We report two cases of temporo-perisylvian epilepsy with habitual seizures consistently inducible by hyperventilation (HV). One case was non-lesional, while the other was a lesional temporo-perisylvian epilepsy. Both underwent surgical resection and were seizure-free or nearly seizure-free thereafter. We discuss the pathophysiological changes evoked by HV in healthy brains, and those with generalized and focal epilepsy. We provide a comprehensive and critical review of the literature on the role of HV in focal epilepsy. We suggest HV should be considered an activation method for patients with focal epilepsy during epilepsy monitoring unit admissions and may help in the localization of the epileptogenic network/zone.

OBJECTIVE The objective of this paper was to investigate the factors associated with successful epileptogenic zone (EZ) identification and postsurgical seizure freedom in pediatric patients with drug-resistant epilepsy who underwent first-time stereoelectroencephalography (SEEG).METHODS The authors conducted a retrospective cohort study of all consecutive patients younger than 18 years of age at the time of recommendation for invasive evaluation with SEEG who were treated from July 2009 to June 2020. The au-thors excluded patients who had undergone failed prior resective epilepsy surgery or prior intracranial electrode evaluation for seizure localization. For their primary outcome, the authors evaluated the relationship between clinical and radiograph-ic factors and successful identification of a putative EZ. For their secondary outcome, the authors investigated whether these factors had a significant relationship with seizure freedom (according to the Engel classification) at last follow-up.RESULTS The authors included 101 patients in this study. SEEG was safe, with no major morbidity or mortality expe-rienced. The population was complex, with an MRI lesion present in less than 40% of patients and patients as young as 2.9 years included. A proposed EZ was identified in 88 (87%) patients. Patients with an older onset of epilepsy (OR 1.20/ year, p = 0.04) or epilepsy etiology suspected to be due to a developmental lesion (OR 8.38, p = 0.02) were more likely to have proposed EZ identification. Patients with a preimplantation bilateral seizure-onset hypothesis (OR 0.29, p = 0.047) and those who underwent longer periods of monitoring (OR 0.86/day, p = 0.006) were somewhat less likely to have proposed EZ identification. The presence of an MRI lesion was a positive factor on secondary analyses (OR 4.18, p = 0.049; 1-tailed test). Fifty percent of patients who underwent surgical treatment with resection or laser ablation achieved Engel class I outcomes, in contrast to 0% of patients who underwent neuromodulation. Patients with a preimplantation hypothesis in the frontal/parietal lobes had increased odds of seizure freedom compared with patients with a hypothesis in other locations (OR 3.64, p = 0.01).CONCLUSIONS Pediatric SEEG is safe and often identifies a proposed resectable EZ. These results suggest that SEEG is effective in patients with frontal/parietal preimplantation hypothesis, with or without identified lesions on MRI.

OBJECTIVE:Epilepsy with eyelid myoclonias(EMA) is a genetic generalized epilepsy (GGE) characterized by eyelid myoclonia, eye-closure sensitivity and photosensitivity. Data on EMA patients who specifically present with photoparoxysmal response on EEG is lacking. EMA is an under-recognized syndrome which is frequently misclassified as another GGE. The main objective of our research is to describe the occurrence of EMA versus other GGEs among patients with photoparoxysmal response and evaluate their distinguishing features.METHODS:We retrospectively identified all patients who had photoparoxysmal response on EEGs performed at Cleveland clinic between 01/01/2012 and 12/31/2019. Initial epilepsy diagnosis and clinical data were collected. EEGs were reviewed for eyelid myoclonia and eye-closure-sensitivity which were used as main diagnostic clues for EMA. If clinical criteria was met, diagnosis was revised as EMA.RESULTS:Of 249 patients with photoparoxysmal response, 70(28.1%) met EMA criteria. Sixty-two (88.6%) were females. Mean age of onset of epilepsy was 7 years (+7.9) and 120(48.2%) had other GGEs. Fifty-four (77.1%) patients with EMA were initially classified as another epilepsy. Initial diagnosis included CAE or JME in 40(57.1%) patients with EMA so we compared EMA with these syndromes. Female preponderance, drug refractoriness, older age of onset and generalized myoclonia were more common in EMA than CAE. Earlier age of onset, absence seizures, and lack of generalized myoclonic jerks were more common EMA than JME.SIGNIFICANCE:Our study demonstrates that EMA is under-recognized among GGE patients with photoparoxysmal response. It highlights distinguishing clinical and electrographic features which separate EMA from other GGEs. It emphasizes the diverse treatments utilized and the need for therapeutic options for patients with refractory EMA.

