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Made available in DSpace on 2021-07-14T10:39:39Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-09. Added 1 bitstream(s) on 2021-07-14T11:35:14Z : No. of bitstreams: 1 S0004-282X2021000400354.pdf: 459704 bytes, checksum: 6a462673c87715786c3acd9404f2f0f1 (MD5) Os canabinoides compreendem os endocanabinoides, fitocanabinoides e os canabinoides sintéticos e desempenham ações no sistema nervoso central e periférico. Uma quantidade enorme de publicações tem sido lançada nos últimos anos, embora a cannabis seja conhecida por milênios. Os Departamentos Científicos da Academia Brasileira de Neurologia descreveram as evidências do uso médico em suas áreas. A literatura está em constantes mudanças e possíveis novas evidências podem surgir nos próximos dias ou meses. A prescrição dessas substâncias deve ser discutida com os pacientes e suas famílias, com conhecimento sobre eventos adversos e sua eficácia. Cannabinoids comprehend endocannabinoids, phytocannabinoids, and synthetic cannabinoids, with actions both in the central and peripherical nervous systems. A considerable amount of publications have been made in recent years, although cannabis has been known for over a thousand years. Scientific Departments from the Brazilian Academy of Neurology described evidence for medical use in their areas. Literature is constantly changing, and possible new evidence can emerge in the next days or months. Prescription of these substances must be discussed with patients and their families, with knowledge about adverse events and their efficacy. Universidade de São Paulo, Hospital das Clínicas Hospital Santa Marcelina, Departamento de Neurologia Hospital Sírio-Libanês, Núcleo de Neurociências Hospital Heliópolis, Departamento de Neurologia Universidade Estadual do Amazonas, Departamento de Neurologia Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto Universidade Estadual Paulista “Júlio de Mesquita Filho”, Faculdade de Ciências Médicas e Biológicas de Botucatu Faculdade de Medicina do ABC, Departamento de Neurociências Hospital Geral de Goiânia Dr Alberto Rassi, Departamento de Neurologia Santa Casa de Belo Horizonte, Departamento de Neurologia Universidade Federal de Minas Gerais, Hospital das Clínicas Universidade do Estado do Amazonas, Escola Superior de Ciências da Saúde Universidade Federal de Santa Catarina Universidade Federal do Rio de Janeiro, Instituto de Neurologia Deolindo Couto Universidade Estadual de Campinas, Departamento de Neurologia Hospital das Clínicas Universidade Estadual de Campinas, Instituto de Biologia, Genética, Imunologia e Bioagentes Faculdade de Medicina do ABC, Departamento de Neurologia Hospital Israelita Albert Einstein Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Clínica Médica Hospital Moinhos de Vento, Serviço de Neurologia e Neurocirurgia Universidade Anhanguera Hospital Federal dos Servidores do Estado, Departamento de Neurologia Hospital da Restauração, Departamento de Neurologia Hospital São Carlos Universidade Federal de São Paulo, Departamento de Neurologia Hospital do Servidor Público Estadual, Departamento de Neurologia Pontifícia Universidade Católica do Rio Grande do Sul, São Lucas Hospital Fundação Oswaldo Cruz Universidade Federal do Ceará, Faculdade de Medicina Hospital Universitário Getúlio Vargas, Departamento de Neuromuscular Universidade Federal de Minas Gerais, Faculdade de Medicina Universidade Federal do Paraná, Hospital de Clínicas Hospital Nossa Senhora das Graças, Epicentro Universidade Federal de São Paulo, Escola Paulista de Medicina Universidade Estadual Paulista “Júlio de Mesquita Filho”, Faculdade de Ciências Médicas e Biológicas de Botucatu

