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BACKGROUND: Patients with neurologic diseases have complex medical needs and may benefit from the addition of clinical pharmacists in their care. OBJECTIVES: This study aimed to describe integration and benefit of clinical pharmacists in neuroimmunology and neuromuscular clinics at an academic medical center. METHODS: This retrospective chart review evaluated patients initiated on a neurology medication for a neuroimmunology or neuromuscular disease state before and after pharmacist integration in neurology clinics. The primary outcome measured access to an initially prescribed neuroimmunology or neuromuscular medication within 90 days of prescription. Secondary outcomes included access to an initially prescribed or alternative neurology medication owing to insurance requirements within 90 days, time from initial prescription to start, and description of pharmacist involvement. RESULTS: There were 101 patients in the pregroup and 101 patients in the postgroup. The percentage of patients with confirmed initially prescribed medication access at 90 days increased in the postgroup compared with the pregroup (87.1% vs. 72.5%, respectively, P = 0.014). For secondary outcomes, the percentage of patients who started on an initially prescribed or alternative neuroimmunology or neuromuscular medication within 90 days also increased in the postgroup compared with the pregroup (90.0% vs. 73.3%, respectively, P = 0.004). Additional pharmacist involvement occurred in 64 patients (63.4%) in the postgroup and included prior authorization approval assistance, drug information support, and medication liaison interventions, with an average of 4.7 pharmacist interventions at each pharmacy-led encounter. CONCLUSION: The addition of pharmacists into neuroimmunology and neuromuscular clinics improved operational access to medications for neuroimmunology and neuromuscular conditions. In addition, pharmacists were able to assist with multiple areas of patient care including medication education, monitoring, and serving as a medication liaison. This study supports continuing to offer clinical pharmacy services in neuroimmunology and neuromuscular departments and may support the addition of clinical pharmacists into neurology services at other institutions.
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Farmacéuticos , Servicio de Farmacia en Hospital , Humanos , Estudios Retrospectivos , Atención al Paciente , Centros Médicos AcadémicosRESUMEN
IgG4-related disease is an immune-mediated systemic inflammatory condition characterized by tissue infiltration of IgG4-positive plasma cells and elevated serum IgG4 concentrations. Peripheral neuropathy is an atypical manifestation of this disease. We describe an unusual case of vasculitic neuropathy in a patient with IgG4-related kidney disease. A 55-year-old woman presented with right leg weakness progressing to bilateral leg weakness, pain and numbness of the legs, and impaired gait. She was previously evaluated for weight loss and anemia with a CT scan of the abdomen due to concern for malignancy. Abnormal enhancement of the kidneys was seen, and laboratory work-up and kidney biopsy were consistent with IgG4-related disease. Myeloperoxidase-antineutrophil cytoplasmic antibodies were also positive. In combination with the patient's asymmetric leg weakness and painful neuropathy, this raised concern for vasculitis. Sural nerve biopsy confirmed vasculitic neuropathy. Recent studies have demonstrated an overlap in the clinical characteristics of IgG4-related disease and the anti-neutrophil cytoplasmic antibody-associated vasculitides, which are known to cause vasculitic neuropathy. Clinicians should recognize this association, and IgG4-related disease should be considered in the differential diagnosis in patients with peripheral neuropathy in the right clinical context.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Enfermedad Relacionada con Inmunoglobulina G4 , Enfermedades del Sistema Nervioso Periférico , Femenino , Humanos , Riñón , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/etiología , PeroxidasaRESUMEN
INTRODUCTION: Paramyotonia congenita (PMC) is a nondystrophic myotonic disorder that is believed to be caused by a defect in Nav 1.4 sodium channel inactivation. Ranolazine, which acts by enhancing slow inactivation of sodium channels, has been proposed as a therapeutic option, but in vivo studies are lacking. METHODS: We conducted an open-label, single-center trial of ranolazine to evaluate efficacy and tolerability in patients with PMC. Subjective symptoms of stiffness, weakness, and pain as well as clinical and electrical myotonia were evaluated. Baseline measures were compared with those after 4 weeks of treatment with ranolazine. RESULTS: Ranolazine was tolerated well without any serious adverse events. Both subjective symptoms and clinical myotonia were significantly improved. Duration of myotonia was reduced according to electromyography, but this change was not statistically significant in all tested muscles. DISCUSSION: Our findings support the use of ranolazine as a treatment for myotonia in PMC and suggest that a randomized, placebo-controlled trial is warranted. Muscle Nerve 59:240-243, 2019.
