Dravet syndrome and Dravet syndrome-like phenotype: a systematic review of the SCN1A and PCDH19 variants.

Dravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients with this syndrome present SCN1A pathogenic variants, which encodes an alpha subunit of a neural voltage-dependent sodium channel. There is a correlation between PCDH19 pathogenic variants, encodes the protocadherin 19, and a similar disease to DS known as DS-like phenotype. The present review aims to clarify the differences between DS and DS-like phenotype according to the SCN1A and PCDH19 variants. A systematic review was conducted in PubMed and Virtual Health Library (VHL) databases, using "Dravet Syndrome" and "Severe Myoclonic Epilepsy in Infancy (SMEI)" search words, selecting cohort of studies published in journal with impact factor of two or greater. The systematic review was according to the Preferred Reporting Items for Systematic Review and Meta-Analysis recommendations. Nineteen studies were included in the present review, and a significant proportion of patients with DS-carrying SCN1A was greater than patients with DS-like phenotype-harboring PCDH19 variants (76.6% versus 23.4%). When clinical and genetic data were correlated, autism was predominantly observed in patients with DS-like-carrying PCDH19 variants compared to SCN1A variant carriers (62.5% versus 37.5%, respectively, P-value = 0.044, P-value corrected = 0.198). In addition, it was noticed a significant predisposition to hyperthermia during epilepsy crisis in individuals carrying PCDH19 variants (P-value = 0.003; P-value corrected = 0.027). The present review is the first to point out differences between the DS and DS-like phenotype according to the SCN1A and PCDH19 variants.

Neuromodulation for Medically Refractory Neuropathic Pain: Spinal Cord Stimulation, Deep Brain Stimulation, Motor Cortex Stimulation, and Posterior Insula Stimulation.

BACKGROUND: The treatment of neuropathic pain (NP) continues to be controversial as well as an economic health issue and a challenge to health care. Neurosurgery can offer different methods of neuromodulation that may improve patients' condition, including deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS), and posterior insula stimulation (PIS). There is no consensus of opinion as to the final effects of these procedures, which stimulation parameters to select, the correct timing, or how to select the patients who will best benefit from these procedures. OBJECTIVE: To review the evidence available regarding these 4 procedures and the management of NP. METHODS: We conducted a PubMed, Embase, and Cochrane Library database search from 1990 to 2020. The strategy of the search concentrated on the following keywords: "neuropathic pain," "chronic pain," "deep brain stimulation," "motor cortex stimulation," "spinal cord stimulation," "insula stimulation," and "neuromodulation." Studies that provided data regarding the immediate and long-term effectiveness of the procedure, anatomic stimulation target, percentage of pain control, and cause of the NP were included. RESULTS: The most frequent causes of NP were phantom limb pain and central poststroke pain in the MCS group; central poststroke pain, phantom limb pain, and spinal cord injury (SCI) in the DBS group; and complex regional pain syndrome and failed back surgery syndrome in the SCS group. Pain improvement varied between 35% and 80% in the MCS group and 50% and 60% in the DBS group. In the SCS group, successful rates varied between 38% and 89%. CONCLUSIONS: This systematic review highlights the literature supporting SCS, DBS, MCS, and PIS methods for the treatment of NP. We found consistent evidence supporting MCS, DBS, and SCS as possible treatments for NP; however, we were not able to define which procedure should be indicated for each cause. Furthermore, we did not find enough evidence to justify the routine use of PIS. We conclude that unanswered points need to be discussed in this controversial field and emphasize that new research must be developed to treat patients with NP, to improve their quality of life.

Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. METHODS: We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. RESULTS: As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. CONCLUSION: Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses.

Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223.

BACKGROUND: In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients with relapsing-remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656). METHODS: In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies. RESULTS: Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7-12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases. CONCLUSIONS: Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials.

Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis.

The expanding therapeutic arsenal in multiple sclerosis (MS) has allowed for more effective and personalized treatment, but the choice and management of disease-modifying therapies (DMTs) is becoming increasingly complex. In this context, experts from the Brazilian Committee on Treatment and Research in Multiple Sclerosis and the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology have convened to establish this Brazilian Consensus for the Treatment of MS, based on their understanding that neurologists should be able to prescribe MS DMTs according to what is better for each patient, based on up-to-date evidence and practice. We herein propose practical recommendations for the treatment of MS, with the main focus on the choice and management of DMTs, as well as present a review of the scientific rationale supporting therapeutic strategies in MS.

Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis / Consenso Brasileiro para o Tratamento da Esclerose Múltipla: Academia Brasileira de Neurologia e Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla

ABSTRACT The expanding therapeutic arsenal in multiple sclerosis (MS) has allowed for more effective and personalized treatment, but the choice and management of disease-modifying therapies (DMTs) is becoming increasingly complex. In this context, experts from the Brazilian Committee on Treatment and Research in Multiple Sclerosis and the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology have convened to establish this Brazilian Consensus for the Treatment of MS, based on their understanding that neurologists should be able to prescribe MS DMTs according to what is better for each patient, based on up-to-date evidence and practice. We herein propose practical recommendations for the treatment of MS, with the main focus on the choice and management of DMTs, as well as present a review of the scientific rationale supporting therapeutic strategies in MS.

RESUMO O crescent arsenal terapêutico na esclerose múltipla (EM) tem permitido tratamentos mais efetivos e personalizados, mas a escolha e o manejo das terapias modificadoras da doença (TMDs) tem se tornado cada vez mais complexos. Neste contexto, especialistas do Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla e do Departamento Científico de Neuroimunologia da Academia Brasileira de Neurologia reuniram-se para estabelecer este Consenso Brasileiro para o Tratamento da EM, baseados no entendimento de que neurologistas devem ter a possibilidade de prescrever TMDs para EM de acordo com o que é melhor para cada paciente, com base em evidências e práticas atualizadas. Por meio deste documento, propomos recomendações práticas para o tratamento da EM, com foco principal na escolha e no manejo das TMDs, e revisamos os argumentos que embasam as estratégias de tratamento na EM.

La Insulectomía podría ser un abordaje ideal para crisis insulares y peri-insulares? / Insulectomy for insular and peri-insular seizures could be an ideal and safe approach?

La insulectomía es una técnica microquirúrgica establecida para el tratamiento de la epilepsia refractaria al tratamiento farmacológico. El origen insular de la epilepsia es inusual, sin embargo, con la investigación a través de electrodos híbridos este tipo de epilepsia ha incrementado su diagnóstico. Los autores hacen hincapié en las funciones insulares, así como los puntos de referencia anatómicos para la cirugía. Se discuten las principales complicaciones y las bases fisiológicas para las indicaciones de cirugía.

Insulectomy is an established microsurgical technique for treatment of insular epilepsy refractory to clinical management. The insular origin of epilepsy is unusual, however with depth investigation through hybrids electrodes such kind of epilepsy is increasing its diagnosis. The authors emphasizes the insular functions as well as the anatomical landmarks for surgery. The main complications are discussed and physiological basis for indications.

Alternatives for reducing relapse rate when switching from natalizumab to fingolimod in multiple sclerosis.

Natalizumab is a therapeutic option for treating multiple sclerosis (MS) and is particularly efficacious for patients with highly active disease. A long washout period has been recommended between withdrawal of natalizumab and start of fingolimod (another option for treating MS). This long washout period has been associated with a significant increase in MS activity. In the present study, a group of 96 patients who were switched from natalizumab to fingolimod had short washout periods between drugs, or monthly corticosteroid pulse therapy if longer washout periods were recommended. This therapeutic approach led to the lowest reported relapse rate so far, among patients with MS switching from natalizumab to fingolimod (8.3%). No complications from short withdrawal were observed in this group of patients.

Natalizumab treatment in multiple sclerosis: the experience from two Brazilian MS centers.

Objective Analyze the demographics, clinical characteristics, efficacy and safety of natalizumab treatment in Brazilian patients with multiple sclerosis (MS) followed up for at least 12 months, in two tertiary MS care centers in São Paulo.Method We evaluated the effect of natalizumab treatment on annualized relapse rate and disability progression in 75 patients with MS treated with natalizumab for at least 12 months. A subgroup analysis was performed to evaluate efficacy of natalizumab treatment in patients with Expanded Disability Status Scale (EDSS) ≤ 3.0 vs patients with EDSS > 3.Results Patients treated for at least one year with natalizumab showed a 91% reduction in aRR, as well and an improvement in neurological disability. The impact of natalizumab treatment was greater in patients with EDSS < 3.0. Overall, natalizumab was safe but one patient developed progressive multifocal leukoencephalopathy.Conclusion Natalizumab as a third line therapy is safe and efficacious, especially in patients with mild neurological disability.

