Preoperative evaluation in children for epilepsy surgery

Handbook of Clinical Neurology, Vol. 108 (3rd series) Epilepsy, Part II H. Stefan and W.H. Theodore, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 49

Preoperative evaluation in children for epilepsy surgery 1

MICHAEL DUCHOWNY 1* AND J. HELEN CROSS 2 Comprehensive Epilepsy Program, Miami Children’s Hospital, University of Miami Leonard Miller School of Medicine, Miami, USA 2

UCL-Institute of Child Health, Great Ormond Street Hospital for Children and National Centre for Young People with Epilepsy, London, UK

INTRODUCTION

ICTAL SEMIOLOGY

Epilepsy surgery has proven to be a valuable therapy in the management of pharmacoresistant seizures. The spectrum of young candidates, however, remains entirely different than that seen in adults; a recent survey of surgical procedures performed across 20 centers in a 12-month period demonstrated the majority to be hemispherectomy or multilobar cases, especially in the young, with cortical dysplasia the underlying pathology (Harvey et al., 2008). Of those infants aged 1 year or less at surgery in the International League Against Epilepsy (ILEA) survey, 90% underwent multilobar resections or hemispherectomy, the most frequent etiologies being multilobar cortical dysplasia (37%), hemimegalencephaly (30%), and Sturge–Weber syndrome (13%). By comparison, 65% of 10-year-old patients had focal or lobar resections, and the substrates were tumors (20%), hippocampal sclerosis (20%), and focal cortical dysplasia (20%). Although seizure freedom remains the primary aim of surgery, secondary benefits may be inferred such as neurodevelopmental or behavioral improvement. The role of the presurgical evaluation, therefore, is, in the first instance, to determine whether seizures are coming from one area, and, second, whether that area can be removed with or without predictable functional consequence. Advances in technology mean that in the majority the evaluation can be noninvasive. However, in some circumstances in which data are discordant or functional tissue may be at risk, invasive recording may be necessary in a specialized centre. The following summarizes the relative contributions of different aspects to the presurgical evaluation in children.

The clinical manifestations of partial seizures in very young patients differ from those in adolescents and adults. Complex behavioral changes and motor stereotypies in early life are unusual, presumably because of immaturity of distributed networks. Auras and sensory alterations are uncommon in preverbal patients or patients with delayed language competence (Jayakar and Duchowny, 1990). Automatisms in infancy typically consist of simple repetitive sucking or chewing movements or primitive gestures rather than more specialized behavioral sequences (Brockhaus and Elger, 1995). In the older child, behavioral arrest reliably lateralizes to the right hemisphere, suggesting the occurrence of an internal sensation with preserved awareness (Fogarasi et al., 2007a). There is a greater tendency for partial seizures in the very young to secondarily generalize, often immediately following seizure onset (Duchowny, 1987). Indeed, the very existence of primarily generalized tonic–clonic seizures in infancy has been questioned as most early life motor convulsions are recognized to result from rapid spread from a lateralized seizure focus (Korff and Nordli, 2005). This particular feature diminishes over the first decade with the development of intrinsic mechanisms to inhibit seizure propagation. Cortical dysplasia may also contribute to this phenomenon as dysplastic tissue propagates to distant brain regions more rapidly (Turkdogan et al., 2005). In contrast, complex partial seizures characterized by loss of awareness are decidedly less common in early childhood and exceedingly rare in infants. Formed hallucinations and illusions

*Correspondence to: Michael Duchowny, Professor of Neurology and Pediatrics, University of Miami Leonard Miller School of Medicine, Department of Neurology, Florida International University College of Medicine, Miami, Florida 33155, USA. Tel: þ 1 305 662 8342, Fax: þ 1 305 669 6472, E-mail: [email protected]

830

M. DUCHOWNY AND J.H. CROSS

are also unusual, attesting to the underdevelopment of limbic–cortical networks in early life (Holmes, 1991). Studies of pediatric temporal lobe epilepsy reveal important age-related changes in ictal semiology (Duchowny, 1987; Jayakar and Duchowny, 1990; Brockhaus and Elger, 1995). Motor phenomena are extremely common in infants and young children with temporal lobe epilepsy. Versive head and eye movement, lateralized tonic, clonic, or bilateral extremity movement all suggest secondary frontal lobe involvement. Early onset temporal lobe seizures may also present as epileptic spasms (Maton et al., 2008). The frequent occurrence of frontal lobe involvement may help to explain the high incidence of neuropsychological deficits in this population (Guimaraes et al., 2007). In later childhood, ictal behaviors evolve into the adult psychomotor seizure patterns with staring and unresponsiveness. Important maturational factors strongly influence ictal emotional expression in partial epilepsy. Peri-ictal emotional features in the child include fearful facial expression, crying, smiling, and laughter, and inner emotional change, e.g., happiness in video-recorded seizures of 35 out of 100 children (Fogarasi et al., 2007b). In contrast to adults, emotionality is more frequently observed in extratemporal epilepsy. Adults also more often report negative emotional experiences, such as fear, whereas positive peri-ictal emotional experiences are more often observed in childhood. Positive experiences are believed to lateralize to the right hemisphere whereas negative experiences are nonlateralizing. Video/EEG analyses of seizure semiology reveal that certain seizure manifestations consistently lateralize seizure origin throughout childhood whereas others lateralize towards the end of the first decade (Fogarasi et al., 2006). Whereas unilateral tonic or clonic seizures, Todd’s paralysis, and nystagmus occur in children of all ages, unilateral manual automatisms, dystonic postures, head version, postictal dysphasia, and postictal facial wipes lateralize only in later childhood. The richer variety and complexity of ictal semiology in older children implies progressive maturation of ictal circuits. Subtle or nonlateralizing ictal manifestations of seizures in infancy compromises accurate International League Against Epilepsy classification (Nordli et al., 1997). Automatisms in the infant are typically brief and simple. Head version, a classic lateralizing feature in adults with partial epilepsy, is more forceful and sustained in the infant, but has less certain lateralizing value (Acharya et al., 1997). However, while focal motor manifestations reliably lateralize to the opposite hemisphere, hypomotor seizures of frontal lobe origin are common in early life and are rarely lateralized or focal (Hamer et al., 1999). Hypomotor seizures that are associated with regional EEG patterns are usually longer and arise in

the temporal or parietal lobes (Kallen et al., 2002). Epileptic spasms more often occur in generalized syndromes but also occur in localization-related syndromes (Dravet et al., 1989; Maton et al., 2008). The absolute lateralizing significance of head version is controversial. While contraversive head turning is generally regarded as a lateralizing sign, its reliability has been questioned. The sternocleidomastoid muscle is the primary agonist turning the head and a clear understanding of its action is therefore crucial to understanding versive motion. The sternocleidomastoid has two heads that insert respectively on the sternum (sternal head) and the clavicle (clavicular head). Each produces a different trajectory and a distinct clinical action: activation of the clavicular head induces contraversive head turning while activation of the sternal head results in ipsiversive head tilting (Jayakar et al., 1992b). Ipsiversive movement from the sternal head is easily misconstrued as “falsely lateralizing” when in fact it legitimately lateralizes the correct hemisphere of seizure onset.

