Pediatric Epilepsy Surgery in Focal Lesions and Generalized Electroencephalogram Abnormalities

Original ArticlesPediatric Epilepsy Surgery inFocal Lesions and Generalized Electroencephalogram Abnormalities Ajay Gupta,MD,Adina Chirla,RN,Elaine Wyllie,MD,Deepak chhwani,MD, Prakash Kotagal,MD,and William E.Bingaman,MDGeneralized abnormalities on scalp electroencephalo-grams(EEG)are not uncommon in children with partial epilepsy in whom a dominant focus of interictal and ictal abnormalities concordant to the brain lesion usually clarifies surgical candidacy.Children with exclusively generalized or multiregional EEG abnormalities and mental retardation are usually not considered surgical candidates,even when brain lesions are seen on imaging. Of176pediatric epilepsy surgeries at our center,we describe10children with exclusively generalized and multiregional interictal and ictal EEG abnormalities who had resection of a focal lesion seen on brain MRI. Surgical decisions were strengthened by clinical data. Surgery was offered as a last resort because of cata-strophic epilepsy and treatment failures.At26months’mean postoperative follow-up,eight had no seizures,and two had infrequent seizures.Six months after surgery, generalized electroencephalographic abnormalities had resolved in all.We conclude that generalized and mul-tiregional EEG abnormalities in the absence of dominant focus may not preclude epilepsy surgery in children with a congenital or acquired lesion seen on MRI.Generalized EEG abnormalities are likely secondary phenomena that resolve after surgery.Maladaptive neural plasticity and secondary epileptogenesis are potential mechanisms that mask an epileptogenic lesion with generalized EEG ab-normalities.©2007by Elsevier Inc.All rights reserved. Gupta A,Chirla A,Wyllie E,Lachhwani DK,Kotagal P, Bingaman WE.Pediatric epilepsy surgery in focal lesions and generalized electroencephalogram abnormalities.Pediatr Neurol2007;37:8-15.IntroductionDuring evaluation for epilepsy surgery,patients with exclusively generalized and bilaterally multiregional interictal and ictal scalp electroencephalogram(EEG) epileptiform abnormalities and cognitive delay are not usually considered surgical candidates,because such findings are presumed to suggest generalized epilepsy. However,this paradigm does not hold true in infants with generalized scalp EEG patterns such as hypsar-rhythmia,and in infantile spasms where seizure free-dom has been obtained after resection of the cortical lesion that was apparent on the brain magnetic reso-nance imaging(MRI)or positron emission tomography [1-3].It is not clear if some children beyond infancy who have exclusively generalized and multiregional EEG abnormal-ities in the presence of a focal brain lesion could benefit from epilepsy surgery.In this case series,we report on10 such children with catastrophic epilepsy who became seizure-free or who significantly improved after surgery. We also discuss the potential mechanisms of generalized EEG abnormalities and the masking of focal epileptiform abnormalities on scalp EEG.Materials and MethodsOf176children(less than16years of age)who underwent epilepsy surgery at the Cleveland Clinic during2001-2003,we identified10 children,aged3-16(mean age,8.5)years,who under went surgical resection of a focal lesion apparent on brain MRI and fluorodeoxy glucose-positron emission tomography,despite the presence of gen-eralized and multiregional scalp EEG abnormalities and a lack of aFrom the Epilepsy Center,Neurological Institute,Lerner College of Medicine,Case Western Reserve University,Cleveland Clinic Foundation,Cleveland,munications should be addressed to:Dr.Gupta;S-51,Epilepsy Center;Neurological Institute;Lerner College of Medicine;Case Western Reserve University;Cleveland Clinic Foundation;Cleveland,OH44195.E-mail:guptaa1@Received November28,2006;accepted March22,2007.8PEDIATRIC NEUROLOGY Vol.37No.1©2007by Elsevier Inc.All rights reserved.doi:10.1016/j.pediatrneurol.2007.03.004●0887-8994/07/$—see front matterpredominant EEG focus.All children were desperately sick,and had catastrophic epilepsy.Six children had a diagnosis of Lennox-Gastaut syndrome,and were previously rejected for epilepsy surgery.A focal or hemispheric lesion was noted at the first instance in7of10(70%) children on brain MRI.However,cognitive delay together with scalp EEG findings were thought to be suggestive of generalized or multiregional epilepsy(symptomatic