- Email: [email protected]
Evolution of Surgical Management for Intractable Epileptic Spasms
Author's Accepted Manuscript
Evolution of Surgical Management for Intractable Epileptic Spasms Salman Rashid MD, Harry T Chugani MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(16)00016-4 http://dx.doi.org/10.1016/j.spen.2016.02.003 YSPEN581
To appear in: Semin Pediatr Neurol
Cite this article as: Salman Rashid MD, Harry T Chugani MD, Evolution of Surgical Management for Intractable Epileptic Spasms, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2016.02.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Rashid, Chugani
EVOLUTION OF SURGICAL MANAGEMENT FOR INTRACTABLE EPILEPTIC SPASMS Salman Rashid, MD 1 Harry T Chugani, MD 2
1 Carman and Ann Adams Department of Pediatrics, and the Departments of Neurology Children s Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan
2 Departmetn of Neurology, Alfred AI Dupond, Nemours Organization, Willmington, DE
Running Title: Surgical management of West syndrome
Key Words: West syndrome, PET, epilepsy surgery, epileptic spasms
Requeest reprint requests to: Salman Rashid M.D., Pediatric Neurology/PET Center Children’s Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201, Email: [email protected]
Abstract The author will have to provide one.
1
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Rashid, Chugani
Introduction
The first historical account of infantile spasms comes from the Letters to the Editor section of “The Lancet” dating back to 1841. Dr. W. J. West described the semiology of infantile spasms in his own son as “bobbings” that “cause a complete heaving of his head forward towards his knees, and then immediately relaxing into the upright position…these bowings and relaxings would be repeated alternately at intervals of a few seconds…he sometimes has 2, 3 or more attacks in a day.” 1 Dr. West also reported the subsequent marked mental retardation and developmental delay.2 More than a century later, hypsarrhythmia was recognized as the characteristic electroencephalographic pattern of infantile spasms.3 The above-described triad of spasms (clusters of axial jerks), neurodevelopmental delay, and electroencephalographic findings was given several different names, but in 1960, Gastaut suggested the eponym of “West syndrome.”4 In 1958, adrenocorticotropic hormone (ACTH) was reported to be the first successful treatment for infantile spasms.5 During the next three decades, various medications including benzodiazepines and valproic acid were tried to control infantile spasms with variable success.2 In 1991, Chiron et. al. reported remarkable efficacy of vigabatrin, especially in cases of infantile spasms related to tuberous sclerosis.6 However, due to the medically intractable nature of infantile spasms in an overwhelming number of cases, the notion that some cases can be offered a curable surgical intervention was welcomed. The aim of curative epilepsy surgery in patients with infantile spasms is to obtain seizure freedom, stop the downhill course of encephalopathy and to allow normal cognitive development.7 To attain this goal epilepsy surgery teams make use of the data obtained from the semiology of seizures, interictal electroencephalogram (EEG), ictal EEG, ictal electrocorticography (ECoG), interictal ECoG, anatomical neuroimaging, functional neuroimaging and neuropsychological testing. This chapter is a review of the history and evolution of the surgical approach in managing West syndrome. As recommended by the international league against epilepsy (ILAE), the term infantile spasms will be replaced by the term epileptic spasms in the remainder of this article.8 2
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Focal onset of Epileptic Spasms
Based on the sleep studies of patients with epileptic spasms, Hrachovy and colleagues postulated that the spasms may originate from areas near the sleep centers in the brainstem.9, 10 This hypothesis was based on the observation that children with epileptic spasms have comparatively decreased rapid eye movement (REM) sleep, which then normalizes in those who are successfully treated with medications. This theory also supported the proposed abnormality of serotonergic metabolism in raphe nuclei as the pathophysiological basis of epileptic spasms.11 The proposal that epileptic spasms originated in the brainstem was challenged in a series of publications demonstrating that surgical removal of focal brain lesions can lead to amelioration of spasms. For example, in 1979, Branch and Dyken reported a 7-monthold infant who recovered from epileptic spasms after the surgical resection of a choroid plexus papilloma in the left lateral ventricle. In this case report, the authors also made a note of focal EEG abnormalities, which were perceived to be an effect of ACTH therapy.12 During the next decade, more case reports appeared describing similar alleviation of epileptic spasms after the surgical resection of a focal lesion.13, 14 In 1988, Palm et. al. reported a case series wherein there was resolution of epileptic spasms after neurosurgical treatment (fenestration) of porencephalic cysts.15 In these case reports, it appears that the surgical resection/treatment of a focal cortical abnormality offered a curative option for refractory epileptic spasms. In addition to these neurosurgical case scenarios, other case reports also supported the idea that epileptic spasms can either be preceded or provoked by partial seizures originating from a focal cortical abnormality.16, 17
A decade after the initial hypothesis regarding the origin of epileptic spasms, a 2deoxy-2(18F)fluoro-D-glucose (FDG) positron emission tomography (PET) scan based study of local cerebral glucose metabolism in 44 infants with epileptic spasms was published. This study identified 32 infants with symmetrical hypermetabolism in the lenticular nuclei and 21 with hypermetabolism in the brainstem with or without the involvement of other structures. Although cortical abnormalities were identified in most 3
