Surgical therapy for medically intractable epilepsy. Department of Neurological Surgery, University of Washington, Seattle, Washington

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1 J Neurosurg 66: , 1987 Review Article Surgical therapy for medically intractable epilepsy GEORGE A. OJEMANN, M.D. Department of Neurological Surgery, University of Washington, Seattle, Washington v" There has been a recent renewal of interest in surgical therapy for medically intractable epilepsies. Cortical resection and callosotomy are the most widely accepted modes of surgical management. The indications for each of these approaches are reviewed. Although there has been much interest in imaging techniques, including positron emission tomography, to identify epileptogenic zones, identification still depends primarily on the electroencephalogram (EEG). There are several approaches to the evaluation and intraoperative management of patients undergoing cortical resection for temporal lobe epileptogenic zones. These range from selection based on scalp interictal EEG criteria, with resections guided by electrocorticography and functional mapping, to selection based on the location of ictal onset as recorded by chronically implanted depth electrodes, with an anatomically standard resection of the temporal lobe or resection limited to amygdalohippocampectomy. No one approach provides the optimum balance of benefits to risks and costs for all patients. The relative value of the different approaches for various populations of patients with medically intractable partial complex seizures is reviewed. Techniques for minimizing the morbidity of these operations, especially in regard to language and memory, are also discussed, as are the contributions to an understanding of the neurobiology of human epilepsy and human higher functions derived from the surgical therapy of epilepsy. KEY WORDS 9 epilepsy temporal lobe resection 9 cortical resection 9 callosotomy I T is commonly accepted that the first report of the surgical treatment of medically intractable epilepsy was that published by Horsley 37 a century ago. Since that time interest in the subject has waxed and waned. The recent renewal of attention to the topic is indicated by two international conferences on the surgery of epilepsy, both held within 6 months, in 1985 and 1986; ~8,92 these followed a lapse of over a decade since the previous conference. TM There are a number of reasons for this renewed interest. Perhaps the most significant influence has been the development of an electroencephalography (EEG) video monitoring capability that allows documentation of EEG events at the onset of the seizures. This type of monitoring is especially useful in two areas: to identify seizures that are not of cerebral origin and to identify the focal onset of seizures, thus selecting potential surgical candidates. A second factor causing the revival of interest in This contribution is the 26th in a series of review articles selected jointly by the Committee on Graduate Education of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons, and the Journal of Neurosurgery. -- Editor. surgery for epilepsy is the quantification of serum levels for anticonvulsant drugs; this has allowed for a more rapid and secure determination of when epilepsy is truly medically intractable. A third factor has been the recognition that uncontrolled seizures are not only psychosocially disabling, but also biologically damaging. Patients with uncontrolled generalized seizures have been found to have a substantially higher risk of death compared to age-matched control individuals. 38 There is a growing body of experimental evidence of ongoing neuronal damage associated with uncontrolled seizures. 35 Patients with poorly controlled seizures demonstrate evolving neuropsychological deficits compared to those with controlled seizures. ~6 In addition, the possibility that kindling may be a phenomenon present in man 54 suggests another factor by which uncontrolled seizures may produce further neuronal damage. All of these factors together have indicated surgical treatment for the disease, and also suggest that surgical therapy should be considered earlier in the course of a seizure disorder. At many epilepsy centers, an adequate medical trial in a patient with frequent partial complex seizures might now involve administration of pheny- J. Neurosurg. / Volume 66/April,

2 G. A. Ojemann toin and carbamazepine, both alone and in combination, to appropriate serum levels and then in a regimen with several secondary antiepileptic drugs. 7~ This trial might require only l to 1~ years in a patient with frequent seizures. In a child, an additional consideration in selecting surgical treatment is whether he will outgrow his seizures. Although this may happen at puberty with seizures associated with localized frontocentral epileptic abnormalities (benign rolandic epilepsy), it is rare with other focal seizure disorders, especially partial complex seizures of temporal lobe origin. Nevertheless, most epileptologists presently require that the seizure disorder be severe with significant confirmatory evidence for focal origin, preferably demonstrated by imaging techniques, before surgery is considered in prepubertal children. 3~ There is general agreement that the indications after puberty are the same as for adults, and most series of epilepsy surgery in children consist of adolescents. 3~176 Moreover, there is much to recommend early surgery (in mid or late teens, at least) in terms of the success of psychosocial rehabilitation if seizures are controlled. 6~ The major effect of all types of operations for medically intractable epilepsy is on seizure frequency. It is important in evaluating patients for surgical therapy, then, to be sure that changes in seizure frequency will have a significant impact on a patient's life. Employment after surgery for epilepsy is reported to depend mainly on preoperative employment and neuropsychological status rather than seizure control alone. Few previously unemployed patients become employed after surgery but, if seizures are controlled surgically, employed patients are likely to upgrade their employment. 3 Occasionally, patients are referred for behavioral difficulties rather than for seizures. Successful surgical treatment of the seizure disorder seldom alters the behavioral problems, although anterior temporal lobectomy has occasionally been associated with a minor reduction in the tendency to anger and aggressive behavior. 87 In particular, the schizoid-like psychosis that has been associated with temporal lobe epilepsy does not appear to be altered for better or for worse by surgical treatment of temporal lobe seizures. 82 At the present time there are only two surgical approaches to the treatment of medically intractable epilepsy in widespread use. One is the older approach of resection of an epileptic focus, and the other is a newer procedure of division of all or a portion of the corpus callosum. Several other procedures that enjoyed popularity within the previous decade have now been largely abandoned. These include cerebellar stimulation ~ and stereotaxic subcortical lesions. 