Psychosocial outcomes are considered to be increasingly important in epilepsy.[1, 2] Around 60% of patients have behavioural problems, often even more disabling than the seizures. However, in only a minority of patients are behavioural problems identified and treated, further limiting integration in society. Structural and electrical abnormalities probably interact with adverse social and genetic factors, particularly in patients with more severe epilepsies, increasing the risk of comorbid psychiatric disorders.
Attention-deficit–hyperactivity disorder (ADHD) is one of the most common psychiatric comorbidities in children with epilepsy, affecting 12% of patients. Greater prevalence of ADHD comorbidity is particularly present in patients with refractory seizures, who are commonly treated in tertiary epilepsy centers.[6, 7] Treating ADHD in children with epilepsy may be difficult because of the long-held view that stimulants decrease the seizure threshold. Although this perspective received some support from a study showing an increased risk of seizures with high doses of osmotic-controlled release oral delivery system (OROS) methylphenidate, it has been challenged by many other studies using lower doses, suggesting that methylphenidate is both safe and effective in patients with epilepsy[10-12] (see Table SI, online supporting information). However, these studies usually included patients with well-controlled seizures. Only one open-label study has shown the safety and efficacy of pharmacological treatment of ADHD symptoms in children with uncontrolled epilepsy. Studying the risk of worsening seizures or improvement of ADHD symptoms with stimulants in children with difficult-to-control or refractory seizures is important, as these patients have the highest risk of comorbid ADHD. Because this clinical profile is often seen in the epilepsy clinic, the aim of this study was to investigate whether methylphenidate is safe and effective to treat ADHD in children and adolescents with difficult-to-control or refractory seizures. We also assessed seizure frequency and severity before and after methylphenidate in this population.
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It is clinically relevant to treat ADHD in children and adolescents with difficult-to-treat epilepsy, because behavioural and cognitive problems worsen health-related quality of life. However, from a clinical point of view, there is some resistance to using psychotropic drugs in patients whose seizures are not under control, and the common view that methylphenidate may decrease the seizure threshold creates a particularly important clinical dilemma.
The aim of this pilot study was to test whether a low dosage of methylphenidate could be used safely in children and adolescents with epilepsy at higher risk of seizures, i.e. those with difficult-to-treat or refractory seizures. We showed that methylphenidate with dosages averaging 0.35mg/kg/day and reaching 0.8mg/kg/day did not lead to loss of seizure control in most patients with difficult-to-control seizures, nor did it lead to worsening in those with refractory seizures. The only patient who had a clinically significant increase in seizure frequency did not have a worsening in severity. Three others had seizure recurrence after full control with AEDs, but with low frequency, comparable to that before enrolment in the study. None of the others had any worsening of seizures.
Furthermore, we showed that methylphenidate was well tolerated. Side effects, occurring in 60% of patients, were primarily limited to reduced appetite. Although the discontinuation rate of 18% is higher than the 4–8% in clinical trials using full dosages, it is lower than in community samples, which reached 33% in 3 months. Severe side effects leading to discontinuation were uncommon, occurred early, and were independent of dosage, suggesting individual susceptibility. As we found no association between IQ and therapeutic response, the results are independent of the presence or severity of cognitive disability. Notwithstanding the limitation of a small sample and thus the possibility of a type II error, the latter confirms previous findings in patients with ADHD and intellectual disability.
We chose a slow methylphenydate titration rate because there were no previous data on the use of this medication for patients with ADHD with active, difficult-to-treat epilepsies. Thus, we did not know whether slow increases in dosage were important in this context.
We found no evidence that AED adjustments alone improved ADHD symptoms. This was not unexpected, because all adjustments involved an increase in AED dosages that could, theoretically, worsen inattention. The need to adjust and often increase AED dosages is an integral part of the management of patients with difficult-to-treat epilepsies. We did not measure AED serum levels or count pills between visits. However, all patients had AED levels monitored over the years at the clinic and the dosages used had been previously shown to be within therapeutic levels. Adherence was indirectly confirmed by the improvement in seizure frequency and severity during the first 3 months of the study. It remains unclear whether such improvement in seizure frequency and severity was accompanied by changes in EEG. Available data do not support the use of EEG as predictors of seizure occurrence with methylphenidate in patients with epilepsy. Thus, we decided not to base any decision upon EEG.
