Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

Abstract

The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous h...

Understanding Lamotrigine’s Role in the CNS and Possible Future Evolution

“…However, other AEDs with different mechanisms of action may be more effective in treating other types of seizures, such as those associated with GABA imbalances or calcium channel dysfunction. Additionally, lamotrigine is less likely to cause sedation or cognitive impairment compared to some other anti-epileptic drugs, which makes it effective for the treatment of certain mood disorders in addition to epilepsy [ 44 ].…”

The therapeutic effects of lacosamide on epilepsy-associated comorbidities

“…The objectives of treatment for epilepsy-associated comorbidities should focus on the positively controlling seizures, as well as reasonable interventions for comorbidities should be developed that can improve the patients' quality of life ( 4 ). As research progresses, it has been found that ASMs might have different psychiatric or psychological effects on patients, including the psychiatric and behavioral side effects (PBSEs) ( 42 , 43 ). Some ASMs have no cognitive effects on PWE (e.g., gabapentin, and lamotrigine), whereas phenytoin sodium, topiramate, and zonisamide can adversely affect the cognition ( 44 ).…”

Lamotrigine (Sazar) in the treatment of epilepsy: four years of experience in Svt. Luka's Association of Medical institutions for the Diagnosis, Treatment, and Rehabilitation of Nervous System Diseases and Epilepsy

“…Отмена препарата в связи с утратой временного эффекта проведена у 8 (7,7 %) пациентов (все пациенты с генетическими эпилептическими энцефалопатиями). В целом в связи с проблемами эффективности препарат отменен у 17 (16,3 %) Безусловно, очень важное значение имеет отсутствие отрицательного влияния ламотриджина (и данные о его потенциально положительном эффекте) на когнитивные функции при ЭРЭ, по данным недавно проведенного обзора литературы, изучающего когнитивные и поведенческие эффекты АЭП именно в популяции пациентов с ЭРЭ [73]. В нашем наблюдении ни в одном из случаев пациентами или их родителями не было отмечено негативного влияния на когнитивные функции и психическую сферу при приеме Сейзара.…”

“…Приводим обобщающие данные отчета рабочей группы ILAE о действии АЭП на когнитивные функции и поведение детей, основанные на результатах обзора литературы [25]. По данным недавно проведенного обзора литературы по вопросу влияния АЭП на поведение, психическую сферу и когнитивные функции при ЭРЭ [73], леветирацетам, перампанел и, в меньшей степени, бриварацетам ассоциированы с психическими и поведенческими нарушениями (включая агрессивность и раздражительность) у пациентов этой категории. Топирамат и, в меньшей степени, зонисамид ассоциированы с речевыми нарушениями, когнитивной заторможенностью и проблемами памяти, а также с негативным влиянием на ряд аспектов когнитивных функций, в то время как ламотриджин, а также леветирацетам и бриварацетам могут оказывать положительный эффект на когнитивные функции.…”