Faculty Bibliography

BACKGROUND/PURPOSE/UNASSIGNED:Downbeat nystagmus (DBN) is an uncommon finding in comatose patients, especially as a manifestation of epileptiform activity. We report a 59-year-old man who developed DBN in the context of myoclonic status epilepticus following anoxic brain injury secondary to cardiac arrest. The DBN was phase-locked with generalized periodic epileptiform discharges (GPDs) on electroencephalography (EEG) and resolved with pharmacologic burst suppression. CONCLUSION/UNASSIGNED:This case suggests a potential link between DBN and cortical epileptiform activity, which we hypothesize may be due to bilateral cortical hyperexcitability and cerebellar disinhibition. The presence of DBN in this setting may indicate a poor prognosis.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

BACKGROUND:Diet may influence MS activity, but most studies use a single dietary measure. The stability of diet over time in pediatric-onset MS (POMS) is unclear. OBJECTIVES/OBJECTIVE:To evaluate the reproducibility and short-term temporal stability of dietary intake in youth with POMS using repeated food frequency questionnaires (FFQ). METHODS:This longitudinal study included participants with a baseline FFQ (the Block Kids Food Screener, 2014). Intraclass correlation coefficients (ICCs) were estimated using random-intercept mixed-effects models to quantify the relative contributions of between-person and within-person variability. Temporal trends in intake were assessed by modeling time since baseline as a fixed effect, using log-transformed dietary variables to estimate percent change over time. RESULTS:Of 419 FFQs from 195 participants, 140 (71.8%) completed ≥2 FFQs over a median of 6.5 months (range 2.8-18). ICCs ranged from 0.41 to 0.78 across dietary measures, with the highest reproducibility observed for vegetables and fiber (ICCs 0.78 and 0.72). Log-transformed models showed small declines in several nutrients over time, corresponding to <10% change over a six-month period. CONCLUSIONS:Dietary intake demonstrated moderate to good reproducibility over the 6 to 18 month follow-up period. Vegetable and fiber intake had the strongest reliability. These findings suggest that reported dietary intake assessed by a single or infrequent FFQ may remain reasonably stable over a 6- to 18-month period in longitudinal POMS studies. However, the moderate-to-good reproducibility observed indicates that within-person variability persists and may attenuate diet-disease associations when only a single dietary assessment is available.

INTRODUCTION/BACKGROUND:Patient and arteriovenous malformation (AVM) characteristics that portend success after treatment for low-grade brain AVMs remain unknown. PATIENTS AND METHODS/METHODS:We utilised the MISTA multicentre registry to identify patients with Spetzler-Martin (SM) grade I or II AVMs treated with stand-alone curative-intent intervention (resection, stereotactic radiosurgery [SRS] or endovascular embolisation). Bivariate and multivariable analyses were performed to identify patient and AVM characteristics predictive of complete obliteration or favourable outcome (complete obliteration without new permanent deficit or post-treatment haemorrhage). RESULTS:A total of 522 patients were included (292 microsurgery, 152 SRS, 78 embolisation). Complete obliteration rates differed between microsurgery (95.9%), SRS (75.0%) and embolisation (71.8%) (P < .001); among patients classified as cured, digital subtraction angiography (DSA) confirmed obliteration in 96.1%, 75.9% and 52.4%, respectively. Favourable outcome was achieved in 89.4%, 64.5% and 67.9% (P < .001). In adjusted models for obliteration, elderly age (odds ratio [OR] 0.49, P = .022), larger nidus (OR 0.64, P = .005) and compacted morphology (OR 1.93, P = .019) were independent predictors overall; paediatric age predicted incomplete obliteration after microsurgery (OR 0.05, P = .045), and elderly age (OR 0.19, P = .001) and larger nidus (OR 0.59, P = .015) after SRS. For favourable outcome, SM grade II overall (adjusted OR [aOR] 0.58, P = .031) and elderly age after SRS (aOR 0.31, P = .019) were independent negative predictors. DISCUSSION/CONCLUSIONS:Low-grade AVMs showed high rates of complete obliteration, though DSA-confirmed rates were substantially lower after embolisation, underscoring the importance of angiographic confirmation. CONCLUSION/CONCLUSIONS:The predictors identified in this study may help guide management when 2 or 3 of the primary treatment options carry clinical equipoise.

