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Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative genetic disease that affects children in early life. Its classic form is rapidly progressive, leading to death within the first 10 years. The urge for earlier diagnosis increases with the availability of enzyme replacement therapy. A panel of nine Brazilian child neurologists combined their expertise in CLN2 with evidence from the medical literature to establish a consensus to manage this disease in Brazil. They voted 92 questions including diagnosis, clinical manifestations, and treatment of the disease, considering the access to healthcare in this country. Clinicians should suspect CLN2 disease in any child, from 2 to 4 years old, with language delay and epilepsy. Even though the classic form is the most prevalent, atypical cases with different phenotypes can be found. Electroencephalogram, magnetic resonance imaging, molecular and biochemical testing are the main tools to investigateand confirm the diagnosis. However, we have limited access to molecular testing in Brazil, and rely on the support from the pharmaceutical industry. The management of CLN2 should involve a multidisciplinary team and focus on the quality of life of patients and on family support. Enzyme replacement therapy with Cerliponase α is an innovative treatment approved in Brazil since 2018; it delays functional decline and provides quality of life. Given the difficulties for the diagnosis and treatment of rare diseases in our public health system, the early diagnosis of CLN2 needs improvement as enzyme replacement therapy is available and modifies the prognosis of patients. Resumo Lipofuscinose ceróide neuronal (CLN2) é uma doença genética neurodegenerativa rara que afeta crianças nos primeiros anos de vida. A sua forma clássica é rapidamente progressiva, levando à morte nos primeiros 10 anos. A necessidade de um diagnóstico precoce aumenta com a disponibilidade do tratamento de terapia enzimática. Um painel de nove neurologistas infantis brasileiros combinou sua experiência em CLN2 com evidências da literatura médica para estabelecer um consenso no manejo desta doença no Brasil. Eles votaram 92 questões abordando diagnóstico, manifestações clínicas e tratamento, considerando o acesso à saúde no Brasil. Deve-se suspeitar de CLN2 em qualquer criança de 2 a 4 anos de idade que apresente atraso de linguagem e epilepsia. Apesar da forma clássica ser a mais prevalente, podem ser encontrados casos atípicos com diferentes fenótipos. Eletroencefalograma, ressonância magnética, testes moleculares e bioquímicos são as principais ferramentas para investigar e confirmar o diagnóstico. No entanto, o acesso aos testes moleculares é limitado no Brasil, necessitando contar com o apoio da indústria farmacêutica. O manejo da CLN2 deve envolver uma equipe multidisciplinar e focar na qualidade de vida dos pacientes e no apoio familiar. A terapia de reposição enzimática com Cerliponase alfa é um tratamento inovador aprovado no Brasil desde 2018; ele retarda o declínio funcional e proporciona qualidade de vida. Diante das dificuldades para o diagnóstico e tratamento de doenças raras em nosso sistema público de saúde, o diagnóstico precoce de CLN2 precisa de melhorias pois a terapia de reposição enzimática está disponível e modifica o prognóstico dos pacientes.

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Neuroimaging and neurophysiology techniques can add a significant contribution to the comprehension of infantile spasms (IS) and hypsarrhythmia. Functional MRI and magnetoencephalography (MEG) are two noninvasive tools that can be used in young children with IS. In the past two decades, interesting data about IS have emerged from functional MRI and MEG studies. Regarding their clinical utility, MEG has supported the concept that epileptic spasms can have a focal origin. Moreover, MEG might contribute to the localization of the epileptogenic zone in children with IS under investigation for epilepsy surgery. Functional MRI data have contributed to improve the knowledge about the physiopathology of IS and hypsarrhythmia. It has demonstrated abnormal brainstem involvement during the high-amplitude slow waves of hypsarrhythmia and cortical involvement during the epileptiform discharges. Since the feasibility of these techniques has been demonstrated in infants, it is possible that, in the future, larger functional MRI and MEG studies might contribute to the treatment and the definition of the long-term prognosis of children with IS.

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the “genetic generalized epilepsies” (GGEs), which contained the “idiopathic generalized epilepsies” (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE’s Task Force on Nosology and Definitions (2017–2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic‐clonic and myoclonic‐tonic‐clonic seizures, with 2.5–5.5 Hz generalized spike‐wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

OBJECTIVE Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.