OBJECTIVE The aim of this study was to investigate seizure outcomes after resective epilepsy surgery following stereoelectroencephalography (SEEG), including group characteristics, comparing surgical and nonsurgical groups and assess predictors of time to seizure recurrence. METHODS Clinical and EEG data of 536 consecutive patients who underwent SEEG at Cleveland Clinic Epilepsy Center between 2009 and 2017 were reviewed. The primary outcome was defined as complete seizure freedom since the resective surgery, discounting any auras or seizures that occurred within the 1st postoperative week. In addition, the rate of seizure freedom based on Engel classification was determined in patients with follow-up of ≥ 1 year. Presumably significant outcome variables were first identified using univariate analysis, and Cox proportional hazards modeling was used to identify outcome predictors. RESULTS Of 527 patients satisfying study criteria, 341 underwent resective surgery. Complete and continuous seizure freedom after surgery was achieved in 55.5% of patients at 1 year postoperatively, 44% of patients at 3 years, and 39% of patients at 5 years. As a secondary outcome point, 58% of patients achieved Engel class I seizure outcome for at least 1 year at last follow-up. Among surgical outcome predictors, in multivariate model analysis, the seizure recurrence rate by type of resection (p = 0.039) remained statistically significant, with the lowest risk of recurrence occurring after frontal and temporal lobe resections compared with multilobar and posterior quadrant surgeries. Patients with a history of previous resection (p = 0.006) and bilateral implantations (p = 0.023) were more likely to have seizure recurrence. The absence of an MRI abnormality prior to resective surgery did not significantly affect seizure outcome in this cohort. CONCLUSIONS This large, single-center series shows that resective surgery leads to continuous seizure freedom in a group of patients with complex and severe pharmacoresistant epilepsy after SEEG evaluation. In addition, up to 58% of patients achieved seizure freedom at last follow-up. The authors' results suggest that SEEG is equally effective in patients with frontal and temporal lobe epilepsy with or without MRI identified lesions.

Summary Objective Drug‐resistant epilepsy (DRE) during the first few months of life is challenging and necessitates aggressive treatment, including surgery. Because the most common causes of DRE in infancy are related to extensive developmental anomalies, surgery often entails extensive tissue resections or disconnection. The literature on “ultra‐early” epilepsy surgery is sparse, with limited data concerning efficacy controlling the seizures, and safety. The current study's goal is to review the safety and efficacy of ultra‐early epilepsy surgery performed before the age of 3 months. Methods To achieve a large sample size and external validity, a multinational, multicenter retrospective study was performed, focusing on epilepsy surgery for infants younger than 3 months of age. Collected data included epilepsy characteristics, surgical details, epilepsy outcome, and complications. Results Sixty‐four patients underwent 69 surgeries before the age of 3 months. The most common pathologies were cortical dysplasia (28), hemimegalencephaly (17), and tubers (5). The most common procedures were hemispheric surgeries (48 procedures). Two cases were intentionally staged, and one was unexpectedly aborted. Nearly all patients received blood products. There were no perioperative deaths and no major unexpected permanent morbidities. Twenty‐five percent of patients undergoing hemispheric surgeries developed hydrocephalus. Excellent epilepsy outcome (International League Against Epilepsy [ILAE] grade I) was achieved in 66% of cases over a median follow‐up of 41 months (19–104 interquartile range [IQR]). The number of antiseizure medications was significantly reduced (median 2 drugs, 1–3 IQR, p < .0001). Outcome was not significantly associated with the type of surgery (hemispheric or more limited resections). Significance Epilepsy surgery during the first few months of life is associated with excellent seizure control, and when performed by highly experienced teams, is not associated with more permanent morbidity than surgery in older infants. Thus surgical treatment should not be postponed to treat DRE in very young infants based on their age.

