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INTRODUCTION/AIMS: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated peripheral nerve disorder with variable prognosis and long-term dependence on immunotherapy. Frequent assessment of grip strength can be a useful tool to identify intravenous immunoglobulin (IVIG) treatment-related fluctuations (TRFs) and optimize IVIG treatment in real-time, but the long-term implications of TRFs are unknown. We aimed to explore the impact that real-time TRFs had on long-term CIDP prognosis, strength impairment, and disability. METHODS: This retrospective observational cohort study analyzed standard of care clinical and treatment outcomes in patients who participated in a published prospective study of intra-IVIG-cycle grip strength quantification. Patients were analyzed based upon the presence or absence of TRFs, as determined in the initial prospective study. RESULTS: Data were available for 23 CIDP patients with a mean follow-up period of 44.7 mo. There were no differences in baseline or follow-up strength, disability, or IVIG usage in patients with a low number of fluctuations compared to those with a high number of fluctuations. In both groups, drug-free remission was achieved in about one-third of patients. DISCUSSION: TRFs are important to identify in order to optimize treatment in real time, but poorly predict long-term disease activity status. The presence of minor TRFs are unlikely to result in substantial accumulation of disability over time. Periodic IVIG optimization trials using objective outcomes are encouraged in all CIDP patients receiving chronic IVIG treatment as a means to identify the lowest effective IVIG dose and frequency.
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Imunoglobulinas Intravenosas , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Data on maintenance therapy with subcutaneous immunoglobulin (SCIg) in myasthenia gravis (MG) are limited. We report on transitioning acetylcholine receptor (AChR) antibody-positive (Ab+) MG patients on stable intravenous immunoglobulin (IVIg) regimens as part of routine clinical care to SCIg 1:1.2. METHODS: This multicenter North American open-label prospective investigator-initiated study had two components: the IVIg Stabilization Period (ISP) enrolling patients already on IVIg as part of routine clinical care (Weeks -10 to -1), followed by transition of stable MG subjects to SCIg in the Experimental Treatment Period (ETP; Weeks 0 to 12). We hypothesized that >65% of patients entering the ETP would have a stable Quantitative Myasthenia Gravis (QMG) score from Week 0 to Week 12. Secondary outcome measures included other efficacy measures, safety, tolerability, IgG levels, and treatment satisfaction. RESULTS: We recruited 23 patients in the ISP, and 22 entered the ETP. A total of 12 subjects (54.5%) were female, and 18 (81.8%) were White, with mean age 51.4 ± 17 years. We obtained Week 12 ETP QMG data on 19 of 22; one subject withdrew from ETP owing to clinical deterioration, and two subjects withdrew due to dislike of needles. On primary analysis, 19 of 22 participants (86.4%, 95% confidence interval = 0.72-1.00) were treatment successes using last observation carried forward (p = 0.018). Secondary efficacy measures supported MG stability. SCIg was safe and well tolerated, and IgG levels were stable. Treatment satisfaction was comparable between ISP and ETP. CONCLUSIONS: MG patients on IVIg as part of their routine clinical care remained stable on monthly IVIg dosage, and most maintained similar disease stability on SCIg.
