Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy that is amenable to surgical treatment. In the carefully selected patient, excellent seizure outcome can be achieved with minimal or no side effects from surgery. This may result in improved psychosocial functioning, achieving higher education, and maintaining or gaining employment. The objective of this paper is to discuss the surgical selection process of a patient with TLE. We define what constitutes a patient that has medically refractory TLE, describe the typical history and physical examination, and distinguish between mesial TLE and neocortical TLE. We then review the role of routine (ambulatory/sleep-deprived electroencephalography (EEG), video EEG, magnetic resonance imaging (MRI), neuropsychological testing, and Wada testing) and ancillary preoperative testing (positron emission tomography, single-photon emission computed tomography (SPECT), subtraction ictal SPECT correlated to MRI (SISCOM), magnetoencephalography, magnetic resonance spectroscopy, and functional MRI) in selecting surgical candidates. We describe the surgical options for resective epilepsy surgery in TLE and its commonly associated risks while highlighting some of the controversies. Lastly, we present teaching cases to illustrate the presurgical workup of patients with medically refractory TLE.
Cerebral localization and electroencephalography (EEG) have together been two fundamental advances that have been paramount in the diagnosis and management of epilepsy. The clinical observations of Broca [
With approximately 1% of the world population affected by epilepsy, it is classified by the International League Against Epilepsy (ILAE) as the most common serious neurological disorder in the world [
Medical intervention is the first step in the management of epilepsy. However, this fails to achieve seizure freedom in up to one-third of patients [
The objective of this paper is to discuss the surgical selection process of a patient with TLE. We will outline the definition of a medically refractory patient with TLE, distinguish between mesial TLE (mTLE) and neocortical TLE (nTLE), review the role of routine and ancillary preoperative testing, describe surgical techniques and discuss common surgical risks. We lastly present several case studies to review the rationale for surgery.
A recent consensus paper defined medically refractory epilepsy as having seizures despite being treated with 2 consecutive first-line antiepileptic medications (AEDs) over 2 years [
From an electrical and clinical perspective, there are two subtypes of TLE: mTLE and nTLE. This distinction is made (although there is indeed overlap) as it has important implications with respect to electrophysiology, neuropsychological profile, underlying pathological substrate, and response to surgery [
Electroclinical and diagnostic differences between mTLE and nTLE.
mTLE | nTLE | |
---|---|---|
Clinical aspects | Auras (simple partial seizures) | Same as mTLE |
Preoperative testing | MRI | Same as mTLE |
Neuropsychological testing | Neuropsychological testing | |
Wada test | ||
Scalp EEG | Scalp EEG | |
Intracranial recordings | Seizures originate from mesial structures | Variable with widespread electrophysiological changes |
The most common pathological substrate for TLE is MTS. This is characterized by segmental loss of pyramidal cells, dispersion of granule cells, and a resultant reactive gliosis. Other pathological entities resulting in TLE include tumors (either malignant or benign, e.g., ganglioglioma, dysembryoplastic neuroepithelial tumour, oligodendroglioma, low- or high-grade glioma, and meningiomas), infections (e.g., herpes, tuberculosis, and cysticercosis), vascular malformations (arteriovenous malformations, cavernous hemangioma, and meningioangiomatosis), migrational disorders (cortical dysplasia and hamartoma), and trauma (encephalomalacia and gliosis). The differential diagnosis of nTLE is similar to mTLE with the exception of MTS.
Approximately 15% of patients with partial epilepsy that have an extratemporal lesion have associated MTS; these cases are referred to as involving dual pathology [
The main goal of surgical management of epilepsy is the removal of the epileptogenic zone: the region which, if resected completely, would result in seizure freedom [
These concepts are simplifications, and they may not be accepted amongst all epileptologists. An alternative method of conceptualizing seizure onset and propagation is the theory of cortical and subcortical neuronal networks (NNs); these are bilateral brain regions that are interconnected functionally and anatomically [
The presurgical workup requires a detailed history and physical exam. Specific components of the history include a detailed account of seizure semiology, past medical history, family history, and attempted AED. Having a family member or friend who has witnessed the episodes can provide useful information, as the individual may not have any recollection of the events. A complete neurological examination can have localization value and, together with the history, can help identify the functional deficit zone.