ELECTROENCEPHALOGRAPHY Detailed electroencephalography (EEG) evaluation in conjunction with ictal semiology remains the cornerstone of the pediatric epilepsy surgery evaluation. Pediatric monitoring units typically employ recording equipment similar to adult units but higher levels of patient activity require modifications of adult recording protocols. Longer EEG cables allow for unrestricted movement while more frequent intervals of unrestrained physical activity assure greater compliance with monitoring. More frequent inspection of electrode contact and system integrity help to minimize movement and related artifacts. Replacing metal crib side-rails with clear Plexiglas improves viewing and video-capture of seizures. Identifying a discrete seizure focus simplifies surgical planning and accuracy and increases the likelihood of seizure freedom. In a retrospective analysis of the value of preoperative scalp EEG in 47 children undergoing focal resection for intractable epilepsy, Vossler et al. (1995) found that children with a single interictal focus (or a single focus with rare discordant discharges) or children with unilateral well-localized or lateralized seizure onsets in serial routine scalp EEG recordings achieved greater seizure relief. Localized EEG findings were especially predictive of favorable outcome if they anatomically colocalized with other diagnostic modalities such as anatomic or functional imaging. Children with generalized and multiregional EEG patterns are generally not considered surgical candidates. However, these patients may still be eligible if the magnetic resonance imaging (MRI) or functional

PREOPERATIVE EVALUATION IN CHILDREN FOR EPILEPSY SURGERY imaging studies provide evidence of a focal or lateralized lesion (Gupta et al., 2007). Identified lesions are often congenital or early acquired, and include malformations of cortical development or cystic encephalomalacia (Wyllie et al., 2007). Generalized or bilateral EEG features in these cases presumably represent an interaction between the lesion and the immature brain. The precise localization of the primary epileptogenic zone in pediatric epilepsy surgery candidates rarely rests exclusively on the scalp-recorded EEG. While the EEG often lateralizes or regionalizes seizure onset, it must be interpreted in conjunction with other diagnostic modalities. For example, an anterior temporal focus in temporal lobe epilepsy implicates the anterior temporal lobe, but MRI evidence of hippocampal sclerosis (HS) suggests a more restricted epileptogenic zone in mesial tempolimbic structures. Similarly, while a discrete lesion is often the point of seizure origin, this may need to be confirmed electrographically. Unfortunately, medically resistant localizationrelated seizures in children are rarely both anatomically and functionally specific. Developmental anomalies of the cerebral cortex are particularly prevalent in children referred for surgical evaluation, and may arise throughout the cortical mantle (Wyllie, 1991; Duchowny et al., 1998). Although a certain proportion of children have discrete lesions amenable to lesional resection, multiple or poorly defined epileptogenic regions are common. Despite advanced neuroimaging techniques, there remain a significant proportion of children with cryptogenic seizures who are MRI negative. Even seizures arising in the temporal lobe pose a significant localization challenge in childhood. Early onset temporal lobe seizures are typically neocortical in origin, and HS more often occurs as a “dual pathology” in conjunction with cortical dysplasia rather than an isolated lesion (Mohamed et al., 2001). In both situations, the spike field may be less well defined on scalp EEG recording. Placement of additional electrodes at sphenoidal or nasopharyngeal sites is unlikely to generate definitive localizing data and is therefore rarely employed at pediatric centers. In contrast, dense array EEG utilizing up to 256 channels holds promise when routine EEG is unhelpful (Holmes, 2008). Dense array EEG increases spatial sampling by decreasing the distance between recording electrodes. Combining dense array EEG data with modeled source analysis can generate precise three-dimensional maps of the epileptogenic zone. The need for epilepsy monitoring in every case has recently been questioned, particularly for children with MRI evidence of localized lesions. In a retrospective review of the decision for eligibility for surgery in 353

831

pediatric epilepsy surgery candidates, Patil et al. (2008) found that, of 236 children offered surgery, 92% with a localized MRI lesion were offered excisional surgery, and EEG monitoring did not modify the clinical decision. Conversely, 78% of children with bilateral MRI abnormalities and localized ictal onset on EEG compared with 9% with nonlocalized ictal patterns were offered surgical intervention.

MAGNETOENCEPHALOGRAPHY Magnetoencephalography (MEG) can assist in the localization of seizure origin in epilepsy surgery candidates (Paulini et al., 2007). In a MEG study of 11 children undergoing evaluation for intractable nonlesional extratemporal epilepsy, 10 had anatomically localized epileptiform discharges corresponding to ictal onset zones established by intracranial EEG recording (Minassian et al., 1999). RamachandranNair et al. (2007) analyzed MEG activity in 22 children with normal, subtle, or nonfocal MRI findings who were candidates for excisional epilepsy surgery. All 17 children who became seizure free evidenced preoperative MEG clusters in the resection area. A restricted ictal onset zone within the MEG spike cluster predicted good surgical outcome. It has been claimed that MEG is more successful than EEG to screen and localize seizure onset in frontal lobe epilepsy (Ossenblok et al., 2007) and to evaluate children with seizure persistence after epilepsy surgery (Mohamed et al., 2007). Three-dimensional magnetic source imaging (MSI) data have been successfully interfaced with neuronavigation in pediatric patients (Holowka et al., 2004). Ictal MEG identification of epileptic foci is correlated with zones of hyperperfusion on ictal single photon emission computed tomography (SPECT) (Yoshinaga et al., 2004). In a prospective study of the utility of MSI to plan intracranial EEG monitoring in 69 patients with partial epilepsy, Sutherling et al. (2008) concluded that MSI provided nonredundant information in one-third and added useful information in 9%. Consistent spike localization within the lesional zone has been confirmed by EEG and MEG source analysis (Morioka et al., 1999; Bast et al., 2004). Cluster analyses reveal localization of onset- and peak-related sources within the visible MRI lesion for both modalities. With highly localized anatomic confirmation, the outcome of lesion resection is frequently favorable.

