Epilepsy neurosurgery in children

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 52

Epilepsy neurosurgery in children JASON S. HAUPTMAN AND GARY W. MATHERN* Departments of Neurosurgery, and Psychiatry & Biobehavioral Sciences, Brain Research Institute, Intellectual and Developmental Disabilities Research Center and David Geffen School of Medicine, University of California, Los Angeles, CA, USA

INTRODUCTION In children, the goal of epilepsy surgery is to stop seizures as soon as possible to prevent epilepsy-induced encephalopathy and associated declines in cognition and neurodevelopment. This is the key factor that distinguishes epilepsy surgery in children from that in adults (Shields et al., 1992). This chapter will focus on this concept by discussing the importance of early diagnosis of therapy-resistant epilepsy in children so that identified candidates are referred to a pediatric epilepsy center for a comprehensive evaluation and treatment. The chapter begins by describing the differences in approach for children with epilepsy based on the idea of preventing an epileptic encephalopathy. Next, we define refractory epilepsy and explore the reasons for early assessment and treatment to avoid the risks of uncontrolled seizures on the developing brain. This will be followed by a discussion of the epidemiology of pharmacoresistant epilepsy in children based on studies of a community-acquired cohort. We will examine the characteristics of children undergoing epilepsy neurosurgery including the various pathologies and operations. Following a review of presurgical evaluations for pediatric epilepsy surgery patients, we will address outcomes after surgery, with emphasis on seizure control, development, function, and quality of life. We conclude by identifying current and future challenges for optimizing care in pediatric epilepsy patients with refractory epilepsy.

WHAT MAKES SURGICAL TREATMENT OF EPILEPSY IN CHILDREN DIFFERENT? Children are not small adults when it comes to surgical treatment of therapy-resistant epilepsy. While surgical

treatment for adults and children aims to eliminate seizures without new neurological deficits (Jacobs et al., 2001), in children the main aim, especially in young children, is to prevent seizure-induced encephalopathy to the developing brain (Cross et al., 2006). In other words, seizures early in life have a profound negative impact on brain development with many children heading for IQ scores as adults of less than 50 if the seizures are not stopped in time (Nolan et al., 2003). The goal of epilepsy surgery in children is to reduce or prevent the epileptic encephalopathy and to do so as early in life as possible. To appreciate why this is so important requires an understanding of the neurobiology of the developing human brain and the consequence of seizures. By age 2 years, a child’s brain is 80% while the rest of the body is only 20% the size of an adult. Thus, most brain development occurs in the first few years of human life. Seizures during this critical time of brain development will adversely alter axon and synaptic maturation, leading to poorer cognition and behavioral problems. Many children with early onset epilepsy have lesions that are very large, often occupying an entire cerebral hemisphere. Thus, children undergoing epilepsy neurosurgery have or are at risk for neurological deficits from their etiology and from the surgical procedure. Surgery early in life can take advantage of developmental brain plasticity. The growing human brain has the ability to transfer cerebral functions, such as language, if the surgery is performed early. Developmental brain plasticity helps mitigate some of the existing and imposed neurological deficits associated with surgery, and is another factor to consider when contemplating epilepsy neurosurgery in children.

*Correspondence to: Gary W. Mathern, M.D., Reed Neurological Research Center, 710 Westwood Plaza, Room 2123, Los Angeles, CA 90095–1769, USA. Tel: 310/206–8777. Fax: 310/825–0922, E-mail: [email protected]

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IDENTIFICATION AND PREDICTION OF TREATMENT-RESISTANT EPILEPSY IN CHILDREN Therapy-resistant epilepsy in children can be identified early without an exhaustive trial of multiple antiepileptic medications. The incidence of new onset epilepsy in children in the general population is about five cases per 10 000 per year (Camfield et al., 1996; Olafsson et al., 2005). Of these, from 23% to 33% will become pharmacoresistant (Berg et al., 2001b, c, 2006). Pharmacoresistant epilepsy is usually defined as one or more seizures per month that persist after trying more than two antiepileptic drugs (AEDs) without significant side-effects (Berg et al., 2001a; Kwan et al., 2010). Pharmacoresistance is best predicted by the initial response to AED treatment. Once a patient has failed two or three AEDs, the chances that additional medications will stop the seizures are less than 5% (Kwan and Brodie, 2000). If there is an associated lesion on magnetic resonance imaging (MRI), the chance that additional medications will stop the seizures is near zero (Spooner et al., 2006; Berg et al., 2009). One can also predict success of medical treatment by the patient’s pediatric epileptic syndrome. Idiopathic (genetic) epilepsy, which constitutes approximately 30% of new onset epilepsy in children, refers to focal or generalized seizures considered to be of genetic etiology. An example is benign Rolandic epilepsy. Children with symptomatic (structural–metabolic) epilepsy, identified by the presence of a neurological deficit or structural abnormalities on neuroimaging, constitute 20% of all new onset pediatric epilepsy cases. Mesial temporal sclerosis and cortical dysplasia, along with dual pathologies, are examples of patients with structural epilepsy. As a group, 11–35% of those with positive MRI scans have a chance of becoming seizure free with medication (Semah et al., 1998; Stephen et al., 2001). Cryptogenic (unknown) epilepsy accounts for half of new onset seizures in children. It is possible that cryptogenic epilepsy results from complex genetic abnormalities or in microstructural abnormalities that are as yet undetectable by current neuroimaging techniques. Of note, while the terms idiopathic, symptomatic, and cryptogenic have been used to classify the different epilepsy syndromes, a recent report from the International League Against Epilepsy Commission on Classification and Terminology has suggested replacing these terms with genetic, structural–metabolic, and unknown, respectively (Berg et al., 2010). Epilepsy syndrome classification predicts response to medical therapy. Nearly all children with idiopathic epilepsy experience near-optimal seizure control with medication. Approximately 59% experience remission at 1 year and 40% of children have less than one seizure

