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Ketamine to treat super-refractory status epilepticus Alkhachroum A, Der-Nigoghossian CA, Mathews E, Massad N, Letchinger R, Doyle K, Chiu W-T, Kromm J, Rubinos C, Velazquez A, Roh D, Agarwal S, Park S, Connolly S, Claassen J. Neurology. 2020;95(16):e2286-e2294. doi: 10.1212/WNL.0000000000010611.Objective:To test ketamine infusion efficacy in the treatment of superrefractory status epilepticus (SRSE), we studied patients with SRSE who were treated with ketamine retrospectively. We also studied the effect of high doses of ketamine on brain physiology as reflected by invasive multimodality monitoring (MMM).Methods:We studied a consecutive series of 68 patients with SRSE who were admitted between 2009 and 2018, treated with ketamine, and monitored with scalp EEG. Eleven of these patients underwent MMM at the time of ketamine administration. We compared patients who had seizure cessation after ketamine initiation to those who did not.Results:Mean age was 53 ± 18 years and 46% of patients were female. Seizure burden decreased by at least 50% within 24 hours of starting ketamine in 55 (81%) patients, with complete cessation in 43 (63%). Average dose of ketamine infusion was 2.2 ± 1.8 mg/kg/h, with median duration of 2 (1-4) days. Average dose of midazolam was 1.0 ± 0.8 mg/kg/h at the time of ketamine initiation and was started at a median of 0.4 (0.1-1.0) days before ketamine. Using a generalized linear mixed effect model, ketamine was associated with stable mean arterial pressure (odds ratio = 1.39, 95% CI: 1.38-1.40) and with decreased vasopressor requirements over time. We found no effect on intracranial pressure, cerebral blood flow, or cerebral perfusion pressure.Conclusion:Ketamine treatment was associated with a decrease in seizure burden in patients with SRSE. Our data support the notion that high-dose ketamine infusions are associated with decreased vasopressor requirements without increased intracranial pressure.Classification of Evidence:This study provides Class IV evidence that ketamine decreases seizures in patients with SRSE.

Resective Surgery Prevents Progressive Cortical Thinning in Temporal Lobe Epilepsy Galovic M, de Tisi J, McEvoy AW, et al. Brain. 2020;43(11):3262-3272. doi:10.1093/brain/awaa284Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal aging. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning. In this longitudinal case–control neuroimaging study, we included patients with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural magnetic resonance imaging scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to aging-related cortical thinning in healthy patients, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 vs healthy volunteers 0.0032 ± 0.0013 mm/year, P < .0001) and right (right TLE 0.0198 ± 0.0016 vs healthy volunteers 0.0037 ± 0.0016 mm/year, P < .0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = .0006) or right (0.0052 ± 0.0020 mm/year, P = .0006) anterior temporal lobe. Directly comparing the post- versus presurgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal aging. Those with postoperative seizures had small areas of continued accelerated thinning after surgery. Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal aging. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.

ObjectiveThis article estimates the incidence and fatality of coronavirus disease 2019 (COVID-19) and identifies potential risk factors for fatality in patients with active epilepsy.MethodsThis is a cross-sectional observational study of patients with active epilepsy and COVID-19. A control group was used to compare the cumulative incidence and case-fatality rate (CFR). The main outcomes of the study were cumulative incidence, defined as number of patients with active epilepsy and COVID-19 admitted to an emergency department divided by the total number of patients with epilepsy at risk, and CFR based on the number of deaths during the enrollment period. Multiple logistic regression analysis was performed to investigate risk factors for fatality in patients with active epilepsy.ResultsOf the 1,537 patients who fulfilled the inclusion criteria, 21 (1.3%) had active epilepsy. The cumulative incidence (95% confidence interval [CI]) of COVID-19 in patients with epilepsy was higher (1.2% [0.6–2.4]) compared to the population without epilepsy (0.5% [0.5–0.5]). In reverse transcription PCR–positive patients, there were no significant differences in CFR in patients with active epilepsy compared to patients without epilepsy (33.3% vs 8.3%; p = 0.266). Of the 21 patients with active epilepsy, 5 (23%) died. In multivariate analysis, the factor associated with fatality in patients with active epilepsy was hypertension (odds ratio [OR] 2.8 [95% CI 1.3–21.6]). In another model, age (OR 1.0 [95% CI 1.0–1.1]) and epilepsy (OR 5.1 [95% CI 1.3–24.0]) were associated with fatality during hospitalization.ConclusionCOVID-19 cumulative incidence was higher in patients with active epilepsy. Epilepsy was associated with fatality during hospitalization. Hypertension was associated with fatality in patients with epilepsy.

Changes in Seizure Frequency and Antiepileptic Therapy During Pregnancy Pennell PB, French JA, May RC, et al. N Engl J Med. 2020;383(26):2547-2556. doi:10.1056/NEJMoa2008663Background:Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups.Methods:In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth) (epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy; epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the 2 groups during the first 9 months of epoch 1.Results:We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the 2 epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 (23%) pregnant women and in 23 (25%) controls (odds ratio, 0.93; 95% CI, 0.54-1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82-10.59).Conclusions:Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.).

A Nationwide, Retrospective, Data-Linkage, Cohort Study of Epilepsy and Incident Dementia Schnier C, Duncan S, Wilkinson T, Mbizvo GK, Chin RFM. Neurology. 2020;95(12):e1686-e1693. doi:10.1212/WNL.0000000000010358Objective:To determine the association of epilepsy with incident dementia by conducting a nationwide, retrospective data-linkage, cohort study to examine whether the association varies according to dementia subtypes and to investigate whether risk factors modify the association.Methods:We used linked health data from hospitalization, mortality records, and primary care consultations to follow up 563 151 Welsh residents from their 60th birthday to estimate dementia rate and associated risk factors. Dementia, epilepsy, and covariates (medication, smoking, comorbid conditions) were classified with the use of previously validated code lists. We studied rate of dementia and dementia subtypes in people with epilepsy (PWE) and without epilepsy using (stratified) Kaplan-Meier plots and flexible parametric survival models.Results:PWE had a 2.5 (95% confidence interval [CI] 2.3-2.6) times higher hazard of incident dementia, a 1.6 (95% CI 1.4-1.8) times higher hazard of incident Alzheimer disease (AD), and a 3.1 (95% CI 2.8-3.4) times higher hazard of incident vascular dementia (VaD). A history of stroke modified the increased incidence in PWE. PWE who were first diagnosed at ≤25 years of age had a dementia rate similar to that of those diagnosed later in life. PWE who had ever been prescribed sodium valproate compared to those who had not were at higher risk of dementia (hazard ratio [HR] 1.6, 99% CI 1.4-1.9) and VaD (HR 1.7, 99% CI 1.4-2.1) but not AD (HR 1.2, 99% CI 0.9-1.5).Conclusion:PWE compared to those without epilepsy have an increased dementia risk.