Scalp EEG is an essential component of the initial patient evaluation. This test is often performed on an outpatient basis both for convenience and its noninvasive nature. For outpatient analysis, a 30-minute awake/sleep-deprived analysis may suffice if there is a typical clinical history and obvious imaging findings, especially if ictal recording with video-EEG telemetry in a monitoring unit is not possible [
Admission to the EMU for continuous scalp EEG and video monitoring is the final common pathway and is usually considered a necessary step in determining surgical candidacy. This provides localizing value for both inter-ictal and ictal onset zones, allowing for correlation of the clinical manifestation of the epileptic event to ictal and inter-ictal EEG activity. The patient may be subjected to provocative measures such as medication reduction, sleep deprivation, hyperventilation, or photic stimulation to increase the likelihood of capturing epileptiform activity [
Magnetic resonance imaging (MRI) scanning has significantly aided the diagnosis and management of epilepsy, and it has been established as the key imaging modality of choice [
A comprehensive neuropsychological evaluation can identify preoperative functional deficits and predict postoperative neuropsychological outcomes [
Memory decline is the most common deficit following TLE surgery. The relationship between verbal memory decline following left sided surgery is more robust compared to the relationship between visuospatial memory decline following right-sided surgery [
The Wada test has been traditionally used to assess language and memory function of the two cerebral hemispheres independently [
Global aphasia develops upon the injection of the dominant hemisphere. The duration of speech arrest can also be used to identify the language-dominant hemisphere. However, some suggest that if the difference in time to development of speech arrest is less than 30 seconds among the two hemispheres, the patient may have bilateral cortical language representation. Other parameters such as dysarthria and paraphasias may also be used to assess language dominance. Recent studies suggest that language lateralization is a continuum between both hemispheres, and that language unilaterality may be secondary to a lesion in the contralateral hemisphere [
For memory evaluation, the patient is required to correctly identify items shown during hemiparesis. An overall passing score is assigned based on the ability of the contralateral side in supporting memory upon injection of the side ipsilateral to the epileptogenic focus. Scores ranging from 50 to 67% have been deemed as a pass [
Despite the high accuracy of the Wada test in lateralizing language and memory function, this test is associated with false negatives and false positives [
The Wada test results can be affected by a variety of factors such as drug dose, unblinding of test assessors, and patient cooperation. Furthermore, the Wada test is associated with risks such as seizures, contrast allergy, catheter site hematoma, dissection, stroke, and infection [
Scalp EEGs are unable to lateralize the epileptogenic side in up to one-third of patients with TLE [
With invasive recordings, the characteristic ictal EEG pattern of mTLE includes periodic spiking activity from the hippocampus followed by episodes of high-voltage rhythms, which can last up to one minute. Subsequently, a regular 5–9 Hz rhythm is commonly observed [
Upon the completion of scalp/invasive EEG video monitoring, some patients will have epilepsy that not amenable to surgery. This can be attributed to a myriad of causes including psychogenic nonepileptic seizures (PNESs), multifocal epilepsy, patients having a generalized seizure disorder, or the inability to accurately localize the ictal focus. However, almost half of the patients that flow through an adult EMU will have a distinctively identifiable symptomatogenic zone or will warrant intracranial recordings to determine surgical candidacy.
Furthermore, as deep seated or even certain superficial epileptiform activities may be missed by scalp EEG due to the filtering effect of the skull on higher frequency signals [
Although in extratemporal epilepsy detection of residual interictal epileptiform activity at the margins of resection can assist in deciding whether further resection is necessary, this approach appears to have little utility in the temporal lobe [
In situations where the standard presurgical assessment does not provide definitive seizure lateralization and/or localization (e.g., when the seizure focus appears to be bilateral, temporal, and extratemporal, mTLE with a larger field of activity than would otherwise be expected from standard mTLE), or there is discrepancy between the presurgical tests, the following ancillary investigations can be performed.
