Faculty Bibliography

Short-chain fatty acids (SCFAs), metabolites found in fermented foods and produced by colonic bacterial fermentation of dietary fibers, may mediate gut-brain axis crosstalk influencing the course of multiple sclerosis (MS). In this study, SCFAs are measured in plasma and paired stool samples by targeted mass spectrometry in a large cohort of deeply phenotyped individuals shortly after MS onset. Propionate is consistently associated with a protective effect on three clinical and imaging activity-related outcomes. Findings are reproduced in an equally large external cohort for plasma and stool measurements. Despite the correlation between plasma SCFAs and SCFA-producing gut microbial taxa, propionate levels are not correlated with dietary fiber, suggesting that intake may not be sufficient to modulate its levels and ensuing inflammation. In conclusion, propionate is consistently associated with lower disease activity, and exogenous administration may be more likely than fiber supplementation to confer protective effects on MS activity in proof-of-concept clinical trials.

OBJECTIVE:The aim of this study was to develop and demonstrate a postprocedural motion analysis platform capable of objectively quantifying intraoperative surgeon micromovements to facilitate evidence-based self-debriefing in suturing superficial temporal artery-middle cerebral artery microanastomosis. METHODS:The authors analyzed microscope-recorded microanastomoses performed by a cerebrovascular neurosurgeon. Seven suture-placement clips were extracted from operative videos. A computer vision tracking pipeline was implemented in Python using OpenCV to track the needle holder position across the video clips. Four motion metrics were computed for each video clip: absolute error, velocity, acceleration, and jerk. A unified reference distribution was constructed from all clips, and 95th percentile thresholds were defined for each metric. The metrics were displayed as dynamic synchronized plots alongside the corresponding video. Spectral decomposition of the position signal was performed to generate time-frequency representations, and average power in the 6- to 8-Hz band was computed as a quantitative tremor measure. To demonstrate reliable longitudinal performance tracking, the authors applied their platform to 8 recorded procedures between 2023 and 2026 and plotted the mean jerk per suture over time. RESULTS:Reliable tracking was achieved across 92.09% of analyzed footage. Two-dimensional trajectories were reconstructed for a total of 13,183 analyzed frames encompassing 219.82 seconds of suture-placement video (7 clips). Jerk analysis revealed multiple segments exceeding the 95th percentile threshold, flagging moments for surgical review. Time-frequency analysis revealed transient broadband power bursts and 2 persistent spectral bands (6-8 Hz and < 4 Hz). Tremor intensity analysis in the 6- to 8-Hz range revealed temporal tremor fluctuations, a finding undetectable by other metrics. Longitudinal performance tracking was feasible and demonstrated a stable jerk profile, consistent with expert-level performance. CONCLUSIONS:A motion-based postprocedural debriefing platform for the performance of microanastomosis is technically feasible and capable of generating objective, quantitative performance metrics from standard operative video. Unlike prior work focused on expert-novice differentiation, this platform was designed to support individualized self-assessment and reflective practice for surgeons at any experience level. Future work should validate the platform prospectively and correlate motion-based metrics with clinical outcomes.

BACKGROUND/UNASSIGNED:We reviewed published studies describing postoperative spinal hematomas (ESH) across all spinal levels, with an emphasis on thoracic cases. Postoperative epidural spinal hematomas (ESH) most commonly occur in the thoracic spine, followed by the lumbar and cervical regions. They may arise in association with anticoagulation or antiplatelet therapy, epidural anesthesia or interventional procedures, trauma, or spinal decompression and/or fusion. Thoracic ESH (TESH) represent the highest risk group, with reported incidences ranging from 0.12% to 4.46%. METHODS/UNASSIGNED:We assessed the varied etiologies of ESH/TESH, and analyzed the multitude of risk factors, imaging findings, and optimal timing of surgical intervention for addressing these lesions. RESULTS/UNASSIGNED:Reported incidences of postoperative epidural spinal hematomas (ESH) ranged from 0.1-3%, with pooled studies showing an overall rate of ~0.52-0.69%. Notably, thoracic procedures (TESH) occurred more frequently, with rates ranging from 0.12% to 4.46%. One review of 40 studies found a 0.52% overall incidence of ESH, including 0.84% thoracic, 0.63% lumbar, and 0.32% cervical lesions. Multilevel ESH/TESH hematomas were more common after posterior (0.70%) vs. anterior (0.24%) surgery, and were five-fold more frequent following minimally invasive (1.94%) vs. open procedures (0.42%). CONCLUSIONS/UNASSIGNED:Postoperative epidural spinal hematomas occur in ~0.52-0.69% of spinal procedures, with thoracic lesions showing higher reported rates (0.12%-4.46%). The strongest predictors of neurological recovery included; the rapid recognition of new postoperative neurological deficits, immediate postoperative MR studies, and emergency surgery. We therefore recommend early/STAT diagnosis and surgery for ESH/TESH (i.e. performed as soon as possible rather than simpley within a < 24 h window) to optimize outcomes.