39"69 A few subcortical stimulation and lesioning procedures remain as investigational studies, including creation of ventroanterior thalamic lesions in cases of simple partial motor seizures 53 and thalamic stimulation of the centromedian nucleus (F Velasco, et al., unpublished data, 1986) or ventral anterior nucleus ~2 in patients with generalized and partial complex seizures. Of the two surgical options in common use now, resection of the epileptic focus has a much higher probability of completely controlling seizures. Thus, the initial evaluation of patients with medically intractable epilepsy should be directed at establishing whether they are candidates for resective surgery. Selection of Patients for Resective Surgery There is general agreement on the overall criteria for selection of patients for resective surgery. A focus of origin of the seizures must be identified, and that focus must be an area of brain where resection is not likely to lead to an unacceptable neurological deficit; resection is not advisable in the sensorimotor cortex if a hemiparesis is not already present, or in areas essential for speech or recent memory. These, of course, are the classic criteria enumerated by the Montreal School. 71 Beyond this general agreement, there is considerable controversy on the more detailed criteria to identify the epileptogenic focus and to determine whether it is in "dispensable" brain. This controversy is particularly applicable to patients with medically intractable epilepsy who are thought to have the epileptogenic zone within the temporal lobe. Patients with partial complex epilepsy, particularly with secondary generalization, are more likely to have medically intractable disease than patients with other types of seizure disorders, z Among patients with medically intractable epilepsy who have demonstrable localized epileptic zones, about 80% have foci within the anterior temporal lobe. Thus, the resective surgical management of medically intractable epilepsy rather commonly involves dealing with an anterior temporal lobe focus. Controversy on the surgical management of medically intractable temporal lobe epilepsy extends to both selection criteria and intraoperative techniques. At one extreme is the approach developed by Penfield and the Montreal Neurologic Institute. 7j In that approach, patient selection is principally based on the location of interictal epileptiform events on scalp EEG, and the resection is carried out under local anesthesia and tailored to the location of the interictal epileptiform events on electrocorticography (ECoG) as well as any individually identified functionally important areas. 63,71,79 At the other extreme are approaches that base patient selection on recording of seizure onset directly from the brain, usually through depth electrodes; the resection in these cases involves an anatomically standardized operation: either a measured anterior temporal lobectomy with resection of both medial and lateral anterior temporal structures 22 or, if the epileptogenic zone is confined to the medial temporal lobe, the recently developed more limited standardized operations such as amygdalohippocampectomy. 93 There are a number of other approaches combining features of 490 J. 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3 Surgical treatment for epilepsy these two extremes, usually along the general principle that the more extensive the intraoperative evaluation of the focus, the less extensive the preoperative evaluation. Series with a large proportion (two-thirds or more) of patients who are postoperatively seizurefree or nearly so, with a minimum follow-up period of l or 2 years have been reported with each approach.7, ,79.85,86.90 However, different surgeons may select for surgical therapy a different population of patients with intractable partial complex seizures, making comparisons difficult. This range of approaches in part represents varying views of medically intractable temporal lobe epilepsy. One view is that most of these patients have a rather uniform pathological process involving neuronal loss and gliosis in mesial temporal structures, particularly in the hippocampus. In that view, the goal of preoperative evaluation is to identify which patients have that pathological abnormality, 19 often using depth electrodes placed in standard locations in the mesial temporal lobe to identify patients with the appropriate pathology; the foci are then removed in an anatomically standardized resection. At the other extreme is the view that temporal lobe epilepsy is a relatively variable process and that the extent of the epileptogenic zone must be determined in each individual patient. With this view, the extent of resection tends to be varied from patient to patient, with the goal of removing as much of the epileptogenic zone as possible without encroaching on areas important for motor, language, or memory function. 79 Different information has been used to determine the extent of the epileptogenic zone, including the location of interictal epileptiform spikes recorded at operation 63'71'79 or the recording of interictal and ictal events by chronically implanted electrodes, placed either subdurally or epidurally 3~ or in the depths at sites thought to represent both the zones of seizure generation and propagation. TM As is apparent from these different approaches, a rather wide range of techniques for direct brain recording has been developed. These include depth electrodes in a variety of flexible and stiff configurations that are chronically implanted in a range of trajectories using stereotaxic technique,~9'85 often bilaterally, symmetrically in some techniques 19"85 and asymmetrically in others. 86 Other techniques use subdural or, more rarely, epidural electrodes in sheets or plates; others place strips and tubes or electrodes often bilaterally through burr holes 96 or by craniotomy, usually unilaterally. 3~ It has become increasingly apparent that no single approach to resective surgery for epilepsy is suitable for all patients, even those with temporal lobe epilepsy. Indeed, much of the discussion at the recent conferences has centered around identifying the appropriate approaches for different patients. These approaches will be discussed here under three headings: I) the criteria that adequately identify the location of the epileptogenic zone; 2) the value of ECoG findings in tailoring the resection to the patient; and 3) the value of individual identification of functionally important areas. Criteria to Identify a Temporal Lobe Epileptic Focus The identification of the site of onset of temporal lobe seizures depends primarily on EEG findings, despite the recent interest in the use of clinical features or imaging techniques to identify the epileptogenic zone. The adequate EEG criteria remain quite controversial. Two recent studies suggest that a group of patients who have a very high probability of being seizure-free after resective surgery can be selected on entirely noninvasive criteria (that is, without the use of any type of intracranial electrodes). Dodrill, et al., ~7 found that a multivariant analysis that included localized interictal epileptiform abnormalities on scalp EEG and a series of findings on standard neuropsychological assessment identified from among 100 patients who had undergone resective surgery a group of 48 patients who had a 92% probability of being seizure-free or nearly so. Engel and his associates 2~ identified a group of patients with a 97% probability of being seizure-free or nearly so using the location of epileptiform events on scalp EEG