Faculty Bibliography

OBJECTIVE:To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS:April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS:Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS:New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

Background: Fatigue is among the most frequent and disabling symptoms in RMS patients.
Objective(s): To measure multiple sclerosis (MS) fatigue and its impact on daily life in a real-world population using a survey including the relapsing MS (RMS)-specific Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS).
Method(s): This is an ongoing noninterventional prospective study of RMS patients recruited across the USA via an online survey. Participants completed questionnaires including disease history, disease status, sleep, social and emotional functioning, and the FSIQ-RMS, administered daily for 7 days. The FSIQ-RMS measures self-reported fatigue, and scores range from 0-100 (higher score = greater severity). The impact of fatigue on several aspects of patient's life was rated from 0 (no impact) to 10 (very high impact).
Result(s): A total of 300 RMS participants completed the 7-day assessment: mean age: 43.0 yrs; 88% women; mean diagnosis age: 32 yrs. Fatigue was reported as the symptom with the greatest impact on daily functioning. Participants with lower disability rated fatigue as the most impactful symptom on daily life. Fatigue was rated as severe, with a mean score: 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Fatigue severity did not vary among patients receiving high efficacy disease modifying therapy (DMT) vs other DMTs (44% [n=111] vs 56% [n=143], with score of 57.8?}17.6 vs 55.9?}19.8). Impact of ability to perform daily activities was rated as the highest (6.9/10) in terms of impact on patient's life. Because of MS, 44% of participants did not work. Among those who were working currently (48%), the impact of fatigue on professional life was rated as 4.5/10. Nearly half of the participants (49% of 300) discussed fatigue at each visit with their neurologists and 35% discussed at most visits, with 'impact of fatigue on quality of life' being the most discussed topic (65% of 289). Participants used different approaches to manage their fatigue including avoided heat exposure (77%), took breaks (65%), managed their energy (59%), took non-medicinal products (58%); however, only 6% (of 293) were totally satisfied with these strategies.
Conclusion(s): In this survey including the novel RMS specific FSIQ-RMS, fatigue occurred in most MS participants and adversely influenced patient's daily functioning and life. Fatigue remains a major concern for those with MS

OBJECTIVE/UNASSIGNED:Little is known about psychiatric symptoms among patients with migraine and newly diagnosed focal epilepsy. The investigators compared symptoms of depression, anxiety, and suicidality among people with newly diagnosed focal epilepsy with migraine versus without migraine. METHODS/UNASSIGNED:The Human Epilepsy Project is a prospective multicenter study of patients with newly diagnosed focal epilepsy. Depression (measured with the Center for Epidemiologic Studies Depression Scale), anxiety (measured with the 7-item Generalized Anxiety Disorder scale), and suicidality scores (measured with the Columbia-Suicide Severity Rating Scale [C-SSRS]) were compared between participants with versus without migraine. Data analysis was performed with the Kolmogorov-Smirnov test for normality assessment, the Mann-Whitney U test, chi-square test, and linear regression. RESULTS/UNASSIGNED:Of 349 patients with new-onset focal epilepsy, 74 (21.2%) had migraine. There were no differences between the patients without migraine versus those with migraine in terms of age, race, and level of education. There were more women in the group with migraine than in the group without migraine (75.7% vs. 55.6%, p=0.0018). The patients with epilepsy and comorbid migraine had more depressive symptoms than the patients with epilepsy without migraine (35.2% vs. 22.7%, p=0.031). Patients with epilepsy with comorbid migraine had more anxiety symptoms than patients with epilepsy without migraine, but this relation was mediated by age in logistic regression, with younger age being associated with anxiety. Comorbid migraine was not associated with C-SSRS ideation or behavior. CONCLUSIONS/UNASSIGNED:Among a sample of patients with newly diagnosed focal epilepsy, 21.2% had migraine. Migraine comorbidity was associated with higher incidence of depressive symptoms. Future studies should be performed to better assess these relationships and possible treatment implications.