Background: Neuropsychiatric disorders are a significant cause of death and disability worldwide. The mechanisms underlying these disorders include a constellation of structural, infectious, immunological, metabolic, and genetic etiologies. Advances in next-generation sequencing techniques have demonstrated that the composition of the enteric microbiome is dynamic and plays a pivotal role in host homeostasis and several diseases. The enteric microbiome acts as a key mediator in neuronal signaling via metabolic, neuroimmune, and neuroendocrine pathways. Objective: In this review, we aim to present and discuss the most current knowledge regarding the putative influence of the gut microbiome in neuropsychiatric disorders. Methods: We examined some of the preclinical and clinical evidence and therapeutic strategies associated with the manipulation of the gut microbiome. Results: targeted taxa were described and grouped from major studies to each disease. Conclusions: Understanding the complexity of these ecological interactions and their association with susceptibility and progression of acute and chronic disorders could lead to novel diagnostic biomarkers based on molecular targets. Moreover, research on the microbiome can also improve some emerging treatment choices, such as fecal transplantation, personalized probiotics, and dietary interventions, which could be used to reduce the impact of specific neuropsychiatric disorders. We expect that this knowledge will help physicians caring for patients with neuropsychiatric disorders. RESUMO Antecedentes: Os transtornos neuropsiquiátricos são uma importante causa de morte e invalidez no mundo. Os mecanismos subjacentes a esses transtornos incluem uma constelação de etiologias estruturais, infecciosas, imunológicas, metabólicas e genéticas. Avanços nas técnicas de sequenciamento do DNA têm demonstrado que a composição do microbioma entérico é dinâmica e desempenha um papel fundamental não apenas na homeostase do hospedeiro, mas também em várias doenças. O microbioma entérico atua como mediador na sinalização das vias metabólica, neuroimune e neuroendócrina. Objetivo: Apresentar os estudos mais recentes sobre a possível influência do microbioma intestinal nas diversas doenças neuropsiquiátricas e discutir tanto os resultados quanto a eficácia dos tratamentos que envolvem a manipulação do microbioma intestinal. Métodos: foram examinadas algumas das evidências pré-clínicas e clínicas e estratégias terapêuticas associadas à manipulação do microbioma intestinal. Resultados: os táxons-alvo foram descritos e agrupados a partir dos principais estudos para cada doença. Conclusões: Entender a fundo a complexidade das interações ecológicas no intestino e sua associação com a suscetibilidade a certas doenças agudas e crônicas pode levar ao desenvolvimento de novos biomarcadores diagnósticos com base em alvos moleculares. Além disso, o estudo do microbioma intestinal pode auxiliar na otimização de tratamentos não farmacológicos emergentes, tais como o transplante de microbiota fecal, o uso de probióticos e intervenções nutricionais personalizadas. Dessa forma, terapias alternativas poderiam ser usadas para reduzir o impacto dos transtornos neuropsiquiátricos na saúde pública. Esperamos que esse conhecimento seja útil para médicos que cuidam de pacientes com diversos transtornos neuropsiquiátricos.

Background: The best therapeutic approach to asymptomatic carotid stenosis (ACS) is still subject to discussion. Previous studies have agreed on the findings that ACS patients present with cerebral atrophy and cognitive decline compared to healthy controls. The present study aims to identify possible alterations in the brain functional network of such patients. Objectives: Study alternations in the connectivity of the Default Mode Network (DNM) in patients with ACS of at least 70%, compared to controls. Design and Setting: A cross-sectional case-control study was carried out at the Neuroimaging Laboratory at Hospital das Clínicas, Universidade Estadual de Campinas (UNICAMP) - Campinas, São Paulo (Brazil). Methods: Two groups of 15 individuals matched by sex and age, the first composed ACS patients with stenosis and the second of healthy volunteers, were submitted to 3 Tesla magnetic resonance imaging. The images were analyzed using Statistical Parametric Mapping 12 and UF2C User Friendly Functional Connectivity Toolbox software. All patients signed the Informed Consent Form. Results: ACS patients were 13 men and 2 women with an average age of 72 years. Regarding DMN connectivity, the control presented higher activity, particularly in the medial segment of the superior frontal gyrus. Conclusion: ACS patients with stenosis higher than 70% displayed prejudiced cerebral connectivity compared to healthy controls.

