Adverse effects of antiepileptic drugs

Over half million people in Italy are affected by epilepsy and require antiepileptic drugs to achieve or maintain seizure control. An even higher number of people are prescribed the same drugs for other indications, some of which are officially approved (i.e. bipolar disorder, migraine, neuropathic pain) and other are off label.
Since antiepileptic drugs have a narrow therapeutic index and their adverse effects can affect any organ and apparatus, their widespread use has significant safety implications. Overall, 10-30% of people with epilepsy discontinue their initially prescribed antiepileptic drug due to intolerance.¹ Among patients chronically treated with antiepileptic drugs, the prevalence of adverse effects varies between 10 and 40% if tolerability is evaluated by means of spontaneous reports or non-structured interviews, and between 60 and 95% when adverse effects are evaluated by using a checklist.²
For people with drug-resistant epilepsy, several studies have shown that adverse effects are the primary determinants of low quality of life and have a more important impact on quality of life than the frequency of seizures.³ Understanding the manifestations of drug toxicity, risk factors involved and effective prevention measures is therefore essential for optimal clinical management.

Neurological adverse effects

Since antiepileptic drugs act by modulating the activity of cerebral neurons, it is no surprise that the majority of their adverse effects affect the central nervous system. Those most frequently observed include sedation, fatigue, dizziness, coordination disturbances (ataxia, dysarthria, diplopia), tremor, cognitive deficits, mood alterations, behavioural changes and sexual disorders (loss of libido, erectile dysfunction).² These effects are often dose-dependent, tend to appear in the early stages of the treatment, can be minimized sometimes by gradual dose titration, and some may regress spontaneously during continuation of therapy. Their frequency varies in relation to type of drug and its dosage (e.g., sedation and cognitive effects are more frequent with barbiturates, benzodiazepines and topiramate), patient’s characteristics (e.g., elderly patients are more susceptible to cognitive effects and motor coordination disturbances, whilst children more often develop behavioural effects) and comedication with specific agents (e.g., co-administration of two or more antiepileptic drugs which act by blocking sodium channels, such as carbamazepine, oxcarbazepine, lamotrigine and lacosamide, increases the risk of side effects secondary to this mechanism of action, such as dizziness and coordination abnormalities).⁴
Among effects on the central nervous system, the possibility of paradoxical worsening of seizures has been reported. This phenomenon may be caused by use of excessive doses, or by prescription of an antiepileptic drug inappropriate for the specific type of epilepsy. For example, carbamazepine and oxcarbazepine can worsen seizures and even precipitate status epilepticus when given to patients with juvenile myoclonic epilepsy.⁵

Idiosyncratic effects

Antiepileptic drugs, in particular lamotrigine, carbamazepine, oxcarbazepine, phenytoin, barbiturates and felbamate, are among the drugs most frequently associated with cutaneous reactions.6 Manifestations can vary from simple morbilliform rashes to potentially fatal reactions such as Stevens-Johnson syndrome, toxic epidermolysis and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). In general, these reactions appear within few days or weeks of initiation of therapy and regress after withdrawal of the offending agent. Their appearance, especially in the case of lamotrigine, can be minimized by starting treatment at low doses and by increasing dosage gradually. Because of significant cross-reactivity, in particular among aromatic antiepileptic drugs, for patients presenting with these manifestations it is preferable to switch to an alternative drug with an unrelated chemical structure. The propensity to develop cutaneous reactions is genetically controlled: in particular, the risk of developing Stevens-Johnson syndrome and toxic epidermolysis induced by carbamazepine, oxcarbazepine, phenytoin and, probably, lamotrigine, is highly increased among patients of Chinese or South East Asian ancestry who are positive for the HLA-B*1502 allele. In these ethnic groups, HLA-B*1502 genotyping is recommended before starting treatment with one of these drugs.⁷ Potentially fatal idiosyncratic reactions can affect other organs and tissues. Examples include aplastic anaemia induced by felbamate, hepatotoxicity induced by valproate or felbamate, and pancreatitis caused by valproate. For some of these effects, important risk factors are known: for example valproate hepatotoxicity is more frequent in paediatric patients (especially under two years of age) and in the presence of certain congenital metabolic defects or concomitant therapy with enzyme inducing antiepileptic drugs.⁶

Chronic effects

Some adverse effects of antiepileptic drugs develop insidiously and may become apparent only after months or even years of therapy.2 Examples include hirsutism and gingival hyperplasia induced by phenytoin, shoulder-hand syndrome and Dupuytren’s contraction induced by barbiturates, weight-gain induced by valproate, gabapentin, pregabalin, perampanel and vigabatrin, weight-loss induced by topiramate, zonisamide and felbamate, and metabolic alterations secondary to enzyme induction (vitamin D deficiency, endocrine disorders, blood lipid abnormalities) in patients chronically treated with carbamazepine, phenytoin and barbiturates.^2,8 Some serious chronic effects have resulted in a drastic reduction in the prescription of certain antiepileptic drugs, as in the case of irreversible visual field defects induced by vigabatrin² and abnormal pigmentation of skin, lips, nails and retina induced by retigabine.⁹

Effects on the offspring

The risk for congenital malformations in newborns of mothers treated with antiepileptic drugs during pregnancy is about 2-6%, versus 1-2% for the general population. The risk varies in relation to the type of drug, the dose and the number of administered drugs (risks are higher with polytherapy than with mono therapy).¹⁰
Valproate is associated with the highest risk: in a recent study, malformation rates among newborns exposed to valproate during gestation was 5.6% with maternal doses ˂700 mg/day, 10.4% with doses between 700 and 1,500 mg/day and 24.2% with doses ≥1,500 mg/day.¹¹ Prenatal exposure to high doses of valproate also increases the risk of postnatal cognitive deficits.¹²
The best strategy to minimize these adverse effects consists in optimizing antiepileptic therapy before pregnancy. Drastic treatment modifications during pregnancy are not indicated and could involve serious risks both for the mother and the fetus.¹⁰

Conclusive remarks

The list of adverse effects discussed in the previous sections is not exhaustive and more detailed information can be found in recent reviews^2,6,10 and in the data sheets for each drug. The goal of antiepileptic therapy is to achieve complete seizure control in the absence of adverse effects impacting negatively on quality of life. There are currently more than 25 drugs in the market for the treatment of epilepsy, many of which have similar efficacy but differ in their tolerability profile.¹³ Optimal therapy consists in tailoring the choice of drug and its dosage to the characteristics of the individual patient. Regular and careful assessment of clinical response, monitoring of plasma drug levels where appropriate, and use of standardised instruments to identify adverse effects are important components of a rational approach to early identification of drug toxicity and implementation of appropriate corrective interventions.