NBEA: Developmental disease gene with early generalized epilepsy phenotypes.

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.

Multicenter retrospective study of patients with PCDH19-related epilepsy: The first Hungarian cohort.

OBJECTIVE: PCDH19-related epilepsy occurs predominantly in girls and is caused by pathogenic variant of the protocadherin-19 gene. The initial seizures usually develop in association with fever, begin on average at 15 months of age, and often occur in clusters. Autistic symptoms, intellectual disability, and sleep disturbance are often associated. METHODS: In our retrospective, multicenter study, we reviewed clinical data of nine children with epilepsy genetically confirmed to be associated with PCDH19. RESULTS: In the Hungarian patient population aged 0-18 years, the prevalence of PCDH19-related epilepsy was found to be lower (1/100000 live births in females) than the reported international data (4-5/100000 live births in females). Four of our nine patients had positive family history of epilepsy (cousins, sister, and mother). We assessed brain anomalies in three patients (in one patient focal cortical dysplasia and left anterior cingulate dysgenesis, and in two children right or left hippocampal sclerosis) and in another three cases incidentally identified benign alterations on brain MRI were found. The first seizure presented as a cluster in seven out of nine children. In seven out of nine cases occurred status epilepticus. Six out of nine children had autistic symptoms and only one child had normal intellectual development. Seven of our patients were seizure free with combined antiseizure medication (ASM). The most effective ASMs were levetiracetam, valproate, and clobazam. SIGNIFICANCE: The prevalence of PCDH19-related epilepsy is presumably underestimated because of the lack of widely performed molecular genetic evaluations. Molecular genetic testing including PCDH19 pathogenic variants is recommended for female patients with an onset of seizures before the age of 3 years.

Sturge-Weber syndrome: clinical and radiological correlates in 86 patients.

BACKGROUNDS AND PURPOSE: To correlate the extent of the leptomeningeal angiomatosis with clinical features in Sturge-Weber syndrome (SWS). METHODS: The study group consisted of 86 consecutive patients aged two months to 56 (mean 7.9 +/- 10.3) years with SWS and epilepsy. Clinical and MRI data were analyzed. RESULTS: Based on the extent of leptomeningeal angiomatosis, patients were divided into two subgroups: 43 patients had hemispheric angiomatosis and atrophy, whereas, another 43 had focal involvement. Nine of the 43 hemispherial patients (10%) showed bilateral involvement: all of these bilateral cases demonstrated dominance in a single side with hemispheric leptomeningeal angiomatosis and contralateral focal extension. Hemispheric and focal subgroups were clinically different. Patients with hemispheric SWS were younger at the age of epilepsy onset (p < 0.001) and age at MRI examination (p < 0.05). Neither gender, lateralization, duration of epilepsy, appearance of secondarily generalized seizures, nor seizure frequency revealed a significant difference between subgroups. CONCLUSION: Bilateral involvement is frequent and occurs in cases with a hemisperic involvement on one side. The age of epilepsy onset is related to the extent of leptomeningeal angiomatosis. Patients with hemispheric form of SWS presented with earlier age of seizure onset. Focal pial angiomatoses do not tend to progress (a longer duration is not associated with more frequent hemispheric involvement). Other variables including seizure frequency and secondary generalized tonic-clonic seizures are not associated with the extent of angiomatosis.

A detailed semiologic analysis of childhood psychogenic nonepileptic seizures.

PURPOSE: Psychogenic nonepileptic seizure (PNES) is an important differential diagnostic problem in patients with or without epilepsy. There are many studies that have analyzed PNES in adults; currently, however, there is no systematic assessment of purely childhood PNES semiology. Our study based on a large pediatric video-electroencephalography (EEG) monitoring (VEM) cohort, provides a detailed analysis of childhood PNES and assesses the usability of the current classification system described in adults. METHODS: Medical and video-EEG records of 568 consecutive children (younger than 18 years) who underwent video-EEG monitoring (VEM) at our hospital were reviewed. Aura, type of movement, anatomic distribution, synchrony, symmetry, eye movement, responsiveness, vocalization, hyperventilation, vegetative and emotional signs, presence of eyewitness, and duration of the event were recorded among children with the diagnosis of PNES. We also compared our data with those of earlier adult studies. KEY FINDINGS: Seventy-five archived PNES of 27 children (21 girls; age 8-18 years) were reanalyzed. Nine children (33%) had the diagnosis of epilepsy currently or in the past. Mean age at the time of PNES onset was 11.6 (standard deviation 3.2) years. Mean duration of PNES was longer (269 s) compared to seizures of the epileptic group (83 s; p = 0.002). Eyewitnesses (mostly parents) were present in 89% of cases. Eighty percent of PNES had an abrupt start, with 68% also ending abruptly. In only 15% of events were the patients eyes closed at the beginning of the attack. Patients were unresponsive in 34%. The most frequent motor sign was tremor (25%) with the upper, rather than lower limbs more frequently involved. Pelvic thrusting was seen in only two attacks. Emotional-mostly negative-signs were observed during 32 PNES (43%). Based on Seneviratne et al.'s classification, 18 events (24%) were classified as rhythmic motor PNES, only half the frequency of that previously described in adults. No hypermotor PNES was found. The frequency of complex motor PNES (13%) and mixed PNES (4%) showed similar frequency in children as in adults. Dialeptic PNES was found more frequently among younger children. All PNES belonged to the same semiologic type in 23 patients (85%). SIGNIFICANCE: Because homogeneity of PNES within a patient was high in the pediatric population, we found it useful to classify PNES into different semiologic categories. Dialeptic PNES seems to be more frequent among younger children. Tremor is the most frequent motor sign and usually accompanied by preserved responsiveness in childhood. Negative emotion is commonly seen in pediatric PNES, but pelvic thrusting is a rare phenomenon. We, therefore, suggest a modification of the present classification system in which PNES with motor activity is divided into minor and major motor PNES, and the latter group is subdivided into synchron rhythmic motor and asynchron motor PNES. We believe that our study, a detailed analysis on the semiology and classification of purely childhood PNES might assist the early and precise diagnosis of nonepileptic paroxysmal events.

Clinical value of subclinical seizures in children with focal epilepsy.

PURPOSE: Subclinical seizures (SCSs) are ictal electrographic discharges lacking clinical seizure signs or subjective symptoms. In this study, frequency, characteristics and diagnostic relevance of SCSs recorded by scalp-EEG were analyzed in a large population of children with focal epilepsy. METHODS: Long-term monitoring (LTM) database of 322 consecutive patients <18 years with focal epilepsy were assessed. Video-EEG data of all children with SCS were re-analyzed. RESULTS: Fifty-nine of 322 (18%) children showed SCS on scalp-EEG, nine (15%) of them had no clinical seizures during LTM. Duration of epilepsy (5.2 vs. 6.9 years; p=0.019) as well as length of LTM (2.8 vs. 3.6 days; p<0.001) were longer in children with SCS. Neither sex, age at onset, age at LTM, nor focus localization showed significant difference. In 85% of cases the presence of SCS had supplementary value during the diagnostic process. It assisted localizing the seizure onset zone in 53%, suggested multiple seizure onset zones in 20% and influenced antiepileptic drug therapy in 12% of cases. DISCUSSION: Scalp-EEG SCS in children with focal epilepsy is a frequent and important phenomenon. Although our therapeutic decisions are usually based on interictal and ictal EEG data and clinical symptoms, SCS is also suggested to be considered during the epilepsy evaluation process. This is the first study assessing SCSs recorded by scalp-EEG.

Ictal smile lateralizes to the right hemisphere in childhood epilepsy.

PURPOSE: To analyze the localizing and lateralizing value of ictal smile (IS) in childhood epilepsy. METHODS: Incidence of IS in 309 videotaped seizures of 114 consecutive patients younger than 12 years with refractory frontal, temporal, or posterior cortex epilepsy were assessed. RESULTS: Among patients with right-sided epileptogenic zone, 12 (21%) of 57 had IS, whereas in patients with left-sided epilepsy, IS occurred only in one patient (1.8%; p < 0.01, chi(2) test). The incidence of IS was 11%, 3%, and 26% in the frontal, temporal, and posterior cortex subgroups, respectively. Logistic regression revealed that the localization of the epileptogenic region in the posterior cortex (p < 0.01), focal cortical dysplasia etiology (p = 0.012), and right-sided lateralization (p = 0.025) were independently associated with the presence of IS. CONCLUSIONS: Childhood IS lateralizes to the right hemisphere and localizes more frequently in the posterior cortex epilepsy.

Hippocampal sclerosis in severe myoclonic epilepsy in infancy: a retrospective MRI study.

PURPOSE: Severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome) is a malignant epilepsy syndrome characterized by early prolonged febrile convulsions (PFCs) with secondary psychomotor delay and a variety of therapy-resistant seizures. Although the initial symptoms are repeated PFCs, the MRI performed at the onset of disease shows no hippocampal structural abnormalities. We aimed to assess clinical and serial MRI data of patients with SMEI with a special attention to the temporomedial structures. To our knowledge, this is the first systematic MRI study in this disease. METHODS: Clinical and MRI data of all SMEI patients treated in our hospitals between 1996 and 2004 were reviewed. RESULTS: Twenty-eight MRIs from 14 children (one to four images/patient) were included. Age at disease onset was between 3 and 9 months; age at initial MRI was 5 months to 13 years. Ten of 14 patients showed hippocampal sclerosis (HS) during the course of the disease (nine unilateral, one bilateral). Six of these 10 had a normal initial MRI. Age at the first verified HS was between 14 months and 13 years. Neither complex partial seizures nor anterior temporal irritative zone was recorded in these children. CONCLUSIONS: After initially normal structures, in most patients with SMEI, HS develops several months or years after the first PFC. These data support the hypothesis that PFC might be responsible for HS, but other factors and individual sensitivity should play a role in this process.