Pediatric Epilepsy Surgery in Focal Lesions and Generalized Electroencephalogram Abnormalities

Original Articles

Pediatric Epilepsy Surgery in Focal Lesions and Generalized Electroencephalogram Abnormalities Ajay Gupta, MD, Adina Chirla, RN, Elaine Wyllie, MD, Deepak K. Lachhwani, MD, Prakash Kotagal, MD, and William E. Bingaman, MD Generalized abnormalities on scalp electroencephalograms (EEG) are not uncommon in children with partial epilepsy in whom a dominant focus of interictal and ictal abnormalities concordant to the brain lesion usually clarifies surgical candidacy. Children with exclusively generalized or multiregional EEG abnormalities and mental retardation are usually not considered surgical candidates, even when brain lesions are seen on imaging. Of 176 pediatric epilepsy surgeries at our center, we describe 10 children with exclusively generalized and multiregional interictal and ictal EEG abnormalities who had resection of a focal lesion seen on brain MRI. Surgical decisions were strengthened by clinical data. Surgery was offered as a last resort because of catastrophic epilepsy and treatment failures. At 26 months’ mean postoperative follow-up, eight had no seizures, and two had infrequent seizures. Six months after surgery, generalized electroencephalographic abnormalities had resolved in all. We conclude that generalized and multiregional EEG abnormalities in the absence of dominant focus may not preclude epilepsy surgery in children with a congenital or acquired lesion seen on MRI. Generalized EEG abnormalities are likely secondary phenomena that resolve after surgery. Maladaptive neural plasticity and secondary epileptogenesis are potential mechanisms that mask an epileptogenic lesion with generalized EEG abnormalities. © 2007 by Elsevier Inc. All rights reserved.

Introduction

Gupta A, Chirla A, Wyllie E, Lachhwani DK, Kotagal P, Bingaman WE. Pediatric epilepsy surgery in focal lesions and generalized electroencephalogram abnormalities. Pediatr Neurol 2007;37:8-15.

Of 176 children (less than 16 years of age) who underwent epilepsy surgery at the Cleveland Clinic during 2001-2003, we identified 10 children, aged 3-16 (mean age, 8.5) years, who under went surgical resection of a focal lesion apparent on brain MRI and fluorodeoxy glucose-positron emission tomography, despite the presence of generalized and multiregional scalp EEG abnormalities and a lack of a

From the Epilepsy Center, Neurological Institute, Lerner College of Medicine, Case Western Reserve University, Cleveland Clinic Foundation, Cleveland, Ohio.

Communications should be addressed to: Dr. Gupta; S-51, Epilepsy Center; Neurological Institute; Lerner College of Medicine; Case Western Reserve University; Cleveland Clinic Foundation; Cleveland, OH 44195. E-mail: [email protected] Received November 28, 2006; accepted March 22, 2007.

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During evaluation for epilepsy surgery, patients with exclusively generalized and bilaterally multiregional interictal and ictal scalp electroencephalogram (EEG) epileptiform abnormalities and cognitive delay are not usually considered surgical candidates, because such findings are presumed to suggest generalized epilepsy. However, this paradigm does not hold true in infants with generalized scalp EEG patterns such as hypsarrhythmia, and in infantile spasms where seizure freedom has been obtained after resection of the cortical lesion that was apparent on the brain magnetic resonance imaging (MRI) or positron emission tomography [1-3]. It is not clear if some children beyond infancy who have exclusively generalized and multiregional EEG abnormalities in the presence of a focal brain lesion could benefit from epilepsy surgery. In this case series, we report on 10 such children with catastrophic epilepsy who became seizure-free or who significantly improved after surgery. We also discuss the potential mechanisms of generalized EEG abnormalities and the masking of focal epileptiform abnormalities on scalp EEG.

