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A Prospective Study of Neurologic Disorders in Hospitalized COVID-19 Patients in New York City
Frontera, Jennifer A; Sabadia, Sakinah; Lalchan, Rebecca; Fang, Taolin; Flusty, Brent; Millar-Vernetti, Patricio; Snyder, Thomas; Berger, Stephen; Yang, Dixon; Granger, Andre; Morgan, Nicole; Patel, Palak; Gutman, Josef; Melmed, Kara; Agarwal, Shashank; Bokhari, Matthew; Andino, Andres; Valdes, Eduard; Omari, Mirza; Kvernland, Alexandra; Lillemoe, Kaitlyn; Chou, Sherry H-Y; McNett, Molly; Helbok, Raimund; Mainali, Shraddha; Fink, Ericka L; Robertson, Courtney; Schober, Michelle; Suarez, Jose I; Ziai, Wendy; Menon, David; Friedman, Daniel; Friedman, David; Holmes, Manisha; Huang, Joshua; Thawani, Sujata; Howard, Jonathan; Abou-Fayssal, Nada; Krieger, Penina; Lewis, Ariane; Lord, Aaron S; Zhou, Ting; Kahn, D Ethan; Czeisler, Barry M; Torres, Jose; Yaghi, Shadi; Ishida, Koto; Scher, Erica; de Havenon, Adam; Placantonakis, Dimitris; Liu, Mengling; Wisniewski, Thomas; Troxel, Andrea B; Balcer, Laura; Galetta, Steven
OBJECTIVE:To determine the prevalence and associated mortality of well-defined neurologic diagnoses among COVID-19 patients, we prospectively followed hospitalized SARS-Cov-2 positive patients and recorded new neurologic disorders and hospital outcomes. METHODS:We conducted a prospective, multi-center, observational study of consecutive hospitalized adults in the NYC metropolitan area with laboratory-confirmed SARS-CoV-2 infection. The prevalence of new neurologic disorders (as diagnosed by a neurologist) was recorded and in-hospital mortality and discharge disposition were compared between COVID-19 patients with and without neurologic disorders. RESULTS:Of 4,491 COVID-19 patients hospitalized during the study timeframe, 606 (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were: toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). No patient had meningitis/encephalitis, or myelopathy/myelitis referable to SARS-CoV-2 infection and 18/18 CSF specimens were RT-PCR negative for SARS-CoV-2. Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment (SOFA) scores (all P<0.05). After adjusting for age, sex, SOFA-scores, intubation, past history, medical complications, medications and comfort-care-status, COVID-19 patients with neurologic disorders had increased risk of in-hospital mortality (Hazard Ratio[HR] 1.38, 95% CI 1.17-1.62, P<0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, P<0.001). CONCLUSIONS:Neurologic disorders were detected in 13.5% of COVID-19 patients and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness.
PMID: 33020166
ISSN: 1526-632x
CID: 4626712
Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy
Vasudevaraja, Varshini; Rodriguez, Javier Hernaez; Pelorosso, Cristiana; Zhu, Kaicen; Buccoliero, Anna Maria; Onozato, Maristela; Mohamed, Hussein; Serrano, Jonathan; Tredwin, Lily; Garonzi, Marianna; Forcato, Claudio; Zeck, Briana; Ramaswami, Sitharam; Stafford, James; Faustin, Arline; Friedman, Daniel; Hidalgo, Eveline Teresa; Zagzag, David; Skok, Jane; Heguy, Adriana; Chiriboga, Luis; Conti, Valerio; Guerrini, Renzo; Iafrate, A John; Devinsky, Orrin; Tsirigos, Aristotelis; Golfinos, John G; Snuderl, Matija
Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders.
