Análise das características clínicas, eletroencefalográficas e genéticas de pacientes com ataxia cerebelar e epilepsia

Orientador: Prof. Dr. Hélio Afonso Ghizoni TeiveDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Medicina Interna. Defesa : Curitiba, 25/08/2023Inclui referênciasÁrea de concentração: Medicina InternaResumo: A relação entre ataxia cerebelar hereditária e epilepsia tem sido alvo de interesse na área de distúrbios do movimento, epilepsia e neurogenética. Há crescente curiosidade na caracterização de seus mecanismos moleculares e correlação destes com aspectos clínicos e achados neurofisiológicos da doença. Apesar de haver relatos detalhadas sobre achados clínicos e eletroencefalográficos de várias dessas doenças isoladamente (como SCA10 e as epilepsias mioclônicas progressivas), inexistem estudos que façam uma avaliação abrangente e sistemática dessas características em correspondência ao genótipo dos pacientes afetados por essas condições. Dessa forma, o presente trabalho realizou a descrição de variáveis clínicas, eletroencefalográficas e de neuroimagem em correlação com o diagnóstico genético de pacientes com ataxia e epilepsia. Analisou-se parâmetros da doença (gravidade, tempo de doença, frequência e tipo de crises), características do eletroencefalograma, neuroimagem e dados de avaliação genética compreensiva por sequenciamento completo do genoma (WGS) e outros métodos complementares. 43 pacientes foram analisados, sendo que em 42% destes foram identificados genes causadores de ataxia e epilepsia. 48% dos pacientes foram analisados por WGS, sendo que em 62% destes houve um diagnóstico genético. 38% dos pacientes submetidos à análise por WGS foram considerados genoma negativo. Em 64% dos pacientes as crises epilépticas apresentavam início generalizado, sendo as crises tônico-clônicas generalizadas (42%) as mais frequentes. A análise do EEG demonstrou presença de atividade epileptiforme em 38% dos pacientes, sendo 21% focal ou multifocal e 17% generalizada. 81% dos pacientes apresentavam atrofia cerebelar na RM crânio, sendo esta anormalidade a única alteração em 60% destes. O aparecimento dos sintomas de epilepsia precedeu os de ataxia em 39%, sendo que a ataxia foi a primeira manifestação em 34% e houve aparecimento simultâneo em 26% dos pacientes. Não houve diferença estatisticamente significativa da gravidade da ataxia entre esses grupos. Para as análises comparativas dos dados clínicos das ataxias e epilepsias, foi realizada análise em 4 grupos: o das ataxias dominantes, ataxias recessivas, epilepsias mioclônicas progressivas e encefalopatias epilépticas. Houve maior frequência de crises nos pacientes do grupo das encefalopatias epilépticas, porém, à comparação, tal dado não se mostrou estatisticamente significativo. Não se verificou maior morbidade dos sintomas de ataxia em pacientes que utilizavam bloqueadores dos canais de sódio e benzodiazepínicos em comparação aos outros pacientes. O presente estudo descreve uma correlação clínica, genética eletroencefalográfica e de imagem em pacientes com ataxia cerebelar e epilepsia. Apesar de a associação entre essas condições ser evidente, são necessários estudos prospectivos para detalhar o real impacto desses achados nessas doençasAbstract: Hereditary cerebellar ataxia and epilepsy is a topic of paramount interest in the fields of movement disorders, epilepsy and neurogenetics. In particular, the characterization of the genetic diagnoses and their correlation to clinical and neurophysiological findings in affected patients is one of the features that receives most of the attention. Although there are thorough isolated descriptions of clinical and electroencephalographic findings of these diseases (such as SCA10 and progressive myoclonic epilepsies), there are no studies that accomplish a systematic evaluation of clinical, EEG and neuroimaging findings in correlation to the genetic profile. This study aimed to describe clinical characteristics (such as severity, disease duration, seizure type and frequency), EEG and neuroimaging findings according to genetic profiling. A comprehensive genetic evaluation that included whole genome sequencing (WGS) was performed. 43 patients were assessed. In 42% genes known to cause cerebellar ataxia and epilepsy were found. 48% of the patients were assessed by WGS and 62%of those were found to have a genetic diagnosis related to these conditions. 38% Ataxia symptoms preceded epilepsy in 39% of the patients. In 64%, seizure onset was determined to be generalized, with a higher frequency of tonic-clonic seizures (42%). EEG analysis showed a prevalence of epileptiform activity (EA) in 38% of the patients, being 21% focal or multifocal (EA) and 17% generalized. 81% of patients presented cerebellar atrophy on brain MRI, being the isolated abnormal finding in 60%. Epilepsy was the first presentation in 35% and 26% had a simultaneous onset for both conditions. There was no difference in severity of ataxia symptoms between those groups. For the description of the clinical results, the patients were divided in 4 groups: autosomal dominant ataxias (AD), recessive ataxias AR), progressive myoclonic epilepsies (PME) and epileptic encephalopathies (EE). Patients from the EE group showed a higher seizure frequency, although this finding did not reach statistical significance. This study did not find worse ataxia symptoms in patients that used sodium channel blockers or benzodiazepines. This study described a genetic, clinical, electroencephalographic and neuroimaging assessment of a group of patients with cerebellar ataxia and epilepsy. Although the association between these conditions is evident, further prospective studies are needed in order to better clarify the real significance of these findings

