Clinical Focus

  • Residency
  • genomics
  • neurology

All Publications

  • Impacts of Climate Change and Air Pollution on Neurologic Health, Disease, and Practice A Scoping Review NEUROLOGY Louis, S., Carlson, A. K., Suresh, A., Rim, J., Mays, M., Ontaneda, D., Dhawan, A. 2023; 100 (10): 474-483


    Although the international community collectively seeks to reduce global temperature rise to less than 1.5°C before 2100, irreversible environmental changes have already occurred, and as the planet warms, these changes will continue to occur. As we witness the effects of a warming planet on human health, it is imperative that neurologists anticipate how the epidemiology and incidence of neurologic disease may change. In this review, we organized our analysis around 3 key themes related to climate change and neurologic health: extreme weather events and temperature fluctuations, emerging neuroinfectious diseases, and pollutant impacts. Across each of these themes, we appraised and reviewed recent literature relevant to neurologic disease and practice.Studies were identified using search terms relating to climate change, pollutants, and neurologic disease in PubMed, OVID MEDLINE, EMBASE, PsycInfo, and gray literature. Studies published between 1990 and 2022 were included if they pertained to human incidence or prevalence of disease, were in English, and were relevant to neurologic disease.We identified a total of 364 articles, grouped into the 3 key themes of our study: extreme weather events and temperature fluctuations (38 studies), emerging neuroinfectious diseases (37 studies), and pollutant impacts (289 studies). The included studies highlighted the relationships between neurologic symptom exacerbation and temperature variability, tick-borne infections and warming climates, and airborne pollutants and cerebrovascular disease incidence and severity.Temperature extremes and variability both associated with stroke incidence and severity, migraine headaches, hospitalization in patients with dementia, and multiple sclerosis exacerbations. Exposure to airborne pollutants, especially PM2.5 and nitrates, associated with stroke incidence and severity, headaches, dementia risk, Parkinson disease, and MS exacerbation. Climate change has demonstrably expanded favorable conditions for zoonotic diseases beyond traditional borders and poses the risk of disease in new, susceptible populations. Articles were biased toward resource-rich regions, suggesting a discordance between where research occurs and where changes are most acute. As such, 3 key priorities emerged for further study: neuroinfectious disease risk mitigation, understanding the pathophysiology of airborne pollutants on the nervous system, and methods to improve delivery of neurologic care in the face of climate-related disruptions.

    View details for DOI 10.1212/WNL.0000000000201630

    View details for Web of Science ID 000971804700004

    View details for PubMedID 36384657

    View details for PubMedCentralID PMC9990849

  • Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study FRONTIERS IN NEUROLOGY Louis, S., Busch, R. M., Lal, D., Hockings, J., Hogue, O., Morita-Sherman, M., Vegh, D., Najm, I., Ghosh, C., Bazeley, P., Eng, C., Jehi, L., Rotroff, D. M. 2022; 13: 942643


    Seizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are very heterogeneous and difficult to predict with models utilizing the current clinical, imaging, and electrophysiological variables. In this pilot study, we investigated whether genetic and molecular biomarkers (e.g., genomic, transcriptomic) can provide additional insight into differential response to surgery.Post-operative seizure-outcomes were collected at last follow-up (>6 months) for 201 adult patients with DRE who underwent surgery between 2004 and 2020. Resected tissue was sent for miRNA sequencing (n = 132) and mRNA sequencing (n = 135). Following the selection of 10 genes (SCN1A, NBEA, PTEN, GABRA1, LGL1, DEPDC5, IL1A, ABCB1, C3, CALHM1), we investigated SNPs in those 10 genes from previously acquired exome sequencing data (n = 106). Logistic regression was performed to test for associations between individual features (mRNAs, miRNAs, and SNPs) and post-operative seizure-outcome with an exploratory FDR P < 0.25 as the threshold for significance. Post-operative time-to-seizure analyses were performed for each SNP using a Cox proportional hazards model.The majority of patients (83%) had temporal lobe epilepsy. Mean age at surgery was 38.3 years, and 56% were female. Three SNPs (rs10276036, rs11975994, rs1128503) in multi-drug resistance gene, ABCB1, were associated with post-operative seizure outcomes. Patients with alternate alleles in ABCB1 were more likely to be seizure-free at last follow-up (52-56% reduction in seizure recurrence; FDR P = 0.24). All three SNPs were in linkage disequilibrium and highly correlated with each other. Median post-operative time-to-seizure was 63 months for patients with 2 alternate alleles, 24-33 months with 1 alternate allele, and 10-11 months with 0 alternate alleles. These SNPs improved outcome prediction beyond MRI and sex alone. No independent miRNAs or mRNAs were significantly associated with seizure-outcome (P > 0.05). However, pathway analysis identified "cancer drug resistance by drug efflux" (mir-154 and mir-379) as enriched (P = 0.02), supporting the role of drug response genes in post-operative seizure recurrence.ABCB1 may have a role in epileptogenesis and surgery outcomes independent of its drug efflux activity necessitating further investigation. SNPs in ABCB1 may serve as independent predictors of post-operative outcome.

