Faculty Bibliography

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug-resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05-.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care.

OBJECTIVE:Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. METHODS:Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. RESULTS:Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. SIGNIFICANCE/CONCLUSIONS:This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS:statistics, and logistic regression analyses. RESULTS:A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION/CONCLUSIONS:In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Identification of an epileptogenic lesion on structural neuroimaging in individuals with focal epilepsy is important for management and treatment planning. The objective of this study was to determine the frequency of MRI-identified potentially epileptogenic structural abnormalities in a large multicenter study of adolescent and adult patients with newly diagnosed focal epilepsy. METHODS:Patients with a new diagnosis of focal epilepsy enrolled in the Human Epilepsy Project observational cohort study underwent 3-Tesla (3T) brain MRI using a standardized protocol. Imaging findings were classified as normal, abnormal, or incidental. Abnormal findings were classified as focal or diffuse, and as likely epilepsy-related or of unknown relationship to epilepsy. Fisher exact tests were performed to determine whether abnormal imaging or abnormality type was associated with clinical characteristics. RESULTS:418 participants were enrolled. 218 participants (59.3%) had no abnormalities detected, 149 (35.6%) had abnormal imaging, and 21 (5.0%) had incidental findings. 78 participants (18.7%) had abnormalities that were considered epilepsy-related and 71 (17.0%) had abnormalities of unknown relationship to epilepsy. Older participants were more likely to have imaging abnormalities, while participants with focal and epilepsy-related imaging abnormalities were younger than those without these abnormalities. 131 participants (31.3%) had a family history of epilepsy. Epilepsy-related abnormalities were not associated with participant sex, family history of epilepsy, or seizure type. DISCUSSION/CONCLUSIONS:We found that one in five patients with newly diagnosed focal epilepsy has an MRI finding that is likely causative and may alter treatment options. An additional one in five patients has abnormalities of unknown significance. This information is important for patient counseling, prognostication, and management.

PURPOSE/OBJECTIVE:A device that provides continuous, long-term, accurate seizure detection information to providers and patients could fundamentally alter epilepsy care. Subgaleal (SG) EEG is a promising modality that offers a minimally invasive, safe, and accurate means of long-term seizure monitoring. METHODS:Subgaleal EEG electrodes were placed, at or near the cranial vertex, simultaneously with intracranial EEG electrodes in 21 epilepsy patients undergoing intracranial EEG studies for up to 13 days. A total of 219, 10-minute single-channel SGEEG samples, including 138 interictal awake or sleep segments and 81 seizures (36 temporal lobe, 32 extra-temporal, and 13 simultaneous temporal/extra-emporal onsets) were reviewed by 3 expert readers blinded to the intracranial EEG results, then analyzed for accuracy and interrater reliability. RESULTS:Using a single-channel of SGEEG, reviewers accurately identified 98% of temporal and extratemporal onset, intracranial, EEG-verified seizures with a sensitivity of 98% and specificity of 99%. All focal to bilateral tonic--clonic seizures were correctly identified. CONCLUSIONS:Single-channel SGEEG, placed at or near the vertex, reliably identifies focal and secondarily generalized seizures. These findings demonstrate that the SG space at the cranial vertex may be an appropriate site for long-term ambulatory seizure monitoring.

AIMS/OBJECTIVE:The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS:Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS:We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS:These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

