Surgical treatment of epilepsy

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EPILEPSY

SURGICAL TREATMENT OF EPILEPSY Nancy Foldvary, DO, William E. Bingaman, MD, and Elaine Wyllie, MD

Epilepsy affectsapproximately 0.4%to 0.8%of the population.54In 30% to 40% of patients, seizures persist despite appropriate medical treatment.53 In the United States, an estimated 150,000 people develop epilepsy each year and approximately 2000 to 5000 may become surgical candidatesM; currently, the number of epilepsy surgeries performed is far lower. Many health-care providers are unaware of the consequences and long-term prognosis of poorly controlled epilepsy, and the benefits of early surgical treatment in carefully selected candidates. Life expectancy is decreased in patients with epilepsy, and mortality is highest among those with poorly controlled seizures.@Among patients treated surgically, complete relief of seizures reduces mortality rates to levels comparable with the general population.'0s Recent advances in neuroimaging have revolutionized the identification and evaluation of surgical candidates. Patients who would have been rejected only one decade ago are now being considered for surgery. RECOGNITIONOF SURGICAL CANDIDATES

Identification of surgical candidacy begins with the determination of medical intractability, a concept that is ill-defined. At most centers, adults are considered to have medically intractable epilepsy when seizures continue despite adequate monotherapy trials of two antiepileptic drugs (AEDs), with or without one trial of polytherapy, over a period of From the Department of Neurology, Section of Epilepsy and Sleep Disorders, Section of Pediatric Epilepsy, Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, Ohio

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2 For many epileptologists, this includes trials of phenytoin and carbamazepine, the drugs of choice for focal seizures75;however, newer agents like lamotrigine and oxcarbazepine are being used as monotherapy with increasing frequency. A second first-linedrug should be administered once the first has failed because of suboptimal seizure control or adverse effects. This strategy results in a significant seizure reduction in less than 50% of patient^.^^,^ If two monotherapy trials are unsuccessful, the chance of achieving seizure control with additional agents is less than 20%.75,104*106 Once several AEDs have proven ineffective, the chance of seizure freedom after additional medical treatment, including experimental agents, is less than 5%.29*58,79 Antiepileptic drugs are chosen according to seizure type and severity and must be administered in appropriate doses. When polytherapy is required, AEDs should be chosen based on the concept of rational polytherapy, that is, combining agents with different mechanisms of action.69The coadministration of agents with similar mechanisms is unlikely to be superior to either drug alone, and adverse effects are likely to i n ~ r e a s e . ~The ',~~,~ duration of medical management prior to referral to a surgical center must be individualized. Two or three drug trials can be accomplished in 1 to 2 years. Most patients presenting for surgical consideration have been treated with multiple agents by the time they are referred to epilepsy centers. This is because of the reluctance of physicians to consider surgery until all medical options have been exhausted. Laboratory monitoring is essential in the determination of medical intractability and helps to exclude noncompliance as a cause of poor seizure control. Gilman et a1& found that 21 (29%) of 72 pediatric surgery candidates failed to meet medical intractability criteria. The most common deficiency was failure to attain maximally tolerated serum concentrations with agents administered as monotherapy; however, in general, correction of the criterion omission failed to produce a significant reduction in seizures. Another criterion of medical intractability is that seizures or adverse effects of AEDs should be of sufficient severity or frequency to interfere with quality of life. Patients with simple partial seizures (SPS)alone are generally not considered for surgery because the risk is likely to exceed the benefit; however, surgical treatment may be a consideration in individuals with exclusively nocturnal seizures or medically resistant SPS, when AED therapy produces significant adverse effects or in patients, with welldefined, surgically accessible lesions. Complex-partial seizures ( C E ) or generalized motor seizures (GMS) occurring as infrequently as once every few months can sufficiently impede academic or job performance, driving, and employment opportunities. Advances in technology and knowledge of the risks and benefits of epilepsy surgery have broadened the pool of surgical candidates. Seizure freedom was achieved in 64% of patients with a mean intelligence quoof 70, despite the presence of multiple lesions on magnetic restient (IQ) onance imaging (MRI) in nearly one half of ~ases.4~ Surgery is effective in older individuals,n, '05 although morbidity may be increased because of

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the presence of vascular disease. Complications of the intracarotid amobarbital test (IAT) may be greater in older patients.73Surgery has also shown to be effective in some patients with multilobar or bilateral seizure foci.89 Surgery is contraindicated in children with benign focal epilepsy of childhood, and in individuals with idiopathic generalized epilepsy, nonepileptic seizures (NES) alone, and progressive medical or neurologic disorders. Surgical decision-making must be individualized in patients with seizures arising from eloquent areas because of the risk of neurologic morbidity. The determination of surgical candidacy in individuals with mental retardation and active psychiatric disease is controversial.Because frequent seizures can exacerbate psychosis and depression, surgery may be considered in subjects with active psychiatric disease, if the perceived benefit outweighs the risks. THE PRESURGICAL EVALUATION

The goal of the presurgical evaluation is to delineate the epileptogenic zone, the region of cortex capable of generating seizures, the complete removal or disconnection of which is required to produce a seizure-free state.n The evaluation includes clinical history, ictal and interictal EEG, neuroimaging (e.g., MR imaging, single photon emission computed tomography [SPECT], positron-emission tomography [PET], computed tomography [CTI, magnetic resonance spectroscopy [MRSI),and neuropsychologic assessment (e.g., neuropsychologicbattery, IAT, and psychosocial evaluation). A recommendation for surgery is made when the epileptogenic zone has been adequately defined, and the proposed resection is believed to be associated with a high likelihood of seizure relief and a low risk of neurologic and cognitive morbidity. Neuroimaging

