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Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients., Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants., Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature., Significance: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication., (© 2023 International League Against Epilepsy.)

Objective: This study investigates the effects of PRAX-562 on sodium current (I Na ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent I Na inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (Na V ) blockers., Methods: Inhibition of I Na  was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA)., Results: PRAX-562 potently and preferentially inhibited persistent I Na induced by ATX-II or the SCN8A mutation N1768D (half-maximal inhibitory concentration [IC 50 ] = 141 and 75 nmol·L -1 , respectively) relative to peak I Na tonic/resting block (60× preference). PRAX-562 also exhibited potent use-dependent block (31× preference to tonic block). This profile is considerably different from standard Na V blockers, including carbamazepine (CBZ; persistent I Na IC 50 = 77 500 nmol·L -1 , preference ratios of 30× [tonic block], less use-dependent block observed at various frequencies). In contrast to CBZ, PRAX-562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX-562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half-maximal efficacious concentration = 4.3 nmol·L -1 , sLMA half-maximal tolerated concentration = 69.7 nmol·L -1 , protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity., Significance: PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard Na V blockers (CBZ and LTG), potentially due to the preference for persistent I Na . Preferential targeting of persistent I Na may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard Na V blockers have demonstrated efficacy but poor tolerability., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Lamotrigine and other sodium-channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy-resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic-clonic seizures seems to play a major role., Methods: We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre-Bötzinger complex (PreBötC) and measured population as well as intracellular activity of the rhythm-generating network under normoxia and hypoxia in the presence or absence of AEDs., Results: We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED-modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBötC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage-dependent bursting activity in PreBötC pacemaker neurons, but led to a hypoxia-dependent shift of the action potential rheobase in all measured PreBötC neurons., Significance: Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium-dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre-Bötzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Voltage-gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain-expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone., Methods: We analyzed genotype-phenotype correlations in large SCN-patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders., Results: Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy-associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain-of-function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed., Significance: Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered., (Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.)

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: Focal edema of the splenium of the corpus callosum (FESCC) is infrequently seen in patients with epilepsy who are undergoing video-electroencephalography (EEG) monitoring. It is diagnosed by qualitative visual inspection of the magnetic resonance imaging (MRI) and is usually assumed to be a dichotomous phenomenon. Rapid reduction of anticonvulsants has been proposed as a cause. In this study we investigate the relationship between dose reduction of anticonvulsants and the occurrence of FESCC, based on absolute drug doses., Methods: We examined in detail the anticonvulsive therapy of all patients during video-EEG monitoring between 2014 and 2018. We compared patients with a radiologically diagnosed FESCC to controls in a 1:2 case-control analysis matched by age, epilepsy syndrome, and adjacent time of admission. In a separate correlation analysis, we examined quantitative effects of reduction of antiseizure drugs on diffusion restriction in the corpus callosum., Results: Of 326 patients who had an MRI following video-EEG monitoring, 12 (3.7%) had FESCC. Antiseizure drugs were reduced to a significantly greater extent in FESCC patients than in the 24 controls (P < 0.001). Sodium channel-blocking antiseizure drugs were reduced (P < 0.001) and reintroduced (P < 0.001) significantly faster in FESCC patients, and the duration of anticonvulsant discontinuation was longer in FESCC patients (P < 0.001). The separate correlation analysis in 325 patients shows a weak correlation between diffusion restriction in the splenium and the reduction rate of sodium channel-blocking anticonvulsants (r = -0.15, P = 0.03) as well as the duration of their discontinuation (r = -0.16, P = 0.01). No such effects were found for anticonvulsants with other modes of action., Significance: Our findings substantiate that FESCC is associated with high rates of dose reduction of anticonvulsants, specifically those acting on sodium channels. Our results cautiously suggest that reducing sodium-channel blockers has a small effect on diffusivity in the splenium below the visual threshold., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers., Methods: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein., Results: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases., Significance: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objectives: To evaluate the effectiveness of lacosamide (LCM) in pediatric patients, using time to treatment failure as the outcome measure, and to assess the impact of concomitant sodium channel blocker (SCB) use on LCM retention., Methods: This is a retrospective cohort study of patients <21 years old receiving LCM from 2010 to 2015. Kaplan-Meier survival curves were generated for time to LCM failure, defined as discontinuation of LCM or addition of another antiepileptic therapy. The impact of concomitant use of traditional SCB agents (phenytoin, carbamazepine, oxcarbazepine, and/or lamotrigine) and other factors including age, seizure types, fast drug titration, and prior antiepileptic drug history were evaluated using Cox regression., Results: The analysis cohort included 223 patients, of whom 116 were taking one or more SCBs, with median follow-up of 7.4 months (1-53 months). For all patients, the probability of remaining on LCM without addition of another therapy was 44.7% at 12 months and 25.6% at 24 months. Concomitant SCB use was an independent predictor of time to LCM failure (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.38-2.65, p < 0.001).Although treatment emergent adverse effects were reported more often in patients taking SCB (65% vs. 39%, p < 0.001), intolerability was rarely the sole reason cited for LCM discontinuation, and SCB use was strongly associated with LCM failure, even when controlling for presence of treatment emergent adverse effects (adjusted HR 1.99, 95% CI 1.36-2.90, p < 0.001)., Significance: This study provides observational evidence for treatment persistence of LCM in children, in a large cohort with long-term follow-up, using time to treatment failure as the outcome measure. Concomitant SCB use was a key factor increasing risk of LCM failure, but not due to treatment-emergent adverse effects alone., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objective: Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV ) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity., Methods: We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2a(Q54) mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2a(Q54) mice., Results: We found that ranolazine was capable of reducing seizure frequency by approximately 50% in Scn2a(Q54) mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90% in Scn2a(Q54) mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2a(Q54) mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2a(Q54) mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting., Significance: Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Monotherapy has been considered the gold standard for drug treatment of epilepsy. However, there is renewed interest in polytherapy because of the advent of new drugs with fewer drug interactions and novel mechanisms of action, and the realization that most patients with refractory epilepsy are eventually treated with drug combinations. Careful consideration must be given to drug additions and conversions; it may be less risky to add a drug than to convert from one monotherapy to another in patients with frequent or severe seizures. Rational choice of drug combinations is, at present, based more on avoidance of pharmacodynamic or pharmacokinetic side effects than on evidence for supra-additive efficacy. There are indications that combinations of two sodium-channel blocking agents are less effective than combinations of drugs with different primary mechanisms of action, and some human studies suggest that lamotrigine and valproate may be synergistic for efficacy. However, more animal and human research is needed, with attention to the effects of various combinations on both toxicity and seizure control.

We report an early infantile patient characterized by intractable hyponatremia, progressive megalencephaly, and epileptic seizures with an EEG pattern that alternated between interictal low-voltage background and ictal burst activity. Repeatedly all the abnormal findings improved in a lidocaine-dependent manner. Given the pharmacologic mechanisms of lidocaine as a sodium channel blocker, we speculate that our patient had a sodium channel dysfunction.