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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.

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. JO has received consulting and/or speaking fees from Biogen Idec, Celgene, EMD Serono, Sanofi, Novartis, and Roche, and grant/research support from Biogen, Roche, and Sanofi. AA has received consulting and/or speaking fees from Biogen, Roche, and Sanofi, and grant/research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Roche, and Sanofi. EGC has received honoraria for advisory boards and/or speaking from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, and Teva, and unrestricted research grants from Genzyme and Novartis. CC was compensated for serving as editor, associate editor, or member of an editorial advisory board for Birth Defects Research Part A: Clinical and Molecular Teratology, and received grant/research support from AAAAI/VAMPS, AbbVie Laboratories, Amgen, Apotex, AstraZeneca, Barr Laboratories, Bristol-Myers Squibb, California Department of Public Health, CDC, Celgene, Hoffmann-La Roche, Genentech, GlaxoSmithKline, HRSA, IHC, Janssen Biotech, NIAAA, NIH/HIGM, Pfizer, Regeneron, Sanofi, Segirus, the State of California, and UCB Pharma. JD reports receiving speaking and consulting fees from Biogen, Celgene, EMD Serono, Genentech, Genzyme, Novartis, and Teva. VD has received consulting and/or speaking fees from Biogen, EMD Serono, Sanofi, Novartis, Roche, and Teva. KH received speaker honoraria and research support from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. GJH has received research support from Adamas, Biogen, EMD Serono, Hoffman-La Roche, Mallinckrodt, MedImmune, Novartis, and Sanofi, and consulting fees from Biogen, Celgene, Novartis, and Sanofi. PM has received consulting and speaker fees from Biogen, Novartis, Sanofi, and Teva. MM has received speaking fees from Genzyme and fees for participating in advisory boards for Celgene. DR has received consulting fees from Bayer-Schering Pharma, Biogen, MedDay, Merck Serono, Novartis, Roche, Sanofi, and Teva Neuroscience, and research support from Actelion, Biogen, GW Pharma, Merck Serono, Mitsubishi, MedDay, Novartis, Sanofi, Teva Neuroscience, and TG Therapeutics. JRS and LS have nothing to disclose. RFS has received fees for advisory boards and consulting from Biogen and Sanofi, and lecture fees from Biogen, Merck, Novartis, and Roche. SGV reports receiving consulting and speaking fees from Sanofi, speaking fees from Genentech, consulting fees from EMD Serono, and fees as a study monitor for Millennium Pharmaceuticals, Inc. LC, ND, and CM are employees of Sanofi. DASC has received consulting fees and grant/research support from Sanofi, and lecture fees from Bayer-Schering Pharma and Sanofi., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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.

Previously reported only a few times before, we present a case of extracranial vertebral dissection and spontaneous frontoparietal subarachnoid hemorrhage (SAH) in the puerperium, discussing possible mechanisms and difficulties in management. A 35-year-old woman presented 10 days postcaesarean section with neck pain and vertigo with normal initial investigations. Following recurrent vertigo, headache, and ataxia, imaging revealed a frontoparietal SAH and vertebral artery dissection. The patient was consequently treated with aspirin, and then following a return of symptoms 3 weeks later, warfarin therapy was continued for 6 months. The possible underlying mechanisms for this case are discussed, including reversible cervical vasoconstriction syndrome and posterior reversible encephalopathy syndrome, although neither was identified. The small SAH alongside recurrent posterior circulation symptoms resulted in the initiation of antithrombotic therapy. This report supports studies demonstrating higher incidence of cervicocephalic arterial dissection in the puerperium. Moreover, the heterogeneous presentation and manifestations of such cases require individualized treatment, and warrant studies into underlying mechanisms behind extracranial dissection and nonaneurysmal SAH., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

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.

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., (© 2014 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

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.

Background: Vasospasm is an important complication observed after subarachnoid hemorrhage (SAH) and is a frequent cause of mortality and morbidity. We present our routine management of vasospasm after SAH and emphasize the importance of transcranial Doppler (TCD) ultrasonography in this management., Method: Historical records and images were sampled from June 2005 to September 2011 for 110 patients with SAH due to ruptured aneurysm in the anterior circulation. All surviving patients were followed after discharge. Vasospasm was defined as mild (Lindegaard index 3-4), moderate (Lindegaard index 4-5), and severe (Lindegaard index greater than 5). We excluded patients treated after 72 h of symptom onset. TCD was performed twice per day., Findings: Ninety-nine patients had surgical clipping of the aneurysm, and 11 had endovascular treatment. Seventy patients treated by clipping and six treated by endovascular procedure had vasospasm. Of the 70 clipped patients with vasospasm, 40 had mild vasospasm, 13 had moderate vasospasm, and 17 had severe vasospasm. All six patients treated by coils had moderate vasospasm. The average duration of vasospasm was 9 days (from 7 to 32 days)., Conclusions: TCD was crucial for monitoring patients with SAH, and to identify which patients will have a higher risk of developing vasospasm.

Background: Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major cause of morbidity and mortality. We studied the effects of clot removal on multiple outcome variables following the clipping of ruptured anterior communicating aneurysms., Methods: From 2007 to 2011, 30 patients with Fisher grade III aneurysmal SAH underwent clipping of an anterior communicating artery aneurysm before SAH day 3. There were 20 women and 10 men, mean age 53.4, range 28-80 years. Seventeen underwent fenestration of lamina terminalis and cisternal removal of clots (group A), and 13 did not (Group B). We compared clinical grades, presence of hydrocephalus at admission, treatment modality, occurrence of clinical vasospasm, the need for interventional vasospasm therapy, and need for ventriculoperitoneal shunting., Findings: Vasospasm affected 5 of 17 (29%) in group A and 8 of 13 (61.5%) in group B (p < 0.05). Endovascular treatment for vasospasm was required in one patient in group A (5.8% of 17, 20% of 5) and in five from group B (38.4% of 13, 62.5% of 8) (p < 0.05). Mortality was observed in one case in group A (5.8% of 17, 20% of 5) and in two cases in group B (15.3% of 13, 25% of 8) and was related to vasospasm after SAH. Ventriculoperitonal shunt (VPS) was required in one case in group A (5.8%) and in five cases in group B (38.4%)., Conclusions: Fenestration of the lamina terminalis and removal of cisternal clots significantly decreased the incidence of post-SAH hydrocephalus and was associated with better outcomes in our series.

Thirty men having Parkinsons disease (PD) and 30 controls were studied prospectively by the use of the International Index of Erectile Function (IIEF) to assess erectile dysfunction (ED). Of the patients with PD (mean age of 59 years), 46.66% referred to the practice of sexual activity. All of the parkinsonians were using antiparkinsonian medication. In the control group (mean age of 63 years), 76.66% referred to the practice of sexual activity, 46.60% to arterial hypertension and 6.66% to diabetes mellitus. The median score for the PD group according to the IIEF was 34, and that for the controls 50. The main differences between the two groups were in the erectile function, orgasmic function and satisfaction with the sexual relationship. The IIEF is a multidimensional scale widely accepted to assess the ED. The data obtained suggest that ED is more frequent among parkinsonians and points out to the role of DP in the genesis of ED.