Results of an international Delphi consensus in epilepsy with myoclonic atonic seizures/ Doose syndrome

OBJECTIVE: To establish a standard framework for early phenotypic diagnosis, investigations, expected findings from investigations, evolution, effective therapies and prognosis in the syndrome of Epilepsy with myoclonic atonic seizures (EMAS) / Doose syndrome. METHODS: A core study group (CSG) interested in EMAS was convened. CSG then identified and nominated 15 experts in the field of EMAS. This expert panel (EP) from English speaking nations was invited to participate in anonymous questionnaires. A literature review was provided to them (supplement 1). Three rounds of questionnaires were sent to identify areas of consensus, strength of consensus and areas of contention. RESULTS: Strong consensus was obtained regarding the clinical phenotype of EMAS: myoclonic atonic seizure was identified among others as a mandatory seizure type with typical onset of afebrile seizures between one and six years. A new term "stormy phase" (SP) was designated to delineate a characteristic phenotypic evolution in EMAS patients associated with seizure worsening. Strong consensus regarding the existence and time of onset of the SP, mandatory investigations to be performed early and later in the clinical course of EMAS, first and second tier treatment and prognostic factors for poor outcome were identified. Areas of lack of consensus included some seizure types that are necessary to diagnose EMAS, interictal EEG findings that prognosticate the course of EMAS, overall duration of SP, time to complete remission, and best approach to treat drug resistant EMAS. SIGNIFICANCE: Expert consensus on core diagnostic criteria of EMAS necessary for natural history studies, phenotype-genotype correlations, and clinical trials including comparative studies was demonstrated. Areas of disagreements (especially prognostic features; treatment options) need further research

Stereo-EEG exploration in the insula/operculum in paediatric patients with refractory epilepsy

PURPOSE: Failure to recognise involvement of the insula / opercula (I/O) region is associated with poor outcome in epilepsy surgery. Recognition is challenging due to high connectivity with adjacent structures resulting in variable and misleading semiology, often subjective and therefore likely to be underreported by children. In this study we explored prevalence and characteristics of I/O involvement in paediatric patients undergoing sEEG exploration. METHOD: We retrospectively included all consecutive patients undergoing sEEG at our centre between 11/2014 and 01/2018 with at least three contacts within I/O and excluded those with undetermined seizure onset zone (SOZ) by sEEG. We divided patients into three groups: 1) SOZ in I/O, 2) spread to I/O and 3) no I/O involvement. We compared pre-invasive characteristics, sEEG results, surgery and outcome for each group. RESULTS: 29 of all 53 consecutive patients had an identified SOZ by sEEG and at least three contacts within the I/O and were included. 41% had I/O SOZ, 38% had I/O spread and 21% had no I/O involvement. Insula associated symptoms described in adult literature were not statistically different between the three groups. Complications due to sEEG were low (2 of 53 patients). Following I/O surgery, 63% were seizure free while an additional 26% of patients achieved seizure reduction. Postoperative deficits were seen in 75% of the patients but completely resolved in all but one patient. CONCLUSIONS: Our data suggest an important role of the I/O region with frequent onset or propagation to the I/O region (at least 64% of all 53 sEEG cases). Semiology appears less specific than in adults. Insula depth electrode insertion is safe with subsequent good surgical outcomes albeit common transient deficits

CLN8 disease caused by large genomic deletions

BACKGROUND: The presence of deletions can complicate genetic diagnosis of autosomal recessive disease. METHOD: The DNA of patients was analyzed in a diagnostic setting. RESULTS: We present three unrelated patients each carrying deletions that encompass the 37 kb CLN8 gene and discuss their phenotype. Two of the cases were hemizygous for a mutant allele - their deletions unmasked a mutation in CLN8 on the other chromosome. CONCLUSION: Microarray analysis is recommended in any patient suspected of NCL who is apparently homozygous for a mutation that is not present in one of the parents or when the family has no known consanguinity

Dietary Management of Children With Super-Refractory Status Epilepticus: A Systematic Review and Experience in a Single UK Tertiary Centre

