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hyperactivity disorder and interictal epileptiform discharges: It is safe to use methylphenidate?
Seizure 25 (2015) 80–83
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Attention deficit/hyperactivity disorder and interictal epileptiform discharges: It is safe to use methylphenidate? Dobrinko Socanski a,*, Dag Aurlien b, Anita Herigstad c, Per Hove Thomsen d, Tor Ketil Larsen e,f a
Stavanger University Hospital, Division of Psychiatry, Department of Child and Adolescent Psychiatry, Stavanger, Norway Stavanger University Hospital, Department of Neurology, Stavanger, Norway Stavanger University Hospital, Department of Clinical Neurophysiology, Stavanger, Norway d Centre for Child and Adolescent Psychiatry, University of Aarhus, Denmark e Stavanger University Hospital, Division of Psychiatry, Stavanger, Norway f Department of Clinical Medicine, University of Bergen, Norway b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 September 2014 Received in revised form 5 November 2014 Accepted 3 January 2015
Purpose: This study investigated whether interictal epileptiform discharges (IED) on a baseline routine EEG in children with ADHD was associated with the occurrence of epileptic seizures (Sz) or influenced the use of methylphenidate (MPH) during 2 years follow-up. Methods: A retrospective chart-review of 517 ADHD children with EEG revealed IED in 39 cases. These patients (IED group) were matched on age and gender with 39 patients without IED (non-IED group). We measured at baseline, 1 year and 2 years Sz occurrence, the use of MPH and antiepileptic drug (AED). Results: At baseline, 12 patients in the IED group had active epilepsy and three of them had Sz during the last year. 36 (92.3%) patients were treated with MPH. Initial positive response to MPH was achieved in 83.3% compared with 89.2% in the non-IED group. At 1 and 2 years follow-up, three patients who also had Sz at baseline and difficult to treat epilepsy, had Sz, without changes in seizure frequency. We found no statistically significant differences between the groups with respect to MPH use at 1 year and at 2 years. Ten patients from IED group, who did not have confirmed epilepsy diagnosis, temporarily used AEDs during the first year of follow-up. Conclusion: Despite the occurrence of IED, the use of MPH was safe during 2 years follow-up. IED predict the Sz occurrence in children with previous epilepsy, but does not necessarily suggest an increased seizure risk. A caution is warranted in order not to overestimate the significance of temporarily occurrence of IED. ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Attention-deficit/hyperactivity disorder (ADHD) Interictal epileptiform discharges (IED) Epilepsy Methylphenidate (MPH) Antiepileptic drug (AED)
1. Introduction Interictal epileptiform discharges (IED) on EEG may occur in children with attention deficit/hyperactivity disorder (ADHD) and contribute to the occurrence of ADHD symptoms [1]. ADHD in children is reported to be a risk factor for incident unprovoked seizures and epilepsy [2], and suggested to predispose for epilepsy development as do autism spectrum disorder and cerebral palsy [3–5]. EEGs performed in children with new onset seizures show IED in approximately 18–50%, and IED occurrence is predictive of
* Corresponding author at: Stavanger University Hospital, Division of Psychiatry, PB 8100, 4068 Stavanger, Norway. Tel.: +47 51515937; fax: +47 51518000. E-mail addresses: [email protected], [email protected] (D. Socanski).
seizure recurrence, particularly in patients with idiopathic epilepsy [6]. However, the prognostic value of IED in ADHD children with and without previous epilepsy, regarding occurrence of seizure during early illness course, is unknown [7]. Methylphenidate (MPH) is the psychostimulant drug most frequently used for the treatment of ADHD and there is overwhelming evidence for its benefit [8–10]. It is considered to be safe in children without epilepsy. On the other hand, there is limited research about the use of MPH in patients with epilepsy [11–15] and children with ADHD and IED [16]. A recent study found that clinicians appeared to be reluctant to diagnose and initiate treatment for ADHD in children with epilepsy [17]. It is thus of clinical importance whether it is safe to use MPH in ADHD with IED. The aims of the present study were to investigate whether IED occurrence at ADHD assessment could predict the occurrence of
http://dx.doi.org/10.1016/j.seizure.2015.01.002 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
D. Socanski et al. / Seizure 25 (2015) 80–83
epileptic seizures (Sz) and influence the use of MPH during 2 years follow-up.