Materials and Methods

© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.03.004 ● 0887-8994/07/$—see front matter

predominant EEG focus. All children were desperately sick, and had catastrophic epilepsy. Six children had a diagnosis of Lennox-Gastaut syndrome, and were previously rejected for epilepsy surgery. A focal or hemispheric lesion was noted at the first instance in 7 of 10 (70%) children on brain MRI. However, cognitive delay together with scalp EEG findings were thought to be suggestive of generalized or multiregional epilepsy (symptomatic generalized epilepsy), and thus epilepsy surgery was not offered. All children underwent a presurgical reevaluation at the Cleveland Clinic (Cleveland, OH). After careful consideration of all risks, benefits, and alternatives, resection of the lesion seen on the brain MRI was offered as a last resort. The surgical plan was approved by the Epilepsy Patient Management Committee of the Cleveland Clinic. An independent bio-ethicist interviewed every patient’s parents or legal guardian to ensure parental understanding of the involved risks and benefits. Postoperative EEG at 6 months and seizure outcome were noted at the last follow-up, using the classification proposed by the International League Against Epilepsy [4].

Results Demographic and Seizure Data In 10 children (6 females), the age of seizure onset was 1 day to 4 years (mean, 22 months; median, 18 months; for a summary of data, see Table 1). The range of ages at surgery was 3-16 (mean, 8.5) years. The interval between seizure onset and surgery was 3-16 (mean, 6.75) years. All patients were previously rejected as epilepsy surgery candidates after one (five patients) or two (five patients) presurgical evaluations at our center and other centers. At the time of their final presurgical evaluation, the mean number of daily seizures associated with falls or altered awareness was 27 (5-120 per day). Three children had a history of frequent prolonged status epilepticus (1-3 per month) with respiratory failure requiring intensive care treatment. All children were on polytherapy with 2-5 (median, 3) antiepileptic medications, and had previously failed polytherapy with 4-9 (median, 5) antiepileptic medications. Four patients had an active vagus nerve stimulator device (Cyberonics, Houston, TX) placed by outside medical centers. All children had reached the end of most of the medical treatment possibilities for epilepsy. Presurgical Evaluation Pertinent presurgical findings are summarized in Table 1. Figure 1 (patient 7 in Table 1) depicts representative findings in one patient. All children had severe cognitive delay. Objective testing for performance intelligence quotient was possible only in two children (performance intelligence quotients, 44 and 53), and revealed severe mental retardation. In six children (aged 3-11 years), the mean neuropsychologic delay in mental age was estimated to be 4.5 years (range, 2-7.5 years). Neuropsychologic evaluation was not possible in two children because of severe chronic encephalopathy. Seven patients had moderate-to-severe hemiparesis, two had associated contralateral, homonymous hemianopsia confirmed by examination, and one had

asymmetric spastic quadriparesis (bilateral left-to-right hemiparesis; patient 4 in Table 1). Ictal semiology evaluated during video EEG monitoring was helpful in lateralization in four patients who had focal motor tonic or clonic seizures involving one side of the body. All other recorded seizures had generalized semiology (Table 1), with no asymmetric or lateralizing features. Interictal scalp EEGs indicated generalized EEG abnormalities with or without independent multiregional spikes or sharp waves, but without any dominant focus. Ictal EEGs indicated a generalized onset or a nonlocalizable and nonlateralized pattern in all patients during every recorded seizure. In one patient (patient 5 in Table 1), during one seizure out of many recorded, the ictal EEG onset was helpful in lateralization in the presence of bilateral lesions. This patient had remote bilateral ischemic strokes in the right middle cerebral and posterior branch of the left middle cerebral distributions. She had a history of daily atypical absence seizures, atonic seizures, and infrequent episodes of generalized motor convulsions leading to status epilepticus (one status epilepticus every 4-6 weeks). She had left hemiparesis. Her interictal EEG revealed a rare, right frontal spike in the first evaluation at age 6 years, with an overwhelming background of generalized slowing and generalized slow spike and wave patterns, and generalized ictal EEG during atypical absence seizures. She had two subsequent video EEGs that again revealed pervasive, generalized, slow spike and wave patterns, with an ictal EEG indicating generalized spikes and waves during a recorded atypical absence seizure. Because of bilateral strokes and the generalized EEG findings, she was rejected as a surgical candidate after each of her three evaluations. In the fourth video EEG evaluation, one motor seizure that went on to become a prolonged seizure (convulsive status epilepticus) had maximum ictal onset in the right frontal region, indicating that the likely seizure onset zone for episodes of status epilepticus was in the right hemisphere. She underwent right functional hemispherectomy at age 8.5 years. Postoperatively, she had immediate resolution of motor seizures and a gradual resolution of atypical absence seizures. Her postoperative EEG at 6-month follow-up also showed resolution of her interictal generalized spike and wave pattern. All patients had abnormalities on their brain MRI, with encephalomalacia in four, malformations of cortical development in three, and remote ischemic stroke in three. In four children with encephalomalacia, two had a history of significant head trauma (perinatal and nonaccidental for one each), one had a history of meningoencephalitis, and one had a remote history of hemiconvulsive-hemiplegic epilepsy syndrome. Brain fluorodeoxyglucose-positron emission tomography was performed in nine patients, and it was concordant with the brain MRI abnormality in eight, and with nonfocal findings in one. Ictal single-photoemission computed tomography was not performed on any patient because of practical limitations such as pervasive