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Trastornos Miotónicos/tratamiento farmacológico , Ranolazina/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Adulto , Electromiografía , Femenino , Fuerza de la Mano/fisiología , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/etiología , Trastornos Miotónicos/complicaciones , Dolor/etiología , Índice de Severidad de la Enfermedad , Síndrome de la Persona Rígida/etiologíaRESUMEN
INTRODUCTION: This study aimed to identify infections in patients with myasthenia gravis, dermatomyositis, and chronic inflammatory demyelinating polyradiculoneuropathy, and to investigate the relationship between infection and immunomodulation. METHODS: A retrospective chart review examined 631 patients with myasthenia gravis (n = 358), chronic inflammatory demyelinating polyradiculoneuropathy (n = 124), and dermatomyositis (n = 149) patients over a 10-year time period. RESULTS: Infection rates were similar at approximately 19% in all 3 diseases. Of the infections in which a causative organism was identified, pneumonia, sepsis, and opportunistic infections were the leading diagnoses. A multivariate model demonstrated a significant association between infection and an increased dose of plasma exchange, mycophenolate mofetil, and corticosteroid therapy. DISCUSSION: There are few large studies investigating rates of infections in patients with autoimmune neuromuscular disorders and the relationship to immunomodulation. This study not only demonstrates the remarkably similar infection rates across the 3 diseases studied, but also shows their relationship to commonly used immunotherapies. Muscle Nerve 57: 927-931, 2018.
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Dermatomiositis/epidemiología , Infecciones/epidemiología , Miastenia Gravis/epidemiología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/epidemiología , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Autoinmunidad/fisiología , Comorbilidad , Dermatomiositis/inmunología , Dermatomiositis/terapia , Femenino , Humanos , Inmunosupresores/uso terapéutico , Incidencia , Infecciones/inmunología , Masculino , Persona de Mediana Edad , Miastenia Gravis/inmunología , Miastenia Gravis/terapia , Plasmaféresis , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Estudios RetrospectivosRESUMEN
INTRODUCTION: A phase 2 study of eculizumab for treating myasthenia gravis (MG) used the quantitative myasthenia gravis score (QMG) and myasthenia gravis activities of daily living profile (MG-ADL) to evaluate baseline disease severity and treatment response. Correlations were then analyzed between these assessments. METHODS: Patients were given eculizumab or placebo during the first 16-week treatment period of the crossover study, with treatment assignments reversed for the second treatment period following a 5-week washout. QMG and MG-ADL scores at baseline and endpoint of each treatment period generated correlation coefficients for baseline status and treatment response during eculizumab therapy. RESULTS: Correlation strength between QMG and MG-ADL scores was higher for treatment response (R = 0.726; 95% confidence interval, 0.264-0.907; P = 0.0036) than for assessing baseline disease status (R = 0.552; 95% confidence interval, -0.022-0.839; P = 0.0495). CONCLUSIONS: MG-ADL may be more sensitive for assessing treatment response than point-in-time disease status. Muscle Nerve 56: 328-330, 2017.
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Actividades Cotidianas/psicología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/psicología , Estudios Cruzados , Femenino , Estudios de Seguimiento , Humanos , Masculino , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
INTRODUCTION: Although formal spirometry is the gold standard for monitoring respiratory function in patients with myasthenia gravis (MG), such testing is often delayed or unavailable. There is a need for a simple bedside test that can accurately measure respiratory function. METHODS: We conducted a prospective, cross-sectional, single-blind study in adults with acetylcholine receptor antibody positive MG. Participants performed the single breath count test (SBCT) and underwent manual muscle strength testing, and a respiratory therapist performed spirometry blinded to SBCT and strength results. RESULTS: Thirty-one patients, aged 57 ± 19 years participated. SBCT showed significant correlations with forced vital capacity (FVC), negative inspiratory force, and neck flexor strength (P < 0.01). FVC showed significant correlation with neck flexor strength (P = 0.02) but no correlation with shoulder abductor strength. CONCLUSIONS: These data suggest that the SBCT and neck flexor strength testing are valuable tools for bedside assessment of respiratory function in MG patients.
