyneuropathy.

Summary: COVID-19 appears to be potentially associated with a wide range of neuromuscular manifestations and complications. Further studies are needed to examine these possible associations, understand the pathogenesis, and develop preventive and treatment strategies.
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http://dx.doi.org/10.1097/WCO.0000000000000970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452251PMC
October 2021

Skeletal Muscle and Peripheral Nerve Histopathology in COVID-19.

Neurology 2021 08 7;97(8):e849-e858. Epub 2021 Jun 7.

From the Departments of Neurology (J.S., A.A.A.) and Pathology (R.F.P., G.S.P., I.H.S.), Brigham and Women's Hospital; Harvard Medical School (J.S., S.S.M., R.F.P., G.S.P., A.A.A., I.H.S.); and Department of Neurology (S.S.M., S.I.C.), Massachusetts General Hospital, Boston.

Objective: To explore the spectrum of skeletal muscle and nerve pathology of patients who died after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to assess for direct viral invasion of these tissues.

Methods: Psoas muscle and femoral nerve sampled from 35 consecutive autopsies of patients who died after SARS-CoV-2 infection and 10 SARS-CoV-2-negative controls were examined under light microscopy. Clinical and laboratory data were obtained by chart review.

Results: In SARS-CoV-2-positive patients, mean age at death was 67.8 years (range 43-96 years), and the duration of symptom onset to death ranged from 1 to 49 days. Four patients had neuromuscular symptoms. Peak creatine kinase was elevated in 74% (mean 959 U/L, range 29-8,413 U/L). Muscle showed type 2 atrophy in 32 patients, necrotizing myopathy in 9, and myositis in 7. Neuritis was seen in 9. Major histocompatibility complex-1 (MHC-1) expression was observed in all cases of necrotizing myopathy and myositis and in 8 additional patients. Abnormal expression of myxovirus resistance protein A (MxA) was present on capillaries in muscle in 9 patients and in nerve in 7 patients. SARS-CoV-2 immunohistochemistry was negative in muscle and nerve in all patients. In the 10 controls, muscle showed type 2 atrophy in all patients, necrotic muscle fibers in 1, MHC-1 expression in nonnecrotic/nonregenerating fibers in 3, MxA expression on capillaries in 2, and inflammatory cells in none, and nerves showed no inflammatory cells or MxA expression.

Conclusions: Muscle and nerve tissue demonstrated inflammatory/immune-mediated damage likely related to release of cytokines. There was no evidence of direct SARS-CoV-2 invasion of these tissues.

Classification Of Evidence: This study provides Class IV evidence that muscle and nerve biopsies document a variety of pathologic changes in patients dying of coronavirus disease 2019 (COVID-19).
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http://dx.doi.org/10.1212/WNL.0000000000012344DOI Listing
August 2021

Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases.

Ann Neurol 2021 06 1;89(6):1240-1247. Epub 2021 Apr 1.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty-four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240-1247.
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http://dx.doi.org/10.1002/ana.26063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494076PMC
June 2021

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

Neurology 2021 03 17;96(12):e1595-e1607. Epub 2021 Feb 17.

