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Epilepsy Surgery in Young Children With Tuberous Sclerosis: Results of a Novel Approach

^a Division of Pediatric Neurosurgery, Department of Neurosurgery, New York University Medical Center, New York, New York
^b Department of Neurosurgery, New York University Medical Center, New York, New York
^c Department of Pediatrics, New York University Medical Center, New York, New York
^d Comprehensive Epilepsy Center, New York University Medical Center, New York, New York
^e Department of Neurology, New York University Medical Center, New York, New York

	ABSTRACT

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OBJECTIVE. Tuberous sclerosis complex (TSC) is associated with medically refractory epilepsy and developmental delay in children and usually results from cortical tubers. Seizures that begin in young patients are often refractory and may contribute to development delay. Functional outcome is improved when seizures are controlled at an early age. Previous reports have shown modest benefit from surgical resection of single tubers/seizure foci in older children; however, many children with TSC develop uncontrolled seizures before age 1. To identify patients who might benefit from surgery and to maximize outcome, we used a novel surgical approach in young children that consists of invasive intracranial monitoring, which is typically 3-staged and often bilateral.

METHODS. Of 110 consecutive children who underwent epilepsy surgery by a single surgeon in the past 6 years, 25 patients (9 boys and 16 girls) had TSC. At the time of their first surgery at our institution, they were a median age of 4.0 years. A total of 31 separate admissions for epilepsy surgery in these 25 patients were identified. Bilateral electrode placement was performed in 13 children whose seizures could not be lateralized definitively preoperatively, and 22 patients underwent 3-stage surgeries.

RESULTS. At 6 months or longer after the initial resection, 21 (84%) children were class I, 2 (8%) children were class II, and 2 (8%) children were class IV. At a mean follow-up of 28 months, 17 (68%) children were class I, 6 (24%) were class II, and 2 (8%) were class III. Four of the 5 children who initially were rejected as surgical candidates because of multifocality and who required initial bilateral electrode study are now seizure-free.

CONCLUSIONS. This approach can help to identify both primary and secondary epileptogenic zones in young TSC patients with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery. Long-term follow-up will determine whether this approach has durable effects.

Key Words: epilepsy surgery • pediatric epilepsy • tuberous sclerosis complex

Abbreviations: TSC—tuberous sclerosis complex • AED—antiepileptic drug • VNS—vagal nerve stimulation

Tuberous sclerosis complex (TSC) is associated with medically refractory seizures and developmental delay in children.^1–12 These epilepsies are often resistant to antiepileptic drug (AED) treatment, may be severe, and usually have a negative impact on the child's neurologic and cognitive development.^1–12 Gomez's pioneering studies strongly correlated early age of epilepsy onset and mental retardation.^4,8 In the past 2 decades, patients who had TSC with a single predominant epileptogenic tuber became candidates for epilepsy surgery, many with successful outcomes.^{4–8,13–16} However, many patients who have TSC with epilepsy have multiple tubers, and seizure foci are multicentric.^6,17,18 Nevertheless, the surgical treatment of intractable epilepsy in children and adults with TSC has gained significant interest in recent years.^{8,13–16,19–22} Several international clinical centers have reported their individual results of operating on patients who have TSC with medically refractory seizures. However, this literature is limited by small sample sizes and variability of data collection methods and analysis. The overall findings from these studies suggest that patients benefit from excisional surgery when seizures can be localized to a single tuber, which concurs with the epilepsy literature in patients without TSC.^{8,13–16,21,23–25}

