- Email: [email protected]
Benign Epilepsy of Childhood With Rolandic Spikes: Typical and Atypical Variants
Original Articles
Benign Epilepsy of Childhood With Rolandic Spikes: Typical and Atypical Variants Anita Datta, MD and D. Barry Sinclair, MD Clinical course and outcome were compared for 126 children with typical and atypical features of benign epilepsy of childhood with rolandic spikes (BECRS). A retrospective case series design was used, in the setting of a tertiary-care pediatric hospital. The subjects were subdivided into two groups, based on clinical presentation. Group A comprised children with typical features of BECRS (n ⴝ 66; 52%) and Group B, those with atypical features (n ⴝ 60; 48%). Patients’ charts were reviewed for demographic data, family history, comorbid conditions, atypical clinical features, antiepileptic drugs, and outcome data. Comorbid disorders (e.g., attention deficit hyperactivity disorder, behavioral problems) were slightly more frequent in the atypical group. Overall, there was no difference between the time to become seizure free between the groups: by two years, 41 of 66 in Group A (62%) and 44 of 60 in Group B (71%) were controlled on medication and seizure free. Twenty of the 126 children (16%) required trial of a second anti-epileptic drug: 7 in Group A and 13 in Group B. Resolution of the epilepsy occurred in about the same length of time in both groups (but at different ages, consistent with different age of onset). Both groups had similar longterm outcome. © 2007 by Elsevier Inc. All rights reserved. Datta A, Sinclair DB. Benign epilepsy of childhood with rolandic spikes: Typical and atypical variants. Pediatr Neurol 2007;36:141-145.
Introduction Benign epilepsy of childhood with rolandic spikes (BECRS) is considered to be the most common childhood
From Comprehensive Epilepsy Program, University of Alberta, Edmonton, Alberta, Canada.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.12.003 ● 0887-8994/07/$—see front matter
epilepsy syndrome, accounting for 15-24% of pediatric patients with epilepsy [1]. It is placed among the idiopathic localization-related epilepsies. It has a characteristic age of onset, seizure pattern, neurodevelopmental profile, imaging, and electroencephalographic pattern, usually activated by sleep. The peak age of onset is 9 years of age, with complete resolution by 16 years. No gene has been identified, but an autosomal dominant inheritance with low penetrance has been postulated [2]. Classically, BECRS occurs in neurodevelopmentally normal children who present with a simple partial seizure during sleep. The seizure begins with increased salivation, gurgling noises, altered sensation of the tongue, and clonic movements of the mouth that may progress to a generalized tonic-clonic seizure. The focal components of the seizure may be missed, given that it occurs during sleep. The characteristic electroencephalogram (EEG) shows high-voltage spikes or spike and waves in the centrotemporal region that may shift from side to side with a normal background. Neuro-imaging is normal [3]. The term benign refers to the excellent prognosis of the disorder regarding seizure control and the long-term seizure and developmental outcome. There are, however, an increasing number of reports indicating that a cohort of children manifest atypical clinical features. Malignant variants are rare, but have been encountered, which raises questions as to whether the prognosis in this group is as benign as previously thought. In fact, some believe that BECRS is part of a spectrum with the continuous spikes and waves during slow-wave sleep (CSWS) and LandauKleffner syndromes [4,5]. The study objective was to compare the clinical course and long-term outcome of children with atypical forms of BECRS with those of children with the classic form. A better understanding of the clinical features and natural
Communications should be addressed to: Dr. Sinclair; Comprehensive Epilepsy Program; University of Alberta; 7317A, Aberhart Centre #1; 11402 University Avenue; Edmonton, AB T6G 2J3; Canada. E-mail: [email protected] Received August 24, 2006; accepted December 4, 2006.
Datta and Sinclair: Benign Epilepsy of Childhood 141
history of the atypical form may help with the management and prognosis of the disorder. Patients and Methods Patients with BECRS seen at the Comprehensive Epilepsy Program at the University of Alberta between 1990 and 2005 were eligible and 126 were selected for this retrospective case-series study. Subjects included had a classical seizure history for BECRS with a nocturnal simple partial seizure and EEGs consistent with BECRS (spikes in one or both centrotemporal region with a typical rolandic morphology and dipole). They also had clinical histories over time that corresponded with the disorder. Children with Landau-Kleffner or CSWS syndrome were excluded from the study. Charts were reviewed for demographic data (sex, age of onset), comorbid conditions (attention deficit-hyperactivity disorder, oppositional defiant disorder or aggression, oral buccal apraxia), personal and family history (seizures, migraines), neuro-imaging, EEG, medications, and outcome. Outcome was determined by the time for the patient to become seizure free. The number of patients who were seizure free at the one-year and two-year follow-up time points was determined. The clinical histories were also examined for atypical features. Based on these data, the children were subdivided into two groups: (A) children with typical features of BECRS and (B) children with atypical features (Table 1). Subjects in Group A met the classic criteria for BECRS. They all had nocturnal simple partial seizures with or without secondary generalization. Age of onset was 3-13 years old (mean, 6.5 years), with offset by age 16. Neurodevelopment was normal at both onset and offset Table 1. Demographic and clinical characteristics, medications, and outcome (n ⴝ 126) Group A Demographic characteristics Number of subjects 66/126 (52%) Male 36 Female 30 Age of onset, years 7.3 Clinical characteristics Behavioral comorbidities 8 ADD/ADHD 7 ODD/aggression 1 Oral-buccal apraxia 0 Personal Hx of migraine 35 Personal Hx of febrile seizures 4 Family Hx of migraine 43 Family Hx of seizures 29 BECRS 2 Febrile 3 Other 24 Medications Drug treatment 52/66 ⬎1 drug tried 7/20 (35%) ⬎1 drug concurrently 0/5 Outcome Seizure free at 1 year 36/66 (54%) Seizure free at 2 years 41/66 (62%) Average age when seizure free, years 9.3 Time to seizure free, years 2.0
Group B
60/126 (48%) 39 21 5.5 23 19 4 4 33 4 42 21 2 3 16 51/60 13/20 (65%) 5/5 33/60 (55%) 44/60 (73%) 7.6 2.1
Except as indicated, values are numbers of subjects. Abbreviations: ADD ⫽ Attention deficit disorder ADHD ⫽ Attention deficit-hyperactivity disorder BECRS ⫽ Benign epilepsy of childhood with rolandic spikes Hx ⫽ History ODD ⫽ Oppositional defiant disorder
142
PEDIATRIC NEUROLOGY
Vol. 36 No. 3
of seizures. EEG showed the characteristic biphasic spike in the centrotemporal regions with a normal background. Neuro-imaging was normal in all children. Group A comprised 66 children (52%). Subjects in Group B did not fulfill the above criteria and were therefore considered atypical. The atypical features included early age of onset (younger than 4 years), developmental delay or learning difficulties, abnormal neurological exam at onset, history of other nonfebrile seizures, or EEG abnormalities not typical of BECRS. Group B comprised 60 children (48%). Sixteen-channel Nicolet EEG recordings were performed on all children with electrodes in bipolar and referential montages (Nicolet Biomedical, Madison, WI). EEGs were performed in the awake state in all children; most children also had sleep studies as part of their testing. Hyperventilation and intermittent photic stimulation were performed in all recordings.
