Faculty Bibliography

PURPOSE/OBJECTIVE:Many studies estimate that more than 50% of non-hospitalized patients with long-COVID develop moderate to severe autonomic dysfunction. However, the specific impact of autonomic dysfunction as it relates to quality of life in long-COVID is not fully understood. The aim of the current study is to assess autonomic symptoms and quality-of-life in patients with Post-Acute Sequelae of COVID-19 (PASC) recruited from a neurology department outpatient setting. METHODOLOGY/METHODS:In a two-year follow-up study of a baseline cohort of 93 non-hospitalized SARS-CoV-2 laboratory-positive patients evaluated for PASC between November 2020-August 2021, 44 participants completed follow-up telephone questionnaires examining quality-of-life as well as neurologic and autonomic symptoms. RESULTS:Among 93 participants, 44 (47 %) completed the two-year follow-up evaluation and 27 (61 %) were female with a median age of 55 years (IQR = 24-88). Most participants (95 %, 42/44) were vaccinated against COVID-19 and 43 % (19/44) had a pre-existing neurological disorder. Median time from index COVID-19 infection to follow-up was 26 months (IQR = 23-17), with a median of 15 months (IQR = 15-16) between visits. Fatigue, word finding difficulty, and changes in memory were the most commonly reported PASC symptoms. Sixty-six percent (29/44) of individuals met criteria for autonomic dysfunction as defined by the Composite Autonomic Symptom Score-31 (COMPASS-31) scale. Secretomotor and gastrointestinal subdomains demonstrated significant associations with Neuro-QoL metrics for Anxiety, Depression, and Fatigue. For every 1 additional PASC symptom reported at a follow-up study visit, there was an average increase of 1.5 points on the COMPASS-31 composite score. In addition, visual disturbances and sleep impairment were both associated with increased autonomic dysfunction. CONCLUSION/CONCLUSIONS:The strong association between autonomic dysfunction and reduced QoL in PASC and the relation to insomnia, visual dysfunction, and functional impairment are valuable findings, reinforcing the clinical impact of these symptoms longitudinally after index COVID-19 infection.

BACKGROUND:Age is the strongest factor determining disease expression in multiple sclerosis (MS). We previously demonstrated biological age acceleration in pediatric-onset MS (POMS) compared to controls with both epigenetic clocks (DNAm) and telomere length (TL). It is unknown whether these markers report overlapping or distinct aging-related processes. OBJECTIVES/OBJECTIVE:To determine the correlation between DNAm and TL aging markers. METHODS:We conducted a cross-sectional case-control study within the US Network of Pediatric MS Centers. We calculated age acceleration residuals for the Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks and measured TL from whole blood samples to estimate telomere to somatic DNA ratios (T/S ratio). We employed multivariable analysis of covariance to assess the correlation between DNAm estimates and TL. RESULTS: = 0.06). CONCLUSIONS:DNAm did not correlate with TL in this sample of POMS and controls, suggesting that these biomarkers may capture complementary and non-overlapping elements of aging-related biology.

OBJECTIVE:To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. METHODS:Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. RESULTS:A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88). INTERPRETATION/CONCLUSIONS:Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.

BACKGROUND:While cognitive processing and brain volume assessments are commonly used in multiple sclerosis (MS) research, they are not routinely incorporated into clinical care. Advances in neuroimaging software now allow for brain volume measurement to be incorporated into standard practice and guide clinical decision-making. METHODS:In this single-center, outpatient, cohort study, pediatric-onset multiple sclerosis (POMS) patients underwent at least two volumetric brain magnetic resonance imagings (MRIs) and two Symbol Digit Modalities Tests (SDMT) at least 6 months apart. Associations were analyzed using Pearson's correlation coefficient and linear regressions. RESULTS:Forty patients with POMS were included. The first volumetric brain MRI occurred at a median of 2.7 years after symptom onset. At the first volumetric MRI, 12% of patients had white matter brain volumes within 1% of normative values (n = 2000 healthy controls). Whole brain volume percentile (r = 0.4, P = 0.01), white matter percentile (r = 0.4, P = 0.01), and white matter lesion volume (r = -0.4, P = 0.005) were associated with SDMT score. Annualized percent brain volume change of the hippocampus (measured a median of 1.6 years apart) significantly correlated with follow-up SDMT (r = 0.4, P = 0.02), and annualized percent brain volume change of the thalamus correlated with annual change in SDMT z-score (r = 0.4, P = 0.009). CONCLUSIONS:Application of new software allows for volumetric assessment to be incorporated into clinical scans and provides clinicians with added data for patient management. This is critical for patients with POMS as the neurological examination often shows few to no abnormalities. Furthermore, a subset of POMS patients have smaller than expected brain volume which links to subsequent poorer cognitive performance.

