Faculty Bibliography

Background/UNASSIGNED:People living with multiple sclerosis (MS) experience a high symptom burden that interferes with daily functioning. Virtual reality (VR) is an emerging technology with a range of potential therapeutic applications that may include ameliorating the experience of some common MS symptoms. Objective/UNASSIGNED:We tested the feasibility and tolerability of a VR intervention and its preliminary effects on affect. Methods/UNASSIGNED:Participants with MS were recruited to complete a pilot study of eight sessions of VR over four weeks. Results/UNASSIGNED: = 0.040). Conclusion/UNASSIGNED:VR interventions are feasible, safe, and tolerable for individuals living with MS and may improve affect.

OBJECTIVE:We sought to identify similarities and differences in the diagnostic requirements for ancillary testing for determination of brain death/death by neurologic criteria (BD/DNC) around the world. METHODS:We reviewed diagnostic requirements for ancillary testing for BD/DNC in 78 unique official national BD/DNC protocols obtained from contacts worldwide between January 2018 and April 2019. RESULTS:Details provided on the performance and interpretation of ancillary tests for determination of BD/DNC were variably provided and inconsistent. Approximately half of all protocols that included each ancillary test provided details about study performance: 63% of protocols that included conventional cerebral angiography, 55% of protocols that included electroencephalography, 50% of protocols that included somatosensory evoked potentials, 48% of protocols that included transcranial Doppler ultrasonography, 43% of protocols that included nuclear medicine flow study and 41% of protocols that included brainstem auditory evoked potentials. Similarly, about half of all protocols that included each ancillary test provided details about study interpretation: 66% of protocols that included electroencephalography, 59% of protocols that included brainstem auditory evoked potentials, 56% of protocols that included somatosensory evoked potentials, 55% of protocols that included transcranial Doppler ultrasonography, 52% of protocols that included conventional cerebral angiography and 49% of protocols that included nuclear medicine flow study. INTERPRETATION/CONCLUSIONS:Diagnostic requirements for ancillary testing in BD/DNC determination vary around the world. We hope that the World Brain Death Project will improve worldwide consensus on the diagnostic requirements for ancillary testing in BD/DNC, both for performance and interpretation.

Objective/UNASSIGNED:To test the hypothesis that many patients presenting with congenital insensitivity to pain have lesser known or unidentified mutations not captured by conventional genetic panels, we performed whole-exome sequencing in a cohort of well-characterized patients with a clinical diagnosis of congenital hereditary sensory and autonomic neuropathy with unrevealing conventional genetic testing. Methods/UNASSIGNED:We performed whole-exome sequencing (WES) in 13 patients with congenital impaired or absent sensation to pain and temperature with no identified molecular diagnosis from a conventional genetic panel. Patients underwent a comprehensive phenotypic assessment including autonomic function testing, and neurologic and ophthalmologic examinations. Results/UNASSIGNED:). Conclusions/UNASSIGNED:Our results expand the genetic landscape of congenital sensory and autonomic neuropathies. Further validation of some identified variants should confirm their pathogenicity. WES should be clinically considered to expedite diagnosis, reduce laboratory investigations, and guide enrollment in future gene therapy trials.

Objective: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.
Method(s): We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.
Result(s): Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.
Significance: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
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OBJECTIVE:Many people with new-onset focal epilepsy initially seek evaluation in emergency departments (EDs), and treatment decisions in EDs can influence likelihood of seizure recurrence. Using data collected for the Human Epilepsy Project (HEP), we assessed the effect of clinical seizure characteristics on ED clinical management. METHODS:There were 447 participants with new-onset focal epilepsy seen within four months of treatment initiation who were eligible and enrolled in HEP. Seizure calendars and medical records were collected. Based on clinical descriptions, seizures were categorized by semiology according to International League Against Epilepsy (ILAE) classifications as either focal non-motor or focal motor seizures. RESULTS:Overall, 279/447(62%) of participants had presented to an ED prior to or at time of epilepsy diagnosis. 132 /246 (53%) with initial non-motor seizures presented to an ED. Of these, 8 (6%) presented with a first-lifetime non-motor seizure. The other 124 (94%) presented after multiple seizures: 7 (5%) with multiple non-motor seizures, and 117 (89%) with a first-lifetime motor seizure after having prior non-motor seizures. 147/ 201 (73%) of participants with initial motor seizures presented to an ED. Of these, 134 (92%) presented with a first-lifetime motor seizure, and 13 (9%) with multiple motor seizures. There was no difference in the likelihood of anti-seizure medication (ASM) initiation between participants who had multiple prior non-motor seizures followed by a motor seizure (thereby fulfilling the criterion for an epilepsy diagnosis), vs those presenting with a single lifetime motor seizure (39% vs 43%). There was no difference in recognition of seizures as the presenting complaint (85% vs 87%), or whether the participant was admitted or referred to a neurologist (87% vs 79%). CONCLUSIONS:This study contributes to evidence of under-recognition of non-motor focal seizure semiologies in ED settings, which can support large-scale interventions aimed at improving recognition, specialist consultation, and treatment in ED settings.

