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Three Part Question

In [a child with epilepsy and ADHD] does [methylphenidate (MPH)compared with placebo or no MPH] increase [the number of seizures]?

Clinical Scenario

A 10-year-old boy with well controlled epilepsy on sodium valproate attends your clinic. On a previous clinic visit his mother complained that he was hyperactive, impulsive and could not concentrate. This was affecting his school work. You sent Conners' Questionnaires to his parents and the school, and asked the attention deficit hyperactivity disorder (ADHD) nurse to observe him in school. The results of these investigations are strongly suggestive of a diagnosis of ADHD. You would like to treat him with methylphenidate (MPH) because you know this works well in other children. However, you remember reading some National Institute for Health and Clinical Excellence (NICE) guidance that suggests caution when treating children with epilepsy with psychostimulants. What should you do?

Search Strategy

A search of the Cochrane database yielded no relevant trials/reviews. The Ovid Medline and EMBASE databases were also searched. MeSH words used were: ‘Methyphenidate’, ‘Epilepsy’, ‘Attention deficit disorder’. Keywords used were: ‘ADHD, attention deficit, attention deficit disorder’, ‘Epilepsy, seizure, fit’ and ‘Methylphenidate, Ritalin’. Limits were: English language and human.

Search Outcome

The Medline search revealed 13 results, of which three were potentially relevant. The EMBASE search revealed 34 results, of which six were potentially relevant. The remaining papers that were not relevant were mainly on the risk of seizures in children with ADHD who did not have epilepsy, or who had EEG abnormalities without seizures. Analysis of the reference lists of two articles revealed a further paper.

The three high quality relevant studies are summarised

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Feldman et al, 1989	10 children with well controlled epilepsy and ADHD	Randomised double-blind medication–placebo crossover controlled trial (level 1b)	Seizure frequency	MPH administered on school days at 0.6 mg/kg/day. No significant effect on seizures (0% increase in seizure frequency – no child had a seizure)	Small numbers studied Only 4 weeks of observation Old study
Gross-Tsur et al, 1997	30 children with epilepsy and ADHD (5 poorly controlled)	Case series (level 4)	Seizure frequency	MPH 0.3 mg/kg/day administered. 25 children with well controlled epilepsy – no seizure increase with MPH 5 children with an average of 1.8 seizures/week before MPH, 3 seizures/week on MPH. Change in seizure frequency NOT significant. Estimated proportion of children who had a change in seizure frequency was 0.03 (CI 0 to 0.12)	Compared MPH to plabebo using continuous performance test in a single day randomised double-blind study – showed MPH improved concentration. Other outcomes: EEG changes (no change), changes in AED levels (no change), ADHD symptoms (improved by 70%)
Gucuyener et al, 2003	119 children with ADHD, 57 with epilepsy	Case series (level 4)	Seizure frequency	MPH 0.3–1 mg/kg/day on school days, titrated to response. Seizure frequency before MPH: 12.9±7.1 or 8.2±3.9 per week, with MPH: 8.1±3.3 per week. No significant effect on seizures (p=0.062)	Method for establishing seizure frequency before MPH not described Discrepancy in rate of seizures before MPH in text/table not explained

Comment(s)

ADHD is common in children with epilepsy (up to approximately 40% prevalence in children with ADHD symptoms (Torres) compared with 3.6% prevalence in the paediatric population without epilepsy (Ford)). As with children without epilepsy, these symptoms can have a detrimental effect on a child's well-being (Schubert). For children with ADHD without epilepsy, medication (usually psychostimulants) is recommended by NICE and the Multimodal Treatment of ADHD Study (MTA Group), because treatment leadsto 70% improvement in ADHD symptoms (Torres). Despite the evidence of impairment from ADHD, clinicians have difficulty in deciding whether to treat children with a dual diagnosis of epilepsy and ADHD because of the lack of good randomised controlled trials of the safety of MPH in children with ADHD and epilepsy.

All three studies included showed an improvement in ADHD symptoms in the children with epilepsy. MPH did not cause a detectable increase in seizure frequency in these small studies, however limitations common to all three studies include the small number of subjects, low baseline seizure rate (so there is low power to detect increases in seizure frequency unless they are very large), short observation periods and behavioural interventions not studied alongside MPH treatment.

More studies with large numbers of patients having active seizures are required to determine clear confidence intervals onthe effect (or not) of MPH on seizures. These studies could be drug surveillance studies or ‘open label’ trials, which despite being open to biases in the detection of adverse events, may have a particularly important role, as clinician biases are unlikely to affect the rates of adverse reactions. It is also important to note that antiepileptic drugs (AEDs) can cause behavioural disturbances and doses or drug type may need to be adjusted.

Editor Comment

ADHD, attention deficit hyperactivity disorder; AED, antiepileptic drug; MPH, methylphenidate.

Clinical Bottom Line

There is no good evidence to suggest an increase in seizure frequency in a child with well controlled epilepsy and attention deficit hyperactivity disorder (ADHD) who is prescribed methylphenidate. (Grade C)

A child with epilepsy starting methylphenidate should be closely monitored for seizure frequency for the first few months. (Grade C)

It is important to treat a child's ADHD just as it is important to treat their epilepsy. (Grade C)

References

1. Torres AR, Whitney J, Gonzalez-Heydrich J. Attention-deficit/hyperactivity disorder in pediatric patients with epilepsy: review of pharmacological treatment. Epilepsy Behav 2008;12:217–33.
2. Ford T, Goodman R, Meltzer H. The British Child and Adolescent Mental Health Survey 1999: the prevalence of DSM-IV disorders. J Am Acad Child Adolesc Psychiatry 2003;42:1203–11.
3. Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 2005;32:1–10.
4. The MTA Cooperative Group. Moderators and Mediators of Treatment Response for Children With Attention-Deficit/ Hyperactivity Disorder. Arch Gen Psychiatry. 1999;56:1088-1096.
5. Feldman H, Crumrine P, Handen BL, et al. Methylphenidate in children with seizures and attention-deficit disorder. Am J Dis Child 1989;143:1081–6.
6. Gross-Tsur V, Manor O, van der Meere J, et al. Epilepsy and attention deficit hyperactivity disorder: is methylphenidate safe and effective? J Pediatr 1997;130:670–4.
7. Gucuyener K, Erdemoglu AK, Senol S, et al. Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities. J Child Neurol 2003;18:109–12.