Objectives: To evaluate the spatial distribution of the epileptiform activity in electrical status epilepticus in sleep (ESES) and to correlate data from electroencephalograms (EEGs) with clinical and neuroimaging variables. Methods: From 2008 to 2015, 162 reports (1.01%) out of 16,000 EEGs, from 23 patients, showed ESES. We selected one representative EEG per patient. Clinical data was collected retrospectively. Neuroimaging examinations were reviewed. The EEGs were classified as generalized ESES (ESESg) and focal ESES (ESESf) according to the distribution of epileptiform discharges. Results: From the 23 patients, 5 were classified as ESESg and 18 as ESESf. In ESESf, there was a prevalence of focal epileptic discharges in the centrotemporal regions. Abnormal neuroimaging occurred in 100% of the patients with ESESg and in 38.9% of the patients with ESESf (p=0.037). Other clinical data did not show significant differences between the groups. All patients with ESESg had structural etiology, while only 39% of patients with ESESf had structural etiology and the remaining 61% potentially genetic epilepsies of the rolandic spectrum. Conclusion: ESESg occurred predominantly in patients with structural lesions, while most patients with ESESf had normal neuroimaging scans and electrical dysfunction mainly in the rolandic region. Significance: ESESg seems to occur mostly in structural epilepsies. Distinctly, ESESf occurs in epileptic syndromes within the functional spectrum of rolandic epilepsy.

To investigate the role of TYRO3, AXL and TIM1 receptors in the Zika virus (ZIKV) cycle, we determined their mRNA expression in different placental sites of ZIKV infected tissue during pregnancy. Unexpectedly, the ZIKV infection was not related with mRNA upregulation of these receptors or changes in expression of type I and III interferons in different placental sites. Instead, a decrease of TYRO3 mRNA expression was observed in positive sites of ZIKV positive placentas in comparison to negative sites. The basis of this downregulation can help to understand how ZIKV persists in placental tissue during pregnancy.

Executive deficits and impulsiveness are extensively reported in juvenile myoclonic epilepsy (JME). Previous literature suggests that intelligence may mediate these deficits. In this study, we evaluated and compared the performance of adults with JME with high and low intelligence quotient (IQ) and controls on tasks for executive function (EF) and impulsive traits. We investigated the neuropsychological performance of 53 adults with JME and below average IQ (57% women; 26.9 [± 7.88] years; mean IQ: 89.8 [± 5.1]), 26 adults with JME and average or above average IQ (53.8% women; 28.2 [± 9.33] years; mean IQ: 110.7 [± 8.3]), 38 controls with below average IQ (55% women; 28.4 [± 8.4] years; mean IQ: 90.1 [± 5.8]), and 31 controls with average or above average IQ (61.3% women; 32.20 [± 11.3] years; mean IQ: 111.6 [± 10.5]) with a comprehensive battery of neuropsychological tests that measure executive/attentional function. Impulsive traits were assessed using the Cloninger et al.'s Temperament and Character Inventory (novelty seeking (NS) domain). The group with JME with higher IQ presented worse performance compared with controls with higher IQ on Controlled Oral Word Association (COWA) and Wisconsin Card Sorting Test (WCST) (errors). This group showed worse performance than controls with lower IQ on Stroop Color–Word Test (SCT) 1, Trail Making (TM) A, COWA, and WCST (errors). Patients with lower IQ showed worse performance than controls with higher IQ on Digit Span Forward (DSF), Digit Span Backward (DSB), SCT1, SCT2, SCT3, TM A, COWA, and WCST (errors and failure to maintain set). Patients with lower IQ showed worse performance than controls with lower IQ on DSF, DSB, SCT1, SCT2, SCT3, TM A, TM B, COWA, and WCST (errors and failure to maintain set). Patients from groups with low and high IQ showed higher scores than controls with higher and lower IQ on impulsivity for NS1 and NS2 (except for patients with higher IQ versus controls with lower IQ). Adults with JME and higher IQ show less evidence of EF deficits compared with those with JME and below average IQ, suggesting that a higher degree of intellectual efficiency may act as a compensatory mechanism. However, it does not minimize some aspects of impulsive traits. Patients with JME and higher cognitive reserve may create strategies to dodge their cognitive obstacles. In this context, intelligence may protect and, at the same time, “mask” impairments that could be detected earlier.

