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INTRODUCTION/AIMS: Myotonic dystrophies (DMs) are autosomal dominant diseases in which expression of a mutant expanded repeat mRNA leads to abnormal splicing of downstream effector genes thought to be responsible for their multisystem involvement. Cancer risk and cancer-related deaths are increased in DM patients relative to the general population. We aimed at determining the frequency and type of cancers in both DM1 and DM2 vs a non-DM muscular dystrophy cohort. METHODS: A retrospective, cross-sectional study was carried out on patients with genetically confirmed DM1, DM2, facioscapulohumeral muscular dystrophy (FSHD), and oculopharyngeal muscular dystrophy (OPMD) at our institutions from 2000 to 2020. RESULTS: One hundred eighty-five DM1, 67 DM2, 187 FSHD, and 109 OPMD patients were included. Relative to non-DM, DM patients had an increased cancer risk that was independent of age and sex. Specifically, an increased risk of sex-related (ovarian) and non-sex-related (non-melanoma skin, urological, and hematological) cancers was observed in DM1 and DM2, respectively. The length of CTG repeat expansion was not associated with cancer occurrence in the DM1 group. DISCUSSION: In addition to current consensus-based care recommendations, our findings prompt consideration of screening for skin, urological, and hematological cancers in DM2 patients, and screening of ovarian malignancies in DM1 female patients.
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Melanoma , Distrofia Muscular Facioescapuloumeral , Distrofia Miotônica , Humanos , Feminino , Distrofia Miotônica/complicações , Distrofia Miotônica/epidemiologia , Distrofia Miotônica/genética , Estudos Transversais , Estudos RetrospectivosRESUMO
INTRODUCTION/AIMS: Nephropathic cystinosis is a lysosomal storage disorder with known myopathic features, including dysphagia. Evaluation of oropharyngeal swallowing physiology can be standardized using the Modified Barium Swallow Impairment Profile (MBSImP), a validated assessment tool used to analyze and rate swallowing across 17 distinct physiologic domains. Our objective was to better characterize swallowing impairments in nephropathic cystinosis using MBSImP analysis. METHODS: We retrospectively evaluated 40 video fluoroscopic swallowing studies performed at two time points over 1 y in patients with nephropathic cystinosis with various levels of oral and pharyngeal stage dysphagia. Patients completed two self-administered dysphagia outcome measures (the M. D. Anderson Dysphagia Inventory [MDADI] and the 10-item Eating Assessment Tool [EAT-10]). RESULTS: We demonstrated oral stage and pharyngeal stage dysphagia across domains that impacted bolus control, transit, and clearance through both the oral cavity and pharyngeal lumen. Also captured were deficits related to onset and completeness of laryngeal closure that impact airway protection during swallow. There were significant correlations between pharyngeal total score and EAT-10 (r = 0.5, p < 0.001) and between oral total score and EAT-10 (r = 0.7, p < 0.001), MDADI-e (r = -0.6, p < 0.001), MDADI-p (r = -0.5, p < 0.001) and MDADI-c (r = -0.6, p < 0.001). There were no differences in oral or pharyngeal total scores across the 1-y time span. DISCUSSION: This study identifies oral and pharyngeal stage dysphagia as crucial to patients with nephropathic cystinosis and paves the path for future studies of treatment targets.
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Cistinose , Transtornos de Deglutição , Adulto , Bário , Cistinose/complicações , Cistinose/diagnóstico por imagem , Deglutição/fisiologia , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Humanos , Estudos RetrospectivosRESUMO
Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.