Recent advances in neuroimaging have revolutionized the approach to patients with focal epilepsy. MR imaging has replaced CT scanning as the study of choice, although CTscanning remains superior in the detection of calcified lesions. The presence of a lesion on MR imaging is an important predictor of good surgical o ~ t c o m e . ’ The ~ , ~use ~,~ of~special imaging sequences increases the detection of small neoplasms, developmental abnormalities, and mesial temporal sclerosis (MTS).SPECTand PET measure functional changes produced by seizures. MRS is a newer tool that demonstrates regional metabolic alterations in epileptogenic tissue. Video Electroencephalogram(VEEG) Monitoring

Video electroencephalogram (VEEG) monitoring identifies interictal epileptiform and nonepileptiform abnormalities, accurate seizure classification, and correlation of clinical behavior and electrographic

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finding^.^, 15, lo9 Patients are generally hospitalized for 3 to 7 days, and AEDs are usually reduced or discontinued to record habitual seizures.” Trained hospital personnel assess level of consciousness, language, memory, and presence of focal neurologic sensory or motor deficits during seizures, which may aid in the localization and lateralization of the epileptogenic region. The presence of focal-clonic activity, unilateral dystonic posturing, postictal language disturbances, ictal speech, automatisms with preserved awareness, and ictal vomiting are helpful clues in the lateralization of focal s e i z u r e ~ . 3 ~ , Clonic ~ ’ , ~ ~activity ,~ of a limb or face, and version (forced, unnatural turning of the head or eyes) occurring in the early part of a clinical seizure reliably predict seizure origin from the contralateral hemisphere in older children and adults,128 although version may be misleading in infants.87The use of closely spaced scalp electrodes improves the yield of spike detection over the standard 10 to 20 System?’ Special recording techniques are particularly helpful in the localization of seizures arising from areas inaccessible to scalp electrodes. Sphenoidal electrodes are comepileptiform activity from monly used to improve the yield of the mesial temporal or orbito-frontal regions. NeuropsychologicAssessment In adolescents and adults, the presurgical neuropsychologic assessment includes formal neuropsychologic testing, IAT for lateralization of language and memory, and a psychosocial evaluation. Neuropsychologic testing consists of a battery of standardized tests that measure global intelligence, language, memory, and other cognitive faculties. Preoperative cognitive and language functioning is used to predict the risk of loss of function after a given type of surgery. Material-specific memory deficits have been reported in adults following temporal lobectomy and are more common after resections of the dominant hemisphere.= Higher preoperative memory scores and absence of a lesion on MR imaging are predictive of postoperative memory deficits in a d ~ l t s . ’The ~ value of neuropsychologic testing in predicting outcome of epilepsy surgery in the pediatric population is unknown; however, a psychosocial evaluation, including an assessment of the goals of the patient or parents and development and behavioral issues that may adversely affect outcome, should be performed in all pediatric epilepsy surgery candidates. The IAT is routinely performed in adolescents and adults with temporal lobe epilepsy (TLE) to identify the hemisphere of language dominance and establish whether the contralateral temporal lobe can support memory. Because the study is performed in an angiography suite and requires patient cooperation, the IAT is not routinely performed in infants and young children; however, in cases where lateralization of memory or language is necessary to proceed with surgery, a modified IAT using pictures only or pictures with simple words can be performed safely and effectively in young children.”’

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lnvasive EEG When noninvasive VEEG and neuroimaging fail to adequately delineate the epileptogenic zone, invasive EEG may be indicated. The decision to proceed with invasive monitoring is made only when the results of noninvasive evaluation provides enough information to ensure appropriate electrode placement, and patient cooperation and maturity are sufficient to assure safety and attainment of the necessary data for surgical decision-making; consequently, young children and patients with severe cognitive impairment are not ideal candidates. Although more sensitive than surface EEG, invasive recordings provide a limited view of cerebral activity, because information is obtained only from areas where electrodes are placed. Cortical stimulation for mapping language and somatosensory cortex can be performed extra- or intraoperatively in cases where the epileptogenic zone is located in or near eloquent areas. The use of tailored resections based on intraoperative electrocorticography(ECoG) is controversial. The value of spiking on ECoG, in guiding the extent of resection, is limited by the variable effects of anesthetic agents on spike rate and the fact that interictal spiking is typically more widespread than the epileptogenic zone.= Invasive monitoring is performed with depth or subdural electrodes. Depth electrodes are bipolar or multiple-contact wires placed stereotactically into the brain. The use of depth electrodes has declined with advances in neuroimaging that have improved visualization of the mesial temporal structures. Depth electrodes are most commonly used to determine seizure origin in patients with TLE and bilateral abnormalities on surface EEG or neuroimaging studies and may also be used to determine the presence of epileptogenicity of circumscribed lesions, such as nodular heterotopias. Depth electrodes are placed through burr holes and may be left in place for up to 4 weeks. The risks of depth electrode implantation include hemorrhage, infection, and infarction. Hemorrhage is the most common major complication, occurring in less than 2% of cases.'07 Subdural electrodes are embedded in thin Silastic plates arranged in various sizes of strips or grids. Electrodes are inserted through a burr hole or craniotomy into the subdural space over cortical regions of interest. This technique records multiple regions over one or both hemispheres and mapping of functional cortex. Infection is the most common complication of subdural electrodes? In a series of 198 subdural grid evaluations performed at the Cleveland Clinic from 1980 to 1997, complications occurred in 26%of patients overall; 12%had infections, and 11%had transient neurologic deficits.52Epidural hematoma (2.5%),increased intracranial pressure (2.5%),and infarction (1.5%)were rarer occurrences. One subject died intraoperatively during electrode placement. The complication rate increases with the number of electrodes, duration of monitoring, and age of the patient?2 A lower morbidity using strips versus grids has been r e p ~ r t e d . ~

