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Methylphenidate treatment of attention deficit
hyperactivity disorder in young people
with learning disability and difficult-to-treat
epilepsy: Evidence of clinical benefit
*†‡Tangunu Fosi, *§Maria T. Lax-Pericall, *†‡Rod C. Scott,
*†‡Brian G. Neville, and *†‡Sarah E. Aylett
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
Dr. Tangunu Fosi
completed a research
fellowship in childhood
epilepsy at Young
Epilepsy in the United
Kingdom.
SUMMARY
Purpose: To establish the efficacy and safety of methylphenidate (MPH) treatment
for attention deficit hyperactivity disorder (ADHD) in a group of children and young
people with learning disability and severe epilepsy.
Methods: This retrospective study systematically reviewed the case notes of all
patients treated with methylphenidate (MPH) for Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) ADHD at a specialist epilepsy center
between 1998 and 2005. Treatment efficacy was ascertained using clinical global
impressions (CGI) scores, and safety was indexed by instances of >25% increase in
monthly seizure count within 3 months of starting MPH.
Key Findings: Eighteen (18) patients were identified with refractory epilepsies (14 gen-
eralized, 4 focal), IQ <70, and ADHD. Male patients predominated (13:5) and ADHD
was diagnosed at a median age of 11.5 years (range 6–18 years). With use of a combi-
nation of a behavioral management program and MPH 0.3–1 mg/kg/day, ADHD symp-
toms improved in 61% of patients (11/18; type A intraclass correlation coefficient of
CGI 0.85, 95% confidence interval [CI] 0.69–0.94). Daily MPH dose, epilepsy variables,
and psychiatric comorbidity did not relate to treatment response across the sample.
MPH adverse effects led to treatment cessation in three patients (dysphoria in two,
anxiety in one). There was no statistical evidence for a deterioration of seizure control
in this group with the use of MPH.
Significance: Methylphenidate with behavioral management was associated with ben-
efit in the management of ADHD in more than half of a group of children with severe
epilepsy and additional cognitive impairments. Eighteen percent had significant side
effects but no attributable increase in seizures. Methylphenidate is useful in this group
and is likely to be under employed.
KEY WORDS: Methylphenidate, Attention deficit hyperactivity disorder, Refractory
epilepsy, Learning disability, Children.
Children with epilepsy show a diminished capacity for
sustained attention (Besag, 2002; Sanchez-Carpentero &
Neville, 2003; Torres et al., 2008). Permanent factors, such
as structural brain abnormality or genetic factors, may
underlie the reduced attention in some cases (Kolk et al.,
2001; Sanchez-Carpentero & Neville, 2003; McLellan
et al., 2005; Hermann et al., 2007; Torres et al., 2008;
Bechtel et al., 2009). Yet, there is also a large number of
patients in whom easily modifiable factors that impair
Accepted August 30, 2013; Early View publication October 15, 2013.
*The National Centre for Young People with Epilepsy (NCYPE), Sur-
rey, United Kingdom; †Great Ormond Street Hospital for Children NHS
Trust, London, United Kingdom; ‡Neurosciences Unit, UCL Institute of
Child Health, London, United Kingdom; and §South London and Maudsley
NHS Mental Health Trust, London, United Kingdom
Address correspondence to Tangunu Fosi, Neurosciences Unit (Wolfson
Centre), UCL Institute of Child Health, 4/5 Long Yard, London WC1N
3LU, U.K. E-mail: sejjtfo@ucl.ac.uk
©2013 The Authors. Epilepsia published by Wiley Periodicals, Inc. on
behalf of International League Against Epilepsy.
This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
2071
FULL-LENGTH ORIGINAL RESEARCH
attention can be identified. Common factors include: the use
of particular antiepileptic drugs (AEDs), frequent periictal
periods, and dysphoric emotional states (Weinberg & Ems-
lie, 1991; Neville, 1999; Besag, 2002; Sanchez-Carpentero
& Neville, 2003; Torres et al., 2008; Hamoda et al., 2009).
Optimal management therefore addresses seizure-related,
AED-related, and psychological factors that impair atten-
tion. It is advisable to use an AED that combines effective-
ness with a low risk for inducing inattention, and to avoid
polypharmacy (National Institute for Health & Clinical
Excellence, 2008, 2012). Where attention difficulties persist
despite the above strategies, behavioral and pharmacologic
treatment for attention deficit hyperactivity disorder
(ADHD) should be considered.
ADHD is an important cause of inattention and reduced
quality of life in children with epilepsy, affecting 12–20%
(Steffenburg et al., 1996; Davies et al., 2003; see
Kaufmann et al., 2009 for review). Among children with
epilepsy, ADHD is more common and more severe in the
subset who have complex epilepsy, defined as epilepsy
associated with additional neurologic impairments (Hoare,
1993; Sherman et al., 2007). Making the diagnosis of
ADHD in children with epilepsy is clinically important, as it
is now recognized that specifically treating ADHD
improves attention in children with epilepsy (see Torres
et al., 2008 for review). The treatment of ADHD comprises
behavioral intervention and, if needed, a stimulant such as
methylphenidate (MPH) or dexamphetamine; or a noradren-
aline re-uptake inhibitor such as atomoxetine (MTA Co-
operative group, 1999; Barkley, 2003; National Institute for
Health & Clinical Excellence, 2008, 2012; Baptista-Neto
et al., 2008; Gonzalez-Heydrich et al., 2010). The most
commonly used stimulant, MPH, appears to improve
ADHD symptoms in 70–80% of children with well-con-
trolled epilepsy and ADHD (Gross-Tsur et al., 1997; for
review see: Tan & Appleton, 2005; Koneski et al., 2011)—
a similar efficacy to that found in the general population.
