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1.
N Engl J Med ; 383(10): 919-930, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32877582

RESUMO

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Ácido Tauroquenodesoxicólico/uso terapêutico , Idoso , Progressão da Doença , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Fenilbutiratos/efeitos adversos , Índice de Gravidade de Doença , Ácido Tauroquenodesoxicólico/administração & dosagem , Resultado do Tratamento
2.
Artigo em Inglês | MEDLINE | ID: mdl-35577511

RESUMO

BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. METHODS: Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. RESULTS: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.

3.
Muscle Nerve ; 63(1): 31-39, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33063909

RESUMO

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/mortalidade , Fármacos Neuroprotetores/uso terapêutico , Fenilbutiratos/uso terapêutico , Ácido Tauroquenodesoxicólico/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo , Adulto Jovem
4.
Muscle Nerve ; 62(4): 485-491, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32678460

RESUMO

Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous viral infections. Recently, there have been many case reports describing the association between coronavirus disease-2019 (COVID-19) and GBS, but much remains unknown about the strength of the association and the features of GBS in this setting. We reviewed 37 published cases of GBS associated with COVID-19 to summarize this information for clinicians and to determine whether a specific clinical or electrodiagnostic (EDx) pattern is emerging. The mean age (59 years), gender (65% male), and COVID-19 features appeared to reflect those of hospitalized COVID-19 patients early in the pandemic. The mean time from COVID-19 symptoms to GBS symptoms was 11 days. The clinical presentation and severity of these GBS cases was similar to those with non-COVID-19 GBS. The EDx pattern was considered demyelinating in approximately half of the cases. Cerebrospinal fluid, when assessed, demonstrated albuminocytologic dissociation in 76% of patients and was negative for severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) in all cases. Serum antiganglioside antibodies were absent in 15 of 17 patients tested. Most patients were treated with a single course of intravenous immunoglobulin, and improvement was noted within 8 weeks in most cases. GBS-associated COVID-19 appears to be an uncommon condition with similar clinical and EDx patterns to GBS before the pandemic. Future studies should compare patients with COVID-19-associated GBS to those with contemporaneous non-COVID-19 GBS and determine whether the incidence of GBS is elevated in those with COVID-19.


Assuntos
Betacoronavirus , Encéfalo/diagnóstico por imagem , Infecções por Coronavirus/complicações , Síndrome de Guillain-Barré/etiologia , Condução Nervosa/fisiologia , Pandemias , Pneumonia Viral/complicações , COVID-19 , Infecções por Coronavirus/epidemiologia , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Fatores de Tempo
6.
Artigo em Inglês | MEDLINE | ID: mdl-36576200

RESUMO

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.


Assuntos
Esclerose Lateral Amiotrófica , COVID-19 , Doença dos Neurônios Motores , Humanos , Doença dos Neurônios Motores/diagnóstico , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/terapia , Estudos Prospectivos , Pandemias
7.
J Clin Neuromuscul Dis ; 23(2): 100-104, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34808651

RESUMO

ABSTRACT: Dermatomyositis (DM) is an autoimmune myopathy characterized by proximal muscle weakness and distinct skin findings. DM is associated with an increased risk of malignancy in adults. We describe a case of dermatomyositis with unusually severe oropharyngeal dysphagia and respiratory muscle weakness on presentation, who was found to have underlying metastatic prostate cancer. Prostate cancer is uncommonly associated with DM. The patient tested positive for antitranscription intermediate family-1 (anti-TIF-1, also known as anti-p155/410) antibodies, which are linked to malignancy-associated DM in adults and are associated with dysphagia and more severe cutaneous findings.


Assuntos
Adenocarcinoma , Dermatomiosite , Neoplasias da Próstata , Adenocarcinoma/complicações , Adulto , Autoanticorpos , Dermatomiosite/complicações , Humanos , Masculino , Debilidade Muscular , Neoplasias da Próstata/complicações
8.
Muscle Nerve ; 41(4): 558-62, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19941344

RESUMO

Both multifocal, demyelinating features and prednisone responsiveness are rare in Charcot-Marie-Tooth (CMT) disease. We report a mother and son with a prednisone-responsive, multifocal, demyelinating, predominantly sensory polyneuropathy that was associated with an isoleucine92valine polymorphism of lipopolysaccharide-induced TNF-alpha factor (LITAF). The mother had a multifocal, acquired, demyelinating sensory and motor polyneuropathy (MADSAM)-like presentation. The son developed left peroneal neuropathy during acute Lyme disease with a subsequent relapsing, MADSAM-like illness, despite antibiotic treatment. Both shared prednisone responsiveness and multifocal, demyelinating features electrophysiologically. MADSAM may be familial (FaDSAM) and respond to prednisone.