Thalamus and Focal to Bilateral Seizures: A Multiscale Cognitive Imaging Study. Caciagli L, Allen AL, He X, et al. Neurology. 2020;95(17):e2427-e2441. doi:10.1212/WNL.0000000000010645Objective:To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based functional magnetic resonance imaging (fMRI) as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, that is, focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality.Methods:Focal to bilateral tonic-clonic seizures occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three (29%) patients had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12–derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality.Results:Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamo-temporal and thalamo-motor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS.Conclusions:In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamo-temporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.

Association of Peri-Ictal Brainstem Posturing With Seizure Severity and Breathing Compromise in Patients With Generalized Convulsive Seizures Vilella L, Lacuey N, Hampson JP, et al. Neurology. 2021;96(3):e352-e365. doi:10.1212/WNL.0000000000011274Objective:To analyze the association between peri-ictal brainstem posturing semiologies with postictal generalized electroencephalographic suppression (PGES) and breathing dysfunction in generalized convulsive seizures (GCS).Methods:In this 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. Postictal posturing was also assessed. Respiration was monitored with thoracoabdominal belts, video, and pulse oximetry.Results:Two hundred ninety-five seizures (180 patients) were analyzed. Ictal decerebration was observed in 122 (41.4%) of 295, decortication in 47 (15.9%) of 295, and hemi-decerebration in 28 (9.5%) of 295 seizures. Tonic phase was absent in 98 (33.2%) of 295 seizures. Postictal posturing occurred in 18 (6.1%) of 295 seizures. Postictal generalized electroencephalographic suppression risk increased with ictal decerebration (odds ratio [OR]: 14.79, 95% CI: 6.18-35.39, P < .001), decortication (OR: 11.26, 95% CI: 2.96-42.93, P < .001), or hemi-decerebration (OR: 48.56, 95% CI: 6.07-388.78, P < .001). Ictal decerebration was associated with longer PGES (P = .011). Postictal posturing was associated with postconvulsive central apnea (PCCA; P = .004), longer hypoxemia (P < .001), and Spo2 recovery (P = .035).Conclusions:Ictal brainstem semiology is associated with increased PGES risk. Ictal decerebration is associated with longer PGES. Postictal posturing is associated with a 6-fold increased risk of PCCA, longer hypoxemia, and Spo2 recovery. Peri-ictal brainstem posturing may be a surrogate biomarker for GCS severity identifiable without in-hospital monitoring.Classification of evidence: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.

Repeated Traumatic Brain Injury and Risk of Epilepsy: A Danish Nationwide Cohort Study Lolk K, Dreier JW, Christensen J. Brain. 2021;awaa448. doi:10.1093/brain/awaa448Traumatic brain injury is associated with increased risk of epilepsy, but the importance of repeated traumatic brain injuries has not yet been established. We performed a nationwide population-based cohort study of 2 476 905 individuals born in Denmark between 1977 and 2016. We estimated hazard ratios (HRs) and the cumulative incidence of epilepsy following traumatic brain injury using Cox and competing risk regression, respectively. To estimate the cumulative incidence of epilepsy in the population without traumatic brain injury, we matched 10 controls for each subject with traumatic brain injury on year of birth, sex, and date of brain insult in the index person. In the cohort, traumatic brain injury was sustained by 167 051 subjects (71 162 females and 95 889 males), and 37 200 individuals developed epilepsy (17 905 females and 19 295 males). Compared with subjects without traumatic brain injury, the relative risk of epilepsy increased after a first traumatic brain injury (HR: 2.04, 95% confidence interval (CI): 1.96-2.13) and even more after a second traumatic brain injury (HR: 4.45, 95% CI: 4.09-4.84). The risk increased with the severity of the first and the second traumatic brain injury, most notably after severe traumatic brain injuries. Females were more likely than males to develop epilepsy after mild traumatic brain injury (HR: 2.13, 95% CI: 2.00-2.28 vs HR: 1.77, 95% CI: 1.66-1.88; P < .0001); in contrast, males were more likely than females to develop epilepsy after severe traumatic brain injury (HR: 5.00, 95% CI: 4.31-5.80 vs HR: 3.21, 95% CI: 2.56-4.03; P = .0012). The risk remained increased for decades after the traumatic brain injury. This knowledge may inform efforts to prevent the development of post-traumatic epilepsy.

Mapping the Insula With Stereo-Electroencephalography: The Emergence of Semiology in Insula Lobe Seizures Singh R, Principe A, Tadel F, et al. Ann Neurol. 2020;88(3):477-488. PMID: 32542728. doi:10.1002/ana.25817Objective:Insula epilepsy is rare and can be evaluated effectively by stereotactic intracerebral electroencephalography. Many previous studies of insulo-opercular seizures have been unable to separate insular and opercular onset. With adequate sampling of the insula, this study shows this is possible.Methods:We analyzed intrainsular dynamics and extrainsular propagation in 12 patients with “pure” insula epilepsy (n = 9) or insular and only deepest opercular involvement (n = 3) at seizure onset. Review of semiology defined clinical groups, agglomerative cluster, and principal component analysis of semiological features were performed. Quantitative epileptogenicity and intrainsular and extrainsular propagation were computed via time frequency analysis and epileptogenicity mapping.Results:Seizure-onset patterns were heterogeneous; the seizure-onset zone was focal. Seizure-onset and first ictal change within insula functional subdivision correlated with aura and reflex component. No paninsular spread occurred; contralateral insular spread was very early. While the discharge was intrainsular, clinical signs were related to aura or vegetative signs. Extrainsular propagation was early and related to the emergence of the majority of clinical signs. Cluster analysis found an anterior, intermediate, and posterior insula seizure-onset group. The largest principal component separated anterior insula manifestations, including early hypermotor signs, early recovery, and no aura from posterior insula features of early dystonia, early tonic motor features, and sensorimotor aura.Interpretation:Aura is vital to identifying seizure onset and relates to insula functional subdivision. Seizures are heterogenous; extrainsular propagation occurs early, accounting for most of the semiology. With adequate sampling, “pure” insula epilepsy can be identified and focal curative resection is possible.

