Recent advances in surgical merit of temmral lobe etilemv J. Engel Jr. Departments of Neurology and Anatomy and the Brain Research Institute UCLA School of Medicine

Introduction The safest, most effective, and most commonly performed surgical treatment for epilepsy is resection of the anterior temporal lobe for medically refractory complex partial seizures (1,2). Complex partial seizures (3), in turn, are the most common among all seizure types in patients with epilepsy (4). Furthermore, complex partial seizures are particularly resistant to standard antiepileptic drug treatment (3,and patients with these ictal events are the most likely of all epileptic patients to be referred to an epilepsy surgery facility. Consequently, there is now extensive worldwide experience with anterior temporal lobe resections for the treatment of medically refractory complex partial seizures, and advances in this area are immediately applicable to a large population of patients (6).This fortunate circumstance has thus made surgically oriented clinical research relatively more feasible for temporal lobe epilepsy than for other epilepsies, and the resultant progress is relatively more rewarding. A major factor directing current approaches to temporal lobe surgery has been the growing appreciation for a syndrome of mesial temporal lobe epilepsy (MTLE) characterized by seizures of mesial temporal limbic origin. Recognition of this syndrome, coupled with the continuing technological development of diagnostic tests that are particularly well suited for identifying mesial temporal epileptiform and nonepileptiform disturbances is greatly increasing our ability to offer surgical treatment to patients with medically refractory complex partial seizures, and to

Address: J. Engel Jr. Reed Neurological Research Center 710 Westwood Plaza Los Angeles, CA. 90024-1769 U.S.A.

determine the appropriate surgical resection noninvasively in a cost-effective manner. This chapter will first consider a proposed syndrome of MTLE, and then review current and future directions for the surgical treatment of temporal lobe epilepsy.

The proposed syndrome of Mesial Temporal Lobe Epilepsy The term “temporal lobe epilepsy” has been used for may years as though is referred to a well defined symptom complex. Indeed, there has been increasing support in recent years for the concept of a syndrome of temporal lobe epilepsy, based primarily on characteristic features of the ictal events which reflect epileptic activation of mesial temporal limbic structures, particularly the hippocampus and its direct projections (5, 7). It is well recognized, however, that epileptogenic regions in temporal, and extratemporal, neocortex can rapidly propagate to mesial temporal limbic structures, producing complex partial seizures that are indistinguishable form those that originate in the mesial temporal lobe. At times specific primary sensory auras or initial focal motor signs may provide adequate clues that the epileptogenic region is extratemporal, but many auras and motor signs have ambiguous localizing significance (3,and some complex partial seizures arise in “silent” neocortical areas with no characteristic initial ictal symptomatology. Distinction between complex partial seizures that originate from an epileptogenic region within the mesial temporal lobe and complex partial seizures that originate in neocortical epileptogenic regions, either temporal or extratemporal, is of paramount importance when selective surgical resections are being considered. Given that complex partial seizures of mesial temporal lobe origin are almost always associated with hippocampal sclerosis (8), the clinical features associated with this lesion provide an opportunity to even more clearly define a syndrome of MTLE that is distinct from epilepsies due to neocortical

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Engel epileptogenic regions that give rise to limbic seizures secondarily.