Gupta et al: Epilepsy Surgery in Generalized Electroencephalograms 9

Table 1.

Summary of findings in 10 children

No. of patient

Age at surgery (years)/sex

Sz onset age (years)

Sz/d with LOC or fall

Preoperative motor/visual deficits

1. 2. 3. 4

8/F 3/F 4.25/F 5/M

1.5 Birth 1.5 1.75

⬎100 40 20 10

5.

8.25/F

3

5 ⫹ SE

L HP R HP, R HO None L ⬎ R HP, in wheel chair L HP

10 50 ⫹ SE 4 8 ⫹ SE

L HP, L HO None L HP L HP

6. 7. 8. 9.

8/M 7/M 14/M 16/F

4 4 0.2 0.1

10.

11/F

0.5

5

R HP

Sz semiology on video

Brain MRI findings

Atonic, atypical absence, GCS, GTCS R arm tonic, GTC Atonic sz GTC, atypical absence

R HS, MCD L HS perinatal injury and SDH R frontal MCD B/L R ⬎ L HS encephalomalacia due to trauma R MCA and L posterior branch of MCA stroke R TO atrophy due to HHE L TO MCD R perinatal MCA stroke R HS extensive encephalomalacia due to remote meningitis, L paracentral lobule abnormalities also seen L MCA stroke

Atonic, absence, myoclonic, GTCS, 1 R versive Sz L body tonic-clonic, GTS Atypical absence, GTS GTC Atypical absence, GCS, GTS

R face clonic, complex partial, atypical absence

Abbreviations: APOS ⫽ Acute postoperative seizures B/L ⫽ Bilateral d ⫽ Day F ⫽ Female GCS ⫽ Generalized clonic seizure Gen ⫽ Generalized GSSW ⫽ Generalized slow spike and wave GTCS ⫽ Generalized tonic-clonic seizures GTS ⫽ Generalized tonic seizure HHE ⫽ Hemiconvulsive hemiplegic epilepsy syndrome HO ⫽ Hemianopsia HP ⫽ Hemiparesis HS ⫽ Hemisphere HSY ⫽ Hemispherectomy

slow spike and wave interictal patterns, high seizure frequency, brief seizure duration, multiple seizure types, and difficulty in accurately pinpointing the clinical seizure onset. Chronic subdural recordings or intraoperative electrocorticography were not considered in any patient, as they were considered unlikely to help localize ictal onset, to salvage any eloquent regions (location, technical limitations because of age, or a patient’s inability to cooperate), or to change the surgical plan of complete resection of the lesion or hemisphere. Surgery and Postsurgery Follow-Up Seven patients had a functional hemispherectomy, two had a multilobar temporo-occipital/posterior parietal resection, and one had a premotor frontal resection. At a mean follow-up of 26 months (range, 18-36 months) after surgery, eight patients were seizure-free, and two had greater than 75% improvement, with freedom from status epilepticus and disappearance of the most disabling seizure type associated with falls. Of two patients (Table 1, patients 5 and 9) who were not seizure-free, the parents of one patient reported two generalized clonic seizures of a few seconds’ duration during febrile illnesses, in addition

