Chapter 61 Epilepsy Surgery in the Pediatric Population
Epilepsy is one of the most common chronic disorders facing children and adolescents. The overall prevalence of epilepsy has been estimated to be 5–8 per 1000 [Hauser et al., 1975, Hauser, 1994, 1996, 1998; Olafsson et al., 1996; Osuntokun et al., 1987]. Extrapolating the Hauser data from Rochester, Minnesota, of 6.66 per 1000 to the total population in 2004, approximately 2.3 million persons in the United States have epilepsy [Hauser et al., 1991]. In children, there are approximately 10.5 million worldwide with epilepsy. The annual incidence of epilepsy in children is reported to be 61–124 per 100,000 in developing countries and 41–50 per 100,000 in developed countries [Guerrini, 2006]. The cumulative risk of developing epilepsy from birth through adolescence is 1 percent [Hauser et al., 1991, 1994]. Unfortunately, only 60–70 percent of patients will achieve seizure freedom with antiepileptic medications [Kwan and Brodie, 2000; Mohanraj and Brodie, 2006]. The introduction of several new antiepileptic drugs over the past 15 years has not changed the fact that approximately 30–40 percent of patients with epilepsy will be medically refractory [Perucca et al., 2007; Mohanraj and Brodie, 2006].
In addition, the longer epilepsy persists without control, the less likely is the chance of remission. Specifically, if seizures remain inadequately controlled for longer than 4 years, the chance of remission decreases to approximately 10 percent [Annegers et al., 1979]. Seizure duration of over 10 years also decreases the likelihood of achieving control in patients who undergo surgery. The presence of multiple seizure types and frequent generalized tonic-clonic seizures also lessens the chance for complete remission. As stated above, 30–40 percent [Mohanraj and Brodie, 2006] of all persons with epilepsy will be intractable. There are approximately 20,000 cases of new-onset epilepsy annually. Therefore, 6000–8000 cases of new-onset epilepsy are intractable each year. In the United States, the number of patients with drug-resistant epilepsy – adult and pediatric – is estimated to be 700,000, a higher number than the number of individuals affected with Parkinson’s disease and multiple sclerosis combined [Hiritiz et al., 2007]. Approximately 60 percent of these patients will have partial seizures. Estimates by several investigators suggest that many of these patients are epilepsy surgery candidates [Hauser, 1993; Unnwongse et al., 2010]. This figure may increase as new technologies enable more precise identification of an underlying epileptogenic focus. Additionally, as medical intractability for children with epilepsy is further defined, the number of pediatric epilepsy surgical procedures will probably increase. However, currently, epilepsy surgery is underutilized in the treatment of intractable epilepsy. In fact, over the past 15 years, the mean duration of epilepsy before referral to a tertiary care epilepsy center for evaluation for epilepsy surgery has been over 20 years [Engel et al., 2003; Unnwongse et al., 2010; Choi et al., 2009].
The developing brain is highly susceptible to recurrent seizures. Until recently, the brain was believed to be relatively resistant to injury. A growing body of evidence in animal models, however, suggests that early seizures, even if brief and recurrent, can result in demonstrable structural and physiologic changes in the developing brain’s circuitry, resulting in aberrant excitation and inhibition. Clinically, these defects produces spontaneous seizures (epilepsy) and cognitive impairments [Holmes and Ben-Ari, 1998; Holmes et al., 1998; Stafstrom et al., 2000; Galanopoulou and Moshé, 2009], with the possibility of missed windows of developmental opportunity. Thus, plasticity of the brain in a young infant and child is a “double-edged sword”. It protects the brain from the neurologic consequences of destructive lesions and status epilepticus; however, recurrent seizures, or even frequent interictal epileptiform discharges, in this age group can produce permanent abnormal neuronal circuitry, resulting in long-term developmental delays and continued, intractable seizures [Holmes and Lenck-Santini, 2006]. In addition, chronic uncontrolled epilepsy in infants and children poses a significant risk for emotional, behavioral, social, cognitive, and family dysfunction. Population studies have demonstrated that epilepsy reduces life expectancy, and poorly controlled seizures further increase the risk of death in children and adults [Nashef et al., 1995; Hitiris et al., 2007]. In population-based studies, the estimated risk of sudden unexpected death in epilepsy (SUDEP) is estimated to be between 1:500 and 1:1000 per year. For those with uncontrolled epilepsy, the rate of SUDEP is approximately 1:200 per year. [Harvey et al., 1993c; Hauser et al., 1980; Meyer et al., 2010; So et al., 2009]. It should be noted that patients being evaluated for epilepsy surgery have the highest risk of SUDEP, estimated at between 2.2 and 9.3 per 1000 patient-years [Hiritiz et al., 2007].
Several studies have examined outcomes after epilepsy surgery. A majority of these studies has been performed in older adolescents and adults. The focus of these studies has been primarily on the improvement of seizure control, with 64–69 percent of patients having seizure-free outcomes [Engel, 1996; Wyllie, 1998; Wyllie et al., 1998]. These studies have placed less emphasis on improvement in quality of life – for example, enhancement of self-image, improvement in academic performance and psychosocial functioning, and increased independence in activities of daily living [Spencer, 1996; Taylor et al., 1997]. An increasing number of long-term follow-up studies have concentrated on infants and young children. Malformations of cortical development are the most frequently cited pathologic abnormalities in pediatric surgical patients [Duchowny et al., 1996; Wyllie et al., 1998; Harvey et al., 2008; Zupanc et al., 2010]. The overall outcome of pediatric epilepsy surgery in young infants and children is roughly comparable to that in the older adolescent and adult population. In infants, 61–65 percent have seizure-free outcomes [Chugani et al., 1993; Duchowny et al., 1998; Sinclair et al., 2003; Wyllie et al., 1996, 1998; Zupanc et al., 2010]. In young children, the rate of seizure-free outcomes varies, ranging from 58 to 74 percent [Paolicchi et al., 2000; Sinclair et al., 2003; Wyllie et al., 1998; Cossu et al., 2008; Kan et al., 2008; Kim et al., 2008; Zupanc et al., 2010]. The etiology of the epilepsy appears to play the major role in determining prognosis, regardless of location (temporal versus extratemporal). In one study, children with malformations of cortical development had a seizure-free outcome of 58 percent, whereas patients with other pathologies had a 77 percent seizure-free outcome. Temporal lobectomies were more commonly performed in our older adolescent patients, consistent with other studies, and demonstrated a seizure-free outcome of 84 percent. Patients who had modified lateral hemispherectomies also demonstrated a high seizure-free outcome (i.e., approximately 100 percent), even those with cortical dysplasias [Zupanc et al., 2010].
Several studies have reported on cognitive function after surgery in children who have undergone temporal lobectomy (predominantly older children and adolescents) [Gillam et al., 1997; Gleissner et al., 2002; Mabbott and Smith, 2004; Meyer et al., 1986; Szabo et al., 1998; Westerveld et al., 2000; Lah, 2004]. These studies have generally found that memory and intelligence are unchanged. Some reports note a decline in verbal memory and improvements in language, attention, and memory, while other studies have reported that good seizure outcomes have been associated with an increase in IQ [Lah, 2004]. Reports on the cognitive effects of extratemporal resections have been relatively few, in part because of the young age of those having surgery. In a follow-up study of 24 children operated on before 3 years of age, younger age at surgery was correlated with an improvement in developmental quotients [Loddenkemper et al., 2007]. In patients who have undergone successful frontal lobe resection, outcomes include improvements in attention and concentration but no change in executive functions, manual coordination, and language [Blanchette and Smith, 2002; Lendt et al., 2002]. Studies on postoperative psychosocial functioning in children have been relatively rare, almost exclusively retrospective, and based on subjective measures. In children who have undergone temporal lobectomies, studies indicate improvement in behavior, mood, and self-esteem, with the changes linked to improvement in seizure control [Danielsson et al., 2002; Davidson and Falconer, 1975; Duchowny et al., 1992; Meyer et al., 1986; Zupanc et al., 2010]. Of children who have undergone extratemporal resections, improved social behavior was found in about 50 percent [Adler et al., 1991]. Other retrospective studies that combine temporal and extratemporal cases suggest that reduction of seizure frequency, although not necessarily complete elimination of seizures, resulted in improved family life, socialization and behavior, and quality of life [Adler et al., 1991; Keene et al., 1998; Lendt et al., 2002; Mihara et al., 1994; Smith et al., 2004; Whittle et al., 1981; Zupanc et al., 1996, 2010]. Other reports indicate that a reduction in seizures may result in a favorable and significant improvement in the quality of life, with behavioral and developmental “catch-up” progress [Asarnow et al., 1997; Bourgeois et al., 1999; Chugani et al., 1990b; Duchowny et al., 1990, 1992; Wyllie et al., 1996; Jonas et al., 2004; Zupanc et al., 2010]. More recent studies indicate that shorter seizure durations and earlier surgical intervention result in better seizure outcome and quality of life [Jonas et al., 2004; Loddenkemper et al., 2007; Zupanc et al., 2010].