Results Demographics A total of 126 patients with BECRS, drawn from the University of Alberta Comprehensive Epilepsy Program, were selected for study. Of these, 66 children (52%) were classified as typical (Group A) and 60 (48%) as atypical (Group B), based on the criteria described under Patients and Methods. Of the total sample of 126 children, 75 (60%) were male and 51 (40%) were female. Within Group B, there were more males (39/60; 65%) than females (21/60; 35%). For the total sample, the average age of onset of onset of seizures was 6.5 years (range, 3-13). Children with seizure onset at age younger than 4 years were included in Group B. A personal history of migraine was seen in 68 of 126 children (54%), distributed evenly across the two groups: (35 in Group A and 33 in Group B). Across both groups, the number of children with a personal history of other seizure types was 15 of 126 (12%). Eight of these children had febrile seizures; the remaining seven had nonfebrile other seizures and were automatically placed in Group B. Of these seven with nonfebrile seizures, four had generalized tonic-clonic seizures, one had a complex partial seizure, one had an absence seizure, and one had atonic seizures. Comorbid Conditions Comorbid conditions, present in 62 of the 126 children (49%), included developmental delay, learning and language difficulties, oral-buccal apraxia, and behavioral disorders, such as attention deficit-hyperactivity disorder, oppositional defiant disorder, and aggression. Thirty-one children (25%) had global developmental delay or learning difficulties. Fifteen (12%) had isolated language delay or reading difficulties. Any child with learning difficulties was automatically placed in Group B. Thirty-one children had behavioral comorbidities: 26 (21%) had attention deficit-hyperactivity disorder and 5 (4%) had oppositional defiant disorder and/or aggression. Of these 31 children, 8 belonged to Group A and 23
belonged to Group B. Four children (3%) had oral-buccal apraxia. Family History A positive family history for migraine headaches was found in 85 children (67%), with almost equal distribution between the two groups: 43 in Group A and 42 in Group B. A positive family history for seizures was found in 50 children (40%). In 6 of the 50 cases (12%), family members had febrile seizures, and in 4 cases (8%) there was documented BECRS; the remainder had other seizure types or unknown seizure types. Imaging The majority of children in the study had neuroimaging performed. Of the 126 children, 105 (83%) had some form of imaging (computerized tomography, magnetic resonance imaging, or both). Of the remainder, 16 children (13%) did not have any imaging and for 5 children the imaging status was unknown. Of the 105 children with imaging records, 93 (89%) had normal and 12 (11%) had abnormal findings. Abnormal neuroimaging findings included a child with a previous right parietal skull fracture and subsequent epidural hematoma; microcephaly in a child with global developmental delay; ischemia and white matter changes in a child with hemiplegic cerebral palsy; atrophy of the occipital region in a child with global developmental delay and dysmorphic features; periventricular leukomalacia in a premature infant; and a Chiari I malformation in one child. None of these imaging abnormalities were thought to be the cause of the seizures. Electroencephalography Electroencephalography was performed on all 126 children in the study. Of these, 57 children (45%) exhibited bilateral spikes or spikes and waves in the characteristic centrotemporal region, and 59 children (47%) had unilateral discharges, either on the right or left; 10 children (8%) had normal EEGs despite having a classic clinical presentation. Several of these children had only an awake EEG, so that any rolandic spikes occurring exclusively in sleep would have been missed. Atypical EEG features involved slow background, epileptic spikes outside the centrotemporal region, or additional epileptic abnormalities. Medications Consensus suggests deferral of treatment of seizures in BECRS until recurrence. This was our practice in the study, but an anti-epileptic drug was started after the first seizure if there was strong parental preference. Most patients (104 of 126, 82%) were tried on anti-epileptic medications when seizures recurred. Carbamazepine was
the first-line drug used for 89 patients (71%); valproic acid was the first-line drug for 8 patients (6%). Twenty patients (16%) had a trial of more than one drug, either because of incomplete seizure control or because of side effects; 7 of the 20 (35%) were in Group A and 13 (65%) in Group B. Five of the 20 patients, all in Group B, had more than one drug tried concurrently for seizure control. All patients, regardless of group, were treated for at least two years. If they remained seizure free and an EEG was normal, a trial off medication was arranged. Outcome To determine outcome, the one- and two-year follow-up visits were used as end points. At the one-year follow-up, 54.5% of subjects in Group A were seizure free. This was similar to Group B, with 58% were seizure free. The rest were unknown or lost to follow-up. At the two-year follow-up, 62% of children were seizure free in Group A and 77% in Group B. Again, the remaining patients were unknown or lost to follow-up. With regard to EEG, 14% of the children in Group A and 12% in Group B had a normal EEG at the one-year follow-up visit. At the two-year follow-up, 24% of the children in Group A and 17% in Group B had a normal EEG. We also measured outcome by determining the age of offset of seizures. The average age of seizure resolution was 9.3 years in Group A and 7.6 years in Group B. Considering that Group B had an earlier age of onset, the length of time to become seizure free was approximately the same: 2.0 