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Imunoglobulinas Intravenosas , Miastenia Gravis , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Imunoglobulinas Intravenosas/uso terapêutico , Estudos Prospectivos , Miastenia Gravis/tratamento farmacológico , Receptores Colinérgicos , AutoanticorposRESUMO
This study investigated the impact of type 2 diabetes and diabetic peripheral neuropathy on grip force control during object manipulation. The study included three age-matched groups: type 2 diabetes alone (n = 11), type 2 diabetes with neuropathy (n = 13), and healthy controls (n = 12). Grip force control variables derived from lifting and holding an experimental cup were the ratio between grip force and load forces during lifting (GFR), latency 1 and latency 2, which represented the time between the object's grip and its lift-off from the table, and the period between object's lift-off and the grip force peak, respectively; time lag, which denoted the time difference between the grip and load force peaks during the lifting phase, and finally static force, which was the grip force average during the holding phase. Grip force control variables were compared between groups using one-way ANOVA and Kruskal-Wallis test. Post-hoc analysis was used to compare differences between groups. GFR and latency 1 showed significant differences between groups; the type 2 diabetes with neuropathy group showed larger GFR than the type 2 diabetes alone and healthy control groups. The latency 1was longer for the group with neuropathy in comparison with the health control group. There were no significant differences between groups for latency 2, time lag, and static force. Our results showed impaired GFR and latency 1 in participants with type 2 diabetes with neuropathy while the time lag was preserved. People with type 2 diabetes alone might not have any deficits in grip force control. Higher grip forces might expose people with type 2 diabetes and diabetic peripheral neuropathy to the risk of fatigue and injuring their hands. Future studies should investigate strategies to help people with type 2 diabetes with neuropathy adjust grip forces during object manipulation.
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Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicações , Força da Mão , Dedos , Extremidade SuperiorRESUMO
BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Hialuronoglucosaminidase/uso terapêutico , Resultado do Tratamento , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
INTRODUCTION/AIMS: Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research. METHODS: Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2). RESULTS: Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time. DISCUSSION: Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.
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Canalopatias , Miotonia Congênita , Miotonia , Distrofia Miotônica , Canais de Cloreto/genética , Força da Mão , Humanos , Mutação , Miotonia/diagnóstico , Miotonia Congênita/diagnóstico , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.
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Esclerose Lateral Amiotrófica , Cãibra Muscular , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/tratamento farmacológico , Humanos , Cãibra Muscular/tratamento farmacológico , Cãibra Muscular/etiologia , Projetos Piloto , Ranolazina/uso terapêuticoRESUMO
INTRODUCTION/AIMS: Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN). METHODS: We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected. RESULTS: Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy. DISCUSSION: Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.
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Atividades Cotidianas , Neuropatias Diabéticas , Teorema de Bayes , Neuropatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Cloridrato de Duloxetina/uso terapêutico , Fadiga/tratamento farmacológico , Fadiga/etiologia , Humanos , Mexiletina/uso terapêutico , Nortriptilina/uso terapêutico , Dor/tratamento farmacológico , Pregabalina/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Sono , Resultado do TratamentoRESUMO
While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed.
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Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Doenças Neuromusculares/terapia , Anticorpos Monoclonais/uso terapêutico , Humanos , Imunização Passiva/métodos , Imunossupressores/uso terapêutico , Doenças Neuromusculares/tratamento farmacológicoRESUMO
Immunosuppressive and immunomodulatory therapies have had a major effect on the treatment of immune-mediated neuromuscular diseases. After the landmark introduction of synthetic corticosteroids, other therapies have become available, including plasma exchange (PLEX), immunoglobulin G (IgG), and steroid-sparing immunosuppressive drugs. More recently, novel biologically derived and antigen-specific pharmaceuticals have entered neuromuscular practice. Various levels of evidence guide the use of these treatments. This article reviews current immune-based therapies in neuromuscular diseases and is divided into two parts. Part I provides an update on the evidence and use of traditional therapies, such as corticosteroids, PLEX, intravenously delivered IgG (IVIG), and steroid-sparing immunosuppressive drugs. Part II focuses on the recently US Food and Drug Administration-approved therapies eculizumab and subcutaneous IgG (SCIG), the current indications for rituximab in neuromuscular disease, and on novel immunosuppressive therapeutic approaches under development.
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Doenças Neuromusculares , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Imunomodulação , Imunossupressores , Troca PlasmáticaRESUMO
INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder in which early effective treatment is important to minimize disability from axonal degeneration. It has been suggested that some patients with CIDP may benefit from rituximab therapy, but there is no definitive evidence for this. METHODS: Baseline and post-rituximab-therapy neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status were assessed in 11 patients with refactory CIDP. RESULTS: The MRC sum score, INCAT disability score, and functional status improved in all patients after rituximab therapy. DISCUSSION: Our study provides evidence of the efficacy of rituximab therapy in at least some patients with CIDP. A placebo-controlled study to assess the effectiveness of rituximab therapy in CIDP with and without nodal antibodies is required to identify disease markers that predict responsiveness.