Historical Background
Epilepsy has always been a part of human existence. A generalized tonic-clonic seizure was first described in Akkadian, the oldest written language, more than 3000 years ago [Goldensohn et al., 1997]. Since that time, many descriptions of epilepsy appear in literature, including the Bible. In “On the Sacred Disease”, written in the 5th century, Hippocrates stated that epilepsy was a brain disease caused by an excess of phlegm that resulted in an abnormal brain consistency. He proposed diet and drugs as therapy [Scott, 1993]. Until the late 19th century, the treatment of epilepsy was surrounded by superstition, exorcism, magic, and alchemy. Caton’s (1842–1926) discovery in 1875 of spontaneous electrical activity of the brain and evoked potentials suggested that seizures might be the result of aberrant electrical activity in the brain [Caton, 1875].
The first effective treatment for epilepsy was potassium bromide, introduced in 1857 [Locock, 1857]. In 1886, Horsley performed the first epilepsy surgery on a patient with intractable post-traumatic epilepsy. Several decades later, the antiepileptic drug phenobarbital was introduced in 1912, followed by phenytoin in 1937. Epilepsy surgery did not advance until 1950, when Penfield published his article on 70 cases of temporal lobectomy [Flanigin et al., 1991; Penfield and Flanigin, 1950]. His neurosurgical career was devoted to the study of seizure semiology (i.e., clinical description) and its correlation with the brain cortex. He used cortical mapping and stimulation in much the same way in which it is used today. He also recognized the substrates of epilepsy, particularly trauma and infection. His seminal clinical research has been instrumental in guiding the hands of contemporary epileptologists and neurosurgeons interested in the surgical approach to epilepsy.
Epilepsy surgery was not regarded as a conventional treatment for intractable epilepsy until recently. In the past 30 years, dramatic improvements in brain imaging that identify specific anatomic substrates of epilepsy have sparked renewed interest in epilepsy surgery. Temporal lobectomy with amygdalohippocampectomy has become the standard of care in adult patients with intractable epilepsy emanating from the temporal lobe. The surgical success rate for a seizure-free outcome in these carefully selected patients approaches 80–90 percent [Duchowny et al., 1992; King et al., 1986; Penfield and Flanigin, 1950]. In a randomized, controlled trial of surgery for temporal lobe epilepsy compared to treatment with antiepileptic drugs, 58 percent of patients demonstrated seizure freedom after 1 year compared to only 8 percent of patients treated with medications [Wiebe et al., 2001]. Unfortunately, surgical success does not necessarily translate to an improved quality of life. The accumulation of years of low self-esteem, loss of independence, poor peer relations, and academic failure, coupled with high financial costs, often without benefit of full insurance coverage, translates to continued lack of employment and depression [Reeves et al., 1997]. The lifetime cost of epilepsy for an estimated 181,000 people with onset in 1995 is projected at $11.1 billion, and the annual cost for the estimated 2.3 million people with epilepsy is estimated at $12.5 billion [Bazil, 2004; Begley et al., 1994, 2000; Hathaway et al., 1995]. In one recent study, the calculated total aggregated annual economic impact of epilepsy on the U.S. economy was $9.6 billion in direct medical costs. This analysis did not consider the indirect costs of loss of productivity, quality of life, and comorbidities [Yoon et al., 2009]. With respect to children, it is estimated that the annual cost of medical care for a child with epilepsy is $6379, compared to $1032 for peers without epilepsy [Yoon et al., 2009]. Indirect costs probably account for 80–85 percent of the total costs, and include delayed or missed educational opportunities, psychiatric and social service needs, and lost employment. The direct costs of epilepsy are concentrated in the patients with intractable epilepsy. The growing recognition of the real costs of epilepsy – medical, psychological, educational – has led to increased interest in the early identification of children who might benefit from epilepsy surgery [Jalava et al., 1997]. In older children and adolescents, temporal lobectomies are common epilepsy surgical procedures [Harvey et al., 2008]. In younger children and infants, however, extratemporal resections, including multilobar resections and hemispherectomies, are the more typical procedures [Harvey et al., 2008].
In recent studies, it has been shown that the costs of epilepsy surgery are offset by a decline in health-care costs after successful surgery. One study documented that the total costs for adult patients who were seizure-free following epilepsy surgery declined by 32 percent by 2 years following surgery. In the 24 months after surgery, epilepsy-related costs were $2068–2094 in patients with persisting seizures, as opposed to $582 in patients who were seizure-free following surgery [Langfitt et al., 2007]. In addition, in adult patients, it appears that epilepsy surgery increases quality-adjusted life expectancy by 7.5 years [Choi et al., 2008]. In the pediatric population, additional benefits of epilepsy surgery appear to be improved long-term developmental outcomes and quality of life [Loddenkemper et al., 2007; Zupanc et al., 2010].
Indications for Epilepsy Surgery
Criteria have been proposed for referral and evaluation of children for epilepsy surgery, although there is currently insufficient class I evidence to produce a practice guideline [Cross et al., 2006]. Practice guidelines for temporal lobe and localized neocortical resections for epilepsy have been proposed for adults [Engel et al., 2003]. In determining whether a child is a candidate for epilepsy surgery, several key issues must be considered. The decision-making task must take into account the following:
Failure of two or three antiepileptic medications in achieving complete seizure control in a child or adolescent.
The proper classification of seizure type and epilepsy syndrome is crucial in the determination of whether or not a patient is an appropriate epilepsy surgery candidate [Aicardi, 1994; Holmes, 1993]. The benign seizure disorders, such as benign rolandic epilepsy or benign epilepsy with centrotemporal spikes, must be recognized. With rare exceptions, these syndromes usually are easily treated, and affected patients do not present to tertiary epilepsy centers.
Children with Sturge–Weber syndrome who have frequent, medically refractory seizures accompanied by progressive hemiparesis and cognitive impairment should be evaluated promptly for hemispherectomy [Thomas-Sohl et al., 2004; Vining et al., 1997]. Clinical outcome studies indicate that early surgical resection can result in the elimination of seizures, improvement in cognitive abilities, and overall improvement in quality of life, despite hemiparesis and visual field defect as residual neurologic deficits [Erba and Cavazzuti, 1990; Hoffman et al., 1979; Ogunmekan et al., 1991; van Empelen et al., 2004].