Vertical structure and physical processes of the Madden-Julian oscillation: exploring key model physics in climate simulations

Aimed at reducing deficiencies in representing the Madden-Julian oscillation (MJO) in general circulation models (GCMs), a global model evaluation project on vertical structure and physical processes of the MJO was coordinated. In this paper, results from the climate simulation component of this project are reported. It is shown that the MJO remains a great challenge in these latest generation GCMs. The systematic eastward propagation of the MJO is only well simulated in about one-fourth of the total participating models. The observed vertical westward tilt with altitude of the MJO is well simulated in good MJO models, but not in the poor ones. Damped Kelvin wave responses to the east of convection in the lower troposphere could be responsible for the missing MJO preconditioning process in these poor MJO models. Several process-oriented diagnostics were conducted to discriminate key processes for realistic MJO simulations. While large-scale rainfall partition and low-level mean zonal winds over the Indo-Pacific in a model are not found to be closely associated with its MJO skill, two metrics, including the low-level relative humidity difference between high and low rain events and seasonal mean gross moist stability, exhibit statistically significant correlations with the MJO performance. It is further indicated that increased cloud-radiative feedback tends to be associated with reduced amplitude of intraseasonal variability, which is incompatible with the radiative instability theory previously proposed for the MJO. Results in this study confirm that inclusion of air-sea interaction can lead to significant improvement in simulating the MJO

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI's major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change

Barriers to technological adoption in Spain and Portugal

Technology barriers, Economic development, Spain, Portugal, E20, O11, O33,

A hiatus in the rivalry between Pierre Marie and Jules Dejerine: a collaborative study on sensory disorders by Andre Pierre Marie and Gustave Roussy

Personal and professional rivalries involving prominent neurologists mark the history of nineteenth-century French neurology. One of the great examples is the feud between Pierre Marie and Jules Dejerine. The dispute between the two, nevertheless, did not prevent Pierre Marie's son, André Marie, and Gustave Roussy – one of Dejerine's favorite pupils, from collaborating on significant research that led to the doctoral dissertation by Andre Marie regarding sensory disturbances associated with painful hemiagnosia found in thalamic lesions

Analysis of Clinical and Demographic Variables in the Treatment of Carotid Stenosis by Endarterectomy and Stent Angioplasty

Introduction: Carotid stenosis plays a major role in the etiology of cerebral ischemic events. We evaluated the variables that impact the evolution of these patients. Methods: Data were retrospectively checked from the medical records of patients treated in the period between 2008 and 2015. Different variables were evaluated to determine the factors that influence the patients clinically. Results: The analysis was conducted based on a sample of 63 patients with carotid stenosis who underwent surgery. Regarding the factors that influenced the outcome, there was significant association with age ≥70 years, smoking and previous ischemic stroke. Although hypertension was the most prevalent comorbidity, no significant association as clinical worsening factor was found, as well as the isolated analysis of each surgery showed no significant difference. Conclusions: The clinical profile and lifestyle habits associated with certain comorbidities are variables that influence the clinical outcome of patients with carotid stenosis.</jats:p

Climate change projections using the IPSL-CM5 Earth System Model: from CMIP3 to CMIP5

