Effect of methylphenidate on the quality of life in children with epilepsy and attention deficit hyperactivity disorder:

ARTICLE

Auteur(s) : Hanik K Yoo¹, Subin Park¹, Hee-Ryung Wang¹, Joong Sun Lee¹, Kunwoo Kim¹, Kyoung-Won Paik², Mi Sun Yum³, Tae-Sung Ko³

¹Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center
²Department of Psychiatry, Hanyang University Medical Center
³Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

Article reçu le 22 Juin 2009, accepté le 22 Septembre 2009

Epilepsy is one of the most prevalent paediatric neurological disorders, with a prevalence of approximately 0.5-1% (Waaler et al., 2000). Children with seizure disorders have been found to suffer from more frequent and severe behavioural and emotional problems than healthy children (Carlton-Ford et al., 1995; Dunn et al., 2003). The causes of the psychiatric complications in epileptic children can include multiple complex etiologies such as organic lesions of the central nervous system, unexpected effects of antiepileptic drugs and negative psycho-social influences related to epilepsy (Domizio et al., 1993; Carlton-Ford et al., 1995). According to previous studies, the incidence of ADHD is higher in patients with epilepsy than in the general population (Carlton-Ford et al., 1995). One fifth to one third of patients with epilepsy have ADHD characteristics (Sanchez-Carpintero and Neville, 2003; Tan and Appleton, 2005) and over 60% of children with severe epilepsy satisfy criteria for ADHD (Sherman et al., 2007). In addition to seizure disorders, accompanying ADHD also reduces the quality of life (QOL) in children with epilepsy, indicating that ADHD symptoms have real-world adverse implications for epileptic children and their families (Sherman et al., 2007).

Although psychostimulants such as methylphenidate and amphetamine are commonly used in children with ADHD to reduce inattention and hyperactivity symptoms (Stein et al., 1996), methylphenidate has been prescribed reluctantly in children with ADHD and epilepsy, owing to its potential adverse effects which include lowering the seizure threshold (Tavakoli and Gleason, 2003). Feldman et al. (1989) reported that methylphenidate was effective in reducing ADHD symptoms in 10 children with ADHD and epilepsy without seizure recurrence. However, conflicting data were also reported for three of five children with ADHD and active seizures who experienced an increased seizure frequency during methylphenidate medication (Gross-Tsur et al., 1997). In a recent study with 57 children and adolescents with ADHD and active seizures, methylphenidate was effective in reducing ADHD symptoms without changing seizure frequency from baseline (Gucuyener et al., 2003). In addition, two studies have reported a low risk of seizure attacks during methylphenidate treatment in adults with ADHD plus epilepsy (Moore et al., 2002; van der Feltz-Cornelis and Aldenkamp, 2006). Moreover, Moore et al. (2002) suggested that, without reducing the seizure threshold, methylphenidate relieved sedation and improved the QOL of adults with epilepsy. However, low baseline seizure frequencies, small numbers of samples and short observation periods limit the power of these studies to detect the effect of methylphenidate to increases in seizure frequency.

Osmotic-controlled release oral delivery system (OROS) methylphenidate has been used widely based on advantages regarding drug adherence and unique pharmacokinetic properties which are used to control the release rate and action for a duration of 12 hours (Chavez et al., 2009), however, there have been no clinical studies examining whether OROS methylphenidate can improve the QOL of children with epilepsy and ADHD.

We therefore investigated whether OROS methylphenidate could be tolerated and effective in improving the QOL as well as ADHD symptoms of this population. We also tried to identify demographic-, seizure-, and ADHD-related variables that affect the change of QOL in this group with an 8-week open trial of OROS methylphenidate.

Materials and methods

Subjects

The seizure type of each child with epilepsy was diagnosed by a paediatric neurologist and classified according to the International League Against Epilepsy criteria (ILAE, 1989), based on clinical descriptions and electroencephalogram (EEG) results. All subjects had been seizure-free for more than three months on a stable antiepileptic drug regimen. This was ascertained from medical records, which noted seizure frequency at each clinic visit during three months prior to enrolment, as well as parents’ reports. Antiepileptic drugs taken by subjects were reviewed by a child psychiatrist to judge whether ADHD symptoms could be improved by changing antiepileptic drug regimen. Only subjects who were not amenable to changing their antiepileptic drugs or for whom this was deemed unnecessary were included. Children with central nervous system lesions, other severe medical conditions or previous exposure or known allergy to methylphenidate were excluded from the study.
Table 1 Descriptive data and medication information for 25 youths with ADHD and seizure disorders.

Procedure

Measurement of quality of life and ADHD symptoms

The Korean version of the ADHD Rating Scale (ARS) (DuPaul et al., 1998), which is a semi-structured clinical interview, the Clinical Global Impression-Improvement scale (CGI-I) (Conners and Barkley, 1985) and the CGI-Severity of Illness scale (CGI-S) (Guy, 1976) were used to measure the secondary endpoints. The ARS was developed to assess the severity of ADHD symptoms and gives three summary scores: inattentive, hyperactive/impulsive and total scores. The ARS was used at baseline and endpoint. The CGI-I consists of seven scores indicating the level of improvement (where 1 = much improved and 7 = much worse). The CGI-S also consists of seven scores indicating the level of symptoms (where 1 = normal and 7 = severely ill). The CGI scores were measured at every visit.

Adverse effects of OROS methylphenidate were assessed using an adverse effect checklist that recorded side effects of OROS methylphenidate including increase in seizure frequency or tics and general health issues. Each patient’s height and weight were also measured at every visit. Physical and neurological examinations, laboratory tests, and ECGs were completed at the end of the study.

Statistical analyses

Results

After eight weeks of OROS methylphenidate treatment, the scores of subscales of the QOLCE such as physical restriction (p = 0.005), self-esteem (p = 0.002), memory (p < 0.001), language (p = 0.005), other cognition (p < 0.001), social interaction (p = 0.002), behaviour (p < 0.001), general health (p = 0.002) and QOL (p < 0.001) were significantly increased (table 2). The total inattentive (p < 0.001) and hyperactive/impulsive scores (p < 0.001) in the ARS were significantly reduced by 41.5%, 42.4% and 41.1%, respectively. The CGI-I scores showed that 16 subjects (64.0%) had improvements rated as “much” or ”very much” improved. In addition, the CGI-S score was lowered by medication with time (p < 0.001) (table 2, figure 1).

There were no significant associations between the QOLCE scores and various demographic and seizure-related characteristics. Change of the CGI-S scores was negatively correlated with changes in self-esteem (r = 0.57, p = 0.003) (figure 2A) and social activity scores (r = 0.53, p = 0.007) from baseline to study end (figure 2B). Changes in the ARS scores were not significantly correlated with changes in the total and subscale scores in the QOLCE after treatment.

Two patients (8.0%) did not complete the study protocol owing to intolerable adverse effects such as anorexia and insomnia. Fifteen subjects (60.0%) experienced adverse events. The most common side effects were anorexia (32.0%; n = 8) and insomnia (table 3). For two subjects that did have seizures during the study, their seizure-free periods prior to study enrolment were 11 months and 20 months, respectively. Both subjects had seizures at about six weeks after taking OROS-methylphenidate, within two weeks after increasing the dose (from 18 mg to 36 mg and from 18 mg to 27 mg, respectively). There were no significant changes in body weight, height, laboratory test results or ECG findings.
Table 2 Effectiveness of OROS methylphenidate in 25 youths with ADHD and seizure disorders.

Discussion

There were insignificant reductions in negative emotions such as depression and anxiety with stimulant treatment in this study (table 2). Exclusion criteria on the observed pattern of mood or anxiety disorders might limit the effects of methylphenidate on emotional function. In general, mood symptoms such as depression and anxiety are common in patients with seizure disorders (Ettinger et al., 1998; Dunn et al., 1999; Alwash et al., 2000), so further study involving the broader population of patients with mood or anxiety disorders is required to identify the effect of methylphenidate on mood or anxiety symptoms. Self-esteem of youths with epilepsy and ADHD increased with medication and was not quantified as just simple mood status but an overall complex perspective of the individual, composed of the individual’s own preference, acceptance and respect. Although a stimulant cannot influence a mood status, other functions such as cognitive, social and behavioural functions that affect the self-esteem of patients may be altered (table 2); in this study a negative correlation between self-esteem and ADHD severity was observed (figure 2B).

Compared with emotional aspects, the cognitive and social functions of youths with epilepsy and ADHD were enhanced after eight weeks of OROS methylphenidate (table 2). Previous studies, in which psychostimulants had improved not only inattentiveness but also various kinds of cognitive functions such as memory (O’Toole et al., 1997; Bedard et al., 2004), execution (Konrad et al., 2005; Fallu et al., 2006), reaction time (Krusch et al., 1996) and language (McInnes et al., 2007) in patients with ADHD, were in line with our results. The dopamine system, which has effects over the whole brain, may be strengthened by methylphenidate and enhance cognitive functions (Mehta and Riedel, 2006). However our results are insufficient to provide strong evidence which can support the improvement of cognition by OROS methylphenidate in epileptics with ADHD because the QOLCE are determined by subjective parental responses, not by objective measures of cognitive function.

The social dysfunctions of youths with epilepsy and ADHD were improved by OROS methylphenidate (table 2). Epilepsy itself can affect the social competence of patients (Sturniolo and Galletti, 1994; Caplan and Austin, 2000) and comorbid ADHD symptoms could also reduce social activities and interaction (Shelton et al., 1998; Bagwell et al., 2001). ADHD symptoms could be more problematic because they are more apparent (Sonuga-Barke et al., 1994; Gresham et al., 1998) than seizure-related social problems, which are mainly introverted and make the patient appear withdrawn (Kim, 1991; Carlton-Ford et al., 1995). Thus, stimulant medication may enhance the social ability of the patient (figure 2B).

Behaviour related to the QOL of youths with epilepsy and ADHD were also altered by stimulant treatment. Several items in the behavioural subscale of the QOLCE overlapped with the clinical features of ADHD, such as hyperactivity, impulsivity and aggressiveness. Therefore improvement of ADHD symptoms by methylphenidate might affect the improvement of behavioural subscale. However, these relationships may be more complex because behavioural subscale also included variable items such as attention-seeking, phobic behaviour and independence, and there was no significant correlation between scores of the ARS and behavioural subscale of the QOLCE.

Every clinical measure including symptom severity and clinical global function level was significantly reduced after 8-week treatment. Even though OROS methylphenidate improved both ADHD symptoms and QOL, there were no significant correlations between them because QOL measure involves complex components beyond just ADHD symptoms (Jacoby, 1992; Sabaz et al., 2000). For instance, improvement of ADHD symptoms by stimulants can have a positive effect on QOL, while side effects of stimulants can reduce QOL (Trimble and Cull, 1988). Therefore, global function changes, rather than symptom changes, showed correlations with changes in some QOL domains (figure 2A, B). Our results suggest that OROS methylphenidate may improve the QOL of children and adolescents with epilepsy and ADHD which is independent of ADHD symptom changes. For instance, OROS methylphenidate may improve social and cognitive function by reducing sedation by antiepileptic drugs (Moore et al., 2002).

In this study, short-term treatment with OROS methylphenidate seemed to be generally tolerated in children and adolescents with ADHD and seizure disorders. Sixty percent of subjects had adverse effects, but most adverse events were tolerable and only 8% of subjects discontinued medication owing to intolerable side effects. Although two patients experienced seizure episodes during stimulant treatment, and this proportion is somewhat higher than previous reports (Feldman et al., 1989; Gross-Tsur et al., 1997; Gucuyener et al., 2003; van der Feltz-Cornelis and Aldenkamp, 2006), no patients who experienced a seizure discontinued the study drug. In such cases, a child neurologist judged these episodes as very mild and non-problematic and both patients and their parents agreed.

Limitations of this study included small sample numbers with three-month, seizure-free periods and short observation periods. An open-label design without a control group was also a limitation. To confirm our results, double-blind, controlled studies should be conducted. In addition, our subjects included a substantial proportion of intellectually disabled children and IQ could be one of the factors affecting a child’s response to methylphenidate. Future studies with more detailed seizure-related information and larger sample sizes will be able to identify the factors that affect the behavioural outcome of ADHD treatment in youths with ADHD and epilepsy.

Despite these limitations, the results of this pilot study suggest that OROS methylphenidate may be tolerated and effectively reduce ADHD symptoms and improve QOL in this patient population. Therefore, OROS methylphenidate could be considered as a therapeutic option when managing children and adolescents with ADHD and epilepsy.

Disclosure

None of the authors has any conflict of interest to disclose.

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