81
3. Results 3.1. Demographic and clinical characteristics at baseline
2. Materials and methods 2.1. Participants and procedure Our study was conducted at Stavanger University Hospital on consecutive patients admitted to assessment during a 6 years period; January 2000–December 2005. We carried out a retrospective chart review of all patients aged 5–14 who were diagnosed with ADHD in accordance with DSM-IV TR [18]. For details see previous publications [7,15]. A digitized 20 min routine awake EEG with 21 electrodes (10–20 system) including hyperventilation and photic stimulation was performed. The EEGs were classified as either epileptiform or nonepileptiform according to the presence or absence of IED. IED were defined as spikes or spikewave complexes, isolated or occurring serially (in runs) without evident clinical signs of a Sz. The IED index was estimated as percentage of time in three categories (0%, <1%, 1%). Sz, epilepsy and epileptic syndromes were diagnosed according to the classification system of the International League Against Epilepsy [19–21]. Sz frequency during the last year was defined as Sz free, 1–12 Sz per year, and >12 Sz per year, and antiepileptic drug (AED) treatment was classified as untreated, monotherapy or polytherapy. We also analyzed data about comorbid disorders of psychological development and IQ level (IQ > 85, IQ < 85). We were able to carry out EEG at baseline in 517 out of 607 cases (85.4%), and 39 cases (7.5%) had IED. We studied 2 years follow-up of these 39 cases (IED group) and compared them with 39 randomly selected cases matched for age and gender without EA (non-IED group). At baseline, 1 and 2 years we measured the Sz occurrence and frequency, the use of AEDs, and the use of MPH. MPH was administered according to the Norwegian Guidelines [22], in dosage 0.5–1.2 mg per kilo either three times daily (shortacting MPH) or once per day (slow- acting MPH). During titration with MPH the use of AEDs was stable. The response to MPH was evaluated after several weeks of treatment (4–6 weeks). The response was considered positive if significant reduction in ADHD symptoms scores assessed with ADHD IV rating scale was found [23], in addition to parents and teachers observations. During follow-up we registered whether MPH was given or not. In the IED group at least one follow-up EEG was carried out, an additional sleep EEG was performed in 15 cases and long-term video-EEG monitoring in five cases because of diagnostic difficulties (suspect Sz).
Due to matching procedures there were no differences between the groups regarding age and gender. Proportion of disorders of psychological development or IQ level >85 showed also no differences (Table 1). As reported in previous publications we found that, among the 39 children with IED, 54% had generalized IED, 41% had focal IED, and 5% had mixed IED [7]. The majority 36/ 39 (92%) of cases with IED had short duration of IED, the IED index was <1%. The IED group had significantly more often predominantly inattentive subtype of ADHD (41%) compared to the nonIED group (15.4%). In the IED group 12 patients had epilepsy with recent seizures (Sz) (last 5 years). During the last year, nine patients were seizure free, two had 1–12 Sz and one had more than 12 Sz. We found that 75% (9/12) had localization-related epilepsy and 25% generalized epilepsy. All patients with epilepsy received AEDs; 10 monotherapy and two polytherapy. No patients in the non-IED group had epilepsy. At baseline, 36/39 (92.3%) patients with IED were treated with MPH. The three patients that were not given MPH had no previous epilepsy. Initial positive response to MPH was achieved in 30/36 (83.3%) of children with IED; 10/12 (83.3%) of the children with epilepsy and 20/24 (83.3%) of the cases without epilepsy. In the non-IED group of the 37 initially treated cases, 33/37 (89.2%) had positive effect of MPH treatment. 3.2. 1 and 2 years follow-up At 1 and 2 years follow-up only three patients, all from IED group, had experienced Sz (Table 2). These three patients had pharmacoresistant epilepsy at baseline and had no change in seizure frequency. We found no significant differences regarding the use of MPH. Within the IED group we did not find statistically significant differences between the cases with and without epilepsy regarding use of MPH at 1 and 2 years follow-up (Table 3). At 1 year follow-up 22 patients in the IED group were treated with AEDs, 12 of them had epilepsy (monotherapy 10, polytherapy two cases). At 2 years 12 children from IED group used AEDs, 10 of them had epilepsy (eight monotherapy, two polytherapy). During follow-up we carried out control EEG in the IED group (one case missing). We found IED in 12 (31.2%) cases; focal in 10 and generalized in 2. In the IED-cases with epilepsy, four cases had only focal IED. 4. Discussion
2.2. Statistical analyses Continuous demographic and clinical variables in subjects with and without IED were compared using Student’s t-tests for continuous and symmetrically distributed data and Mann– Whitney tests for continuous and skewed data. Proportions were compared using Chi-squared test or Fisher’s exact test. Methods for matched samples (paired-samples t-tests, McNemar’s tests) were also applied. However, the application of methods for matched samples did not alter the conclusions. A p-value of <0.05 was considered statistically significant. 2.3. Approval The study was approved by the Norwegian Data Inspectorate and by the Regional Committee on Medical Research Ethics in region West (nr. 010.07). The study was performed in accordance with ethical standards of the Declaration of Helsinki. Written informed consent was obtained from parents.
