Electron microscopy in the diagnosis of skeletal muscle disorders: Its utility and limitations

Electron microscopy (EM) has a substantial role in the diagnosis of skeletal muscle disorders. The ultrastructural changes can be observed in muscle fibers and other components of the muscle tissue. EM serves as a confirmatory tool where the diagnosis is already established by enzyme histochemistry staining. Although it is indispensable in the diagnosis of rare forms of congenital myopathies not appreciated by light microscope, such as cylindrical spiral myopathy, zebra body myopathy, fingerprint body myopathy, and intranuclear rod myopathy, in cases not subjected to histochemical staining, it is required for definitive diagnosis in certain groups of muscle disorders, which includes congenital myopathies, metabolic myopathies in particular mitochondrial myopathies and glycogenosis, and in vacuolar myopathies. It does not have diagnostic implications in muscular dystrophies and neurogenic disorders. In the recent past, despite the availability of advanced diagnostic techniques, electron microscopy continues to play a vital role in the diagnosis of skeletal muscle disorders. This review gives an account of ultrastructural features of skeletal muscle disorders, the role of EM in the diagnosis, and its limitations.

Recomendaciones para el manejo de los pacientes con enfermedades neuromusculares en el contexto de la pandemia covid-19 / Recommendations for the treatment of patients with neuromuscular disorders in the context of the COVID-19 pandemic

RESUMEN Los trastornos neuromusculares, constituyen un grupo heterogéneo de padecimientos crónicos, genéticos o de origen inmunológico que afectan a todos los grupos etarios. Muchos de los pacientes afectados, cursan con debilidad muscular, trastornos respiratorios, cardiovasculares y algunos de ellos requieren del uso de medicamentos inmunosupresores o terapias de infusión en el ámbito hospitalario. En la actualidad, el mundo se enfrenta a la pandemia generada por la enfermedad por Coronavirus 2019, (Coronavirus Disease 2019, covid-19), que es la entidad causada por la infección por el Coronavirus del Síndrome-Respiratorio Agudo Severo o Grave 2 (severe respiratory acute syndrome 2, SARS-CoV-2). En esta patología, se han descrito factores de mal pronóstico entre los que se encuentran edad mayor de 60 años, comorbilidades como diabetes mellitus, enfermedad pulmonar, enfermedad cardiovascular, hipertensión arterial, cáncer e inmunosupresión. Teniendo en cuenta lo anterior, surge la necesidad de establecer unas recomendaciones generales para el cuidado de los pacientes con patologías neuromusculares durante la pandemia, basadas en la literatura disponible que permitan una orientación inicial en el manejo de los pacientes.

SUMMARY Neuromuscular disorders constitute a heterogeneous group of chronic, genetic or immunological disorders that affect all age groups. Many of the affected patients have muscle weakness, respiratory and cardiovascular disorders, and some of them require the use of immunosuppressive drugs or infusion therapies in the hospital setting. Currently, the world is facing the pandemic caused by Coronavirus Disease 2019, (Coronavirus Disease 2019, COVID-19), which is the entity caused by infection by the severe respiratory acute syndrome 2, SARS-CoV-2). In this pathology, factors of poor prognosis have been described, among which are age over 60 years, comorbidities such as diabetes mellitus, lung disease, cardiovascular disease, high blood pressure, cancer and immunosuppression. Taking into account the aforementioned, the need arises to establish general recommendations for the care of patients with neuromuscular pathologies during the pandemic, based on the available literature that allows initial orientation in the management of patients.

Childhood Neuromuscular Disorders

@#Infantile and childhood neuromuscular disorders are a significant cause of motor delays in childhood. Neuromuscular disorders may present either with hypotonia and weakness in early infancy or falls and difficulties in walking later in childhood. The first goal in approaching a patient with suspected muscle disease is to ascertain the correct site of the lesion, followed by the cause of the lesion. Extraordinary breakthroughs in the area of genetic testing have resulted in a decrease in reliance on muscle biopsies and neurophysiological testing. The importance of recognising such disorders is because viable treatment options are now available for the treatment of affected children. Early recognition allows patients to receive therapy at a stage of the disease that will give the best long-term outcomes. Even in the absence of definitive treatment, supportive management and preventive care have revolutionized the care of neuromuscular disorders with longer quality life spans in a good majority of patients.