years in Group A and 2.1 years in Group B. Despite similarities in clinical improvement, Group B had a longer time for normalization of EEG than Group A. The average age of a normal EEG was 10.0 years in Group A and 9.9 years in Group B. However, considering the difference in age of onset, children in Group B took longer to reach that normal EEG: 2.75 years in Group A but 4.4 years in Group B. Discussion The present findings confirm our suspicion that atypical clinical features of BECRS not only exist but are common. Almost half of the subjects (48%) had atypical features that did not correspond with the classic definition. These findings correspond with those of other studies. In a smaller study of 42 children, Wirrell [6] found that atypical clinical features and electroencephalographic features occurred in 50% and 31% of patients, respectively. In contrast, Verrotti et al. [7] found that a smaller proportion (13%) of the patients in a follow-up study had atypical features. Although an autosomal pattern of inheritance with variable penetrance is thought to be the mode of inheritance, seeing BECRS as a heterogeneous entity can
Datta and Sinclair: Benign Epilepsy of Childhood 143
account for the phenotypic variability and atypical features. A higher frequency of behavioral and learning difficulties in children with BECRS than in controls has been noted in previous studies. This observation has been linked to underlying electroencephalographic abnormalities rather than overt seizures. In support of such a linkage, it is well known that that many children with developmental delay or behavioral disturbances may have the characteristic centrotemporal spike and waves without clinical seizures. Children with other seizure types or syndromes may have superimposed clinical and/or EEG features of BECRS. For example, in the present study some subjects who had generalized seizures or partial complex seizures had an additional finding of BECRS on EEG. Aicardi [8] found that these EEG features are often accompanied by cognitive or behavioral disturbances and may represent an atypical BECRS, or perhaps belong to several syndromes such as Landau-Kleffner syndrome or status epilepticus in rolandic epilepsy. Doose and Baier [9] indicated that multiple factors, with a polygenetic component, may be responsible for determining the clinical picture, including which children go on to develop seizures and how severe the disorder will be. It has been postulated that the syndrome is accounted for by a hereditary predisposition for a delayed maturation of the central nervous system. This could account for developmental and behavioral problems often seen in children with rolandic spikes on EEG without clinical seizures or those in the atypical group. The delayed maturation in some patients may explain a longer time to seizure offset in certain patients. Some believe that BECRS is part of a spectrum, with the classic benign form at one end and Landau-Kleffner and CSWS syndromes at the other end. By definition, BECRS occurs in children of normal intellect with no neurological deficit. In the present study, 31 of the 126 children (25%) had global developmental delay or learning difficulties, and 15 (12%) had isolated language or reading difficulties. Other studies have also shown similar results. Yung et al. [4] conducted a study looking at children with BECRS, without subdividing children into typical and atypical forms. They concluded that more children with BECRS have learning or behavioral problems that require intervention than in the general population; specifically, 9% were diagnosed with mild intellectual disability, 10% with borderline functioning, and 17% with specific learning disabilities. Piccirilli et al. [10] looked at language lateralization in patients with BECRS. They showed that children with left centrotemporal discharges have bihemispheric representation of language. One can infer from this that focal epileptiform activity may alter cerebral cognitive function. In fact, a small number may demonstrate language outcome similar to children with Landau-Kleffner and CSWS syndromes [4,5]. In terms of behavioral disorders, in the present study 21% of the children in (26/126) had attention deficit-
144
PEDIATRIC NEUROLOGY
Vol. 36 No. 3
hyperactivity disorder and 4% (5/126) had oppositional defiant disorder and/or aggressive behavior. In the study by Yung et al. [4], 31% of the children (without regard to typical or atypical features) had behavioral disturbances. In the present study, of the 31 children with behavioral disturbances, 8 were in Group A (26%) and 23 in Group B (74%). Thus, although behavioral comorbid conditions are found in both groups, the present findings are in accord with previous understanding that those with atypical features have a much higher incidence of behavioral comorbidities [11]. There has been controversy regarding the association of migraine headaches and BECRS. Many believe that the association of the disorders comes from the co-occurrence of two frequent diseases. Andermann [12] described how such an association may be more than chance alone and suggested that there may be common factors between idiopathic epilepsies and migraine. In support of this idea, migraine has also been associated with benign occipital epilepsy of childhood and, to a lesser degree, absence epilepsy. Septien et al. [13] found that 63% of patients with BECRS suffered from migraine headaches, again suggesting a nonfortuitous association. Epilepsy affects 0.5-1% of the general population, and BECRS affects approximately 15% of epileptic children. Migraine affects 4-10% of children and 8-15% of people with epilepsy. This high incidence may be related to a neurochemical disturbance common to both disorders. Septien et al. [13] postulated a common defect with neurotransmitters. It may also