Prehospital Midazolam Use and Outcomes Among Patients With Out-of-Hospital Status Epilepticus Guterman EL, Sanford JK, Betjemann JP, et al. Neurology. 2020;95(24):e3203-e3212. doi:10.1212/WNL.0000000000010913Objective:To examine the use of benzodiazepines and the association between low benzodiazepine dose, breakthrough seizures, and respiratory support in patients with status epilepticus.Methods:Cross-sectional analysis of adult patients with status epilepticus treated by an emergency medical services agency from 2013 to 2018. The primary outcome was treatment with a second benzodiazepine dose, an indicator for breakthrough seizure. The secondary outcome was receiving respiratory support. Midazolam was the only benzodiazepine administered.Results:Among 2494 cases of status epilepticus, mean age was 54.0 years and 1146 (46%) were female. There were 1537 patients given midazolam at any dose, yielding an administration rate of 62%. No patients received a dose and route consistent with national guidelines. Rescue therapy with a second midazolam dose was required in 282 (18%) patients. Higher midazolam doses were associated with lower odds of rescue therapy (odds ratio [OR]: 0.8, 95% CI: 0.7-0.9) and were not associated with increased respiratory support. If anything, higher doses of midazolam were associated with decreased need for respiratory support after adjustment (OR: 0.9, 95% CI: 0.8-1.0).Conclusions:An overwhelming majority of patients with status epilepticus did not receive evidence-based benzodiazepine treatment. Higher midazolam doses were associated with reduced use of rescue therapy, and there was no evidence of respiratory harm suggesting that benzodiazepines are withheld without clinical benefit.Classification of Evidence:This study provides class III evidence that for patients with status epilepticus, higher doses of midazolam led to a reduced use of rescue therapy without an increased need for ventilatory support.

Pharmacologic Treatment and SUDEP risk: A Nationwide, Population-Based, Case-Control Study Sveinsson O, Andersson T, Mattsson P, et al. Neurology. 2020;95(18):e2509-e2518. doi:10.1212/WNL.0000000000010874Objective:We conducted a nationwide case–control study in Sweden to test the hypothesis that antiepileptic drugs (AEDs) mono- or polytherapy, adherence, antidepressants, neuroleptics, β-blockers, and statins are associated with sudden unexpected death in epilepsy (SUDEP) risk.Methods:Included were 255 SUDEP cases and 1148 matched controls. Information on clinical factors and medications came from medical records and the National Patient and Prescription Registers. The association between SUDEP and medications was assessed by odds ratios (ORs) with 95% CIs adjusted for potential risk factors including type of epilepsy, living conditions, comorbidity, and frequency of generalized tonic–clonic seizures (GTCS).Results:Polytherapy, especially taking 3 or more AEDs, was associated with a substantially reduced risk of SUDEP (OR: 0.31, 95% CI: 0.14-0.67). Combinations including lamotrigine (OR: 0.55, 95% CI: 0.31-0.97), valproic acid (OR: 0.53, 95% CI: 0.29-0.98), and levetiracetam (OR: 0.49, 95% CI: 0.27-0.90) were associated with reduced risk. No specific AED was associated with increased risk. Regarding monotherapy, although numbers were limited, the lowest SUDEP risk was seen in users of levetiracetam (0.10, 95% CI: 0.02-0.61). Having nonadherence mentioned in the medical record was associated with an OR of 2.75 (95% CI: 1.58-4.78). Statin use was associated with a reduced SUDEP risk (OR: 0.34, 95% CI: 0.11-0.99) but selective serotonin reuptake inhibitor use was not.Conclusion:These results provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled GTCS in the effort to reduce SUDEP risk and suggest that comedication with statins may reduce risk.

Activation of Functional Brain Networks in Children With Psychogenic Non-Epileptic Seizures Radmanesh M, Jalili M, Kozlowska K. Front Hum Neurosci. 2020. doi:10.3389/fnhum.2020.00339.Objectives:Psychogenic nonepileptic seizures (PNES) have been hypothesized to emerge in the context of neural networks instability. To explore this hypothesis in children, we applied a graph theory approach to examine connectivity in neural networks in the resting-state electroencephalogram in 35 children with PNES, 31 children with other functional neurological symptoms (but no PNES), and 75 healthy controls.Methods:The networks were extracted from Laplacian-transformed time series by a coherence connectivity estimation method.Results:Children with PNES (vs controls) showed widespread changes in network metrics: increased global efficiency (α and β bands), increased local efficiency (γ band), and increased modularity (γ and α bands). Compared to controls, they also had higher levels of autonomic arousal (eg, lower heart variability); more anxiety, depression, and stress on the Depression Anxiety and Stress Scales; and more adverse childhood experiences on the Early Life Stress Questionnaire. Increases in network metrics correlated with arousal. Children with other functional neurological symptoms (but no PNES) showed scattered and less pronounced changes in network metrics.Conclusion:The results indicate that children with PNES present with increased activation of neural networks coupled with increased physiological arousal. Although this shift in functional organization may confer a short-term adaptive advantage—one that facilitates neural communication and the child’s capacity to respond self-protectively in the face of stressful life events—it may also have a significant biological cost. It may predispose the child’s neural networks to periods of instability—presenting clinically as PNES—when the neural networks are faced with perturbations in energy flow or with additional demands.

White Matter Abnormalities Across Different Epilepsy Syndromes in Adults: An ENIGMA-Epilepsy Study Hatton SN, Huynh KH, Bonilha L, et al. Brain. 2020;143(8):2454-2473. doi:10.1093/brain/awaa200. PMID: 32814957The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicenter sample of adult epilepsy patients. Diffusion-weighted magnetic resonance imaging (MRI) data were analyzed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182), and nonlesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < .001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum, and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiate, and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicenter study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum, and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric comorbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.

