Attention deficit hyperactivity disorder in children with epilepsy

Brain & Development 32 (2010) 10–16 www.elsevier.com/locate/braindev

Review article

Attention deficit hyperactivity disorder in children with epilepsy Pasquale Parisi a, Romina Moavero c, Alberto Verrotti b, Paolo Curatolo c,* a

Department of Pediatrics – ‘‘La Sapienza” University of Rome, Rome, Italy b Department of Pediatrics, University of Chieti, Chieti, Italy c Department of Neuroscience, Pediatric Neurology, Psychiatric Unit, ‘‘Tor Vergata” University of Rome, Rome 00133, Italy Received 21 January 2009; received in revised form 17 March 2009; accepted 22 March 2009

Abstract Attention deficit hyperactivity disorder (ADHD) is more frequent in children with epilepsy than in general pediatric population. Several factors may contribute to this comorbidity, including the underlying brain pathology, the chronic effects of seizures and of the epileptiform EEG discharges, and the effects of antiepileptic drugs. Symptoms of ADHD are more common in some specific types of epilepsies, such as frontal lobe epilepsy, childhood absence epilepsy and Rolandic epilepsy, and may antedate seizure onset in a significant proportion of cases. In epileptic children with symptoms of ADHD, treatment might become a challenge for child neurologists, who are forced to prescribe drugs combinations, to improve the long-term cognitive and behavioral prognosis. Treatment with psychotropic drugs can be initiated safely in most children with epilepsy and ADHD symptoms. Ó 2009 Elsevier B.V. All rights reserved. Keywords: ADHD; Frontal lobe epilepsy; Childhood absence epilepsy; Rolandic epilepsy; Methylphenidate; Antiepileptic drugs

1. Introduction Attention deficit/hyperactivity disorder (ADHD) is a common brain disorder with onset in early childhood, due to structural and functional abnormalities in widespread, but specific areas of the brain [1]. ADHD is a frequent comorbidity experienced by children with epilepsy, has a negative impact on their quality of life, and represents a significant risk factor for academic underachievement [2]. ADHD has been reported in epilepsy since the Fifties of the 20th century [3]. More recently a high association between the two disorders, with an increasing evidence of a bidirectional relationship, has been postulated [4– 7]. The mechanisms underlying attention deficits are still unknown and appear to be different between focal and generalized epilepsies. In the clinical practice, this association may represent a challenge for child neurologists *

Corresponding author. Tel.: +39 6 20900249; fax: +39 6 20900018. E-mail address: [email protected] (P. Curatolo).

0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.03.005

since antiepileptic therapy and drugs used to treat ADHD may aggravate the clinical picture of each other [8,9]. The purpose of this article is to discuss the current understanding of the pathogenesis and the neurobiological links among ADHD and epilepsy, and provide a practical review of the major considerations that guide child neurologists to tailor treatments according to clinical needs. 2. Literature search strategy A scoping search on PubMed was undertaken to identify pertinent articles using ‘‘epilepsy and ADHD” as key words. Trials recruiting only patients with single seizure or febrile convulsions, people over 18 years old and mixed age groups were not considered. 3. Epidemiology An increased risk for seizures is a symptom that is often associated with ADHD [10]. In ADHD children

P. Parisi et al. / Brain & Development 32 (2010) 10–16

the prevalence for epileptiform EEG discharges range from 5% to 60% [11]. The predictive value of epileptiform EEG abnormalities for developing subsequent seizures in ADHD children is 14% [11]. Children with epilepsy have a significant risk for ADHD, with clinical studies suggesting a prevalence of 30–40% [12,13], that is much higher than in the general pediatric population [14,15]. ADHD was reported to be the most common disorder in preschoolers and schoolaged children with epilepsy [12], with equal representation of boys and girls [10,14]. In an epilepsy sample observed in a Tertiary Centre characterized by early age of onset, significant duration of epilepsy, high seizure frequency, and intractability, the proportion of children meeting DSM-IV criteria for either ADHD-C or ADHD-I was over 60% [16]. However, ADHD is also significantly more prevalent in new onset epilepsy than healthy controls (31% versus 6%) [17,18]. The interpretation of these studies is difficult, as they differ widely in the number of patients studied, and the severity and type of epilepsy, as well as in the methods used to make the ADHD diagnosis.