    View details for DOI 10.3389/fneur.2022.942643

    View details for Web of Science ID 000862661900001

    View details for PubMedID 36188379

    View details for PubMedCentralID PMC9524264

  • Disparities in the nationwide distribution of epilepsy centers EPILEPSY & BEHAVIOR Louis, S., Rabah, N., Rammo, R., Bingaman, W., Jehi, L. 2021; 125: 108409


    Prior studies in the field of epilepsy surgical disparities have examined barriers in undergoing epilepsy surgical resections in disadvantaged populations involving trust in health providers, education level, social support, and fear of treatment. Few studies have analyzed the geographical locations of specialized epilepsy centers and their role in nationwide epilepsy surgical access and disparities.To better visualize the locations of epilepsy level IV centers in the United States with respect to epilepsy prevalence and socioeconomic disadvantage.We created heat maps of the United States to visualize geographical locations of level IV epilepsy centers with respect to the 2015 state-wide epilepsy prevalence and 2017 county-wide Area Deprivation Index (ADI) scores, a composite measure of socioeconomic disadvantage. Univariate logistic regression was used to test for associations between the presence or absence of epilepsy centers and socioeconomic disadvantage.We found eight states within the United States without any level IV epilepsy centers. In states with level IV centers, centers were clustered in populated and metropolitan regions. Disadvantaged counties (with increased ADI scores) were less likely to have level IV centers compared to counties that were less disadvantaged (lower ADI scores) (p < 0.00001).Further work is required to remedy the decreased access to specialized epilepsy care due to geographical disparities, and to better understand its contribution to overall disparities affecting epilepsy surgery referrals.

    View details for DOI 10.1016/j.yebeh.2021.108409

    View details for Web of Science ID 000728113000016

    View details for PubMedID 34788733

  • Incorporation of quantitative MRI in a mode to predict temporal lobe epilepsy surgery outcome BRAIN COMMUNICATIONS Morita-Sherman, M., Li, M., Joseph, B., Yasuda, C., Vegh, D., De Campos, B., Alvim, M. M., Louis, S., Bingaman, W., Najm, I., Jones, S., Wang, X., Bluemcke, I., Brinkmann, B. H., Worrell, G., Cendes, F., Jehi, L. 2021; 3 (3): fcab164