Historical features Patients with MTLE have an increased incidence of family history of epilepsy and an increased incidence of febrile convulsions which are usually prolonged (9). Although there is considerable evidence that prolonged convulsions can produce hippocampal damage similar to that seen with hippocampal sclerosis (lo), there is controversy concerning whether the febrile convulsions in patients with MTLE actually produce the epileptogenic region, or are merely a reflection of an abnormal susceptibility to epileptic seizures. The increased incidence of a positive family history for epilepsy supports the latter interpretation. When other family members have experienced epileptic seizures, they are usually not the same complex partial seizures reported by the patient. Rather, there may be a history of a variety of epileptic disturbances from febrile convulsions to post-traumatic seizures. There are likely to be many genetic factors that contribute to a lowered familial susceptibility to develop seizures, given a specific transient or chronic insult (5, 1 I). Habitual complex partial seizures of MTLE typically begin in the latter half of the first decade of life and occasionally become secondarily generalized. Most patients have auras which also occur in isolation as simple partial seizures. The complex partial and secondarily generalized seizures are usually controlled with antiepileptic medication initially. Commonly, there is a seizure-free period which may last many years, occasionally off medication. When complex partial seizures return, however, they can be very difficult to control with medication, and in a large proportion of patients with this syndrome, eventually become medically refractory. If habitual seizures do not occur frequently, patients are usually otherwise normal. With more frequent ictal events, however, there are often complaints of poor memory and increasing psychosocial problems, the latter resulting, at least in part, from the associated disability. Interictal behavioral disturbances, most commonly depression, are reported to be more common in patients with MTLE than in patients with other epileptic disorders, but this remains a controversial issue (1 2). The clinical seizure The great majority of patients with MTLE report an aura which most commonly consists of a sensation of epigastric rising. Auras can also consist of other vegetative autonomic symptoms, psychic symptoms, particularly fear, and gustatory, olfactory, and complex multimodal sensory phenomena. Typically, the aura will occur more often in isolation as a simple partial seizure than as the beginning of a complex partial seizure. When the latter 72

occurs, there is usually some form of arrest with a motionless stare, often associated with oral alimentary automatisms such as lip smacking and chewing movements. Other more complicated automatisms also commonly occur as part of the ictal event, and postictally as well. Careful observation in many patients will reveal gestural automatisms with one upper extremity and posturing with the other. In this situation, the seizures are reported to originate on the side contralateral to the posturing (1 3). Postictal symptoms include amnesia for the ictal event, recent memory disturbance and more generalized disorientation. Aphasic deficits preceding or following the complex partial seizure strongly suggest that the epileptogenic region is in the language-dominant hemisphere. Auras usually last a few seconds, the complex partial seizure one to two minutes, and the postictal confusion many minutes, depending upon the length of the ictal event. Secondarily generalized seizures may never occur, but when they do they are infrequent and should be easily controlled by antiepileptic medication. The frequency of complex partial seizures typically ranges from several times a month to may times a week, with no specific temporal pattern. Simple partial seizures can occur up to several times a day. Ictal events are more likely, during periods of rest and relaxation, and least likely during periods of high concentration. Patients often report that their condition is made worse by stress or sleepdeprivation. Women experience exacerbation of seizures preceding and during their menses.

Neurological examination Patients with MTLE have no characteristic neurological deficits or mental status disturbances that can be identified on routine neurologic examination, except for occasional disturbances in recent memory. Asymmetries and stigmata on the general examination, specific neurological deficits, localizing cognitive disturbances, and more diffuse mental impairment are reasons to reconsider this diagnosis. Electroencephalography The interictal scalp EEG in the vast majority of patients with MTLE will demonstrate unilateral or bilateral, independent, anterior temporal spike discharges. When basal (e.g., earlobe, true temporal, and sphenoidal) electrodes are used, these spikes demonstrate a field with a maximum amplitude in the basal derivation. There is no particular frequency or spike-and-wave morphology that is characteristic of this syndrome. Some patients may have intermittent, or even continuous interictal rhythmic slowing in one anterior temporal region which presumably reflects the slow wave portion of recurrent spike-and-wave discharges. There is typically no change in the scalp EEG recording during the simple partial seizure (aura); however, if

Temporal Lobe Surgery

Fg 1. EEGtelemetry-recordedictalonset.