Positron emission tomography (PET) is an imaging modality that uses radioactive isotopes linked to metabolically active molecules (such as glucose) to analyze functionality in various regions of the body depending on metabolic activity. The nuclei of these tracers emit positrons which generate photons upon collision with electrons in the surrounding environment. The concentration of radioactive glucose, and hence amount of photon emission, within a region depends on the relative metabolic activity. Hypometabolism is not correlated with the amount of cell loss or hippocampal atrophy. In the investigation of TLE, this test seeks to identify the region of interictal hypometabolism which is slightly larger than the ictal onset zone. Occasionally in TLE, hypometabolism can be detected in regions other than the temporal lobe. This may reflect the extratemporal connections of the seizure focus [
Although obtaining a truly ictal PET study is rare, it can be valuable in identifying the seizure focus, by demonstrating a marked area of hypermetabolism [
Fluorodeoxyglucose (FDG) is the most commonly used isotope in PET. The inter-ictal FDG-PET has a high specificity for mTLE (MTS is associated with hypometabolism localized to the hippocampus, amygdala, entorhinal cortex, and temporal pole) [
PET is generally utilized in the evaluation of symptomatic (formerly referred to as cryptogenic) cases and for identifying seizure-spread patterns, thus guiding the placement of intracranial electrodes. If PET and MRI are concordant, there is prognostic utility as better seizure outcomes are predicted following surgery. However, PET does not usually provide any additional information if MTS is demonstrated on MRI [
Cerebral blood flow is increased within regions of the brain undergoing epileptic seizures to match the increased metabolic demand. Single photon emission computed tomography (SPECT) measures local cerebral perfusion using either technetium-99m hexamethyl propelene amine oxime or technetium-99m bicisate. These can be maximally extracted into the neurons within seconds of injection and remain within the cell for several hours [
When independent seizure foci reside in the temporal lobes bilaterally, ictal SPECT studies must be interpreted with caution. Furthermore, SPECT may provide falsely lateralizing information if the epileptiform activity has terminated in the temporal lobe of origin but is ongoing in the contralateral temporal lobe. In certain cases of nTLE, the regional cerebral blood flow cannot be accurately identified by inter-ictal SPECT; therefore, SPECT is overall less sensitive for nTLE. Currently, SPECT imaging can only be used to provide information that is complementary to EEG. However, modifications to the SPECT analysis (as discussed below) can increase its utility in identifying the ictal zone.
With a higher accuracy than SPECT, subtraction ictal SPECT correlated to MRI (SISCOM) is another imaging modality that can be used to localize the epileptogenic zone, especially for those with nonlesional MRI or extensive focal cortical dysplasia [
To improve the diagnostic yield of SISCOM, injection of radiotracers should be performed within 45 seconds of seizure onset and ideally the seizure lasting greater than 5–10 seconds [
The neurophysiologic process that generates the magnetoencephalogram (MEG) signal is identical as to what produces the EEG [
The current indication for MEG in TLE is unknown, and its potential advantage must be weighed against the high cost and limited availability. In a retrospective study, it was found that MEG utilized in the presurgical evaluation did not provide any additional information in over half of the patients [
N-Acetylaspartate (NAA) is primarily found in neurons, and its decrease is often indicative of neuronal loss or dysfunction. In contrast, creatinine (Cr) and choline (Cho) are present at higher concentrations within glial cells. By studying the levels of NAA, Cr, and Cho, 1H magnetic resonance spectroscopy (MRS) can also be helpful in localizing the epileptogenic zone. A decrease in the ratio of NAA to Cr + Cho has been suggested to be correlated with HS with correct seizure lateralization in greater than 90% of cases [
Functional MRI (fMRI) studies neural activity by measurement of alteration in the MRI signal due to changes in oxygenation levels (an increase in T2 signal is observed during epileptiform activity) [
The extent of lateral resection is variable and commonly dependent on strategies to avoid postoperative language deficits and whether or not the patient has mTLE or nTLE.
One approach to mTLE is to resect a predetermined amount of neocortex according to language dominance: 4.5 cm and 5 cm along the Sylvian fissure in the dominant and nondominant sides, respectively [
The most conservative approach to the resection of the mesial structures can be accomplished by various
The amount of neocortex to be resected in nTLE should include the epileptogenic zone as determined by preoperative testing and possibly intra-operative ECOG which seeks to identify the irritative zone through recording pre-resection IEDs. In the dominant hemisphere, the extent of posterior resection is limited by language areas. Complete removal of a radiographically identified lesion usually results in cessation of seizures when lesions are well circumscribed (e.g., benign tumors or cavernous hemangiomas) [
Since the introduction of the en bloc ATL and the subsequent advent of selective procedures, there is much debate regarding the identity of the critical structures that should be removed to achieve seizure freedom in a temporal resection.
