Prediction tools and risk stratification in epilepsy surgery.

OBJECTIVE: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2). METHODS: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures. RESULTS: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05). SIGNIFICANCE: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties.

OBJECTIVE: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. METHODS: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells. RESULTS: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. INTERPRETATION: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.

IRF2BPL as a novel causative gene for progressive myoclonus epilepsy.

IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs. We describe a novel IRF2BPL phenotype consistent with progressive myoclonus epilepsy (PME) in three novel subjects and review the features of the 31 subjects with IRF2BPL-related disorders previously reported. Our three probands, aged 28-40 years, harbored de novo nonsense variants in IRF2BPL (c.370C > T, p.[Gln124*] and c.364C > T; p.[Gln122*], respectively). From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome. The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders. Whereas the two older probands were severely affected, the younger proband had a milder PME phenotype, partially overlapping with some of the previously reported IRF2BPL cases, suggesting that some of them might be unrecognized PME. Interestingly, all three patients harbored protein-truncating variants clustered in a proximal, highly conserved gene region around the "coiled-coil" domain. Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel causative gene for PME.

Trisomy 20p/monosomy 18p associated with congenital bilateral perisylvian syndrome.

We report the association, not previously described, between trisomy 20/ monosomy 18 and congenital bilateral perisylvian syndrome (CBPS), a condition featuring intellectual disability, epilepsy, oro-motor dysfunction and bilateral perisylvian polymicrogyria (BPP) in a 29-year-old individual. Detailed clinical evaluation, long-term EEG and EEG analysis by means of electrical source imaging (ESI), 3T MRI and array-CGH were performed. Clinical examination showed moderate/severe intellectual disability, dysmorphic features, oro-motor dysfunction, short stature, abnormal hands and feet, bradykinesia and abnormal posture. The patient had suffered from drug-resistant epilepsy since infancy. Brain MRI showed that BPP was consistent with CBPS. Additional imaging features revealed corpus callosum and cerebellar hypoplasia and fusion of the C1-C2 vertebrae. Ictal EEG and ESI documented tonic seizures originating from the right polymicrogyric cortex. Facial gestalt included dysmorphic features reported in patients with 18- and 20+ chromosomal rearrangements. Array-CGH showed an unbalanced translocation, arr(18p)x1(20p)x3. In conclusion, we provide a detailed electro-clinical and MRI description of a novel condition characterized by the association between trisomy 20p/monosomy 18p and CBPS, also illustrating its clinical evolution into adulthood. This information may help paediatricians, neurologists and geneticists to better counsel families about the developmental prognosis of this rare unbalanced chromosomal rearrangement.

Genetic paroxysmal neurological disorders featuring episodic ataxia and epilepsy.

OBJECTIVE: This review article focuses on clinical and genetic features of paroxysmal neurological disorders featuring episodic ataxia (EA) and epilepsy and help clinicians recognize, diagnose, and treat patients with co-existing EA and epilepsy. It also provides an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders. METHODS: Based on a literature review on Pubmed database, a list of genes linked to paroxysmal neurological disorders featuring EA and epilepsy were compiled. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Among the various forms of EAs, only EA1 (KCNA1), EA2 (CACNA1A), EA5 (CACNB4), EA6 (SLC1A3), and EA9 (SCN2A) phenotypes with associated epilepsy have been described. Next-generation sequencing (NGS) has helped in the identification of other genes (e.g.: KCNA2, ATP1A3, SLC2A1, PRRT2) which have shown an overlapping phenotype with EA and epilepsy. CONCLUSION: Overlapping clinical features between EA and epilepsy may hinder an accurate classification, and complex genotype-phenotype correlation may often lead to misdiagnosis. NGS has increased the awareness of common genetic etiologies for these conditions. In the future, extensive genetic and phenotypic characterizations can help us to elucidate the boundaries of a wide phenotypic spectrum. These insights may help develop new precision therapies in paroxysmal neurological disorders featuring EA and epilepsy.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: EEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. METHODS: We have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. RESULTS: We analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66-85.37%). CONCLUSIONS: Automated ictal ESI has a high accuracy for localizing the seizure onset zone. SIGNIFICANCE: Automating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Magnetic evoked potential polyphasia in idiopathic/genetic generalized epilepsy: An endophenotype not associated with treatment response.

