Medial temporal lobe epilepsy: selective amygdalohippocampectomy versus anterior temporal lobectomy

Introduction

Temporal lobe epilepsy (TLE), especially medial temporal lobe epilepsy (mTLE), is the most frequent from of epilepsy that is resistant to medication, that is, drug-resistant epilepsy (DRE). The benefits of surgery have been convincingly demonstrated over the last few decades, and this is due in no small part to the randomized trial conducted by Wiebe et al. in 2001, which showed that resection is more effective than continued medical therapy Also in children, surgery for DRE has proven its efficacy. The question regarding the optimal extent of resection has been both long-standing and controversial and it has not yet been resolved.

During the early 1990s, several institutions published their experience with TLE surgery, often leaving the medial temporal structures behind. However, it has become generally acknowledged over the last few decades that mesial structures need to be included to achieve seizure freedom. Nevertheless, there are instances that challenge this perspective. For instance, Feindel et al. achieved a seizure freedom rate of 53% without removing the hippocampus in 100 cases Similarly, Goldring et al. did not remove the amygdala in 70 cases, yet achieved a satisfactory seizure outcome in 60% of those cases Keogan et al. left the amygdala and hippocampus intact, achieving seizure freedom in 46% of the 50 patients included in their report

Today, the crucial importance of including the medial temporal structures into the resection is generally accepted. However, the extent to which they need to be included, as well as the extent of the neocortical temporal cortex that needs to be resected in the individual patient, has been a matter of ongoing debate Despite this debate, anterior temporal lobectomy (ATL), which includes all of the aforementioned anatomical structures, has become the most frequently used technique worldwide for various reasons, which will be discussed later in this chapter under various aspects.

The postoperative decline in neuropsychological function has always been a concern and while some patients experience an improvement after surgery, neuropsychological deficits are often aggravated with surgery With the aim of achieving better neuropsychological outcomes with less brain tissue included in the resection, it is an intuitively appealing concept to minimize the extent of resection to the minimum necessary to achieve the same seizure freedom rate as with extended resection

Beginning with Niemeyer in 1958, several authors have suggested that selective resection of the mesial temporal structures could yield equivalent seizure outcomes as a complete resection of the anterior temporal lobe . Given the fact that a direct comparison of different resection volumes is difficult, as most centers have specific indications for specific methods and comparisons were mostly performed with historical case series, ATL has remained the most frequently used approach

With the advancement of minimally invasive approaches such as laser interstitial thermal therapy (LITT), which is able to selectively damage the mesial structures, the pendulum seems to swing over to selective approaches The long-standing discussion about selective versus nonselective resection in TLE has been re-ignited with this new surgical technique.

Anterior temporal lobectomy

Description of technique

The standard ATL (e.g., anterior 2/3 temporal lobectomy) technique is either performed as an en-bloc resection of the lateral and polar cortex including the medial structures or in two steps with resection of the lateral and polar cortex first and the medial temporal lobe in the second step. The posterior extension of the resection depends on the laterality of the resection with usually 4.5 cm on the dominant side and 5–5.5 cm on the nondominant temporal lobe. In certain cases, the course of the vena anastomotica Labbe has to be taken into account and the resection line is made just anterior to it. The resection is performed in a subpial technique to the inferior insular sulcus in order to protect the MCA branches within the Sylvian fissure. The temporal horn is reached through the middle temporal gyrus and opened dorsally to resect the hippocampus and the underlying parahippocampal gyrus over a distance of 2–3.5 cm. Given the proximity of the mesencephalon and the critical vascular structures in the cisterna ambiens (anterior choroidal artery, posterior cerebral artery), this part of the resection is the most challenging. The amygdala, peri/rhinal cortices and temporal piriform cortex are included in the resection.

The anteromedial temporal resection (e.g., Spencer resection) has the aim to minimize the resection of the lateral temporal cortex. With the exclusion of the superior temporal gyrus the anterior temporal pole is resected for 3–3.5 cm followed by resection of the 3–4 cm of hippocampus.