PURPOSE/OBJECTIVE:Resting state functional magnetic resonance imaging (rsfMRI) is an emerging tool to explore the functional connectivity of different brain regions. We aimed to assess the disruption of functional connectivity of the Default Mode Network (DMN), Dorsal Attention Network(DAN) and Fronto-Parietal Network (FPN) in patients with glial tumors. METHODS:rsfMRI data acquired on 3T-MR of treatment-naive glioma patients prospectively recruited (2015-2019) and matched controls from the 1000 functional-connectomes-project were analyzed using the CONN functional toolbox. Seed-Based Connectivity Analysis (SBCA) and Independent Component Analysis (ICA, with 10 to 100 components) were performed to study reliably the three networks of interest. RESULTS:). For the FPN, increased connectivity was noted in the precuneus, posterior cingulate gyrus, and frontal cortex. No difference in the connectivity of the networks of interest was demonstrated between low- and high-grade gliomas, as well as when stratified by their IDH1-R132H (isocitrate dehydrogenase) mutation status. CONCLUSION/CONCLUSIONS:Altered functional connectivity is reliably found with SBCA and ICA in the DMN, DAN, and FPN in glioma patients, possibly explained by decreased connectivity between the cerebral hemispheres across the corpus callosum due to disruption of the connections.

Cerebrovascular disease (stroke) is one of the ten leading causes of death in children and adolescents. Multiple etiologies, from arteriopathies to prothrombic states, can cause stroke in youth. In adult stroke, hypertension has been shown to be the single most important modifiable risk factor. Although hypertension has not been strongly identified as a risk factor in childhood stroke to date, there is preliminary evidence that suggests that hypertension may also be associated with stroke in children. In this review, we summarize the literature that may link hypertension to stroke in the young. We have identified a series of barriers and limitations in the fields of pediatric hypertension and pediatric neurology that might explain why hypertension has been overlooked in childhood stroke. We suggest that hypertension may be a relevant risk factor that, alone or in combination with other multiple factors, contributes to the development of stroke in children. Currently, there are no consensus guidelines for the management of post-stroke hypertension in children. Thus, we recommend that blood pressure be assessed carefully in every child presenting with acute stroke in order to better understand the effects of hypertension in the development and the outcome of childhood stroke. We suggest a treatment algorithm to help practitioners manage hypertension after a stroke.

BACKGROUND:Ice hockey has significant workload demands. Research of other sports has suggested that decreased rest between games as well as an increased workload may increase the risk of injuries. PURPOSE/OBJECTIVE:To evaluate whether condensed game schedules increase the frequency and severity of injuries in the National Hockey League (NHL). STUDY DESIGN/METHODS:Descriptive epidemiology study. METHODS:Data were obtained from publicly available online sources on game schedules and injuries for all NHL teams for the 2005-2006 through 2018-2019 seasons. Injury rates (per team per game) and the proportion of severe and nonsevere injuries were determined. The game-spacing analysis assessed the risk of injuries in relation to the number of days between games played (range, 0-≥6 days). The game-density analysis assessed the risk of injuries in relation to the number of games played within 7 days (range, 1-5 games). Results were assessed by analysis of variance, the post hoc Tukey test, and the chi-square test of distribution. RESULTS:), with significant differences between all groups except for the comparison between 1 versus 2 games in 7 days. CONCLUSION/CONCLUSIONS:We found that a condensed schedule and <1 day of rest between games were associated with an increased rate of injuries in the NHL. These findings may help in the design of future game schedules.

Large hemispheric infarcts occur in up to 10% of all ischemic strokes and can cause devastating disability. Significant research and clinical efforts have been made in hopes of mitigating the morbidity and mortality of this disease. Areas of interest include identifying predictors of malignant edema, optimizing medical and surgical techniques, selecting the patient population that would benefit most from decompressive hemicraniectomy, and studying the impact on quality of life of those who survive. Decompressive surgery can be a life-saving measure, and here we discuss the most up-to-date literature and provide a review on the surgical management of large hemispheric ischemic strokes.