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of the cases, subcortical activation was observed regardless of an associated focal cortical abnormality. Based on these findings, a model of neuronal circuitry involved in the pathogenesis of epileptic spasms was proposed. (Figure I) It was theorized that a focal or diffuse cortical abnormality, at a critical stage of maturation, causes abnormal functional interaction with the subcortical structures, thus resulting in spasms.18 Here it is important to mention that the secondary generalization pattern observed in epileptic spasms does not appear to utilize the corpus callosum circuitry, as epileptic spasms have been observed in patients with complete agenesis of the corpus callosum.19 Epileptic spasms were initially viewed as a form of generalized epilepsy,20 but as mentioned above, with the combined use of rapidly advancing neuroimaging techniques and neurophysiological data analysis, an epilepsy pattern of focal onset with a unique pattern of secondary generalization was suggested. This proposal played an instrumental role in the current understanding and development of new concepts in the management of some children with this catastrophic disorder. However, it is important to mention that according to the ILAE, “There was an inadequate knowledge to make a firm decision regarding whether spasms may be classified as focal, generalized, or both; consequently, they have been placed in their own group as unknown.”8 It is interesting to note that the timing of onset of epileptic spasms in patients who had structural cortical abnormalities correlated with the location (or topography) of the abnormality. For example, if the cortical abnormalities were in the posterior regions of the brain, epileptic spasms would manifest earlier, as opposed to the later onset of symptoms seen with more anterior (frontal) lesions.21 This observation was in concordance with the normal pattern of brain maturation and indicated that the maturation of these focal cortical abnormalities played a role in the development of epileptic spasms. Thus, the idea that epileptic spasms originate from the brainstem was not viable.18, 22
Introduction and Success of a Neurosurgical Approach
In several functional neuroimaging based studies on epileptic spasms, the focal abnormalities were most commonly seen in the temporo-parieto-occipital regions.23-25 4
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One such study was done in 1987 and used single photon emission computed tomography (SPECT) technology. These patients had normal prior computed tomography (CT) scans, but SPECT imaging further revealed findings of focal hypoperfusion corresponding with the EEG abnormalities seen in the temporo-parieto-occipital regions.24 Three years later, an FDG PET based study done on 13 patients with presumed cryptogenic epileptic spasms showed unilateral hypometabolism involving parieto-occipito-temporal regions in 5 infants. These patients had normal prior brain CT scans. In 4 out of these 5 patients, prior magnetic resonance imaging (MRI) scans had also failed to identify these abnormalities: however, in the 5th patient there was a subtle finding of focal poor occipital grey-white matter differentiation. EEGs of these patients manifested hypsarrhythmia,
as
well
as
abnormal
discharges
lateralized/localized
to
the
hypometabolic areas seen on the PET scan. Because of poor seizure control, 4 of these infants underwent surgical resection. Following resection, all 4 patients became seizure free, and the neuropathological examination of the resected specimens revealed microscopic cortical dysplasia.23 By suggesting an aggressive search for a potentially resectable focus, the authors introduced a new dimension to the management of cryptogenic epileptic spasms. Initially, the idea of surgical treatment of epileptic spasms received some criticism,26 but later other authors supported the concept of a surgical approach.27-29 In 1993, an analysis on 23 infants who underwent surgery for epileptic spasms was presented. Based on the PET scans, surface and intraoperative EEG findings, 15 patients received cortical resection while the remaining 8 had hemispherectomies. The results were very encouraging: 15 children became seizure free, 3 had 90% seizure control and one had 75% seizure control. Only four patients did not benefit significantly from the surgery. Interestingly, PET scan was the only imaging modality to identify a focal lesion in more than half of these cases.30 In 2009, Seo et. al. published a retrospective review on the outcome of surgical treatment in non-lesional (no detectable lesions on MRI) intractable childhood epilepsies. Out of the 27 children studied, 7 carried the diagnosis of epileptic spasms. Imaging modalities of SPECT and FDG PET scans were used to identify the lesions that were not initially visualized on MRI scans. After surgery, 6 out of 7 patients with epileptic spasms achieved seizure freedom.31 5
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Role of PET Technology
Within the last three decades, PET scans have played a significant role in the identification of epileptic foci in cases of intractable epileptic spasms when conventional anatomical neuroimaging failed to reveal focal abnormalities. A review of 140 cases of medically intractable epileptic spasms revealed that without the use of PET imaging, only 30% (n=42) of cases were classified to have symptomatic epileptic spasms. Out of the 42 patients, 13 were included in the symptomatic group on neurocutaneous, metabolic or genetic etiological basis. Conventional CT and MRI detected lesions in another 29 children. However, PET scanning uncovered another 30 cases of unifocal and 62 cases of multifocal abnormalities. Thus, with the use of PET technology the number of symptomatic cases rose to 134 (95.7%).32 This study recognized four abnormal PET scan patterns: focal, multifocal, diffuse and bilateral temporal hypometabolism. (Figures II-V) Thus, with the use of PET technology, many patients who were thought to have “cryptogenic” spasms could now be re-categorized as cases of “symptomatic” spasms. The importance of PET scan in pre-surgical planning of patients with intractable epileptic spasms is supported for many reasons. To start, within the first year of life, poor grey-white matter differentiation limits the sensitivity of MRI scans in identifying an anatomical abnormality. This makes PET scan more desirable, and it may also detect contralateral brain abnormalities that could be missed by MRI scans. This could provide important information regarding postsurgical prognostication.33-35 Secondly, MRI scans frequently underestimate the extent of cortical malformations. Lastly, PET scans also provides valuable information for guiding the placement of subdural electrodes to maximize the gain from subdural ECoG. In order to obtain the best cognitive outcome, it is important to identify and resect the entire “nociferous area” rather than just the focal anatomical abnormality that might be underestimated on conventional MRI or CT scans.34 Hence, PET scanning is highly recommended in determining potential surgical candidates in cases of intractable cryptogenic epileptic spasms. However, it is important to recognize that PET scan imaging of glucose metabolism has limited value in patients
