Patient Selection for Epilepsy Surgery in Adults
A 35-year-old, right-handed woman presents with a generalized tonicoclonic (GTC) seizure. Her first generalized seizure was witnessed at the age of 25 years. She was started on phenytoin and was seizure free for 8 years. However, for the past 2 years, she has experienced monthly episodes of confusion with blank staring, lip smacking, and loss of awareness, lasting for ~ 2 to 3 minutes. Subsequently, her phenytoin dose was increased and lamotrigine was added and optimized. She reports a warning preceding these episodes described as déjà vu, a “funny feeling,” and nausea. She reports being compliant with her medication regimen, but she acknowledges recent sleep deprivation and excess stress at work prior to her recent GTC seizure.
Approximately 1 million Americans have drug-resistant epilepsy (DRE).1 DRE is defined as failure of adequate trials of two tolerated and appropriately chosen and used seizure medication schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.2,3 The likelihood of seizure freedom from a trial of a third medication is 5%. Epidemiological data suggest between 100,000 and 200,000 people with DRE are surgical candidates.1 In North America, temporal lobe epilepsy (TLE) is the most prevalent form of partial epilepsy, and one that is most frequently treated surgically. The most common type of extratemporal localization-related epilepsy is that of the frontal lobe. However, ~ 15% of patients with partial complex epilepsy arising from other regions of the brain have associated mesial temporal sclerosis (MTS); these cases are referred to as involving dual pathology.4 Causes of epilepsy other than MTS include the following:
The success of resective epilepsy surgery is based on the ability to localize a discrete area that is essential for the generation and propagation of seizures and to minimize adverse effects related to that area′s removal. Clinical history, seizure semiology, electrographic features, and imaging all contribute to the formulation of a localization hypothesis. When presurgical diagnostic evaluation reveals discordant findings or fails to fully identify a discrete epileptogenic zone, implantation of intracranial electrodes should be considered. However, there needs to be a hypothesis of where the epileptogenic zone is before implantation, because the volume of brain tissue recorded by intracranial electrodes is limited. This chapter focuses on the multidisciplinary approach involved in evaluating candidacy for resective epilepsy surgery. In patients for whom the epileptogenic zone (EZ) cannot be localized or when resection of the EZ poses unacceptable risks, palliative options, such as vagal nerve stimulation, corpus callosotomy, or responsive neurostimulation, should be considered.
The characteristics of the seizures are essential to determining whether the seizures are likely to respond to surgery.5,6 Special attention should be paid to the onset of the seizure before electrical activity becomes more generalized. For example, visual auras suggest an occipital origin. Mesial temporal seizures are often characterized by a rising epigastric sensation or déjà vu. Preservation of speech during a seizure suggests involvement of the nondominant temporal lobe, whereas the absence of speech suggests involvement of the dominant temporal lobe. Semiology during secondary generalization, such as eye deviation and head turning, also suggests lateralization, usually contralateral to the seizure onset.
Epileptic activity does not spread as quickly between the archicortex, paleocortex, and neocortex. Quick secondary generalization suggests a neo-cortical focus. The more stereotypical the seizures are, especially at their onset, the more likely the epileptogenic focus will be discrete. If there are multiple, distinct seizure types, a single, discrete, resectable seizure focus is less likely.
Although seizure type can be diagnosed with scalp electroencephalography (EEG) lasting 1 to 8 hours, determining the presence and localization of an epileptogenic zone requires prolonged recording of simultaneous video and EEG to correlate the semiology of seizures and electrographic patterns. This is commonly referred to as phase 1 monitoring and typically involves a several-day admission to the epilepsy monitoring unit (EMU) with tapering of seizure medications. In addition, it is necessary to exclude psychogenic nonepileptic seizures, which represent ~ 20 to 40% of referrals to EMUs in the United States. Provocative techniques, including sleep deprivation, may be tried to trigger seizures in patients with complex partial seizures. Multiple seizures are recorded to ensure stereotypy of clinical and electrographic findings, and both ictal and interictal data are analyzed.