Effect of Combined Physical Training on Cognitive Function in People With Epilepsy: Results From a Randomized Controlled Trial Feter N, Alt R, Häfele CA, et al. Epilepsia. 2020;61(8):1649-1658. doi:10.1111/epi.16588. PMID: 32602966.Objective:To examine the effect of 12-week exercise program on cognitive function in people with epilepsy.Methods:Twenty-one physically inactive patients were randomized into 2 groups: the exercise group (EG) or the control group. Exercise group performed 12 weeks of combined physical training. Control group was advised to maintain usual daily activities. Exercise group received a structured, individually supervised exercise program with two 60-minute sessions per week. Each session included warmup (5 minutes), aerobic (15-20 minutes at 14-17 on Borg scale), strength (2-3 sets, 10-15 repetitions), and 5-minute active stretches. Sociodemographic characteristics, clinical information, memory (Digit Span Test [DST]), executive function (Trail Making Test [TMT] A and B), Stroop Color and Word Test, a verbal fluency task, global cognitive function (Montreal Cognitive Assessment [MoCA]), anthropometric measurements (weight, height, and hip and waist circumferences), cardiorespiratory fitness (maximal oxygen consumption [V. o 2max]), and strength (dynamometer) were measured at baseline and after the 12-week intervention.Results:Exercise decreased time spent on TMT-A from baseline to postintervention (difference = −7.9 seconds, 95% CI = −14.5 to −1.3, P = .023). Exercise group improved total number of words on the verbal fluency task after intervention (difference = 8.1 words, 95% CI = 3.0-13.2, P = .002). Exercise group also improved the score on MoCA at 1.7 (95% CI = 0.1-3.3, P = .043) points. We observed a 22.4% (95% CI = 13.1-31.6, P = .021) improvement in executive function in EG. No effect of group, time, or group × time was observed on any other cognitive test. Changes in V˙ o 2max were negatively associated with changes in performance on DST (r = −0.445, P = .049) and overall memory score (r = −0.544, P = .042).Significance:This randomized controlled trial provided the first evidence that combined physical training improves executive function in adults with epilepsy, showing main improvements in attention and language tasks. Physical exercise should be encouraged for people with epilepsy to reduce the burden on cognitive function associated with this disease.

Socioeconomic Disparities in SUDEP in the US Cihan E, Hesdorffer DC, Brandsoy M, et al. Neurology. 2020;94(24): e2555-e2566. doi:10.1212/WNL.0000000000009463Objective:To determine the impact of socioeconomic status (SES) on sudden unexpected death in epilepsy (SUDEP) rates.Methods:We queried all decedents presented for medicolegal investigation at 3 medical examiner offices across the country (New York City, Maryland, San Diego County) in 2009 to 2010 and 2014 to 2015. We identified all decedents for whom epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate. We then reviewed all available reports. Decedents determined to have SUDEP were included for analysis. We used median income in the ZIP code of residence as a surrogate for SES. For each region, zip code regions were ranked by median household income and divided into quartiles based on total population for 2 time periods. Region-, age-, and income-adjusted epilepsy prevalence were estimated in each zip code. Sudden unexpected death in epilepsy rates in the highest and lowest SES quartiles were evaluated to determine disparity. Examined SUDEP rates in 2 time periods were also compared.Results:There were 159 and 43 SUDEP cases in the lowest and highest SES quartiles. Medical examiner–investigated SUDEP rate ratio between the lowest and highest SES quartiles was 2.6 (95% CI: 1.7-4.1, P < .0001) in 2009 to 2010 and 3.3 (95% CI: 1.9-6.0, P < .0001) in 2014 to 2015. There was a significant decline in overall SUDEP rate between the 2 study periods (36% decrease, 95% CI: 22%-48%, P < .0001).Conclusion:Medical examiner–investigated SUDEP incidence was significantly higher in people with the lowest SES compared to the highest SES. The difference persisted over a 5-year period despite decreased overall SUDEP rates.

The Bi-Directional Association Between Epilepsy and Dementia. The Framingham Heart Study Stefanidou M, Beiser AS, Himali JJ, et al. Neurology. 2020. doi:10.1212/WNL.0000000000011077.Objectives:To assess the risk of incident epilepsy among participants with prevalent dementia, and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS).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:A total of 4906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1980 dementia-free controls there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases versus controls yielded (hazards ratio [HR] = 1.82 [95% CI:1.05-3.16], P = .034). Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases versus controls yielded (HR = 1.99 [1.11-3.57], P = .021). In this group, among participants with any post-high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia (HR = 4.67 [1.82-12.01], P = .001) compared to controls of the same educational attainment.Conclusions:There is a bidirectional association between epilepsy and dementia with either condition carrying a nearly 2-fold risk of developing the other when compared with controls. Dementia in Late Onset Epilepsy: The Atherosclerosis Risk in Communities Study Johnson EL, Krauss GL, Kucharska-Newton A, et al. Neurology. 2020.Objective:To determine the risk of dementia after the development of late-onset epilepsy (LOE).Methods:We used data from the Atherosclerosis Risk in Communities (ARIC) cohort study, which started in 1987 to 1989 with 15 792 mostly black and white men and women from 4 US communities. We identified LOE (seizures starting at age 67 or later) from linked Medicare claims data. We used a Cox proportional hazards regression model to evaluate associations between LOE and dementia through 2017 as ascertained from neuropsychological testing, interviews, and hospital discharge surveillance; and we used multinomial logistic regression to assess the risk of dementia and mild cognitive impairment in the subset with full neuropsychological assessments available. We adjusted for demographics, and vascular and Alzheimer disease risk factors.Results:Of 9033 ARIC participants with sufficient Medicare coverage data (4980 [55.1%] female, 1993 [22.1%] black), 671 met the definition of LOE. 279 (41.6%) participants with LOE and 1408 (16.8%) without LOE developed dementia (P < .001). After a diagnosis of LOE, the adjusted hazard ratio for developing subsequent dementia was 3.05 (95% CI: 2.65-3.51). The median time to dementia ascertainment after the onset of LOE was 3.66 years (Q1-Q3 1.28-8.28 years).Interpretation:The risk of incident dementia is substantially elevated in individuals with LOE. Further work is needed to explore causes for the increased risk of dementia in this growing population.

Mortality in Patients With Psychogenic Nonepileptic Seizures Nightscales R, McCartney L, Auvrez C, et al. Neurology. 2020;95(6):e643-e652. doi:10.1212/WNL.0000000000009855Objective:To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population.Methods:This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports.Results:A total of 5508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% CI: 2.0-3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI: 3.4-19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and “epilepsy” was recorded as the cause of death in 24%.Conclusions:Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.