Children with hemimegalencephaly, a unilateral or focal malformation of cortical development, can present in infancy with multiple daily seizures, developmental stagnation or decline, and hemiparesis. Hemispherectomy provides relief from seizures (especially in those patients with unilateral epileptiform abnormalities) and improved developmental outcome [Andermann et al., 1993; Vigevano and DiRocco, 1990; Vigevano et al., 1989; Jonas et al., 2004]. The patients with symptomatic infantile spasms who have underlying focal cortical dysplasias, usually temporal-parietal-occipital, should be considered for early focal cortical resection. University of California at Los Angeles investigators have provided the seminal clinical research in this area and have documented a significant improvement in seizure control and enhanced developmental gains following epilepsy surgery, greater than would have been predicted using the natural history of infantile spasms as a comparison [Asarnow et al., 1997; Chugani et al., 1990a, 1993; Duchowny et al., 1990].
Rasmussen’s encephalitis is characterized by intractable focal motor seizures, often evolving into epilepsia partialis continua, cognitive decline, and progressive hemiparesis. Recent findings of glutamate receptor antibodies in some patients with Rasmussen’s encephalitis implicate a possible autoimmune pathophysiology [Antel and Rasmussen, 1996; Pardo et al., 2004; Rogers et al., 1994]. Although initial trials of intravenous immunoglobulin and plasmapheresis have been encouraging, long-term studies have not confirmed efficacy [Andrews et al., 1996; Hart et al., 1994; Krauss et al., 1996]. Therefore, the only definitive treatment for Rasmussen’s encephalitis remains hemispherectomy [van Empelen et al., 2004; Jonas et al., 2004].
In addition to those with the catastrophic epilepsies of infancy and childhood, all children with tumors and concomitant localization-related epilepsy should be considered for early surgical intervention. Compelling reasons for such intervention exist. Most tumors need to be biopsied or excised. Additionally, although the tumors associated with epilepsy usually are slow-growing, cortical, and well circumscribed, some tumors, especially astrocytomas, are not necessarily benign and can undergo malignant change [Jack, 1995]. Without resection, the natural history of these tumor-associated epilepsy syndromes is one of continued seizures with little hope of remission. Antiepileptic drugs produce side effects that can affect cognitive function and behaviors, with concomitant impact on psychosocial development [Meador, 2002] Examples of tumors that usually are easily resectable are the gangliogliomas and dysembryonic neuroectodermal tumors, which have a predilection for the temporal lobe (Figure 61-1) [Duchowny et al., 1992; Tice et al., 1993; Vali et al., 1993].
Children with other types of lesional symptomatic localization-related epilepsy also should be considered as epilepsy surgery candidates. Common substrates of epilepsy include encephalomalacias, vascular malformations, tubers, and malformations of cortical development [Harvey et al., 2008; Zupanc et al., 2010].
Patients who have generalized epilepsy syndromes may also be candidates for epilepsy surgery. The presence of generalized or multifocal epileptiform discharges on surface EEG monitoring should not necessarily exclude someone from epilepsy surgery. Children with generalized or multifocal epilepsy should be considered for epilepsy surgery, if data suggest an underlying focal generator for the epileptic condition [Wyllie, 1995; Wyllie et al., 2007; Zupanc et al., 2010]. Specifically, in the presence of a lesion on magnetic resonance imaging (MRI), the epilepsy syndrome is most likely to be due to a symptomatic localization-related epilepsy with rapid secondary bisynchrony. The mechanisms of underlying generalized epileptiform discharges in focal cerebral lesions can be seen as a form of “maladaptive plasticity” of the immature brain, whereby the lesions in the immature neural network of the young brain permanently alter the neural circuitry, producing spontaneous hypersynchrony and generalized discharges [Sutula, 2004]. These generalized discharges may also involve the thalamocortical network, resulting in generalized rhythmic discharges [Van Hirtum-Das et al., 2006]. Approximately 10–15 percent of children with Lennox–Gastaut syndrome, one of the most common symptomatic “generalized” epilepsy syndromes, have underlying focal malformations of cortical development and should be evaluated carefully for epilepsy surgery. In one study, children who had generalized discharges and focal lesions had identical seizure-free outcomes (72 percent seizure-free) to children with similar lesions and ipsilateral focal epileptiform discharges [Wyllie et al., 2007]. In addition, children with intractable epilepsy who have tonic-atonic seizures associated with generalized spikes/polyspikes (usually Lennox–Gastaut syndrome) and no identifiable lesion on neuroimaging may respond to a complete corpus callosotomy, a palliative treatment that can have a significant impact on quality of life [Wyllie et al., 1993; Zupanc et al., 2010]. An alternative approach is that of a multistaged epilepsy surgery, initially performing a complete corpus callosotomy, then placing lateralizing strip electrodes with the hope of identifying epileptogenic cortex that can be resected. In one study of 14 patients undergoing this approach, 9 went on to have a focal cortical resection and 5 out of 9 (56 percent) were seizure-free [Zupanc et al., 2011).
Patients with tuberous sclerosis and medically refractory, symptomatic, localization-related epilepsy should also be considered for epilepsy surgery. In patients with multiple tubers, emerging neuroimaging techniques, particularly interictal α-[11C]methyl-l-tryptophan (AMT) positron emission tomography (PET) scans, offer promise in identifying the most highly epileptogenic tuber [Asano et al., 2000; Chugani et al., 1998; Juhasz et al., 2003]. If the presurgical evaluation points to a specific tuber, studies have shown that it can be successfully removed, with a significant improvement in seizure control [Bebin et al., 1993; Koh et al., 2000; Romanelli et al., 2004]. There is also precedent for removing multiple tubers in the brain, as several tubers may be producing medically refractory seizures [Weiner et al., 2006].
In summary, factors that favor early intervention with epilepsy surgery include the following:
Even if the lesion is outside the temporal lobe, in carefully selected patients, epilepsy surgery can generally be performed with little risk of neurologic sequelae and a high rate of surgical success [Britton et al., 1994; Cascino et al., 1990, 1992, 1993, 1994; Montes et al., 1995; Paolicchi et al., 2000; Zupanc et al., 2010].
The suspected central nervous system pathology, based on MRI, may also have an impact on whether or not a patient is an epilepsy surgery candidate. For example, patients with low-grade tumors, infarctions, and mesial temporal sclerosis are likely to undergo remission of their epilepsy and typically have an excellent seizure-free outcome. If the epilepsy is temporal in onset and pathologic features include associated hippocampal formation atrophy or mesial temporal sclerosis, the surgical success rate approaches 80–90 percent [Cascino et al., 1993; Sinclair et al., 2001] (Figure 61-2). Data from our own retrospective study and from the work of Palmini and co-workers suggest that malformations of cortical development, no matter where the cortical location, carry a significant risk for status epilepticus and intractability [Laoprasert et al., 1997; Palmini et al., 1997]. Epilepsy surgery in patients with underlying malformations of cortical development have a lower seizure-free outcome, but it is still close to 60 percent, which is significantly better than additional trials of antiepileptic medication. Patients with mild malformations of cortical development, such as focal cortical dysplasia (FCD) type 1a, fared better than patients with more severe malformations of cortical development, such as FCD type 2a [Fauser et al., 2004]. In addition, the patients with known central nervous system lesions can be identified early, with detailed MR imaging.
Preoperative Evaluation
Techniques and Technologies
Seizure Semiology
Seizure semiology can provide insightful clues to the lateralization and localization of the underlying epileptogenic focus. The presence of versive head movements, unilateral motor clonic activity, and eye deviation may constitute critical lateralizing information. Specifically, versive head movements indicate that the epileptogenic zone resides in the contralateral hemisphere. In similar fashion, seizures consisting of olfactory or gustatory hallucinations, followed by complex motor automatisms and staring unresponsively, are virtually diagnostic of involvement of the temporal lobe. These seizures generally are seen in older children or adolescents, but also may occur in younger children. It should be noted, however, that seizures emanating from the temporal lobe in infants and young children commonly are associated with behavioral arrest, motor dystonic posturing, and fewer automatisms [Brockhaus and Elger, 1995; Jayakar and Duchowny, 1990; Wyllie et al., 1993]. Additionally, young children are typically incapable of describing the premonitory symptoms before the onset of the more overt clinical seizure. Video EEG monitoring has been helpful in fully elucidating the seizure semiology in these patients. Children with infantile spasms may have partial seizures before, during, or after the onset of the infantile spasms [Kobayashi et al., 2001; Watanabe et al., 2001]. Partial seizures can be a helpful clue that prompts the epileptologist to screen carefully for an underlying focal abnormality, such as a tuber or focal cortical dysplasia.