INVASIVE RECORDING Limitations of scalp-recorded EEG and the higher proportion of cryptogenic cases in childhood contribute to a greater need for invasive EEG recording. Children

832

M. DUCHOWNY AND J.H. CROSS

who are MRI negative are more likely to be implanted, particularly with divergent preoperative studies. Depth electrodes are classically employed in adults to record from mesial temporal structures. Whereas few data points are needed to identify this narrow spatially defined area, neocortical epilepsy and multilobar involvement often necessitate extensive monitoring of the cortical convexity and basal and interhemispheric cortical surfaces. The pediatric evaluation, therefore, relies more heavily on subdural electrodes to localize seizure origin and functionally map the neocortex. Subdural grid and strip electrodes are proven to accurately localize seizure origin with acceptable complication rates (Wyllie et al., 1996; Duchowny et al., 1998). Subdural electrodes are configured as strips and grids of flexible Silastic or Teflon containing embedded stainless steel, platinum, silver, or nichrome electrode contact disks 2–4 mm in diameter spaced 10 mm apart. Electrodes are arranged into parallel rows of variable dimension. Commonly employed designs include 8 8 cm, 8 6 cm, 4 5 cm, 4 4 cm, 1 8 cm, 2 8 cm, and 1 4 cm. Subdural grids are placed at open craniotomy while strips are inserted through burr holes and manually slipped into the subdural space. Indications for subdural electrode placement in children include: ●

●

Normal or nonlocalizing neuroimaging: intracranial EEG provides useful information for surgical planning in patients who lack congruence between MRI and EEG (Pondal-Sordo et al., 2007). Without convergent localizing information, it is rarely possible to localize the surgical target. While electrocorticography defines the epileptogenic zone, it is often insufficient in MRI-negative patients under general anesthesia. Ill-defined borders of cortical malformations may also contribute to incomplete resection. In a series of 53 children undergoing excisional procedures for intractable epilepsy, seizure freedom was achieved in 70% of patients with complete resections. In contrast, only 10% were seizure free if the resection was incomplete (Jayakar and Duchowny, 1997). Incomplete removal resulted from poor delineation of the epileptogenic region and overlapping of the epileptogenic region with critical cortex. The utility of invasive recording in children with normal or non-focal MRI was recently confirmed in 102 patients undergoing excisional (lobar and multilobar) procedures for intractable epilepsy (Jayakar et al., 2008). Eighty patients required subdural monitoring and 22 had electrocorticography. At 2 years post-operation, 44 of 101 patients (44%) were seizure-free, and at 10-year follow-up, 16 of

●

●

●

43 patients (38%) remained seizure-free. Completeness of resection was the most significant variable predicting seizure freedom. Widespread epileptogenic zone: lesionectomy guided by Electrocorticography (ECoG) is often sufficient for patients with discrete lesions, but the boundaries of dysplastic tissue are rarely well defined. This situation leads to uncertainty with regard to the choice of surgical plane. If MRI and scalp EEG data are widespread, nonlocalizing, or discordant, especially with subtle malformations such as focal cortical dysplasia, subdural recording may assist in tailoring the resection planes. There is little information defining the usefulness of intracranial EEG in children but congruence has been observed in adults lacking MRI–EEG agreement (Pondal-Sordo et al., 2007). In 171 patients undergoing invasive monitoring, implanted electrodes yielded data that assisted surgical planning in 86%. Patients with divergent data achieved the greatest benefit but invasive recording also benefited patients with weakly convergent findings. Multilesional and multifocal epileptiform activity: subdural electrode placement assists in selecting a lesion or epileptogenic region that is clinically relevant. For example, it is often difficult to accurately identify the single tuber responsible for seizure origin in children with tuberous sclerosis complex and multiple tubers. Ictal SPECT is an important localizing tool (Koh et al., 1999) but is not always reliable. Alternatively, more than one tuber may trigger seizures, necessitating a more complex presurgical evaluation of multiple sites. Subcortical epilepsy: subcortical lesions are rarely responsible for intractable partial seizures. Hypothalamic hamartomas are readily identified on MRI but direct recording from the hamartoma has revealed focal spiking confirming seizure origin (Kuzniecky et al., 1997a). Heterotopic gray matter (Kuzniecky and Barkovich, 1996) and cerebellar gangliogliomas in infants (Harvey et al., 1996) have also been confirmed to cause intractable seizures through invasive EEG studies.

FUNCTIONAL CORTICAL MAPPING Adult cortical stimulation parameters yield equivocal results in children. The typical adult stimulation paradigm utilizes sequential increments of stimulus intensity to a maximum of 15 mA. When controlling electrical stimulation for age, reduced motor responses are often observed, especially in the first decade of life (Nespeca et al., 1990; Schevon et al., 2007). Careful analyses of the elicited responses reveal an inverse linear correlation

PREOPERATIVE EVALUATION IN CHILDREN FOR EPILEPSY SURGERY with age in threshold for afterdischarges and sensorimotor responses (Alvarez and Jayakar, 1990). A declining afterdischarge threshold with age has been confirmed by Chitoku et al. (2003), who suggested that cortical responsiveness is influenced by the underlying pathology. Focal cortical dysplasia had significantly more prolonged and more remote evoked afterdischarges. Using alternating stepwise increments in stimulus intensity and duration rather than simple stepwise increases in amplitude alone, functional cortical responses in children can be reliably generated at the chronaxie, the point on the strength–duration curve corresponding to the lowest amount of energy (Jayakar et al., 1992a). Eliciting responses at the chronaxie is preferable as there are no established guidelines for the electrical safety of prolonged stimulation in immature cortex. This “dual stimulation” paradigm successfully elicits sensorimotor responses in infants younger than 2 years (Duchowny and Jayakar, 1993).

