Behavioral and psychiatric adverse events associated with antiepileptic drugs commonly used in pediatric patients

Multiple factors-including the efficacy of the antiepileptic drug for the particular seizure type, availability of pediatrics-friendly formulations, the ease of dosing and titration, and tolerability issues, such as possible drug interactions and adverse events-affect the selection of the best antiepileptic drug for a child with epilepsy. Behavioral problems are common in children with epilepsy and can be aggravated or initiated by antiepileptic drug therapy. The types and frequencies of antiepileptic drug-associated behavioral events can influence a clinician's drug selection, drug management, and counseling of parents. Unfortunately, appreciating differences among antiepileptic drugs in behavioral adverse event profiles is problematic because, among other reasons, methodologies for reporting, collecting, and analyzing adverse events are not uniform across trials, and there is marked heterogeneity in study design among trials. This review summarizes incidence rates for behavioral and psychiatric adverse events taken from studies of children with epilepsy. These rates are reported for the 10 most commonly prescribed antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, lamotrigine, phenytoin, levetiracetam, oxcarbazepine, topiramate, zonisamide, and gabapentin), grouped according to their predominant mechanism of action. Despite the numerous methodologic inconsistencies, some similarities in adverse event profiles among antiepileptic drugs that share mechanisms of action are apparent. Moreover, the overwhelming body of data on the behavioral effects of phenobarbital should convince clinicians that, whenever possible, it should not be used as the initial-or even the second-monotherapy in children with epilepsy.     

Behaviour, cognition and epilepsy

Cognitive and behavioural impairments have been observed as a consequence even of single seizures. In individuals with high seizure frequency, such impairments may accumulate and have a much greater impact on daily life than hitherto suspected. In addition, the risk of behavioural impairments is increased for some seizure types, such as secondary generalized seizures. Moreover, for all epilepsy types, increased risk is associated with persistent or poorly controlled seizures. Clinical studies show that cognitive impairments induced by seizures are reversible for most seizure types when seizures are controlled adequately. Additionally, for some seizure types there may be a kind of time window within which impairments are reversible. Exceeding the time window may result in irreversible impairment. These studies suggest that antiepileptic drug treatment can thus protect against such secondary behavioural impairments or at least correct these when seizures are controlled. This emphasizes the need to achieve complete and early seizure control. On the contrary, all antiepileptic drugs have a detrimental effect on the central nervous system and may affect cognitive function, behaviour and mood to some extent. Some treatments may undo the beneficial effects of antiepileptic drug treatment by inducing new or other cognitive impairments. This once more illustrates the need for the emphasis of clinical practice to evolve from mere seizure control to a more comprehensive approach, in which the prevention of central cognitive effects and effects on daily life of both seizures and drugs is given due attention. Optimal management requires a careful balance between, on the one hand, the desire to reach early and maximal seizure control and, on the other, the need to avoid tolerability problems related to cognitive and behavioural impairments. This article reviews how this balance can be achieved for older and newer antiepileptic drugs.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Antiepileptic drug-induced encephalopathy

The clinical features of an antiepileptic drug-induced encephalopathy (ADE) are confusion, reduction of vigilance, neurological deficits or an increase of the seizure frequency. In the electroencephalogram a general slowing or epileptic discharges are found. Characteristic are non-toxic blood levels of the antiepileptic drugs. So far an ADE was reported under phenytoin, carbamazepine or valproatic acid (valproate) therapy. More seldom, an ADE has been described after the intake of vigabatrine, lamotrigine und topiramate. Potential pathogenic mechanisms of AED are hyperammonemia, intrinsic effects on cerebral receptors, drug interactions, hepatic enzyme interactions, metabolic reasons or paradoxical proconvulsive effects of antiepileptic drugs. The medicamentous therapy consists of an immediate discontinuation of the antiepileptic drug.     

Aggravation of epilepsy by antiepileptic drugs

Antiepileptic drugs may paradoxically worsen seizure frequency or induce new seizure types in some patients with epilepsy. The mechanisms of seizure aggravation by antiepileptic drugs are mostly unknown and may be related to specific pharmacodynamic properties of these drugs. This article provides a review of the various clinical circumstances of seizure exacerbation and aggravation of epilepsy by antiepileptic drugs as well as a discussion of possible mechanisms underlying the occasional paradoxical effect of these drugs. Antiepileptic drug-induced seizure aggravation can occur virtually with all antiepileptic medications. Drugs that aggravate seizures are more likely to have only one or two mechanisms of action, either enhanced gamma-aminobutyric acid-mediated transmission or blockade of voltage-gated sodium channels. Antiepileptic drug-induced seizure exacerbation should be considered and the accuracy of diagnosis of the seizure type should be questioned whenever there is seizure worsening or the appearance of new seizure types after the introduction of any antiepileptic medication.     