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Fatores Imunológicos/uso terapêutico , Limitação da Mobilidade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Quadriplegia/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Azatioprina/uso terapêutico , Bengala , Ciclofosfamida/uso terapêutico , Feminino , Órtoses do Pé , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Troca Plasmática , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/etiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologia , Quadriplegia/etiologia , Quadriplegia/fisiopatologia , Falha de Tratamento , Resultado do Tratamento , AndadoresRESUMO
INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.
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Agrina/imunologia , Autoanticorpos , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/epidemiologia , Miastenia Gravis/imunologia , Prevalência , Avaliação de Sintomas , Estados UnidosRESUMO
INTRODUCTION: The Inclusion Body Myositis Functional Rating Scale (IBMRFS) is a 10-item clinician-rated ordinal scale developed for people with inclusion body myositis. METHODS: Single observations of the IBMFRS were collected from 132 patients. After Rasch analysis, modifications were made to the scale to optimize fit to the Rasch model while maintaining clinical validity and utility. RESULTS: The original IBMFRS did not fit the assumptions of the Rasch model because of multidimensionality of the scale. Items assessed local dependence, disordered step thresholds, and differential item functioning. Deconstructing the scale into upper limb (IBMFRS-UL) and lower limb (IBMFRS-LL) scales improved fit to the Rasch model. A 9-item scale with the swallowing item removed (IBMFRS-9) remained multidimensional but demonstrated the ability to discriminate patients along the severity continuum. IBMFRS-UL, IBMFRS-LL, and IBMFRS-9 scores were transformed to a 0-100 scale for comparability. DISCUSSION: This analysis has led to the development of 3 optimized versions of the IBMFRS. Muscle Nerve 60: 161-168, 2019.
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Extremidade Inferior/fisiopatologia , Miosite de Corpos de Inclusão/fisiopatologia , Extremidade Superior/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.
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Miastenia Gravis/genética , Miastenia Gravis/terapia , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genética , Timectomia , Adolescente , Adulto , Idade de Início , Idoso , Criança , Estudos de Coortes , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
This study aims to investigate the impact of type 2 diabetes (T2D) and diabetic peripheral neuropathy (DPN) on pinch proprioception and to establish the correlations with sensory impairments. We collected data from a total of 36 participants (healthy, n = 12; T2D without DPN, n = 11; and T2D + DPN, n = 13), all matched for age, 60 ± 6 years. Pinch proprioception was determined through 3 trials of attempts to actively reproduce 15° of pinch position without visual feedback. Target accuracy and precision was compared between groups using Kruskal-Wallis test. Sensation was tested through the two-point discrimination and Semmes-Weinstein monofilaments applied on the fingers. Sensory measures were correlated with pinch proprioception measures via Spearman's rank test. The T2D + DPN group showed significant decrements in accuracy and precision as compared to the T2D-only (p = 0.003 and p = 0.006, respectively) and the healthy groups (both p = 0.002); no significant differences were found between T2D-only and healthy. Spearman's rank showed moderate (r = 0.45-0.66, p < 0.001) correlations between pinch proprioception and sensory measures. Our results showed pinch proprioception disruption in people with T2D + DPN, but not in people with T2D-only. The awareness of pinch proprioceptive deficits is paramount for the safety of individuals with T2D and DPN. Moderate correlations between sensory impairments and pinch proprioceptive deficits suggest that not only superficial/discriminative sensation is implicated in proprioceptive decrements. Other mechanisms such as damage to muscle spindles or central nervous system associated with T2D + DPN warrant further investigations.