The first report of successful epilepsy surgery in a patient with TSC came from the Montreal Neurologic Institute in 1966.²¹ Several subsequent reports demonstrated good short- and long-term seizure outcome in 50% to 60% of drug-resistant patients who were selected for surgical treatment.^8,19,20,22 These studies share a similar surgical approach that restricts the pool of candidates. First, these studies included relatively older children, adolescents, and adults. Although refractory epilepsy often develops in the first 2 years of life, in 9 studies that were published after 1989, the average age at surgery was 10 years. Because substantial development occurs before this age, the potential benefit of surgical intervention may be reduced because a critical developmental epoch has passed. Second, most groups selected surgical candidates on the basis of the identification of a single tuber/epileptogenic focus that was based on a correlation between electrographic and imaging data. However, this is often very difficult in many patients with TSC.^6,13,18 The potential for residual tubers to become epileptogenic after removal of the predominant epileptogenic focus or tuber was discussed. However, for patients with documented multifocal partial seizures associated with multiple tubers, epilepsy surgery was often deferred. These are often the patients with the most severe and debilitating forms of epilepsy.^2,3 Although complete seizure control might not be possible for many of these children, the question that arises is whether some would benefit from a palliative surgery that reduced seizure burden. Finally, the literature suggests that resection of the primary tuber and surrounding epileptogenic zone is the goal of surgery. However, defining the margins of the epileptogenic zone is often difficult in patients with TSC.^6,13 The question that arises is whether the potential benefits of invasive monitoring outweigh the potential risks in these patients.

We developed a novel surgical approach using invasive intracranial monitoring, which often involved multiple stages and bilateral coverage.^13,22 Patients with multiple or poorly localized seizure foci were considered for invasive monitoring, on the basis of the rationale that patients with TSC have partial epilepsy. Although many patients had multifocal partial epilepsy, if the primary and secondary foci were identified, then focal resection(s) might significantly reduce seizure burden. The 3-stage invasive approach allowed us the opportunity to remove the main seizure focus or foci during the second stage and then have an opportunity to identify residual foci. Our aim was to resect the areas with very abnormal physiology and structure; removal of this nociferous cortex could reduce seizure burden and thereby possibly improve function. This is the largest series of epilepsy surgery in young children with TSC by a single surgeon reported in the literature.

	METHODS

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This series is composed of a consecutive group of children who had TSC and underwent resective surgery by a single pediatric neurosurgeon (H.L.W.) at the NYU Comprehensive Epilepsy Center. For all patients, we retrospectively reviewed the medical records for preoperative evaluation, perioperative strategy, peri- and postoperative complications, and outcome. All patients had presurgical evaluations with video electroencephalographic (EEG) recording, neuropsychological testing, and computerized tomography and MRI studies, which were supplemented by ictal/interictal single-photon emission tomography, positron emission tomography, and magnetoencephalography in many patients. Our peri- and intraoperative protocol has been reported in detail.¹⁷

Outcome was classified as follows: class I, seizure-free or only nondisabling simple partial seizures; class II, >90% reduction of seizure frequency but rare complex partial seizures still occur; class III, 50% to 90% reduction in seizure frequency; and class IV, <50% reduction in seizure frequency. Seizure frequency was determined by report of the family both before and after surgery. The neuropsychological and developmental outcomes of 6 of the 25 patients was reported previously.²⁶

	RESULTS

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Of 110 consecutive children who underwent epilepsy surgery by a single surgeon in the past 6 years, 25 patients (9 boys and 16 girls) had TSC. At the time of their first surgery at our institution, they were a median age of 4.0 years (mean: 4.4 years; range: 7 months to 16.6 years). Two patients were previously reported (patient 5²¹ and patient 12^4,21 in Tables 1–3). Six failed vagal nerve stimulation (VNS), and 1 failed previous resection elsewhere. A total of 31 separate admissions for epilepsy surgery in these 25 patients were identified. Two patients underwent an initial bilateral strips study without resection, followed by a 3-stage procedure for resection of the epileptic foci. Two children underwent a total of 3 admissions, 1 bilateral strip study without resection, and two 3-stage procedures with resection of the epileptic foci. Bilateral electrode placement was performed in 13 children whose seizures were not clearly lateralized preoperatively. Five of these children had a bilateral strip study. Eight had a grid plus strips placed on the side with the most frequent or predominant ictal onsets and tuber(s) and contralateral strips placed via a burr hole (Table 1). Twenty-two patients had 3-stage surgery, and 3 had 2-stage (72 total initial operations with a total of 84 operations). Twenty patients underwent resection of 2 or more tubers. Seventeen patients underwent multilobar resections. Two children (patients 12 and 20) underwent bilateral resections.

View larger version (44K): [in this window] [in a new window]   FIGURE 1 Surgical outcome at 6 months and at present.

