Sodium Channel-blocking Antiepileptic Drugs Research Articles

Further delineation of phenotypic spectrum of SCN2A-related disorder.

SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.

The effect of lamotrigine and other antiepileptic drugs on respiratory rhythm generation in the pre-Bötzinger complex.

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. 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. 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. 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.

Cohort of Phenotype, Genotype, and Outcome of SCN Developmental and Epileptic Encephalopathies from Southern Part of India.

The SCN encephalopathies are one of the rare early childhood intractable epileptic encephalopathies associated with pleomorphic seizures, cognitive decline, motor, and behavioral abnormalities that begin in early infancy. There is a dearth of data on phenotype and genotype of SCN encephalopathies from the Indian subcontinent, hence we are reporting clinical and molecular profile and outcome of SCN developmental and epileptic encephalopathies. This is a retrospective chart review of SCN developmental and epileptic encephalopathies in a tertiary care center, Bangalore, India between January 2015 and March 2020. All children with clinical features of SCN developmental and epileptic encephalopathies and confirmed with pathogenic variants were included. A total of 50 cases of SCN developmental and epileptic encephalopathies were analyzed, 31 of them were male and the mean age of presentation was 7.8 months. Precipitating factors for the first episode of seizure were fever and vaccination accounting for 33 and 8 children, respectively. Forty (80%) children had prolonged seizures and 15 (30%) had epileptic spasms. All children had a normal birth history and normal development before the onset of seizures, which was followed by developmental delay and regression. Thirty (60%) children had behavioral difficulties, notable hyperactivity, and autistic features. Neuroimaging and the initial electroencephalogram (EEG) were normal in all patients. The mean age of abnormal EEG was 14 months. The various subtypes of SCN variants were SCN1A in 31 children followed by SCN2A and SCN9A in eight children each and SCN1B in three children. Frameshift and nonsense mutations were associated with more severe phenotype and poor outcome compared with missense mutations. Thirty-four patients partially responded to treatment and the rest were refractory. The results of genetic testing were used to guide treatment; sodium channel blocking antiepileptic drugs were discontinued in 15 patients and sodium channel blocking agents were started in 3 patients with partial response. Three out of four children on stiripentol had a partial response. The SCN developmental and epileptic encephalopathies can present with epileptic spasms in addition to other types of seizures. Epileptic spasms are more common in nonsense and frameshift mutations. The outcome is poor in children with epileptic spasms compared with those without epileptic spasms. Genetic testing helps to select antiepileptic drugs that lead to seizure reduction.

LGI1-antibody associated epilepsy successfully treated in the outpatient setting

We report six patients with anti-LGI1 associated epilepsy. Two patients presented with new-onset generalized tonic-clonic seizures, four developed faciobrachial dystonic seizures and two piloerection. All patients had significant cognitive complaints at the time of diagnosis. All patients described seizure reduction during the first week of carbamazepine, and seizure freedom was obtained at a median of 13 days (range 7–22), sustained after the initiation of immunosuppression. Median time from symptom onset to carbamazepine initiation was 164 days (range 38–206 days). We discuss the particular seizure response to sodium channel blocking antiepileptic drugs, alone or associated with immunosuppression in this antibody mediated seizures.

Changes in drug load during lacosamide combination therapy: A noninterventional, observational study in German and Austrian clinical practice.

IntroductionEffects of antiepileptic drug (AED) load changes in patients with focal seizures have not been well evaluated.MethodsSP1065 (NCT01673282) was a noninterventional, prospective, observational study conducted in a clinical practice setting. Patients (aged ≥18 years) with focal seizures were enrolled within 7 days of being prescribed adjunctive lacosamide. Observation period was ~6 months. Drug load was assessed using percentage change in ratio of actual prescribed dose and World Health Organization defined daily dose (DDD) for concomitant AEDs and all AEDs (including lacosamide). Subgroups were defined for patients with at least one concomitant sodium channel–blocking AED (SCB [+]) and those without (SCB [−]).ResultsA total of 311 patients were assessed for safety, 302 for measurement of drug load, and 240 for effectiveness. Ratio of AED dose to DDD decreased for concomitant AEDs (−9.6%) and increased for all AEDs (including lacosamide; 15.5%). Median reduction in focal seizure frequency per 28 days was 100% (range: −100, 2275.8). 70.4% and 61.7% of patients had a ≥50% or ≥75% reduction in seizure frequency, respectively; 50.8% became seizure‐free. In the SCB (+) subgroup (n = 149), ratio of AED dose to DDD decreased for concomitant AEDs (−15.0%) and increased for all AEDs (10.7%). In the SCB (−) subgroup (n = 153), ratio of AED dose to DDD decreased for concomitant AEDs (−4.4%) and increased for all AEDs (20.2%). Fifty‐seven patients (18.3%) reported ADRs, most commonly dose >400 mg/d (7.1%). Seventeen patients (5.5%) had ADRs leading to discontinuation.SignificanceAddition of lacosamide resulted in reduction of concomitant AED drug load regardless of whether concomitant AEDs were SCB (+) or SCB (−). These results indicate that addition of lacosamide in patients with focal seizures could allow clinicians to withdraw or reduce the dose of less well‐tolerated or less effective AEDs.

