Chapter 18 – Surgical approaches and techniques in MRI-negative focal epilepsy

Chapter 18 Surgical approaches and techniques in MRI-negative focal epilepsy

MRI-Negative Epilepsy, ed. Elson L. So and Philippe Ryvlin. Published by Cambridge University Press. © Cambridge University Press 2015.

Sumeet Vadera

William Bingaman

Introduction

There are approximately 50 million people in the world affected by epilepsy. Chronic epilepsy is associated with devastating socioeconomic and psychosocial consequences as well as increased risk of injury and sudden death for the patient¹. In patients with clear lesions on magnetic resonance imaging (MRI), several surgical series have shown that complete resection of the abnormality and damaged surrounding cortex is one of the most important prognostic factors associated with seizure freedom postoperatively and may lead to a better long-term outcome¹^–4. Patients with MRI-negative epilepsy pose a much greater challenge to the neurosurgeon, and the work-up and surgical treatment require a greater reliance on invasive epilepsy mapping techniques. It is also important to note that seizure-free outcomes in patients with MRI-negative epilepsy may not be as good as for lesional epilepsy⁵^–6.

Patients with MRI-negative epilepsy often undergo an extensive work-up, which may include invasive intracranial electrode monitoring, to better localize the epileptogenic zone (EZ). Because the preoperative work-up is so important in evaluating patients with MRI-negative epilepsy, we will discuss each of the methods that may be used by the epilepsy team to aid with the localization of the EZ. We will then describe the most relevant surgical techniques and approaches used to treat these challenging patients, and finally, the most common histopathologies will be discussed.

Preoperative work-up

During the preoperative work-up, all epilepsy patients considered to be surgical candidates should undergo thorough history and physical exam, a video-electroencephalography (vEEG) study, neuropsychological testing, and high-resolution “epilepsy protocol” 3-Tesla MRI (Table 18.1). Other tests that may be performed include 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET), magnetoencephalography (MEG), difference in single photon emission computed tomography studies (subtraction SPECT), functional MRI, or sodium amytal intracarotid testing (WADA). Whether these tests are performed or not depend on the patient’s semiology, imaging, and EEG findings.

Table 18.1 Sequences obtained during “epilepsy-protocol MRI”

Additionally, patients should be discussed in a multidisciplinary epilepsy management conference, which includes neurosurgeons, epileptologists, neuroradiologists, psychiatrists, and neuropsychologists to incorporate a variety of different management opinions and options.

With regards to surgical management options in the setting of MRI-negative epilepsy, if all available studies do not clearly localize to a specific region, or if the lesion is close to eloquent cortex, patients are then further evaluated with intracranial subdural grid and depth electrodes (SGD) or stereoelectroencephalography (SEEG). Placement of electrodes is individualized based on the patient’s clinical, electrophysiologic, and neuropsychologic data. These electrodes are able to localize the hypothetical EZ, as well as map eloquent cortex in the comfort of an extraoperative setting. After implantation, patients remain in the epilepsy monitoring unit with the electrodes in place until they generate enough seizures to localize the ictal onset zone. This usually lasts between 7 to 10 days, but patients should be counseled that it might take much longer.

Preoperative evaluation

The epileptogenic zone is simply defined as the region of the brain that generates seizures. The complete removal of this area is required for seizure freedom after epilepsy surgery⁷. To date, there is no single test or imaging study that can adequately identify the EZ. The preoperative evaluation includes video-electroencephalography (vEEG), interpretation of seizure semiology, and imaging studies, and this information is used to create a hypothesis of the EZ. When the noninvasive data is concordant, a surgical plan can be generated. When the data are not concordant, or an MRI lesion is absent, invasive intracranial recordings are often necessary to gain ictal onset and functional information to further guide a possible surgical intervention.

MRI

Despite several advancements in the quality and sequences available with MRI, there are still many patients that are found to have MRI-negative epilepsy⁷. Studies have shown that an estimated 20% of patients with medically refractory MRI-negative focal epilepsy will be found to have lesions on higher-field (3-Tesla and above) MRI scans¹^, ⁷^, ⁸. For this reason, the authors believe that it is appropriate to reimage patients with MRI-negative epilepsy on higher-field MRI scanners when possible. Most centers have specific sequences which are performed on all epilepsy patients (“epilepsy protocol”) which usually include sagittal T1, axial T2, axial and coronal fluid attenuated inversion recovery (FLAIR), and coronal magnetization prepared rapid gradient echo (MPRAGE) sequences (see Table 18.1 for complete list). Contrast is not routinely administered unless neoplastic disease is suspected.

It is also very important that an experienced neuroradiologist examine the MRI scans because subtle lesions (cortical dysplasia) are common and can be easily missed by the untrained eye. The most common histopathologic abnormality identified in patients with MRI-negative epilepsy is focal cortical dysplasia (FCD) and is reported to be invisible on standard imaging studies in approximately 30% of cases⁷^–9.