a month. Thus, 99% of children with idiopathic epilepsy have near-complete seizure control. Approximately 92% of children with cryptogenic–unknown epilepsy achieve near-optimal seizure control at 2 years. Remission rates for structural–metabolic epilepsy, on the other hand, are not as high with medical therapy, with about 50% uncontrolled on AEDs. Most children considered for epilepsy surgery have seizures from uni-hemispheric structural lesions. The development of new AEDs over the past 15 years has not had a significant impact on the number of patients with pharmacoresistant epilepsy (Chapell et al., 2003). Certain risk factors are associated with not being controlled with AEDs. These include mental retardation, perinatal anoxia, a history of neonatal convulsions, a history of status epilepticus, and symptomatic etiology in children (Altunbasak et al., 2007). Younger age at seizure onset and frequent seizures (more than once per month) are also independent risk factors for the development of treatment resistance. Furthermore, high initial seizure frequency and focal electroencephalography (EEG) findings correlate with becoming medically intractable.

WHEN TO REFER PHARMACORESISTANT CHILDREN FOR COMPREHENSIVE EPILEPSY EVALUATION Expert consensus has identified criteria for when to refer children for a comprehensive epilepsy evaluation (Table 52.1). The identification of symptomatic epilepsy can be made by neurological examination and MRI scan in most pediatric patients. However, there can be challenges in the evaluation of pediatric epilepsy surgery patients. Often, pediatric symptomatic epilepsy does not manifest with a clear neuroradiological structural abnormality with congruent semiology and EEG. For example, uni-hemispheric lesions may appear as symptomatic generalized epilepsy by EEG in infants and young children. Symptomatic epilepsy can manifest itself with focal EEG findings and a negative MRI. Yet, there may be an underlying focal cortical abnormality causing the seizures by other neuroimaging tools (Salamon et al., 2008). Because of growth and myelination during brain development, cortical dysplasia may be difficult to identify in an infant. Conversely, children with multiple brain lesions can often benefit from surgical therapy. Children with cortical tubers, as seen in tuberous sclerosis complex, may have EEG localization to one tuber and hence be surgical candidates with the potential for excellent seizure control (Wu et al., 2010a). Even in cases of diffuse unilateral hemispheric involvement, such as Rasmussen syndrome or hemimegalencephaly, generalized seizures and bilateral EEG abnormalities do not

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Table 52.1

Table 52.2

When to refer children for a comprehensive epilepsy evaluation: expert consensus

Clinical factors associated with epileptic encephalopathy and rate of mortality in pediatric epilepsy surgery patients

All children ● Persistent generalized or partial seizures after failure of two or three antiepileptic drugs, or unacceptable side-effects of drugs. Referral is especially important if more than one seizure per day even if initial magnetic resonance imaging is “negative” Children under age 2 years ● Urgent referral to prevent developmental delay and epileptic encephalopathy, especially if daily seizures Special circumstances ● Children with temporal lobe epilepsy, cortical dysplasia, tumors with seizures, evidence of prior ischemic brain injury, tuberous sclerosis complex, Sturge–Weber syndrome, hemimegalencephaly, Rasmussen encephalitis, hypothalamic hamartomas, and other rarer conditions associated with epilepsy

Clinical factors associated with developmental delay/ epilepsy encephalopathy ● Generalized and partial epilepsies, especially from frontal and parietal lobes ● Seizure onset less than age 1 year ● Seizure frequency of one or more per day ● Failure of seizure control after three antiepilepsy medications ● Epilepsy duration over 18–24 months (Fig. 52.1) Mortality of pharmacoresistant epilepsy in children (1–14 years) ● Rate ● All causes of death: 4/1000 person years (95% CI 1.7–9.8) ● SUDEP and accidents: 2.4/1000 person years (95% CI 0.8–7.6) ● Mortality ratio ● All causes: 16.4 (95% CI 4.5–41) ● SUDEP and accidents: 9.6 (95% CI 3.2–30)

From Cross et al. (2006).

preclude the child from successful surgical treatment (Cook et al., 2004; Jonas et al., 2004, 2005). Thus, pediatric patients with symptomatic epilepsy can have a wide range of presentations, underscoring the importance of referral to a center with experience in treating young patients. Experts recommend referral to a pediatric epilepsy specialty center for children under age 2 years with uncontrolled seizures to determine the etiology and allow for multidisciplinary treatment planning (Cross et al., 2006; Shim et al., 2008).

