Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Diagnostic Yield of Epilepsy-Genes Sequencing and Chromosomal Microarray in Pediatric Epilepsy.

BACKGROUND: Around 40% of individuals with epilepsy have an underlying identifiable genetic etiology. Common methods for epilepsy genetic testing are chromosomal microarray (CMA) and epilepsy-genes sequencing (EGS). Historically, CMA was the first-line test for patients with epilepsy, but recent studies have shown that EGS has a superior diagnostic yield. To further optimize testing algorithms for epilepsy, we compared these tests' diagnostic yields and explored how they are influenced by age of onset and phenotype complexity. METHODS: Genetic test results from a cohort of patients with epilepsy were used to determine the diagnostic yield of CMA (n = 366) versus EGS (n = 370) for genetic epilepsy etiologies. Further analysis examined the probability of diagnostic results based on age of seizure onset and patients' phenotype complexity. RESULTS: For patients who underwent CMA, causative variants were found in 28 of 366 cases (7.7%), and 60 of 366 patients (16.4%) had at least one variant of uncertain significance (VUS). For EGS, 65 of 370 (17.6%) cases had causative variants, whereas 155 of 370 (41.9%) had at least one VUS. EGS had a significantly higher diagnostic yield than CMA (odds ratio [OR] = 2.63, P < 0.001). This difference in diagnostic yield was further pronounced among patients with infantile seizure onset (OR = 4.69, P < 0.001) and patients with additional neurological findings (OR = 2.99, P < 0.001). CONCLUSION: To minimize the time and resources required to reach a diagnosis, clinicians and insurers alike should consider using EGS as an initial diagnostic tool.

An epilepsy-associated KV1.2 charge-transfer-center mutation impairs KV1.2 and KV1.4 trafficking.

We report on a heterozygous KCNA2 variant in a child with epilepsy. KCNA2 encodes KV1.2 subunits, which form homotetrameric potassium channels and participate in heterotetrameric channel complexes with other KV1-family subunits, regulating neuronal excitability. The mutation causes substitution F233S at the KV1.2 charge transfer center of the voltage-sensing domain. Immunocytochemical trafficking assays showed that KV1.2(F233S) subunits are trafficking deficient and reduce the surface expression of wild-type KV1.2 and KV1.4: a dominant-negative phenotype extending beyond KCNA2, likely profoundly perturbing electrical signaling. Yet some KV1.2(F233S) trafficking was rescued by wild-type KV1.2 and KV1.4 subunits, likely in permissible heterotetrameric stoichiometries: electrophysiological studies utilizing applied transcriptomics and concatemer constructs support that up to one or two KV1.2(F233S) subunits can participate in trafficking-capable heterotetramers with wild-type KV1.2 or KV1.4, respectively, and that both early and late events along the biosynthesis and secretion pathway impair trafficking. These studies suggested that F233S causes a depolarizing shift of ∼48 mV on KV1.2 voltage dependence. Optical tracking of the KV1.2(F233S) voltage-sensing domain (rescued by wild-type KV1.2 or KV1.4) revealed that it operates with modestly perturbed voltage dependence and retains pore coupling, evidenced by off-charge immobilization. The equivalent mutation in the Shaker K+ channel (F290S) was reported to modestly affect trafficking and strongly affect function: an ∼80-mV depolarizing shift, disrupted voltage sensor activation and pore coupling. Our work exposes the multigenic, molecular etiology of a variant associated with epilepsy and reveals that charge-transfer-center disruption has different effects in KV1.2 and Shaker, the archetypes for potassium channel structure and function.

Clinical value of the first dedicated, commercially available automatic injector for ictal brain SPECT in presurgical evaluation of pediatric epilepsy: comparison with manual injection.

UNLABELLED: The most challenging technical problem in ictal brain SPECT for localization of an epileptogenic focus is obtaining a timely injection of a radiopharmaceutical. In our institution, the first dedicated commercially available, remotely controlled automatic injector has been used in the pediatric epilepsy unit in conjunction with 24-h video and electroencephalogram monitoring. The goal of this study was to demonstrate the improved success rate of ictal injection by use of the automatic injector in the pediatric population. METHODS: Eighty-four pediatric patients and eighty-four (99m)Tc-ethylcysteinate dimer ((99m)Tc-ECD) ictal brain SPECT studies were retrospectively analyzed in a masked manner. The group with manual injection consisted of 45 studies performed from 2004 to 2010 before the introduction of the automatic injector. The group with automatic injection consisted of 39 studies performed from 2010 to 2011 after the introduction of the automatic injector. The 2 groups were comparable in the total duration of seizure, injected dose, and time from the injection to the image acquisition. The latency time from the seizure onset to the initiation time of injection, the ratio of latency time to total duration of seizure (L/T), the number of patients with repeated studies, the number of days of additional hospitalization for each study, and the localization rate for identifying a single focus in each study were compared between the groups. RESULTS: The median latency time in the group with automatic injection (8 s) was significantly lower than that of the group with manual injection (18 s) (P < 0.05). Also there was a statistically significant decrease in the number of patients with repeated studies in the group with automatic injection (2/39 [5%]), compared with the group with manual injection (14/45 [31%]) (P < 0.05). The median number of days of additional hospitalization in the group with manual injection (range, 0-7) was statistically significantly different, compared with the group with automatic injection (range, 0-1) (P < 0.05). In the group with automatic injection, 31 of 39 scans demonstrated a single localizing focus, compared to 22 of 45 scans from the manual-injection group, a significant difference (P < 0.05). The radiation exposure rate to nursing staff during the periods with automatic injection was lower than during the periods with manual injection. CONCLUSION: The automatic injector combined with 24-h video and electroencephalogram monitoring demonstrated significant clinical value by decreasing latency time, the number of patients with repeated studies, and the number of days of additional hospitalization while increasing the number of studies with a single localizing focus.

Dravet syndrome: a technologist's perspective.

Dravet Syndrome (DS), also known as Severe Myoclonic Epilepsy in Infancy (SMEI) is a rare, primarily genetic disorder which develops in infancy. The characteristics of DS are frequent, prolonged, primarily generalized seizures which occur initially with fever and eventually evolve to multiple afebrile seizure types such as myoclonic, atypical absence, and complex partial seizures. Patients, who are initially developmentally normal, will experience concomitant developmental regression as the syndrome progresses. Because it is a childhood disorder, DS is not well known outside the realm of pediatrics. An astute EEG technologist should be able to recognize key factors both clinically and electrographically which point suspicion to the diagnosis of Dravet Syndrome.

Times change, and so do managed care strategies.

Gateway Health System in Clarksville, Tenn., developed a strategy to enhance revenue and improve cash flow. The health system's objectives were to create better business office practices that would allow staff to more effectively monitor payment and capture lost revenue and to improve the system's financial position with commercial and public sector payers.