Neonatal seizures during extra corporeal membrane oxygenation support.

To evaluate EEG monitoring during neonatal ECMO and to identify any correlations between seizure detection to abnormal neuroimaging. Eight-year, service evaluation of neonates who received at least one continuous EEG (cEEG) whilst on ECMO at Great Ormond Street Hospital. Pearson's chi-square test and multivariate logistic regression analysis were used to assess clinical and EEG variables association with seizures and neuroimaging findings. Fifty-seven neonates were studied; 57 cEEG recordings were reviewed. The incidence of seizures was 33% (19/57); of these 74% (14/19) were electrographic-only. The incidence of status epilepticus was 42%, (8/19 with 6 neonates having electrographic-only status and 2 electro-clinical status. Seizures were detected within an hour of recording in 84%, (16/19). The overall mortality rate was 39% (22/57). Seizure detection was strongly associated with female gender (OR 4.8, 95% CI: 1.1-20.4, p = 0.03), abnormal EEG background activity (OR 2.8, 95% CI: 1.1-7.4, p = 0.03) and abnormal EEG focal features (OR 23.6, 95% CI: 5.4-103.9, p = 0.001). There was a strong association between the presence of seizures and abnormal neuroimaging findings (OR 10.9, 95% CI: 2.8-41.9, p = 0.001). Neonates were highly likely to have abnormal neuroimaging findings in the presence of severely abnormal background EEG (OR 9.5, 95% CI 1.7-52.02, p = 0.01) and focal EEG abnormalities (OR 6.35, 95% CI 1.97-20.5, p = 0.002)Conclusion: The study highlights the importance of cEEG in neonates undergoing ECMO. An association between seizure detection and abnormal neuroimaging findings was described. What is Known: • Patients on ECMO are at a higher risk of seiures. • Continuous EEG monitoring is recommended by the ACNS for high risk and ECMO patients. What is New: • In this cohort, neonates with sezirues were 11 times more likely of having abnromal neuroimaging findings. • Neonates with burst suppressed or suppressed EEG background were 9.5 times more likely to have abnormal neuroimaging findings. What does this study add? • This study reports a 33% incidence of neonatal seizures during ECMO. • Neonates with seizures were 11 times more likely to have an abnormal brain scan. • The study captures the real-time approach of EEG monitoring. • Recommended cEEG monitoring should last at least 24 h for ECMO patients. • This is the first study to assess this in neonates only.

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

Sleep homeostasis, seizures, and cognition in children with focal epilepsy.

AIM: To investigate the link between sleep disruption and cognitive impairment in childhood epilepsy by studying the effect of epilepsy on sleep homeostasis, as reflected in slow-wave activity (SWA). METHOD: We examined SWA from overnight EEG-polysomnography in 19 children with focal epilepsy (mean [SD] age 11 years 6 months [3 years], range 6 years 6 months-15 years 6 months; 6 females, 13 males) and 18 age- and sex-matched typically developing controls, correlating this with contemporaneous memory consolidation task scores, full-scale IQ, seizures, and focal interictal discharges. RESULTS: Children with epilepsy did not differ significantly from controls in overnight SWA decline (p = 0.12) or gain in memory performance with sleep (p = 0.27). SWA was lower in patients compared to controls in the first hour of non-rapid eye movement sleep (p = 0.021), although not in those who remained seizure-free (p = 0.26). Full-scale IQ did not correlate with measures of SWA in patients or controls. There was no significant difference in SWA measures between focal and non-focal electrodes. INTERPRETATION: Overnight SWA decline is conserved in children with focal epilepsy and may underpin the preservation of sleep-related memory consolidation in this patient group. Reduced early-night SWA may reflect impaired or immature sleep homeostasis in those with a higher seizure burden. WHAT THIS PAPER ADDS: The decline in slow-wave activity (SWA) across the night, reflecting global synaptic downscaling, was preserved in children with focal lesional epilepsies. Sleep benefited memory consolidation in this group of patients, as in typically developing children. Reduced early-night SWA was associated with increased likelihood of a subsequent seizure.

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.

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.

SEEG-guided radiofrequency thermocoagulation of epileptic foci in the paediatric population: Feasibility, safety and efficacy.