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SURGICAL PROCEDURES

The types of surgery performed in patients for refractory epilepsy include corticedomy, lobectomy, lesionectomy, hemispherectomy, corpus callosotomy, multiple subpial transection, and newer procedures including gamma knife surgery and deep brain stimulation. Temporal Lobe Resection Temporal lobe epilepsy is the most common type of focal e ilepsy in adolescents and adults, constituting nearly two thirds of cases? In most cases, seizures arise from the mesial temporal structures (amygdala, hippocampus, and parahippocampal gyrus)." Mesial temporal lobe epilepsy (MTLE) is the most widely recognized of the symptomatic focal epilepsies. Febrile seizures in infancy or childhood represent the most common risk factor, present in as many as 67% of cases.&Other risk factors include central nervous system (CNS) infection, head trauma, and perinatal injury. Seizure onset ranges from the latter half of the first decade of life to early adulthood, typically beginning after a latency period following the presumed cerebral insult. The majority of patients with MTLE report auras, with rising abdominal sensations, and fearful feelings being the most common. Virtually all patients have complex partial seizures ( C E ) associated with oral or manual automatisms, and approximately 50%of atients experience secondary, generalized tonic-clonic seizures (GTCS). Over 90% of patients with MTLE have epileptic discharges localized to the sphenoidal or anterior temporal electrodes, and bi-temporal-independent discharges occur in 25% to 50% of cases (Fig. 1).40,'22 Lateralized rhythmic theta or alpha activity in the ipsilateral temporal region within the first 30 seconds of seizure onset is observed in approximately 80% of patients (Fig. 2).40,99 High-resolution MR imaging most commonly reveals hippocampal atrophy and abnormal signal intensity in the mesial temporal region, suggestive of mesial temporal sclerosis (MTS) (Fig. 3). Mesial temporal sclerosis is the most common pathologic substrate of MTLE.'I9 Marked neuronal loss in the CAI, CA3, CA4, and the dentate granule cells is observed; whereas, the pyramidal cells the CA2, subiculum, entorhinal cortex, and temporal neocortex are relatively spared. Loss of granule cell innervation leads to reactive synaptogenesis that results in an excitatory process capable of initiating and propagating seizures. Other etiologies include neoplasms, vascular malformations, and malformations of development. Dual pathology is observed in approximately 30%of surgical speci~nens.~' The incidence of dual pathology (e.g., M E with malformations of cortical development) may be higher in children with MTLE.78 Temporal lobectomy was pioneered by Wilder Penfield and Flaniginw at the Montreal Neurological Institute in the 1930sfor the treatment of medically refractory TLE. The extent of temporal lobe resection has evolved over the last several decades. Anterior temporal lobectomy (ATL) is the most common surgical procedure performed in adolescents and adults.

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Flgure 1. lnterictal EEG from a 22-year-old woman with a history of febrile seizures in infancy and poorly controlled partial seizures since 7 years of age. Seizures began with a sensation of fear and were characterized by oral and manual automatisms with partial responsiveness and dystonic posturing of the left upper extremity. Repetitive sharp waves are seen in the right anteromesial region maximal at the sphenoidal electrode.

The resection includes the anterior 3.0 to 3.5 cm of the inferior and middle temporal gyri, uncus, part of the amygdala, and the anterior 2.0 to 3.0 cm of the hippocampus and adjacent parahippocampal gyrus (see Fig. 3).%In recent years, more precise delineation of the epileptogenic focus has led to more limited resections. Selective excision of the epileptogenic mesial temporal structures, sparing temporal neocortex may be considered for patients with MTLE. Amygdalohippocampectomy (AH) was first described who gained access to the mesial temporal structures in 1958 by Nieme~er;~ through the middle temporal gyrus. The operation gained popularity in the 1980s after Ya~argil's'~~ description of the transsylvian AH. Amygdalohippocampectomy can also be accomplished through transcortical, transsulcal, and subtemporal approaches. Temporal lobe resection produces a seizure-freestate in 60%to 80% of patients, although auras may p e r ~ i s t . " ~ In ' , ~a 1992 survey of 100 epilepsy surgery centers worldwide, seizure freedom was achieved in 67.9%of 3579 patients treated with ATL and 68.8%of 413 patients following AH.4' Less than 10% of patients are unimproved.4' Dependency of surgical success on the extent of hippocampal resection is controversial?,lz4 Electrocorticography may be used to define the extent of mesial temporal Other investigators have reported comparable results following ATL and AH.6.45.118a tcome is less satisfactoryin patients with bilateral hippocampal atrophy and normal, symmetric hippocampal formations.6 Similarly, the presence of significant unilateral temporal hypometabolism on "FDG (fludeoxyglucose)PET is associated with a higher likelihood of seizure

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Figure 2. A, lctal tracing from the patient in Figure 1. Rhythmic theta activity is seen in the right anteromesial region at EEG onset. B, Evolving in frequency 13 seconds later.

