Effectiveness and Side Effect Profile of Stimulant Medication for the Treatment of Attention-Deficit/Hyperactivity Disorder in Youth with Epilepsy

Abstract

Objectives:

This clinical case series examined the effectiveness and potential side effects associated with stimulant medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in 20 youth with epilepsy.

Methods:

Response to stimulant medication was examined through symptom reduction on the Conners–Third Edition: Parent Rating Scale, Short Form [Conner 3-P(S)], which was administered to caregivers before initiation of treatment and following dosage titration to achieve therapeutic efficacy. Stimulant medication side effects were examined with the Side Effect Rating Scale before treatment and following dosage titration. Repeated measures mixed model approach was used to compare symptom reduction and side effects between the two time points.

Results:

Repeated measures ANOVA revealed significant ADHD symptom reduction as measured by the Conner 3-P(S). Review of patient medical records and caregiver report did not reveal seizure exacerbation. Caregivers, in fact, reported fewer side effects following treatment for ADHD compared with baseline.

Conclusion:

These results contribute to growing evidence in support of the effectiveness of stimulant medication, without seizure exacerbation or medication side effects, for treatment of ADHD in youth with epilepsy.

Introduction

Children and adolescents with epilepsy are at increased risk for attention-deficit/hyperactivity disorder (ADHD; Reilly et al. 2014). A sociodemographic study using data from the National Survey of Children's Health found a significantly higher incidence of ADHD among children with epilepsy (23%) compared with the general pediatric population (5%–9%; Russ et al. 2012). Reported rates of ADHD in clinic-referred samples of children with epilepsy have ranged from 32% to 37%, indicating that ADHD is potentially five times more common in youth with epilepsy compared with youth with developmental ADHD (Dunn et al. 2003; Hermann et al. 2007).

In children with epilepsy, the etiology of inattention is multifactorial in nature and stems not only from underlying cerebral differences but also from the effects of seizures themselves, interictal discharges seen on electroencephalogram (EEG), side effects of antiepilepsy drugs, and even sleep disruption due to seizures. Investigations of morphological differences between children with epilepsy and ADHD and children with developmental ADHD reveal deficient cerebellar connections in both groups compared with controls using diffusion tensor imaging (Bechtel et al. 2009). In a study using functional MRI, a similar pattern of hypoactivation in the working memory networks (cerebellum, frontal, inferior parietal, right thalamus, and caudate regions) was demonstrated for children with epilepsy and ADHD and children with developmental ADHD compared with controls (Bechtel et al. 2012). A quantitative MRI study also revealed significantly increased gray matter in distributed regions of the frontal lobe and significantly smaller brainstem volume in children with epilepsy and ADHD (Hermann et al. 2007). Taken together, seizures and ADHD appear to be a manifestation of a common underlying pathophysiology.

Historically, pediatricians have been reluctant to treat ADHD in their patients with epilepsy due to concern that stimulant medication may lower the seizure threshold. For example, the Physicians' Desk Reference (2013) lists under warnings and precautions: “Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures.” As such, many children with epilepsy and comorbid ADHD likely have unmet mental health needs. Identification and treatment of ADHD in youth with epilepsy are particularly important given the adverse outcomes associated with this neurodevelopmental disorder, including social dysfunction, academic underachievement, underemployment, and risk-taking behaviors, such as substance use/abuse and driving accidents (Barkley et al. 2006). Children with epilepsy and comorbid ADHD also report a poorer quality of life compared with children with epilepsy and no ADHD (Sherman et al. 2012). Clearly, identification and treatment of ADHD are important for youth with epilepsy.

A growing body of research suggests that treatment of ADHD in youth with epilepsy is both safe and effective. Double-blind, placebo-controlled crossover trials of methylphenidate (MPH) in children with epilepsy document improvements in symptoms of ADHD without seizure exacerbation (Feldman et al. 1989; Gonzalez-Heydrich et al. 2010). A number of prospective open-label trials of MPH for the treatment of ADHD in children with epilepsy reveal significant ADHD symptom reduction without seizure exacerbation for those patients with well-controlled epilepsy (Gross-Tsur et al. 1997; Gucuyener et al. 2003; Koneski et al. 2011), even over a prolonged period of treatment for ADHD (McBride et al. 1986). Treatment effectiveness without seizure exacerbation also has been reported for a sample of children with medically refractory epilepsy (Santos et al. 2013).