Epilepsy in the Elderly: Some Clinical and Pharmacotherapeutic Aspects

Summary: The majority of epileptic seizures and epilepsies are no longer manifested in childhood and adolescence; instead their incidence is higher at the age of 65 years or older than during the first two decades of life. After cerebrovascular disorders and dementias, epileptic seizures and epilepsies now constitute the third most frequent neurologic problem encountered in the elderly. Important clinical features of epilepsy in the elderly related to the diagnosis include the most common seizure types and causes. Special features of drug treatment for epilepsy in the elderly result not only from the physiologic changes in the elderly but also from the particular pharmacology of the respective drugs. Because elderly patients very often require other long-term medication in addition to antiepileptic therapy, drug interactions between different antiepileptic drugs and between antiepileptics and other drugs can be of major significance. Other special features of pharmacotherapy for epilepsy in the elderly include the presence of liver and kidney diseases.     

Antiepileptic Drug Development Program: A Cooperative Effort of Government and Industry

Summary: The most important step in antiepileptic drug discovery is the choice of an appropriate animal model for the initial screening as well as for the more complex procedures that elucidate mechanisms of action. The currently available models fall short in their inability to identify ail drugs for all types of seizures in a mechanism-independent manner. Nevertheless, spontaneous models of epilepsy are the most commonly used, and chemically or electrically induced seizures in rodents can also identify potential anticonvulsants. In the latter models, the intensity of the seizure stimulus is of paramount importance. The Antiepileptic Drug Development Program evaluates approximately 800 compounds each year, using two models for preliminary screening. One model assesses the ability of a compound to prevent seizure spread; the other weighs the ability to raise seizure threshold. In vivo tests, featuring amygdala- and corneal-kindled seizures, and in vitro assays, employing γ-aminobutyric acid (GABA) receptors and synaptosomal uptake of adenosine, define drug-drug interactions and elucidate the pharmacological profiles of potential anticonvulsants.     

Sexual hormones and epilepsy: threat and opportunities

PURPOSE OF REVIEW: This article reviews recent developments in our knowledge of the reciprocal interactions between epilepsy and sex hormones and how these interactions may play a role in the pathophysiology and treatment of both. RECENT FINDINGS: Community studies confirm that menstrual disorders are overrepresented among women with epilepsy, especially among women with high seizure frequency and in those on valproate or polytherapy. Reproductive function is not affected in women with epilepsy who discontinued antiepileptic drug therapy during pubertal maturation. While valproate has been implicated as having particularly notable disruptive effects on reproductive function in women with epilepsy (polycystic ovaries and hyperandrogenemia), this was not evident in non-epileptic primates. The role of epilepsy itself is evident from a study that showed that the laterality of unilateral temporolimbic discharges is associated with predictable directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis. Epilepsy in men is associated with reduced levels of sexual function, bioactive testosterone and sperm. Various antiepileptic drugs may differ in this regard. SUMMARY: Epilepsy and antiepileptic drugs can alter sex hormone levels to promote the development of reproductive endocrine disorders in both women and men. Reproductive endocrine disorders may adversely affect both reproductive function and seizure control. Treatment of epilepsy and selection of antiepileptic drugs may be important to reproductive health in women and men with epilepsy. Sex steroids and their metabolites may also provide treatment for seizures.     

Wirkungsmechanismen von Antiepileptika

Antiepileptic drugs have primarily been developed to suppress epileptic seizure activity. However, different antiepileptic drugs also show a relevant clinical efficacy for other indications. With regard to seizure control antiepileptic drugs aim to support inhibitory neurotransmission and to suppress excitatory neurotransmission. Respective effects are achieved using drugs which enhance GABAergic signalling, reduce glutamatergic signalling or modulate ion channel function. This series of review articles will give an overview about the different antiepileptic drug target sites and their relevance for clinical efficacy. In this first article the modulation of GABAergic neurotransmission will be discussed.     

