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Repeated seizures induce prefrontal growth disturbance in frontal lobe epilepsy
Brain & Development 34 (2012) 175–180 www.elsevier.com/locate/braindev
Original article
Repeated seizures induce prefrontal growth disturbance in frontal lobe epilepsy Hideaki Kanemura a,⇑, Fumikazu Sano a, Tomoko Tando a, Kanji Sugita a, Masao Aihara b b
a Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Japan Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan
Received 3 February 2011; received in revised form 11 April 2011; accepted 12 April 2011
Abstract Background: The possible consequences of seizures in the immature brain have been the subject of much conjecture. We prospectively measured frontal and prefrontal lobe volumes using three-dimensional (3D) magnetic resonance imaging (MRI)-based volumetry in patients with frontal lobe epilepsy (FLE) presenting with the same seizure semiology. The pathogenesis of repeated seizure-induced brain damage is discussed herein. Methods: Serial changes in regional cerebral volumes were measured in two patients with FLE presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)) and four FLE patients without cognitive impairments/behavioral problems (FLE( )). Eleven normal subjects (4–13 years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal lobe volume ratio was calculated. Results: Frontal and prefrontal lobe volumes revealed growth disturbance in FLE(+) compared with those of FLE( ) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in FLE( ) similarly to controls, but was stagnant or decreased in FLE(+). Prefrontal growth also revealed more rapid recovery in a FLE(+) patient with shorter active seizure period. Conclusion: These findings suggest that repeated seizures may lead to prefrontal growth disturbance. The occurrence of frequent seizures in patients with FLE may be associated with prefrontal lobe growth retardation, which relates to neuropsychological problems and ultimate neuropsychological outcome. Ó 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Frontal lobe epilepsy (FLE); Repeated seizures; Brain damage; Frontal lobe dysfunction; Brain volumetry
1. Introduction Frontal lobe epilepsies, as with other focal epilepsies, were formerly invariably considered to be the consequences of overt or obscure brain lesions. HowAbbreviations: FLE, frontal lobe epilepsy; FLE( ), the FLE group without neuropsychiatric deficits; FLE(+), the FLE group with intractable clinical course and neuropsychiatric deficits; FIQ, full IQ; VIQ, verbal IQ; PIQ, performance IQ; WISC-III, Wechsler Intelligence Scale for Children version III; AEDs, anti-epileptic drugs; CBZ, carbamazepine; VPA, valproate sodium; CLB, clobazam; ZNS, zonisamide ⇑ Corresponding author. Address: Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 1110 Chuo, Yamanashi 4093898, Japan. Tel.: +81 55 273 9606; fax: +81 55 273 6745. E-mail address: [email protected] (H. Kanemura).
ever, frontal lobe epilepsy (FLE) is poorly understood. Some authors have reported differences in seizure semiology in childhood and also that FLE in childhood differs from that in adults [1,2]. Seizures of frontal lobe origin are difficult to control [3]. In addition, children with FLE manifest significant psychosocial problems relative to normative standards [3]. The discussion regarding the possible consequences of seizures in the immature brain has been long and contentious. The initial observation that the immature brain was resistant to seizure-induced morphological damage has been progressively overruled by data demonstrating age- and model-specific brain damage [4], and recent review articles have reached the conclusion that seizures
0387-7604/$ - see front matter Ó 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2011.04.009
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impair the developing brain [5]. The likelihood that even morphological damage may depend on the age at which epileptic seizures develop must be taken into account [6]. Repeated seizures may lead to cognitive and behavioral impairments. Magnetic resonance imaging (MRI)-based volumetry has become established as a versatile, reliable method for investigating the biology of the human brain [7]. Stronger correlations have been found between disability and MRI markers, such as the quantitative assessment of cerebral atrophy in various brain diseases. We have already reported development of the prefrontal lobe using three-dimensional (3D) MRI in patients with various epilepsies [8–10]. Those findings suggested that frequent seizures and paroxysms on electroencephalography (EEG) might be associated with prefrontal lobe growth disturbance, which relates to neuropsychological problems in benign childhood epilepsy with centrotemporal spikes (BCECTS) or epilepsy with continuous spike-waves during slow sleep (CSWS). However, these findings are insufficient to prove that repeated seizures themselves can lead to prefrontal growth disturbance. On the basis of these observations, we prospectively measured frontal and prefrontal lobe volumes using 3D-MRI-based volumetry in patients with FLE presenting with the same seizures. The pathogenesis of repeated seizure-induced brain damage is discussed herein. 2. Subjects and methods 2.1. Subjects We registered all patients with FLE at our hospital between July 1999 and June 2003. The patients with structural, metabolic, or genetic abnormalities were excluded in the study. This report is based on six FLE patients. All of them could complete the longitudinal studies.