The main finding of this study was that it seems to be safe to give MPH to patients with ADHD even if they have IED on routine Table 1 ADHD patients with and without IED at baseline. Demographics
IED-group (n = 39)
Non-IED group (n = 39)
Age, mean SD Gender, female (%) Developmental disorders IQ >85 (%) ADHD-I (%) Epilepsy Sz during the last 5 years Sz during the last year MPH, at baseline MPH, positive response
9.7 2.7 11 (28.2%) 22/39 (56.4%) 21/38 (55.3%) 16/39 (41%) 12/39 (30.8%) 12/12 (100%) 3/12 (25%) 36/39 (92.3%) 30/36 (83.3%)
9.7 2.7 11 (28.2) 17/39 (43.6%) 23/34 (67.6%) 6/39 (15.4%) 0 0 0 37/39 (94.9%) 33/37 (89.2%)
p-Value
0.26 0.28 0.01
0.64 0.47
ADHD-I, ADHD predominantly inattentive subtype; MPH, methylphenidate; IED, interictal epileptiform discharges; IQ, intelligence quotient; Sz, epileptic seizures.
D. Socanski et al. / Seizure 25 (2015) 80–83
82 Table 2 1 and 2 years follow-up. IED-group (n = 39)
Non-IED group (n = 39)
Age, mean SD Gender, female (%)
9.7 2.7 11 (28.2%)
9.7 2.7 11 (28.2%)
1 year Sz occurrence MPH AED monotherapy AED polytherapy
3 28/36 (77.8%) 20 2
0 33/37 (89.2%) 0 0
2 years Sz occurrence MPH AED monotherapy AED polytherapy
3 26/36 (72.2%) 10 2
0 27/37 (73%) 0 0
p-Value
0.19
0.49
AED, antiepileptic drug; MPH, methylphenidate; IED, interictal epileptiform discharges; Sz, epileptic seizure.
EEG or epilepsy at baseline. We found no increased occurrence of Sz during 2 years follow-up. Among children with IED, Sz did occur only in those with a previous history of difficult to treat epilepsy. No other cases in this study had Sz during follow-up. The use of MPH was similar in the both groups (with and without IED). 4.1. Seizure risk in ADHD children with IED and the use of MPH and AEDs The seizure risk in ADHD children with IED in the EEG has been discussed in some publications [11,24]. Hemmer et al. [24] investigated the seizure risk in non-epileptic patients with ADHD who used stimulants. The patients were diagnosed between 1993 and 1998 and were followed either by office visit or by telephone in 1999. They found that three out of 30 patients with IED had a seizure during follow-up. The patients had long latencies to seizure occurrence, (10 months, 14 months and 3 years). They concluded that epileptiform EEG in patients with ADHD was suggested to predict considerable risk for the eventual occurrence of seizure. In contrast to their study, none of our 27 children with IED without previous history of epilepsy, developed seizure during follow-up. In addition, seizure frequency in cases with active epilepsy, did not change from baseline. Our finding is concordant with the study by Gucuyener et al. [11], which investigated use of MPH for ADHD in patients with epilepsy or EEG abnormalities. In this study a subgroup of 15 nonepileptic patients had epileptiform EEG at baseline and none of them had a seizure during the study period of
1 year. Several short term studies have reported that MPH is safe to use in both ADHD children with well controlled [25–27], and difficult to treat epilepsy [28–30], and that 61–73% of children with epilepsy had benefit from MPH. One study reported that use of combination of a behavioral management and MPH 0.3–1 mg/kg/day for 3 months improved ADHD symptoms in 61% of 18 patients with refractory epilepsy [29]. Our finding was similar regarding the use of MPH. In addition, we found no differences in maintenance on MPH at 1 and 2 years follow-up between the IED and the non-IED groups. In recent studies it was suggested that clinicians appeared to be reluctant to diagnose and initiate treatment for ADHD in children with epilepsy [17,28]. We could not confirm these findings. All our children with epilepsy were initially treated with MPH and the patients with epilepsy were assessed at younger age (8.5 years) compared to the patients without epilepsy (10.3 years). One can hypothesize that children with epilepsy may have more ADHD symptoms which may contribute to early detection. It may be difficult to delineate ADHD symptoms from subtle seizures, especially in cases with inattentive subtype of ADHD which predominate in both epilepsy patients [2,15,31,32], and in patients with IED [7]. Another enigmatic association is that frequent IED (in more than 10% of the record) in the awake EEG can impair cognitive performance in children [33], and in some cases ADHD symptoms may be related to frequent epileptiform discharges activated by sleep as previously reported [34–37]. In these patients a careful assessment including neuropsychological examination is needed before an eventual trial