generalized epilepsy),and thus epilepsy surgery was not offered.All children underwent a presurgical reevaluation at the Cleveland Clinic(Cleveland,OH).After careful consideration of all risks,benefits,and alternatives,resection of the lesion seen on the brain MRI was offered as a last resort.The surgical plan was approved by the Epilepsy Patient Management Committee of the Cleveland Clinic.An independent bio-ethicist interviewed every patient’s parents or legal guardian to ensure parental understanding of the involved risks and benefits.Postoperative EEG at6months and seizure outcome were noted at the last follow-up,using the classifi-cation proposed by the International League Against Epilepsy[4]. ResultsDemographic and Seizure DataIn10children(6females),the age of seizure onset was 1day to4years(mean,22months;median,18months;for a summary of data,see Table1).The range of ages at surgery was3-16(mean,8.5)years.The interval between seizure onset and surgery was3-16(mean,6.75)years.All patients were previously rejected as epilepsy surgery candidates after one(five patients)or two(five patients) presurgical evaluations at our center and other centers.At the time of their final presurgical evaluation,the mean number of daily seizures associated with falls or altered awareness was27(5-120per day).Three children had a history of frequent prolonged status epilepticus(1-3per month)with respiratory failure requiring intensive care treatment.All children were on polytherapy with2-5 (median,3)antiepileptic medications,and had previously failed polytherapy with4-9(median,5)antiepileptic medications.Four patients had an active vagus nerve stimulator device(Cyberonics,Houston,TX)placed by outside medical centers.All children had reached the end of most of the medical treatment possibilities for epilepsy. Presurgical EvaluationPertinent presurgical findings are summarized in Table1. Figure1(patient7in Table1)depicts representative findings in one patient.All children had severe cognitive delay.Objective testing for performance intelligence quotient was possible only in two children(performance intelligence quotients, 44and53),and revealed severe mental retardation.In six children(aged3-11years),the mean neuropsychologic delay in mental age was estimated to be4.5years(range, 2-7.5years).Neuropsychologic evaluation was not pos-sible in two children because of severe chronic enceph-alopathy.Seven patients had moderate-to-severe hemipa-resis,two had associated contralateral,homonymous hemianopsia confirmed by examination,and one hadasymmetric spastic quadriparesis(bilateral left-to-right hemiparesis;patient4in Table1).Ictal semiology evaluated during video EEG monitoring was helpful in lateralization in four patients who had focal motor tonic or clonic seizures involving one side of the body.All other recorded seizures had generalized semiol-ogy(Table1),with no asymmetric or lateralizing features. Interictal scalp EEGs indicated generalized EEG abnor-malities with or without independent multiregional spikes or sharp waves,but without any dominant focus.Ictal EEGs indicated a generalized onset or a nonlocalizable and nonlateralized pattern in all patients during every recorded seizure.In one patient(patient5in Table1), during one seizure out of many recorded,the ictal EEG onset was helpful in lateralization in the presence of bilateral lesions.This patient had remote bilateral ischemic strokes in the right middle cerebral and posterior branch of the left middle cerebral distributions.She had a history of daily atypical absence seizures,atonic seizures,and infre-quent episodes of generalized motor convulsions leading to status epilepticus(one status epilepticus every4-6 weeks).She had left hemiparesis.Her interictal EEG revealed a rare,right frontal spike in the first evaluation at age6years,with an overwhelming background of gener-alized slowing and generalized slow spike and wave patterns,and generalized ictal EEG during atypical ab-sence seizures.She had two subsequent video EEGs that again revealed pervasive,generalized,slow spike and wave patterns,with an ictal EEG indicating generalized spikes and waves during a recorded atypical absence seizure.Because of bilateral strokes and the generalized EEG findings,she was rejected as a surgical candidate after each of her three evaluations.In the fourth video EEG evaluation,one motor seizure that went on to become a prolonged seizure(convulsive status