Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neurology
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23427
Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy
OBJECTIVE:Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS:We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS:Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION/CONCLUSIONS:Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.
PMID: 36534060
ISSN: 1531-8249
CID: 5409262
Extracellular Vesicles as Mediators of Nickel-Induced Cancer Progression
Emerging evidence suggests that extracellular vesicles (EVs), which represent a crucial mode of intercellular communication, play important roles in cancer progression by transferring oncogenic materials. Nickel (Ni) has been identified as a human group I carcinogen; however, the underlying mechanisms governing Ni-induced carcinogenesis are still being elucidated. Here, we present data demonstrating that Ni exposure generates EVs that contribute to Ni-mediated carcinogenesis and cancer progression. Human bronchial epithelial (BEAS-2B) cells and human embryonic kidney-293 (HEK293) cells were chronically exposed to Ni to generate Ni-treated cells (Ni-6W), Ni-transformed BEAS-2B cells (Ni-3) and Ni-transformed HEK293 cells (HNi-4). The signatures of EVs isolated from Ni-6W, Ni-3, HNi-4, BEAS-2B, and HEK293 were analyzed. Compared to their respective untreated cells, Ni-6W, Ni-3, and HNi-4 released more EVs. This change in EV release coincided with increased transcription of the EV biogenesis markers CD82, CD63, and flotillin-1 (FLOT). Additionally, EVs from Ni-transformed cells had enriched protein and RNA, a phenotype also observed in other studies characterizing EVs from cancer cells. Interestingly, both epithelial cells and human umbilical vein endothelial (HUVEC) cells showed a preference for taking up Ni-altered EVs compared to EVs released from the untreated cells. Moreover, these Ni-altered EVs induced inflammatory responses in both epithelial and endothelial cells and increased the expression of coagulation markers in endothelial cells. Prolonged treatment of Ni-alerted EVs for two weeks induced the epithelial-to-mesenchymal transition (EMT) in BEAS-2B cells. This study is the first to characterize the effect of Ni on EVs and suggests the potential role of EVs in Ni-induced cancer progression.
PMCID:9785150
PMID: 36555753
ISSN: 1422-0067
CID: 5394752
Life stressors significantly impact long-term outcomes and post-acute symptoms 12-months after COVID-19 hospitalization
BACKGROUND:Limited data exists evaluating predictors of long-term outcomes after hospitalization for COVID-19. METHODS:We conducted a prospective, longitudinal cohort study of patients hospitalized for COVID-19. The following outcomes were collected at 6 and 12-months post-diagnosis: disability using the modified Rankin Scale (mRS), activities of daily living assessed with the Barthel Index, cognition assessed with the telephone Montreal Cognitive Assessment (t-MoCA), Neuro-QoL batteries for anxiety, depression, fatigue and sleep, and post-acute symptoms of COVID-19. Predictors of these outcomes, including demographics, pre-COVID-19 comorbidities, index COVID-19 hospitalization metrics, and life stressors, were evaluated using multivariable logistic regression. RESULTS:Of 790 COVID-19 patients who survived hospitalization, 451(57%) completed 6-month (N = 383) and/or 12-month (N = 242) follow-up, and 77/451 (17%) died between discharge and 12-month follow-up. Significant life stressors were reported in 121/239 (51%) at 12-months. In multivariable analyses, life stressors including financial insecurity, food insecurity, death of a close contact and new disability were the strongest independent predictors of worse mRS, Barthel Index, depression, fatigue, and sleep scores, and prolonged symptoms, with adjusted odds ratios ranging from 2.5 to 20.8. Other predictors of poor outcome included older age (associated with worse mRS, Barthel, t-MoCA, depression scores), baseline disability (associated with worse mRS, fatigue, Barthel scores), female sex (associated with worse Barthel, anxiety scores) and index COVID-19 severity (associated with worse Barthel index, prolonged symptoms). CONCLUSIONS:Life stressors contribute substantially to worse functional, cognitive and neuropsychiatric outcomes 12-months after COVID-19 hospitalization. Other predictors of poor outcome include older age, female sex, baseline disability and severity of index COVID-19.
PMCID:9637014
PMID: 36379135
ISSN: 1878-5883
CID: 5383312
Temporal judgments of actions following unilateral brain damage
Sense of time is a complex construct, and its neural correlates remain to date in most part unknown. To complicate the frame, physical attributes of the stimulus, such as its intensity or movement, influence temporal perception. Although previous studies have shown that time perception can be compromised after a brain lesion, the evidence on the role of the left and right hemispheres are meager. In two experiments, the study explores the ability of temporal estimation of multi-second actions and non-biological movements in 33 patients suffering from unilateral brain lesion. Furthermore, the modulatory role of induced embodiment processes is investigated. The results reveal a joint contribution of the two hemispheres depending not only on different durations but also on the presence of actions. Indeed, the left hemisphere damaged patients find it difficult to estimate 4500 ms or longer durations, while the right hemisphere damaged patients fail in 3000 ms durations. Furthermore, the former fail when a biological action is shown, while the latter fail in non-biological movement. Embodiment processes have a modulatory effect only after right hemisphere lesions. Among neuropsychological variables, only spatial neglect influences estimation of non-biological movement.