freedom after temporal resection."2 Bitemporal hypometabolism is associated with a worse seizure outcome and higher rate of bilateral, diffuse, extratemporal, or independent seizure onsets, and bilateral or diffuse findings on MR imaging.'*," Although not absolute, earlier age of onset, definable etiology, temporal lobe seizure symptomatology, and EEG and neuropsychologic localization to the operated temporal lobe, are associated with a more favorable outcome after temporal resecti0n.9~

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Figure 3. A, Preoperative coronal T1 (leff) and FLAIR (right) images in the patient presented in Figures 1 and 2. Mild right hippocampal atrophy, confirmed by volumetric analysis is demonstrated on the coronal T1 image. An increase in signal intensity in the same area is seen on the FLAIR image. B, Postoperative sagittal (leff) and coronal T1 (right) images demonstrate complete resectionof the mesial temporal structuresand a 4 cm resection of the lateral neocortex. The patient has been seizure-freefor 3 years and off medication for 1 year.

Significant decrements in material specific memory are observed in 40% to 60% of atients following left ATL and in 10% to 30% of patients after right ATL!,”,” These changes are strongly correlated with the preoperative structural and functional integrity of the resected hippocampus.’ Patients without hippocampal atrophy or histologically confirmed MTS have the greatest risk for marked memory decrement^?^," Amygdalohippocampectomy may be associated with selective preservation of listlearning ability despite decrements in narrative prose recall and figural memory?

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Modest decrements in visual confrontation naming are frequently observed following resection of the language-dominant temporal lobe.12,103 The risk of decline in namin is eater with more extensive resection of the lateral temporal neocortex In2ddition to memory and language disturbances, hemiparesis, psychiatric disturbances, hematoma, meningitis, and diplopia caused by third or fourth cranial neuropathy have been reported after temporal lobe re~ection.’~,~’ Superior quadrant defects are found in over 50% of patients after ATL.I2In a recent series, bilateral incongruous defects were detected by automated perimetry in 31 of 32 patients who underwent Extratemporal Resection Extratemporal resection is the most common type of epilepsy surgery performed in infancy and early childhood. Postoperative seizure freedom is less frequent than following temporal resection and is dependent on completeness of resection of the epileptogenic zone. Seizure freedom is achieved in 23%to 54%of patients, and another 25%of 35%are markedly impr0ved.4~. 95, 113, 127 In infants and children with severe extratemporal epilepsy, outcome may be very satisfymg.The most common etiologiesare malformations of cortical development, vascular malformations, and lowgrade tumors. The absence of a lesion on MR imaging or functional imaging studies is associated with a lower likelihood of seizure freedom. Invasive monitoring and cortical stimulation are usually required to delineate the epileptogenic zone and identify eloquent areas. Surgical treatment of frontal lobe epilepsy (FLE) is complicated by a variety of factors limiting the localizing value of surface EEG recordings in patients with seizures arising from deep or midline regions. These include the inaccessibility of much of the frontal lobes to surface electrodes, the rapid spread of seizures within and outside the frontal lobe, secondary bilateral synchrony, and bilateral epileptogenesis caused by bifrontal injury, and variability in size of seizure onset zones.% Ictal symptomatology is typically more helpful than EEG in the localization of frontal lobe seizures. Epilepsy arising from the supplementary sensorimotor area (SSMA) is one example. Brief seizures characterized by sudden asymmetric tonic posturing (fencing posture), vocalization, and preserved awareness are observed.B1In many cases, the interictal EEG is normal, and the ictal EEG is either nonlocalized or obscured by muscle or movement artifact. Similarly, seizures arising from the pen-rolandic area are characterized by focal motor or sensory disturbances involving the contralateral face, arm, or leg, depending on the specificarea of cortex activated. Other typical features include postictal hemiparesis (Todd’s paralysis) and a tendency for epilepsia partialis continua. Seizureoutcomes are similar between FLE series. Of 100frontal cortectomies performed with or without partial corpus callosotomy or extension to the parietal or temporal cortex, 23%of patients were rendered seizure free, and an additional 32% experienced a marked seizure reduction.”’

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The best results were obtained following resection of the central, posterior medial frontal, and frontotemporal regions. These figures are comparable with a series of 257 patients with nontumorous FLE operated prior to the advent of MR imaging, in which 26% were rendered seizure free and an additional 30% were markedly improved.%In a smaller, more recent series of 16 patients with FLE, 67%were rendered seizure free after frontal lobe resection with or without anterior corpus callosotomy (ACC) or ACC alone, despite the absence of a lesion on MR imaging in 37%of cases.68 Motor deficits are common immediately after frontal lobe resection. In a recent series of 28 patients with supplementary sensorimotor area epilepsy (SSMA), aphasia or hemiparesis was observed in 89%of patients, resolving within days or weeks in all cases.'3oMajor, but transient akinetic syndromes can occur following resection of the posterior aspect of the mesial frontal lobe."' In general, no significant disturbances of fine motor function or speech are observed long-term after resections involving the SSMA.28The occurrence of motor deficits following premotor and precentral resections was directly related to the extent of resection of the SSMA and lateral convexity and was greater when the resection involved the dominant hemisphere." In patients with preexisting severe motor deficits, resections involving primary motor areas can be performed without incurring additional permanent morbidity2',"'; however, in patients without severe motor deficits, resections in the central region produce permanent motor deficits, including spastic hemiparesis or worsening of preexisting deficits?' Parietal and occipital lobe resections constitute a relatively small percentage of surgery cases. Parietal lobe seizures have a variety of manifestations, including asymmetric tonic posturing, version, focal clonic activity, and automatisms, suggesting variable propagation patterns.'01*'21 Noninvasive ictal and interictal EEG findings are restricted to the affected lobe in a minority of cases'0'~'21 and may be falsely localized or lateralized.@ Consequently, invasive monitoring is often required to delineate the epileptogenic zone and identify primary sensory and motor areas. In two preMR imaging surgical series from the Montreal Neurological Institute, a seizure-free state was achieved in 23% to 36% of patients.'01,'02In most cases, intraoperative ECoG was performed to guide the extent of resection. In a smaller series, an excellent outcome was attained after complete lesionectomy in 10%of patients.'" Transient sensorimotor deficits or mild aphasic syndromes are obsemed in approximately 20%of patients following surgery of the parietal lobe.'O'*lm Transient lower quadrantal visual field deficits are less common. Permanent sensorimotor deficits were reported in 12% and worsenin of preoperative sensory deficits in 15%of patients with parietal tumors.'% Right-left disorientation and a partial Gerstmann's syndrome are rarely observed. Similar to PLE, the ictal semiology and noninvasive electrographic manifestations of occipital lobe epilepsy (OLE) are often referable to other areas.", 1oo,123 Elementary visual hallucinations, eye movement sensations, forced blinking, amaurosis, and visual field defects are observed in the majority of cases'"''*'B;however, these signs and symptoms are commonly