BACKGROUND:Many electroencephalography (EEG) based seizure detection paradigms have been developed and validated over the last two decades. The majority of clinical approaches use scalp or intracranial EEG electrodes. Scalp EEG is limited by patient discomfort and short duration of useful EEG signals. Intracranial EEG involves an invasive surgical procedure associated with significant risk making it unsuitable for widespread use as a practical clinical biometric. A less invasive EEG monitoring approach, that is between invasive intracranial procedures and noninvasive methods, would fill the need of a safe, accurate, chronic (ultra-long term) and objective seizure detection method. We present validation of a continuous EEG seizure detection paradigm using human single-channel EEG recordings from subcutaneously placed electrodes that could be used to fulfill this need. METHODS:Ten-minute long sleep, awake and ictal EEG epochs obtained from 21 human subjects with subscalp electrodes and validated against simultaneous iEEG recordings were analyzed by three experienced clinical neurophysiologists. The 201subscalp EEG time series epochs where classified as diagnostic for awake, asleep, or seizure by the clinicians who were blinded to all other information. Seventy of the epochs were classified in this way as representing seizure activity. A subject specific seizure detection algorithm was trained and then evaluated offline for each patient in the data set using the expert consensus classification as the gold standard. RESULTS:The average seizure detection performance of the algorithm across 21 subjects exceeded 90 % accuracy: 97 % sensitivity, 91 % specificity, and 93 % accuracy. For 19 of 21 patient datasets the algorithm achieved 100 % sensitivity. For 15 of 21 patients, the algorithm achieved 100 % specificity. For 13 of 21 patients the algorithm achieved 100 % accuracy. COMPARISON/UNASSIGNED:No comparable published methods are available for subgaleal EEG seizure detection. CONCLUSIONS:These findings suggest that a simple seizure detection algorithm using subcutaneous EEG signals could provide sufficient accuracy and clinical utility for use in a low power, long-term subcutaneous brain monitoring device. Such a device would fill a need for a large number of people with epilepsy who currently have no means for accurately quantifying their seizures thereby providing important information to healthcare providers not currently available.

Objective: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.
Method(s): We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.
Result(s): Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.
Significance: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
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BACKGROUND AND PURPOSE/OBJECTIVE:Coronavirus disease 2019 (COVID-19) appears to be an independent risk factor for stroke. We hypothesize that patients who develop stroke while hospitalized for severe COVID-19 will have higher inflammatory markers and distinct stroke imaging patterns compared with patients positive for COVID-19 with out-of-hospital stroke onset and milder or no COVID-19 symptoms. MATERIALS AND METHODS/METHODS:This is a retrospective case series of patients positive for COVID-19 on polymerase chain reaction testing with imaging-confirmed stroke treated within a large health care network in New York City and Long Island between March 14 and April 26, 2020. Clinical and laboratory data collected retrospectively included complete blood counts and creatinine, alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer levels. All CT and MR imaging studies were independently reviewed by 2 neuroradiologists who recorded stroke subtype and patterns of infarction and intracranial hemorrhage. RESULTS:< .003). CONCLUSIONS:Patients with stroke hospitalized with severe COVID-19 are characterized by higher inflammatory, coagulopathy, and tissue-damage biomarkers, supporting proposed pathogenic mechanisms of hyperinflammation activating a prothrombotic state. Cautious balancing of thrombosis and the risk of hemorrhagic transformation is warranted when considering anticoagulation.

PURPOSE/OBJECTIVE:Surgical planning for people with drug resistant non-lesional focal epilepsy can be challenging. Prior studies focus on cases that are only MRI-negative or MRI-negative with PET-positive imaging, but little is known about outcomes in patients with non-lesional findings on both MRI and PET imaging. In this study, we investigate 5-year surgical outcomes in patients who underwent epilepsy surgery for drug resistant MRI/PET-negative focal epilepsy. METHODS:We collected clinical and testing data on 131 consecutive patients with drug resistant non-lesional epilepsy who were presented at a multidisciplinary epilepsy surgery conference at the New York University Comprehensive Epilepsy Center between 2010 and 2014, and identified those who underwent epilepsy surgery in order to review 5-year surgical outcomes. RESULTS:There were 103 with non-lesional MRI studies, and of these, 22 had corresponding non-lesional PET imaging. 14 MRI/PET-negative patients pursued a surgical treatment option and 9 underwent resections after intracranial EEG. At 5 years, 77.8 % of patients had favorable (ILAE class 1 and 2) outcomes. Most (77.8 %) had focal cortical dysplasia type Ia (FCDIa) on pathology. CONCLUSION/CONCLUSIONS:These findings suggest that with careful planning and patient selection, surgery for patients with drug resistant MRI/PET-negative focal epilepsy can be successful.