There are case series in which seizure exacerbation has been
reported with use of MPH (Gross-Tsur et al., 1997; Hem-
mer et al., 2001; Gonzalez-Heydrich et al., 2004). There
are, however, no randomized controlled trials that show an
increased seizure frequency or severity in patients with epi-
lepsy who are treated for ADHD with MPH. Current evi-
dence from retrospective chart studies, open-label trials,
and controlled trials does not support the view that MPH
increases seizure frequency in well-controlled epilepsy
(Gross-Tsur et al., 1997; Baptista-Neto et al., 2008; Torres
et al., 2008).
There is, however, less evidence regarding the use of
MPH in children with difficult-to-control epilepsy and
learning disability (LD) (Simonoff et al., 2006) (LD refers
to permanent impairments of cognitive function having
onset in childhood, a term equivalent to ‘mental retardation’
Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition [DSM IV] or intellectual ‘disability’[DSM
V] in the North American usage). Population prevalence
studies of ADHD in this patient group are unavailable, but
in tertiary clinic populations of children with epilepsy that is
difficult-to-control and associated with LD, ADHD may be
present in 30–40% (Hempel & Frost, 1995; Semrud-Clikeman
& Wical, 1999; Dunn et al., 2003). There is clinical
uncertainty regarding the efficacy of the pharmacologic
management of this patient group (Torres et al., 2008).
There are no published randomized controlled trials (RCTs)
or cohort studies specifically addressing the use of MPH in
this group. These patients are commonly excluded from
major MPH treatment studies (MTA Co-Operative group,
1999; Abikoff et al., 2004). There are concerns about MPH
aggravating seizures, and whether adverse effects are
increased in children with complex epilepsy (Gross-Tsur
et al., 1997; Gonzalez-Heydrich et al., 2010). This group of
children with difficult-to-control epilepsy has additional
impairments including psychiatric syndromes, neurologic
deficits, and LD.
This study helps to bridge this gap. The clinical experi-
ence with MPH for treating ADHD in children with severe
LD and difficult-to-control epilepsy over a 7-year period
(1998–2005) at a national center for epilepsy and LD was
reviewed. MPH treatment efficacy was assessed, and the
incidences of deterioration of seizure frequency and
medication discontinuation due to adverse effects were
monitored.
Methods
A retrospective case note review was conducted for the
period 1998–2005 at a residential center providing specialist
multidisciplinary (including educational, psychological,
and medical) care for children and young people with com-
plex epilepsy and LD (www.youngepilepsy.org.uk). The
medication database at Young Epilepsy (formerly known as
the National Centre for Young People with Epilepsy,
NCYPE) covers all medications given to patients: MPH was
used for ADHD (n =18). Clinical notes and medication
administration records ascertained MPH dose data, the tim-
ing of medication discontinuation, and the reason for this
(therapeutic nonresponse and adverse reactions).
Clinical assessment and diagnosis of ADHD and
learning disability
The clinical case notes for the 18 patients were reviewed
by the first author, and the following details were extracted:
brain neuroimaging result, category of LD, age at diagnosis
of epilepsy, type of epilepsy, seizure frequency prior to and
on MPH treatment, chronological age at ADHD diagnosis,
additional psychiatric comorbidity, treatment dose of MPH
administered for ADHD, treatment response to MPH, dura-
tion of MPH treatment, and the occurrence of adverse reac-
tions leading to the discontinuation of MPH. Instances
where MPH was discontinued owing to intolerable adverse
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2072
T. Fosi et al.
effects can be ascertained reliably, and thus were chosen to
index the tolerability of MPH in this sample. Minor MPH
adverse effects that did not result in medication discontinua-
tion were expected to be a less reliable indicator of the toler-
ability of MPH in this sample, and were therefore not
examined.
The diagnosis of ADHD was made following referral to a
child and adolescent psychiatrist, and a team comprising a
clinical psychologist, a pediatric neurologist, an epilepsy
nurse specialist, an educator, and the child’s carer all pro-
vided reports on the child as part of routine clinical manage-
ment. The assessments of this multidisciplinary team
formed the basis for making a clinical diagnosis of ADHD
according to DSM-IV-TR criteria (American Psychiatric
Association, 2000). The diagnosis requires six or more inat-
tentive symptoms; or six or more hyperactive-impulsive
symptoms, with ADHD being classified as inattention-
predominant, hyperactivity-predominant, or combined type.
Behavioral observations on each child were combined by
intersection (‘AND’), that is, parent/care and teacher reports
had to concur for a given DSM-IV criterion (Rowland et al.,
2008). The multidisciplinary team’s contemporaneous clini-
cal note records of the child’s response to treatment were
examined systematically.
The procedure used for subtype assignment in different
studies has been shown to have a significant influence on
the relative prevalence of ADHD subtypes reported (Row-
land et al., 2008). Specifically, single-informant teacher
reports increase the likelihood of diagnosing predominantly
inattentive ADHD; single-informant parent reports increase
the likelihood of diagnosing predominantly hyperactive-
impulsive ADHD; and combined parent and teacher reports
increase the likelihood of diagnosing combined ADHD.