Examplesof EEGtelemetry-recordedictalonsetsfrom four patientsM complex parM seizures.(A)Lowvoitage5to 7-per-secrhythmicabity appearsatthe rightsphenoidalelectrode(arrow) 5secbeforeitisseenovertherighttemporalconvexity.(B)Followingadiffuseburstofmuscleandeyemovementartefact, low-voltage5to7-per-secactMtyisrecordedbytherightsphenoidal electrode(arrow).This becomesprogressivelyslower andthe amplitudeincrease;5 sec laterit is seen diffuselyover the right hemisphere.(C)lrregular,sharplycontouredslowwaves demonstrate phasereversalattherightsphenoidalelectrode(arrow)andarereRectedaslowamplLdedelta,~outphasereversal,overrighthemisphere.(D)lnthislateralizedbut not localizedictalonset, voltagesuppressiona~dlow-voltagefasta~ityoccurovertherightfrontotemporal areaandarebestseenattherightsphenoidalelectrode(arrow).Thispr&s by3sectheappearanceof diffuse3lsec spike-and-wavedischarges,which are also moreprominentfromthe rightfrontotempraland sphenoidalderivations.After 10 secthislatteractivityevolvesinto high-voltage7-persecsh~,waves,~chshowphasereversalattherightsphenoidalel~odeandlaterallyattherightanteriortomidtemporal region(delayedfcca1onset). Calibration 1sec 100mV.Notethat sensitivityisthesamefor A, BandC,andthefirst halfof D, butdecreasedto halfinDatthefirstcalibrafionmark. From41,withpermission.

interictal spikes are frequent they can be seen to disappear at this time. Ictal EEG changes usually begin at the time of altered consciousness and most often consist of theta activity in one or both anterior temporal regions. Other ictal onset EEG patterns include unilateral or bilateral suppression, and irregular slowing. The ictal EEG discharge pattern characteristically evolves and, in most patients, 5 to 7-per-second sharp waves, phase reversing in one basilar electrode, occur at some time during the frst 30 seconds (Figure 1) (14). When interictal spikes occur only in one anterior temporal lobe, or are much more predominant on one side, this correlates with the side of the epileptogenic region in approximately 85% of patients (15). Bilateral independent mesial temporal interictal spikes, however, do not necessarily indicate the presence of bilateral epileptogenic regions capable of generating spontaneous seizures; the majority of patients with such interictal EEG abnormalities have habitual seizures that originate from only one

temporal lobe (16). Focal onset ictal EEG patterns are also localizing in only approximately 85% of patients (14, 15). The appearance of 5 to 7-per-second sharp waves in one mesial temporal area within 30 seconds after a nonspecific ipsilateral, or bilateral, ictal onset pattern (delayed focal onset) is reported to have the same localizing value as a clear initial focal onset pattern (14). Direct chronic recording with depth electrodes is the most accurate way to demonstrate that spontaneous habitual seizures originate unilaterally in mesial temporal limbic structures. With multiple recording contacts in hippocampal pes, hippocampal g y m , and amygdala, focal onset patterns are defined as those which begin initially from one or two contacts and gradually spread to the others, whereas regional onset patterns are defined as those which begin simultaneously in all or most of the contacts in one mesial temporal lobe (17). Regional onset patterns can represent propagation from an epileptogenic region outside the recording range of available intracranial

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fi@2 EEG actbity duringseizureonsetatselecteddepthele3rdes. Telemebyrecordingshowing EEGa~atselecteddepthelectrodes(bipolarfps)duringtheonsetofawmplexparbalseizure.Threewntinuoussegmentsshowacommonictalonset pattern,beginningwith rhythmic highamplitude sharp and slow transients(arrow), inEally widespacedbut becomingfaster andsharper. This eventuallygivesway to a lowvoltage fast discharge, whichthen evolves into higheramplitude repefitivespikesorspike-and-wavedischarges. RA, rightamygdala; RAH,rigMantenorhippocampalpes, RPSrigMpresubiculum; RMH, right midhippocampalpes.Calibra~on1second.From42,with permission.