From the Department of Neurology (A.A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Medical Research Council Centre for Neuromuscular Diseases (M.G.H., P.M.M.) and Institute of Neurology, Department of Neuromuscular Diseases & Centre for Rheumatology (P.M.M.), University College London; Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases (P.M.M.), University College London Hospitals NHS Foundation Trust; Department of Rheumatology (P.M.M.), Northwick Park Hospital, London North West University Healthcare NHS Trust, UK; Department of Neurology (U.A.B.), Leiden University Medical Center, Netherlands; National Institute for Health Research Manchester Biomedical Research Centre (H.C.), Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, UK; Department of Internal Medicine and Clinical Immunology (O.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; Novartis Healthcare Pvt. Ltd. (K.A.K), Hyderabad, India; Novartis Pharmaceuticals (M.W., D.A.P.), East Hanover, NJ; Novartis Pharma AG (L.B.T., A.A.S-T.), Basel, Switzerland; Department of Neurology (T.E.L.), The Johns Hopkins University School of Medicine, Baltimore, MD; Institute for Immunology & Infectious Diseases (M.N.), Fiona Stanley Hospital, Murdoch University and Notre Dame University, Perth; Department of Neurology (C.L.), Royal North Shore Hospital, New South Wales; Calvary Health Care Bethlehem (K.A.R.), Caulfield South, Australia; Department of Neurology (M.d.V), Amsterdam University Medical Centre, the Netherlands; Department of Medicine (D.P.A.), University of Miami, FL; Department of Neurology (R.J.B., M.M.D.), University of Kansas Medical Center, Kansas City; Department of Neurology (J.A.L.M.), Newcastle upon Tyne Hospitals NHS Foundation Trust, UK; Department of Neurology (J.T.K.), The Ohio State University Wexner Medical Center, Columbus; Neuromuscular Research Center (B.O., N.C.J.), UC Davis School of Medicine, Sacramento, CA; Department of Neurology (P.V.d.B.), University Hospital Saint-Luc, University of Louvain, Brussels; Neuromuscular Reference Centre, Department of Neurology (J.B.), Antwerp University Hospital; Institute Born-Bunge (J.B.), University of Antwerp; Department of Neurology (J.L.d.B.), Ghent University Hospital, Belgium; Department of Neurology (C.K.), Oregon Health & Science University, Portland; Department of Neurology (W.S.D.), Massachusetts General Hospital, Neuromuscular Diagnostic Center and Electromyography Laboratory, Boston; Department of Neurology (M.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Università Cattolica del Sacro Cuore (M.M.), Rome, Italy; Department of Neurology (S.P.N.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (H.H.J.), University Hospital and University of Zurich, Switzerland; Department of Neurosciences (E.P.), University of Padova School of Medicine; Fondazione IRCCS Istituto Neurologico Carlo Besta (L.M.), Milan; Unit of Neurology and Neuromuscular Disorders (C.R.), Azienda Ospedaliera Universitaria Policlinico G Martino, University of Messina; Center for Neuromuscular Diseases (M.F.), Unit of Neurology, ASST Spedali Civili and University of Brescia, Italy; Nerve and Muscle Center of Texas (A.I.S.), Houston; Neuromuscular Research Center (K.S.), Phoenix, AZ; Department of Neurology (N.A.G.), ALS & Neuromuscular Center, University of California Irvine, Orange; Department of Neurology (M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (S.Y.), Kumamoto University Hospital; Department of Neurology (N.S.), Tohoku University Hospital, Miyagi; Department of Neurology (M.A.), Tohoku University School of Medicine, Sendai; Department of Neurology (M.K.), Nagoya University Hospital, Aichi; Department of Neurology (H.M.), Osaka City General Hospital; Wakayama Medical University Hospital (K.M.); Tokushima University Hospital (H.N.); Department of Neuromuscular Research (I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; RTI Health Solutions (C.D.R., V.S.L.W.), Research Triangle Park, NC; Copenhagen Neuromuscular Center (J.V.), Rigshospitalet, University of Copenhagen, Denmark; and UCB (L.Z.A.), Bulle, Switzerland. H.N. is currently affiliated with the Department of Neurology, Kanazawa Medical University, Ishikawa, Japan. B.O. is currently affiliated with the Department of Neurology, Mayo Clinic, Jacksonville, FL.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).

Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.

Results: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).

Conclusion: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT02573467.

Classification Of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
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http://dx.doi.org/10.1212/WNL.0000000000011626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032371PMC
March 2021

Sensory Ganglionopathy. Reply.

N Engl J Med 2021 01;384(2):193-194

Brigham and Women's Hospital, Boston, MA

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http://dx.doi.org/10.1056/NEJMc2033783DOI Listing
January 2021

Using Solution Electrowriting to Control the Properties of Tubular Fibrous Conduits.

ACS Biomater Sci Eng 2021 02 18;7(2):400-407. Epub 2021 Jan 18.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, 134 Hollister Drive, 283 Kimball Hall, Ithaca, New York 14853-0001, United States.