PMCID:9755153
PMID: 36522442
ISSN: 2045-2322
CID: 5382422
Progressive multifocal leukoencephalopathy in anti-CD20 and other monoclonal antibody (mAb) therapies used in multiple sclerosis: A review
Progressive multifocal leukoencephalopathy (PML) is a subacute CNS inflammatory disease seen primarily among immunocompromised patients. It is caused by the JC virus (JCV), a polyomavirus that otherwise induces an insidious, latent infection in the general population. This reactivated disease is characterized by cognitive and behavioral changes, language disturbances, motor weakness, or visual deficits. Median survival in patients with AIDS is approximately 2-4 months, and mortality is high (around 4% in untreated AIDS). Recent scientific developments indicate that PML can also be associated with the increased utilization of monoclonal antibody (mAb) immunotherapy. In fact, PML has been witnessed with several mAbs, including natalizumab in multiple sclerosis, rituximab for lymphoma or lupus, efalizumab for psoriasis, and ofatumumab in leukemia; this leads us to the risk reassessment of PML due to treatment-induced immunosuppression. The range of clinical presentations of JCV-related disease has transformed over time and can pose significant challenges to the current diagnostic criteria. Most cases with PML suffer from persistent and irreversible neurological conditions, and some with chronic, low-level viral replication in the CNS. With the expanded use of mAbs for various autoimmune and lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and other recently approved therapies. This article aims to review the relationship between the incidence of PML and all four mAbs used in the treatment of MS. Currently, at least 18 FDA-approved medications carry label warnings for PML;to this date, no treatment has been convincingly effective.
PMID: 36283150
ISSN: 1878-5883
CID: 5843562
Clinical Reasoning: Patient With Prior Spinal Cord Injury Who Developed Altered Mental Status After a Fall
An 18-year-old male with a history of complete traumatic spinal cord injury (SCI) at C5-C7 three years prior presented with unresponsiveness and hypoxia after a fall. There were no overt signs of bruising or swelling. After extensive and unrevealing initial workup, MRI brain without contrast showed numerous diffusely scattered punctate foci of diffusion restriction and evidence of numerous microhemorrhages. A full body skeletal survey revealed mildly impacted, nondisplaced, incomplete fractures in the distal femoral metaphyses bilaterally. This case presentation discusses specific considerations for patients with SCI, reviewing the differential diagnosis, workup and management of altered mental status after minor falls or other trauma in this population.
PMID: 36175149
ISSN: 1526-632x
CID: 5334552
An evaluation of surrogate decision maker health literacy in the neurology ward and neuroscience ICU
PURPOSE/OBJECTIVE:There has been little investigation into surrogate comprehension of education provided by the neuroscience healthcare team. We sought to evaluate 1) surrogate understanding about a patient's clinical condition and 2) the relationship between how surrogates and the neuroscience team perceive surrogate comprehension of a patient's condition. METHODS:We prospectively surveyed surrogates of patients who lacked decision making capacity while admitted to the neurology ward or neuroscience ICU for >48 h from 10/2018-05/2021. The survey investigated the surrogate's communication with the neuroscience team and understanding of the hospitalization. A member of the neuroscience team was asked to provide clinical data about the patient and indicate how well they perceived the surrogate understood the situation. RESULTS:We surveyed 50 surrogates at a median of 10 (IQR 5-17) days after hospitalization. There were 38 (76%) surrogates who correctly identified the reason for admission, and 21 (42%) who correctly identified all the assessments/interventions performed. Nearly all surrogates rated their understanding of the patient's medical condition as excellent (47%) or good (49%). There was no to slight agreement (kappa = 0.133) between surrogate self-perception of understanding and neuroscience team perception of the surrogate's understanding. Although only 20% of surrogates used institutional electronic education materials, 74% discussed the hospitalization with friends/family who work in healthcare. CONCLUSION/CONCLUSIONS:Objective and subjective assessments of surrogate comprehension demonstrate that there is a need to improve communication with the surrogates of patients with neurological conditions. Neuroscience healthcare teams must be taught how to educate surrogates and assess their understanding.
PMID: 36525907
ISSN: 1878-5883
CID: 5382542
Phenotyping autonomic neuropathy using principal component analysis
To identify autonomic neuropathy (AN) phenotypes, we used principal component analysis on data from participants (N = 209) who underwent standardized autonomic testing including quantitative sudomotor axon reflex testing, and heart rate and blood pressure at rest and during tilt, Valsalva, and standardized deep breathing. The analysis identified seven clusters: 1) normal, 2) hyperadrenergic features without AN, 3) mild AN with hyperadrenergic features, 4) moderate AN, 5) mild AN with hypoadrenergic features, 6) borderline AN with hypoadrenergic features, 7) mild balanced deficits across parasympathetic, sympathetic and sudomotor domains. These findings demonstrate a complex relationship between adrenergic and other aspects of autonomic function.
PMID: 36525943
ISSN: 1872-7484
CID: 5382552
First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B
Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.
PMID: 36299240
ISSN: 1525-0024
CID: 5359542
Federated learning enables big data for rare cancer boundary detection
Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing.
PMCID:9722782
PMID: 36470898
ISSN: 2041-1723
CID: 5381682