The following clinical case series examines the effectiveness of stimulant medication for the treatment of ADHD in a sample of children and adolescents with epilepsy. In addition, unique to this clinical case series, pretreatment and post-treatment side effects were ascertained. We hypothesized that treatment of ADHD in this sample of youth with epilepsy would be effective (i.e., significant ADHD symptom reduction) without exacerbating the frequency of seizures or medication side effects.

Methods

Sample

Our sample comprised children and adolescents with epilepsy who were formally diagnosed with ADHD through comprehensive neuropsychological evaluation and then referred to an outpatient developmental–behavioral pediatric clinic of an academic medical center for treatment of ADHD. A diagnosis of ADHD was carefully determined through extensive review of medical and educational records, parent and teacher-completed behavior rating scales (as described in the Outcome Measures section), and a structured clinical interview documenting criteria for ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR, 2000). An epilepsy diagnosis was made by board-certified epileptologists through neurological evaluation that included an electroencephalogram according to the International League Against Epilepsy. All patients were prescribed stimulant medication [methylphenidate extended release (brand name, Concerta) or dexmethylphenidate (brand name, Focalin XR)], with dosage titration to achieve clinical efficacy. All clinical and treatment decisions were made as part of routine patient care and thus not carried out under a study protocol; all the prescriptions, treatment monitoring with behavior rating scales, and other aspects of patient care were completed before inception of the clinical case series analysis.

Through electronic medical record review, all youth with epilepsy and ADHD referred for treatment between 2012 and 2014 were included in the sample. Retrospective analysis of archival clinical data was approved by the Medical University of South Carolina Institutional Review Board.

Outcome measures

As part of routine clinical care, the Conners–Third Edition: Parent Rating Scale, Short Form [Conner 3-P (S) (Conners 2008)], was administered to patients' caregivers at the time of diagnosis (before medication was prescribed) and at subsequent follow-up visits to monitor treatment effectiveness. The Conners 3-P (S) is a 45-item parent-completed behavior rating scale designed to assess symptoms of inattention, hyperactivity/impulsivity, learning problems, executive functioning, aggression, and social problems in children and adolescents. The Conners 3-P (S) is a widely used tool in the assessment and diagnosis of ADHD as item content is based on criteria specified in the DSM-IV-TR. The Conners 3-P (S) subscales have good internal consistency (Cronbach's alpha of 0.85–0.92), test–retest reliability (adjusted r = 0.73–0.97), and inter-rater reliability (adjusted r = 0.79–0.87). Comparisons of scores between children with ADHD and the general population result in significant differences, supporting the validity of the questionnaire.

Stimulant medication side effects were assessed with the Side Effect Rating Scale (SERS; Barkley 2006). The SERS is a parent-completed rating scale assessing the frequency and severity of 17 common side effects of stimulant medication (e.g., sleep and appetite disturbance, irritability, stomachaches and headaches, and tics) on a scale from 0 (absent) to 9 (severe). The SERS was administered to the patients' caregiver at the time of diagnosis (before medication was prescribed) and at subsequent follow-up visits to monitor medication side effects.

Seizure-related variables, ascertained through archival review of each patient's neurology documentation in the electronic medical record, included seizure type (i.e., generalized, partial, or unspecified), number of antiepilepsy drugs, and seizure frequency. Frequency of seizures was classified 1 year before diagnosis of ADHD and within 1 year following treatment for ADHD. Seizure frequency was classified as (1) none, (2) 11 or less per year, (3) 1–3 per month, (4) 1 or more per week, or (5) 1 or more per day in accordance with the current International League Against Epilepsy classifications (Fisher et al. 2014) and the National Institute of Neurological Disorders and Stroke Common Data Elements for epilepsy (Loring et al. 2011).

Data analyses

The Inattention and Hyperactivity/Impulsivity Scales of the Conners 3-P (S) and the total raw score of the SERS were compared between two time points: at the time of ADHD diagnosis (before stimulant medication was prescribed) and following treatment for ADHD with stimulant medication and dosage titration to achieve clinical efficacy. A repeated measures mixed model approach was used to compare symptom reduction and side effects between the two time points with predicted means reported. Statistical analysis was performed using SAS V9.4 (SAS Institute, Inc., Cary, NC). Results were deemed significant at the p < 0.05 level.