Indications and contra-indications

The ATL is certainly the most widely used technique in pharmaco-resistant TLE and is considered the standard in many centers. The observation that some patients with TLE demonstrate an epileptogenic zone primarily in the temporal lobe but extending to temporal or extra-temporal neighboring areas, prompted the conceptualization of the framework of temporal plus epilepsy (TPE) about two decades ago These neighbouring regions include perisylvian, frontobasal or temporo-parieto-occipital regions, which may harbor significant surgical morbidity especially if the dominant hemisphere is affected. As such, TPE represents a distinct form of epilepsy where standard ATL should not be offered given the high likelihood of failure to achieve seizure freedom. The challenge comes with the need to distinguish between these two entities, which can currently only be tackled by stereotactic electroencephalography (SEEG) given the paucity of independent and robust biomarkers

Relative advantages and disadvantages

ATL is considered a more definite and complete approach. Selective approaches do harbor the risk of the need for reoperation in case seizure freedom is not achieved. The clinical problem then comes with the discussion of whether reoperation and resection of the temporal lobe have a high enough probability to result in seizure freedom that outweighs the drawbacks of a reoperation or whether the patient may have a TPE translating to a worse outcome.

The problem of a potentially unnecessary resection of functionally intact tissue cannot be neglected. Even though it seems that resection of the temporal pole especially of the nondominant hemisphere does not convey clinically measurable deficits, this does not mean that this is uncritically justified.

Seizure outcome

Children with TLE achieve a comparable high level of seizure control as adults with 67% to 93% achieving freedom from seizures A series by Clusmann et al., who analyzed 35 children after ATL, reported a 94.3% rate of seizure freedom. They encountered that children with left-sided surgery did worse than those with right-sided TLE, reaching class I and II Engel outcomes in only 84.6% compared to 100%, respectively. The majority of patients with unsatisfactory seizure control demonstrated some disadvantageous features in their EEG activity patterns, that is, disconcordant activity or no specific EEG pattern at all.

Concerning imaging, mesial temporal sclerosis has become the most relevant predictor for seizure freedom. However, subtle magentic resonance imaging (MRI) findings, such as temporal polar gray/white matter demarcation loss and white matter changes have been reported to occur in up to 65% of the patients in the ATL series . For instance, Bothwell et al. described cytological changes reflecting a loss in neuropil volume without loss of neurons. This implies that larger cells are associated with increased perikaryal innervation, especially from excitatory synapses, making them more prone to hyperexcitability. Sisodiya et al. correlated subtle widespread MRI changes with unsuccessful outcomes after selective surgery in patients with hippocampal sclerosis The evaluation of these features, especially among young children, is challenging because physiological myelination of the temporal lobe, compared with other brain areas, occurs relatively late in childhood . For patients with better-defined lesions on MRI, such as tumors, ATL seems specifically important. While the proportion of patients and type of tumors varies significantly between series, the majority of pediatric cohorts harbor developmental tumors, which are today summarized as long-term epilepsy-associated tumors. Seizure control was generally not significantly different between the histologic entities, except for focal cortical dysplasia, which is mostly associated with less favorable seizure control Lesionectomy plus selective amygdalohippocampectomy (SAH) was reported to convey less successful seizure control compared to ATL, reaching 77% versus 94%, respectively, in the series by Clusmann et al. .

In summary, among children, the prevalence of patients with coexisting pathological conditions exceeds that seen among adults As current diagnostic tools available have not easily captured these lesions, standard approaches have been favored.

Neuropsychological outcome

Cognitive impairments after ATL may include difficulties in verbal memory, figural memory, attention, language, visuo-construction, and verbal recall For ATL resections, it was demonstrated early that lateral extent of resection (< 3 cm), consideration of cortical eloquent sites for language or memory and the presence or absence of a hippocampal pathology were decisive determinants for memory decline While Wolf et al. reported no difference in memory outcome taking the extent of mesial or lateral resection into consideration, others have reported that resection of the language-dominant temporal neocortex affects learning capabilities Nonlanguage dominant temporal lobe dysfunction has been attributed to figural, visual-spatial memory, object processing, allocentric object location, face memory, rhythm, and learning musical associations As right temporal lobe dysfunctions are not easily captured, these are prone to be underreported In a study by Helmstaedter et al., 45% of the patients after right ATL had memory loss and 8% had a loss in both performances In left temporal lobe resections, 54% presented with loss of either verbal or figural memory and 16% presented with loss of both. This left/right temporal lobe differences in verbal memory, however, seem to only become evident in the mature brain and not in young children

With regards to the extent of mesial temporal lobe resection in ATL and its impact on the neuropsychological outcome, no sound consensus seems available. While Wyler et al. showed that the extent of mesial resection is important to obtain seizure freedom with no impact on memory outcome , Katz et al. reported greater loss of memory performances related to the mesial extent of resection This is significant when considering the extent of functional hippocampal tissue. Thus, a large resection of an atrophied hippocampus will have less impact than a limited resection of a nonatrophied hippocampus.