interictal and ictal recordings, supplemented by localization of "focal functional deficits." These "focal functional deficits" included an absence of drug-induced EEG fast activity, the presence of deficits on standard neuropsychological assessments that related to function of the particular brain area suspected as the epileptogenic zone, loss of memory when the contralateral hemisphere was inactivated by intracarotid administration of amobarbital, and evidence of hypometabolism on positron emission tomography (PET) scanning. Although these two studies strongly suggest that there is a group of patients who can be selected for resective surgery entirely on techniques that do not require any type of intracranial electrode placement, the exact criteria for this group are still in doubt. These two studies utilized quite different approaches. In the study of Dodrill, et al., the intraoperative approach involved tailoring the resection to epileptic events observed on the interictal ECoG, while avoiding any individual functionally important areas intraoperatively identified. The intraoperative approach used by Engel, et al., involved anatomically standard anterior temporal lobectomies. It is possible, of course, that different intraoperative approaches may require different noninvasive criteria. In the selection of patients for resective surgery, it is important that the clinical features of the patient's seizures be appropriate to the site of the epileptogenic zone as indicated by EEG studies. However, attempts to predict surgical outcome based entirely on clinical features of the seizures have not been particularly successful. The recent suggestion that the presence of a motionless stare at the beginning of the seizure was highly predictive of a satisfactory surgical outcome ~5 J. Neurosurg. / Volume 66/April

4 G. A. Ojernann has not been substantiated? If the clinical features of a patient's seizures show clearly that the epileptogenic zone is not likely to be the site suggested by the EEG, then further work-up is in order. Similarly, the presence of a structural lesion on imaging studies is highly suggestive of the site of origin of seizures, but the relationship is not absolute and the work-up should continue if the EEG findings and the structural findings do not agree. There has been much recent interest in the development of imaging techniques to aid in the preoperative identification of the epileptic focus. These have included specific computerized tomography (CT) and PET techniques to look for the epileptogenic zone in the temporal lobe. A subtle enhancement evident on numerical analysis of CT scans obtained following intravenous contrast infusion was noticed on the side of the epileptic focus compared to the ipsilateral zone? 8 Structural changes in the temporal lobe along the tentorial edge, suggestive of an element of herniation on the side of the focus, have been demonstrated by computer analysis of CT scans following contrast enhancement of cerebrospinal fluid with metrizamide. 95 Measurements taken during or very shortly after a seizure have shown substantial increases in both blood flow and local metabolic activity as measured by emission CT of fluorine-18 deoxyglucose (~SFDG). 4~ Such recordings have been of relatively limited value in terms of identifying the focus, however, since the increased metabolism seems to be present not only at the site of seizure onset, but also where the seizure activity has spread. Of greater value has been the demonstration of local hypometabolism on the side of a temporal lobe focus on PET scans obtained in the interictal state following the injection of lsfdg. This metabolic change has been lateralized to the side of the temporal lobe focus with about the same frequency as scalprecorded interictal spikes. Thus, although they are not an absolute indicator of the site of the focus, these PET findings have been a very useful adjuvant to EEG studies. In all cases, however, the imaging studies remain as supportive data, rather than the primary data for the identification of the epileptic focus. The outcome of the patients identified by noninvasive criteria is as good as that in most of the cases where selection was based on the depth electrode localization of ictal onset. 84 Because of this, it seems clear that there is little justification for implanting intracranial electrodes in patients who meet these noninvasive criteria. The use of intracranial electrodes clearly introduces some element of additional risk and, although that risk is quite small with modern approaches, 68 it is almost as great as the small risk of resective surgery. 63'79 Thus, the use of intracranial electrodes almost doubles the risk to the patient who is selected for resection and exposes those patients not selected for resection to some risk without direct therapeutic benefit. Placement of intracranial electrodes also adds substantial costs to the preoperative evaluation, especially when compared to approaches using noninvasive criteria based on interictal EEG recordings. The additional risks and costs of an approach involving intracranial electrodes must be balanced by the additional benefits, including a higher percentage of seizure-free patients. This approach also helps to avoid resections being performed on the wrong side. When that happens, the chance of a postoperative functional deficit is greatly increased and there is not only a failure to control the seizures, but potentially effective contralateral resective surgery is now precluded. 68 However, it is not clear how often the failure of temporal lobe resective surgery represents selection of the wrong side, as the majority of failures involve persistence of epileptiform events on the side containing the pathology. 1,79 There is also some evidence that false findings of tack of lateralization on depth recording result in denying operation to at least a few patients who would have been helped. 68 Thus, a balance of risks and costs versus benefits must be struck for the use of intracranial electrodes in each patient population. For patients who meet some of the noninvasive criteria, that balance does not support the use of intracranial electrodes. Several less invasive EEG electrode placements are of value in identifying a temporal lobe epileptogenic zone in these cases, particularly the use of sphenoidal electrodes. 4~ Use of electrodes introduced through a needle placed in the foramen ovale has also been advocated in these patients as a means of identifying a mesial temporal epileptogenic zone with accuracy similar to that of implanted depth electrodes, but with a presumably lower risk. 9~ Foramen ovale electrodes have been used principally to select candidates for amygdalohippocampectomy. Recent data also clearly indicate that in another group of patients where noninvasive studies have narrowed the likely site of the epileptogenic zone to a few areas but have not precisely identified its location, the use of chronic intracranial electrodes will identify an epileptogenic zone the resection of which is likely to benefit the patient's seizures. This seems to be particularly true of the patients with bitemporal epileptiform abnormalities on scalp EEG evaluation. Gloor, eta[., 29 found that in 80% of such patients all seizure activity, or all the major socially disabling seizure activity, arose from one temporal lobe, and that resection of that temporal lobe was associated with a substantial proportion of patients being seizure-free. However, only 17% of their patients had all their recorded ictal events from one side, when electrical seizures unassociated with any clinical concomitants were also included. It appears, therefore, that in patients with bitemporal abnormalities one temporal lobe may be generating all of the major socially disabling seizures, and resection of that temporal lobe may be of considerable benefit to the patient, although the probability of being seizure-free is less than that following resections in patients with unilateral temporal lobe abnormalities. Patients with 492 J. 