electrode contacts, while focal onsets localize a mesial temporal epileptogenic region with a high degree of accuracy. The most common depth electrode-recorded ictal onset pattern in mesial temporal lobe epilepsy is a high amplitude repetitive sharp wave, spike, or spike-and-wave, which may be slower than one-per-second, gradually increasing in frequency, or a much more rapid spike-and-wave at onset, resembling a localized petit ma1 type pattern (Figure 2). Typically, this hypersynchronous discharge will be associated with the aura, or there will be no clinical signs or symptoms. After some time, the high amplitude rhythmic discharge can give way to a low voltage high frequency recruiting rhythm which usually is associated with propagation to the contralateral hemisphere and the onset of the complex partial seizure (Figure 2). In one third or less of patients with complex partial seizures, the initial depth-recorded EEG ictal onset is of the low voltage fast recruiting rhythm pattern. In these patients, the onset is less likely to be focal, less likely to correlate with the presence of hippocampal sclerosis in the resected specimen (i.e., not MTLE), and usually propagates more rapidly to the contralateral hemisphere, than in patients with the hypersynchronous ictal onset (1 8). In patients with h4TLE, focal depth electrode recorded ictal EEG onsets most often occur in hippocampal pes, 74

specifically the anterior portion. Focal onsets from hippocampal gyrus are also encountered; however, focal onsets from amygdala are extremely rare. The ictal discharge typically remains in one temporal lobe for prolonged periods of time, often minutes, before spreading to the contralateral side (19). When the interhemispheric propagation time is less than five seconds, a diagnosis of MTLE should be questioned.

Focal functional deficits Patients with MTLE often demonstrate evidence of interictal dysfunction in -mesial temporal limbic structures that can be identified by a variety of tests of focal functional deficit (20). The most useful at UCLA has been positron emission tomography (PET) with '*F-fluorodeoxyglucose (FDG).Interictal FDG-PET reveals hypometabolism of the epileptogenic temporal lobe in over 85% of patients referred for surgical treatrrient of medically refractory complex partial seizures (21). The zone of hypometabolism is much larger than the epileptogenic region identified electrophysiologically, and the epileptogenic lesion defined pathologically. In the majority of patients, the ipsilateral thalamus and basal ganglia are also hypometabolic, and ipsilateral extratemporal neocortical areas, most commonly frontal, can be involved (22) (Figure 3).

Temporal Lobe Surgery

F@3. Intencta118F-tluorodeoxyglumsq. PETscanwithFDGfromapatient\Klthwmplexprtialseizuresofleftmesial ternporalo~in.ThisscanwasperformedonaSiemensGTl831 tornographwithaninplaneresolutionof sagittal,orotherplanesasdesired. approximately5mrn.Fifteenhorizontalplanesof~onareobtainedsimultaneouslyandoneormoresetsofplanescanthenbereformattedintowronal, ThePETscanofthispatientdemonstrateslefltemporalhypometabolismwhichcanbeseenonall horizontalplanesofsectionthroughthetemporall&showninA,andenlargedforone sectionin B.The hypometabolismcnalsobeappreciatedinthewronalsection(C)~in~g~s~onthrough~elefltemporall&(D),~enwmparedtothe~g~s~on~roughthe righttemporallobe (E). From5,with permission.

Patients with MTLE also may show unilateral temporal hypoperfusion on interictal single photon emission computed tomography (SPECT), although the spatial resolution, and therefore the yield, is considerably less with SPECT than with PET. Recently, studies with ictal SPECT have demonstrated a consistent ictal-postictal pattern of regional cerebral blood flow in patients with complex partial seizures, consisting of temporal hyperperfusion during the seizure, mesial hyperperfusion with lateral

hypoperfusion in the immediate postictal period, and hypoperfusion of the entire temporal lobe with later postictal injections (23). Although the sensitivity of this ictal SPECT pattern for seizures originating in mesial temporal lobe appears to be much better than with interictal SPECT, and perhaps comparable to interictal PET, specificity has not yet been adequately determined. Neuropsychological evaluations of patients with MTLE typically reveal memory deficits which are material