The second patient was a 4-year-old girl who initially underwent a 3-stage resection of right frontal and temporal tuber/epileptogenic zones. Postoperatively, she was not significantly improved. Subsequent workup could not lateralize her seizures sufficiently, and she required a bilateral strip study, which revealed a right hemisphere ictal onset. She later required extensive right frontal, parietal, and posterior temporal resections. She has remained seizure free in the 16 months since surgery, with developmental improvement in eye contact and motor function. Before surgeries, development had been stagnant.

Illustrative Case
A 5-year-old boy with TSC experienced the onset of seizures at 2 months of age. He began having infantile spasms at 9 months of age. His seizures consisted of multiple daily events, including complex partial, tonic, and generalized tonic-clonic seizures. He experienced significant developmental delay with subsequent regression. He failed 10 AEDs, as well as VNS and the ketogenic diet. He underwent an extensive evaluation at a major epilepsy center, including MRI scanning of the brain (Fig 2), scalp EEG, video EEG monitoring, and neuropsychological testing. These data revealed that he had multiple bilateral tubers with multifocal epilepsy. He therefore was not considered a surgical candidate. Given the poor quality of life and developmental regression, we considered using our approach in this case. The plan that we proposed was a bilateral strip electrode study to identify 1 or 2 predominant seizure foci that could be studied further with grid/strip coverage. We performed a vertex craniotomy and bilateral frontotemporal burr holes for bilateral strip electrode placement (Fig 3A). During the 8 days of initial monitoring, we recorded 17 seizures with left hemisphere onset and 77 seizures with right hemisphere onset. These right-sided seizures were arising from the right frontal polar region, corresponding to a large tuber (Fig 3B). At the second operative stage, we resected this right frontal tuber/seizure focus and reimplanted electrodes for a second phase of monitoring (Fig 3C).¹⁷ Once again, the predominant seizures were recorded from the anterior, lateral, and mesial margin of the right frontal resection cavity. At the third and final surgical stage, we resected a wider area of dysplastic brain along this margin (Fig 3D). In the 22 months since surgery, he has had only rare, very mild seizures, compared with between 6 and 14 intense seizures per day before surgery (class II outcome). After surgery, there was a dramatic improvement in his development and overall quality of life for both the patient and the family. This case raises the intriguing question of how removal of the primary seizure focus may alter the remaining epileptogenic network.

View larger version (131K): [in this window] [in a new window]   FIGURE 2 Preoperative T2-weighted axial MRI demonstrating multiple subcortical T2 hyperintensities bilaterally (right more than left), representing tubers.

View larger version (56K): [in this window] [in a new window]   FIGURE 3 Schematic drawings of the electrode placement for stages 1 to 3. A, Bilateral electrode placement via vertex craniotomy and bilateral burr holes. B, Depiction of the ictal, ictal spread, and interictal discharges captured during stage 1 of intracranial monitoring. Seventy-seven seizures arose from the right hemisphere, and 17 arose independently from the left hemisphere. C, The resection at stage 2 is depicted with reimplantation of electrodes. Continued, bilateral independent ictal and interictal discharges were seen during intracranial monitoring. D, Depiction of the extension of the initial resection projected onto the schematic representing stage 2 ictal and interictal data. Red, seizure (ictal) onset; yellow, ictal rapid spread; green, interictal discharges.

	DISCUSSION

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Previous series in patients with TSC reported modest rates of seizure freedom from surgical resection of single tubers/seizure foci in older children. However, many children with TSC develop uncontrolled seizures before age 1 year and often have multiple potentially epileptogenic tubers. Current criteria for epilepsy surgery often reject these children as potential candidates because of the multiplicity of foci or tubers. Unfortunately, these children are at greatest risk for adverse developmental outcome from their high seizure and tuber burden.^1–14 Functional outcome may improve if seizures are controlled at an early age.^1–14 To identify patients who might benefit from surgery and to maximize outcome, we developed a novel surgical approach in young children that consists of invasive intracranial monitoring, which typically is multistaged and bilateral.^14,17,21,25