Combined informants’observations may be combined by
union (‘OR’) or intersection (‘AND’) rules, with the choice
of method influencing the ADHD subtype diagnosed. Union
rules assess the criteria for an ADHD subtype in either the
parent or teacher report; whereas intersection rules require
both parent and teacher reports to concur on a subtype crite-
rion for it to be valid in the particular child. Union rules
result in an increased diagnosis of combined ADHD,
whereas intersection rules increase the diagnosis of inatten-
tive ADHD (Rowland et al., 2008).
Behavioral management as part of the general approach
to this group of children and young people was the first line
of management, and if this was unsuccessful in improving
the patient’s functional level in relation to their ADHD,
stimulant treatment was added. Behavioral interventions
alone were not sufficient to control the ADHD symptoms of
any of the patients in this study. Consequently, medication
was instituted as add-on to behavioral intervention in all
patients in this study. Prior to start of the medication, the
parents of the child were contacted and informed consent
obtained after face-to-face discussion. MPH was the stimu-
lant used in 17 children after behavioral management. In
another child (patient 17), dexamphetamine was used after
behavioral management, but owing to a lack of success this
was changed to MPH. Data were therefore available for 18
patients on MPH. MPH was titrated to within a range of
0.5–1 mg/kg/day against the patient’s ADHD symptoms
and function as observed by carers and educators, until a
stable improvement was obtained.
Psychological assessment and behavioral interventions
At NCYPE each child was seen on admission and at
regular follow-up by a clinical psychologist who assessed
their learning ability on clinical grounds and with psycho-
metric tests when the child was able to cooperate. The
psychologist’s choice of test instrument was made on
clinical grounds, and included the Wechsler Intelligence
Scale for Children-revised (WISC-R) (Wechsler, 1974) or
Stanford–Binet test (Thorndike et al., 1986). The clinical
classification of learning disability at the center was: mild
(IQ 50–70), moderate (IQ 35–49), or severe (IQ 20–34)
(American Psychiatric Association, 2000, 2013). The
clinical psychologist’s case note records and the cognitive
test results were reviewed.
Behavioral management was the first-line intervention
for ADHD, teaching the child response delay techniques. A
comprehensive, individually adapted behavioral interven-
tion plan was implemented for each child. The following
interventions were affected: increased environmental struc-
ture; one-step task instructions with repeat and visual rein-
forcement; immediate feedback for appropriate and
problem behaviors; and operant conditioning, involving
coupling rewards for appropriate behavior (e.g., impulse
control) with loss of rewards for problem behaviors. Each
child received 24-h supervision from adult carers and
education staff.
Clinical assessment and diagnosis of epilepsy
Where possible the patients’epilepsy syndromes were
classified according to the International League Against
Epilepsy framework (Engel, 2006). Active epilepsy was
defined by the occurrence of at least one seizure in the
2-year period preceding the initiation of pharmacologic
treatment for ADHD. Refractory epilepsy was active epi-
lepsy in which seizures occurred at least weekly despite the
adequate trial of at least two appropriate AEDs, or active
epilepsy despite cotherapy on two or more AEDs (Arroyo
et al., 2002; Mohanraj & Brodie, 2006; Kwan et al., 2010).
The total number of AEDs that each patient received con-
currently with MPH and prior to MPH was recorded.
Seizure frequency data were obtained from the routine
daily seizure frequency chart. The baseline monthly seizure
frequency at the initiation of first-line stimulant treatment
was calculated as the mean monthly seizure frequency for
the preceding 6 months (epoch A). The mean monthly sei-
zure frequency for the 3 months after the initiation of first-
line stimulant treatment was calculated (epoch B). For
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2073
MPH in Learning Disability and Epilepsy
patients who received less than 3 months of stimulant treat-
ment, epoch B was calculated as the mean monthly seizure
frequency for the period of treatment. Where MPH was
taken for <3 months, epoch B was the average over that
period. A 25% or greater rise in mean monthly seizure count
between the two epochs (A and B) was regarded as
significant.
We could find no published value of ideal cutoff that
defines a significant increase from baseline seizure fre-
quency and that is uniformly applicable across the popula-
tion of children with refractory epilepsy. The cutoff of a
25% or greater rise in mean monthly seizure count was cho-
sen to assess seizure deterioration on MPH in this study for
two reasons. First, the 25% cutoff provides quantification of
the relative change in seizure control in a manner commonly
understood in clinical epilepsy research (Hosain et al.,
2006). Second, because the patients in this sample have a
wide range of seizure frequencies, this calculation provides
for each patient’s on-treatment period to be expressed rela-
tive to their pretreatment period, with the latter serving as a
control. This simple index provides a summary view of the
relative change in seizure frequency over a 3-month period
from initiating MPH. Time-series modeling methods have
been applied for seizure frequency analysis in refractory
epilepsy to permit more sensitive analyses (Balish et al.,
1991; Pujar et al., 2010). Given the potential for recording
bias that exists with retrospective data, these methods
would, however, perform suboptimally in this context, in
contrast to the relatively simple method used in this study.
Clinical global impressions scoring
The response of ADHD symptoms to MPH treatment was
scored by four clinicians who independently reviewed each
child’s records while blinded. The blinding procedure used
was the following: one author who did not participate in the
scoring (TF) photocopied the case notes, removing all per-
sonal identifiers (name, date of birth, hospital number) from
the resulting record. This record was provided to each of the
remaining four authors to score. The four assessors were
three consultant pediatric neurologists (SA, BN, and RS)
and a consultant child psychiatrist (TLP).
