Cognitive epilepsy: ADHD related to focal EEG discharges

Cognitive Epilepsy: ADHD Related to Focal EEG Discharges Nicole Laporte*, Guillaume Se´bire, MD, PhD*, Yves Gillerot†, Renzo Guerrini, MD, PhD‡, and Sophie Ghariani* This study was undertaken to determine the effect of antiepileptic treatment on a child with attention-deficit– hyperactivity disorder and subclinical electroencephalographic discharges without seizures. We performed a longitudinal follow-up study correlating clinical, neuropsychologic, and electroencephalographic features with antiepileptic drug therapy. The results revealed a temporal relation between subclinical epileptiform discharges and cognitive dysfunction and a significant effectiveness of antiepileptic drugs on attention-deficit– hyperactivity disorder and electroencephalographic discharges. The practice of monitoring antiepileptic treatment limited to seizure control should be revised; cognitive impairments also need to be taken into account even without occurrence of seizure. The classical principle of treating only seizures needs to be reconsidered. © 2002 by Elsevier Science Inc. All rights reserved.

including etiology, age at onset, type of epilepsy, and treatment. A causal link between epilepsy and neuropsychologic impairment is established in several conditions, including epilepsy with continuous spike-waves during sleep and Landau-Kleffner syndrome [1]. Interictal electroencephalogram (EEG) discharges have also been demonstrated to cause transitory cognitive impairment through a deleterious effect on attention, perception, reaction times, short-term memory, and more complex intellectual tasks in epileptic patients [2-7] Furthermore, some children present transient behavioral and learning difficulties correlated with epileptiform discharges without clinical epilepsy [8,9]. The neuropsychologic approach of epilepsy is essential for improving the characterization of the cognitive symptoms, to better correlate EEG anomalies and clinical features, and to determine the appropriate therapeutic management. Taking an opportunity to study with a patient with attention-deficit– hyperactivity disorder (ADHD) associated with EEG focal sharp-waves discharges, we studied the relation between the neuropsychologic disturbances, subclinical epileptic discharges, and antiepileptic treatments. Case Report Methods

Cognitive disorders are widely described in association with epilepsy in childhood. The relation between epilepsy and cognitive disturbances is influenced by several factors,

The neuropsychologic analyses were based on the following tests: intelligence, Wechsler Intelligence Scale for Children, Version III (WISC III) scale; hyperactivity, Diagnostic and Statistical Manual of Mental Disorders, Version IV (DSM IV) scale; sequential immediate verbal and nonverbal memory, Kaufman Assessment Battery for Children; nonsequential verbal and visual memory test, Batterie d’Efficience Mne´sique and 15 Words of Rey, Rey’s Constant Attention Test, and Zazzo’s Selective Attention Dam Test. Oral language was evaluated by Lee’s Northwestern Syntax Screening Test (NSST). Academic knowledge was objectified for reading by the One-Minute Test and Le Poucet and by Jaspar’s test for mathematical reasoning [10-20]. We applied classic methods to perform a longitudinal follow-up of neurologic observations correlated with EEG features and treatments [21]: baseline assessment before initiation of therapy, neuropsychologic measures, 24-hour EEG, and antiepileptic drug titrations were repeated in four different therapeutic conditions. Neuropsychologic assessment was performed using tasks sensitive to subtle changes in cognitive functions. We avoided learning effect by choosing several alternative items in the batteries or by selecting items considered as nonsensitive to learning effect. To determine whether infraclinical EEG anomalies were correlated with specific cognitive impairments we raised the following issues: (1) Is

From the Departments of *Pediatric Neurology and †Genetics; Cliniques Universitaires Saint-Luc; Universite´ Catholique de Louvain; Brussels, Belgium; and the ‡Institute of Child Health and Great Ormond Street Hospital for Children; University College; London, United Kingdom

Communications should be addressed to: Dr. Ghariani; Service de Neurope´diatrie; Centre Neurologique William Lennox; Universite´ Catholique de Louvain; Alle´e de Clerlande; 1340 Ottignies, Belgium. Received January 16, 2002; accepted April 22, 2002.

Laporte N, Se´bire G, Gillerot Y, Guerrini R, Ghariani S. Cognitive epilepsy: ADHD related to focal EEG discharges. Pediatr Neurol 2002;27:307-311.

Introduction

© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(02)00441-1 ● 0887-8994/02/$—see front matter

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Table 1.