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir-ritonavir improved long COVID symptoms. METHODS:We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir-100 mg ritonavir twice daily, then 100 mg ritonavir-placebo); 25 days of active intervention (300 mg nirmatrelvir-100 mg ritonavir twice daily); or 25 days of placebo-ritonavir (100 mg ritonavir-placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete. FINDINGS/RESULTS:Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38-59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI -10·4 to 16·8, p=0·65) for the 25-day regimen and -2·2% (-15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were -6·4% (-18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and -0·1% (-12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were -7·8% (-19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (-11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study. INTERPRETATION/CONCLUSIONS:Nirmatrelvir-ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed. FUNDING/BACKGROUND:National Institutes of Health.

BACKGROUND:Cognitive impairments are consistently associated with the actual number of falls and future fall risk in people with multiple sclerosis (PwMS), but their influence and predictive usefulness regarding fear of falling (FoF) are not well understood. Since FoF can greatly affect a patient's lived experience and is essential for evaluating overall fall risk in PwMS, we aimed to explore how cognitive performance relates to, and forecasts, individuals' perceptions of their fall risk, and whether disease severity impacts this relationship. METHODS:FoF (Modified Falls Efficacy Scale, MFES) and neurocognitive function (NeuroTrax computerized cognitive assessment battery) were assessed in 188 PwMS. The NeuroTrax battery provided index scores for global cognition and specific cognitive domains such as memory, executive function, attention, processing speed, visuo-spatial, verbal function, and motor skills. The predictive value of cognitive performance on FoF was examined through hierarchical regression models. RESULTS: = 9.15, p < 0.001). CONCLUSION/CONCLUSIONS:FoF in PwMS can affect day-to-day planning and quality of life but is often overlooked as a meaningful aspect of the patient's lived experience. Our findings suggest that cognitive deficits are associated with greater FoF, and that the cognitive domain related to FoF varies as a function of disability level. Deficits in executive functioning and motor skills, in particular, may indicate broader disease impact on the patient's perception of their physical capabilities.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Former American football players exposed to repetitive head impacts (RHI) are at a risk of chronic traumatic encephalopathy (CTE), but chronic pain, polypharmacy, and extensive orthopedic surgeries may also contribute to cognitive and behavioral symptoms. This study evaluated associations between chronic pain, centrally acting medications (CAMs), and orthopedic surgeries with cognitive and behavioral symptoms among former American football players. METHODS:The sample included former professional (PRO) and collegiate (COL) football players and unexposed, asymptomatic men (UE) from DIAGNOSE CTE. Number of CAMs, orthopedic surgeries, and average pain scores were compared between the groups. Among former football players, logistic regression tested associations between CAMs, average pain score, and orthopedic surgeries with diagnoses of cognitive impairment and neurobehavioral dysregulation (NBD) using traumatic encephalopathy syndrome (TES) research criteria. Linear regression tested associations between CAMs, average pain score, and orthopedic surgeries with the Montreal Cognitive Assessment (MoCA) and behavioral and mood symptom scales. Covariates included age, education, race, and total years of football. RESULTS:The study included 236 men (120 PRO, 60 COL, 56 UE). The mean ages were 59.1 (PRO), 53.5 (COL) and 59.6 (UE) years. PRO and COL used more CAMs (mean PRO = 0.76, COL = 1.14, UE = 0.14), had higher average pain scores (PRO = 4.22, COL = 3.21, UE = 1.05), and more orthopedic surgeries than the UE (mean PRO = 2.76, COL = 1.22, UE = 0.34). CAMs and average pain scores were associated with increased odds of consensus diagnosed NBD (CAMs OR = 2.15, 95% CI 1.53 to 3.26; average pain score OR = 1.55, 95% CI 1.32 to 1.85). CAMs and average pain scores were associated with increased measures of impulsivity, depression, anxiety, behavioral regulation, and aggression. CAMs and average pain scores were not associated with consensus diagnosed cognitive impairment, but CAMs were negatively associated with MoCA score (estimate = -0.47, 95% CI -0.81 to -0.13). There was no association between number of orthopedic surgeries and cognition or NBD. DISCUSSION/CONCLUSIONS:CAMs and chronic pain are associated with NBD and CAMs are associated with reduced MoCA scores in former American football players.