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Antineoplásicos Imunológicos/efeitos adversos , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/etiologia , HumanosRESUMO
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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Fatores Imunológicos , Miastenia Gravis , Idoso , Humanos , Fatores Imunológicos/efeitos adversos , Miastenia Gravis/induzido quimicamente , Miastenia Gravis/tratamento farmacológico , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/efeitos adversosRESUMO
INTRODUCTION: Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic, but little is known about its potential impact on patients with myasthenia gravis (MG). METHODS: We studied the clinical course of COVID-19 in five hospitalized patients with autoimmune MG (four with acetylcholine receptor antibodies, one with muscle-specific tyrosine kinase antibodies) between April 1, 2020-April 30-2020. RESULTS: Two patients required intubation for hypoxemic respiratory failure, whereas one required significant supplemental oxygen. One patient with previously stable MG had myasthenic exacerbation. One patient treated with tocilizumab for COVID-19 was successfully extubated. Two patients were treated for MG with intravenous immunoglobulin without thromboembolic complications. DISCUSSION: Our findings suggest that the clinical course and outcomes in patients with MG and COVID-19 are highly variable. Further large studies are needed to define best practices and determinants of outcomes in this unique population.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/terapia , Hipóxia/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Miastenia Gravis/terapia , Pneumonia Viral/terapia , Insuficiência Respiratória/terapia , Adulto , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Hipóxia/etiologia , Imunossupressores/uso terapêutico , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/complicações , Miastenia Gravis/imunologia , Oxigenoterapia , Pandemias , Pneumonia Viral/complicações , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Respiração Artificial , Insuficiência Respiratória/etiologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND: Nephropathic cystinosis is a lysosomal storage disorder with late-onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness. METHODS: We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia. RESULTS: There were significant differences in the Timed Up and Go Test (TUG) and Timed 25-Foot Walk (25-FW) between baseline and 1-y follow-up (P < .05). Maximum expiratory pressure (MEP) and peak cough flow (PCF) significantly improved following respiratory training (P < .05). CONCLUSIONS: Improved respiratory outcomes may enhance patients ability to expel aspirated material from the airway, stave off pulmonary sequelae associated with chronic aspiration, and yield an overall improvement in physical health and well-being.
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Cistinose/fisiopatologia , Transtornos de Deglutição/fisiopatologia , Doenças Musculares/fisiopatologia , Adulto , Exercícios Respiratórios/métodos , Ensaios Clínicos como Assunto , Transtornos de Deglutição/reabilitação , Miopatias Distais/fisiopatologia , Miopatias Distais/reabilitação , Feminino , Força da Mão , Humanos , Masculino , Pressões Respiratórias Máximas , Pessoa de Meia-Idade , Força Muscular , Doenças Musculares/reabilitação , Avaliação de Resultados em Cuidados de Saúde , Medidas de Resultados Relatados pelo Paciente , Desempenho Físico Funcional , Aspiração Respiratória/prevenção & controle , Teste de Caminhada , Adulto JovemAssuntos
Cobre/deficiência , Deficiências Nutricionais/diagnóstico , Hipestesia/etiologia , Doenças da Medula Espinal/diagnóstico , Zinco/efeitos adversos , Deficiências Nutricionais/induzido quimicamente , Deficiências Nutricionais/complicações , Diagnóstico Diferencial , Técnicas de Diagnóstico Neurológico , Eletromiografia , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Derivação Gástrica , Humanos , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Doenças da Medula Espinal/etiologia , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina E/diagnósticoAssuntos
Linfoma Difuso de Grandes Células B/patologia , Raízes Nervosas Espinhais/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/citologia , Diagnóstico Diferencial , Feminino , Humanos , Hipestesia/etiologia , Vértebras Lombares/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Sistema Nervoso Periférico/anatomia & histologia , Sistema Nervoso Periférico/fisiologia , Sarcoidose/diagnóstico , Tuberculose/diagnósticoRESUMO
INTRODUCTION: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. METHODS: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. RESULTS: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14-54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = -0.8) and median motor amplitude (r2 = -0.75). CONCLUSIONS: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials.