Seizure Outcome and Use of Antiepileptic Drugs After Epilepsy Surgery According to Histopathological Diagnosis: A Retrospective Multicenter Cohort Study Lamberink HJ, Otte WM, Blümcke I, et al; European Epilepsy Brain Bank writing group; study group; European Reference Network EpiCARE. Lancet Neurol. 2020;19(9):748-757. doi:10.1016/s1474-4422(20)30220-9Background:Surgery is a widely accepted treatment option for drug-resistant focal epilepsy. A detailed analysis of longitudinal postoperative seizure outcomes and use of antiepileptic drugs for different brain lesions causing epilepsy is not available. We aimed to analyze the association between histopathology and seizure outcome and drug freedom up to 5 years after epilepsy surgery, to improve presurgical decision-making and counselling.Methods:In this retrospective, multicenter, longitudinal, cohort study, patients who had epilepsy surgery between January 1, 2000, and December 31, 2012, at 37 collaborating tertiary referral centers across 18 European countries of the European Epilepsy Brain Bank consortium were assessed. We included patients of all ages with histopathology available after epilepsy surgery. Histopathological diagnoses and a minimal data set of clinical variables were collected from existing local databases and patient records. The primary outcomes were freedom from disabling seizures (Engel class 1) and drug freedom at 1, 2, and 5 years after surgery. Proportions of individuals who were Engel class 1 and drug-free were reported for the 11 main categories of histopathological diagnosis. We analyzed the association between histopathology, duration of epilepsy, and age at surgery, and the primary outcomes using random effects multivariable logistic regression to control for confounding.Findings:A total of 9147 patients were included, of whom seizure outcomes were available for 8191 (89.5%) participants at 2 years, and for 5577 (61.0%) at 5 years. The diagnoses of low-grade epilepsy-associated neuroepithelial tumor (LEAT), vascular malformation, and hippocampal sclerosis had the best seizure outcome at 2 years after surgery, with 77.5% (1027 of 1325) of patients free from disabling seizures for LEAT, 74.0% (328 of 443) for vascular malformation, and 71.5% (2108 of 2948) for hippocampal sclerosis. The worst seizure outcomes at 2 years were seen for patients with focal cortical dysplasia type I or mild malformation of cortical development (50.0%, 213 of 426 free from disabling seizures), those with malformation of cortical development-other (52.3%, 212 of 405 free from disabling seizures), and for those with no histopathological lesion (53.5%, 396 of 740 free from disabling seizures). The proportion of patients being both Engel class 1 and drug-free was 0% to 14% at 1 year and increased to 14% to 51% at 5 years. Children were more often drug-free; temporal lobe surgeries had the best seizure outcomes; and a longer duration of epilepsy was associated with reduced chance of favorable seizure outcomes and drug freedom. This effect of duration was evident for all lesions, except for hippocampal sclerosis.Interpretation:Histopathological diagnosis, age at surgery, and duration of epilepsy are important prognostic factors for outcomes of epilepsy surgery. In every patient with refractory focal epilepsy presumed to be lesional, evaluation for surgery should be considered.

IMPORTANCE Focal epilepsy is characterized by the cyclical recurrence of seizures, but, to our knowledge, the prevalence and patterns of seizure cycles are unknown. OBJECTIVE To establish the prevalence, strength, and temporal patterns of seizure cycles over timescales of hours to years. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study analyzed data from continuous intracranial electroencephalography (cEEG) and seizure diaries collected between January 19, 2004, and May 18, 2018, with durations up to 10 years. A total of 222 adults with medically refractory focal epilepsy were selected from 256 total participants in a clinical trial of an implanted responsive neurostimulation device. Selection was based on availability of cEEG and/or self-reports of disabling seizures. EXPOSURES Antiseizure medications and responsive neurostimulation, based on clinical indications. MAIN OUTCOMES AND MEASURES Measures involved (1) self-reported daily seizure counts, (2) cEEG-based hourly counts of electrographic seizures, and (3) detections of interictal epileptiform activity (IEA), which fluctuates in daily (circadian) and multiday (multidien) cycles. Outcomes involved descriptive characteristics of cycles of IEA and seizures: (1) prevalence, defined as the percentage of patients with a given type of seizure cycle; (2) strength, defined as the degree of consistency with which seizures occur at certain phases of an underlying cycle, measured as the phase-locking value (PLV); and (3) seizure chronotypes, defined as patterns in seizure timing evident at the group level. RESULTS Of the 222 participants, 112 (50%) were male, and the median age was 35 years (range, 18-66 years). The prevalence of circannual (approximately 1 year) seizure cycles was 12%(24 of 194), the prevalence of multidien (approximately weekly to approximately monthly) seizure cycles was 60%(112 of 186), and the prevalence of circadian (approximately 24 hours) seizure cycles was 89%(76 of 85). Strengths of circadian (mean [SD] PLV, 0.34 [0.18]) and multidien (mean [SD] PLV, 0.34 [0.17]) seizure cycles were comparable, whereas circannual seizure cycles were weaker (mean [SD] PLV, 0.17 [0.10]). Across individuals, circadian seizure cycles showed 5 peaks: morning, mid-afternoon, evening, early night, and late night. Multidien cycles of IEA showed peak periodicities centered around 7, 15, 20, and 30 days. Independent of multidien period length, self-reported and electrographic seizures consistently occurred during the days-long rising phase of multidien cycles of IEA. CONCLUSIONS AND RELEVANCE Findings in this large cohort establish the high prevalence of plural seizure cycles and help explain the natural variability in seizure timing. The results have the potential to inform the scheduling of diagnostic studies, the delivery of time-varying therapies, and the design of clinical trials in epilepsy. Dr Leguia is supported through a grant for a postdoctoral fellowship from theWyss Center for Bio and Neuroengineering. Dr Rao is supported by the Ernest Gallo Foundation Distinguished Professorship in Neurology at the University of California, San Francisco. Dr Baud is supported by an Ambizione grant (PZ00P3_179929) from the Swiss National Science Foundation and by a grant from the Velux Stiftung (1232).

Clinical Features Which Predict Neuronal Surface Autoantibodies in New-Onset Focal Epilepsy: Implications for Immunotherapies McGinty RN, Handel A, Moloney T, et al. J Neurol Neurosurg Psychiatry. 2020;92(3):291-294. doi:10.1136/jnnp-2020-325011Objective:To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy and evaluate the value of immunotherapy in this clinical setting.Methods:Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy.Results:A total of 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. Nine of 23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (P < .0001). Multivariate analysis identified 6 features which predicted autoantibody positivity (area under the curve = 0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, magnetic resonance imaging limbic system changes, and the absence of conventional epilepsy risk factors. Eleven (79%) of 14 patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score = 0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (P < .05).Conclusions:Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggest immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis. Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score. de Bruijn M, Bastiaansen AEM, Mojzisova H, et al. Ann Neurol. 2021;89(4):698-710. doi:https://doi.org/10.1002/ana.26013.Objective:Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology and to create a score to preselect patients requiring testing.Methods:In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic.Results:We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty (3.4%) patients had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-d-aspartate receptor, and 13 had antiglutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10 000 IU/mL). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% CI = 19.6-3332.2, P < .0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, P = .0005), behavioral changes (OR = 12.3, 95% CI = 3.2-49.9, P = .0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, P = .0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, P = .009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, P = .005). The internally validated C-statistic was 0.95 and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%.Interpretation:Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing.