PMID: 33274363
ISSN: 1554-6578
CID: 4694512
Association of peri-ictal brainstem posturing with seizure severity and breathing compromise in patients with generalized convulsive seizures
Vilella, Laura; Lacuey, Nuria; Hampson, Johnson P; Zhu, Liang; Omidi, Shirin; Ochoa-Urrea, Manuela; Tao, Shiqiang; Rani, M R Sandhya; Sainju, Rup K; Friedman, Daniel; Nei, Maromi; Strohl, Kingman; Scott, Catherine; Allen, Luke; Gehlbach, Brian K; Hupp, Norma J; Hampson, Jaison S; Shafiabadi, Nassim; Zhao, Xiuhe; Reick-Mitrisin, Victoria; Schuele, Stephan; Ogren, Jennifer; Harper, Ronald M; Diehl, Beate; Bateman, Lisa M; Devinsky, Orrin; Richerson, George B; Ryvlin, Philippe; Zhang, G Q; Lhatoo, Samden D
OBJECTIVE:To analyze the association between peri-ictal brainstem posturing semiologies with post-ictal generalized electroencephalographic suppression (PGES) and breathing dysfunction in generalized convulsive seizures (GCS). METHODS:Prospective, multicenter analysis of GCS. Ictal brainstem semiology was classified as (1) decerebration: bilateral symmetric tonic arm extension, (2) decortication: bilateral symmetric tonic arm flexion only, (3) hemi-decerebration: unilateral tonic arm extension with contralateral flexion and (4) absence of ictal tonic phase. Post-ictal posturing was also assessed. Respiration was monitored using thoraco-abdominal belts, video and pulse oximetry. RESULTS:= 0.035). CONCLUSIONS:recovery. Peri-ictal brainstem posturing may be surrogate biomarkers for GCS severity identifiable without in-hospital monitoring. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that peri-ictal brainstem posturing is associated with the GCS with more prolonged PGES and more severe breathing dysfunction.
PMID: 33268557
ISSN: 1526-632x
CID: 4694292
Automated Analysis of Risk Factors for Postictal Generalized EEG Suppression
Zhao, Xiuhe; Vilella, Laura; Zhu, Liang; Rani, M R Sandhya; Hampson, Johnson P; Hampson, Jaison; Hupp, Norma J; Sainju, Rup K; Friedman, Daniel; Nei, Maromi; Scott, Catherine; Allen, Luke; Gehlbach, Brian K; Schuele, Stephan; Harper, Ronald M; Diehl, Beate; Bateman, Lisa M; Devinsky, Orrin; Richerson, George B; Zhang, Guo-Qiang; Lhatoo, Samden D; Lacuey, Nuria
Rationale: Currently, there is some ambiguity over the role of postictal generalized electro-encephalographic suppression (PGES) as a biomarker in sudden unexpected death in epilepsy (SUDEP). Visual analysis of PGES, known to be subjective, may account for this. In this study, we set out to perform an analysis of PGES presence and duration using a validated signal processing tool, specifically to examine the association between PGES and seizure features previously reported to be associated with visually analyzed PGES. Methods: This is a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of SUDEP in adult patients with intractable epilepsy. We studied videoelectroencephalogram (vEEG) recordings of generalized convulsive seizures (GCS) in a cohort of patients in whom respiratory and vEEG recording were carried out during the evaluation in the epilepsy monitoring unit. A validated automated EEG suppression detection tool was used to determine presence and duration of PGES. Results: We studied 148 GCS in 87 patients. PGES occurred in 106/148 (71.6%) seizures in 70/87 (80.5%) of patients. PGES mean duration was 38.7 ± 23.7 (37; 1-169) seconds. Presence of tonic phase during GCS, including decerebration, decortication and hemi-decerebration, were 8.29 (CI 2.6-26.39, p = 0.0003), 7.17 (CI 1.29-39.76, p = 0.02), and 4.77 (CI 1.25-18.20, p = 0.02) times more likely to have PGES, respectively. In addition, presence of decerebration (p = 0.004) and decortication (p = 0.02), older age (p = 0.009), and hypoxemia duration (p = 0.03) were associated with longer PGES durations. Conclusions: In this study, we confirmed observations made with visual analysis, that presence of tonic phase during GCS, longer hypoxemia, and older age are reliably associated with PGES. We found that of the different types of tonic phase posturing, decerebration has the strongest association with PGES, followed by decortication, followed by hemi-decerebration. This suggests that these factors are likely indicative of seizure severity and may or may not be associated with SUDEP. An automated signal processing tool enables objective metrics, and may resolve apparent ambiguities in the role of PGES in SUDEP and seizure severity studies.
