Genetic epidemiology of familial ALS in Brazil.

Many genes associated with familial forms of the amyotrophic lateral sclerosis (fALS) have been identified in European and North American cohorts. However, little is known about the genetic bases of fALS in Latin America and Brazil, in particular. To address this question, we recruited 107 patients with fALS from 93 unrelated families from Southeastern, Southern, and Northeastern regions of the country. A 3-step diagnostic approach was used: 1) Triplet repeat primed polymerase chain reaction to search for C9orf72 expansions, then 2) fragment digestion to search for the c.166 C>T VAPB variant, and finally, 3) whole exome sequencing for those who tested negative. We identified the genetic cause for fALS in 70% of the families. VAPB and C9orf72 were the most frequent genes (30% and 22%, respectively), followed by SOD1, TARDBP, ANXA11, and FUS. Five novel variants in known ALS genes were found, including the SOD1 Val120Leu and ANXA11 Asp40Tyr, which were seen in 2 unrelated families each. In conclusion, VAPB and then C9orf72 are the genes most commonly related to fALS in Brazil.

CAG repeats ≥ 34 in Ataxin-1 gene are associated with amyotrophic lateral sclerosis in a Brazilian cohort.

Little is known about the genetic basis of amyotrophic lateral sclerosis (ALS) outside Europe and US. In this study, we investigated whether intermediate CAG expansions at ATXN1 were associated to ALS in the Brazilian population. To accomplish that, representative samples from 411 unrelated patients and 436 neurologically normal controls from 6 centers spread over the territory were genotyped to quantify ATXN1 expansions. We found that ATXN1 intermediate-length expansion (≥34 CAG repeats) are associated with the disease (odds ratio = 2.19, 95% CI = 1.081-4.441, p = .026). Most ATXN1-positive patients had classical phenotype, but some of them presented predominant lower motor neuron involvement. None of them had associated ataxia. Frontotemporal dementia was concomitantly found in 12.5% of patients carrying the intermediate ATXN1 expansion. Further studies are needed to validate these findings and to understand the pathophysiological mechanisms that connect ataxin-1 and ALS.

Clinical Characteristics of Patients With Neuromyelitis Optica Spectrum Disorders With Early Onset.

Neuromyelitis optica spectrum disorder is a severe and disabling disease that manifests with severe relapses of optic neuritis, longitudinally extensive myelitis, and/or brainstem syndromes. The disease is complex and, although onset typically occurs in middle age, children and adolescents may be affected. The present study adds to the literature through detailed clinical data from 36 Brazilian patients with neuromyelitis optica spectrum disorder starting before age 21. This was a retrospective assessment of medical records from 14 specialized units in Brazil. The results showed that the course of neuromyelitis optica spectrum disorder was worse in patients with disease onset before the age of 12 years. Gender and ethnic background did not influence disability accumulation. Over a median period of 8 years, 14% of the patients who presented the initial symptoms of neuromyelitis optica spectrum disorder before the age of 21 years died. In conclusion, the present study adds to the reports from other authors examining the severity of early-onset neuromyelitis optica spectrum disorder.

Intermediate-length CAG repeat in ATXN2 is associated with increased risk for amyotrophic lateral sclerosis in Brazilian patients.

Intermediate-length cytosine-adenine-guanine nucleotide repeat expansions in the ATXN2 gene (which encodes for the protein Ataxin-2) have been linked to increased risk for amyotrophic lateral sclerosis (ALS) in different populations. There is no such study in the Brazilian population, which has a mixed ethnic background. We have thus selected 459 patients with ALS (372 Sporadic ALS and 87 Familial ALS) and 468 control subjects from 6 Brazilian centers to investigate this point. We performed polymerase chain reaction to determine the length of the ATXN2 alleles. Polymerase chain reaction products were resolved using capillary electrophoresis on ABI 3500 × l capillary sequencer. We found that ATXN2 intermediate-length expansions (larger than 26 repeats) were associated with an increased risk for ALS (odds ratio = 2.56, 95% confidence interval: 1.29-5.08, p = 0.005). Phenotype in patients with and without ATXN2 expansions was similar. Our findings support the hypothesis that ATXN2 plays an important role in the pathogenesis of ALS also in the Brazilian population.