11

hyperactivity [26]. Neuroimaging studies have reported several abnormalities in brain structure in ADHD, including decreased overall cerebral tissue volume with preferential involvement of the prefrontal areas, cerebellum, and caudate, also giving convincing evidence of fronto-striatal dysregulation in ADHD [19]. Although there are suggestions of predominance of frontal cortex abnormalities [27], more recent data showed a significant reduction in all lobes bilaterally [28]; ADHD children also showed a significant decrease in surface area in cortical folding bilaterally. These findings could be consistent with onset early in neural development, during gestation through infancy when folding is increasing. fMRI findings suggest that children with ADHD have anomalous development of cortical systems and atypical motor and sensory cortex activation [29]. Furthermore, striatal glutamate concentration is higher in ADHD children than in the controls [30]. Animal models of ADHD suggest that synaptic abnormality in excitatory glutamatergic transmission may contribute to vulnerability for epilepsy and ADHD, and could help to identify common pathophysiological events between these two conditions [31–33].

4. Pathophysiology 5. Epilepsies usually associated with ADHD Attention is subserved by many brain structures, and neuroimaging studies showed evidence of at least three anatomic networks that function separately and together to support various aspects of attention [19,20]. These interacting networks are (1) a vigilance network comprising the right frontal and right parietal lobes; (2) an executive attention network including the left lateral frontal areas and the anterior cingulated; (3) an orienting network consisting of parietal, midbrain and thalamic circuits [19,21,22]. Different impairment of these systems may cause inattention, hyperactivity/ impulsivity, or both. Several hypotheses have been proposed regarding the possible pathophysiology of the comorbidity between ADHD and epilepsy in the context of brain development, including the effects of chronic seizures and of EEG epileptiform discharges, as well as the AEDs [23,24]. However, ADHD with epilepsy and ADHD without epilepsy seem to have common pathogenetic mechanisms, suggesting that inattention and hyperactive/impulsive behavior commonly observed in children with epilepsy truly constitute ADHD [25]. Increasing evidence suggests that ADHD may sometimes antedate the onset of epilepsy, indicating that both these conditions may represent epiphenomena of underlying neurobiological abnormalities that remain to be identified [10]. Quantitative MRI demonstrated that ADHD in epilepsy is associated with significantly increased grey matter in distributed regions of the frontal lobe and significant smaller brainstem volume [18]. It is known that lesions to the prefrontal cortex produce a profile of inattention, impulsivity, poor planning and

Attention problems are frequently reported in children with intractable symptomatic epilepsy, as well as in idiopathic epilepsies [13,34,35]. Patients who have generalized epilepsies are more frequently reported to have attentional difficulties than patients suffering from partial seizures. Furthermore, certain epilepsy syndromes may predispose to ADHD-like behavior [14,15,36]. ADHD is a prevalent comorbidity of new onset idiopathic epilepsy, associated with a series of cognitive and behavioral complications that antedate epilepsy onset in a significant proportion of cases, and appear related to neurodevelopmental abnormalities in brain structures [18]. The presence of ADHD symptoms at the time of epilepsy onset is a major marker of abnormal cognitive development [37]. 5.1. Frontal lobe epilepsy (FLE) Frontal lobe epilepsy shares behavioral features with ADHD, presenting in some patients with impulsivity, disinhibition, and excitement/irritability [38,39]. The prefrontal cortex plays a key role in the neuronal networks responsible for executive functions, including inhibition control and set shifting [40,41]. Therefore, the pattern of behavioral and cognitive impairment observed in some patients with FLE might be related to an epilepsy-induced impairment of these networks [42,43]. There is a critical early stage of brain maturation during which frontal lobes epileptiform EEG discharges perturb the development of brain system that underpin