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on ketogenic diet since glucose metabolism in the brain has been altered and will thus utilize ketones as an alternative source of energy. One of the genetic etiologies of epileptic spasms that can pose significant challenges in the planning of epilepsy surgery is tuberous sclerosis. Because of the presence of multiple tubers, it may become difficult to identify the perpetrating tuber. In addition, an epileptogenic tuber located within the medial brain regions may show a generalized pattern of epileptic discharges (i.e., secondary bilateral synchrony). In such cases, anatomical neuroimaging and even conventional functional neuroimaging may fail to provide evidence of a pathogenic focus. To tackle this problem, AMT PET scans were employed. This approach utilizes alpha-(11C)-methyl-L-tryptophan (AMT) as a biomarker. AMT accumulates around the seizure focus and results in the better localization of the epileptic focus, especially in cases where there are numerous potentially epileptogenic foci but not all are actively pathogenic.36 (Figure VI) In 2005, an AMT PET scan based study of 17 patients with tuberous sclerosis suggested that resection of tubers with increased AMT uptake is highly desirable to achieve seizure freedom.37 In a recent study of 191 children with tuberous sclerosis complex, use of AMT PET scan showed an almost precise correlation with ictal scalp EEG in seizure focus lateralization. In some of the cases with non-lateralizing ictal EEG, AMT PET scan was still able to localize the seizure focus.38 It has been observed that resection of a common epileptogenic focus identified by EEG and FDG PET images not only results in seizure control but also in complete or partial reversal of developmental delay.39
Outcome of Epileptic Spasms without a Resectable Surgical Focus
In patients with multifocal PET scan abnormalities and a single epileptogenic focus on EEG, cortical resection provided improvement in seizure control, but patients remained developmentally delayed post-resection.30, 40,
41
In 1996, another study was published,
which focused on the outcome of those infants who were not considered surgical candidates because of multifocal glucose metabolism PET scan abnormalities, multifocal or bilateral ECoG changes or the absence of a recognizable epileptic focus. Fourteen such 7
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patients were followed over the next 8 years. Only four of these patients learned to walk, 13 children did not learn to talk, and 10 patients satisfied the DSM-IV diagnostic criteria for autism. Based on the findings from this study, it was suggested that the infants who had bilateral temporal brain involvement on PET scan represent a homogeneous group of patients with poor developmental outcomes.40
‘Subtotal’ Hemispherectomy
Not infrequently, the epileptogenic/nociferous cortex in a surgical case is very extensive, involving much of one hemisphere. When the child is not significantly hemiparetic, we have attempted to spare primary motor/sensory cortex in order not to introduce a motor deficit. The concept of subtotal hemispherectomy is a relatively recent development regarding the surgical approach for intractable epileptic spasms. In 2014, a study evaluated 23 patients on whom subtotal hemispherectomies were performed, and this included 11 patients diagnosed with epileptic spasms. In an effort to spare the motor function in these patients, MR diffusion tensor tractography was utilized for localization of corticospinal tracts. With the use of electrographic and functional neuroimaging data analysis (glucose, flumazenil and AMT PET scans), it was determined that these patients could have subtotal hemispherectomies while still preserving motor function. The surgical outcome was reported according to the ILAE classification.42 Eight out of the 11 patients had a class 1 outcome (complete seizure freedom without auras), while 1 patient had a class 2 outcome (seizure freedom with auras). The remaining 2 patients had at least 50% reduction in seizures compared to the baseline seizures.43 Thus, it was concluded that in selected cases of unilateral multifocal epileptogenic foci, complete hemispeherectomies could be replaced with more favorable subtotal resections.
Palliative Epilepsy Surgery The overall success rate for curative epilepsy surgery is 60 to 80%.44, 45 However, in patients who have bilateral multifocal epileptogenic foci, curative surgery is not feasible. In some such cases, palliative surgery, such as hemispherectomy, lobectomy, multilobar 8
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resection or tuberectomy, targeting the major focus of seizures can still be considered. The aim of this surgical approach is to decrease the patient’s seizure burden and improve quality of life. In a recent retrospective chart review of palliative epileptic surgeries done in the last 20 years at a level IV epilepsy surgery center, Ilyas et. al. reported four cases of epileptic spasms who underwent palliative resection. Three of these four patients had a favorable outcome, which was defined as either seizure freedom on antiepileptic medications or a 50% reduction in seizure burden.46
Conclusions The finding of a focal onset with secondary generalization epilepsy pattern was a major breakthrough in the management of patients with medically intractable epileptic spasms. FDG PET played an immense role in identification of a surgically resectable epileptic focus in many of these children. Curative surgical resection led to resolution of symptoms, which profoundly changed the clinical course of these children. Proper identification and resection of a nociferous area not only led to improved seizure control, but also allowed for improved neurodevelopment of growing infants. The preference of subtotal hemispherectomies with preservation of sensorimotor cortex has further improved the quality of life in a number of these children. Furthermore, for children with epileptic spasms where curative surgery is not feasible, palliative surgery holds reasonable promise in improving seizure control and quality of life but should be carefully considered on a case-by-case basis.
Disclosure None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References 1. 2.