BACKGROUND AND PURPOSE/OBJECTIVE:Although visibility of Deep Medullary Veins (DMVs) has been suggested as an imaging biomarker for cerebral small vessel disease (CSVD) and brain atrophy, qualitative visual assessment of DMVs may lack reliability. In this study, we used a rigorous, automated approach to segment DMVs on SWI and to estimate a vein voxel fraction (VVF). We hypothesized that VVF would be associated with vascular risk factors, imaging markers of CSVD, and brain volumes. MATERIAL AND METHODS/METHODS:A retrospective analysis of data from participants enrolled in studies of brain aging and prediction of Alzheimer's disease. All underwent 3T MRI (T1WI, FLAIR, SWI, and arterial spin labeling), clinical evaluations, and laboratory tests to assess vascular risks. A SWI image processing pipeline included denoising, bias field correction, adaptive histogram equalization, and multi-scale Jerman filtering that yielded vesselness maps. The vein voxel fraction (VVF) was calculated as a ratio of DMVs voxels in a periventricular region to the volume of the periventricular region. White matter hyperintensities, microbleeds, brain volumes, and CBF were also assessed. RESULTS:This study included 131 cognitively healthy participants, 71 (65, 76) years (median, Q1, Q3), (51%) female, and a subgroup of subjects with cognitive impairment (n=30, 69 (59, 76) years, 43% female). In the unimpaired group, the VVF positively correlated with systolic blood pressure and body mass index. It showed an inverse association with lateral ventricle volume (all at p < 0.05). It was related to white matter hyperintensities volume only in unadjusted analysis. CONCLUSION/CONCLUSIONS:Vein voxel fraction was associated with increased weight and high blood pressure. Possibly, these observations reflect venous stasis. These factors should be accounted for while evaluating brain venous system with SWI. In addition, subcortical atrophy was related to less visible DMVs.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Patients with epilepsy (PWE), especially temporal lobe epilepsy (TLE), experience impaired memory for personally experienced events. However, current assessments of episodic memory are limited in their ecological validity with a potential to miss detection of subtle cognitive decline. We conducted an exploratory study to determine whether a naturalistic film-viewing task with open-ended spoken recall could detect memory differences between TLE patients and healthy controls (HCs). METHODS:TLE patients (ages 18-60, fluent in English, not legally blind) were recruited from a Level 4 Epilepsy Center (2018-2024). TLE diagnosis was based on seizure semiology, MRI Brain, and EEG. TLE patients scored 22/30 on the Montreal Cognitive Assessment (MOCA); HCs scored 26/30. Subjects watched 6 short films and then freely recalled film details. Spoken responses were recorded, transcribed, segmented, and scored for film- and event-level recall. Recall order was assessed using the Damerau-Levenshtein distance. Semantic and causal centrality were quantified using sentence embeddings and rater-identified causal links, respectively. Beta regression with cluster-robust standard errors assessed group and centrality effects on recall probability. Beta regression evaluated the influence of age, MOCA, and testing platform on sequence recall error. RESULTS:We recruited 51 subjects (27 TLEs; 24 HCs, 70.1% F, mean 29.9 ±8.3 years). TLE patients and HCs showed similar recall of films (HC 89% ±11% vs TLE 88% ±18%, p = 0.54), coarse-grained events (HC 50% ±16% vs TLE 44% ±18%, p = 0.19) and fine-grained events (HC 25%±10% vs. TLE 22%±12%, p=0.17). Both groups recalled high causal centrality events better. However, TLE patients showed significantly greater fine-grained event sequence deviations at recall than HCs (HC 15% ±13% vs TLE 23% ±18%, p = 0.02, Hedges' g = 0.85, Cliff's δ = 0.51), with RTLE demonstrating more sequence deviations than HCs (15%±13 vs. 29%±21% p = 0.021) Age, education, MOCA, and performance on standard verbal and visual memory tasks were unrelated to film, event, and sequence recall performance. DISCUSSION/CONCLUSIONS:We demonstrate that a short film task with spontaneous spoken recall can identify group level differences in episodic memory. TLE patients demonstrate impaired sequence memory despite intact film- and event-level recall compared to healthy controls. Sequence memory may represent a subtle manifestation of memory impairment that is not detected by standard cognitive testing.