Electroencephalography
In the adult preoperative evaluation, prolonged video EEG monitoring provides the baseline data with which all of the other data are compared. In children, however, it is becoming increasingly clear that the surface EEG data may be poorly localized and at times misleading in the preoperative evaluation [Wyllie, 1995]. Therefore, this modality may be less important in localizing the epileptogenic focus. In these children, other modalities, particularly neuroimaging studies (MRI, MR spectroscopy, PET, and SPECT), may provide the pivotal information that determines the location of the epileptogenic zone and may reduce the need for invasive subdural EEG monitoring. Indeed, in the near future, the improvement of noninvasive functional brain imaging techniques may obviate the need for invasive EEG monitoring. Even now, invasive EEG monitoring may be deferred if surface EEG monitoring and MRI data are congruent [Wyllie et al., 1998; Zupanc et al., 2010].
Magnetic Resonance Imaging
MRI scans have greatly enhanced the ability to visualize intraparenchymal brain structures. The linkage between intracranial abnormalities and epilepsy is well accepted [Zupanc, 1997a]. The mechanism(s) involved in the production of epilepsy is an area of intense research and involves structural changes, synaptic reorganization, stimulation of mossy fibers, astroglial proliferation with neuronal cell loss, and neurotransmitter or corresponding receptor changes. With the recent advances in MRI technology, the ability to identify the substrates of epilepsy has been greatly enhanced. This modality provides some of the most sensitive and specific neuroimaging data for localization of the epileptogenic zone [Brooks et al., 1990; Cascino, 1994; Cascino et al., 1989, 1991; Kuzniecky et al., 1993a, 1993c; Madan and Grant, 2009]. The following new technologies are exciting and innovative [Jack, 1995; Madan and Grant, 2009]:
Use of thin contiguous cuts of 1.5–1.6 mm in multiple sections of the cortex, in combination with a three-dimensional volumetric pulse sequence, provides the necessary resolution to detect small lesions that would be missed with conventional MRI scans. Specific areas can be targeted, and images can be reformatted to correct for head rotation and other perturbations in data collection. This technique has allowed detection of even small amounts of unilateral hippocampal atrophy (see Figure 61-2), as well as identification of small areas of focal cortical dysplasia.
The fluid-attenuated inversion recovery imaging (FLAIR) technique highlights lesions such as mesial temporal sclerosis and malformations of cortical development and allows detection of previously unidentifiable small lesions. This sequence produces a T2-weighted image that subtracts the cerebrospinal fluid signal (white and bright on T2), but keeps the T2 signal from intraparenchymal structures (Figure 61-3 and Figure 61-4).
Diffusion tensor imaging is an MRI imaging technique that can identify white-matter tracts [Rugg-Gunn et al., 2001] that may be disrupted in areas of cortical dysplasia.
Multichannel coils (32 phased array and beyond and higher field strengths (3 Tesla, 7 Tesla, and greater), coupled with newer imaging sequences, including arterial spin labeling (ASL) and susceptibility weighted imaging (SWI), as well as diffusion tensor imaging (DTI/DSI), are likely to increase our detection of focal cortical dysplasias [Madan and Grant, 2009].
Fig. 61-3 MRI scans from a patient with focal cortical dysplasia of the posterior left parasagittal region.
With use of these techniques, MRI scans can identify many substrates of epilepsy, including malformations of cortical development, tumors, vascular malformations, and encephalomalacias secondary to trauma, infection, and infarction. Malformations of cortical development are increasingly recognized as being highly epileptogenic [Kuzniecky and Ruben, 1995; Kuzniecky and Barkovich, 2001; Palmini et al., 1995; Raymond et al., 1995]. Advances in MRI technology have greatly improved the ability to identify these abnormalities. They may account for more than 60 percent of the intractable localization-related epilepsies of childhood [Kuzniecky et al., 1993c]. These malformations can be small and difficult to detect, even with sophisticated MRI scans of the brain, or can be widespread and diffuse, as with lissencephaly [Dobyns and Truwit, 1995; Dobyns et al., 1996] (Figure 61-5 and Figure 61-6). The unilateral and focal malformations of cortical development are most often targeted for surgical excision. Clinically, information on the natural history of the malformations of cortical development is emerging. Status epilepticus is a common initial presentation, usually in the latter half of the first decade of life [Laoprasert and Zupanc, 1997]. Many of the malformations of cortical development produce an epilepsy syndrome that is intractable to medical management [Palmini et al., 1997].
Fig. 61-6 MRI scan from a patient with unilateral perisylvian dysplasia with polymicrogyria (left hemisphere).
Finally, although mesial temporal sclerosis and hippocampal atrophy are not commonly found in children with intractable epilepsy who are younger than 10 years of age, identification of these abnormalities is a powerful indicator of the zone of epileptogenesis [Cascino, 1994; Cascino et al., 1991; Jack, 1995; Swartz et al., 1992]. The pathophysiology of mesial temporal sclerosis and hippocampal formation atrophy is poorly understood. Do the seizures themselves cause mesial temporal sclerosis and hippocampal formation atrophy? Does an underlying malformation of cortical development cause the initial seizures, ultimately resulting in mesial temporal sclerosis and hippocampal formation atrophy [Cendes et al., 1993; Kuks et al., 1993; Trenerry et al., 1993]? Prolonged febrile seizures, head injury, nonfebrile status epilepticus, encephalitis, hypertensive encephalopathy, and viruses, including human herpesvirus 6 (HHV6), have also been implicated as potential causes of mesial temporal sclerosis [Scott et al., 2001; Solinas et al., 2003; Donati et al., 2003; Theodore et al., 2008]. These questions have not yet been clearly answered. It is known, however, that the degree of volume loss correlates with the amount of cellular loss, as measured in pathologic specimens [Cascino et al., 1991]. The neuronal cell loss, coupled with the presence of aberrant mossy fibers, and synaptic reorganization and excessive glutamatergic activity, probably accounts for the recurrent, recalcitrant seizures [Fuerst et al., 2003; Holmes and Ben-Ari, 1998; Jokeit et al., 1999; Kalviainen et al., 1998; Kotloski et al., 2002; Sutula et al., 1988, 1989; Tasch et al., 1999; Eid et al., 2008].
Co-registration of scalp EEG and MRI data has become an important tool in the determination of source localization relative to the patient’s brain anatomy [Lamm et al., 2001]. This technique provides a three-dimensional rendition of the topographic EEG activity on to the patient’s head, taking into consideration anatomical differences specific to the patient. More recently, co-registration of the intracranial EEG and MRI data has provided the epileptologist and neurosurgeon with a three-dimensional map of electrode placement used to define the epileptogenic zone, and hence, the boundaries of surgical resection [LaViolette et al., 2011] (Figure 61-7).
