- Email: [email protected]
Pediatric Epilepsy Surgery: Lessons and Challenges
Pediatric Epilepsy Surgery: Lessons and Challenges Deepak K. Lachhwani, MBBS, MD Pediatric epilepsy surgery has come of age, from being considered as a last resort in medically refractory focal epilepsy, after failure of numerous antiepileptic drug trials spanning many years, to a preferred treatment option in carefully selected candidates. There have been certain key developments that have catalyzed this change. First, we are able to predict medical intractability earlier during the course of epilepsy. Second, improved understanding of how the maturing brain recovers from neurologic insults has led to earlier consideration of surgical intervention during a window of developmental plasticity. Finally, improved diagnostic and surgical capabilities now enable us to identify more candidates suitable for surgery. At the same time, as the surgical frontier has been rapidly pushed to new horizons, we have also unearthed new challenges. In this review, several pediatric epilepsy syndromes are discussed to highlight these important developments. Semin Pediatr Neurol 12:114-118 © 2005 Elsevier Inc. All rights reserved. KEYWORDS Medically refractory epilepsy, early intervention with surgery, goals for surgery, surgery in specific situations
E
pilepsy is a major cause of long-term neurologic morbidity and imposes a substantial financial burden to society. It is estimated that 2 million Americans suffer from epilepsy and that approximately 20% to 30% of afflicted individuals prove to be medically intractable.1 Pediatric and adolescent patients form a significant portion of this patient population. For many of these patients with medically refractory epilepsy, surgical approaches would clearly be better than continued medication trials and may offer the potential for a complete cure. In support of this, Weibe and coworkers2 published findings of the first and only randomized, controlled trial comparing surgical versus medical treatment for adults with temporal lobe epilepsy. They showed that seizure control and quality of life are significantly improved with surgery over medical therapy for temporal lobe epilepsy patients. Clinical experience suggests that results will not be vastly different with other surgically amenable focal epilepsies. However, the utilization of epilepsy surgery, especially in the pediatric patient population, is yet to realize its full potential. Pediatric surgical outcome data are encouraging and no different from the adult surgical outcome data.3-6 There has been a surge in awareness of age-related differences such as
Division of Pediatric Epilepsy and Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Deepak K. Lachhwani, MBBS, MD, S-51, Division of Pediatric Epilepsy and Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, OH 44122. E-mail: [email protected].
114
1071-9091/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2005.04.001
(1) infants and young children exhibit varied etiologies and a greater number of epileptic syndromes than adults and (2) vulnerability of the immature brain to ongoing seizures as well as its potential to recover from neurologic insult. Recent data on low rates of therapeutic success after failing 2 appropriate antiepileptic drug (AED) trials in newly diagnosed epileptic patients enable us to predict medical intractability early in the course of treatment.7,8 We are perhaps at the verge of witnessing a significant change in our perceptions of pediatric epilepsy surgery. However, the path of progress, to no one’s surprise, is continuously paved with lessons and challenges.
Medically Refractory Epilepsy Even for the most ideal epilepsy surgery candidate, there is a considerable delay between the onset of epilepsy and time to surgery. Although this delay to surgery is multi-factorial, lack of a precise definition of medical refractoriness has contributed significantly to this phenomenon. There is mounting evidence that drug-resistant epilepsy can be predicted successfully after failure of only 1 or 2 carefully chosen pharmaceutical agents.9 In 1 study, 47% of the patients became seizure free after treatment with the first AED; however, among those who had no response to the first drug, only 11% became seizure free with further medical management.10 Pediatric data also suggest that if the first AED is ineffective, the outcome is less favorable and failure of at least 2 AEDs should
Pediatric epilepsy surgery be an indication for consideration of options such as surgery.7 Trials of multiple AEDs over a span of several years are therefore not necessary to establish that a patient has medically refractory epilepsy. Multiple AED trials in children who are favorable surgical candidates are likely to be futile. Every new drug regimen not only delays a definitive surgical procedure but also continues to expose the young patient to a significant risk of morbidity (and mortality) from ongoing seizures, not to mention long-term adverse effects of AEDs.11 For patients deemed unsuitable for epilepsy surgery or those suffering from refractory generalized epilepsy, optimizing medical therapy with medications is, regretfully, the only course.
Early Intervention The first few years of life are unique because of the neurodevelopmental plasticity inherent to the immature brain. These are also the years when some catastrophic epilepsies may manifest with multiple daily seizures that are very difficult to control. Fortunately, these children represent a small subset of children in whom epilepsy is largely a benign disorder. Catastrophic epilepsies during these early years result from uncommon disorders such as severe myoclonic epilepsy of infancy, epilepsy with myoclonic-astatic seizures, early infantile epileptic encephalopathy, neurometabolic disorders, or an underlying malformation of cortical development. Many children with catastrophic epilepsy will have cognitive impairment because of the underlying brain condition, regardless of the degree of seizure control. In some patients, however, uncontrolled seizures will result in cognitive impairment.12 A cross-sectional analysis of children with epilepsy showed a direct detrimental relationship between the duration of intractable epilepsy and IQ scores.13 Early and careful evaluation for the etiology may lead to identification of surgically amenable syndromes. Thus, epilepsy surgery, if offered during the period of developmental plasticity, may provide children with the potential for improved intellectual development.14,15 The risk of new postoperative deficits, such as speech and language impairment, may also be modified if surgery is performed before the window of opportunity of the young brain’s potential for recovery is lost.
