Faculty Bibliography

Despite its popularity in the neuropsychological evaluation of children, the utility of the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) has not yet been investigated in children with epilepsy. Eighty clinically referred children and adolescents with epilepsy were administered the WISC-V as part of a comprehensive assessment and scores were compared to matched controls from the WISC-V standardization sample. T tests compared WISC-V indices and subtests between patients and controls and Chi-square analyses compared the rates of low scores. Correlational analyses assessed the relationships between epilepsy severity variables (e.g., age of onset, duration of epilepsy, number of antiepileptic drugs, seizure frequency). All WISC-V composites and subtests were significantly lower in patients versus controls and the rate of low scores was higher in patients than controls for all composites and subtests with the exception of Figure Weights. The Working Memory Index and Processing Speed Index were most sensitive to impairment, while the Verbal Comprehension Index and Fluid Reasoning Index were least sensitive. Of the epilepsy severity variables, age of seizure onset and number of antiepileptic drugs were strong predictors of deficits, whereas seizure frequency was the weakest predictor. Importantly, no significant differences were seen in children with right hemisphere epilepsy versus left on the five WISC-V composites, though a trend was seen towards a lower Visual-Spatial Index in those with right-sided focal seizures.

A 2016 survey of pediatric neuropsychologists found that 92% of clinicians reported use of "at least one" performance validity test (PVT) in each assessment. The present investigation sought to verify documented PVT use among clinicians by review of actual reports. A convenience sample of pediatric neuropsychological reports of children ages 6-17 were reviewed over an 24-month period (January 2015-January 2017); reports were those seen as part of our routine practice, including reports on children we were reevaluating, cases that we consulted on, or cases evaluated elsewhere presenting to our centers that required record review for clinical decision making (e.g., presurgical epilepsy evaluations). A total of 131 reports, from 102 unique neuropsychologists were reviewed. PVT usage was documented in only six reports, from six unique clinicians, representing only 4.58% of the reports (or 5.88% of clinicians), far below expectations recent survey results. Though sampling differences and documentation factors may account for some of this disparity, a "social desirability bias" on surveys is likely a major factor in explaining these discordant findings.

OBJECTIVE:To better understand how the essential skill of interpreting various neuroimaging studies is taught to neurology residents in Accreditation Council for Graduate Medical Education (ACGME)-accredited training programs. METHODS:A 22-question survey was sent electronically to 150 ACGME adult neurology program directors. We collected data regarding the presence of a neuroimaging curriculum, frequency of review sessions and testing, resource availability, and program director confidence in neuroimaging skills of graduating residents. We collected average scores on the neuroimaging section of the Resident In-service Training Examination of graduating residents for the past 3 years, which we attempted to correlate with resource availability. RESULTS:One-third of neurology residency programs do not have a neuroimaging curriculum, and half of training programs do not require a neuroimaging rotation. On average, trainees spend 1 hour per week reviewing imaging with radiologists. Program directors believed trainees receive insufficient neuroimaging training, with a median satisfaction rating on a Likert scale (0-100) of 35 (interquartile range 27-47). Few programs take advantage of online training resources. CONCLUSION/CONCLUSIONS:Opportunities exist to improve neuroimaging education in neurology resident education. This can be done by closer adherence to the American Academy of Neurology neuroimaging curriculum guidelines, especially by expanding access to online resources and additional emphasis on imaging review with neurology subspecialists.

BACKGROUND:Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS:APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS:In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS:Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

PURPOSE OF REVIEW/OBJECTIVE:In other disease states, adherence to behavioral therapies has gained attention, with a greater amount of studies discussing, defining, and optimizing adherence. For example, a meta-analysis formally discussed adherence in 25 studies of CBT for 11 different disorders, with only 6 of the 25 omitting addressing or defining adherence. Many studies have discussed the use of text messages, graph-based adherence rates, and email/telephone reminders to improve adherence. This paper examined the available literature regarding adherence to behavioral therapy for migraine as well as adherence to similar therapies in other disease states. The goal of this research is to apply lessons learned from adherence to behavioral therapy for other diseases in better understanding how we can improve adherence to behavioral therapy for migraine. RECENT FINDINGS/RESULTS:Treatment for migraine typically includes both pharmacologic and non-pharmacologic therapies, including progressive muscle relaxation (PMR), cognitive behavioral therapy (CBT), and biofeedback. Behavioral therapies have been shown to significantly reduce headache frequency and intensity, but high attrition rates and suboptimal adherence can undermine their efficacy. Traditionally, adherence to behavioral therapy has been defined by self-report, including paper headache diaries and assignments. In person attendance has also been employed as a method of defining and monitoring adherence. With the advent of personal electronics, measurements of adherence have shifted to include electronic-based methods such as computer-based programs and mobile-based therapies. Furthermore, some studies have taken advantage of electronic methods such as email reminders, push notifications, and other mobile-based reminders to optimize adherence. The JITA-I, a novel method of engaging individual patient adherence, has also been suggested as a possible method to improve adherence by tailoring engagement with a mobile health app-based on patient input. These novel methods may be utilized in behavioral therapy for migraine for further optimizing adherence. Few intervention studies to date have addressed the optimal ways to impact adherence to migraine behavioral therapy. Further research is required regarding adherence with behavioral therapies, specifically via mobile health interventions to better understand how to define and improve adherence via this novel forum. Once we are able to understand optimal methods of tracking adherence, we will be better equipped to understand the role of adherence in shaping outcomes for behavioral therapy in migraine.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

OBJECTIVE:To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. METHODS:This was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed. RESULTS:= 0.009). CONCLUSIONS:PCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.

Intratumoural heterogeneity underlies tumour escape from molecularly targeted therapy in glioblastoma. A cell-based model preserving the evolving molecular profiles of a tumour during treatment is key to understanding the recurrence mechanisms and development of strategies to overcome resistance. In this study, we established a matched pair of glioblastoma stem-like cell (GSC) cultures from patient glioblastoma samples before and after epidermal growth factor receptor (EGFR)-targeted therapy. A patient with recurrent glioblastoma (MGG70R) harboring focal, high-level EGFR amplification received the irreversible EGFR tyrosine kinase inhibitor dacomitinib. The tumour that subsequently recurred (MGG70RR) showed diploid EGFR, suggesting inhibitor-mediated elimination of EGFR-amplified tumour cells and propagation of EGFR non-amplified cell subpopulations. The MGG70R-GSC line established from MGG70R formed xenografts retaining EGFR amplification and EGFR overexpression, while MGG70RR-GSC established from MGG70RR generated tumours that lacked EGFR amplification and EGFR overexpression. MGG70R-GSC-derived intracranial xenografts were more proliferative than MGG70RR-GSC xenografts, which had upregulated mesenchymal markers, mirroring the pathological observation in the corresponding patient tumours. In vitro MGG70R-GSC was more sensitive to EGFR inhibitors than MGG70RR-GSC. Thus, these molecularly distinct GSC lines recapitulated the subpopulation alteration that occurred during glioblastoma evasion of targeted therapy, and offer a valuable model facilitating therapeutic development for recurrent glioblastoma.