Faculty Bibliography

De novo, heterozygous, loss of function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared to wild-type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome. This article is protected by copyright. All rights reserved.

INTRODUCTION/BACKGROUND:Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson's disease (PD) when other treatments have not given satisfactory results. Reduction in 'off'-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on 'off'-time. METHODS:Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and 'off'-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: 'off'-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson's Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes. RESULTS:Twenty-seven studies were included in this review. The improvement in 'off'-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. 'Off'-time was reduced from baseline to end of follow-up by 38-84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of 'off'-time demonstrated mean relative reductions of 47-82% at 3-6 months and up to 83% reduction at 3-5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device. CONCLUSION/CONCLUSIONS:In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing 'off'-time. INFOGRAPHIC/UNASSIGNED:Video Abstract.

Background and aims: The Work Productivity and Activity Impairment (WPAI) questionnaire is a patientreported outcome assessing percentage of work time missed, impairment while working, overall work impairment and activity impairment over seven days prior. We report 2-year changes in WPAI, and associations with the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and SymptoMScreen (self-reported symptom burden) among patients with relapsing-remitting MS (RRMS) in the Phase IIIb CASTING trial (NCT02861014). Method(s): Patients (n=680; Expanded Disability Status Scale score <=4.0) with a suboptimal response to one or two prior disease-modifying therapies (DMTs) received intravenous ocrelizumab 600mg every 24 weeks for 96 weeks. WPAI, MSIS-29 and SymptoMScreen were completed at baseline, Week 24, Year 1 and Year 2. Spearman correlations were assessed between change in WPAI subscores from baseline to Year 2, MSIS-29 subscores, and SymptoMScreen total score. Result(s): WPAI improved from baseline to Year 2, with significant reduction in overall work impairment (-3.08, p=0.020) and activity impairment (-5.69, p<0.001), and consistent trends in work time missed (-2.54, p=0.102) and impairment while working (-1.66, p=0.129). Improvement in SymptoMScreen score correlated with reduction in all WPAI measures: work time missed (rs=0.196), impairment while working (rs=0.387), overall work impairment (rs=0.362) and activity impairment (rs=0.421) over two years (all p<0.01). MSIS-29 improvements correlated with WPAI improvements over two years (Table 1). Table 1 Conclusion(s): Patients with a suboptimal response to one or two prior DMTs who switched to ocrelizumab showed improvement in work productivity (WPAI), which correlated with improvement in physical/psychological impacts of MS (MSIS-29) and decrease in symptom burden (SymptoMScreen) over two years

Migraine is a prevalent primary headache disorder and is usually considered as benign. However, structural and functional changes in the brain of individuals with migraine have been reported. High frequency of white matter abnormalities, silent infarct-like lesions, and volumetric changes in both gray and white matter in individuals with migraine compared to controls have been demonstrated. Functional magnetic resonance imaging (MRI) studies found altered connectivity in both the interictal and ictal phase of migraine. MR spectroscopy and positron emission tomography studies suggest abnormal energy metabolism and mitochondrial dysfunction, as well as other metabolic changes in individuals with migraine. In this review, we provide a brief overview of neuroimaging studies that have helped us to characterize some of these changes and discuss their limitations, including small sample sizes and poorly defined control groups. A better understanding of alterations in the brains of patients with migraine could help not only in the diagnosis but may potentially lead to the optimization of a targeted anti-migraine therapy.