Results

Information about baseline patient demographic and clinical characteristics is included in Table 1. Patients ranged in age from 5 years 1 month to 14 years 0 months (mean = 99.15 months, standard deviation [SD] = 30.26 months). Fifty percent of the sample was female. Fifty-five percent of the patients received a diagnosis of ADHD–combined type (n = 11) and 45% received a diagnosis of ADHD–predominantly inattentive type (n = 9). Before initiation of treatment for ADHD, the majority (80%) of the sample had well-controlled epilepsy (i.e., ≤11 seizures per year), while 20% of the sample had medically refractory epilepsy (i.e., ≥3 seizures per month). Following treatment for ADHD and, in some cases, changes in antiepilepsy drugs, the percentage of the sample with well-controlled epilepsy improved to 90%.

Table 1.

Patient Demographic and Epilepsy Characteristics

Characteristics	All ADHD subtypes (N = 20)	ADHD–predominantly inattentive type (n = 9)	ADHD–combined type (n = 11)
Female, n (%)	10 (50.00)	4 (44.44)	6 (54.55)
Age, months, mean (SD)	99.15 (30.26)	109.89 (36.26)	90.36 (22.34)
IQ score, mean (SD)	81.05 (15.65)	86.67 (17.63)	76.45 (12.85)
Seizure type, n (%)
Generalized	5 (25.00)	3 (33.33)	2 (18.18)
Partial (focal)	10 (50.00)	4 (44.44)	6 (54.55)
Unspecified	5 (25.00)	2 (22.22)	3 (27.27)
Seizure frequency
Pretreatment, n (%)
None	7 (35.00)	3 (33.33)	4 (36.36)
11 or less per year	9 (45.00)	5 (55.56)	4 (36.36)
1–3 per month	1 (5.00)	0 (0)	1 (9.09)
1 or more per week	2 (10.00)	1 (11.11)	1 (9.09)
1 or more per day	1 (5.00)	0 (0)	1 (9.09)
Seizure frequency
Post-treatment, n (%)
None	9 (45.00)	4 (44.44)	5 (45.45)
11 or less per year	9 (45.00)	5 (55.56)	4 (36.36)
1–3 per month	1 (5.00)	0 (0)	1 (9.09)
1 or more per week	0 (0)	0 (0)	0 (0)
1 or more per day	1 (5.00)	0 (0)	1 (9.09)
Number of AEDs, mean (SD)	1.35 (0.75)	1.44 (0.88)	1.27 (0.65)

ADHD, attention-deficit/hyperactivity disorder; AEDs, antiepilepsy drugs; IQ, intelligence quotient; n, sample number; SD, standard deviation.

Information about patient treatment characteristics is presented in Table 2. All patients demonstrated clinically significant symptoms of ADHD as measured by the Conners 3-P (S) at baseline (i.e., T-scores ≥65). The average time between baseline/initiation of stimulant medication and prescription of a titrated dosage to achieve clinical efficacy was 57.63 days (SD = 33.33, minimum = 24 days and maximum = 119 days). In many cases, the initial dosage of stimulant medication was efficacious and did not require titration.

Table 2.

Patient Treatment Characteristics

					Conner's 3-P (S) Inattention		Conner's 3-P (S) Hyperactivity		SERS
ID	Seizure type	AEDs	ADHD Subtype	Stimulant Medication (mg)	Pre-Tx	Post-Tx	Pre-Tx	Post-Tx	Pre-Tx	Post-Tx
1	U	None	CT	Concerta (18)	67	60	63	61	16	14
2	U	Carbamazepine	CT	Focalin (2.5)	90	65	90	65	30	19
3	P	Levetiracetam	CT	Focalin (2.5)	90	51	66	44	.	5
4	P	Divalproex	PIT	Concerta (18)	89	72	72	58	34	31
5	G	Divalproex Zonisamide	PIT	Concerta (36)	74	56	90	58	66	40
6	G	Divalproex Lamotrigine	PIT	Concerta (27)	86	68	57	44	24	13
7	U	None	PIT	Focalin XR (5)	74	61	74	52	18	11
8	P	Carbamazepine	CT	Concerta (27)	90		80		84
9	P	Oxcarbazepine	CT	Concerta (18)	90		90		52	8
10	P	Levetiracetam Carbamazepine	PIT	Concerta (18)	90	69	57	58	61	50
11	P	Zonisamide Oxcarbazepine	CT	Focalin XR (15)	90	75	90	78	80	63
12	U	Divalproex	PIT	Concerta (36)	90	52	57	55	42	8
13	U	Levetiracetam	CT	Focalin XR (5)	89	77	81	57	43	16
14	G	Levetiracetam	PIT	Concerta (18)	80	66	78	65	24	9
15	G	Levetiracetam Lamotrigine	CT	Concerta (27)	90		90		74	57
16	P	Lacosamide Valproic acid Lamotrigine	PIT	Concerta (18)	90	66	85	61	96	25
17	P	Rufinamide Ethosuximide	CT	Focalin XR (5)	90	87	90	78	47	29
18	P	Levetiracetam	CT	Concerta (36)	79	59	77	58	13	13
19	G	Divalproex	CT	Focalin XR (10)	66	46	90	58	19	22
20	P	Oxcarbazepine	PIT	Focalin XR (5)	80	60	80	61	43	42