Neuropsychologic data compared with 24-hour EEG features and treatment Age

7 yr, 8 mo

9 yr, 2 mo

9 yr, 5 mo

9 yr, 11 mo

10 yr, 1 mo

WISC III [18] Verbal scale: Performance scale: Rey visual sustained attention [16] Zazzo visual selective attention [17] KABC [19] Manual motor sequences Digit span Words sequences Narrative memory BEM [11] Rey words list learning [10] 24 figures BEM [15] DSM IV [20] Words list reading [13] 1-Minute Test LCM-R Narrative reading: Poucet Verbal comprehension NSST [14] Arithmetic : Jasper [12] Treatment

IQ: 93 86 102 S: P20 Pr: P10 S: M PR: ⫺3 SD

IQ: 95 92 99 S: P0 Pr: P0 S: ⫹4 SD Pr: ⫺8 SD

S: P5 Pr: P9 S: ⫹4 SD Pr: ⫺2.5 SD

S: P8 Pr: P10 S: ⫹4 SD Pr: ⫺0.5 SD

S: P2 Pr: P50 S: ⫹3 SD Pr: ⫺0.5 SD

8 5 4 ⫺2 SD P50, P40, P25, P25 M 3/18

10 8

10 10

P75, P25, P20, P50 M 3/18

10 5 5 ⫺3 SD P20, P20, P10, P10 M 13/18

⫺1 SD P50, P40, P15 M 3/18

M P25, P40, P25, P25 M 4/18

⫹1 SD M

M M M

M

P70

P70

M Carbamazepine

M None

Carbamazepine (30 mg/kg/day)

Vigabatrin (50 mg/kg/day)

Normal

Sharp-waves, sleep

Carbamazepine (20 mg/kg/day) Normal

24-hour EEG Abbreviations: BEM IQ KABC M P

⫽ ⫽ ⫽ ⫽ ⫽

Batterie efficience mne´ sique [11] Intellectual quotient Kaufman Assessment Battery for Children Mean Percentile

Pr S SD WISC

there a temporal relation between infraclinical EEG anomalies and cognitive dysfunction? (2) Do antiepileptic drugs improve simultaneously the cognitive, behavioral, and EEG anomalies?

Patient This female was the first of two children born of nonconsanguineous healthy parents. Her sister had presented with febrile seizures. There was no history of febrile seizure or epilepsy in the rest of the family. Her first seizure (complex partial with secondary generalization of 2 hours’ duration) occurred when she was 3 years of age and prompted initiation of phenobarbital. Between 4 and 5 years of age she suffered two generalized tonic-clonic seizures with fever. Phenobarbital was then replaced with carbamazepine. The behavioral and cognitive development was normal (Terman test performed at 4 years, 4 months of age). Clinical examination revealed epicanthus and synophrys. The neurologic examination was normal. Her school adaptation was good. Because of the lack of seizure for 4 years, antiepileptic treatment was discontinued at 8 years, 10 months of age. During the following 8 weeks her behavior dramatically deteriorated, which was manifested by the appearance of agitation, lack of inhibition, intolerance to frustration, disobedience, verbal aggressiveness, lack of attention, and restless sleep. At that time, we began studying the correlation between cognitive impairment, EEG anomalies, and antiepileptic drug treatments. The results of this study are presented in the Results section below. Brain tomodensitometry and magnetic resonance imaging were normal. High-resolution karyotype (G-banding) revealed an apparently balanced translocation between chromosomes 2 and 12, the breakpoints being in q22 for both chromosomes 2 and 12, with a karyotype 46,XX,t(2;12) (q22;q22). The father’s karyotype revealed a seemingly identical translocation. Her sister’s karyotype was normal.

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⫽ ⫽ ⫽ ⫽

Precision Speed Standard deviation Wechsler Intelligence Scale for Children

Neuropsychologic Testing The cognitive assessment performed with the WISC-R was normal at the age of 7 years, 9 months (intelligence quotient: 93). Attention was normal (Table 1, 7 years of age). Neuropsychologic performances worsened significantly immediately after carbamazepine withdrawal, although no clinical seizures were reported. Continuous and selective attention abilities deteriorated significantly. The immediate verbal sequential memory and nonsequential verbal memory tasks, particularly sensitive to attention level, were impaired (Table 1, 9 years, 5 months). ADHD was diagnosed according to DSM-IV criteria. She presented seven of the nine symptoms of inattention, four of the six symptoms of hyperactivity, and two of the three symptoms of impulsiveness. There were neither psychologic nor social difficulties in her family. Because neuropsychologic impairment was temporally related to electrophysiologic anomalies (Table 1), antiepileptic drug treatment was restarted with carbamazepine (20 mg/kg/day). Her behavior rapidly improved. Six weeks after restarting the drug, neuropsychologic assessment demonstrated a full recovery, with the exception of a slight impairment of sequential verbal memory (Table 1, 9 years, 5 months). Her behavior also improved. Increasing the dose of carbamazepine to 30 mg/kg/day improved attention performances (Table 1, 9 years, 11 months) but was accompanied by apathy and an increased need for sleep. To exclude a direct behavioral effect of carbamazepine, independent of the effect on EEG discharges, we switched to vigabatrin monotherapy. Two months after starting vigabatrin the neuropsychologic profile was similar to that observed with carbamazepine (Table 1, 10 years, 1 month). All EEGs, including a 24-hour recording at 7 years, 8 months of age, were normal before carbamazepine withdrawal (see Table 1). A 24-hour EEG performed while the patient was cognitively impaired at 9 years, 1 month of age revealed left central sharp-waves (sporadic waves or bursts)

