Surgical Management of Extratemporal Lobe Epilepsy

Introduction

Extratemporal lobe epilepsy (ETLE) comprises debilitating conditions of heterogeneous symptomatology and pathology, both challenging to diagnose and to treat yet amenable to several surgical interventions.

ETLE is defined as localization-related epilepsy with the electrophysiological epileptogenic zone outside the temporal lobe of focal epilepsies with and without secondary generalization. ETLE include frontal lobe, parietal lobe, occipital lobe, and multilobar neocortical epilepsies. Depending on the presence or absence of a structural abnormality on MRI that is concordant with the epileptogenic zone, ETLE is denoted lesional and nonlesional, respectively. Extratemporal lesions on MRI, not necessarily epileptogenic, can coexist with mesial temporal sclerosis as dual pathology. Four percent to 15% of adult temporal lobe resections involve dual temporal and extratemporal pathology. The extratemporal pathology is most commonly cortical dysplasia followed by vascular malformations, infarction, and dysembryoplastic neuroepithelial tumors, in descending order of frequency. The higher childhood prevalence of dual pathology suggests earlier progression to intractable epilepsy and hence surgery. In this chapter, we consider adult extratemporal epilepsy surgery, childhood epilepsy surgery having been described in the pediatric section of this book. Available procedures account for less than half of all epilepsy surgery and can either be resective for an identified seizure-generating region or palliative. ^, In one highly specialized center, the surgical procedures for ETLE comprised 16% (147 interventions) of the epilepsy surgical workload over a 25-year period. The management of ETLE is therefore tailored case-by-case and empirical although evidence-based interventions and algorithms are being explored with technological advancement, for example, in imaging, neuronavigation, surgical robotics, and neuromodulation. Surgical ablative and resective procedures include topectomy (excision of nonlesional epileptogenic zone), lesionectomy, lobectomy, hemispherectomy; stereotactic ablative procedures; functional disconnective procedures including multiple subpial transections, corpus callosotomy, and hemispherotomy, all detailed in the following chapters. Neuromodulatory procedures include deep brain stimulation (DBS) and vagus nerve stimulation, both modalities with availability of closed-loop responsive stimulation. Vagus nerve stimulation has also been described elsewhere in this section. We briefly review the above techniques before focusing upon DBS for epilepsy, describing its history, operative technique, and reviewing clinical outcomes and complications in the context of these other procedures. We do not review diagnostic intracranial electrode placement techniques and presurgical recording, which are covered in a preceding chapter.

History

If the sufferer acts like a goat, and if he roars, or has convulsions involving the right side, they say the Mother of the Gods is responsible. If he utters a higher-pitched and louder cry, they say he is like a horse and blame Poseidon. If the sufferer should be incontinent of faeces, as sometimes happens under the stress of an attack, Enodia is the name.

Hippocrates of Kos (460–370 BC)

Little was understood about anatomical localization of brain function and thus epilepsy until the late nineteenth century when David Ferrier and John Hughlings Jackson characterized cerebral functions in monkey and man, respectively. ^, Hughlings Jackson rightly commented “a convulsion is but a symptom, and implies only that there is an occasional, an excessive, and a disorderly discharge of nerve tissue on the muscles. This discharge occurs in all degrees; it occurs with all sorts of conditions of ill health, at all ages, and under innumerable circumstances.” A prevailing British culture of cerebral localization emboldened first the Glaswegian William Macewen in 1879 and later the Englishman Sir Rickman Godlee in 1884 to perform exploratory craniotomies upon young patients with contralateral focal seizures. ^, Both were vindicated, Macewen discovering of an acute subdural hematoma and Godlee finding a brain tumor. Sir Victor Horsley also performed extratemporal surgery for focal seizures in the late nineteenth century, describing in 10 cases a combination of subpial and lobar resections. Horsley’s cortical escharotomies of his patients led Hughlings Jackson to conclude of three cases that “there was in every case of epileptiform seizures a very local change of some kind,” and that because “the starting point of the fit was the sign to us of a discharging lesion, he would advise cutting out that lesion, whether it was produced by tumour or not.” Thus resective extratemporal epilepsy surgery was commenced.