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Fuerza Muscular/fisiología , Miastenia Gravis/diagnóstico , Miastenia Gravis/fisiopatología , Músculos del Cuello/fisiopatología , Músculos Respiratorios/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Método Simple Ciego , Espirometría , Estadística como Asunto , Capacidad Vital/fisiología , Adulto JovenRESUMEN
INTRODUCTION: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. METHODS: There were 33 subjects, aged 2055 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (1020 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. RESULTS: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. CONCLUSIONS: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.
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Inhibidores de Histona Desacetilasas/uso terapéutico , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/fisiopatología , Ácido Valproico/uso terapéutico , Adulto , Atención Ambulatoria , Estudios de Cohortes , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/fisiología , Estudios Prospectivos , Resultado del Tratamiento , Ácido Valproico/farmacologíaRESUMEN
BACKGROUND: Fatigue is a debilitating symptom of myasthenia gravis (MG). The impact of fatigue on MG can be assessed by Quality of Life in Neurological Disorders (Neuro-QoL) Short Form Fatigue scale. Transformation of raw Neuro-QoL fatigue scores to T-scores is a known approach for facilitating clinical interpretation of clinically meaningful and fatigue severity thresholds. METHODS: In the Phase 3, double-blind, placebo-controlled RAISE study (NCT04115293), adults with acetylcholine receptor autoantibody-positive generalised MG (MG Foundation of America Disease Class II-IV) were randomised 1:1 to daily subcutaneous zilucoplan 0.3 mg/kg or placebo for 12 weeks. Patients completing RAISE could opt to receive zilucoplan 0.3 mg/kg in an ongoing, open-label extension study, RAISE-XT (NCT04225871). In this post-hoc analysis, we evaluated the long-term effect of zilucoplan on fatigue in RAISE patients who entered RAISE-XT. We report change in Neuro-QoL Short Form Fatigue T-scores and fatigue severity levels from RAISE baseline to Week 60. RESULTS: Mean Neuro-QoL Short Form Fatigue T-scores improved from baseline to Week 12 in the zilucoplan group (n = 86) with a clinically meaningful difference versus placebo (n = 88; least squares mean difference: - 3.61 (nominal p-value = 0.0060]), and these improvements continued further to Week 60. At Week 12, more patients on zilucoplan (n = 34, 47.2%) experienced improvements in ≥ 1 fatigue severity level from baseline versus placebo (n = 23, 28.4%; p = 0.017). At Week 60, most (n = 55, 65.5%) patients had mild fatigue or none. CONCLUSION: Treatment with zilucoplan demonstrated statistical and clinically meaningful improvements in fatigue scores and severity versus placebo during RAISE, which were sustained to Week 60 in RAISE-XT.
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Fatiga , Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/complicaciones , Método Doble Ciego , Fatiga/etiología , Fatiga/tratamiento farmacológico , Fatiga/fisiopatología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Calidad de Vida , Anciano , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Evaluación de Resultado en la Atención de SaludRESUMEN
Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).
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BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.
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Distrofia Muscular Facioescapulohumeral , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Método Doble Ciego , Piridinas/efectos adversos , Piridinas/uso terapéutico , Resultado del TratamientoRESUMEN
INTRODUCTION: Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 (C5). METHODS: This study was a randomized, double-blind, placebo-controlled, crossover trial involving 14 patients with severe, refractory generalized MG (gMG). RESULTS: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3-point reduction in the quantitative myasthenia gravis (QMG) score. Examining both treatment periods, the overall change in mean QMG total score was significantly different between eculizumab and placebo (P = 0.0144). After assessing data obtained from all visits, the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo (P < 0.0001). Eculizumab was well tolerated. CONCLUSION: The data suggest that eculizumab may have a role in treating severe, refractory MG.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/epidemiología , Adulto , Anciano , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/diagnóstico , Proyectos PilotoRESUMEN
Valosin-containing protein (VCP)-associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP-associated MSP have myopathy, but there is no consensus-based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb-girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single-variant testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and magnetic resonance imaging can also help rule out disease mimics. Standardized management of VCP myopathy will optimize patient care and help future research initiatives.
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Enfermedades Musculares , Distrofia Muscular de Cinturas , Deficiencias en la Proteostasis , Humanos , Proteína que Contiene Valosina/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/terapia , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/terapia , FenotipoRESUMEN
BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.