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Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Condução Nervosa/fisiologia , Pele/inervação , Pele/patologia , Adolescente , Adulto , Idoso , Biomarcadores/análise , Doença de Charcot-Marie-Tooth/fisiopatologia , Coleta de Dados , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. METHODS: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and motor unit number estimation (MUNE). RESULTS: Moderate strength correlations between EIM parameters and HHD were observed for both whole-body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS-R upper and lower extremity subscores, but not total ALSFRS-R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. CONCLUSIONS: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/fisiopatologia , Impedância Elétrica , Músculo Esquelético/fisiopatologia , Miografia/métodos , Idoso , Progressão da Doença , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dinamômetro de Força Muscular , Miografia/normasRESUMO
RATIONALE: Controversy persists regarding the presence and importance of hypoglossal nerve dysfunction in obstructive sleep apnea (OSA). OBJECTIVES: We assessed quantitative parameters related to motor unit potential (MUP) morphology derived from electromyographic (EMG) signals in patients with OSA versus control subjects and hypothesized that signs of neurogenic remodeling would be present in the patients with OSA. METHODS: Participants underwent diagnostic sleep studies to obtain apnea-hypopnea indices. Muscle activity was detected with 50-mm concentric needle electrodes. The concentric needle was positioned at more than 10 independent sites per subject, after the local anatomy of the upper airway musculature was examined by ultrasonography. All activity was quantified with subjects awake, during supine eupneic breathing while wearing a nasal mask connected to a pneumotachograph. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which extracted motor unit potential trains (MUPTs) contributed by individual motor units from the composite EMG signals. Quantitative measurements of MUP templates, including duration, peak-to-peak amplitude, area, area-to-amplitude ratio, and size index, were compared between the untreated patients with OSA and healthy control subjects. MEASUREMENTS AND MAIN RESULTS: A total of 1,655 MUPTs from patients with OSA (n = 17; AHI, 55 ± 6/h) and control subjects (n = 14; AHI, 4 ± 1/h) were extracted from the genioglossus muscle EMG signals. MUP peak-to-peak amplitudes in the patients with OSA were not different compared with the control subjects (397.5 ± 9.0 vs. 382.5 ± 10.0 µV). However, the MUPs of the patients with OSA were longer in duration (11.5 ± 0.1 vs. 10.3 ± 0.1 ms; P < 0.001) and had a larger size index (4.09 ± 0.02 vs. 3.92 ± 0.02; P < 0.001) compared with control subjects. CONCLUSIONS: These results confirm and quantify the extent and existence of structural neural remodeling in OSA.
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Remodelação das Vias Aéreas , Nervo Hipoglosso/fisiopatologia , Músculo Esquelético/inervação , Neurogênese , Apneia Obstrutiva do Sono/fisiopatologia , Potenciais de Ação , Adulto , Estudos de Casos e Controles , Eletromiografia , Feminino , Humanos , Masculino , Neurônios Motores/fisiologia , Músculo Esquelético/fisiopatologia , Língua/fisiopatologiaRESUMO
Background and Objectives: The existence of clinical anticipation, congenital form, and parent-of-origin effect in myotonic dystrophy type 2 (DM2) remains uncertain. Here, we aimed at investigating whether there is a parent-of-origin effect on the age at the first DM2-related clinical manifestation. Methods: We identified patients with genetically confirmed DM2 with known parental inheritance from (1) the electronic medical records of our institutions and (2) a systematic review of the literature following the PRISMA 2020 guidelines and recorded their age at and type of first disease-related symptom. We also interrogated the Myotonic Dystrophy Foundation Family Registry (MDFFR) for patients with DM2 who completed a survey including questions about parental inheritance and age at the first medical problem which they related to their DM2 diagnosis. Results: A total of 26 patients with DM2 from 18 families were identified at our institutions as having maternal (n = 14) or paternal (n = 12) inheritance of the disease, whereas our systematic review of the literature rendered a total of 61 patients with DM2 from 41 families reported by 24 eligible articles as having maternal (n = 40) or paternal (n = 21) inheritance of the disease. Both cohorts were combined for downstream analyses. Up to 61% and 58% of patients had muscle-related symptoms as the first disease manifestation in maternally and paternally inherited DM2 subgroups, respectively. Four patients developed hypotonia at birth and/or delayed motor milestones early in life, and 7 had nonmuscular presentations (2 had cardiac events within the second decade of life and 5 had cataracts), all of them with maternal inheritance. A maternal inheritance was associated with an earlier (within the first 3 decades of life) age at symptom onset relative to a paternal inheritance in this combined cohort, and this association was independent of the patient's sex (OR [95% CI] = 4.245 [1.429-13.820], p = 0.0117). However, this association was not observed in the MDFFR DM2 cohort (n = 127), possibly because age at onset was self-reported, and the information about the type of first symptom or medical problem that patients related to DM2 was lacking. Discussion: A maternal inheritance may increase the risk of an early DM2 onset and of cataracts and cardiovascular events as first DM2 manifestations.