Corpus callosotomy arose in the 1930s from Van Wagenen’s serendipitous observation that patients with stroke involving the corpus callosum often had improvements in seizures. “It was decided to divide the corpus callosum surgically in an effort to limit the spread of a convulsive wave to one half of the cerebrum.” In both children and adults, corpus callosotomy appears, on average, to improve drop attacks and generalized tonic and tonic-clonic seizure frequency by 80% in 70% of patients and complex partial, myoclonic, and absence seizure frequency by 50% in 50% of patients. Hemispherectomy was first described for infantile hemiplegia by Krynauw in 1950. Having late complications of hemosiderosis, hydrocephalus, brain shift, and hemorrhagic membrane formation, it was abandoned in the 1970s in favor of functional hemispherectomy advocated by Rasmussen. Most studies relate to children, three published adult studies reporting, respectively, 4 of 4, 5 of 9, and 5 of 12 patients becoming seizure free. Multiple subpial transection aims to limit the horizontal spread of epileptiform activity across functional columns of eloquent cortex. A meta-analysis of adults and children has shown more than 95% seizure frequency reduction in 87% of patients with generalized seizures and 68% with partial seizures, compared to cortical transections alone. It has been recommended for acquired epileptic aphasia (Landau-Kleffner syndrome). Late seizure recurrence in adults has however been reported in other adult groups.

Electrical neuromodulatory approaches to extratemporal epilepsy are indicated where epilepsy persists despite resection of epileptogenic foci or in the palliative circumstance where no seizure focus is demonstrated using scalp recording, noninvasive neuroimaging, and invasive recording described elsewhere. Vagus nerve stimulation has been approved in many countries for partial seizures with or without secondary generalization based upon trials showing differences in seizure frequency reduction between high-frequency (25% to 30% reduction) and low-frequency (6% to 15% reduction) stimulation groups. Median seizure reductions in 454 patients were 44% from baseline after 3 years, with 43% of patients having at least 50% seizure frequency reduction, although 20% had persisting hoarseness at 2 years’ follow-up. Trigeminal nerve stimulation has also recently been reported, 12 patients having a median 66% seizure frequency reduction at 3 months with occasional side effects of orbicularis oculi twitching and dental discomfort and paresthesia. The results augur for larger trials given its advantage over vagus nerve stimulation of transcutaneous test stimulation.

DBS for epilepsy is almost as old as human stereotactic surgery, having first been attempted acutely in 1952 by Heath. He recorded interictal spikes from the septum in a patient with complex partial seizures and then stimulated him. “Almost instantly, his behavioral state changed from one of disorganization, rage and persecution to one of happiness and mild euphoria.” Cooper first treated epilepsy with implantable DBS throughout the 1970s, targeting the superomedial cerebellar cortex and reporting seizure reduction first in 6 of 7, then later, 18 of 32 patients ( Fig. 101.1 ). Eleven unblinded case series have reported benefits in 88 of 116 patients (76%), but two small double-blinded studies comprising 14 patients have shown no benefit. ^, Cerebellar stimulation therefore fell out of favor, with the exception of one recent report of five patients with generalized tonic-clonic seizures showing mean seizure frequency reduction of 59% at 6 months after surgery. Current deep brain targets under evaluation for epilepsy are the anterior thalamic nucleus, centromedian thalamus, subthalamic nucleus, posterior hypothalamus, caudal zona incerta, nucleus accumbens, hippocampus caudate, corpus callosum, and brainstem. ^, We review current clinical outcomes information for these brain regions below.

Anterior Thalamic Nucleus Stimulation

Bilateral DBS of the anterior thalamic nuclei (ANT-DBS) has been undertaken by several groups and reported in a total of 230 to 240 patients and include a long-term follow-up multicenter, double-blind, randomized clinical trial—stimulation of the anterior nucleus of the thalamus for epilepsy (SANTE), the first results of which were published in 2010. Results of the SANTE study and other clinical studies are summarized in Table 101.1 .

The pre-SANTE trials pioneered ANT-DBS for seizure control in small open-labeled studies. In 1988, Sussman et al. in their preliminary report obtained seizure control in three of five patients at 12 to 18 months follow-up. Kerrigan et al. reported four of five patients (80% responders) showing significant reductions in frequency (78% of baseline) and severity of seizures after 6 to 36 months. Hodaie et al. reported a mean reduction from baseline of 54% in seizure frequency at mean follow-up of 15 months, also without adverse effects and with a stun effect reducing seizure frequency before turning on stimulation. Andrade et al. later described five of six patients from the latter center with improvements of at least 50% in their seizure frequency over a mean follow-up period of 5 years. In 2005, ANT stimulation in a closed-loop responsive system reduced seizure frequency to 72% to 75% in two of four patients. While the SANTE trial was going on, Lee et al. studied three patients, finding a 75% reduction in seizure frequency at mean follow-up of 13 months. Lim et al. found seizure frequency reduced to 75% from baseline in one of four patients. Osorio et al. showed seizure frequency reductions of 75% in four of four patients at 36 months delivering stimulation only with detection of EEG changes. In 2012, Lee et al. extended their previous findings and reported seizure control in 12 of 15 patients (80% responders) with seizure frequency of 70% at median follow-up 39 months.

Fisher et al., in their SANTE study, recruited 110 patients with medically refractory partial or secondarily generalized seizures. Bilateral ANT-DBS was standardized to monopolar stimulation at a frequency of 145 Hz, pulse width of 90 μs, and cycle time on for 1 minute then off for 5 minutes using quadripolar electrodes (Medtronic Inc., Minneapolis, MN). After 1 month postsurgery patients were randomized in the blinded phase lasting for 3 months. The highest median seizure frequency reduction was 42.1% in the stimulated group at the second month. Significant seizure reduction from a median baseline of 19.5 seizures per month was seen in the group stimulated (33 of 54 patients, 61% responders) at amplitude of 5 V compared to the placebo group nonstimulated (29 of 55 patients, 53% responders) at 0 V, with a 29% seizure reduction in the last month of a 3-month blinded phase. After this phase, all patients were transferred to 5 V DBS and enrolled in the open-labeled and unblinded follow-up. The greater than 50% responder rate was 43% ( n = 99) at 13 months, 54% ( n = 81) at 25 months, and 67% at 37 months ( n = 42). The median seizure frequency reduction continued to improve with DBS throughout the trial: 41% at year 1 and 56% at year 2. The follow-up report showed greater than 50% responder rate of 69% with median frequency seizure reduction of 68% at year 5. Six-month seizure freedom after 5 years was reported by 16% of the patients. The modest but significant improvement in quality of life in epilepsy from baseline reported by Fisher et al. remained unchanged at year 5. Cognition and mood changes have been subject to elaborate analysis as self-reported changes during the blinded trial period were reported significantly higher in the stimulation group, although no significant changes were measured at objective neuropsychological testing. At 7-year follow-up no cognitive decline or worsening of mood was observed.

Post-SANTE clinical reports of open-labeled small cohorts have emphasized technical aspects of the surgery such as imaging and intraoperative recording of evoked potentials and clinical correlation with respect to a “sweet-spot” for stimulation associated with seizure control. Stillova et al. reported three patients with ANT-DBS and recorded hippocampal event–related potentials that suggested a role of the ANT in the memory of recognition. The effects on seizures were not available. Van Goempel et al. has suggested targeting the ANT with a posterior trajectory and recorded hippocampal-evoked potentials confirming ANT targeting obtained seizure reduction in both their patients with seizure reduction by 53% and 80%. Sun et al. recorded event-related potentials and demonstrated that ANT stimulation increased the attention to emotional stimuli. Piacentino et al. showed in a heterogeneous case mix of patients, five of six responders with long-term results more than 3 years in four patients achieving seizure reduction rates of 60% to 100%. Lahtimaki et al. reported 10 of 15 patients with mean seizure reduction of 68% after 5 years follow-up and showed that favorable outcome was associated with contacts in the anterior aspect of the ANT. Kim et al. reported a long-term cohort of 29 patients with 75% responders and overall 70% seizure reduction during the 11-year follow-up and did not find difference in outcome between focal and generalized epilepsies and between temporal lobe epilepsy and ETLE. Guan et al. reported 9 of 17 patients with 53% responders and mean seizure reduction 56% at 1 year after surgery.

The mechanisms of anterior thalamic nucleus stimulation remain unclear. Animal models have shown seizure reduction in drug-induced seizure models, postulating current dependent- and serotonin-mediated effects. ^, Anatomical evidence suggests widespread limbic system sclerosis in epilepsy, including projections to and from anterior thalamic nucleus to cingulate cortex and hippocampus. Concurrent thalamic and scalp EEG recording studies after surgery suggest a recruiting rhythm, elicited with low-frequency stimulation, correlating with clinical improvement. The nucleus is small and projects to and from many limbic and cortical structures, yet is less deep and proximal to subarachnoid vessels as the mammillary bodies, enabling safer targeting. Stereotactic ablation of the target demonstrated seizure reduction four decades ago, motivating its intensive experimental and clinical study.