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Inmunoglobulinas Intravenosas , Miastenia Gravis , Adulto , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Método Doble Ciego , Corticoesteroides/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme.
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Miositis por Cuerpos de Inclusión , Estados Unidos , Adulto , Humanos , Animales , Femenino , Masculino , Ratones , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Proyectos Piloto , Método Doble Ciego , Progresión de la EnfermedadRESUMEN
INTRODUCTION: Small published case series suggest that compressive radial neuropathy is often a self-limited phenomenon with a favorable prognosis. Due to paucity of data, we sought to clearly define prognosis. METHODS: To define clinical and electrodiagnostic features in this condition, we retrospectively reviewed consecutive cases of compressive radial neuropathy confirmed using electrodiagnostic studies at a large tertiary center over a 10-year period. RESULTS: A total of 51 patients (26 men, 25 women, mean age 46 years ± 15; range, 19-83 years) with compressive radial neuropathy were identified and reviewed. All patients in whom clinical follow-up was available (23 [45%] of the 51 patients identified) experienced complete recovery. Mean duration from onset to resolution of symptoms was 3.4 months. CONCLUSIONS: Our results support a good prognosis in essentially all patients with acute compressive radial neuropathies. This report provides valuable information to assist in counseling patients who may present with profound clinical deficits.
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Neuropatía Radial/diagnóstico , Neuropatía Radial/fisiopatología , Potenciales de Acción/fisiología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Electrodiagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVES: The purpose of this study was to document and analyze intraneural vascular flow within the median nerve using power and spectral Doppler sonography and to determine the relationship of this vascular flow with diagnosis of carpal tunnel syndrome based on electrodiagnostic testing. METHODS: Power and spectral Doppler sonograms in the median nerve were prospectively collected in 47 symptomatic and 44 asymptomatic subjects. Doppler studies were conducted with a 12-MHz linear transducer. Strict inclusion criteria were established for postexamination assessment of waveforms; routine quality assurance was completed; electrodiagnostic tests were conducted on the same day as sonographic measurements; and the skin temperature was controlled. Included waveforms were categorized by location and averaged by individual for comparative analysis to electrodiagnostic testing. RESULTS: A total of 416 waveforms were collected, and 245 were retained for statistical analysis based on strict inclusion criteria. The mean spectral peak velocity among all waveforms was 4.42 (SD, 2.15) cm/s. At the level of the pisiform, the most consistent data point, mean peak systole, was 3.75 cm/s in symptomatic patients versus 4.26 cm/s in asymptomatic controls. Statistical trending showed an initial increase in the mean spectral peak velocity in symptomatic but diagnostically negative cases, with decreasing velocity as diagnostic categories progressed from mild to severe. CONCLUSIONS: An inverse relationship may exist between intraneural vascular flow in the median nerve and an increasing severity of carpal tunnel syndrome based on nerve conduction results. Randomized controlled trials are needed to determine whether spectral Doppler sonography can provide an additive benefit for diagnosing the severity of carpal tunnel syndrome.
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Síndrome del Túnel Carpiano/diagnóstico por imagen , Nervio Mediano/diagnóstico por imagen , Ultrasonografía Doppler , Adulto , Análisis de Varianza , Velocidad del Flujo Sanguíneo/fisiología , Síndrome del Túnel Carpiano/fisiopatología , Electrodiagnóstico , Femenino , Humanos , Masculino , Nervio Mediano/fisiopatología , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Amyloidosis refers to a group of conditions where abnormal protein-or amyloid-deposits in tissues or organs, often leading to organ malfunction. Amyloidosis affects nearly any organ system, but especially the heart, kidneys, liver, peripheral nervous system, and gastrointestinal tract. Neuromuscular deficits comprise some of its ubiquitous manifestations. Amyloidosis can be quite challenging to diagnose given its clinical heterogeneity and multi-system nature. Early diagnosis with accurate genetic and serologic subtyping is key for effective management and prevention of organ decline. In this review, we highlight the value of a multidisciplinary comprehensive amyloidosis clinic. While such a model exists at numerous clinical and research centers across the globe, the lack of more widespread adoption of such a model remains a major hindrance to the timely diagnosis of amyloidosis. Such a multidisciplinary care model allows for the timely and effective diagnosis of amyloidosis, be it acquired amyloid light amyloidosis (AL), hereditary transthyretin amyloidosis (hATTR), or wild type amyloidosis (TTR-wt), especially in the current era of personalized genomic medicine. A multidisciplinary clinic optimizes the delivery of singular or combinatorial drug therapies, depending on amyloid type, fibril deposition location, and disease progression. Such an arrangement also helps advance research in the field. We present our experience at The Ohio State University, as one example out of many, to highlight the centrality of a multi-disciplinary clinic in amyloidosis care.