The score used was a modified version of the global
improvement item of the Clinical Global Impressions (CGI)
scale (National Institute of Mental Health, 1970). The CGI
scale has been used reliably in psychiatry research on chil-
dren to assess clinical response to treatment (Santosh et al.,
2006). The global improvement item of the CGI, is a seven
(7)-point Likert scale (1 =very much improved to 7 =very
much worse). The CGI was scored by each of the four asses-
sors, with a dichotomization of each assessor’s result into an
outcome: “improved”(scores 1–3) or “not improved”
(scores 4–7). The assessment data for each subject by the
four independent assessors were combined to classify the
therapeutic outcome for the patient. A patient was assigned
to the treatment response group (“improved”or “not
improved”) to which the majority of assessors had assigned
him/her. The treatment response was classified as “equivo-
cal”if the assessors were equally likely to assign the patient
to either outcome group. There were, consequently, three
groups of primary treatment response to MPH: responders,
nonresponders and equivocal. The response rate was the
number in the responder group as a proportion of the total
number of subjects. The formal expression used was:
Response rate ¼
nðrespondersÞ
nðrespondersÞþnðnonrespondersÞþnðequivocalÞ
The mean agreement between the ratings made by the
assessors was also quantified. This was done using the type
A intraclass correlation coefficient (ICC) for absolute agree-
ment between the assessors’CGI ratings. This technique is
an application of a two-way mixed model (Landis & Koch,
1977; Shrout & Fleiss, 1979).
Results
Patient characteristics
Group characteristics (ADHD)
Eighteen patients with epilepsy (13 boys, 5 girls: all with
combined-type ADHD) were treated with MPH, of a popu-
lation of 198 children admitted to the center between 1998
and 2005. The median age at ADHD diagnosis was
11.5 years (range 6–18 years) and the median duration of
stay at the center prior to the diagnosis of ADHD being
made was 1 year (range 0.1–11.0 years; mean 1.6, standard
deviation [SD] 2.9 years: Fig. 1). The median duration of
Figure 1.
Seizure frequency of patient 7 on MPH and dexamphetamine.
▲MPH started (0.1 mg/kg/day). ▼MPH stopped (0.1 mg/kg/day).
Dexamphetamine started (0.2 mg/kg/day). Dexamphetamine
stopped (0.4 mg/kg/day).
Epilepsia ILAE
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2074
T. Fosi et al.
treatment with MPH was 12 months (range 2–108 months),
and the median maximum dose of MPH attained during
treatment was 0.5 mg/kg/day (range 0.2–1.2 mg/kg/day).
Nearly all patients (16/18) had at least one other DSM-IV
psychiatric diagnosis. The psychiatric comorbidities seen,
in descending frequency were the following: oppositional
defiant disorder, autism spectrum disorder, conduct disor-
der, mood disorders, and tic disorder. All patients had LD.
This was severe in two thirds (12/18), with the remaining
patients being equally distributed between moderate LD
(3/18) and mild LD (3/18) groups. These are summarized
in Tables 1 and 2.
Table 1. Individual patient characteristics (ADHD)
Patient Sex
Learning
disability
severity
Age at ADHD
diagnosis (years)
Psychiatric
comorbidity
Responder
to MPH
Max MPH dose
(mg/kg/day)
Duration on
MPH (month)
Cessation for
adverse drug event
1 M Severe 14 2, 3 Yes 0.3 30 No
2 F Mild 11 2 Yes 0.6 32 No
3 M Severe 17 Yes 0.5 24 No
4 M Severe 8 1, 2 Yes 0.6 2 No
5 F Severe 12 1, 2, 3 Yes 1.2 4 No
6 F Severe 11 2 No 0.2 3 Yes
7 M Severe 6 2 Yes 0.5 3 No
8 M Mild 10 Yes 0.5 6 No
9 M Mild 12 2, 3 No 0.3 2 Yes
10 M Severe 11 1 No 0.5 12 No
11 M Severe 9 2, 4 Yes 0.4 108 No
12 M Severe 16 3 No 0.8 21 No
13 M Severe 13 1, 2 No 0.8 4 Yes
14 M Moderate 12 1 Yes 0.6 84 No
15 M Moderate 17 2 Yes 0.5 12 No
16 F Severe 18 2 Equivo. 0.8 15 No
17 M Severe 9 2 Yes 0.5 69 No
18 F Moderate 11 2 Equivo. 0.3 2 No
Psychiatric comorbidity: 1, autism spectrum disorder; 2, oppositional defiant disorder; 3, mood disorder; 4, tics.
Table 2. Group characteristics (ADHD)
Median Mean SD Range
Age at ADHD diagnosis (years)
a
11.5 12.1 3.3 6–18
Duration of MPH treatment (months) 2 24 31 2–108
Maximum MPH dose (mg/kg/day) 0.5 0.6 0.2 0.2–1.2
Duration before ADHD diagnosis (years) 1 1.6 2.9 0.1–11
Number of subjects
Sex
Male 13
Female 5
ADHD type
Combined 18
Inattentive-predominant 0
Hyperactive-predominant
Comorbidity
Oppositional defiant disorder (ODD) 13
Autism spectrum disorder 4
Emotional disorder
Tics 1
Learning disability
Mild (IQ 50 –70) 3
Moderate (IQ 35 –49) 3
Severe (IQ 20 –34) 12
a
Same as age at start of MPH.
