关键词： Cerebral amyloid angiopathy   Amyloid spells   Intracerebral hemorrhage   Cortical superficial siderosis   Microbleeds  

摘要： Background: Transient focal neurological episodes (TFNEs) are a recently recognized clinical presentation of cerebral amyloid angiopathy (CAA). Our aim was to describe the clinical and radiological features of a series of patients with AS. Methods: We included 11 patients presenting with recurrent transient focal neurological symptoms and radiological features related to CAA. Results: Mean age was 76,6 and 5 patients were women. All patients reported transient, stereotyped, and recurrent episodes (6 patients had > 10 episodes). Gradual spread of the symptoms was recorded in 9 patients. Initially, 3 patients were misdiagnosed as having recurrent transient ischemic attack (TIA), 6 as having seizures, and 2 as having both. Two patients were prescribed antiplatelet therapy. A cerebral MRI with T2* gradient-recalled echo sequence revealed cortical superficial siderosis (cSS) in 5 patients, cortical microbleeds in 1 patient, and both features in 5 cases. After a median follow-up of 36 months, intracranial hemorrhage (ICH) was recorded in 4 patients. All 4 had cSS in the previous cerebral MRI, and 1 was on antiplatelet therapy. Conclusion: CAA-related TFNEs are an underdiagnosed entity, often mimicking TIA, seizures, or migraine aura. This misdiagnosis can lead to the prescription of antiplatelet or anticoagulant therapy, which increases the risk of ICH. Our results suggest that cSS might be a radiological marker that is closely related to an increased risk of bleeding. A T2* gradient-recalled echo MRI should be performed in elderly patients with transient focal neurological symptoms suggestive of CAA.

关键词： Cerebral amyloid angiopathy   Cortical superficial siderosis   TIA   Cerebral microbleeds  

关键词： CRISPR-Cas9   Functional genetics   sgRNA   CRISIPR KO   CRISPRi   CRISPRa   Neurological diseases   Neurodegenerative diseases   Survival screens   Marker selection screens  

摘要： The adoption of CRISPR-Cas9 technology for functional genetic screens has been a transformative advance. Due to its modular nature, this technology can be customized to address a myriad of questions. To date, pooled, genome-scale studies have uncovered genes responsible for survival, proliferation, drug resistance, viral susceptibility, and many other functions. The technology has even been applied to the functional interrogation of the non-coding genome. However, applications of this technology to neurological diseases remain scarce. This shortfall motivated the assembly of a review that will hopefully help researchers moving in this direction find their footing. The emphasis here will be on design considerations and concepts underlying this methodology. We will highlight groundbreaking studies in the CRISPR-Cas9 functional genetics field and discuss strengths and limitations of this technology for neurological disease applications. Finally, we will provide practical guidance on navigating the many choices that need to be made when implementing a CRISPR-Cas9 functional genetic screen for the study of neurological diseases.

摘要： Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations of children with SCA in sub-Saharan Africa are limited, especially magnetic resonance imaging and angiography (MRI/MRA). In a sample of Ugandan children receiving care at the Mulago Hospital sickle cell clinic in Kampala and were not on disease-modifying therapy, we examined the range of MR imaging findings, and how those findings correlated with standardized demographic, clinical, neurological and neurocognitive assessments. Methods: From within a larger sample of 265 participants with HbSS ages 1-12 years not taking disease-modifying therapy and enrolled in the BRAIN SAFE study, a sub-sample of 81 underwent non-contrast MRI/MRA on a 1.5 Telsa scanner. Participants also underwent 3 standardized assessments: neurocognitive testing by experienced testers using the Mullen Scales of Early Learning (for ages 1-4 years) or Kaufman Assessment Battery for Children, 2nd edition (for ages 5-12) (abnormal z-score of -2 or lower), stroke examination (PedsNIHSS) and transcranial Doppler ultrasound (TCD) using criteria for pediatric SCA. Participants undergoing MRI/MRA intentionally included 29 without any abnormal findings. MRI scans included T1- and T2- weighted images, T2 FLAIR and MRA three-dimensional time-of-flight technique. MR scans were interpreted by clinical and research methods, the latter per SWiTCH protocol (Helton, Blood 2014). Adjudication of differing reads was performed by a blinded third neuroradiologist. Results: A total of 81 children with SCA were examined by MRI/MRA. Mean age was 6.48 ± 2.75 years; 50.6% were male. Mean hemoglobin was 7.26±0.90 g/dl; 75% had hemoglobin <8.0. In all, 16.7% were malnourished using standard international measures established by age and sex. Infarcts and/or arterial stenoses on MRI/MRA were detected in 42 (52%), including 13 (25%) with no other abnormalities detec