be related to a common channelopathy shared by both disorders. The present study confirms this theory of a shared defect, in that 68 of 126 children (54%) had migraine headaches, and 85 children (67%) had a positive family history for migraine. Study criteria classified children as Group B if the age of onset was earlier than 4 years, and so children in Group B had an earlier average age of onset of seizures: 5.5 years, compared to 7.3 years in Group A. There are reports of earlier age of onset for children with atypical features of BECRS, especially with frequent seizure recurrences, medical refractoriness, and cognitive dysfunction [11,14]. Other researchers, however, have found no such difference in age of onset [15,16]. Most of the patients in the present study were started on an anti-epileptic medication after the second seizure, with carbamazepine being the first line drug of choice. Nearly twice the number of children in Group B than in Group A were on more than one drug, due to incomplete seizure control, and only children in Group B were on more than one drug concurrently. We can infer from this that the atypical group may have an increased frequency of seizures that are more difficult to control than the typical group. In a study looking at response to medications, Al-Twaijri and Shevell [11] similarly found that a subset of children with BECRS experienced more seizures and often required polypharmacy to control seizures. A possible explanation is that the atypical group has brain
abnormalities beyond what is seen in classic BECRS. In some children with BECRS, hippocampal asymmetries and white-matter abnormalities have been reported [17,18]. Individual phenotypic differences in response to medications provide another conceptual explanation. Despite these differences in response to medications, the overall clinical course is the same. Both groups were seizure free by two years after seizure onset. Seizure control at one-year follow-up was similar between the two groups: 36 of 66 children in Group A (54%) and 33 of 60 in Group B (55%) were seizure free. At two years, however, Group B appeared to have a slightly better success rate: 44 of 60 (73%), compared with 41 of 66 (62%) in Group A. This information is useful for the clinician: even though a child has atypical features with a possibly more difficult course, the outcome should be no different from that of a child with classic BECRS. Conclusion Atypical features in BECRS are common. Comorbid disorders are seen in both groups but are more frequent in the atypical BECRS patients. Personal or family history of migraine appears to be associated with the disorder. Overall, the long-term outcome is similar in both groups, although the atypical cases may be initially more difficult to control. Neither resolution of the epilepsy nor a good long-term outcome was affected by the presence of atypical clinical features. References [1] Pazzaglia P, D’Alessandro R, Lozito A, Lugaresi E. Classification of partial epilepsies according to the symptomatology of seizures: Practical value and prognostic implications. Epilepsia 1982;23:343-50. [2] Scheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Berkovic S. Autosomal dominant rolandic epilepsy and speech dyspraxia: A new syndrome with anticipation. Ann Neurol 1995;38:633-42. [3] Wirrell EC. Benign epilepsy of childhood with centrotemporal spikes. Epilepsia 1998;39(Suppl 4):S32-41.
[4] Yung AWY, Park YD, Cohen MJ, Garrison TN. Cognitive and behavioral problems in children with centrotemporal spikes. Pediatr Neurol 2000;23:391-5. [5] Hahn A, Pistohl J, Neubauer BA, Stephani U. Atypical “benign” partial epilepsy or pseudo-Lennox syndrome. Part 1: Symptomatology and long-term prognosis. Neuropediatrics 2001;32:1-8. [6] Wirrell EC, Camfield PR, Gordon KE, Dooley JM, Camfield CS. Benign rolandic epilepsy: Atypical features are very common. J Child Neurol 1995;10:455-8. [7] Verrotti A, Latini G, Trotta D, et al. Typical and atypical rolandic epilepsy in childhood: A follow-up study. Pediatr Neurol 2002;26:26-9. [8] Aicardi J. Atypical semiology of rolandic epilepsy in some related syndromes. Epilept Disord 2000;2(Suppl 1):S5-9. [9] Doose H, Baier WK. Benign partial epilepsy and related conditions: Multifactorial pathogenesis with hereditary impairment of brain maturation. Eur J Pediatr 1989;149:152-8. [10] Piccirilli M, D’Alessandro P, Tiacci C, Ferroni A. Language lateralization in children with benign partial epilepsy. Epilepsia 1988;29: 19-25. [11] Al-Twaijri WA, Shevell MI. Atypical benign epilepsy of childhood with rolandic spikes: Features of a subset requiring more than one medication for seizure control. J Child Neurol 2002;17:900-3. [12] Andermann F. Migraine and the benign partial epilepsies of childhood: Evidence for an association. Epilept Disord 2000;2(Suppl 1): S37-9. [13] Septien L, Pelletier JL, Brunotte F, Giroud M, Dumas R. Migraine in patients with history of centro-temporal epilepsy in childhood: A Hm-PAO SPECT study. Cephalgia 1991;11:281-4. [14] Fejerman N, Caraballo R, Tenembaum SN. Atypical evolutions of benign localization-related epilepsies in children: Are they predictable? Epilepsia 2000;41:380-90. [15] Ong HT, Wyllie E. Benign childhood epilepsy with centrotemporal spikes: Is it always benign? Neurology 2000;54:1182-5. [16] Kramer U, Zelnik N, Lerman-Sagie T, Shahar E. Benign childhood epilepsy with centrotemporal spikes: Clinical characteristics and identification of patients at risk for multiple seizures. J Child Neurol 2002;17:17-9. [17] Eeg-Olofsson O, Lundberg S, Raininko R. MRI in rolandic epilepsy. Epilept Disord 2000;2(Suppl 1):S51-3. [18] Lundberg S, Eeg-Olofsson O, Raininko R, Eeg-Olofsson KE. Hippocampal asymmetries and white matter abnormalities on MRI in benign childhood epilepsy with centrotemporal spikes. Epilepsia 1999; 40:1808-15.