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2075
MPH in Learning Disability and Epilepsy
Epilepsy
The median age at onset of epilepsy was 2.3 years (range
0.5–11 years), with epilepsy having started at or before age
6 years in 16 cases and in the two remaining cases, at 9 and
11 years of age.
Fourteen patients had generalized epilepsy, meeting the
clinical criteria for epilepsy within the Lennox-Gastaut
spectrum (13) and Doose syndrome (1). Four patients had
symptomatic focal epilepsy: two had bilateral hippocampal
sclerosis with temporal lobe epilepsy; one had tuberous
sclerosis, and the other had a congenital noncommunicating
hydrocephalus.
All patients were taking AED treatment for at least 6
months at the time of starting MPH. Across the entire sam-
ple, a median of two (2) concurrent AEDs was being
received at the initiation of MPH. The median cumulative
number of previous AEDs received was 4 (range 2–13
AEDs). All patients with active epilepsy at the initiation of
MPH (10 patients, 55%) fulfilled the criteria for refractory
epilepsy. For those with treated, inactive epilepsy at the ini-
tiation of MPH (eight patients, 45%), seizure-freedom was
being maintained on one AED (four patients: 3, 11, 15, and
18) or on two concurrent AEDs (four patients: 1, 5, 9, and
13). Three of the four patients who were maintained sei-
zure-free on monotherapy had met the criteria for refractory
epilepsy at some point in the course of their epilepsy. There-
fore, all but one patient in the entire sample (patient 18) sat-
isfied the label of refractory epilepsy either preceding or
while on ADHD treatment. In summary, the epilepsies in
this group of patients were, over their long-term course,
clinically difficult-to-treat. We retained all, envisaging the
possibility of gaining useful data on the recrudescence of
seizures in patients who had gained seizure freedom prior to
MPH being initiated.
Tables 3 and 4 summarize the epilepsy-related features
of this group.
Response to MPH treatment
Interrater agreement of CGI ratings
CGI ratings by the four independent assessors concurred,
with a type A intraclass correlation coefficient (ICC) of 0.85
(95% confidence interval [CI] 0.69–0.94), Table S1. This
magnitude of agreement is considered high (Landis & Koch,
1977). CGI ratings from at least three assessors were consis-
tent for 16 of 18 patients: 12 patients received the same CGI
rating from all four assessors, and 4 patients received the
same rating from 3 of the 4 assessors. The remaining two (2)
patients each had conflicting ratings from half of the asses-
sors, so their response was classified as equivocal. Both
patients were female.
Treatment response rate
The three categories of treatment response were the
following: improved (11/18), not improved (5/18), and
equivocal (2/18). The positive treatment response rate in
this sample of patients with severe epilepsy and learning
disability was 61% (11/18, 95% CI 47–75%).
Characteristics of responders versus nonresponders
Differences between responders and nonresponders were
assessed as a function of gender, LD severity, age at start of
MPH, duration of MPH treatment, maximum MPH dose
attained, age at epilepsy onset, type of epilepsy (generalized
or focal), activity of epilepsy (active or inactive), number of
concurrent AEDs, and cumulative number of previous
AEDs received. Nonparametric tests were used in view of
nonnormal variable distributions: the Mann-Whitney Utest
for continuous variables, and the chi-square test for categor-
ical variables. There was evidence that more nonresponders
than responders experienced an adverse effect leading to
cessation of MPH (p =0.02, but p >0.05 after Bonferroni
correction for multiple comparisons). Some evidence
existed that nonresponders had a mood disorder more fre-
quently, and received MPH for a shorter time than respond-
ers, but these were not statistically significant (p =0.097
and p =0.084, respectively).
Seizure control on MPH
MPH was stopped in one patient (patient 7) as a result of
increased seizure frequency after initiating the drug. This
patient met the study’s criterion for significant increase in
monthly seizure. The patient’s seizure frequency remained
elevated after the discontinuation of MPH. A positive
behavioral response to MPH had been obtained, and an
increase in ADHD symptoms became increasingly evident
off MPH. After a trial of behavioral intervention alone, dex-
amphetamine was initiated 2 months after stopping MPH.
On dexamphetamine the patient’s seizure frequency showed
a downward trend during the subsequent 5 months (Fig. 1).
MPH discontinuation due to adverse reactions
MPH was discontinued in three patients (patients 6, 9, 13)
owing to adverse drug reactions. Patient 6 experienced
marked loss of appetite and became highly withdrawn
(‘zombie-like’according to parents and carers). Patient 9
experienced heightened anxiety and deterioration of his
oppositional defiant disorder behaviors. Patient 13 became
very withdrawn on MPH.
Discussion
Clinical response rate and tolerability of MPH
The treatment response rate of 61% (95% CI 47–75%) in
this sample of patients with current or previous refractory
epilepsy and severe LD is comparable to the rate (54–75%)
reported for children with mild-to-moderate learning dis-
ability without epilepsy (Handen et al., 1990, 1992). The
rate reported in children with well-controlled epilepsy with-
out significant LD is 70% (Gross-Tsur et al., 1997; Tan &
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2076
T. Fosi et al.
Appleton, 2005). Most patients who responded to MPH did
so within the relatively narrow dose range of 0.4–0.5 mg/
kg/day. The dose range at which MPH produced a stable
therapeutic effect on ADHD symptoms ranges in the child-
hood epilepsy literature from 0.3 to 1 mg/kg/day (Gross-
Tsur et al., 1997; Gucuyener et al., 2003). Gross-Tsur et al.