Subjects comprised six patients with a final diagnosis of FLE, including two cases presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)). The FLE group without cognitive impairments/behavioral problems (FLE( )) comprised two boys and two girls, with a mean age of 6 years (range, 5–7 years). Clinical profiles are provided in Table 1. Clinical features included explosive onset and adversive seizures. Seizures were brief (15–30 s), stereotypic and clustered. Interictal EEG demonstrated frontopolar discharges. Rhythmical frontal slowing was often observed on EEG after seizures and paralleled unilateral features of the epileptic discharges. All patients were followed up regularly for >3 years after the onset of seizures. All four FLE( ) patients were prescribed carbamazepine (CBZ) combined with one another antiepileptic drug (AED), leading to immediate improvement. Active seizure periods for the four FLE( ) patients were 5–6 months. No relapses were encountered and patients remained free of cognitive or behavioral problems after seizure onset. Clinical courses of two cases presenting with FLE(+) are outlined as follows. 2.2. Patient 1 The patient was a 10-year-old right-handed boy with normal initial psychomotor development. He had frequently experienced seizures as head and eyeball adversity to right side since the age of 5 years 1 month. Seizures were brief (15–30 s), stereotypic, and frequent. None of his family had experienced epileptic seizure. Routine MRI showed normal results. Interictal EEG revealed left frontopolar discharges superimposed on normal background activity. FLE was diagnosed based on the types of seizures and the localization of EEG paroxysms. CBZ was administered, but seizures were not easily controlled. Treatment was therefore changed to an addition of zonisamide (ZNS), which did not lead
Table 1 Clinical profiles of the two groups of patients with FLE. Age at onset
Seizure frequency (times)
Seizure duration
Effective AEDs
Behavioral problems
Neuropsychological test (WISC-III; FIQ) (onset)
Neuropsychological test (WISC-III; FIQ) (4 years after)
FLE(+) Patient 1
5 years 1 month
3–6/weeks
2 years 8 months
CBZ + VPA + CLB
98
72
Patient 2
4 years 2 months
2–6/weeks
1 years 4 months
ZNS + VPA
Hyperactivity, impulsiveness, poor school performance Hyperactivity, impulsiveness
94
83
FLE( ) Patient 1 Patient 2 Patient 3 Patient 4
5 years 6 years 6 years 7 years
1–4/months 1–2/months 1–3/months 1–2/months
5 months 6 months 5 months 6 months
CBZ + ZNS CBZ + ZNS CBZ + VPA CBZ + ZNS
92 101 89 97
91 99 88 95
8 months 2 months 3 months 11 months
None None None None
H. Kanemura et al. / Brain & Development 34 (2012) 175–180
to improvement in seizures, which recurred almost daily for years. Furthermore, he showed poor school performance and behavioral problems, such as hyperactivity, impulsiveness, aggressiveness and emotional instability. Addition of valproate sodium (VPA) and clobazam led to immediate improvements in seizures. However, cognitive impairments and behavioral problems remained evident even after the remission of seizure disorder. The patient is currently 12 years old and has not shown any further seizures. However, he sometimes gets into trouble with his family, teacher and friends because of hyperactivity and impulsiveness. He had difficulty on the Wisconsin Card-Sorting Test (WCST). Active seizure period was 2 years 8 months (seizure-free since the age of 7 years 9 months). 2.3. Patient 2 A 9-year-old right-handed boy had an uneventful medical history and normal initial psychomotor development. None of his family had experienced epileptic seizure. He experienced a first adversive seizure at 4 years 3 months old, and the first clinical examinations, including routine brain MRI, yielded normal results. Seizures were brief (10–30 s), stereotypic, and frequent. Interictal EEG revealed typical left-sided frontopolar discharges superimposed on normal background activity. FLE was diagnosed based on seizure types and the localization of EEG paroxysms. CBZ was administered, but many relapses were seen. Seizures recurred almost weekly for months. Furthermore, he showed behavioral problems, such as hyperactivity and impulsiveness. Treatment was changed to ZNS combined with VPA, leading to immediate improvements in seizures. After seizure remission, behavioral problems disappeared. Active seizure period was 1 year 4 months (seizure-free since the age of 5 years, 7 months). 3. Serial 3D-MRI volumetric study Serial 3D-MRI studies were performed five times (at onset of clinical symptoms, and 1, 2, 3, and 4 years after onset) in both the above FLE(+) patients and in four FLE( ) patients. A control group comprising 11 agematched children (eight boys, three girls) with a mean age of 7.8 years (range, 4–13 years) was also examined using MRI. Clinical indications for MRI in controls were suspected brain trauma/tumor, short stature, and migraine. These factors proved to be neurologically and neuropsychologically insignificant during a clinical follow-up period of 2–4 years after MRI. All subjects showed no abnormalities on routine MRI. All MRI scans were performed using a 1.5-T system (Siemens, Wisconsin, MW, USA). The 3D-MRI data were acquired using a fast spoiled gradient recalled echo in steady state with 3D Fourier transformation sequence
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(contiguous 1.0–1.2 mm slices obtained through the head; flip angle, 30°; matrix size, 256 256; repetition time, 14.5 ms; echo time, 4.5 ms; field of view, 18 18–22 22 cm), and 3D images of the whole brain surface were obtained from the 124 sections using an Advantage Windows RP 3D Analyzer workstation (General Electric, Wisconsin, MW, USA). Thereafter, the frontal lobe was determined and confirmed using our published method [11]. The central and precentral sulci were identified in left and right lateral as well as superior 3D views of the brain surface. The frontal and prefrontal lobes were determined as the regions anterior to the central and precentral sulcus, respectively. We also confirmed frontal and prefrontal lobe extent by comparison of scans with images resliced in the axial plane parallel to the anterior and posterior commissure (AC-PC) line. Finally, we measured frontal and prefrontal lobe volumes using the volume measurement function of the workstation on the 3D image data. Informed consent and agreement was obtained from each patient and their parents prior to enrolment in this study. 4. Results Measured volumes for frontal and prefrontal lobes, and prefrontal-to-frontal lobe volume ratio in the FLE( ) and control group are shown in Fig. 1. Frontal and prefrontal lobe volumes and prefrontal-to-frontal lobe volume ratio increased serially in FLE( ) patients in a similar manner to controls. Measured volumes for frontal and prefrontal lobes and prefrontal-to-frontal lobe volume ratio in the two FLE(+) patients and controls are shown in Fig. 2. Frontal and prefrontal lobe volumes showed no obvious growth during the active seizure period in the two FLE(+) patients. Prefrontalto-frontal lobe volume ratio was stagnant, with a reduction in Patient 1, during the active seizure period in the two FLE(+) patients (Fig. 2C). Patient 2, with a shorter active seizure period, soon achieved a restored growth ratio. Conversely, growth ratio was delayed in Patient 1, who experienced a longer active seizure period. Growth of the prefrontal lobe volume gradually normalized in both patients after seizure disappearance (Fig. 2). 5. Discussion FLE is one of the most complicated and least understood forms of epilepsy. The characteristics are more variable and less well known than those of temporal lobe epilepsy [12]. Several studies have helped to delineate the clinical and EEG features of this condition [13]. Seizures in all cases are characteristically brief, stereotypical, and frequent. In addition, all cases demonstrate frontopolar EEG paroxysms, fulfilling the clinical criteria for FLE. However, outcomes differ in
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A
B
(cm3)
(cm3)
C
130
320
0.43 0.41
120
300
0.39 110 0.37
280 100
0.35
90
0.33
260
0.31
240 80
0.29 220
70
200
0.27
60 4
6
8
10
12
14
0.25 4
6
8
10
12
14
4
6
8
10
12
14
Age (years) Fig. 1. Serial changes in frontal lobe volumes (A), prefrontal lobe volumes (B), and prefrontal-to-frontal lobe volume ratio (C) in patients with FLE( ) and control subjects. Scatter plots for FLE( ) patients (Patient 1, brown diamonds; Patient 2, cyan squares; Patient 3, yellow triangles; Patient 4, green circles) and age-matched controls (black circles).