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Engel specific for the involved hemisphere (24). Often the mesial temporal memory deficit can be easily demonstrated by contralateral intracarotid amobarbital injection (the WADA test), when this procedure demonstrates that the involved hemisphere is unable to support memory (24). Focal nonepileptiform EEG abnormalities can also indicate dysfunction in mesial temporal areas. Continuous slowing in one basal electrode derivation can represent epileptiform activity, as noted previously, but could also provide evidence for a focal functional deficit. When depth electrodes are used, contacts in the mesial temporal epileptogenic regions often reveal an attenuation of normal rhythmic EEG activity as well as abnormal slow waves, compared to the contralateral side. Sphenoidal and depth electrode recorded asymmetries can be more easily demonstrated with the use of intravenous barbiturates or benzodiazepines, when the induced beta activity is attenuated in the epileptogenk mesial temporal area (20).

Pathophysiology

Hippocampal sclerosis is the pathological substrate of MTLE (8) (Figure 4). New high resolution MRI is often able to demonstrate an asymmetry in hippocampal size corresponding to the presence of hippocampal sclerosis. (Figure 5 ) , and quantitative volumetric analysis might increase the sensitivity and specificity of this diagnostic tool (25). Fifty percent cell loss can usually be appreciated by visual inspection of the pathological specimen, but a diagnosis may be missed with routine analysis when the degree of damage is less. Quantitative cell counts suggest that a diagnosis of hippocampal sclerosis is warranted with cell loss greater than 30% (26). Loss of principal neurons in hippocampal sclerosis is most marked in the CAI region, and there is relative sparing of the CA2 region. Dentate granule cells are also lost, but principal neurons in presubiculum are not. A more diffuse pattern of hippocampal cell loss can be seen following a variety of toxic and metabolic insults and is considered to be nonspecific (8). Nonspecific hippocampal cell loss is also encountered in the temporal lobes of patients with other forms of epilepsy. Examination of temporal lobe specimens removed from patients with apparent MTLE may occasionally reveal other lesions (8). When hamartomas and heterotopias are found, careful analysis usually reveals hippocampal sclerosis as well, or so-called “dual pathology”, while glial tumors are rarely associated with hippocampal sclerosis (27). Patients with these latter lesions, therefore, do not have MTLE as defmed here. Microanatomical and immunocytochemical studies of PRE sclerotic hippocampus have demonstrated loss of specific cell types, particularly in the hilus, including those containing somatostatin and neuropeptide Y (28), and sprouting of dentate granule cell mossy fibers, to produce monosynaptic recurrent excitatory circuits (29). These changes occur in patients with MTLE and classical hippocampal sclerosis, but are not seen in the hippocampi of patients with complex partial seizures due to glial tumors (28). Such studies provide a further basis for identifying a syndrome of WILE as separate from temporal lobe epilepsies resulting from temporal neocortical ‘tumours or other lesions unassociated with hippocampal sclerosis. \ fig 4 Cellsinnonnalandatrophiedepileptichippocarnpus. A combined hereditary/environmental etiology for W o o d w e d platebyBrak(l899)ofcellsinnonal (top)andatrophiedepileptic(bottom) MTLE can be postulated. Dysgenetic lesions, such as hippocampus.Althoughthenumbersof pyramidalcells areover-representedattcp,the heterotopias and at least some hamartomas, appear to be Ammon’s horn(CA),fasciadentata(FD)andsubicularcomplexare identifiableinboth markers of MTLE rather than epileptogenic lesions normalandsclerotichippocampus.Theirnpoltantsubfieldsarelabeledandonecannotein themselves, while glial tumors produce a different disorder thenormalhippocarnpus(top)largechpyramids,properly-orientedpyramidsaround Arnmon’s horntothepresubiculurn (PRE),smallergranulecellsoftheFDandthewhiie where the epileptogenic region is cortex immediately rnatterofthefimbria-formix(F).IntheepileptlchippocampusgranulecellsofheFDandCA, adjacent to the tumour. When direct intracranial recording andCA, andprosubculum(PRO).MostnotableisthepreservationofCA,andtherela~elyis carried out in patients with glial tumors’in temporal intactpresubiculum(PRE)adjacenttothedamagedsubiculum(SUB).Tllisepileptic-pattern neocortex, seizures are usually seen to originate in adjacent isfoundpresentlyinternporalloberes~onsandautopsiesofpatientshavingsufferedfrom Cortical areas and then propagate to hippocampus; in temporallobeepilepsy.From8,withpermission. /--