THE IMPORTANCE OF EARLY SEIZURE CONTROL FOR THE DEVELOPING HUMAN BRAIN Suboptimal seizure control in infants, children, and adolescents poses serious neurodevelopmental consequences, spanning cognitive, behavioral, and psychosocial domains (Table 52.2). Intellectual dysfunction (IQ <79) can be detected in 57% of children with uncontrolled unilateral temporal lobe epilepsy (Cormack et al., 2007). Independent of etiology, intractable seizures during the first 24 months of life is a significant risk factor for severe mental retardation (Vasconcellos et al., 2001). Intellectual deterioration is particularly rampant when seizures occur daily. When uncontrolled epilepsy begins in the first 12 months of life, the incidence of intellectual impairment is approximately 83%. Inadequately controlled infantile spasms may result in severe impairments of cognition, language, social skills, and communication abilities that appear to be clinically similar to autism (Caplan et al., 2002).

CI, confidence interval; SUDEP, sudden unexpected death due to epilepsy. From Bourgeois et al. (1983), Racoosin et al. (2001), Vasconcellos et al. (2001), and Tellez-Zenteno et al. (2005b).

Beyond cognition, suboptimal seizure control may result in poor psychosocial outcomes compared with patients whose epilepsy is controlled (Sillanpaa et al., 1998). Psychosocial deficiencies include lower rates of high school completion, employment, marriage, and overall socioeconomic productivity. Studies indicate that early surgical intervention for intractable seizures may result in improved IQ scores and developmental indices (Fig. 52.1) (Asarnow et al., 1997; Jonas et al., 2004, 2005; Freitag and Tuxhorn, 2005; Loddenkemper et al., 2007; Steinbok et al., 2009). Early intervention to control seizures is also critical to reducing seizure-related morbidity and mortality (Table 52.2). Compared with children without intractable seizures, those with refractory epilepsy are at higher risk of death (Tellez-Zenteno et al., 2005a, b, 2007). The mortality risk of uncontrolled epilepsy is approximately 0.5% per year and accumulates over the child’s lifetime. Hence, over 20 years a child has a 10% chance of dying from their uncontrolled seizures. Examples of this seizurerelated mortality include sudden unexplained death due to epilepsy, aspiration pneumonia, trauma, accidents, drowning, and status epilepticus. Because of the risk of seizure-related morbidity and mortality, surgical therapy should be considered as a viable and important therapeutic option in the management of therapy-resistant epilepsy in children. This is especially important for children whose seizures begin

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DQ evaluation before

1.0 R = -0.192 p = 0.043

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Fig. 52.1. Scatter plots comparing Vineland ABS developmental quotations (DQ; y-axis) with seizure duration (x-axis) for pediatric epilepsy surgery patients from University of California, Los Angeles, before (A) and after (B) surgery. DQ scores negatively correlated with seizure duration before and after surgery. Notice that very few patients had DQ scores >0.5 if seizure duration was longer than 2 years. These graphs indicate that an important clinical factor that determines cognitive and developmental outcomes with epilepsy surgery is if the child has seizure durations of less than 2 years before the operation. Modified from Jonas et al. (2004, 2005).

in the first year of life, are more than one per day, and are associated with an MRI-identified lesion. Furthermore, psychosocial function and quality of life indices may benefit greatly from early seizure control in these at-risk children.

EPIDEMIOLOGY OF PHARMACORESISTANCE AND SURGERY IN CHILDREN Studies from a community-acquired cohort are beginning to define the frequency of treatment-resistant epilepsy in children along with the rate of comprehensive epilepsy evaluations and surgical treatment (Berg et al., 2009). The cohort consists of children with newly diagnosed epilepsy from age 1 month to 16 years

collected from 16 of 17 practicing pediatric neurologists in the state of Connecticut from 1993 to 1997. In the USA, almost all children with new onset epilepsy are referred by the primary care physician to a pediatric neurologist. The cohort consisted of 613 patients, of whom 518 (85%) had had an MRI scan. This is the largest cohort of children with extensive neuroimaging. Median follow-up is now over 12 years. Several clinical factors are associated with pharmacoresistant epilepsy, but the two most important were epilepsy syndrome and if the MRI scans were positive for a lesion linked with the seizures. Children with nonidiopathic epilepsy syndromes (e.g., structural and unknown) had a higher frequency of treatment-resistant epilepsy (Fig. 52.2). Those with nonidiopathic epilepsy and a positive MRI scan had the highest frequency of

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885 MRI negative (157; 97%) 9.5% drug resistant

Idiopathic syndromes (162; 31%) 9.3% drug resistant

MRI positive (5; 3%) 0% drug resistant

New onset epilepsy with MRI (85% of cohort)