12

P. Parisi et al. / Brain & Development 32 (2010) 10–16

attention and hyperactive disorders, therefore interfering with the normal development of learning processes [44,45]. In executive functions, children with epilepsy and ADHD scored significantly lower than both controls and children with epilepsy without ADHD [18]. The co-occurrence of ADHD in children with symptomatic epilepsy and frontal lobe lesions is well-known; high rates of ADHD have been reported in FLE associated with tuberous sclerosis [46,98]. However, the majority (about 67%) of children affected by nonlesional FLE also exhibit symptoms of ADHD, and in these patients seizure control does not guarantee the concomitant improvement of the hyperactive/impulsive behavior and of inattention [47]. The side of the seizure focus may contribute to executive dysfunction in patients with epilepsy; in particular, a left frontal focus can interfere with inhibitory processes [48]. 5.2. Childhood absence epilepsy (CAE) Children affected by CAE are known to have difficulty in visual sustained attention, verbal and non-verbal attention, and memory, despite a good response to antiepileptic medications and normal intelligence [49– 54]. ADHD is the most common psychiatric diagnosis in children affected by CAE, with a prevalence of the inattentive subtype [14,34]. The recent study by Caplan et al. reported a psychiatric comorbidity, including ADHD, in 61% of children with CAE, with only a minority having this comorbidity adequately treated [55]. Behavioral outcome is significantly worse in the patients with poor seizure control, even if a poor educational and social outcome can also be found in those children reaching an adequate seizure control [34,56]. 5.3. Rolandic epilepsy Rolandic spikes are clearly more frequent in ADHD children than in the general pediatric population, even if there is still no clear explanation for this association. According to a neuropsychological study on ADHD children with and without Rolandic epileptiform discharges, Rolandic spikes aggravate the course of ADHD and predispose to increased impulsivity [57]. Children suffering from benign epilepsy with centrotemporal spikes have been shown to have a greater susceptibility to distracters occurring in their visual field compared to healthy children and children affected by idiopathic generalized epilepsies [58]. These findings suggest that less efficient attentional control could be a specific feature of benign epilepsy with centrotemporal spikes. ADHD children with Rolandic spikes show a deficient inhibition of an ongoing response, and an increased impulsivity, compared to ADHD children without EEG abnormalities [59]. These problems are

considered a result of the frequent discharges during sleep, or of a poor daytime alertness related to sleep fragmentation [60–62]. More recent studies reported subtle neurocognitive deficits, such as in the domain of visuo-spatial memory, related to Rolandic focus [61,63]. 5.4. Sleep-related epilepsies Epileptic syndromes with nocturnal seizures and unfavourable outcomes are associated with poor sleep habits and significant psychiatric problems [64,65]. Prolonged focal epileptic activity during sleep, as occurring in electrical status epilepticus during slow-wave sleep (ESES), would interfere with local slow wave activity, impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions [66]. ESES has been associated with attentional deficits and hyperactivity [67]. Sleep activates both focal and generalized spikes in about one third of all epileptic patients. Nocturnal seizures significantly reduce sleep efficiency, increase time to first REM period, and increase drowsiness as measured by the maintenance of wakefulness test [68]. Sleep fragmentation/disruption could be a cause of inattention and hyperactivity, as a consequence of the epileptic disease course. Nocturnal frontal lobe epilepsy, a condition primarily characterized by seizures occurring during sleep, originating from the orbitofrontal or mesial frontal regions, can be frequently associated with ADHD symptoms [69]. There is a topographic link among frontal EEG discharges, impaired executive functions and progressive decline of sleep-related cognitive functions. 5.5. Assessment A child with epilepsy and symptoms of ADHD should be assessed carefully before initiating treatment. Formal neuropsychological testing can help assess cognitive functions, and can detect the presence of learning disabilities. EEG monitoring can be useful to detect the presence of unrecognized seizures, particularly if inattention is the predominant symptom. Epileptiform EEG discharges may have subtle effects on brain function and can affect attention. The proper identification and treatment of common sleep disorders represents an essential part of the overall evaluation and management of patients with ADHD and epilepsy. Video-polysomnography is able to recognize and identify all types of possible sleep disorders which are often associated both to epilepsy and ADHD [70]; overnight sleep-EEG studies are recommended particularly in patients presenting a cognitive worsening. In particular the child neurologist should: (1) look for temporal relationships between the course of the epilepsy, and the onset of ADHD; (2) check sleep qual-

P. Parisi et al. / Brain & Development 32 (2010) 10–16

13

ity/fragmentation/efficiency or even specific sleep disorders; (3) perform a comprehensive neuropsychological evaluation, particularly among children whose academic skills/abilities are clearly worsening; (4) assess for additional comorbid illnesses, such as learning and psychiatric disorders.

symptoms may improve by achieving better seizure control, decreasing AED polytherapy and possible drug interactions, or switching to an AED with fewer cognitive and behavioral effects [9].