Assuntos
Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Adolescente , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/fisiopatologia , Feminino , Neuropatia Hereditária Motora e Sensorial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa/genética , Polimorfismo Genético , Polineuropatias/diagnóstico , Polineuropatias/genética , Polineuropatias/fisiopatologia
10.
Amyotroph Lateral Scler ; 11(4): 364-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20132084

RESUMO

Our objective was to study the clinical course of patients diagnosed with progressive bulbar palsy (PBP). We reviewed all 392 medical records of ALS patients seen between 1 January 2000 and 31 July 2007. Patients with isolated PBP at presentation were selected and classified into those with normal EMG of the limbs (PBP-N) and those with active denervation on EMG (PBP-A). We studied the time to progression of these patients to ALS. We compared patients with PBP-N to patients with PBP-A. Fifteen patients were diagnosed with PBP-N. The remaining 17 had PBP-A. Thirteen of the 15 patients with PBP-N (87%) progressed to definite ALS. The two patients who did not progress to ALS died at 22 and 60 months, respectively. The median survival time was 35 months for the PBP-N group and 40 months for the PBP-A group (p = 0.92). Except for the rate of depression, patients with PBP-N did not differ from patients with PBP-A in the basic demographics, time of presentation, clinical course, survival and treatment received. All patients with FTD died within 40 months of onset of symptoms. In conclusion, almost all PBP patients progress to ALS regardless of the presence of upper motor signs or generalized denervation on EMG of the limbs.


Assuntos
Paralisia Bulbar Progressiva/diagnóstico , Paralisia Bulbar Progressiva/mortalidade , Progressão da Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/diagnóstico , Paralisia Bulbar Progressiva/classificação , Eletromiografia/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Amyotroph Lateral Scler ; 9(4): 212-22, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18608093

RESUMO

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Creatina/uso terapêutico , Minociclina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Celecoxib , Creatina/administração & dosagem , Método Duplo-Cego , Toxidermias , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Minociclina/efeitos adversos , Fármacos Neuroprotetores/administração & dosagem , Seleção de Pacientes , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento
12.
J Clin Neuromuscul Dis ; 17(4): 187-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27224432

RESUMO

OBJECTIVES: Patients with carpal tunnel syndrome (CTS) and paracervical pain (PCP) are often incorrectly diagnosed with cervical radiculopathy. The objective of the study is to determine how frequently such patients have electrophysiologic evidence of radiculopathy. METHODS: We reviewed charts of patients with clinical features of CTS and at least 1 median nerve conduction parameter showing slowing across the wrist. Patients were divided into those with and without PCP. Radiculopathy was defined electrophysiologically. We assessed group differences in the frequency of radiculopathy and how radiculopathy frequency varied with median nerve entrapment severity. RESULTS: Of 108 patients meeting criteria, 56 had PCP and 52 did not. Eight of 56 patients with PCP and 4 of 52 without pain had cervical radiculopathy (P = 0.36). There was no difference in the frequency of radiculopathy related to the severity of median nerve entrapment (P = 0.64). DISCUSSION: In patients with CTS, PCP is not associated with cervical radiculopathy. Cervical radiculopathy is not more frequent in more severe CTS.


Assuntos
Síndrome do Túnel Carpal/diagnóstico , Cervicalgia/diagnóstico , Condução Nervosa/fisiologia , Radiculopatia/diagnóstico , Síndrome do Túnel Carpal/fisiopatologia , Erros de Diagnóstico , Eletrodiagnóstico , Feminino , Humanos , Masculino , Nervo Mediano/fisiopatologia , Cervicalgia/fisiopatologia , Exame Neurológico , Radiculopatia/fisiopatologia , Estudos Retrospectivos
13.
Med Hypotheses ; 76(5): 643-5, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21310542

RESUMO

The pathogenesis of amyotrophic lateral sclerosis (ALS) is multifactorial and a treatment targeting only one aspect of the disease is unlikely to be beneficial. Vitamin D is safe and may delay progression of ALS by acting on several aspects of the disease. In this article we explore how vitamin D may promote VGEF, IGF-1 and axonal regeneration delaying ALS progression. In addition, we discuss how vitamin D may increase calcium binding protein in motor neuron cells conferring a greater resistance to the underlying disease process, as seen in the oculomotor nerve and Onuf's nucleus. Finally, we discuss vitamin D immunomodulator role, decreasing the reactive gliosis in ALS.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/terapia , Vitamina D/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Axônios/metabolismo , Cálcio/metabolismo , Progressão da Doença , Gliose/metabolismo , Humanos , Inflamação , Modelos Biológicos , Modelos Teóricos , Neurônios Motores/metabolismo , Regeneração Nervosa , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vitamina D/uso terapêutico
14.
J Clin Neuromuscul Dis ; 11(3): 120-3, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20215984