Single-Photon Emission Computed Tomography
SPECT also has enhanced the ability to identify the epileptogenic zone. Penfield and colleagues observed relative hyperperfusion in the epileptogenic zone during a seizure [Penfield, 1958]. Interictally, blood flow and metabolism decrease. SPECT scan technology enables quantification of cerebral blood flow and identification of areas of relative blood flow change. SPECT images are reconstructed from data obtained by recording photon emissions from radiotracers injected intravenously. These radiotracers rapidly cross the blood–brain barrier because of their lipophilic nature and bind within minutes to the brain, producing an instantaneous picture of cerebral blood flow [English and Brown, 1990]. Clinical research has focused on both interictal and ictal SPECT scans, with a substantial portion of the clinical research using the radioisotope 99mtechnetium-hexamethylpropyleneamine oxime (99mTc-HMPAO) [Cross et al., 1995, 1997; Harvey et al., 1993a, b]. More recently, 99mTc ethyl cysteinate dimer (ECD) (i.e., 99mTc-N,N′(1,2-ethylenediyl)bis-l-cysteine diethyl ester), prepared as technetium 99mTc bicisate (Neurolite), has been introduced [Lanceman et al., 1997]. Logistically, Neurolite provides distinct advantages for ictal SPECT scans because it is a stable isotope tracer that can be mixed well ahead of the time of injection, as opposed to 99mTc-HMPAO, which decomposes quickly in vitro and must be used less than 30 minutes after it is reconstituted. For ictal SPECT scans, a technologist or nurse trained in the delivery of these radioisotopes can sit at the bedside and deliver the Neurolite within seconds after the onset of a seizure. Spatial resolution with SPECT scans also has improved because of the development of gamma cameras with multiple detectors that provide more data points, with subsequent enhanced sensitivity.
Interictal SPECT scans have been used for longer than 10 years as a method of identifying the epileptogenic focus in patients with medically intractable localization-related epilepsy who are candidates for epilepsy surgery. With interictal SPECT scans, the epileptogenic zone can be identified by a regional area of reduced cerebral blood flow [Adams et al., 1992; Berkovic et al., 1992, 1993; Cordes et al., 1990; Coubes et al., 1993; Denays et al., 1988; Dietrich et al., 1991; Grunwald et al., 1991; Hajek et al., 1991; Kuzniecky et al., 1993b; Lamanna et al., 1989; Launes et al., 1992; Lee et al., 1988; Rowe et al., 1989, 1991; Ryding et al., 1988; Ryvlin et al., 1992; Shen et al., 1990; Verhoeff et al., 1992]. Clinical research clearly indicates that interictal studies alone have a relatively low sensitivity for identification of the epileptogenic focus in adults with temporal lobe epilepsy and even lower sensitivity with extratemporal epilepsy. Data pooled from several studies yield estimates of interictal SPECT sensitivity of 66 percent for temporal lobe epilepsy and 60 percent for extratemporal epilepsy localized by EEG [Spencer, 1994; Knowlton, 2006].
Ictal SPECT scan data, however, have proved valuable with respect to localization of the epileptogenic focus. Ictal SPECT scans typically reveal an area of regional hyperperfusion that corresponds to the underlying epileptogenic focus, as verified by surgical pathology and surface EEG localization [Bauer et al., 1989; Grunwald et al., 1991; Ho et al., 1994; Hwang et al., 1990; Katz et al., 1990; Lee et al., 1988; Marks et al., 1992; Newton et al., 1992b; Rowe et al., 1989, 1991; Shen et al., 1990; Stefan et al., 1990]. Using data pooled from several centers, the sensitivity of ictal SPECT (as judged by EEG correlation) has been estimated at 90 percent for temporal and 81 percent for extratemporal epilepsy, with specificity at 77 percent and 93 percent, respectively [Spencer, 1994; Knowlton, 2006]. Critical to the efficacy of the ictal SPECT scan is the timing of the injection. If the injection can be given within 30 seconds of the seizure onset, the isotope remains localized and can “capture” the epileptogenic focus or generator before the epileptogenic discharge spreads [Newton et al., 1995]. If the seizure propagation is rapid, ictal injections are less sensitive and unreliable.
Comparison of ictal and interictal scans also is important in determining whether any abnormality in blood flow is significant. With the assistance of computerized technology and surface matching techniques, co-registration of the ictal SPECT scan to the volumetric MRI scan has demonstrated a close relationship between the region of ictal hyperperfusion and MRI structural lesions [Hogan et al., 1996; Mountz et al., 1994]. A technique has been developed whereby the ictal and interictal SPECT scan data are co-registered with one another and the interictal image is subtracted from the ictal image, producing the area of true ictal hyperperfusion [Zubal et al., 1995]. This difference image, called a subtraction SPECT scan, is then co-registered with a three-dimensional representation of the MRI scan. In nonlesional extratemporal epilepsy, this information has been proven to be especially helpful in either guiding placement for subdural invasive EEG monitoring or obviating the need for invasive monitoring altogether. Several studies have demonstrated that peri-ictal subtraction SPECT provides useful information for seizure localization in patients with focal malformations of cortical development, even when the MRI study is nonlocalizing (i.e., “nonlesional”) [O’Brien et al., 1998, 2000, 2004; Tan et al., 2008]. In a large series involving pediatric and adult epilepsy patients, if the site of the surgical resection was concordant with the subtraction SPECT localization (using SISCOM technology, a Mayo Clinic-patented computer program that performs subtraction SPECT and then co-registers the results to a volumetric MRI scan of the brain), postoperative seizure frequency scores were significantly lower and postoperative improvement was greater [O’Brien et al., 1998] (Figure 61-8). A recent multicenter study further confirmed the incremental benefit of the SISCOM technology over traditional side-by-side comparison in the presurgical evaluation, particularly in patients with extratemporal lobe epilepsy [Matsuda et al., 2009].
Positron Emission Tomography
PET is another imaging modality used for localization of the epileptogenic focus [Mohan et al., 1999]. It uses radiotracers labeled with specific positron-emitting isotopes (11C, 15O, and 18F) to measure a variety of biochemical brain functions. With the aid of computerized technology and mathematical modeling, the source and concentration of the emission are either qualitatively or quantitatively plotted on a three-dimensional representation of the brain. Cerebral glucose metabolism is the most commonly measured parameter, using 18F-fluorodeoxyglucose (FDG) (Figure 61-9). Other tracers also can be used to measure cerebral blood flow, benzodiazepine and opiate receptors, pH, serotonin metabolism, and amino acid transport [Henry et al., 1993; Mohan et al., 1999; Shah et al., 1995].
FDG PET images are averaged over a 40-minute time interval, suggesting the limited value of this technique for ictal studies. The interictal images, on the other hand, are highly sensitive in complex partial seizures emanating from the temporal lobe. In several studies in adult patients with medically refractory epilepsy of temporal lobe origin, glucose hypometabolism in the temporal lobe correlated highly with localized ictal EEGs and MRI abnormalities in this region [Abou-Khali et al., 1987; Chugani et al., 1990b; Coubes et al., 1993; Debets et al., 1990; Engel et al., 1982; Hajek et al., 1993; Henry et al., 1993; Leiderman et al., 1992; Radtke et al., 1993; Sackellares et al., 1990; Stefan et al., 1987, 1990; Swartz et al., 1992; Theodore et al., 1986, 1990; Valk et al., 1993]. Glucose hypometabolism in the temporal lobe, as obtained on interictal FDG PET scan, has been found to have an overall sensitivity of 84 percent and a specificity of 86 percent [Spencer, 1994; Knowlton, 2006].
In a study by Theodore et al. [1997], the presence of temporal lobe glucose hypometabolism in the presence of a nonlocalizing surface ictal EEG predicted successful outcome with temporal lobectomy. Localization to the temporal lobe was confirmed with invasive EEG monitoring but the authors make the point that invasive EEG monitoring may be unnecessary and may even provide false localizing information in some patients being evaluated for epilepsy surgery. As technology improves, concordance of noninvasive neuroimaging techniques may be all that is necessary before proceeding with the surgery.
Analysis of nonlesional extratemporal epilepsy in adult patients undergoing PET scans has provided data that have been less definitive [Chugani et al., 1990a; Sackellares et al., 1990; Stefan et al., 1990]. In one recent analysis, the sensitivity and specificity of FDG PET scans decreased to 40 percent in MRI-negative extratemporal cases [Yun et al., 2006]. In children with refractory epilepsy, however, with poor localization on surface EEG and negative findings on MRI scans of the brain, FDG PET scans may still provide useful information in identifying an underlying epileptogenic focus. Specifically, University of California at Los Angeles investigators were the first to recognize a small subset of children with intractable infantile spasms and underlying deficits of focal glucose metabolism [Chugani et al., 1988, 1990a; Olson et al., 1990]. These deficits usually were temporal-parietal-occipital in origin. Many of these patients had partial seizures before, during, or after the onset of their infantile spasms, often providing a clue to localization. Additionally, interictal surface EEG examined retrospectively often disclosed focal delta slowing or an asymmetry in beta activity. Large cortical resections of the underlying epileptogenic zone were performed, guided by PET scan data and electrocorticography. After surgery, the seizures (infantile spasms and/or partial seizures) disappeared. Results indicate, not only that seizure control improved, but also that these patients’ development improved at a faster rate and to a greater degree than would have been predicted without surgery [Asarnow et al., 1997; Chugani et al., 1988].
Newer ligands also have been developed. In flumazenil PET scans, the flumazenil binds to benzodiazepine receptors [Juhasz et al., 1999; Mohan et al., 1999]. In the area of the epileptogenic zone, benzodiazepine binding appears to be decreased. In one clinical study, the flumazenil PET scan demonstrated a more restricted area of decreased binding than was apparent on the FDG PET scan; the resection of this cortical region was associated with good surgical outcome [Juhasz et al., 2000]. In addition, diffuse cortical abnormalities on flumazenil PET scans predict poor seizure control following epilepsy surgery [Juhasz et al., 2001].
C-alphamethyl-l-tryptophan (AMT) PET scans also have been studied. AMT is an analog of trytophan and a precursor for serotonin synthesis [Chugani et al., 1998; Juhasz et al., 2003]. Data suggest that the AMT PET scans may be useful in identifying the most epileptogenic tuber in patients with tuberous sclerosis, multiple tubers, and medically intractable epilepsy. Concordance of the epileptogenic tuber with increased AMT uptake has been observed in PET scans [Asano et al., 2000; Chugani et al., 1998, Chugani and Muzik, 2000]. In addition, AMT PET scans may also be helpful in reevaluating patients in whom epilepsy surgery has failed to improve seizure control. In the patients studied with AMT PET, the area of increased AMT binding correlated closely with the epileptogenic zone [Juhasz et al., 2004].
Magnetic Resonance Spectroscopy
MR spectroscopy has been used in the study of patients with intractable epilepsy [Kuzniecky et al., 1992; Laxer et al., 1992; Matthews et al., 1990; Novotny, 1995; Connelly et al., 1994]. Specifically, phosphorus MR spectroscopy measures phospholipid metabolism. In the region of the epileptogenic focus, investigators have found abnormal phosphocreatine to inorganic phosphate ratios. Phosphocreatine (Pcr), intracellular pH, and inorganic phosphorus (Pi) increase during a seizure. The adenosine triphosphate concentration, however, only decreases slightly [Duncan, 1997; Prichard, 1994]. Proton MR spectroscopy can also measure regional abnormalities in lactate, N-acetyl-aspartate (NAA), creatine (Cr), and choline (Cho). Lactate levels increase during a seizure and remain elevated for several hours. Data also indicate reductions in the NAA/Cho and NAA/Cr ratios in the region of the epileptogenic zone, presumed to reflect neuronal loss and reactive astrocytosis [Petroff et al., 1984, 1986; Prichard, 1994]. Therefore, abnormal NAA/Cr and NAA/Cho ratios may serve as indices of regional cellular pathology. MR spectroscopy holds promise as an important adjunctive noninvasive technique for assisting with the identification of the underlying epileptogenic zone.
Magnetoencephalography
MEG is another technology that has been developed to improve the ability to identify epileptogenic foci. It measures tiny magnetic fields in the brain that are created by the electrical activity of the brain. Most institutions are using 128-channel MEG technology to enhance resolution. MEG offers several advantages over EEG. First, the magnetic fields are not attenuated by the skull, scalp, and skin, as are electrical potentials. Therefore, the MEG signal contains fewer distortions or changes [Barth, 1993]. Second, MEG is a monopolar measure and does not require a dipolar montage, eliminating the possibility of artifact associated with an “active reference.” Third, MEG provides high temporal resolution, which can be useful in determining the functional activity of different brain areas (i.e., motor cortex) or propagation of seizure activity. Finally, and of greatest importance, MEG measures postsynaptic intracellular currents in the dendrites of neurons situated tangentially to the skull, whereas the EEG measures the extracellular postsynaptic ionic currents [Tovar-Spinoza et al., 2008; Barth, 1993; Barth et al., 1984].
Clinical research suggests that, although surface interictal EEG spike recordings may indicate multifocal activity, MEG can more precisely localize the underlying epileptogenic focus [Barth, 1993; Stefan et al., 2003; Sutherling et al., 1988; Wheless et al., 1999]. In this regard, MEG provides complementary data to EEG and there is a growing belief that combined MEG/EEG data should be used routinely in the presurgical evaluation of patients with intractable epilepsy [Funke et al., 2009]. MEG has provided pivotal information and may become the most precise way of identifying the size, location, and dipole orientation of the epileptogenic zone [Minassian et al., 1999; Stefan et al., 2003; Wheless et al., 1999, 2004]. In particular, there is widespread agreement that MEG provides the best tool to distinguish a temporal from an extratemporal epileptogenic zone [Funke et al., 2009]. In fact, MEG has been employed in children with intractable epilepsy to provide spatial information to be used in planning the excision area [Iida et al., 2005]. MEG spike source clusters have been used to indicate the epileptogenic zone [Iida et al., 2005]. Figure 61-10 demonstrates simultaneously recorded MEG and EEG data obtained at our center and used to map the epileptogenic focus of a child with frontal lobe epilepsy. As shown in Figure 61-10A and B, a left frontal MEG spike is observed while the EEG demonstrates theta range activity without clear epileptiform activity. Figure 61-10C demonstrates the distributed source estimates for the MEG data displayed on a representation of the cortical surface reconstructed from MRI data from the same patient. Note the basomesial frontal location of the epileptogenic zone, which would have been difficult to observe on scalp EEG. In addition, MEG may be a very useful tool in children with respect to functional imaging, particularly imaging language cortex [Stufflebeam et al., 2009; Tovar-Spinoza et al., 2008; Papanicolaou et al., 2004; Simos et al., 1999]. Figure 61-11A demonstrates locations of the equivalent current dipoles (ECD) for the MEG data for a visual reading task displayed in sagittal slices of an anatomical representation of the same patient’s brain as in Figure 61-10. The high temporal resolution of MEG allows for the dissociation of functional brain activity in different areas. The patient’s language was localized to the left hemisphere, based on the Wada procedure (see below). The extraordinary temporal resolution of MEG also enables us to understand the propagation patterns of interictal activity occurring over a period of 50 msec or less (Figure 61-11B)!
Fig. 61-10 Magnetoencephalography (MEG) complements EEG data in the presurgical evaluation.
(Courtesy of Dr. Sylvain Baillet, Medical College of Wisconsin, Milwaukee, Wisconsin.)
Functional Mapping
Classically, in the older child and adolescent, the sodium amytal test (Wada test) is used in the preoperative evaluation for the localization of speech and language and to determine whether memory can be supported in the contralateral hemisphere [Loring, 1997; Wyllie et al., 1990]. This test involves injecting sodium amytal into either the left or the right internal carotid artery, in an attempt to ameliorate ipsilateral hemispheric function chemically and to determine which hemisphere is “dominant” (i.e., responsible for speech and language function and, to a lesser extent, memory). It is a time-consuming test that is invasive and provides a broad but nonspecific overview of hemispheric function. Additionally, controversy continues over its interpretation and its ability to predict postoperative function, particularly with respect to memory [Loring et al., 1992; Perrine, 1994]. As an example, language is a complex function. Although speech arrest after sodium amytal injection usually is in the dominant hemisphere, this is not always the case [Loring et al., 1992]. Language involves spontaneous speech, repetition, comprehension, reading, and counting. These aspects of language are all interactive, but their corresponding cortical areas may be located in different areas of the brain, making it difficult to relegate language to one specific hemisphere or region. In younger children, the Wada test can be even more challenging and technically difficult. Obtaining full cooperation from a child requires preparation, time, and patience. If the child becomes frightened during the test, test validity becomes questionable. Two other techniques also used frequently to identify eloquent cortex (i.e., cortex controlling vital motor, language, or memory functions) are somatosensory-evoked potentials and stimulation mapping. The measurement of somatosensory-evoked potentials has the advantage of being able to be applied successfully, regardless of the state of the patient. This modality can be used in the operating room in the anesthetized patient, or in an awake and cooperative patient. Somatosensory-evoked potentials are used primarily to identify the sensorimotor cortex. Stimulation mapping involves the application of subdural electrodes followed by sequential electrical stimuli at various intensities and durations. Penfield pioneered this technique during the 1930s through the 1950s to localize language and motor functions intraoperatively, in order to avoid postoperative neurologic deficits. Subsequent investigators have used cortical stimulation preoperatively (using implanted grid electrodes) and intraoperatively to map out functional cortex, such as the sensorimotor cortex or expressive language cortex [Ojemann, 1978, 1979, 1993; Ojemann and Dodrill, 1987]. Although cortical stimulation mapping has yielded a tremendous amount of information about the localization of functions, several other emerging techniques are providing valid, noninvasive methods for mapping out functional areas of the brain. These techniques include functional MRI (fMRI) scans, MEG and magnetic source imaging, and transcranial magnetic stimulation [Binder, 1997; Detre, 2004; Knowlton and Shih, 2004; Peresson et al., 1998; Perrine, 1994; Powell et al., 2004; Sabsevitz et al., 2003; Wheless et al., 2004]. In view of the limitations of the previously described techniques for functional mapping, these noninvasive techniques, which might provide more specific and salient information, are being developed. fMRI scans are being used in a number of epilepsy centers as adjunctive techniques to define eloquent cortex [Kwong et al., 1992; Lee et al., 1996; Ogawa et al., 1992].
fMRI is based on the fact that performance of a specific act will activate the anatomically appropriate cortex in the brain. With activation, a concomitant increase in blood flow occurs, resulting in a change in the paramagnetic properties of the affected cortex. This produces a signal that can then be detected by the MRI scanner. fMRI is a technique that will be increasingly used to map out eloquent functions, such as sensorimotor cortex and speech and language centers [Logan et al., 1995, 1997, 1998; Sachs et al., 2003; O’Shaughnessy et al., 2008]. It is still not suitable for the young, uncooperative infant or child, except for fMRI of the sensorimotor cortex, which can be performed under sedation. Language and memory testing using fMRI can be utilized in cooperative older children and adolescents. In fact, clinical research has yielded increasing proof that fMRI can provide important localization data. With respect to language lateralization, fMRI language examinations, in combination with comprehensive neuropsychometric testing, can play a very important role in estimating the risk for postoperative cognitive changes and in selecting patients for invasive functional mapping procedures [Sachs et al., 2003; O’Shaughnessy et al., 2008; Liegeois et al., 2002; Hertz-Pannier et al., 1997; Stapleton et al., 1997; Anderson et al., 2006]. In the young infant and child, functional studies are less likely to alter the surgical plan because brain plasticity in these age groups makes localization less critical [Shields, 2000; Stafstrom et al., 2000; Wyllie, 1998, Liegeois et al., 2004; Kadis et al., 2007].
An example of a functional MRI scan is illustrated in Figure 61-12.
Concept of Congruence
Under ideal conditions, identification of the epileptogenic focus is made by the congruence of data obtained during the preoperative evaluation, with the precise localization based on seizure semiology, physical examination, surface ictal and interictal EEG monitoring (and, if necessary, invasive-depth electrodes or subdural electrode strips or grid), MRI scan of the brain, ictal and interictal SPECT scans, interictal PET scan, MEG, fMRI scan, and/or MR spectroscopy. Each case must be individualized, with some cases requiring the acquisition of data from all of these studies. Other cases may be resolved with a less complicated approach. At a minimum, seizure semiology, surface ictal EEG monitoring, and MRI scan of the brain should be congruent. With lesional localization-related epilepsy, the use of invasive EEG monitoring may not be necessary. Electrocorticography at the time of surgery usually can assist with identifying the dimensions of the epileptogenic zone. The sensorimotor cortex can be identified intraoperatively using motor-evoked potentials, somatosensory-evoked potentials, or direct electrical cortical stimulation mapping. In a cooperative patient, fMRI brain imaging or MEG may be able to identify the sensorimotor cortex accurately and display it on a three-dimensional volumetric MRI scan of the brain. If the surgical excision is near functional speech and language cortex, older children and adolescents usually can be cooperative enough to tolerate an awake surgical procedure. In addition, in older cooperative children and adolescents, fMRI has also been very helpful in identifying cortex involved with receptive and expressive language. In younger children (before the age of 5–6 years), brain plasticity is still adequate, so that removal of primary speech and language cortex will result in transition of these functions to the contralateral hemisphere [Peacock, 1995; Shields, 2000].
Types of Surgery
Several types of epilepsy surgery are performed in children and adults, depending on the identification of the epileptogenic focus and its location and extent [Zupanc, 1997b]. The most common surgical procedures are:
Implantation of a vagus nerve stimulator accounts for approximately 16 percent of the total number of operations, while multiple subpial transections are relatively uncommon procedures, accounting for only 0.6 percent [Harvey et al., 2008].
Temporal lobectomy is the most common epilepsy surgery performed in adolescents and adults. This procedure is almost exclusively a temporal lobectomy with amygdalohippocampectomy, because removal of the mesial temporal structures is correlated with a better surgical outcome. Often an associated abnormality or lesion, such as a tumor (dysembryoplastic neuroepithelial tumor [DNET] or ganglioglioma), mesial temporal sclerosis, hippocampal formation atrophy, or malformation of cortical development, is found to be present. The new MRI technologies have been helpful in identification of these substrates of epilepsy. Those patients with mesial temporal sclerosis or hippocampal atrophy concordant with ictal surface EEG abnormalities have an excellent prognosis for successful epilepsy surgery, with a 90 percent chance of becoming seizure-free [Duchowny et al., 1992; Falconer, 1970; Mizrahi et al., 1990]. Younger children do not commonly have mesial temporal sclerosis or hippocampal atrophy [Ng et al., 2004]. Many of the intractable epilepsies in childhood are extratemporal and nonlesional.
Extratemporal cortical resection is more commonly performed in children, often involving extensive lobar or multilobar resections. The extent of the resection is dictated primarily by the extent of the lesion: e.g., a tuberectomy in a patient with tuberous sclerosis versus a multilobar resection in a child with infantile spasms and an underlying focal cortical dysplasia involving the temporal-parietal-occipital lobes. As the ability to identify focal cortical dysplasias and the concomitant epileptogenic zone improves, epilepsy surgical outcomes also will improve. Focal cortical dysplasias are a common cause of intractable partial epilepsy in children, accounting for 60 percent of the cases [Kuzniecky and Barkovich, 2001; Kuzniecky et al., 1993c]. The best predictive factors in successful surgical outcome in focal cortical dysplasia are completeness of the resection and the presence of an identifiable lesion on MRI brain imaging [ILAE Pediatric Epilepsy Surgery Consortium data, submitted for publication].