Background: We studied the natural history, genotype influence, and inter-relationship of epilepsy and neuropsychiatric disorders in tuberous sclerosis complex. Methods: Patients were identified using the TSC Natural History Database, the largest repository of longitudinally studied patients enrolled by the TSC Clinics Consortium. Results: A cohort of 1657 TSC Natural History Database patients was analyzed. Eighty-eight percent patients (91% TSC2 vs 82% TSC1; P= 0.002) had epilepsy; TSC2 was more frequent with epilepsy onset at age less than two years (TSC2 82% vs ISC154%; P< 0.001 ) and infantile spasms (TSC2 56% vs TSC1 27%; P< 0.001). Frequency of intellectual disability (intelligence quotient less than 70) was higher when epilepsy coexisted (P < 0.001), but was not impacted by genotype (P = 0.08). Severe intellectual disability (intelligence quotient less than 50) was associated with epilepsy onset at age less than two years (P = 0.007), but not with the epilepsy duration (P= 0.45). Autism was diagnosed in 23% and was associated with epilepsy (P <0.001), particularly with epilepsy onset at age less than two years (P = 0.02) but not with genotype (P = 0.06). Attention-deficit/hyperactivity disorder (age greater than four years) was diagnosed in 18% and was associated with epilepsy (P < 0.001), but genotype made no difference. Nine percent had anxiety (age greater than seven years) and 6% had depression (age greater than nine years), but neither showed association with epilepsy or genotype. Conclusions: Epilepsy is associated with intellectual disability, and when epilepsy begins before age two years the frequency and severity of intellectual disability is much higher. Epilepsy is also associated with autism and attention-deficit/hyperactivity disorder but not with anxiety and depression. Additional trials, blinded, prospective, and adequately powered, will help clarify if early and effective treatment of epilepsy may also mitigate intellectual disability, autism, and attention-deficit/hyperactivity disorder. (C) 2020 Elsevier Inc. All rights reserved.

Objective To examine longitudinal seizure and functional outcomes after hemispherectomy in adults and adolescents. Methods We reviewed 47 consecutive patients older than 16 years who underwent hemispherectomy between 1996 and 2016 at our center. Clinical, electroencephalographic (EEG), imaging, neuropsychological, surgical, and functional status data were analyzed. Results Thirty-six patients were 18 years or older at surgery; 11 were aged between 16 and 18 years. Brain injury leading to hemispheric epilepsy occurred before 10 years of age in 41 (87%) patients. At a mean follow-up of 5.3 postoperative years (median = 2.9 years), 36 (77%) had Engel class I outcome. Longitudinal outcome analysis showed 84% seizure freedom (Engel IA) at 6 months, 76% at 2 years, and 76% at 5 years and beyond, with stable longitudinal outcomes up to 12 years from surgery. Multivariate analysis demonstrated that acute postoperative seizures and contralateral interictal spikes at 6-month follow-up EEG were associated with seizure recurrence. Patients who could walk unaided preoperatively and had no cerebral peduncle atrophy on brain magnetic resonance imaging were more likely to experience worsening of motor function postoperatively. Otherwise, postoperative ambulatory status and hand function were unchanged. Of the 19 patients who completed neuropsychological testing, 17 demonstrated stable or improved postoperative outcomes. Significance Hemispherectomy in adults is a safe and effective procedure, with seizure freedom rates and functional outcome similar to those observed in children.

BACKGROUND AND RATIONALE: Magnetoencephalography has emerged as a tool for preoperative evaluation in children. We studied magnetoencephalography characteristics in subtypes of focal cortical dysplasia and correlated the findings with postoperative seizure outcome. METHODS: Inclusion criteria were children <= 18 years who underwent magnetoencephalography during the preoperative evaluation followed by epilepsy surgery and a histopathologic diagnosis of focal cortical dysplasia between February 2008 and February 2013. Patient demographics, MRI, video electroencephalography, and magnetoencephalography data were reviewed. Postoperative seizure outcome data were categorized per International League against Epilepsy definitions. RESULTS: Of 178 magnetoencephalography studies performed in children during the study period, 33 patients met inclusion criteria. Focal cortical dysplasia type I, II, and III were found on histopathology in 52%, 39%, and 9% of patients, respectively. Thirty patients had positive magnetoencephalography dipoles, including all patients with focal cortical dysplasia type II and III and 82% of patients with focal cortical dysplasia type I. Three patients had magnetoencephalography unique spikes. Brain MRI lesions were noted preoperatively in 21 patients (64%). Twenty-three patients (77%) had surgical resection of magnetoencephalography dipoles and 11 (48%) of them achieved favorable outcome. CONCLUSIONS: Magnetoencephalography supplemented scalp electroencephalography data in spike source localization and showed unique spikes in 10% of the focal cortical dysplasia patients. Magnetoencephalography spikes and tight magnetoencephalography clusters were found more frequently in patients with focal cortical dysplasia type II and III as compared with focal cortical dysplasia type I. Presence of an MRI lesion and complete versus incomplete resection of magnetoencephalography cluster did not result in significant difference in postoperative seizure outcome, likely reflecting selection bias of doing magnetoencephalography in only difficult-to-localize epilepsies.