After stroke, upper extremity (UE) motor recovery may be mediated in part by transcallosal projections between hemispheres. The interhemispheric competition model posits that transcallosal inhibition (TI) from the contralesional hemisphere is abnormally strengthened following stroke and interferes with motor recovery. This model has recently been questioned. In this longitudinal study, we aimed to definitively confirm or refute a maladaptive role of contralesional TI in subacute motor recovery. We assessed 30 mild-to-moderately impaired subjects over the six months following ischemic stroke. We tracked contralesional TI and motor functions in the proximal and distal segments of the paretic UE. We used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP) in an arm and hand muscle. We used quantitative and clinical testing to examine deficits in muscle strength, motor control, and individuation; UE segmental impairment; and UE activity limitation. We assessed the relationships of contralesional TI to motor functions in the subacute period. Despite recovery of most motor functions in the proximal and distal UE, contralesional TI was largely static and unrelated to recovery of any motor function. There were inconsistent associations between stronger TI, less hand impairment, and less activity limitation in the subacute period overall. We found no compelling evidence to suggest a maladaptive role of contralesional TI in UE motor recovery in mild-to-moderately impaired stroke subjects. The scattered associations between stronger TI and better levels of paretic UE function suggest a potential supportive role rather than a limiting one. These findings challenge the validity of the interhemispheric competition model in the subacute recovery period, and prompt reconsideration of neuromodulatory strategies that subacutely target contralesional TI.

BACKGROUND AND PURPOSE/OBJECTIVE:Cerebrovascular reactivity (CVR) is a widely studied biomarker of cerebral hemodynamics, commonly used in risk stratification and treatment planning in patients with steno-occlusive disease (SOD). Conventional use relies on normalization of estimates to contralateral hemisphere reference values, which is unsuitable for bilateral or indeterminate distributions of disease. We report upon a custom data-driven approach leveraging random forest classifiers (RFc) to identify candidate voxels for normalization in order to facilitate interrogation outside conditions of known unilateral SOD MATERIALS AND METHODS: We retrospectively analyzed 16 patients with unilateral SOD who underwent acetazolamide-augmented BOLD-MRI and DSC perfusion. Three RFc models were trained using leave-one-out cross-validation (LOOCV) to identify candidate voxels brain-wide whose CVR were within 10% of the normal hemispheric median: i. all voxels; ii. gray matter only; and iii. white matter only. Model input features included time-to-maximum (Tmax), mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV) from contemporaneous DSC. The median model-predicted reference CVR (CVRref) was compared to ground-truth medians in LOOCV, and its impact on threshold-based volumetric classification of CVR reduction assessed. RESULTS:RFc models effectively predicted ground-truth CVR voxels, achieving median absolute percent differences of 12.8% (IQR: 5.0%-18.9%) using all voxels, 11.3% (IQR: 9.3%-16.1%) for gray matter, and 9.8% (IQR: 4.4%-16.9%) for white matter. Volumetric estimates of CVR reduction across thresholds for the models revealed excellent agreement between ground-truth and model estimates without statistically significant differences (p>0.01), excepting lowest white matter CVR thresholds. Model use in a small pilot deployment of bilateral SOD cases demonstrated the potential utility, enabling voxel-wise CVR assessment without reliance on contralateral reference. CONCLUSIONS:We present a novel data-driven approach for normalizing CVR maps in patients with bilateral or indeterminate SOD. Using an RFc, our method provides an individualized, brain-wide reference CVR, expanding the utility of CVR estimates beyond the typical constraints of unilateral disease, and with potential application to other, similarly constrained scenarios such as for SPECT or PET hemodynamic studies. ABBREVIATIONS/BACKGROUND:CVR = cerebrovascular reactivity; RFc = random forest classifier; SOD = steno-occlusive disease.