Figure 1. Twenty-four-hour electroencephalogram (ambulatory eight-channel electroencephalogram), recorded during cognitive impairment at 9 years, 1 month of age reveals left central sharp-waves (sporadic or bursts) occurring during stage 2 of sleep.

occurring during stage 2 sleep: 10-20% of the total amount of sleep (Fig 1). However, sleep stages were preserved, and wake EEG was normal. Six weeks after restarting carbamazepine the 24-hour EEG was normal. The EEG while awake remained normal during vigabatrin therapy.

Discussion Our patient disclosed a specific attention disorder with classical deterioration of sequential memory. The EEG revealed epileptiform activity without overt clinical seizures. The clinical evaluation revealed partial seizures with secondary generalization earlier in life and a cytogenetic abnormality consisting of an apparently balanced translocation 46,XX,t(2;12)(q22;q22). Our patient met the clinical criteria for Generalized epilepsy with febrile seizure plus (GEFS)⫹, that is, seizures with fever in early childhood that continued beyond 6 years of age or that were associated with afebrile seizures [22]. As already reported [22-25], SCN1A gene involved in generalized epilepsy with febrile seizures plus (GEFS⫹) has been located in 2q22 in some families. Association of GEFS⫹ with specific learning disabilities have also been reported in some patients, although without any detailed cognitive description [22]. The association between epilepsy and attention deficit has already been described [26]. The question as to

whether the attention deficit is only due to seizures, to an underlying central nervous system defect, to drug treatment, or to a combination of all these factors remains to be determined. In 1980, Cavazzuti et al. [27] described epileptiform EEG discharges in 3% of nonepileptic children. Among them, 17% presented poor attention and motor hyperactivity. The relation between subclinical EEG discharges and ADHD was unknown, and the authors postulated that these “alterations express difficulties in affective or motor adaptation during childhood.” Some epileptic syndromes, such as continuous spikewaves during sleep and Landau-Kleffner syndrome, provide good examples of a cause-effect correlation between severe epileptiform EEG discharges and specific cognitive deterioration. In 1992, Tassinari et al. [28] described hyperactivity with reduced attention span in 29 patients with continuous spike-waves during sleep. Benign focal epilepsies of childhood are also responsible for cognitive impairment [29]. “Subclinical discharges” may explain learning difficulties in well-controlled children with epilepsy [30]. This possibility raises the question of whether antiepileptic drugs would improve behavioral and learning disabilities in children with such “subclinical” EEG activity [9,30].

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Our patient presented with a specific cognitive and behavioral disorder associated with subclinical discharges occurring during sleep. Several observations are in favor of a causal relationship between the EEG abnormalities and the neuropsychologic impairment, including the temporal relation between infraclinical epileptic discharges and cognitive dysfunction, and the significant effectiveness of antiepileptic treatments correlated to EEG and attention improvement. Moreover there is no evidence for a direct behavioral effect, especially on attention, as a result of the medications used. Carbamazepine is described as having a therapeutic effect in bipolar disorder [31], but it is not known to have any positive effect on attention disorder. We must also take into consideration that the same neuropsychologic effect was observed with a different antiepileptic drug, such as vigabatrin. However, it is not absolutely clear why an EEG abnormality present only during a restricted portion of sleep should so profoundly affect daytime behavior. An interesting observation was reported by Gordon et al. [32] who used valproate to treat a 7-year-old male who presented with unsatisfactory progress in school and whose EEG had active frontal spike discharges without having suffered any clinical seizures. Serial EEG recording, cognitive testing, and questionnaires repeated during the randomized four valproate treatment periods and four placebo periods over 8 weeks revealed a valproic acid cognitive-enhancing effect, likely related to reduced epileptiform discharges. The principle of treating only the seizures seems therefore too rigid. Treatment of EEG discharges is justified even without any seizure when neuropsychologic impairment is present and a possible causative role of subclinical abnormal EEG activity is suspected [33]. Furthermore, the specific cognitive defect, herein reported, illustrates the need to investigate the whole spectrum of neuropsychologic functions of children with epilepsy by a large battery of tests to detect specific subtle neuropsychologic disorders. An additional point stressed by our observation is the importance of sleep EEG recordings in specific cognitive disorders in view of the potential for antiepileptic drug treatment to produce a clinical benefit. We are grateful to Genevie`ve Aubert, MD, PhD, Colette Brichard, MD, Genevie`ve Quenum, MD, and Brigitte Hermans, for their collaboration.

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