Goals for Surgery Freedom from seizures (as well as AEDs) is clearly the immediate goal for epilepsy surgery across all age groups. The intermediate and long-term goals pertaining to the overall impact on quality of life are different in the younger patient as compared with an adult patient. Important quality-of-life (QOL) measures after epilepsy surgery in adults include driving, independence, marriage, and gainful employment. Adult patients who have surgery at a later age show lesser improvement in their QOL scales than those who had surgery at an earlier age. This is due to the negative impact of a long-lasting epileptic process on social handicaps, psychological conflicts, and behavioral and cognitive impairment.16
115 The factors influencing QOL are different at different stages of life within the pediatric population. For infants and young children with catastrophic epilepsy, even a substantial relief from seizure burden is an improvement for the patient and makes a significant positive impact in the lives of the family caring for such a child. Halting developmental regression because of unchecked seizures and preventing an irreversible cognitive arrest are some of the other age-related phenomena that influence earlier intervention in pediatric patients, whenever possible.17 A study involving 14 children who underwent modified functional hemispherectomy at or before 6 years of age found that a high preoperative developmental quotient and cessation of seizures were associated with better postoperative intellectual development.15 Relief from the sedative effects of AED in large doses, returning to school, dating, and social respite for parent(s) and other caregivers weigh in as important goals when considering medical versus surgical options for a child with epilepsy.4,17-19
Surgery in Specific Syndromes Tuberous Sclerosis Complex Epilepsy is the most common neurologic manifestation of tuberous sclerosis complex (TSC), and seizures are frequently severe and refractory to medical therapy.20-22 Presence of multiple bilateral cerebral cortical lesions poses several challenges in the presurgical evaluation of refractory patients.23,24 Furthermore, it may not be straightforward to identify a single epileptogenic lesion because of multi-focal interictal epileptiform abnormalities on the electroencephalogram (EEG). Even if one clear epileptogenic region is identified and removed, there remain concerns for future recurrence of epilepsy because of the other cortical lesions.25 Long-term data from surgical series are awaited and likely to substantiate that early relief from epilepsy may help prevent secondary epileptogenesis and have a favorable impact on neurodevelopmental outcome. These reasons would support an early consideration of a surgical cure in carefully selected candidates. Three broad scenarios may be encountered in TSC patients with refractory focal epilepsy1: patients with a clear, unifocal epileptogenic region;2 patients with a suggestive but not a clear, unifocal epileptogenic region; and3 patients with clearly multifocal epileptogenic areas. Patients in whom seizure semiology and surface EEG points to a single epileptogenic region and the brain magnetic resonance imaging (MRI) reveals either a concordant single or 1 major cortical lesion, epilepsy surgery offers similar seizure-free results as compared with other focal etiologies. Surgical experience from various epilepsy centers shows that up to 70% to 89% of such patients may be expected to attain seizure-free outcome.23,24,26,27 Therefore, this first subset of patients should not be viewed differently for surgical considerations from any other focal substrate (with concordant MRI and surface EEG findings) leading to refractory epilepsy. In patients with poorly localized findings, functional neuroimaging modalities and invasive methods of evaluation may be used. PET imaging with newer ligands such as alpha-
116 [11C]-methyl-L-tryptophan and flumazenil have shown promise in distinguishing epileptogenic from quiescent tubers.28,29 SISCOM (subtraction ictal single photon-emission computed tomography coregistered to MRI) may help in some cases by identifying focal areas of hyperperfusion during a seizure, thus implicating an epileptogenic zone.30 These developments are exciting and await studies to define their exact role. In selected candidates, invasive recording with subdural grids and strips is useful to define epileptogenic zone as well as eloquent cortex. Use of such additional tests may help to delineate a focal resectable epileptogenic zone, aiding in surgical planning. More experience and data are needed in patients with poorly localized findings. Patients with clearly multifocal epileptogenic regions may find hope in the recently advanced technique of multistaged surgery.31,32 In complicated patients with multiple epileptogenic tubers in distant brain regions, the authors report favorable outcome with multistaged sequential removal of tubers with the aid of subdural recording of residual seizure onsets. Novel surgical approaches together with studies exploring the role of functional and nuclear imaging modalities in complicated TSC cases may serve to improve outcome in this subgroup of patients. Rasmussen’s Encephalitis This syndrome of chronic focal encephalitis of unknown origin, presents with medically refractory focal epilepsy, progressive neurologic deficits, and cortical atrophy as evident on MRI. With rare exceptions, a clinical diagnosis may be made by the presence of these 3 cardinal features within 4 to 12 months of onset.33 After more than 4 decades since the first description of this syndrome, the etiologic basis remains uncertain and therapeutic options remain limited.34-37 AEDs, together with immuno-modulation, are the preferred approach early in the course of disease when neurologic deficits are absent or very subtle.33 However, despite aggressive trials with multiple AEDs and immune-modulating agents, control of either seizures or disease progression in most cases is temporary and modest. Surgical resection of the affected hemisphere (hemispherectomy) is the only definitive intervention which halts disease progression and relieves the epilepsy.33 Decisions regarding timing of surgery are difficult in patients with only minimal or no neurologic deficits. One must carefully weigh risks versus benefits when anticipating potential neurologic deficits after hemispherectomy, such as hemiparesis, hemianopia, and speech and language impairment (with dominant hemisphere resection). Hemispherectomy may be recommended at a time when there is evidence of preexisting motor neurologic deficit because no further deterioration is expected as a result of surgical intervention. Available experience suggests that the developmental plasticity of a young brain will enable transfer of language to the nondominant hemisphere after surgery, even as late as early adolescence.38-40 Postsurgical hemianopia is irreversible, and although patients adapt well to it for daily activities of life, it precludes them from driving in the future. However, this may be an acceptable tradeoff for freedom from morbidity and