6. Treatment

In patients with epilepsy, particular consideration should be given to the possibility that seizures may worsen during treatment with ADHD medications. Methylphenidate (MPH) has been the most studied ADHD medication for children with comorbid epilepsy. Although case reports have warned about new onset seizures in patients treated with MPH, controlled trials of MPH in patients with epilepsy and ADHD have noted significant improvements in ADHD symptoms without an exacerbation of seizures [84–86]. Only a small number of patients with active epilepsy experiences seizure exacerbation [84]. Despite the paucity of data, studies suggest that MPH should be considered as a treatment option in children with moderate or severe ADHD and well-controlled seizures [84]. One year treatment with MPH may be beneficial to cause an enduring normalization of neural correlates of attention. In a single open label trial of atomoxetine in patients with ADHD and epilepsy, only 1 out of 17 patients showed an increase in the number of epileptic seizures in the first 2 weeks of treatment [87]. Only one isolated case of atomoxetine-induced seizure, following a drug overdose, was reported [88]. A more recent meta-analysis has confirmed that incidence rates of seizures as adverse events were not significantly different between methylphenidate, atomoxetine, and placebo [89]. Furthermore, particular caution should be used in this group of patients, to avoid negative pharmacokinetic interactions between drugs used to treat ADHD and AEDs. No interactions with any of the AEDs has been reported for atomoxetine [90], while MPH can increase phenytoin serum concentrations [91]. Furthermore, MPH serum concentrations may be lowered by the contemporary administration of carbamazepine, thus leading to a loss of efficacy [92]. If the seizures are occurring less than once per month, and there is at least moderate impairment from the ADHD, then either MPH or atomoxetine should be started, keeping in mind that MPH has the strongest evidence base for efficacy and safety in this population. If these fail, then a trial of guanfacine or clonidine can be considered depending on the ADHD’s severity [93,94]. Modafinil and tricyclic antidepressants should be reserved for children with marked impairment from ADHD plus epilepsy whose ADHD symptoms have failed to improve with other treatments [9]. In epileptic children with ADHD, sleep disruption should be promptly identified and properly treated. Melatonin therapy, due to improving sleep organization,

Treatment of children with combined symptoms of ADHD and epilepsy can represent a challenge for clinicians, since several AEDs are known to cause behavioral activity that may exacerbate underlying ADHD symptoms, and psychotropic medications used in ADHD may lower the seizure threshold. Methylphenidate and Atomoxetine are the most effective drugs in reducing ADHD symptoms, and they both significantly increase activation in key cortical and subcortical regions subserving attention and executive function [71,72]. 6.1. Choosing the best antiepileptic drug in ADHD comorbidity Barbiturates can exacerbate existing behavior problems, especially hyperactivity, while having minimal effect on children with average abilities and no previous behavior disturbance [73]. Valproate has been established as a mood stabilizer and could be effective in reducing impulsivity in children with ADHD and comorbid oppositional-defiant disorder [74,75]. Topiramate, one of the newer antiepileptic agents which have proved to be highly effective in controlling seizures, may cause relevant behavioral changes, so it must be used with caution in epileptic children with ADHD [9]. Levetiracetam does not impair frontal lobe functions and could be a treatment option in children with ADHD and nocturnal focal epileptic discharges [76]. For some patients with partial epilepsy, it might be helpful to switch to an AED like carbamazepine or oxcarbazepine, for which there is evidence of positive effects on the behavioral and mood problems that accompany ADHD [15,77], showing the possibility of improving alertness and attentiveness in some patients [78–81]. Lamotrigine has a great efficacy in suppressing EEG discharges, and it has also been demonstrated to cause improvement in behavior and attention in epileptic children [15,82]. This improvement appears not to be related to a direct action of lamotrigine, but more likely to an indirect effect being reported only in those children who showed a reduction of epileptiform activity [83]. Taking into account the frequent comorbidity with sleep disorders, in this population lamotrigine (among the newer drugs), clobazam and nitrazepam (among the older ones), might represent a good compromise for choosing an AED treatment not interfering on cognitive/executive functions and sleep physiology. ADHD