Background: Paroxysmal fast activity (PFA) is defined by fast paroxysmal events in the electroencephalogram (EEG), usually associated with Lennox-Gastaut syndrome (LGS). Our aims were to verify the frequency of LGS and non-LGS in EEGs with PFA; and to correlate the EEG features (spatial distribution, frequency, amplitude and duration) between the two clinical groups. Methods: We analyzed 38 EEG tracings with PFA from 38 patients. We evaluated the spatial distribution, frequency, amplitude and duration of fast paroxysms. The two clinical groups (LGS and non-LGS) were statistically compared relative to the EEG data. Results: With regard to epileptic syndromes, 23 patients (60%) were classified as LGS and 15 patients (40%) as non-LGS. Concerning spatial distribution, our results showed that 86.8% of the examinations showed symmetrical PFA and 13.2% showed asymmetrical PFA. The statistical analysis did not show any difference between the two groups regarding the EEG spatial distribution or other EEG data. Conclusions: PFA can occur in other epileptic syndromes apart from LGS. The EEG features did not offer any distinction between the two clinical groups. The PFA is not a specific EEG marker of LGS.

Focal cortical dysplasia (FCD) is a malformation of cortical development and a common cause of pharmacoresistant epilepsy. Resective surgery of clear-cut lesions may be curative. However, the localization of the seizure focus and the evaluation of its spatial extent can be challenging in many situations. For concordance assessment, medical studies show the relevance of accurate correlation of multisource imaging sequences. to improve the sensitivity and specificity of the evaluation. In this paper, we share the process we went through to reach our simple, but effective, solution for integrating multi-volume rendering into an exploratory visualization environment for the diagnosis of FCD. We focus on fetching of multiple data assigned to a sample when they are rendered. Knowing that the major diagnostic role of multiple volumes is to complement information, we demonstrate that appropriate geometric transformations in the texture space are sufficient for accomplishing this task. This allows us to fully implement our proposal in the OpenGL rendering pipeline and to easily integrate it into the existing visual diagnostic application. Both time performance and the visual quality of our proposal were evaluated with a set of clinical data volumes for assessing the potential practical impact of our solution in routine diagnostic use.

OBJECTIVE Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II. METHODS We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study. RESULTS hsa-let-7f (p = 0.039), hsa-miR-31 (p = 0.0078), and hsa-miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p

Background: Atrial fibrillation (AF) is a widely accepted risk for causing stroke. However, recent studies show AF as a risk factor for dementia, even without causing stroke. The mechanisms by which dementia develops in stroke-free patients with AF are still poorly understood and the association of AF with abnormal function of brain networks activities, such as the default mode network (DMN), has not been previously studied. We aimed to determine whether, in the absence of stroke and dementia, patients with AF have abnormal resting-state brain networks compared to controls without AF. Methods: Twenty-one stroke-free patients with AF and 21 age- and sex-matched controls without AF underwent brain functional magnetic resonance imaging acquired at a 3.0 Tesla scanner. During the exam, the subjects were instructed to lie still with eyes closed. At first-level analysis, connectivity of the DMN was obtained for all subjects. Second-level analysis compared the DMN connectivity between AF patients and controls with a general linear model (two-sample t test, p < 0.05, False Discovery Rate corrected, minimum of 50 contiguous voxels). Results: Patients with AF compared with controls showed decreased connectivity in regions of the DMN including the frontal lobe (left medial frontal gyrus, left superior frontal gyrus and anterior cingulate), left angular gyrus, and bilateral precuneus. Conclusions: Stroke-free patients with AF have evidence of abnormal DMN connectivity. This study adds evidence to the occurrence of cerebral dysfunction in patients with AF.