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to staring spells of a few seconds’ duration, with 1-2 seen per month (not confirmed to be epileptic seizures). The other child had continuing but improved axial tonic seizures, 10-30 seconds in duration, occurring 1-2 per month, usually during a febrile illness. Two patients had acute postoperative seizures within the first week after surgery: one underwent repeat surgical resection (extension) of the previous left temporo-occipital malformation, and in the other, only the medications were adjusted. Both patients with acute postoperative seizures had a gradual but complete resolution of seizures by 6 weeks after surgery. Perioperative complications occurred in two patients after functional hemispherectomy: one had hydrocephalus requiring a ventriculoperitoneal shunt, and one developed sterile chemical meningitis. No new postoperative deficits were noted on neurological examination at 6 months and 1 year after surgery. At the most recent follow-up, seven children were on monotherapy, and three were on two antiepileptic medications in modest doses. Parents reported improvements in the level of alertness, attention, learning, and behavior in all children. Of 10 patients, nine had a scalp EEG at 6 months after surgery (Table 1). The EEGs revealed persistent, but only sporadic, sharp waves and slowing in the operated hemi-

Table 1.

Continued

Resective surgery

Histopathologic findings

Postoperative follow-up (months)

GSSW Gen and B/L MR GSSW Gen and B/L MR

R HSY L HSY R frontal R HSY

MCD Gliosis MCD Remote ischemia, gliosis

36 34 28 28

Sz-free Sz-free Sz-free Sz-free

Isolated R HS SW L HS SW at O1 NA Few SW R HS and L HS at C3

GSSW and B/L MR

R HSY

Remote ischemic injury

27

Stares, brief febrile GCS

Gen and B/L MR rare P3 SW Gen and R and L temporal GSSW and rare SW R HS GSSW max bifrontal

R TO L TO R HSY R HSY

Remote ischemic injury MCD Remote ischemia, gliosis Gliosis

26 24 19 19

APOS, none subsequently APOS, surgery ⫻ 2 Sz-free Brief GCS ⬃2/month

L HS SW at C3-T7 (new finding in nonoperated HS) Rare R HS SW at C4, Cz No SW Isolated Gen max R frontal SW Gen and MR SW, no GSSW

GSSW max bifrontal

L HSY

Remote ischemic injury

18

Sz-free

Few R HS sharp transients

Interictal EEG

L LOC M max MCA MCD MR NA R SDH SE SW Sz TO

⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

Sz outcome

⬃6-month postoperative EEG

Left Loss of consciousness Male Maximum Middle cerebral artery Malformation of cortical development Multiregional Not available Right Subdural hematoma Status epilepticus Sharp waves Seizure Temporo-posterior temporal-occipital

sphere in eight patients. Of these eight patients, additional contralateral (patients 4 and 5 in Table 1) or generalized (patient 9 in Table 1) sharp waves were seen in three patients (one who was seizure-free, and two with persistent but greater than 75% improved seizures), all of whom had preoperative bihemispheric evidence of injury on brain MRI (patients 4, 5, and 9 in Table 1). One patient had no epileptiform abnormalities on 6-month postoperative EEG. One patient did not report for an EEG (patient 3 in Table 1), and only clinical follow-up was available for her. Pervasive runs of generalized slow spikes and waves, and generalized polyspikes and sharp waves, resolved in the postoperative EEGs of all patients. Discussion Epilepsy Surgery Despite Generalized EEG Findings Our surgical series indicates that even in older children with surgically remediable epilepsy, interictal and ictal scalp EEGs may reveal generalized and multiregional abnormalities with no dominant EEG focus. In these patients, freedom from seizures, or significant improvement after complete resection of a lesion seen on MRI, suggests that the localized epileptogenic process was