Multiple additive manufacturing techniques have been developed in recent years to produce structures with tunable physical, chemical, and mechanical properties and defined architecture. Solution electrospinning, although an older and more established technique, normally cannot achieve the pattern resolution and tunability of these newer manufacturing techniques. In this study, we present solution electrowriting as a method to produce fibrous conduits from various polymers with tunable patterns, dimensions, and scaffold porosity. We demonstrate the importance of solvent selection during solution electrowriting and discuss how solvent polarity and volatility can be exploited to controllably alter the structure of the resulting scaffolds. The technique can be readily implemented with equipment for conventional electrospinning and offers versatility, control, and customization that is uncommon in the solution electrospinning field.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01419DOI Listing
February 2021

Covid-19-Associated Myopathy Caused by Type I Interferonopathy.

N Engl J Med 2020 12 20;383(24):2389-2390. Epub 2020 Nov 20.

Brigham and Women's Hospital, Boston, MA

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http://dx.doi.org/10.1056/NEJMc2031085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722689PMC
December 2020

Clinical Reasoning: A 63-Year-Old Woman Presenting With Bilateral Leg Pain.

Neurology 2021 02 18;96(7):343-348. Epub 2020 Nov 18.

From the Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1212/WNL.0000000000011220DOI Listing
February 2021

Three-Dimensional Printing of Poly(glycerol sebacate) Acrylate Scaffolds Digital Light Processing.

ACS Appl Bio Mater 2020 Nov 26;3(11):7575-7588. Epub 2020 Oct 26.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14853-0001, United States.

Digital light processing (DLP)-based three-dimensional (3D) printing offers large improvements in fabrication throughput and spatial resolution when compared to various other additive manufacturing techniques. Both properties are highly desirable when fabricating biomaterial scaffolds that require design precision. Poly(glycerol sebacate) acrylate (PGSA) is a degradable, biocompatible, and photocurable elastomer. In this work, PGSA ink was developed for DLP 3D printing of porous tubular structures. Ink formulations with varying prepolymer concentrations (10-60 wt %), diluent (dimethyl sulfoxide (DMSO), 2-butoxyethyl acetate (EGBEA), and 1:1 DMSO/EGBEA), and degree of PGSA acrylation (17-75%) were studied to optimize printing efficiency and bulk properties of the printed scaffolds. Prepolymer inks with viscosity (<5 Pa·s) and photopolymerization kinetics (exposure time <10 s) appropriate for DLP were developed. Photocrosslinked PGSA scaffolds were further exposed to postfabrication treatments including additional UV exposure or thermal curing (150 °C) to demonstrate tunability in scaffold degradation kinetics and mechanical properties. Complementary to this effort, a 3D model-generation tool was developed to enable user-friendly customization of tubular scaffold design by controlling the pore and strut size of the volumetric mesh. The resulting DLP-printed PGSA scaffolds present high mimicry to complex 3D models with a minimum feature thickness of 80 μm. The tunable properties of PGSA coupled with enhanced precision in microstructure geometry provide a fabrication platform for a variety of tissue regeneration applications.
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http://dx.doi.org/10.1021/acsabm.0c00804DOI Listing
November 2020

Sensory Ganglionopathy.

N Engl J Med 2020 Oct;383(17):1657-1662

From Brigham and Women's Hospital and Harvard Medical School, Boston (A.A.A.).

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http://dx.doi.org/10.1056/NEJMra2023935DOI Listing
October 2020

TGFβ3 is neuroprotective and alleviates the neurotoxic response induced by aligned poly-l-lactic acid fibers on naïve and activated primary astrocytes.

Acta Biomater 2020 11 6;117:273-282. Epub 2020 Oct 6.

Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA. Electronic address:

Following spinal cord injury, astrocytes at the site of injury become reactive and exhibit a neurotoxic (A1) phenotype, which leads to neuronal death. In addition, the glial scar, which is composed of reactive astrocytes, acts as a chemical and physical barrier to subsequent axonal regeneration. Biomaterials, specifically electrospun fibers, induce a migratory phenotype of astrocytes and promote regeneration of axons following acute spinal cord injury in preclinical models. However, no study has examined the potential of electrospun fibers or biomaterials in general to modulate neurotoxic (A1) or neuroprotective (A2) astrocytic phenotypes. To assess astrocyte reactivity in response to aligned poly-l-lactic acid microfibers, naïve spinal cord astrocytes or spinal cord astrocytes primed towards the neurotoxic phenotype (A1) were cultured on fibrous scaffolds. Gene expression analysis of the pan-reactive astrocyte makers (GFAP, Lcn2, SerpinA3), A1 specific markers (H2-D1, SerpinG1), and A2 specific makers (Emp1, S100a10) was done using quantitative polymerase chain reaction (qPCR). Electrospun fibers mildly increased the expression of the pan-reactive and A1-specific markers, showing the ability of fibrous materials to induce a more reactive, A1 phenotype. However, when naïve or activated astrocytes were cultured on fibers in the presence of transforming growth factor β3 (TGFβ3), the expression of A1-specific markers was greatly reduced, which in turn improved neuronal survival in culture.
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http://dx.doi.org/10.1016/j.actbio.2020.09.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645246PMC
November 2020

Aligned Fingolimod-Releasing Electrospun Fibers Increase Dorsal Root Ganglia Neurite Extension and Decrease Schwann Cell Expression of Promyelinating Factors.

Front Bioeng Biotechnol 2020 14;8:937. Epub 2020 Aug 14.

Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States.

Researchers are investigating the use of biomaterials with aligned guidance cues, like those provided by aligned electrospun fibers, to facilitate axonal growth across critical-length peripheral nerve defects. To enhance the regenerative outcomes further, these aligned fibers can be designed to provide local, sustained release of therapeutics. The drug fingolimod improved peripheral nerve regeneration in preclinical rodent models by stimulating a pro-regenerative Schwann cell phenotype and axonal growth. However, the systemic delivery of fingolimod for nerve repair can lead to adverse effects, so it is necessary to develop a means of providing sustained delivery of fingolimod local to the injury. Here we created aligned fingolimod-releasing electrospun fibers that provide directional guidance cues in combination with the local, sustained release of fingolimod to enhance neurite outgrowth and stimulate a pro-regenerative Schwann cell phenotype. Electrospun fiber scaffolds were created by blending fingolimod into poly(lactic-co-glycolic acid) (PLGA) at a w/w% (drug/polymer) of 0.0004, 0.02, or 0.04%. We examined the effectiveness of these scaffolds to stimulate neurite extension by measuring neurite outgrowth from whole and dissociated dorsal root ganglia (DRG). Subsequently, we characterized Schwann cell migration and gene expression . The results show that drug-loaded PLGA fibers released fingolimod for 28 days, which is the longest reported release of fingolimod from electrospun fibers. Furthermore, the 0.02% fingolimod-loaded fibers enhanced neurite outgrowth from whole and dissociated DRG neurons, increased Schwann cell migration, and reduced the Schwann cell expression of promyelinating factors. The findings show the potential of the aligned fingolimod-releasing electrospun fibers to enhance peripheral nerve regeneration and serve as a basis for future studies.
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http://dx.doi.org/10.3389/fbioe.2020.00937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456907PMC
August 2020

Forest density intensifies the importance of snowpack to growth in water-limited pine forests.

Ecol Appl 2021 01 16;31(1):e02211. Epub 2020 Sep 16.

USDA Forest Service, Rocky Mountain Research Station, 240 West Prospect Road, Fort Collins, Colorado, 80526, USA.