Other epilepsies: symptomatic and cryptogenic (365; 69%) 32.9% drug resistant

MRI negative (279; 78.4%) 28.0% drug resistant

MRI positive (77; 21.6%) 54.5% drug resistant

Fig. 52.2. Flow diagram showing the frequency of pharmacoresistant epilepsy (failure after two antiepileptic drugs) in a community population of children age 16 years or less at time of seizure onset by epilepsy syndrome and if their magnetic resonance imaging (MRI) scan was positive or negative. Of the entire cohort of 613 children, 85% had an MRI scan. If the child had a traditional idiopathic syndrome (e.g., Rolandic, absence seizures), 9.3% were pharmacoresistant, and all of these cases were MRI negative (upper row of boxes). By comparison, if the child had any other epilepsy syndrome (e.g., symptomatic or cryptogenic), 32.9% were pharmacoresistant (lower row of boxes). Of this latter group, pharmacoresistance was higher if the MRI was positive (54.5%) than if it was negative (28.0%). Thus, children with a nonidiopathic seizure type and a positive MRI scan have a significant chance of having pharmacoresistant epilepsy. From Berg et al. (2009).

pharmacoresistant epilepsy. The chance of a positive MRI is highest in patients with nonidiopathic epilepsy syndromes and in those with abnormal motor–sensory findings on neurological examination (Fig. 52.3). From this information, in children with new onset epilepsy the frequency of refractory epilepsy ranges from 23% for all patients to 33% for those with nonidiopathic syndromes, the frequency of a comprehensive epilepsy evaluation is from 10% to 15%, and the incidence of a surgical procedure is from 4% to 6% (Fig. 52.4). This means that, of those children with refractory epilepsy, currently 12–33% are candidates for surgical treatment. In addition, MRI will be positive in one of five children with new onset nonidiopathic epilepsy.

CLINICAL CHARACTERISTICS OF PEDIATRIC EPILEPSY SURGERY PATIENTS The clinical features of pediatric epilepsy surgery patients are those associated with a high risk of inducing an epileptic encephalopathy. This is best illustrated from the results of a multicenter international survey of

pediatric epilepsy surgery centers for the calendar year 2004 (Harvey et al., 2008). For example, age at seizure onset is 2 years or less in 83%, and seizure frequency is daily or greater in 65% of cases (Table 52.3). Of note, fewer than 32% of children receive their epilepsy surgery within 2 years of onset. Thus, many children in this survey were exposed to an epilepsy duration that is associated with the poorest developmental outcomes after surgery (Fig. 52.1). Etiologies are variable in patients undergoing pediatric epilepsy neurosurgery, and are another difference from adult epilepsy surgery patients (Table 52.4; Fig. 52.5). Cortical dysplasia, a congenital structural aberration consisting of cortical dyslamination and columnar disorganization, is the most commonly encountered substrate in pediatric epilepsy surgery. Cortical dysplasia can be graded as severe or mild (Vinters, 2002; Palmini et al., 2004; Blumcke et al., 2011). While milder forms of cortical dysplasia involve defects in lamination, severe cortical dysplasia consists of cortical dyslamination with the addition of abnormal cytomegalic neurons and balloon cells in the cortex and subcortical white matter (Cepeda et al., 2005, 2006). Recently, a third classification of cortical dysplasia has

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J.S. HAUPTMAN AND G.W. MATHERN All children MRI+ 15.8%

Idiopathic epilepsy MRI+ 3%

Other epilepsies MRI+ 21.6%

Normal motor–sensory MRI+ 13.0%

Controlled on AEDs MRI+ 10.1% Tumors in this group

Abnormal motor–sensory MRI+ 60.0% Controlled on AEDs MRI+ 53.3% Seizures on AEDs MRI+ 65.7%

Seizures on AEDs MRI+ 20.7%

Fig. 52.3. Flow diagram showing the frequency of children with positive (þ) magnetic resonance imaging (MRI) scans in a community population. Three percent of children with idiopathic epilepsy had positive MRI scans. A child with nonidiopathic epilepsy (other epilepsies) will have a positive MRI scan related to their seizures in 21.6% of cases. If the child with other epilepsy also has an abnormal motor–sensory examination, the chance of a positive MRI scan increases to 60%, with mild differences in the chance of being controlled on antiepileptic drugs (AEDs). Those with other epilepsies and a normal motor–sensory examination still have a 13% chance of a positive MRI scan, and this group contained all the cases of tumors in this cohort. From Berg et al. (2009).

Epilepsy in children 500/million/year Refractory 127/million/year Comprehensive evaluations 52/million/year Tumor surgery without epilepsy 6/1 000 000/year

Epilepsy surgery 21/million/year Total surgery 27/1 000 000/year

Fig. 52.4. Flow diagram showing the frequency of epilepsy, comprehensive epilepsy evaluations, and surgery in a communitybased cohort of children. The frequency of refractory epilepsy ranges from 23% for all children to 33% for those with nonidiopathic epilepsy syndromes. Approximately 10–15% of the population (41% of refractory cases) underwent a comprehensive epilepsy evaluation. Epilepsy surgery (including palliative operations and resection of tumors in patients controlled on drugs) will occur in 4–6% of all children with new onset epilepsy. This represents 16% of those with refractory epilepsy, and 40% of those who had a comprehensive epilepsy evaluation. With approximately 4 million live births per year and based on these estimates from the cohort, there should be about 3300 comprehensive evaluations and 1600 epilepsy surgeries in children under age 16 years within the USA per year. From Berg et al. (2009).

