Methylphenidate: Effect on Cognition in Epilepsy

Immediate release methylphenidate (MPH) may help improve cognitive problems associated with epilepsy without increasing seizure risk, according to a study published online in Neurology.

 “MPH improved scores on objective cognitive measures in this single-dose study and may be a safe and effective treatment for cognitive difficulties experienced by adult patients with epilepsy,” wrote first author Jesse Adams, MD, of Stanford University (Stanford, CA), and colleagues.

Patients with epilepsy often describe problems with attention, memory, and mental processing speed, and stimulants have been proposed as one way to improve cognitive issues in epilepsy. However, the medication packaging lists increased risk for seizures in those with a past history of seizures, raising concerns about its use in epilepsy. 

Yet evidence of increased seizure risk with MPH use in epilepsy is sparse and comes from animal studies, case reports, and seizures linked to MPH-overdose, according to the authors. However, studies in children and adults have found that MPH is not linked to a clinically significant increase in seizure risk.  Admittedly, such studies have suffered from small numbers and methodological issues, such as lack of blinding.

The new study used a double-blind, randomized design to evaluate how a single dose of immediate release MPH affects cognitive function and seizure risk in adults. Researchers randomized participants with epilepsy and chronic cognitive symptom to MPH 10 mg, MPH 20 mg, or placebo. Patients received the medication in a randomized order at three separate clinic visits, separated by one week, at Stanford University. They switched groups at each visit, so that each patient received each dose of MPH as well as placebo by the end of the study.

At clinic visits, patients received a double blinded capsule, waited one hour, and then completed cognitive tests, after which they reported side effects of the medication. Researchers assessed cognitive outcome using the Connors Continuous Performance Test 3 (which measures attention-related issues), the Symbol Digit modalities test (which measures mental processing speed) and the Medical College of Georgia Paragraph Memory Test (which measures immediate verbal recall).

The analysis included 31 patients, with a mean age of 35.3 years and a baseline seizure frequency of 2.8 per month. Most patients had focal epilepsy (n=24), with a mean epilepsy duration of 12.5 years.

The study controlled for the effects on cognition of caffeine, nicotine, and other medication, as well as the effect of food on absorption of MPH.

Key Results:

• Cognitive function combined outcome: significantly improved with MPH 10 mg vs placebo (P=0.030) and MPH 20 mg vs placebo (P=0.034)

• Processing speed: significantly improved for both doses of MPH vs placebo (P=0.008)

• Attention: significantly improved for both doses of MPH (P=0.037)

• Verbal Recall: no significant difference for MPH vs placebo (P=0.154)

• Placebo was worse than both MPH doses for all measures of cognitive function

• No seizures or change in seizure frequency linked to MPH use

The authors noted that these results are similar to those from single dose studies in children with ADHD, adults with multiple sclerosis, and adults with traumatic brain injury. Results are also similar to studies in children and adults with ADHD and epilepsy, which have suggested that MPH improves ADHD without increasing the risk of seizures.

They pointed out several limitations, including small sample size, though this study was larger than past studies. Also, the results may not generalize to long-term clinical dosing schedules, and improvement on cognitive tests may not necessarily translate to clinical improvement. Finally, other patient groups, like those with traumatic brain injury or stroke, may show a different response to MPH.

An open-label follow-up study is underway, which may address some of these limitations.

“Additional double-blind, placebo-controlled, long-term trials using standard clinical dosing and standardized cognitive measures are needed,” the authors concluded.

Take-home Points

• Small double-blind, randomized, crossover study at Stanford University found that immediate release methylphenidate 10 mg and 20 mg improved cognitive symptoms in adults with epilepsy, without increasing seizures.

• Longer trials and larger, more diverse patient groups are needed.

Reference: Adams J, et al. Methylphenidate, cognition, and epilepsy: a double-blind, placebo-controlled, single-dose study. Neurology. 2016 Dec 28.