PURPOSE: Focal epilepsy in children may be refractory to pharmacological treatment and surgical resection may be an appropriate option. When invasive electroencephalogram is required in the presurgical evaluation, depth electrodes can be used to create focal lesions in the epileptogenic zone using radiofrequency thermocoagulation (RFTC), to disrupt the epileptogenic zone. METHODS: This study aimed to assess the efficacy and safety of RFTC in a paediatric population of 46 patients. RESULTS: The mean age of onset was 3.3 years and the mean age at SEEG was 8.2 years. MRI lesions were identified in 71.7% of the series, among them 60% of malformation of cortical development. 43.5% of the patients were seizure free at 1 month, 26.1% were responders. The mean duration of improvement was 6.8 months. 8 children were seizure free for >8 months and among them, 6 are currently seizure free for 8-24 months. 5 patients had functional deficits post-procedures, transient in 4 patients and prolonged in one of whom. 3/5 were anticipated following the results of cortical stimulation. Multivariate analysis found 3 independent criteria linked to RFTC efficiency one month after RFTC: frequency of the seizures before RFTC, age and number of contacts used. CONCLUSION: RFTC is a safe method for the paediatric population providing important predictive information for surgical resection. An improvement in seizure frequency, often transient, is seen in 2/3 of our patients. RTFC could be useful as a palliative technique for children with an epileptogenic zone overlapping with eloquent areas, with minimal risk of sequelae.

Intraoperative neurophysiological monitoring in paediatric Chiari surgery-help or hindrance?

INTRODUCTION: The role of intraoperative neurophysiological monitoring (IONM) during surgery for Chiari I malformation has not been fully elucidated. Questions remain regarding its utility as an adjunct to foramen magnum decompression surgery, specifically, does IONM improve the safety profile of foramen magnum decompression surgery and can IONM parameters help in intraoperative surgical decision-making. This study aimed to describe a single institution experience of IOM during paediatric Chiari I surgery. METHODS: The methodology comprised a retrospective review of prospectively collected electronic neurosurgical departmental operative database. Inclusion criteria were children under 16 years of age who had undergone foramen magnum decompression for Chiari I malformation with IONM. In addition to basic demographic data, details pertaining to presenting features and post-operative outcomes were obtained. These included primary symptoms of Chiari I malformation and indications for surgery. MRI findings, including the presence of syringomyelia on pre-and post-operative imaging, were reviewed. Details of the surgical technique for each patient were recorded. Only patients with either serial brainstem auditory evoked potential (BAEP) and/or upper limb somatosensory evoked potential (SSEP) recordings were included. Two time points were used for the purposes of analysing IONM data; initial baseline before skin incision and final at the time of skin closure. RESULTS: Thirty-seven children underwent foramen magnum decompression (FMD) with IONM. Mean age was 10.5 years (range 1-16 years) with a male:female ratio 13:24. The commonest clinical features on presentation included headaches (15) and scoliosis (13). Twenty-four patients had evidence of associated syringomyelia (24/37 = 64.9%). A reduction in the SSEP latency was observed in all patients. SSEP amplitude was more variable, with a decrease seen in 18 patients and an increase observed in 12 patients. BAEP recordings decreased in 13 patients and increased in 4 patients. There were no adverse neurological events following surgery; the primary symptom was resolved or improved in all patients at 3-month follow-up. Resolution or improvement in syringomyelia was observed in 19/24 cases. CONCLUSIONS: Our data shows that FMD for Chiari malformation (CM) is associated with changes in SSEPs and BAEPs. However, we did not identify a definite link between clinical outcomes and IONM, nor did syrinx outcome correlate with IONM. There may be a role for IONM in CM surgery but more robust data with better-defined parameters are required to further understand the impact of IONM in CM surgery.

SYT1-associated neurodevelopmental disorder: a case series.

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

Consensus-based guidelines for Video EEG monitoring in the pre-surgical evaluation of children with epilepsy in the UK.

PURPOSE: Paediatric Epilepsy surgery in the UK has recently been centralised in order to improve expertise and quality of service available to children. Video EEG monitoring or telemetry is a highly specialised and a crucial component of the pre-surgical evaluation. Although many Epilepsy Monitoring Units work to certain standards, there is no national or international guideline for paediatric video telemetry. METHODS: Due to lack of evidence we used a modified Delphi process utilizing the clinical and academic expertise of the clinical neurophysiology sub-specialty group of Children's Epilepsy Surgical Service (CESS) centres in England and Wales. This process consisted of the following stages I: Identification of the consensus working group, II: Identification of key areas for guidelines, III: Consensus practice points and IV: Final review. Statements that gained consensus (median score of either 4 or 5 using a five-point Likerttype scale) were included in the guideline. RESULTS: Two rounds of feedback and amendments were undertaken. The consensus guidelines includes the following topics: referral pathways, neurophysiological equipment standards, standards of recording techniques, with specific emphasis on safety of video EEG monitoring both with and without drug withdrawal, a protocol for testing patient's behaviours, data storage and guidelines for writing factual reports and conclusions. All statements developed received a median score of 5 and were adopted by the group. CONCLUSION: Using a modified Delphi process we were able to develop universally-accepted video EEG guidelines for the UK CESS. Although these recommendations have been specifically developed for the pre-surgical evaluation of children with epilepsy, it is assumed that most components are transferable to any paediatric video EEG monitoring setting.

TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus.

BACKGROUND: Advances in molecular genetic technologies have improved our understanding of genetic causes of rare neurological disorders with features of myoclonus. CASE REPORT: A family with two affected siblings, presenting with multifocal polymyoclonus and neurodevelopmental delay, was recruited for whole-exome sequencing following unyielding diagnostic neurometabolic investigations. Compound heterozygous mutations in TBC1D24, a gene previously associated with various epilepsy phenotypes and hearing loss, were identified in both siblings. The mutations included a missense change c.457G>A (p.Glu157Lys), and a novel frameshift mutation c.545del (p.Thr182Serfs*6). DISCUSSION: We propose that TBC1D24-related diseases should be in the differential diagnosis for children with polymyoclonus.

Auditory processing following infantile spasms: An event-related potential study.

OBJECTIVES: To investigate acoustic auditory processing in patients with recent infantile spasms (IS). METHODS: Patients (n = 22; 12 female; median age 8 months; range 5-11 months) had normal preceding development, brain magnetic resonance imaging (MRI), and neurometabolic testing (West syndrome of unknown cause, uWS). Controls were healthy babies (n = 22; 11 female; median age 6 months; range 3-12 months). Event-related potentials (ERPs) and psychometry (Bayley Scales of Infant Development, Second Edition, BSID-II) took place at a month following IS remission. RESULTS: Following a repeated pure tone, uWS patients showed less suppression of the N100 at the mid-temporal electrodes (p = 0.006), and a prolonged response latency (p = 0.019). Their novelty P300 amplitude over the mid-temporal electrodes was halved (p = 0.001). The peak of the novelty P300 to environmental broadband sounds emerged later over the left temporal lobe in patients (p = 0.015), the lag correlating with duration of spasms (r = 0.547, p = 0.015). BSID-II scores were lower in patients (p < 0.001), with no correlation to ERP. SIGNIFICANCE: Complex acoustic information is processed poorly following IS. This would impair language. Treatment did not reverse this phenomenon, but may have limited its severity. The data are most consistent with altered connectivity of the cortical acoustic processing areas induced by IS.

Does sleep benefit memory consolidation in children with focal epilepsy?

OBJECTIVE: Children with epilepsy have high rates of both cognitive impairment and sleep disruption. It is thus assumed that sleep-dependent memory consolidation is vulnerable to ongoing epileptic activity, but direct evidence of this is limited. METHODS: We performed a within-subject comparison of memory retention across intervals of wake or overnight sleep. Healthy children (n = 21, 6-16 years, 12 female) and children with focal epilepsy (n = 22, 6-16 years, 9 female) performed verbal and visuospatial memory tasks under each condition. Sleep was assessed with electroencephalography (EEG) polysomnography during the overnight interval. Interictal discharges were quantified manually. RESULTS: Memory retention was greater in the sleep condition in both the verbal (F1,39 = 10.8, p = 0.002, Cohen's d = 0.67) and the visuospatial (F1,36 = 4.23, p = 0.05, Cohen's d = 0.40) tasks, with no significant interaction of group by condition in either task. Across the total sample, gain in memory retention with sleep in the verbal task correlated with duration of slow wave sleep (r = 0.4, p = 0.01). In patients, sleep-dependent memory consolidation was negatively correlated with interictal discharge rate in both the verbal (ρ = -0.49, p = 0.04) and visuospatial (ρ = -0.45, p = 0.08) tasks. On post hoc analysis, a longer history of epilepsy (r = 0.53, p = 0.01) and a temporal (t10 = 1.8, p = 0.1, Cohen's d = 0.86) rather than an extratemporal seizure focus (t10 = 0.8, p = 0.4, Cohen's d = 0.30) was associated with greater contribution of sleep to verbal memory retention. SIGNIFICANCE: We have demonstrated that memory consolidation in children with focal epilepsy benefits from sleep, showing the same correlation with slow wave sleep as in healthy children, but an inverse relationship with the interictal discharge load during sleep. This mechanism appears to be increasingly recruited with longer duration of illness, indicating a resilient homeostatic function which may be harnessed to aid learning.

Interictal epileptiform discharges have an independent association with cognitive impairment in children with lesional epilepsy.

OBJECTIVES: The relative contribution of interictal epileptiform discharges (IEDs) to cognitive dysfunction in comparison with the underlying brain pathology is not yet understood in children with lesional focal epilepsy. METHODS: The current study investigated the association of IEDs with intellectual functioning in 103 children with medication-resistant focal epilepsy. Hierarchical multiple regression analyses were used to determine the independent contribution of IED features on intellectual functioning, after controlling for effects of lesional pathology, epilepsy duration, and medication. Exploratory analyses were conducted for language and memory scores as well as academic skills available in a subset of participants. RESULTS: The results reveal that IEDs have a negative association with IQ with independent, additive effects documented for frequent and bilaterally distributed IEDs as well as discharge enhancement in sleep. Left-lateralized IEDs had a prominent effect on verbal intelligence, in excess of the influence of left-sided brain pathology. These effects extended to other cognitive functions, most prominently for sleep-enhanced IEDs to be associated with deficits in expressive and receptive language, reading, spelling and numerical skills. SIGNIFICANCE: Overall, IED effects on cognition were of a magnitude similar to lesional influences or drug effects (topiramate use). This study demonstrates an association between IEDs and cognitive dysfunction, independent of the underlying focal brain pathology.

Electroencephalography during general anaesthesia differs between term-born and premature-born children.

OBJECTIVES: Premature birth is associated with a wide range of complications in later life, including structural and functional neurological abnormalities and altered pain sensitivity. We investigated whether during anaesthesia premature-born children display different patterns of background EEG activity and exhibit increased responses to nociceptive stimuli. METHODS: We examined background EEG and time-locked responses to clinical cannulation in 45 children (mean age (±SD) at study: 4.9(±3.0)years) under sevoflurane monoanaesthesia maintained at a steady-state end-tidal concentration of 2.5%. 15 were born prematurely (mean gestational age at birth: 29.2 ± 3.9 weeks) and 30 were age-matched term-born children. RESULTS: Background levels of alpha and beta power were significantly lower in the premature-born children compared to term-born controls (p=0.048). Clinical cannulation evoked a significant increase in delta activity (p=0.032), which was not significantly different between the two groups (p=0.44). CONCLUSIONS: The results indicate that whilst under anaesthesia premature-born children display different patterns of background brain activity compared to term-born children. SIGNIFICANCE: As electrophysiological techniques are increasingly used by anaesthetists to gauge anaesthetic depth, differences in background levels of electrophysiological brain activity between premature and term-born children may be relevant when considering titration of anaesthetic dose.

Seizures Due to a KCNQ2 Mutation: Treatment with Vitamin B6.

There is increasing evidence that vitamin B6, given either as pyridoxine or pyridoxal 5'-phosphate, can sometimes result in improved seizure control in idiopathic epilepsy. Whole-exome sequencing was used to identify a de novo mutation (c.629G>A; p.Arg210His) in KCNQ2 in a 7-year-old patient whose neonatal seizures showed a response to pyridoxine and who had a high plasma to CSF pyridoxal 5'-phosphate ratio, usually indicative of an inborn error of vitamin B6 metabolism. This mutation has been described in three other patients with neonatal epileptic encephalopathy. A review of the literature was performed to assess the effectiveness of vitamin B6 treatment in patients with a KCNQ2 channelopathy. Twenty-three patients have been reported to have been trialled with B6; in three of which B6 treatment was used alone or in combination with other antiepileptic drugs to control seizures. The anticonvulsant effect of B6 vitamers may be propagated by multiple mechanisms including direct antagonist action on ion channels, antioxidant action on excess reactive oxygen species generated by increased neuronal firing and replenishing the pool of pyridoxal 5'-phosphate needed for the synthesis of some inhibitory neurotransmitters. Vitamin B6 may be a promising adjunctive treatment for patients with channelopathies and the wider epileptic population. This report also demonstrates that an abnormal plasma to CSF pyridoxal 5'-phosphate ratio may not be exclusive to inborn errors of vitamin B6 metabolism.

Outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression.