The current focus for epilepsy surgery in patients with TSC is to identify patients with a single focus of epileptogenic cortex, with best results reported for those in whom this focus corresponds with the largest tuber.^{1–6,8,16,27} This approach is concordant with surgery in children and adults without TSC: the best outcomes occur in individuals with well-localized EEG seizure foci that correspond with a structural lesion. However, the major dilemma for many children with TSC, refractory epilepsy, and developmental delays is the presence multiple potentially epileptogenic tubers.^{14,18,21,25,27} These patients have the worst theoretical prognosis for successful epilepsy surgery because of several factors: epileptogenic tubers are often extratemporal, multifocal, and bilateral and may overlap with functional cortex.^21,25 Intracranial electrode monitoring is also limited by the wide distribution of tubers, many of which extend subcortically, and the presence of secondary epileptogenic foci. In our experience, some of these secondary foci can be identified only after the primary focus is resected.^17,21,25

This phenomenon likely is related to many of the failures of epilepsy surgery in patients without TSC. For example, even with intracranial monitoring, patients who have extratemporal seizure foci without structural lesions often have a <50% chance of seizure freedom.¹⁷ Although other factors (eg, failure to cover adequate tissue and identify the focus, failure to resect the entire single focus) contribute, the presence of a secondary foci, distinct from or overlapping with the principle focus, may become more active after the dominant focus is removed.

The reported TSC surgical series demonstrate that when a single seizure focus, generally corresponding to a single tuber, can be identified, the results are good. Bye et al¹³ reported the resection of right frontal cortex and 2 associated tubers in a 5-year-old child with 10 to 20 seizures per day, based on scalp EEG. In the year after surgery, the child experienced 2 brief seizures. Bebin et al¹⁵ identified the seizure focus that was concordant with the prominent neuroimaging lesion in 9 patients (mean age: 11 years), although 3 had multifocal interictal scalp epileptiform EEG activity. Two underwent cortical resection, and 7 underwent stereotactic lesionectomy. Six were seizure-free at follow-up, and only 1 failed surgery.¹⁵ Baumgartner et al¹⁶ used subdural monitoring in 2 of their 4 patients (mean age: 9.3 years) in whom clinical and EEG data suggested an epileptic focus near a prominent lesion. Two patients were seizure-free at follow-up.¹⁶ Avellino et al²⁴ reported 11 patients who had TSC (mean age: 19.6 years) and in whom they altered their approach when EEG discharges were focal versus multifocal/generalized. The latter group were evaluated with subdural grid/strip monitoring, whereas the others were studied with intraoperative electrocorticography. Five patients underwent awake craniotomy. Six of the 11 were seizure-free at follow-up. Guerreiro et al¹⁹ stratified patients to resection when they had a well-localized epileptogenic lesion or to corpus callosotomy when they did not. Twelve patients (mean age: 16.9 years) underwent resection, with excellent results in 7 patients. They observed the best outcome in patients who had focal seizures and good imaging and EEG correlation, although they might have multiple seizure types, other imaging abnormalities, and multifocal or generalized EEG findings.¹⁹ Koh et al⁸ evaluated the role of noninvasive imaging to localize the epileptogenic tuber/region and the outcome of focal resection. Thirteen patients underwent resection, 6 guided by subdural monitoring. The epileptogenic tuber/region corresponded to a large discrete tuber in 8 patients and a calcified tuber in 13 patients.⁸ Nine of the 13 were seizure-free at 26 months of follow-up. Lacchwani et al²⁷ reported 17 patients (median age: 12 years) who had TSC and underwent resection for treatment of refractory epilepsy; 8 of 9 patients with concordant MRI and EEG abnormalities were seizure-free at a median follow-up of 25 months. Three of 8 patients in whom the MRI findings were discordant with the EEG were seizure-free. Karenfort et al²⁰ identified a main epileptogenic tuber in all 8 surgical resection patients, with good correlation between neuroimaging and EEG. Three of the 8 were seizure-free at follow-up. Surgical failures were attributed to nonresected epileptogenic tubers or other areas.²⁰ Consistent with these reports and data from non-TSC populations, Jarrar et al²⁸ found that single seizure foci and mild to no developmental delay at the time of surgery predict excellent long-term outcome in patients with TSC.