    Quantitative volumetric brain MRI measurement is important in research applications, but translating it into patient care is challenging. We explore the incorporation of clinical automated quantitative MRI measurements in statistical models predicting outcomes of surgery for temporal lobe epilepsy. Four hundred and thirty-five patients with drug-resistant epilepsy who underwent temporal lobe surgery at Cleveland Clinic, Mayo Clinic and University of Campinas were studied. We obtained volumetric measurements from the pre-operative T1-weighted MRI using NeuroQuant, a Food and Drug Administration approved software package. We created sets of statistical models to predict the probability of complete seizure-freedom or an Engel score of I at the last follow-up. The cohort was randomly split into training and testing sets, with a ratio of 7:3. Model discrimination was assessed using the concordance statistic (C-statistic). We compared four sets of models and selected the one with the highest concordance index. Volumetric differences in pre-surgical MRI located predominantly in the frontocentral and temporal regions were associated with poorer outcomes. The addition of volumetric measurements to the model with clinical variables alone increased the model's C-statistic from 0.58 to 0.70 (right-sided surgery) and from 0.61 to 0.66 (left-sided surgery) for complete seizure freedom and from 0.62 to 0.67 (right-sided surgery) and from 0.68 to 0.73 (left-sided surgery) for an Engel I outcome score. 57% of patients with extra-temporal abnormalities were seizure-free at last follow-up, compared to 68% of those with no such abnormalities (P-value = 0.02). Adding quantitative MRI data increases the performance of a model developed to predict post-operative seizure outcomes. The distribution of the regions of interest included in the final model supports the notion that focal epilepsies are network disorders and that subtle cortical volume loss outside the surgical site influences seizure outcome.

    View details for DOI 10.1093/braincomms/fcab164

    View details for Web of Science ID 000734327400036

    View details for PubMedID 34396113

    View details for PubMedCentralID PMC8361423

  • Continuous electroencephalography characteristics and acute symptomatic seizures in COVID-19 patients CLINICAL NEUROPHYSIOLOGY Louis, S., Dhawan, A., Newey, C., Nair, D., Jehi, L., Hantus, S., Punia, V. 2020; 131 (11): 2651-2656


    As concerns regarding neurological manifestations in COVID-19 (coronavirus disease 2019) patients increase, limited data exists on continuous electroencephalography (cEEG) findings in these patients. We present a retrospective cohort study of cEEG monitoring in COVID-19 patients to better explore this knowledge gap.Among 22 COVID-19 patients, 19 underwent cEEGs, and 3 underwent routine EEGs (<1 h). Demographic and clinical variables, including comorbid conditions, discharge disposition, survival and cEEG findings, were collected.cEEG was performed for evaluation of altered mental status (n = 17) or seizure-like events (n = 5). Five patients, including 2 with epilepsy, had epileptiform abnormalities on cEEG. Two patients had electrographic seizures without a prior epilepsy history. There were no acute neuroimaging findings. Periodic discharges were noted in one-third of patients and encephalopathic EEG findings were not associated with IV anesthetic use.Interictal epileptiform abnormalities in the absence of prior epilepsy history were rare. However, the discovery of asymptomatic seizures in two of twenty-two patients was higher than previously reported and is therefore of concern.cEEG monitoring in COVID-19 patients may aid in better understanding an epileptogenic potential of SARS-CoV2 infection. Nevertheless, larger studies utilizing cEEG are required to better examine acute epileptic risk in COVID-19 patients.

    View details for DOI 10.1016/j.clinph.2020.08.003

    View details for Web of Science ID 000580661200016

    View details for PubMedID 32949985

    View details for PubMedCentralID PMC7448875

  • Outcomes of resections that spare vs remove an MRI-normal hippocampus EPILEPSIA Morita-Sherman, M., Louis, S., Vegh, D., Busch, R. M., Ferguson, L., Bingaman, J., Bulacio, J., Najm, I., Jones, S., Zajichek, A., Hogue, O., Kattan, M. W., Blumcke, I., Cendes, F., Jehi, L. 2020; 61 (11): 2545-2557