Datta and Sinclair: Benign Epilepsy of Childhood 145
Benign Epilepsy of Childhood With Rolandic Spikes: Typical and Atypical Variants Anita Datta, MD and D. Barry Sinclair, MD Clinical course and outcome were compared for 126 children with typical and atypical features of benign epilepsy of childhood with rolandic spikes (BECRS). A retrospective case series design was used, in the setting of a tertiary-care pediatric hospital. The subjects were subdivided into two groups, based on clinical presentation. Group A comprised children with typical features of BECRS (n ⴝ 66; 52%) and Group B, those with atypical features (n ⴝ 60; 48%). Patients’ charts were reviewed for demographic data, family history, comorbid conditions, atypical clinical features, antiepileptic drugs, and outcome data. Comorbid disorders (e.g., attention deficit hyperactivity disorder, behavioral problems) were slightly more frequent in the atypical group. Overall, there was no difference between the time to become seizure free between the groups: by two years, 41 of 66 in Group A (62%) and 44 of 60 in Group B (71%) were controlled on medication and seizure free. Twenty of the 126 children (16%) required trial of a second anti-epileptic drug: 7 in Group A and 13 in Group B. Resolution of the epilepsy occurred in about the same length of time in both groups (but at different ages, consistent with different age of onset). Both groups had similar longterm outcome. © 2007 by Elsevier Inc. All rights reserved. Datta A, Sinclair DB. Benign epilepsy of childhood with rolandic spikes: Typical and atypical variants. Pediatr Neurol 2007;36:141-145.
Introduction Benign epilepsy of childhood with rolandic spikes (BECRS) is considered to be the most common childhood
From Comprehensive Epilepsy Program, University of Alberta, Edmonton, Alberta, Canada.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.12.003 ● 0887-8994/07/$—see front matter
epilepsy syndrome, accounting for 15-24% of pediatric patients with epilepsy [1]. It is placed among the idiopathic localization-related epilepsies. It has a characteristic age of onset, seizure pattern, neurodevelopmental profile, imaging, and electroencephalographic pattern, usually activated by sleep. The peak age of onset is 9 years of age, with complete resolution by 16 years. No gene has been identified, but an autosomal dominant inheritance with low penetrance has been postulated [2]. Classically, BECRS occurs in neurodevelopmentally normal children who present with a simple partial seizure during sleep. The seizure begins with increased salivation, gurgling noises, altered sensation of the tongue, and clonic movements of the mouth that may progress to a generalized tonic-clonic seizure. The focal components of the seizure may be missed, given that it occurs during sleep. The characteristic electroencephalogram (EEG) shows high-voltage spikes or spike and waves in the centrotemporal region that may shift from side to side with a normal background. Neuro-imaging is normal [3]. The term benign refers to the excellent prognosis of the disorder regarding seizure control and the long-term seizure and developmental outcome. There are, however, an increasing number of reports indicating that a cohort of children manifest atypical clinical features. Malignant variants are rare, but have been encountered, which raises questions as to whether the prognosis in this group is as benign as previously thought. In fact, some believe that BECRS is part of a spectrum with the continuous spikes and waves during slow-wave sleep (CSWS) and LandauKleffner syndromes [4,5]. The study objective was to compare the clinical course and long-term outcome of children with atypical forms of BECRS with those of children with the classic form. A better understanding of the clinical features and natural
Communications should be addressed to: Dr. Sinclair; Comprehensive Epilepsy Program; University of Alberta; 7317A, Aberhart Centre #1; 11402 University Avenue; Edmonton, AB T6G 2J3; Canada. E-mail: [email protected] Received August 24, 2006; accepted December 4, 2006.
Datta and Sinclair: Benign Epilepsy of Childhood 141
history of the atypical form may help with the management and prognosis of the disorder. Patients and Methods Patients with BECRS seen at the Comprehensive Epilepsy Program at the University of Alberta between 1990 and 2005 were eligible and 126 were selected for this retrospective case-series study. Subjects included had a classical seizure history for BECRS with a nocturnal simple partial seizure and EEGs consistent with BECRS (spikes in one or both centrotemporal region with a typical rolandic morphology and dipole). They also had clinical histories over time that corresponded with the disorder. Children with Landau-Kleffner or CSWS syndrome were excluded from the study. Charts were reviewed for demographic data (sex, age of onset), comorbid conditions (attention deficit-hyperactivity disorder, oppositional defiant disorder or aggression, oral buccal apraxia), personal and family history (seizures, migraines), neuro-imaging, EEG, medications, and outcome. Outcome was determined by the time for the patient to become seizure free. The number of patients who were seizure free at the one-year and two-year follow-up time points was determined. The clinical histories were also examined for atypical features. Based on these data, the children were subdivided into two groups: (A) children with typical features of BECRS and (B) children with atypical features (Table 1). Subjects in Group A met the classic criteria for BECRS. They all had nocturnal simple partial seizures with or without secondary generalization. Age of onset was 3-13 years old (mean, 6.5 years), with offset by age 16. Neurodevelopment was normal at both onset and offset Table 1. Demographic and clinical characteristics, medications, and outcome (n ⴝ 126) Group A Demographic characteristics Number of subjects 66/126 (52%) Male 36 Female 30 Age of onset, years 7.3 Clinical characteristics Behavioral comorbidities 8 ADD/ADHD 7 ODD/aggression 1 Oral-buccal apraxia 0 Personal Hx of migraine 35 Personal Hx of febrile seizures 4 Family Hx of migraine 43 Family Hx of seizures 29 BECRS 2 Febrile 3 Other 24 Medications Drug treatment 52/66 ⬎1 drug tried 7/20 (35%) ⬎1 drug concurrently 0/5 Outcome Seizure free at 1 year 36/66 (54%) Seizure free at 2 years 41/66 (62%) Average age when seizure free, years 9.3 Time to seizure free, years 2.0
Group B
60/126 (48%) 39 21 5.5 23 19 4 4 33 4 42 21 2 3 16 51/60 13/20 (65%) 5/5 33/60 (55%) 44/60 (73%) 7.6 2.1
Except as indicated, values are numbers of subjects. Abbreviations: ADD ⫽ Attention deficit disorder ADHD ⫽ Attention deficit-hyperactivity disorder BECRS ⫽ Benign epilepsy of childhood with rolandic spikes Hx ⫽ History ODD ⫽ Oppositional defiant disorder
142
PEDIATRIC NEUROLOGY
Vol. 36 No. 3
of seizures. EEG showed the characteristic biphasic spike in the centrotemporal regions with a normal background. Neuro-imaging was normal in all children. Group A comprised 66 children (52%). Subjects in Group B did not fulfill the above criteria and were therefore considered atypical. The atypical features included early age of onset (younger than 4 years), developmental delay or learning difficulties, abnormal neurological exam at onset, history of other nonfebrile seizures, or EEG abnormalities not typical of BECRS. Group B comprised 60 children (48%). Sixteen-channel Nicolet EEG recordings were performed on all children with electrodes in bipolar and referential montages (Nicolet Biomedical, Madison, WI). EEGs were performed in the awake state in all children; most children also had sleep studies as part of their testing. Hyperventilation and intermittent photic stimulation were performed in all recordings.