Previous studies using whole exome sequencing (WES) have shown that a significant proportion of adult patients with undiagnosed ataxia in European and North American cohorts have a known genetic cause. Little is known about the diagnostic yield of WES in non-Caucasian ataxic populations. Herein, we used WES to investigate a Brazilian cohort of 76 adult patients with idiopathic ataxia previously screened for trinucleotide expansions in known ataxia genes. We collected clinical and radiological data from each patient. WES was performed following standard procedures. Only variants labeled as pathogenic or likely pathogenic according to American college of medical genetics and genomics (ACMG) criteria were retrieved. We determined the diagnostic yield of WES for the whole cohort and also for subgroups defined according to presence or not of pyramidal signs, peripheral neuropathy, and cerebellar atrophy. There were 41 women and 35 men. Mean age at testing was 48 years. Pyramidal signs, peripheral neuropathy, tremor, and cerebellar atrophy were found in 38.1%, 13.1%, 10.5%, and 68.3% of all subjects, respectively. Diagnostic yield of WES was 35.5%. Thirty-six distinct mutations were found in 20 different genes, determining the diagnosis of 18 autosomal recessive and 9 autosomal dominant ataxias. SACS and SPG7 were the most frequently found underlying genes. WES performed better in the subgroup with vs the subgroup without spasticity (p = 0.005). WES was diagnostic in 35.5% of cases of the Brazilian cohort of ataxia cases. These results have implications for diagnosis, genetic counseling and eventually treatment.

Orientador: Marcondes Cavalcante França Junior Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: A neuronopatia sensitiva (NS) representa a doença caracterizada pelo dano ao gânglio sensitivo da raíz dorsal. Sua expressão é de ataxia sensitiva e déficits exclusivamente sensitivos, multifocais que não comprimento-dependentes. O reconhecimento desse padrão é fundamental para a identificação de doenças associadas à NS. Todavia, sintomas como dor e a disautonomia ainda foram pouco explorados. A raridade da NS associada a sinais e sintomas como a pseudoparesia e a pseudoatetose tornam o cenário favorável ao erro e atraso diagnóstico. Além disso, a falta de instrumentos capazes de mensurar a evolução da doença torna impossível a avaliação da historia natural da doença bem como o delineamento de estudos de tratamento. Portanto, os objetivos desse trabalho são: 1.investigar novas etiologias de NS utilizando ferramentas de imunologia clínica e genética molecular; 2.descrever aspectos clínicos, topográficos e a resposta terapêutica da dor nas NS; 3.avaliar o comprometimento autonômico por meio de escala clínica e de exames neurofisiológicos nos pacientes com NS; 4.avaliar o atraso e o erro diagnóstico aos quais estão submetidos os pacientes com NS e, 5.propor e validar um instrumento capaz de quantificar as alterações clínicas dos pacientes com NS. Um total de 61 pacientes foram avaliados e frações deste número foram incluídas em cada um dos estudos. Foram descritos dois pacientes com NS associada a causas infecciosas: a primeira descrição clínica da associação entre NS e a infecção pelo vírus da Zika e a descrição da associação da infecção pelo HTLV-1 e o fenótipo combinado de NS e paraparesia espástica. A avaliação dos anticorpos anti-FGFR3 demonstrou positividade em 38% (16/42) explicando 37,5% (9/24) dos pacientes com etiologia até então, idiopática. Cinco pacientes com a associação NS-hepatite autoimune foram identificados, representando 7% do total de pacientes avaliados (5/70). Esses pacientes destacam-se pela positividade do anti-FGFR3 (3/5 ¿ 60%) e pela não-responsividade do quadro neurológico contraposta à remissão do quadro hepático instituída a imunossupressão. Dando prosseguimento à investigação etiológica, 22 pacietes com NS idiopática foram submetidos ao sequenciamento completo do exoma por tecnologia de nova geração. Nenhum paciente teve seu diagnóstico realizado. Todavia, variantes relacionada a genes que podem levar à ataxia sensitiva, foram encontradas em quatro pacientes (CUBN, POLG, FXN e FLVCR1). Queixas álgicas estavam presentes em 76%, com assimetria e características neuropáticas em mais da metade dos pacientes cuja terapia medicamentosa promoveu remissão satisfatória em 19%(7/36). Uma prevalência ainda maior foi observada na investigação autonômica. Alteracões do volume de sudorese pelo reflexo axonal sudomotor estavam presentes em 91% indicando disfunção simpática pós-ganglionar a qual estava associada à disfunção parassimpática descrita por alterações nas provas cardiovagais dos testes de variabilidade cardíaca. Os pacientes com NS em média levam 5,4±5,4 anos entre o início de sintomas e a conclusão diagnóstica, passando por 4,3 ± 2,4 especialistas com 3,08±1,4 diagnósticos incorretos. Por fim, propusemos um instrumento com 10 itens capazes de avaliar os pacientes com NS. Essa escala apresentou consistência interna com alfa de Cronbach padronizado de 0,83 com coeficientes de correlação interclasse para concordância inter/intraobservador de 0,96 e 0,98 respectivamente Abstract: Sensory neuronopathies (SN) represent a disorder characterized by dorsal root ganglia damage. The emerging