A
B
(cm3)
(cm3)
C 0.43
130
320
0.41
120
300
0.39 110 0.37
280 100
0.35
90
0.33
260
0.31
240 80
0.29 220
70
200
0.27
60 4
6
8
10
12
14
4
6
8
10
12
14
0.25 4
6
8
10
12
14
Age (years) Fig. 2. Serial changes in frontal lobe volumes (A), prefrontal lobe volumes (B), and prefrontal-to-frontal lobe volume ratio (C) in the two patients with FLE(+) and control subjects. Scatter plots for Patient 1 (red squares), Patient 2 (blue diamonds) and age-matched controls (black circles). Horizontal bars for Patient 1 (red) and Patient 2 (blue) indicate the active seizure period.
terms of seizure, cognition and behavior. Frontal lobe seizures in childhood may have different outcomes to those observed in adult patients [1]. The main difference in the two groups is seizure frequency, so the present results may indicate the effects of repeated seizures. Given the possibility that some functional changes may have structural correlates, MRI could also play a pivotal role in elucidating the mechanisms underlying epileptogenesis. Quantitation of brain volume using 3D MRI is thus a useful way of characterizing normal growth and abnormal development due to various
diseases [11]. Furthermore, volumetric analysis of the brain may predict function in corresponding regions [8]. However, it is difficult to measure the gray and white matter separately in our method. We have used the same method for image acquisition, frontal lobe determination, and volumetric measurements as our previous report. Therefore, frontal lobe was determined and confirmed using the same method as our previous report. In our four FLE( ) patients, frontal and prefrontal lobe volumes showed growth patterns similar to control subjects. In the two FLE(+) patients, conversely, frontal
H. Kanemura et al. / Brain & Development 34 (2012) 175–180
and prefrontal lobe volumes and the prefrontal-to-frontal lobe volume ratio in particular showed growth disturbances during the seizure period. This suggests that repeated seizures may lead to prefrontal growth disturbance, reflecting cognitive and behavioral impairments. In the developing brain, the effects of seizures on neuronal survival and brain growth have remained controversial [14,15]. The immature brain appears to be more resistant to the toxic effects of glutamate than the mature brain [16]. However, excitotoxic neuronal death is influenced by brain maturation [17]. As apoptosis plays an important role in early brain development, the immature brain may be particularly vulnerable to programmed cell death in response to seizures. These findings provide strong evidence for the vulnerability of the immature brain to seizure-induced damage, which bears features of both necrotic and apoptotic death and contributes to synaptic reorganization [4]. Moreover, since the prefrontal lobe is among the last cortical regions to reach full structural development [11,18], prefrontal function and its disorders are not immediately apparent. Prefrontal functions therefore show an unusually long period of increased vulnerability, in which neurons and glial cells are readily affected by many factors including genetic influences, the hormonal milieu, and external insults, such as infections, toxins, and trauma [18]. Among the cortical regions, the prefrontal lobe appears highly vulnerable to repeated seizures. More frequent and severe seizures have been associated with behavioral problems in many prior studies [19,20]. Schoenfeld et al. found that frequency of complex partial seizures in the previous year was the strongest predictor of behavioral problems [21]. In addition, Lendt et al. found a reduction in behavioral problems in a group of children after successful surgery for epilepsy compared with children experiencing persistent focal seizures [22]. However, some studies have not shown any association between behavioral problems and more frequent seizures [23]. In more recent research by Austin et al. seizure recurrence significantly predicted behavioral problems [24]. They speculated that possible explanations for this relationship are that: (a) seizures and behavioral problems are associated because both are related to an underlying factor; (b) seizure activity per se disrupts behavior; or (c) children have a negative psychological response to seizures [24]. Our major finding is that repeated seizures may lead to prefrontal growth disturbance. Current research suggests that damage to the frontal regions during childhood may interrupt normal maturational processes and organization, resulting in impairments to neurobehavioral development. Integrative executive functions may thus rely on the health of frontal lobe tissue and connectivity with the rest of the cortex [25]. In our previous reports with BCECTS or CSWS [8–10], active seizure period as frequent spike-waves coupled with the occurrence of