ADHD, attention-deficit/hyperactivity disorder; AEDs, antiepilepsy drugs; CT, ADHD–combined type; Concerta, methylphenidate extended release; Conners 3-P (S), Conners–Third Edition: Parent Rating Scale, Short Form, Inattention Scale and Hyperactivity/Impulsivity Scale T-scores; Focalin XR, dexmethylphenidate extended release; PIT, ADHD–predominantly inattentive type; mg, milligrams per daily dose; Post-Tx, post-treatment/following stimulant medication titration to clinical effectiveness; Pre-Tx, pretreatment/baseline; Seizure type: G, generalized; P, partial (focal); U, unspecified; SERS, Side Effect Rating Scale, total raw score.

Following treatment of ADHD with stimulant medication and dosage titration to achieve clinical efficacy, patients demonstrated a significant reduction in symptoms of inattention [Conners 3-P (S) Inattention Scale mean T-score = 64.38] compared with baseline [Conners 3-P (S) Inattention Scale mean T-score = 84.20, p < 0.0001]. A significant reduction in symptoms of hyperactivity/impulsivity also was demonstrated following treatment with stimulant medication [Conners 3-P (S) Hyperactivity/Impulsivity Scale mean T-score = 59.37] compared with baseline [Conners 3-P (S) Hyperactivity/Impulsivity Scale mean T-score = 77.85, p < 0.0001]. Table 3 presents statistically significant differences between the two time points for the predicted means.

Table 3.

Stimulant Medication Treatment Effectiveness and Side Effects

Outcome measure	Pretreatment LSM (SE)	Post-treatment LSM (SE)	LSM reduction (SE)	p
Conners 3-P (S) inattention scale	75.97 (2.42)	65.67 (2.56)	10.29 (2.25)	<0.0001
Conners 3-P (S) hyperactivity/impulsivity scale	77.85 (2.46)	60.42 (2.67)	17.43 (2.47)	<0.0001
SERS total score	35.31 (5.20)	30.63 (5.22)	4.68 (1.49)	0.0024

Conners 3-P (S), Conners–Third Edition: Parent Rating Scale, Short Form; LSM, least squares mean; SE, standard error; SERS, Side Effect Rating Scale.

Seizure frequency did not change for any of the patients during the time between initiation of treatment for ADHD with stimulant medication and titration of stimulant medication to achieve clinical efficacy. Moreover, as ascertained by caregiver report and medical record review, for most patients, seizure frequency did not change over the course of one year following initiation of stimulant medication. In fact, following initiation of treatment for ADHD and a change in antiepilepsy drug, seizure frequency decreased for two patients (10% of the sample).

No serious adverse medication side effects were reported by patients' caregivers. To the contrary, there was a significant mean reduction in side effects following treatment with stimulant medication [SERS mean total score = 23.22] compared with baseline [SERS mean total score = 45.58, p = 0.0012]. Table 3 presents statistically significant differences between the two time points for the predicted means.

Table 4 presents the total number of side effects endorsed by patient caregivers before initiation of treatment of ADHD (pretreatment) and following treatment of ADHD and dosage titration to achieve clinical efficacy (post-treatment). The total number of side effects reported by patient caregivers is grouped in Table 4 according to frequency: mild to moderate (scores of 0–4) or moderate to severe (scores of 5–9). The most commonly reported pretreatment side effects included stares a lot or daydreams, irritable, sad/unhappy, insomnia or trouble sleeping, anxious, and euphoric/unusually happy. The most commonly reported post-treatment side effects included decreased appetite, stares a lot or daydreams, irritable, and sad/unhappy.

Table 4.