6.2. Recommendations for ADHD treatment in epilepsy

14

P. Parisi et al. / Brain & Development 32 (2010) 10–16

may help in epilepsy and sleep efficiency as well [95,96]. The treatment of epilepsy-related sleep disorders was recently reported to clearly improve executive functions, both in REM and NON-REM-related disorders [97]. In summary, the child neurologist should: (1) evaluate, in the presence of a deterioration in ADHD symptoms, whether a change in AED regimen is more indicated than an ADHD medication, decreasing AED polytherapy or switching to an AED with fewer cognitive or behavioral effects; (2) look for opportunities to improve sleep disorders and/or ADHD symptoms by achieving better seizure control; (3) periodically reassess for the possibility that ADHD medication is no longer needed. 7. Conclusions Increased evidence points to a complex relationship between ADHD and seizure disorders. Furthermore, the findings of high prevalence of ADHD in recent onset idiopathic epilepsy, and the appearance of ADHD symptoms prior to the first recognized seizure suggest that recurrent seizures and their treatment may not represent the core etiological factor underlying ADHD in children with epilepsy. Early identification of this comorbidity is crucial and is a challenge for neuropediatricians when planning the treatment. Treatment with stimulant medication can be initiated safely in most children with well-controlled epilepsy and severe ADHD symptoms. It is of fundamental importance to gain a full grasp of the pharmacodynamic and pharmacokinetic interactions between AEDs and psychotropic drugs, to ensure the effectiveness of psychotropic drugs while avoiding any unnecessary adverse cognitive outcome. References [1] Denckla M. ADHD: topic update. Brain Dev 2003;25:383–9. [2] Fastenau PS, Jianzhao S, Dunn DW, Austin JK. Academic underachievement among children with epilepsy: proportion exceeding psychometric criteria for learning disability and associated risk factors. J Learn Disabil 2008;41:195–207. [3] Ounsted C. The hyperkinetic syndrome in epileptic children. Lancet 1955;269:303–11. [4] Dunn DW, Austin JK, Huster GA. Behaviour problems in children with new-onset epilepsy. Seizure 1997;6:283–7. [5] Kanner AM. The use of psychotropic drugs in epilepsy: what every neurologist should know. Semin Neurol 2008;28: 379–88. [6] Kirov R, Kinkelbur J, Banaschewski T, Rothenberger A. Sleep patterns in children with attention-deficit/hyperactivity disorder, tic disorder, and comorbidity. J Child Psychol Psychiatry 2007;48:561–70. [7] Malow BA. The interaction between sleep and epilepsy. Epilepsia 2007;48(Suppl. 9):36–8. [8] Steer CR. Managing attention deficit/hyperactivity disorder: unmet needs and future directions. Arch Dis Child 2005;90(Suppl. 1): i19–25.

[9] 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. [10] 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. [11] Richer LP, Shevell MI, Rosenblatt BR. Epileptiform abnormalities in children with attention-deficit-hyperactivity disorder. Pediatr Neurol 2002;26:125–9. [12] Thome-Souza S, Kuczynski E, Assumpcao Jr F, Rzezak P, Fuentes D, Fiore L, et al. Which factors may play a pivotal role on determining the type of psychiatric disorder in children and adolescents with epilepsy? Epilepsy Behav 2004;5:988–94. [13] Dunn DWKronenberger WG. Childhood epilepsy, attention problems, and ADHD: review and practical considerations. Semin Pediatr Neurol 2005;12:222–8. [14] Dunn DW, Austin JK, Harezlak J, Ambrosius WT. ADHD and epilepsy in childhood. Dev Med Child Neurol 2003;45:50–4. [15] Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 2005;32:1–10. [16] Sherman EM, Slick DJ, Connolly MB, Eyrl KL. ADHD, neurological correlates and health-related quality of life in severe pediatric epilepsy. Epilepsia 2007;48:1083–91. [17] Jones JE, Watson R, Sheth R, Caplan R, Koehn M, Seidenberg M, et al. Psychiatric comorbidity in children with new onset epilepsy. Dev Med Child Neurol 2007;49:493–7. [18] Hermann B, Jones J, Dabbs K, Allen CA, Sheth R, Fine J, et al. The frequency, complications and aetiology of ADHD in new onset paediatric epilepsy. Brain 2007;130:3135–48. [19] Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007;61:1361–9. [20] Curatolo P. The neurology of attention deficit/hyperactivity disorder. Brain Dev 2005;27:541–3. [21] Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, et al. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry 1999;156:891–6. [22] Suskauer SJ, Simmonds DJ, Fotedar S, Blankner JG, Pekar JJ, Denckla MB, et al. Functional magnetic resonance imaging evidence for abnormalities in response selection in attention deficit hyperactivity disorder: differences in activation associated with response inhibition but not habitual motor response. J Cogn Neurosci 2008;20:478–93. [23] Aldenkamp AP, Arends J, Overweg-Plandsoen TC, van Bronswijk KC, Schyns-Soeterboek A, Linden I, et al. Acute cognitive effects of nonconvulsive difficult-to-detect epileptic seizures and epileptiform electroencephalographic discharges. J Child Neurol 2001;16:119–23. [24] Semrud-Clikeman MWical B. Components of attention in children with complex partial seizures with and without ADHD. Epilepsia 1999;40:211–5. [25] Gonzalez-Heydrich J, Dodds A, Whitney J, MacMillan C, Waber D, Faraone SV, et al. Psychiatric disorders and behavioral characteristics of pediatric patients with both epilepsy and attention-deficit hyperactivity disorder. Epilepsy Behav 2007;10:384–8. [26] Curatolo P, Paloscia C, D’Agati E, Moavero R, Pasini A. The neurobiology of attention deficit/hyperactivity disorder. Eur J Paediatr Neurol 2008 [Epub ahead of print]. [27] Sowell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS. Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 2003;362:1699–707.