Positron emission tomography

Positron emission tomography (PET) studies utilize the radioactive tracer 18-fluorodeoxyglucose (18-FDG) to quantify cerebral metabolism, usually during the interictal state. The interaction between negatively charged particles in the brain and the positively charged 18-FDG particles is detected by the PET scanner. The epileptic focus is often incorporated within areas of hypometabolism on PET scans, and therefore this study can be very helpful in surgical planning in MRI-negative epilepsy cases (Figure 18.1). One drawback to PET scans is that the areas of hypometabolism often overestimate the location of the EZ⁹. Nevertheless, in the 1990s (preMRI), Dr. Chugani showed that in patients with infantile spasms, PET was able to effectively identify areas of FCD and guide surgical treatment when the MRI showed no lesion¹⁰^, ¹¹.

Figure 18.1 A PET study showing mild reduction in FDG activity in left lateral frontal lobe compared with the right side, in a patient with MRI-negative epilepsy.

Single photon emission computed tomography

Single photon emission computed tomography (SPECT) studies utilize intravenous injection of radiolabeled tracers at the onset of the seizure to evaluate cerebral blood flow. Increased perfusion (compared to the interictal state) suggest ictal onset, while surrounding areas are often noted to have postictal suppression of perfusion (Figure 18.2). Difficulties in obtaining radioactive tracer, the logistics of injecting the patient at seizure onset, and costs associated with the test make SPECT an unrealistic part of the routine preoperative evaluation.

Figure 18.2 Ictal hyperperfusion in right posterior orbitofrontal region on subtraction SPECT study.

Magnetoencephalography

Magnetoencephalography (MEG) studies evaluate magnetic dipoles generated by cerebral activity in normal and abnormally functioning brain tissue. The MEG method has some benefits over standard scalp EEG in that it is able to evaluate dipoles that arise in deeper structures and dipoles that are not orthogonal to the skull. The dipole maps that are generated can be useful in defining the irritative zone. This is most useful when the dipoles are found to be close to one another, which is labeled a cluster. A cluster is defined as at least five dipoles with less than 1 cm between adjacent sources¹². The limited availability of MEG has made this option more useful for research purposes and less popular within the clinical realm. In patients with MRI-negative epilepsy, this can be a useful supplemental test, especially when a cluster is noted that is concordant with other functional imaging studies.

Several studies have shown that in MRI-negative epilepsy, resection of clusters, or “clusterectomy,” improves postoperative seizure-free outcomes¹³. In our institution, we recently evaluated the outcomes in patients undergoing resective surgery for epilepsy; we found a statistically significant correlation between seizure freedom and the complete removal of MEG clusters in patients undergoing extratemporal lobe resections. This was independent of underlying etiology and presence or absence of a lesion.

Subdural grid and depth (SGD) electrode implantation

The main implantation strategy is designed to prove the hypothesis formed during the epilepsy management conference and is based upon semiology, vEEG, and any other additional tests required (PET, SPECT, MEG). Therefore, the area covered by subdural grids and depth electrodes is usually decided prior to the commencement of surgery based upon the preoperative work-up. A volumetric MRI scan is performed the day prior to surgery with fiducials placed along the scalp to allow for coregistration of the MRI to the patient’s anatomy intraoperatively.

A craniotomy is performed around the area of interest and the dura is opened to allow for placement of the grids and depths. Stereotactic guidance is used to assist with the placement of the depth electrodes in the region of interest within the deeper structures of the brain (i.e., hippocampus, amygdala, cingulate gyrus) and the grids are then laid across the cortex to cover the areas of interest as well as eloquent cortical areas. All leads are sutured down to the dural edges to prevent them from being dislodged while the patient is being monitored.

Postoperatively, patients undergo thin-cut CT scans and AP and lateral skull X-rays to better visualize the location of the electrodes with respect to anatomical landmarks. These steps are all performed to assist the epileptologists with interpreting the EEG data and mapping areas of eloquent cortex. It also helps the surgeons decide where to safely plan the resection at a later time.When the patient has been monitored for a sufficient amount of time for the ictal onset zone to be mapped, the patient will then undergo cortical stimulation, at which point the electrodes are individually stimulated and electrodes with underlying cortical functions are noted. A map is created that incorporates both the functional and ictal onset zones. The options available for resection are then discussed with the patient prior to the second surgery, at which point electrodes are removed and a tailored resection is performed. In performing the resection, it is important to include ictal onset electrodes, early-spread electrodes, and electrodes with frequent interictal spiking when safe to do so. The surgeon must also utilize tactile feedback intraoperatively and respect the functional cortex limitations (i.e., “Take what you can” theory).

Although medically refractory epilepsy patients with MRI-negative focal epilepsy are a challenging group to treat, a recent study from our institution looking at MRI-negative extratemporal epilepsy undergoing invasive electrodes showed a 42% seizure-free rate at 2 years¹⁹. This rate is comparable to what is reported in the literature. For this reason, it is still important to consider surgery in this difficult-to-treat group of patients.