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Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Atividade Motora/fisiologia , Força de Pinça/fisiologia , Propriocepção/fisiologia , Adulto , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Feminino , Dedos/fisiopatologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE OF REVIEW: Our aim is to highlight major advances reported in the last few years in drug-induced muscle toxicity. RECENT FINDINGS: Our focus is on myopathies induced by statins and immune checkpoint inhibitors with a brief overview of rare steroid myopathies. Statin muscle injury is frequently because of direct toxicity rather than an autoimmune mechanism. Laboratory testing and muscle pathologic features distinguish these two conditions. Statin-associated necrotizing autoimmune myopathy (SANAM) is associated with an autoantibody in 66% of cases targeting the HMGCR enzyme. The later autoantibody is a marker for necrotizing autoimmune myopathy, regardless of statin exposure. In SANAM, MHC-I antigens are expressed on the surface of intact muscle fibers. Genetic HLA loci predispose patients exposed to statins to immunologic toxicity. SANAM requires long-term therapy with multiple immunosuppressive therapies. Immune checkpoint inhibitors are powerful emerging therapies for advanced cancer that pause a novel therapeutic challenge. SUMMARY: This review is focused on statins, the most prevalent myotoxic drug class. In addition, we examine the accumulating body of evidence of muscle injury and its management with immune checkpoint inhibitors. We anticipate the reader to become more knowledgeable in recent discoveries related to these myotoxic drugs, and their mechanisms of action and management.
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Doenças Musculares/induzido quimicamente , Anticorpos Monoclonais Humanizados/efeitos adversos , Autoanticorpos/imunologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/diagnóstico , Doenças Musculares/imunologia , Doenças Musculares/terapiaRESUMO
INTRODUCTION: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction. METHODS: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants using a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test-retest reliability. Gait parameters in FSHD participants were compared with a normative database, FSHD clinical severity score, manual muscle testing, and patient-reported functional disability. RESULTS: Gait parameters in FSHD participants were significantly (P < 0.05) altered compared with normative values, and reliability was excellent (intraclass correlation coefficient 0.84-0.99). Stride velocity and trunk sagittal range of motion had moderate to strong correlations to other FSHD disease measures. DISCUSSION: The iTUG was reliable, abnormal in FSHD, and could distinguish between participants with differing disease severities. Instrumenting timed functional tasks may prove to be useful in FSHD clinical trials. Muscle Nerve 57: 503-506, 2018.
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Marcha/fisiologia , Distrofia Muscular Facioescapuloumeral/diagnóstico , Equilíbrio Postural/fisiologia , Amplitude de Movimento Articular/fisiologia , Caminhada/fisiologia , Adulto , Idoso , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular Facioescapuloumeral/fisiopatologia , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
AIMS: Aerobic exercise improves vascular endothelial function in people with Type 2 diabetes mellitus (T2DM). There is minimal information available regarding vascular health in people with T2DM and diabetic peripheral neuropathy (DPN). Thus, the primary aim of this secondary analysis was to determine whether a 16-week aerobic exercise intervention could improve vascular health in people with T2DM and DPN. A secondary aim was to explore the relationship between changes in flow-mediated dilation (FMD) and the number of years since diagnosis of DPN. METHODS: We examined whether a 16-week aerobic exercise intervention would improve vascular health in people with T2DM and DPN. We used Doppler ultrasound to assess brachial artery diameter and peak shear at baseline and post-exercise. Paired t-tests were used to determine whether the outcome measures improved from baseline to post-intervention. Pearson correlation assessed the relationship between DPN (years) and the percent change score (pre- to post-intervention) for FMD. RESULTS: Seventeen individuals were included in the data analysis. After the intervention, peak diameter increased (3.9 (0.5) to 4.0 (0.5) mm; p = 0.07). Time to peak shear occurred at 60.5 (24.6) seconds when compared to baseline at 68.2 (22.7) seconds; p = 0.17. We found that a longer duration (in years) of DPN demonstrated a fair, negative relationship (r = -0.41, p = 0.19) with the percent change in FMD. CONCLUSION: Aerobic exercise was beneficial for improving measures of vascular health but these were not statistically significant. The magnitude of change may be affected by the duration of DPN.