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Temporal Lobe Surgery

Fg 5 Highresolution1.5TeslaMRITlweighted imageof the humanbrain incoronal section.Theexquisiteanatomicaldetail that is revealedallowsdear~sualizationof mesial temporalstructures.lnthispatientwithtemporal lobeepilepsy dueto hippocampalsclerosis, the hippocampalasymmetryis apparent,withthe smaller hippocampusbeingthesieof seizure onset.From43,withpermission.

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Engel patients with heterotopias and hamartomas, seizures appear to originate in the sclerotic hippocampus, and clinical features are identical to those of patients with hippocampal sclerosis alone (unpublished data). Microdysgenesis, seen in patients with primary generalized epilepsies, is also frequently encountered in subcortical white matter of temporal lobe specimens removed from patients with hippocampal sclerosis (30). Hippocampal cell loss in patients who undergo temporal lobe resections for complex partial seizures is more likely to show the typical CA2 sparing when there is a positive family history of epilepsy, than when this family history is absent (unpublished data). There is often abnormal laminar dispersion of the dentate granule cell layer in hippocampal sclerosis, suggesting a preexisting disturbance of migration of these neurons (31). All of these observations suggest that migration disturbances could reflect a genetic, or perhaps in some situations an acquired congenital, predisposition to develop hippocampal sclerosis and subsequent MTLE following postnatal insults that damage hippocampal neurons.Prolonged febrile convulsions could constitute such an insult in some patients but in others it might be more insidious; for instance a benign childhood viral infection. Although the structural changes in MTLE appear to be limited to the hippocampus and immediately adjacent areas, there is increasing evidence that the epileptogenic region is much larger. It is commonly known from depth electrode studies that interictal spikes can be recorded from a wide area of ipsilateral, as well as contralateral, temporal lobe structures ( I , 2). When selective amygdalohippocampectomies are performed to treat intractable complex partial seizures in these patients, the outcome with respect to residual seizures depends on the amount of hippocampal gyrus removed (32), indicating that this adjacent neocortex, which contains no structural abnormality, is capable of seizure generation. In many patients with mesial temporal lobe epilepsy and hippocampal sclerosis, even a standard anterior temporal lobectomy will not abolish all simple partial seizures (auras) (1, 2), suggesting an even greater area of primary epileptogenic tissue presumably involving, at least, the insula. The typical electrographic ictal onset of high amplitude rhythmically recurring spikes or sharp waves indicates underlying neuronal hypersynchrony, as opposed to disinhibition, which would be more likely to give rise to the low voltage fast recruiting rhythm seen more commonly with other seizure types (33). Electrophysiological, morphological, and pharmacological studies of human hippocampal sclerosis and some chronic animal models of temporal lobe epilepsy suggest that enhanced inhibition, as well as enhanced excitation, may be responsible for some of the epileptiform phenomena encountered. This has led

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to the hypothesis that there are at least two categories of epileptic disturbances: one involving enhanced excitation and decreased inhibition characterized ictally by the recruiting rhythm of generalized convulsions (and perhaps most neocortical partial seizures), also seen interictally as generalized paroxysmal fast activity (GPFA); the other consisting of enhanced excitation and enhanced inhibition giving rise to hypersynchronous discharges seen ictally with absences (and most mesial temporal limbic seizures), and also interictally as the typical interictal spike-andwave. This view that the fundamental mechanisms of ictal generation in MTLE are different from those of other types or partial and generalized convulsive epilepsies might explain the fact that complex partial seizures in this disorder are often refractory to common anticonvulsant medications. These medications are developed by testing with experimental animal models that mimic the disinhibitory epileptic disorders, whereas no adequate experimental model of MTLE has been developed that can be used efficiently for screening new potentially antiepileptic compounds.