West W. On a particular from of infantile convulsions. Lancet. 1841;1:2. Shields WD. Infantile spasms: little seizures, BIG consequences. Epilepsy currents / American Epilepsy Society. 2006;6:63-69. 9
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Gibbs FA GE. Atlas of electroencephalography (EEG). Cambridge.2. Eling P, Renier WO, Pomper J, Baram TZ. The mystery of the Doctor's son, or the riddle of West syndrome. Neurology. 2002;58:953-955. Sorel L, Dusaucy-Bauloye A. [Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH]. Acta neurologica et psychiatrica Belgica. 1958;58:130-141. Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. Journal of child neurology. 1991;Suppl 2:S52-59. Van Schooneveld MM, Braun KP. Cognitive outcome after epilepsy surgery in children. Brain & development. 2013;35:721-729. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-685. Hrachovy RA, Frost JD, Jr., Kellaway P. Sleep characteristics in infantile spasms. Neurology. 1981;31:688-693. Hrachovy RA, Frost JD, Jr. Infantile spasms. Pediatric clinics of North America. 1989;36:311-329. Silverstein F, Johnston MV. Cerebrospinal fluid monoamine metabolites in patients with infantile spasms. Neurology. 1984;34:102-105. Branch CE, Dyken PR. Choroid plexus papilloma and infantile spasms. Annals of neurology. 1979;5:302-304. Mimaki T, Ono J, Yabuuchi H. Temporal lobe astrocytoma with infantile spasms. Annals of neurology. 1983;14:695-696. Ruggieri V, Caraballo R, Fejerman N. Intracranial tumors and West syndrome. Pediatric neurology. 1989;5:327-329. Koch CA, Moore JL, Krahling KH, Palm DG. Fenestration of porencephalic cysts to the lateral ventricle: experience with a new technique for treatment of seizures. Surgical neurology. 1998;49:524-532; discussion 532-523. Yamamoto N, Watanabe K, Negoro T, et al. Partial seizures evolving to infantile spasms. Epilepsia. 1988;29:34-40. Donat JF, Wright FS. Simultaneous infantile spasms and partial seizures. Journal of child neurology. 1991;6:246-250. Chugani HT, Shewmon DA, Sankar R, Chen BC, Phelps ME. Infantile spasms: II. Lenticular nuclei and brain stem activation on positron emission tomography. Annals of neurology. 1992;31:212-219. Carrazana EJ, Lombroso CT, Mikati M, Helmers S, Holmes GL. Facilitation of infantile spasms by partial seizures. Epilepsia. 1993;34:97-109. Jeavons PM, Bower BD. Infantile spasms : a review of the literature and a study of 112 cases. London,: Spastics Society Medical Education and Information Unit; 1964. Chugani HT, Phelps ME. Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography. Science. 1986;231:840843. Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of human brain functional development. Annals of neurology. 1987;22:487-497. 10
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Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Annals of neurology. 1990;27:406-413. Dulac O, Raynaud C, Chiron C, Plouin P, Syrota A, Arthuis M. [Cerebral blood flow in idiopathic West syndrome: correlation with electroencephalographic findings]. Revue d'electroencephalographie et de neurophysiologie clinique. 1987;17:169-182. Cusmai R, Dulac O, Diebler C. [Focal lesions in infantile spasms]. Neurophysiologie clinique = Clinical neurophysiology. 1988;18:235-241. Hrachovy RA, Frost JD, Jr., Glaze DG, Kellaway P. Surgical treatment for infantile spasms? Annals of neurology. 1991;29:110-112. Kramer U, Sue WC, Mikati MA. Focal features in West syndrome indicating candidacy for surgery. Pediatric neurology. 1997;16:213-217. Wyllie E, Lachhwani DK, Gupta A, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology. 2007;69:389397. de la Vaissiere S, Milh M, Scavarda D, et al. Cortical involvement in focal epilepsies with epileptic spasms. Epilepsy research. 2014;108:1572-1580. Chugani HT, Shewmon DA, Shields WD, et al. Surgery for intractable infantile spasms: neuroimaging perspectives. Epilepsia. 1993;34:764-771. Seo JH, Noh BH, Lee JS, et al. Outcome of surgical treatment in non-lesional intractable childhood epilepsy. Seizure. 2009;18:625-629. Chugani HT, Conti JR. Etiologic classification of infantile spasms in 140 cases: role of positron emission tomography. Journal of child neurology. 1996;11:44-48. Sankar R, Curran JG, Kevill JW, Rintahaka PJ, Shewmon DA, Vinters HV. Microscopic cortical dysplasia in infantile spasms: evolution of white matter abnormalities. AJNR. American journal of neuroradiology. 1995;16:1265-1272. Asano E, Chugani DC, Juhasz C, Muzik O, Chugani HT. Surgical treatment of West syndrome. Brain & development. 2001;23:668-676. Kumar A, Chugani HT. Functional imaging: PET. Handbook of clinical neurology. 2013;111:767-776. Asano E, Chugani DC, Muzik O, et al. Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology. 2000;54:1976-1984. Kagawa K, Chugani DC, Asano E, et al. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). Journal of child neurology. 2005;20:429438. Chugani HT, Luat AF, Kumar A, Govindan R, Pawlik K, Asano E. alpha-[11C]Methyl-L-tryptophan--PET in 191 patients with tuberous sclerosis complex. Neurology. 2013;81:674-680. Asarnow RF, LoPresti C, Guthrie D, et al. Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Developmental medicine and child neurology. 1997;39:430-440.
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Chugani HT, Da Silva E, Chugani DC. Infantile spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography. Annals of neurology. 1996;39:643-649. Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegalencephaly: evaluation with positron emission tomography. Pediatric neurology. 1993;9:2128. Wieser HG, Blume WT, Fish D, et al. ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42:282-286. Chugani HT, Asano E, Juhasz C, Kumar A, Kupsky WJ, Sood S. "Subtotal" hemispherectomy in children with intractable focal epilepsy. Epilepsia. 2014;55:1926-1933. Tellez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain : a journal of neurology. 2005;128:1188-1198. Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Annals of neurology. 1998;44:740-748. Ilyas M, Sivaswamy L, Asano E, Sood S, Zidan M, Chugani H. Seizure control following palliative resective surgery for intractable epilepsy-a pilot study. Pediatric neurology. 2014;51:330-335.