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5 Surgical treatment for epilepsy bitemporal abnormalities represent a group in which one must be particularly concerned about the functional (especially memory) capabilities of the opposite temporal lobe, since cases have been reported where the other temporal lobe was neither generating seizures nor capable of sustaining memory function. 72 The various EEG techniques for identifying the epileptogenic zone have been compared for their probability of successfully identifying an area the resection of which resulted in a seizure-free patient. No one technique is absolutely certain of identifying such an area for all patients. The site of ictal onset on depth EEG recording has the highest probability of identifying such an area, followed, in order, by the location of interictal epileptic activity on scalp EEG recording, and the location of hypometabolism in PET. 21 Scalp EEG-recorded ictal onset has been surprisingly unreliable in terms of identifying the area the excision of which is likely to lead to a seizure-free patient. ~7"2~ At some institutions, the sites of "focal functional deficit" are considered of substantial value, in that these deficits are reported to have a very low incidence of falsenegative findings; that is, when focal functional deficits are present, resection is likely to help, although it may also help under circumstances when such deficits are not present. 2 Use of Electrocorticography In those approaches that tailor the resection to epileptic events recorded by ECoG, two sets of techniques have developed. One set includes the traditional method developed at the Montreal Neurologic Institute, where ECoG is carried out at the time of operation under local anesthesia. 7~ More recently, at some institutions, ECoG is recorded under general anesthesia. 5~ There is no comparative study of the reliability of ECoG tracings recorded under local or general anesthesia, although there is some evidence that nitrous oxide anesthesia is particularly likely to inhibit epileptic events (H Clark, et al., unpublished data). A number of drugs have been developed to enhance epileptic events on the ECoG recordings, particularly Brevital (methohexital sodium). 94 There has been no comparative study of the value of enhancing agents in identifying interictal foci. However, there is some reason to think that ictal events precipitated pharmacologically may not always accurately identify the site of onset of spontaneous ictal events. 91 A second set of approaches that tailor resections to the ECoG findings utilize chronic intracranial electrodes placed widely over the side of the suspected focus. Electrodes in plates or grids have generally been used, 3~ in either epidural or subdural placements. The advantages that are given for these latter techniques are: that the ECoG can be recorded without induction of anesthesia; that the stability of the interictal ECoG focus over time can be assessed (with a suggestion that it changes in extent although not in general location from day to day: R Lesser, personal communication, 1986); that sites of ictal onset can be determined; and that any functional mapping is obtained through the electrodes in a relatively leisurely environment. The disadvantages, of course, are that a craniotomy is required for the placement of these types of chronic electrodes and that there is clearly an additional risk, particularly of infection, involved in their use. Surgical outcomes with these different techniques of ECoG recording have not been directly compared, although the reported outcomes with each approach are little different, raising some question about whether the additional risks associated with the use of the chronic subdural or epidural plates are justified in those cases that could be handled with either technique. The use of the chronic subdural or epidural grids and plates, however, does allow determination of ECoG localization and functional mapping in patients who cannot tolerate operations under local anesthesia, such as young children. Whether there is any advantage to tailoring resections to the extent of the interictal epileptiform events recorded on ECoG is also not determined. The reviews of Bengzon, et al., 5 and Rasmussen 76 have suggested that patients who are seizure-free after temporal lobectomy have fewer epileptiform abnormalities in the postresection ECoG than patients who were not seizurefree. On the other hand, in both studies there were still a number of patients who had no post-resection epileptiform abnormalities but were not seizure-free, and up to one-third of the patients in the seizure-free group still had persistent abnormalities. Thus, epileptiform abnormalities on ECoG can sometimes be ignored, but when that is appropriate is controversial. There is general agreement that epileptiform abnormalities in the ECoG recorded from the insula do not indicate further resection. 79 The appearance of epileptiform abnormalities posterior to a resection when they were not there in the pre-resection ECoG has been considered an indication for further resection by some v i but not by others. 63 Similarly, epileptiform abnormalities in the ECoG recorded from remaining hippocampus and hippocampal gyrus have been interpreted as an indication for resection of those structures, 79 but others consider these changes an indication of injury discharges in relatively healthy tissue. 2~ The presence of epileptiform events in remaining posterior hippocampal gyrus following a resection does not seem to be a predictor of an adverse outcome (GA Ojemann, unpublished data). At present, the outcomes with temporal lobectomy guided by ECoG seem to be quite similar to those following anatomically standard temporal lobe resections, although the very different preoperative evaluations and selection criteria confound this comparison. Value of Functional Mapping With the increased interest in resective surgery, particularly for temporal lobe epilepsy, there has been J. Neurosurg. / Volume 66/April,