D.K. Lachhwani mortality risks due to prolonged medical management of recalcitrant seizures. The decision and timing for surgical intervention, therefore, must be tailored to individual clinical cases. The first manifestation of motor deficit during the course of illness may be the point for considering surgery to maximize the potential for brain plasticity to aid in recovery. Hemispheric Malformations of Cortical Development Infants with hemispheric malformations of cortical development may present with developmental delay, contralateral motor deficit, and epilepsy. Refractory seizures may present shortly after birth, resulting in prolonged repeated hospitalizations and the need for escalating doses of AEDs or suppressive therapy. If unihemispheric epileptogenesis can be established, hemispherectomy may be the preferred option to prevent severe risks of morbidity and mortality resulting from uncontrolled seizures. In a series of 11 patients with available follow-up who underwent hemispherectomy for intractable epilepsy because of hemispheric cortical dysgenesis, 9 patients were either seizure free (n ⫽ 5) or had a ⬎90% reduction in the seizure burden (n ⫽ 4), whereas 2 had a 50% to 90% reduction in seizures.14 Similar results were noted in another surgical series involving 12 patients with hemispheric malformations who underwent functional hemispherectomy.41 Ten of the 12 patients either became seizure free (n ⫽ 5) or had a significant reduction in seizure activity (n ⫽ 5). As a group, these patients appear to have lower seizure-free rates after surgery compared to patients with a discrete and small substrate of focal epileptogenesis.17,41,42 Careful consideration of certain MRI features may be helpful in predicting which patients would fare better with seizure control. Patients with an enlarged and malformed hemisphere (hemimegalencephaly) seem to have a smaller probability of attaining seizure freedom compared with patients with a relative preservation of 1 lobe as evident on MRI.41 This may be because of the presence of extensive microdysgenesis in deep gray structures, as well as contralateral microscopic abnormalities in patients with total unihemispheric abnormality on MRI. An anatomic hemispherectomy with a more extensive resection of the abnormal hemisphere may be preferred over a functional hemispherectomy (a smaller brain resection which accomplishes a disconnection). Combined experience from surgical centers will help in identifying the surgical procedure of choice in this patient population with multilobar or hemispheric cortical abnormalities. Medically Refractory Focal Status Epilepticus Status epilepticus is a medical emergency that is managed by aggressive use of intravenous AEDs. Refractory status epilepticus is defined as status epilepticus, which fails to respond to high-dose suppressive therapy (HDST). Improvements in pediatric intensive care have enabled us to prolong HDST. However, this therapeutic approach is associated with significant mortality and morbidity. Sahin and coworkers43,44 found that none of the children who were treated with HDST returned to pretreatment neurologic function and all developed epilepsy. Mortality rates in children after RSE range from 16% to 43.5%.45,46
Pediatric epilepsy surgery If Refractory Status Epilepticus (RSE) of focal origin is encountered, surgical options may be a consideration. Isolated case reports have found good results with multiple subpial transections, corpus callosotomy, implantation of vagus nerve stimulator, or cortical resection.47-50 In a recent report involving 10 pediatric patients, RSE was successfully stopped by resective surgery in all patients without any perioperative deaths.51 At the most recent follow-up, 70% (n ⫽ 7) patients continued to remain seizure free, whereas those with recurrence of seizures were either significantly improved (n ⫽ 2) or did not show worsening of the epilepsy compared with prestatus baseline (n ⫽ 1). Surgical morbidity compared favorably with that seen during prolonged HDST. With 10 patients, this is perhaps the largest series reported from a single center and more experience with resective surgery in RSE of focal origin is needed. It must be emphasized that epilepsy surgery in the midst of a medical emergency is challenging and must be considered only at centers with adequate expertise and experience. Infantile Spasms The syndrome of infantile spasms comprises of epileptic spasms presenting during infancy (3-7 months of age), associated with psychomotor retardation and hypsarrhythmia on EEG. The spasms themselves are electroclinically unique; on EEG, they are time locked with generalized electrodecrements preceded by slow-wave transients. It is now well accepted that a variety of pathological insults, occurring early in the course of development, can lead to infantile spasms.52 Many pharmacological treatments have been proposed; however, only few have proven to be efficacious and there is a lack of consensus about the drug of choice.53 Consideration of pharmacologic and nonpharmacologic avenues must be done in earnest because poor seizure control is likely to result in severe cognitive impairment and marked behavioral disorders.54 Patients with evidence of focal features either on clinical examination (eg, hemiparesis), seizure semiology, and/or neurodiagnostic testing (including structural [eg, MRI] and functional [eg, positron emission tomography] neuroimaging, as well as EEG) may be candidates for resective surgery. The UCLA Pediatric Epilepsy Surgery Program pioneered the concept of resective surgery for infantile spasms in the late 1980s and early 1990s.55,56 The focal epileptogenic substrates may include cortical dysplasia, infarction, infection, tuberous sclerosis, and neoplasm. The surgical strategy is individually tailored to optimize resection of the epileptogenic zone and may range from focal or lobar-multilobar resections to hemispherectomy with good seizure control.56 Surgical series have also documented improved neurodevelopmental outcome after seizure control with resective epilepsy surgery in patients with infantile spasms. Experience from UCLA showed a significant increase in developmental level 2 years after surgery, when compared with medically treated patients. Furthermore, the best developmental outcomes were observed in children in whom surgery was accomplished at a younger age and who had the highest level of developmental level presurgically. Available evidence since
117 then further substantiates the need for early surgical intervention in appropriate candidates to minimize the long term developmental impairment, which is otherwise very likely with this disorder.19,54,56-58
References 1. Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. 1-51. 1991. Ref Type: Data File 2. Wiebe S, Blume WT, Girvin JP, et al: A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345:311-318, 2001 3. Wyllie E, Comair YG, Kotagal P, et al: Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 44:740-748, 1998 4. Bittar RG, Rosenfeld JV, Klug GL, et al: Resective surgery in infants and young children with intractable epilepsy. J Clin Neurosci 9:142-146, 2002 5. Buchhalter JR, Jarrar RG: Therapeutics in pediatric epilepsy, part 2: epilepsy surgery and vagus nerve stimulation. Mayo Clin Proc 78:371378, 2003 6. Khajavi K, Comair YG, Wyllie E, et al: Surgical management of pediatric tumor-associated epilepsy. J Child Neurol 14:15-25, 1999 7. Camfield PR, Camfield CS, Gordon K, et al: If a first antiepileptic drug fails to control a child’s epilepsy, what are the chances of success with the next drug? J Pediatr 131:821-824, 1997 8. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314-319, 2000 9. Berg AT, Shinnar S, Levy SR, et al: Early development of intractable epilepsy in children: a prospective study. Neurology 56:1445-1452, 2001 10. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314-319, 2000 11. Sperling MR, Feldman H, Kinman J, et al: Seizure control and mortality in epilepsy. Ann Neurol 46:45-50, 1999 12. Shields WD: Catastrophic epilepsy in childhood. Epilepsia 41:S2-S6, 2000 (suppl 2) 13. Farwell JR, Dodrill CB, Batzel LW: Neuropsychological abilities of children with epilepsy. Epilepsia 26:395-400, 1985 14. Maehara T, Shimizu H, Shigetomo R, et al: [Functional hemispherectomy for children aged 2 years or less for the treatment of intractable epilepsy caused by cortical dysgenesis]. No To Hattatsu 32:395-400, 2000 15. Maehara T, Shimizu H, Kawai K, et al: Postoperative development of children after hemispherotomy. Brain Dev 24:155-160, 2002 16. Mihara T, Inoue Y, Matsuda K, et al: Recommendation of early surgery from the viewpoint of daily quality of life. Epilepsia 37:33-36, 1996 (suppl 3) 17. Devlin AM, Cross JH, Harkness W, et al: Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 126: 556-566, 2003 18. Battaglia D, Di Rocco C, Iuvone L, et al: Neuro-cognitive development and epilepsy outcome in children with surgically treated hemimegalencephaly. Neuropediatrics 30:307-313, 1999 19. Wyllie E, Comair YG, Kotagal P, et al: Epilepsy surgery in infants. Epilepsia 37:625-637, 1996 20. Curatolo P, Verdecchia M, Bombardieri R: Tuberous sclerosis complex: a review of neurological aspects. Eur J Paediatr Neurol 6:15-23, 2002 21. Gomez MR: History of the tuberous sclerosis complex. Brain Dev 17: 55-57, 1995 (suppl) 22. Goodman M, Lamm SH, Engel A, et al: Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol 12:85-90, 1997 23. Bebin EM, Kelly PJ, Gomez MR: Surgical treatment for epilepsy in cerebral tuberous sclerosis. Epilepsia 34:651-657, 1993 24. Guerreiro MM, Andermann F, Andermann E, et al: Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 51:1263-1269, 1998 25. Morrell F: Varieties of human secondary epileptogenesis. J Clin Neurophysiol 6:227-275, 1989 26. Karenfort M, Kruse B, Freitag H, et al: Epilepsy surgery outcome in
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27.
28.
29.
30. 31.
32. 33.
34.
35.
36.
37. 38.
39.
40. 41.
children with focal epilepsy due to tuberous sclerosis complex. Neuropediatrics 33:255-261, 2002 Lachhwani DK, Pestana E, Kotagal P, et al: Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology 64:1651-1654, 2005 Asano E, Chugani DC, Muzik O, et al: Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology 54:1976-1984, 2000 Fedi M, Reutens DC, Andermann F, et al: alpha-[11C]-Methyl-L-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency. Epilepsy Res 52:203-213, 2003 Duchowny M: Recent advances in candidate selection for pediatric epilepsy surgery. Semin Pediatr Neurol 7:178-186, 2000 Romanelli P, Najjar S, Weiner HL, et al: Epilepsy surgery in tuberous sclerosis: multistage procedures with bilateral or multilobar foci. J Child Neurol 17:689-692, 2002 Romanelli P, Verdecchia M, Rodas R, et al: Epilepsy surgery for tuberous sclerosis. Pediatr Neurol 31:239-247, 2004 Granata T, Fusco L, Gobbi G, et al: Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology 61:1807-1810, 2003 Rogers SW, Andrews PI, Gahring LC, et al: Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 265:648-651, 1994 Wiendl H, Bien CG, Bernasconi P, et al: GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen’s encephalitis. Neurology 57:1511-1514, 2001 Mantegazza R, Bernasconi P, Baggi F, et al: Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 131:179-185, 2002 Rasmussen T, Olszewski J, Lloyd-Smith D: Focal seizures due to chronic localized encephalitis. Neurology 8:435-445, 1958 Boatman D, Freeman J, Vining E, et al: Language recovery after left hemispherectomy in children with late-onset seizures. Ann Neurol 46: 579-586, 1999 Hertz-Pannier L, Chiron C, Jambaque I, et al: Late plasticity for language in a child’s non-dominant hemisphere: a pre- and post-surgery fMRI study. Brain 125:361-372, 2002 Loddenkemper T, Wyllie E, Lardizabal D, et al: Late language transfer in patients with Rasmussen encephalitis. Epilepsia 44:870-871, 2003 Carreno M, Wyllie E, Bingaman W, et al: Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 57:331-333, 2001
42. Kossoff EH, Vining EP, Pillas DJ, et al: Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology 61:887-890, 2003 43. Sahin M, Menache CC, Holmes GL, et al: Outcome of severe refractory status epilepticus in children. Epilepsia 42:1461-1467, 2001 44. Sahin M, Menache CC, Holmes GL, et al: Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children. Neurology 61:398-401, 2003 45. Gilbert DL, Gartside PS, Glauser TA: Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis. J Child Neurol 14:602-609, 1999 46. Kim SJ, Lee DY, Kim JS: Neurologic outcomes of pediatric epileptic patients with pentobarbital coma. Pediatr Neurol 25:217-220, 2001 47. Gorman DG, Shields WD, Shewmon DA, et al: Neurosurgical treatment of refractory status epilepticus. Epilepsia 33:546-549, 1992 48. Krsek P, Tichy M, Belsan T, et al: Life-saving epilepsy surgery for status epilepticus caused by cortical dysplasia. Epileptic Disord 4:203-208, 2002 49. Ma X, Liporace J, O’Connor MJ, et al: Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res 46:33-38, 2001 50. Winston KR, Levisohn P, Miller BR, et al: Vagal nerve stimulation for status epilepticus. Pediatr Neurosurg 34:190-192, 2001 51. Alexopoulos A, Lachhwani DK, Gupta A, et al: Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis. Neurology 64(3):567-570, 2005 52. Dulac O, Soufflet C, Chiron C, et al: What is West Syndrome? Int Rev Neurobiol 49:1-22, 2002 53. Mackay M, Weiss S, Snead OC III: Treatment of infantile spasms: an evidence-based approach. Int Rev Neurobiol 49:157-184, 2002 54. Caplan R, Siddarth P, Mathern G, et al: Developmental outcome with and without successful intervention. Int Rev Neurobiol 49:269-284, 2002 55. Chugani HT, Shields WD, Shewmon DA, et al: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 27:406-413, 1990 56. Shields WD: Medical vs. surgical treatment: which treatment when? Int Rev Neurobiol 49:253-267, 2002 57. Arsanow RF, LoPresti C, Guthrie D, et al: Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol 39:430-440, 1997 58. Jonas R, Asarnow RF, LoPresti C, et al: Surgery for symptomatic infantonset epileptic encephalopathy with and without infantile spasms. Neurology 64:746-750, 2005
E
pilepsy is a major cause of long-term neurologic morbidity and imposes a substantial financial burden to society. It is estimated that 2 million Americans suffer from epilepsy and that approximately 20% to 30% of afflicted individuals prove to be medically intractable.1 Pediatric and adolescent patients form a significant portion of this patient population. For many of these patients with medically refractory epilepsy, surgical approaches would clearly be better than continued medication trials and may offer the potential for a complete cure. In support of this, Weibe and coworkers2 published findings of the first and only randomized, controlled trial comparing surgical versus medical treatment for adults with temporal lobe epilepsy. They showed that seizure control and quality of life are significantly improved with surgery over medical therapy for temporal lobe epilepsy patients. Clinical experience suggests that results will not be vastly different with other surgically amenable focal epilepsies. However, the utilization of epilepsy surgery, especially in the pediatric patient population, is yet to realize its full potential. Pediatric surgical outcome data are encouraging and no different from the adult surgical outcome data.3-6 There has been a surge in awareness of age-related differences such as
Division of Pediatric Epilepsy and Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Deepak K. Lachhwani, MBBS, MD, S-51, Division of Pediatric Epilepsy and Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, OH 44122. E-mail: [email protected].