Results Demographics A total of 126 patients with BECRS, drawn from the University of Alberta Comprehensive Epilepsy Program, were selected for study. Of these, 66 children (52%) were classified as typical (Group A) and 60 (48%) as atypical (Group B), based on the criteria described under Patients and Methods. Of the total sample of 126 children, 75 (60%) were male and 51 (40%) were female. Within Group B, there were more males (39/60; 65%) than females (21/60; 35%). For the total sample, the average age of onset of onset of seizures was 6.5 years (range, 3-13). Children with seizure onset at age younger than 4 years were included in Group B. A personal history of migraine was seen in 68 of 126 children (54%), distributed evenly across the two groups: (35 in Group A and 33 in Group B). Across both groups, the number of children with a personal history of other seizure types was 15 of 126 (12%). Eight of these children had febrile seizures; the remaining seven had nonfebrile other seizures and were automatically placed in Group B. Of these seven with nonfebrile seizures, four had generalized tonic-clonic seizures, one had a complex partial seizure, one had an absence seizure, and one had atonic seizures. Comorbid Conditions Comorbid conditions, present in 62 of the 126 children (49%), included developmental delay, learning and language difficulties, oral-buccal apraxia, and behavioral disorders, such as attention deficit-hyperactivity disorder, oppositional defiant disorder, and aggression. Thirty-one children (25%) had global developmental delay or learning difficulties. Fifteen (12%) had isolated language delay or reading difficulties. Any child with learning difficulties was automatically placed in Group B. Thirty-one children had behavioral comorbidities: 26 (21%) had attention deficit-hyperactivity disorder and 5 (4%) had oppositional defiant disorder and/or aggression. Of these 31 children, 8 belonged to Group A and 23
belonged to Group B. Four children (3%) had oral-buccal apraxia. Family History A positive family history for migraine headaches was found in 85 children (67%), with almost equal distribution between the two groups: 43 in Group A and 42 in Group B. A positive family history for seizures was found in 50 children (40%). In 6 of the 50 cases (12%), family members had febrile seizures, and in 4 cases (8%) there was documented BECRS; the remainder had other seizure types or unknown seizure types. Imaging The majority of children in the study had neuroimaging performed. Of the 126 children, 105 (83%) had some form of imaging (computerized tomography, magnetic resonance imaging, or both). Of the remainder, 16 children (13%) did not have any imaging and for 5 children the imaging status was unknown. Of the 105 children with imaging records, 93 (89%) had normal and 12 (11%) had abnormal findings. Abnormal neuroimaging findings included a child with a previous right parietal skull fracture and subsequent epidural hematoma; microcephaly in a child with global developmental delay; ischemia and white matter changes in a child with hemiplegic cerebral palsy; atrophy of the occipital region in a child with global developmental delay and dysmorphic features; periventricular leukomalacia in a premature infant; and a Chiari I malformation in one child. None of these imaging abnormalities were thought to be the cause of the seizures. Electroencephalography Electroencephalography was performed on all 126 children in the study. Of these, 57 children (45%) exhibited bilateral spikes or spikes and waves in the characteristic centrotemporal region, and 59 children (47%) had unilateral discharges, either on the right or left; 10 children (8%) had normal EEGs despite having a classic clinical presentation. Several of these children had only an awake EEG, so that any rolandic spikes occurring exclusively in sleep would have been missed. Atypical EEG features involved slow background, epileptic spikes outside the centrotemporal region, or additional epileptic abnormalities. Medications Consensus suggests deferral of treatment of seizures in BECRS until recurrence. This was our practice in the study, but an anti-epileptic drug was started after the first seizure if there was strong parental preference. Most patients (104 of 126, 82%) were tried on anti-epileptic medications when seizures recurred. Carbamazepine was
the first-line drug used for 89 patients (71%); valproic acid was the first-line drug for 8 patients (6%). Twenty patients (16%) had a trial of more than one drug, either because of incomplete seizure control or because of side effects; 7 of the 20 (35%) were in Group A and 13 (65%) in Group B. Five of the 20 patients, all in Group B, had more than one drug tried concurrently for seizure control. All patients, regardless of group, were treated for at least two years. If they remained seizure free and an EEG was normal, a trial off medication was arranged. Outcome To determine outcome, the one- and two-year follow-up visits were used as end points. At the one-year follow-up, 54.5% of subjects in Group A were seizure free. This was similar to Group B, with 58% were seizure free. The rest were unknown or lost to follow-up. At the two-year follow-up, 62% of children were seizure free in Group A and 77% in Group B. Again, the remaining patients were unknown or lost to follow-up. With regard to EEG, 14% of the children in Group A and 12% in Group B had a normal EEG at the one-year follow-up visit. At the two-year follow-up, 24% of the children in Group A and 17% in Group B had a normal EEG. We also measured outcome by determining the age of offset of seizures. The average age of seizure resolution was 9.3 years in Group A and 7.6 years in Group B. Considering that Group B had an earlier age of onset, the length of time to become seizure free was approximately the same: 2.0 years in Group A