Characteristics and Treatment Outcomes of Newly Diagnosed Epilepsy in Older People: A 30-Year Longitudinal Cohort Study Alsfouk BAA, Hakeem H, Chen Z, Walters M, Brodie MJ, Kwan P. Epilepsia. 2020;61(12):2720-2728. doi:10.1111/epi.16721Objectives:To describe the clinical characteristics and evaluate the long-term treatment outcomes in older people with newly diagnosed epilepsy over the past 30 years. Methods: We included patients newly diagnosed with epilepsy and commenced on anti-seizure medications (ASMs) at age 65 years or older between July 1982 and October 2012 at the Western infirmary in Glasgow, Scotland. They were followed up until April 2016 or death. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow-up. Results: A total of 201 patients (median age 73 years, 59% male) were included. The median duration from initial seizure to starting treatment was 8 months (interquartile range: 3.0-24.0 months); 42.2% (85/201) patients had more than 5 seizures before commencing treatment. Brain imaging showed potentially epileptogenic lesions in 19.7% (38/193) of patients and other abnormalities in 56.5% (109/193); 78.6% patients (158/201) were seizure-free at the last follow-up, of whom 94.9% were taking monotherapy. Concomitant aspirin use (n = 80) was associated with a lower probability of being seizure-free (relative risk 0.82, 95% confidence interval 0.70-0.97; P = .02). The use of second-generation ASMs as the initial monotherapy increased from 31.5% (23/73) before 2000 to 70.3% (90/128, P < .001) from 2000 onward. However, the seizure freedom rates (67.1% vs 55.5%; P = .35) and intolerable adverse-effect rates (16.4% vs 19.5%; P = .45) did not show any significant difference. Significance: There was often a long interval between seizure onset and the initiation of treatment in older people with new-onset epilepsy, although the majority responded well to ASM treatment. Brain imaging showed a high rate of abnormalities. Despite the increased use of second-generation ASMs, treatment outcomes in later-onset epilepsy have not improved over time. The possible effect of aspirin on treatment response warrants further investigation.

Focal Nonmotor Versus Motor Seizures: The Impact on Diagnostic Delay in Focal Epilepsy Pellinen J, Tafuro E, Yang A, et al. Epilepsia. 2020;61(12):2643-2652. doi:10.1111/epi.16707Objective: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 United States, 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 (55%) participants with nonmotor seizures and 201 (45%) participants 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 (P < .001). The number and severity of injuries were similar between groups. However, 82.6% of MVAs occurred in patients with undiagnosed nonmotor seizures.Significance: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.

ObjectiveTo determine whether the nucleus basalis of Meynert (NBM) may be a key network structure of altered functional connectivity in temporal lobe epilepsy (TLE), we examined fMRI with network-based analyses.MethodsWe acquired resting-state fMRI in 40 adults with TLE and 40 matched healthy control participants. We calculated functional connectivity of NBM and used multiple complementary network-based analyses to explore the importance of NBM in TLE networks without biasing our results by our approach. We compared patients to controls and examined associations of network properties with disease metrics and neurocognitive testing.ResultsWe observed marked decreases in connectivity between NBM and the rest of the brain in patients with TLE (0.91 ± 0.88, mean ± SD) vs controls (1.96 ± 1.13, p < 0.001, t test). Larger decreases in connectivity between NBM and fronto-parietal-insular regions were associated with higher frequency of consciousness-impairing seizures (r = −0.41, p = 0.008, Pearson). A core network of altered nodes in TLE included NBM ipsilateral to the epileptogenic side and bilateral limbic structures. Furthermore, normal community affiliation of ipsilateral NBM was lost in patients, and this structure displayed the most altered clustering coefficient of any node examined (3.46 ± 1.17 in controls vs 2.23 ± 0.93 in patients). Abnormal connectivity between NBM and subcortical arousal community was associated with modest neurocognitive deficits. Finally, a logistic regression model incorporating connectivity properties of ipsilateral NBM successfully distinguished patients from control datasets with moderately high accuracy (78%).ConclusionsThese results suggest that while NBM is rarely studied in epilepsy, it may be one of the most perturbed network nodes in TLE, contributing to widespread neural effects in this disabling disorder.

Commentary on Scalp Ripples Can Predict Development of Epilepsy After First Unprovoked Seizure in Childhood Klotz, Sag Y, Schönberger J, Jacobs J. Ann Neurol. 2021;89(1):134-142. doi:10.1002/ana.25939Objective:Identification of children at risk of developing epilepsy after a first unprovoked seizure can be challenging. Interictal epileptiform discharges are associated with higher risk but have limited sensitivity and specificity. High-frequency oscillations (HFOs) are newer biomarkers for epileptogenesis. We prospectively evaluated the predictive value of HFOs for developing epilepsy in scalp electroencephalogram (EEG) of children after a first unprovoked seizure.Methods:After their first seizure, 56 children were followed prospectively over 12 months and then grouped in “epilepsy” or “no epilepsy.” Initial EEGs were visually analyzed for spikes, spike ripples, and ripples. Intergroup comparisons of spike-rates and HFO-rates were done by Mann-Whitney U test. Predictive values and optimal thresholds were calculated by receiver operating characteristic curves.Results:In the epilepsy group (n = 26, 46%), mean rates of ripples (0.3 vs 0.09/minute, P < .0001) and spike ripples (0.6 vs 0.06/minute, P < .05) were significantly higher, with no difference in spike rates (1.7 vs 3.0/minute, P = .38). Of those 3 markers, ripples showed the best predictive value (area under the curve ripples = 0.88). The optimal threshold for ripples was calculated to be ≥0.125/minute with a sensitivity of 87% and specificity of 85%. Ripple rates were negatively correlated with days passing before epilepsy diagnosis (R = −0.59, P < .0001) and time to a second seizure (R = −0.64, 95% CI = −0.77 to 0.43, P < .0001).Interpretation:We could show that in a cohort of children with a first unprovoked seizure, ripples predict the development of epilepsy better than spikes or spike ripples and might be useful biomarkers in the estimation of prognosis and question of treatment.