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followed by automatisms with loss of awareness or asymmetric tonic or clonic activity suggesting propagation to the temporal or frontal regions.'O*lW*lu In a recent series of lesional OLE, 16 (46%)of 35 patients achieved seizure freedom.'O A good seizure outcome was more common with tumors than developmental abnormalities, and outcome was not influenced by lesion location and size of resection.'O In another series, 27% of patients with OLE became seizure free and 41% were markedly improvedlW;however, because of active spiking on ECoG, resections extended beyond the occipital lobe in the majority of cases. Temporal resection was ineffective in four of five patients in whom depth electrode evaluation demonstrated seizure propagation to the temporal lobe.'WComplete homonymous hemianopsia following occipital resection was present in 76% of cases, over two-thirds of whom had partial visual field deficits preoperatively.'@' Lesionectomy Lesionectomy refers to the resection of circumscribed, epileptogenic lesions, including neoplasms, vascular malformations,and well-delineated malformations of cortical development. In many cases, seizure symptomatology is consistent with origin from the lobe harboring the lesion; however, misleading features may be observed.'6 Ictal and interictal noninvasive EEG findings are concordant with the lesioned hemisphere in over 50%of cases and bilateral hemisphere in over one-third of cases.16Localization to the hemisphere and lobe harboring the lesion is more likely in temporal versus extratemporal epilepsy.16Complete resection of an epilep togenic lesion has a greater likelihood of producing seizure freedom compared with subtotal resection?*19 Lesionectomy with mar in resection produces a seizure-free state in 67% to 83% of patients.I6,' Using subdural electrodes, Awad et a19 studied 47 patients with lesional focal epilepsy and found that the epileptogenic zone was contiguous with, but extended beyond, the margins of the lesion in 38% of cases and remote from the lesion in another 38% of cases. In this series, complete lesionectomy, regardless of the extent of resection of the surrounding epileptogenic zone, produced a seizure-freestate in 94%of cases; whereas, only 52%of patients with incomplete resection of the lesion and epileptogenic zone achieved the same result. Surgical outcome in patients with neocortical temporal lesions is complicated by the presence of dual pathology in as many as 30%of cases." Intraoperative ECoG may improve seizure outcome in patients with temporal lobe tumors by providing electrophysiologic recordings of the ipsilateral mesial temporal structures.6' Temporal lobectomy as a second procedure after unsuccessful neocortical lesionectomy produces seizure freedom in over 60% of cases!' Based on these data, visual and volumetric analysis of the ipsilateral amygdala and hippocampal formation should be performed when neocortical temporal lesionectomy sparing mesial temporal structures is considered. As compared with cortical resection, lesionectomy is associated with a lower complication rate, shorter

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intubation period, and a shorter postoperative hospital stay.IgBecause of the favorable seizure outcome and low incidenceof complications, patients with lesions that can be completely resected with minimal risk should be considered for early surgery. Hemispherectomy

Hemispherectomy is performed for the treatment of intractable focal and secondarily generalized seizures when an entire hemisphere is considered epileptogenic and little or no functional cortex remains. The procedure is usually performed in patients with Rasmussen’s aneurysm, Sturge-Weber syndrome, hemianencephaly, or large hemispheric infarctions. Functional hemispherectomy consists of the removal of the central region of the hemisphere, followed by disconnection of the frontal, parietooccipital, and temporal lobes. A corpus callosotomy and mesial temporal resection complete the procedure. Seizures are completely abolished in 50% to 80%of case^.^,^'^,'^^ In the single largest series, 54%of patients were rendered seizure free, 24% had nondisabling seizures, and 23% had persistent disabling seizure^."^ Four perioperative deaths occurred, highlighting the risk of large resections in young patients. Corpus Callosotomy