摘要： Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Inflammation is a risk factor for acute stroke. In a cross-sectional study of Ugandan children, we asked whether inflammatory markers correlated with findings on neurological and neurocognitive testing and magnetic resonance imaging (MRI). Methods: Stored plasma samples were obtained at a well study visit from 81 children, a subset within a larger sample of study participants with HbSS ages 1-12 years recruited at the Mulago Hospital sickle cell clinic in Kampala. Participants underwent 4 standardized assessments: neurocognitive testing using the Mullen Scales of Early Learning (for ages 1-4 years) or Kaufman Assessment Battery for Children, 2nd edition (for ages 5-12) (abnormal at z-score of -2 or lower), examination for prior stroke (PedsNIHSS) and transcranial Doppler ultrasound (TCD) using criteria for pediatric SCA, plus a non-contrast MRI/MRA on a 1.5 Telsa scanner, analyzed for T1- and T2- weighted images and T2 FLAIR. MR scans were interpreted by clinical and research methods, the latter per SWiTCH protocol (Helton, Blood 2014). Adjudication of differing reads was performed by a blinded third neuroradiologist. Participants undergoing MRI intentionally included 29 without any abnormal findings on the three other evaluations. Plasma samples were examined for key cytokines and markers of vascular activation by a 20-plex Luminex immunoassay. Immune markers included IL1b, IL1RA, IL2, IL4, IL10, IL18, IL22, IFNg, TNFa, TNFb, sFasL, CXCL1, CXCL8 (IL8), PDGFBB, VEGFA, serpin E1 (Plasminogen Activator Inhibitor (PAI)-1), sICAM1, VCAM1, TGFa, plus assay of hsCRP. Raw immune data were transformed using Box-Cox transformations and standardized; markers with persistently skewed (non-Gaussian) distributions after transformation were dichotomized for analysis. Continuous immune variables were analyzed by repeated measures ANOVA (u

摘要： Background Immunoglobulin (IVIG) is used to treat autoimmune conditions, but there are reports of brisk hemolysis within 48 hours (hrs) of treatment due to anti-A isohemogglutinins(1). Despite these reports, hemolysis remains an unrecognized side effect of IVIG. Methods We presented a series of 3 cases of IVIG-induced hemolysis in patients with autoimmune neurological disorders. In the investigative phase, we traced the cases to a common IVIG lot number. The sample was tested to determine the anti-A titer levels. Case Studies (See Table 1) Case 1 75-year-old man presented with SOB and dysarthria from myasthenia gravis (MG). He received IVIG for 4 days. He developed a hemolytic anemia with 3 g drop in hemoglobin (Hb) 48 hours later. He needed a pRBC transfusion and folic acid. Case 2 59-year-old female with history of MG treated with IVIG at another hospital until 3 months earlier in crisis, with SOB and dysphagia. She received IVIG for 5 days and rituximab. She improved and was discharged, but returned to the ER 7 days later with SOB. Her Hb fell to 8.0 g/dL from 13 g/dL on last admission. She required a pRBC transfusion, folic acid, and vitamin B12 with improvement of SOB. Case 3 20-year-old female admitted for lower extremity weakness, diagnosed with presumed syndrome (GBS). She received IVIG for 4 days. On the 5th day, her Hb fell from 15 g/dL to 9 g/dL. She began prednisone, folic acid, and vitamin B12 with improvement in her Hb. Conclusions Although acute hemolysis is well described in the literature, it is under recognized, as exemplified by the first two cases. Their initial SOB was due to MG, so when SOB recurred, they were misdiagnosed with recurrent MG. A hemolytic anemia was later suspected, and a work up revealed a positive DAT. The initial eluate was negative against type O panel cells, suggesting a drug related hemolysis. It was only when the eluate was tested against type A cells that the etiology became clear. The third patient's hemolytic reaction w