We present the global general circulation model IPSL-CM5 developed to study the long-term response of the climate system to natural and anthropogenic forcings as part of the 5th Phase of the Coupled Model Intercomparison Project (CMIP5). This model includes an interactive carbon cycle, a representation of tropospheric and stratospheric chemistry, and a comprehensive representation of aerosols. As it represents the principal dynamical, physical, and bio-geochemical processes relevant to the climate system, it may be referred to as an Earth System Model. However, the IPSL-CM5 model may be used in a multitude of configurations associated with different boundary conditions and with a range of complexities in terms of processes and interactions. This paper presents an overview of the different model components and explains how they were coupled and used to simulate historical climate changes over the past 150 years and different scenarios of future climate change. A single version of the IPSL-CM5 model (IPSL-CM5A-LR) was used to provide climate projections associated with different socio-economic scenarios, including the different Representative Concentration Pathways considered by CMIP5 and several scenarios from the Special Report on Emission Scenarios considered by CMIP3. Results suggest that the magnitude of global warming projections primarily depends on the socio-economic scenario considered, that there is potential for an aggressive mitigation policy to limit global warming to about two degrees, and that the behavior of some components of the climate system such as the Arctic sea ice and the Atlantic Meridional Overturning Circulation may change drastically by the end of the twenty-first century in the case of a no climate policy scenario. Although the magnitude of regional temperature and precipitation changes depends fairly linearly on the magnitude of the projected global warming (and thus on the scenario considered), the geographical pattern of these changes is strikingly similar for the different scenarios. The representation of atmospheric physical processes in the model is shown to strongly influence the simulated climate variability and both the magnitude and pattern of the projected climate changes

SIDEROSE IDIOPÁTICA DO SNC: UM RELATO E REVISÃO

Superficial siderosis (SS) of the central nervous system (CNS) is a potentially disabling disorder characterized by the deposition of ferrous iron and hemosiderin, products of hemolysis, in the leptomeninges and superficial layers of the cerebral and cerebellar cortexes, as well as the brainstem and spinal cord. Persisting in the subarachnoid space, accumulation leads to demyelination, axonal loss and subsequent atrophy and neurodegeneration mediated by free radicals. In most cases, a potentially causative spinal or cranial dural abnormality is identified. The classification of SS is based on anatomical distribution, etiology and clinical manifestations, resulting in distinct subtypes: Classical infratentorial (i) SS (type 1), secondary SSi (type 2) and cortical SS (c). The classical clinic manifests with sensorineural hypoacusis, cerebellar ataxia and occasionally myelopathic and radicular signs. Although it is not a classic symptom of SS, infrequently some patients develop chronic intracranial hypertension, which is believed to be associated with obstruction of the interventricular foramen and/or malabsorption of cerebrospinal fluid (CSF). When present, the headache is usually a consequence of intracranial hypotension and its intensity varies according to the type of dural defect and the rate of bleeding or CSF leakage through a fistula. Diagnosis is established by means of magnetic resonance imaging (MRI) of the entire neuroaxis combined with clinical assessment. As alternatives aimed at preventing the progression of the disease and preserving the patient\u27s functional integrity, in addition to controlling the deficits generated by siderosis, surgical closure of the dura mater and chelation are the main therapeutic alternatives.A siderose superficial (SS) do sistema nervoso central (SNC) é um distúrbio potencialmente incapacitante caracterizado pela deposição de ferro ferroso e hemossiderina, produtos da hemólise, nas leptomeninges e camadas superficiais dos córtices cerebral e cerebelar, além do tronco encefálico e medula espinhal.2,1,4,5,6 Persistindo no espaço subaracnóideo, o acúmulo leva à desmielinização, perda axonal e subsequente atrofia e neurodegeneração mediada por radicais livres.2,5 Na maioria dos casos, identifica-se uma anormalidade dural espinal ou craniana potencialmente causal.2 A classificação da SS baseia-se na distribuição anatômica, etiologia e manifestações clínicas, resultando em subtipos distintos: SS infratentorial (i) clássica (tipo 1), SSi secundária (tipo 2) e SS cortical (c).1,2 A clínica clássica manifesta-se com hipoacusia neurossensorial, ataxia cerebelar e ocasionalmente sinais de mielopatia e radiculares.3,2,1 Apesar de não ser um sintoma clássico da SS, infrequentemente, alguns pacientes desenvolvem hipertensão intracraniana crônica, onde acredita-se estar associada à obstrução do forame interventricular e/ou má absorção do líquido cefalorraquidiano (LCR).4 Quando presente, a cefaleia geralmente é consequência de hipotensão intracraniana e sua intensidade varia de acordo com o tipo de defeito dural e da taxa de sangramento ou vazão liquórica por uma fístula.1,2,6 O diagnóstico é estabelecido por meio da ressonância nuclear magnética (RNM) de neuroeixo em associação com a avaliação clínica1. Como alternativas visando prevenir a progressão da doença e preservar a integridade funcional do paciente, além do controle dos défices gerados pela siderose, o fechamento cirúrgico da fistula dural e a quelação são as principais alternativas terapêuticas.3,2&nbsp