P. Parisi et al. / Brain & Development 32 (2010) 10–16 [28] Wolosin SM, Richardson ME, Hennessey JG, Denckla MB, Mostofsky SH. Abnormal cerebral cortex structure in children with ADHD. Hum Brain Mapp 2009;30:175–84. [29] Mostofsky SH, Rimrodt SL, Schafer JG, Boyce A, Goldberg MC, Pekar JJ, et al. Atypical motor and sensory cortex activation in attention-deficit/hyperactivity disorder: a functional magnetic resonance imaging study of simple sequential finger tapping. Biol Psychiatry 2006;59:48–56. [30] Carrey NJ, MacMaster FP, Gaudet L, Schmidt MH. Striatal creatine and glutamate/glutamine in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2007;17:11–7. [31] Jensen V, Rinholm JE, Johansen TJ, Medin T, Storm-Mathisen J, Sagvolden T, et al. N-methyl-D-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder. Neuroscience 2008;158:353–64. [32] Howells FMRussell VA. Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attentiondeficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat). Brain Res 2008;1200:107–15. [33] Gilby KL. A new rat model for vulnerability to epilepsy and autism spectrum disorders. Epilepsia 2008;49(Suppl. 8):108–10. [34] Caplan R, Siddarth P, Stahl L, Lanphier E, Vona P, Gurbani S, et al. Childhood absence epilepsy: behavioral, cognitive, and linguistic comorbidities. Epilepsia 2008;49:1838–46. [35] Davies S, Heyman I, Goodman R. A population survey of mental health problems in children with epilepsy. Dev Med Child Neurol 2003;45:292–5. [36] Trimble MRThompson PJ. Memory, anticonvulsant drugs and seizures. Acta Neurol Scand 1981;89(Suppl.):31–41. [37] Hermann BP, Jones JE, Sheth R, Koehn M, Becker T, Fine J, et al. Growing up with epilepsy: a two-year investigation of cognitive development in children with new onset epilepsy. Epilepsia 2008;49:1847–58. [38] Delgado-Escueta AV, Swartz BE, Walsh GO, Chauvel P, Bancaud J, Broglin D. Frontal lobe seizures and epilepsies in neurobehavioral disorders. Adv Neurol 1991;55:317–40. [39] Powell AL, Yudd A, Zee P, Mandelbaum DE. Attention deficit hyperactivity disorder associated with orbitofrontal epilepsy in a father and a son. Neuropsychiatry Neuropsychol Behav Neurol 1997;10:151–4. [40] Steriade MTimofeev I. Neuronal plasticity in thalamocortical networks during sleep and waking oscillations. Neuron 2003;37:563–76. [41] Pasini A, Paloscia C, Alessandrelli R, Porfirio MC, Curatolo P. Attention and executive functions profile in drug naive ADHD subtypes. Brain Dev 2007;29:400–8. [42] Aldenkamp AArends J. The relative influence of epileptic EEG discharges, short nonconvulsive seizures, and type of epilepsy on cognitive function. Epilepsia 2004;45:54–63. [43] Holmes GLLenck-Santini PP. Role of interictal epileptiform abnormalities in cognitive impairment. Epilepsy Behav 2006;8:504–15. [44] Ben-Ari YHolmes GL. Effects of seizures on developmental processes in the immature brain. Lancet Neurol 2006;5: 1055–63. [45] Deonna T, Zesiger P, Davidoff V, Maeder M, Mayor C, Roulet E. Benign partial epilepsy of childhood: a longitudinal neuropsychological and EEG study of cognitive function. Dev Med Child Neurol 2000;42:595–603. [46] Prather Pde Vries PJ. Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol 2004;19:666–74. [47] Prevost J, Lortie A, Nguyen D, Lassonde M, Carmant L. Nonlesional frontal lobe epilepsy (FLE) of childhood: clinical presentation, response to treatment and comorbidity. Epilepsia 2006;47:2198–201.