been introduced to reflect cortical dysplasia in association with hippocampal sclerosis or epilepsy-associated tumors (Blumcke et al., 2011). Severe cortical dysplasia is more likely to present at younger ages, have higher seizure frequencies, and be extratemporal (Lerner et al., 2009). Although cortical dysplasia is most often detected using conventional structural MRI, abnormalities may be subtle or undetectable. In addition, scalp EEG may be

nonlocalized in 23–50% of cases. For this reason, adjunctive neuroimaging such as 2-deoxy-2-[18 F]fluoro-Dglucose (FDG) positron emission tomography (PET), magnetoencephalography (MEG), and ictal single photon emission computed tomography (SPECT) may be utilized. FDG-PET, in particular, is positive in 75–90% of cortical dysplasia cases (Salamon et al., 2008). Focal cortical dysplasia is most often found in the frontal and temporal

EPILEPSY NEUROSURGERY IN CHILDREN Table 52.3 Clinical characteristics of pediatric epilepsy surgery patients in 2004 Clinical variable Age at seizure onset By age 1 year By age 2 years Epilepsy duration of 2 years before surgery Frequency of seizures Daily or greater Weekly More than weekly

Percent of cases

36 47 32 65 26 9

Modified from Harvey et al. (2008).

Table 52.4 Etiologies in pediatric epilepsy surgery patients under age 18 years in 2004 Etiology Cortical dysplasia Tumor Atrophy/stroke Hippocampal sclerosis Hypothalamic hamartoma Hemimegalencephaly Tuberous sclerosis complex Rasmussen encephalitis Sturge–Weber syndrome Vascular (cavernous angiomas) Normal/gliosis

Percent of cases 33 20 11 9 6 5 4 3 2 2 5

Modified from Harvey et al. (2008).

lobes, although larger lesions may involve multiple lobes or a cerebral hemisphere. In our experience, children with early onset epilepsy tend to have larger dysplastic lesions with more severe cortical dysplasia histopathology. The second most common substrate found in pediatric epilepsy surgery patients is low-grade neoplastic tumors, such as gangliogliomas and dysembryoplastic neuroepithelial tumors (DNETs). Seizures are the first clinical presentation in about 80% of patients with low-grade tumors (Chang et al., 2008; Lee et al., 2009). DNETs may also be found in association with regions of cortical dysplasia. Fortunately, high seizure remission rates result from complete resection of these tumors (Minkin et al., 2008). Other structural abnormalities leading to pediatric epilepsy surgery may result from perinatal infarcts or infections such as bacterial or viral encephalitides

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associated with cerebral atrophy (Lee et al., 2008). While hippocampal sclerosis is the most common etiology in adult epilepsy surgery patients, it is the fourth most frequent etiology in children undergoing epilepsy neurosurgery. Other etiologies are much less frequent in pediatric epilepsy surgery patients. In Sturge–Weber syndrome, for example, suboptimal seizure control may lead to developmental delay and progressive hemiparesis. For this reason, children may require focal or hemispheric resections to prevent developmental decline (Di Rocco and Tamburrini, 2006). Tuberous sclerosis complex (TSC), a phakomatosis that results in hamartomatous lesions throughout the body, is another fairly rare condition referred for epilepsy surgery consideration. In TSC patients, seizures may be focal or multifocal, are often treatment resistant, and may impair neurocognitive development (Chandra et al., 2006, 2007; Curatolo et al., 2008). Even though there are several tubers as well as multifocal interictal EEG abnormalities, optimal seizure control may result from resection of the epileptogenic cortical tuber(s) (Weiner et al., 2006; Wu et al., 2006, 2010a). Rasmussen syndrome, hypothalamic hamartoma, and hemimegaloencephaly are other less frequently encountered substrates in pediatric epilepsy surgery. Rasmussen syndrome is a disease of unknown cause in which progressive involvement of one hemisphere leads to hemiparesis and intractable seizures (Bien et al., 2005). While steroids, immunoglobulins, and plasmapheresis provide temporary relief, hemispherectomy is the only known effective treatment. Laundau–Kleffner syndrome, an epileptic aphasia associated with severe developmental regression and intractable seizures, may respond to surgical intervention (Irwin et al., 2001). Hemimegalencephaly is a phenomenon in which one hemisphere is hypertrophied and contains abnormal and dysplastic glioneuronal proliferation while the other hemisphere is usually smaller than normal (Salamon et al., 2006). Children with hemimegalencephaly have unilateral or bilateral EEG abnormalities often with hypsarrhythmia or EEG suppression bursts. These children also present with macrocrania, mental retardation, and contralateral paresis. Hemispherectomy provides the best chances for seizure control and normalization of psychomotor development velocity (Cook et al., 2004).

