Multicenter Validation of the Charcot-Marie-Tooth Functional Outcome Measure.

BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of PMP22, is the most common hereditary peripheral neuropathy. For participants with CMT1A, few clinical trials have been performed; however, multiple therapies have reached an advanced stage of preclinical development. In preparation for imminent clinical trials in participants with CMT1A, we have produced a Clinical Outcome Assessment (COA), known as the CMT-Functional Outcome Measure (CMT-FOM), in accordance with the FDA Roadmap to Patient-Focused Outcome Measurement to capture the key clinical end point of function. METHODS: Participants were recruited through CMT clinics in the United States (n = 130), the United Kingdom (n = 52), and Italy (n = 32). To derive the most accurate signal with the fewest items to identify a therapeutic response, a series of validation studies were conducted including item and factor analysis, Rasch model analysis and testing of interrater reliability, discriminative ability, and convergent validity. RESULTS: A total of 214 participants aged 18-75 years with CMT1A (58% female) were included in this study. Item, factor, and Rasch analysis supported the viability of the 12-item CMT-FOM as a unidimensional interval scale of function in adults with CMT1A. The CMT-FOM covers strength, upper and lower limb function, balance, and mobility. The 0-100 point scoring system showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for adults with CMT1A exhibiting high inter-rater reliability across a range of clinical settings and evaluators. The CMT-FOM was significantly correlated with the CMT Examination Score (r = 0.643; p < 0.001) and the Overall Neuropathy Limitation Scale (r = 0.516; p < 0.001). Significantly higher CMT-FOM total scores were observed in participants self-reporting daily trips and falls, unsteady ankles, hand tremor, and hand weakness (p < 0.05). DISCUSSION: The CMT-FOM is a psychometrically robust multi-item, unidimensional, disease-specific COA covering strength, upper and lower limb function, balance, and mobility to capture how participants with CMT1A function to identify therapeutic efficacy.

Clinical Outcome Assessments in Encephalitis: A Systematic Review

BACKGROUND AND OBJECTIVES: Most patients with encephalitis experience persisting neurocognitive and neuropsychiatric sequelae in the years following this acute illness. Reported outcomes are often based on generic clinical outcome assessments that rarely capture the patient perspective. This may result in an underestimation of disease-specific sequelae. Disease-specific clinical outcome assessments can improve clinical relevance of reported outcomes and increase the power of research and trials. There are no patient-reported outcome measures (PROMs) developed or validated specifically for patients with encephalitis. The primary objective of this systematic literature review was to identify PROMs that have been developed for or validated in patients with encephalitis. METHODS: We performed a systematic review of the literature published from inception until May 2023 in 3 large international databases (MEDLINE, EMBASE and Cochrane libraries). Eligible studies should have developed or validated a PROM in patients with encephalitis or encephalopathy. Methodologic quality was evaluated using the Consensus-based Standards for the selection of health status Measurement Instruments study design checklist for PROMs. RESULTS: We identified no disease-specific PROMs developed or validated for patients with encephalitis. We identified one study on the development and validation of a disease-specific PROM for hepatic encephalopathy, although this disease course is substantially different to that of patients with encephalitis. The methodologic quality of the included study was generally rated as "doubtful." We identified 30 PROMs that have been applied in 46 studies on encephalitis or encephalopathy, although not validated in these populations. The most commonly applied PROMs for measuring Health-Related Quality of Life were the Medical Outcomes Study Short Form-36 and the Sickness Impact Profile. Emotional well-being was often assessed with the Beck Depression Inventory (BDI-II). Sporadically, PROMs were applied to address other aspects of outcome including daily functioning and sleep quality. DISCUSSION: This systematic review confirms a critical gap in clinical outcome assessments in patients with encephalitis, failing to identify a validated measuring tool for detecting neurocognitive, functional, and health status. It is therefore essential to develop and/or validate disease-specific PROMs for the population with encephalitis to capture relevant information for patient management and clinical trials about the effects of disease that are at risk of being overlooked.

[Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps]. / Guía basada en la evidencia. Diagnóstico y manejo del síndrome de Guillain-Barré en diez pasos.

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

El síndrome de Guillain-Barré (SGB) es una enfermedad inmunológica del nervio periférico y las raíces nerviosas, poco frecuente, potencialmente mortal y que suele desencadenarse por infecciones. La incidencia del SGB puede aumentar durante el brote de enfermedades infecciosas, tal como se observó en las epidemias del virus Zika en la Polinesia Francesa en 2013 y en América Latina en 2015. El diagnóstico y el manejo clínico del SGB pueden ser complicados ya que su presentación y el curso de la enfermedad son heterogéneos, y actualmente no se cuenta con guías clínicas internacionales. Para respaldar a los médicos, especialmente en el contexto de un brote de una enfermedad infecciosa, hemos desarrollado una guía clínica aplicable en todo el mundo para el diagnóstico y el tratamiento del SGB. La guía se basa en literatura actualizada y el consenso de expertos, y tiene una estructura de diez pasos para facilitar su uso en la práctica clínica. Inicialmente, brindamos una introducción a los criterios de diagnóstico, variantes clínicas y diagnósticos diferenciales del SGB. Los diez pasos luego abordan el reconocimiento y el diagnóstico temprano del SGB, la admisión a la unidad de cuidados intensivos, indicación y selección de tratamiento, seguimiento y tratamiento de la progresión de la enfermedad, predicción del curso clínico, resultados y tratamiento de complicaciones y secuelas.