epilepticus)had maximum ictal onset in the right frontal region,indicating that the likely seizure onset zone for episodes of status epilepticus was in the right hemisphere.She underwent right functional hemispherectomy at age8.5years.Post-operatively,she had immediate resolution of motor sei-zures and a gradual resolution of atypical absence seizures. Her postoperative EEG at6-month follow-up also showed resolution of her interictal generalized spike and wave pattern.All patients had abnormalities on their brain MRI,with encephalomalacia in four,malformations of cortical de-velopment in three,and remote ischemic stroke in three.In four children with encephalomalacia,two had a history of significant head trauma(perinatal and nonaccidental for one each),one had a history of meningoencephalitis,and one had a remote history of hemiconvulsive-hemiplegic epilepsy syndrome.Brain fluorodeoxyglucose-positron emission tomography was performed in nine patients,and it was concordant with the brain MRI abnormality in eight, and with nonfocal findings in one.Ictal single-photoemis-sion computed tomography was not performed on any patient because of practical limitations such as pervasive9 Gupta et al:Epilepsy Surgery in Generalized Electroencephalogramsslow spike and wave interictal patterns,high seizure frequency,brief seizure duration,multiple seizure types, and difficulty in accurately pinpointing the clinical seizure onset.Chronic subdural recordings or intraoperative elec-trocorticography were not considered in any patient,as they were considered unlikely to help localize ictal onset,to salvage any eloquent regions(location,technical limita-tions because of age,or a patient’s inability to cooperate), or to change the surgical plan of complete resection of the lesion or hemisphere.Surgery and Postsurgery Follow-UpSeven patients had a functional hemispherectomy,two had a multilobar temporo-occipital/posterior parietal re-section,and one had a premotor frontal resection.At a mean follow-up of26months(range,18-36months)after surgery,eight patients were seizure-free,and two had greater than75%improvement,with freedom from status epilepticus and disappearance of the most disabling sei-zure type associated with falls.Of two patients(Table1, patients5and9)who were not seizure-free,the parents of one patient reported two generalized clonic seizures of a few seconds’duration during febrile illnesses,in addition to staring spells of a few seconds’duration,with1-2seen per month(not confirmed to be epileptic seizures).The other child had continuing but improved axial tonic seizures,10-30seconds in duration,occurring1-2per month,usually during a febrile illness.Two patients had acute postoperative seizures within the first week after surgery:one underwent repeat surgical resection(exten-sion)of the previous left temporo-occipital malformation, and in the other,only the medications were adjusted.Both patients with acute postoperative seizures had a gradual but complete resolution of seizures by6weeks after surgery.Perioperative complications occurred in two pa-tients after functional hemispherectomy:one had hydro-cephalus requiring a ventriculoperitoneal shunt,and one developed sterile chemical meningitis.No new postoper-ative deficits were noted on neurological examination at6 months and1year after surgery.At the most recent follow-up,seven children were on monotherapy,and three were on two antiepileptic medications in modest doses. Parents reported improvements in the level of alertness, attention,learning,and behavior in all children.Of10patients,nine had a scalp EEG at6months after surgery(Table1).The EEGs revealed persistent,but only sporadic,sharp waves and slowing in the operated hemi-Table1.Summary of findings in10childrenNo.of patientAge atsurgery(years)/sexSz onsetage(years)Sz/d withLOC orfallPreoperativemotor/visualdeficits Sz semiology on video Brain MRI findings1.8/F 1.5Ͼ100L HP Atonic,atypical absence,GCS,GTCS R HS,MCD2.3/F Birth40R HP,R HO R arm tonic,GTC L HS perinatal injury and SDH3. 