Complications

The observed cumulative morbidity of ATL in a recent literature review varied between 0% and 9.3% in the review series The most common neurological deficit is the development of a postoperative visual field deficit (VFD), typically a homonymous superior quadrantanopsia. The frequency of VFD is highly variable, ranging between 1.5% in a series by Lopez-Gonzalez and 22% in a series by Kim et al. . This high variability may also be attributed to the different methods of visual field testing that have been applied . More recently, the use of intraoperative overlay of the optic radiation tractography during ATL with neuronavigation has shown to be beneficial in reducing the rate of significant VFD Postoperative hemiparesis has been reported to occur from 0.7% to 8.5%

Selective amygdalohippocampectomy

The clinical-radiological-electrophysiological characterization of the mTLE with hippocampal sclerosis initiated the development of surgical approaches aiming at resecting the medial temporal lobe and avoiding resection of the lateral cortex. This resection includes the amygdala and hippocampus with the accompanying parahippocampal and uncal cortices. The name of the different techniques is related to the specific surgical approach to these structures.

Description of technique

In the trans-Sylvian SAH technique the approach is performed through the opening of the proximal Sylvian fissure The resection is started just antero-basally of the M1 segment of the middle cerebral artery by resection of the amygdala and the uncal cortex followed by the resection of the hippocampus and parahippocampal gyrus through the opened temporal horn. Also with this technique, the knee of the optic radiation within the roof of the temporal horn can be affected.

In the transcortical technique, the temporal horn is reached by transgressing the middle temporal gyrus also crossing the optic radiation Once the temporal horn is opened the medial temporal lobe can be resected. This is probably the most widely used selective technique. The incision in the cortex and the approach to the ventricle can be optimized with the help of neuronavigation.

The subtemporal technique was proposed in order to reach the temporal horn from basally through an incision in the fusiform gyrus or parahippocampal gyrus thereby avoiding dissection of the roof of the temporal horn with the optic radiation Some authors feel that the view of the amygdala is limited with this approach. Furthermore, the variable anatomy of the basal veins and the inclination of the middle temporal fossa can make the approach challenging potentially leading to damage of the temporal lobe by a need to retract it with brain spatulas.

In addition to these three widely adopted techniques, the supracerebellar-transtentorial (SCTT) approach has been suggested, particularly for reaching the most posterior parts of the hippocampus or in case of posterior hippocampal remnants after anterior approaches In this technique, the tentorium is incised and the posterior medio-basal temporal lobe is approached completely avoiding the overlying optic radiations. However, the exposure of the amygdala and uncus is limited and the resection may be hampered by the firmness of the epileptogenic medial temporal structures.

Indications and contra-indications

As mentioned previously, ATL is considered the standard approach in many institutions. Centers that systematically perform selective resections have distinct criteria such as (1) concordant results from video EEG monitoring pointing to mesial temporal onset ipsilateral unitemporal ictal epileptic discharges, ipsilateral temporal ictal EEG patterns, and clinical lateralizing signs corresponding to the ipsilateral temporal region or nonlateralizable signs clearly corresponding to temporal lobe origin, that is, oral automatisms, behavioral arrest, and so forth, (2) ipsilateral hippocampal sclerosis and/or atrophy on MRI, (3) absence of unequivocal atrophy in the lateral temporal lobe, and (4) absence of any other pathology in the temporal lobe.

Relative advantages and disadvantages

The relative advantage of SAH is a less extensive resection of potentially functionally intact brain tissue. Less-extensive resections may, however, leave the patient susceptible to seizure recurrence if the entire epileptogenic tissue is inadequately excised. The risk of undergoing SAH may outweigh the benefits if there is a greater frequency of seizure recurrence coupled with similar neuropsychological outcomes when compared with ATL. Likewise, the need for a reoperation exposes the patient to all the risks and consequences of another brain surgery.

Seizure outcome

The seizure outcome following SAH, in general, has been reported in similar ranges as after ATL, with seizure freedom rates between 60% and 90%. The number of series focusing solely on pediatric TLE patients, however, is limited Additionally, in the pediatric population, SAH is far less frequently used than in adults, and studies have suggested that SAH seems to result in less favorable seizure outcomes compared to ATL. In a recent review of the literature, only 27.1% of children with TLE had undergone SAH . Clusmann et al. analyzed a series of 89 children with TLE who underwent different resection strategies While the overall seizure outcome was excellent, with 87% attaining satisfactory seizure control, Transylvanian SAH resulted in significantly less satisfying results with a success rate of only 74%. The discrepancy is especially evident for left-sided surgery, where SAH performed significantly worse, attaining seizure control in only 58% compared to 85% after left-sided ATL. All operated patients were thought to have clear features of purely mesial TLE, which was supported by imaging or electrophysiological results during preoperative evaluation. However, SAH was chosen for the treatment of presumed mTLE among children even if there were some structural abnormalities of the lateral temporal lobe (demarcation loss). By becoming more selective in which patients underwent SAH alone since 2001, the results in SAH patients improved significantly from the previously reported 74.1% to 86.7% in their 2019 report. This translates into the same effectiveness of SAH compared to ATL in a carefully selected group of children in whom structural abnormalities are limited to the mesial structures

