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.

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.

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.

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.

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.

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.

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.

Association of the Achondroplasia Foramen Magnum Score and intraoperative neuromonitoring.

INTRODUCTION: Foramen magnum stenosis in achondroplasia carries a risk of sudden death. A proportion of these patients benefit from foramen magnum decompression (FMD). The Achondroplasia Foramen Magnum Score (AFMS) was developed to stratify those most at risk. We hypothesise that this score may be reflected in neurophysiological findings. METHODS: Patients with achondroplasia who had undergone FMD (n=20) were retrospectively grouped into AFMS 2, 3 and 4. Amplitude from tibialis anterior (TA) and the percentage change in somatosensory evoked potential (SSEP) latency after FMD were reported. RESULTS: Baseline motor evoked potential amplitudes for patients with AFMS=4 were significantly lower left (p=0.0017 and p=0.02 for right and left TA, respectively) compared with AFMS grades 2 and 3. Median reduction (% change) in SSEP latency (ms) after surgery was not significantly different in any of the patients. CONCLUSIONS: This short report cross-references AFMS to intraoperative neuromonitoring. Baseline amplitudes were noticeably lower in the most severe AFMS group. This observation supports the notion that AFMS can help risk stratify patients and aid in surgical selection.

Evolution of the EEG in children with Rasmussen's syndrome.

PURPOSE: The early diagnosis of Rasmussen's syndrome (RS) is often difficult, with differentiation between RS and focal cortical dysplasia (FCD) at epilepsy onset problematic. This study reviewed electroencephalography (EEG) in the two conditions for early indicators of either pathology. METHODS: All children with either suspected RS or with unilateral FCD undergoing evaluation for epilepsy surgery between 1992 and 2005 were identified. Case notes and standard EEG recordings were reviewed. EEG findings were compared where available at <3, 3-6 months, and 3-5 years after seizure onset. KEY FINDINGS: Nineteen children with RS and 17 with FCD were ascertained. In EEG studies performed <3 months after seizure onset, 50% (5/10) of the RS group showed background abnormalities, with 80% of these (4/5) showing persistent high-amplitude delta activity over the affected hemisphere. This compared to 66% (6/9) of the FCD group with 17% (1/6) showing marked background asymmetry. By 3-6 months after seizure onset, independent interictal abnormalities over the nonaffected hemisphere were seen in 25% (2/8) of the RS group and by 3-5 years in 62% (5/8) compared to none in the FCD group at any time points measured. These independent contralateral interictal abnormalities were notably associated with a significant decline in cognitive skills over time. SIGNIFICANCE: No specific EEG changes at diagnosis of epilepsy were identified to help differentiate between RS and FCD. Emerging persistent delta activity over the affected hemisphere with contralateral normal background rhythms, followed in due course by independent interictal epileptiform abnormalities over the unaffected hemisphere may support the diagnosis of RS as the condition evolves, and highlight the risk of overall cognitive dysfunction.

Language deficits and altered hemispheric lateralization in young people in remission from BECTS.

Benign epilepsy with centrotemporal spikes (BECTS) is associated with language disturbances during the active phase of the seizure disorder. However, it is not yet known whether these deficits are reversible or have long-term impact on the development of language skills. We report on a study conducted in 13 patients in remission from BECTS and 13 age-matched controls, who underwent neuropsychological assessments. We also recorded event-related potentials (ERPs) during a verb generation task, to determine cortical lateralization of language. The BECTS group showed significant language deficits compared to controls as well as a pattern of atypical ERP lateralization in frontal regions. These findings support the view that BECTS in childhood may lead to enduring effects on brain maturation and language development.

Single-pulse electrical stimulation helps to identify epileptogenic cortex in children.

PURPOSE: The usefulness of single-pulse electrical stimulation (SPES) during intracranial recordings was evaluated in a pediatric population. This method is useful in identifying epileptogenic cortex in adult subjects. METHODS: We studied 35 children who were undergoing intracranial electroencephalography (EEG) recordings from two hospitals (King's College Hospital and Great Ormond Street Hospital for Sick Children, London, United Kingdom). In each patient we studied all available contacts using a series of 10 or more single, brief (1ms) electrical stimuli. The cortical responses were reviewed in detail. The data were examined for associations between response type, ictal onset zone, lesion boundary, and seizure outcome. RESULTS: We identified cortical responses to SPES that were similar to those reported in adults. In agreement with previous studies we found that two types of responses ("delayed" and "repetitive" responses) were associated with the ictal onset zone and the area of the presumed epileptogenic lesion. When these responses were present (54% of cases), the removal of the entire area responsible for the abnormal responses to SPES was associated with good outcome. CONCLUSION: Cortical responses to SPES in children provide new and additional information in the investigation of epileptogenic cortex in children during assessment for epilepsy surgery. This may improve the outcome for this difficult but important group.

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.

Is streamlined evaluation of children for epilepsy surgery possible?

