Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants

ObjectivePatients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.MethodsWe recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.ResultsWe identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.ConclusionOur patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.     

High-throughput liquid chromatography tandem mass spectrometry method for simultaneous determination of fampridine,paroxetine, and quinidine in rat plasma: Application to in vivo perfusion study

A selective and high-throughput liquid chromatography–mass spectrometry method has been developed and validated for the simultaneous quantification of paroxetine, fampridine, and quinidine in rat plasma using imipramine as an internal standard. Following protein precipitation extraction, the analytes and internal standard were run on X Bridge C18 column (150 mm × 4.6 mm, 5 μm) using a gradient mobile phase consisting of 5mM ammonium formate in water (pH 9.0) and acetonitrile in a flow gradience program. The precursor and product ions of the drugs were monitored on a triple quadrupole instrument operated in the positive ionization mode. The method was validated over a concentration range of 0.1–100 ng/mL for all the three analytes, with relative recoveries ranging from 69% to 82%. The intra- and interbatch precision (percent coefficient of variation) across four validation runs were less than 13.4%. The accuracy determined at four quality control (QC) levels (lower limit of quantitation, low QC, medium QC, and high QC) was within ±6.5% of coefficient of variation values. The method proved highly reproducible and sensitive, and was successfully applied in a pharmacokinetic study after single-dose oral administration to rats and also in perfusion study sample analysis.     

Monotherapy and polytherapy for intractable epilepsies

A retrospective survey on 66 adults with epilepsy who received multiple drug therapy after the failure of single drugs showed: a reduction of seizure frequency of 75% or more in 16.5%, no change in 67% and an increase in seizure frequency of 100% or more in 16.5%. Multiple drug therapy is of limited value in severe epilepsies.

---

Sommario Lo studio comprende una analisi retrospettica su 66 pazienti adulti con epilessia che, dopo non aver ottenuto la scomparsa completa delle crisi con differenti monoterapie, hanno intrapreso un trattamento combinato. Nel 16,5% dei casi si è osservata, con l'introduzione della politerapia, una riduzione delle crisi del 75% ed oltre; nel 67% non si è assistito ad alcuna modificazione della frequenza critica, mentre questa è aumentata del 100% ed oltre in un altro 16,5% dei casi. La politerapia sembra essere di valore limitato nei casi di epilessia farmaco-resistente.

     

Advancing pharmacologic treatment options for pharmacologic treatment options for children with epilepsy

Introduction: The pharmacological management of epilepsy is continually modified by the increase in our knowledge about the efficacy and the safety on antiepileptic drugs.

Areas covered: This review covers the published data (2010–2015) on the pharmacological management of epilepsy in children and adolescent. We review the data from the most recent randomized controlled and open-label trials.

Expert opinion: Even if there is an increasing number of antiepileptic drugs approved for focal seizure in children and adolescent with epilepsy, each new approval would be considered as a significant addition to the current therapeutic options. Refractory epilepsy with focal seizure should not be regarded as a single disease but as numerous various patients. Because most of evidence of efficacy is primarily from placebo-controlled trials, there is no evidence to choose a treatment based on efficacy. In case of focal seizure, we explain how possible cognitive impact, mechanisms of action, pharmacologic characteristics and side effect profile are the factors taken into an account to propose a treatment. In case of childhood absence epilepsy, there are evidences showing the ethosuximide should be the first line treatment. Finally, we stress that trials in the pediatric epilepsy syndromes are required to propose better evidence-based pharmacological management.     

Pharmacological principles as a basis for polytherapy

Most patients with newly diagnosed epilepsy can be optimally controlled by prescribing a single anti-epilepsy drug, selected on the basis of its efficacy and safety profile. In about one-third of patients, however, seizures persist during monotherapy, despite the intake of the maximally tolerated drug dose. In such cases, substantial therapeutic benefit may be achieved by prescribing appropriate drug combinations. Safe use of multiple drug therapy requires a good knowledge of clinical pharmacology, particularly an awareness of potentially adverse drug interactions. As many older anti-epilepsy drugs have similar modes of action, their interaction may not always be of clinical benefit, because drug side-effects may also be additive. There is, however, evidence that specific combinations may be particularly advantageous; for example, valproate and ethosuximide in the management of refractory absence seizures. Compared with older drugs, some of the recently developed agents possess different and more selective mechanisms of action, which may result in enhanced therapeutic benefit when specific combinations are used. Preliminary observations do suggest that, in some cases, the efficacy exhibited by certain new drugs could be explained in terms of their pharmacological effect being'complementary' to that of concurrently used agents.     

Unilateral radius aplasia due to lamotrigine and oxcarbazepine use in pregnancy

Lamotrigine (LTG) has been used in epilepsia patients for treatment of partial seizures. It can cross the placenta and there are limited data about its use in pregnancy and foetal adverse effects. Extremity and cardiac malformations, dysmorphic facial appearance, coanal atresia and upper respiratory and gastrointestinal anomalies have been reported because of LTG use in pregnancy. Oxcarbazepine (OXC) is one of the new antiepileptic agents. Although the drug and its metabolites can easily pass from placenta to the foetus, available data suggest that it can be safely used during pregnancy because no teratogenicity has been reported. One infant with atrial septal defect and patent ductus arteriosus due to use of LTG and OXC in pregnancy has been reported in literature. Here, we report a female infant with micrognatia, low-set ears, facial dysmorphism and unilateral radius aplasia born to a mother who used LTG 100 mg/day and OXC 1200 mg/day during pregnancy for seizures. To our knowledge, this is the first major anomaly case associated with the combined use of these drugs. This case can provide useful data about the teratogenicity of LTG and OXC combination therapy.