NEUROIMAGING MRI protocols for epilepsy in children are generally similar to those in adults (Gaillard et al., 2009). There is general agreement that protocols should include an anatomic, thin slice, volumetric T1-weighted gradient recalled echo sequence, axial and coronal T2, fluid-attenuated inversion–recovery (FLAIR), and high-resolution oblique coronal T2-weighted imaging of the hippocampus. With specialized protocols the incidence of hippocampal sclerosis in pediatric intractable temporal lobe epilepsy has been shown to approach 60% (Grattan-Smith et al., 1993). Children younger than 2 years require special sequences as immature myelination limits the ability to determine cortical abnormality. High-resolution MRI enhances detection of subtle surgically amenable lesions. In 13 children undergoing four-coil phased surface array, previously undiagnosed focal abnormalities were identified in five of nine nonlesional patients (Goyal et al., 2004). These included hippocampal dysplasia, hippocampal atrophy, and dual pathology. Hippocampal pathology may be age dependent as children with a younger age at seizure onset are less likely to have histological evidence of HS (Kothare et al., 2001; Riney et al., 2006). The contribution of phased array (PA) surface coil MRI studies at 3 T was recently analyzed prospectively in a cohort of 40 patients with intractable focal epilepsy (Knake et al., 2005). Compared with standard MRI at 1.5 T, 3-T PA MRI interpreted by an experienced neuroradiologist provided additional diagnostic information in 19 of 40 (48%) patients and identified a new lesion in 15 of 23 (65%) patients with previously normal

833

studies. Even five of 15 patients with known lesions had better definition of the lesion (33%). Postprocessing of the MRI utilizing voxel-based three-dimensional analysis has shown exceptional promise for detecting subtle malformative lesions involving the cortex and subcortical white matter in children with intractable epilepsy. By combining gray and white matter segments in the statistical analysis, Bruggemann et al. (2007) demonstrated that both malformation and neoplastic lesions were detected and characterized with a high degree of accuracy. Utilizing voxel-based analysis of whole brain FLAIR at 3 T, focal cortical dysplasia was detected in 88% of patients (Focke et al., 2008). Subtle gyral abnormalities that are absent even on highresolution MRI can be detected utilizing postprocessing methodologies (Sisodiya et al., 1996). Standard T2 FLAIR scans at 3 T automatically detect focal cortical dysplasia (Focke et al., 2008). This process provides additional screening for subtle lesions and complements routine visual analysis. Imaging of deep white matter tracts also helps to characterize epileptogenic regions and malformations of cortical development (Chen et al., 2008). In a study of 14 children with intractable epilepsy due to cortical malformation, deep white matter tracts subjacent to the malformations were compared with tracts on the normal side (Widjaja et al., 2007). Diffusion tensor imaging revealed alterations in 12 cases, with the most significant changes associated with focal cortical dysplasia and transmantle dysplasia. While it is still too early to assess the contribution of white matter abnormalities to the presurgical evaluation, the potential localizing value is a promising diagnostic tool. MRS successfully lateralizes seizure onset in children with temporal lobe epilepsy (Cross et al., 1996). While MRS findings generally complement the MRI examination, children rarely evidence a previously undetected localized abnormality or unrecognized bilateral involvement. There are no systematic studies of MRS in children with cortical malformations, but adults show variable pathologically based metabolic abnormalities (Kuzniecky et al., 1997b). Compared with patients with heterotopia and polymicrogyria, patients with focal cortical dysplasia show significant metabolic abnormalities that correspond to underlying structural lesions. Multimodality imaging involving coregistration of functional studies with the anatomic MRI has shown promise for localizing seizure origin in children with intractable epilepsy. Precise coregistration of functional imaging modalities (PET, SPECT, fMRI) and EEG can overcome limitations intrinsic to each individual modality. The resulting spatial–temporal–anatomic–functional map may help to characterize the primary seizure focus. In an analysis of postoperative status in

834

M. DUCHOWNY AND J.H. CROSS

50 child and adolescent surgical candidates, seizure freedom in 39 (78%) correlated significantly to concordant coregistered data from multiple imaging modalities (Kurian et al., 2007).

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY The widespread availability of SPECT cameras in nuclear medicine facilities, low cost of gamma-emitting isotopes, and availability of stable radiopharmaceuticals have increased utilization of SPECT imaging at many pediatric epilepsy centers. SPECT has been employed successfully in a wide spectrum of pediatric epilepsy surgical disorders including the Sturge–Weber syndrome (Chiron et al., 1989), tuberous sclerosis complex (Koh et al., 2000), Rasmussen syndrome (English et al., 1989), hemimegalencephaly (Bar-Server et al., 1997), and focal cortical dysplasia (Gupta et al., 2004). Ictal SPECT remains the functional localizing procedure of choice for many children with partial epilepsy (Hertz-Pannier et al., 2001). Ictal SPECT revealed hyperperfusion in 14 out of 15 children with temporal lobe epilepsy undergoing preoperative evaluation (Harvey et al., 1993). In four children, ictal SPECT provided additional localizing information that was absent from ictal EEG recordings. Similarly, Cross et al. (1995) reported abnormalities on ictal SPECT in the majority (13 out of 14) of children with temporal and extratemporal seizures. Timing of injection was critical as injections 30 seconds postictally were less likely to yield reliable measurements of regional cerebral blood flow. Pediatric ictal SPECT studies also colocalize the epileptogenic zone on intracranial EEG recording, and correlate with higher rates of surgical success (Kaminska et al., 2003). Ictal SPECT studies may confirm localizing EEG and MRI investigations, or define the epileptogenic region with normal or discordant EEG and imaging data. SPECT may also clarify the extent of the epileptogenic region and assist in intracranial electrode placement. In contrast, the use of interictal SPECT is problematic (Harvey and Berkovic, 1994). Normal studies or uncertain regions of hypoperfusion may be misleading and rarely assist in surgical decision-making.

POSITRON EMISSION TOMOGRAPHY Functional imaging with PET can localize seizure origin in patients with West syndrome (Chugani et al., 1990), epileptic encephalopathy (Parker et al., 1998), Sturge– Weber syndrome (Chugani et al., 1989), tuberous sclerosis complex (Kagawa et al., 2005), frontal lobe epilepsy (Lee et al., 2008), and generalized tonic–clonic seizures (Korinthenberg et al., 2004). PET studies are particularly useful in children with MRI-negative extratemporal

epilepsy, and childhood syndromes with apparently generalized epileptic discharges. Localized regions of increased 2-deoxy-2-[18 F]fluoro-D-glucose (FDG)-PET uptake in focal malformations has been reported (Poduri et al., 2007). PET helps define eloquent cortex in pediatric epilepsy surgical candidates. PET mapping of eloquent language, motor, and visual areas was accomplished in 15 children by coregistering PET images of task-activated cerebral blood flow onto anatomic MR images (Duncan et al., 1997). All patients had lesional epilepsy and PET mapping was well tolerated in all cases. The absolute reliability of FDG-PET as a stand-alone investigative tool in the pediatric epilepsy surgical evaluation has been questioned (Snead et al., 1996). Whereas FDG-PET studies in older children and adolescents yield results similar to adults (Gaillard et al., 1995), with one exception (Parker et al., 1998), there are no longitudinal studies of PET in younger children. It has also been shown that [11 C]flumazenil PET is significantly more sensitive than FDG for detecting cortical regions of seizure onset and frequent spiking in children with extratemporal epilepsy, and that both radioisotopes have low sensitivity with rapid seizure spread (Muzik et al., 2000). a-Methyl-L-tryptophan (AMT)-PET, a tracer for PRT measurement of serotonin synthesis, has been advocated to localize the epileptogenic zone in children with focal epilepsy, particularly cortical dysplasia and tuberous sclerosis complex (Juhasz et al., 2003). AMT-PET studies also reveal increased uptake in periventricular nodular heterotopia (Natsume et al., 2008). The pathological basis of AMT uptake is poorly understood.