Stereotactic lesionectomy is performed in highly selected cases in children and adults, with a reported 50–60 percent chance of rendering the patient seizure-free [Britton et al., 1994; Cascino et al., 1990, 1992, 1993, 1994]. Outcome is improved if intraoperative electrocorticography is used to remove not only the lesion, but also the surrounding “epileptogenic zone” [Jooma et al., 1995; Montes et al., 1995; Palmini et al., 1995; Pilcher et al., 1993]. To date, no prospective, controlled studies of statistically significant numbers of patients have critically compared the different operative strategies with respect to outcome [Shields, 2000; Tonini et al., 2004; Wyllie, 1998]. The surgical outcome in these patients may vary, depending on the age of the patient, the location of the lesion, and most important, the type of lesion. In a review of 47 published articles about epilepsy surgery outcome, the best predictors for seizure-free outcome included a history of febrile seizures as a child, mesial temporal sclerosis, tumors, EEG and MRI data concordance, and an extensive surgical resection [Tonini et al., 2004].
Hemispherectomy also is performed in young children [Vining et al., 1997]. The indications for this type of surgery are catastrophic epilepsies in which the substrate of epilepsy is limited to one hemisphere. Epilepsy syndromes that frequently meet these criteria include the following:
In Sturge–Weber syndrome, the pathologic features consist of unilateral leptomeningeal angiomatosis, frequently resulting in changes in the involved hemisphere with concomitant focal seizures, progressive hemiparesis, and cognitive decline [Roach et al., 1994]. Hemimegalencephaly, by definition, is a malformation of cortical development involving one hemisphere, and is characterized by general disorganization and overgrowth of the neuronal tissue. Early hemispherectomy, particularly if the EEG reveals unilateral discharges, can significantly alter the prognosis in affected children [Andermann et al., 1993; Vigevano et al., 1989; Vigevano and DiRocco, 1990]. With Rasmussen’s encephalitis, children have intractable focal seizures, often progressing to epilepsia partialis continua, accompanied by progressive hemiparesis and cognitive decline. Although debate is on-going about the pathophysiology (autoimmune versus infectious), the only long-term successful treatment has been hemispherectomy [Antel and Rasmussen, 1996].
Multiple subpial transection is a newer surgical technique that is used when the epileptogenic zone overlies an area of functional cortex. Multiple subpial transection involves the disruption of connecting horizontal fibers, rather than resection of actual tissue [Blount et al., 2004; Devinsky et al., 2003; Schramm et al., 2002; Spencer et al., 2002]. This technique has been used in the treatment of Landau–Kleffner syndrome [Morrell et al., 1995]. Children with this syndrome have an acquired epileptic aphasia, often intractable to medication. The multiple subpial transection technique has been used over the area deemed to be the epileptogenic zone on electrocorticography. Although good surgical results have been reported, the technique remains controversial. Multiple subpial transection also is being used in areas involving functional cortex. Data indicate that, although multiple subpial transection may be an appropriate adjunctive surgical technique, it will not eliminate seizures if the primary epileptogenic focus is not completely removed [Hufnagel et al., 1997; Spencer et al., 2002].
A complete corpus callosotomy is a palliative surgery that can reduce the seizure burden in carefully selected patients. It most commonly is used in children with Lennox–Gastaut syndrome, with the goal being reduction of tonic and atonic seizures. It can be highly effective [Carson, 2000; Maehara and Shimizu, 2001; McInerney et al., 1999; Sassower et al., 2001; Sorenson et al., 1997; Wyler, 1993]. It is now known that sectioning of the anterior two-thirds corpus callosotomy is rarely effective in controlling seizures long-term. The use of a complete corpus callosotomy, coupled with lateralizing strips, has been demonstrated to be very effective in identifying an epileptogenic zone as part of a multistage surgery [Zupanc et al., 2011].
Goals of Surgery
With use of innovative, noninvasive technologies, the ability of the clinician to identify the underlying epileptogenic zone has improved. In patients with medically intractable epilepsy, this ability allows one of the principal goals of epilepsy surgery to be achieved – that is, the elimination of seizures. The goals of epilepsy surgery, however, may vary, depending on the epilepsy syndrome, the underlying pathophysiology, the cognitive and developmental status of the child or adolescent, and the identification and location of an epileptogenic zone [Taylor et al., 1997]. Specifically, if a cognitively normal patient has temporal lobe epilepsy, as documented by congruence of seizure semiology and EEG and MRI data, the goals of epilepsy surgery are clear: elimination of seizures and improvement in psychosocial, behavioral, emotional, and family functioning without significant loss of cognitive abilities. On the other hand, a cognitively impaired patient with an extensive bilateral malformation of cortical development might be considered for a corpus callosotomy. In this case, the primary goals of epilepsy surgery would be palliative, with the reduction of seizures and possible improvement in cognitive and behavioral functions. Although improvement in cognition, development, and behavior usually is achieved by virtue of decreased seizure frequency and reduction of antiepileptic drug doses, such results are not always obtained, and outcomes will vary with each patient, depending on the epilepsy syndrome and the identified etiology for the epilepsy. The goals of epilepsy surgery and potential limitations of the results of surgery need to be discussed openly with the family before any decision is made.
In patients with malformations of cortical development (in children, typically extratemporal), epilepsy surgery usually has involved lobar or multilobar resections, as well as hemispherectomies. Approximately 60–65 percent of these patients are seizure-free after surgery, and a majority achieves a significant reduction in seizure burden [Shields, 2000; Wyllie, 1998; Zupanc et al., 2010]. At critical stages of development, this reduction in seizure burden is associated with an improvement in development that appears to be sustained. In patients with malformations of cortical development and medically refractory epilepsy who undergo surgical resection, withdrawal of antiepileptic medication is rarely successful. The cortical dysplasia often is very extensive, involving multiple lobes. On the other hand, children with lesions such as mesial temporal sclerosis, low-grade tumors, or middle cerebral artery infarctions can achieve seizure-free status, with eventual discontinuation of antiepileptic medication.
Deep Brain Stimulation
Deep brain stimulation has been known to be effective in the treatment of movement disorders for years. However, there is increasing interest in deep brain stimulation in the treatment of epilepsy [Kahane and Depaulis, 2010]. Several neurology and neurosurgical groups have applied this technique in the treatment of pharmacoresistant epilepsy. Recently, the SANTE study group has published their results. This was a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. The stimulation of the anterior nucleus of the thalamus was chosen because it projects to both the superior frontal and the temporal lobe structures commonly involved in epileptic seizures, produces discrete EEG changes, and inhibits chemically induced seizures in animal models. In this study, which involved adult patients only, with localization-related epilepsy, bilateral stimulation of the anterior nuclei of the thalamus significantly reduced seizure frequency. Specifically, by 2 years, there was a 56 percent median reduction in seizure frequency; 54 percent of patients had a seizure reduction of at least 50 percent. Fourteen patients were seizure-free for over 6 months [Fischer et al., 2010].
In addition to the anterior nucleus, the centromedian nucleus has also been the subject of both clinical and experimental interest. This nucleus is part of the reticulothalamocortical system, which modulates cortical excitability. There have been several studies that have documented significant improvement in seizure control, particularly in patients with generalized tonic-clonic seizures and atypical absence seizures found in Lennox–Gastaut syndrome [Velasco et al., 1997, 2006; Cukiert et al., 2009].
Research Issues: Trends for the Future
What are the age-specific developmental mechanisms in childhood epilepsy? Can they be targeted for the development of new and more effective antiepileptic drugs or surgical therapy?
Future trends for exploration will involve several avenues of research: source localization and predictive EEG patterns for identification of the epileptogenic zone [Smart et al., 2004; Worrell et al., 2004]; implantable devices that can detect predictive EEG patterns before a clinical seizure and deliver either an abortive dose of antiepileptic medication or an abortive electrical stimulus; deep brain cortical-thalamic stimulation to diminish seizure frequency in those patients with subcortical-cortical epileptogenic networks (intractable nonlesional, generalized epilepsy syndromes); and, finally, “designer” antiepileptic drugs targeting specific mechanisms of epilepsy – most likely sodium, potassium, calcium, and Gamma-aminobutyric acid (GABA) channels – to be delivered locally or systemically.
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The complete list of references for this chapter is available online at www.expertconsult.com.
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