6 G. A. Ojemann concern about the side effects of these procedures relating to language and memory, especially with surgery in the language-dominant hemisphere. At its extreme, that concern elicited the statement that temporal lobe resections in the dominant hemisphere should not be undertaken in anyone who depends on a facile memory for his livelihood. 14 The approaches to avoiding language and memory problems with resection in the dominant hemisphere parallel the views on temporal lobe localization. In one view, the preoperative work-up establishes the relationship of the hemisphere thought to contain the epileptogenic zone to language and memory function, with the use of standard anatomic landmarks for the posterior limit of the resection considered to be adequate to avoid language or memory deficits. 19,22 At the other extreme is the view that the location of such essential areas is highly variable between individuals and must be identified in each patient, and the resection should then be tailored to avoid the essential areas in that patient.a7,6 In approaches that use anatomically standardized temporal lobe resections, the resection is modified if language is present in the hemisphere with the epileptogenic zone, by limiting the posterior extent of the resection, either to 4.5 cm from the tip of the temporal lobe or to the vein of Labbr. In some centers, the superior temporal gyrus is also spared. Whether this approach is adequate to avoid postoperative language disturbances is unclear. Language deficits have been reported in one series of patients handled in this way 44 but not in another. 8~ Approaches that tailor resections to functional mapping of language areas commonly use an electricalstimulation mapping technique. 43,59,73 Sites where repeated errors in naming are evoked by stimulation indicate areas essential for language 59 and are spared in the resection. There is substantial individual variability in the location of these sites on the lateral surface of the anterior temporal lobe, 59,61 and sites essential for language have recently been described relatively anteriorly on the ventral surface of the dominant temporal lobe in some, but not all, patients. 47 Functional mapping of areas essential for language, either at craniotomy under local anesthesia or through chronically implanted subdural electrodes, seems important for resection of foci in the posterior temporal lobe of the dominant hemisphere. Whether it is needed for resection of anterior temporal epileptogenic zones is not determined. There is much more variability in the approaches to avoiding memory deficits with temporal lobe resections. Memory deficits after temporal lobectomy are of two types: global deficits of all types of recent memory have been associated with bilateral medial temporal damage, 72 while more mild material-specific deficits have been reported for verbal material after left anterior temporal resection or spatial material after right temporal resection. 5~ Spatial memory generally improves when seizures are controlled with a left temporal resection, whereas verbal memory is often improved with an effective right temporal resection. 56 In general, any clinically significant memory deficits have developed following resections in the dominant hemisphere. The intracarotid Amytal (amobarbital) test is used to screen for the ability of the contralateral temporal lobe to sustain memory? 2 The details of memory testing used with the Amytal techniques vary substantially between institutions and have not been systematically compared. In addition, the criteria used to define a major memory deficit with Amytal perfusion are rather arbitrary and also have not been systematically evaluated. The response to what is considered to be a major memory deficit with Amytal perfusion of the side of the proposed resection also varies. This finding has been interpreted as indicating that the contralateral temporal lobe alone is apparently not capable of sustaining memory; 52 this defect is thought to reflect hippocampal damage. 72 At some institutions, patients are evaluated only as to the presence or absence of adequate memory function. If the other temporal lobe is not capable of sustaining memory adequately during Amytal inactivation of the side of the proposed resection, surgery is not undertaken or, if a resection is done, it is not modified based on memory performance on the Amytal test. 19 Follow-up study of patients managed in this way, however, has shown substantial sustained memory losses following such anatomically standardized left anterior temporal lobectomy? 6,8~ Another approach has been to modify the resection if there is evidence of a significant memory deficit with the left-side perfusion of Amytal by sparing the hippocampus. 6,63 Follow-up examination of these patients has shown a somewhat lesser degree of postoperative memory deficit, 67 but there is no matched comparative study between the two approaches. Ojemann and Dodril166"67 found that a residual memory deficit was present in half of the patients managed with hippocampal sparing. That deficit 1) was more likely in patients with facile presurgical memories; 2) was related to the lateral but not the medial extent of the resection; and 3) could be predicted by the relationship of the resection to sites in the lateral cortex related to either naming or to the input or storage aspects of short-term verbal memory measure. They reported resection of epileptic foci in the left temporal lobe when memory was totally dependent on that hemisphere (as judged by intracarotid Amytal assessment), where sparing of both the hippocampus and the lateral cortical components of memory resulted in no measurable postoperative memory deficits. Wieser and Ya~argi193 reported little memory deficit in patients who had undergone resections confined to the amygdala and hippocampus while sparing the lateral cortex. However, one case of a global memory deficit following such a resection has recently been reported, when the Amytal study suggested that the opposite temporal lobe could 494 J. 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7 Surgical treatment for epilepsy not sustain any memory (R Rausch, et al., data presented at the International Neuropsychological Society Meeting, Denver, Colorado, February, 1986). Thus, both the hippocampus and portions of the lateral cortex of the anterior temporal lobe seem to be involved in short-term verbal memory mechanisms, and avoiding a memory deficit may require sparing both areas in a resection. There is essentially no information presently available on the strategies to be used when a patient with a right nondominant-hemisphere epileptogenic zone cannot sustain memory with Amytal perfusion of the right carotid artery, other than to minimize resection of the hippocampus. Resections Other Than in the Temporal Lobe There is considerably less variability in approaches to epileptogenic zones outside the temporal lobe compared with temporal lobe resection. There are no anatomically standard operations at present. The extent of the resection is generally indicated either by techniques of chronic intracranial recording or by intraoperative ECoG. One center has reported the frequent finding of frontal lobe epileptogenic zones on chronically implanted intracranial electrode evaluation of patients with medically intractable complex partial seizures suspected of temporal lobe onset. 8~ This apparent masquerading of frontal as temporal lobe foci has been less commonly observed at other institutions (J Engel, Jr, and GA Ojemann, unpublished data). Moreover, patients with unequivocal frontal lobe epileptogenic zones are usually clearly distinguishable on noninvasive criteria from those with temporal lobe zones. 75 Results with resection of localized epileptogenic zones outside the temporal lobe have been reported as similar to those in patients with temporal lobe resection. 