FUNCTIONAL MRI Functional MRI (fMRI) reliably localizes language, sensory, motor, and visual function in children and influences surgical planning (Bernal et al., 2003; Liegeois et al., 2006). Language mapping with developmentally appropriate paradigms generates localizing data in children similar to adults. Children as young as 5 years can be studied successfully (Gaillard et al., 2003) and it is now clear that networks for auditory processing are already regionally localized and lateralized by age 5 years (Ahmad et al., 2003). Receptive language sites are located primarily along the superior temporal sulcus, similar to the adult, suggesting that language localization and network formation is established in early life. False lateralization of language cortex to the homologous nondominant hemisphere may occur in children studied postictally (Jayakar et al., 2002). Sensorimotor cortex can be positively identified in a child who taps a finger or toe, wiggles the tongue, or has

PREOPERATIVE EVALUATION IN CHILDREN FOR EPILEPSY SURGERY an extremity brushed. These activation paradigms are simple to perform and achieve reliable results, even in very young children. The location of sensorimotor function by fMRI agrees with localization data obtained by direct cortical stimulation. The concordance between fMRI and cortical stimulation mapping indicate that fMRI has a high sensitivity and can readily identify language cortex. Coregistration of simultaneously acquired EEG and fMRI is a promising tool for seizure focus localization. By coupling interictal spikes with fMRI activation sequences, regions of blood oxygenation level-dependent (BOLD) changes can help identify the seizure focus. Hemodynamic responses to spikes were investigated in 25 studies performed in 13 children (Jacobs et al., 2007). In 84% of the studies, BOLD responses localized to the lesion or brain area were presumed to be generating spikes. Activation occurred in 48% and deactivation in 36%.

OPTICAL IMAGING Optical recording of intrinsic brain signals holds promise for prediction and localizing focal seizure origin. The technique takes advantage of vascular perfusion through measurements of hemoglobin oxygenation and provides excellent temporal resolution. Direct optical imaging of the cerebral cortex during spontaneous seizures reveals focal increases in deoxyhemoglobin that precede seizure onset and persist for the duration of the seizure (Zhao et al., 2007). Near infrared spectroscopy (NIRS), which also measures concentration changes in oxy- and deoxyhemoglobin concentrations, has been used to map language cortex in children and adults. Language lateralization was achieved in all 12 patients with NIRS using a verbal fluency task (Gallagher et al., 2007).

NEUROPSYCHOLOGY Integral to the presurgical evaluation is an assessment of cognitive functioning, including memory, determination of language dominance, and specific subtesting to determine problems that may relate to dysfunction of different areas of the brain. Imaging techniques described above have considerably enhanced the noninvasive assessment of language localization, but ultimately accuracy has to be individually assessed and Wada or even invasive EEG monitoring may still be required if the seizure focus lies close to the language cortex. Further it is important to be aware of the neurodevelopmental ability of a child at the time of surgery, and possible expectations for the future. Neurodevelopmental assessment and the monitoring of gains with time in the very young is important, particularly when children are to undergo surgery. While parental report of educational progress can give a

835

general judgment of how a child may be progressing, it is very subjective, and related highly to the degree of awareness and behavior. Parental expectation may also heavily weight such a judgment. Standardized tests appropriate for the age and developmental level of the child need to be used; the Wechsler scales are the most detailed, but are lengthy to administer and score. Such scales are not adapted to children under 3 years, so the Bayley scales are often used up to this age but are not directly comparable. More specifically, tests should be administered that are most likely to answer questions to be addressed, whether it be differential problems in different domains that may relate to a specific lateralization or localization or progress over time.

EXPECTATIONS As stated above, the primary aim of epilepsy surgery is seizure freedom or reduction, and following presurgical assessment some sort of discussion with the family should take place about what the likelihood of seizure freedom will be if surgery is offered. Outcome is likely to be between 40% and 80% chance of seizure freedom, dependent on the underlying pathology and extent of removal of the epileptogenic lesion. Seizure freedom is more likely following surgery for tumors or acquired/ vascular lesions. The chance of seizure freedom following surgery for cortical dysplasia, however, can be as high as 60% (Edwards et al., 2000; Paolicchi, et al., 2000), but is highly dependent on whether the area responsible for seizures has been removed entirely. Seizure freedom may be one thing, but families are also often anxious to know the likelihood of a reduction of medication. This cannot be guaranteed; studies to date have suggested that approximately 50% of individuals are able to wean and remain seizure free (Hoppe et al., 2006). Timing of a reduction is less clear, with no study addressing this to date. However, families often are looking for secondary gains, namely developmental and behavioral improvement. Early onset epilepsy has a major impact on cognition. Ultimate cognitive outcome of children with epilepsy will depend on a range of variables, not least age of onset of epilepsy but also extent and side of lesion, pathology, medication, and environmental factors. There is no question, however, that seizures may have a major impact on early developmental progress – the term “epileptic encephalopathy” has been adopted for the condition whereby neurodevelopmental impairment is believed to be related to ongoing epileptic activity, and therefore could be seen to be potentially reversible. The rate of cognitive dysfunction in those coming to surgery is high, an early onset epilepsy highly correlated with poor developmental outcome (Vasconcellos et al., 2001;

836

M. DUCHOWNY AND J.H. CROSS

Cormack et al., 2005). A key question remains as to whether early cessation of seizures can have an impact. Group cross-sectional studies have suggested, at the very least, a maintenance of IQ (Pulsifer et al., 2004; Gleissner et al., 2005), as has short-term follow-up of younger children (Freitag and Tuxhorn, 2005). Longitudinal studies of children with longstanding epilepsy suggest a reduction in IQ with time – intelligence or developmental quotient is a measure of ability relative to normal peers. A reduction therefore indicates the gap to be widening between those being assessed and normal peers – it does not imply a loss of skills. A stable IQ score therefore suggests maintenance of the learning trajectory, which may not otherwise have been achieved in children in whom seizure control is not seen. Behaviorally there may be similar concerns. In one study of children coming to temporal lobe resection, 83% had at least one Diagnostic and Statistical Manual of Mental Disorders IV psychiatric diagnosis at any time, 72% preoperatively and 72% postoperatively (Mclellan et al., 2005). It was not possible to be predictive of any improvement or indeed evolution of a disorder. Similarly, therefore, consideration needs to be given to behavioral diagnoses seen in the child, the relevance to the underlying epilepsy, and the fact that there is no guarantee as to what the progress will be postoperatively. Expectations therefore need to be fully explored with the family prior to surgery as part of the presurgical evaluation, and a contract drawn up that can be revisited at a suitable time after surgery.

