Comorbidities in Dravet Syndrome and Lennox–Gastaut Syndrome

AbstractThis study aims to describe the main cognitive and behavioral comorbidities of Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS), their impact on the health-related quality of life (QOL) of patients and their caregivers, and provide a summary of the neuropsychological tools available for the evaluation of these comorbidities. The cognitive and behavioral comorbidities in patients with DS and LGS have a profound effect on the QOL of affected individuals and their caregivers and, as patients grow, tend to surpass the impact of the seizures. DS is a genetic condition associated with loss-of-function mutations in the SCNA1 sodium channel gene; LGS is an etiologically heterogeneous condition that is often secondary to structural brain abnormalities. The first seizures associated with DS typically present in the first year of life, and developmental delay becomes progressively evident thereafter. LGS usually starts between the ages of 3 and 8 years, with cognitive impairment becoming clinically evident in most patients within 5 years from the onset. In both DS and LGS, cognitive impairment is generally moderate to severe and is often accompanied by behavioral problems such as hyperactivity and inattention. In addition to optimal seizure control, regular assessment and active management of cognitive and behavioral comorbidities are required to meet the complex needs of patients with DS or LGS

West syndrome in three patients with brain injury and a benign course

Infants with West Syndrome and underlying structural pathology typically experience persistent symptomatic focal seizures and intellectual disability. We performed a retrospective case review of 84 patients with West Syndrome evaluated at one institution between 1990 and 2013. From this group we identified three patients with West syndrome and congenital hemiplegia who later developed genetic epilepsy features and had normal intellectual development. This outcome is highly unusual and raises important questions about the relationship and possible influence of genetic epilepsy in patients with pre-existent West Syndrome and brain injury

Extrastriate visual cortex in idiopathic occipital epilepsies: The contribution of retinotopic areas to spike generation

none14noOBJECTIVES: To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity. METHODS: Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables. RESULTS: The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex. SIGNIFICANCE: Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.Meletti, Stefano; Ruggieri, Andrea; Avanzini, Pietro; Caramaschi, Elisa; Filippini, Melissa; Bergonzini, Patrizia; Monti, Giulia; Vignoli, Aglaia; Olivotto, Sara; Mastrangelo, Massimo; Santucci, Margherita; Gobbi, Giuseppe; Veggiotti, Pierangelo; Vaudano, Anna ElisabettaMeletti, Stefano; Ruggieri, Andrea; Avanzini, Pietro; Caramaschi, Elisa; Filippini, Melissa; Bergonzini, Patrizia; Monti, Giulia; Vignoli, Aglaia; Olivotto, Sara; Mastrangelo, Massimo; Santucci, Margherita; Gobbi, Giuseppe; Veggiotti, Pierangelo; Vaudano, Anna Elisabett

Molecular Basis for the Sorting of the SNARE VAMP7 into Endocytic Clathrin-Coated Vesicles by the ArfGAP Hrb

SNAREs provide the specificity and energy for the fusion of vesicles with their target membrane, but how they are sorted into the appropriate vesicles on post-Golgi trafficking pathways is largely unknown. We demonstrate that the clathrin-mediated endocytosis of the SNARE VAMP7 is directly mediated by Hrb, a clathrin adaptor and ArfGAP. Hrb wraps 20 residues of its unstructured C-terminal tail around the folded VAMP7 longin domain, demonstrating that unstructured regions of clathrin adaptors can select cargo. Disrupting this interaction by mutation of the VAMP7 longin domain or depletion of Hrb causes VAMP7 to accumulate on the cell's surface. However, the SNARE helix of VAMP7 binds back onto its longin domain, outcompeting Hrb for binding to the same groove and suggesting that Hrb-mediated endocytosis of VAMP7 occurs only when VAMP7 is incorporated into a cis-SNARE complex. These results elucidate the mechanism of retrieval of a postfusion SNARE complex in clathrin-coated vesicles

Safety of abatacept in rheumatoid arthritis with serological evidence of past or present hepatitis B virus infection.

OBJECTIVE: Rheumatoid arthritis (RA) with concomitant hepatitis B virus (HBV) infection represents a therapeutic challenge due to the risk of HBV reactivation under immunosuppressive treatment. To date there are few data concerning the HBV reactivation following treatment with abatacept coming from anecdotal case reports. This observational retrospective study was aimed to assess the safety profile of abatacept in this particular clinical setting. METHODS: Eleven Italian rheumatologic centres provided data from patients with RA and positive HBV serology treated with intravenously abatacept. HBV markers, clinical and laboratory data were checked at follow up visits every 3 months. RESULTS: In total 72 patients were included in the study, 47 inactive carrier, 21 occult carries and 4 chronic active carriers for HBV. At baseline all of the patients had normal liver function tests and low or undetectable HBV DNA levels except for those with chronic active hepatitis. 13 patients received prophylaxis with lamivudine and 4 treatment with adefovir or tenofovir. At the end of 24 months period of follow up, 49 patients were being treated. Data from 316 follow up visits showed that abatacept was safe. No patients experienced reactivation of hepatitis B. Treatment withdrawals (23 patients) were due to lack of efficacy, subject decision/lost at follow up or adverse events not related to HBV infection. CONCLUSIONS: Our study provides reassuring data about the safety profile of abatacept in RA with concomitant HBV infection also without universal antiviral prophilaxys. Further prospective studies are needed to confirm these preliminary results. This article is protected by copyright. All rights reserved