(1997) using the lower dose of MPH (0.3 mg/kg/day as a
single dose) found that ADHD symptoms improved in 70%
of children who had ADHD and epilepsy. The patients in
the study of Gross-Tsur et al. mostly had well-controlled
epilepsy, were on AED monotherapy, and did not have sig-
nificant LD. This patient group is different from that
reported here. The patient cohort reported here showed
additional DSM-IV psychiatric comorbidities in 89% (16/
18) (see Table 1). This is similar to the finding by Steffen-
burg et al. (1996), who found about 90% prevalence of
a psychiatric disorder in children with epilepsy and ‘men-
tal retardation’whose psychiatric conditions could be
categorized. We did not find statistical evidence for a rela-
tionship between response to MPH and having comorbid
Table 3. Patient characteristics (epilepsy)
Patient
Age at
epilepsy
onset
(years)
Electroclinical epilepsy
diagnosis Neuroimaging
No. of
AEDs
tried
AED Rx
at start
of MPH
Epilepsy
activity
Avg monthly
sz count
6 month
before MPH
Avg monthly
sz count 3 month
after start of MPH
↑Monthly sz
count >25%
1 1 Myoclonic Astatic
(Doose syndrome)
Normal 2 LTG
ESX
Inactive 0 0 No
2 2.5 Symptomatic focal Bilateral
hippocampal
sclerosis
10 OXC
STI
CLO
Active RE 29 15 No
3 2.5 Lennox-Gastaut N/A 3 CLO Inactive,
(Prev R.E)
00 No
4 2 Lennox-Gastaut Normal 4 TOP
CLO
R.E 85 0 No
5 1 Lennox-Gastaut Atrophy of corpus
callosum
2 TOP
VPA
Inactive 0 0 No
6 0.5 Lennox-Gastaut Normal 11 VPA
TOP
ZON
R.E 300 300 No
7 0.5 Lennox-Gastaut Normal 13 VPA
PHT
ESX
R.E 42 157 Yes
8 4 Symptomatic focal Cortical tubers 5 VPA
LTG
CLO
R.E 5 5 No
9 2 Lennox-Gastaut N/A 4 LTG
CLO
Inactive,
(Prev R.E)
00 No
10 6 Lennox-Gastaut N/A 4 VPA
LTG
R.E 7 7 No
11 2.5 Symptomatic Focal Bilateral
Hippocampal
sclerosis
4 LTG Inactive,
(Prev R.E)
00 No
12 4 Lennox-Gastaut Normal 7 VPA
LTG
ESX
R.E 14 12 No
13 5 Lennox-Gastaut Normal 5 VPA
LTG
Inactive,
(Prev R.E)
62 No
14 9 Lennox-Gastaut Normal 2 VPA R.E 1 0 No
15 0.5 Lennox-Gastaut Normal 4 None Inactive,
(Prev R.E)
00 No
16 2 Symptomatic focal Hydrocephalus 2 VPA
LTG
R.E 4 1 No
17 1 Lennox-Gastaut Normal 6 CBZ
LTG
MSX
R.E 29 28 No
18 11 Lennox-Gastaut Perinatal
hypoxic-ischemic
cerebral damage
2 VPA Inactive 0 0 No
CBZ, carbamazepine; CLO, clobazam; ESX, ethosuximide; LTG, lamotrigine; MSX, methsuximide; OXC, oxcarba zepine; STI, stiripentol; TOP, topiramate; VPA,
sodium valproate; ZON, zonisamide; PHT, phenytoin; N/A, not available; R.E., refractory epilepsy.
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2077
MPH in Learning Disability and Epilepsy
oppositional-defiant disorder or comorbid autism spectrum
disorder (Santosh et al., 2006). Despite the increased preva-
lence of additional psychiatric comorbidities in our sample,
a clinical response to MPH was obtained in more than half
of the patients, and patients who responded to MPH did so
within the usual therapeutic dose range.
The study used CGI ratings, which provide information
on global improvement in behavior following pharmaco-
logic treatment of ADHD rather than quantifying the
response of individual ADHD symptoms. The goal of treat-
ment with MPH was to improve the patient’s function, by
enhancing concentration, increasing impulse control, and
reducing hyperactivity. The assumption in this study is that
the combined effect of MPH on these separate symptoms
underlies the improvement in the patient’s overall behav-
ioral profile measured by the CGI. The differential extent to
which each separate symptom is altered by MPH can be
highly variable in clinical practice (Sonuga-Barke et al.,
2008; Takon, 2011). The CGI as implemented in this study
would not be informative on this aspect. There is a potential
critique that the behavioral improvement measured by the
CGI in this study reflects a sedative effect on the treated
patients, which renders them unable to manifest problematic
behaviors. We do not consider this to have been the case.
MPH is not a nonspecific sedative, but there is evidence that
MPH lessens the salience within memory of material that
would normally be emotionally arousing (Brignell et al.,
2007). The resultant lowering of emotional arousal may be
misinterpreted as a “sedative effect.”The presumption that
the functional improvement in this study emerged from low-
ering emotional arousal in the patient group would lead logi-
cally to a particular prediction. Those patients who
developed more marked emotional blunting ought to be
likely to demonstrate a concomitant improvement of CGI.