Natalizumab treatment in multiple sclerosis: the experience from two Brazilian MS centers / Natalizumabe no tratamento da esclerose múltipla: a experiência de dois centros brasileiros

Objective Analyze the demographics, clinical characteristics, efficacy and safety of natalizumab treatment in Brazilian patients with multiple sclerosis (MS) followed up for at least 12 months, in two tertiary MS care centers in São Paulo.Method We evaluated the effect of natalizumab treatment on annualized relapse rate and disability progression in 75 patients with MS treated with natalizumab for at least 12 months. A subgroup analysis was performed to evaluate efficacy of natalizumab treatment in patients with Expanded Disability Status Scale (EDSS) ≤ 3.0 vs patients with EDSS > 3.Results Patients treated for at least one year with natalizumab showed a 91% reduction in aRR, as well and an improvement in neurological disability. The impact of natalizumab treatment was greater in patients with EDSS < 3.0. Overall, natalizumab was safe but one patient developed progressive multifocal leukoencephalopathy.Conclusion Natalizumab as a third line therapy is safe and efficacious, especially in patients with mild neurological disability.

Objetivo Analisar as características clínicas e demográficas, assim como a eficácia e segurança do tratamento com natalizumabe (usado em terceira linha), por no mínimo 12 meses, em pacientes brasileiros acompanhados em dois centros de tratamento de esclerose múltipla, na cidade de São Paulo.Método Avaliamos o efeito do tratamento com natalizumabe na taxa anualizada de surto (aRR) e progressão de incapacidade (medida por Expanded Disability Status Scale (EDSS)) em 75 pacientes tratados por, no mínimo 12 meses. Realizamos uma análise de subgrupo em pacientes com EDSS ≤ 3,0 e com EDSS > 3, para avaliar o impacto no tratamento, considerando-se o grau de incapacidade neurológica.Resultados O tratamento com natalizumabe, por pelo menos um ano, reduziu a aRR em 91%, assim como melhorou a incapacidade neurológica. Em pacientes com EDSS ≤ 3,0 observamos um impacto maior do tratamento na incapacidade neurológica, reduzindo sua progressão em 51%, durante o período do estudo. O tratamento com natalizumabe é seguro, porém um paciente desenvolveu leucoencefalopatia multifocal progressiva.Conclusão O tratamento com natalizumabe, em terceira linha terapêutica é seguro e eficaz especialmente, em pacientes com incapacidade neurológica leve (EDSS ≤ 3.0).

Cerebrospinal fluid aquaporin-4 antibody levels in neuromyelitis optica attacks.

To elucidate immunopathogenetic roles of aquaporin-4 antibodies in the cerebrospinal fluid (CSF) of neuromyelitis optica spectrum disorders (NMOSD), we analyzed aquaporin-4 antibody titers, cellular and inflammatory markers in the CSF collected from 11 aquaporin-4 antibody seropositive patients. The CSF aquaporin-4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis, inflammatory cytokines including interleukin-6 that can regulate antibody-producing plasmablasts, and glial fibrillary acidic protein levels in the CSF. The amount of aquaporin-4 antibodies present in the central nervous system may have therapeutic implications, as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks.

Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.

OBJECTIVE: To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies. METHODS: Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells. RESULTS: Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack. CONCLUSIONS: Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.

Apnéia do sono associada a obesidade: alguma influência na formação dos aneurismas cerebrais? / May sleep apnea associated with obesity play a role in brain aneurysm grouth?

Os autores selecionaram um grupo de pacientes com apnéia do sono e aneurismas cerebrais e procuraram correlacionar com casos de sobrepeso e obesidade, encontrando 80% de pacientes com obesidade do sexo feminino, com idades entre49 e 72 anos (média de 60,6 anos), todas submetidas a gastroplastia prévia, e tendo sido submetidas a repetidos regimes para emagrecer , com 60% de aneurismas rotos, todos Hunt-Hess entre III e V e Fisher 4 .. Aqueles com sobrepeso, idadeentre 53 e 70 anos ( média 60,5 anos), 50% tabagistas, 75%com aneurismas rotos, com gradação Hunt-Hess 3.3 em média,e Fisher de 3.3 em média. Concluir sobre a correlação é muito incipiente e mais estudos devem ser feitos neste sentido.

The authors have selected a group of patients with sleep apnea and brain aneurysms and sought to correlate with cases of overweight and obesity. They have found a high incidence of bleeding among those patients in both groups of obesity, most of them at computed tomography with Fisher score of III to IV,in patients with ruptured aneurysms (60% of rupture in severe obesity and 75% in overweight), and clinical status of Fisher I Vin obese patients and 3.3 in over weighed patients. Beyond any doubts, further studies should be accomplished to establish a strong correlation between associated obesity and sleep apnea and the patophysiology of brain aneurysms.

Tratamento cirúrgico dos aneurismas da circulação anterior / Tratamento cirúrgico dos aneurismas da circulação anterior

Objetivos: Os autores fazem uma análise crítica dos métodos atuais de tratamento dos aneurismas da circulação anterior, além de salientarem os aspectos anatômicos e acessos cirúrgicos.Métodos: Os aspectos evolutivos da técnica cirúrgica e endovascular de tratamento de aneurismas são discutidos, bem como as indicações e principais complicações. Resultados: Uma análise dos aneurismas da circulação anterior é feita e discutida quanto aos aspectos de sua localização, classificação e formas de tratamento. Os aneurismas paraclinóideos são os mais difíceis de serem abordados e tratados. Conclusão: A via pterional é a mais adequada e em aneurismas gigantes a ponte com enxerto venoso da carótida externa para cerebral média pode ser muito útil.

Avaliaçäo da disfunçäo erétil em pacientes com doença de Parkinson / Assessment of erectile dysfunction in patients with Parkinson's disease

Trinta indivíduos portadores de doença de Parkinson (DP) e 30 indivíduos controle foram estudados prospectivamente, através do Índice Internacional de Função Erétil (IIFE) a propósito de avaliar a ocorrência de disfunção erétil (DE). Dos pacientes com DP (idade mediana de 59 anos), 46,66 por cento referiram prática de atividade sexual. Todos parkinsonianos usavam medicação antiparkinsoniana. Neste grupo, 30,00 por cento tinham hipertensão arterial e 6,66 por cento diabetes melitus. No grupo controle (idade mediana de 63 anos), 76,66 por cento declararam prática de atividade sexual; 46,6 por cento tinham hipertensão arterial e 6,66 por cento diabetes mellitus. Escore médio para portadores de DP no IIFE foi 34 e para os controles 50. As principais diferenças entre os dois grupos foram quanto à função erétil, função orgasmo e satisfação com a relação sexual. O IIFE é uma escala amplamente aceita para avaliação da disfunção erétil. Os dados obtidos sugerem que a DE é mais frequente entre parkinsonianos, ressaltando o papel da DP como causa de DE nesse grupo.

Carcinoma brônquico de pequenas células: comparaçäo entre 2 realidades / Bronchogenic carcinoma of small cells carcinoma: a comparison between 2 realities

O câncer de pequenas células (SCLC) representa 15 a 25 por cento dos carcinoma brônquicos. Atravé de estudo retrospectivo comparou-se pacientes atendidos HURNPr/HEL (Londrina) e no Brompton Hospital (Londres). Foram estudados 15 pacientes com diagnóstico de SCLC e comparados ao oitenta pacientes analisados no Brompton Hospital. Estadios I, II e IIIa (sem comprometimento de lonfonodos) foram encontrados em dois pacientes (13,3 por cento) e estadios IIIª (compromentendo linfonodos), IIIb e IV em 13 (86,7 por cento) dos pacientes no estudo de Londrina, comparados a 30 (34,5 por cento) e 57 (65,5 por cento), respectivamente no Brompton Hospital. Foram considerados operáveis apenas 2 (13,3 por cento) casos em Londrina (apenas um ressecável) contra 30 (34,5 por cento) em Londres (93,3 por cento ressecáveis). O tratamento no grupo de Londrina foi basicamente näo-cirúrgico (86,7 por cento), a sobrevida observada foi menor que 3 meses em 8 casos (53,8 por cento), em 4 (26,7 por cento) perdeu-se o acompanhamento e 19,5 por cento encontram-se em seguimento, enquanto nos casos de Londres, com tratamento exclusivamente cirúrgico, observou-se sobrevida de 5 anos em 43,3 por cento. O tratamento cirúrgico do SCLC depende de seu estadiamento. A indicaçä cirúrgica dos 15 pacientes estudados foi limitado pelo estadio avançado da doença, diferentemente de Londres. Concluiu-se, portanto, que há necessidade de se realizar diagnóstico precoce para promoçäo de tratamento eficaz, por vezes curativo, evidenciando-se, em Londrina, o contrário do observado no Brompton Hospital, uma realidade desfavorável