PMCID:8148040
PMID: 34046007
ISSN: 1664-2295
CID: 4888312
Seizure Clusters, Seizure Severity Markers, and SUDEP Risk
Ochoa-Urrea, Manuela; Lacuey, Nuria; Vilella, Laura; Zhu, Liang; Jamal-Omidi, Shirin; Rani, M R Sandhya; Hampson, Johnson P; Dayyani, Mojtaba; Hampson, Jaison; Hupp, Norma J; Tao, Shiqiang; Sainju, Rup K; Friedman, Daniel; Nei, Maromi; Scott, Catherine; Allen, Luke; Gehlbach, Brian K; Reick-Mitrisin, Victoria; Schuele, Stephan; Ogren, Jennifer; Harper, Ronald M; Diehl, Beate; Bateman, Lisa M; Devinsky, Orrin; Richerson, George B; Zhang, Guo-Qiang; Lhatoo, Samden D
Rationale: Seizure clusters may be related to Sudden Unexpected Death in Epilepsy (SUDEP). Two or more generalized convulsive seizures (GCS) were captured during video electroencephalography in 7/11 (64%) patients with monitored SUDEP in the MORTEMUS study. It follows that seizure clusters may be associated with epilepsy severity and possibly with SUDEP risk. We aimed to determine if electroclinical seizure features worsen from seizure to seizure within a cluster and possible associations between GCS clusters, markers of seizure severity, and SUDEP risk. Methods: Patients were consecutive, prospectively consented participants with drug-resistant epilepsy from a multi-center study. Seizure clusters were defined as two or more GCS in a 24-h period during the recording of prolonged video-electroencephalography in the Epilepsy monitoring unit (EMU). We measured heart rate variability (HRV), pulse oximetry, plethysmography, postictal generalized electroencephalographic suppression (PGES), and electroencephalography (EEG) recovery duration. A linear mixed effects model was used to study the difference between the first and subsequent seizures, with a level of significance set at p < 0.05. Results: We identified 112 GCS clusters in 105 patients with 285 seizures. GCS lasted on average 48.7 ± 19 s (mean 49, range 2-137). PGES emerged in 184 (64.6%) seizures and postconvulsive central apnea (PCCA) was present in 38 (13.3%) seizures. Changes in seizure features from seizure to seizure such as seizure and convulsive phase durations appeared random. In grouped analysis, some seizure features underwent significant deterioration, whereas others improved. Clonic phase and postconvulsive central apnea (PCCA) were significantly shorter in the fourth seizure compared to the first. By contrast, duration of decerebrate posturing and ictal central apnea were longer. Four SUDEP cases in the cluster cohort were reported on follow-up. Conclusion: Seizure clusters show variable changes from seizure to seizure. Although clusters may reflect epilepsy severity, they alone may be unrelated to SUDEP risk. We suggest a stochastic nature to SUDEP occurrence, where seizure clusters may be more likely to contribute to SUDEP if an underlying progressive tendency toward SUDEP has matured toward a critical SUDEP threshold.