preoperatively masked by generalized EEG abnormalities. In addition to the evidence of a focal lesion (presumed to be epileptogenic) on brain MRI and positron emission tomography, the case for surgical candidacy was strengthened by concordant findings of contralateral fixed hemiparesis (functional deficit zone) in seven patients, contralateral hemianopsia in two, and ictal semiology in four with a focal motor component (symptomatogenic zone). The decision in favor of surgery for every patient in our series was made as a last resort, after careful consideration of the risks of surgery, of new postoperative deficits, and of the risk of continuing seizures on medical treatment. Our series thus expands the age for surgical treatment of epilepsy, in the presence of generalized scalp EEG abnormalities, that was previously reported to be mainly successful in infants with epileptic (infantile) spasms and hypsarrhythmia who had successful seizure outcome after resection of a lesion seen on brain MRI or fluorodeoxyglucose positron emission tomography [1]. It is well-known that congenital epileptogenic lesions may manifest first with partial clinical and focal EEG seizures during early infancy. However, later in infancy, infantile spasms and hypsarrhythmia [2,5-7] appear as a dominant phenotype, with the disappearance or dissolution

Gupta et al: Epilepsy Surgery in Generalized Electroencephalograms 11

Figure 1. Patient 7 in Table 1. Interictal scalp EEG with runs of slow spike and wave complexes in left temporal (A), right temporal (B), and generalized (C) distribution. (D) Ictal scalp EEG during generalized tonic seizures reveals low-voltage beta rhythms and disappearance of slow spike and wave. Preoperative high-resolution (2-mm slices with no intersplice gap) coronal T1 brain MRI indicates left temporal malformation, with blurred gray-white junction and dysmorphic left hippocampus (E, left, TR/TE ⫽ 11.40/4.4 ms). The posterior margin of the dysplasia extended into the occipital lobe. Postoperative T1 brain MRI (E, right, TR/TE ⫽ 700/12 ms) reveals resected left temporal and basal occipital region. (F) An EEG 6 months after surgery indicated return of normal right hemispheric background, with expected decreased background over the left hemisphere. Horizontal ruler bars under EEG tracings represent 1 second.

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Fig. 1. Continued.

Gupta et al: Epilepsy Surgery in Generalized Electroencephalograms 13

of partial seizures and focal EEG abnormalities. All children in our group had hemispheric or large lobar or multilobar lesions that were congenital or acquired early in life. It is possible that early focal EEG findings at the onset of epilepsy were not recognized in some children in our series. We reviewed all records of every patient to the extent that they were available at the time of final evaluation. However, from the time they were seen by us or another tertiary-care center for presurgical evaluation, except for one patient (patient 5 in Table 1, with a bilateral stroke with right frontal sharp waves and seizure onset), the scalp EEG findings were exclusively generalized and multiregional. With the advent of high-resolution brain MRI and fluorodeoxyglucose positron emission tomography, careful study of MRI and positron emission tomography data is necessary, and importance should be attached to any neuroimaging finding that is concordant with a patient’s history, examination, and seizure semiology, despite the presence of generalized and multiregional EEG abnormalities. It is possible that after a comprehensive evaluation, some older children with congenital or acquired lesions, who are excluded from further detailed evaluation for epilepsy surgery because of Lennox-Gastaut syndrome or symptomatic generalized epilepsy, may become candidates for surgical treatment of epilepsy. It remains unclear why a finding of generalized and bilaterally multiregional EEG abnormalities does not develop in all children with epilepsy because of congenital or early onset-acquired lesions. The location or etiology of a lesion may not be likely factors, because patients in our series had diverse locations and pathological substrates. Age at time of brain injury, age of onset of epilepsy, duration of epilepsy, and size of the lesion may be relevant factors, because all children in our study had long-standing intractable epilepsy because of large congenital or early onset-acquired brain lesions. There may be additional genetic factors giving rise to susceptibility for excessive or maladaptive plasticity in some children. Our series has the limitation of the small number of patients who were retrospectively studied. However, our experience is significant in expanding the selection criteria for pediatric epilepsy surgery beyond infancy. Generalized Seizures and Scalp EEG Abnormalities in Focal Lesions: Potential Mechanisms Few mechanisms could be hypothesized to explain a generalized and multiregional scalp EEG in children with focal lesions. Recently, excessive or maladaptive neural plasticity was suggested to explain the progressive nature of certain types of human epilepsy [8,9]. The available evidence regarding the maladaptive neural-plasticity theory suggests that initial precipitating injuries or insults to a developing brain and seizures may set into motion a sequence of slowly evolving cellular events that presumably alter neural circuits and eventually render these circuits vulnerable to spontaneous synchronization and

