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1.
Neuromuscul Disord ; 29(3): 167-186, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30770310

RESUMO

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

2.
J Clin Apher ; 34(4): 416-422, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30779438

RESUMO

INTRODUCTION: The primary objective of this study was to assess response to plasma exchange (PLEX) in myasthenia gravis (MG) patients with and without autoantibodies (Ab) to acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). Analysis was also done to determine if correlation existed between sex, early or late onset MG, thymoma, or thymectomy and response to PLEX. MATERIALS AND METHODS: Data was analyzed on 58 consecutive MG patients treated with PLEX. Responses were categorized as complete response, clinical improvement requiring maintenance PLEX, or no/minimal response to PLEX. RESULTS: Eighty-eight percent (51/58) of patients were Ab-positive; 44 had AChR and 7 had MuSK Ab. Complete response was seen in 26 patients (24 Ab+), 24 remain on maintenance PLEX (19 Ab+), and 2 had no/minimal response (both AChR Ab+). Ab status (P = 0.43), AChR Ab (P = 0.10), MuSK Ab (P = 0.45), early onset MG (P = 0.63), thymoma (P = 0.46), and thymectomy (P = 0.16) were not significantly associated with outcome. Patient sex did show significant association with outcome (P = 0.01), with men more likely to have complete response and women more likely to require maintenance. Late onset MG is significantly associated with higher likelihood of complete response (P = 0.03). Antibody titers declined after PLEX in 83% of patients with complete response, in whom pre- and post-PLEX titers were available (n = 6). CONCLUSIONS: In conclusion, our study showed 96% response rate to PLEX in MG; however, only patient gender and late onset MG were significantly associated with treatment response.

3.
JAMA ; 320(22): 2344-2353, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30535218

RESUMO

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases. Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.


Assuntos
Mexiletina/uso terapêutico , Miotonia/tratamento farmacológico , Transtornos Miotônicos/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Adulto , Teorema de Bayes , Método Duplo-Cego , Feminino , Humanos , Masculino , Mexiletina/efeitos adversos , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Raras , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
4.
Neurotherapeutics ; 15(4): 954-965, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30341599

RESUMO

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. These disorders cause lifetime disability and impact quality of life. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis, therapeutic, genetic counseling, and research planning. Electrodiagnostic testing is useful in directing the diagnosis, but has several limitations: patient discomfort, time consuming, and significant overlap of findings in muscle channelopathies. Although genetic testing is the gold standard in making a definitive diagnosis, a mutation might not be identified in many patients with a well-supported clinical diagnosis of periodic paralysis. In the recent past, there have been landmark clinical trials in non-dystrophic myotonia and periodic paralysis which are encouraging as they demonstrate the ability of robust clinical research consortia to conduct well-controlled trials of rare diseases.

5.
Muscle Nerve ; 57(4): 522-530, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29125635

RESUMO

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522-530, 2018.

6.
Neurology ; 86(15): 1408-1416, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-26865514

RESUMO

OBJECTIVE: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. METHODS: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. RESULTS: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). CONCLUSIONS: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. CLASSIFICATION OF EVIDENCE: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Diclorofenamida/uso terapêutico , Paralisias Periódicas Familiares/diagnóstico , Paralisias Periódicas Familiares/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade
7.
Neurology ; 86(16): 1474-81, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26911633

RESUMO

OBJECTIVE: To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS). METHODS: Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity. RESULTS: The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p < 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005). CONCLUSIONS: Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Mexiletina/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Esclerose Amiotrófica Lateral/fisiopatologia , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Mexiletina/efeitos adversos , Mexiletina/farmacocinética , Pessoa de Meia-Idade , Cãibra Muscular/tratamento farmacológico , Cãibra Muscular/fisiopatologia , Equilíbrio Postural/efeitos dos fármacos , Resultado do Tratamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
8.
Neurol India ; 64(1): 97-100, 2016 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26754999

RESUMO

OBJECTIVE: To evaluate the disparity in authorship based on gender and nationality of institutional affiliation among journals from developed and developing countries. MATERIALS AND METHODS: Original articles from two neuroscience journals, with a 5 year impact factor >15 (Neuron and Nature Neuroscience) and from two neurology journals from a developing country (Neurology India and Annals of Indian Academy of Neurology) were categorized by gender and institutional affiliation of first and senior authors. Articles were further divided by the type of research (basic/translational/clinical), study/target population (adult/pediatrics/both) and field of neurology. Data was collected for the years 2002 and 2012. RESULTS: There are large disparities in authorship by women and from developing countries in high impact factor neuroscience journals. However, there was a non-statistical rise in female first and senior authorship over a 10 year period. Additionally there was a significant increase in first authorship from institutions based in developing countries in the two neuroscience journals examined (P < 0.05). In the two neurology journals based in India there was a significant increase in the number of articles published by international investigators between 2002 and 2012 (P < 0.05). CONCLUSIONS: Over the last decade, there has been a non-statistical increase in proportion of female first and senior authors, and a significant increase in authors from developing countries in high impact factor neuroscience journals. However they continue to constitute a minority. The disparity in authorship based on gender also exists in neurology journals based in a developing country (India).