The corpus callosum is a major commissural system important in the propagation of focal neocortical seizures to the contralateral hemisphere. Corpus callosotomy (CC) is occasionally used in the treatment of frequent secondary generalized tonic-clonic, tonic, and atonic seizures leading to falls and injuries.The procedure is performed in patients with symptomatic generalized epilepsy who are not candidates for resective surgery. The goal of CC is to disrupt the major central pathways necessary for the propagation of generalized seizures. Complete callosal resection may result in mutism, apraxia, or frontal lobe dysfunction. For this reason, the procedure is often performed in two stages beginning with sectioning of the anterior two-thirds (ACC) and followed by section of the remainder of the corpus callosum, if necessary. Seizures are reduced by at least 50% in one-half to two-thirds of patients, although few become seizure free.92*125 As many as 25% to 30% of patients experience new onset focal seizures or an increase in the frequency or severity of focal seizures postoperatively.92The use of CC has declined markedly in recent years with the advent of new AEDs and vagal nerve stimulation. Multiple Subpial Transection

Multiple subpial transection (MST) is occasionally used in the treatment of focal epilepsy arising in or around eloquent areas. The rationale

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behind MST lies in the dependency of the functional integrity of the cortex on its columnar organization, coupled with propagation of epileptic activity along horizontal fiber networks.s0The technique consists of a series of parallel cortical transections at five-mm intervals guided by intraoperative ECoG. Transedions are made in the epileptogenic region through an opening in the pia mater with a specificallydesigned instrument. The procedure is typically performed in combination with resection of noneloquent cortex. Multiple subpial transection may be used in the treatment of epilepsy arising from the peri-rolandic region and language, visual, auditory, and association cortices. The procedure has also been used for Landau-Kleffner syndrome, or acquired epileptic aphasia, a disorder in which epileptic activity arises from the perisylvian and language cortex. Following MST with or without cortical resection for the treatment of focal epilepsy, 38%to 49% of patients become seizure free.s0Of 16children with Landau-Kleffner syndrome treated with MST and resective surgery, 75% were seizure free and 44% had recovered age-appropriate language.s0In the majority of children with Landau-Kleffner syndrome, significant gains in language function are achieved over a period of years from the time of surgery.50As a result of cerebral edema, transient neurologic deficits lasting for 2 to 3 weeks are not uncommon. Permanent neurologic deficits are less frequent, occurring in 7%to 14%of patients.80The role of MST remains controversial. Gamma Knife Surgery

Stereotaxicradiosurgery using the gamma knife was developed in the 1960s and has been used worldwide for the treatment of vascular malformations and neoplasms of the brain. More recently, this technique has been shown to be effectivein patients with MTLE caused by MTS.98Gamma knife surgery involves the delivery of a focused dose of radiation to the mesial temporal structures. The target of the radiation is identified on MR imaging using a stereotaxic frame. The dose of radiation is administered under local anesthesia. Following treatment, the patient is observed for 1to 2 hours, discharged from the hospital, and is able to return to usual activities within 5 to 7 days. Seizures typically diminish gradually over several months and often stop completely after 9 to 12 Long-term neoplasias have not been reported after gamma knife surgery. The procedure does not require excision of brain tissue or craniotomy and the risk of surgical complications, such as bleeding and infection, is substantially lower than conventional surgery. Deep Brain Stimulation Deep brain stimulation (DBS) recently has been applied to the treatment of intractable epi1ep~y.I~ Activation of a deep-seated nucleus called dorsal midbrain antiepileptic zone (DMAZ) results in si nificant seizure reduction in a number of animal models of epilepsy.Z6,' The DMAZ is

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located in the most caudal deep layers of the superior colliculus. Activation can be achieved by destruction, chemical activation or inhibition, or direct stimulation of a number of subcortical nuclei connected to the DMAZ, including the substantia nigra pars reti~ularis,~,~’ striatum,2°,26,30 and subthalamic nucleus (STN).I7High-frequency electrical stimulation of the STN, an effective treatment for patients with advanced Parkinson’s disease, produces a reversible inactivation that has been used successfully in a few patients with intractable epi1ep~y.I~ PEDIATRIC CONSIDERATIONS

The widespread application of surgery for intractable epilepsy has led to an increased awareness of differences between adult and pediatric epilepsy surgery candidates. Stringent medical intractability applied to infants and young children with catastrophic epilepsy may not only delay referral to a comprehensive epilepsy center but can have devastating consequences for the developing brain. Neuropsychological performance appears to be worse in children who develop generalized motor seizures prior to 5 years of age compared with those with later age of 0nset.3~In infants and children with catastrophic epilepsy, the risk of frequent seizures often outweighs the risks and cost of surgical intervention. In a 12-year prognosis study of childhood epilepsy in Sweden, 11 of 194 children died during the course of the study, all of whom had active epilepsy.18 Abnormal neurologic examination, mental retardation, and frequent seizures were factors predicting a worse seizure outcome. The risk of mortality was found to be 1to 295 ratio in a cohort of children and adolescents with severe epilepsy and learning disabilities.84 Infants and children should be referred for surgical consideration when seizures continue despite adequate trials of AEDs and interfere with behavior or development. Infants with devastating seizures caused by hemispheric lesions, such as large perinatal infarction, Sturge-Weber syndrome, and hemimegancephaly,should be considered for early surgery for cognitive and motor development to be optimized. Rarely, patients with multiple lesions, such as tuberous sclerosis, are surgical candidates if it can be demonstrated that a single lesion is responsible for most or all of the seizures. Seizure symptomatology in infants and young children often differs from symptoms found in adults and adolescents.The current classification of epileptic seizures does not take into account the difficultiesencountered when classifying seizures in infants and children. It often is not possible to assess level of consciousness and amnesia for seizures in young patients and infants, and young children are unable to describe auras. To address these limitations, seizure classifications designed s ecifically for infants and young children have recently been proposed.’,’;PIn a series of 23 infants with focal epilepsy, seven patients had seizures characterized by either an arrest or marked reduction of behavioral motor activity with minimal or no automatisms and an indeterminate level of consciousness