SummaryObjective To investigate whether mood disorders (MD) and anxiety disorders (AD) are associated with seizure control in patients with mesial temporal lobe epilepsy (MTLE). We compared patients without any current psychiatric disorder, patients with current MD and/or AD, patients with subsyndromic depression episodes (SSDE) and anxiety episodes (SSAE), and patients with family psychiatric history. Methods In a cross-sectional study, we included 144 consecutive patients with MTLE (82 pharmacoresistant and 62 treatment-responsive patients). Every patient underwent a psychiatric evaluation including the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Axis I (SCID-I), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), and Interictal Dysphoric Disorder Inventory (IDDI). Patients were divided into four groups: PsychNeg (G1, n = 61), current SSDE and SSAE (G2, n = 26), Current MD or AD (G3, n = 25), and current mixed MD/AD (G4, n = 32). Results Among patients with pharmacoresistant MTLE, 68.3% (56/82) experienced symptoms of depression and/or anxiety (G2, G3, and G4) (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.41–5.53, p < 0.01). Patients with mixed MD/AD (G4, n = 24/32) were more likely to have pharmacoresistant MTLE (OR 4.04, 95% CI 1.57–10.42, p < 0.01) than psychiatric asymptomatic patients (G1, n = 26/61), and their seizure frequency was significantly higher (p < 0.01). Positive family psychiatric history was more frequent in pharmacoresistant patients (n = 27/82, OR 2.28, 95% CI 1.02–5.05, p = 0.04). Finally, 31.6% of patients with MD and or AD were not receiving psychiatric treatment. Significance Identification of comorbid MD/AD and of family psychiatric history is of the essence in patients with MTLE, as they appear to be associated with worse seizure control.

Summary Objective Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED‐naive patients with GGE at disease onset. We hypothesize that drug‐naive patients at disease onset have gray matter changes compared to age‐matched healthy controls. Methods We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED‐naive patients with new‐onset GGE and compared them to 32 age‐matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. Results The thalamus was the only structure to show reduced gray matter volume in AED‐naive patients with new‐onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. Significance Structural abnormalities in the thalamus are present at the initial onset of GGE in AED‐naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.

Objective: We aimed to improve the classification of SCN1A missense variants in patients with Dravet syndrome (DS) by combining and modifying the current variants classification criteria to minimize inconclusive test results. Methods: We established a score classification workflow based on evidence of pathogenicity to adapt the classification of DS-related SCN1A missense variants. In addition, we compiled the variants reported in the literature and our cohort and assessed the proposed pathogenic classification criteria. We combined information regarding previously established pathogenic amino acid changes, mode of inheritance, population-specific allele frequencies, localization within protein domains, and deleterious effect prediction analysis. Results: Our meta-analysis showed that 46% (506/1,101) of DS-associated SCN1A variants are missense. We applied the score classification workflow and 56.5% (286/506) of the variants had their classification changed from VUS: 17.8% (90/506) into “pathogenic” and 38.7% (196/506) as “likely pathogenic.” Conclusion: Our results indicate that using multimodal analysis seems to be the best approach to interpret the pathogenic impact of SCN1A missense changes for the molecular diagnosis of patients with DS. By applying the proposed workflow, most DS related SCN1A variants had their classification improved.

This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/175, 46%), with statistical significance (p < 0.0001). Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.52) between treatments with CBD-rich extracts (122/330, 37%) and purified CBD (94/223, 42%). Patients treated with CBD-rich extracts reported lower average dose (6.0 mg/kg/day) than those using purified CBD (25.3 mg/kg/day). The reports of mild (158/216, 76% vs. 148/447, 33%, p < 0.001) and severe (41/155, 26% vs. 23/328, 7%, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.