and 2.1 years in Group B. Despite similarities in clinical improvement, Group B had a longer time for normalization of EEG than Group A. The average age of a normal EEG was 10.0 years in Group A and 9.9 years in Group B. However, considering the difference in age of onset, children in Group B took longer to reach that normal EEG: 2.75 years in Group A but 4.4 years in Group B. Discussion The present findings confirm our suspicion that atypical clinical features of BECRS not only exist but are common. Almost half of the subjects (48%) had atypical features that did not correspond with the classic definition. These findings correspond with those of other studies. In a smaller study of 42 children, Wirrell [6] found that atypical clinical features and electroencephalographic features occurred in 50% and 31% of patients, respectively. In contrast, Verrotti et al. [7] found that a smaller proportion (13%) of the patients in a follow-up study had atypical features. Although an autosomal pattern of inheritance with variable penetrance is thought to be the mode of inheritance, seeing BECRS as a heterogeneous entity can
Datta and Sinclair: Benign Epilepsy of Childhood 143
account for the phenotypic variability and atypical features. A higher frequency of behavioral and learning difficulties in children with BECRS than in controls has been noted in previous studies. This observation has been linked to underlying electroencephalographic abnormalities rather than overt seizures. In support of such a linkage, it is well known that that many children with developmental delay or behavioral disturbances may have the characteristic centrotemporal spike and waves without clinical seizures. Children with other seizure types or syndromes may have superimposed clinical and/or EEG features of BECRS. For example, in the present study some subjects who had generalized seizures or partial complex seizures had an additional finding of BECRS on EEG. Aicardi [8] found that these EEG features are often accompanied by cognitive or behavioral disturbances and may represent an atypical BECRS, or perhaps belong to several syndromes such as Landau-Kleffner syndrome or status epilepticus in rolandic epilepsy. Doose and Baier [9] indicated that multiple factors, with a polygenetic component, may be responsible for determining the clinical picture, including which children go on to develop seizures and how severe the disorder will be. It has been postulated that the syndrome is accounted for by a hereditary predisposition for a delayed maturation of the central nervous system. This could account for developmental and behavioral problems often seen in children with rolandic spikes on EEG without clinical seizures or those in the atypical group. The delayed maturation in some patients may explain a longer time to seizure offset in certain patients. Some believe that BECRS is part of a spectrum, with the classic benign form at one end and Landau-Kleffner and CSWS syndromes at the other end. By definition, BECRS occurs in children of normal intellect with no neurological deficit. In the present study, 31 of the 126 children (25%) had global developmental delay or learning difficulties, and 15 (12%) had isolated language or reading difficulties. Other studies have also shown similar results. Yung et al. [4] conducted a study looking at children with BECRS, without subdividing children into typical and atypical forms. They concluded that more children with BECRS have learning or behavioral problems that require intervention than in the general population; specifically, 9% were diagnosed with mild intellectual disability, 10% with borderline functioning, and 17% with specific learning disabilities. Piccirilli et al. [10] looked at language lateralization in patients with BECRS. They showed that children with left centrotemporal discharges have bihemispheric representation of language. One can infer from this that focal epileptiform activity may alter cerebral cognitive function. In fact, a small number may demonstrate language outcome similar to children with Landau-Kleffner and CSWS syndromes [4,5]. In terms of behavioral disorders, in the present study 21% of the children in (26/126) had attention deficit-
144
PEDIATRIC NEUROLOGY
Vol. 36 No. 3
hyperactivity disorder and 4% (5/126) had oppositional defiant disorder and/or aggressive behavior. In the study by Yung et al. [4], 31% of the children (without regard to typical or atypical features) had behavioral disturbances. In the present study, of the 31 children with behavioral disturbances, 8 were in Group A (26%) and 23 in Group B (74%). Thus, although behavioral comorbid conditions are found in both groups, the present findings are in accord with previous understanding that those with atypical features have a much higher incidence of behavioral comorbidities [11]. There has been controversy regarding the association of migraine headaches and BECRS. Many believe that the association of the disorders comes from the co-occurrence of two frequent diseases. Andermann [12] described how such an association may be more than chance alone and suggested that there may be common factors between idiopathic epilepsies and migraine. In support of this idea, migraine has also been associated with benign occipital epilepsy of childhood and, to a lesser degree, absence epilepsy. Septien et al. [13] found that 63% of patients with BECRS suffered from migraine headaches, again suggesting a nonfortuitous association. Epilepsy affects 0.5-1% of the general population, and BECRS affects approximately 15% of epileptic children. Migraine affects 4-10% of children and 8-15% of people with epilepsy. This high incidence may be related to a neurochemical disturbance common to both disorders. Septien et al. [13] postulated a common defect with neurotransmitters. It may also be related to a common channelopathy