Warming climate and resulting declines in seasonal snowpack have been associated with drought stress and tree mortality in seasonally snow-covered watersheds worldwide. Meanwhile, increasing forest density has further exacerbated drought stress due to intensified tree-tree competition. Using a uniquely detailed data set of population-level forest growth (n = 2,495 sampled trees), we examined how inter-annual variability in growth relates to snow volume across a range of forest densities (e.g., competitive environments) in sites spanning a broad aridity gradient across the United States. Forest growth was positively related to snowpack in water-limited forests located at low latitude, and this relationship was intensified by forest density. However, forest growth was negatively related to snowpack in a higher latitude more energy-limited forest, and this relationship did not interact with forest density. Future reductions in snowpack may have contrasting consequences, as growth may respond positively in energy-limited forests and negatively in water-limited forests; however, these declines may be mitigated by reducing stand density through forest thinning.
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http://dx.doi.org/10.1002/eap.2211DOI Listing
January 2021

Long-term safety and tolerability of bimagrumab (BYM338) in sporadic inclusion body myositis.

Neurology 2020 10 20;95(14):e1971-e1978. Epub 2020 Jul 20.

From the Neuromuscular Research Center (K.S.), Phoenix, AZ; Department of Neurology (T.I.C., A.A.A), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Novartis Institutes for BioMedical Research (B.S., D.L.), Basel, Switzerland; Novartis Healthcare Pvt Ltd (H.A.), Hyderabad, India; Novartis Pharma AG (L.B.T), Basel, Switzerland. Dr. Cochrane is now at Biogen Inc, Cambridge, MA. Dr. Sloth is now at Novo Nordisk, Copenhagen, Denmark.

Objective: To assess the long-term safety and tolerability and to monitor benefits of extended use of bimagrumab in individuals with sporadic inclusion body myositis (sIBM) who completed a single-dose core study.

Methods: In this multicenter, open-label extension study, 10 adults received bimagrumab 10 mg/kg IV every 4 weeks up to 2 years (104 weeks). Safety (primary endpoint) was assessed by recording adverse events (AEs). Clinical benefits were assessed by changes from baseline in thigh muscle volume (TMV), lean body mass (LBM), 6-minute walk distance (6MWD), handgrip, and quadriceps strength.

Results: Participants had a mean age of 70.1 (SD 10.4) years. All participants (n = 10) discontinued the treatment due to early termination of the study (n = 7) or AEs (n = 3; myocardial infarction, esophageal carcinoma, and dementia, none of which were treatment related). The most common AEs were muscle spasms and falls (both 9 of 10, 90%), followed by diarrhea (6 of 10, 60%) and acne and skin eruption (both 5 of 10, 50%). At weeks 8 and 16, mean TMV increased from baseline by 4.1% (SD 4.3%) and 4.5% (SD 6.3%). Mean LBM increased from baseline and was sustained at 6.9% (SD 3.9%) at week 76. Means of 6MWD showed a progressive decline from baseline to week 76, during which there was a modest numerical increase in handgrip strength and no significant changes in quadriceps strength.

Conclusions: Long-term treatment up to 2 years with bimagrumab had a good safety profile and was well tolerated in individuals with sIBM. An increase in muscle mass was noted on a group level; however, there was no evidence of clinical improvement.

Clinicaltrialsgov Identifier: NCT02250443.

Classification Of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term bimagrumab treatment was safe and well tolerated and did not lead to functional improvement.
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http://dx.doi.org/10.1212/WNL.0000000000010417DOI Listing
October 2020

Minimal manifestation status and prednisone withdrawal in the MGTX trial.

Neurology 2020 08 1;95(6):e755-e766. Epub 2020 Jul 1.