A Human Amygdala Site That Inhibits Respiration and Elicits Apnea in Pediatric Epilepsy Rhone AE, Kovach CK, Harmata GIS, et al. JCI Insight. 2020;5(6):e134852. doi:10.1172/jci.insight.134852Background:Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown.Methods:We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine learning algorithm was used to delineate brain regions that inhibit respiration.Results:In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 patients (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site, includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.Conclusions:A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target. Seizure-Related Apneas Have an Inconsistent Linkage to Amygdala Seizure Spread Park K, Kanth K, Bajwa S, et al. Epilepsia. 2020;61(6):1253-1260.Objective:Sudden unexpected death in epilepsy (SUDEP) is a frequent cause of death in epilepsy. Respiratory dysfunction is implicated as a critical factor in SUDEP pathophysiology. Human studies have shown that electrical stimulation of the amygdala resulted in apnea, indicating that the amygdala has a role in respiration control. Unilateral amygdala stimulation resulted in immediate onset of respiratory dysfunction occurring only during nose breathing. In small numbers of patients, some but not all spontaneous seizures resulted in apnea occurring shortly after seizure spread to the amygdala. With this study, we aimed to determine whether seizure onset or spread to the amygdala was necessary and sufficient to cause apnea.Methods:We investigated the temporal relationship between apnea/hypopnea (AH) onset and initial seizure involvement within the amygdala in patients with implanted depth electrodes.Results:Data from 17 patients (11 female) with 47 seizures were analyzed. With 7 seizures (3 patients), AH preceded amygdala seizure involvement by 2 to 55 seconds. There was no AH with 4 seizures (3 patients) that involved the amygdala. With 8 seizures (4 patients), AH occurred within 2 seconds following amygdala seizure onset. With 28 seizures, AH started >2 seconds after amygdala seizure onset (range: 3-158 seconds). Following seizure onset, there was a significant difference between AH onset time and amygdala seizure onset (P < .001). The mean ± standard deviation AH onset was 27.8 ± 41.06 seconds, and the mean time to amygdala involvement was 8.83 ± 20.19 seconds.Significance:There is a wide range of AH onset times relative to amygdala seizure involvement. With some seizures, amygdala seizure involvement occurs without AH. With other seizures, AH precedes amygdala seizures, suggesting that, with spontaneous seizures, involvement of the amygdala may not be crucial to induction of AH with all seizures. Other pathophysiology impacting brain stem respiratory networks may be of greater relevance to seizure-triggered apneas.

ObjectiveTo develop a diagnostic test that stratifies epileptic seizures (ES) from psychogenic nonepileptic seizures (PNES) by developing a multimodal algorithm that integrates plasma concentrations of selected immune response–associated proteins and patient clinical risk factors for seizure.MethodsDaily blood samples were collected from patients evaluated in the epilepsy monitoring unit within 24 hours after EEG confirmed ES or PNES and plasma was isolated. Levels of 51 candidate plasma proteins were quantified using an automated, multiplexed, sandwich ELISA and then integrated and analyzed using our diagnostic algorithm.ResultsA 51-protein multiplexed ELISA panel was used to determine the plasma concentrations of patients with ES, patients with PNES, and healthy controls. A combination of protein concentrations, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein-2 (MCP-2), and tumor necrosis factor–receptor 1 (TNF-R1) indicated a probability that a patient recently experienced a seizure, with TRAIL and ICAM-1 levels higher in PNES than ES and MCP-2 and TNF-R1 levels higher in ES than PNES. The diagnostic algorithm yielded an area under the receiver operating characteristic curve (AUC) of 0.94 ± 0.07, sensitivity of 82.6% (95% confidence interval [CI] 62.9–93.0), and specificity of 91.6% (95% CI 74.2–97.7). Expanding the diagnostic algorithm to include previously identified PNES risk factors enhanced diagnostic performance, with AUC of 0.97 ± 0.05, sensitivity of 91.3% (95% CI 73.2–97.6), and specificity of 95.8% (95% CI 79.8–99.3).ConclusionsThese 4 plasma proteins could provide a rapid, cost-effective, and accurate blood-based diagnostic test to confirm recent ES or PNES.Classification of EvidenceThis study provides Class III evidence that variable levels of 4 plasma proteins, when analyzed by a diagnostic algorithm, can distinguish PNES from ES with sensitivity of 82.6% and specificity of 91.6%.

Association of Epileptiform Abnormalities and Seizures in Alzheimer Disease Lam AD, Sarkis RA, Pellerin KR, et al. Neurology. 2020;95(16):e2259-e2270. doi:10.1212/WNL.0000000000010612Objective:To examine the relationship between scalp electroencephalography (EEG) biomarkers of hyperexcitability in Alzheimer disease (AD) and to determine how these electric biomarkers relate to the clinical expression of seizures in AD.Methods:In this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 participants with early-stage AD with no history or risk factors for epilepsy (AD-NoEp), and 15 participants with early-stage AD with late-onset epilepsy related to AD (AD-Ep). Two epileptologists blinded to diagnosis visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists blinded to diagnosis was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG.Results:Epileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and rapid eye movement (REM), were associated with clinical seizures in AD. Multiple EEG biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bitemporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD.Conclusion:Epileptiform abnormalities are common in AD but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which patients with AD are at high risk of clinical seizures.

Self-Injurious and Suicidal Behavior in Young Adults, Teens, and Children With Epilepsy: A Population-Based Study Wirrell EC, Bieber EW, Vanderwiel A, et al. Epilepsia. 2020;61(9):1919-1930. doi:10.1111/epi.16618Objective:Whereas studies in adult epilepsy patients have shown higher rates of suicidal ideation and attempt, such studies in children are limited. Using the Rochester Epidemiology Project database, we compared the risk of self-injurious behavior and suicidal ideation in a population-based cohort of childhood epilepsy to controls.Methods:We studied 339 cases with epilepsy and 678 age- and sex-matched controls followed to a median age of 24.7 and 23.4 years and identified 98 patients with self-injurious behavior or suicidal ideation (43 with epilepsy and 55 controls). All behaviors were categorized using the Columbia Suicide Severity Rating Scale.Results:Those with epilepsy had a significantly higher rate of any self-injurious behavior and suicidal ideation (hazard ratio [HR] = 1.56, 95% CI = 1.04-2.35) and tended to have an increased risk of suicidal ideation and attempt (HR = 1.48, 95% CI = 0.93-2.37). The prevalence of preceding mood and substance abuse disorders was similarly high in both cases and controls with self-injurious behavior or suicidal ideation; however, preceding attention-deficit/hyperactivity disorder was more than twice as common in the epilepsy cases. Among cases with epilepsy, we did not identify any specific epilepsy-related variable that was significantly correlated with risk of self-injurious behavior or suicidal ideation.Significance:Children, teens, and young adults with a history of childhood epilepsy are at greater risk of self-injurious behavior, highlighting the need for careful screening of mental health concerns as part of routine epilepsy care.