REFERENCES Acharya JN, Wyllie E, Luders HO et al. (1997). Seizure symptomatology in infants with localization-related epilepsy. Neurology 48: 189–196. Ahmad Z, Balsamo LM, Sachs BC et al. (2003). Auditory comprehension of language in young children. Neural networks identified with fMRI. Neurology 60: 1598–1605. Alvarez L, Jayakar P (1990). Cortical stimulation with subdural electrodes: special considerations in infancy and childhood. J Epilepsy 3: 125–130. Bar-Sever Z, Connolly LP, Barnes PD, Treves ST (1997). Brain SPECT evaluation of cerebral perfusion in hemimegalencephaly. Clin Nucl Med 22: 250–252. Bast T, Oezkan O, Rona S et al. (2004). EEG and MEG source analysis of single and averaged interictal spikes reveals intrinsic epileptogenicity in focal cortical dysplasia. Epilepsia 45: 621–631. Bernal B, Medina S, Dunoyer C et al. (2003). The role of fMRI in surgical planning of intractable epilepsy. Epilepsia 44: 337. Brockhaus A, Elger CE (1995). Complex partial seizures of temporal lobe origin in children of different age groups. Epilepsia 36: 1173–1181.

Bruggemann J, Wilke M, Som S et al. (2007). Voxel-based morphometry in the detection of dysplasia and neoplasia in childhood epilepsy: combined grey/white matter analysis augments detection. Epilepsy Res 77: 93–101. Chen Q, Lui S, Li C-X et al. (2008). MRI-negative refractory partial epilepsy: role for diffusion tensor imaging in high field MRI. Epilepsy Res 80: 83–89. Chiron C, Raynaud C, Tzourio N et al. (1989). Regional cerebral blood flow by SPECT imaging in Sturge-Weber disease: an aid for diagnosis. J Neurol Neurosurg Psychiatry 52: 1402–1409. Chitoku S, Otsubo H, Harada Y et al. (2003). Characteristics of prolonged afterdischarges in children with malformations of cortical development. J Child Neurol 18: 247–253. Chugani HT, Mazziotta JC, Phelps ME (1989). Sturge-Weber syndrome: a study of cerebral glucose utilization with positron emission tomography. J Pediatr 114: 244–253. Chugani HT, Shields WD, Shewmon DA et al. (1990). Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 27: 406–413. Cormack F, Cross JH, Harkness W et al. (2005). Cognitive function in children with temporal love epilepsy: impact of early onset seizures. Dev Med Child Neurol 47: 22. Cross JH, Gordon I, Jackson GD et al. (1995). Children with intractable focal epilepsy: ictal and interictal 99TcM HMPAO single photon emission computed tomography. Dev Med Child Neurol 37: 673–681. Cross JH, Connelly A, Jackson GD et al. (1996). Proton magnetic resonance spectroscopy in children with temporal lobe epilepsy. Ann Neurol 39: 107–113. Dravet C, Catani C, Bureau M et al. (1989). Partial epilepsies in infancy: a study of 40 cases. Epilepsia 30: 807–812. Duchowny M (1987). Complex partial seizures of infancy. Arch Neurol 44: 911–914. Duchowny M, Jayakar P (1993). Functional cortical mapping in children. In: O Devinsky, A Beric, M Dogali (Eds.), Electrical and Magnetic Stimulation of the Brain and Spinal Cord. Raven Press, New York, pp. 149–154. Duchowny M, Jayakar P, Resnick T et al. (1998). Epilepsy surgery in the first three years of life. Epilepsia 39: 737–743. Duncan JD, Moss SD, Bandy DJ et al. (1997). Use of positron emission tomography for presurgical localization of eloquent brain areas in children with seizures. Pediatr Neurosurg 26: 144–156. Edwards JC, Wyllie E, Ruggieri PM et al. (2000). Seizure outcome after surgery for epilepsy due to malformation of cortical development. Neurology 55: 1110–1114. English R, Soper N, Shepstone BJ et al. (1989). Five patients with Rasmussens’s syndrome investigated by single-photonemission computed tomography. Nucl Med Commun 10: 5–14. Focke N, Symms M, Burdett J et al. (2008). Voxel-based analysis of whole brain FLAIR at 3 T detects focal cortical dysplasia. Epilepsia 49: 786–793. Fogarasi A, Janszky J, Tuxtorn I (2006). Peri-ictal lateralizing signs in children: blinded multi-observer study of 100 children <12 years. Neurology 66: 271–274. Fogarasi A, Janszky J, Tuxtorn I (2007a). Localizing and lateralizing value of behavioral change in childhood partial seizures. Epilepsia 48: 196–200.