Definition and diagnosis of small fiber neuropathy: consensus from the Peripheral Neuropathy Scientific Department of the Brazilian Academy of Neurology.

The aim of this study was to describe the results of a Brazilian Consensus on Small Fiber Neuropathy (SFN). Fifteen neurologists (members of the Brazilian Academy of Neurology) reviewed a preliminary draft. Eleven panelists got together in the city of Fortaleza to discuss and finish the text for the manuscript submission. Small fiber neuropathy can be defined as a subtype of neuropathy characterized by selective involvement of unmyelinated or thinly myelinated sensory fibers. Its clinical picture includes both negative and positive manifestations: sensory (pain/dysesthesias/pruritus) or combined sensory and autonomic complaints, associated with an almost entirely normal neurological examination. Standard electromyography is normal. A growing list of medical conditions is associated with SFN. The classification of SFN may also serve as a useful terminology to uncover minor discrepancies in the normal values from different neurophysiology laboratories. Several techniques may disclose sensory and/or autonomic impairment. Further studies are necessary to refine these techniques and develop specific therapies.

Definition and diagnosis of small fiber neuropathy: consensus from the Peripheral Neuropathy Scientific Department of the Brazilian Academy of Neurology / Definição e diagnóstico de neuropatia de fibras finas: consenso do Departamento Científico de Neuropatias Periféricas da Academia Brasileira de Neurologia

ABSTRACT The aim of this study was to describe the results of a Brazilian Consensus on Small Fiber Neuropathy (SFN). Fifteen neurologists (members of the Brazilian Academy of Neurology) reviewed a preliminary draft. Eleven panelists got together in the city of Fortaleza to discuss and finish the text for the manuscript submission. Small fiber neuropathy can be defined as a subtype of neuropathy characterized by selective involvement of unmyelinated or thinly myelinated sensory fibers. Its clinical picture includes both negative and positive manifestations: sensory (pain/dysesthesias/pruritus) or combined sensory and autonomic complaints, associated with an almost entirely normal neurological examination. Standard electromyography is normal. A growing list of medical conditions is associated with SFN. The classification of SFN may also serve as a useful terminology to uncover minor discrepancies in the normal values from different neurophysiology laboratories. Several techniques may disclose sensory and/or autonomic impairment. Further studies are necessary to refine these techniques and develop specific therapies.

RESUMO O objetivo deste estudo é descrever os resultados de um Consenso Brasileiro sobre Neuropatia de Fibras Finas (NFF). Quinze neurologistas (membros da Academia Brasileira de Neurologia) revisaram uma versão preliminar do artigo. Onze panelistas se reuniram na cidade de Fortaleza para discutir e terminar o texto para a submissão do manuscrito. NFF pode ser definida como um subtipo de neuropatia caracterizada pelo envolvimento seletivo de fibras sensitivas amielínicas ou pouco mielinizadas. Seu quadro clínico inclui manifestações negativas e positivas: sensitivas (dor/disestesias/prurido) ou queixas sensitivas e autonômicas combinadas, associadas a exame neurológico quase totalmente normal. A eletromiografia convencional é normal. Uma lista crescente de condições médicas causa NFF. NFF também pode servir como uma terminologia útil para referenciar pequenas discrepâncias nos valores normais de diferentes laboratórios de neurofisiologia. Diferentes técnicas podem evidenciar anormalidades sensitivas e/ou autonômicas. São necessários mais estudos para refiná-las e para o desenvolvimento de terapias específicas.

The frequency of the C9orf72 expansion in a Brazilian population.