Cognitive outcome

In general, SAH appears to yield a more favorable impact on neuropsychological outcomes after surgery, although this is by far not a consistent finding. Differential cognitive sequelae of SAH and ATL surgeries for various aspects of verbal learning and memory have been demonstrated Helmstaedter et al. reported that in left TLE, SAH mainly caused a loss in long-term memory aspects of verbal learning and memory, whereas ATL patients showed a significant loss in the short-term and working memory aspects of verbal learning and memory. This difference in the neuropsychological outcome was later confirmed by several other studies . The Bonn group reviewed the cognitive performance in a series of 321 patients, indicating that limited resections resulted in a better outcome of attention, verbal memory and a compound measure of cognitive performance. In a multicenter study by Jones-Gotman, however, 71 seizure-free patients were compared after different extend of resections and no advantage of one type of surgery over another could be found. Furthermore, the size of extent of mesial resection did not have a differential effect on postoperative memory

Complications

One of the arguments in favor of a selective resection is the assumption that VFD may be reduced. Here, the approach to the mesial temporal lobe is important and has been a determinant in the decision to favor one approach over the other. Meneshga et al. conducted an analysis of Humphrey visual field examinations in 18 patients who underwent transcortical SAH and 33 patients after ATL Among the 18 SAH patients, all but 2 experienced a homonymous superior quadrantic visual cut, while in the ATL group all but 3 out of 33 patients had these cuts. The coordinates close to the horizontal meridian were significantly spared by a transcortical SAH. More recently, Pruckner et al. showed in a homogenous cohort of 62 patients that the VFD were significantly less after Transylvanian SAH compared to ATL Delev et al. prospectively compared vision after Transylvanian and subtemporal SAH, showing that subtemporal SAH resulted in significantly fewer VFDs than the Transylvanian route Moreover, the VFDs that occur following SAH are generally less severe and are less likely to impact the ability to drive a vehicle A SAH via a SCTT approach theoretically spares transection of the optic radiation completely as mesial resection is performed without the need to unroof the temporal horn of the ventricle. Very low rates of VFD reaching 0% in some series have been achieved Also, LITT offers the potential advantage of sparing the optic radiation reflected by low rates of VFD in recent reports

Discussion

It seems intuitively right to minimize the extent of resection to the least necessary to achieve seizure freedom. From a neuropsychological point of view, the functional integrity of brain tissue to be sacrificed or preserved appears to be of major importance. However, the evaluation of the impact of resection of nonlesional tissue is complicated by the quest to determine the proportion of functional and epileptogenic tissues in ATL and SAH.

Before the improvements in high-resolution structural and functional MRI and the ability to detect subtle lesions such as dysplasias, hippocampal sclerosis and white matter blurring, ATL was considered the standard in most centers and selective surgery was performed exclusively at very few centers These centers were aiming to show that they can achieve the same good seizure control rate with SAH as already documented after ATL . Many of these, indeed, succeeded in showing that SAH did not translate into a worse seizure outcome The largest studies were reported by the Bonn group. The most striking finding in the two studies published by Clusmann et al. in 2002 and Omonden et al. in 2018, was that after being more selective in stratifying children for SAH instead of ATL since 2001, seizure freedom rates increased from 74.1% to 86.7% . Accordingly, if children are strictly selected, meaning that they have clinically concordant findings for mesial temporal epilepsy and hippocampal sclerosis and no other pathology seen on high-resolution MRI, excellent seizure control can be achieved with SAH

If the assumption holds true that a selective approach in this group of children leads to the same seizure outcome rate, it is still not fully clear what the optimal extent of mesial resection is needed Results in this regard remained conflicting. Wyler et al. and Nayel et al. found the greater the extent of mesial resection the better the seizure outcome Siegel et al. found that the more tissue of the parahippocampmal gyrus is included in the resection the greater the likelihood of seizure freedom Hermann et al. defined four different types of temporal lobe resections and did not find any differences between the four groups Similarily, Renowden et al. showed that the extent of hippocampal and amygdala resection did not make a difference in SAH . Finally, Schramm et al. performed the only randomized trial allocating patients for either a 2.5 cm or 3.5 cm hippocampal resection and did not find a difference

In general, a direct comparison between different surgical approaches is difficult as most centers had specific indications for each approach and comparisons were mostly performed with historical controls Most importantly, most studies were not performed in the pediatric population.