Assuntos
Autoria , Neurociências/tendências , Publicações , Grupos Étnicos , Feminino , Humanos , Índia , Fator de Impacto de Revistas , Neurologia
9.
Semin Musculoskelet Radiol ; 19(2): 130-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25764237

RESUMO

Polyneuropathies can be classified as either primarily demyelinating or axonal, and further as hereditary or acquired. It is important to recognize acquired neuropathies because some are amenable to treatment. Clinical findings and electrophysiology are used in the routine diagnosis of these conditions. Magnetic resonance neurography (MRN) is a helpful supplementary diagnostic tool. This article discusses the typical clinical findings, electrophysiology findings, and MRN appearances of common hereditary or acquired neuropathies such as chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, and postsurgical neuropathy.


Assuntos
Imagem por Ressonância Magnética/métodos , Nervos Periféricos/patologia , Polineuropatias/diagnóstico , Polineuropatias/genética , Humanos
10.
Curr Treat Options Neurol ; 16(10): 313, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25118992

RESUMO

OPINION STATEMENT: Neuromuscular channelopathies are heterogeneous disorders with marked phenotypic and genotypic variability. These include non-dystrophic myotonia (NDM), periodic paralysis (PP), and congenital myasthenic syndrome (CMS). Their diverse clinical manifestations remain a challenge in diagnosis and management to this date. These disorders impact quality of life and cause lifelong disabling symptoms. Treatment options are few and not FDA-approved. This is largely due to a paucity of large, randomized clinical trials in these rare diseases. Challenges of conducting such trials include the rarity of these disorders and the genetic heterogeneity. Physicians rely on off-label use of drugs to treat muscle channelopathies to reduce morbidity and improve quality of life. Besides pharmacological treatment, dietary modifications, lifestyle changes, awareness of triggers, and genetic counseling also play an important role in long-term disease management. This article reviews the current management strategies for neuromuscular channelopathies.

11.
Neurol Clin ; 32(3): 801-15, x, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25037091

RESUMO

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis and therapeutics. These disorders can cause lifetime disability and affect quality of life. There is no treatment of these disorders approved by the US Food and Drug Administration at this time. Recognition and treatment of symptoms might reduce morbidity and improve quality of life. This article summarizes the clinical manifestations, diagnostic studies, pathophysiology, and treatment options in nondystrophic myotonia, congenital myasthenic syndrome, and periodic paralyses.


Assuntos
Canalopatias/diagnóstico , Canais Iônicos/genética , Canalopatias/genética , Canalopatias/fisiopatologia , Canalopatias/terapia , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mutação , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/fisiopatologia , Miotonia/diagnóstico , Miotonia/genética , Miotonia/fisiopatologia , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Transtornos Miotônicos/fisiopatologia
12.
Exp Neurol ; 253: 28-30, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24361411

RESUMO

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Common symptoms include muscle stiffness, transitory weakness, fatigue, and pain. Although seldom life-shortening, these myotonias cause life-time disability and affected individuals cannot perform many daily activities. A notable feature of the recessive form of chloride channelopathies is the presence of transient weakness. While there has been considerable progress in skeletal muscle channelopathies with regards to identifying biophysical abnormalities, the mechanism of transient weakness remains unclear. A recent study published in Experimental Neurology (Desaphy et al., 2013) explored this question further by comparing the biophysical properties of 3 chloride channel mutations associated with recessive myotonia congenita, with varying susceptibility to transient weakness. The authors identified a variety of functional defects in channel behavior among the 3 mutations, suggesting that this variability contributes to the differing phenotypes among chloride channelopathies. This commentary discusses nondystrophic myotonias, the results of Desaphy et al., and the treatment challenges in this rare disease.


Assuntos
Canais de Cloreto/genética , Mutação , Miotonia Congênita/genética , Fenótipo , Humanos
13.
Brain ; 136(Pt 7): 2189-200, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23771340

RESUMO

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.


Assuntos
Canais de Cloreto/genética , Força Muscular/fisiologia , Debilidade Muscular/etiologia , Mutação/genética , Miotonia/classificação , Miotonia/diagnóstico , Miotonia/genética , Adulto , Estudos de Coortes , Eletrodiagnóstico , Exercício/fisiologia , Feminino , Humanos , Cooperação Internacional , Masculino , Mexiletina/uso terapêutico , Pessoa de Meia-Idade , Força Muscular/genética , Debilidade Muscular/genética , Miotonia/psicologia , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Exame Neurológico , Qualidade de Vida , Proteínas de Ligação a RNA/genética , Estudos Retrospectivos , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
14.
Neurol Clin ; 31(2): 377-403, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23642715

RESUMO

Neuropathic pain management is an important aspect in the management of painful peripheral neuropathy. Anticonvulsants and antidepressants have been studied extensively and are often used as first-line agents in the management of neuropathic pain. In this article, data from multiple randomized controlled studies on painful peripheral neuropathies are summarized to guide physicians in treating neuropathic pain. Treatment is a challenge given the diverse mechanisms of pain and variable responses in individuals. However, most patients derive pain relief from a well-chosen monotherapy or well-designed polypharmacy that combines agents with different mechanisms of action.