77'78 There has also been controversy concerning approaches to patients with the infantile hemiplegia syndrome and medically intractable seizures. This controversy centers around the relative values and risks of hemispherectomy compared to division of the corpus callosum in the management of the seizure disorder in these patients. The effectiveness of hemispherectomy in the control of seizures is well documented: over 80% of the patients are seizure-free after surgery. 77 The problem has concerned the late postoperative complications of hemorrhage into the resection site and the development of secondary communicating hydrocephalus. The advent of modern scanning techniques allows for more accurate follow-up monitoring of these patients, and may reduce the occurrence of this complication. In addition, Rasmussen 77 suggested modifications in the hemispherectomy technique: leaving, but disconnecting, the frontal and occipital lobes. This approach seems to diminish late complications. In view of these apparent reductions in the long-term morbidity of hemispherectomy and the very high proportion of patients who are seizure-free following this procedure, it is the author's suggestion that patients with infantile hemiplegia syndrome be evaluated for that option before cal- losal section is considered. Although some of the very best results following callosal resection have been reported in these patients, 83 the percentage of individuals who are seizure-free is still substantially less than that following the modified hemispherectomy. The Indications for Callosotomy Continuing experience with partial or complete section of the corpus callosum in patients with intractable seizure disorders has facilitated the definition of a number of indications for callosotomy. 26'48'83 This has been accomplished largely by consensus rather than by any systematic comparative study. Callosal section seems most effective in treating generalized major motor seizures. Patients with generalized seizure disorders and unilateral hemispheric damage, such as individuals with infantile hemiplegia syndrome, represent one group that has shown substantial reductions in seizure frequency following partial or total callosal division. Indeed, a few patients in this group have become completely seizure-free after callosotomy. Callosotomy also seems to be of value in patients with partial seizures characterized by loss of postural tone so that the patient frequently falls and injures himself. 26 In that situation, the callosotomy seldom renders the patient seizure-free, but will often control the type of atonic seizure that is particularly injurious to the patient. On the other hand, callosotomy has been of relatively little benefit in patients with simple or complex partial seizures, even when there is early secondary generalization. Whether the entire callosum, or only its anterior twothirds, should be divided in these patient groups remains controversial. Marino and Ragazzo 48 have determined the extent of callosal division by intraoperative recording, continuing the division until the bisynchronous discharges that are usually present in patients with generalized major motor seizure disorders become asynchronous. Magnetic resonance imaging is an effective way to determine the extent of callosal division, and suggests that some patients in whom division was thought to be complete have residual fibers at the anterior and posterior extremes. 27 Whether an adequate callosotomy requires both an anterior and posterior approach to the callosum or can be performed entirely from anteriorly is also controversial. In most patients, callosotomy has been a relatively benign procedure. A transient period of reduced verbal output and reduced activity, a minor form of akinetic mutism, has been commonly seen after callosal division. A very few cases have been reported where this syndrome has not resolved within a few days to weeks? 3 However, there are several groups of patients who are at risk for major behavioral deficits after callosotomy. These include patients with speech and primary handedness lateralized to opposite hemispheres) 3 Amytal assessment of speech lateralization in all left-handed patients has been recommended, with even partial callosotomy deferred in the setting where language (and perhaps verbal memory) is in the hemisphere ipsilateral J. Neurosurg. / Volume 66/April,

8 G. A. Ojemann to the preferred hand. Some patients who had recovered from neurological deficits related to a unilateral hemispheric lesion have had a reappearance of those deficits after callosotomy. 1~ It has been suggested that this represents a disconnection of the brain areas responsible for the recovery of those functions from the primarily damaged functional area. Utilization of Surgical Therapy of Epilepsy Statistics suggest that surgical therapy for medically intractable seizures is relatively underutilized. 89 Seizure disorders are thought to occur in about 1% of the population. Drug therapy is said to control seizures, either completely or at least to the satisfaction of the physician or patient, in about 80% of cases. However, a recent cooperative Veterans Administration study 49 of seizure control with drugs has suggested that somewhat less than half of the patients really achieve complete seizure control with drug therapy. Based on the older figures, there are over 400,000 medically intractable epileptic patients in the United States. If only 10% of these are candidates for resective surgery, there are 40,000 candidates for resective operations; the number performed in any one year is no more than 1% to 2% of this. Thus, an expansion in the surgical therapy for epilepsy, a likely consequence of the recent renewed interest, seems appropriate. However, that expansion in our present era of finite health care resources requires the use of approaches that maximize the return on the invested resources in terms of number of patients seizure-free, with minimum risk and maximum functional return. Adherence to arbitrary protocols is not likely to accomplish that end. Research and Surgical Treatment of Epilepsy The surgery of epilepsy has had a unique and unusually productive relationship with investigative studies of human brain function. The limitations of this review allow only an indexing of some of these studies. The detailed cortical organization of language, verbal memory, and other related verbal functions has been investigated in the context of resective surgery, 43,47,59,73 including the electrophysiological correlates of these behaviors in the ECoG 25'64 and single-neuron recording. 13'64'65 The detailed cortical organization of some visuospatial functions in the nondominant hemisphere has also been studied. 24 Chronic intracranial electrodes have provided similar opportunities to investigate the role of medial temporal structures in higher human function, using stimulation techniques, 34 and recording of ECoG 33 and single-neuron activity 3z,36 correlates. Assessment of behavioral changes prior to and following surgery has provided major information on the role of the temporal lobe in memory 5~ and on the separate abilities of the two hemispheres after callosotomy. 28 Surgical therapy of epilepsy has also provided opportunities to investigate the pathophysiology of epilepsy in man. There is a large number of such studies using EEG techniques, but the pathophysiology of human epilepsy has also been investigated at the single-cell level 4"97 and morphologically. 