PRESURGICAL EVALUATIONS FOR CHILDREN WITH TREATMENTRESISTANT EPILEPSY While early referral ensures rapid assessment and diagnosis, not all patients referred to a pediatric epilepsy center will be offered surgery. Only about one in four to one in six children undergoing a comprehensive

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Fig. 52.5. Magnetic resonance imaging (MRI) examples of different etiologies in children undergoing epilepsy surgery. (A) Patient with a left hemimegalencephaly. Notice the enlarged left cerebral hemisphere with thickened cortex (arrow) and white matter. (B) Child with a focal cortical dysplasia (Pamini type IIB) in the left temporal lobe (arrow). (C) Child with new onset epilepsy from a left mesial frontal lesion (arrow) that on histopathology was a low-grade cystic astrocytoma. (D) A 6-yearold with a history of a left perinatal middle cerebral artery infarct and intractable epilepsy. (E) An 11-year-old with complex–partial limbic epilepsy from left hippocampal sclerosis (arrow). (F) Child with tuberous sclerosis complex with multiple bi-hemispheric cortical tubers (arrows). Seizures originated from the left frontal tuber. (G) A 9-year-old with a 1-year history of progressively worse seizures involving the motor–sensory system Epilepsy partialis continua (EPC) and MRI evidence of progressive atrophy of the right cerebral hemisphere and perisylvian region. Histopathology was consistent with Rasmussen encephalitis. (H) Contrast MRI showing the typical enhancement pattern associated with Sturge–Weber syndrome.

presurgical evaluation will eventually have some sort of epilepsy neurosurgery (Fig. 52.4). The others will sometimes be controlled on alternative medical treatments after identification of an idiopathic syndrome, have bi-hemispheric lesions and epileptogenic foci, or

are image negative. Scalp EEG, structural and functional neuroimaging, neuropsychological testing, and psychiatric assessments are all appropriate components of the presurgical evaluation (Obeid et al., 2009a, b). The utilization of these tests varies widely in pediatric

EPILEPSY NEUROSURGERY IN CHILDREN Table 52.5 Presurgical evaluation in pediatric epilepsy surgery patients under age 18 years in 2004 Etiology MRI Video EEG Intracranial EEG electrodes FDG-PET Ictal SPECT FDG-PET or SPECT fMRI IAP/Wada MEG/MSI

Percent of cases 99.7 89 28 28 26 44 12 10 7

EEG, electroencephalography; FDG-PET, 2-deoxy-2-[18 F] fluoro-D-glucose positron emission tomography; IAP, Intracarotid amobarbital procedure; fMRI, functional magnetic resonance imaging; MEG, magnetoencephalography; MSI, Magnetic Source Imaging; SPECT, single photon emission computed tomography. Modified from Harvey et al. (2008).

epilepsy surgery patients (Table 52.5). Interictal EEG and video-EEG telemetry localize the seizure origin and record the semiology, but are not necessary in all cases such as those with tumors on MRI. Invasive EEG recordings, using grid or depth electrodes, are used when noninvasive alternatives prove inconclusive, and are performed on 28% of pediatric epilepsy surgery patients (Harvey et al., 2008). At our institution, structural neuroimaging is performed using specific epilepsy MRI protocols for the developing brain, including T2 fast spin echo, T2 gradient echo (GE), T1 inversion–recovery, fluid attenuation inversion–recovery, three-dimensional thinly sliced T1-weighted GE in three planes, magnetization transfer, spoiled gradient recalled, and diffusionweighted imaging. Though nascent in use, fractional anisotropy and diffusion tensor imaging aid in viewing normal white matter tract anatomy for surgical planning. Because myelination in infants less than 24 months old is still immature, specialized MR sequences and serial MRI imaging may be necessary. As the child develops, an initial negative scan may eventually discover a lesion. Also, lesions once thought to be small on initial MRI scans are often larger with subsequent neuroimaging as the child’s brain matures. Additional neuroimaging techniques in the presurgical workup include ictal and interictal SPECT, FDG-PET, MEG/ Magnetic Source Imaging (MSI), and Blood Oxygen Level-Dependent (BOLD)–functional MRI (fMRI) for mapping eloquent cortex (Knowlton et al., 2006; Raybaud et al., 2006). The application of fMRI is usually indicated for older children who are able to comply with the examination. This ensures that the surgical plan

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spares normally functioning areas, identifies abnormal areas that are functionally active, and demonstrates areas of reorganized cortex (Liegeois et al., 2006). That being said, fMRI is being investigated in identification of eloquent cortex in younger children as well (Shurtleff et al., 2010). Current trends are to integrate multiple modalities of imaging (such as PET-MRI fusion) and intraoperative neuronavigation to provide the surgeon with the greatest amount of structural and functional information at the time of surgery. The psychiatric and cognitive comorbidities present in many surgical candidates should be evaluated by an interdisciplinary team of developmental neuropsychologists, psychiatrists, and social workers. One important component of this assessment is the evaluation of family dynamics and realistic expectations for surgery. Clinicians and families together must decide whether the risk of continued medical therapy with a low chance of seizure control compare or contrast with the benefits and risks of surgical intervention. This includes an honest appraisal of any expected postoperative deficits relative to the risks of continued seizures and the chance that surgery will be successful.