4.25/F 1.520None Atonic sz R frontal MCD45/M 1.7510LϾR HP,inwheel chair GTC,atypical absence B/L RϾL HS encephalomalaciadue to trauma5.8.25/F35ϩSE L HP Atonic,absence,myoclonic,GTCS,1R versive Sz R MCA and L posterior branch of MCA stroke6.8/M410L HP,L HO L body tonic-clonic,GTS R TO atrophy due to HHE7.7/M450ϩSE None Atypical absence,GTS L TO MCD8.14/M0.24L HP GTC R perinatal MCA stroke9.16/F0.18ϩSE L HP Atypical absence,GCS,GTS R HS extensive encephalomalaciadue to remote meningitis,Lparacentral lobuleabnormalities also seen10.11/F0.55R HP R face clonic,complex partial,atypical absenceL MCA strokeAbbreviations:APOSϭAcute postoperative seizuresB/LϭBilateraldϭDayFϭFemaleGCSϭGeneralized clonic seizureGenϭGeneralizedGSSWϭGeneralized slow spike and waveGTCSϭGeneralized tonic-clonic seizuresGTSϭGeneralized tonic seizureHHEϭHemiconvulsive hemiplegic epilepsy syndromeHOϭHemianopsiaHPϭHemiparesisHSϭHemisphereHSYϭHemispherectomy10PEDIATRIC NEUROLOGY Vol.37No.1sphere in eight patients.Of these eight patients,additional contralateral(patients4and5in Table1)or generalized (patient9in Table1)sharp waves were seen in three patients(one who was seizure-free,and two with persis-tent but greater than75%improved seizures),all of whom had preoperative bihemispheric evidence of injury on brain MRI(patients4,5,and9in Table1).One patient had no epileptiform abnormalities on6-month postopera-tive EEG.One patient did not report for an EEG(patient 3in Table1),and only clinical follow-up was available for her.Pervasive runs of generalized slow spikes and waves, and generalized polyspikes and sharp waves,resolved in the postoperative EEGs of all patients.DiscussionEpilepsy Surgery Despite Generalized EEG Findings Our surgical series indicates that even in older children with surgically remediable epilepsy,interictal and ictal scalp EEGs may reveal generalized and multiregional abnormalities with no dominant EEG focus.In these patients,freedom from seizures,or significant improve-ment after complete resection of a lesion seen on MRI, suggests that the localized epileptogenic process was preoperatively masked by generalized EEG abnormalities. In addition to the evidence of a focal lesion(presumed to be epileptogenic)on brain MRI and positron emission tomography,the case for surgical candidacy was strength-ened by concordant findings of contralateral fixed hemi-paresis(functional deficit zone)in seven patients,con-tralateral hemianopsia in two,and ictal semiology in four with a focal motor component(symptomatogenic zone). The decision in favor of surgery for every patient in our series was made as a last resort,after careful consideration of the risks of surgery,of new postoperative deficits,and of the risk of continuing seizures on medical treatment. Our series thus expands the age for surgical treatment of epilepsy,in the presence of generalized scalp EEG abnor-malities,that was previously reported to be mainly suc-cessful in infants with epileptic(infantile)spasms and hypsarrhythmia who had successful seizure outcome after resection of a lesion seen on brain MRI or fluorodeoxy-glucose positron emission tomography[1].It is well-known that congenital epileptogenic lesions may manifest first with partial clinical and focal EEG seizures during early infancy.However,later in infancy, infantile spasms and hypsarrhythmia[2,5-7]appear as a dominant phenotype,with the disappearance or dissolutionTable1.ContinuedInterictal EEG ResectivesurgeryHistopathologicfindingsPostoperativefollow-up(months)Sz outcomeϳ6-month postoperative EEGGSSW R HSY MCD36Sz-free Isolated R HS SWGen and B/L MR L HSY Gliosis34Sz-free L HS SW at O1GSSW R frontal MCD28Sz-free NAGen and B/L MR R HSY Remote ischemia,gliosis28Sz-free Few SW R HS and L HS at C3 GSSW and B/L MR R HSY Remote ischemic injury27Stares,brief febrile GCS L HS SW at C3-T7(newfinding in nonoperated HS) Gen and B/L MR rare P3SW R TO Remote ischemic injury26APOS,none subsequently Rare R HS SW at C4,CzGen and R and L temporal L TO MCD24APOS,surgeryϫ2No SWGSSW and rare SW R HS R HSY Remote ischemia,gliosis19Sz-free Isolated Gen max R frontal SW GSSW max bifrontal R HSY Gliosis19Brief GCSϳ2/month Gen and MR SW,no GSSW GSSW max bifrontal L HSY Remote ischemic injury18Sz-free Few R HS sharp transientsLϭLeftLOCϭLoss of consciousnessMϭMalemaxϭMaximumMCAϭMiddle cerebral arteryMCDϭMalformation of cortical developmentMRϭMultiregionalNAϭNot availableRϭRightSDHϭSubdural hematomaSEϭStatus epilepticusSWϭSharp wavesSzϭSeizureTOϭTemporo-posterior temporal-occipital11Gupta et al:Epilepsy Surgery in Generalized ElectroencephalogramsFigure 1.Patient 7in Table 1.Interictal scalp EEG with runs of slow spike and wave com-plexes in left temporal (A),right temporal (B),and generalized (C)distribution.