shared by both disorders. The present study confirms this theory of a shared defect, in that 68 of 126 children (54%) had migraine headaches, and 85 children (67%) had a positive family history for migraine. Study criteria classified children as Group B if the age of onset was earlier than 4 years, and so children in Group B had an earlier average age of onset of seizures: 5.5 years, compared to 7.3 years in Group A. There are reports of earlier age of onset for children with atypical features of BECRS, especially with frequent seizure recurrences, medical refractoriness, and cognitive dysfunction [11,14]. Other researchers, however, have found no such difference in age of onset [15,16]. Most of the patients in the present study were started on an anti-epileptic medication after the second seizure, with carbamazepine being the first line drug of choice. Nearly twice the number of children in Group B than in Group A were on more than one drug, due to incomplete seizure control, and only children in Group B were on more than one drug concurrently. We can infer from this that the atypical group may have an increased frequency of seizures that are more difficult to control than the typical group. In a study looking at response to medications, Al-Twaijri and Shevell [11] similarly found that a subset of children with BECRS experienced more seizures and often required polypharmacy to control seizures. A possible explanation is that the atypical group has brain
abnormalities beyond what is seen in classic BECRS. In some children with BECRS, hippocampal asymmetries and white-matter abnormalities have been reported [17,18]. Individual phenotypic differences in response to medications provide another conceptual explanation. Despite these differences in response to medications, the overall clinical course is the same. Both groups were seizure free by two years after seizure onset. Seizure control at one-year follow-up was similar between the two groups: 36 of 66 children in Group A (54%) and 33 of 60 in Group B (55%) were seizure free. At two years, however, Group B appeared to have a slightly better success rate: 44 of 60 (73%), compared with 41 of 66 (62%) in Group A. This information is useful for the clinician: even though a child has atypical features with a possibly more difficult course, the outcome should be no different from that of a child with classic BECRS. Conclusion Atypical features in BECRS are common. Comorbid disorders are seen in both groups but are more frequent in the atypical BECRS patients. Personal or family history of migraine appears to be associated with the disorder. Overall, the long-term outcome is similar in both groups, although the atypical cases may be initially more difficult to control. Neither resolution of the epilepsy nor a good long-term outcome was affected by the presence of atypical clinical features. References [1] Pazzaglia P, D’Alessandro R, Lozito A, Lugaresi E. Classification of partial epilepsies according to the symptomatology of seizures: Practical value and prognostic implications. Epilepsia 1982;23:343-50. [2] Scheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Berkovic S. Autosomal dominant rolandic epilepsy and speech dyspraxia: A new syndrome with anticipation. Ann Neurol 1995;38:633-42. [3] Wirrell EC. Benign epilepsy of childhood with centrotemporal spikes. Epilepsia 1998;39(Suppl 4):S32-41.
[4] Yung AWY, Park YD, Cohen MJ, Garrison TN. Cognitive and behavioral problems in children with centrotemporal spikes. Pediatr Neurol 2000;23:391-5. [5] Hahn A, Pistohl J, Neubauer BA, Stephani U. Atypical “benign” partial epilepsy or pseudo-Lennox syndrome. Part 1: Symptomatology and long-term prognosis. Neuropediatrics 2001;32:1-8. [6] Wirrell EC, Camfield PR, Gordon KE, Dooley JM, Camfield CS. Benign rolandic epilepsy: Atypical features are very common. J Child Neurol 1995;10:455-8. [7] Verrotti A, Latini G, Trotta D, et al. Typical and atypical rolandic epilepsy in childhood: A follow-up study. Pediatr Neurol 2002;26:26-9. [8] Aicardi J. Atypical semiology of rolandic epilepsy in some related syndromes. Epilept Disord 2000;2(Suppl 1):S5-9. [9] Doose H, Baier WK. Benign partial epilepsy and related conditions: Multifactorial pathogenesis with hereditary impairment of brain maturation. Eur J Pediatr 1989;149:152-8. [10] Piccirilli M, D’Alessandro P, Tiacci C, Ferroni A. Language lateralization in children with benign partial epilepsy. Epilepsia 1988;29: 19-25. [11] Al-Twaijri WA, Shevell MI. Atypical benign epilepsy of childhood with rolandic spikes: Features of a subset requiring more than one medication for seizure control. J Child Neurol 2002;17:900-3. [12] Andermann F. Migraine and the benign partial epilepsies of childhood: Evidence for an association. Epilept Disord 2000;2(Suppl 1): S37-9. [13] Septien L, Pelletier JL, Brunotte F, Giroud M, Dumas R. Migraine in patients with history of centro-temporal epilepsy in childhood: A Hm-PAO SPECT study. Cephalgia 1991;11:281-4. [14] Fejerman N, Caraballo R, Tenembaum SN. Atypical evolutions of benign localization-related epilepsies in children: Are they predictable? Epilepsia 2000;41:380-90. [15] Ong HT, Wyllie E. Benign childhood epilepsy with centrotemporal spikes: Is it always benign? Neurology 2000;54:1182-5. [16] Kramer U, Zelnik N, Lerman-Sagie T, Shahar E. Benign childhood epilepsy with centrotemporal spikes: Clinical characteristics and identification of patients at risk for multiple seizures. J Child Neurol 2002;17:17-9. [17] Eeg-Olofsson O, Lundberg S, Raininko R. MRI in rolandic epilepsy. Epilept Disord 2000;2(Suppl 1):S51-3. [18] Lundberg S, Eeg-Olofsson O, Raininko R, Eeg-Olofsson KE. Hippocampal asymmetries and white matter abnormalities on MRI in benign childhood epilepsy with centrotemporal spikes. Epilepsia 1999; 40:1808-15.
Datta and Sinclair: Benign Epilepsy of Childhood 145