with AED. In our study in order to clarify differential diagnosis, and treatment choices an additional sleep EEG was performed in 15 and longterm video-EEG monitoring in five cases. One of our cases had continuous spike wave during slow sleep on EEG recording. This case was treated with levetiracetam, but significant reduction of ADHD symptoms was not detected in this case. In addition, one may be aware of the possibility of temporary overtreatment with AEDs in cases with IED without confirmed epilepsy diagnosis. The patients with IED without epilepsy were temporarily treated with AEDs during the first year of follow up (10 children) because this was a study on real-life patients. In these cases the clinicians chose to treat due to uncertainty regarding diagnosis. Our findings warranted caution regarding to assessment and use of AED (in order not to overestimate the temporarily occurrence of IED) in ADHD children with IED. Overall we believe that our findings may have two implications for clinical practice: (1) the use of MPH is safe in ADHD children with IED regardless of previous history of epilepsy; (2) the maintenance on MPH was similar in the groups of children with and without IED. 4.2. Limitations and strengths of study
Table 3 39 ADHD patients with IED. Demographics
IED-epilepsy (n = 12)
IED-non-epilepsy (n = 27)
Age, mean SD Gender, female (%) MPH at baseline n (%) MPH positive response
8.5 2.3 3 (25%) 12 (100%) 10/12 (83.3%)
10.3 2.7 8 (29.6%) 24/27 (88.9%) 20/24 (83.3%)
1 year Sz occurrence MPH AED monotherapy AED polytherapy
3 8/12 (66.7%) 10 2
0 20/24 (83.3%) 10 0
2 years Sz occurrence MPH AED monotherapy AED polytherapy
3 7/12 (58.3%) 8 2
0 19/24 (79.2%) 2 0
p-Value
1 0.46
0.26
The low number of cases with EA (n = 39) is a limitation in our study as well as the lack of a prospective and randomized controlled trial. We did not carry out a reliability test of diagnosis or measure the exact dosage of MPH, which also are limitations of our study. Strengths include the relatively large and unselected cohort, as all children with suspected ADHD were referred to the center. Our findings may be helpful to clinicians concerning MPH as a safe treatment option in this group of patients. In order to strengthen and confirm these findings future studies might include large and prospective samples within ADHD and IED, and who be able to compare follow-up for large subgroups (with and without previous epilepsy).
0.19
AED, antiepileptic drug; MPH, methylphenidate; IED, interictal epileptiform discharges; Sz, epileptic seizures.
5. Conclusions The study demonstrated that despite the occurrence of IED and epilepsy the use of MPH for patients with ADHD was safe during
D. Socanski et al. / Seizure 25 (2015) 80–83
2 years of follow-up. IED predict the Sz occurrence in children with previous epilepsy, but does not necessarily suggest an increased seizure risk. Conflict of interest The authors declare that there is no conflict of interest. References [1] Holtmann M, Becker K, Kentner-Figura B, Schmidt MH. Increased frequency of rolandic spikes in ADHD children. Epilepsia 2003;44:1241–4. [2] Hesdorffer DC, Ludvigsson P, Olafsson E, Gudmundsson G, Kjartansson O, Hauser WA. ADHD as a risk factor for incident unprovoked seizures and epilepsy in children. Arch Gen Psychiatry 2004;61:731–6. [3] So EL. Interictal epileptiform discharges in persons without a history of seizures: what do they mean? J Clin Neurophysiol 2010;2(27):9–238. [4] Boutros N. Epileptiform discharges in psychiatric patients: a controversy in need of resurrection. Clin EEG Neurosci 2009;40:239–44. [5] Shelley BP, Trimble MR. All that spikes is not fits, mistaking the woods for the trees: the interictal spikes – an EEG chameleon in the interface disorders of brain and mind: a critical review. Clin EEG Neurosci 2009;40:245–61. [6] Wirrell EC. Prognostic significance of interictal epileptiform discharges in newly diagnosed seizure disorders. J Clin Neurophysiol 2010;27:239–48. [7] Socanski D, Herigstad A, Thomsen PH, Dag A, Larsen TK. Epileptiform abnormalities in children diagnosed with attention deficit/hyperactivity disorder. Epilepsy Behav 2010;19:483–6. [8] The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999;56:1073–86. [9] Buitelaar J, Medori R. Treating attention-deficit/hyperactivity disorder beyond symptom control alone in children and adolescents: a review of the potential benefits of long-acting stimulants. Eur Child Adolesc Psychiatry 2010;19: 325–40. [10] Curatolo P, Paloscia C, D’Agati E, Moavero R, Pasini A. The neurobiology of attention deficit/hyperactivity disorder. Eur J Paediatr Neurol 2009;13: 299–304. [11] Gucuyener K, Erdemoglu AK, Senol S, Serdaroglu A, Soysal S, Kockar AI. Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities. J Child Neurol 2003;18: 109–12. [12] Baptista-Neto L, Dodds A, Rao S, Whitney J, Torres A, Gonzalez-Heydrich J. An expert opinion on methylphenidate treatment for attention deficit hyperactivity disorder in pediatric patients with epilepsy. Expert Opin Investig Drugs 2008;17:77–84. [13] Torres AR, Whitney J, Gonzalez-Heydrich J. Attention-deficit/hyperactivity disorder in pediatric patients with epilepsy: review of pharmacological treatment. Epilepsy Behav 2008;12:217–33. [14] Parisi P, Moavero R, Verrotti A, Curatolo P. Attention deficit hyperactivity disorder in children with epilepsy. Brain Dev 2010;32:10–6. [15] Socanski D, Aurlien D, Herigstad A, Thomsen PH, Larsen TK. Epilepsy in a large cohort of children diagnosed with attention deficit/hyperactivity disorders (ADHD). Seizure 2013;22:651–5. [16] Richer LP, Shevell MI, Rosenblatt BR. Epileptiform abnormalities in children with attention-deficit-hyperactivity disorder. Pediatr Neurol 2002;26:125–9.
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Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Attention deficit/hyperactivity disorder and interictal epileptiform discharges: It is safe to use methylphenidate? Dobrinko Socanski a,*, Dag Aurlien b, Anita Herigstad c, Per Hove Thomsen d, Tor Ketil Larsen e,f a
Stavanger University Hospital, Division of Psychiatry, Department of Child and Adolescent Psychiatry, Stavanger, Norway Stavanger University Hospital, Department of Neurology, Stavanger, Norway Stavanger University Hospital, Department of Clinical Neurophysiology, Stavanger, Norway d Centre for Child and Adolescent Psychiatry, University of Aarhus, Denmark e Stavanger University Hospital, Division of Psychiatry, Stavanger, Norway f Department of Clinical Medicine, University of Bergen, Norway b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 September 2014 Received in revised form 5 November 2014 Accepted 3 January 2015
Purpose: This study investigated whether interictal epileptiform discharges (IED) on a baseline routine EEG in children with ADHD was associated with the occurrence of epileptic seizures (Sz) or influenced the use of methylphenidate (MPH) during 2 years follow-up. Methods: A retrospective chart-review of 517 ADHD children with EEG revealed IED in 39 cases. These patients (IED group) were matched on age and gender with 39 patients without IED (non-IED group). We measured at baseline, 1 year and 2 years Sz occurrence, the use of MPH and antiepileptic drug (AED). Results: At baseline, 12 patients in the IED group had active epilepsy and three of them had Sz during the last year. 36 (92.3%) patients were treated with MPH. Initial positive response to MPH was achieved in 83.3% compared with 89.2% in the non-IED group. At 1 and 2 years follow-up, three patients who also had Sz at baseline and difficult to treat epilepsy, had Sz, without changes in seizure frequency. We found no statistically significant differences between the groups with respect to MPH use at 1 year and at 2 years. Ten patients from IED group, who did not have confirmed epilepsy diagnosis, temporarily used AEDs during the first year of follow-up. Conclusion: Despite the occurrence of IED, the use of MPH was safe during 2 years follow-up. IED predict the Sz occurrence in children with previous epilepsy, but does not necessarily suggest an increased seizure risk. A caution is warranted in order not to overestimate the significance of temporarily occurrence of IED. ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Attention-deficit/hyperactivity disorder (ADHD) Interictal epileptiform discharges (IED) Epilepsy Methylphenidate (MPH) Antiepileptic drug (AED)
1. Introduction Interictal epileptiform discharges (IED) on EEG may occur in children with attention deficit/hyperactivity disorder (ADHD) and contribute to the occurrence of ADHD symptoms [1]. ADHD in children is reported to be a risk factor for incident unprovoked seizures and epilepsy [2], and suggested to predispose for epilepsy development as do autism spectrum disorder and cerebral palsy [3–5]. EEGs performed in children with new onset seizures show IED in approximately 18–50%, and IED occurrence is predictive of
* Corresponding author at: Stavanger University Hospital, Division of Psychiatry, PB 8100, 4068 Stavanger, Norway. Tel.: +47 51515937; fax: +47 51518000. E-mail addresses: [email protected], [email protected] (D. Socanski).