(D)Ictal scalp EEG during generalized tonic seizures reveals low-voltage beta rhythms and disappear-ance of slow spike and wave.Preoperative high-resolution (2-mm slices with no inter-splice gap)coronal T 1brain MRI indicates left temporal malformation,with blurred gray-white junction and dysmorphic left hip-pocampus (E,left,TR/TE ϭ11.40/4.4ms).The posterior margin of the dysplasia ex-tended into the occipital lobe.Postoperative T 1brain MRI (E,right,TR/TE ϭ700/12ms)reveals resected left temporal and basal occipital region.(F)An EEG 6months after surgery indicated return of normal right hemispheric background,with expected de-creased background over the left hemi-sphere.Horizontal ruler bars under EEG tracings represent 1second.12PEDIATRIC NEUROLOGY Vol.37No.113Gupta et al:Epilepsy Surgery in Generalized Electroencephalogramsof partial seizures and focal EEG abnormalities.All children in our group had hemispheric or large lobar or multilobar lesions that were congenital or acquired early in life.It is possible that early focal EEG findings at the onset of epilepsy were not recognized in some children in our series.We reviewed all records of every patient to the extent that they were available at the time of final evaluation. However,from the time they were seen by us or another tertiary-care center for presurgical evaluation,except for one patient(patient5in Table1,with a bilateral stroke with right frontal sharp waves and seizure onset),the scalp EEG findings were exclusively generalized and multiregional. With the advent of high-resolution brain MRI and fluorodeoxyglucose positron emission tomography,care-ful study of MRI and positron emission tomography data is necessary,and importance should be attached to any neuroimaging finding that is concordant with a patient’s history,examination,and seizure semiology,despite the presence of generalized and multiregional EEG abnormal-ities.It is possible that after a comprehensive evaluation, some older children with congenital or acquired lesions, who are excluded from further detailed evaluation for epilepsy surgery because of Lennox-Gastaut syndrome or symptomatic generalized epilepsy,may become candi-dates for surgical treatment of epilepsy.It remains unclear why a finding of generalized and bilaterally multiregional EEG abnormalities does not de-velop in all children with epilepsy because of congenital or early onset-acquired lesions.The location or etiology of a lesion may not be likely factors,because patients in our series had diverse locations and pathological substrates. Age at time of brain injury,age of onset of epilepsy, duration of epilepsy,and size of the lesion may be relevant factors,because all children in our study had long-standing intractable epilepsy because of large congenital or early onset-acquired brain lesions.There may be additional genetic factors giving rise to susceptibility for excessive or maladaptive plasticity in some children.Our series has the limitation of the small number of patients who were retrospectively studied.However,our experience is significant in expanding the selection criteria for pediatric epilepsy surgery beyond infancy. Generalized Seizures and Scalp EEG Abnormalities in Focal Lesions:Potential MechanismsFew mechanisms could be hypothesized to explain a generalized and multiregional scalp EEG in children with focal lesions.Recently,excessive or maladaptive neural plasticity was suggested to explain the progressive nature of certain types of human epilepsy[8,9].The available evidence regarding the maladaptive neural-plasticity the-ory suggests that initial precipitating injuries or insults to a developing brain and seizures may set into motion a sequence of slowly evolving cellular events that presum-ably alter neural circuits and eventually render these circuits vulnerable to spontaneous synchronization and progressive susceptibility to seizures[9].A previously well-known phenomenon in epilepsy,kindling,was also viewed recently as a phenomenon of neural plasticity [9,10].The process of a progressive and permanent in-crease in seizure susceptibility via kindling in animal models requires repeated after-discharges(equivalent to clinical seizures)or the occurrence of frequent subclinical episodes of network synchronization(possibly equivalent to a pervasive interictal slow spike and wave pattern in scalp EEG)after an initial injury[11].Kindling leads to abnormal network synchronization and circuit alterations, and ultimately results in progressive,spontaneous seizures [9].The occurrence of kindling