Recognizing and Addressing Antiepileptic Drug Side Effects

A personalized approach to treating epileptic seizures ensures a balance of effectiveness and tolerability for each patient.

For some people with epilepsy, side effects of antiepileptic drugs (AEDs) may affect quality of life even more than seizures.1

Because all AEDs suppress neuronal excitability or neurotransmission to control seizures, they also have an effect on cognitive brain functions. Common side effects include depressed cognition, somnolence, distractibility, and dizziness. Children with depressed cognition may exhibit aggression and hyperactivity.2

Several consistent risk factors for AED side effects have been established. These include frequency and severity of seizures, polypharmacy of AEDs, and the need to maintain a high AED blood level. There are many AEDs to choose from, and some are more likely to cause side effects than others.2

In a study of 1,694 adults with epilepsy, patient-reported cognitive side effects were most common with topiramate, zonisamide, phenytoin, and oxcarbazepine. Best tolerated drugs were gabapentin, valproate, lamotrigine, carbamazepine, and levetiracetam. The study, published in Epilepsy & Behavior,found an intolerability rate of about 13% overall.1

Additionally, a review of cognitive side effects of AEDs in children, published in the Handbook of Clinical Neurology, found that use of phenobarbital, topiramate, and high-dose phenytoin were all associated with possible cognitive impairment.3

Balancing Tolerability and Effectiveness

Choosing an AED is a clinical decision based on several factors. “The primary driver of choice is type of seizure. Then you need to consider individual patient characteristics such as age, possibility of pregnancy, comorbidities, weight, and other medications. It may be a bit of trial and error, but in most cases you can find a drug with good seizure control and minimal cognitive and sedative side effects,” said Ruben Kuzniecky, MD, co-director of the New York University Comprehensive Epilepsy Center in New York City.

Some AEDs, including valproate and lamotrigine, are broad spectrum and can be used for most types of seizures.  Narrow spectrum AEDs may be a first choice for seizure types including simple partial, complex partial, secondary generalized, absence, and infantile spasms.

If weight gain is a problem, valproate and gabapentin may need to be avoided. Alternately, weight loss has been associated with zonisamide and topiramate.4

“You always need to avoid valproic acid if there is a possibility of pregnancy because it can cause birth defects,” said Kuzniecky. AEDs that are hepatic enzyme inducers may decrease the effects of oral contraceptives. Phenytoin may speed up the metabolism of warfarin, whereas valproate may have the opposite effect. AEDs that are metabolized by the liver or excreted by the kidneys may need to be used with caution in people with liver or kidney disease.4

Psychiatric comorbidities, such as mood disorders and anxiety, may affect about one-third of people with epilepsy during their lifetime. These disorders may have a major social and behavioral impact on quality of life. Living with epilepsy certainly contributes to depression and anxiety, but AEDs may also play a role.5

Increased risk of suicide has been reported with some AEDs. A 2014 case report in Annals of General Psychiatry reviewed an incident of depression and a suicide attempt in a patient taking pregabalin.6

On the other hand, some AEDs have been shown to stabilize or improve mood. These include lamotrigine, valproate, and carbamazepine.4 All patients should be screened for depression and anxiety, since these disorders are frequently missed and undertreated in people with epilepsy.5

“It is complicated, but if you individualize your choices according to patients’ risk factors, start slowly, use the lowest effective dose, and add medications carefully, there are actually few patients that are very difficult to control,” said Kuzniecky.

The top five medications for effectiveness and tolerability, include levetiracetam, lamotrigine, lacosamide, oxcarbazepine, and eslicarbazepine, he said.

Special Concerns for Children

Health-related quality of life (HRQL) is a special concern for children with epilepsy. Many children with epilepsy have at least one other neurological problem, most commonly a cognitive delay or learning disability.6

In a meta-analysis of risk factors for HRQL in children with epilepsy, seizure type, frequency, severity, duration of epilepsy, number of AEDs, side effects of AEDs, comorbidities, and parental anxiety were all associated with HRQL. The study was published in Epilepsia.7

“Side effects, number of medications, seizure severity, seizure frequency, and epilepsy-related comorbidities can be conceptualized as representing difficult-to-control epilepsy. Seen in this way, the two strongest risk factors for HRQL in children are difficult-to-control epilepsy and parental anxiety,” said Mark A. Ferro, PhD, who authored the meta-analysis. Ferro is assistant professor in the departments of psychiatry and behavioral neurosciences and pediatrics at McMaster University in Hamilton, Ontario.

The value of being familiar with these risk factors is that they may be partially modifiable. Finding the most effective drug or drugs with the fewest side effects is most important, but addressing parental anxiety is also important.

“Epilepsy does not occur in isolation. It affects the entire family. A family-centered approach to pediatric epilepsy is essential. Primary care providers are in a unique position to provide education and support services to families who have a child with epilepsy,” said Ferro.

Multidimensional Management

A brief, patient-reported outcome instrument, the Personal Impact of Epilepsy Scale (PIES), was introduced in 2014 in Epilepsy & Behavior and can help measure quality of life issues.

PIES is comprised of 25 open-ended questions addressing medication side effects, seizure characteristics, comorbidities, and quality of life, and can be used alongside  other screening tools, such as the Quality of Life in Epilepsy Scale and the Beck Depression Inventory.8

The Epilepsy Foundation ( and Canadian Epilepsy Alliance ( are both good sources of patient education and support.

Managing epilepsy well involves much more than controlling seizures. Balancing medication effectiveness with tolerability as well as screening for quality of life issues should be the standard of care.5

Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts.

This article was medically reviewed by Pat F. Bass III, MD, MS, MPH.


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