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Figure Legends: Figure 1: Neuronal circuitry involved in the pathogenesis of infantile spasms: 1. “Nociferous” influence of abnormal cortical region on brainstem (raphe area). 2. Raphe-striatal pathway, serotonergic (5HT1D), under tonic control by corticosteroids. 3. Generation of hypsarrhythmic pattern. 4. Generation of spasms. 5. Surgical excision of primary cortical abnormality abolishes activation of circuitry Figure 2: FDG PET scan showing focal glucose hypometabolism (see arrows) in a patient with epileptic spasms and a normal MRI scan Figure 3: FDG PET scan illustrating multiple areas of cortical glucose hypometabolism in a child with intractable epileptic spasms Figure IV: FDG PET scan showing diffuse symmetric glucose hypometabolism affecting the entire cerebral cortex Figure V: FDG PET scan in a child with epileptic spasms and autism showing the pattern of symmetric bilateral temporal glucose hypometabolism Figure VI:
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Glucose metabolism and tryptophan PET scans in a child with epileptic spasms and tuberous sclerosis. A: Multifocal hypometabolism (arrows) corresponding to the tubers is seen on the glucose metabolism scan without any indication of which lesion is the epileptogenic one. B: The tryptophan scan identifies the epileptopgenic tuber (arrow) as the one with increased uptake while the remaining tubers show decreased uptake. This was confirmed by intracranial ictal EEG recordings
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Figure I
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Figure 3
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Figure V
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Evolution of Surgical Management for Intractable Epileptic Spasms Salman Rashid MD, Harry T Chugani MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(16)00016-4 http://dx.doi.org/10.1016/j.spen.2016.02.003 YSPEN581
To appear in: Semin Pediatr Neurol
Cite this article as: Salman Rashid MD, Harry T Chugani MD, Evolution of Surgical Management for Intractable Epileptic Spasms, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2016.02.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Page 1
Rashid, Chugani
EVOLUTION OF SURGICAL MANAGEMENT FOR INTRACTABLE EPILEPTIC SPASMS Salman Rashid, MD 1 Harry T Chugani, MD 2
1 Carman and Ann Adams Department of Pediatrics, and the Departments of Neurology Children s Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan
2 Departmetn of Neurology, Alfred AI Dupond, Nemours Organization, Willmington, DE
Running Title: Surgical management of West syndrome
Key Words: West syndrome, PET, epilepsy surgery, epileptic spasms
Requeest reprint requests to: Salman Rashid M.D., Pediatric Neurology/PET Center Children’s Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201, Email: [email protected]
Abstract The author will have to provide one.
1
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Rashid, Chugani
Introduction
The first historical account of infantile spasms comes from the Letters to the Editor section of “The Lancet” dating back to 1841. Dr. W. J. West described the semiology of infantile spasms in his own son as “bobbings” that “cause a complete heaving of his head forward towards his knees, and then immediately relaxing into the upright position…these bowings and relaxings would be repeated alternately at intervals of a few seconds…he sometimes has 2, 3 or more attacks in a day.” 1 Dr. West also reported the subsequent marked mental retardation and developmental delay.2 More than a century later, hypsarrhythmia was recognized as the characteristic electroencephalographic pattern of infantile spasms.3 The above-described triad of spasms (clusters of axial jerks), neurodevelopmental delay, and electroencephalographic findings was given several different names, but in 1960, Gastaut suggested the eponym of “West syndrome.”4 In 1958, adrenocorticotropic hormone (ACTH) was reported to be the first successful treatment for infantile spasms.5 During the next three decades, various medications including benzodiazepines and valproic acid were tried to control infantile spasms with variable success.2 In 1991, Chiron et. al. reported remarkable efficacy of vigabatrin, especially in cases of infantile spasms related to tuberous sclerosis.6 However, due to the medically intractable nature of infantile spasms in an overwhelming number of cases, the notion that some cases can be offered a curable surgical intervention was welcomed. The aim of curative epilepsy surgery in patients with infantile spasms is to obtain seizure freedom, stop the downhill course of encephalopathy and to allow normal cognitive development.7 To attain this goal epilepsy surgery teams make use of the data obtained from the semiology of seizures, interictal electroencephalogram (EEG), ictal EEG, ictal electrocorticography (ECoG), interictal ECoG, anatomical neuroimaging, functional neuroimaging and neuropsychological testing. This chapter is a review of the history and evolution of the surgical approach in managing West syndrome. As recommended by the international league against epilepsy (ILAE), the term infantile spasms will be replaced by the term epileptic spasms in the remainder of this article.8 2
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Focal onset of Epileptic Spasms
Based on the sleep studies of patients with epileptic spasms, Hrachovy and colleagues postulated that the spasms may originate from areas near the sleep centers in the brainstem.9, 10 This hypothesis was based on the observation that children with epileptic spasms have comparatively decreased rapid eye movement (REM) sleep, which then normalizes in those who are successfully treated with medications. This theory also supported the proposed abnormality of serotonergic metabolism in raphe nuclei as the pathophysiological basis of epileptic spasms.11 The proposal that epileptic spasms originated in the brainstem was challenged in a series of publications demonstrating that surgical removal of focal brain lesions can lead to amelioration of spasms. For example, in 1979, Branch and Dyken reported a 7-monthold infant who recovered from epileptic spasms after the surgical resection of a choroid plexus papilloma in the left lateral ventricle. In this case report, the authors also made a note of focal EEG abnormalities, which were perceived to be an effect of ACTH therapy.12 During the next decade, more case reports appeared describing similar alleviation of epileptic spasms after the surgical resection of a focal lesion.13, 14 In 1988, Palm et. al. reported a case series wherein there was resolution of epileptic spasms after neurosurgical treatment (fenestration) of porencephalic cysts.15 In these case reports, it appears that the surgical resection/treatment of a focal cortical abnormality offered a curative option for refractory epileptic spasms. In addition to these neurosurgical case scenarios, other case reports also supported the idea that epileptic spasms can either be preceded or provoked by partial seizures originating from a focal cortical abnormality.16, 17