Approach to surgical treatment for temporal lobe epilepsy When structural neuroimaging studies reveal an obvious mass lesion which, itself, requires surgical treatment and the surgical intervention is not for epilepsy per se, the following protocol does not apply: such patients will not be considered further here. Also, patients with diffuse brain damage who are candidates for corpus callosotomy or multilobar resections, and patients with simple partial seizures of extratemporal neocortical origin who are candidates for a localized cortical resection, will not be discussed. The following is a commonly used protocol for presurgical evaluation of patients with medically refractory complex partial seizures (34), representative of the current approach to temporal lobe resections. Phase I evaluation Patients are admitted for inpatient scalp/sphenoidal EEG telemetry and video monitoring, in order to characterize the electroclinical correlates of their habitual seizures. In addition, an interictal FDG-PET scan, a neuropsychological test battery, and a high resolution MRI scan with volumemc analysis of the hippocampi are performed. The patient is considered for anterior temporal lobectomy without invasive recording i f 1) the clinical picture is that of MTLE; 2.) habitual seizures have an initial or delayed focal sphenoidal EEG onset pattern; 3.) either the same temporal lobe is hypometabolic on interictal FDG-PET or the MRI reveals unequivocal appropriate hippocampal asymmetry; and 4.) there is no conflicting information obtained from seizure semiology, structural imaging studies, or other tests of focal functional deficit. The patient then undergoes an intracarotid sodium amobarbital test (WADA test) to document that contralateral mesial

Temporal Lobe Surgery temporal structures can support memory. When umtdateral carotid amobarbital injection produces amnesh, this adds additional information supporting the existence of mesial temporal dysfunction. Further evidence of focal functional deficit is provided, when necessary, by attenuation of barbiturate-induced fast activity in the appropriate sphenoidal derivation following intravenous injection of thiopental. When MRI reveals a well CircUmscriW @al tumour or other specifically identified lesion (for instance an angioma or cyst), there is no evidence of hippocampal sclerosis, and typical =is not suspected,selectiveremoval (lesionectomy) may be considered This would require evidence from interictal and ictal EEG that seizures were originating from the area of the structural lesion, and that there is no conflicting evidence suggesting an epileptogenicregion elsewhere. Patients with less well-defined structural abnormalities, such as nonspeafic atrophy or migration disturbances, are not candidates for lesionectomy; however, if the structural changes are within the anterior temporal lobe and epileptic and nonepileptic functional changes localize to this area, they can be considered for anterior temporal lobectomy.

Phase I1evaluation When data obtained from the Phase I evaluation are inadequate to recommend anterior temporal lobectomy, but strongly suggests that the patient is likely to have an epileptogenic region in one temporal lobe, a second inpatient telemetry evaluation with in&icranial electmdes may allow therapeutic surgery to be performed. This usually requires stemtactic implantation of depth electrodes into mesial temporal structures bilaterally and other potentially epileptogenic cortical areas. Subdural strip electrodes may also be added to sample lateral n m r t e x . When patients do not fit the criteria for a diagnosis of MTLE, have complex partial seizures that might be arising from either temporal or extmtemporal n m r t e x , and the side of ictal onset is certain, subduralgrid electrodes are preferred Localization of the epileptogenic region with ictal infncranial electrode recordings can lead to a standard anterior temporal lobectomy, or more selected resections. If it is clear that habitual seizures originate in the hippocampus, amygdalohippocampectomy can be perf om^ when the epileptogenic region is demonstrated to be confined to the temporal n m r t e x , the temporal resection may spare mesial temporal structures. Future directions Advances in noninvasive EEG telemetry technology and newimaging have greatly enhanced our ability to confidently iden* a resectable temporal lobe epileptogenic region without requiring invasive EEG monitorhg..Lmpvements in the safety and accuracy of invasive monitoring techniques have also contributed to the efficacy of presurgical evaluation. The combined result is that most centrestoday report an average of 70% of patients undergoing temporal lobe resection become seizure-fire,whereas fewerthan 10%experiencenoworthwhile