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frequent seizures may be associated with prefrontal lobe growth disturbance. In contrast, similar EEG abnormalities were revealed in both patients with FLE( ) and FLE(+). The main difference between FLE( ) and FLE(+) was seizure frequency. Therefore, this finding may clarify the factors that influence the volumetric abnormalities as seizure frequency. Our results may support the second speculation by Austin et al. Though we have excluded the patients with structural, metabolic, or genetic abnormalities because of exclusion of the influence of these factors, there is a possibility that original pathology (cryptogenic factor or the first speculation by Austin et al. [24]) may cause both frontal growth disturbance and frequent seizures. Further investigations are needed to discuss this point. Consideration needs to be given to the effects of antiepileptic drug treatment. The two FLE(+) patients had been treated using VPA. It may be that VPA serves as a marker of relative risk from an academic perspective as compared with CBZ [26]. In addition, VPA can induce reversible brain atrophy. No clear cause-effect relationship between use of VPA and prefrontal lobe growth disturbance has been identified. However, the prefrontal lobe and prefrontal-to-frontal lobe volume ratio in the present patients were restored to the growth ratio, although VPA was given throughout the clinical course. Consideration therefore does not need to be given to effects of VPA on brain atrophy. Furthermore, ZNS may exacerbate cognitive impairments/behavioral problems [27]. However, ZNS was effective for seizure and behavioral problems in Patient 2 of FLE(+). In addition, ZNS was effective drug in three of four FLE( ) patients. Therefore, it needs not be given consideration to effect of ZNS for the cognitive impairments/behavioral problems in this study. Seizures originating from the frontal lobe may be difficult to control. A previous report found that seizure control was difficult, with only half of patients being controlled on anti-epileptic medications [3]. The two FLE(+) patients in this study revealed prefrontal growth disturbance. In addition, poor outcome is evident in a patient with prolonged repeated seizures. We should consider that, from a therapeutic viewpoint, the most critical fact is whether seizures themselves can damage the brain. Undoubtedly, the immature brain, with its massively lower metabolic rate, liberates less glutamate than the adult brain per unit time and takes longer to develop ATP depletion and damage [15]. The relative resistance of the immature brain to seizureinduced damage is thus genuine. However, as suggested by the present results, seizures can induce prefrontal growth disturbance. Moreover, in our previous studies, outcomes appeared to be related to the duration of the active seizure period [9,10]. In considering outcomes for children with FLE, therefore, control of seizures must be weighed against the incidence of neurological
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impairments, either transiently or persistently. Based on our prospective study, management of treatment to remit seizures as soon as possible may be required to achieve optimal prognosis in FLE with cognitive or behavioral involvement. In conclusion, we have shown that repeated seizures themselves can induce brain damage. Occurrence of frequent seizures in patients with FLE may be associated with retardation of prefrontal lobe growth, which relates to neuropsychological problems and ultimate neuropsychological outcome. Management of treatment may be required to remit seizures as soon as possible to achieve optimal prognosis in FLE. Conflict of interest We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflict of interest to disclose. Acknowledgments This work was supported by Grants-in-Aid for Scientific Research (C) (22591124 and 22591123) and the Japan Epilepsy Research Foundation. References [1] Fogarasi A, Janszky J, Faveret E, Pieper T, Tuxhorn I. A detailed analysis of frontal lobe seizures semiology in children younger than seven years. Epilepsia 2001;42:80–5. [2] Vigevano F, Fusco L. Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia 1993;34:110–9. [3] Sinclair DB, Wheatley M, Snyder T. Frontal lobe epilepsy in childhood. Pediatr Neurol 2004;30:169–76. [4] Sankar R, Shin D, Mazarati AM, Liu H, Katsumori H, Lezama R, et al. Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity. Ann Neurol 2000;48:580–9. [5] Holmes GL, Ben-Ari Y. The neurobiology and consequences of epilepsy in the developing brain. Pediatr Res 2001;49:320–5. [6] Mares P. Cognitive and affective effects of seizures: immature developing animals. In: Schachter SC, Holmes GL, KasteleijnNolst Trenite DGA, editors. Behavioral Aspects of Epilepsy: Principles and Practice. New York: Demos; 2008. p. 29–33. [7] Caviness Jr VS, Lange NT, Makris N, Herbert MR, Kennedy DN. MRI-based brain volumetrics: emergence of developmental brain science. Brain Dev 1999;21:289–95. [8] Kanemura H, Aihara M. Growth disturbance of frontal lobe in BCECTS presenting with frontal dysfunction. Brain Dev 2009;31:771–4. [9] Kanemura H, Sugita K, Aihara M. Prefrontal lobe growth in a patient with continuous spike-waves during slow sleep. Neuropediatrics 2009;40:192–4.