Mesial temporal lobe epilepsy (MTLE) with hippocampus sclerosis (HS) is associated with functional and structural alterations extending beyond the temporal regions and abnormal pattern of brain resting state networks (RSNs) connectivity. We hypothesized that the interaction of large‐scale RSNs is differently affected in patients with right‐ and left‐MTLE with HS compared to controls. We aimed to determine and characterize these alterations through the analysis of 12 RSNs, functionally parceled in 70 regions of interest (ROIs), from resting‐state functional‐MRIs of 99 subjects (52 controls, 26 right‐ and 21 left‐MTLE patients with HS). Image preprocessing and statistical analysis were performed using UF2C‐toolbox, which provided ROI‐wise results for intranetwork and internetwork connectivity. Intranetwork abnormalities were observed in the dorsal default mode network (DMN) in both groups of patients and in the posterior salience network in right‐MTLE. Both groups showed abnormal correlation between the dorsal‐DMN and the posterior salience, as well as between the dorsal‐DMN and the executive‐control network. Patients with left‐MTLE also showed reduced correlation between the dorsal‐DMN and visuospatial network and increased correlation between bilateral thalamus and the posterior salience network. The ipsilateral hippocampus stood out as a central area of abnormalities. Alterations on left‐MTLE expressed a low cluster coefficient, whereas the altered connections on right‐MTLE showed low cluster coefficient in the DMN but high in the posterior salience regions. Both right‐ and left‐MTLE patients with HS have widespread abnormal interactions of large‐scale brain networks; however, all parameters evaluated indicate that left‐MTLE has a more intricate bihemispheric dysfunction compared to right‐MTLE. Hum Brain Mapp 37:3137–3152, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

SummaryObjectives To investigate the presence and progression of gray matter (GM) reduction in seizure-free patients with temporal lobe epilepsy (TLE). Methods We enrolled 39 consecutive TLE patients, seizure-free for at least 2 years—20 with magnetic resonance imaging (MRI) signs of hippocampal sclerosis (TLE-HS), 19 with normal MRI (TLE-NL), and 74 healthy controls. For longitudinal analysis, we included individuals who had a second MRI with minimum interval of 18 months: 21 patients (10 TLE-HS, 11 TLE-NL) and 11 controls. Three-dimensional (3D) T1-weighted images acquired in 3 Tesla MRI were analyzed with voxel-based morphometry (VBM). The images of patients with right-sided interictal epileptogenic zone (EZ) were right–left flipped, as well as a comparable proportion of controls. Cross-sectional analysis: The patients' images from each group were compared to controls to investigate differences in GM volumes. Longitudinal analysis: The first and second images were compared in each group to look for decreased GM volume. Results Cross-sectional analysis: Patients with TLE-HS had diffuse GM atrophy, including hippocampus and parahippocampal gyrus, insula, frontal, and occipital lobes ipsilateral to EZ, bilateral thalamus and contralateral orbitofrontal gyrus, and caudate. In contrast, TLE-NL group did not present significant differences compared to controls. Longitudinal analysis: TLE-HS presented progressive GM reduction in ipsilateral insula and occipital lobe, contralateral motor area, and bilateral temporal and frontal lobes. TLE-NL had GM progression in ipsilateral hypothalamus and parietal lobe, contralateral cerebellum, and bilateral temporal lobe. Controls did not show changes in GM volume between MRIs. Significance Diffuse extrahippocampal GM atrophy is present in seizure-free patients with TLE-HS. In addition, there is progressive GM atrophy in patients with and without HS. These results demonstrate that not only ongoing seizures are involved in the progression of GM atrophy. An underlying pathologic mechanism could be responsible for progressive brain volume loss in TLE patients even in seizure-free periods.

Introduction Patients with juvenile myoclonic epilepsy (JME) have executive dysfunction and impulsive traits. There are lines of evidence that JME is a heterogeneous epilepsy syndrome considering outcome. In this study, we aimed to analyze this heterogeneity beyond seizure control. The objective was to identify whether the pattern of cognitive dysfunction and impulse control is also heterogeneous, in an attempt to establish possible differences in patients with easy- and hard-to-control epilepsies. Methods Essentially, 57 patients with JME were compared with 44 controls. Patients and controls were assessed with a neuropsychological battery for executive, attention, and memory functions. The expression of impulsive traits was evaluated with the Temperament and Character Inventory — novelty seeking domain. Then, patients were categorized according to seizure control as having easy- and hard-to-control JME. Results Patients with hard-to-control JME showed worse performance in 12 out of 25 neuropsychological tests than those with easy-to-control JME. Patients with hard-to-control JME also demonstrated significantly higher scores in novelty seeking — subfactor impulsiveness (p = 0.002). Significance Our study demonstrated the existence of distinct or more severe cognitive and psychiatric profiles in a subset of patients with JME. Patients with treatment-refractory seizures seem to present a broader impairment related to both cognitive deficits and impulsive traits. These findings suggest that patients with JME are not equally compromised by executive and memory deficits or dysfunction, neither by their impulsive traits. Thus, there is a need for a better characterization of patients with JME to include diverse phenotypes since our results suggest a possible existence of distinct groups of patients with JME.