Objective/UNASSIGNED:At the time of multiple sclerosis (MS) diagnosis, identifying those at risk for poorer health-related quality of life and emotional well-being can be a critical consideration for treatment planning. This study aimed to test whether adverse childhood experiences predict MS patients' health-related quality of life and emotional functioning at time of diagnosis and initial course of disease. Methods/UNASSIGNED:We recruited patients at the time of new MS diagnosis to complete self-report surveys at baseline and a one-year follow-up. Questionnaires included the Adverse Childhood Experiences (ACEs), as well as the MS Knowledge Questionnaire (MSKQ), the 36-Item Short Form Health Survey (SF-36), and Self-Management Screening (SeMaS). Results/UNASSIGNED: Conclusions/UNASSIGNED:Childhood adversity predicts health-related quality of life and emotional well-being at time of MS diagnosis and over the initial course of the disease. Measured using a brief screening inventory (ACEs), routine administration may be useful for identifying patients in need of increased supportive services.

BACKGROUND:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. METHODS:The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. RESULTS:Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. CONCLUSIONS:Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. TRIAL REGISTRATION:NCT02798185.

OBJECTIVE:To compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BA) and White Americans (WA) and evaluate the role of socioeconomic status. METHODS:We compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit ZIP codes. RESULTS:Of 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs. mild disability, 95% CI 1.18, 1.86) and worse performances on tests of cognitive processing speed (-5.06 fewer correct, CI -5.72, -4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96) and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (-0.77 mL, 95% CI -0.91, -0.64), cortical (-30.63 mL, 95% CI -35.93, -25.33), and deep (-1.58 mL, 95% CI -1.92, -1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BA. CONCLUSION/CONCLUSIONS:We observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors and optimal treatment strategies among BAs with MS is warranted.

Background and aims: Natalizumab extended interval dosing (EID) is associated with lower progressive multifocal leukoencephalopathy risk than standard interval dosing (SID) in anti-JC virus antibody positive multiple sclerosis patients. However, EID efficacy has yet to be demonstrated in a randomised controlled trial, and real-world efficacy data would be valuable. Method(s): This study compared Multiple Sclerosis Performance Test (MSPT) functional changes occurring during treatment with natalizumab EID versus SID in MS PATHS, a network of healthcare institutions providing access to real-world clinical data. An MSPT segment was defined as the time between two MSPT assessments six months apart. MSPT segments with average infusion cycles >35 days and 35 days were defined as EID and SID, respectively. Patients could contribute multiple segments to both groups. Missing covariate data were multiply imputed. Covariates at segment start (Table) were balanced between groups by inverse probability weighting (IPW) based on a logistic propensity score model. Differences in annualized change in MSPT scores were compared between EID/SID arms with weighted linear regression. Result(s): Data from 152 EID and 1,079 SID segments were analysed. After IPW, all baseline factors exhibited a standard mean difference 0.05. Annualised change in MSPT scores of processing speed, manual dexterity, and ambulation did not differ significantly between EID and SID. On average, MSPT scores were maintained or improved while on natalizumab (Figure). Conclusion(s): Functional outcomes between patients treated with natalizumab EID versus SID were comparable. Cognitive processing speed, manual dexterity, and walking speed were maintained or improved over time for both treatment groups

This paper addresses the absence of an international diagnostic taxonomy for cognitive disorders in patients with epilepsy. Initiated through the 2020 Memorandum of Understanding between the International League Against Epilepsy and the International Neuropsychological Society, neuropsychological representatives from both organizations met to address the problem and consequences of the absence of an international diagnostic taxonomy for cognitive disorders in epilepsy, overview potential solutions, and propose specific solutions going forward. The group concluded that a classification of cognitive disorders in epilepsy, including an overall taxonomy and associated operational criteria, was clearly lacking and sorely needed. This paper reviews the advantages and shortcomings of four existing cognitive diagnostic approaches, including taxonomies derived from the US National Neuropsychology Network, DSM-V Neurocognitive Disorders, the Mild Cognitive Impairment classification from the aging/preclinical dementia literature, and the Research Domain Criteria Initiative. We propose a framework to develop a consensus-based classification system for cognitive disorders in epilepsy that will be international in scope and be applicable for clinical practice and research globally and introduce the International Classification of Cognitive Disorders in Epilepsy (IC-CODE) project.