Petia Dimova

Objective: Invasive presurgical evaluation plays a key role in pediatric epilepsy surgery, particularly in magnetic resonance imaging (MRI)‐negative cases, by guiding resective, disconnective, or ablative procedures. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Taskforce study provides an updated global overview of current invasive evaluation practices. Methods: Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) in 29 countries across six continents. Included were children and adolescents who underwent presurgical evaluation and epilepsy surgery in 2023. The study was designed to enable comparison with the similar ILAE survey conducted in 2004. Results: A total of 2427 patients were included. Invasive evaluations were performed in 21.1% of cases, most frequently in North America (33.7%, higher than Europe: 18.0%, p = .003). Among invasive cases, 32.3% had no detectable MRI abnormalities. The main indication for invasive evaluation was seizure onset localization (88.1%), followed by motor or sensory mapping (17.2%) and language mapping (14.2%). Stereoelectroencephalography (SEEG) was the predominant technique (19.8% overall, 93.6% of invasive cases), more common in North America (30.0%, p = .021) and less common in South America (7.4%, p < .001). Subdural electrodes were used in only 3.2% of invasive cases, and combined depth and subdural approaches in 3.2%. SEEG‐guided radiofrequency thermocoagulation (RF‐TC) was performed in 40.9% of SEEG cases, most commonly in Asia (63.8%). In 16.2% of invasive evaluations, patients did not proceed to resection, disconnection, or ablation, with the highest rate in Europe (28.5%). Significance: This global survey provides the first broad overview of invasive evaluation practices in pediatric epilepsy surgery across participating centers worldwide. It highlights the widespread adoption of SEEG, declining use of subdural electrodes, and increasing application of SEEG‐guided RF‐TC. The high proportion of MRI‐negative cases and the considerable proportion of patients not proceeding to resection, disconnection, or ablation underscore the complexity of contemporary surgical candidates and the need for further refinement of selection strategies.

Objective: Developmental and epileptic encephalopathy with spike–wave activation in sleep ((D)EE‐SWAS) is associated with acquired cognitive and behavioral deficits. This international multicenter study aimed to compare cognitive and safety outcomes following initial treatment with corticosteroid and clobazam in patients not eligible for the Randomized European trial of Steroids versus Clobazam Usage for Encephalopathy with Electrical Status Epilepticus in Sleep (RESCUE ESES). Methods: Ten centers participated in this retrospective study. Inclusion criteria were diagnosis of (D)EE‐SWAS between 2 and 12 years of age; treatment with either clobazam or corticosteroid for a consecutive period of more than 1 month within 1 year of diagnosis; and no prior treatment with clobazam or corticosteroid. Primary outcome was defined as improvement in daily functioning after 6 months of treatment, as judged by a principal investigator. Spike–wave index (SWI) was measured as secondary outcome and occurrence of adverse events was assessed. Data were analyzed by an intention‐to‐treat principle. In addition, an as‐treated analysis was conducted to compare outcomes between patients who received oral prednisolone and intravenous methylprednisolone at any point during the 6‐month treatment course, regardless of their initial selected treatment (corticosteroid or clobazam). Results: Seventy‐two patients met eligibility criteria and were initially treated with corticosteroid ( n = 24) or clobazam ( n = 48) between June 2011 and March 2020. Baseline characteristics did not differ between groups. After 6 months, 84% of patients in the corticosteroid group showed improvement in daily functioning, compared to 51% in the clobazam group (relative risk [RR] 1.6, 95% confidence interval [CI] 1.2–1.8, p = .012). SWI improved in the corticosteroid group (median change from baseline −10, interquartile range [IQR] −26 to −1), but not in the clobazam group (median change 0, IQR −20 to 7, p = .036). Both treatments were well tolerated. In patients treated with corticosteroid, intravenous pulse methylprednisolone therapy was better tolerated than daily oral prednisolone. Significance: These findings complement the results of the RESCUE ESES trial and are consistent with the superiority of corticosteroid over clobazam in the early management of children with (D)EE‐SWAS.

Objective: We performed a systematic review on the localizing value of ictal hypersalivation and ictal spitting in focal epilepsy with the aim of summarizing the state‐of‐the‐art anatomo‐clinical correlations in the field and aiding the interpretation of ictal semiology within the framework of pre‐surgical evaluation.Methods: We conducted a review and meta‐analysis of the published evidence and reported the results according to the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) statement. We searched in PubMed for relevant articles using the following key words: (hyper)salivation, sialorrhea, drooling, spitting, insular, opercular, epilepsy, seizure, ictal, EEG, and surgery. We evaluated the risk of bias and the diagnostic accuracy quality of each publication using the Quality of Diagnostic Accuracy Studies (QUADAS)‐2‐adapted tool. We assessed the level of confidence (very high, high, moderate, and low) in the reported epileptogenic zone (EZ) based on the availability of findings from MRI, intracerebral EEG, and postoperative outcomes.Results: We reviewed the full text of 65 articles that fulfilled the criteria for evidence synthesis. Thirty‐two studies and 11 case reports (173 patients) on ictal hypersalivation and 15 studies and 13 case reports (54 patients) on ictal spitting were eligible. Ictal hypersalivation was reported in approximately 11% of (mesio)‐temporal and approximately 23% of insular, opercular, and insulo‐opercular epilepsies with >70% high‐confidence cases due to seizure‐free postsurgical outcomes. Ictal spitting was very rarely observed in focal epilepsies, including mesio‐temporal epilepsies (incidence of 1% and 1.6%, respectively), but was significantly associated with a nondominant mesio‐temporal EZ.Significance: There is strong evidence that ictal hypersalivation is more common in insular, opercular, and insulo‐opercular seizures than in temporal lobe seizures, with the mid‐insula and central operculum most consistently identified as symptomatogenic zones. Ictal spitting is a rare complex motor automatism pointing to seizures originating in nondominant mesio‐temporal structures.