[10] Kanemura H, Hata S, Aoyagi K, Sugita K, Aihara M. Serial changes of prefrontal lobe growth in the patients with benign childhood epilepsy with centrotemporal spikes presenting with cognitive impairments/behavioral problems. Brain Dev 2011;33:106–13. [11] Kanemura H, Aihara M, Aoki S, Araki T, Nakazawa S. Development of the prefrontal lobe in infants and children: a three-dimensional magnetic resonance volumetric study. Brain Dev 2003;25:195–9. [12] Williamson PD, Spencer SS. Clinical and EEG features of complex partial seizures of extratemporal origin. Epilepsia 1986;27(suppl. 2):S46–63. [13] Jobst BC, Siegel AM, Thadani VM, Roberts DW, Rhodes HC, Williamson PD. Intractable seizures of frontal lobe origin: Clinical characteristics, localizing signs and results of surgery. Epilepsia 2000;41:1139–52. [14] Camfield PR. Recurrent seizures in the developing brain are not harmful. Epilepsia 1997;38:735–7. [15] Wasterlain CG. Recurrent seizures in the developing brain are harmful. Epilepsia 1997;38:728–34. [16] Marks JD, Friedman JE, Haddad GG. Vulnerability of CA1 neurons to glutamate is developmentally regulated. Dev Brain Res 1996;97:194–206. [17] Portera-Cailliau C, Price DL, Martin LJ. Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol 1997;378:70–87. [18] Dobbing J, Sands J. Vulnerability of developing brain. IX. The effect of nutritional growth retardation on the timing of the brain growth spurt. Biol Neonate 1971;19:363–78. [19] Hoare P. The development of psychiatric disorder among school children with epilepsy. Dev Med Child Neurol 1984;26:3–13. [20] Austin JK, Risinger MW, Beckett LA. Correlates of behavior problems in children with epilepsy. Epilepsia 1992;33:1115–22. [21] Schoenfeld J, Seidenberg M, Woodard A, Hecox K, Inglese C, Mack K, et al. Neuropsychological and behavioral status of children with complex partial seizures. Dev Med Child Neurol 1999;41:724–31. [22] Lendt M, Helmstaedter C, Kuczaty S, Schramm J, Elger CE. Behavioral disorders in children with epilepsy: early improvement after surgery. J Neurol Neurosurg Psychiatry 2000;69:739–44. [23] Mitchell WG, Scheier LM, Baker SA. Psychological, behavioral, and medical outcomes in children with epilepsy: a developmental risk factor model using longitudinal data. Pediatrics 1994;94:471–7. [24] Austin JK, Dunn DW, Caffrey HM, Perkins SM, Harezlak J, Rose DF. Recurrent seizures and behavior problems in children with first recognized seizures: a prospective study. Epilepsia 2002;43:1564–73. [25] Aihara M, Aoyagi K, Goldberg E, Nakazawa S. Age shifts frontal cortical control in a cognitive bias task from right to left: part I. Neuropsychological study. Brain Dev 2003;25:555–9. [26] Bailet LL, Turk WR. The impact of childhood epilepsy on neurocognitive and behavioral performance: a prospective longitudinal study. Epilepsia 2000;41:426–31. [27] White JR, Walczak TS, Marino SE, Beniak TE, Leppik IE, Birnbaum AK. Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study. Neurology 2010;75:513–8.
Original article
Repeated seizures induce prefrontal growth disturbance in frontal lobe epilepsy Hideaki Kanemura a,⇑, Fumikazu Sano a, Tomoko Tando a, Kanji Sugita a, Masao Aihara b b
a Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Japan Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan
Received 3 February 2011; received in revised form 11 April 2011; accepted 12 April 2011
Abstract Background: The possible consequences of seizures in the immature brain have been the subject of much conjecture. We prospectively measured frontal and prefrontal lobe volumes using three-dimensional (3D) magnetic resonance imaging (MRI)-based volumetry in patients with frontal lobe epilepsy (FLE) presenting with the same seizure semiology. The pathogenesis of repeated seizure-induced brain damage is discussed herein. Methods: Serial changes in regional cerebral volumes were measured in two patients with FLE presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)) and four FLE patients without cognitive impairments/behavioral problems (FLE( )). Eleven normal subjects (4–13 years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to-frontal lobe volume ratio was calculated. Results: Frontal and prefrontal lobe volumes revealed growth disturbance in FLE(+) compared with those of FLE( ) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in FLE( ) similarly to controls, but was stagnant or decreased in FLE(+). Prefrontal growth also revealed more rapid recovery in a FLE(+) patient with shorter active seizure period. Conclusion: These findings suggest that repeated seizures may lead to prefrontal growth disturbance. The occurrence of frequent seizures in patients with FLE may be associated with prefrontal lobe growth retardation, which relates to neuropsychological problems and ultimate neuropsychological outcome. Ó 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Frontal lobe epilepsy (FLE); Repeated seizures; Brain damage; Frontal lobe dysfunction; Brain volumetry
1. Introduction Frontal lobe epilepsies, as with other focal epilepsies, were formerly invariably considered to be the consequences of overt or obscure brain lesions. HowAbbreviations: FLE, frontal lobe epilepsy; FLE( ), the FLE group without neuropsychiatric deficits; FLE(+), the FLE group with intractable clinical course and neuropsychiatric deficits; FIQ, full IQ; VIQ, verbal IQ; PIQ, performance IQ; WISC-III, Wechsler Intelligence Scale for Children version III; AEDs, anti-epileptic drugs; CBZ, carbamazepine; VPA, valproate sodium; CLB, clobazam; ZNS, zonisamide ⇑ Corresponding author. Address: Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 1110 Chuo, Yamanashi 4093898, Japan. Tel.: +81 55 273 9606; fax: +81 55 273 6745. E-mail address: [email protected] (H. Kanemura).
ever, frontal lobe epilepsy (FLE) is poorly understood. Some authors have reported differences in seizure semiology in childhood and also that FLE in childhood differs from that in adults [1,2]. Seizures of frontal lobe origin are difficult to control [3]. In addition, children with FLE manifest significant psychosocial problems relative to normative standards [3]. The discussion regarding the possible consequences of seizures in the immature brain has been long and contentious. The initial observation that the immature brain was resistant to seizure-induced morphological damage has been progressively overruled by data demonstrating age- and model-specific brain damage [4], and recent review articles have reached the conclusion that seizures
0387-7604/$ - see front matter Ó 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2011.04.009
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H. Kanemura et al. / Brain & Development 34 (2012) 175–180
impair the developing brain [5]. The likelihood that even morphological damage may depend on the age at which epileptic seizures develop must be taken into account [6]. Repeated seizures may lead to cognitive and behavioral impairments. Magnetic resonance imaging (MRI)-based volumetry has become established as a versatile, reliable method for investigating the biology of the human brain [7]. Stronger correlations have been found between disability and MRI markers, such as the quantitative assessment of cerebral atrophy in various brain diseases. We have already reported development of the prefrontal lobe using three-dimensional (3D) MRI in patients with various epilepsies [8–10]. Those findings suggested that frequent seizures and paroxysms on electroencephalography (EEG) might be associated with prefrontal lobe growth disturbance, which relates to neuropsychological problems in benign childhood epilepsy with centrotemporal spikes (BCECTS) or epilepsy with continuous spike-waves during slow sleep (CSWS). However, these findings are insufficient to prove that repeated seizures themselves can lead to prefrontal growth disturbance. On the basis of these observations, we prospectively measured frontal and prefrontal lobe volumes using 3D-MRI-based volumetry in patients with FLE presenting with the same seizures. The pathogenesis of repeated seizure-induced brain damage is discussed herein. 2. Subjects and methods 2.1. Subjects We registered all patients with FLE at our hospital between July 1999 and June 2003. The patients with structural, metabolic, or genetic abnormalities were excluded in the study. This report is based on six FLE patients. All of them could complete the longitudinal studies.