PERIOPERATIVE CONSIDERATIONS AND SURGICAL APPROACHES Children undergoing resections for intractable epilepsy require an experienced and well-trained surgical and anesthesia team along with pediatric intensive therapy specialists (Pietrini et al., 2006). Infants have a lower cerebrovascular autoregulatory reserve and a relatively high cerebral blood volume. They are at greater hemodynamic risk during extensive neurosurgical procedures. Hemodynamic considerations also include that infants have a limited capacity to handle large changes in fluid and solute loads. From a metabolic perspective, liver function may be abnormal in children on chronic AED therapy, and effects on drug metabolism and coagulation must be anticipated. The anesthesia team must plan accordingly for these pediatric-specific issues. This is particularly true in cases of hemimegalencephaly, in which the dysplastic hemisphere is extremely vascular and blood transfusion requirements are common. Hematological and metabolic laboratories, and possibly an echocardiogram, should all be included as part of the preoperative anesthesia evaluation. Additional imaging may be required in children with extracranial disease, such as those with tuberous sclerosis complex. These children may have lesions in the heart and kidneys, which may affect intraoperative physiology. Intraoperative monitoring should focus on continuous hemodynamic assessment, with placement of appropriate invasive hemodynamic monitors. After surgery, monitoring of hematological

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and coagulation parameters, surgical drains, and intracranial pressure management are important. The particular surgical treatment and timing of surgery are customized to the individual child. Children may present with acute status epilepticus and urgent surgery may be needed to control life-threatening seizures (Koh et al., 2005). Operations that may be offered include invasive recording using grid and depth electrodes, resection of the epileptogenic lesion, disconnection of the abnormal cortex, or palliation of seizure frequency. About 80% of operations are resections, while 20% are palliative. The most common types of surgery range from cerebral hemispherectomy to focal resections (Table 52.6). Of the multiple techniques of hemispherectomy–hemispherotomy, many have similar seizure control rates. Cerebral hemispherectomy operations have similar efficacy to temporal lobectomy for complex partial limbic seizures. At our institution, we use a modified lateral hemispherotomy, which, when compared with other methods, results in lower intraoperative blood loss, reduced complication rates, and shorter intensive care unit stays (Cook et al., 2004; Jonas et al., 2004). The majority of palliative procedures in the USA are vagus nerve stimulators, with corpus callosotomy performed in rarer instances. Palliative surgery is offered to children with unresectable epilepsy, such as those with Lennox–Gastaut syndrome (Patwardhan and Mathern, 2004; Wong et al., 2006). Additionally, palliative procedures may be considered in children with symptomatic disorders, such as tuberous sclerosis, who are not candidates for surgical resection (Zamponi et al., 2010). Radiosurgery is currently being investigated as an alternative procedure to resections, particularly for hypothalamic hamartoma and medial temporal lobe epilepsy (Regis et al., 2007; Bartolomei et al., 2008; Hoggard et al., 2008; Quigg and Barbaro, 2008; Table 52.6 Types of operations in pediatric epilepsy surgery patients under age 18 years in 2004 Location Temporal lobe Frontal lobe Hemispherectomy Multilobar resection Parietal lobe Hypothalamic Occipital Multiple subpial transection/no resection Modified from Harvey et al. (2008).

Percent of cases 30 23 20 18 3 3 2 1

Romanelli et al., 2008). To date, the use of radiosurgery to treat infants and children has not been adequately studied. Another surgical technology being investigated involves stereoendoscopy, particularly for treating hypothalamic hamartomas (Procaccini et al., 2006; Ng et al., 2008). Resective and palliative surgeries continue to be the mainstay of treatment in a majority of children with treatment-resistant epilepsy.

OUTCOMES AFTER EPILEPSY NEUROSURGERY IN CHILDREN Results of multiple studies including meta-analysis over the past decade indicate that from 65–80% of children will become seizure free after epilepsy neurosurgery (Davidson and Falconer, 1975; Gilliam et al., 1997; Wyllie et al., 1998; Wiebe et al., 2001; Chapell et al., 2003; Sinclair et al., 2003; Tellez-Zenteno et al., 2005a; TerraBustamante et al., 2005; Gleissner et al., 2006; Khan et al., 2006; Van Oijen et al., 2006; Kan et al., 2008; Kim et al., 2008). Success at individual pediatric surgical centers improves over time (Hemb et al., 2010). The two most consistent factors associated with the highest chance of seizure control are a lesion identified on MRI scan before surgery, and complete excision of the lesion after surgery (Mathern and Delalande, 2008; Krsek et al., 2009; Mathern, 2009a, b). Seizure remission rates are higher in children who have temporal resections than in those who have extratemporal resections. Recent work has suggested that using the appearance of fast ripples (250–500 Hz) on electrocorticography (ECoG) at the time of resection to guide resection may also help to improve postoperative seizure-free outcomes (Wu et al., 2010b). The best predictor, however, of long-term optimal seizure control is early seizure control after epilepsy surgery. If the patient has no seizures during the first 6 months after surgery, they have up to a 95% chance of remaining completely seizure free over time (Lachhwani et al., 2008). Between 30% and 50% of children will have AEDs withdrawn following successful epilepsy surgery (Hoppe et al., 2006; Sinclair et al., 2007; Tellez-Zenteno et al., 2007). Focal resections may result in a seizure remission rate that approaches 88% for hippocampal sclerosis, 81% for tumor, and 62% for cortical dysplasia (Kan et al., 2008). Compared with focal or lobar resections, patients with more widespread and/or diffuse pathology (e.g., hemimegalencephaly) requiring hemispheric surgery or disconnection have lower seizure remission rates (Mathern et al., 1999). It is possible that these diffuse EEG patterns indicate an interface between the early lesion and the developing brain (Wyllie et al., 2007). Surgical mortality is from 0.25% to 2% for procedures such as temporal lobectomy and hemispherectomy, while permanent surgical morbidity is reported to be less than