A decade after the initial hypothesis regarding the origin of epileptic spasms, a 2deoxy-2(18F)fluoro-D-glucose (FDG) positron emission tomography (PET) scan based study of local cerebral glucose metabolism in 44 infants with epileptic spasms was published. This study identified 32 infants with symmetrical hypermetabolism in the lenticular nuclei and 21 with hypermetabolism in the brainstem with or without the involvement of other structures. Although cortical abnormalities were identified in most 3
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of the cases, subcortical activation was observed regardless of an associated focal cortical abnormality. Based on these findings, a model of neuronal circuitry involved in the pathogenesis of epileptic spasms was proposed. (Figure I) It was theorized that a focal or diffuse cortical abnormality, at a critical stage of maturation, causes abnormal functional interaction with the subcortical structures, thus resulting in spasms.18 Here it is important to mention that the secondary generalization pattern observed in epileptic spasms does not appear to utilize the corpus callosum circuitry, as epileptic spasms have been observed in patients with complete agenesis of the corpus callosum.19 Epileptic spasms were initially viewed as a form of generalized epilepsy,20 but as mentioned above, with the combined use of rapidly advancing neuroimaging techniques and neurophysiological data analysis, an epilepsy pattern of focal onset with a unique pattern of secondary generalization was suggested. This proposal played an instrumental role in the current understanding and development of new concepts in the management of some children with this catastrophic disorder. However, it is important to mention that according to the ILAE, “There was an inadequate knowledge to make a firm decision regarding whether spasms may be classified as focal, generalized, or both; consequently, they have been placed in their own group as unknown.”8 It is interesting to note that the timing of onset of epileptic spasms in patients who had structural cortical abnormalities correlated with the location (or topography) of the abnormality. For example, if the cortical abnormalities were in the posterior regions of the brain, epileptic spasms would manifest earlier, as opposed to the later onset of symptoms seen with more anterior (frontal) lesions.21 This observation was in concordance with the normal pattern of brain maturation and indicated that the maturation of these focal cortical abnormalities played a role in the development of epileptic spasms. Thus, the idea that epileptic spasms originate from the brainstem was not viable.18, 22
Introduction and Success of a Neurosurgical Approach
In several functional neuroimaging based studies on epileptic spasms, the focal abnormalities were most commonly seen in the temporo-parieto-occipital regions.23-25 4
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One such study was done in 1987 and used single photon emission computed tomography (SPECT) technology. These patients had normal prior computed tomography (CT) scans, but SPECT imaging further revealed findings of focal hypoperfusion corresponding with the EEG abnormalities seen in the temporo-parieto-occipital regions.24 Three years later, an FDG PET based study done on 13 patients with presumed cryptogenic epileptic spasms showed unilateral hypometabolism involving parieto-occipito-temporal regions in 5 infants. These patients had normal prior brain CT scans. In 4 out of these 5 patients, prior magnetic resonance imaging (MRI) scans had also failed to identify these abnormalities: however, in the 5th patient there was a subtle finding of focal poor occipital grey-white matter differentiation. EEGs of these patients manifested hypsarrhythmia,
as
well
as
abnormal
discharges
lateralized/localized
to
the
hypometabolic areas seen on the PET scan. Because of poor seizure control, 4 of these infants underwent surgical resection. Following resection, all 4 patients became seizure free, and the neuropathological examination of the resected specimens revealed microscopic cortical dysplasia.23 By suggesting an aggressive search for a potentially resectable focus, the authors introduced a new dimension to the management of cryptogenic epileptic spasms. Initially, the idea of surgical treatment of epileptic spasms received some criticism,26 but later other authors supported the concept of a surgical approach.27-29 In 1993, an analysis on 23 infants who underwent surgery for epileptic spasms was presented. Based on the PET scans, surface and intraoperative EEG findings, 15 patients received cortical resection while the remaining 8 had hemispherectomies. The results were very encouraging: 15 children became seizure free, 3 had 90% seizure control and one had 75% seizure control. Only four patients did not benefit significantly from the surgery. Interestingly, PET scan was the only imaging modality to identify a focal lesion in more than half of these cases.30 In 2009, Seo et. al. published a retrospective review on the outcome of surgical treatment in non-lesional (no detectable lesions on MRI) intractable childhood epilepsies. Out of the 27 children studied, 7 carried the diagnosis of epileptic spasms. Imaging modalities of SPECT and FDG PET scans were used to identify the lesions that were not initially visualized on MRI scans. After surgery, 6 out of 7 patients with epileptic spasms achieved seizure freedom.31 5
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Role of PET Technology
Within the last three decades, PET scans have played a significant role in the identification of epileptic foci in cases of intractable epileptic spasms when conventional anatomical neuroimaging failed to reveal focal abnormalities. A review of 140 cases of medically intractable epileptic spasms revealed that without the use of PET imaging, only 30% (n=42) of cases were classified to have symptomatic epileptic spasms. Out of the 42 patients, 13 were included in the symptomatic group on neurocutaneous, metabolic or genetic etiological basis. Conventional CT and MRI detected lesions in another 29 children. However, PET scanning uncovered another 30 cases of unifocal and 62 cases of multifocal abnormalities. Thus, with the use of PET technology the number of symptomatic cases rose to 134 (95.7%).32 This study recognized four abnormal PET scan patterns: focal, multifocal, diffuse and bilateral temporal hypometabolism. (Figures II-V) Thus, with the use of PET technology, many patients who were thought to have “cryptogenic” spasms could now be re-categorized as cases of “symptomatic” spasms. The importance of PET scan in pre-surgical planning of patients with intractable epileptic spasms is supported for many reasons. To start, within the first year of life, poor grey-white matter differentiation limits the sensitivity of MRI scans in identifying an anatomical abnormality. This makes PET scan more desirable, and it may also detect contralateral brain abnormalities that could be missed by MRI scans. This could provide important information regarding postsurgical prognostication.33-35 Secondly, MRI scans frequently underestimate the extent of cortical malformations. Lastly, PET scans also provides valuable information for guiding the placement of subdural electrodes to maximize the gain from subdural ECoG. In order to obtain the best cognitive outcome, it is important to identify and resect the entire “nociferous area” rather than just the focal anatomical abnormality that might be underestimated on conventional MRI or CT scans.34 Hence, PET scanning is highly recommended in determining potential surgical candidates in cases of intractable cryptogenic epileptic spasms. However, it is important to recognize that PET scan imaging of glucose metabolism has limited value in patients