114
1071-9091/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2005.04.001
(1) infants and young children exhibit varied etiologies and a greater number of epileptic syndromes than adults and (2) vulnerability of the immature brain to ongoing seizures as well as its potential to recover from neurologic insult. Recent data on low rates of therapeutic success after failing 2 appropriate antiepileptic drug (AED) trials in newly diagnosed epileptic patients enable us to predict medical intractability early in the course of treatment.7,8 We are perhaps at the verge of witnessing a significant change in our perceptions of pediatric epilepsy surgery. However, the path of progress, to no one’s surprise, is continuously paved with lessons and challenges.
Medically Refractory Epilepsy Even for the most ideal epilepsy surgery candidate, there is a considerable delay between the onset of epilepsy and time to surgery. Although this delay to surgery is multi-factorial, lack of a precise definition of medical refractoriness has contributed significantly to this phenomenon. There is mounting evidence that drug-resistant epilepsy can be predicted successfully after failure of only 1 or 2 carefully chosen pharmaceutical agents.9 In 1 study, 47% of the patients became seizure free after treatment with the first AED; however, among those who had no response to the first drug, only 11% became seizure free with further medical management.10 Pediatric data also suggest that if the first AED is ineffective, the outcome is less favorable and failure of at least 2 AEDs should
Pediatric epilepsy surgery be an indication for consideration of options such as surgery.7 Trials of multiple AEDs over a span of several years are therefore not necessary to establish that a patient has medically refractory epilepsy. Multiple AED trials in children who are favorable surgical candidates are likely to be futile. Every new drug regimen not only delays a definitive surgical procedure but also continues to expose the young patient to a significant risk of morbidity (and mortality) from ongoing seizures, not to mention long-term adverse effects of AEDs.11 For patients deemed unsuitable for epilepsy surgery or those suffering from refractory generalized epilepsy, optimizing medical therapy with medications is, regretfully, the only course.
Early Intervention The first few years of life are unique because of the neurodevelopmental plasticity inherent to the immature brain. These are also the years when some catastrophic epilepsies may manifest with multiple daily seizures that are very difficult to control. Fortunately, these children represent a small subset of children in whom epilepsy is largely a benign disorder. Catastrophic epilepsies during these early years result from uncommon disorders such as severe myoclonic epilepsy of infancy, epilepsy with myoclonic-astatic seizures, early infantile epileptic encephalopathy, neurometabolic disorders, or an underlying malformation of cortical development. Many children with catastrophic epilepsy will have cognitive impairment because of the underlying brain condition, regardless of the degree of seizure control. In some patients, however, uncontrolled seizures will result in cognitive impairment.12 A cross-sectional analysis of children with epilepsy showed a direct detrimental relationship between the duration of intractable epilepsy and IQ scores.13 Early and careful evaluation for the etiology may lead to identification of surgically amenable syndromes. Thus, epilepsy surgery, if offered during the period of developmental plasticity, may provide children with the potential for improved intellectual development.14,15 The risk of new postoperative deficits, such as speech and language impairment, may also be modified if surgery is performed before the window of opportunity of the young brain’s potential for recovery is lost.