Assuntos
Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Antidepressivos/uso terapêutico , Cloridrato de Duloxetina , Humanos , Neuralgia/fisiopatologia , Neuralgia/psicologia , Manejo da Dor , Pregabalina , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiofenos/uso terapêutico , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/uso terapêutico
15.
Int J Neurosci ; 123(8): 563-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23461611

RESUMO

Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV-1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America.


Assuntos
Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia , Bases de Dados Factuais , Humanos , América do Norte/epidemiologia , América do Sul/epidemiologia
16.
JAMA ; 308(13): 1357-65, 2012 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23032552

RESUMO

CONTEXT: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. OBJECTIVE: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. INTERVENTION: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. MAIN OUTCOME MEASURES: Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). RESULTS: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. CONCLUSION: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00832000.


Assuntos
Antiarrítmicos/uso terapêutico , Mexiletina/uso terapêutico , Miotonia/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Antiarrítmicos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Mexiletina/efeitos adversos , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Dor/tratamento farmacológico , Dor/etiologia , Qualidade de Vida , Índice de Gravidade de Doença , Canais de Sódio/efeitos dos fármacos , Adulto Jovem
17.
Muscle Nerve ; 46(4): 482-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22987687

RESUMO

INTRODUCTION: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials. METHODS: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods. RESULTS: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning. CONCLUSION: QMA is an automated, non-invasive technique for evaluating myotonia in NDM.


Assuntos
Teste de Esforço/métodos , Força da Mão/fisiologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Miotonia/diagnóstico , Miotonia/fisiopatologia , Adulto , Idoso , Canais de Cloreto/genética , Diagnóstico por Computador/métodos , Diagnóstico por Computador/normas , Teste de Esforço/normas , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Mutação , Miotonia/genética , Canais de Sódio/genética , Adulto Jovem
18.
Arch Neurol ; 69(9): 1213, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23753893
19.
Muscle Nerve ; 44(1): 30-5, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21674518

RESUMO

INTRODUCTION: Non-dystrophic myotonia (NDM) is caused by mutations in muscle chloride and sodium channels. Currently, there is no standardized instrument for documenting symptom frequency and severity in NDM. METHODS: Subjects used an automated, interactive, telephone-based voice response diary (IVR) to record frequency and severity of stiffness, weakness, pain, and tiredness once a week for 8 weeks, after their baseline visits. RESULTS: We describe the IVR and report data on 76 subjects for a total of 385 person-weeks. Overall there were 5.1 calls per subject. Forty-eight subjects called in 5 or more times, and 14 called in 8 times. Stiffness was both the most frequent and severe symptom. Warm-up and handgrip myotonia were associated with higher severity scores for stiffness. CONCLUSIONS: IVR is a convenient technology to allow patient reporting of repeated and real-time symptom frequency and severity, and it is presently being used in a trial of mexiletine in NDM.


Assuntos
Registros Médicos , Miotonia , Índice de Gravidade de Doença , Telefone , Voz , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Miotonia/patologia , Miotonia/psicologia , Miotonia/terapia , Adulto Jovem
20.
Arch Neurol ; 68(5): 650-2, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21555641

RESUMO

BACKGROUND: There have been a few case reports of motor neuron disease in association with Huntington disease (HD). OBJECTIVE: To describe a patient presenting with prominent fasciculations, chorea, and possible amyotrophic lateral sclerosis (ALS) in whom genetic testing revealed HD mutation. DESIGN: Case report. SETTING: University of Texas Southwestern Medical Center, Dallas. Patient  A 69-year-old man with chorea and fasciculations. INTERVENTIONS: Genetic and electrophysiologic testing. MAIN OUTCOME MEASURES: Genetic test result, electrophysiologic test result, and physical examination. RESULTS: A 69-year-old man with long-standing depression and failing memory presented with muscle twitches of 8 months' duration. He was found to have choreoathetoid movements and distal weakness on neurological examination. Electrophysiologic studies revealed evidence of motor neuron disease. Genetic test showed CAG repeat of 40 on chromosome 4, confirming the diagnosis of HD. CONCLUSION: Motor neuron disease can rarely occur in patients with HD and could be one of its presenting features.


Assuntos
Cromossomos Humanos Par 4/genética , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Doença dos Neurônios Motores/genética , Idoso , Esclerose Amiotrófica Lateral/genética , Vértebras Cervicais , Diagnóstico Diferencial , Eletrofisiologia , Fasciculação/genética , Testes Genéticos , Humanos , Doença de Huntington/complicações , Doença de Huntington/fisiopatologia , Masculino , Doença dos Neurônios Motores/diagnóstico , Exame Neurológico , Espondilose/complicações , Espondilose/cirurgia , Expansão das Repetições de Trinucleotídeos
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