The general consensus is that the hippocampus should be included in resective procedures for TLE; however, the degree of hippocampal resection is controversial. Wyler et al.’s randomized trial demonstrated that patients that underwent a total hippocampectomy (extending to the superior colliculus) were more likely to be seizure free at 1-year followup compared to patients that underwent a partial hippocampectomy (extending to the lateral edge of the cerebral peduncle) [
The parahippocampal gyrus (PHG) is generally removed along with the hippocampus. There is evidence from depth electrode studies to suggest that epileptiform activity originating from the PHG and amygdala is more likely to manifest clinically than activity from the hippocampus [
The amygdala has intricate connections with both limbic and neocortical structures and a great propensity to generate seizures as demonstrated following kindling experiments [
Despite the potential to achieve excellent seizure control, TLE surgery is associated with several risks specific to the procedure: motor, visual field, cranial nerve, language, memory, cognitive, and psychiatric deficits. The cumulative morbidity for TLE surgery, not considering adverse psychiatric outcomes, is approximately 11% with permanent deficits in approximately 3% [
Contralateral hemiplegia is a well-described complication of TLE surgery. It is thought to result due to manipulation of the anterior choroidal artery with subsequent infarction of the posterior limb of the internal capsule. This is estimated to occur in 2% of the cases with the majority of patients improving over the course of several months to a year [
Cranial nerve morbidity is mainly associated with the oculomotor (CNIII) and the trochlear (CNIV) nerves. The oculomotor nerve traverses the ambient cistern bordering the medial aspect of the temporal lobe on route to the cavernous sinus. The trochlear nerve travels lateral to the cerebral peduncles and between the posterior cerebral and superior cerebellar arteries lateral to the oculomotor nerve prior to entering the cavernous sinus. Cranial nerve injury occurs most commonly due to traction, is estimated at 1.5–3%, and is usually transient [
The most common visual field deficit following TLE is a superior quadrantanopsia, resulting from damage to the optic radiations comprising the most lateral aspect of Meyer’s loops as they course inferomedially. However, visual deficits can range from small triangular defects to a complete homonymous hemianopsia. A more extensive hemianopsia has been attributed to a greater amount of resection as well as individual variance on the course of the optic radiations. A randomized trial of temporal lobe epilepsy surgery found quadtrantic visual field defects in 55% of the patients [
Dominant TLE surgery is associated with a language risk due to the close proximity of Broca’s and Wernicke’s area localized to the inferior frontal gyrus and the posterior STG, respectively. However, the most common language deficit is a transient anomia [
While the Wada test is an important adjunct that assesses the ability of the contralateral hemisphere in supporting memory function, carefully selected patients may still suffer significant memory deficits following TLE surgery. The lateral neocortical temporal lobe is associated with naming and short-term working memory while the mesial temporal lobe is implicated in long-term consolidation of memory and retrieval [
TLE has been associated with a high risk (almost 50%) of depression [
Ms. A is a 34-year-old, right-hand-dominant female who presented with her first convulsive seizure at the age of 27 years although a detailed past history suggested that she may have been suffering from brief partial seizures without loss of awareness for many years prior to that. These seizures were confirmed on EEG. Initial drug therapy, with 400 mg per day of carbamazepine, maintained her seizure free for 7 years until she presented again with a generalized tonic-clonic seizure (GTCS) during sleep. Subsequently her dose was increased to 800 mg per day, but this did not fully prevent the GTCSs. Also, she had been suffering from simple partial seizures as well as up to 7 CPSs per month. She described auras of nausea and a “funny feeling” up her spine. She also felt that she tried to remember something that had not happened. This would then tend to be followed by a blank stare and lip smacking. From a neuropsychological point of view, she complained of blunted emotions and poor memory.
Ms. A was admitted to the EMU where 7 seizures from the right temporal lobe, all with maximal onset over the anterior/mid and basolateral structures were detected. One of the seizures secondarily generalization towards the end of this event ictal discharges was recorded over the left posterior temporal structures. MRI demonstrated sclerosis of the right mesial temporal lobe (Figure
Ms. A—FLAIR and T2-weighted MR demonstrating right MTS as can be identified based on the loss of architecture and high signal of flair images.
Mr. B is a 28-year-old, right-hand dominant who was first seen at the age of 22 for evaluation of a long-standing seizure disorder. He had been suffering from complex partial seizures from the age of 10, which were described as periods of disorientation, twitching, lip smacking, picking at his shirt, and difficulties with speech lasting 1-2 minutes. He also described auras of epigastric discomfort and fear. He had not experienced any GTCSs seizures or secondary generalization of his seizures. Carbamazepine, valproic acid, and phenytoin had been attempted without significant benefit. Previous MRI with supplementary detailed views of the temporal lobes was normal (Figure
Mr. B—normal MR.
Abnormalities, concentrated in the left anterior quadrant of the head, consisted of continuous dysrhythmia with spread to the frontal regions in the form of long-lasting 4-5 Hz, monorhythmic trains of activity with abrupt onset and offset without clinical accompaniment. He demonstrated interictal slow wave activity localizing to the left mesial temporal as well as left temporal region. Furthermore, distinctive phase reversals were identified in electrodes approximating Wernicke’s area and inferior. Ictal activity always began on the left side starting anteriorly and then proceeding posteriorly. Main source imaging spikes all localized to the mesial temporal region. No inter-ictal activity was noted in the posterior temporal region.