6
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on ketogenic diet since glucose metabolism in the brain has been altered and will thus utilize ketones as an alternative source of energy. One of the genetic etiologies of epileptic spasms that can pose significant challenges in the planning of epilepsy surgery is tuberous sclerosis. Because of the presence of multiple tubers, it may become difficult to identify the perpetrating tuber. In addition, an epileptogenic tuber located within the medial brain regions may show a generalized pattern of epileptic discharges (i.e., secondary bilateral synchrony). In such cases, anatomical neuroimaging and even conventional functional neuroimaging may fail to provide evidence of a pathogenic focus. To tackle this problem, AMT PET scans were employed. This approach utilizes alpha-(11C)-methyl-L-tryptophan (AMT) as a biomarker. AMT accumulates around the seizure focus and results in the better localization of the epileptic focus, especially in cases where there are numerous potentially epileptogenic foci but not all are actively pathogenic.36 (Figure VI) In 2005, an AMT PET scan based study of 17 patients with tuberous sclerosis suggested that resection of tubers with increased AMT uptake is highly desirable to achieve seizure freedom.37 In a recent study of 191 children with tuberous sclerosis complex, use of AMT PET scan showed an almost precise correlation with ictal scalp EEG in seizure focus lateralization. In some of the cases with non-lateralizing ictal EEG, AMT PET scan was still able to localize the seizure focus.38 It has been observed that resection of a common epileptogenic focus identified by EEG and FDG PET images not only results in seizure control but also in complete or partial reversal of developmental delay.39
Outcome of Epileptic Spasms without a Resectable Surgical Focus
In patients with multifocal PET scan abnormalities and a single epileptogenic focus on EEG, cortical resection provided improvement in seizure control, but patients remained developmentally delayed post-resection.30, 40,
41
In 1996, another study was published,
which focused on the outcome of those infants who were not considered surgical candidates because of multifocal glucose metabolism PET scan abnormalities, multifocal or bilateral ECoG changes or the absence of a recognizable epileptic focus. Fourteen such 7
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patients were followed over the next 8 years. Only four of these patients learned to walk, 13 children did not learn to talk, and 10 patients satisfied the DSM-IV diagnostic criteria for autism. Based on the findings from this study, it was suggested that the infants who had bilateral temporal brain involvement on PET scan represent a homogeneous group of patients with poor developmental outcomes.40
‘Subtotal’ Hemispherectomy
Not infrequently, the epileptogenic/nociferous cortex in a surgical case is very extensive, involving much of one hemisphere. When the child is not significantly hemiparetic, we have attempted to spare primary motor/sensory cortex in order not to introduce a motor deficit. The concept of subtotal hemispherectomy is a relatively recent development regarding the surgical approach for intractable epileptic spasms. In 2014, a study evaluated 23 patients on whom subtotal hemispherectomies were performed, and this included 11 patients diagnosed with epileptic spasms. In an effort to spare the motor function in these patients, MR diffusion tensor tractography was utilized for localization of corticospinal tracts. With the use of electrographic and functional neuroimaging data analysis (glucose, flumazenil and AMT PET scans), it was determined that these patients could have subtotal hemispherectomies while still preserving motor function. The surgical outcome was reported according to the ILAE classification.42 Eight out of the 11 patients had a class 1 outcome (complete seizure freedom without auras), while 1 patient had a class 2 outcome (seizure freedom with auras). The remaining 2 patients had at least 50% reduction in seizures compared to the baseline seizures.43 Thus, it was concluded that in selected cases of unilateral multifocal epileptogenic foci, complete hemispeherectomies could be replaced with more favorable subtotal resections.
Palliative Epilepsy Surgery The overall success rate for curative epilepsy surgery is 60 to 80%.44, 45 However, in patients who have bilateral multifocal epileptogenic foci, curative surgery is not feasible. In some such cases, palliative surgery, such as hemispherectomy, lobectomy, multilobar 8
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resection or tuberectomy, targeting the major focus of seizures can still be considered. The aim of this surgical approach is to decrease the patient’s seizure burden and improve quality of life. In a recent retrospective chart review of palliative epileptic surgeries done in the last 20 years at a level IV epilepsy surgery center, Ilyas et. al. reported four cases of epileptic spasms who underwent palliative resection. Three of these four patients had a favorable outcome, which was defined as either seizure freedom on antiepileptic medications or a 50% reduction in seizure burden.46
Conclusions The finding of a focal onset with secondary generalization epilepsy pattern was a major breakthrough in the management of patients with medically intractable epileptic spasms. FDG PET played an immense role in identification of a surgically resectable epileptic focus in many of these children. Curative surgical resection led to resolution of symptoms, which profoundly changed the clinical course of these children. Proper identification and resection of a nociferous area not only led to improved seizure control, but also allowed for improved neurodevelopment of growing infants. The preference of subtotal hemispherectomies with preservation of sensorimotor cortex has further improved the quality of life in a number of these children. Furthermore, for children with epileptic spasms where curative surgery is not feasible, palliative surgery holds reasonable promise in improving seizure control and quality of life but should be carefully considered on a case-by-case basis.