Total Number of Caregiver-Reported Side Effects Pre- and Post-Treatment

	Pretreatment			Post-treatment
SERS side effects	Mild to moderate (0–4)	Moderate to severe (5–9)	Total	Mild to moderate (0–4)	Moderate to severe (5–9)	Total
Insomnia or trouble sleeping	8	7	15	6	2	8
Nightmares	8	0	8	4	1	5
Stares a lot or daydreams	8	10	18	11	3	14
Talks less with others	6	3	9	8	2	10
Uninterested in others	5	4	9	5	1	6
Decreased appetite	9	5	14	9	8	17
Irritable	10	7	17	8	4	12
Stomachaches	9	3	12	6	2	8
Headaches	8	3	11	7	1	8
Drowsiness	8	4	12	6	0	6
Sad/unhappy	4	6	10	9	0	9
Prone to crying	9	6	15	5	3	8
Anxious	4	10	14	4	3	7
Bites fingernails	2	7	9	3	4	7
Euphoric/unusually happy	7	6	13	7	1	8
Dizziness	3	2	5	1	1	2
Tics or nervous movements	5	4	9	6	2	8

SERS, Side Effect Rating Scale.

Discussion

The results of this clinical case series revealed significant improvement in symptoms of ADHD in children and adolescents with epilepsy following treatment with stimulant medication. Specifically, a statistically significant reduction in the mean score on Conners 3-P (S) Inattention Scale from clinically significant (T-score >65) to not clinically significant (T-score <65) was found when patients with epilepsy and ADHD were prescribed stimulant medication and the dosage was titrated to achieve clinical efficacy. Similarly, a statistically significant reduction in the mean score on Conners 3-P (S) Hyperactivity Scale from clinically significant (T-score >65) to not clinically significant (T-score <65) was found when patients with epilepsy and ADHD were prescribed stimulant medication and the dosage was titrated to achieve clinical efficacy. There was no seizure exacerbation, and 10% of the sample experienced a reduced frequency of seizures following initiation of treatment for ADHD and a change in antiepilepsy drugs. Finally, a reduction in medication side effects, as measured by the SERS questionnaire, was reported by patient caregivers following treatment of ADHD compared with pretreatment.

The most commonly reported side effects at baseline, before initiation of treatment for ADHD, included frequent staring/daydreams, irritability, sadness, insomnia, anxiety, and euphoria. These side effects represent common symptoms among children with untreated ADHD (i.e., staring/inattention and emotional dysregulation). The most commonly reported side effects following treatment for ADHD and dosage titration to achieve clinical efficacy included decreased appetite, frequent staring/daydreams, irritability, and sadness. Decreased appetite is a common side effect of stimulant medication and is to be expected. While the other commonly reported side effects also were reported at baseline, these side effects were reported with less frequency following treatment initiation, suggesting improvements in inattention and emotional dysregulation following treatment of ADHD.

The findings of this clinical case series must be interpreted within the context of the assessment limitations. First, the sample was one of convenience, comprising patients followed in an outpatient setting. All clinical and treatment decisions in this clinical case series were made as part of routine patient care. The results would be strengthened by a randomized, double-blind, placebo-controlled clinical trial. Even so, the results of this clinical case series are consistent with published clinical trials (Feldman et al. 1989; Gonzalez-Heydrich et al. 2010). Second, the small sample size may have mitigated significant effects that might have occurred in a larger sample. Nonetheless, results were significant beyond the established 0.05 level. Future investigations should include larger samples, a randomized, double-blind placebo-controlled methodology, and investigation of the efficacy of amphetamine stimulants versus methylphenidate in youth with epilepsy and ADHD.

Conclusion

Youth with epilepsy are at high risk for ADHD. Given the impairing nature of ADHD, treatment can make a significant difference in quality of life and the academic and social functioning of youth with epilepsy who struggle with this common comorbidity. The results of this clinical case series add to growing empirical support for the effectiveness of stimulant medication for the treatment of ADHD in youth with epilepsy, without seizure exacerbation. These findings are important for treating physicians, who historically have been reluctant to treat ADHD in youth with epilepsy secondary to concerns about lowering the seizure threshold.

Clinical Significance

This clinical case series examined the effectiveness and potential side effects associated with stimulant medication for the treatment of ADHD in youth with epilepsy. ADHD symptoms and medication side effects were ascertained through parent-completed behavior rating scales before initiation of treatment for ADHD and following dosage titration to achieve therapeutic efficacy. Significant ADHD symptom reduction and fewer medication side effects were revealed, without seizure exacerbation, following dosage titration to achieve therapeutic efficacy. These results contribute to growing evidence in support of the effectiveness of stimulant medication for treatment of ADHD in youth with epilepsy, without seizure or medication side effect exacerbation.

Footnotes

Disclosures

No competing financial interests exist.

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