Neuropsychological evaluation demonstrated diminished verbal functioning with a pattern most consistent with left-sided neocortical dysfunction rather than mesial temporal (verbal learning and retention were excellent). fMRI revealed left hemispheric language dominance. As a result of these investigations, the benefit of a surgical resection was unknown. He was discharged on 100 mg per day of topiramate, which also failed to decrease his seizures. Therefore, to better delineate the site of seizure onset and for functional mapping, intracranial monitoring was recommended.
A large square grid was placed at the end of the distal sylvian fissure and overlying the inferior and superior parietal lobules. Three subtemporal strip electrodes (labeled as frontal, middle, and posterior temporal) were also placed. Subsequent monitoring in the EMU demonstrated the middle temporal subdural strip electrode to be most epileptogenic. MRI correlated these leads to the left inferior temporal and fusiform gyri.
Surgical resection, guided by ECOG and language mapping, was performed. The mesial temporal structures were spared to avoid memory deficits. Pathological examination revealed mild cortical and subcortical gliosis. Postoperatively, he experienced a few very brief auras (similar to ones experienced in the past) but no progression to CPSs. He also complained of poor memory and reading ability, but spoken language was intact. He was maintained on 400 mg per day of topiramate. At 2 years postoperative followup, Mr. B was seizure free although he did complain of intermittent sensations of his typical aura. He also complained of mild word finding difficulties which did not interfere with daily life. He maintained a full-time job without any difficulties.
Mr. C is a 34-year-old, left-hand-dominant man who started having seizures at 25 years of age. His family described his episodes as starting with a few minutes of increased rate and volume of speech followed by fatigue, slowed speech, and occasional automatisms. Postictally, he would fall asleep and rarely remember these episodes. Seizures occurred approximately twice a week. He presented to the hospital following his first episode of a GTCS.
EMU studies at a peripheral hospital had been able to record eight seizures of similar clinical semiology. Two were electrographically of left temporal origin while the remaining six were poorly lateralized, appearing bi-hemispheric and perhaps even right hemispheric predominancy at onset followed by rhythmic activity localized to the left temporal head regions within 3-4 seconds. An ictal SPECT scan during one of these episodes demonstrated left temporal activation. MRI at that point had been interpreted as normal. Conservative medical management with trials of phenytoin, topiramate, and pregabalin was attempted without success.
For further clarification, he was monitored in the EMU at our institution where bilateral inter-ictal abnormalities from both the left anterior temporal regions as well as the right midlateral or midposterior temporal regions were demonstrated. On certain days, seizures, of a 3 : 1 ratio, favoring the right hemisphere was observed. He also had multiple electrographic seizures that were either poorly lateralized or not lateralized at onset. Subsequent MRI demonstrated left HS in addition to signal abnormalities in the inferior right temporal region as well, likely representing cortical dysplasia (Figure
Mr. C—T2-weighted and FSTIR sequence MR demonstrating a right inferior temporal lobe lesion in addition to left MTS.
During this stay, many CPSs, all stereotypically involving the right temporal mesial and neocortical structures before spreading to involve the left temporal mesial and neocortical structures, were noted. The exact localization within the right temporal lobe was not clear given that the first electrographic changes were subtle and comprising of an attenuation of background activity over the right hippocampal depth and RMT electrode contacts. Occasional low-amplitude 20 Hz rhythms at right hippocampal depth electrode 2 prior to subsequent spread were also detected. Left temporal spiking, occurring more frequently than right temporal spiking, raised the concern regarding the role of the left temporal lobe being involved; however, brief ictal rhythmic discharges appeared solely from the right temporal lobe structures which correlated well with the patient’s clinically relevant seizures. Given that the seizures were primarily right-sided but that he also demonstrated left-sided HS, a WADA test was performed which showed left-sided memory dominance. He has been scheduled for a right TLY.
Once a patient has been deemed medically refractory, the main requirement to determine surgical candidacy is the ability to accurately localize the epileptogenic zone [
TLE is the most common epilepsy syndrome that is responsive to surgical treatment. Although various pathologies can give rise to TLE including cortical dysplasia, tumours, and vascular malformations, HS remains the most common entity. Surgical patient selection is made after a thorough discussion of each case in a multidisciplinary conference including epileptologists, epilepsy surgeons, neuroradiologists, neuropsychologists, clinical psychologists, EEG technologists, and nurses. In the appropriately selected patients, seizure freedom can be achieved with no or manageable neurological deficits following surgery.
A. Mansouri and A. Fallah should be considered co-first authors as they equally contributed to preparing the first draft of the paper. A. Fallah was responsible for several revisions of the paper. T. A. Valiante was responsible for the final editing of the paper.
There are no sources of support for this paper. It has not been published or presented in any form.