Subjects comprised six patients with a final diagnosis of FLE, including two cases presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)). The FLE group without cognitive impairments/behavioral problems (FLE( )) comprised two boys and two girls, with a mean age of 6 years (range, 5–7 years). Clinical profiles are provided in Table 1. Clinical features included explosive onset and adversive seizures. Seizures were brief (15–30 s), stereotypic and clustered. Interictal EEG demonstrated frontopolar discharges. Rhythmical frontal slowing was often observed on EEG after seizures and paralleled unilateral features of the epileptic discharges. All patients were followed up regularly for >3 years after the onset of seizures. All four FLE( ) patients were prescribed carbamazepine (CBZ) combined with one another antiepileptic drug (AED), leading to immediate improvement. Active seizure periods for the four FLE( ) patients were 5–6 months. No relapses were encountered and patients remained free of cognitive or behavioral problems after seizure onset. Clinical courses of two cases presenting with FLE(+) are outlined as follows. 2.2. Patient 1 The patient was a 10-year-old right-handed boy with normal initial psychomotor development. He had frequently experienced seizures as head and eyeball adversity to right side since the age of 5 years 1 month. Seizures were brief (15–30 s), stereotypic, and frequent. None of his family had experienced epileptic seizure. Routine MRI showed normal results. Interictal EEG revealed left frontopolar discharges superimposed on normal background activity. FLE was diagnosed based on the types of seizures and the localization of EEG paroxysms. CBZ was administered, but seizures were not easily controlled. Treatment was therefore changed to an addition of zonisamide (ZNS), which did not lead
Table 1 Clinical profiles of the two groups of patients with FLE. Age at onset
Seizure frequency (times)
Seizure duration
Effective AEDs
Behavioral problems
Neuropsychological test (WISC-III; FIQ) (onset)
Neuropsychological test (WISC-III; FIQ) (4 years after)
FLE(+) Patient 1
5 years 1 month
3–6/weeks
2 years 8 months
CBZ + VPA + CLB
98
72
Patient 2
4 years 2 months
2–6/weeks
1 years 4 months
ZNS + VPA
Hyperactivity, impulsiveness, poor school performance Hyperactivity, impulsiveness
94
83
FLE( ) Patient 1 Patient 2 Patient 3 Patient 4
5 years 6 years 6 years 7 years
1–4/months 1–2/months 1–3/months 1–2/months
5 months 6 months 5 months 6 months
CBZ + ZNS CBZ + ZNS CBZ + VPA CBZ + ZNS
92 101 89 97
91 99 88 95
8 months 2 months 3 months 11 months
None None None None
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to improvement in seizures, which recurred almost daily for years. Furthermore, he showed poor school performance and behavioral problems, such as hyperactivity, impulsiveness, aggressiveness and emotional instability. Addition of valproate sodium (VPA) and clobazam led to immediate improvements in seizures. However, cognitive impairments and behavioral problems remained evident even after the remission of seizure disorder. The patient is currently 12 years old and has not shown any further seizures. However, he sometimes gets into trouble with his family, teacher and friends because of hyperactivity and impulsiveness. He had difficulty on the Wisconsin Card-Sorting Test (WCST). Active seizure period was 2 years 8 months (seizure-free since the age of 7 years 9 months). 2.3. Patient 2 A 9-year-old right-handed boy had an uneventful medical history and normal initial psychomotor development. None of his family had experienced epileptic seizure. He experienced a first adversive seizure at 4 years 3 months old, and the first clinical examinations, including routine brain MRI, yielded normal results. Seizures were brief (10–30 s), stereotypic, and frequent. Interictal EEG revealed typical left-sided frontopolar discharges superimposed on normal background activity. FLE was diagnosed based on seizure types and the localization of EEG paroxysms. CBZ was administered, but many relapses were seen. Seizures recurred almost weekly for months. Furthermore, he showed behavioral problems, such as hyperactivity and impulsiveness. Treatment was changed to ZNS combined with VPA, leading to immediate improvements in seizures. After seizure remission, behavioral problems disappeared. Active seizure period was 1 year 4 months (seizure-free since the age of 5 years, 7 months). 3. Serial 3D-MRI volumetric study Serial 3D-MRI studies were performed five times (at onset of clinical symptoms, and 1, 2, 3, and 4 years after onset) in both the above FLE(+) patients and in four FLE( ) patients. A control group comprising 11 agematched children (eight boys, three girls) with a mean age of 7.8 years (range, 4–13 years) was also examined using MRI. Clinical indications for MRI in controls were suspected brain trauma/tumor, short stature, and migraine. These factors proved to be neurologically and neuropsychologically insignificant during a clinical follow-up period of 2–4 years after MRI. All subjects showed no abnormalities on routine MRI. All MRI scans were performed using a 1.5-T system (Siemens, Wisconsin, MW, USA). The 3D-MRI data were acquired using a fast spoiled gradient recalled echo in steady state with 3D Fourier transformation sequence
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(contiguous 1.0–1.2 mm slices obtained through the head; flip angle, 30°; matrix size, 256 256; repetition time, 14.5 ms; echo time, 4.5 ms; field of view, 18 18–22 22 cm), and 3D images of the whole brain surface were obtained from the 124 sections using an Advantage Windows RP 3D Analyzer workstation (General Electric, Wisconsin, MW, USA). Thereafter, the frontal lobe was determined and confirmed using our published method [11]. The central and precentral sulci were identified in left and right lateral as well as superior 3D views of the brain surface. The frontal and prefrontal lobes were determined as the regions anterior to the central and precentral sulcus, respectively. We also confirmed frontal and prefrontal lobe extent by comparison of scans with images resliced in the axial plane parallel to the anterior and posterior commissure (AC-PC) line. Finally, we measured frontal and prefrontal lobe volumes using the volume measurement function of the workstation on the 3D image data. Informed consent and agreement was obtained from each patient and their parents prior to enrolment in this study. 