Stereoelectroencephalography (SEEG)

This method allows for individualized implantation of intracerebral electrodes designed according to the individual patient’s electrophysiology, anatomy, and semiology. Among the areas that can be explored with SEEG electrodes are the anatomic lesion (if present), the structure(s) of ictal onset, and the possible pathway(s) of propagation of the seizures (functional networks). The desired targets are accessed using commercially available depth electrodes, and implantation is performed using conventional stereotactic technique through 2.5 mm drill holes. Implanted electrodes have a variable number of contacts (four to 16), depending on the location and the desirable recording space (distance from target to dura). The SEEG electrodes are usually placed with a straight lateral trajectory but also can be implanted using oblique orientations. This flexibility allows for intracranial recording from lateral, intermediate, or deep cortical and subcortical structures in a three-dimensional arrangement. After placement, the patient may be transported directly to the epilepsy monitoring unit and treatment progresses in a similar manner as for the subdural electrode patient. A recent study from our center showed that in patients undergoing SEEG with a negative preoperative MRI, 57% were seizure-free at 1 year, and so this is certainly another viable option when utilized in the correct patient population²⁰.

Temporal lobe surgery

Temporal lobe epilepsy is the most common cause of complex partial seizures in adults, and mesial temporal sclerosis (MTS) is the most common pathology¹⁴. Postoperative seizure-free outcomes have been quoted in the literature as ranging from 70–90% seizure-free after temporal lobectomy in this group¹⁴^–15. As discussed previously in this chapter, patients with clear lesions on MRI have better postoperative seizure-free outcomes than those without a lesion. It is also important to note that the presence of hippocampal atrophy lessens the risk of postoperative memory deficits, whereas normal hippocampal volume is associated with higher risk for postoperative deficits, especially in dominant lobe resection.

When determining a surgical strategy in patients with MRI-negative epilepsy that localizes to the temporal lobe, there are several factors that should be considered.

One of the most important factors to consider is where language and verbal memory reside. If the patient is right-handed, there is a high likelihood that verbal memory and language areas lateralize to the left hemisphere. If this patient also has epilepsy that appears to lateralize to the left temporal lobe, the risk of neuropsychological decline following surgery must be estimated. Generally, formal neuropsychological testing, fMRI, and/or WADA testing may be performed to evaluate language lateralization and verbal/visual memory status. If these studies show that the patient is left hemisphere dominant, then invasive electrode implantation may be used to better localize the ictal onset zone and predict the impact on the patient’s language and memory. On the other hand, if the patient has temporal lobe epilepsy that localizes to the right hemisphere, then an aggressive resection of the complete lateral temporal lobe and mesial structures may be performed with minimal risk to language and memory.

Extratemporal surgery

In adults, extratemporal lobe epilepsy is not as common as temporal lobe epilepsy. As previously discussed, the underlying pathology is often cortical dysplasia and this often results in a diffuse epileptic focus, which can be difficult to visualize and resect entirely. Seizure-free outcomes in extratemporal lobe epilepsy are also not as favorable as for temporal lobe epilepsy³^, ⁶. Surgical planning in these challenging cases almost always mandates implantation of invasive electrodes to define the ictal onset region. When the EZ is suspected to involve eloquent cortex, subdural electrode application allows for cortical stimulation and functional mapping.

The following clinical case helps to illustrate the work-up and treatment options related to patients with MRI-negative epilepsy. The patient was a 20-year-old right-handed male with a history of epilepsy that began at the age of 11. He had no past major medical disorder, nor risk factors for seizure development. His developmental milestones were normal, and he had a normal neurological exam. The patient described a somatosensory aura that involved his left arm and face, which then progressed to an akinetic seizure. The patient had seven to eight seizures per day, and had failed eight different antiepileptic drugs. Most seizures were focal and involve only the left arm and face but they occasionally evolved into generalized tonic–clonic seizures.

The patient was monitored in the epilepsy-monitoring unit with video-EEG and was found to have clinical seizures with the inability to move the left arm, followed by a change in facial expression where he would appear stunned while attempting to reposition the left arm using the right. His larger seizures involved face pulling towards the left with head and eye deviation to the left followed by initial flexion, then extension of the left arm, and then flexion of the right arm and leg. Scalp EEG seizures involved the right frontocentral region (F4/C4) with subsequent spread to also involve the right centroparietal leads.

A 3-Tesla MRI brain scan study was normal; PET showed mild symmetric hypometabolism involving both temporal poles, and SPECT showed right posterior frontal hyperperfusion; MEG showed no interictal spikes but patient did have one clinical seizure while in the MEG machine and a spike cluster was noted in the right frontocentral region. At this point the patient’s seizure semiology was in agreement with a regional localization to the right frontocentral region of the brain. Whereas the MRI was nonlesional, the ictal SPECT, MEG, and scalp EEG were in agreement with the proposed hypothesis of localization of the seizure onset zone at the right frontocentral region. Surgical decision making at this point involved localizing the region of ictal onset and defining its relationship to functional cortex. Subdural grid and depth electrodes were recommended to accomplish these goals and after informed consent and discussion about the not insignificant risks of resection of the perirolandic cortex, the electrodes were implanted to target the right dorsolateral and mesial perirolandic, premotor and parietal cortex, and depth electrodes were placed in the precentral and posterior frontal regions to evaluate the areas of interest (Figure 18.3a).