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although expressed in different cell types, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation in untreated culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.

PURPOSE OF REVIEW/OBJECTIVE:GAD65 autoimmune-associated epilepsy (AAE) is an underrecognized cause of epilepsy with common delays to immunotherapy. We review advances in its pathophysiology, diagnosis and management. RECENT FINDINGS/RESULTS:GAD65 AAE predominantly affects young women, presenting as drug resistant temporal lobe epilepsy (TLE), often without mesial temporal sclerosis. Patients lie within a continuum where T cell mediated inflammation predominates in early disease, temporally overlapping with progressive structural injury, which leads to chronic epilepsy. Diagnosis is supported by high-level antibody detection in serum (RIA > 20 nmol/L or > 2000 U/mL, ELISA > 10,000 IU/mL), and in select cases CSF testing may be helpful. Treatment requires both immunotherapy and antiseizure medications. Immunotherapy response is greatest in early disease but can occur at later stages. Epilepsy surgery workup and neuromodulation may benefit some patients, although seizure freedom is rare. GAD65 AAE can resemble non-autoimmune TLE. Phenotype-based antibody testing and early recognition are important to guide timely, individualized treatment.

Athletes exposed to repetitive head impacts (RHI) may seek clinical evaluation because of concerns about chronic traumatic encephalopathy (CTE), a neuropathologically defined disease that cannot currently be diagnosed during life. As public awareness of CTE has expanded, clinicians face challenges communicating diagnostic uncertainty, interpreting non-specific symptoms, and addressing concerns about future neurological health. This Current Opinion examines the widening gap between public expectations and scientific capability and considers its implications for athlete-centered care. We discuss how clinicians can acknowledge uncertainty without dismissing patients' concerns, identify potentially treatable contributors to symptoms without prematurely attributing them to neurodegenerative disease, and use shared decision-making to guide individualized evaluation and management. We also consider how concerns about CTE may influence decisions about continued participation and return-to-sport among current athletes. Meeting these challenges requires coordinated interdisciplinary care, evidence-based communication, and clinical approaches that prioritize meaningful intervention even when diagnostic certainty remains unavailable.