Because mean effective methylphenidate dosages were lower than those commonly used and recommended in practice (the MTA Cooperative Group), i.e. 0.35mg/kg/day, the favorable impact upon ADHD symptoms is somewhat intriguing but may be related to the cognitive impairment seen in many of our patients. In this specific population, dosages between 0.3 and 0.6mg/kg/day have been found effective. Thus, it is possible that lower dosages of methylphenidate are required in patients with severe epilepsies or more diffuse neurological dysfunction, for putative pharmacodynamic mechanisms involving cathecolaminergic systems. Another possibility we entertained for these findings was that serum levels of methylphenidate were increased by concomitant use of valproate. Because both drugs share a common cytochrome P450 metabolic pathway, valproate may inhibit methylphenidate metabolism. This hypothesis, however, was not supported by the comparison of the level of improvement in the 12 patients who were using and the 10 who were not using valproate concomitant with methylphenidate. Therefore, the pharmacodynamics of low dosages of methylphenidate should be tested in future studies.
Though preliminary, it is of interest that a low dosage of methylphenidate was not only associated with a low risk of worsening seizures but, in fact, had a positive therapeutic impact in seizure severity. The level of vigilance in patients with severe epilepsies may be adversely affected by epileptic discharges, AED polytherapy, and sleep inefficiency. In the past, methylphenidate was used to improve vigilance in patients with epilepsy, because it modulates catecholaminergic tonus through an increase in synaptic dopamine and stimulation of noradrenergic receptors. Improvement in seizure frequency and severity with methylphenidate may thus relate to heightened vigilance.
Because the present study involves an open label, non-controlled trial in which outcome measures postintervention had very large standard deviations, we cannot rule out additional factors affecting our findings. For instance, a placebo effect on rating scales cannot be excluded, as ratings for ADHD symptoms, seizure frequency, and severity were completed by individuals who knew the intent and design of the study. Moreover, it could be argued that seizure frequency and severity in patients with difficult-to-treat or refractory epilepsies may have led to better compliance with AED treatment schedules and, as a corollary, better seizure control. We cannot also disregard the possibility that seizure control or ADHD symptoms would have improved with AED adjustments alone, or that better seizure control could have had an independent impact on ADHD symptoms. The latter is unlikely, however, because these patients had been followed at the clinic for several years with irregular and difficult seizure control and significant behavioural abnormalities, irrespective of repeated AED adjustments. Furthermore, parent-rated CBCL scores could be seen as confirming the behavioural results. This notwithstanding, the importance of this issue for the daily management and quality of life of these children dictates that the data presented here should be viewed with caution and considered as preliminary findings.
Despite the study limitations, results suggest that a low dose of methylphenidate can be safely used in children and adolescents with ADHD and difficult-to-treat epilepsies. It is noteworthy that the rate of improvement in ADHD symptoms observed in the present study is very similar to the improvement rate observed in a recent study in a sample of children and adolescents with uncontrolled epilepsy (73 vs 70.8%). Interestingly, a comparison between the patients in the two studies suggests that our sample had a more severe form of epilepsy. Hence, the present study extends the previous findings to a more difficult-to-treat sample and shows that methylphenidate may also have a beneficial effect on seizure severity and frequency.
The findings presented here highlight the need to investigate further the efficacy and safety of low to medium doses of methylphenidate in children and adolescents with ADHD and difficult-to-treat or refractory seizures. That dosage may be an issue has been suggested by a study showing an increase in seizure risk with high doses of methylphenidate. Randomized, placebo-controlled, double-blind trials in longitudinally followed samples and studies focusing on the interactions between methylphenidate and AEDs with variable pharmacokinetic profiles should prove useful.
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We are indebted for help in framing and conducting this study, as well as for suggestions on the final form of this manuscript, to our colleagues from the ADHD Program (PRODAH), Hospital de Clinicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, particularly Luis Augusto Rohde, Cristian Zeni, and Breno Matte. We also thank Guilherme Polanczyk, from the Universidade de São Paulo, for advice. Ceres Oliveira, a consultant in statistics, performed the statistical analyses. Andre Palmini received support from, and has served as a paid consultant and speaker for, Novartis, Abbott Laboratories, and Janssen-Cilag. Linda Booij was supported by a career award from the Fonds de Recherche du Québec-Santé. This study was self-funded and performed in the context of the Graduate Courses in Health Sciences of Pontifícia Universidade Católica do Rio Grande do Sul as part of Dr Santos's master's degree.