    To characterize seizure and cognitive outcomes of sparing vs removing an magnetic resonance imaging (MRI)-normal hippocampus in patients with temporal lobe epilepsy.In this retrospective cohort study, we reviewed clinical, imaging, surgical, and histopathological data on 152 individuals with temporal lobe epilepsy and nonlesional hippocampi categorized into hippocampus-spared (n = 74) or hippocampus-resected (n = 78). Extra-hippocampal lesions were allowed. Pre- and postoperative cognitive data were available on 86 patients. Predictors of seizure and cognitive outcomes were identified using Cox-proportional hazard modeling followed by treatment-specific model reduction according to Akaike information criterion, and built into an online risk calculator.Seizures recurred in 40% within one postoperative year, and in 63% within six postoperative years. Male gender (P = .03), longer epilepsy duration (P < .01), normal MRI (P = .04), invasive evaluation (P = .02), and acute postoperative seizures (P < .01) were associated with a higher risk of recurrence. We found no significant difference in postoperative seizure freedom rates at 5 years between those whose hippocampus was spared and those whose hippocampus was resected (P = .17). Seizure outcome models built with pre- and postoperative data had bootstrap validated concordance indices of 0.65 and 0.72. The dominant hippocampus-spared group had lower rates of decline in verbal memory (39% vs 70%; P = .03) and naming (41% vs 79%; P = .01) compared to the hippocampus-resected group. Partial hippocampus sparing had the same risk of verbal memory decline as for complete removal.Sparing or removing an MRI-normal hippocampus yielded similar long-term seizure outcome. A more conservative approach, sparing the hippocampus, only partially shields patients from postoperative cognitive deficits. Risk calculators are provided to facilitate clinical counseling.

    View details for DOI 10.1111/epi.16694

    View details for Web of Science ID 000578378600001

    View details for PubMedID 33063852

    View details for PubMedCentralID PMC7879196

  • Hippocampal Sclerosis Detection with NeuroQuant Compared with Neuroradiologists AMERICAN JOURNAL OF NEURORADIOLOGY Louis, S., Morita-Sherman, M., Jones, S., Vegh, D., Bingaman, W., Blumcke, I., Obuchowski, N., Cendes, F., Jehi, L. 2020; 41 (4): 591-597


    NeuroQuant is an FDA-approved software that performs automated MR imaging quantitative volumetric analysis. This study aimed to compare the accuracy of NeuroQuant analysis with visual MR imaging analysis by neuroradiologists with expertise in epilepsy in identifying hippocampal sclerosis.We reviewed 144 adult patients who underwent presurgical evaluation for temporal lobe epilepsy. The reference standard for hippocampal sclerosis was defined by having hippocampal sclerosis on pathology (n = 61) or not having hippocampal sclerosis on pathology (n = 83). Sensitivities, specificities, positive predictive values, and negative predictive values were compared between NeuroQuant analysis and visual MR imaging analysis by using a McNemar paired test of proportions and the Bayes theorem.NeuroQuant analysis had a similar specificity to neuroradiologist visual MR imaging analysis (90.4% versus 91.6%; P = .99) but a lower sensitivity (69.0% versus 93.0%, P < .001). The positive predictive value of NeuroQuant analysis was comparable with visual MR imaging analysis (84.0% versus 89.1%), whereas the negative predictive value was not comparable (79.8% versus 95.0%).Visual MR imaging analysis by a neuroradiologist with expertise in epilepsy had a higher sensitivity than did NeuroQuant analysis, likely due to the inability of NeuroQuant to evaluate changes in hippocampal T2 signal or architecture. Given that there was no significant difference in specificity between NeuroQuant analysis and visual MR imaging analysis, NeuroQuant can be a valuable tool when the results are positive, particularly in centers that lack neuroradiologists with expertise in epilepsy, to help identify and refer candidates for temporal lobe epilepsy resection. In contrast, a negative test could justify a case referral for further evaluation to ensure that false-negatives are detected.

    View details for DOI 10.3174/ajnr.A6454

    View details for Web of Science ID 000526820700013

    View details for PubMedID 32217554

    View details for PubMedCentralID PMC7144657

  • The efficacy of intraoperative multimodal monitoring in pedicle subtraction osteotomies of the lumbar spine Shao, J., Lee, M. Y., Louis, S., Knusel, K., Lee, B. S., Pelle, D. W., Savage, J., Tanenbaum, J. E., Mroz, T. E., Steinmetz, M. P. AMER ASSOC NEUROLOGICAL SURGEONS. 2019: 683-690