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(i.e., hypomotor seizures) arising from the temporal or temporoparietal region.' Localized or bilateral clonic, tonic, versive, or atonic seizures arose from the frontal, frontocentral,or frontoparietal regions in 13cases. Two infants with infantile spasms had epileptogenic zones in the frontal and temporoparietal regions. Absence of ictal manifestations typically observed in older children and adults, including automatisms and unilateral dystonic posturing, and the inability to assess level of consciousnessin infants with focal epilepsy have also been reported by The presence of asymmetric spasms, focal seizures and radiologic findings, hemiparesis, and lateralized hypsarrhythmia were stron ly predictive of focal pathology in 66%of infants with West's syndrome. Six of nine infants with West's syndrome became seizure free following surgery, several of whom had diffuse hemispheric pathology because of malformations of cortical development. Conversely, patients with infantile spasms and hypsarrhythmia, or other generalized EEG patterns with regional or lateralized findings on MR imaging or PET have been successfully treated with surgery (Figs.4,5, and 6)F7These data underscore the importance of subtle, focal-clinical, electrographic, and radiologic findings in pediatric epilepsy surgery candidates. The etiologies, types of resection, and the goals and risks of epilepsy surgery in pediatric patients differ considerably from adults. The most common etiologies of refractory epilepsy in pediatric surgical series include malformations of cortical development and low-grade tumors.2*38*127 Hippocampal sclerosis is uncommon in children, constituting less than 15%of cases.127 In a Cleveland Clinic series,'27focal malformations of cortical development and low-grade tumors were the cause of epilepsy in 90% of infants under the age of 3 years, 70%of children, and 57%of adolescents. In another series, cortical dysplasia accounted for 68%, developmental tumors 23%, and pen- and postnatal lesions 10% of infants unHemispheric der 3 years of age with medically refractory focal epilep~y.3~

2

Fpl-F7 F7-T7 T7-P7 P7-01 Fp2-F8 Fa-T8 T8-P8 P8-02 Fpl-F3 F3-C3 C3-P3 P3-01 Fp2-F4 F4-C4 C4-P4 P4-02 2MlpV'

1 SEC.

Figure 4. lnterictal EEG of a 4-month-old boy with clusters of infantilespasms since birth,occurring several times a day. Hypsarrhythmialateralizedto the right hemispherewas observed.

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Fpl-F7 F7-T7 T7-P7 P7-01 Fp2-FB F8-TB TB-PB PB-02 Fpl-F3 F3-C3 C3-P3 P3-0 1 Fp2-F4 F4-C4 C4-P4 P4-02

A Fpl-F7 F7-T7 T7-P7 P7-01 Fp2-FB Fa-TB TB-PB PB-02 Fp 1-F3 F3-C3 C3-P3 P3-01 Fp2-FI F4-C4 C4-P4 P4-02

6 Figure 5. A, Serial 10-second tracings during a typical seizure of the patient described in Figure 4. Repetitive spiking maximal in the right posterior quadrant evolved from a hypsarrhythmic pattern. 6, Fifteen seconds later, the seizure pattern involves the entire right hemisphere.

disorders, such as Sturge-Weber syndrome, hemimegencephaly, and perinatal cerebral infarction are much more common in infants and children than adults. Similarly, the types of surgical procedures performed in children for medically refractory focal epilepsy vary considerably from adults. In the series of Duchowny et al,3745% of patients under the age of 3 years underwent functional hemispherectomy; 10%had multilobar resections, and the remainder had lobar resections. Temporal lobectomies constituted only 36% of lobar resections. Extratemporal or multilobar resections or hemispherectomiesconstituted 44% of surgeries in adolescents,50%in children, and 90% in infants in the Cleveland Clinic series.'27 Despite the tendency for more widespread pathology and the need for larger resections, the rate of surgical complications, neurologic morbidity,

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Figure 6. A, Preoperative MR image of the patient in Figure 4 showing right hernimegalencephaly with lissencephalic cortex. The more normal left hemisphere appears small with many gyri and a paucity of left parietooccipitalwhite matter. An extra-axial mass in the superior vermian cistern thought to represent a lipoma was an incidental finding. 6,The patient underwent right functional hemispherectorny and had been seizure-freefor 18 months at the last follow-up.

and mortality remains relatively low in young patient^."^,'" Among the nearly 150 patients in a pediatric series, wound infections occurred in four (2.9%) patients and two (1.3%)patients died in the immediate postoperative period.'27Nearly identical mortality was reported in another recent pediatric series.@After functional hemispherectomy, deep venous thrombosis, contralateral subdural hematoma, and entrapped temporal horn relieved by marsupialization, occurred in one case each. Some patients had transient worsening of hemiparesis with recovery to baseline within weeks. In another series, two of 31 infants (6%)died postoperatively; one as a result of sepsis, inappropriate ADH syndrome and dehydration, and another