seizure recurrence, particularly in patients with idiopathic epilepsy [6]. However, the prognostic value of IED in ADHD children with and without previous epilepsy, regarding occurrence of seizure during early illness course, is unknown [7]. Methylphenidate (MPH) is the psychostimulant drug most frequently used for the treatment of ADHD and there is overwhelming evidence for its benefit [8–10]. It is considered to be safe in children without epilepsy. On the other hand, there is limited research about the use of MPH in patients with epilepsy [11–15] and children with ADHD and IED [16]. A recent study found that clinicians appeared to be reluctant to diagnose and initiate treatment for ADHD in children with epilepsy [17]. It is thus of clinical importance whether it is safe to use MPH in ADHD with IED. The aims of the present study were to investigate whether IED occurrence at ADHD assessment could predict the occurrence of
http://dx.doi.org/10.1016/j.seizure.2015.01.002 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
D. Socanski et al. / Seizure 25 (2015) 80–83
epileptic seizures (Sz) and influence the use of MPH during 2 years follow-up.
81
3. Results 3.1. Demographic and clinical characteristics at baseline
2. Materials and methods 2.1. Participants and procedure Our study was conducted at Stavanger University Hospital on consecutive patients admitted to assessment during a 6 years period; January 2000–December 2005. We carried out a retrospective chart review of all patients aged 5–14 who were diagnosed with ADHD in accordance with DSM-IV TR [18]. For details see previous publications [7,15]. A digitized 20 min routine awake EEG with 21 electrodes (10–20 system) including hyperventilation and photic stimulation was performed. The EEGs were classified as either epileptiform or nonepileptiform according to the presence or absence of IED. IED were defined as spikes or spikewave complexes, isolated or occurring serially (in runs) without evident clinical signs of a Sz. The IED index was estimated as percentage of time in three categories (0%, <1%, 1%). Sz, epilepsy and epileptic syndromes were diagnosed according to the classification system of the International League Against Epilepsy [19–21]. Sz frequency during the last year was defined as Sz free, 1–12 Sz per year, and >12 Sz per year, and antiepileptic drug (AED) treatment was classified as untreated, monotherapy or polytherapy. We also analyzed data about comorbid disorders of psychological development and IQ level (IQ > 85, IQ < 85). We were able to carry out EEG at baseline in 517 out of 607 cases (85.4%), and 39 cases (7.5%) had IED. We studied 2 years follow-up of these 39 cases (IED group) and compared them with 39 randomly selected cases matched for age and gender without EA (non-IED group). At baseline, 1 and 2 years we measured the Sz occurrence and frequency, the use of AEDs, and the use of MPH. MPH was administered according to the Norwegian Guidelines [22], in dosage 0.5–1.2 mg per kilo either three times daily (shortacting MPH) or once per day (slow- acting MPH). During titration with MPH the use of AEDs was stable. The response to MPH was evaluated after several weeks of treatment (4–6 weeks). The response was considered positive if significant reduction in ADHD symptoms scores assessed with ADHD IV rating scale was found [23], in addition to parents and teachers observations. During follow-up we registered whether MPH was given or not. In the IED group at least one follow-up EEG was carried out, an additional sleep EEG was performed in 15 cases and long-term video-EEG monitoring in five cases because of diagnostic difficulties (suspect Sz).