Multiple seizure foci, seizure propagation and epileptic spasms complicate presurgical seizure localization in tuberous sclerosis. Furthermore, controversy exists about the contribution of tubers, perituberal cortex and the underlying genetic abnormality to epileptogenesis. We aimed to determine the epileptogenic substrate in tuberous sclerosis by studying spatio-temporal patterns of seizure onset and propagation on intracranial EEG recordings in which multiple depth and surface electrodes sampled multiple tubers and perituberal cortex. Ten intracranial EEG recordings (seven extraoperative, three intraoperative) from 10 children with tuberous sclerosis were analysed. Notable thickening and signal abnormality in the centre of many tubers on magnetic resonance imaging led to tuber centres being recorded with depth electrodes. Spatially-meaningful bipolar montages were reformatted incorporating channels recording only from the tuber centre, tuber rim and perituberal cortex. Interictal epileptiform discharges and ictal rhythms were analysed visually for location, field, morphology, frequency, latency and temporal dispersion. Fifteen electroclinically distinct seizures were recorded in the 10 patients. Seizure onset was recorded in tubers in all 15 electroclinically distinct seizures; in 9/10 electroclinically distinct seizures recorded with optimal spatial sampling, seizure onset was recorded in the tuber centre, with or without involvement of the tuber rim but not perituberal cortex. Quantitative electroencephalography analysis by pairwise cross-correlation confirmed that the tuber centre led the tuber rim and perituberal cortex during interictal, preictal and ictal spike trains. Seizure propagation was observed in 10/15 electroclinically distinct seizures, being tuber-to-tuber in all. Seven of the 17 tubers showing seizure propagation activated an independent ictal rhythm, morphologically distinct from that seen in seizure onset region (intra-ictal activation). Of the total 48 tubers sampled, 16 exhibited seizure onset, 17 were involved in seizure propagation and 40 exhibited interictal epileptiform discharges, 33 independent and seven propagated. Seizure onsets were recorded in 16/33 tubers with independent interictal epileptiform discharges, but 0/7 tubers with only propagated epileptiform discharges or 0/8 tubers with no epileptiform discharges (P = 0.003). Seizure onsets were recorded from 4/7 tubers with and 0/10 tubers without intra-ictal activation (P = 0.015). Thus, focal seizures and interictal epileptiform discharges in tuberous sclerosis arise in the centre of epileptogenic tubers and propagate to the tuber rim, perituberal cortex and other epileptogenic tubers. Rhythmic interictal epileptiform discharges and intra-ictal activation of propagated ictal rhythms are potential biomarkers of epileptogenic tubers. Interictal and ictal EEG features of epileptogenic tubers have similarities to focal cortical dysplasia type II, consistent with the reported imaging, histological and molecular similarities.

Purpose: Children with generalized seizures are often excluded as epilepsy surgery candidates. This prospective study was conducted to evaluate the utility of magnetoencephalography (MEG) to refine the location of the "irritative zone" in children with single lesions on magnetic resonance imaging (MRI) but with generalized ictal electroencephalographic (EEG) findings. Methods: Patients admitted with refractory epilepsy with imaging studies showing focal or hemispheric abnormalities but scalp video EEG showing generalized or multiregional epileptiform abnormalities were included. Patients were encouraged into natural sleep, and simultaneous whole-head MEG/EEG was recorded. Source localization of epileptic spikes on MEG was carried out while blinded to other results. Acceptable dipoles were classified into 3 groups: focal, hemispheric clusters, and single focal cluster with additional widespread dipoles. Results: Nine patients (4 female, 5 males; ages 10 months to 15 years) were included. Two had focal features on clinical semiology, whereas all had generalized or multiregional interictal and ictal EEG. Etiologies included tuberous sclerosis complex (2), postencephalitic sequelae (1), focal cortical dysplasia (1), and unknown (2). Five patients had clear focal lesions on brain MRI whereas the other 2 had focal positron emission tomography (PET) abnormalities. An average of 38 spikes were accepted (average goodness of fit = 85.3%). A single tight cluster of dipoles was identified in 5 patients, 1 had dipoles with propagation from left occipital to right temporal. One patient had 2 distinct dipole clusters. MEG demonstrated focal findings 9 times more often than the simultaneously recorded scalp EEG, and 3 times more often than the associated multiday video EEG recordings. Conclusion: This study shows that neurophysiologic evidence of focal epileptiform abnormalities in patients with focal brain lesions and generalized EEG findings can be strengthened using MEG. Further feasibility of surgical candidacy should be evaluated in these patients.