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with unrecognized hydro~ephalus~~; however, permanent, nondisabling complicationsoccurred in 4.2% and transient neurologic deficits in 6.4% of cases. Plasticity of the developing brain allows some young children to undergo epilepsy surgery involving language and sensorimotor cortices with minimal functional loss. Some children transfer language dominance to the right hemisphere after an injury to the left hemisphere before the age of 6 years.% Duchowny et alJ6reported the results of six children with perinatal or postnatal cerebral insults and refractory epilepsy who underwent left hemisphere language mapping. No language areas were identified in three children who were 5 years or younger at the time of insult, and language cortex was identified in the other three cases, all of whom suffered left hemisphere insults after the age of 5 years. In children with epilepsy caused by developmental pathology and tumors near left hemisphere language areas, language function is not dis laced even when the epileptomotor function may genic cortex and language areas ~ v e r l a p .Similarly, ~ be displaced in patients with lesions involving the perirolandic area and unaffected following resection of the lesion.'26 Despite differences in etiologies and surgery types, seizure outcome after epilepsy surgery in children is quite comparable with that of adults. In one series, 61% of infants were seizure free and 15%achieved greater than 90%seizure reducti0n.3~A better seizure outcome was achieved in patients with single structural lesions on MR imaging in whom complete resection of the epileptogenic zone was performed. In the Cleveland Clinic series,'27 patients were more likely to be rendered seizure free after temporal resection (78%)than after hemispherectomy (68%)or multilobar resection (54%);however, independent of type of surgery and age, a seizure-free outcome was more likely in patients with low-grade tumor (82%)than malformations of cortical development (52%).Sixty-seven percent of children with hippocampal sclerosis were rendered seizure free after temporal lobectomy, a figure that compares favorably with adults.127 The goals of epilepsy surgery in infants and children differ significantly from those in adolescents and adults. The primary goals of adolescents and adults with medically refractory epilepsy focus on driving, employment, independence, and the establishment of interpersonal relationships; however, for infants and young children with catastrophic epilepsy, improvement of seizures and behavior, and resumption of developmental progression are the expectations of parents and caregivers. Data on the effects of epilepsy surgery on development in infants and young children are sparse and conflicting. In one series, no significant changes in development were found postoperatively, despite reports of accelerated motor and cognitive development by parents of seizure-free ~hildren.~' In another series, developmental gains were observed in 24 children with infantile spasms who were treated with surgery at a mean of 20.8 months of age.7 Earlier age at surgery and higher presurgical developmental status were associated with better developmental outcomes.Among 100pediatric surgical patients, younger age at seizure onset was associated with lower functional status (Fs)IQ score^."^ The frequency of mental retardation

P

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was significantly greater in patients with onset of epilepsy at more than 24 months of age (46%)than for older patients (12%), independent of the etiology of the epilepsy. This was particularly true for the subgroup of patients with daily seizures, highlighting the importance of surgery timing in young patients with catastrophic focal epilepsy. SUMMARY

The impact of medically refractory epilepsy on the quality of life in pediatric and adult patients is tremendous. Poorly controlled seizures and the effect of medical therapy can have devastating effects on development, academic and job performance, and independent living. Epilepsy surgery is an important treatment option for these patients. As technology continues to facilitate the identificationof epileptogenic lesions, more patients are becoming surgical candidates. Although medical management offers varying degrees of seizure control, surgery offers some patients the possibility of a cure. References 1. Acharya JN, Wyllie E, Liiders HO, et al: Seizure symptomatology in infants with localization-related epilepsy. Neurology 48189-196,1997 2. Adelson PD, Peacock WJ, Chugani HT,et al: Temporal and extended temporal resections for the treatment of intractable seizures in early childhood. Pediatr Neurosurg 18169-

178,1992 3. American Electroencephalographic Society Guidelines for Long-term Monitoring for Epilepsy: J Clin Neurophysiol11:88-110,1994 4. Andermann F, Rasmussen TB, Villemure J: Hemispherectomy: Results for control of seizures in patients with hemiparesis. In: Liiders HO (ed)Epilepsy Surgery. New York, Raven Press Ltd, 1991, p p 62!j-632 5. Arroyo S, Lesser RP, Awad IA, et al: Subdural and epidural grids and strips. In: Engel J Jr (ed)Surgical Treatment of the Epilepsies, ed 2.New York, Raven Press, 1993,pp 377386 6. Armda F,Cendes F, Andermann F, et al: Mesial atrophy and outcome after amygdalohippocampectomy or temporal lobe removal. Ann Neuro140:446-450,1996 7. Asamow, LoPresti C, Guthrie D, et a 1 Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol 39430440,1997 8. Awad IA, Katz A, Hahn JF, et al: Extent of resection in temporal lobectomy for epilepsy. I. Inter-observer analysis and correlation with seizure outcome. Epilepsia 30756-762, 1989 9. Awad IA, Rosenfeld J, Ah1 J, et a 1 Intractable epilepsy and structural lesions of the brain: Mapping, resection strategies, and seizure outcome. Epilepsia 32179-186,1991 10. Aykut-Bingo1C, Bronen RA, Kim JH, et al: Surgical outcome in occipital lobe epilepsy: Implications for pathophysiology. AM Neurol44:60-69,1998 11. Bardy AH: Reduction of antiepileptic drug dosage for monitoring epileptic seizures. Acta Neurol Scand 86:46&469,1992 12. Benbadis SR, Chelune GJ, Stanford LD, et al: Outcome and complications of epilepsy surgery. In: Wyllie E (ed) The Treatment of Epilepsy: Principles and Practice, ed 2. Baltimore, Williams & Wilkiis, 1996,pp 1103-1118 13. Berkovic SF, McIntosh AM, Kalnins RM, et al: Preoperative MRI predicts outcome of temporal lobectomy: An actuarial analysis. Neurology 451358-1363,1995

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Nancy Foldvary, DO Department of Neurology Section of Epilepsy and Sleep Disorders The Cleveland Clinic Foundation, S51 9500 Euclid Avenue Cleveland. Ohio 44195 e-mail: [email protected]