IMPORTANCE/UNASSIGNED:Leptomeningeal metastasis (LM) is associated with limited survival and few treatment options. Photon involved-field radiotherapy (IFRT) is the most common radiotherapy treatment for patients with LM from solid tumors. OBJECTIVE/UNASSIGNED:To assess whether proton craniospinal irradiation (pCSI) would result in superior central nervous system progression-free survival (CNS-PFS) compared with IFRT. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized, phase 2 trial of pCSI vs IFRT was conducted between April 16, 2020, and October 11, 2021, and included patients with non-small cell lung cancer and breast cancer with LM. Patients with other solid tumors were also enrolled in an exploratory pCSI cohort. INTERVENTION/UNASSIGNED:For the randomized groups, after stratifying by histology and systemic disease status, patients were assigned (2:1) to pCSI or IFRT. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was CNS-PFS. Secondary end points included overall survival (OS). RESULTS/UNASSIGNED:Of 98 total patients, 72 individuals (73.5%) were female, and the median (IQR) age was 59 (50-65) years. A total of 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In this final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median, 8.2 months; 95% CI, 6.6-15.3) vs IFRT (median, 2.3 months; 95% CI, 1.2-4.0; P < .001). A statistically significant and clinically meaningful OS benefit with pCSI (median, 11.3 months; 95% CI, 7.5-18.3) vs IFRT (median, 4.9 months; 95% CI, 3.9-15.0; P = .04) was also observed. For the exploratory pCSI cohort (n = 35), the median CNS-PFS was 5.8 months (95% CI, 4.4-9.1) and OS was 7.0 months (95% CI, 5.4-10.6). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This randomized clinical trial that assessed the optimal radiotherapy treatment for LM found improved CNS-PFS and OS with pCSI compared with IFRT. The results suggest that pCSI should be considered when available. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04343573.

OBJECTIVE:Up to 30% of people with epilepsy are refractory to current antiseizure medications (ASMs). JNJ-40411813 is a positive allosteric modulator of metabotropic glutamate 2 receptor, a presynaptic glutamate release inhibitor, and was hypothesized to reduce glutamate-mediated neuronal toxicity through inhibition of excessive glutamate release during seizures. METHODS:This 12-week, double-blinded, placebo-controlled phase 2a study, which employed a rational polypharmacy approach using a novel time-to-event endpoint for epilepsy clinical trials, evaluated JNJ-40411813 (Cohort 1: 50/100 mg; Cohort 2: 100/200 mg) as adjunctive treatment for focal seizures in participants aged 18-64 years receiving levetiracetam or brivaracetam and ≤3 other ASMs. Participants were stratified as induced or noninduced based on treatment or no treatment with a cytochrome P450 3A4 enzyme-inducing ASM. The primary endpoint was time-to-baseline monthly seizure count. RESULTS:Cohorts 1 and 2 randomized 60 and 50 patients, respectively. No significant clinical benefits were observed in the median time (95% confidence interval [CI]) to reach the baseline monthly seizure count in Cohort 1 (JNJ-40411813: 34 days [27-48], placebo 32 days [28-37], hazard ratio [HR] = .75 [.41-1.38], p = .36) or Cohort 2 (JNJ-40411813: 38 days [28-48], placebo: 29 days [22-69], HR = .83 [.40-1.75], p = .63). Similarly, no clinical benefits of JNJ-40411813 were observed for any of the secondary endpoints. JNJ-40411813 displayed an acceptable safety profile; treatment-emergent adverse events were mild to moderate in severity and not treatment limiting. SIGNIFICANCE/CONCLUSIONS:JNJ-40411813 adjunctive to levetiracetam or brivaracetam showed no significant clinical benefit over placebo in reducing time-to-baseline monthly seizure count or improvement in other key measures in patients with focal onset seizures. The time-to-event study design was successful at reducing participant exposure to ineffective treatment. Despite an acceptable safety profile, the overall efficacy and benefit-risk assessment of JNJ-40411813 does not support its use for patients with focal seizures.

IMPORTANCE/UNASSIGNED:The Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). OBJECTIVE/UNASSIGNED:To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson's Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. INTERVENTION/UNASSIGNED:Bilateral STN-DBS for moderate to advanced PD. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. RESULTS/UNASSIGNED:A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-III improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.