In adult patients with hippocampal sclerosis, two recent metaanalyses independently concluded that ATL is superior to SAH in terms of seizure outcome In the study by Josephson et al., the risk ratio of achieving seizure freedom for those undergoing ATL compared to SAH was 1.26 [95% CI 1.05–1.51], p =0.01; risk difference 7% [95% CI 1%–12%]; number needed to treat NNT=14 [95% CI 8–100] In addition, Hu et al. revealed comparable effects on intelligence between ATL and SAH Only four studies, however, met the inclusion criteria, in which all the patients were adults and were right-handed or had left hemisphere language dominance. Tanriverdi et al. compared the neuropsychological outcome of 123 patients after ATL with 133 patients after SAH and found no clear difference between the two approaches but the same seizure outcome

Despite the fact that the assumed reduction in the risk of selective surgery-related deterioration did not unequivocally stand the test of time, selective resections remain an appealing concept for some centers. While an upfront complete resection with an ATL reduces the risk of facing the discussion for a reoperation, this can also be viewed from a different perspective. If 75% to 85% of the children are seizure-free following SAH only, an upfront ATL would put those children to an unnecessary resection of their temporal pole. Just because all measures that we have today cannot convincingly show that this is functionally relevant tissue, does not mean we can resect it uncritically if we do not completely understand how this part of the brain is contributing to the network function of the rest of the brain in the individual patient. In the era of precision medicine, this would be counterintuitive and against the incentive to individualize our therapies to the patient.

At the same time, reoperations following SAH have been reported to be safe and effective In our series of 11 patients who were not seizure-free after SAH, eight became seizure-free after completion of the resection More importantly, we did not experience any complications. In the series by Mittal et al., none of the 25 children who underwent repeated surgery suffered from neurological morbidity Counseling of the parents for a potential second surgery after SAH is key and should be discussed with all the different aspects.

In the era of LITT, this discussion becomes especially interesting. Many centers now routinely perform selective ablations of the mesial temporal lobe somewhat neglecting the discussion on ATL versus SAH. Many of those, who previously performed an ATL instead of an SAH, apparently convinced that a more complete resection leads to better seizure outcomes, have now switched to the selective concept, certainly driven by this new minimally invasive technology. In addition, Drane et al. indicated that LITT resulted in a better object recognition and naming outcome compared to open resection. Although this new technology has taken over in many centers in the US, initial evidence suggests a slightly lower seizure freedom than with open resections and long-term outcomes are still pending . Improved seizure outcomes following LITT have been associated with targeted resection of more anterior and mesial structures, including the amygdala, hippocampal head, parahippocampal gyrus and rhinal cortices . We will, however, likely face a good number of patients needing a reoperation. Initial experiences with re-operating on an ablated mesial temporal lobe suggest that we may expect a noninsignificant morbidity in these patients in the future.

This further raises the question of whether achieving seizure freedom early on is beneficial or whether a possibly safer surgical strategy with limited resections thus sparing cortical areas could be more advantageous for children. Longer duration of epilepsy is associated with impaired cognitive development and development after surgery does not necessarily catch up rather than improve slowly and steadily The age at which patients experience the largest benefits remains debated, but not losing any time when cognitive, psychological, and social development are at a critical phase could be an argument for early, definitive treatment Conversely, losing larger areas of brain parenchyma could cause serious long-lasting sequelae. For example, in pediatric stroke, lesion volume and a greater loss of network hubs are correlated with worse cognitive outcomes. However, additional surgery after a first, failed epilepsy surgery also entails the risk for lasting neuropsychological deficits Therefore, it remains a clinical challenge to differentiate children, who would likely benefit from larger resections and those for whom a more limited resection would be sufficient.

Evidence-based recommendations (agreed upon by majority of experts)

In children with TLE, ATL leads to excellent seizure control rates across centers. Even though the goal of reducing the neuropsychological impact of surgery by SAH and at the same time pertaining to the same seizure outcome as with ATL has not been convincingly achieved, SAH remains a valuable option in carefully selected cases. Selection criteria include (1) clear electro-clinical mesial TLE, (2) hippocampal sclerosis and/or atrophy on MRI, (3) absence of unequivocal atrophy in the lateral temporal lobe, and (4) absence of any other pathology in the temporal lobe ( Figs. 6.1 and 6.2 , Table 6.1 ).