improvement (6). Additional new developments p m i s e to further improve the benefits of surgical treatment and to reduce the cost of presurgical evaluation. The most expensive part of the presurgical evaluation is inpatient EEG telemetry. A more reliable means of using interictal spike discharges to localize the epileptogenic region may eventually obviate the need for extended inpatient ictal recordings in some patients. This could result from a better understanding of the temporal relationship between interictal spikes and seizures, their variations during the sleep wake cycle, and the sigruficance of specific morphological features. Magnetoencephalography (MEG) may provide additional information abut the spatial distribution and propagation patterns of current generators that underlie interictal EEG spikes (35). Also, new techniques are now available for 16 and more channel EEG telemetry recordings on an outpatient basis (36). Further reiinements in the application of ictal and postictal SPECT will undoubtedly make this approach more useful. Recent experience with new PET tracers that image neurotransmitter function, specifically opiate (37) and benzodiazepine (38) receptor binding, indicates that there may be a number of localized interictal abnormalities that could reliably identlfy the epileptogenic region. MRI approaches to visualize dynamic functional changes, particularly in cerebral blood flow (39), may gain a role in presurgical evaluation of patients with temporal lobe epilepsy. Magnetic resonance spectroscopy (hIRS) can be used to idenhfy characteristic epilepsyrelated cerebral dysfunction that could offer some advantages over other existing techniques and provide usehl complementary mformation (40). Finally, the burgeoning technology for precisely superimposing data from all of these diagnostic approaches on MRI-displayed cerebd anatomy will offer an unprecedented opportunity to create a three dimensional image of the human brain revealing epilepsyrelated structural and functional deficits that combine the high spatial resolution of MRI, the high temporal resolution of EEG and MEG, and the ability of PET, SPECT and M R S to distinguishbetweenavariety of specdicaspects ofbrainactivities, including glucose and oxygen metabolism, blood flow, and bthpre- and postsynaptic neurotransmitterfunctions. With appreciation for the fact that temporal lobe epilepsy is surgically remediable disorder, and that outcome, at least with respect to psychosocial adaptation if not with respect to seizures themselves, is dependent to some extent on age of o p t i o n , there are increasing arguments for early surgical intervention. One form of temporal lobe epilepsy, MTLE, appears to be an easily identified syndrome, associated with a high risk of medically Idi-actory seizures and severe psychosocial disability. The surgical resections used to treat this syndrome have very low morbidity and mortality, and abolishhabitualcomplexpdalsehresinaveryhighpercentage of patients (6). The combined use of currently available noninvasive tests for localizing a unilateral mesial temporal

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Engel epileptogenic region yields highly accmte results. Recent improvements in these technologies promise to further increase the safety and efficacy, and decrease the cost, of presurgical evaluation. We are rapidly reaching the point where the superiority of drug treatment over surgical treatment for MTLE, with respect to riskbenefit ratio, can be seriously questioned. Given that early surgical intervention is likely to prevent the irreversible psychosocial disabjlity caused by IS-equent epileptic seizures during the critical period of adolescent and early adult lift, it might soon be reasonable to

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propose a clinical trial comparing medical and surgical treatment in patients with MTLE as soon as it is determined that seizures cannot be completely controlled by antiepileptic drugs.

Acknowledgements Original research reported by the author was supported in part by Grants NS-02808, NS-15654 and GM-24839, from theNational Institutesof Health, and Contract DE-AC03-76SF00012 from the Department of Energy.

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