Commentary Childhood onset intractable epilepsy remains the most common and defining morbidity of tuberous sclerosis complex (TSC) (1). Traditional antiepileptic drugs and dietary therapies fall woefully short in most children to induce a long-term seizure remission, and to allow learning and independence. Epilepsy surgery can be offered to few selected children despite the multi-modal presurgical evaluation with newer tests and tools designed to map the “epileptogenic” tuber complex and a safe surgical strategy (2). After discovery that the mTOR pathway upregulation is the pivotal mechanism of TSC pathology in human disease, interest in using already available mTOR inhibitors was only natural. Clinical trials led to the FDA approval of mTOR inhibitor drugs in selected cases of subependymal giant cell astrocytomas (SEGA), renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis (LAM). However, proving the usefulness of mTOR inhibitors in epilepsy turned out to be much more difficult. Preclinical studies and mouse models have shown that mTORC1 inhibition can prevent and reverse epileptogenesis in TSC (3, 4). Treatment with mTORC1 inhibitors has been shown to fully rescue the phenotype, suggesting that mTORC1 inhibitors might be useful for targeted treatment of epileptogenesis in TSC (4). However, such convincing evidence is yet to be established in human epilepsy thus far. This could partly be due to the multi-faceted pathophysiological mechanisms set in motion at the onset of epilepsy, the influence of other environmental and genetic factors, as well the complexity inherent in defining and measuring outcomes in epilepsy associated with a rarer disease especially in cognitively impaired children. Overwater and colleagues should be congratulated on conducting an astutely designed trial of sirolimus in epilepsy for TSC. Unfortunately, the trial was negative and could not confirm the benefit of sirolimus in epilepsy. However, it lacked the precision to exclude a possible benefit from sirolimus, and therefore has set the bar for future trials. This trial was an add-on, open-label sirolimus treatment in 23 children (age 1.8-10.9 years) with TSC. The one year trial had a cross-over design divided into two phases of 6 months each: the sirolimus phase (SP), when sirolimus was added to the patient’s antiepileptic drug regimen; and the standard antiepileptic drugs phase (SADP), without sirolimus. Each patient was randomly assigned to SP or SADP in the first phase and then crossed over to the alternative phase. Primary outcome measures of median seizure frequency were 25 seizures per month (interquartile range [IQR], 7–47) after the SP versus 32 (IQR, Sirolimus for Epilepsy in Children With Tuberous Sclerosis Complex: A Randomized Controlled Trial.

A 27-year-old woman was evaluated for developmental delay and intractable epilepsy. She was born via cesarean section at 42-week gestational age. Developmental delay for gross motor skills, fine motor skills, and language was noted since infancy. She was hypotonic and walked by age 3 years. She began speaking at age 2 years. Her social skills were preserved.

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

PURPOSE OF REVIEW:This article provides an update on the current understanding and management of febrile seizures. Febrile seizures are one of the most common age-related epileptic convulsions that lead to outpatient consultations, emergency department visits, and hospital or intensive care admissions.RECENT FINDINGS:The Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study, an ongoing multicenter prospective longitudinal study, is providing valuable insights into the subset of patients who develop febrile status epilepticus, the most life-threatening type of febrile seizures with potential long-term consequences. Mutations in voltage-gated ion channels and neurotransmitter receptor genes have been shown to result in familial occurrence of febrile seizures and epilepsy. Acute abortive treatment of febrile seizures using a commercially available rectal delivery kit has gained widespread use by nonmedical caregivers as a first-line treatment at home.SUMMARY:Most febrile seizures are self-limiting episodes with low risk of injury, death, and long-term neurologic consequences. Most fevers and infections that cause febrile seizures are relatively benign and do not require extensive testing or procedures. Long-term management requires thorough assessment and risk stratification to devise a customized plan for each child, paying attention to the caregiver situation at home and day care. Most important treatment efforts are directed at caregiver education and, when appropriate, on effective use of abortive seizure treatment at home.

BACKGROUND:There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC).OBJECTIVE:We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery.METHODS:A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery.RESULTS:Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 ± 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1- and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom.CONCLUSION:In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber.