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Three Part Question

In [a child age 6-18, with moderate ADHD and uncontrolled epilepsy] does [Methylphenidate compared with no methylphenidate] cause [increase in the seizures and/or improvement in the symptoms of ADHD].

Clinical Scenario

13 years old boy attends clinic with uncontrolled epilepsy-Idiopathic generalized epilepsy- on lamotrigine having failed to respond to sodium valproate in adequate dosages. Prior to onset of epilepsy from primary school he had sustained elements of hyperactivity and impulsivity which on observations and connors questionares were thought to be ADHD. These have escalated and now need treatment with stimulants in their own right. Question is whether stimulants are safe in the presence of especially uncontrolled epilepsy.

Search Strategy

Most of literature reviewed is Medline indexed articles with the use of MeSH words - Attention deficit disorder, Methylphenidate and epilepsy. The keywords-Ritalin, Epilepsy, fits, seizure, ADHD- were used with the age limits of 6-16.
No relevant trials were retrieved from Cochrane databases.
Total of 52 studies were retrieved and looked at. Only five were relevant as others looked at risk of seizures in children with \'controlled\' epilepsy or EEG abnormalities without fits.

Search Outcome

Only 5 papers which looked at children with uncontrolled seizures were included. Three of these relevant and good quality papers are relatively recent -Gucuyener et al(2003), Gonzalez-Heydrich et al(2004) and Koneski et al(2011) and are summarised here along with two old ones.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kivilcim Gucuyener, A Kemal Erdemoglu et al 2003 Turkey	119 Patients, age 6-16, out of which 57 with ADHD and active seizures and the rest with ADHD and EEG abnormalities	Case series designed to evaluate the efficacy and safety of methylphenidate in the management of patients with ADHD and active seizure disorder and patients with abnormalities on EEG without epilepsy.Of the 57 patients with epilepsy, 52 were receiving monotherapy and 5 were receiving polytherapy. Methylphenidate at a dose of 0.3-1.0mg/kg/day was administered to all patients and titrated to produce maximum benefits. Observatios made over a year.	EEG findings	Beneficial effect on EEG changes. EEGs improved noticeably in both groups(P=.01)Anti-epileptic activity was detected in 24.2% of patients with ADHD and EEG abnormalities and 35.1% of patients with ADHD and seizures group, decreasing to 12.9% and 19.3% respectively.	Limited power of study due to nature and design of study, heterogeniety of condition and variety of epilepsies. Improvement in EEG might well be a maturational change with change.
			Seizure frequency	No significan change in mean seizure frequency which was 8.2 pre-treatment and 8.1 post-treatment with stimulants.
Julio AS Koneski, Erasmo B Casella, Fabio Agrett, Maria gabriela Ferriera 2011 Brazil	24 patients, 7-16 years, who took Methylphenidate for 6 months and who had atleast two epileptic seizures in the previous 6 months	Case series	Seizure frequency	No increase in 22(91.6%) in the first six months after starting methylphenidate. Worsening occured in 2 patients(8.3%, p<.001)	Limitations are small sample size, variety of fits and anti-epileptic drugs used and lack of specificity of co-morbid groups
			ADHD symptoms based on MTA-SNAP-IV scores	Improvement in 70.8%(17) with no change in 20.8%(5) and worsening in 803%(2) cases.
Gonzalez-Heydrich J, Whitney J, waber D 2010 Boston, USA	33 children, 6-17 years, with ADHD and eplepsy, were administered OROS-MPH at a target dose of less than 1mg/kg/day for 11 patients, 1-1.5mg/kg/day for 13 and 1.5-2.0mg/kg/day for 9 patients. to assess the safety, efficacy and tolerability	Double blind placebo controlled crossover study design	Safety:Seizure recurrence	5 seizure events in OROS-MPH group and 3 in placebo group; risk higher with higher dose of drug.	small sample size, Too few seizures in active and placebo arms to confidently assess seizure risk
Wroblewski BA, Leary JM, Phelan AM 1992 USA	30 with active seizures following traumatic brain injury on MPH for ADHD	Retrospective	Seizure frequency	No increase in 26 patients	Small sample size with a short follow-up of 3 months
Gross-Tsur V 1997 Israel	30 children, 6.4-16.4 years age, with epilepsy and ADHD(25 children with controlled seizures and 5 with uncontrolled seizures) were studied over 4 months on MPH	Open label double-blind cross-over study with 8 weeks observation followed by 8 weeks of MPH(0.3mg/kg/day)	Seizure frequency	Increased in 3 out of 5 children with active seizure group after MPH from 1.8/week to 3/week(p<0.01)	Small sample size with heterogenity of epilepsy and variety of anti-epilepsy medications
			ADHD symptoms	70% showed an improvement

Comment(s)

ADHD is a common source of functional impairment in children with epilepsy as the two are quite common conditions of childhood and often co-exist. ADHD is seen in 3-5% of school going children and epilepsy in 0.8% of childhood population. 30% or more children with epilepsy have ADHD. Stimulants-Methylphenidate provide benefits in more than 70% cases of ADHD but there is a common belief that they lower the seizure threshold. There is no good evidence from ample number of studies to suggest that seizure frequency increases with the use of methylphenidate in children with well controlled epieplsy. The power of all these studies, however, is limited because the low baseline rate of seizures makes it very difficult to detect any change in seizure frequency. That is further complicated by the heterogenity among the epilepsy patients in terms of type, frequency, severity and use of various anti-epileptic drugs and their effects on behaviour. Until the results of more rigorous population based, randomized and double blind studies are published the situation is unclear with regards to usage, efficacy and safety of methylphenidate for ADHD symptoms in children with active seizures.

Clinical Bottom Line

1)Methylphenidate improves the symptoms of ADHD in children with epilepsy. 2)Seizure frequency does not increase in children with well controlled epiepsy. 3) The drug can be prescribed with reasonable certainity in children with uncontrolled seizures with following recommendations: a) patients must be fully informed about the current status of evidence which is not absolute. b) careful observation and monitoring of seizure frequency especially in the early part of the treatment c) Make sure that there is an adequate indication for the use of methylphenidate and sufficient psycho-social and educational interventions are in place. d) Thoroughly evaluate the diagnosis of epilepsy and optimize the use of anti-epileptic drugs. e) Do not use methylphenidate longer than necessary.

References

1. Kivilcim Gucuyener et al Use of Methylphenidate for ADHD in patients with epilepsy or EEG abnormalities J Child Neurology 2003;18:109-112
2. Koneski et al Efficacy and safety of methylphenidate in treating ADHD symptoms in children and adolescents with uncontrolled seizures. Epilepsy and Behaviour 21(2011):228-32
3. Gonzalez-Heydrich et al Adaptive Phase 1-Study of OROS-Methylphenidate treatment of ADHD with epilepsy Epilepsy Behaviour 2010 July;18(3):229-37
4. Wroblewski et al Methylphenidate and seizure frequency in brain injured patients with seizure disorders J Clinical Psychiatry 53:86-9
5. Gross-Tsur V et al Epilepsy and ADHD:Is methylphenidate safe and efective J Paediatrics 130:40-44