Disclosure None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References 1. 2.
West W. On a particular from of infantile convulsions. Lancet. 1841;1:2. Shields WD. Infantile spasms: little seizures, BIG consequences. Epilepsy currents / American Epilepsy Society. 2006;6:63-69. 9
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Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Annals of neurology. 1990;27:406-413. Dulac O, Raynaud C, Chiron C, Plouin P, Syrota A, Arthuis M. [Cerebral blood flow in idiopathic West syndrome: correlation with electroencephalographic findings]. Revue d'electroencephalographie et de neurophysiologie clinique. 1987;17:169-182. Cusmai R, Dulac O, Diebler C. [Focal lesions in infantile spasms]. Neurophysiologie clinique = Clinical neurophysiology. 1988;18:235-241. Hrachovy RA, Frost JD, Jr., Glaze DG, Kellaway P. Surgical treatment for infantile spasms? Annals of neurology. 1991;29:110-112. Kramer U, Sue WC, Mikati MA. Focal features in West syndrome indicating candidacy for surgery. Pediatric neurology. 1997;16:213-217. Wyllie E, Lachhwani DK, Gupta A, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology. 2007;69:389397. de la Vaissiere S, Milh M, Scavarda D, et al. Cortical involvement in focal epilepsies with epileptic spasms. Epilepsy research. 2014;108:1572-1580. Chugani HT, Shewmon DA, Shields WD, et al. Surgery for intractable infantile spasms: neuroimaging perspectives. Epilepsia. 1993;34:764-771. Seo JH, Noh BH, Lee JS, et al. Outcome of surgical treatment in non-lesional intractable childhood epilepsy. Seizure. 2009;18:625-629. Chugani HT, Conti JR. Etiologic classification of infantile spasms in 140 cases: role of positron emission tomography. Journal of child neurology. 1996;11:44-48. Sankar R, Curran JG, Kevill JW, Rintahaka PJ, Shewmon DA, Vinters HV. Microscopic cortical dysplasia in infantile spasms: evolution of white matter abnormalities. AJNR. American journal of neuroradiology. 1995;16:1265-1272. Asano E, Chugani DC, Juhasz C, Muzik O, Chugani HT. Surgical treatment of West syndrome. Brain & development. 2001;23:668-676. Kumar A, Chugani HT. Functional imaging: PET. Handbook of clinical neurology. 2013;111:767-776. Asano E, Chugani DC, Muzik O, et al. Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology. 2000;54:1976-1984. Kagawa K, Chugani DC, Asano E, et al. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). Journal of child neurology. 2005;20:429438. Chugani HT, Luat AF, Kumar A, Govindan R, Pawlik K, Asano E. alpha-[11C]Methyl-L-tryptophan--PET in 191 patients with tuberous sclerosis complex. Neurology. 2013;81:674-680. Asarnow RF, LoPresti C, Guthrie D, et al. Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Developmental medicine and child neurology. 1997;39:430-440.
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Chugani HT, Da Silva E, Chugani DC. Infantile spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography. Annals of neurology. 1996;39:643-649. Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegalencephaly: evaluation with positron emission tomography. Pediatric neurology. 1993;9:2128. Wieser HG, Blume WT, Fish D, et al. ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42:282-286. Chugani HT, Asano E, Juhasz C, Kumar A, Kupsky WJ, Sood S. "Subtotal" hemispherectomy in children with intractable focal epilepsy. Epilepsia. 2014;55:1926-1933. Tellez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain : a journal of neurology. 2005;128:1188-1198. Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Annals of neurology. 1998;44:740-748. Ilyas M, Sivaswamy L, Asano E, Sood S, Zidan M, Chugani H. Seizure control following palliative resective surgery for intractable epilepsy-a pilot study. Pediatric neurology. 2014;51:330-335.
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Figure Legends: Figure 1: Neuronal circuitry involved in the pathogenesis of infantile spasms: 1. “Nociferous” influence of abnormal cortical region on brainstem (raphe area). 2. Raphe-striatal pathway, serotonergic (5HT1D), under tonic control by corticosteroids. 3. Generation of hypsarrhythmic pattern. 4. Generation of spasms. 5. Surgical excision of primary cortical abnormality abolishes activation of circuitry Figure 2: FDG PET scan showing focal glucose hypometabolism (see arrows) in a patient with epileptic spasms and a normal MRI scan Figure 3: FDG PET scan illustrating multiple areas of cortical glucose hypometabolism in a child with intractable epileptic spasms Figure IV: FDG PET scan showing diffuse symmetric glucose hypometabolism affecting the entire cerebral cortex Figure V: FDG PET scan in a child with epileptic spasms and autism showing the pattern of symmetric bilateral temporal glucose hypometabolism Figure VI:
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Glucose metabolism and tryptophan PET scans in a child with epileptic spasms and tuberous sclerosis. A: Multifocal hypometabolism (arrows) corresponding to the tubers is seen on the glucose metabolism scan without any indication of which lesion is the epileptogenic one. B: The tryptophan scan identifies the epileptopgenic tuber (arrow) as the one with increased uptake while the remaining tubers show decreased uptake. This was confirmed by intracranial ictal EEG recordings
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Figure I
Figure 2
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Figure 3
Figure IV
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Figure V
Figure VI
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