G4C2 hexanucleotide repeat expansions in the C9orf72 gene seem to be the cause of numerous cases of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). In this study, we investigated the presence of the G4C2 repeat expansion in 463 Brazilian probands, of whom 404 had ALS/motor neuron disease and 67 FTD, and in 63 healthy controls in the southeastern region of Brazil. The highest frequencies of the C9orf72 mutation were in the ALS-FTD group (50% of familial and 17.6% of sporadic cases), although it was also present in 5% of pure ALS/motor neuron disease patients (11.8% of familial and 3.6% of sporadic cases) and in 7.1% of pure familial FTD. Among G4C2 repeat mutation carriers, 68.8% of the subjects who developed dementia symptoms were females. This frequency was significantly higher than the percentage reached by men with C9orf72 expansion who had this phenotype (p = 0.047). No abnormal repeat expansion was found in control groups. Inclusion of the C9orf72 genetic test in the molecular panels for Brazilian populations with these neurodegenerative diseases should be strongly considered.

Real-life experience with fampridine (Fampyra®) for patients with multiple sclerosis and gait disorders.

BACKGROUND: Fampridine is a broad-spectrum voltage-dependent potassium channel blocker that enhances synaptic transmission. The drug has been shown to be able to ameliorate conduction in demyelinated axons, thereby leading to improved gait in patients with multiple sclerosis (MS). OBJECTIVE: To assess the "real-life" efficacy and safety of fampridine prescribed for gait disorders in MS. This was an observational and prospective study carried out at MS Units participating in the Brazilian Multiple Sclerosis Study Group. METHODS: Patients with MS and gait disorders were prescribed fampridine (10 mg twice a day), irrespectively of the degree of disability determined by MS. Neurological disability determined by MS was assessed with the expanded disability scale score (EDSS). Outcomes for efficacy and safety of the drug were evaluated by the 25 foot-walk test and by the adverse events of fampridine. RESULTS: The time taken to walk 25 feet decreased by 20% or more in 62 patients (70%). Twenty-five patients were considered to be non-responders to this treatment. Improvement in walking speed was independent of improvement of disability. Mild or moderate adverse events were reported in 8% of patients. CONCLUSION: Fampridine is an efficient and safe therapeutic option for patients with MS and gait disorders.

Aspectos neuropsicológicos da Esclerose Lateral Amiotrófica: relato de caso / Neuropsychological aspects of Amyotrophic Lateral Sclerosis: case report

A Esclerose Lateral Amiotrófica (ELA) é uma doença neurológica degenerativa e progressiva, com comprometimento dos neurônios motores, e consequente incapacidade na realização de atividades de vida diária do paciente, podendo apresentar distúrbios psicológicos (emocionais e cognitivos), repercutindo na dinâmica familiar e exigindo uma abordagem multidisciplinar. Relato de caso: Sujeito do sexo masculino, 55 anos, casado com filhos, comerciante, com 2º grau, procedente de Florianópolis, SC, com diagnóstico de ELA há 1 ano, com piora progressiva da doença, com acometimento da musculatura respiratória, atendido no Hospital Universitário ­ Universidade Federal de Santa Catarina (UFSC). A Avaliação Neuropsicológica utilizou subtestes da Escala de Inteligência de Wechsler para adultos e da Escala de Memória de Wechsler, tarefas de fluência verbal semântica e fonética, Inventário de Alterações Neuropsicológicas de Schlindwein-Zanini e Cruz (SZC), e a Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised. De modo geral, apresentou funções corticais preservadas, apresentando QI Estimado Médio; desempenho normal em orientação, memória operacional, atenção e flexibilidade mental, vocabulário, conhecimento de palavras, praxia construtiva e organização perceptual; sendo que em memória verbal recente e tardia mostrava performance um pouco pobre para o esperado, mas próximo a faixa de normalidade; discriminação visual classificada como médio inferior;e déficit em fluência verbal semântica (-2,6 dp) e fluência verbal fonética (-1,7 dp). No entanto, percebeu-se sintomatologia depressiva e prejuízo nas atividades de vida diária com redução da autonomia e funções motoras, além de crescente irritabilidade e baixa tolerância a frustração, que repercutem nas relações familiares do mesmo.

