Abstract, published in Epilepsia

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Also investigated were the relationships between plasma rufinamide concentrations and dose as well as the influence of “add-on” medications

Assay results in the two tested fluids correlated well, but concentrations in saliva were moderately lower than those in plasma. In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. However, patients receiving valproic acid (Depakote®) “add-on” medication had higher dose-normalized plasma rufinamide levels than patients taking “add-on” medications metabolized by a different enzyme than that for rufinamide.

Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Nevertheless, because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.

Abstract, published in Epilepsia

Objective: This study aims to evaluate the impact of zonisamide (ZNS) compared to topiramate (TPM) on cognition in patients with epilepsy. Although the risk of cognitive side effects has been clearly demonstrated for TPM, comparable side effects in ZNS have been suggested but evidence from studies is inconclusive.

Methods: In this retrospective observational study, the team analyzed patients’ records from before and after introduction or withdrawal of ZNS vs TPM. Data were gathered during routine clinical care protocols. Standardized monitoring of executive functions verbal memory and subjective health was performed in 73 patients when TPM (n = 45) or ZNS (n = 28) was introduced and 62 patients when TPM (n = 29) or ZNS (n = 33) was withdrawn.

Results: There was decisive evidence for a negative effect of “add-on” antiseizure therapy with ZNS and TPM on executive function and a positive effect of their withdrawal. The ZNS effect seemed smaller, although the difference was inconclusive. Verbal memory and subjective quality of life were not significantly affected. Subjectively, ZNS was connected to lower anxiety and fewer headaches, whereas TPM had a perceived effect on weight, fluent speech and comprehension, headaches, and balance.

Significance: This is the first study to provide objective evidence for a considerable negative effect of ZNS treatment on executive function. Comparable to the well-known TPM effect, cognition worsens when ZNS is used as add-on therapy and recovers when it is withdrawn. However, most patients do not show a significant negative effect, suggesting disparate susceptibilities to adverse events. The findings emphasize the need for routine monitoring of cognitive side effects to identify early on those patients who are negatively affected by new AED.

Summary, published on MDLinx

In individuals with epilepsy, researchers assessed if epilepsy-related factors are correlated with suicide risk independent of depression. Participants in the cross-sectional study were adults (n = 212; 52.4% men) with epilepsy. Study participants were divided into two age groups (under 40 vs over?40 years). The risk of suicide was reported in 31.6% of candidates, while risk of depression was reported in 22.2% of candidates. Independent of depression and a past or family history of psychiatric disorders, there was a significant link between an antiepileptic drug load greater than one and suicide risk. Independent of current depression, use of pregabalin (Lyrica®) in the younger group and frequent seizures in the older group were associated with a risk of suicide.

The risk of suicide in people with epilepsy may be linked to epilepsy-related factors such as high antiepileptic drug load, frequent seizures (over one per month), and pregabalin use, regardless of depression. Such risk factors can vary according to the patient’s age.

Press Release from NIHR Maudsley Biomedical Research Centre 

Scientists have found that adding cognitive behavioral therapy (CBT) to standardized medical care gives patients with dissociative seizures longer periods of seizure freedom, less bothersome seizures and a greater quality of life, in a study published in Lancet Psychiatry today and by the Cognitive behavioral therapy for adults with dissociative seizures (CODES) study group funded by National Institute for Health Research (NIHR).

Psychogenic nonepileptic seizures, also called functional and dissociative seizures, look similar in appearance to epileptic seizures or fainting but are related to a different type of involuntary blackout that is typically distressing and disabling for patients and their carers. Up to 1 in 5 adults presenting in epilepsy clinics have this hidden condition which is one of several types of Functional Neurological Disorder (FND). Historically patients with dissociative seizures have often been ignored or disbelieved by doctors and research on treatment is limited. They are more likely to be found in women and usually have a poor outcome with a worse quality of life than people with epilepsy alone. People with dissociative seizures have a marked increase in health service use.

In the largest treatment trial to date for dissociative seizures, 368 patients from centers across England, Scotland, and Wales were followed up 6 months and 12 months after treatment courses began. Researchers found patients treated with dissociative seizure specific CBT alongside standardized medical care reported the highest number of consecutive dissociative seizure-free days in the previous 6 months, along with greater functional status, self-rated and doctor-rated change in global impression scores, and satisfaction with treatment when compared with standardized medical care alone.

Abstract, published in Epilepsy & Behavior

Purpose: This study compared health service utilization and costs for patients with epilepsy before and after initiation of perampanel and compared with matched controls.

Results: Three hundred and forty-three patients treated with perampanel were identified. One hundred and eighty-three (53.4%) were male, with an average age of 39 and an average epilepsy duration of 21 years. Two hundred and eighty-seven (83.7%) were matched to controls. Inpatient admissions with a primary diagnosis of epilepsy and neurology specific outpatient appointments were significantly reduced following initiation with perampanel. Total costs attributable to epilepsy and overall secondary costs were also significantly reduced. There was no significant difference in primary care, outpatient, or general inpatient admissions. Compared with controls, there was a significant reduction in primary epilepsy admissions but a significant increase in outpatient appointments and accident and emergency contacts for patients treated with perampanel.

Conclusion: Treatment with perampanel is associated with reduced epilepsy-related inpatient admissions and accident and emergency contacts.

Abstract, published in Epilepsia

Objective: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), that is, generalized epilepsy cause by a mutation,  dramatically increases the risk of a range of birth defects. Although the mechanisms underlying these birth defects are not known, they may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects.

Results: The team used three different rat models of epilepsy, each of which had a different genetic mutation. VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls. Specifically, VPA treatment altered the distances between individual vertebrae in the backbone in all three rat models, more frequently than in controls.

Significance: Exposure of embryos to VPA during pregnancy results in similar developmental and morphological abnormalities in three different rat models, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. These models may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug–induced birth defects.

Abstract, published in Epilepsy Research

Stiripentol is an orphan drug successfully used in combination with valproate (Depakote®) and clobazam (Onfi®) in the treatment of Dravet syndrome. Perampanel has also been added by experts. In this study, we investigated the influence of stiripentol on perampanel serum levels by using the doses and corresponding perampanel serum levels of 10 patients. The impact of stiripentol on the perampanel serum levels was significant, with perampanel serum levels increasing linearly with the stiripentol doses.

Researchers conclude that dose adjustments of stiripentol and perampanel when administered together, should be done carefully to avoid side effects or even severe intoxication. Hence, perampanel serum level monitoring seems advisable.

Abstract, published in Epilepsy Research

Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A, a protein located on the surface of nerve cells in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed, extensively metabolized, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes.

The favorable pharmacokinetic profile of brivaracetam and lack of clinically relevant drug – drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug – drug interaction. Few agents have been reported to affect the pharmacokinetics of brivaracetam.

The strong enzyme-inducing AEDs carbamazepine (Tegretol®), phenytoin (Dilantin®) and primidone (Mysoline®), along with its metabolite phenobarbital, have been shown to moderately lower brivaracetam plasma concentrations, with no adjustment of brivaracetam dose needed. Dose adjustment should be considered when brivaracetam is coadministered with the more potent enzyme-inducer, rifampin (Rifadin). Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John’s wort. In summary, brivaracetam (50–200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug–drug interactions.