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progressive susceptibility to seizures [9]. A previously well-known phenomenon in epilepsy, kindling, was also viewed recently as a phenomenon of neural plasticity [9,10]. The process of a progressive and permanent increase in seizure susceptibility via kindling in animal models requires repeated after-discharges (equivalent to clinical seizures) or the occurrence of frequent subclinical episodes of network synchronization (possibly equivalent to a pervasive interictal slow spike and wave pattern in scalp EEG) after an initial injury [11]. Kindling leads to abnormal network synchronization and circuit alterations, and ultimately results in progressive, spontaneous seizures [9]. The occurrence of kindling regardless of the site of initial stimulation (injury or lesion) in the brain, together with the unique characteristics of a developing brain [12,13], may explain the observed clinical course of cognitive decline, generalized seizures, and emergence of generalized and multiregional discharges with a loss (or lack) of focal abnormalities. Another previously described mechanism that was proposed to explain similar findings is secondary epileptogenesis. Secondary epileptogenesis refers to a process whereby an actively discharging epileptogenic region (i.e., primary focus) gradually induces similar paroxysmal epileptogenic properties in the synaptically related or remote cerebral regions of the network (i.e., satellite or secondary foci). Recently, in patients with hypothalamic hamartoma, secondary epileptogenesis was proposed as a mechanism to explain the emergence of generalized EEG seizures and interictal slow spike and wave patterns [14]. It was demonstrated that gelastic seizures, the signature partial seizures associated with hypothalamic hamartoma, originate from the hamartoma (the primary focus of secondary epileptogenesis), and can be reproduced by electric stimulation of the hamartoma by stereotactically placed depth electrodes [15]. On the other hand, gradually evolving interictal generalized spike and wave EEG patterns, and other types of generalized and complex partial seizures seen later in life in patients with hypothalamic hamartoma, are not consistently observed to originate from the hypothalamic hamartoma on scalp and intracranial EEG recordings [14,16], implying that these findings may represent an extralesional (secondary focus of the secondary epileptogenesis) phenomenon. After successful resection of hamartoma in 12 patients in one series [14], 11 of 12 patients had a remission of generalized and gelastic seizures, associated with a marked reduction or disappearance of interictal generalized slow spike and wave activity and neurobehavioral improvement. The presence of generalized slow spike and wave discharges in our patients, and their disappearance on postoperative EEGs, suggest that this secondary phenomenon may not be unique to hypothalamic hamartoma, but could well occur in supratentorial cortical lesions. Another poorly understood concept is the secondary bilateral synchrony that was proposed in the pre-neuroimaging era to explain the presence of bilateral synchronous

spike and wave discharges in 26 patients (out of 31) with seizures originating from a focal lesion in the parasagittal region [17]. Freedom from seizures, or significant improvement, was reported in 24 of 31 patients after resection of a mesial cortical lesion. The concept of secondary bilateral synchrony was later used as a basis to devise tests for differentiating between primary and secondary bilateral synchrony [18,19]. Intracarotid sodium amobarbital and its various modifications were used to determine the “driving cerebral hemisphere” by the suppression of generalized spike and wave discharges when the epileptogenic hemisphere was injected [19,20]. Because the invasive nature of the tests and the need for general anesthesia or sedation in children complicate the interpretation of these tests, fractional intravenous sodium pentothal injection was used in children to study dose-dependent differential effects upon synchronous spikes and waves [18,21]. However, these tests were often difficult to interpret, and were not found to be reliable enough to use as routine diagnostic tools [22,23]. No patient in our study had a localized mesial cortical lesion. We did not conduct intracarotid or intravenous barbiturate injections, because we did not believe that the tests would provide any strong complementary data to alter surgical decisions regarding our patients. Conclusions The exclusively generalized expression of EEG abnormalities in the presence of a focal cortical lesion (congenital or acquired during infancy) may occur beyond infancy. Freedom from seizures is possible in some older children after resection of a brain lesion seen on MRI, despite the presence of generalized scalp EEG abnormalities and the absence of dominant or concordant focal EEG abnormalities. When present, focal motor deficits such as hemiparesis, carefully observed focal features of seizure semiology, or focal findings on an ictal EEG earlier in life may strengthen the case for considering epilepsy surgery. Carefully conducted larger series in the future may help to expand the selection criteria for surgical epilepsy candidates. References [1] Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990;27:406-13. [2] Kramer U, Sue WC, Mikati MA. Focal features in West syndrome indicating candidacy for surgery. Pediatr Neurol 1997;16: 213-7.

