Special Considerations for Pediatric Epilepsy Surgery

Michael S. Duchowny

J. Helen Cross

Gary W. Mathern

Introduction

The surgical treatment of pharmacoresistant partial seizures in children has come into its own as a primary therapeutic option. Several factors have contributed to this important trend. First, an increasing body of information concerning the natural evolution of many clearly defined pediatric epilepsy syndromes suggests that early definitive surgical intervention is the most effective and perhaps the only way to completely eliminate seizures. Second, chronic epilepsy is now understood to be a progressive disorder with deleterious consequences for cognition, behavior, and socialization. Finally, evidence is now emerging that surgically induced seizure freedom may have positive and lasting benefits on the quality of a child’s life and improve overall family functioning. This chapter reviews key elements of the evaluation of pediatric patients for epilepsy surgery, special aspects of the surgical procedures, and the outcome of epilepsy surgery.

Preoperative Evaluation

Ictal Semiology

The presurgical evaluation of children with medically resistant seizures must accurately assess the nuances of ictal semiology in the developing brain. The manifestations of partial seizures in very young patients often differ considerably from those in adolescents and adults. For example, complicated behavioral disturbances, auras, and other sensory alterations are decidedly unusual in young children.⁵⁷ Automatisms in the infant are typically primitive, consisting of simple sucking or chewing movements or simple gestures.¹⁰ There is also an enhanced tendency for partial seizures to secondarily generalize in infants and toddlers, not uncommonly almost immediately after seizure onset. In contrast, complex partial seizures with pure loss of awareness are less common in children and rare in infants. Similarly, formed hallucinations and illusions are uncommon, suggesting that limbic-cortical networks have not fully matured.⁵²

Video/electroencephalographic (EEG) analysis of seizure patterns in children reveals that certain ictal seizure manifestations consistently lateralize seizure onset throughout childhood, whereas others have lateralizing value only at the end of the first decade.³⁴ Unilateral tonic or clonic seizures, Todd paralysis, nystagmus, and postictal nose wiping lateralized seizure onset in children of all ages. In contrast, unilateral manual automatism, dystonic posturing, version, postictal dysphasia, and postictal facial wiping occur more frequently in older children. Thus, older children have a greater tendency to manifest lateralizing seizure semiologies, which suggests that the evolution of seizure manifestations in childhood occurs in step with increasing brain maturation.

Infants constitute a particularly challenging population to evaluate for surgery because their ictal manifestations may be subtle or nonlateralizing. Attempts to classify seizures in infants according to International League Against Epilepsy (ILAE) criteria are often difficult.⁸⁵ Automatisms are typically brief and simplified in appearance. Head version, a classical lateralizing finding in adults with partial epilepsy, may be less forceful and sustained and less likely to have true lateralizing value.¹ Whereas focal motor seizures are reliably contralateral to the hemisphere of seizure onset, hypomotor patterns are common in childhood and more likely to be accompanied by generalized EEG discharges.⁴⁵ Hypomotor seizures associated with regional EEG onsets are usually of longer duration and begin in the temporal or parietal lobes.⁶² Epileptic spasms are particularly frequent in infants with intractable epilepsy. They are more often observed in the context of generalized syndromes but may also accompany localization-related epilepsy syndromes.²⁴

Electroencephalogram

The EEG evaluation continues to be the cornerstone of the pediatric evaluation for epilepsy surgery. The identification of a discrete focus of seizure origin greatly simplifies surgical planning and increases the likelihood of seizure freedom. In a study of the value of preoperative scalp EEG in 47 children who had focal resections for intractable epilepsy, Vossler et al.⁹⁷ found that children with a single interictal focus (or a single focus with rare discordant discharges) or who demonstrated unilateral well-localized or lateralized seizure onsets in serial routine scalp EEG recordings obtained high rates of seizure relief. Localized EEG findings are especially useful when they converge to the same anatomic location represented in other diagnostic modalities such as anatomic or functional imaging.

Pediatric long-term monitoring units use recording equipment similar to that in adult units. Higher overall activity level in children, however, requires certain modifications in the recording protocol. More frequent periods of physical activity may be necessary to ensure completion of the monitoring. Frequent assessment of electrode contact and integrity of the recording system will prevent excessive movement artifact. For infants and toddlers, replacing the metal side rails of the hospital crib with a sheet of clear Plexiglas assists in viewing video-recorded seizures.