Due to matching procedures there were no differences between the groups regarding age and gender. Proportion of disorders of psychological development or IQ level >85 showed also no differences (Table 1). As reported in previous publications we found that, among the 39 children with IED, 54% had generalized IED, 41% had focal IED, and 5% had mixed IED [7]. The majority 36/ 39 (92%) of cases with IED had short duration of IED, the IED index was <1%. The IED group had significantly more often predominantly inattentive subtype of ADHD (41%) compared to the nonIED group (15.4%). In the IED group 12 patients had epilepsy with recent seizures (Sz) (last 5 years). During the last year, nine patients were seizure free, two had 1–12 Sz and one had more than 12 Sz. We found that 75% (9/12) had localization-related epilepsy and 25% generalized epilepsy. All patients with epilepsy received AEDs; 10 monotherapy and two polytherapy. No patients in the non-IED group had epilepsy. At baseline, 36/39 (92.3%) patients with IED were treated with MPH. The three patients that were not given MPH had no previous epilepsy. Initial positive response to MPH was achieved in 30/36 (83.3%) of children with IED; 10/12 (83.3%) of the children with epilepsy and 20/24 (83.3%) of the cases without epilepsy. In the non-IED group of the 37 initially treated cases, 33/37 (89.2%) had positive effect of MPH treatment. 3.2. 1 and 2 years follow-up At 1 and 2 years follow-up only three patients, all from IED group, had experienced Sz (Table 2). These three patients had pharmacoresistant epilepsy at baseline and had no change in seizure frequency. We found no significant differences regarding the use of MPH. Within the IED group we did not find statistically significant differences between the cases with and without epilepsy regarding use of MPH at 1 and 2 years follow-up (Table 3). At 1 year follow-up 22 patients in the IED group were treated with AEDs, 12 of them had epilepsy (monotherapy 10, polytherapy two cases). At 2 years 12 children from IED group used AEDs, 10 of them had epilepsy (eight monotherapy, two polytherapy). During follow-up we carried out control EEG in the IED group (one case missing). We found IED in 12 (31.2%) cases; focal in 10 and generalized in 2. In the IED-cases with epilepsy, four cases had only focal IED. 4. Discussion
2.2. Statistical analyses Continuous demographic and clinical variables in subjects with and without IED were compared using Student’s t-tests for continuous and symmetrically distributed data and Mann– Whitney tests for continuous and skewed data. Proportions were compared using Chi-squared test or Fisher’s exact test. Methods for matched samples (paired-samples t-tests, McNemar’s tests) were also applied. However, the application of methods for matched samples did not alter the conclusions. A p-value of <0.05 was considered statistically significant. 2.3. Approval The study was approved by the Norwegian Data Inspectorate and by the Regional Committee on Medical Research Ethics in region West (nr. 010.07). The study was performed in accordance with ethical standards of the Declaration of Helsinki. Written informed consent was obtained from parents.
The main finding of this study was that it seems to be safe to give MPH to patients with ADHD even if they have IED on routine Table 1 ADHD patients with and without IED at baseline. Demographics
IED-group (n = 39)
Non-IED group (n = 39)
Age, mean SD Gender, female (%) Developmental disorders IQ >85 (%) ADHD-I (%) Epilepsy Sz during the last 5 years Sz during the last year MPH, at baseline MPH, positive response
9.7 2.7 11 (28.2%) 22/39 (56.4%) 21/38 (55.3%) 16/39 (41%) 12/39 (30.8%) 12/12 (100%) 3/12 (25%) 36/39 (92.3%) 30/36 (83.3%)
9.7 2.7 11 (28.2) 17/39 (43.6%) 23/34 (67.6%) 6/39 (15.4%) 0 0 0 37/39 (94.9%) 33/37 (89.2%)
p-Value
0.26 0.28 0.01
0.64 0.47
ADHD-I, ADHD predominantly inattentive subtype; MPH, methylphenidate; IED, interictal epileptiform discharges; IQ, intelligence quotient; Sz, epileptic seizures.
D. Socanski et al. / Seizure 25 (2015) 80–83
82 Table 2 1 and 2 years follow-up. IED-group (n = 39)
Non-IED group (n = 39)
Age, mean SD Gender, female (%)
9.7 2.7 11 (28.2%)
9.7 2.7 11 (28.2%)
1 year Sz occurrence MPH AED monotherapy AED polytherapy
3 28/36 (77.8%) 20 2
0 33/37 (89.2%) 0 0
2 years Sz occurrence MPH AED monotherapy AED polytherapy
3 26/36 (72.2%) 10 2
0 27/37 (73%) 0 0
p-Value
0.19
0.49
AED, antiepileptic drug; MPH, methylphenidate; IED, interictal epileptiform discharges; Sz, epileptic seizure.