Daily Iron Requirements in Healthy Indian Children and Adolescents

Objective: This study aimed to define the estimated average requirement and therecommended dietary allowance of iron for Indian children and adolescents. Methods: TheEstimated average requirement was derived for children aged 1-17y, from the meanbioavailability-adjusted daily physiological iron requirement, which in turn was estimatedusing a factorial method. This consisted of mean daily iron losses from the body andadditional iron required for tissue growth and storage, while also defining the variance of eachfactor to derive the Recommended dietary allowance. Results: The estimated averagerequirement of iron for children ranged from 5.6 to 11.0 mg/d in children aged 1-9y. Foradolescents aged 10-17y, these ranged from 10.8 to 18.4 mg/d and 15.4 to 18.5 mg/d foradolescent boys and girls, respectively. Conclusion: New estimates of estimated averagerequirement for iron in Indian children are presented, and same may be used to inform ironsupplementation and food fortification policies.

Translation and validation of the Life Satisfaction Index for Adolescents scale with neuromuscular disorders: LSI-A Brazil / Tradução e validação da escala de qualidade de vida para adolescentes com doenças neuromusculares para português do Brasil: LSI-A Brasil

ABSTRACT Objective To validate the Life Satisfaction Index for Adolescents (LSI-A) scale, parent version and patient version, for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and limb-girdle muscular dystrophy (LGMD). Methods The parent version of the instrument was divided into Groups A, B, C and D; and the patient version, divided into B, C and D. For the statistical calculation, the following tests were used: Cronbach's α, ICC, Pearson and the ROC Curve. Results The parent and patient versions of the instrument are presented, with the following results in the overall score, respectively: Cronbach's α, 0.87 and 0.89; reliability, r 0.98 and 0.97; reproducibility, ICC 0.69 and 0.80; sensitivity, 0.78 and 0.72; specificity, 0.5 and 0.69; and accuracy, 64% and 70.4%. Conclusion According to the validity and reproducibility values, the LSI-A Brazil parent and patient versions, are clinically useful to assess quality of life in DMD, SMA or LGMD and may also be useful for other neuromuscular disorders.

RESUMO Objetivo Validar a escala Life Satisfaction Index for Adolescents (LSI-A) versão pais e versão paciente para doenças neuromusculares. Método O instrumento versão pais foi dividido nos Grupos A,B, C e D; e paciente, em B, C e D. Para cálculo estatístico utilizou-se os testes α de Cronbach, CIC, Pearson e Curva ROC. Resultados Valor de Cronbach versão pais e paciente no escore geral, 0.87 e 0.89; confiabilidade,0.98 e 0.97;reprodutibilidade,entre 0.59 e 0.69 e, entre 0.58 e 0.80; sensibilidade, 0.78 e 0.72; especificidade, 0.5 e 0.69; e acurácia, 64% e 70.4% respectivamente. Conclusão Conforme a validade e reprodutibilidade, o LSI-A Brasil versão pais e paciente é útil clinicamente para avaliar a Qualidade de Vida da Distrofia Muscular de Duchenne, Amiotrofia Espinhal Progressiva ou Distrofia Muscular tipo Cinturas e pode ser usado para outras doenças neuromusculares.

Trastornos del sueño en niños y adolescentes con enfermedades neurológicas / Sleep disorders in children and adolescents with neurological diseases

Resumen Los trastornos del ciclo circadiano vigilia-sueño son primarios y secundarios. Los primarios o intrínsecos son menos frecuentes (31%) que los secundarios o extrínsecos pero más rápido diagnosticados y tratados (69%). Los primarios se deben a alteraciones intrínsecas anatómico y/o funcionales del ciclo circadiano sueño-vigilia. Su tratamiento está bien definido en caso de que exista. Los trastornos del sueño secundarios son alteraciones extrínsecas del sueño de origen adquirido cuyo diagnóstico de certeza es más clínico que polisomnográfico y su tratamiento dirigido a la condición asociada así como a la manifestación anormal onírica. Aunque las secundarias son más comunes que las primarias (69% contra 31%) se diagnostican y tratan menos que las primarias. Cuando no se diagnostican y tratan correctamente inducen problemas significativos emocionales, conductuales y cognoscitivos en niños y adolescentes comparados con aquellos sin tales sin trastornos del sueño. El propósito de esta revisión es que los pediatras generales, pediatras neurólogos y paidopsiquiatras tengan en mente la alta incidencia de los trastornos secundarios del sueño en niños con enfermedades neurológicas y que pregunten a los padres y pacientes sobre la calidad del sueño de sus hijos y realicen un diagnóstico y tratamiento precoz para evitar consecuencias en algunos casos fatales.