Malformations of cortical development (MCD) are a heterogeneous group of diseases, that cause epileptic seizures, motor deficit and mental retardation. We analysed the clinical course, seizure characteristics and neuroimaging data in patients with cortical malformations, treated between 2006 and 2021 in the Clinic of Child Neurology of MHATNP “St. Naum”. We studied 205 patients with MCD, 94 girls (45.9%) and 111 boys (54.1%), with a mean age of 7.7 years, ranging from one month to 18 years of age. Ac- cording to the type of cortical malformation, patients were divided into five groups: 31 patients (15.12%) with heterotopia, 52 (25.3%) – with polymicro- gyria, 47 (22.9%) – with lissencephaly, 59 (28.9%) – with cortical dysplasia and 16 (7.8%) – with schizencephaly. Ninety-five (46.3%) of our patients were with intellectual disability. Mo- tor deficit was reported in 122 children (59.5%) and 173 patients (84.4%) had epileptic seizures. The seizures were focal in 42 (20.57%) of the cases, with mo- tor manifestation in 20 and secondary generalisation – in 7 of them. Forty-six patients experienced generalised seizures. Mixed type of seizures were regis- tered in 83 patients. In two children, the seizures could not be classified. The seizures frequency varied significantly, but patients with cortical dysplasia had the highest rate of daily seizures – 52.5% (n = 31), followed by patients with polymicrogyria – 25% (n = 13). Malformations of cortical development are a heterogeneous group of dis- orders, associated with mental retardation, epilepsy and motor deficit in childhood. Our study provides phenotypic information that would be useful for future genotype-phenotype correlations.

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction.

Objective: Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a recently described, histopathologically and molecularly defined (SLC35A2‐mutated) type of cortical malformation. Although increasingly recognized, the diagnosis of MOGHE remains a challenge. We present the characteristics of the first six patients diagnosed in Bulgaria, with the aim to facilitate identification, proper presurgical evaluation, and surgical treatment approach in this disease.Methods: Revision of histopathological specimens of 202 patients operated on for drug‐resistant focal epilepsy identified four cases with MOGHE. Another two were suggested, based on clinical characteristics and subsequently, were histologically confirmed. Sanger SLC35A2 sequencing on paraffin‐embedded or fresh‐frozen brain tissue was performed. Analysis of seizure types, neuropsychological profiles, electroencephalographic (EEG), imaging features and epilepsy surgery outcomes was done.Results: Three out of the six cases (50%) harbored pathogenic SLC35A2 mutations. One patient had a heterozygous somatic variant with uncertain significance. Clinical characteristics included epilepsy onset in infancy (in 100% under 3 years of age), multiple seizure types, and moderate or severe intellectual/developmental delay. Epileptic spasms with hypsarrhythmia on EEG were the initial seizure type in five patients. The subsequent seizure types resembled those in Lennox–Gastaut syndrome. The majority of the patients (n = 4) presented prominent and persisting autistic features. Magnetic resonance imaging (MRI) showed multilobar (n = 6) and bilateral (n = 3) lesions, affecting the frontal lobes (n = 5; bilaterally in three) and characterized by increased signal on T2/fluid‐attenuated inversion recovery (FLAIR). Voxel‐based morphometric MRI post‐processing and positron emission tomography helped determining the localization and extent of the lesions and presumed epileptogenic zones. After surgery, four patients (66.7%) were seizure‐free ≥2 years. Interestingly, all seizure‐free patients carried somatic SLC35A2‐alterations.Significance: Epileptic spasms, early prominent neuropsychological disturbances, MRI‐T2/FLAIR hyperintense lesions with cortico‐subcortical blurring, frequently multilobar and especially frontal, can preoperatively help to suspect MOGHE. Epilepsy surgery is still the only successful treatment option in MOGHE.