EEG or epilepsy at baseline. We found no increased occurrence of Sz during 2 years follow-up. Among children with IED, Sz did occur only in those with a previous history of difficult to treat epilepsy. No other cases in this study had Sz during follow-up. The use of MPH was similar in the both groups (with and without IED). 4.1. Seizure risk in ADHD children with IED and the use of MPH and AEDs The seizure risk in ADHD children with IED in the EEG has been discussed in some publications [11,24]. Hemmer et al. [24] investigated the seizure risk in non-epileptic patients with ADHD who used stimulants. The patients were diagnosed between 1993 and 1998 and were followed either by office visit or by telephone in 1999. They found that three out of 30 patients with IED had a seizure during follow-up. The patients had long latencies to seizure occurrence, (10 months, 14 months and 3 years). They concluded that epileptiform EEG in patients with ADHD was suggested to predict considerable risk for the eventual occurrence of seizure. In contrast to their study, none of our 27 children with IED without previous history of epilepsy, developed seizure during follow-up. In addition, seizure frequency in cases with active epilepsy, did not change from baseline. Our finding is concordant with the study by Gucuyener et al. [11], which investigated use of MPH for ADHD in patients with epilepsy or EEG abnormalities. In this study a subgroup of 15 nonepileptic patients had epileptiform EEG at baseline and none of them had a seizure during the study period of
1 year. Several short term studies have reported that MPH is safe to use in both ADHD children with well controlled [25–27], and difficult to treat epilepsy [28–30], and that 61–73% of children with epilepsy had benefit from MPH. One study reported that use of combination of a behavioral management and MPH 0.3–1 mg/kg/day for 3 months improved ADHD symptoms in 61% of 18 patients with refractory epilepsy [29]. Our finding was similar regarding the use of MPH. In addition, we found no differences in maintenance on MPH at 1 and 2 years follow-up between the IED and the non-IED groups. In recent studies it was suggested that clinicians appeared to be reluctant to diagnose and initiate treatment for ADHD in children with epilepsy [17,28]. We could not confirm these findings. All our children with epilepsy were initially treated with MPH and the patients with epilepsy were assessed at younger age (8.5 years) compared to the patients without epilepsy (10.3 years). One can hypothesize that children with epilepsy may have more ADHD symptoms which may contribute to early detection. It may be difficult to delineate ADHD symptoms from subtle seizures, especially in cases with inattentive subtype of ADHD which predominate in both epilepsy patients [2,15,31,32], and in patients with IED [7]. Another enigmatic association is that frequent IED (in more than 10% of the record) in the awake EEG can impair cognitive performance in children [33], and in some cases ADHD symptoms may be related to frequent epileptiform discharges activated by sleep as previously reported [34–37]. In these patients a careful assessment including neuropsychological examination is needed before an eventual trial with AED. In our study in order to clarify differential diagnosis, and treatment choices an additional sleep EEG was performed in 15 and longterm video-EEG monitoring in five cases. One of our cases had continuous spike wave during slow sleep on EEG recording. This case was treated with levetiracetam, but significant reduction of ADHD symptoms was not detected in this case. In addition, one may be aware of the possibility of temporary overtreatment with AEDs in cases with IED without confirmed epilepsy diagnosis. The patients with IED without epilepsy were temporarily treated with AEDs during the first year of follow up (10 children) because this was a study on real-life patients. In these cases the clinicians chose to treat due to uncertainty regarding diagnosis. Our findings warranted caution regarding to assessment and use of AED (in order not to overestimate the temporarily occurrence of IED) in ADHD children with IED. Overall we believe that our findings may have two implications for clinical practice: (1) the use of MPH is safe in ADHD children with IED regardless of previous history of epilepsy; (2) the maintenance on MPH was similar in the groups of children with and without IED. 4.2. Limitations and strengths of study
Table 3 39 ADHD patients with IED. Demographics
IED-epilepsy (n = 12)
IED-non-epilepsy (n = 27)
Age, mean SD Gender, female (%) MPH at baseline n (%) MPH positive response
8.5 2.3 3 (25%) 12 (100%) 10/12 (83.3%)
10.3 2.7 8 (29.6%) 24/27 (88.9%) 20/24 (83.3%)
1 year Sz occurrence MPH AED monotherapy AED polytherapy
3 8/12 (66.7%) 10 2
0 20/24 (83.3%) 10 0
2 years Sz occurrence MPH AED monotherapy AED polytherapy
3 7/12 (58.3%) 8 2
0 19/24 (79.2%) 2 0
p-Value
1 0.46
0.26
The low number of cases with EA (n = 39) is a limitation in our study as well as the lack of a prospective and randomized controlled trial. We did not carry out a reliability test of diagnosis or measure the exact dosage of MPH, which also are limitations of our study. Strengths include the relatively large and unselected cohort, as all children with suspected ADHD were referred to the center. Our findings may be helpful to clinicians concerning MPH as a safe treatment option in this group of patients. In order to strengthen and confirm these findings future studies might include large and prospective samples within ADHD and IED, and who be able to compare follow-up for large subgroups (with and without previous epilepsy).
0.19
AED, antiepileptic drug; MPH, methylphenidate; IED, interictal epileptiform discharges; Sz, epileptic seizures.
5. Conclusions The study demonstrated that despite the occurrence of IED and epilepsy the use of MPH for patients with ADHD was safe during
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