We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

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OBJECTIVE There is an increasing interest in stereo-electroencephalography (SEEG) for invasive evaluation of insular epilepsy. The implantation of insular SEEG electrodes, however, is still challenging due to the anatomical location and complex functional segmentation in both an anteroposterior and ventrodorsal (i.e., superoinferior) direction. While the orthogonal approach (OA) is the shortest trajectory to the insula, it might insufficiently cover these networks. In contrast, the anterior approach (AOA) or posterior oblique approach (POA) has the potential for full insular coverage, with fewer electrodes bearing a risk of being more inaccurate due to the longer trajectory. Here, the authors evaluated the implantation accuracy and the detection of epilepsy-related SEEG activity with AOA and POA insular trajectories. METHODS This retrospective study evaluated the accuracy of 220 SEEG electrodes in 27 patients. Twelve patients underwent a stereotactic frame-based procedure (frame group), and 15 patients underwent a frameless robot-assisted surgery (robot group). In total, 55 insular electrodes were implanted using the AOA or POA considering the insular anteroposterior and ventrodorsal functional organization. The entry point error (EPE) and target point error (TPE) were related to the implantation technique (frame vs robot), the length of the trajectory, and the location of the target (insular vs noninsular). Finally, the spatial distribution of epilepsy-related SEEG activity within the insula is described. RESULTS There were no significant differences in EPE (mean 0.9 ± 0.6 for the nonsinsular electrodes and 1.1 ± 0.7 mm for the insular electrodes) and TPE (1.5 ± 0.8 and 1.6 ± 0.9 mm, respectively), although the length of trajectories differed significantly (34.1 ± 10.9 and 70.1 ± 9.0 mm, repsectively). There was a significantly larger EPE in the frame group than in the robot group (1.5 ± 0.6 vs 0.7 ± 0.5 mm). However, there was no group difference in the TPE (1.5 ± 0.8 vs 1.6 ± 0.8 mm). Epilepsy-related SEEG activity was detected in 42% (23/55) of the insular electrodes. Spatial distribution of this activity showed a clustering in both anteroposterior and ventrodorsal directions. In purely insular onset cases, subsequent insular lesionectomy resulted in a good seizure outcome. CONCLUSIONS The implantation of insular electrodes via the AOA or POA is safe and efficient for SEEG implantation covering both anteroposterior and ventrodorsal functional organization with few electrodes. In this series, there was no decrease in accuracy due to the longer trajectory of insular SEEG electrodes in comparison with noninsular SEEG electrodes. The results of frame-based and robot-assisted implantations were comparable.

We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.