PREOPERATIVE EVALUATION IN CHILDREN FOR EPILEPSY SURGERY Fogarasi A, Janszky J, Tuxtorn I (2007b). Ictal emotional expressions of children with partial epilepsy. Epilepsia 48: 120–123. Freitag H, Tuxhorn I (2005). Cognitive function in preschool children after epilepsy surgery: rationale for early intervention. Epilepsia 46: 561–567. Gaillard WD, White S, Malow B et al. (1995). FDG-PET in children and adolescents with partial seizures: role in epilepsy surgery evaluation. Epilepsy Res 20: 77–84. Gaillard WD, Balsamo LM, Ibrahim Z et al. (2003). fMRI identifies regional specialization of neural networks for reading in young children. Neurology 60: 94–100. Gaillard WD, Chiron C, Cross JH et al. (2009). Guidelines for imaging infants and children with recent-onset epilepsy. Epilepsia 50: 2147–2153. Gallagher A, Theriault M, Maclin E et al. (2007). Nearinfrared spectroscopy as an alternative to the Wada test for language mapping in children, adults and special populations. Epileptic Disord 9: 241–255. Gleissner U, Sassen R, Schramm J et al. (2005). Greater functional recovery after temporal lobe epilepsy surgery in children. Brain 128: 2822–2829. Goyal M, Bangert BA, Lewin JS et al. (2004). High-resolution MRI enhances identification of lesions amenable to surgical therapy in children with intractable epilepsy. Epilepsia 45: 954–959. Grattan-Smith ID, Harvey AS, Desmond PM et al. (1993). Hippocampal sclerosis in children with intractable epilepsy: detection with MR imaging. AJR Am J Roentgenol 161: 1045–1048. Guinmares C, Li M, Rzezak P et al. (2007). Temporal lobe epilepsy in childhood: comprehensive neuropsychological assessment. J Clin Neurol 22: 836–840. Gupta A, Raja S, Kotagal P et al. (2004). Ictal SPECT in children with partial epilepsy due to focal cortical dysplasia. Pediatr Neurol 31: 89–95. Gupta A, Chirla A, Wyllie E et al. (2007). Pediatric epilepsy surgery in focal lesions and generalized electroencephalogram abnormalities. Pediatr Neurol 37: 8–15. Hamer HM, Wyllie E, Luders HO et al. (1999). Symptomatology of epileptic seizures in the first three years of life. Epilepsia 40: 837–844. Harvey AS, Berkovic SF (1994). SPECT imaging of regional cerebral blood flow in children with partial epilepsy. Acta Neuropediatr 1: 9–27. Harvey AS, Bowe JM, Hopkins IJ et al. (1993). Ictal 99mTcHMPAO single photon emission computed tomography in children with temporal lobe epilepsy. Epilepsia 34: 869–877. Harvey AS, Jayakar P, Duchowny M et al. (1996). Hemifacial seizures and cerebellar ganglioglioma: an epilepsy syndrome of infancy with seizures of cerebellar origin. Ann Neurol 40: 91–98. Harvey AS, Cross JH, Shinnar S et al. (2008). Epilepsy surgery in children: results from an international survey. Epilepsia 49: 146–155. Hertz-Pannier L, Chiron C, Vera P et al. (2001). Functional imaging in the work-up of childhood epilepsy. Childs Nerv Syst 17: 223–228.

837

Holmes G (1991). Temporal lobe epilepsy in children. Int Pediatr 6: 201–213. Holmes M (2008). Dense array EEG: Methodology and new hypothesis on epilepsy syndromes. Epilepsia 49: 3–14. Holowka SA, Otsubo H, Iida K et al. (2004). Threedimensionally reconstructed magnetic source imaging and neuronavigation in pediatric epilepsy: technical note. Neurosurgery 55: 1226. Hoppe C, Poepel A, Sassen R et al. (2006). Discontinuation of anticonvulsant medication after epilepsy surgery. Epilepsia 47: 580–583. Jacobs J, Kobayashi E, Boor R et al. (2007). Hemodynamic responses to interictal epileptiform discharges in children with symptomatic epilepsy. Epilepsia 48: 2068–2078. Jayakar P, Duchowny M (1990). Complex partial seizures of temporal lobe origin in early childhood. J Epilepsy 3: 41–45. Jayakar P, Duchowny M (1997). Invasive EEG and functional cortical mapping. In: I Tuxhorn, H Holthausen, H Boenigk (Eds.), Pediatric Epilepsy Syndromes and their Surgical Treatment. John Libbey, London, pp. 547–556. Jayakar P, Alvarez LA, Duchowny M et al. (1992a). A safe and effective paradigm to functionally map the cortex in childhood. J Clin Neurophysiol 9: 288–293. Jayakar P, Duchowny M, Resnick T et al. (1992b). Ictal head deviation: lateralizing significance of the pattern of head movement. Neurology 42: 1989–1992. Jayakar P, Bernal B, Altman N et al. (2002). False lateralization of language cortex on functional MRI after a cluster of focal seizures. Neurology 58: 490–492. Jayakar P, Dunoyer C, Dean P et al. (2008). Epilepsy surgery in children with normal or non-focal MRI scans: Integrative strategies offer long-term seizure relief. Epilepsia 49: 758–764. Juhasz C, Chugani D, Muzik O et al. (2003). Alpha-methyl-Ltryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 60: 960–968. Kagawa K, Chugani DC, Asano E et al. (2005). Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha- [11 C]-L-tryptophan positron emission tomography (PET). J Child Neurol 20: 399. Kallen K, Wyllie E, Luders HO et al. (2002). Hypomotor seizures in infants and children. Epilepsia 43: 882–888. Kaminska A, Chiron C, Ville D et al. (2003). Ictal SPECT in children with epilepsy: comparison with intracranial EEG and relation to postsurgical outcome. Brain 126: 248–260. Knake S, Triantaflyllou C, Wald L et al. (2005). 3 T phased array MRI improves the presurgical evaluation in focal epilepsies. A prospective study. Neurology 65: 1026–1031. Koh S, Jayakar P, Resnick T et al. (1999). The localizing value of ictal SPECT in children with tuberous sclerosis complex and refractory partial epilepsy. Epileptic Disord 1: 41–46. Koh S, Jayakar P, Dunoyer C et al. (2000). Epilepsy surgery with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia 41: 1206–1213.