PMCID:7907515
PMID: 33643216
ISSN: 1664-2295
CID: 4801082
Prospective Study of a Multimodal Convulsive Seizure Detection Wearable System on Pediatric and Adult Patients in the Epilepsy Monitoring Unit
Onorati, Francesco; Regalia, Giulia; Caborni, Chiara; LaFrance, W Curt; Blum, Andrew S; Bidwell, Jonathan; De Liso, Paola; El Atrache, Rima; Loddenkemper, Tobias; Mohammadpour-Touserkani, Fatemeh; Sarkis, Rani A; Friedman, Daniel; Jeschke, Jay; Picard, Rosalind
PMCID:8418082
PMID: 34489858
ISSN: 1664-2295
CID: 5011942
Proteomic differences in the hippocampus and cortex of epilepsy brain tissue
Pires, Geoffrey; Leitner, Dominique; Drummond, Eleanor; Kanshin, Evgeny; Nayak, Shruti; Askenazi, Manor; Faustin, Arline; Friedman, Daniel; Debure, Ludovic; Ueberheide, Beatrix; Wisniewski, Thomas; Devinsky, Orrin
Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioural disorders, and increased mortality from direct (e.g. sudden unexpected death in epilepsy, accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signalling networks associated with seizures in epilepsy with a broad range of aetiologies, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry was performed on the hippocampal cornu ammonis 1-3 region (CA1-3), frontal cortex and dentate gyrus microdissected from epilepsy and control cases (n = 14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1 - 3 region, 296 proteins in the frontal cortex and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signalling and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein subunit beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signalling and G-protein-coupled receptors in epilepsy. Our results provide insights into common molecular mechanisms underlying epilepsy across various aetiologies, which may allow for novel targeted therapeutic strategies.
PMCID:8214864
PMID: 34159317
ISSN: 2632-1297
CID: 5387022
Neuropathology in the North American sudden unexpected death in epilepsy registry
Leitner, Dominique F; Faustin, Arline; Verducci, Chloe; Friedman, Daniel; William, Christopher; Devore, Sasha; Wisniewski, Thomas; Devinsky, Orrin
Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.
PMCID:8417454
PMID: 34514397
ISSN: 2632-1297
CID: 5007112
The bi-directional association between epilepsy and dementia. The Framingham Heart Study
Stefanidou, Maria; Beiser, Alexa S; Himali, Jayandra Jung; Peng, Teng J; Devinsky, Orrin; Seshadri, Sudha; Friedman, Daniel
OBJECTIVES/OBJECTIVE:METHODS: We analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy we used separate, nested, case-control designs and matched each case to 3 age-, sex- and FHS cohort-matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and apolipoprotein ε4 allele status in modifying the association between epilepsy and dementia. RESULTS:= 0.001) compared to controls of the same educational attainment. CONCLUSIONS:There is a bi-directional association between epilepsy and dementia with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.
PMID: 33097599
ISSN: 1526-632x
CID: 4655722
Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy
Pellinen, Jacob; Tafuro, Erica; Yang, Annie; Price, Dana; Friedman, Daniel; Holmes, Manisha; Barnard, Sarah; Detyniecki, Kamil; Hegde, Manu; Hixson, John; Haut, Sheryl; Kälviäinen, Reetta; French, Jacqueline
OBJECTIVE:To test the hypothesis that people with focal epilepsy experience diagnostic delays that may be associated with preventable morbidity, particularly when seizures have only nonmotor symptoms, we compared time to diagnosis, injuries, and motor vehicle accidents (MVAs) in people with focal nonmotor versus focal seizures with motor involvement at epilepsy onset. METHODS:This retrospective study analyzed the enrollment data from the Human Epilepsy Project, which enrolled participants between 2012 and 2017 across 34 sites in the USA, Canada, Europe, and Australia, within 4 months of treatment for focal epilepsy. A total of 447 participants were grouped by initial seizure semiology (focal nonmotor or focal with motor involvement) to compare time to diagnosis and prediagnostic injuries including MVAs. RESULTS:Demographic characteristics were similar between groups. There were 246 participants (55%) with nonmotor seizures and 201 participants (45%) with motor seizures at epilepsy onset. Median time to diagnosis from first seizure was 10 times longer in patients with nonmotor seizures compared to motor seizures at onset (PÂ <Â .001). The number and severity of injuries were similar between groups. However, 82.6% of MVAs occurred in patients with undiagnosed nonmotor seizures. SIGNIFICANCE/CONCLUSIONS:This study identifies reasons for delayed diagnosis and consequences of delay in patients with new onset focal epilepsy, highlighting a treatment gap that is particularly significant in patients who experience nonmotor seizures at epilepsy onset.
PMID: 33078409
ISSN: 1528-1167
CID: 4647112