[3] Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 1998;44:740-8. [4] Wieser HG, Blume WT, Fish D, et al. ILAE commission report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia 2001;42:282-6. [5] Kubota T, Aso K, Negoro T, et al. Epileptic spasms preceded by partial seizures with a close temporal association. Epilepsia 1999;40: 1572-9. [6] Wyllie E, Comair YG, Kotagal P, Raja S, Ruggieri P. Epilepsy surgery in infants. Epilepsia 1996;37:625-37. [7] Yamamoto N, Watanabe K, Negoro T, et al. Partial seizures evolving to infantile spasms. Epilepsia 1988;29:34-40. [8] Johnston MV. Clinical disorders of brain plasticity. Brain Dev 2004;26:73-80. [9] Sutula TP. Mechanisms of epilepsy progression: Current theories and perspectives from neuroplasticity in adulthood and development. Epilepsy Res 2004;60:161-71. [10] Stafstrom CE, Sutula TP. Models of epilepsy in the developing and adult brain: Implications for neuroprotection. Epilepsy Behav 2005; 7(Suppl. 3):18-24. [11] Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 1969;25:295-330. [12] Sanchez RM, Jensen FE. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Epilepsia 2001; 42:577-85. [13] Sankar R, Shin D, Liu H, Wasterlain C, Mazarati A. Epileptogenesis during development: Injury, circuit recruitment, and plasticity. Epilepsia 2002;43(Suppl. 5):47-53. [14] Freeman JL, Harvey AS, Rosenfeld JV, Wrennall JA, Bailey CA, Berkovic SF. Generalized epilepsy in hypothalamic hamartoma: Evolution and postoperative resolution. Neurology 2003;60:762-7. [15] Kuzniecky R, Guthrie B, Mountz J, et al. Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann Neurol 1997;42:60-7. [16] Munari C, Kahane P, Francione S, et al. Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study). Electroencephalogr Clin Neurophysiol 1995;95:154-60. [17] Tukel K, Jasper H. The electroencephalogram in parasagittal lesions. Electroencephalogr Clin Neurophysiol 1952;4(Suppl.):481-94. [18] Lombroso CT, Erba G. A test for separating secondary from primary bilateral synchrony in epileptic subjects. Trans Am Neurol Assoc 1969;94:204-9. [19] Rovit RL, Gloor P, Rasmussen T. Intracarotid amobarbital in epileptic patients. A new diagnostic tool in clinical electroencephalography. Arch Neurol 1961;5:606-26. [20] Coceani F, Libman I, Gloor P. The effect of intracarotid amobarbital injections upon experimentally induced epileptiform activity. Electroencephalogr Clin Neurophysiol 1966;20:542-58. [21] Lombroso CT, Erba G. Primary and secondary bilateral synchrony in epilepsy: A clinical and electroencephalographic study. Arch Neurol 1970;22:321-34. [22] Blume WT, Pillay N. Electrographic and clinical correlates of secondary bilateral synchrony. Epilepsia 1985;26:636-41. [23] Gloor P, Rasmussen T, Altuzarra A, Garretson H. Role of the intracarotid amobarbital-pentylenetetrazol EEG test in the diagnosis and surgical treatment of patients with complex seizure problems. Epilepsia 1976;17:15-31.

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