During treatment the team specifically looked for the devel-
opment of either a sedative reaction that impaired the
patient’s usual daily activities (significant sedative reac-
tion); or affective reactions (behavioral signs of labile or
low mood). These are recognized serious adverse reactions
to MPH. The management of these reactions was a dose
reduction in the first instance or medication withdrawal if
the former did not reverse the effect. This is consistent with
the agreed clinical practice for discontinuing medication
in the context of intolerable side effects or a lack of efficacy
(National Institute for Health & Clinical Excellence, 2008).
There were two patients (patients 6 and 13) who developed
dysphoric features, and a third patient (patient 9) had
marked worsening of anxiety symptoms. These effects are
likely related to MPH, since the affective and behavioral
changes resolved in all following the discontinuation of the
drug. The CGI response for the three patients who showed
affective reactions was “nonresponder.”This finding is
inconsistent with a hypothesis that lowering the emotional
arousal necessarily results in the treatment response falling
into the “improved”CGI category.
The rate of MPH treatment cessation due to adverse-
effects in this study (3/18: 17%) was similar to the rate
(19%) reported by Handen et al. (1991) in their study of
children with “mental retardation.”Our experience is that
during the treatment of ADHD in patients with difficult-to-
control epilepsy, a significant sedative reaction is neither
invariable nor typical at standard doses of MPH. The doses
of MPH in two of the three patients who developed affective
reactions to MPH were relatively low, pointing toward the
Table 4. Group characteristics (epilepsy)
Median Mean SD Range
Age at onset (years) 2.3 3.1 3.0 0.5–11
Duration of epilepsy (years) 8.2 8.9 4.5 0–16.5
Number of AEDs 2 2 0.8 1–3
Number of failed AEDs 4 5 3.3 2–13
Seizure frequency (number/month)
Epoch A 1.5 30 73 0–300
Epoch B 1.5 30 73 0–300
Number of subjects
Type of epilepsy
Generalized 14
Focal 4
Epilepsy control
Active epilepsy
a
10
Inactive epilepsy 8
Neuroimaging
Normal 9
Abnormalities on MRI 6
AED, antiepileptic drug; MRI, magnetic resonance imaging.
a
Active epilepsy: defined as having had at least one seizure in the 2 year period preceding the initiation of methylphenidate.
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2078
T. Fosi et al.
inference of the affective reactions not being dose-
determined. This impression is supported by clinical trial
data (Sonuga-Barke et al., 2009). MPH can induce dyspho-
ria in some children, especially those with a genetic suscep-
tibility to low mood (Weinberg & Emslie, 1991). The
dysphoric and vegetative symptoms in patients 6 and 13 at
low doses of MPH (0.2–0.3 mg/kg/day of MPH) may reflect
an existing predisposition. Mood disorders affect 16% of
children with epilepsy in population studies (Davies et al.,
2003), and up to one third in tertiary clinic populations
(Thome-Souza et al., 2004). Establishing the diagnosis of a
mood disorder in a child with refractory epilepsy and LD is
difficult but important (Thome-Souza et al., 2004; Gonz-
alez-Heydrich et al., 2007). Both patients were on sodium
valproate at the initiation of MPH. This may have exerted a
mood-stabilizing effect upon a preexisting depressive disor-
der, thereby preventing it from coming to clinical recogni-
tion. The treatment of ADHD with MPH in this subgroup of
patients should be monitored, as a deterioration of attention
abilities may ensue on MPH if an anxiety disorder coexists
(Goez et al., 2007). The present study evidences a trend for
children with a mood disorder to be more frequently nonre-
sponders to MPH.
The view has been advanced that a genetic defect common
to ADHD and epilepsy may explain their co-occurrence in
patients such as those in the present study (Hamoda et al.,
2009). An alternative view is ADHD in the context of
refractory epilepsy reflects an alteration of cortical circuits
as a result of early brain damage or dysfunction and seizures
(Neville, 1999; Sanchez-Carpentero & Neville, 2003; Her-
mann et al., 2007; Bechtel et al., 2009). The response of
ADHD symptoms to MPH in the patient group studied here
may suggest that some behavioral manifestations of the
long-term effects of seizures on the developing brain can be
successfully contained (Neville, 1999).
MPH treatment and seizure control
The one patient (patient 7, Fig. 1) who experienced an
increase in seizures while on MPH did not regain baseline
seizure frequency after MPH was withdrawn. It is uncertain
if the increased seizure frequency while on MPH in part
reflected the patient’s pattern of severe epilepsy, indepen-
dently of the use of MPH. The study did not find an instance
of a patient whose epilepsy was in remission (inactive epi-
lepsy), and which recrudesced following the initiation of
MPH. A statistically significant incidence of increase in
monthly seizure frequency could not be demonstrated
within 3 months of initiating MPH in the 18 patients in this
study at a group level (Wilcoxon rank-sum test Z =0.169,
p=0.866).
It is proposed that larger studies investigate these obser-
vations further. The risk of a type 2 error (failing to detect
an adverse effect of MPH on seizure control) cannot be dis-
counted in view of the small sample size in the present
study.