15

[48] McDonald CR, Delis DC, Norman MA, Wetter SR, Tecoma ES, Iragui VJ. Response inhibition and set shifting in patients with frontal lobe epilepsy or temporal lobe epilepsy. Epilepsy Behav 2005;7:438–46. [49] Levav M, Mirsky AF, Herault J, Xiong L, Amir N, Andermann E. Familial association of neuropsychological traits in patients with generalized and partial seizure disorders. J Clin Exp Neuropsychol 2002;24:311–26. [50] Loiseau P, Pestre M, Dartigues JF, Commenges D, BarbergerGateau C, Cohadon S. Long-term prognosis in two forms of childhood epilepsy: typical absence seizures and epilepsy with rolandic (centrotemporal) EEG foci. Ann Neurol 1983;13:642–8. [51] Henkin Y, Sadeh M, Kivity S, Shabtai E, Kishon-Rabin L, Gadoth N. Cognitive function in idiopathic generalized epilepsy of childhood. Dev Med Child Neurol 2005;47:126–32. [52] Pavone P, Bianchini R, Trifiletti RR, Incorpora G, Pavone L, Parano E. Neuropsychological assessment in children with absence epilepsy. Neurology 2001;56:1047–51. [53] Hoie B, Mykletun A, Waaler PE, Skeidsvoll H, Sommerfelt K. Executive functions and seizure-related factors in children with epilepsy in Western Norway. Dev Med Child Neurol 2006;48:519–25. [54] Nolan MA, Redoblado MA, Lah S, Sabaz M, Lawson JA, Cunningham AM, et al. Memory function in childhood epilepsy syndromes. J Paediatr Child Health 2004;40:20–7. [55] Barnes GNPaolicchi JM. Neuropsychiatric comorbidities in childhood absence epilepsy. Nat Clin Pract Neurol 2008;4:650–1. [56] Wirrell EC, Camfield CS, Camfield PR, Dooley JM, Gordon KE, Smith B. Long-term psychosocial outcome in typical absence epilepsy. Sometimes a wolf in sheeps’ clothing. Arch Pediatr Adolesc Med 1997;151:152–8. [57] Holtmann M, Becker K, Kentner-Figura B, Schmidt MH. Increased frequency of rolandic spikes in ADHD children. Epilepsia 2003;44:1241–4. [58] Deltour L, Barathon M, Quaglino V, Vernier MP, Despretz P, Boucart M, et al. Children with benign epilepsy with centrotemporal spikes (BECTS) show impaired attentional control: evidence from an attentional capture paradigm. Epileptic Disord 2007;9:32–8. [59] Holtmann M, Matei A, Hellmann U, Becker K, Poustka F, Schmidt MH. Rolandic spikes increase impulsivity in ADHD – a neuropsychological pilot study. Brain Dev 2006;28:633–40. [60] Kohrman MH, Carney PR. Sleep-related disorders in neurologic disease during childhood. Pediatr Neurol 2000;23:107–13. [61] Pinton F, Ducot B, Motte J, Arbues AS, Barondiot C, Barthez MA, et al. Cognitive functions in children with benign childhood epilepsy with centrotemporal spikes (BECTS). Epileptic Disord 2006;8:11–23. [62] Sanchez-Carpintero RNeville BG. Attentional ability in children with epilepsy. Epilepsia 2003;44:1340–9. [63] Northcott E, Connolly AM, McIntyre J, Christie J, Berroya A, Taylor A, et al. Longitudinal assessment of neuropsychologic and language function in children with benign rolandic epilepsy. J Child Neurol 2006;21:518–22. [64] Batista BHNunes ML. Evaluation of sleep habits in children with epilepsy. Epilepsy Behav 2007;11:60–4. [65] Wirrell E, Blackman M, Barlow K, Mah J, Hamiwka L. Sleep disturbances in children with epilepsy compared with their nearest-aged siblings. Dev Med Child Neurol 2005;47:754–9. [66] Nickels KWirrell E. Electrical status epilepticus in sleep. Semin Pediatr Neurol 2008;15:50–60. [67] Stores G. Electroencephalographic parameters in assessing the cognitive function of children with epilepsy. Epilepsia 1990;31(Suppl. 4):S45–9. [68] Foldvary-Schaefer NGrigg-Damberger M. Sleep and epilepsy: what we know, don’t know, and need to know. J Clin Neurophysiol 2006;23:4–20.