Understanding the Cognitive Side Effects of Antiepileptic Drugs: Can Functional Imaging Be Helpful?

Effects of Carbamazepine and Lamotrigine on Functional Magnetic Resonance Imaging Cognitive Networks Xiao F, Caciagli L, Wandschneider B, Sander JW, Sidhu M, Winston G, Burdett J, Trimmel K, Hill A, Vollmar C, Vos SB, Ourselin S, Thompson PJ, Zhou D, Duncan JS, Koepp MJ. Epilepsia. 2018;59:1362-1371. doi:10.1111/epi.14448Objective: To investigate the effects of sodium channel–blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy. Methods: In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel–blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as “patient-controls” and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency. Results: Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation. Significance: Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel–blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.

Association between two SCN1A polymorphisms and resistance to sodium channel blocking AEDs: a meta-analysis.

Sodium channel blocking antiepileptic drugs (SCB-AEDs) are common effective medications available for epilepsy. However, not all patients respond to this regimen and drug resistance is frequently encountered. Rs2298771(c.3184A > G/p.Thr1067Ala) and rs3812718(IVS5N +5G > A) polymorphisms are two of the most common polymorphisms in the SCN1A gene, which is closely related to resistance to SCB-AEDs. Therefore, we have conducted a meta-analysis to investigate the contribution of the two polymorphisms to resistance of SCB-AEDs. The PubMed, Embase, MEDLINE, and Cochrane Library databases were searched up to September 2017, for studies on the association of SCN1A polymorphisms with resistance to SCB-AEDs. A fixed-effects or random-effects model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests. A total of eight studies were eligible for the pooled analysis, of which eight studies included SCN1A rs3812718 polymorphism and four studies included SCN1A rs2298771 polymorphism. The results showed that SCN1A rs2298771 polymorphism was significantly associated with resistance to SCB-AEDs. (A vs. G: OR = 0.76, 95% CI 0.61-0.95, P = 0.02; AA vs. AG + GG: OR = 0.71, 95% CI 0.54-0.94, P = 0.022). However, no association was observed between SCN1A rs3812718 polymorphism and resistance to SCB-AEDs. Our results indicate that the A-allele of SCN1A rs2298771 polymorphism, especially AA genotype, may play an important role in responsiveness to SCB-AEDs, while SCN1A rs3812718 polymorphism is not associated with SCB-AEDs.

Painful tonic spasm in neuromyelitis optica spectrum disorders: Prevalence, clinical implications and treatment options

BackgroundPainful tonic spasm (PTS) is a common symptom in patients with neuromyelitis optica spectrum disorders (NMOSD). This study aimed to obtain further insights into the prevalence, characteristics, and treatment of PTS in patients with NMOSD, and to systematically investigate and compare the clinical features and prognosis of NMOSD with and without PTS. MethodsWe reviewed the medical records and prospectively interviewed patients with NMOSD who attended the West China Hospital of Sichuan University in Chengdu, China between September 2014 and December 2016. ResultsIn total, 52 of the 230 patients with NMOSD experienced PTS (22.61%). Patients with NMOSD and PTS were characterized by a higher age at onset (P = 0.017), higher annual relapse rate (ARR) (P = 0.003), higher ARR of myelitis (P = 0.011), and a tendency to experience pruritus (P = 0.025). Sodium channel blocking antiepileptic drugs (carbamazepine or oxcarbazepine) had higher efficacy than gabapentin in the treatment of PTS (P = 0.001). Although the progression index was higher in patients with PTS, this difference did not reach statistical significance (P = 0.05). ConclusionsOur study suggested that immunosuppressors for the prevention of relapse should be administered without delay in patients with NMOSD and PTS. Owing to the side effects of carbamazepine, we recommend oxcarbazepine as the first-line of treatment for PTS in patients with NMOSD. Whether PTS is a marker of disease severity in NMOSD remains to be determined, requiring a long-term prospective observational study.