Satisfactory localization of the primary epileptogenic zone is more often achieved in adults who are more likely to have temporal lobe epilepsy and hippocampal sclerosis (HS) as the underlying pathologic substrate. The detection of HS is now
routine using high-field-strength magnetic resonance imaging (MRI) magnets, and the scalp EEG is then viewed as a confirmatory tool in preparation for temporal lobectomy. Even the necessity of long-term monitoring in adult patients has been questioned at some centers because MRI evidence of HS in conjunction with the ictal semiology is deemed sufficient for establishing the diagnosis of the temporal lobe syndrome.

In contrast, medically resistant localization-related seizures in children are less often anatomically and functionally specific. Developmental anomalies of the cerebral cortex are particularly prevalent in children referred for surgical evaluation and arise throughout the cortical mantle.²⁷^,¹⁰⁰ Although a certain proportion of children have discrete lesions that are amenable to resection, multiple or poorly defined epileptogenic regions are common. Despite advanced neuroimaging techniques, there remain a significant proportion of children with cryptogenic seizures with normal imaging.

Even seizures arising in the temporal lobe pose a significant challenge in the child. Early-onset temporal lobe seizures are often neocortical in origin, and HS typically occurs as “dual pathology” with cortical dysplasia rather than as an isolated lesion. In these situations, the spike field may be less well defined on scalp EEG recording. Additional electrodes such as sphenoidal or nasopharyngeal recording are unlikely to yield definitive localizing data and are rarely employed at pediatric centers.

Magnetoencephalography (MEG) has recently been advocated for localizing seizure origin in pediatric epilepsy surgery candidates. In an MEG study of 11 children undergoing evaluation for intractable, nonlesional, extratemporal localization-related epilepsy, 10 demonstrated anatomic localization of epileptiform discharges that corresponded to the ictal onset zone established by intracranial EEG recording.⁸⁰ Three-dimensional magnetic source imaging (MSI) data has been successfully interfaced with neuronavigation in pediatric patients.⁵³ Ictal MEG identification of epileptic foci has also been correlated with zones of hyperperfusion on ictal SPECT studies.¹⁰³

Invasive Recording

The limitations of the scalp-recorded EEG and the higher proportion of cryptogenic cases in childhood have led to the use of invasive EEG recording in many children. Depth electrodes record very few data points and are employed primarily in adults with temporal lobe epilepsy where targeted recording from mesial temporal structures provides adequate localization. Children with neocortical epilepsy are less likely to benefit from depth electrodes due to their limited ability to monitor widespread convexity and basal cortical surfaces. The pediatric epilepsy surgical evaluation therefore relies more on subdural electrodes accurately to localize seizure origin and functionally map the neocortex. Subdural electrodes accurately localize seizure origin while maintaining an acceptably low complication rate, even in very young children and infants.²⁹^,¹⁰¹

Potential indications for implanting subdural electrodes in children include the following:

Normal or nonlocalizing neuroimaging. Without accurate localizing information, it is often difficult precisely to define a surgical target. Electrocorticography has been advocated for defining the epileptogenic zone but is often inadequate. Intraoperative recording under general anesthesia provides only limited interictal data. Furthermore, cortical malformations often present with diffuse borders that are not easily characterized. In a series of 53 children undergoing excisional procedures for intractable epilepsy, seizure freedom was achieved in 70% of patients who had complete resections. In contrast, only 10% became seizure free when the resection was incomplete, typically due to critical cortex precluding complete removal of the epileptogenic region.⁵⁸
Widespread epileptogenic zone. Lesionectomy guided by electrocorticography is generally adequate for evaluating developmental tumors and other noninfiltrative lesions rather than low-grade cortical dysplasia. If MRI and scalp EEG data are discordant, especially with regard to subtle developmental lesions, subdural recording may yield valuable information to help tailor the resection.
Multilesional and multifocal epileptiform activity. This situation is not uncommon in children with intractable epilepsy. Subdural electrode placement assists in determining which lesion and which epileptogenic region are clinically relevant. For example, children with tuberous sclerosis complex may have so many tubers that it proves difficult to accurately identify the tuber responsible for seizure origin. Alternatively, more than one tuber may be triggering seizures, necessitating a more complex presurgical evaluation of multiple sites.
Subcortical epilepsy. In rare situations, subcortical lesions may be responsible for intractable partial seizures. Hypothalamic hamartomas are most often defined on neuroimaging, but direct recording from the hamartoma reveals focal spiking and confirms seizure origin.⁷² Heterotopic gray matter⁷¹ and cerebellar gangliogliomas in infants⁴⁹ have also been implicated in intractable seizures through the use of invasive EEG recording.