838

M. DUCHOWNY AND J.H. CROSS

Korff C, Nordli D (2005). Do tonic-clonic seizures in infancy exist? Neurology 1750–1753. Korinthenberg R, Bauer-Schied C, Burkart P et al. (2004). 18FDG-PET in epilepsies of infantile onset with pharmacoresistant generalized tonic-clonic seizures. Epilepsy Res 60: 53–61. Kothare SV, Sotrel A, Duchowny M et al. (2001). Absence of hippocampal sclerosis in children with multiple daily seizures since infancy. J Child Neurol 16: 562–564. Kurian M, Spineli L, Willi J et al. (2007). Multimodality imaging for focus localization in pediatric pharmacoresistant epilepsy. Epileptic Disord 9: 20–31. Kuzniecky RJ, Barkovich AJ (1996). Pathogenesis and pathology of focal malformations of cortical development and epilepsy. J Clin Neurophysiol 13: 468–480. Kuzniecky RJ, Guthrie B, Mountz J et al. (1997a). Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann Neurol 42: 60–67. Kuzniecky R, Hetherington H, Pan J et al. (1997b). Proton spectroscopic imaging at 4.1 tesla in patients with malformations of cortical development and epilepsy. Neurology 48: 1018–1024. Liegeois F, Connelly A, Cross JH et al. (2006). Epilepsy surgery for children: the role of fMRI in the decision making process. J Magn Reson 23: 933–940. Lee JJ, Lee SK, Lee SY et al. (2008). Frontal lobe epilepsy: clinical characteristics, surgical outcomes and diagnostic modalities. Seizure 17: 514–523. Maton B, Jayakar P, Resnick T et al. (2008). Surgery for medically intractable temporal lobe epilepsy during early life. Epilepsia 49: 80–87. Mclellan A, Davies S, Heyman I et al. (2005). Psychopathology in children undergoing temporal lobe resection: a pre and postoperative assessment. Dev Med Child Neurol 47: 666–672. Minassian BA, Otsubo H, Weiss S et al. (1999). Magnetoencephalographic localization in pediatric epilepsy surgery: comparison with invasive intracranial electroencephalography. Ann Neurol 46: 627–633. Mohamed A, Wyllie E, Ruggieri PM et al. (2001). Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery. Neurology 56: 1643–1649. Mohamed I, Otsubo H, Ochi A et al. (2007). Utility of magnetoencephalography in the evaluation of recurrent seizures after epilepsy surgery. Epilepsia 48: 2150–2159. Morioka T, Nishio S, Ishibashi H et al. (1999). Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electrocorticography. Epilepsy Res 33: 177–187. Muzik O, da Silva EA, Juhasz C et al. (2000). Intracranial EEG versus flumazenil and deoxyglucose PET in children with extratemporal lobe epilepsy. Neurology 54: 171–179. Natsume J, Bernasconi N, Aghakhani Y et al. (2008). Alpha [11 C] methyl-L-tryptophan uptake in patients with nodular periventricular heterotopia and epilepsy. Epilepsia 49: 826–831. Nespeca M, Wyllie E, Luders H et al. (1990). EEG recording and functional localization studies with subdural electrodes in infancy and childhood. J Epilepsy 3: 107–124.

Nordli DR, Bazil CW, Scheuer ML et al. (1997). Recognition and classification of seizures in infants. Epilepsia 38: 553–560. Ossenblok P, de Munck J, Colon A et al. (2007). Magnetoencephalography is more successful for screening and localizing frontal lobe epilepsy than electroencephalography. Epilepsia 48: 2139–2149. Paolicchi JM, Jayakar P, Dean P et al. (2000). Predictors of outcome in pediatric epilepsy surgery. Neurology 54: 642–647. Parker AP, Ferrie CD, Keevil S et al. (1998). Neuroimaging and spectroscopy in children with epileptic encephalopathies. Arch Dis Child 79: 39–43. Patil SG, Cross JH, Chong WK et al. (2008). Is streamlined evaluation of children for epilepsy surgery possible? Epilepsia 49: 1340–1347. Paulini A, Fischer M, Rampp S et al. (2007). Lobar localization information in epilepsy patients: MEG – a useful tool in routine presurgical diagnosis. Epilepsy Res 76: 124–130. Poduri A, Golja A, Takeoka M et al. (2007). Focal cortical malformations can show asymmetrically higher uptake on interictal fluorine-18 fluorodeoxyglucose positron emission tomography (PET). J Child Neurol 22: 232–237. Pondal-Sordo M, Diosy D, Tellez-Zenteno JF et al. (2007). Usefulness of intracranial EEG in the decision process for epilepsy surgery. Epilepsy Res 74: 176–182. Pulsifer M, Brandt J, Salorio CF (2004). The cognitive outcome of hemispherectomy in 71 children. Epilepsia 45: 243–254. RamachandranNair R, Otsubo H, Shroff M et al. (2007). MEG predicts outcome following surgery for intractable epilepsy in children with normal or nonfocal MRI findings. Epilepsia 48: 149–157. Riney CJ, Harding B, Harkness WJF et al. (2006). Hippocampal sclerosis in children with lesional epilepsy is influenced by age at seizure onset. Epilepsia 47: 159–166. Schevon C, Carlson C, Zaroff C et al. (2007). Pediatric language mapping: sensitivity of neurostimulation and Wada testing in epilepsy surgery. Epilepsia 48: 539–545. Sisodiya S, Stevens J, Fish D et al. (1996). The demonstration of gyral abnormalities in patients with cryptogenic partial epilepsy using three-dimensional MRI. Arch Neurol 53: 28–34. Snead OC, 3rd, Chen LS, Mitchell WG et al. (1996). Usefulness of [18 F] fluorodeoxyglucose positron emission tomography in pediatric epilepsy surgery. Pediatr Neurol 14: 98–107. Sutherling WW, Mamelak AN, Thyerlei D et al. (2008). Influence of magnetic source imaging for planning intracranial EEG in epilepsy. Neurology 71: 990–996. Turkdogan D, Duchowny M, Resnick T et al. (2005). Subdural EEG patterns in children with Taylor-type cortical dysplasia: comparison with non-dysplastic lesions. J Clin Neurophysiol 22: 37–42. Vasconcellos E, Wyllie E, Sullivan S et al. (2001). Mental retardation in pediatric candidates for epilepsy surgery: the role of early seizure onset. Epilepsia 42: 268–274. Vossler DG, Wilkus RJ, Ojemann GA (1995). Preoperative EEG correlates of seizure outcome from epilepsy surgery in children. J Epilepsy 8: 236–245.

PREOPERATIVE EVALUATION IN CHILDREN FOR EPILEPSY SURGERY Widjaja E, Blaser S, Miller E et al. (2007). Evaluation of subcortical white matter and deep white matter tracts in malformations of cortical development. Epilepsia 48: 1460–1469. Wyllie E (1991). Cortical resection for children with epilepsy: perspectives in pediatrics. Am J Dis Child 145: 314–320. Wyllie E, Comair YG, Kotagal P et al. (1996). Epilepsy surgery in infants. Epilepsia 37: 625–637.

839

Wyllie E, Lachwani D, Gupta A et al. (2007). Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 69: 389–397. Yoshinaga H, Ohtsuka Y, Watanabe Y et al. (2004). Ictal MEG in two children with partial seizures. Brain Dev 26: 403–408. Zhao M, Suh M, Hongtao M et al. (2007). Focal increases in perfusion and focal decreases in hemoglobin oxygenation precede seizure onset in spontaneous human epilepsy. Epilepsia 48: 2059–2067.