From the Departments of Neurology (I.L.) and Biostatistics (H.-C.K., I.B.A., G.R.C., T.M., G.M.), University of Alabama at Birmingham; Department of Neurology (H.J.K.), George Washington University School of Medicine and Health Sciences, Washington, DC; Department of Neurology (J.S.), Greater Manchester Neuroscience Center, Salford, Greater Manchester, UK; Institute of Pathology (P.S.), University Medical Center Göttingen; Division of Neurology (J.O.), University of British Columbia, Vancouver, Canada; Department of Neurology (G.C.), University of Chile, Santiago; Division of Neurology (J.M.H.), Department of Medicine, University of Cape Town, South Africa; Department of Neurology (A.E.), Catholic University, Rome, Italy; Department of Neurology (W.N.), Johannes Gutenberg University, Mainz, Germany; Department of Neurology (E.C.), University of Rochester Medical Center, NY; Department of Neurosciences (G.A.), Mental Health and Sensory Organs, Sapienza University of Rome, Italy; Division of Neurology (R.W.), Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Department of Neurology (J.O.K.), Royal Melbourne Hospital, Victoria, Australia; Department of Neurology (S.R.B.), University of Southern California, Los Angeles; Department of Neurology (C.H.C.), McGill University, Montreal, Canada; Department of Neurology (A.C.B.), Medical College of Wisconsin, Milwaukee; Department of Neurology (A.A.A.), Harvard Medical School, Boston, MA; Nerve and Muscle Center of Texas (A.I.S.), Houston; Department of Neurology (B.K.), Case Western Reserve University, Cleveland, OH; Walton Centre for Neurology and Neurosurgery (B.R.F.L.), Liverpool; Nuffield Department of Clinical Neurosciences (C.B., A.V.), Oxford University, UK; Unit of Neurology (E.D.-T.), University of Brasilia, Brazil; Department of Neurology (H.Y.), Kanazawa University, Japan; Department of Neurology (M.W.-C.), Federal University, Rio de Janeiro, Brazil; Department of Neurology (M.T.P.), University of Florida, Jacksonville; Department of Neurology (M.H.R.), Augusta University, GA; Department of Neurology (A.K.-P.), Medical University of Warsaw, Poland; Department of Neurology (R.M.P.), Indiana School of Medicine, Indianapolis; Department of Neurology (C.E.J.), University of Texas Health Science Center, San Antonio; Department of Neurology (J.J.G.V.), Leiden University Medical Center, the Netherlands; Department of Neurology (J.M.M.), Duke University Medical Center, Durham, NC; Department of Neurology (J.T.K.), Ohio State University Wexner Medical Center, Columbus; Department of Neurology (L.C.W.), Universidade Federal do Parana, Curitiba, Brazil; Department of Neurology (M.B.), University of Miami, FL; Department of Neurology (R.J.B.), University of Kansas Medical Center, Kansas City; Department of Neurological Sciences (R.T.), University of Vermont College of Medicine, Burlington; Department of Neurology (T.M.), University of California Irvine Medical Center, Orange; Division of Extramural Research (R.C.), NIH, National Institute of Neurological Disorders and Stroke, Bethesda, MD; Section of General Thoracic Surgery (J.R.S.), Columbia University Medical Center, New York; and Department of Neurology (G.I.W.), University at Buffalo Jacobs School of Medicine and Biomedical Sciences, NY.

Objective: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).

Methods: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.

Results: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.

Conclusions: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.

Clinicaltrialsgov Identifier: NCT00294658.

Classification Of Evidence: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.
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http://dx.doi.org/10.1212/WNL.0000000000010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455358PMC
August 2020

COVID-19 and neuromuscular disorders.

Neurology 2020 06 13;94(22):959-969. Epub 2020 Apr 13.

From the Division of Neuromuscular Medicine, Department of Neurology, Massachusetts General Hospital (A.C.G.), and Division of Neuromuscular Medicine, Department of Neurology, Brigham and Woman's Hospital (A.A.A.), Harvard Medical School, Boston, MA.

The coronavirus 2019 (COVID-19) pandemic has potential to disproportionately and severely affect patients with neuromuscular disorders. In a short period of time, it has already caused reorganization of neuromuscular clinical care delivery and education, which will likely have lasting effects on the field. This article reviews (1) potential neuromuscular complications of COVID-19, (2) assessment and mitigation of COVID-19-related risk for patients with preexisting neuromuscular disease, (3) guidance for management of immunosuppressive and immunomodulatory therapies, (4) practical guidance regarding neuromuscular care delivery, telemedicine, and education, and (5) effect on neuromuscular research. We outline key unanswered clinical questions and highlight the need for team-based and interspecialty collaboration. Primary goals of clinical research during this time are to develop evidence-based best practices and to minimize morbidity and mortality related to COVID-19 for patients with neuromuscular disorders.
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http://dx.doi.org/10.1212/WNL.0000000000009566DOI Listing
June 2020
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