4. Results Measured volumes for frontal and prefrontal lobes, and prefrontal-to-frontal lobe volume ratio in the FLE( ) and control group are shown in Fig. 1. Frontal and prefrontal lobe volumes and prefrontal-to-frontal lobe volume ratio increased serially in FLE( ) patients in a similar manner to controls. Measured volumes for frontal and prefrontal lobes and prefrontal-to-frontal lobe volume ratio in the two FLE(+) patients and controls are shown in Fig. 2. Frontal and prefrontal lobe volumes showed no obvious growth during the active seizure period in the two FLE(+) patients. Prefrontalto-frontal lobe volume ratio was stagnant, with a reduction in Patient 1, during the active seizure period in the two FLE(+) patients (Fig. 2C). Patient 2, with a shorter active seizure period, soon achieved a restored growth ratio. Conversely, growth ratio was delayed in Patient 1, who experienced a longer active seizure period. Growth of the prefrontal lobe volume gradually normalized in both patients after seizure disappearance (Fig. 2). 5. Discussion FLE is one of the most complicated and least understood forms of epilepsy. The characteristics are more variable and less well known than those of temporal lobe epilepsy [12]. Several studies have helped to delineate the clinical and EEG features of this condition [13]. Seizures in all cases are characteristically brief, stereotypical, and frequent. In addition, all cases demonstrate frontopolar EEG paroxysms, fulfilling the clinical criteria for FLE. However, outcomes differ in
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A
B
(cm3)
(cm3)
C
130
320
0.43 0.41
120
300
0.39 110 0.37
280 100
0.35
90
0.33
260
0.31
240 80
0.29 220
70
200
0.27
60 4
6
8
10
12
14
0.25 4
6
8
10
12
14
4
6
8
10
12
14
Age (years) Fig. 1. Serial changes in frontal lobe volumes (A), prefrontal lobe volumes (B), and prefrontal-to-frontal lobe volume ratio (C) in patients with FLE( ) and control subjects. Scatter plots for FLE( ) patients (Patient 1, brown diamonds; Patient 2, cyan squares; Patient 3, yellow triangles; Patient 4, green circles) and age-matched controls (black circles).
A
B
(cm3)
(cm3)
C 0.43
130
320
0.41
120
300
0.39 110 0.37
280 100
0.35
90
0.33
260
0.31
240 80
0.29 220
70
200
0.27
60 4
6
8
10
12
14
4
6
8
10
12
14
0.25 4
6
8
10
12
14
Age (years) Fig. 2. Serial changes in frontal lobe volumes (A), prefrontal lobe volumes (B), and prefrontal-to-frontal lobe volume ratio (C) in the two patients with FLE(+) and control subjects. Scatter plots for Patient 1 (red squares), Patient 2 (blue diamonds) and age-matched controls (black circles). Horizontal bars for Patient 1 (red) and Patient 2 (blue) indicate the active seizure period.
terms of seizure, cognition and behavior. Frontal lobe seizures in childhood may have different outcomes to those observed in adult patients [1]. The main difference in the two groups is seizure frequency, so the present results may indicate the effects of repeated seizures. Given the possibility that some functional changes may have structural correlates, MRI could also play a pivotal role in elucidating the mechanisms underlying epileptogenesis. Quantitation of brain volume using 3D MRI is thus a useful way of characterizing normal growth and abnormal development due to various
diseases [11]. Furthermore, volumetric analysis of the brain may predict function in corresponding regions [8]. However, it is difficult to measure the gray and white matter separately in our method. We have used the same method for image acquisition, frontal lobe determination, and volumetric measurements as our previous report. Therefore, frontal lobe was determined and confirmed using the same method as our previous report. In our four FLE( ) patients, frontal and prefrontal lobe volumes showed growth patterns similar to control subjects. In the two FLE(+) patients, conversely, frontal
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and prefrontal lobe volumes and the prefrontal-to-frontal lobe volume ratio in particular showed growth disturbances during the seizure period. This suggests that repeated seizures may lead to prefrontal growth disturbance, reflecting cognitive and behavioral impairments. In the developing brain, the effects of seizures on neuronal survival and brain growth have remained controversial [14,15]. The immature brain appears to be more resistant to the toxic effects of glutamate than the mature brain [16]. However, excitotoxic neuronal death is influenced by brain maturation [17]. As apoptosis plays an important role in early brain development, the immature brain may be particularly vulnerable to programmed cell death in response to seizures. These findings provide strong evidence for the vulnerability of the immature brain to seizure-induced damage, which bears features of both necrotic and apoptotic death and contributes to synaptic reorganization [4]. Moreover, since the prefrontal lobe is among the last cortical regions to reach full structural development [11,18], prefrontal function and its disorders are not immediately apparent. Prefrontal functions therefore show an unusually long period of increased vulnerability, in which neurons and glial cells are readily affected by many factors including genetic influences, the hormonal milieu, and external insults, such as infections, toxins, and trauma [18]. Among the cortical regions, the prefrontal lobe appears highly vulnerable to repeated seizures. More frequent and severe seizures have been associated with behavioral problems in many prior studies [19,20]. Schoenfeld et al. found that frequency of complex partial seizures in the previous year was the strongest predictor of behavioral problems [21]. In addition, Lendt et al. found a reduction in behavioral problems in a group of children after successful surgery for epilepsy compared with children experiencing persistent focal seizures [22]. However, some studies have not shown any association between behavioral problems and more frequent seizures [23]. In more recent research by Austin et al. seizure recurrence significantly predicted behavioral problems [24]. They speculated that possible explanations for this relationship are that: (a) seizures and behavioral problems are associated because both are related to an underlying factor; (b) seizure activity per se disrupts behavior; or (c) children have a negative psychological response to seizures [24]. Our major finding is that repeated seizures may lead to prefrontal growth disturbance. Current research suggests that damage to the frontal regions during childhood may interrupt normal maturational processes and organization, resulting in impairments to neurobehavioral development. Integrative executive functions may thus rely on the health of frontal lobe tissue and connectivity with the rest of the cortex [25]. In our previous reports with BCECTS or CSWS [8–10], active seizure period as frequent spike-waves coupled with the occurrence of