Subthalamic Nucleus Stimulation Modulates Motor Epileptic Activity in Humans. Ren SL, Yu T, Wang D, et al. Ann Neurol. 2020;88(2):283-296. doi:10.1002/ana.25776.Objective:Pharmacorefractory focal motor epileptic seizures pose a significant challenge. Deep brain stimulation is a recently recognized therapeutic option for the treatment of refractory epilepsy. To identify the specific target for focal motor seizures, we evaluate the modulatory effects of the subthalamic nucleus (STN) stimulation because of the critical role of STN in cortico–subcortical motor processing.Methods:Seven patients with epilepsy with refractory seizures who underwent chronic stereoelectroencephalography monitoring were studied in presurgical evaluation. Seizure onset zone was hypothesized to be partially involved in the motor areas in 6 patients. For each patient, 1 electrode was temporally implanted into the STN that was ipsilateral to the seizure onset zone. The cortical–subcortical seizure propagation was systemically evaluated. The simultaneously electrophysiological responses over distributed cortical areas to STN stimulation at varied frequencies were quantitatively assessed.Results:We observed the consistent downstream propagation of seizures from the motor cortex toward the ipsilateral STN and remarkable cortical responses on motor cortex to single-pulse STN stimulation. Furthermore, we showed frequency-dependent upstream modulatory effect of STN stimulation on motor cortex specifically. In contrast to the enhanced effects of low-frequency stimulation, high-frequency stimulation of the STN can significantly reduce interictal spikes, high-frequency oscillations over motor cortex disclosing effective connections to the STN.Interpretation:This result showed that the STN is not only engaged in as a propagation network of focal motor seizures but STN stimulation can profoundly modulate the epileptic activity of motor cortex in humans, suggesting a mechanism-based alternative for patients suffering from refractory focal motor seizures.

Sleep Disruption in Epilepsy: Ictal and Interictal Epileptic Activity Matter Peter-Derex L, Klimes P, Latreille V, et al. Ann Neurol. 2020;88(5):907-920. doi:10.1002/ana.25884. PMID: 32833279.Objective:Disturbed sleep is common in epilepsy. The direct influence of nocturnal epileptic activity on sleep fragmentation remains poorly understood. Stereo-electroencephalography paired with polysomnography is the ideal tool to study this relationship. We investigated whether sleep-related epileptic activity is associated with sleep disruption.Methods:We visually marked sleep stages, arousals, seizures, and epileptic bursts in 36 patients with focal drug resistant epilepsy who underwent combined stereo-electroencephalography/polysomnography during presurgical evaluation. Epileptic spikes were detected automatically. Spike and burst indices (n/sec/channel) were computed across four 3-second time windows (baseline sleep, prearousal, arousal, and postarousal). Sleep stage and anatomic localization were tested as modulating factors. We assessed the intra-arousal dynamics of spikes and their relationship with the slow-wave component of nonrapid eye movement sleep (NR) arousals.Results:The vast majority of sleep-related seizures (82.4%; 76.5% asymptomatic) were followed by awakenings or arousals. The epileptic burst index increased significantly before arousals as compared to baseline and postarousal, irrespective of sleep stage or brain area. A similar prearousal increase was observed for the spike index in NR stage 2 and rapid eye movement sleep. In addition, the spike index increased during the arousal itself in neocortical channels and was strongly correlated with the slow-wave component of NR arousals (r = 0.99, P < .0001).Interpretation:Sleep fragmentation in focal drug-resistant epilepsy is associated with ictal and interictal epileptic activity. The increase in interictal epileptic activity before arousals suggests its participation in sleep disruption. An additional increase in the spike rate during arousals may result from a sleep–wake boundary instability, suggesting a bidirectional relationship.

A Pragmatic Algorithm to Select Appropriate Antiseizure Medications in Patients With Epilepsy. Asadi-Pooya AA, Beniczky S, Rubboli G, et al. Epilepsia. 2020;61(8):1668-1677. doi:10.1111/epi.16610.Objective:Antiseizure medications (ASMs) are the first-line treatment for epilepsy. Many ASMs are available; this offers the opportunity to improve therapy by tailoring it to individual characteristics but also increases the possibility of health care professionals making inappropriate treatment choices. To assist health care professionals, we developed a pragmatic algorithm aimed at facilitating medication selection for individuals whose epilepsy begins at age 10 years and older.Methods:Utilizing available evidence and a Delphi panel-based consensus process, a group of epilepsy experts developed an algorithm for selection of ASMs, depending on the seizure type(s) and the presence of relevant clinical variables (age, gender, comorbidities, and comedications). The algorithm was implemented into a web-based application that was tested and improved in an iterative process.Results:The algorithm categorizes ASMs deemed to be appropriate for each seizure type or combination of seizure types into 3 groups, with group 1 ASMs considered preferred, group 2 considered second line, and group 3 considered third line. Depending on the presence of relevant clinical variables, the ranking of individual ASMs is adjusted in the prioritization scheme to tailor recommendations to the characteristics of the individual. The algorithm is available on a web-based application at: https://epipick.org/#/.Significance:The proposed algorithm is user-friendly, requires less than 2 minutes to complete, and provides the user with a range of appropriate treatment options from which to choose. This should facilitate its broad utilization and contribute to improve epilepsy management for health care providers who desire advice, particularly those who lack special expertise in the field.

ObjectiveSurgery is an effective but costly treatment for many patients with drug-resistant temporal lobe epilepsy (DR-TLE). We aim to evaluate whether, in the United States, surgery is cost-effective compared to medical management for patients deemed surgical candidates and whether surgical evaluation is cost-effective for patients with DR-TLE in general.MethodsWe use a semi-Markov model to assess the cost-effectiveness of surgery and surgical evaluation over a lifetime horizon. We use second-order Monte Carlo simulations to conduct probabilistic sensitivity analyses to estimate variation in model output. We adopt both health care and societal perspectives, including direct health care costs (e.g., surgery, antiepileptic drugs) and indirect costs (e.g., lost earnings by patients and care providers.) We compare the incremental cost-effectiveness ratio to societal willingness to pay (∼$100,000 per quality-adjusted life-year [QALY]) to determine whether surgery is cost-effective.ResultsEpilepsy surgery is cost-effective compared to medical management in surgically eligible patients by virtue of being cost-saving ($328,000 vs $423,000) and more effective (16.6 vs 13.6 QALY) than medical management in the long run. Surgical evaluation is cost-effective in patients with DR-TLE even if the probability of being deemed a surgical candidate is only 5%. From a societal perspective, surgery becomes cost-effective within 3 years, and 89% of simulations favor surgery over the lifetime horizon.ConclusionFor surgically eligible patients with DR-TLE, surgery is cost-effective. For patients with DR-TLE in general, referral for surgical evaluation (and possible subsequent surgery) is cost-effective. Patients with DR-TLE should be referred for surgical evaluation without hesitation on cost-effectiveness grounds.