Amyotrophic Lateral Sclerosis (ALS) is a degenerative and gradual neurological illness. It damages motor neurons and consequently impairs the patient's capacity to perform daily life activities. Patients may present psychological disorders (emotional and cognitive) that reflects on family dynamics and requires a multi-displinary approach. Case report: The subject is male, 55 years old, married with children, trader, with high school studies, from Florianópolis, Santa Catarina, diagnosed with ALS 1 ago, presenting gradual worsening of the illness, with impairment of respiratory muscles, attended at University Hospital ­ Federal University of Santa Catarina (UFSC). The Neuropsychological Assessment used Wechsler Adult Intelligence Scale subtests and Wechsler Memory Scale , verbal, semantic and phonetics fluency tasks, Schlindwein-Zanini and Cruz (SZC) Inventory of Neuropsychological Changes, and Lateral Amyotrophic Sclerosis Functional Rating Scale-Revised. Generally speaking, cortical functions were preserved, showing Estimated Average IQ; normal performance in orientation, operational memory, attention and mental flexibility, vocabulary, word knowledge, constructional praxes and perceptual organization; being that recent and delayed verbal memory showed rather poor performance than expected (next to normality nonetheless); visual discrimination was classified as lower middle; semantic verbal fluency deficit (- 2,6 dp) and phonetic verbal fluency (- 1,7 dp). However, depressive symptomatology and damage in the daily life activities were perceived, followed by autonomy and motor functions' reduction in addition to increasing irritability and low tolerance to frustration, which had effects in his family relationships.

Postpartum Treatment With Immunoglobulin Does Not Prevent Relapses of Multiple Sclerosis in the Mother.

Multiple sclerosis (MS) is a chronic, neurological, immune-mediated disease that can worsen in the postpartum period. There is no consensus on the use of immunoglobulin for prevention of disease relapses after delivery. We have shown that the controversial beneficial effect of immunoglobulin given immediately after birth could not be observed in patients with MS.

How do we manage and treat a patient with multiple sclerosis at risk of tuberculosis?

Tuberculosis continues to be a serious health problem worldwide. The disease continues to be underdiagnosed and not properly treated. In conditions that affect the immune system, such as multiple sclerosis (MS), latent tuberculosis may thrive and reactivate during the use of immunomodulatory and immunosuppressive drugs. Among the best treatment options for patients with latent or active tuberculosis who have MS are IFN-ß, glatiramer acetate and mitoxantrone. Drugs leading to a reduced number and/or function of lymphocytes should be avoided or used with caution. Tuberculosis must always be investigated in patients with MS and treated with rigor.

Neuromyelitis optica with onset in childhood and adolescence.

BACKGROUND: Neuromyelitis optica with onset before the age of 18 years is a relatively rare, yet potentially devastating condition. The objective of the present study was to contribute to the study of early-onset neuromyelitis optica with a case series. PATIENTS: Data were collected from medical records of Brazilian neurologists caring for patients with neuromyelitis optica occurring in childhood and adolescence. RESULTS: Twenty-nine patients with neuromyelitis optica occurring before the age of 18 years and fulfilling the diagnostic criteria were identified. The average age at disease onset was 13 years and the patients had had an average disease duration of 6 years. The expanded disability scale score at the latest consultation was, on average, 4.7, and one patient had died from the disease. The 29 patients had had an average 4.5 relapses during the disease, accounting for 0.75 relapses per year, irrespective of the medication used. All patients were using one or more of the following medications: azathioprine, prednisone, immunoglobulin, and glatiramer acetate. CONCLUSIONS: Neuromyelitis optica with onset in childhood and adolescence is a poorly understood condition that is often disabling and difficult to manage.

Long-term effects of exposure to disease-modifying drugs in the offspring of mothers with multiple sclerosis: a retrospective chart review.

INTRODUCTION: Multiple sclerosis (MS) mainly affects women of fertile age. To date, the only recommendation for women with MS intending to become pregnant is to stop all treatment. This recommendation reflects the concerns about the effects of disease-modifying drugs (DMDs) on the offspring. The objective of the present study was to assess the potential long-term effects of maternal exposure to DMDs on the offspring. METHOD: This was a retrospective study revising medical data on the offspring of women with MS. These women now have children aged at least 1 year and include a group of patients that were not exposed to any DMDs for at least 3 months prior to pregnancy and during the whole gestation (control group). Another group of patients had at least 2 weeks of exposure to DMDs, mainly to interferon beta or glatiramer acetate RESULTS: The women with MS participating in this study have children currently aged, on average, 6.6 years (range 1-39 years). There was no pattern of drug-related adverse events or complications in the children whose mothers were exposed to DMDs. No specific long-term adverse events were observed in the offspring of women with MS who were exposed to drugs during pregnancy. The profile of relevant diagnoses in their children was similar to that of children whose mothers had not been exposed to DMDs. CONCLUSIONS: The present retrospective study did not show a specific profile of long-term deleterious drug effects on children born from mothers who were exposed to drugs for MS treatment.

Multiple sclerosis in South America: month of birth in different latitudes does not seem to interfere with the prevalence or progression of the disease.

OBJECTIVE: To assess whether the month of birth in different latitudes of South America might influence the presence or severity of multiple sclerosis (MS) later in life. METHODS: Neurologists in four South American countries working at MS units collected data on their patients' month of birth, gender, age, and disease progression. RESULTS: Analysis of data from 1207 MS patients and 1207 control subjects did not show any significant variation in the month of birth regarding the prevalence of MS in four latitude bands (0-10; 11-20; 21-30; and 31-40 degrees). There was no relationship between the month of birth and the severity of disease in each latitude band. CONCLUSION: The results from this study show that MS patients born to mothers who were pregnant at different Southern latitudes do not follow the seasonal pattern observed at high Northern latitudes.

Multiple sclerosis in South America: month of birth in different latitudes does not seem to interfere with the prevalence or progression of the disease / Esclerose multipla na America do Sul: mes de nascimento em diferentes latitudes nao parece interferir com a prevalencia ou progressao da doenca

Objective To assess whether the month of birth in different latitudes of South America might influence the presence or severity of multiple sclerosis (MS) later in life. Methods Neurologists in four South American countries working at MS units collected data on their patients' month of birth, gender, age, and disease progression. Results Analysis of data from 1207 MS patients and 1207 control subjects did not show any significant variation in the month of birth regarding the prevalence of MS in four latitude bands (0–10; 11–20; 21–30; and 31–40 degrees). There was no relationship between the month of birth and the severity of disease in each latitude band. Conclusion The results from this study show that MS patients born to mothers who were pregnant at different Southern latitudes do not follow the seasonal pattern observed at high Northern latitudes. .

Objetivo Avaliar se o mês de nascimento em diferentes latitudes da América do Sul pode influenciar a presença ou gravidade da esclerose múltipla (EM) na vida. Método Neurologistas de quatro países da América do Sul trabalhando em unidades de EM coletaram os dados de seus pacientes com referência ao mês de nascimento, gênero, idade e progressão da doença. Resultados A análise dos dados mostrou que, para 1207 pacientes com EM e 1207 controles, não havia diferença significativa no mês de nascimento com relação à prevalência de EM em quatro zonas de latitude (0–10; 11–20; 21–30; e 31–40 graus). Não houve relação entre o mês de nascimento e a gravidade da doença em nenhuma destas zonas. Conclusão Os resultados deste estudo mostram que pacientes com EM nascidos de mães grávidas em diferentes latitudes sul não seguem o padrão dos resultados sazonais encontrados nas latitudes norte. .

Excessive sleepiness and sleep patterns in patients with epilepsy: a case-control study.

The aim of this study was to assess excessive daytime sleepiness (EDS), sleep quality, and sleep disorders in a cohort of patients with epilepsy in the city of Florianopolis in southern Brazil. One hundred and forty patients diagnosed with epilepsy were assessed by questionnaires that included demographic and clinical variables, the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale (SSS), and the Fletcher & Luckett Adapted Questionnaire (FLAQ). These data were then compared to data from a control group (n=85). Compared to controls, patients with epilepsy (PWE) had significantly higher scores on the ESS (p=0.003), higher scores on the "daytime dysfunction" domain of the PSQI (p=0.002), and more symptoms that suggested obstructive sleep apnea in the FLAQ (p<0.001). By performing multiple linear regression models, we demonstrated that age, male gender, the presence of secondarily generalized seizures, and phenobarbital use were slightly to moderately correlated with PSQI (r=0.38) and FLAQ (r=0.51) but not with SSS scores. We concluded that PWE had more EDS, daytime dysfunction, and sleep disorders compared to a control group.

Análise dos pacientes internados com Acidente Vascular Encefálico Isquêmico em um hospital do sul de Santa Catarina / Analysis of patients interned with stroke at a hospital in the south of Santa Catarina

Objetivo: Analisar pacientes internados por Acidente Vascular Encefálico Isquêmico no HNSC. Descrevendo seus fatores de risco, tempo decorrido do início dos sintomas até internação e morbimortalidade da patologia. Verificar a possibilidade de futura implementação trombolítica no referido hospital. Métodos: Estudo observacional, envolvendo 40 pacientes. Foram utilizados questionário, prontuário, NIHSS e IIB. Resultados: 55% eram homens. Apresentavam idade média de 68 anos. Maioria caucasiana (77,5%). Fator de risco mais frequente foi a HAS. O tempo médio de início de sintomas até internação foi de 5 horas e 23 minutos. Grande parte dos pacientes apresentavam sintomatologia leve na chegada. Na alta hospitalar, o desfecho mais comum foi a incapacidade leve. Conclusão: Os dados epidemiológicos encontrados foram semelhantes ao da literatura. A alta taxa de ocorrência de AVEI em nosso meio, a baixa pontuação NIHSS e o curto tempo de chegada, são fatores que falam a favor da implementação da terapia trombolítica.

Objetive: To analyse patients interned due to Stroke at the Nossa Senhora da Conceição Hospital. Describing risk factors, time passed from the onset of the symptoms until the internment and the morbidity. To verify the possibility of the use of thrombolitic treatment in the future at the referred hospital. Methods: Observational study, in which questionnaire, prontuary, NIHSS and BI was used. Results: 55% were men. An average age of 68 years. 77,5% were Caucasian. The most common risk factor was a Systemic Arterial Hypertension. The average time from the onset of the symptoms until the internment was 5 hours and 23 minutes. The majority of the patients presented mild symptoms on arrival. Conclusion: The epidemiological data found were similar to the literature. The elevated level of IEVA, the punctuation in the NIHSS and the short arrival time, are factors that speak in favour of the implementation of thrombotic therapy

Esclerose concêntrica de Baló: relato de caso / Balo's concentric sclerosis: case report

Objetivos: O caso descrito a seguir busca incentivar a suspeição do médicofrente a um provável diagnóstico de Esclerose Concêntrica de Baló (ECB). Métodos: Relato de caso associado à revisão da literatura científi ca a partir artigos publicados sobre o tema. Resultados: Há grande difi culdade na determinação da etiopatologia daECB, já que há amplas áreas de desmielinização do sistema nervoso central (SNC) que podem ser observadas em várias doenças neurológicas. A RNM faz grande suspeição diagnóstica, mas a confi rmação só é realmente obtida através de biópsia cerebral...

Goals: The case described forward search to motivate the medical suspicionin front of a probable diagnose of Balo’s Concentric Sclerosis (BCS) establishing a routine diagnostic. Methods: Case report with cientifi c review of articles published about the subject. Results: It is really diffi cult to determine the BCS’s etiology-fi siopathology because of thedifuse demyelinating’s areas of the central nervous system (CNS) that are seen in a variety of CNS’s diseases. Magnetic resonance (MR) is very important to the diagnosis of BCS, butthe diagnosis’s key is the brain biopsy. The therapy consists of high dose of steroidals being controled by magnetic resonance imaging...