8~ Present medical and surgical therapeutic techniques do not solve the problem of seizures for a significant number of patients. Another area of research is to develop new surgical approaches for those patients who do not meet the present indications for resective surgery or callosotomy. Most of the surgical approaches to epilepsy were not derived through systematic investigative studies, but rather empirically in a clinical setting. However, there have been several experimental investigations of potential surgical therapies in addition to the clinical research mentioned at the beginning of this article. The effects of creating ventral anterior stereotaxic thalamic lesions, 42 of cooling the focus, 55 and of electrical stimulation of the cerebellum 45 and caudate nucleus 57 on the frequency of seizures have been determined in a chronic primate model of focal motor and secondarily generalized epilepsy. However, this has not been an area of active research, partly because of the lack of suitable animal models for some types of medically intractable epilepsy, particularly that of temporal lobe origin. A resurgence of interest in this investigative area would seem important to developing effective surgical therapies for those patients who are not candidates for the presently available techniques. Those studies might examine new surgical therapies involving local drug delivery to the focus or perhaps local implantation of inhibitory tissue into the focus (R Schmidt, personal communication, 1986). Coupled with renewed interest in the use of resective surgery and callosotomy, an expansion of investigation into new surgical therapies should provide options for effective treatment of a substantial number of patients with seizures not controlled by drugs. References 1. Ajmone-Marsan C: Depth electrography and electrocorticography, in Aminoff MJ (ed): Electrodiagnosis in Clinical Neurology. New York: Churchill Livingstone, 1980, pp Annegers JF, Hauser WA, Elveback LR, et al: Remission and relapse of seizures in epilepsy, in Wada JA, Penry JK (eds): Advances in Epileptology. The Xth Epilepsy International Symposium. New York: Raven Press, 1980, pp Augustine EA, Novelly RA, Mattson RH, et al: Occupational adjustment following neurosurgical treatment of epilepsy. Ann Neurol 15:68-72, Babb TL, Crandall PH: Epileptogenesis of human limbic neurons in psychomotor epileptics. Electroencephalogr Clin Neurophysiol 40: , Bengzon ARA, Rasmussen T, Gloor P, et al: Prognostic factors in the surgical treatment of temporal lobe epileptics. Neurology 18: , Blume WT, Grabow JD, Darley FL, et al: Intracarotid amobarbital test of language and memory before temporal lobectomy for seizure control. Neurology 23: , Bouvier G, Mercier C, St Hilaire JM, et al: Anterior callosotomy and chronic depth electrode recording in the 496 J. Neurosurg. / Volume 66/April, 1987

9 Surgical treatment for epilepsy surgical management of some intractable seizures. Appl Neurophysiol 46:52-56, Brey R, Laxer KD: Type I/II complex partial seizures: no correlation with surgical outcome. Epilepsia 26: , Brown WJ: Structural substrates of seizure foci in the human temporal lobe (a combined electrophysiological optical microscopic and ultrastructural study), in Brazier MAB (ed): Epilepsy. Its Phenomena in Man. New York: Academic Press, 1973, pp Campbell AL Jr, Bogen JE, Smith A: Disorganization and reorganization of cognitive and sensorimotor function in cerebral commissurotomy. Compensatory role of the forebrain commissures and cerebral hemispheres in man. Brain 104: , Cooper IS, Riklan M, Amin I, et al: A long-term followup study of cerebellar stimulation for the control of epilepsy, in Cooper IS (ed): Cerebellar Stimulation in Man. New York: Raven Press, 1978, pp Cooper IS, Upton ARM: Therapeutic implications of modulation of metabolism and functional activity of cerebral cortex by chronic stimulation of cerebellum and thalamus. Biol Psychiatry 20: , Creutzfeldt OD, Ojemann G, Lettich E: Single neuron activity in the human temporal lobe: I. Listening and speaking. Soc Neurosci Abst 11:879, 1985 (Abstract) 14. Delgado-Escueta AV, Treiman DM, Walsh GO: The treatable epilepsies (second of two parts). N Engl J Med 308: , Delgado-Escueta AV, Walsh GO: The selection process for surgery of intractable complex partial seizures: surface EEG and depth electrography, in Ward AA Jr, Penry JK, Purpura DP (eds): Epilepsy. New York: Raven Press, 1983, pp Dodrill CB, Troupin AS: Seizures and adaptive abilities. A case of identical twins. Arch Neurol 33: , Dodrill CB, Wilkus RJ, Ojemann GA, et al: Multidisciplinary prediction of seizure relief from cortical resection surgery. Ann Neurol 20:2-12, Engel J Jr: Surgical Treatment of Epilepsy. New York: Raven Press (In press, 1987) 19. Engel J Jr, Crandall PH, Rausch R: The partial epilepsies, in Rosenberg R, Grossman R (eds): The Clinical Neurosciences. Section II: Neurosurgery. New York: Churchill Livingstone, 1983, pp II: 1349-II: Engel J Jr, Driver MV, Falconer MA: Electrophysiological correlates of pathology and surgical results in temporal lobe epilepsy. Brain 98: , Engel J Jr, Sutherling W, Cahan L, et al: The role of positron emission tomography in the surgical therapy of epilepsy, in Porter RJ, Mattson RH, Ward AA Jr, et al (eds): Advances in Epileptology. The XVth Epilepsy International Symposium. New York: Raven Press, 1984, pp Falconer M: Anterior temporal lobectomy for epilepsy, in Logue V (ed): Neurosurgery, ed 2. Operative Surgery, Vol 14. London: Butterworths, 1971, pp Ferguson SM, Rayport M, Corrie WS: Neuropsychiatric observations on behavioral consequences of corpus cap losum section for seizure control, in Reeves AG (ed): Epilepsy and the Corpus Callosum. New York: Plenum Press, 1985, pp Fried I, Mateer C, Ojemann G, et al: Organization of visuospatial functions in human cortex. Evidence from electrical stimulation. Brain 105: , Fried I, Ojemann GA, Fetz EE: Language-related potentials specific to human language cortex. Science 212: , Gates JR, Leppik IE, Yap J, et al: Corpus callosotomy: clinical and electroencephalographic effects. Epilepsia 25: , Gates JR, Mireles R, Maxwell R, et al: Nuclear magnetic resonance scan documentation of the extent of corpus callosotomy. Epilepsia 25: , 1984 (Abstract) 28. Gazzaniga MS: The Bisected Brain. New York: Appleton- Century-Crofts, Gloor P, Olivier A, Ives J: Prolonged seizure monitoring with stereotaxically implanted depth electrodes in patients with bilateral interictal temporal epileptogenic foci: how bilateral is bitemporal epilepsy?, in Wada JA, Penry JK (eds): Advances in Epileptology. The Xth Epilepsy International Symposium. New York: Raven Press, 1980, pp Goldring S: Epilepsy surgery. Clin Neurosurg 31: , Green JR: Temporal lobectomy, with special reference to selection of epileptic patients. J Neurosurg 26: , Halgren E, Babb TL, Crandall PH: Activity of human hippocampal formation and amygdala neurons during memory, testing. Electroencephalogr Clin Neurophysiol 45: , Halgren E, Squires NK, Wilson CL, et al: Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events. Science 210: , Halgren E, Wilson C, Stapleton J: Human medial temporal lobe stimulation disrupts both formation and retrieval of recent memories. Brain Cognition 4: , Harris AB: Degeneration from experimental seizures. Soc Neurosci Abst 2:246, 1976 (Abstract) 36. Heit G, Smith M, Halgren E: Multiunit neuronal responses in the human medial temporal lobe during a verbal recent memory