9 Apr 2020

Toxic effects of anti-epileptic drugs 'overstated'

Dr Emma Foster is a neurologist and

PhD student working on epilepsy
by Anne Crawford

Anti-epileptic drugs (AEDs) have frequently been linked to cognitive impairment such as difficulties in concentrating, learning, understanding and remembering, which can be more disabling to the patients taking them than the seizures for which they are prescribed.\

But studies looking into this in the past haven’t always taken into account other factors affecting the patient that may also affect cognition such as advanced age, increased frequency of seizures and mood disorders such as depression, said Central Clinical School (CCS) PhD student Emma Foster.

Dr Foster, a neurologist, is joint first author with fellow Department of Neuroscience researcher Dr Charles Malpas on a study published recently in Neurology that aimed to tease out the extent to which AEDs affected cognitive impairment from the tangle of other factors.

“Anti-epileptic drugs are certainly a risk factor that people have concentrated on because it’s modifiable, unlike factors such as age,” Dr Foster said. “It’s got a lot of attention in research.”

Caution about the potential effects of some AEDs on cognition has prompted clinicians to avoid prescribing certain medications in favour of others that are perceived to be better for cognition but which are actually less beneficial for seizure control, she said. Or they might not increase the medication to a dose level sufficient to control seizures.

The CCS researchers hypothesised that although AEDs may contribute to adverse cognitive effects in some patients, that their effect overall was overstated.

“Clinical experience would suggest that in complex epilepsy cases the influence of antiepileptic drugs on cognitive impairment is smaller than we might think,” Dr Foster said.

Dr Foster and Dr Malpas designed a study which, instead of controlling for other confounding factors, looked at a spectrum of complex patients with multiple other contributory factors such as differing ages and disease states.

“We wanted to have a real-life study cohort because the reality is that in clinics and hospitals you don’t get patients who are well controlled for everything except anti-epileptic drugs,” she said.

The study enrolled 331 patients admitted to The Royal Melbourne Hospital’s VEM (video-EEG monitoring) unit between January 2009 and December 2016. The patients had a variety of diagnoses including epilepsy (47.1%) and PNES or psychogenic nonepileptic seizures (25.7%). PNES are often misdiagnosed as epileptic seizures but are psychological – emotional or stress-related – in nature.

The participants were taking 12 drugs broadly representative of what are commonly used in clinics. They were given a subjective cognitive function test in which they self-reported any self-perceived cognitive impairment, and an objective cognitive function screening test. Their seizure frequency was monitored.

“When we analysed each of these drugs we didn’t find any association with the drugs with either the objective or subjective cognitive impairment that were significantly above or beyond any other variable,” Dr Foster said.

The clinical variables that were the best predictors of objective cognitive function were age and seizure frequency, and for subjective cognitive function, depressive symptoms. These should be the focus of management strategies to optimise cognitive function and control symptoms, the study recommends.

“This is an important study because the findings challenge the sometime dogmatic view that anti-seizure medications are necessarily ’toxic’,” senior author Professor Patrick Kwan said. “It also shows the value of 'real world' studies by providing the relevant clinical context that randomised controlled trials are unable to afford.”

The study notes that the findings may be reassuring to clinicians and patients, and may lessen concerns regarding effects of AEDs on cognitive function and promote appropriate dosing of AEDs for optimal seizure control.

Dr Foster cautioned, however, that while the real-life aspect of the study design was a strength, it did not show causation.

A neurological consultant at The Alfred in the final year of her PhD, she conducted the study as the sixth of 12 papers.

Professor Kwan has received grants and personal fees from pharmaceutical companies. This funding is unrelated to this study.

Foster E, Malpas CB, Ye K, Johnstone B, Carney PW, Velakoulis D, O'Brien TJ, Kwan P. Antiepileptic drugs are not independently associated with cognitive dysfunction. Neurology. 2020 Feb 3. pii: 10.1212/WNL.0000000000009061. doi: 10.1212/WNL.0000000000009061. [Epub ahead of print]

See also http://ccsmonash.blogspot.com/2019/02/studies-point-to-need-for-better.html#more

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