Goals for Surgery Freedom from seizures (as well as AEDs) is clearly the immediate goal for epilepsy surgery across all age groups. The intermediate and long-term goals pertaining to the overall impact on quality of life are different in the younger patient as compared with an adult patient. Important quality-of-life (QOL) measures after epilepsy surgery in adults include driving, independence, marriage, and gainful employment. Adult patients who have surgery at a later age show lesser improvement in their QOL scales than those who had surgery at an earlier age. This is due to the negative impact of a long-lasting epileptic process on social handicaps, psychological conflicts, and behavioral and cognitive impairment.16
115 The factors influencing QOL are different at different stages of life within the pediatric population. For infants and young children with catastrophic epilepsy, even a substantial relief from seizure burden is an improvement for the patient and makes a significant positive impact in the lives of the family caring for such a child. Halting developmental regression because of unchecked seizures and preventing an irreversible cognitive arrest are some of the other age-related phenomena that influence earlier intervention in pediatric patients, whenever possible.17 A study involving 14 children who underwent modified functional hemispherectomy at or before 6 years of age found that a high preoperative developmental quotient and cessation of seizures were associated with better postoperative intellectual development.15 Relief from the sedative effects of AED in large doses, returning to school, dating, and social respite for parent(s) and other caregivers weigh in as important goals when considering medical versus surgical options for a child with epilepsy.4,17-19
Surgery in Specific Syndromes Tuberous Sclerosis Complex Epilepsy is the most common neurologic manifestation of tuberous sclerosis complex (TSC), and seizures are frequently severe and refractory to medical therapy.20-22 Presence of multiple bilateral cerebral cortical lesions poses several challenges in the presurgical evaluation of refractory patients.23,24 Furthermore, it may not be straightforward to identify a single epileptogenic lesion because of multi-focal interictal epileptiform abnormalities on the electroencephalogram (EEG). Even if one clear epileptogenic region is identified and removed, there remain concerns for future recurrence of epilepsy because of the other cortical lesions.25 Long-term data from surgical series are awaited and likely to substantiate that early relief from epilepsy may help prevent secondary epileptogenesis and have a favorable impact on neurodevelopmental outcome. These reasons would support an early consideration of a surgical cure in carefully selected candidates. Three broad scenarios may be encountered in TSC patients with refractory focal epilepsy1: patients with a clear, unifocal epileptogenic region;2 patients with a suggestive but not a clear, unifocal epileptogenic region; and3 patients with clearly multifocal epileptogenic areas. Patients in whom seizure semiology and surface EEG points to a single epileptogenic region and the brain magnetic resonance imaging (MRI) reveals either a concordant single or 1 major cortical lesion, epilepsy surgery offers similar seizure-free results as compared with other focal etiologies. Surgical experience from various epilepsy centers shows that up to 70% to 89% of such patients may be expected to attain seizure-free outcome.23,24,26,27 Therefore, this first subset of patients should not be viewed differently for surgical considerations from any other focal substrate (with concordant MRI and surface EEG findings) leading to refractory epilepsy. In patients with poorly localized findings, functional neuroimaging modalities and invasive methods of evaluation may be used. PET imaging with newer ligands such as alpha-
116 [11C]-methyl-L-tryptophan and flumazenil have shown promise in distinguishing epileptogenic from quiescent tubers.28,29 SISCOM (subtraction ictal single photon-emission computed tomography coregistered to MRI) may help in some cases by identifying focal areas of hyperperfusion during a seizure, thus implicating an epileptogenic zone.30 These developments are exciting and await studies to define their exact role. In selected candidates, invasive recording with subdural grids and strips is useful to define epileptogenic zone as well as eloquent cortex. Use of such additional tests may help to delineate a focal resectable epileptogenic zone, aiding in surgical planning. More experience and data are needed in patients with poorly localized findings. Patients with clearly multifocal epileptogenic regions may find hope in the recently advanced technique of multistaged surgery.31,32 In complicated patients with multiple epileptogenic tubers in distant brain regions, the authors report favorable outcome with multistaged sequential removal of tubers with the aid of subdural recording of residual seizure onsets. Novel surgical approaches together with studies exploring the role of functional and nuclear imaging modalities in complicated TSC cases may serve to improve outcome in this subgroup of patients. Rasmussen’s Encephalitis This syndrome of chronic focal encephalitis of unknown origin, presents with medically refractory focal epilepsy, progressive neurologic deficits, and cortical atrophy as evident on MRI. With rare exceptions, a clinical diagnosis may be made by the presence of these 3 cardinal features within 4 to 12 months of onset.33 After more than 4 decades since the first description of this syndrome, the etiologic basis remains uncertain and therapeutic options remain limited.34-37 AEDs, together with immuno-modulation, are the preferred approach early in the course of disease when neurologic deficits are absent or very subtle.33 However, despite aggressive trials with multiple AEDs and immune-modulating agents, control of either seizures or disease progression in most cases is temporary and modest. Surgical resection of the affected hemisphere (hemispherectomy) is the only definitive intervention which halts disease progression and relieves the epilepsy.33 Decisions regarding timing of surgery are difficult in patients with only minimal or no neurologic deficits. One must carefully weigh risks versus benefits when anticipating potential neurologic deficits after hemispherectomy, such as hemiparesis, hemianopia, and speech and language impairment (with dominant hemisphere resection). Hemispherectomy may be recommended at a time when there is evidence of preexisting motor neurologic deficit because no further deterioration is expected as a result of surgical intervention. Available experience suggests that the developmental plasticity of a young brain will enable transfer of language to the nondominant hemisphere after surgery, even as late as early adolescence.38-40 Postsurgical hemianopia is irreversible, and although patients adapt well to it for daily activities of life, it precludes them from driving in the future. However, this may be an acceptable tradeoff for freedom from morbidity and
D.K. Lachhwani mortality risks due to prolonged medical management of recalcitrant seizures. The decision and timing for surgical intervention, therefore, must be tailored to individual clinical cases. The first manifestation of motor deficit during the course of illness may be the point for considering surgery to maximize the potential for brain plasticity to aid in recovery. Hemispheric Malformations of Cortical Development Infants with hemispheric malformations of cortical development may present with developmental delay, contralateral motor deficit, and epilepsy. Refractory seizures may present shortly after birth, resulting in prolonged repeated hospitalizations and the need for escalating doses of AEDs or suppressive therapy. If unihemispheric epileptogenesis can be established, hemispherectomy may be the preferred option to prevent severe risks of morbidity and mortality resulting from uncontrolled seizures. In a series of 11 patients with available follow-up who underwent hemispherectomy for intractable epilepsy because of hemispheric cortical dysgenesis, 9 patients were either seizure free (n ⫽ 5) or had a ⬎90% reduction in the seizure burden (n ⫽ 4), whereas 2 had a 50% to 90% reduction in seizures.14 Similar results were noted in another surgical series involving 12 patients with hemispheric malformations who underwent functional hemispherectomy.41 