RESUMEN
Background: Beta-adrenergic antagonists or blockers (BB) are a cornerstone of cardiac therapy for multiple indications. However, BB are considered relatively contraindicated in amyloid cardiomyopathy due to poor tolerance. This intolerance is hypothesized to be due to concomitant neuropathy and significant restrictive cardiomyopathy. This study analyzes the incidence and characteristics of BB tolerance in patients with amyloid cardiomyopathy. Methods: Through a single-center retrospective chart review, patients with amyloid cardiomyopathy, confirmed by endomyocardial biopsy or technetium-99 pyrophosphate scan, were identified and clinical data was collected. Statistical methods included Chi-square test and two sample t-tests. Results: Of 135 cardiac amyloidosis patients, 27 patients (20.0%) had no BB use, 56 patients (41.5%) were current BB users, and 52 patients (38.5%) were prior BB users. The most frequent indications for BB use were heart failure, hypertension, coronary artery disease, and arrhythmia. The most common reason for stopping BB therapy was hypotension (62.8%) followed by fatigue, bradycardia, and orthostasis. Neurologic symptoms at the initial BB prescription or most recent evaluation were not significantly different between current and prior BB users. Their cardiovascular profiles were similar by ejection fraction, wall thickness, troponin I, and brain natriuretic peptide. There was no association for BB discontinuation based on amyloid subtype, sex, or race. Conclusion: The majority of patients with amyloid cardiomyopathy were prescribed BB, and over half of these patients still tolerated BB therapy. Current and prior BB users had similar profiles from a cardiovascular and neurologic perspective, with no association identified to predict BB discontinuation.
Asunto(s)
4-Aminopiridina/análogos & derivados , Enfermedades de la Unión Neuromuscular/tratamiento farmacológico , Producción de Medicamentos sin Interés Comercial , Médicos/psicología , Bloqueadores de los Canales de Potasio/uso terapéutico , 4-Aminopiridina/uso terapéutico , Amifampridina , Humanos , Enfermedades de la Unión Neuromuscular/economía , Producción de Medicamentos sin Interés Comercial/economía , Producción de Medicamentos sin Interés Comercial/métodosRESUMEN
OBJECTIVES: The use of sonography in musculoskeletal research and clinical applications is increasing; however, measurement techniques for diagnosing carpal tunnel syndrome with sonography continue to be inconsistent. Novel methods of measurement using internal comparisons to identify swelling of the median nerve require investigation and comparison to currently used techniques. METHODS: The flattening ratio of the median nerve, bowing of the flexor retinaculum, and cross-sectional area of the median nerve were collected in the forearm, at the radiocarpal joint, and at the level of the pisiform in both symptomatic patients and asymptomatic control participants. Electrodiagnostic testing was completed in symptomatic patients as a diagnostic standard. RESULTS: Median nerve measurements were collected from 166 wrists of symptomatic and asymptomatic participants. The flattening ratio did not show any correlation to electrodiagnostic testing and was identical between both symptomatic and asymptomatic participants. Moderate to strong correlations were noted between electrodiagnostic testing results and sonographic measurements of the cross-sectional area at the pisiform, retinacular bowing, and both the ratio and change of the cross-sectional area between the forearm and pisiform. The area under the curve was large for all receiver operating characteristic curves for each measurement (0.759-0.899), and sensitivity was high (80.4%-82.4%). CONCLUSIONS: Measurement of swelling through a ratio or absolute change had similar diagnostic accuracy as individual measurement of the cross-sectional area within the carpal tunnel. These measures may be useful for improving accuracy in more diverse clinical populations. Further refinement of protocols to identify the largest cross-sectional area within the carpal tunnel region and statistical methods to analyze clustered, multilevel outcome data are recommended to improve diagnostics.