BACKGROUND: The presurgical evaluation of children with intractable epilepsy includes evaluation by an experienced clinician, MRI, video EEG, and functional imaging techniques to localize seizure onset. However, the contributions of each investigation to surgical decision making has not been systematically assessed. METHOD: Data used for decision on eligibility for surgery on 353 children was discussed at a presurgical multidisciplinary meeting and systematically recorded. The relationships between MRI, EEG, SPECT findings, and the probability of being offered epilepsy surgery were investigated retrospectively using a quick unbiased statistical tree (QUEST). RESULTS: Sixteen children were offered nonresective surgery. Of the remaining, 236 (70%) were offered resective surgery. The proportion of children with a localized lesion on MRI offered resective surgery was 92%[95% CI: 88 to 95%], and EEG telemetry did not modify decision making in this group (p < 0.001). In children with bilateral MRI changes or normal scan the probability of being offered resective surgery was 78% in those with localized ictal onset on EEG compared to 9% with nonlocalized EEG (p < 0.001). SPECT did not appear to systematically influence decision making in any group. CONCLUSION: Children with medically intractable epilepsy and localized lesions on MRI may not necessarily need ictal EEG recordings or SPECT prior to offering resective surgery. More targeted use of EEG telemetry could allow more children with less obvious surgical targets to be investigated without increasing resources.

Are there distinctive sleep problems in Angelman syndrome?

Angelman syndrome is a neurogenetic condition characterized by developmental delay, absence of speech, motor impairment, epilepsy and a peculiar behavioral phenotype that includes sleep problems. It is caused by lack of expression of the UBE3A gene on the maternal chromosome 15q11-q13. Although part of the diagnostic description, 'sleep problems' are not well characterized. A pattern emerges from the available reports. It includes reduced total sleep time, increased sleep onset latency, disrupted sleep architecture with frequent nocturnal awakenings, reduced rapid eye movement (REM) sleep and periodic leg movements. Poor sleep does not significantly interfere with daytime alertness and sleep problems commonly diminish by late childhood, with continuing improvement through adolescence and adulthood. Sleep problems in Angelman syndrome reflect abnormal neurodevelopmental functioning presumably involving dysregulation of GABA-mediated inhibitory influences in thalamocortical interactions. Management may be difficult, particularly in young children; it primarily involves behavioral approaches, though pharmacological treatment may be required. The relationship between sleep and seizure disorder, and between sleep and learning raises critical questions, but more studies are needed to address these relationships adequately.

Epilepsy in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder caused by lack of UBE3A gene expression from the maternally inherited chromosome 15 due to various 15q11-q13 abnormalities. In addition to severe developmental delay, virtual absence of speech, motor impairment, a behavioural phenotype that includes happy demeanor, and distinctive rhythmic electroencephalographic features, over 90% of patients have epilepsy. Many different seizure types may occur, atypical absences and myoclonic seizures being particularly prevalent. Non-convulsive status epilepticus is common, sometimes in the context of the epileptic syndrome referred to as myoclonic status in non-progressive encephalopathies. Epilepsy predominates in childhood, but may persist or reappear in adulthood. Management is difficult in a proportion of patients. It might be improved by better understanding of pathophysiology. Current hypotheses involve abnormal inhibitory transmission due to impaired regulation of GABAA receptors related to functional absence of UBE3A and abnormal hippocampal CaMKII activity.

"Tonic-absence seizures": an unusual seizure phenotype, but not necessarily in that order.

Video telemetry in a 15-year-old boy with moderate learning difficulties revealed episodes of staring and cessation of activity, followed by sudden stiffening of the body for several seconds, abduction of the arms and a brief vocal utterance ("ugh"). Each episode lasts around 30 seconds, 3-4 times/day despite treatment. The EEG showed generalized 3-4Hz spike-wave discharges during the "absence" period followed immediately by a run of fast polyspikes typical of a tonic seizure, terminating in a run of 1-2 Hz sharp-slow wave complexes. Although tonic-absence seizures have been reported rarely, the clinical sequence appears to be reversed in this patient, with the occurrence of "absence-tonic" attacks. We present video documentation of such attacks and discuss their nosology.[Published with video sequences].

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.

Stimulus-sensitive burst-spiking in burst-suppression in children: implications for management of refractory status epilepticus.

Status epilepticus refractory to sequential trials of multiple medication is a rare but significant problem in children. We describe stimulus sensitivity arising during the treatment of convulsive status epilepticus in children (stimulus-sensitive burst-spiking in burst-suppression). We reviewed retrospectively clinical and EEG features in six children (three months to ten years), with status epilepticus requiring intensive care, in whom tactile, auditory and visual stimulation induced myoclonic jerks and bursts of EEG spikes. Sensitivity was not present at onset, but appeared after 24 hours as myoclonic jerks of the eyes, face and limbs, irrespective of the modality and site of stimulation. These were associated with burst-suppression in the EEG, the induced spiking forming the burst component. Various antiepileptic drugs, including GABAergic and NMDA blockers had no effect, but halogenated agents (used in two patients) abolished the sensitivity. Two children died, but the remainder returned to their previous clinical state. We conclude that stimulus sensitivity may appear in the context of refractory status epilepticus treated with high-dose barbiturates. Outcome may be more favorable than previously reported in adults, mostly in the context of post-anoxic or toxic coma. Evaluation of ventilated children in status epilepticus should include electroclinical assessment using sensory stimulation. If present, the drug regime should be reviewed and halogenated agents considered.

Epileptic spasms and early-onset photosensitive epilepsy in Patau syndrome: An EEG study.

INTRODUCTION: Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25-50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients. MATERIALS/PATIENTS: We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011. METHODS: All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed. RESULTS: Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz's grade 2-4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1s to a maximum of 9s. CONCLUSIONS: In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset.

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.