Patients who have TSC and whose seizures begin during the first year of life and are refractory have high rates of mental retardation and autism.^6,9–12 Many of these patients have multiple and diffuse seizure foci on scalp-recorded EEG and multiple bilateral tubers on MRI. For many patients, the standard approach has been trials of multiple AEDs and, often after 5 to 15 years of refractory epilepsy, consider a palliative procedure such as callosotomy or VNS. Harvey et al¹⁸ reported a series of 6 children who had TSC and underwent resection of 2 to 5 tubers for control of seizures. In all patients, corroborating data, including scalp EEG, seizure semiology, ictal single-photon emission tomography, and ictal propagation, suggested that multiple tubers composed the epileptic focus. Intracranial monitoring for lateralization and localization was performed in 1 patient before resection. After resection, 2 patients were seizure-free and the remaining 4 had >75% reduction in seizures. One of our patients who successfully underwent a bilateral resection was offered hemispherectomy, which could have led to resection of nonepileptogenic functional tissue and left behind a contralateral seizure focus. We asked whether one could consider a different approach for patients who have TSC with >1 primary seizure focus.^14,17,21,25

The traditional 2-stage subdural grid/strip surgical approach initially consists of electrode placement to map seizure onset and function and is followed by resection of the seizure focus at the second stage.^17,21,25 In 3-stage surgery, after resection of the primary seizure focus during the second stage, electrodes are replaced to determine whether a second epileptogenic region or additional parts of the primary focus can be identified and resected at the third and final operative stage. Three-stage invasive monitoring can detect residual adjacent or distal epileptogenesis and is especially useful when the presurgical data suggest multifocal, bi-hemispheric involvement or seizure foci involving eloquent cortex. In the latter case, if the seizure focus and the tuber, for example, extend into primary motor cortex, then the initial resection (stage 2) can allow for sparing of critical function but the replacement of electrodes can allow a more refined mapping of the seizure focus directly involving motor cortex with the bulk of the focus already resected. Furthermore, the presence or absence of any weakness between these stages can provide critical clinical correlation of the functionality of resected tissue. Because functional mapping can be difficult in young children as a result of high motor thresholds, this additional stage can guide both the need and the safety of additional surgery.^8,21

In selected patients with bilateral tuber seizure foci, aggressive bilateral surgery can be safe and effective. This 3-stage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in patients who have TSC with multiple tubers. We have used this approach on 18 young children with TSC, 65% of whom are seizure-free at follow-up. Many of these patients were previously rejected as surgical candidates. Multiple or bilateral seizure foci are not a definitive contraindication to surgery in all patients with TSC. Resection of homologous brain regions bilaterally is avoided because of the risk for neurologic/neuropsychological deficits. Long-term follow-up will determine whether this approach has durable effects. Nevertheless, significant reduction in seizure burden during a critical developmental epoch likely will have significant benefits, even if seizures subsequently recur with diminished frequency or intensity.^6,9

The long-term benefit of surgery with respect to seizure control; cognitive, social, and behavioral development; academic/employment status; and quality of life are not known. Zaroff et al²⁶ reported the pre- and postoperative developmental assessments in a subset of 6 of the patients reported here. Developmental progress, evidenced by increases in the developmental age equivalents, was seen in all patients. The data demonstrate no evidence for a detrimental effect of surgery on developmental progress. The effect of maturation complicates the assessment of the effects of surgery on development. However, several patients experienced marked progress in development within weeks after surgery, whereas before surgery, there was stagnation or regression of developmental milestones. The benefits for seizure control and possible developmental progress must be weighed against the risks of epilepsy surgery and the natural history of TSC. For this reason, we have undertaken coordinating a multicenter, retrospective analysis of surgery outcome in patients with TSC and medically refractory seizures. Several international centers will provide data that will be analyzed retrospectively to determine any significant predictors of surgical outcome and to assess the overall therapeutic efficacy of surgery. This study will serve as the basis for a prospective study on the long-term effects of early surgery for medically refractory epilepsy on seizure control and developmental outcome in children with TSC.

	FOOTNOTES

 
Accepted Oct 20, 2005.

Address correspondence to Howard L. Weiner, MD, Division of Pediatric Neurosurgery, NYU Medical Center, 317 East 34th St, New York, NY 10016. E-mail: howard.weiner{at}med.nyu.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Weiner, H. L. Articles by Devinsky, O. Search for Related Content PubMed Articles by Weiner, H. L. Articles by Devinsky, O. Related Collections Surgery

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