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Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.
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Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Impedância Elétrica , Miografia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: To update the 2011 American Academy of Neurology (AAN) guideline on the treatment of painful diabetic neuropathy (PDN) with a focus on topical and oral medications and medical class effects. METHODS: The authors systematically searched the literature from January 2008 to April 2020 using a structured review process to classify the evidence and develop practice recommendations using the AAN 2017 Clinical Practice Guideline Process Manual. RESULTS: Gabapentinoids (standardized mean difference [SMD] 0.44; 95% confidence interval [CI], 0.21-0.67), serotonin-norepinephrine reuptake inhibitors (SNRIs) (SMD 0.47; 95% CI, 0.34-0.60), sodium channel blockers (SMD 0.56; 95% CI, 0.25-0.87), and SNRI/opioid dual mechanism agents (SMD 0.62; 95% CI, 0.38-0.86) all have comparable effect sizes just above or just below our cutoff for a medium effect size (SMD 0.5). Tricyclic antidepressants (TCAs) (SMD 0.95; 95% CI, 0.15-1.8) have a large effect size, but this result is tempered by a low confidence in the estimate. RECOMMENDATIONS SUMMARY: Clinicians should assess patients with diabetes for PDN (Level B) and those with PDN for concurrent mood and sleep disorders (Level B). In patients with PDN, clinicians should offer TCAs, SNRIs, gabapentinoids, and/or sodium channel blockers to reduce pain (Level B) and consider factors other than efficacy (Level B). Clinicians should offer patients a trial of medication from a different effective class when they do not achieve meaningful improvement or experience significant adverse effects with the initial therapeutic class (Level B) and not use opioids for the treatment of PDN (Level B).
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Diabetes Mellitus , Neuropatias Diabéticas , Neurologia , Antidepressivos Tricíclicos , Diabetes Mellitus/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Humanos , Dor/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Estados UnidosAssuntos
4-Aminopiridina/análogos & derivados , Doenças da Junção Neuromuscular/tratamento farmacológico , Produção de Droga sem Interesse Comercial , Médicos/psicologia , Bloqueadores dos Canais de Potássio/uso terapêutico , 4-Aminopiridina/uso terapêutico , Amifampridina , Humanos , Doenças da Junção Neuromuscular/economia , Produção de Droga sem Interesse Comercial/economia , Produção de Droga sem Interesse Comercial/métodosRESUMO
Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. Design, Setting, and Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. Main Outcomes and Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001). Conclusions and Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/tratamento farmacológico , Carbamatos/uso terapêutico , Córtex Cerebral/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Fenilenodiaminas/uso terapêutico , Medula Espinal/efeitos dos fármacos , Idoso , Esclerose Lateral Amiotrófica/fisiopatologia , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Carbamatos/farmacologia , Córtex Cerebral/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Fenilenodiaminas/farmacologia , Medula Espinal/fisiologia , Resultado do TratamentoRESUMO
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.