regardless of the site of initial stimulation(injury or lesion)in the brain,together with the unique characteristics of a developing brain [12,13],may explain the observed clinical course of cognitive decline,generalized seizures,and emergence of generalized and multiregional discharges with a loss(or lack)of focal abnormalities.Another previously described mechanism that was pro-posed to explain similar findings is secondary epilepto-genesis.Secondary epileptogenesis refers to a process whereby an actively discharging epileptogenic region(i.e., primary focus)gradually induces similar paroxysmal epileptogenic properties in the synaptically related or remote cerebral regions of the network(i.e.,satellite or secondary foci).Recently,in patients with hypothalamic hamartoma,secondary epileptogenesis was proposed as a mechanism to explain the emergence of generalized EEG seizures and interictal slow spike and wave patterns [14].It was demonstrated that gelastic seizures,the signature partial seizures associated with hypothalamic hamartoma,originate from the hamartoma(the primary focus of secondary epileptogenesis),and can be repro-duced by electric stimulation of the hamartoma by ster-eotactically placed depth electrodes[15].On the other hand,gradually evolving interictal generalized spike and wave EEG patterns,and other types of generalized and complex partial seizures seen later in life in patients with hypothalamic hamartoma,are not consistently observed to originate from the hypothalamic hamartoma on scalp and intracranial EEG recordings[14,16],implying that these findings may represent an extralesional(secondary focus of the secondary epileptogenesis)phenomenon.After successful resection of hamartoma in12patients in one series[14],11of12patients had a remission of general-ized and gelastic seizures,associated with a marked reduction or disappearance of interictal generalized slow spike and wave activity and neurobehavioral improve-ment.The presence of generalized slow spike and wave discharges in our patients,and their disappearance on postoperative EEGs,suggest that this secondary phenom-enon may not be unique to hypothalamic hamartoma,but could well occur in supratentorial cortical lesions. Another poorly understood concept is the secondary bilateral synchrony that was proposed in the pre-neuroim-aging era to explain the presence of bilateral synchronous14PEDIATRIC NEUROLOGY Vol.37No.1spike and wave discharges in26patients(out of31)with seizures originating from a focal lesion in the parasagittal region[17].Freedom from seizures,or significant im-provement,was reported in24of31patients after resec-tion of a mesial cortical lesion.The concept of secondary bilateral synchrony was later used as a basis to devise tests for differentiating between primary and secondary bilat-eral synchrony[18,19].Intracarotid sodium amobarbital and its various modifications were used to determine the “driving cerebral hemisphere”by the suppression of gen-eralized spike and wave discharges when the epileptogenic hemisphere was injected[19,20].Because the invasive nature of the tests and the need for general anesthesia or sedation in children complicate the interpretation of these tests,fractional intravenous sodium pentothal injection was used in children to study dose-dependent differential effects upon synchronous spikes and waves[18,21].How-ever,these tests were often difficult to interpret,and were not found to be reliable enough to use as routine diagnostic tools[22,23].No patient in our study had a localized mesial cortical lesion.We did not conduct intracarotid or intravenous barbiturate injections,because we did not believe that the tests would provide any strong comple-mentary data to alter surgical decisions regarding our patients.ConclusionsThe exclusively generalized expression of EEG abnor-malities in the presence of a focal cortical lesion(congen-ital or acquired during infancy)may occur beyond infancy. Freedom from seizures is possible in some older children after resection of a brain lesion seen on MRI,despite the presence of generalized scalp EEG abnormalities and the absence of dominant or concordant focal EEG abnormal-ities.When present,focal motor deficits such as hemipa-resis,carefully observed focal features of seizure semiol-ogy,or focal findings on an ictal EEG earlier in life may strengthen the case for considering epilepsy surgery. 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