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frequent seizures may be associated with prefrontal lobe growth disturbance. In contrast, similar EEG abnormalities were revealed in both patients with FLE( ) and FLE(+). The main difference between FLE( ) and FLE(+) was seizure frequency. Therefore, this finding may clarify the factors that influence the volumetric abnormalities as seizure frequency. Our results may support the second speculation by Austin et al. Though we have excluded the patients with structural, metabolic, or genetic abnormalities because of exclusion of the influence of these factors, there is a possibility that original pathology (cryptogenic factor or the first speculation by Austin et al. [24]) may cause both frontal growth disturbance and frequent seizures. Further investigations are needed to discuss this point. Consideration needs to be given to the effects of antiepileptic drug treatment. The two FLE(+) patients had been treated using VPA. It may be that VPA serves as a marker of relative risk from an academic perspective as compared with CBZ [26]. In addition, VPA can induce reversible brain atrophy. No clear cause-effect relationship between use of VPA and prefrontal lobe growth disturbance has been identified. However, the prefrontal lobe and prefrontal-to-frontal lobe volume ratio in the present patients were restored to the growth ratio, although VPA was given throughout the clinical course. Consideration therefore does not need to be given to effects of VPA on brain atrophy. Furthermore, ZNS may exacerbate cognitive impairments/behavioral problems [27]. However, ZNS was effective for seizure and behavioral problems in Patient 2 of FLE(+). In addition, ZNS was effective drug in three of four FLE( ) patients. Therefore, it needs not be given consideration to effect of ZNS for the cognitive impairments/behavioral problems in this study. Seizures originating from the frontal lobe may be difficult to control. A previous report found that seizure control was difficult, with only half of patients being controlled on anti-epileptic medications [3]. The two FLE(+) patients in this study revealed prefrontal growth disturbance. In addition, poor outcome is evident in a patient with prolonged repeated seizures. We should consider that, from a therapeutic viewpoint, the most critical fact is whether seizures themselves can damage the brain. Undoubtedly, the immature brain, with its massively lower metabolic rate, liberates less glutamate than the adult brain per unit time and takes longer to develop ATP depletion and damage [15]. The relative resistance of the immature brain to seizureinduced damage is thus genuine. However, as suggested by the present results, seizures can induce prefrontal growth disturbance. Moreover, in our previous studies, outcomes appeared to be related to the duration of the active seizure period [9,10]. In considering outcomes for children with FLE, therefore, control of seizures must be weighed against the incidence of neurological
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impairments, either transiently or persistently. Based on our prospective study, management of treatment to remit seizures as soon as possible may be required to achieve optimal prognosis in FLE with cognitive or behavioral involvement. In conclusion, we have shown that repeated seizures themselves can induce brain damage. Occurrence of frequent seizures in patients with FLE may be associated with retardation of prefrontal lobe growth, which relates to neuropsychological problems and ultimate neuropsychological outcome. Management of treatment may be required to remit seizures as soon as possible to achieve optimal prognosis in FLE. Conflict of interest We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflict of interest to disclose. Acknowledgments This work was supported by Grants-in-Aid for Scientific Research (C) (22591124 and 22591123) and the Japan Epilepsy Research Foundation. References [1] Fogarasi A, Janszky J, Faveret E, Pieper T, Tuxhorn I. A detailed analysis of frontal lobe seizures semiology in children younger than seven years. Epilepsia 2001;42:80–5. [2] Vigevano F, Fusco L. Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia 1993;34:110–9. [3] Sinclair DB, Wheatley M, Snyder T. Frontal lobe epilepsy in childhood. Pediatr Neurol 2004;30:169–76. [4] Sankar R, Shin D, Mazarati AM, Liu H, Katsumori H, Lezama R, et al. Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity. Ann Neurol 2000;48:580–9. [5] Holmes GL, Ben-Ari Y. The neurobiology and consequences of epilepsy in the developing brain. Pediatr Res 2001;49:320–5. [6] Mares P. Cognitive and affective effects of seizures: immature developing animals. In: Schachter SC, Holmes GL, KasteleijnNolst Trenite DGA, editors. Behavioral Aspects of Epilepsy: Principles and Practice. New York: Demos; 2008. p. 29–33. [7] Caviness Jr VS, Lange NT, Makris N, Herbert MR, Kennedy DN. MRI-based brain volumetrics: emergence of developmental brain science. Brain Dev 1999;21:289–95. [8] Kanemura H, Aihara M. Growth disturbance of frontal lobe in BCECTS presenting with frontal dysfunction. Brain Dev 2009;31:771–4. [9] Kanemura H, Sugita K, Aihara M. Prefrontal lobe growth in a patient with continuous spike-waves during slow sleep. Neuropediatrics 2009;40:192–4.
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