    Iatrogenic spine injury remains one of the most dreaded complications of pedicle subtraction osteotomies (PSOs) and spine deformity surgeries. Thus, intraoperative multimodal monitoring (IOM), which has the potential to provide real-time feedback on spinal cord signal transmission, has become the gold standard in such operations. However, while the benefits of IOM are well established in PSOs of the thoracic spine and scoliosis surgery, its utility in PSOs of the lumbar spine has not been robustly documented. The authors' aim was to determine the impact of IOM on outcomes in patients undergoing PSO of the lumbar spine.All patients older than 18 years who underwent lumbar PSOs at the authors' institution from 2007 to 2017 were analyzed via retrospective chart review and categorized into one of two groups: those who had IOM guidance and those who did not. Perioperative complications were designated as the primary outcome measure and postoperative quality of life (QOL) scores, specifically the Parkinson's Disease Questionnaire-39 (PDQ-39) and Patient Health Questionnaire-9 (PHQ-9), were designated as secondary outcome measures. Data on patient demographics, surgical and monitoring parameters, and outcomes were gathered, and statistical analysis was performed to compare the development of perioperative complications and QOL scores between the two cohorts. In addition, the proportion of patients who reached minimal clinically important difference (MCID), defined as an increase of 4.72 points in the PDQ-39 score or a decrease of 5 points in the PHQ-9 score, in the two cohorts was also determined.A total of 95 patients were included in the final analysis. IOM was not found to significantly impact the development of new postoperative deficits (p = 0.107). However, the presence of preoperative neurological comorbidities was found to significantly correlate with postoperative neurological complications (p = 0.009). Univariate analysis showed that age was positively correlated with MCID achievement 3 months after surgery (p = 0.018), but this significance disappeared at the 12-month postoperative time point (p = 0.858). IOM was not found to significantly impact MCID achievement at either the 3- or 12-month postoperative period as measured by PDQ-39 (p = 0.398 and p = 0.156, respectively). Similarly, IOM was not found to significantly impact MCID achievement at either the 3- or 12-month postoperative period, as measured by PHQ-9 (p = 0.230 and p = 0.542, respectively). Multivariate analysis showed that female sex was significantly correlated with MCID achievement (p = 0.024), but this significance disappeared at the 12-month postoperative time point (p = 0.064). IOM was not found to independently correlate with MCID achievement in PDQ-39 scores at either the 3- or 12-month postoperative time points (p = 0.220 and p = 0.097, respectively).In this particular cohort, IOM did not lead to statistically significant improvement in outcomes in patients undergoing PSOs of the lumbar spine (p = 0.220). The existing clinical equipoise, however, indicates that future studies in this arena are necessary to achieve systematic guidelines on IOM usage in PSOs of the lumbar spine.

    View details for DOI 10.3171/2019.5.SPINE19125

    View details for Web of Science ID 000493980000008

    View details for PubMedID 31349220

  • Discovering human diabetes-risk gene function with genetics and physiological assays NATURE COMMUNICATIONS Peiris, H., Park, S., Louis, S., Gu, X., Lam, J. Y., Asplund, O., Ippolito, G. C., Bottino, R., Groop, L., Tucker, H., Kim, S. K. 2018; 9: 3855


    Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.

    View details for PubMedID 30242153

  • Germline Chd8 haploinsufficiency alters brain development in mouse NATURE NEUROSCIENCE Gompers, A. L., Su-Feher, L., Ellegood, J., Copping, N. A., Riyadh, M., Stradleigh, T. W., Pride, M. C., Schaffler, M. D., Wade, A., Catta-Preta, R., Zdilar, I., Louis, S., Kaushik, G., Mannion, B. J., Plajzer-Frick, I., Afzal, V., Visel, A., Pennacchio, L. A., Dickel, D. E., Lerch, J. P., Crawley, J. N., Zarbalis, K. S., Silverman, J. L., Nord, A. S. 2017; 20 (8): 1062-+


    The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.

    View details for DOI 10.1038/nn.4592

    View details for Web of Science ID 000406298900007

    View details for PubMedID 28671691

    View details for PubMedCentralID PMC6008102