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Artéria Braquial/diagnóstico por imagem , Diabetes Mellitus Tipo 2/reabilitação , Neuropatias Diabéticas/reabilitação , Terapia por Exercício/métodos , Exercício Físico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ultrassonografia DopplerRESUMO
The time is right for the use of Bayesian Adaptive Designs (BAD) in comparative effectiveness trials. For example, Patient Centered Outcomes Research Institute has joined the Food and Drug Administration and National Intitutes of Health in adopting policies/guidelines encouraging their use. There are multiple aspects to BAD that need to be considered when designing a comparative effectiveness design. First, the adaptation rules can determine the expected size of the trial. Second, a utility function can be used to combine extremely important co-endpoints (e.g., efficacy and tolerability) and is a valuable tool for incorporating clinical expertise and potentially patient preference. Third, accrual rate is also very, very important. Specifically, there is a juxtaposition related to accrual and BAD. If accrual rate is too fast we never gain efficient information for adapting. If accrual rate is too slow we never finish the clinical trial. We propose methodology for finding the 'sweet spot' for BAD that addresses these as design parameters. We demonstrate the methodology on a comparative effectiveness BAD of pharmaceutical agents in cryptogenic sensory polyneuropathy. The study has five arms with two endpoints that are combined with a utility function. The accrual rate is assumed to stem from multiple sites. We perform simulations from which the composite accrual rates across sites result in various piecewise Poisson distributions as parameter inputs. We balance both average number of patients needed and average length of time to finish the study.
Assuntos
Bioestatística/métodos , Ensaios Clínicos como Assunto/métodos , Algoritmos , Teorema de Bayes , Ensaios Clínicos como Assunto/estatística & dados numéricos , Simulação por Computador , Humanos , Modelos Estatísticos , Avaliação de Resultados da Assistência ao Paciente , Polineuropatias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , SoftwareRESUMO
OBJECTIVE: Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes. While the beneficial effect of exercise on diabetes is well established, its effect specifically on painful DPN has not been thoroughly explored. The objective of this pilot study was to examine the effect of aerobic exercise on pain in people with DPN. METHODS: Fourteen sedentary individuals (mean age 57 ± 5.11 years) with painful DPN were enrolled in a 16-week, supervised aerobic exercise program. The Brief Pain Inventory-Diabetic Peripheral Neuropathy was used to assess pain intensity (worst, least, average, now) and pain interference with daily life (activity, mood, walk, normal work, relationship, sleep, enjoyment of life) pre intervention and postintervention. Body mass index (BMI), maximum oxygen uptake (VO2max ), hemoglobin A1c (HbA1c), and blood pressure were also measured preintervention and postintervention as secondary outcomes of interest. RESULTS: Significant reductions in pain interference were observed with walking (4.93 ± 3.03 pre to 3.29 ± 2.89 post, P = 0.016), normal work (5.39 ± 3.32 pre to 3.79 ± 3.04 post, P = 0.032), relationship with others (3.96 ± 3.53 pre to 1.29 ± 1.27 post, P = 0.006), sleep (5.11 ± 3.04 pre to 3.5 ± 3.03 post, P = 0.02), and the overall pain interference (4.65 ± 2.70 pre to 2.97 ± 2.22 post, P = 0.013) following the intervention; however, there was no change in pain intensity. VO2max increased significantly postintervention (16.02 ± 3.84 ml/kg/min pre to 17.18 ± 4.19 ml/kg/min, P = 0.028), while BMI, HbA1c, and blood pressure remained unchanged. CONCLUSION: These preliminary results suggest that perceived pain interference may be reduced following an aerobic exercise intervention among people with painful DPN, without a change in pain intensity. Further validation by a RCT is needed.