Juvenile absence epilepsy exacerbated by valproic acid

Valproic acid is commonly and effectively used in the treatment of idiopathic generalized epilepsies, including juvenile absence epilepsy. Although several adverse effects are associated with this drug, it has only rarely been known to exacerbate seizures. Similar to antiarrhythmic drugs aggravating particular arrhythmias, antiepileptic drugs can paradoxically induce new seizure types or exacerbate existing ones. This reaction is better known with carbamazepine and phenytoin, but is less common with broad-spectrum antiepileptic drugs such as valproic acid. This report describes a case of paradoxical, intravenous valproic acid-induced seizure exacerbation in a child with juvenile absence epilepsy, documented by video-electroencephalography.     

Neuroendocrinological aspects of epilepsy: important issues and trends in future research

Neuroendocrine research in epilepsy focuses on the interface among neurology, endocrinology, gynecology/andrology and psychiatry as it pertains to epilepsy. There are clinically important reciprocal interactions between hormones and the brain such that neuroactive hormones can modulate neuronal excitability and seizure occurrence while epileptiform discharges can disrupt hormonal secretion and promote the development of reproductive disorders. An understanding of these interactions and their mechanisms is important to the comprehensive management of individuals with epilepsy. The interactions are relevant not only to the management of seizure disorder but also epilepsy comorbidities such as reproductive dysfunction, hyposexuality and emotional disorders. This review focuses on some of the established biological underpinnings of the relationship and their clinical relevance. It identifies gaps in our knowledge and areas of promising research. The research has led to ongoing clinical trials to develop hormonal therapies for the treatment of epilepsy. The review also focuses on complications of epilepsy treatment with antiepileptic drugs. Although antiepileptic drugs have been the mainstay of epilepsy treatment, they can also have some adverse effects on sexual and reproductive function as well as bone density. As longevity increases, the prevention, diagnosis and treatment of osteoporosis becomes an increasingly more important topic, especially for individuals with epilepsy. The differential effects of antiepileptic drugs on bone density and their various mechanisms of action are reviewed and some guidelines and future directions for prevention of osteoporosis and treatment are presented.     

Antiepileptic drug discovery: does mechanism of action matter?

This commentary discusses briefly the role of the mechanism of antiepileptic action in discovery of drugs for the treatment of epilepsy. More specifically, two questions are addressed. (1) Has mechanism-driven antiepileptic drug discovery brought us better epilepsy treatment? Although this question is difficult to answer, the short answer is "not yet." Modern antiepileptic drugs with new or modified mechanisms of action do not seem to have substantially improved the efficacy or the safety of epilepsy treatment. In fact, some modern antiepileptic drugs such as progabide, tiagabine, and vigabatrin have been associated with a number of safety issues. (2) Why do drugs with new mechanisms seem to have failed to deliver better treatment? Although it is always difficult to know why something did not occur, one putative explanation may be worthwhile to consider. The past development of new antiepileptic drugs targeted putative mechanisms of seizure generation. As seizures are only symptoms of the underlying epilepsy, blocking seizure generation can provide at best only symptomatic treatment. It may be that the failure in treating drug-resistant seizures is related, at least in part, to the failure of current drugs in targeting the mechanisms underlying epilepsy. In conclusion, continuing to develop new antiepileptic drugs for drug-resistant epilepsy by targeting seizure generation may be futile and one possible explanation of why we do not seem to make substantial progress in the treatment of drug-resistant epilepsy. Developing antiepileptic drugs with antiepileptogenic activity may be a clue to better treatment of presently drug-resistant epilepsy.     