摘要： The PLASMIC score was recently developed for rapid diagnosis of thrombotic thrombocytopenic purpura (TTP) and therapeutic decision, as ADAMTS13 is frequently unavailable. The score consists of a scale from 1 to 7 that considers clinical and laboratory factors. PLASMIC score 6 - 7, 4 - 5 and below 4 are associated with high, intermediate and low probability of ADAMTS13 deficiency, respectively. Although the PLASMIC score is validated to predict ADAMTS13 values, its role as a predictor of adverse clinical outcomes in TTP is not established. The primary aim of this study was to evaluate whether the PLASMIC score is associated with neurological complications during TTP episodes. We also evaluated the association of the score with treatment outcomes, such as number of plasma exchange procedures, need for a second line immunosuppression therapy, days in hospital and death. In the present study, we retrospectively applied the PLASMIC score at the time of diagnosis of TTP episodes treated at the UNICAMP Clinical Hospital (University of Campinas - Brazil) between 1995 and 2016. All clinical data were retrieved from medical charts. We grouped the episodes according to the PLASMIC score, calculated at diagnosis, and compared the occurrence of neurological symptoms and other clinical manifestation between the PLASMIC score groups. The association between the PLASMIC score and neurological symptoms was evaluated by regression analysis. A total of 50 episodes of TTP were identified, of these 47 episodes, and 34 patients, were included in the study. Three episodes were excluded due to lack of clinical data. Twenty-seven (79.4%) patients were women, and the mean age was 35.7 years (SD 12.7). At the diagnosis, the mean PLASMIC score was 6, no PLASMIC score below 4 was detected, and the most common clinical features were thrombocytopenia (mean platelet count = 21,029 x 109 / L [SD 18,371 x 109]) and reticulocytosis (mean count = 7.83% [SD 5.29]). Plasma exchange was the main treatmen

摘要： Nilotinib is a tyrosine kinase inhibitor used to treat patients with chronic myeloid leukemia (CML). This agent is also being studied in neurodegenerative disorders including Parkinson disease. Studies have shown that nilotinib may decrease the accumulation of parkin substrates and decrease the loss of dopaminergic cells. The use of nilotinib in neurologic disorders is relatively new, and little information about this use has been published. We report on a patient receiving nilotinib for CML. The patient had no previous neurologic deficits, and developed intermittent dystonic posturing of the left upper extremity and cognitive impairment after she began nilotinib treatment. The mechanisms behind this adverse effect are not clear;however, her symptoms began after nilotinib was introduced, decreased with dose reduction, stopped with its cessation, and re-emerged when the medication was restarted. To our knowledge, this is the first reported patient with neurologic symptoms secondary to nilotinib use.

关键词： GOSR2   Membrin   Golgi   secretory pathway   progressive myoclonus epilepsy  

摘要： Successive fusion events between transport vesicles and their target membranes mediate trafficking of secreted, membrane- and organelle-localised proteins. During the initial steps of this process, termed the secretory pathway, COPII vesicles bud from the endoplasmic reticulum (ER) and fuse with the cis-Golgi membrane, thus depositing their cargo. This fusion step is driven by a quartet of SNARE proteins that includes the cis-Golgi t-SNARE Membrin, encoded by the GOSR2 gene. Mis-sense mutations in GOSR2 result in Progressive Myoclonus Epilepsy (PME), a severe neurological disorder characterised by ataxia, myoclonus and seizures in the absence of significant cognitive impairment. However, given the ubiquitous and essential function of ER-to-Golgi transport, why GOSR2 mutations cause neurological dysfunction and not lethality or a broader range of developmental defects has remained an enigma. Here we highlight new work that has shed light on this issue and incorporate insights into canonical and non-canonical secretory trafficking pathways in neurons to speculate as to the cellular and molecular mechanisms underlying GOSR2 PME. This article is part of a Special Issue entitled: SNARE proteins: a long journey of science in brain physiology and pathology: from molecular. (C) 2019 Published by Elsevier Ltd. on behalf of IBRO.

关键词： Community based   patient centered   process quality   self-efficacy   self-management   service redesign  

摘要： Objectives: The objective of this study is to identify patient reported experiences of using community rehabilitation and/or support services whilst living with a long-term neurological condition, and perceptions of their impact on quality of life. Methods: Nine electronic databases were searched for peer-reviewed qualitative studies from 2005 to 2016, which met the inclusion criteria. Critical appraisal, data extraction, and quality assessment of 37 included papers were performed by three reviewers. One hundred and one findings were extracted. Meta-aggregation was used to synthesize findings. Findings: Seven ?synthesized findings? [SF] were produced: Interactions with some professionals provide active participation, choice, confidence and autonomy [SF1];Interactions with some professionals are disempowering and depersonalized [SF2];Effective communication, specialist knowledge and an individualized approach to information provision is needed [SF3];Indicators of success vary and may not be clear [SF4];Informal support from family/friends is valued [SF5];Opportunities for peer support/social interaction is valued [SF6];Coordination required to ensure continuity during transition to community [SF7]. Conclusion: Patient reported experiences identified common factors associated with process quality (respect, choice, autonomy, information provision, communication) and activities of patient centered care (personalized care, shared decision-making, self-management support) despite heterogeneity of neurological conditions, service configurations, and geographical location. These factors impact quality of life.