Ten of the 12 patients either became seizure free (n ⫽ 5) or had a significant reduction in seizure activity (n ⫽ 5). As a group, these patients appear to have lower seizure-free rates after surgery compared to patients with a discrete and small substrate of focal epileptogenesis.17,41,42 Careful consideration of certain MRI features may be helpful in predicting which patients would fare better with seizure control. Patients with an enlarged and malformed hemisphere (hemimegalencephaly) seem to have a smaller probability of attaining seizure freedom compared with patients with a relative preservation of 1 lobe as evident on MRI.41 This may be because of the presence of extensive microdysgenesis in deep gray structures, as well as contralateral microscopic abnormalities in patients with total unihemispheric abnormality on MRI. An anatomic hemispherectomy with a more extensive resection of the abnormal hemisphere may be preferred over a functional hemispherectomy (a smaller brain resection which accomplishes a disconnection). Combined experience from surgical centers will help in identifying the surgical procedure of choice in this patient population with multilobar or hemispheric cortical abnormalities. Medically Refractory Focal Status Epilepticus Status epilepticus is a medical emergency that is managed by aggressive use of intravenous AEDs. Refractory status epilepticus is defined as status epilepticus, which fails to respond to high-dose suppressive therapy (HDST). Improvements in pediatric intensive care have enabled us to prolong HDST. However, this therapeutic approach is associated with significant mortality and morbidity. Sahin and coworkers43,44 found that none of the children who were treated with HDST returned to pretreatment neurologic function and all developed epilepsy. Mortality rates in children after RSE range from 16% to 43.5%.45,46
Pediatric epilepsy surgery If Refractory Status Epilepticus (RSE) of focal origin is encountered, surgical options may be a consideration. Isolated case reports have found good results with multiple subpial transections, corpus callosotomy, implantation of vagus nerve stimulator, or cortical resection.47-50 In a recent report involving 10 pediatric patients, RSE was successfully stopped by resective surgery in all patients without any perioperative deaths.51 At the most recent follow-up, 70% (n ⫽ 7) patients continued to remain seizure free, whereas those with recurrence of seizures were either significantly improved (n ⫽ 2) or did not show worsening of the epilepsy compared with prestatus baseline (n ⫽ 1). Surgical morbidity compared favorably with that seen during prolonged HDST. With 10 patients, this is perhaps the largest series reported from a single center and more experience with resective surgery in RSE of focal origin is needed. It must be emphasized that epilepsy surgery in the midst of a medical emergency is challenging and must be considered only at centers with adequate expertise and experience. Infantile Spasms The syndrome of infantile spasms comprises of epileptic spasms presenting during infancy (3-7 months of age), associated with psychomotor retardation and hypsarrhythmia on EEG. The spasms themselves are electroclinically unique; on EEG, they are time locked with generalized electrodecrements preceded by slow-wave transients. It is now well accepted that a variety of pathological insults, occurring early in the course of development, can lead to infantile spasms.52 Many pharmacological treatments have been proposed; however, only few have proven to be efficacious and there is a lack of consensus about the drug of choice.53 Consideration of pharmacologic and nonpharmacologic avenues must be done in earnest because poor seizure control is likely to result in severe cognitive impairment and marked behavioral disorders.54 Patients with evidence of focal features either on clinical examination (eg, hemiparesis), seizure semiology, and/or neurodiagnostic testing (including structural [eg, MRI] and functional [eg, positron emission tomography] neuroimaging, as well as EEG) may be candidates for resective surgery. The UCLA Pediatric Epilepsy Surgery Program pioneered the concept of resective surgery for infantile spasms in the late 1980s and early 1990s.55,56 The focal epileptogenic substrates may include cortical dysplasia, infarction, infection, tuberous sclerosis, and neoplasm. The surgical strategy is individually tailored to optimize resection of the epileptogenic zone and may range from focal or lobar-multilobar resections to hemispherectomy with good seizure control.56 Surgical series have also documented improved neurodevelopmental outcome after seizure control with resective epilepsy surgery in patients with infantile spasms. Experience from UCLA showed a significant increase in developmental level 2 years after surgery, when compared with medically treated patients. Furthermore, the best developmental outcomes were observed in children in whom surgery was accomplished at a younger age and who had the highest level of developmental level presurgically. Available evidence since
117 then further substantiates the need for early surgical intervention in appropriate candidates to minimize the long term developmental impairment, which is otherwise very likely with this disorder.19,54,56-58
References 1. Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. 1-51. 1991. Ref Type: Data File 2. Wiebe S, Blume WT, Girvin JP, et al: A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345:311-318, 2001 3. Wyllie E, Comair YG, Kotagal P, et al: Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 44:740-748, 1998 4. Bittar RG, Rosenfeld JV, Klug GL, et al: Resective surgery in infants and young children with intractable epilepsy. J Clin Neurosci 9:142-146, 2002 5. Buchhalter JR, Jarrar RG: Therapeutics in pediatric epilepsy, part 2: epilepsy surgery and vagus nerve stimulation. Mayo Clin Proc 78:371378, 2003 6. Khajavi K, Comair YG, Wyllie E, et al: Surgical management of pediatric tumor-associated epilepsy. J Child Neurol 14:15-25, 1999 7. Camfield PR, Camfield CS, Gordon K, et al: If a first antiepileptic drug fails to control a child’s epilepsy, what are the chances of success with the next drug? J Pediatr 131:821-824, 1997 8. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314-319, 2000 9. Berg AT, Shinnar S, Levy SR, et al: Early development of intractable epilepsy in children: a prospective study. Neurology 56:1445-1452, 2001 10. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314-319, 2000 11. Sperling MR, Feldman H, Kinman J, et al: Seizure control and mortality in epilepsy. Ann Neurol 46:45-50, 1999 12. Shields WD: Catastrophic epilepsy in childhood. Epilepsia 41:S2-S6, 2000 (suppl 2) 13. Farwell JR, Dodrill CB, Batzel LW: Neuropsychological abilities of children with epilepsy. Epilepsia 26:395-400, 1985 14. Maehara T, Shimizu H, Shigetomo R, et al: [Functional hemispherectomy for children aged 2 years or less for the treatment of intractable epilepsy caused by cortical dysgenesis]. No To Hattatsu 32:395-400, 2000 15. Maehara T, Shimizu H, Kawai K, et al: Postoperative development of children after hemispherotomy. Brain Dev 24:155-160, 2002 16. Mihara T, Inoue Y, Matsuda K, et al: Recommendation of early surgery from the viewpoint of daily quality of life. Epilepsia 37:33-36, 1996 (suppl 3) 17. Devlin AM, Cross JH, Harkness W, et al: Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 126: 556-566, 2003 18. Battaglia D, Di Rocco C, Iuvone L, et al: Neuro-cognitive development and epilepsy outcome in children with surgically treated hemimegalencephaly. Neuropediatrics 30:307-313, 1999 19. Wyllie E, Comair YG, Kotagal P, et al: Epilepsy surgery in infants. Epilepsia 37:625-637, 1996 20. Curatolo P, Verdecchia M, Bombardieri R: Tuberous sclerosis complex: a review of neurological aspects. Eur J Paediatr Neurol 6:15-23, 2002 21. Gomez MR: History of the tuberous sclerosis complex. Brain Dev 17: 55-57, 1995 (suppl) 22. Goodman M, Lamm SH, Engel A, et al: Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol 12:85-90, 1997 23. Bebin EM, Kelly PJ, Gomez MR: Surgical treatment for epilepsy in cerebral tuberous sclerosis. Epilepsia 34:651-657, 1993 24. Guerreiro MM, Andermann F, Andermann E, et al: Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 51:1263-1269, 1998 25. Morrell F: Varieties of human secondary epileptogenesis. J Clin Neurophysiol 6:227-275, 1989 26. Karenfort M, Kruse B, Freitag H, et al: Epilepsy surgery outcome in
D.K. Lachhwani
118
27.