Guía basada en la evidencia. Diagnóstico y manejo del síndrome de Guillain-Barré en diez pasos / Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps

Resumen El síndrome de Guillain-Barré (SGB) es una enfermedad inmunológica del nervio periférico y las raíces nerviosas, poco frecuente, potencialmente mortal y que suele desencadenarse por infecciones. La incidencia del SGB puede aumentar durante el brote de enfermedades infecciosas, tal como se observó en las epidemias del virus Zika en la Polinesia Francesa en 2013 y en América Latina en 2015. El diagnóstico y el manejo clínico del SGB pueden ser complicados ya que su presentación y el curso de la enfermedad son heterogéneos, y actualmente no se cuenta con guías clínicas internacionales. Para respaldar a los médicos, especialmente en el contexto de un brote de una enfermedad infecciosa, hemos desarrollado una guía clínica aplicable en todo el mundo para el diagnóstico y el tratamiento del SGB. La guía se basa en literatura actualizada y el consenso de expertos, y tiene una estructura de diez pasos para facilitar su uso en la práctica clínica. Inicialmente, brindamos una introducción a los criterios de diagnóstico, variantes clínicas y diagnósticos diferenciales del SGB. Los diez pasos luego abordan el reconocimiento y el diagnóstico temprano del SGB, la admisión a la unidad de cuidados intensivos, indicación y selección de tratamiento, seguimiento y tratamiento de la progresión de la enfermedad, predicción del curso clínico, resultados y tratamiento de complicaciones y secuelas.

Abstract Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diag nostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Neuromuscular rehabilitation - what to do?

PURPOSE OF REVIEW: Rehabilitation for patients with neuromuscular disorders (NMDs) has undisputed health benefits and is potentially therapeutic for targeting impairments, improving quality of life, and enabling activities of daily living. Whilst rehabilitation is commonly prescribed, unequivocal evidence and disease-related guidelines are lacking. This review highlights recent studies of exercise, assistive devices, respiratory management and manual therapy and stretching for patients with NMDs. RECENT FINDINGS: Randomised controlled trials of neuromuscular rehabilitation are scant, often underpowered and lack a control group. Recent case studies, clinical trials and cohort studies support rehabilitative therapies such as exercise, respiratory muscle training, assistive devices, and manual therapy and stretching, to provide systemic health benefits, with the possibility to retain or improve function. No evidence of overwork weakness or muscle damage have been reported in exercise trials, and rehabilitative exercise programs in many cases lead to positive psychosocial impacts. Tele-rehab is an emerging area of interest, as a response to the COVID-19 pandemic. SUMMARY: Robust evidence for the benefits of neuromuscular rehabilitation is lacking, and clinical trial quality can be improved. Tele-rehab is a tantalising development to improve access to neuromuscular rehabilitation in both metropolitan and remote settings during and beyond the COVID-19 pandemic.

Diagnosis and management of Guillain-Barré syndrome in ten steps.

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.

Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.

Functional outcome measures for infantile Charcot-Marie-Tooth disease: a systematic review.

A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.

Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial.

BACKGROUND: Exercise is potentially therapeutic for neuromuscular disorders, but a risk of harm exists due to overwork weakness. We aimed to assess the safety and efficacy of progressive resistance exercise for foot dorsiflexion weakness in children with Charcot-Marie-Tooth disease. METHODS: We did this randomised, double-blind, sham-controlled trial across the Sydney Children's Hospitals Network (NSW, Australia). Children aged 6-17 years with Charcot-Marie-Tooth disease were eligible if they had foot dorsiflexion weakness (negative Z score based on age-matched and sex-matched normative reference values). We randomly allocated (1:1) children, with random block sizes of 4, 6, and 8 and stratification by age, to receive 6 months (three times per week on non-consecutive days; 72 sessions in total) of progressive resistance training (from 50% to 70% of the most recent one repetition maximum) or sham training (negligible non-progressed intensity), using an adjustable exercise cuff to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength assessed by hand-held dynamometry (expressed as a Z score) from baseline to months 6, 12, and 24. The primary safety outcome was the between-group difference in muscle and intramuscular fat volume of the anterior compartment of the lower leg assessed by MRI (expressed as a scaled volume) from baseline to 6 months and 24 months. Participants, parents, outcome evaluators, and investigators other than the treatment team were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000552785. FINDINGS: From Sept 2, 2013, to Dec 11, 2014, we randomly assigned 60 children to receive progressive resistance exercise (n=30) or sham training (n=30), and 55 (92%) children completed the trial. ANCOVA-adjusted Z score differences in dorsiflexion strength between groups were 0 (95% CI -0·37 to 0·42; p=0·91) at 6 months, 0·3 (-0·23 to 0·81; p=0·27) at 12 months, and 0·6 (95% CI 0·03 to 1·12; p=0·041) at 24 months. Scaled muscle and fat volume was comparable between groups at 6 months (ANCOVA-adjusted muscle volume difference 0, 95% CI -0·03 to 0·10, p=0·24; and fat volume difference 0, 95% CI -0·01 to 0·05, p=0·25) and 24 months (0, -0·08 to 0·12, p=0·67; and 0, -0·05 to 0·03, p=0·58). No serious adverse events were reported. INTERPRETATION: 6 months of targeted progressive resistance exercise attenuated long-term progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in paediatric patients with Charcot-Marie-Tooth disease. FUNDING: Muscular Dystrophy Association and Australian National Health and Medical Research Council.