Focal lesions in the splenium of the corpus callosum in patients with epilepsy

Purpose:   A focal lesion in the splenium of the corpus callosum is a rare finding in patients with epilepsy. Intoxication with antiepileptic drugs, edema after generalized seizures, or a rapid change of antiepileptic drug levels have been proposed as possible mechanisms. The aim of the present study was to analyze the relationship between this lesion and possible etiologic factors.
Patients and methods:   We analyzed the magnetic resonance imaging (MRI) scans of 1,050 patients undergoing prolonged video-EEG (electroencephalography) monitoring and identified 24 patients with a focal lesion in the splenium of the corpus callosum. Twenty-four age- and gender-matched temporal lobe epilepsy patients without such a lesion served as a control group. We evaluated the following parameters for their possible etiologic significance: epilepsy syndrome, seizure types in medical history, seizure frequency during the past year prior to admission for prolonged video-EEG monitoring, localization of interictal spikes and ictal EEG patterns in patients with focal epilepsies as documented during prolonged video-EEG-monitoring, seizure types and seizure frequency during prolonged video-EEG monitoring, past as well as current antiepileptic medication, withdrawal of antiepileptic drugs during monitoring including duration of medication withdrawal, and finally drug levels above the therapeutic range.
Results :  The parameters analyzed showed no significant difference between the group of patients with focal lesions in the splenium of the corpus callosum and the control group.
Conclusion:   We could not identify a single etiologic factor responsible for the lesion in the splenium of the corpus callosum.     

The Role of the Old and the New Antiepileptic Drugs in Special Populations: Mental and Multiple Handicaps

Summary: Epilepsy is common in individuals who are mentally retarded and/or otherwise multiply handi capped. These patients often display several seizure types. Seizure control may be difficult and drug interac tions common because of polytherapy. Cognitive, behav ioral, affective, and motor problems in these patients of ten confound accurate diagnosis and effective manage ment. Treatment often requires not only antiepileptic drugs (AEDs) but also psychoactive drugs and/or envi ronmental and personal support. To minimize unwanted drug effects, therapeutic strategies should focus on the administration of the fewest possible drugs at the lowest effective dose. The new AEDs may be of special value at times in these populations because they offer potential for improved efficacy, but especially because many of them provide better safety profiles and fewer pharmacokinetic interactions with other drugs.     

Newer antiepileptic drugs]

Ten newer antiepileptic drugs have been developed since 1990s. These drugs have wider therapeutic spectra, fewer side-effects, and lesser drug-to-drug interactions compared with the older typical antiepileptic drugs. Among them, zonisamide was developed in Japan and has been used from 1989. Gabapentin was at length approved in 2006. The other newer antiepileptic drugs are not approved yet in Japan. Felbamate can not be used in Europe because it may induce lethal hepatic toxicity and aplastic anemia. Vigabatrin is not approved in USA because it may induce permanent visual field deficit. The USA guideline for epilepsy treatment recommends that patients with newly diagnosed epilepsy can be treated with gabapentin, lamotrigine, topiramate, and oxcarbazepine. In contrast, based on epilepsy treatment guideline in England, newer antiepileptic drugs are considered only when patients with newly diagnosed epilepsy are unable to use the older antiepileptic drugs for some reasons. All newer antiepileptic drugs are used for intractable partial epilepsies, and lamotrigine and topiramate can also be used for idiopathic generalized epilepsies. The response rate (seizure reduction rate with 50% or more) and drop-out rate are overlapping among all newer antiepileptic drugs. Gabapentin, levetiracetam, and pregabalin are eliminated from kidney, and they had no drug-to-drug interactions and can be titrated rapidly. The serum concentration of lamotrigine is decreased with co-administration of hepatic enzyme inducing drugs and is increased with co-administration of valproic acid. Hypersensitivity reactions are rare with gavapentin, levetiracetam, topiramate, and tiagabin. Psychoses are reported to be induced with zonisamide, however, they can be induced with the other newer drugs (topiramate, levetiracetam, etc.). Drug-induced psychiatric symptoms, especially depression, may be often underdiagnosed. Many of these newer drugs (gabapentine, lamotrigine, levetiracetam, oxycarbazepine, etc.) have effects on chronic neuropathic pain. Some newer drugs show mood stabilizing effects (lamotrigine, oxycarbazepine, etc.), or antianxiety effect (gabapentin, topiramate, levetiracetam, pregavalin, etc.). Wide range of action to central nervous system of these newer antiepileptic drugs may serve not only for clinical seizure suppression, but also for neuroprotection.     