OBJECTIVE: To determine whether multiple subpial transection in the posterior temporal lobe has an impact on long-term outcome in children who have drug-resistant Landau-Kleffner syndrome (LKS) or other "electrical status epilepticus during sleep" (ESES)-related regression. Given the wide variability in outcomes reported in the literature, a secondary aim was to explore predictors of outcome. METHODS: The current study includes a surgery group (n = 14) comprising patients who underwent multiple subpial transection of the posterior temporal lobe and a nonsurgery comparison group (n = 21) comprising patients who underwent presurgical investigations for the procedure, but who did not undergo surgery. Outcomes were assessed utilizing clinical note review as well as direct assessment and questionnaires. RESULTS: The distribution of nonclassical cases was comparable between groups. There were some differences between the surgery and nonsurgery groups at presurgical investigation including laterality of discharges, level of language impairment, and age; therefore, follow-up analyses focused on change over time and predictors of outcome. There were no statistically significant differences between the groups in language, nonverbal ability, adaptive behavior, or quality of life at follow-up. There was no difference in the proportion of patients showing improvement or deterioration in language category over time for either group. Continuing seizures and an earlier age of onset were most predictive of poorer quality of life at long-term follow-up (F2,23 = 26.2, p = <0.001, R(2) = 0.714). SIGNIFICANCE: Both surgery and nonsurgery groups had similar proportions of classic LKS and ESES-related regression. Because no significant differences were found in the changes observed from baseline to follow-up between the two groups, it is argued that there is insufficient evidence to suggest that multiple subpial transection provides additional benefits over and above the mixed recovery often seen in LKS and related regressive epilepsies.

Quantitative magnetic resonance imaging evidence for altered structural remodeling of the temporal lobe in West syndrome.

OBJECTIVE: To explore the structure-function relation of the temporal lobe in newly diagnosed West syndrome of unknown cause (uWS). METHODS: Quantitative magnetic resonance imaging (three-dimensional [3D] structural MRI and diffusion tensor imaging [DTI]) was analyzed using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) in 22 patients and healthy age-matched controls. The electrophysiologic responsiveness of the temporal lobe was measured using the N100 auditory event-related potential (aERP) to a repeated 1,000 Hz tone. Neurocognitive function was assessed using the Bayley Scales of Infant Development, Second Edition (BSID-II). Tests followed first-line treatment with vigabatrin (17 patients) or high-dose oral prednisolone (5 patients). RESULTS: Total temporal lobe volume was similar in patients and controls. Patients had a smaller temporal stem (TS) (p < 0.0001) and planum temporale (PT) (p = 0.029) bilaterally. TS width asymmetry with a larger right-sided width in controls was absent in patients (p = 0.033). PT asymmetry was present in both groups, being larger on the right (p = 0.048). VBM gray matter volume was increased at the left temporal lobe (superior and middle temporal gyri, the peri-rhinal cortex, and medial temporal lobe) (p < 0.005, family wise error-corrected). VBM gray matter volume correlated with the duration of infantile spasms (Pearson's r = -0.630, p = 0.009). DTI metrics did not differ between patients and controls on TBSS. Mean BSID-II scores were lower (p < 0.001) and auditory N100 ERP attenuated less in patients than in controls (p = 0.002). SIGNIFICANCE: The functional networking and white matter development of the temporal lobe are impaired following infantile spasms. Treatment may promote structural plasticity within the temporal lobe following infantile spasms, manifest as increased gray matter volume on VBM. It remains to be investigated further whether this predicts patients' long-term cognitive difficulties.

Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling.

Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development.

Temporal lobe impairment in West syndrome: event-related potential evidence.

OBJECTIVE: This study investigates auditory processing in infants with West syndrome (WS) using event-related potentials (ERPs). METHODS: ERPs were measured in 25 infants with mainly symptomatic WS (age range = 3-10 months) and 26 healthy term infants (age range = 3-9 months) using an auditory novelty oddball paradigm. The ERP recordings were made during wakefulness and repeated in stage II sleep. RESULTS: The obligatory components (P150, N250, P350) and novelty response components (P300, Nc) were recordable during both sleep and wakefulness in patients and controls. All ERP latencies decreased with age in controls but not in the WS group (age × group interaction, F = 22.3, p < 0.0001). These ERP latency alterations were not affected by pharmacological treatment for WS. INTERPRETATION: This study demonstrated a persistently altered ERP signature in patients with a recent history of infantile spasms. The prolongation of auditory obligatory and novelty ERPs in WS patients indicates a severe failure of temporal lobe maturation during infancy. It remains to be investigated whether this predicts long-term cognitive impairments characteristic for this epileptic encephalopathy.