Summary Objective Although altered large-scale brain network organization in patients with temporal lobe epilepsy (TLE) has been shown using morphologic measurements such as cortical thickness, these studies, have not included critical subcortical structures (such as hippocampus and amygdala) and have had relatively small sample sizes. Here, we investigated differences in topological organization of the brain volumetric networks between patients with right TLE (RTLE) and left TLE (LTLE) with unilateral hippocampal atrophy. Methods We performed a cross-sectional analysis of 86 LTLE patients, 70 RTLE patients, and 116 controls. RTLE and LTLE groups were balanced for gender (p = 0.64), seizure frequency (Mann-Whitney U test, p = 0.94), age (p = 0.39), age of seizure onset (p = 0.21), and duration of disease (p = 0.69). Brain networks were constructed by thresholding correlation matrices of volumes from 80 cortical/subcortical regions (parcellated with Freesurfer v5.3 https://surfer.nmr.mgh.harvard.edu/) that were then analyzed using graph theoretical approaches. Results We identified reduced cortical/subcortical connectivity including bilateral hippocampus in both TLE groups, with the most significant interregional correlation increases occurring within the limbic system in LTLE and contralateral hemisphere in RTLE. Both TLE groups demonstrated less optimal topological organization, with decreased global efficiency and increased local efficiency and clustering coefficient. LTLE also displayed a more pronounced network disruption. Contrary to controls, hub nodes in both TLE groups were not distributed across whole brain, but rather found primarily in the paralimbic/limbic and temporal association cortices. Regions with increased centrality were concentrated in occipital lobes for LTLE and contralateral limbic/temporal areas for RTLE. Significance These findings provide first evidence of altered topological organization of the whole brain volumetric network in TLE, with disruption of the coordinated patterns of cortical/subcortical morphology.

Objective To compare surgical outcome in mesial temporal lobe epilepsy (MTLE) patients with unilateral hippocampal sclerosis (MTLE-HS) who had or did not have preoperative video-electroencephalographic monitoring (VEEG). Methods A prospective study was undertaken with 166 consecutive pharmacoresistant unilateral MTLE-HS patients. All patients were investigated with detailed seizure semiology, serial routine outpatient EEG, magnetic resonance imaging, neuropsychological evaluation, and if necessary, other examinations. Postoperative follow-up ranged between 2 and 16 years. Patients were divided into: (1) patients operated on based on routine outpatient EEG information, with >80% of EEGs with unilateral interictal epileptiform discharges (IEDs) ipsilateral to HS or ictal events (n = 71); and (2) patients submitted to preoperative VEEG (n = 95). To avoid the bias generated by ictal recordings, we performed a subanalysis of: (1) patients without preoperatively ictal recordings (n = 80) and (2) patients with ictal recordings in VEEG or routine outpatient EEG (n = 86). Results Groups were similar regarding gender, age at surgery, seizure onset, preoperative seizure frequency, and duration of follow-up. Overall, 136/166 (81.92%) were classified as Engel I seizure outcome, with no difference between groups; 76.84% and 88.73% of patients with and without VEEG, respectively, had Engel I postoperative seizure outcome (P = .77). The time lag until surgery was shorter in the group without VEEG (80 vs 38 months; P = .01). Considering ictal recordings, 76.74% of patients with seizures recorded and 87.50% without ictal recordings had Engel I outcome (P = .11). Significance We performed the first prospective study in a tertiary epilepsy center comparing surgical outcomes in unilateral MTLE-HS patients investigated preoperatively with and without VEEG. Based on the surgical outcome, VEEG is not imperative in patients with unilateral MTLE-HS who have compatible semiology and clearly ipsilateralized IEDs evaluated by a multidisciplinary and experienced epilepsy group.