ADHD phenomenology in patients with complex
epilepsy
A recent study of children with epilepsy, LD, and ADHD
also found that the combined ADHD subtype predominates
(Gonzalez-Heydrich et al., 2007). In childhood idiopathic
epilepsy, ADHD is more often of the inattentive-type, a
finding replicated using two different ascertainment meth-
ods: single-informant parent reports in Dunn et al. (2003)
and combined expert assessment and parent interview in
Hermann et al. (2007). In childhood complex epilepsy, the
influence of methodology on the classification of ADHD is
not known and requires further study.
The present study combined information (expert assess-
ment, parent/carer informant report, and teacher report).
This may be expected to increase the diagnosis of com-
bined-type ADHD if union rules are applied. However,
intersection rules were used, so the diagnosis of combined
type ADHD made in these patients is not expected to simply
indicate a methodologic bias. The combined ADHD sub-
type, which was present in all our patients, is considered the
most severe clinically and has the highest rate of psychiatric
comorbidity (Faraone et al., 1998).
Potentially late ADHD diagnosis in this patient group
In this study, children with refractory epilepsy had a mean
age at ADHD diagnosis of 12 years (median 11.7 years).
This is older than reported in the general population of chil-
dren diagnosed with ADHD in the United Kingdom
(9 years, Parr et al., 2003). This study therefore provides
evidence that ADHD is potentially diagnosed late in chil-
dren with refractory epilepsy compared to their peers in the
general population.
Factors that may make the diagnosis of ADHD more dif-
ficult in refractory epilepsy include the high rate of comor-
bidities and diagnostic overshadowing (Simonoff, 2003).
Comorbidities, for example depression, may produce a sim-
ilar symptom presentation (Weinberg & Emslie, 1991).
Steffenburg et al. (1996) in a Swedish population-based
study found that even with parental concern, a large number
of psychiatric disorders in children with LD and epilepsy
are not diagnosed promptly or remain undiagnosed. There is
still a reluctance to diagnose and treat ADHD in these
patients (termed “diagnostic overshadowing,”Simonoff,
2003). This may in part reflect the expectation that the com-
plete cessation of seizures must be first achieved, and the
concern that seizure frequency may increase on MPH. The
first expectation is unlikely to be realized in this population
with refractory epilepsy, and the second does not have a
strong empirical basis. Diagnostic overshadowing should
slowly recede in the light of evidence that indicates the ben-
efit of managing ADHD in children with learning disability
and severe epilepsy. It should be emphasized that effective
control of ADHD can make a significant contribution to the
management, wellbeing, and possibility for relative inde-
pendence in this highly dependent group.
Epilepsia, 54(12):2071–2081, 2013
doi: 10.1111/epi.12399
2079
MPH in Learning Disability and Epilepsy
Limitations
This was an audit of the clinical use of MPH with struc-
tured criteria in place. Although a randomized placebo-
controlled study could be performed in a severely affected
group with epilepsy the evidence for the positive value in
children with milder epilepsy is clear and combined with
this study strongly suggests that MPH should not be with-
held on theoretical grounds in the severely affected. The
theoretical grounds are weak, the response is similar to other
studies, and the adverse effects in a minority resolve on
withdrawal of MPH.
Conclusion
There is overwhelming evidence for the benefit of MPH
in ADHD in the literature (MTA Co-Operative Group,
1999) and significant evidence that such benefits apply to
those with a LD (Handen et al., 1990, 1992) and in general
to children with epilepsy (Gonzalez-Heydrich et al., 2010).
This small study of children with intractable epilepsy and
severe LD fills a gap in showing, perhaps not surprisingly,
that similar benefits apply to this group, with a minority
incurring adverse effects. The response rate to MPH treat-
ment was 61% in this pediatric sample with ADHD, severe
epilepsy, cognitive impairment, and a high rate of psychiat-
ric comorbidity. The rate of adverse effects leading to dis-
continuation of medication was comparable to that reported
in children with primary ADHD. There was no statistical
evidence that the treatment of ADHD with MPH directly
increased the seizure rate for the majority of patients with
refractory epilepsy.
The treatment of ADHD in young people with learning
disability and complex epilepsy under specialist care using
behavioral interventions and MPH may improve ADHD
symptoms without causing a clinically significant increase
in seizure frequency. The lack of use of MPH in this group
would seem to result from lack of recognition of ADHD and
an exaggeration of original concerns that MPH might aggra-
vate seizures. We suggest that, although this is a small
study, there is not a strong case for a larger one but that these
patients should have the benefit of consideration of this
treatment. Children with epilepsy and LD should be evalu-
ated for ADHD, as this may be underrecognized; meanwhile
they stand to benefit from multimodal treatment for ADHD.
The available data do not exclude a small number of chil-
dren with epilepsy experiencing an increase in seizures.
This study, although not an RCT, would be helpful to
clinicians and parents concerned about possible adverse
reactions.
Acknowledgments
This work involves a collaboration between the National Centre for
Young Epilepsy (www.youngepilepsy.org.uk) and the Great Ormond Street
hospital/Institute of Child Health who receive a proportion of their funding
from the United Kingdom Department of Health’s NIHR Biomedical
Research Centre funding scheme.
Disclosure
None of the authors has any conflict of interest to disclose. We confirm
that we have read the Journal’s position on issues involved in ethical publi-
cation and affirm that this report is consistent with those guidelines.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Treatment outcome as measured by CGI.
Epilepsia, 54(12):2071–2081, 2013
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