The Victoria Symptom Validity Test (VSVT) is a performance validity test (PVT) with over two decades of empirical backing, although methodological limitations within the extant literature restrict its clinical and research generalizability. Chief among these constraints includes limited consensus on the most accurate index within the VSVT and the most appropriate cut-scores within each VSVT validity index. The current systematic review synthesizes existing VSVT validation studies and provides additional cross-validation in an independent sample using a known-groups design. We completed a systematic search of the literature, identifying 17 peer-reviewed studies for synthesis (7 simulation designs, 7 differential prevalence designs, and 3 known-groups designs). The independent cross-validation sample consisted of 200 mixed clinical neuropsychiatric patients referred for outpatient neuropsychological evaluation. Across all indices, Total item accuracy produced the strongest psychometric properties at an optimal cut-score of ≤ 40 (62% sensitivity/88% specificity). However, ROC curve analyses for all VSVT indices yielded statistically significant areas under the curve (AUCs; .73-81), suggestive of moderate classification accuracy. Cut-scores derived using the independent cross-validation sample converged with some previous findings supporting cut-scores of ≤ 22 for Easy item accuracy and ≤ 40 for Total item accuracy, although divergent findings were noted for Difficult item accuracy. Overall, VSVT validity indicators have adequate diagnostic accuracy across populations, with the current study providing additional support for its use as a psychometrically sound PVT in clinical settings. However, caution is recommended among patients with certain verified clinical conditions (e.g., dementia) and those with pronounced working memory deficits due to concerns for increased risk of false positives.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R² = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Background and Purpose:Antiplatelet therapy is key for preventing thrombotic events after transient ischemic attack or ischemic stroke. Although the role of aspirin is well established, there is emerging evidence for the role of short-term dual antiplatelet therapy (DAPT) in preventing recurrent stroke. Methods:We conducted a systematic review and study-level meta-analyses of randomized controlled trials comparing outcomes of early initiation of short-term DAPT (aspirin+P2Y12 inhibitor for up to 3 months) versus aspirin alone in patients with acute stroke or transient ischemic attack. Primary efficacy outcome was risk of recurrent stroke and primary safety outcome was incidence of major bleeding. Secondary outcomes studied were risk of any ischemic stroke, hemorrhagic stroke, major adverse cardiovascular events, and all-cause death. Pooled risk ratios (RRs) and CIs were calculated using a random-effects model. Results:Four trials with a total of 21 459 patients were included. As compared to aspirin alone, DAPT had a lower risk of recurrent stroke (RR, 0.76 [95% CI, 0.68–0.83]; P<0.001; I2=0%) but a higher risk of major bleeding events (RR, 2.22 [95% CI, 1.14–4.34], P=0.02, I2=46.5%). Patients receiving DAPT had a lower risk of major adverse cardiovascular events (RR, 0.76 [95% CI, 0.69–0.84], P<0.001, I2=0%) and recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82], P<0.001, I2=0%). Conclusions:As compared to aspirin alone, short-term DAPT within 24 hours of high-risk transient ischemic attack or mild-moderate ischemic stroke reduces the risk of recurrent stroke at the expense of higher risk of major bleeding.

Recently the coronavirus disease (COVID-19) outbreak has been declared a pandemic. Despite its aggressive extension and significant morbidity and mortality, risk factors are poorly characterized outside China. We designed a registry, HOPE COVID-19 (NCT04334291), assessing data of 1021 patients discharged (dead or alive) after COVID-19, from 23 hospitals in 4 countries, between 8 February and 1 April. The primary end-point was all-cause mortality aiming to produce a mortality risk score calculator. The median age was 68 years (IQR 52-79), and 59.5% were male. Most frequent comorbidities were hypertension (46.8%) and dyslipidemia (35.8%). A relevant heart or lung disease were depicted in 20%. And renal, neurological, or oncological disease, respectively, were detected in nearly 10%. Most common symptoms were fever, cough, and dyspnea at admission. 311 patients died and 710 were discharged alive. In the death-multivariate analysis, raised as most relevant: age, hypertension, obesity, renal insufficiency, any immunosuppressive disease, 02 saturation < 92% and an elevated C reactive protein (AUC = 0.87; Hosmer-Lemeshow test, p > 0.999; bootstrap-optimist: 0.0018). We provide a simple clinical score to estimate probability of death, dividing patients in four grades (I-IV) of increasing probability. Hydroxychloroquine (79.2%) and antivirals (67.6%) were the specific drugs most commonly used. After a propensity score adjustment, the results suggested a slight improvement in mortality rates (adjusted-OR_{hydroxychloroquine} 0.88; 95% CI 0.81-0.91, p = 0.005; adjusted-OR_antiviral 0.94; 95% CI 0.87-1.01; p = 0.115). COVID-19 produces important mortality, mostly in patients with comorbidities with respiratory symptoms. Hydroxychloroquine could be associated with survival benefit, but this data need to be confirmed with further trials. Trial Registration: NCT04334291/EUPAS34399.

BACKGROUND AND PURPOSE/OBJECTIVE:Indirect consequences of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic include those related to failure of patients to seek or receive timely medical attention for seemingly unrelated disease. We report our experience with stroke code imaging during the early pandemic months of 2020. MATERIALS AND METHODS/METHODS:Retrospective review of stroke codes during the 2020 pandemic and both 2020 and matched 2019 prepandemic months was performed. Patient variables were age, sex, hospital location, and severity of symptoms based on the NIHSS. We reviewed the results of CT of the head, CTA, CTP, and MR imaging examinations and classified a case as imaging-positive if any of the imaging studies yielded a result that related to the clinical indication for the study. Both year-to-year and sequential comparisons were performed between pandemic and prepandemic months. RESULTS:= .03). CONCLUSIONS:During our pandemic period, there was a significantly decreased number of stroke codes but simultaneous increases in positivity rates, symptom severity, and inpatient codes. We postulate that this finding reflects the documented reluctance of patients to seek medical care during the pandemic, with the shift toward a greater proportion of inpatient stroke codes potentially reflecting the neurologic complications of the virus itself.