Abstract The disorders of the circadian cycle sleep-wake are primary and secondary. The primary or intrinsic are less frequent (31%) than the secondary or extrinsic but early diagnosed and treated (69%). The primary intrinsic alterations are due to anatomical and/or functional process circadian rhythm sleep-wake cycle. Its treatment is well defined in case it exists. The secondary sleep alterations are extrinsic and their diagnosis is more clinical than polysomnographic and its treatment directed to the associated condition as well as the manifestation abnormal sleep. Although the secondary are more common than the primary (69% vs. 31%) they are diagnosed and treated less than the primaries. When not properly diagnosed and treated induce significant problems with emotional, behavioral and cognitive changes in children and adolescents compared with those without sleep disorders. The purpose of this review is that the general pediatricians, pediatric neurologists and pediatric psychiatric bear in mind the high incidence of side effects of sleep disorders in children with neurological diseases and to ask parents and patients about the quality of sleep of their children and adolescents and make a diagnosis and early treatment to avoid fatal consequences in some cases.

INCLEN Diagnostic Tool for Neuromotor Impairments (INDT-NMI) for Primary Care Physician: Development and Validation.

Objectives: To develop and validate a diagnostic tool for use by primary care physicians for diagnosing neuro-motor impairment among 2-9 year old children in primary care settings. Study design: Modified Delphi technique involving national (n=49) and international (n=6) experts was used for development of INDT-NMI. The tool was then validated through a cross sectional study. Setting: Neurology specialty clinics of three tertiary care pediatric centers in New Delhi, India. Participants: 454 children aged 2-9 years [mean (SD) age: 60.4 (23.7) mo], selected through systematic random sampling, underwent assessment for identification and classification of neuromotor impairments (NMI). Intervention: All study subjects were first administered INDTNMI (candidate test) by a trained physician followed by expert assessment for NMI and other neurodevelopment disorders (NDD) by team of two pediatric neurologists (Gold standard). Results: According to expert evaluation, 171 (37.8%) children had neuromotor impairments. There were four categories of subjects: NMI alone (n=66); NMI+other NDDs (n=105); Other NDDs without NMI (n=225) and ‘Normal’ group (n=58). Using expert evaluation as gold standard, overall sensitivity of the INDTNMI was 75.4% and specificity was 86.8%. INDT-NMI helped graduate physicians to correctly classify 86.6% (112/129) children with NMI into different types (cerebral palsy, neuromotor diseases and other NMI). Graduate physicians assigned 40 children (8.8%) as ‘indeterminate’, 38 (95%) of whom had either NDD and/or NMI and thus merited referral. Misclassification of NMI occurred in those with mild changes in muscle tone, dystonia, or ataxia and associated NDDs. Conclusion: Graduate primary care physicians with a structured short training can administer the new tool and diagnose NMI in 2-9 year old children with high validity. INDT-NMI requires further evaluation in actual primary care settings.

Analysis of calpain-3 protein in muscle biopsies of different muscular dystrophies from India.

Background & objectives: Calpain-3, a Ca2+-dependent protease has been implicated in the pathology of neuromuscular disorders (NMDs). The current study aimed to analyze calpain-3 expression in cases diagnosed as muscular dystrophy from the Indian population. Methods: Calpain-3 Western blot analysis in muscle biopsies of immunohistochemically confirmed cases of Duchenne muscular dystrophy (DMD) (n=10), dysferlinopathy (n=30) and sarcoglycanopathy (n=8) was carried out. Calpain-3 Western blotting was also used in a blinded study to identify cases of calpain-3 deficiency in 28 NMD patients with potential muscular dystrophy. Results: Calpain-3 appeared as a full length 94 kDa band with an autolytic product (~60 kDa) on Western blots with antibody NCL-CALP-12A2 (Ab-2). Eight of the 10 DMD samples showed absence of 94 kDa band but presence of 60 kDa band while one case of sarcoglycanopathy showed absence of both. Twenty one of the 30 dysferlinopathy samples showed both bands while six showed only the 60 kDa band and three showed absence of both. In the blinded study, five NMD cases with potential muscular dystrophy that showed complete absence of both bands in retrospect exhibited clinical features of limb girdle muscular dystrophy 2A (LGMD2A). Interpretation & conclusions: While the study revealed a consistent pattern of calpain-3 in DMD, one sarcoglycanopathy and three dysferlinopathy samples exhibited secondary reduction in calpain-3. It was recognized that both calpain-3 bands should be considered to confirm calpain deficiency. Further, western blot offers an economical and fast preliminary screening method for LGMD2A especially in cases of complete absence of calpain-3 prior to conclusive diagnosis by genetic testing.

Pitfalls in Using Electrophysiological Studies to Diagnose Neuromuscular Disorders

Electrodiagnostic testing is used widely for the full characterization of neuromuscular disorders and for providing unique information on the processes underlying the pathology of peripheral nerves and muscles. However, such testing should be considered as an extension of anamnesis and physical examination, not as pathognomonic of a specific disease entity. There are many pitfalls that could lead to erroneous interpretation of electrophysiological study results when the studies are not performed properly or if they are performed in the presence of anatomical aberrations. The diagnostic reliability of electrodiagnostic studies can be improved and the associated pitfalls overcome if the physician is familiar with all of those possible pitfalls. In this article we discuss the most common and important pitfalls associated with electrodiagnostic medicine.

Manejo de longo prazo em crianças com transtornos neuromusculares / Long-term management of children with neuromuscular disorders

OBJETIVO: A distrofia muscular de Duchenne é o tipo mais comum de miopatia genética. Contudo, existe um grande número de doenças neuromusculares hereditárias que são individualmente muito raras e sobre as quais não há muita informação clínica disponível. Este artigo de revisão baseia-se na experiência do autor em uma clínica pediátrica para tratamento de doenças musculares e apresenta orientação prática e planos terapêuticos para os problemas frequentemente encontrados. FONTES DE DADOS: O banco de dados da MEDLINE foi pesquisado com o objetivo de localizar artigos recentes e relevantes para o manejo de crianças com miopatias e neuropatias hereditárias. Uma coorte de 200 pacientes foi avaliada através de análise estatística descritiva. SÍNTESE DOS DADOS: A distrofia muscular de Duchenne representou quase metade dos diagnósticos, seguida da atrofia muscular espinhal (12 por cento), da distrofia muscular de Becker e da distrofia miotônica (7 por cento cada). Dezesseis pacientes (9 por cento) apresentaram miopatia de origem desconhecida. CONCLUSÕES: Assim como ocorre com outras doenças crônicas, esses pacientes devem passar por acompanhamento periódico realizado por profissionais de saúde desde cedo para aumentar sua expectativa de vida e melhorar sua qualidade de vida. É útil para os médicos adotarem uma abordagem estruturada ao atender crianças com transtornos neuromusculares e monitorar todos os sistemas de órgãos afetados.

OBJECTIVE: Duchenne muscular dystrophy is the commonest genetic myopathy but there exist a large number of inherited neuromuscular diseases which individually are very rare and where clinical information is not widely available. This review is based on the author's experience in a pediatric muscle clinic and provides practical guidance and treatment plans for frequently encountered problems. SOURCES: A MEDLINE search was conducted to retrieve recent articles relevant to the management of children with inherited myopathies and neuropathies. A patient cohort (n = 200) was evaluated using descriptive statistics. SUMMARY PF THE FINDINGS: Duchenne muscular dystrophy accounted for almost half of the diagnoses, followed by spinal muscular atrophy (12 percent), Becker muscular dystrophy and myotonic dystrophy (7 percent each). Sixteen patients (9 percent) had an unknown myopathy. CONCLUSIONS: As with other chronic illnesses, these patients should be regularly reviewed by health professionals from an early age to increase life expectancy and improve quality of life. It is useful for physicians to take a structured approach when looking after children with neuromuscular disorders and to monitor all affected organ systems.

Medida da função motora: versão da escala para o português e estudo de confiabilidade / Motor function measure scale: portuguese version and reliability analysis

CONTEXTUALIZAÇÃO: Instrumentos de avaliação funcional de pacientes com doenças neuromusculares são escassos. A escala Medida da Função Motora (MFM) está disponível no original francês e nas versões inglesa e espanhola. OBJETIVOS: Realizar a versão da escala para o português e identificar a confiabilidade de sua aplicação intra e interexaminador. MATERIAIS E MÉTODOS: Duas traduções da MFM de 2004 foram realizadas em separado, por neurologistas proficientes na língua francesa, resultando em texto consensual, após avaliação dos autores. A escala em português foi aplicada em 58 pacientes de seis a 61 anos, com diagnósticos clínico-laboratoriais de variados tipos de distrofias musculares e miopatias congênitas, documentados em vídeo. O primeiro autor realizou o teste e reteste e outros três fisioterapeutas analisaram os mesmos vídeos para confiabilidade interexaminador. Para análises estatísticas foram utilizados os coeficientes de Kendall, Kappa e Pearson. RESULTADOS: Apresenta-se a escala em seus 32 itens e três dimensões. Os coeficientes de concordância de Kendall para a análise interexaminador e os coeficientes Kappa e de Pearson para o teste e reteste foram estatisticamente significativos (p-valor<0,0001) nos 32 itens da escala e no escore total. CONCLUSÕES: A versão portuguesa da MFM mostrou confiabilidade e mínima variabilidade na sua aplicação, podendo ser utilizada como instrumento de diagnóstico clínico e seguimento das doenças neuromusculares. A alta confiabilidade na aplicação da MFM permitirá incluir pacientes brasileiros em ensaios clínicos internacionais que utilizarão a escala.

BACKGROUND: Functional evaluation instruments for patients with neuromuscular disorders are rare. The Motor Function Measure (MFM) scale is available in the original French and in English and Spanish translations. OBJECTIVE: To make a Portuguese translation of the MFM and to identify its intra and inter-examiner reliability. METHODS: Two translations of the 2004 MFM were produced separately by neurologists who were proficient in French. This procedure resulted in a consensual text after evaluation by the authors. The MFM in Portuguese was applied to 58 patients aged six to 61 years, with clinical and laboratory diagnoses of various types of muscular dystrophy and congenital myopathy that were documented on video. The first author performed the test and retest and another three physical therapists analyzed the same videos to assess the inter-examiner reliability. Statistical analyses were performed using the Kendall, kappa and Pearson coefficients. RESULTS: The scale is presented with its 32 items and three dimensions. The Kendall concordance coefficients for inter-examiner analysis and the kappa and Pearson coefficients for the test-retest comparison were statistically significant (p-value<0.0001) for the 32 items on the scale and for the total score. CONCLUSIONS: The Portuguese version of the MFM showed high reliability and minimal variability when it was applied. It can be used as an instrument for clinical diagnosis and follow-up of neuromuscular disorders. The high reliability in applying the MFM will allow Brazilian patients to be included in international clinical trials that use this scale.

Appearance of lipid storage in muscle fiber in neuromuscular disorders / 中国康复理论与实践

@#ObjectiveTo compare the appearance of abnormal lipid accumulation in skeletal muscle fibers in various neuromuscular disorders by analyzing the results of Oil-Red-O staining of muscle biopsy samples. Methods523 muscle biopsies performed in 1998—2002,consisted of lipid storage myopathy, mitochondrial diseases, inflammatory myopathy, muscular dystrophy, steroid myopathy, alcoholic myopathy and neurogenic muscle atrophy,were studed. ResultsType Ⅰ fibers were selectively involved in lipid storage of muscle fibers.In all diseases, men were more frequently affected than momen in which men to women was 3∶2.Marked uniformity lipid storage in muscle fibers was found most frequently in patients with lipid storage myopathy and mitochondrien-lipid-glycogene storage diseases. Moderate uniformity lipid storage in the muscle fibers was found in patients with steroid myopathy, alcoholic myopathy and malnutrition. Moderate or marked non-uniformity lipid storage in muscle fibers was found in patients with mitochondrial cytopathy, inflammatory myopathy, muscular dystrophy. Moderate non-uniformity lipid storage in muscle fibers was found in patients with neurogenic muscle atrophy. Mild lipid storage in muscle fibers was found in numerous systemic disease and neuromuscular disorders. ConclusionNumerous neuromuscular diseases can associated with abnormal lipid metabolism in muscle fibers, in which the men are more involved than women. The appearance of lipid accumulation in the muscle fibers markedly changes in different neuromuscular diseases. The diagnostic value of lipid storage in muscle fibers should be considered under analysis clinical symptoms and other myopathological findings.