RESUMO

The objective of this study was to describe a case of sensory neuronopathy syndrome (SNS) with Ro antibodies who had nearly complete functional recovery with combination immunosuppression. Plasma exchange, azathioprine, and hydroxychloroquine were used in combination. The gait ataxia, kinesthetic sensation, and sensory response amplitudes showed considerable recovery with excellent functional outcomes. Prompt combined therapy with azathioprine and hydroxychloroquine is a promising therapy for patients with sensory neuronopathy syndrome and Ro antibodies.


Assuntos
Anticorpos Antinucleares/metabolismo , Anticorpos/administração & dosagem , Imunossupressores/uso terapêutico , Mononeuropatias/imunologia , Mononeuropatias/terapia , Anticorpos Antinucleares/imunologia , Quimioterapia Combinada/métodos , Feminino , Humanos , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-12710515

RESUMO

BACKGROUND: Respiratory failure (RF) in ALS typically occurs as a late manifestation. While there are uncommon patient reports of early RF, most had moderate limb and bulbar weakness. DESIGN/METHODS: We reviewed clinical and laboratory data from 3 patients with ALS, early RF, and minor motor signs. RESULTS: Patients were male, ages 62, 75 and 80 years. The patients presented with 6 months to 2 years of exertional and nocturnal dyspnea, daytime hypersomnolence, limb fatigability, and weight loss. Exam showed tachypnea, slight distal limb weakness, and hyperreflexia. All three patients had prominent fasciculations, insomnia, supportive EMG findings, FVC (32-74% predicted), PO2 (50-80 mmHg), PCO2(52-76 mmHg) and required BiPAP (Bi-level positive airway pressure). One patient had a reduced FEV1/FVC of 0.55 and a 15% increase in FEV1 post-bronchodilator suggesting concurrent chronic obstructive pulmonary disease (COPD). However, his P(A-a)O2 was only 7 mmHg suggesting COPD was not the major factor causing respiratory failure; his extreme hypercapnea could not be explained by ALS or COPD alone. CONCLUSIONS: ALS may present with unexplained RF, or sleep disturbance resembling sleep apnea, without significant bulbar or limb weakness. In our experience, such patients are elderly with dyspnea, fasciculations, and other minor motor signs: the Dyspnea-Fasciculation Syndrome. Concurrent COPD may augment the effect of ALS, resulting in earlier RF. FVC may be relatively preserved, despite hypercapnia.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Dispneia/fisiopatologia , Fasciculação/fisiopatologia , Insuficiência Respiratória/etiologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Testes de Função Respiratória , Síndrome
20.
Muscle Nerve ; 30(4): 423-32, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15372439

RESUMO

The gammadelta T cells participate in microbial defense, are prevalent in intestinal epithelia, and are activated in autoimmune diseases. We studied whether peripheral blood gammadelta cells and gammadelta subsets are increased in Guillain-Barré syndrome (GBS) and whether elevations are associated with Campylobacter jejuni infection or GM1 elevations. In 20 GBS patients, we performed serial flow cytometry studies of blood gammadelta, Vdelta1, and Vdelta2 cells (+/- CD8+), C jejuni, and ganglioside titers. There was no significant difference in median gammadelta T-cell percentages between GBS patients and controls at onset and at convalescence. However, 5 patients had marked Vdelta1/CD8+ elevations. Elevated Vdelta1 or Vdelta1/CD8+ cells occurred in 3 of 6 patients with C jejuni or GM1 titer elevations. A minority of GBS patients have elevations of Vdelta1/CD8+ cells, possibly associated with elevated C jejuni or GM1 titers. The gammadelta T cells may have a cytotoxic (or suppressor) role in the disease.


Assuntos
Infecções por Campylobacter/complicações , Campylobacter jejuni , Gangliosidose GM1/metabolismo , Síndrome de Guillain-Barré/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/metabolismo , Anticorpos Antibacterianos/análise , Anticorpos Monoclonais , Linfócitos T CD8-Positivos/metabolismo , Infecções por Campylobacter/metabolismo , Eletrofisiologia , Citometria de Fluxo , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Contagem de Linfócitos
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