task. Soc Neurosci Abst 11:877, 1985 (Abstract) 37. Horsley V: Brain surgery. Br Med J 2: , Jay GW, Leestma JE: Sudden death in epilepsy. A comprehensive review of the literature and proposed mechanisms. Acta Neurol Scand 63 (Suppl 82): 1-66, Jinnai D, Mukawa J, Iwata Y, et al: Forel-H-tomy for the treatment of intractable epilepsy, in Wada JA, Penry JK (eds): Advances in Epileptology. The Xth Epilepsy International Symposium. New York: Raven Press, 1980, pp King D, So E, Marcus R, et al: Techniques and applications of sphenoidal recording. J Clin Neurophysiol 3: 51-56, Kuhl DE, Engel J Jr, Phelps ME, et al: Epileptic patterns of local cerebral metabolism and perfusion in humans determined by emission computed tomography of 18FDG and 13NH3. Ann Neuroi 8: , Kusske JA, Ojemann GA, Ward AA Jr: Effects of lesions in ventral anterior thalamus on experimental focal epilepsy. Exp Neuroi 34: , Lesser RB, Lueders H, Dinner DS, et al: The location of speech and writing functions in the frontal language area. Results of extraoperative cortical stimulation. Brain 107: , Lifrak MD, Novelly RA: Language deficits in patients with temporal lobectomy for complex-partial epilepsy, in Porter R J, Mattson RH, Ward AA Jr, et al (eds): Advances in Epileptology. The XVth Epilepsy International Symposium. New York: Raven Press, 1984, pp Lockard JS, Ojemann GA, Congdon WC, et at: Cerebellar stimulation in alumina-gel monkey model: inverse rela- J. Neurosurg. / Volume 66/April,

10 G. A. Ojemann tionship between clinical seizures and EEG interictal bursts. Epilepsia 20: , Liiders H, Hahn J, Lesser R, et al: Localization of epileptogenic spike foci: comparative study of closely spaced scalp electrodes, nasopharyngeal, sphenoidal, subdural and depth electrodes, in Akimoto H, et al (eds): Advances in Epileptology. The XIIIth Epilepsy International Symposium. New York: Raven Press, 1982, pp Liiders H, Lesser RP, Hahn J, et al: Basal temporal language area demonstrated by electrical stimulation. Neurology 36: , Marino R Jr, Ragazzo PC: Selective criteria and results of selective partial callosotomy, in Reeves AG (ed): Epilepsy and the Corpus Callosum. New York: Plenum Press, 1985, pp Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313: , Meyer FB, Marsh WR, Laws ER Jr, et al: Temporal lobectomy in children with epilepsy. J Neurosurg 64: , Milner B: Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg 19: , Milner B, Branch C, Rasmussen T: Study of short-term memory after intracarotid injection of sodium Amytal. Trans Am Neurol Assoc 87: , Mori K, Ono H, Iwayama K: Role of ventroanterior lesions in the control of focal motor seizures: experimental and clinical studies, in Wada JA, Penry JK (eds): Advances in Epileptology. The Xth Epilepsy International Symposium. New York: Raven Press, 1980, pp l 54. Morrell F: Secondary epileptogenesis in man. Arch Neurol 42: , Moseley JI, Ojemann GA, Ward AA Jr: Unit activity in experimental epileptic foci during focal cortical hypothermia. Exp Nearol 37: , Novelly RA, Augustine EA, Mattson RH, et al: Selective memory improvement and impairment in temporal lobectomy for epilepsy. Ann Neurol 15:64-67, Oakley J, Ojemann GA: Effects of chronic stimulation of the caudate nucleus on a preexisting alumina seizure focus. Exp Neurol 75: , Oakley J, Ojemann GA, Ojemann LM, et al: Identifying epileptic foci on contrast-enhanced computerized tomographic scans. Arch Neurol 36: , Ojemann GA: Brain organization for language from the perspective of electrical stimulation mapping. Behav Brain Sci 6: , Ojemann GA: The future role of surgery in the treatment of epilepsy, in Wada JA (ed): Modern Perspectives in Epilepsy. Montreal: Eden Press, 1978, pp Ojemann GA: Individual variability in cortical localization of language. J Neurosurg 50: , Ojemann GA: Neurosurgical management of epilepsy: a personal perspective in Appl Neurophysiol 46: 11-18, Ojemann GA: Surgical treatment of epilepsy, in Wilkins RH, Rengachary SS (eds): Neurosurgery. New York: McGraw-Hill, 1985, pp Ojemann GA, Creutzfeldt O: The contribution of brain stimulation and recording to the understanding of language in humans and animals, in Plum F (ed): Behavior. Handbook of Physiology, Section on Neurophysiology. (In press, 1987) 65. Ojemann GA, Creutzfeldt O, Lettich E: Single neuron activity in the human temporal lobe: II. Naming, reading memory, face and figure matching. Soc Neurosci Abst 11:879, 1985 (Abstract) 66. Ojemann GA, Dodrill C: Intraoperative techniques for reducing language and memory deficits with left temporal lobectomy, in Wolf P, et al (eds): Advances in Epileptology XVI (In press, 1987) 67. Ojemann GA, Dodrill CB: Verbal memory deficits after left temporal lobectomy for epilepsy. Mechanism and intraoperative prediction. J Nearosurg 62: , Ojemann GA, Engel J Jr: Acute and chronic intracranial recording and stimulation in the surgical treatment of epilepsy, in: Surgical Treatment of Epilepsy. New York: Raven Press (In press, 1987) 69. Ojemann GA, Ward AA Jr: Stereotactic and other procedures for epilepsy, in Purpura DP, Penry JK, Walter RD (eds): Neurosurgical Management of the Epilepsies. Advances in Neurology, Voi 8. New York: Raven Press, 1975, pp Ojemann LM, Ojemann GA: Treatment of epilepsy. Am Faro Physician 30(2): , Penfield W, Jasper HH: Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown & Co, Penfield W, Mathieson G: Memory. Autopsy findings and comments on the role of hippocampus in experiential recall. Arch Neurol 31: , Penfield W, Roberts L: Speech and Brain Mechanisms. Princeton: Princeton University Press, Purpura DP, Penry JK, Walter RD (eds): Neurosurgical Management of the Epilepsies. Advances in Neurology, Vol 8. New York: Raven Press, Rasmussen T: Characteristics of a pure culture of frontal lobe epilepsy. Epilepsia 24: , Rasmussen T: Localizational aspects of epileptic seizure phenomena, in Thompson R, Green J (eds): New Perspectives in Cerebral Localization. New York: Raven Press, 1982, pp Rasmussen T: Surgery for epilepsy arising in regions other than the temporal and frontal lobes, in Purpura DP, Penry JK, Walter RD (eds): Neurosurgical Management of the Epilepsies. Advances in Neurology, Vol 8. New York: Raven Press, 1975, pp Rasmussen T: Surgery of frontal lobe epilepsy, in Purpura DP, Penry JK, Walter RD (eds): Neurosurgical Management of the Epilepsies. Advances in Neurology, Vol 8. New York: Raven Press, 1975, pp Rasmussen T: Surgical treatment of patients with complex partial seizures, in Penry JK, Daly DD (eds): Complex Partial Seizures and Their Treatment. Advances in Neurology, Voi 11. New York: Raven Press, 1975, pp Rausch R, Crandall PH: Psychological status related to surgical control of temporal lobe seizures. Epilepsia 23: , Scheibel ME, Crandall PH, Scheibel AB: The hippocampal-dentate complex in temporal lobe epilepsy. A Golgi study. Epilepsia 15:55-80, Sherwin I, Peron-Magnan P, Bancaud J, et al: Prevalence of psychosis in epilepsy as a function of the laterality of the epileptogenic lesion. Arch Neurol 39: , Spencer SS: Corpus callosum resection, in Engel J Jr (ed): Surgical Treatment of Epilepsy. New York: Raven Press (In press, 1987) 84. Spencer SS: Depth electroencephalography in selection of refractory epilepsy for surgery. Ann Neurol 9: , Spencer SS, Spencer DD, Williamson PD, et al: The localizing value of depth electroencephalography in 32 pa- 498 J. Neurosurg. / Volume 66/April, 1987