PURPOSE OF REVIEW/OBJECTIVE:gene result in the development of neurofibromatosis type 1 (NF1), a neurogenetic disease and multisystem disorder that includes a predilection for benign and malignant tumors of the central and peripheral nervous systems. Patients with NF1 experience a wide variety of comorbidities, such as chronic pain conditions, learning disabilities, and signs and symptoms that include migraines and NF1-associated plexiform neurofibromas (PNs), which can cause disfigurement and pain. All of these factors can severely affect health-related quality of life (HRQoL). Although treatment options are limited, advances in targeted therapies have led to the approval of the mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors selumetinib and mirdametinib, which reduce target PN volume and improve HRQoL in patients with NF1-PNs. RECENT FINDINGS/RESULTS:A multidisciplinary team is necessary to evaluate patients and determine appropriate treatments that may reduce the burden of NF1. For adult patients with NF1, neurologists or neuro-oncologists may determine individual patient imaging and serial monitoring needs based on clinical evaluations and patient history. Imaging is useful to identify and determine the extent of potentially concerning tumors, although the specific imaging methods available depend on individual institutional capabilities. Biopsies may be conducted on areas of clinical or radiologic concern to determine the presence of malignant peripheral nerve sheath tumors or atypical neurofibromatous neoplasm of uncertain biological potential. Systemic treatment or surgical debulking may be recommended to reduce PN symptoms caused by tumor size, inflammation, and compression of vital organs. However, in patients with inoperable symptomatic NF1-PN, systemic MEK inhibitors may be considered to target PN volume reductions. Currently, 2 MEK1/2 inhibitors (selumetinib and mirdametinib) are approved by the US Food and Drug Administration and European Commission for the treatment of NF1-PN. SUMMARY/CONCLUSIONS:Because of the complexity of how and when to administer treatment and the impact of symptoms on HRQoL, a multidisciplinary team is essential to manage the manifestations of NF1, including PN, to achieve the greatest benefit from currently available therapies.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Antidopaminergic medications (ADMs), including vesicular monoamine transporter-2 (VMAT2) inhibitors and antipsychotics, are widely used to manage motor and psychiatric symptoms in Huntington disease (HD). Observational evidence suggests that ADM use may be associated with accelerated worsening of clinical outcome measures used in HD trials, but this relationship has not been examined in a controlled trial setting. We assessed the association between ADM exposure and longitudinal clinical outcomes in the Pridopidine's Outcome On Function in Huntington Disease (PROOF-HD) placebo arm. METHODS:This post hoc analysis included placebo-arm participants from PROOF-HD (NCT04556656), a randomized controlled trial in adults with Total Functional Capacity (TFC) 7-13 and cytosine-adenine-guanine (CAG) ≥36. Participants were categorized as on-ADMs or off-ADMs based on concurrent medication use across the study period. Outcomes included TFC, composite Unified Huntington's Disease Rating Scale (cUHDRS), Symbol Digit Modalities Test (SDMT), Stroop Word Reading (SWR), and Total Motor Score (TMS). Primary analyses used mixed-effects models for repeated measures, corroborated by propensity score weighting (PSW) and time-varying sensitivity analyses. RESULTS:< 0.0001) for TFC as compared with on-ADMs. Significant or directionally consistent findings for SDMT, SWR, and TMS emerged from week 39 onward. All TMS subdomain scores, except chorea, directionally favored off-ADMs at all visits. Antipsychotic-only, VMAT2 inhibitor-only, and higher-dose ADMs were each associated with greater clinical decline in cUHDRS and TFC as compared with off-ADMs. PSW-adjusted and time-varying analyses were directionally consistent with primary findings. DISCUSSION/CONCLUSIONS:In this study of the PROOF-HD placebo arm, ADM use was associated with greater worsening across global, functional, cognitive, and motor outcome measures as compared with off-ADM participants. Residual confounding by disease severity cannot be fully excluded, although sensitivity analyses were directionally consistent. Taken together, ADM exposure, class, and dose should be systematically considered when designing and interpreting HD clinical trials. TRIAL REGISTRATION INFORMATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04556656. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class II evidence that in patients with HD, the use of ADMs is associated with greater worsening across global, functional, cognitive, and motor outcome measures as compared with patients not on ADMs.

Cancer immunotherapy has transformed many areas of oncologic care. Neurological immune-related adverse events, particularly encephalopathy, represent potentially life-threatening complications requiring prompt recognition and intervention. Encephalopathic syndromes occur across immunotherapy modalities, including immune checkpoint inhibitors, chimeric antigen receptor-T cell therapy, and bispecific antibodies. The diagnostic challenge lies in distinguishing immune-mediated neurotoxicity from infection, metabolic derangements, disease progression, and paraneoplastic syndromes. A systematic evaluation incorporates detailed clinical assessment with neuroimaging, cerebrospinal fluid analysis, electroencephalography, and autoimmune antibody testing as appropriate. This review provides a practical approach to recognizing and assessing encephalopathy in patients receiving immunotherapy. Early multidisciplinary collaboration between neurology and oncology teams is critical for recognizing symptoms, managing adverse effects, and guiding cancer-directed treatment.