Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features.

Our current knowledge of genetically determined forms of epilepsy has shortened the diagnostic pathway usually experienced by the families of infants diagnosed with early-onset developmental and epileptic encephalopathies. Genetic causes can be found in up to 80% of infants presenting with early-onset developmental and epileptic encephalopathies, often in the context of an uneventful perinatal history and with no clear underlying brain abnormalities. Although current disease-specific therapies remain limited and patient outcomes are often guarded, a genetic diagnosis may lead to early therapeutic intervention using new and/or repurposed therapies. In this review, an overview of epilepsy genetics, the indications for genetic testing in infants, the advantages and limitations of each test, and the challenges and ethical implications of genetic testing are discussed. In addition, the following causative genes associated with early-onset developmental and epileptic encephalopathies are discussed in detail: KCNT1, KCNQ2, KCNA2, SCN2A, SCN8A, STXBP1, CDKL5, PIGA, SPTAN1, and GNAO1. The epilepsy phenotypes, comorbidities, electroencephalgraphic findings, neuroimaging findings, and potential targeted therapies for each gene are reviewed.

KCNT1-related epilepsy: An international multicenter cohort of 27 pediatric cases.

OBJECTIVE: Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants. METHODS: A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. RESULTS: Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. SIGNIFICANCE: Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.

Children with autism spectrum disorders and drug-resistant epilepsy can benefit from epilepsy surgery.

OBJECTIVE: The objective of this research was to evaluate a cohort of children with both autism spectrum disorder (ASD) and drug-resistant epilepsy (DRE) after epilepsy surgery to determine predictors of best outcome. METHODS: Retrospective chart review was done for 29 children ages 2 to 18 years with ASD and DRE who had neurosurgical intervention for seizure management over 15 years at one institution. All subjects had at least 1 year of follow-up. Data abstraction included demographic information, seizure diagnosis, treatment, investigations, surgical intervention, neuropsychological assessment, and outcome. Statistical analysis software (SAS) was used for statistical analysis. Engel classification was used to assess seizure outcome. RESULTS: Fifteen subjects had resective surgery. Fourteen had palliative surgery with vagal nerve stimulator (VNS) insertion (13) and corpus callosotomy (1). Of the 29 subjects, 35% had class I outcome (all in the resective group). When combining all subjects (resective and palliative), 66% of subjects benefited with class I-III outcomes. In the total cohort, age at time of surgery was significant, with class I outcome more frequently seen in the younger age group when compared with classes II-IV (p = 0.01). CONCLUSION: A subset of children with ASD can benefit from resective surgery, and for those who are not candidates, a VNS can offer significant improvements in seizure control.

Transcranial Doppler velocity among Jamaican children with sickle cell anaemia: determining the significance of haematological values and nutrition.

This study investigated the association of nutritional and haematological variables with maximum time-averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (<170 cm/s), conditional (170-199 cm/s) and abnormal (≥200 cm/s) based on TAMV in distal internal carotid artery (dICA), middle cerebral artery (MCA), internal carotid bifurcation, anterior and posterior cerebral arteries. Of 358 children with sickle cell anaemia (SCA) examined, the mean age (±standard deviation) was 7·4 ± 2·7 years; 13·1% and 6·7% had conditional and abnormal velocities, respectively. Children with abnormal TCD velocities had higher prevalence of prior stroke (P = 0·006). Increased TAMV was associated with younger age (P = 0·001), lower weight (P = 0·001), height (P = 0·007) and oxygen saturation (P = 0·005). There was no association of TAMV with height-age or body mass index (BMI) z-scores. Adjusting for gender, BMI z-score, age, previous stroke and oxygen saturation, mean corpuscular volume (P = 0·005) and reticulocyte count (P = 0·013) were positively associated with TAMV, while haemoglobin concentration (P = 0·009) was negatively associated. There was good agreement [99%; weighted Kappa 0·98 (95% confidence interval 0·89-1), P = 0·0001] in TCD classification using data from five vessels versus two vessels (dICA and MCA). Haematological variables, rather than nutritional status, may be useful markers that identify high-risk children with SCA.