OBJECTIVE: Increased Motor Evoked Potential (MEP) polyphasia was recently described in idiopathic/genetic generalized epilepsy (IGE). Here, we studied the association of MEP polyphasia with treatment response and other clinical characteristics in patients with IGE. METHODS: MEPs were recorded from the biceps brachii, flexor carpi radialis and interosseus dorsalis muscles bilaterally during tonic contraction in IGE patients (n = 72) and historical controls (n = 54) after single pulse transcranial magnetic stimulation. Detailed clinical data was available for all IGE patients; predefined endpoint was the association of MEP polyphasia with treatment response. RESULTS: The mean number of phases was higher in the interosseus dorsalis muscle (2.33 vs. 2.13, p = 0.002) in IGE patients as compared to normal controls, as was the proportion of MEPs with more than two phases in at least one test (59.4% vs. 30%, p < 0.002). MEP polyphasia did not differ between IGE patients and controls in the biceps brachii or the flexor carpi radialis muscles and was not associated with treatment response. Extensive exploratory analyses unveiled fewer phases under valproic acid treatment (p = 0.04) but no additional associations of MEP polyphasia in the interosseous muscle with other clinical characteristics. CONCLUSION: MEP polyphasia is a subclinical symptom of IGE patients but is not associated with treatment response or other routinely assessed clinical characteristics. SIGNIFICANCE: MEP polyphasia is a fixed feature of IGE not modified by clinical variables.

A European questionnaire survey on epilepsy monitoring units' current practice for postoperative psychogenic nonepileptic seizures' detection.

BACKGROUND: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. METHODS: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. RESULTS: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 ( ±â€¯19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 ±â€¯7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. CONCLUSION: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Diagnostic added value of electrical source imaging in presurgical evaluation of patients with epilepsy: A prospective study.

OBJECTIVE: To investigate the diagnostic added value of electrical source imaging (ESI) in presurgical evaluation of patients with drug resistant focal epilepsy. METHODS: Eighty-two consecutive patients were included. We analyzed both low density (LD) and high density (HD) EEG recordings. LD ESI was done on interictal and ictal signals recorded during long-term video-EEG monitoring (LTM), with standard 25 electrodes and age-matched template head models. HD ESI was done on shorter recordings (90-120 min), with 256 electrodes, using individual head model. The multidisciplinary team made decisions first blinded to ESI (based on all other modalities) and then discussed the results of the ESI. We considered that ESI had diagnostic added value, when it provided non-redundant information that changed the patients management plan. RESULTS: ESI had diagnostic added value in 28 patients (34%). In most cases (85.7%), these changes were related to planning of the invasive recordings. In nine out of 13 patients, invasive recordings confirmed the localization. Out of eight patients in whom the ESI source was resected, six became seizure-free. CONCLUSIONS: ESI provides non-redundant information in one third of the patients undergoing presurgical evaluation. SIGNIFICANCE: This study provides evidence for the diagnostic added value of ESI in presurgical evaluation.

Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations.

Mutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies.

The landscape of epilepsy-related GATOR1 variants.

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Automated EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: To evaluate the accuracy of automated EEG source imaging (ESI) in localizing epileptogenic zone. METHODS: Long-term EEG, recorded with the standard 25-electrode array of the IFCN, from 41 consecutive patients with focal epilepsy who underwent resective surgery, were analyzed blinded to the surgical outcome. The automated analysis comprised spike-detection, clustering and source imaging at the half-rising time and at the peak of each spike-cluster, using individual head-models with six tissue-layers and a distributed source model (sLORETA). The fully automated approach presented ESI of the cluster with the highest number of spikes, at the half-rising time. In addition, a physician involved in the presurgical evaluation of the patients, evaluated the automated ESI results (up to four clusters per patient) in clinical context and selected the dominant cluster and the analysis time-point (semi-automated approach). The reference standard was location of the resected area and outcome one year after operation. RESULTS: Accuracy was 61% (95% CI: 45-76%) for the fully automated approach and 78% (95% CI: 62-89%) for the semi-automated approach. CONCLUSION: Automated ESI has an accuracy similar to previously reported neuroimaging methods. SIGNIFICANCE: Automated ESI will contribute to increased utilization of source imaging in the presurgical evaluation of patients with epilepsy.

[Epilepsy surgery].

Surgery is the only treatment option with the potential to cure epilepsy. This review is a description of the multidisciplinary and multimodal presurgical evaluation process and the outcome of the Danish epilepsy surgery programme. The outcome aligns with international results and serious complications to surgery are very rare. The annual number of operations per capita compares to neighbouring countries and is equally distributed across Denmark. In accordance with international recommendations, Danish drug-resistant patients should be referred to epilepsy surgery evaluation at an early stage of the disease.

Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study.

OBJECTIVE: The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. METHODS: A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. RESULTS: Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. SIGNIFICANCE: This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.

Epilepsy surgery of "low grade epilepsy associated neuroepithelial tumors": A retrospective nationwide Italian study.

OBJECTIVE: To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of "low grade epilepsy associated neuroepithelial tumors" (LEATs). METHODS: We conducted a retrospective study enrolling 339 consecutive patients with LEATs who underwent surgery between January 2009 and June 2015 at eight Italian epilepsy surgery centers. We compared demographic, clinical, pathologic, and surgical features of patients with favorable (Engel class I) and unfavorable (Engel class II, III, and IV) seizure outcome. In addition, we compared patients with tumor-associated focal cortical dysplasia (FCD) and patients with solitary tumors to identify factors correlated with FCD diagnosis. RESULTS: Fifty-five (98.2%) of 56 patients with medically controlled epilepsy were seizure-free after surgery, compared to 249 (88.0%) of 283 patients with refractory epilepsy. At multivariate analysis, three variables independently predict unfavorable seizure outcome in the drug-resistant group. Age at surgery is largely the most significant (p = 0.001), with an odds ratio (OR) of 1.04. This means that the probability of seizure recurrence grows by 4% for every waited year. The resection site is also significant (p = 0.039), with a relative risk (RR) of 1.99 for extratemporal tumors. Finally, the completeness of tumor resection has a trend toward significance (p = 0.092), with an RR of 1.82 for incomplete resection. Among pediatric patients, a longer duration of epilepsy was significantly associated with preoperative neuropsychological deficits (p < 0.001). A statistically significant association was observed between FCD diagnosis and the following variables: tailored surgery (p < 0.001), temporal resection (p = 0.001), and surgical center (p = 0.012). SIGNIFICANCE: Our nationwide LEATs study gives important insights on factors predicting seizure outcome in refractory epilepsy and determining variability in FCD detection. Timely surgery, regardless of pharmacoresistance and oriented to optimize epileptologic, neuropsychological, and oncologic outcomes should be warranted.

Management of Antiepileptic Treatment After Epilepsy Surgery - Practices and Problems.

BACKGROUND: Although epilepsy surgery is a recognized treatment option for drug-resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic controlled trials have been specifically conducted so far and no consensus or standardized guidelines regarding postsurgical drug discontinuation policy and procedures are available. METHODS: In this paper, we aim to provide an updated overview on the present knowledge on this topic, which is based mainly on retrospective studies reporting practices used in individual centers. RESULTS: Currently available data suggest that: 1) rate of seizure recurrence appears to be higher in patients undergoing early (before 6 months or 9 months according to different studies) AED withdrawal; 2) seizures that recur during AED tapering are easier to control than unprovoked postoperative seizure relapses; 3) there is no evidence to support negative long-term implications on seizure outcomes in patients who attempted AED withdrawal. In the pediatric age group, shorter intervals from surgery to AED reduction and to complete AED discontinuation predict seizure relapse during or after AED reduction/withdrawal. However, this does not correlate with the chances of regaining seizure freedom after drug reintroduction. CONCLUSION: Carefully conducted prospective longitudinal studies and randomized controlled trials are warranted to establish the correct post-surgical pharmacologic treatment and to identify the best candidates for AEDs discontinuation.

Alternating hemiplegia of childhood and a pathogenic variant of ATP1A3: a case report and pathophysiological considerations.

We describe a case of a child suffering from alternating hemiplegia with a heterozygous p. E815K pathogenic variant of ATP1A3. The patient started to present abnormal eye movements in the first days of life, followed by the appearance at 2 months of dystonic episodes, and later on, by recurrent episodes of alternating hemiplegia more often on the right side. A severe epilepsy started at the age of 2 years with episodes of status epilepticus since the onset which frequently recurred, requiring admission to the intensive care unit. MRI showed bilateral mesial temporal sclerosis and a left-sided ischaemic lesion. Interictal EEG showed bilateral abnormalities, whereas postictal EEG after status epilepticus showed overt slowing on the left side, suggesting a predominant involvement of ictal activity of the left hemisphere. We hypothesize that in our patient, the left hemisphere might have been more prominently affected by the pathogenetic abnormalities underlying alternating hemiplegia of childhood, rendering it more prone to early ischaemic lesions and recurrent unilateral status epilepticus. We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2.