Pharmacotherapy of epilepsy

Antiepileptic drug treatment is essential and provides excellent therapeutic effects in more than the two-third of the epileptic patients. The antiepileptic drugs influence the chronic hyperexcitability of the brain developed during the epileptogenesis. As an effect, it decreases the excitability and/or increases the inhibition of the pathological cells, which prevents the precipitation of the epileptic seizure (anticonvulsive effect). The anticonvulsive effect comes into operation by the influence of the transport of one ore more ion-channels. The anticonvulsive effect is only symptomatic and it doesn't cure the disorder. The drug selection is based on the knowledge of the therapeutic markers and the effectiveness of the drug to be used. This can occur on the basis of the action of the drug or in syndrome-specific way. The pharmacokinetic properties of the drugs determine how they can be used in the practice. The drug interactions can take place in several levels. Among them, the change of the metabolism is the most important. Acute dose-dependent side effects, organ-specific chronic interactions and idiosyncratic reactions must be taken into consideration during the use of antiepileptic drugs. The patient's individual aspects must be considerably taken into account during the treatment. There are other medical areas that can benefit from the antiepileptic drugs. Among them, the most important diseases are: restless legs syndrome, neuropathic pain, trigeminal neuralgia, essential tremor, bulimia and bipolar disorders. There are other pharmacological (adrenocorticotropic hormone, immunoglobulins, neurosteroids) and dietary methods, which may be effective at certain epileptic syndromes. The principles of the pharmacotherapy have been changing continuously during the past decades and since. New drugs have been introduced into the marketing and new expectations are coming into the limelight concerning the treatment. As a consequence this will bring on the modification of antiepileptic drug therapeutic habits.     

Selection of drugs for the treatment of epilepsy

Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.     

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models

Although seizure models using systemic administration of the chemoconvulsant pentylenetetrazol (PTZ) for induction of generalized clonic seizures in rodents are widely employed to identify potential anticonvulsants, the important role of diverse technical, biological and pharmacological factors in interpretation of results obtained with these models is often not recognized. The aim of this study was to delineate factors other than sex, age, diet, climate, and circadian rhythms, which are generally known. For this purpose, experiments with 8 clinically established antiepileptic drugs were undertaken in the following PTZ models: (1) the threshold for different types of PTZ seizures, i.e., initial myoclonic twitch, generalized clonus with loss of righting reflexes, and tonic backward extension of forelimbs (forelimb tonus), in mice; (2) the traditional PTZ seizure test with s.c. injection of the CD97 for generalized clonic seizures in mice; and (3) the s.c. PTZ seizure test in rats. In rats, in addition to evaluating drug effects on generalized clonic seizures, a ranking system was used to determine drug effects on other seizure types. When drugs were dissolved in vehicles which themselves did not exert effects on seizure susceptibility, the most important factors which influenced drug potencies were: (1) bishaped dose-response curves, i.e., a decline in anticonvulsant dose-response at high doses of some drugs, leading to misinterpretations of drug efficacy if only a single high drug dosage is tested; (2) effects of route of PTZ administration (i.v. infusion vs. s.c. injection) on estimation of anticonvulsant potency; (3) species differences in drug metabolism; (4) differences in drug potencies calculated on the basis of administered doses compared to potency calculations based on 'active' drug concentrations in plasma; (5) qualitative and quantitative species differences in drug actions; (6) endpoints used for PTZ tests; (7) misleading predictions from PTZ seizure models. Analysis of anticonvulsant drug actions indicated that myoclonic or clonic seizures induced by i.v. or s.c. PTZ might be suitable for predicting efficacy against myoclonic petit mal seizures in humans, but certainly not to predict efficacy against absence seizures. Tonic seizures induced by PTZ were blocked by drugs, such as ethosuximide, which exert no effect on tonic seizures in humans. In order to reduce the variability among estimates of anticonvulsant activity in PTZ seizure models, the various factors delineated in this study should be rigidly controlled in experimental situations involving assay of anticonvulsant agents.     

Reducing overtreatment

Although treatment of epilepsy easily evolves into a situation of overtreatment, reversing the process can be difficult and time consuming. Benefits of reducing overtreatment may include a decrease in side effects, better seizure control, a simplification in the medication regimen, improved compliance, and reduced costs. The risks include seizure exacerbation due to withdrawal or due to loss of protection. Reversal of pharmacokinetic interactions may also lead to seizure aggravation or to drug toxicity. When reducing overtreatment, there are three main challenges: to select the drugs that should be eliminated, to choose an appropriate rate of reduction, and to anticipate reversible pharmacokinetic interactions that can have clinically significant consequences. Overall, there is a lack of published data to properly support recommendations for implementing reduction of overtreatment. This is particularly the case in the pediatric population and for the newer antiepileptic drugs.