Psychiatric side effects and antiepileptic drugs: Observations from prospective audits.

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a+/−) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a+/− mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker. Unexpectedly, GS967 significantly improved survival of Scn1a+/− mice and suppressed spontaneous seizures. By contrast, lamotrigine exacerbated the seizure phenotype. Electrophysiological recordings of acutely dissociated neurons revealed that chronic GS967-treatment had no impact on evoked action potential firing frequency of interneurons, but did suppress aberrant spontaneous firing of pyramidal neurons and was associated with significantly lower sodium current density. Lamotrigine had no effects on neuronal excitability of either neuron subtype. Additionally, chronically GS967-treated Scn1a+/− mice exhibited normalized pyramidal neuron sodium current density and reduced hippocampal NaV1.6 protein levels, whereas lamotrigine treatment had no effect on either pyramidal neuron sodium current or hippocampal NaV1.6 levels. Our findings demonstrate unexpected efficacy of a novel sodium channel blocker in Dravet syndrome and suggest a potential mechanism involving a secondary change in NaV1.6.

Lacosamide (vimpat). Prospects for clinical application

This article presents the review of the most significant studies of the efficacy and tolerability of lacosamide (LCM) in treatment of patients with focal epilepsy. The review includes the results of the main studies which preceded the official approval of LCM use in mono- and polytherapy. Results on the efficacy of LCM in long-term use and treatment retention in clinical practice, most effective LCM combinations, tolerability, an influence on cognitive and mental functions, advantages in treatment of elderly patients are presented. Characteristics of LCM in comparison with other sodium channel-blocking antiepileptic drugs and selection priorities are shown. The authors assess perspectives of further use of LCM in clinical practice.

Polytherapy with sodium channel-blocking antiepileptic drugs is associated with arrhythmogenic ST-T abnormality in patients with epilepsy

PurposeRecent reports have documented the appearance of Brugada-type ST elevation in cases of overdose of antiepileptic drugs (AEDs). However, little is known about changes on electrocardiographs (ECGs) during AED use at therapeutic doses. AEDs may cause Brugada-type ST elevation or J-wave-like intraventricular conduction delays through an ion channel-blocking effect. In the present study, we sought to elucidate ECG abnormalities in patients on AED therapy. MethodsThe study population consisted of 120 consecutive patients with epilepsy who continued to take AEDs and had ECGs recorded during these therapies. Their clinical background and ECGs were retrospectively analyzed. Brugada-type ST elevation was classified according to the consensus report on Brugada syndrome. A J-wave-like ECG abnormality was defined as the appearance of notching or slurring of the QRS complex (>0.1mV) in the inferior/lateral leads. ResultsOf the 120 patients, 15 (12.5%) exhibited Brugada-type ST elevation and 35 (29.2%) showed a J-wave-like ECG abnormality. Polytherapy with sodium channel-blocking AEDs (e.g., carbamazepine, phenytoin, lamotrigine) was more frequently observed in patients with Brugada-type ST elevation (p=0.048). However, the serum concentrations of these medicines did not differ between patients with and without ECG abnormalities (carbamazepine: 7.9±4.1 vs. 7.2±5.9μg/dL; phenytoin: 12.7±4.1 vs. 15.5±9.5μg/dL, NS). ConclusionST-T abnormalities were frequently seen in patients using AEDs. The presence of Brugada-type ST elevation was associated with polytherapy with sodium channel-blocking AEDs.

Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases.

Purpose: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases.Methods: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association.Results: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study.Conclusion: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.

Cardiac safety of lacosamide: the non-clinical perspective.

Lacosamide is indicated for the adjunctive treatment of partial-onset seizures in adult patients. Unlike other sodium channel-blocking antiepileptic drugs, lacosamide selectively enhances sodium channel slow inactivation. Potential effects of lacosamide on cardiac sodium channels and their cardiovascular consequences were comprehensively assessed. This manuscript presents the non-clinical cardiac safety profile of lacosamide. Lacosamide was tested in vitro on sodium and L-type calcium currents from isolated human atrial myocytes and on hERG-mediated potassium currents from stably transfected HEK293 cells. Cardiac action potentials were recorded in guinea pig ventricular myocytes. In vivo, hemodynamic and ECG parameters were evaluated in anesthetized dogs and monkeys receiving acute cumulative intravenous doses of lacosamide. Following intravenous dosing with lacosamide, dose-dependent PR and QRS prolongation and ECG abnormalities (loss of P waves, atrioventricular and intraventricular blocks, junctional premature contractions) were observed in anesthetized dogs and monkeys. In vitro, lacosamide reduced human cardiac sodium currents in a concentration-, voltage- and state-dependent manner. Lacosamide reductions in Vmax in guinea pig myocytes were similar to lamotrigine and carbamazepine. Lacosamide showed no relevant inhibitory effects on hERG and L-type calcium channels and did not prolong QTc in vivo. ECG findings in anesthetized animals correlate well with in vitro sodium channel-related effects and are also consistent with those (PR prolongation, first-degree atrioventricular block) reported in healthy volunteers and patients with epilepsy. Both in vivo and in vitro effects were detected from exposure levels 1.5- to 2-fold above those achieved with the maximum-recommended human lacosamide dose (400 mg/day).

The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis.

BackgroundVoltage-gated Na+ channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets.FindingsWe have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen.ConclusionsThis is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-014-0277-x) contains supplementary material, which is available to authorized users.

Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na+ channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na+ channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na+ channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na+ channel blocker antiepileptic therapies. Thus, Na+ channel blockers should be considered for the clinical management of LQT in individuals with RTT.

Music and its association with epileptic disorders.

The association between music and epileptic seizures is complex and intriguing. Musical processing within the human brain recruits a network which involves many cortical areas that could activate as part of a temporal lobe seizure or become hyperexcitable on musical exposure as in the case of musicogenic epilepsy. The dichotomous effect of music on seizures may be explained by modification of dopaminergic circuitry or counteractive cognitive and sensory input in ictogenesis. Research has explored the utility of music as a therapy in epilepsy and while limited studies show some evidence of an effect on seizure activity; further work is required to ascertain its clinical potential. Sodium channel-blocking antiepileptic drugs, e.g., carbamazepine and oxcarbazepine, appear to effect pitch perception particularly in native-born Japanese, a rare but important adverse effect, particularly if a professional musician. Temporal lobe surgery for right lateralizing epilepsy has the capacity to effect all facets of musical processing, although risk and correlation to resection area need further research. There is a need for the development of investigative tools of musical processing that could be utilized along the surgical pathway. Similarly, work is also required in devising a musical paradigm as part of electroencephalography to improve surveillance of musicogenic seizures. These clinical applications could aid the management of epilepsy and preservation of musical ability.

Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

Adjunctive use of ezogabine/retigabine with either traditional sodium channel blocking antiepileptic drugs (AEDs) or AEDs with other mechanisms of action: Evaluation of efficacy and tolerability

Integrated data from three double-blind, randomized, placebo-controlled trials were analyzed to evaluate the efficacy and tolerability of ezogabine (EZG; US adopted name)/retigabine (RTG; international non-proprietary name) when used in combination with ≥1 sodium channel blocking antiepileptic drug (AED), ≥1 non-sodium channel blocking AED, or ≥1 AED from both the sodium channel and non-sodium channel mechanistic groups. Efficacy and tolerability appeared to be similar across all three groups of patients.

A common SCN1A splice‐site polymorphism modifies the effect of carbamazepine on cortical excitability—A pharmacogenetic transcranial magnetic stimulation study

SCN1A encodes the alpha subunit of the voltage-gated sodium channel and plays a crucial role in several epilepsy syndromes. The common SCN1A splice-site polymorphism rs3812718 (IVS5N+5 G>A) might contribute to the pathophysiology underlying genetic generalized epilepsies and is associated with electrophysiologic properties of the channel and the effect of sodium-channel blocking antiepileptic drugs. We assessed the effects of the rs3812718 genotype on cortical excitability at baseline and after administration of carbamazepine in order to investigate the mechanism of this association. Paired-pulse transcranial magnetic stimulation (TMS) was applied in 92 healthy volunteers with the homozygous genotypes AA or GG of rs3812718 at baseline and after application of 400mg of carbamazepine or placebo in a double-blind, randomized, crossover design. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP) were determined. At baseline there was no significant difference in any TMS parameter. Genotype GG was associated with a higher carbamazepine-induced increase in CSP duration as compared to AA (multivariate analysis of covariance [MANCOVA], p=0.013). An expected significant increase in RMT was genotype independent. We found that the rs3812718 genotype modifies the effect of carbamazepine on CSP duration (mainly reflecting modulation of γ-aminobutyric acid (GABA)ergic inhibition), but not on RMT (mainly reflecting modulation of voltage-gated sodium channels). This provides evidence that rs3812718 affects the pharmacoresponse to carbamazepine via an effect on GABAergic cortical interneurons. Our results also confirm that TMS is useful to investigate the effect of genetic variants on cortical excitability and pharmacoresponse.