EPILEPSY NEUROSURGERY IN CHILDREN 891 5% (Tonini et al., 2004). Temporal resections are most ofSUMMARYAND FUTURE DIRECTIONS ten complicated by visual field deficits, while extraEarly referral to a pediatric epilepsy center for evaluatemporal resections may have transient hemiparesis. tion and treatment of pharmacoresistant epilepsy is imInfrequently, infarcts, permanent hemiparesis (temporal portant to reduce seizure-induced encephalopathy to the lobe resections), and language deficits may occur. In gendeveloping human brain. This concept distinguishes peeral, the risks of surgery are less than the risks associated diatric epilepsy surgery from that in adults. Unconwith the natural history of treatment-resistant epilepsy trolled seizures increase mortality, decrease cognitive (Mathern and Delalande, 2008). Reoperations for a failed and developmental indices, and adversely affect quality first epilepsy surgery occur in approximately 14% of peof life. If a child has treatment-resistant epilepsy the diatric patients (Harvey et al., 2008). Most reoperations family should know why, and it is strongly recominvolve extending the resection to include areas thought mended that all of these children be referred to a spenot to be involved with the epileptogenic process with cialty center for a comprehensive epilepsy evaluation. the first operation. An important factor that clinicians can control in Following surgery, developmental quotients may children is epilepsy duration, and children should be improve, with preoperative development predicting referred promptly for a comprehensive epilepsy evaluapostoperative measurements (Fig. 52.1) (Asarnow et al., tion after failure of two or three AEDs. 1997; Jonas et al., 2004, 2005; Loddenkemper et al., Etiologies of symptomatic treatment-resistant epilepsy 2007). Thus, epilepsy neurosurgery benefits the youngest include cortical dysplasia, tuberous sclerosis complex, patients with the shortest seizure duration, as children and low-grade neoplasms. Children with symptomatic epioperated on at younger ages show the greatest increases lepsy have an approximately 50% chance of developing in developmental quotients (Curtiss et al., 2001; de Bode treatment resistance. Once surgical therapy is offered, et al., 2005, 2009). Mental and social age, gross motor, preoperative studies such as scalp and/or video EEG fine motor, adaptive, and personal social skills showed telemetry, structural and functional neuroimaging, and a steady increase after surgery (Thomas et al., 2010). psychosocial evaluations may be necessary. The type of Motor performance of daily activities and level of caresurgery depends on underlying etiology and size of the legiver assistance also appear to be improved after epilepsy sion, and may involve focal resections, lobar resections, or surgery (van Empelen et al., 2005a). Behavior, attention, hemispherectomy. When no lesion is present, epilepsy can and IQ scores are better following surgery, while memory and executive functions remain intact (Gleissner et al., also be treated with palliative procedures such as vagal 2006; Liu et al., 2007). Improvement in cognitive and nerve stimulation and corpus callosotomy. The particular behavioral domains may then translate into better school surgery selected is aimed at reducing seizure frequency and minimizing neurological morbidity. Expected seizure performance and social adaptation. remission rates following epilepsy surgery are 65–80%, In addition to seizure control and better developmental indices, quality of life (QOL) measures for pediatric with less than 5% morbidity and less than 1% mortality. epilepsy surgery patients are enhanced, with significant The relatively low risks of surgery compare favorably improvements occurring in the first 6 months after with the risks associated with the natural history of unconsurgery (van Empelen et al., 2005b). As in adults, seizure trolled epilepsy and continued medical therapy. Besides control appears to be the best predictor of improved reducing seizure frequency, epilepsy surgery enhances QOL changes in children after surgery (Griffiths development and QOL for children. In children with treatment-resistant epilepsy, surgery should be considered et al., 2007; Larysz et al., 2007; Zupanc et al., 2009). when appropriate to improve seizure control and halt or By comparison, intractable temporal lobe epilepsy treated without surgical therapy is associated with low prevent development of epileptic encephalopathy. QOL scores despite attempts at optimizing AED manThere are still many challenges in treating children agement (Mikati et al., 2006). In those children who unwith refractory epilepsy. For example, in the future it dergo temporal lobectomy, QOL indices normalize to would be appropriate to develop technologies that better those of matched healthy individuals after 3 years. Folidentify symptomatic lesions in children who are pharlowing surgery, children experience greater feelings of macoresistant and who are currently MRI negative. Such tools will likely reduce the need for intracranial self-worth and social competence and adolescents feel EEG studies in children. Surgical procedures will need better about their athletic competence and capacity for social interactions. QOL improvements are importo be refined or new ones created that effectively tant for social integration. Because reduced seizure freremove the epileptogenic lesion without inducing quency and improved QOL allows other members of the new neurological deficits. Just as important, we need family to engage in work and school, epilepsy surgery new creative ideas on how to treat the 66–75% of chilhas been deemed cost-effective. dren with pharmacoresistant epilepsy who are currently

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not surgical candidates. Hence, there is still considerable work necessary to develop and refine epilepsy surgery for children over the coming years.

ACKNOWLEDGMENT This work was supported by the National Institutes of Health grant R01 NS38992 to G.W.M.

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