Stereotactic electroencephalography (SEEG) is an important method for invasive presurgical exploration of candidates for epilepsy surgery by means of stereotactic implantation of intracerebral electrodes without craniotomy. Implantations of intracerebral electrodes through craniotomy in drug-resistant epileptic patients have been performed in Bulgaria in the 1980s, but no further development of epilepsy surgery followed. The aim of our study is to present the first Bulgarian series of patients with drug-resistant epilepsy explored by SEEG. Our study included 53 patients with drug-resistant epilepsy explored by SEEG. Stereotactic Leksell frame, stereotactic software for avascular trajectory planning and depth electrodes with diameter of 0.8 mm and 8–18 contacts were used in all patients. Subsequently, long-term video-SEEG monitoring of various duration was performed and registered interictal and ictal EEG activity in order to evaluate the putative epileptogenic zone. Fifty-three patients were explored by 62 SEEGs because one patient underwent three SEEG procedures and seven patients – two SEEG procedures. We implanted 753 electrodes in these 62 SEEGs (mean: 12 electrodes per exploration; range: 5–20 electrodes). The mean age in our cohort was 23.6 years (4–60 years). The main indication for SEEG was MRI-negative epilepsy (20 patients). Focal cortical dysplasia was found in 17 cases, and hippocampal sclerosis in 8 cases. Surgical intervention was done in 48 patients (91%). Surgical resection of the epileptogenic zone (EZ) as defined by the SEEG was performed in 27 patients; radiofrequency stereotactic thermocoagulation (RFTC) on selected electrode contacts was applied in seven patients, and both procedures (i.e. RFTC followed by resective surgery) were performed on 14 patients. Full seizure control (Engel class I) was achieved in 28 patients (58.3%) and significant improvement – in 17 patients (35.4%). Three patients (6.2%) had no effect from surgery. No complications were observed in our series of 62 SEEGs. SEEG is a major tool for the determination of the EZ in patients with drug-resistant epilepsy who are candidates for epilepsy surgery, including MRI-negative cases or such without congruent data from the clinical, neurophysiological and neuroimaging perspectives. SEEG is a low-risk invasive diagnostic and even a therapeutic method when performed by experienced epilepsy surgery team.

Glutamic acid decarboxylase (GAD) antibodies are associated with disabling conditions such as stiff person syndrome, temporal lobe epilepsy (TLE), limbic encephalitis, cerebellar ataxia (CA), and ocular movement disorders, which are usually chronic and difficult to treat. GAD-related TLE has poor response to anti-seizure medications and immune therapies, and epilepsy surgery is rarely successful. We report on a 47-year-old female with history of migraine, autoimmune thyroid disease, ankylosing spondylitis, and drug-resistant TLE. A video electroencephalography recorded frequent seizures with temporo-insular semiology, correlating to left temporal epileptiform activity and left mesiotemporal hyperintensity on magnetic resonance imaging. GAD autoimmunity was confirmed by very high GAD antibody titers in serum and cerebrospinal fluid. Steroids, immunoglobulins, and cyclophosphamide had no effect, and selective left amygdalectomy was performed based on very restricted hypermetabolism on positron-emission tomography. After transient seizure freedom, significant epilepsy improvement was observed in spite of memory decline. Transient worsening was noted 1 year later during diabetes mellitus manifestation and 5 years later during presentation of progressive CA, which stabilized on rituximab treatment. We believe this case illustrates the diversity and the frequent overlap of GAD-associated disorders, the need of early and aggressive immunotherapy in severe patients, as well as the possible benefit from epilepsy surgery in some GAD-TLE.

Summary: Objective: To assess long‐term outcome and identify prognostic factors of radiofrequency thermocoagulation (RFTC) following stereoelectroencephalography (SEEG) explorations in particularly complex cases of focal epilepsy.Methods: We retrospectively reviewed the medical charts, video‐SEEGrecordings, and outcomes for 23 patients (aged 6–53 years) treated withSEEG‐guidedRFTC, of whom 15 had negative magnetic resonance imaging (MRI) findings, and 10 were considered noneligible for resective surgery afterSEEG. Two to 11RFTCs per patient (mean 5) were produced by applying 40–50 V, 75–110 mAcurrent for 10–60 s onSEEGelectrode contacts within the epileptogenic region, which was very close to eloquent cortices in 12 cases. The general features,SEEGfindings, andRFTCextent of the patients were analyzed to extract potential preoperative predictors of post‐RFTCseizure outcomes.Results: After a mean follow‐up of 32 months (range 2–119 months), eight patients experienced a ≥50% decrease of seizure frequency afterRFTC(R+, 34.8%), of whom one had a sustained seizure freedom and 15 patients did not benefit fromRFTC(R−, 65.2%). The presence of anMRIlesion was the only significant predictor of a positive outcome, whereas location of epilepsy, extent of interictal epileptiform discharges (IEDs) and of the seizure onset zone, induction of seizures by electrical stimulation, as well as the ratio of the coagulated sites did not show a significant correlation to theRFTCresponse. However, (sub‐)continuousIEDs were more frequently found in R+ than in R− patients, thus suggesting that thisEEGmarker of the epileptogenic tissue might predict a positive outcome even in patients without obviousMRIlesion.Significance: Our study confirms thatRFTC, although less effective than resective surgery, can be a reasonable therapeutic option in complex cases where anatomic constraints make impossible any cortical resection. Further prospective studies are needed to better defineRFTCindications and to optimize its methodology.