Approximately 10% of adult patients with new-onset seizures have an obvious abnormality on intracranial imaging.7 MRI is preferable to computed tomography (CT), when possible, due to the better anatomical detail. Generally, patients undergo brain MRI both with and without contrast to rule out a mass lesion. However, MTS and developmental abnormalities may not be apparent on such imaging. Dedicated sequences are necessary, including thin-cut, no-gap, coronal fluid-attenuated inversion recovery (FLAIR) T2-weighted (T2W) and three-dimensional (3D) volumetric gradient-echo T1-weighted (T1W) spoiled gradient (SPGR) echo images. There should either be no angulation of the head within the gantry or the images should be adjusted using 3D reconstructions. This can be checked by ensuring that both internal auditory meati are on the same image. Characteristic findings consistent with MTS are disruption of internal architecture of the hippocampus, increased FLAIR signal, and decreased size of the hippocampus, which may be made more obvious by looking for expansion of the adjacent temporal horn (Fig. 42.1).
Fig. 42.1 Imaging characteristics of right mesial temporal lobe sclerosis on (a) fluid-attenuated inversion recovery and (b) inversion recovery spoiled gradient echo sequences showing hippocampal atrophy, loss of internal architecture, and expansion of the temporal horn.
More advanced quantitative volumetric and signal intensity analysis can be done, but it is labor intensive. MRI spectroscopy can show a decreased N-acetyl aspartate to choline + creatine + phosphocreatine (NAA: Ch + Cr) ratio in the affected hippocampus. Schizencephaly, focal polymicrogyria, macrogyria, and lissencephaly are often reasonably obvious, but focal cortical dysplasias (FCDs) are often much harder to find because they can be anywhere between the subventricular zone and the cortex. They can appear as thickening of the gray matter, loss of gray–white matter differentiation, a region of double cortex, a periventricular gray matter nodule (Fig. 42.2), or a transmantle sign, defined as a funnel-shaped mass of gray matter extending from the subventricular zone to the cortex. Without specialized cortical unfolding techniques, it is difficult to differentiate between cortical thickening and catching a gyrus or sulcus on an angle due to angulation of the gantry.8
Neuropsychological testing is essential in the workup of a patient for surgical resection. It is helpful in determining the epileptogenic focus as well as predicting possible deficits from resection. The normal function of the epileptogenic focus is generally impaired; for example, patients with dominant-lobe TLE typically display verbal memory impairment, whereas those with nondominant TLE display visuospatial memory deficits. Lack of a focal deficit in verbal or visuospatial memory suggests that the epileptogenic focus may not be mesial temporal. If additional studies confirm that it is mesial temporal, the lack of deficit suggests that the patient has more to lose from an open surgical resection, especially if the dominant mesial temporal lobe is the culprit.9 Loss of cortical function in the contralateral hemisphere also portends a poor outcome with surgery. Presumably, the epileptogenic focus is not as discrete as hoped or having long-standing poorly controlled epilepsy has created more global damage. Patients with little to no deficit on neuropsychological testing are at a higher risk of postoperative neurocognitive deficits following resection.
First described in 1949 by Juhn Wada, selective carotid angiography with administration of a short-acting barbiturate such as sodium amytal has been a mainstay of the workup of patients with presumed temporal lobe epilepsy. More recently, intra-arterial methohexital, propofol, and etomidate have also been used. Function in each hemisphere is suppressed sequentially to determine language dominance and whether the temporal lobe that is not to be resected will support memory. In addition, the angiogram can be helpful in surgical planning, especially the venous phase, to determine the location of the vein of Labbé. However, the Wada test is invasive and has associated risks of arterial dissection, stroke, and groin hematoma. The ability to suppress hippocampal function with intracarotid infusion is not always consistent because much of the blood supply can be from the posterior circulation.
If the semiology, EEG, MRI, neuropsychology, and Wada testing are all concordant and consistent with unilateral MTS, no further testing is needed before surgical resection.10 Many have questioned the need for the Wada test in this battery due to the ability of fMRI to lateralize language and the ability of neuropsychological testing to predict postoperative memory deficits.11 Some authors have questioned the accuracy of the Wada test in predicting surgical outcome,12 although this may be due to heterogeneity in testing paradigms.
For patients with discordant testing and in those with possible extratemporal epilepsy, the tests described next can be used to facilitate localization and strategy development for the implantation of intracranial electrodes for long-term monitoring (phase II).
fMRI compares blood oxygenation and regional blood flow at rest and during a task. Tasks can be used to determine language lateralization and predict language deficits after surgery.13 fMRI can also be used to map blood flow changes related to other cortical functions, such as memory, somatosensory and motor function, and vision. However, results may vary based on the testing paradigm. Whereas fMRI can give information about localization of critical functions, it does not necessarily predict the ability of other areas of the brain to take over those functions after resection.
Because there is increased regional blood flow in areas of epileptiform discharges, investigators have developed MRI-compatible EEG electrodes so that EEG changes can be correlated with changes in regional blood flow detected with fMRI. However, this specialized technology is limited to only a few centers.
Similar to fMRI, SPECT measures increases in regional blood flow by detecting emitted gamma rays, generally from technetium pertechnetate (Tc 99m) compounds. The diagnostic accuracy of interictal SPECT is limited. Ictal SPECT is performed after intravenous (IV) injection of the radioligand at the onset of seizure activity in the EMU. Hyperperfusion of a discrete area is associated with the epileptogenic zone with an ictal injection. However, hyperperfusion and spatial specificity are decreased the longer the delay in radioligand injection from seizure onset. More advanced techniques comparing ictal and interictal SPECT (ictal–interictal SPECT analysis by statistical parametric mapping [ISAS]), sometimes overlaid onto MRI (subtraction ictal SPECT with coregistration on MRI [SISCOM] or statistical ictal SPECT coregistered to MRI [STATISCOM]) may increase the spatial specificity and aid in surgical planning for phase II monitoring.14
Unlike SPECT, positron emission tomography (PET) is performed interictally. Most studies demonstrate reduced regional glucose metabolism, as measured with fluorodeoxyglucose F 18 (18F-FDG), in and around the epileptogenic focus. Interictal hypometabolism is common in patients with temporal lobe epilepsy, with > 80% sensitivity and a low rate of false lateralization. PET hypometabolism is correlated with surgical outcome.15 The spatial resolution for extratemporal epilepsy is poor. However, PET can help guide the clinician in looking for subtle extratemporal MRI abnormalities and in developing phase II implantation strategies.
Magnetoencephalography (MEG) directly measures small magnetic fields generated by neuronal activity rather than relying on the accompanying hemodynamic or metabolic changes.16 Unlike EEG recordings, magnetic fields are not influenced by the conductors of the head, such as the skin, skull, and cerebrospinal fluid. MEG has better spatial resolution than EEG, and it is better at measuring activity in the sulci. The temporal resolution is superb as well. Localization of epileptiform dipoles can be performed using the equivalent current dipole (ECD) estimation algorithm. However, the use of this algorithm is limited when there are multiple areas of concurrent seizure onset. Initial capital costs are high, so this technology is restricted to a few centers in the United States.
Successful surgical resection for epilepsy is based on successful identification of a discrete area of the brain essential for initiation of seizures. Various modalities are used to accomplish this and to assess the risks of resection.
Patients who have concordant semiology, video EEG, neuropsychology, MRI, and Wada testing suggesting unilateral mesial temporal sclerosis do not require additional testing before proceeding to temporal resection. Some authors feel that Wada testing can be replaced with fMRI.
When presurgical evaluation fails to fully identify a discrete epileptogenic zone or if the evidence is conflicting, implantation of intracranial electrodes should be considered. Multiple modalities are used to develop an implantation strategy.
2. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077
This classic article showed that patients who fail to obtain seizure control with two medications are very unlikely to obtain benefit with additional trials of medications. There has been no difference noted between the efficacy of established and newer-generation medications.
7. Krumholz A, Wiebe S, Gronseth G, et al; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Practice Parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2007;69(21):1996–2007
Although many of the techniques are limited to research centers, this review from the group at the Montreal Neurologic Institute gives an excellent overview of current technology for advanced MRI analysis.
11. Lineweaver TT, Morris HH, Naugle RI, Najm IM, Diehl B, Bingaman W. Evaluating the contributions of state-of-the-art assessment techniques to predicting memory outcome after unilateral anterior temporal lobectomy. Epilepsia 2006;47(11):1895–1903
A large series from the group at Cleveland Clinic that used logistic regression in their patients to show that Wada testing did not contribute to the ability to predict memory outcome after anterior temporal lobectomy.
In this article, the authors obtained Wada tests but did not use the results to determine whether to offer surgery. They found that the Wada results did not predict neuropsychological deficits after left-sided resections. However, their testing paradigm has been criticized for its use of verbal memory items in patients who were temporarily aphasic from their left-sided injections.
This paper suggests that patients with concordant EEG, neuropsychological testing, PET-positive changes, but without MTS on MRI, do not need additional testing or phase II monitoring because the surgical results are comparable to those for patients with MTS on MRI.