Ketogenic diet therapies (KDT) are high-fat, low carbohydrate diets used as an effective treatment option for drug-resistant epilepsy. There is limited research on the efficacy of KDT for super-refractory status epilepticus (SRSE). We systematically review evidence for use of KDT in children with SRSE and present a single UK tertiary centre's experience. Thirty one articles were included, of which 24 were “medium” or “low” quality. One hundred and forty seven children with SRSE started KDT, of which 141 (96%) achieved ketosis. KDT was started mean 5.3 days (range 1–420) after status epilepticus (SE) started. SRSE resolved in 85/141 (60%) children after mean 6.3 days (range 0–19) post SE onset, but it is unclear whether further treatments were initiated post-KDT. 13/141 (9%) children died. Response to KDT was more likely when initiated earlier (p = 0.03) and in females (p = 0.01). Adverse side effects were reported in 48/141 (34%), mostly gastrointestinal; potentially serious adverse effects occurred in ≤4%. Eight children with SRSE, all diagnosed with febrile infection-related epilepsy syndrome, were treated with KDT at Great Ormond Street Hospital for Children. KDT was initiated enterally at mean day 13.6+/− 5.1 of admission. Seven of 8 (88%) children reported adverse side effects, which were potentially serious in 4/8 (50%), including metabolic acidosis, hypoglycaemia and raised amylase. SE ceased in 6/8 (75%) children after mean 25+/− 9.4 days post onset, but other treatments were often started concomitantly and all children started other treatments post-KDT. Two of 8 (25%) children died during admission and another died post-admission. Four of the remaining 5 children continue to have drug-resistant seizures, one of whom remains on KDT; seizure burden was unknown for one child. Our findings indicate that KDT is possible and safe in children with SRSE. Cessation of SRSE may occur in almost two-thirds of children initiated with KDT, but a causal effect is difficult to determine due to concomitant treatments, treatments started post-KDT and the variable length of time post-KDT onset when SRSE cessation occurs. Given that serious adverse side effects seem rare and response rates are (cautiously) favorable, KDT should be considered as an early treatment option in this group

Anti-seizure medications for Lennox-Gastaut syndrome

Background Lennox‐Gastaut syndrome (LGS) is an age‐specific epilepsy syndrome characterised by multiple seizure types. LGS has a characteristic electroencephalogram, an onset before age eight years, and drug resistance. This is an updated version of the Cochrane Review published in 2013. Objectives To assess the efficacy and tolerability of anti‐seizure medications (ASMs) for LGS. Search methods We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi‐RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. Selection criteria We considered RCTs, including cross‐over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as add‐on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. Data collection and analysis We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias, and applying the GRADE approach to rate the evidence certainty for outcomes. Main results We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow‐up after randomisation) using add‐on ASMs for LGS in children, adolescents, and adults. Two studies compared add‐on cannabidiol (two doses) with add‐on placebo in children, adolescents, and adults. Insufficient information was provided for calculation of different response rate proportions in all seizures. We found high‐certainty evidence that 82 more people per 1000 (confidence interval (CI) 19 more to 350 more) had adverse events (AE) leading to study discontinuation with add‐on cannabidiol, compared to add‐on placebo (two studies; 396 participants; risk ratio (RR) 6.62, 95% CI 1.56 to 28.15). One study compared add‐on cinromide with add‐on placebo in children and adolescents only. We found very low‐certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add‐on cinromide compared to add‐on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add‐on clobazam (three doses) with add‐on placebo. This study did not report overall seizure cessation or reduction. We found high‐certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add‐on clobazam compared to add‐on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add‐on felbamate with add‐on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low‐certainty evidence). There was low‐certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add‐on felbamate were seizure‐free during an EEG recording at the end of the treatment phase, compared to add‐on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low‐certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add‐on felbamate had AE leading to study discontinuation compared to add‐on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add‐on lamotrigine with add‐on placebo. Neither study reported overall seizure cessation. We found high‐certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add‐on lamotrigine compared to add‐on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low‐certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study‐discontinuation with add‐on lamotrigine compared to add‐on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add‐on rufinamide with add‐on placebo. Neither study reported seizure cessation. We found high‐certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low‐certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add‐on rufinamide compared to add‐on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add‐on rufinamide with another add‐on ASM. This study did not report overall seizure cessation or reduction. We found low‐certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add‐on rufinamide compared to another add‐on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add‐on topiramate with add‐on placebo. This study did not report overall seizure cessation. We found low‐certainty evidence for ≥ 75% average seizure reduction with add‐on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add‐on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low‐certainty evidence). Authors' conclusions RCTs of monotherapy and head‐to‐head comparison of add‐on ASMs are currently lacking. However, we found high‐certainty evidence for overall seizure reduction with add‐on lamotrigine and rufinamide, with low‐certainty evidence for AE leading to study discontinuation compared with add‐on placebo or another add‐on ASM. The evidence for other add‐on ASMs for overall seizure cessation or reduction was low to very low with high‐ to low‐certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age‐specific efficacy of ASMs and target underlying aetiologies