Functional Cortical Mapping

The application of adult stimulation parameters to children has produced equivocal results. In childhood, the response to direct cortical stimulation using increments in stimulus intensity to a maximum of 15 mA can be inconsistent, and when studies of electrical stimulation are controlled for age, reduced motor responses are observed, especially in children younger than age 4 years.⁸⁴ Careful analyses of elicited responses reveal that the thresholds for afterdischarges and sensorimotor responses both have an inverse linear correlation with age.⁴

One solution to the problem of maturational influences on cortical responsiveness is to modify the standard adult stimulation paradigm by delivering stimulation in stepwise increments.⁵⁵ By alternating the stimulation sequence between increases in amplitude and time rather than amplitude alone, responses in children are reliably generated at the chronaxie, the point on the strength–duration curve corresponding to the lowest amount of energy. Eliciting responses at the chronaxie is especially welcome because there are no established guidelines for electrical safety using prolonged stimulation. The dual-stimulation paradigm successfully elicits sensorimotor responses in infants <2 years of age.²⁵

Neuroimaging

The application of magnetic resonance imaging (MRI) and spectroscopy (MRS) protocols in the pediatric evaluation for surgery is similar to that in adults. For example, protocols for imaging hippocampal sclerosis are similar because the incidence of hippocampal sclerosis in children with intractable temporal lobe epilepsy is approximately 60%.⁴³ Recent evidence suggests that high-resolution MRI also enhances the detection of subtle surgically amenable lesions in children with intractable epilepsy. In a study of 13 children who underwent MRI examination using four-coil phased surface array MRI after a recent standard MRI evaluation, high-resolution MRI identified previously undiagnosed focal abnormalities in 5 of 9
nonlesional patients.⁴² These included hippocampal dysplasia, hippocampal atrophy, and dual pathology.

MRS has been used successfully to lateralize seizure onset in children with temporal lobe epilepsy.¹⁷ MRS findings generally complement the MRI exam, but rare children will demonstrate a previously undetected localized abnormality or evidence of bilateral involvement. Although no systematic studies of MRS have been performed in children with cortical malformations, studies conducted in adults indicate variability in the detection of metabolic abnormalities that are pathologically based. Patients with focal cortical dysplasia showed significant metabolic abnormalities corresponding to structural lesions, whereas patients with heterotopia and polymicrogyria did not.

Single Photon Emission Computed Tomography

The widespread availability of single photon emission computed tomography (SPECT) cameras in nuclear medicine facilities, the low cost of γ-emitting isotopes, and the introduction of more stable radiopharmaceuticals have facilitated SPECT studies at many pediatric epilepsy centers. SPECT has been employed successfully to evaluate a wide spectrum of pediatric epilepsy surgical syndromes, including Sturge-Weber syndrome,¹¹ tuberous sclerosis complex,⁶⁵ Rasmussen syndrome,³³ hemimegalencephaly,⁹⁶ and focal cortical dysplasia.⁴⁴

Ictal SPECT studies remain the procedure of choice for localizing a high proportion of children with partial epilepsy.⁵¹ Ictal SPECT revealed hyperperfusion in 14 of 15 children with temporal lobe epilepsy undergoing preoperative evaluation.⁴⁸ In 4 children, ictal SPECT provided additional localizing information that was absent from ictal EEG recordings. Similarly, Cross et al.¹⁷ reported abnormalities on ictal SPECT in 13 of 14 children with both temporal and extratemporal seizures. The timing of injection was critical because injections >30 seconds postictally were less likely to yield reliable measurements of regional cerebral blood flow. Pediatric ictal SPECT studies also reliably colocalize the epileptogenic zone demonstrated by intracranial EEG recording and correlate with higher rates of surgical success.⁶⁴