28.
29.
30. 31.
32. 33.
34.
35.
36.
37. 38.
39.
40. 41.
children with focal epilepsy due to tuberous sclerosis complex. Neuropediatrics 33:255-261, 2002 Lachhwani DK, Pestana E, Kotagal P, et al: Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology 64:1651-1654, 2005 Asano E, Chugani DC, Muzik O, et al: Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology 54:1976-1984, 2000 Fedi M, Reutens DC, Andermann F, et al: alpha-[11C]-Methyl-L-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency. Epilepsy Res 52:203-213, 2003 Duchowny M: Recent advances in candidate selection for pediatric epilepsy surgery. Semin Pediatr Neurol 7:178-186, 2000 Romanelli P, Najjar S, Weiner HL, et al: Epilepsy surgery in tuberous sclerosis: multistage procedures with bilateral or multilobar foci. J Child Neurol 17:689-692, 2002 Romanelli P, Verdecchia M, Rodas R, et al: Epilepsy surgery for tuberous sclerosis. Pediatr Neurol 31:239-247, 2004 Granata T, Fusco L, Gobbi G, et al: Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology 61:1807-1810, 2003 Rogers SW, Andrews PI, Gahring LC, et al: Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 265:648-651, 1994 Wiendl H, Bien CG, Bernasconi P, et al: GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen’s encephalitis. Neurology 57:1511-1514, 2001 Mantegazza R, Bernasconi P, Baggi F, et al: Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 131:179-185, 2002 Rasmussen T, Olszewski J, Lloyd-Smith D: Focal seizures due to chronic localized encephalitis. Neurology 8:435-445, 1958 Boatman D, Freeman J, Vining E, et al: Language recovery after left hemispherectomy in children with late-onset seizures. Ann Neurol 46: 579-586, 1999 Hertz-Pannier L, Chiron C, Jambaque I, et al: Late plasticity for language in a child’s non-dominant hemisphere: a pre- and post-surgery fMRI study. Brain 125:361-372, 2002 Loddenkemper T, Wyllie E, Lardizabal D, et al: Late language transfer in patients with Rasmussen encephalitis. Epilepsia 44:870-871, 2003 Carreno M, Wyllie E, Bingaman W, et al: Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 57:331-333, 2001
42. Kossoff EH, Vining EP, Pillas DJ, et al: Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology 61:887-890, 2003 43. Sahin M, Menache CC, Holmes GL, et al: Outcome of severe refractory status epilepticus in children. Epilepsia 42:1461-1467, 2001 44. Sahin M, Menache CC, Holmes GL, et al: Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children. Neurology 61:398-401, 2003 45. Gilbert DL, Gartside PS, Glauser TA: Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis. J Child Neurol 14:602-609, 1999 46. Kim SJ, Lee DY, Kim JS: Neurologic outcomes of pediatric epileptic patients with pentobarbital coma. Pediatr Neurol 25:217-220, 2001 47. Gorman DG, Shields WD, Shewmon DA, et al: Neurosurgical treatment of refractory status epilepticus. Epilepsia 33:546-549, 1992 48. Krsek P, Tichy M, Belsan T, et al: Life-saving epilepsy surgery for status epilepticus caused by cortical dysplasia. Epileptic Disord 4:203-208, 2002 49. Ma X, Liporace J, O’Connor MJ, et al: Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res 46:33-38, 2001 50. Winston KR, Levisohn P, Miller BR, et al: Vagal nerve stimulation for status epilepticus. Pediatr Neurosurg 34:190-192, 2001 51. Alexopoulos A, Lachhwani DK, Gupta A, et al: Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis. Neurology 64(3):567-570, 2005 52. Dulac O, Soufflet C, Chiron C, et al: What is West Syndrome? Int Rev Neurobiol 49:1-22, 2002 53. Mackay M, Weiss S, Snead OC III: Treatment of infantile spasms: an evidence-based approach. Int Rev Neurobiol 49:157-184, 2002 54. Caplan R, Siddarth P, Mathern G, et al: Developmental outcome with and without successful intervention. Int Rev Neurobiol 49:269-284, 2002 55. Chugani HT, Shields WD, Shewmon DA, et al: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 27:406-413, 1990 56. Shields WD: Medical vs. surgical treatment: which treatment when? Int Rev Neurobiol 49:253-267, 2002 57. Arsanow RF, LoPresti C, Guthrie D, et al: Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol 39:430-440, 1997 58. Jonas R, Asarnow RF, LoPresti C, et al: Surgery for symptomatic infantonset epileptic encephalopathy with and without infantile spasms. Neurology 64:746-750, 2005