Proportion of resected seizure onset zone contacts in pediatric stereo-EEG-guided resective surgery does not correlate with outcome

Objective: We aimed to determine whether the proportion of putative seizure onset zone (SOZ) contacts resected associates with seizure outcome in a cohort of children undergoing stereoelectroencephalography (SEEG)-guided resective epilepsy surgery. / Methods: Patients who underwent SEEG-guided resective surgery over a six-year period were included. The proportion of SOZ contacts resected was determined by co-registration of pre- and post-operative imaging. Outcome was classified as seizure free (SF, Engel class I) or not seizure-free (NSF, Engel class II-IV) at last clinical follow-up. / Results: Twenty-nine patients underwent resection of whom 22 had sufficient imaging data for analysis (median age at surgery of 10 years, range 5–18). Fifteen (68.2%) were SF at median follow-up of 19.5 months (range 12–46). On univariate analysis, histopathology, was the only significant factor associated with SF (p < 0.05). The percentage of defined SOZ contacts resected ranged from 25-100% and was not associated with SF (p = 0.89). In a binary logistic regression model, it was highly likely that histology was the only independent predictor of outcome. / Conclusions: The percentage of SOZ contacts resected was not associated with SF in children undergoing SEEG-guided resective epilepsy surgery. / Significance: Factors such as spatial organisation of the epileptogenic zone, neurophysiological biomarkers and the prospective identification of pathological tissue may therefore play an important role

Epileptogenic Tubers Are Associated with Increased Kurtosis of Susceptibility Values: A Combined Quantitative Susceptibility Mapping and Stereoelectroencephalography Pilot Study

BACKGROUND AND PURPOSE: Prior studies have found an association between calcification and the epileptogenicity of tubers in tuberous sclerosis complex. Quantitative susceptibility mapping is a novel tool sensitive to magnetic susceptibility alterations due to tissue calcification. We assessed the utility of quantitative susceptibility mapping in identifying putative epileptogenic tubers in tuberous sclerosis complex using stereoelectroencephalography data as ground truth. MATERIALS AND METHODS: We studied patients with tuberous sclerosis complex undergoing stereoelectroencephalography at a single center who had multiecho gradient-echo sequences available. Quantitative susceptibility mapping and R2* values were extracted for all tubers on the basis of manually drawn 3D ROIs using T1- and T2-FLAIR sequences. Characteristics of quantitative susceptibility mapping and R2* distributions from implanted tubers were compared using binary logistic generalized estimating equation models designed to identify ictal (involved in seizure onset) and interictal (persistent interictal epileptiform activity) tubers. These models were then applied to the unimplanted tubers to identify potential ictal and interictal tubers that were not sampled by stereoelectroencephalography. RESULTS: A total of 146 tubers were identified in 10 patients, 76 of which were sampled using stereoelectroencephalography. Increased kurtosis of the tuber quantitative susceptibility mapping values was associated with epileptogenicity (P = .04 for the ictal group and P = .005 for the interictal group) by the generalized estimating equation model. Both groups had poor sensitivity (35.0% and 44.1%, respectively) but high specificity (94.6% and 78.6%, respectively). CONCLUSIONS: Our finding of increased kurtosis of quantitative susceptibility mapping values (heavy-tailed distribution) was highly specific, suggesting that it may be a useful biomarker to identify putative epileptogenic tubers in tuberous sclerosis complex. This finding motivates the investigation of underlying tuber mineralization and other properties driving kurtosis changes in quantitative susceptibility mapping values

Diagnostic algorithm for children presenting with epilepsia partialis continua

Objective: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. / Methods: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. / Results: Fifty‐four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6‐15), with median follow‐up of 4.3 years (range 0.2‐16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion‐positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3‐15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole‐exome sequencing on blood‐derived DNA should be performed. / Significance: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis

Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study

OBJECTIVES: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE). METHODS: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records. RESULTS: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not. INTERPRETATION: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort