Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization.

Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the "typical" form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.

Cognitive impairment in neuromuscular diseases: A systematic review.

Neuromuscular diseases are multifactorial pathologies characterized by extensive muscle fiber damage that leads to the activation of satellite cells and to the exhaustion of their pool, with consequent impairment of neurobiological aspects, such as cognition and motor control. To review the knowledge and obtain a broad view of the cognitive impairment on Neuromuscular Diseases. Cognitive impairment in neuromuscular disease was explored; a literature search up to October 2017 was conducted, including experimental studies, case reports and reviews written in English. Keywords included Cognitive Impairment, Neuromuscular Diseases, Motor Neuron Diseases, Dystrophinopathies and Mitochondrial Disorders. Several cognitive evaluation scales, neuroimaging scans, genetic analysis and laboratory applications in neuromuscular diseases, especially when it comes to the Motor Neuron Diseases, Dystrophinopathies and Mitochondrial Disorders. In addition, organisms model using rats in the genetic analysis and laboratory applications to verify the cognitive and neuromuscular impacts. Several studies indicate that congenital molecular alterations in neuromuscular diseases promote cognitive dysfunctions. Understanding these mechanisms may in the future guide the proper management of the patient, evaluation, establishment of prognosis, choice of treatment and development of innovative interventions such as gene therapy.

Esclerose lateral amiotrófica: novas possibilidades terapêuticas em um arcabouço fisiopatológico ainda em construção / Amyotrophic lateral sclerosis: new therapeutic possibilities in a pathophysiological framework still under construction

Introdução: A Esclerose Lateral Amiotrófica (ELA) é definida como uma doença neurológica progressiva e inexorável, com cerca de 80% dos casos de etiologia desconhecida. Novos medicamentos têm emergido no tratamento de doenças neurodegenerativas, inclusive na ELA, redesenhando o modelo fisiopatológico. Dentre eles, destacam-se o uso da: Edaravone, Vitamina K2, Serina, Metilcobalamina, Pirroloquinolina quinona (PQQ), Ubiquinol e Glutationa. Especificamente na ELA, alguns já foram validados em estudos randomizados-controlados. Metodologia: Atualização da literatura (PUBMED, Medline) sobre a utilização desses fármacos em doenças neurológicas degenerativas, com enfoque para a Doença do Neurônio Motor (DNM-ELA), nos idiomas Português, Inglês, Espanhol e Francês, compreendidos entre os anos de (2010-2017). Discussão: A associação desses medicamentos tem mostrado resultados positivos em inúmeras doenças neurológicas. Alguns, como, por exemplo, a Metilcobalamina e o Edaravone,exerceriam mecanismos de ação capazes de interferir no processo de depleção dos neurônios motores da ponta anterior e do feixe piramidal em pacientes com ELA. Conclusão: Seria precipitado concluir que o uso associado desses fármacos poderia modificar ou mesmo restaurar os danos às unidades motoras; entretanto, faz-se necessário destacar seus mecanismos de ação e potencial capacidade de intervir na evolução da doença, principalmente, a partir de estudos em modelos fisiopatológico que culminam na degeneração dos neurônios motores.(AU)

Introduction: Amyotrophic Lateral Sclerosis (ALS) is defined as a progressive and inexorable neurological disease, with about 80% of cases of unknown etiology. New drugs have emerged in the treatment of neurodegenerative diseases, including ALS, redesigning the pathophysiological model. Among them, the use of: Edaravone, Vitamin K2, Serine, Methylcobalamin, Pyrroloquinoline quinone (PQQ), Ubiquinol and Glutathione are noteworthy. Specifically in ALS, some have been validated in randomized controlled trials. Methodology: Update of the literature (PUBMED, Medline) on the use of these drugs in degenerative neurological diseases, with a focus on Motor Neuron Disease (DNM-ELA) in the Portuguese, English, Spanish and French languages, of (2010-2017). Discussion: The association of these drugs has shown positive results in neurological diseases. Some, such as Methylcobalamin and Edaravone, would exert mechanisms of action capable of interfering in the process of depletion of the motor neurons of the anterior horn and pyramidal tracts in patients with ALS. Conclusion: It would be precipitate to conclude that the associated use of these drugs could modify or even restore damage to motor units; however, it is necessary to highlight its mechanisms of action and potential ability to intervene in the evolution of the disease, mainly from studies in pathophysiological models that culminate in the degeneration of motor neurons (AU)

Cervical Spondylotic Myelopathy: What the Neurologist Should Know.

Cervical spondylotic myelopathy is a well-known cause of disability among older people. A significant amount of these patients is asymptomatic. Once the symptoms start, the worsening may follow a progressive manner. We should suspect of spondylotic myelopathy in any individual over 55 years presenting progressive changes in gait or losing fine motor control of the upper limbs. Despite its frequent prevalence, this condition is still neglected and many times confused with other supratentorial lesions regarding diagnostic. Here we address some of most important aspects of this disease, calling attention to pathophysiology, the natural history, presentation, differential diagnosis, clinical assessment, and treatment.

Augmented movement strategies for postural control in patients with spinocerebellar ataxia type 3: a case-control study / Estratégias aumentadas de movimento para controle postural em pacientes com ataxia espinocerebellar tipo 3: caso-controle

INTRODUCTION: This study investigated the movement strategies for postural control in patients with spinocerebellar ataxia type 3 (SCA3). METHODS: This case-control study enrolled 5 patients with SCA3 (aged 41 to 51 years) and 5 healthy participants group-matched by age, body mass and body height.Participants performed 3 trials lasting 30 s each of postural tasks characterized by: feet apart or together; eyes open or closed. Center of pressure (CoP) data was quantified using three-dimensional (3D: number of high-density and high-speed regions, average and maximal distances among regions), two-dimensional (2D: elliptical area, average velocity) and one-dimensional (1D: standard deviation, velocity) parameters. RESULTS: Analysis of variance revealed significant interaction effect between group*task for 1D (F12,238=3.496, p<0.001), 2D (F6,184=11.472, p<0.001), and 3D parameters (F12,238=2.543, p=0.004). Significant univariate effects for postural task were observed for all parameters, with higher body sway values under visual and biomechanical constraints, either separated or combined. CONCLUSIONS: Patients with SCA3 presented augmented movement strategiescompared with healthy subjects, characterized by increasing body sway under more demanding biomechanical and/ or visual constraints. Three-dimensional kinematic mapping revealed either random movement strategies or a unique movement strategy characterized by a stochastic CoP distribution, with high CoP speed to correct for large body sway deviations.

INTRODUÇÃO: Este estudo investigou as estratégias de movimento para controle postural em pacientes com ataxia espinocerebelar tipo 3 (SCA3). MÉTODOS: Este estudo de caso-controle incluiu cinco pacientes com SCA3 (idade 41 a 51 anos) e cinco participantes saudáveis, agrupados por idade, massa corporal e altura corporal. Os participantes realizaram três ensaios 30 s cada uma das tarefas posturais caracterizadas por: pés separados ou juntos; olhos abertos ou fechados. Os dados do centro de pressão (CoP) foram quantificados usando tridimensional (3D: número de alta densidade e alta velocidade regiões, distâncias médias e máximas entre regiões), bidimensional (2D: área elíptica, velocidade média) e unidimensional (1D: Desvio padrão, velocidade). RESULTADOS: Análise de variância Revelou um efeito de interação significativo entre a tarefa * grupo 1D (F12.238 = 3.496, p <0.001), 2D (F6.184 = 11.472, p <0.001) e os parâmetros 3D (F12,238 = 2,543, p = 0,004). Efeitos univariados significativos foram observados para todos os parâmetros, com maiores valores de balanço corporal sob restrições visuais e biomecânicas, separadas ou combinados. CONCLUSÕES: Os pacientes com SCA3 apresentaram estratégias de movimento comparadas com indivíduos saudáveis, aumentando o balanço do corpo sob condições biomecânicas e / ou restrições visuais. O mapeamento cinemático tridimensional revelou estratégias de movimento aleatório ou uma estratégia de movimento caracterizada por uma distribuição estocástica de CoP, com alta velocidade de correção para os grandes desvios.

Revisiting the Term Neuroprotection in Chronic and Degenerative Diseases.

Thanks to the development of several new researches, the lifetime presented a significant increase, even so, we still have many obstacles to overcome - among them, manage and get responses regarding neurodegenerative diseases. Where we are in the understanding of neuroprotection? Do we really have protective therapies for diseases considered degeneratives such as amyotrophic lateral sclerosis and its variants, Parkinson's disease, Alzheimer's disease and many others? Neuroprotection is defined by many researches as interactions and interventions that can slow down or even inhibit the progression of neuronal degeneration process. We make some considerations on this neuroprotective effect.

Amyotrophic Lateral Sclerosis: New Perpectives and Update.

Amyotrophic lateral sclerosis (ALS), Charcot's disease or Lou Gehrig's disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades - or even one decade - ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion.

Botulinum Neurotoxin Type A in Neurology: Update.

This paper reviews the current and most neurological (central nervous system, CNS) uses of the botulinum neurotoxin type A. The effect of these toxins at neuromuscular junction lends themselves to neurological diseases of muscle overactivity, particularly abnormalities of muscle control. There are seven serotypes of the toxin, each with a specific activity at the molecular level. Currently, serotypes A (in two preparations) and B are available for clinical purpose, and they have proved to be safe and effective for the treatment of dystonia, spasticity, headache, and other CNS disorders in which muscle hyperactivity gives rise to symptoms. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neuro-transmitters involved in pain regulation. Its effects are transient and nondestructive, and largely limited to the area in which it is administered. These effects are also graded according to the dose, allowing individualized treatment of patients and disorders. It may also prove to be useful in the control of autonomic dysfunction and sialorrhea. In over 20 years of use in humans, botulinum toxin has accumulated a considerable safety record, and in many cases represents relief for thousands of patients unaided by other therapy.

Current issues in the respiratory care of patients with amyotrophic lateral sclerosis / Tópicos atuais no tratamento respiratório de pacientes com esclerose lateral amiotrófica

Amyotrophic lateral sclerosis is a progressive neuromuscular disease, resulting in respiratory muscle weakness, reduced pulmonary volumes, ineffective cough, secretion retention, and respiratory failure. Measures as vital capacity, maximal inspiratory and expiratory pressures, sniff nasal inspiratory pressure, cough peak flow and pulse oximetry are recommended to monitor the respiratory function. The patients should be followed up by a multidisciplinary team, focused in improving the quality of life and deal with the respiratory symptoms. The respiratory care approach includes airway clearance techniques, mechanically assisted cough and noninvasive mechanical ventilation. Vaccination and respiratory pharmacological support are also recommended. To date, there is no enough evidence supporting the inspiratory muscle training and diaphragmatic pacing.

Esclerose lateral amiotrófica é uma doença neuromuscular progressiva que resulta em fraqueza muscular, redução dos volumes pulmonares, tosse ineficaz, retenção de secreção e insuficiência respiratória. Medidas como a capacidade vital, pressão inspiratória e pressão expiratória máximas, pressão inspiratória máxima nasal, pico de fluxo de tosse e oximetria de pulso são recomendados para monitorar a função respiratória. Os pacientes devem ser acompanhados por uma equipe multidisciplinar, buscando melhorias na qualidade de vida e melhores estratégias para lidar com os sintomas respiratórios. A abordagem de cuidados respiratórios inclui técnicas de desobstrução das vias respiratórias, tosse assistida mecanicamente e ventilação mecânica não invasiva. Vacinação e suporte farmacológico também são recomendados. Até o momento, não existem provas suficientes que suportam o treinamento muscular inspiratório e a estimulação diafragmática.

Current issues in the respiratory care of patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a progressive neuromuscular disease, resulting in respiratory muscle weakness, reduced pulmonary volumes, ineffective cough, secretion retention, and respiratory failure. Measures as vital capacity, maximal inspiratory and expiratory pressures, sniff nasal inspiratory pressure, cough peak flow and pulse oximetry are recommended to monitor the respiratory function. The patients should be followed up by a multidisciplinary team, focused in improving the quality of life and deal with the respiratory symptoms. The respiratory care approach includes airway clearance techniques, mechanically assisted cough and noninvasive mechanical ventilation. Vaccination and respiratory pharmacological support are also recommended. To date, there is no enough evidence supporting the inspiratory muscle training and diaphragmatic pacing.

Histochemical analysis of paraspinal rotator muscles from patients with adolescent idiopathic scoliosis: a cross-sectional study.

Morphological, biochemical, and histopathological alterations in the paraspinal skeletal muscle of patients with adolescent idiopathic scoliosis (AIS) have been extensively reported. We evaluated rotator muscle fibers from the apex vertebra of AIS patients through histological and immunohistochemical analysis. A population of 21 female AIS patients who underwent corrective surgery between 2010 and 2013 had biopsies taken from the paraspinal muscle in the convex and concave sides of the thoracic curve apical vertebra. Serial sections were stained following routine protocols for hematoxylin and eosin (HE), Sudan red, Gomori trichrome, NADH, ATPase, and cytochrome oxidase. We assessed muscular atrophy and hypertrophy, fatty proliferation, endomysial and perimysial fibrosis, the presence of hyaline fibers, mitochondrial proliferation, muscular necrosis, nuclear centralization, and inflammation. Two independent professionals evaluated the slices. The thoracic curves had an average Cobb angle of 68 degree. Comparative analysis of the concave and convex sides was performed with McNemar test at a significance level of 5%. Results showed significant differences in both endomysial and perimysial fibrosis and fatty involution between the two sides of the apex vertebra. Paraspinal muscles in the concave side of the scoliosis apex had significantly more fibrosis and fatty involution. However, both sides showed signs of myopathy, muscular atrophy due to necrosis, presence of hyaline fibers, and mitochondrial proliferation.

Another Perspective on Fasciculations: When is it not Caused by the Classic form of Amyotrophic Lateral Sclerosis or Progressive Spinal Atrophy?

Fasciculations are visible, fine and fast, sometimes vermicular contractions of fine muscle fibers that occur spontaneously and intermittently. The aim of this article is to discuss the main causes for fasciculations and their pathophysiology in different sites of the central/peripheral injury and in particular to disprove that the presence of this finding in the neurological examination is indicative of amyotrophic lateral sclerosis. Undoubtedly, most fasciculations have a distal origin in the motor nerve both in normal subjects and in patients with motor neuron disease. Most of them spread to other dendritic spines often producing an antidromic impulse in the main axon. The clinical and neurophysiological diagnosis must be thorough. It may often take long to record fasciculations with electroneuromyography. In other cases, temporal monitoring is necessary before the diagnosis. The treatment, which may be adequate in some cases, is not always necessary.

Gerenciamento da dor na Síndrome Pós-poliomielite: estudo de caso / Pain management in Postpoliomyelitis Syndrome: case study

A Síndrome Pós-Pólio (SPP) caracteriza-se por um novo episódio de fraqueza muscular e/ou fadiga muscular anormal em indivíduos que apresentaram poliomielite anterior aguda (PAA) anos antes. Ainda são poucos os relatos na literatura sobre o gerenciamento da dor na SSP. O objetivo deste trabalho é analisar o controle da dor na síndrome pós-pólio por meio de um relato de caso. Um homem de 57 anos com SPP foi submetido a 24 sessões de fisioterapia para controle do quadro álgico na síndrome, baseada em recursos eletrotermofototerápicos e cinesioterapia. Para análise da dor pré e pós-intervenção fisioterapêutica foram aplicados dois instrumentos: a Escala Analógica Visual (EVA) e a Intensidade de Dor Presente (ID). O quadro álgico no joelho direito sofreu redução de grau 8 para 4 pela EVA e grau 5 para 2 pela ID, enquanto a dor no tornozelo direito reduziu de grau 2 pela EVA e grau 1 pela ID para zero em ambas as escalas. A dor é apontada como um sintoma predominante por muitos pacientes com SPP. O sujeito deste relato, após o programa de tratamento, apresentou melhora expressiva da dor. Entretanto, devido à escassez da literatura sobre dados substanciais referentes ao seu gerenciamento, especialmente na fisioterapia, novos estudos devem ser propostos para gerar maior fundamentação teórica à abordagem fisioterapêutica na SPP.

The Post-polio Syndrome (PPS) is characterized by a new episode of muscular weakness and/or abnormal muscular fatigue in subjects that presented acute previous polio (APP) years ago. There still are few studies about the pain management at PPS. The aim of this study is to analyze pain´s management in PPS by a case report. A men with PPS, 57 years, was submitted to 24 sessions of physical therapy for pain´s control in PPS, based at electro-thermo physical therapy features and therapeutics exercises. For pain´s analysis, pre and post physical therapy interventions were applied two instruments: the Analogic Visual Scale (AVS) and Present Pain Intensity (PPI). The pain in right knee was reduced from grade 8 to 4 on AVS, grade 5 to 2 on PPI, while the pain in his right ankle decreased from grade 2 on AVS and 1 on PPI to zero in both scales. The pain is the predominant symptom for many patients with PPS. This relate, the patient after program of treatment presented an improvement of pain. However, because of there are few studies in the literature about the pain management, especially in physical therapy, new studies must be proposed to generate more theorical at Physical therapy intervention in PSS.

Benign fasciculations and corticosteroid use: possible association? An update.

Fasciculations are characterized by visible subtle and fast contractions of muscle, even wormlike in movement, by the contraction of a fascicle of muscle fibers. The authors present the case study of a 28-year-old patient with the appearance of migratory and diffuse fasciculations with an onset after partial tapering off of oral corticosteroides (60 mg total dose) indicated for treatment of Minimal change Glomerulopathy. Clinical Neurological physical exam allied with an ENMG, besides other complementary laboratory exams were used for screening the above-mentioned patient. Afterwards, current research relating to the topic at hand was made in order to update the data available in the Bireme, Scielo and PubMed Data Banks using the following key words: Fasciculation's, motor neuron disease, and benign fasciculations in the Portuguese, English as well as Spanish language. Although fasciculation's are most commonly associated with Motor neuron disease as well as with certain metabolic disorders, they may also be present in individuals with absolutely no underlying pathological disorders. In our case, fasciculation potentials that have been present for six months, with no other signs of a neurogenic disorder as well as absence of laboratory findings, the patient received a diagnosis of Benign Fasciculation Syndrome (BFS).We believe that the use of corticosteroides in high doses with subsequent tapering contributed to the fasciculation's, especially due to the changes that this causes on the ionic channels. Fasciculation's are symptoms seen in a large range of conditions, and also being the main symptom of the so-called Benign Fasciculation Syndrome. We have presented an example of this clinical syndrome in a patient whose complaint was fasciculation's, with complete clinical remission of symptoms following complete tapering off of corticosteroid six months previously.