clinical picture is composed by sensory ataxia and multifocal non-length dependent sensory deficits. The identification of this pattern opens a window of opportunity for the recognition of possible underlying diseases. Moreover, frequent symptoms such as pain and those related to autonomic dysfunction have not been clinically nor neurophysiologically evaluated. Another milestone to be mentioned is the rarity of SN added to unusual signs such as pseudoathetosis and pseudoparesis that turn usual the diagnostic delay. Additionally, the lack of reliable instruments capable of measuring the disease progression makes impossible natural history studies and the design of clinical trials. Hence, our objectives were: 1.to investigate novel etiologies for SN using clinical immunology and molecular biology techniques; 2.to describe clinical, topographic and treatment response characteristics of SN-related pain; 3.to evaluate clinical and neurophysiological functioning of the autonomic nervous system in SN patients; 4.to assess diagnostic delay and misdiagnoses of SN and 5.design and validate a clinical instrument capable to measure sensory ataxia. A total of 61 SN patients were enrolled, and different proportions of this group were included in each study. Two patients with infectious diseases-related SN were described: the first one was the first description of Zika virus-related SN and the second one was also the first description of a patient with SN and spastic paraparesis related to the HTLV1 infection. Anti-FGFR3 antibodies tested positive in 38% (16/42) of the patients and likely explained the disease cause in a significant proportion of the "idiopathic cases" 37.5% (9/24). Five patients (7% - 5/70) were diagnosed with the SN-autoimmune hepatitis association. These patients had positive screening for anti-FGFR3 antibodies (3/5 - 60%) and had, characteristically, unresponsiveness to the immunosuppressive treatment regarding the neurological clinical picture, whereas the hepatic disease underwent remission. Exome sequencing through new generation technology was another effort towards the etiologic approach of NS. Twenty-two idiopathic SN patients were enrolled but none of them had a definite diagnosis. Four patients had heterozygote variants in genes related to sensory ataxias (CUBN, POLG, FXN e FLVCR1) what raises the hypothesis that these are predisposing genes for SN. Pain complaints were present in 75% of the SN patients in this cohort, and more than half of them had asymmetric and neuropathic characteristics. Only 19% of the treated patients reached satisfactory pain remission. Autonomic manifestations were even more prevalent. Indeed, axonal sudomotor reflex evaluation disclosed abnormal sweat volumes in 91% of the patients what represents a post-ganglionic sympathetic dysfunction. Parasympathetic dysfunction was also revealed by the abnormal cardiovagal tests observed during heart rate variability tests. Considering the diagnostic delay, the mean interval from disease onset to the correct diagnosis was 5.4±5.4 years. On average, each patient had 3.08±1.4 misdiagnoses after consulting 4,3 ± 2,4 specialists. At last, we have proposed a clinical instrument to evaluate SN patients. This 10-item scale had a standardized Cronbach's alpha of 0.83 and intraclass correlation coefficient for interrater and intrarater evaluations of 0.96 and 0.98 respectively Doutorado Fisiopatologia Médica Doutor em Ciências FAPESP 2013/26410-0 CAPES

Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)-based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12).All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1-multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord.There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age- and sex-matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex.Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401-408.

Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias.To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa.Patients and controls underwent single-photon emission computed tomography imaging utilizingReduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial.Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.

Sensory neuronopathies (SN) are a group of disorders characterized by primary damage to the dorsal root ganglia neurons. Clinical features include multifocal areas of hypoaesthesia, pain, dysautonomia, and sensory ataxia, which is the major source of disability. Diagnosis relies upon clinical assessment and nerve conductions studies, but sometimes it is difficult to distinguish SN from similar conditions, such as axonal polyneuropathies and some myelopathies. In this scenario, underdiagnosis is certainly an important issue for SN patients and additional diagnostic tools are needed. MRI is able to evaluate the dorsal columns of the spinal cord and has proven useful in the workup of SN patients. Although T2 weighted hyperintensity restricted to the posterior fasciculi without contrast enhancement is the typical finding, additional abnormalities have been recently reported. The aim of this review is to gather available information on neuroimaging findings of SN, discuss their clinical correlates and the potential impact of novel MRI-based techniques.