Abstract
Methylphenidate, Cognition, and Epilepsy: A Double-Blind, Placebo-Controlled, Single-Dose Study
Adams J, Alipio-Jocson V, Inoyama K, Bartlett V, Sandhu S, Oso J, Barry JJ, Loring DW, Meador K. Neurology 2017;88:470–476.
OBJECTIVE: To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy. METHODS: This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d′] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere. RESULTS: Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20–62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive “fogginess” (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect. CONCLUSIONS: This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required. ClinicalTrials.gov identifier: NCT02178995. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints.
Commentary
Cognitive dysfunction in patients with epilepsy is common; it starts early (1) and persists through the patient's lifetime (2). Previous studies have identified distinct—though likely overlapping—domains of cognitive impairment in patients with epilepsy (3, 4): memory impairments in 24 to 47 percent, attention/executive/speed dysfunction in 29 to 49 percent, and no impairment in only 29 to 47 percent. The etiology is likely multifactorial, with contribution from comorbid psychiatric disorders, medications and surgery, sleep disturbance, and particularly seizures themselves. This phenomenon has been well recognized, and although various strategies have been articulated to minimize its effects (5), specific treatments are lacking.
The purpose of the current study by Adams et al. is to determine whether methylphenidate (MPH) improves cognitive performance in adults with epilepsy. It is a conceptually simple double-blind crossover study in which patients were given a single dose of placebo, MPH 10 mg, or MPH 20 mg in random order over the course of three visits occurring 1 week apart. The study included adult patients between the ages 18 and 65 with epilepsy of any cause who had cognitive complaints. Patients with obvious confounders, such as recent neurosurgical procedure, comorbid conditions or medication use that can cause cognitive dysfunction, or contraindication to MPH were excluded. The patients were asked not to take any sedating medications 24 hours prior to the study and were asked to avoid caffeine, nicotine, or food 2 hours prior to the examination.
Outcome was assessed by three tests that are relatively standard measures of attention and processing speed. The Symbol Digit Modalities Test (SDMT) involves a simple substitution task in which the patient pairs specific numbers with geometric shapes using a reference table; this is a reliable measure of processing speed. During the Medical College of Georgia Paragraph Memory Test (MCG), patients are read a story of ~300 words after which immediate free recall is scored, thus a test of immediate verbal recall. The Conners Continuous Performance Test 3rd edition (CPT) consists of a 14-minute, 360-item trial during which patients are asked to push the spacebar on a keyboard when any letter except “X” appears. Various measures from this procedure test for inattentiveness and impulsivity. From these tests, the following measures were obtained: the SDMT total correct score, the MCG total score, the CPT d′ (ability to discriminate between target and nontarget stimuli), and the hit reaction time standard deviation. To avoid multiple comparisons testing, all scores were converted to a z-score and then combined into a single score that served as the primary outcome measure. Effect of the intervention on seizures was determined by obtaining a 28-day baseline seizure frequency calendar prior to the study, obtaining a weekly seizure calendar that was extrapolated to 28 patient-days, and observing for seizures temporally proximal to the study drug administration.
The number of patients was modest: Thirty-one patients completed the study. Statistically, benefit was seen at both 10 and 20 mg as per primary outcome measure. In terms of safety and tolerability, there was no change in seizure frequency, nor were there any seizures that were thought to be directly provoked by MPH. One patient had tachycardia sufficient to withdraw from the study at an initially planned dose of 40mg, leading to the smaller doses for the other subjects. In clinical settings, a slower titration would be recommended.
This is a well-designed and executed study that achieved its stated goal of improving cognitive performance in patients with epilepsy. Given the nature of the intervention and measured goals, it would have been extremely surprising if MPH was found not to have the desired effect. As the authors note, MPH has been shown to be effective in improving attention and processing speed across a wide variety of neurological and psychiatric disorders. There is likely cognitive benefit even in healthy control subjects (6).
Several questions need to be addressed:
Are the Benefits Meaningfully Large?
The authors present the nontransformed individual scores for the various individual tests and curiously present the less meaningful mean scores. On initial examination, an increase in the mean SDMT score from 49.8 (placebo) to 52.2 (10 mg of MPH) or 50.6 (20 mg) may not appear particularly impressive, but this likely underscores the variability of these measures across subjects. A percent improvement measure would have been more informative. They did perform an analysis of effect size, which demonstrated that for most submeasures, the effect size statistically was generally moderate to robust. My guess is that the effects are likely clinically meaningful.
Is this Better than a Large Cup of Coffee?
The authors specifically had asked patients to avoid caffeine prior to taking this test. It is almost a certainty that a substantial portion of these patients do drink coffee, possibly to self-medicate. Previous studies have shown that caffeine does have effects—though not as potent as MPH—on ADHD symptoms (7, 8). Caffeine, however, is inexpensive, socially acceptable, well tolerated, likely safe from a seizure perspective, at least has the perception of being relatively devoid of abuse potential, is widely available without insurance authorization, and (as coffee) is almost certainly a more enjoyable experience. Although allowing coffee drinking would have been informative, this may have caused some confounding and created difficulties in obtaining the answer to the study hypothesis posed by the authors. In practice, though, it remains uncertain whether there is any cognitive benefit in coffee drinkers, though some studies suggest a combination of MPH and low dose caffeine may be effective (8). On the other hand, though it may be tempting to combine caffeine with MPH, stimulants have an inverted U-shaped dose response curve, and thus may be detrimental at higher doses (9).
To the authors’ credit, none of their cited references of MPH in other neurological conditions, nor any of the numerous studies that I sampled in the literature, even addressed this rather obvious point. It is likely that most studies asked patients to continue their usual regimen. The question remains unanswered, but it remains a possibility that MPH could be beneficial even with coffee intake, though side effects may become amplified as well.
Is Administration of MPH Safe?
Does this satisfactorily address the other major question as to the safety of MPH use in these patients? Although weekly single dosing certainly appears to be safe, the authors admit that this study cannot be extrapolated to continuous daily use. As such, this study should not be used to make determination regarding the safety of long-term continuous use of MPH. Inevitably, in a certain number of patients, there will be increased seizures, as one would expect whenever there is a change in psychoactive medication regimen. One may particularly be concerned as to whether sleep disruption may increase seizures. In the optimal scenario, a well-reasoned individualized risk–benefit analysis would allow for judicious use of stimulants in certain symptomatic patients.
Will Administration of MPH Improve Patient Care in a Clinically Relevant Way?
It is difficult to conclude that the study would have broad clinical impact due to its single dose administration design. An omission from this study is the lack of any measurement of fatigue or excessive daytime sleepiness. Fatigue is one of the strongest predictors of quality of life in patients with epilepsy (10). Excessive daytime sleepiness is a closely related but separate disorder and a frequent problematic complaint in patients with epilepsy. MPH has long been used as wakefulness promoting agent, and an effect (however transient) may have been seen in this population. However, currently used scales to measure fatigue and excessive daytime sleepiness would be more applicable with chronic administration of MPH.
This study also does not attempt to address the other main domain of cognitive dysfunction, namely, memory issues. It is unclear how much benefit a mere increase in attention will benefit memory, but one can perhaps hope for some effect. Subject performance in the Medical College of Georgia Paragraph Memory test in this study did not show a benefit. Attempts to improve memory function generally have been far more difficult than addressing attention and processing speed. To date, there are no agents that enhance memory in patients with epilepsy (11). This gap thus remains a challenge to the epilepsy community.