16

P. Parisi et al. / Brain & Development 32 (2010) 10–16

[69] Ryvlin P, Rheims S, Risse G. Nocturnal frontal lobe epilepsy. Epilepsia 2006;47(Suppl. 2):83–6. [70] Silvestri R, Gagliano A, Calarese T, Arico I, Cedro C, Condurso R, et al. Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography. Epilepsy Res 2007;75:130–7. [71] Bush G, Spencer TJ, Holmes J, Shin LM, Valera EM, Seidman LJ, et al. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry 2008;65:102–14. [72] Pliszka SR. The neuropsychopharmacology of attention-deficit/ hyperactivity disorder. Biol Psychiatry 2005;57:1385–90. [73] Trimble MRCull C. Children of school age: the influence of antiepileptic drugs on behavior and intellect. Epilepsia 1988;29(Suppl. 3):S15–9. [74] Golden AS, Haut SR, Moshe SL. Nonepileptic uses of antiepileptic drugs in children and adolescents. Pediatr Neurol 2006;34:421–32. [75] Saxena K, Howe M, Simeonova D, Steiner H, Chang K. Divalproex sodium reduces overall aggression in youth at high risk for bipolar disorder. J Child Adolesc Psychopharmacol 2006;16:252–9. [76] Gomer B, Wagner K, Frings L, Saar J, Carius A, Harle M, et al. The influence of antiepileptic drugs on cognition: a comparison of levetiracetam with topiramate. Epilepsy Behav 2007;10:486–94. [77] Pellock JM. Understanding co-morbidities affecting children with epilepsy. Neurology 2004;62:S17–23. [78] Aikia M, Kalviainen R, Sivenius J, Halonen T, Riekkinen PJ. Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow-up. Epilepsy Res 1992;11:199–203. [79] Aman MG, Werry JS, Paxton JW, Turbott SH, Stewart AW. Effects of carbamazepine on psychomotor performance in children as a function of drug concentration, seizure type, and time of medication. Epilepsia 1990;31:51–60. [80] Riva DDevoti M. Carbamazepine withdrawal in children with previous symptomatic partial epilepsy: effects on neuropsychologic function. J Child Neurol 1999;14:357–62. [81] Schain RJ, Ward JW, Guthrie D. Carbamazepine as an anticonvulsant in children. Neurology 1977;27:476–80. [82] Uvebrant PBauziene R. Intractable epilepsy in children. The efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics 1994;25:284–9. [83] Pressler RM, Robinson RO, Wilson GA, Binnie CD. Treatment of interictal epileptiform discharges can improve behavior in children with behavioral problems and epilepsy. J Pediatr 2005;146:112–7.

[84] 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. [85] Feldman H, Crumrine P, Handen BL, Alvin R, Teodori J. Methylphenidate in children with seizures and attention-deficit disorder. Am J Dis Child 1989;143:1081–6. [86] Gross-Tsur V, Manor O, van der Meere J, Joseph A, Shalev RS. Epilepsy and attention deficit hyperactivity disorder: is methylphenidate safe and effective? J Pediatr 1997;130:670–4. [87] Hernandez ABarragan P. Efficacy of atomoxetine treatment in children with ADHD and epilepsy. Epilepsia 2005;46:718. [88] Kashani JRuha AM. Isolated atomoxetine overdose resulting in seizure. J Emerg Med 2007;32:175–8. [89] Wernicke JF, Holdridge KC, Jin L, Edison T, Zhang S, Bangs ME, et al. Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine. Dev Med Child Neurol 2007;49:498–502. [90] Kanner AMGidal BE. Pharmacodynamic and pharmacokinetic interactions of psychotropic drugs with antiepileptic drugs. Int Rev Neurobiol 2008;83:397–416. [91] Markowitz JS, Morrison SD, DeVane CL. Drug interactions with psychostimulants. Int Clin Psychopharmacol 1999;14:1–18. [92] Schaller JLBehar D. Carbamazepine and methylphenidate in ADHD. J Am Acad Child Adolesc Psychiatry 1999;38:112–3. [93] Handen BL, Sahl R, Hardan AY. Guanfacine in children with autism and/or intellectual disabilities. J Dev Behav Pediatr 2008;29:303–8. [94] Palumbo DR, Sallee FR, Pelham Jr WE, Bukstein OG, Daviss WB, McDermott MP. Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes. J Am Acad Child Adolesc Psychiatry 2008;47:180–8. [95] Coppola G, Iervolino G, Mastrosimone M, La Torre G, Ruiu F, Pascotto A. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Brain Dev 2004;26:373–6. [96] Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 2008;44:57–64. [97] Karpinski AC, Scullin MH, Montgomery-Downs HE. Risk for sleep-disordered breathing and executive function in preschoolers. Sleep Med 2008;9:418–24. [98] D’Agati, Moavero, Cerminara, Curatolo. Attention deficit/hyperactivity disorder and tuberous sclerosis, in press