In contrast, interictal SPECT injections are a significantly less reliable localizing tool in pediatric patients.⁴⁷ Normal studies or uncertainty regarding regions of hypoperfusion may potentially be misleading and are rarely relied on for surgical decision making. Ictal SPECT studies may be used to confirm localizing data from EEG and MRI investigations or to define the epileptogenic region in children with normal or discordant EEG and imaging data. SPECT may also play a role in clarifying the extent of the epileptogenic region and assist in placing intracranial electrodes.

Positron Emission Tomography

Although it is less widely used in the pediatric setting, positron emission tomography (PET) studies successfully localize seizure origin in patients with West syndrome¹⁴ and other epileptic encephalopathies,⁸⁷ Sturge-Weber syndrome,¹³ tuberous sclerosis complex,⁶¹ frontal lobe epilepsy,²¹ and generalized tonic–clonic seizures.⁶⁷ PET studies are particularly useful in children with extratemporal epilepsy and childhood syndromes with apparently generalized epileptic discharges.

PET also has been used in the presurgical localization of eloquent cortex in children with seizures. PET mapping of eloquent language, motor, and visual areas was accomplished in 15 children by coregistering PET images of task-activated cerebral blood flow onto MR images.³⁰ All patients had lesional epilepsy. PET mapping was well tolerated in all cases.

The absolute reliability of PET as a stand-alone localizing tool in the pediatric epilepsy surgical evaluation has been questioned.⁹³ Whereas [¹⁸F]fluorodeoxyglucose (FDG)-PET studies in older children and adolescents yield results similar to those in adults,³⁸ with one exception,⁸⁷ there are no longitudinal studies of PET in younger children. It has also been shown that [¹¹C]flumazenil PET is significantly more sensitive than 2-deoxy-2-[¹⁸F]fluoro-D-glucose for detecting cortical regions of seizure onset and frequent spiking in children with extratemporal epilepsy and that both radioisotopes have low sensitivity with rapid seizure spread.⁸³

Functional Magnetic Resonance Imaging

Functional MRI (fMRI) has reliably been used to localize language, sensory, motor, and visual functions in children and can influence surgical planning.⁷

Language mapping with developmentally appropriate paradigms generates localizing data in children that are similar to those in adults. Cooperative children as young as age 5 years have been studied successfully.³⁷ It is now clear that networks for auditory processing are regionally localized and lateralized by age 5 years.² Receptive language sites are located primarily along the superior temporal sulcus, similar to the case in adults, suggesting that language localization and network formation are established in early life. False lateralization of language cortex to the homologous nondominant hemisphere may occur in children in the postictal state.⁵⁶

Sensorimotor cortex can be positively identified using paradigms in which the child taps a finger or toe, wiggles the tongue, or has an extremity brushed. All of these paradigms are simple to apply and achieve reliable results, even in very young children. The location of sensorimotor function by fMRI agrees with localization data obtained by direct cortical stimulation.

Surgical Procedure Issues

Neurosurgical procedures pose special challenges for smaller children, and this is especially true for epilepsy surgery, in which younger patients undergo larger cortical resections than do older children and adults. In 2004, the Pediatric Sub-Commission of the ILAE conducted a survey of 20 pediatric epilepsy surgery centers in Europe, Australia, and the United States, collecting presurgery information on >500 patients of age <18 years.⁵⁰ Of infants of age 1 year or less at surgery in the ILAE survey, 90% underwent multilobar resections or hemispherectomy, and the most frequent etiologies were multilobar cortical dysplasia (37%), hemimegalencephaly (30%), and Sturge-Weber syndrome (13%). By comparison, 65% of 10-year-olds had focal or lobar resections, and the substrates were tumors (20%), hippocampal sclerosis (20%), and focal cortical dysplasia (20%). In other words, the younger the child at epilepsy surgery, the greater was the likelihood that his or her symptomatic substrate involved hemispheric etiologies requiring large cerebral cortical resections.⁷⁸

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