History

Little was understood about anatomic localization of brain function and thus epilepsy until the late 19th century when David Ferrier and John Hughlings Jackson characterized cerebral functions in monkeys and humans, respectively.^6,7 Hughlings Jackson rightly commented that “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 then the Englishman Sir Rickman Godlee in 1884 to perform exploratory craniotomies upon young patients with contralateral focal seizures.^8,9 Both were vindicated, Macewen discovering of an acute subdural haematoma and Godlee finding a brain tumor. Sir Victor Horsley also performed extratemporal surgery for focal seizures in the late 19th century, describing in 10 cases a combination of subpial and lobar resections.¹⁰ 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.”¹¹ 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.”¹² 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.¹³ Hemispherectomy was first described for infantile hemiplegia by Krynauw in 1950.¹⁴ 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.¹⁵ 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.^16–18 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 greater than 95% seizure frequency reduction in 87% of patients with generalized seizures and 68% with partial seizures, compared to cortical transections alone.¹⁹ It has been recommended for acquired epileptic aphasia (Landau-Kleffner syndrome).²⁰ Late seizure recurrence in adults has, however, been reported in other adult groups.²¹

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. Nonnoninvasive neuroimaging and invasive recording are described elsewhere. Vagus nerve stimulation has been approved in many countries for partial seizures with or without secondary generalization based on trials showing differences in seizure frequency reduction between high-frequency (25%–30% reduction) and low-frequency (6%–15% reduction) stimulation groups.²² 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 of follow-up.²³ 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 paraesthesia. The results augur for larger trials given its potential advantages over vagus nerve stimulation or transcutaneous test stimulation.²⁴

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 behavioural state changed from one of disorganisation, rage and persecution to one of happiness and mild euphoria.”²⁵ Cooper first treated epilepsy with implantable DBS throughout the 1970s, targeting the superomedial cerebellar cortex and reporting seizure reduction first in 6 of 7 and then later 18 of 32 patients (Fig. 110-1).²⁶ Eleven unblinded case series have reported benefits in 88 of 116 patients (76%),²⁷ but two small double-blinded studies comprising 14 patients have shown no benefit.²⁸ 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.²⁹ Current deep brain targets under evaluation for epilepsy are the anterior thalamic nucleus, centromedian thalamus, subthalamic nucleus, posterior hypothalamus, hippocampus caudate, corpus callosum, and brain stem.^30,31 We review current clinical outcomes information for these brain regions below.

FIGURE 110-1 Irving Cooper’s cerebellar stimulator, consisting of internally implanted electrode plates and receiver (left), external antenna and transmitter (center), positioned over the internal receiver during stimulation (right).

Anterior Thalamic Nucleus Stimulation

Bilateral DBS of the anterior thalamic nuclei has been undertaken by several groups and is currently being investigated in a 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 2010.³² Several small recent studies showed clinical benefits leading to the trial. Lim et al. found seizure frequency reduced 49% from baseline on average in four patients with a mean 44 months of follow-up.³³ Osorio et al. showed mean reductions of 75% in four patients delivering stimulation only with detection of electroencephalogram (EEG) changes.³⁴ Lee et al. studied three patients, finding a 75% reduction in seizure frequency at a mean follow-up of 13 months.³⁵

Ten patients were studied in two centers as pilot data for SANTE. Kerrigan et al. reported four of five patients showing significant reductions in frequency and severity of seizures after 6 to 36 months without complications.³⁶ 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.³⁷ 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.³⁸

SANTE recruited 110 patients with medically refractory partial or secondarily generalized seizures.³² Bilateral DBS was standardized to monopolar stimulation at a frequency of 145 Hz, pulse width of 90 μs and cycle time on for 1 minute, and then off for 5 minutes using quadripolar electrodes (Medtronic Inc., Minneapolis, MN, USA). Significant seizure reduction from a median baseline of 19.5 seizures per month was seen in the group stimulated at an amplitude of 5 volts compared to the placebo-implanted group stimulated at 0 volts, with a 29% seizure reduction in the last month of a 3-month blinded phase. After 3 months, all patients were transferred to 5-volt DBS. Median seizure frequency reduction continued to improve with DBS throughout 3 years of the trial, with a 41% median seizure frequency reduction at 1 year, 56% reduction in 102 patients at 2 years, and 68% reduction in 57 patients at 3 years, 54% of patients having a seizure reduction of at least 50%, and 14 patients being seizure free at 6 months. No surgery-related symptomatic hemorrhages or deaths were reported, although two participants had transient, stimulation-induced seizures. Results of SANTE and other clinical studies are summarized in Table 110-1.

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.^39,40 Anatomic evidence suggests widespread limbic system sclerosis in epilepsy, including projections to and from anterior thalamic nucleus to cingulate cortex and hippocampus.⁴¹ Concurrent thalamic and scalp EEG recording studies after surgery suggest a recruiting rhythm, elicited with low-frequency stimulation, correlating with clinical improvement.⁴² The nucleus is small and projects to and from many limbic and cortical structures, yet is less deep and proximal to subarachnoid vessels than the mammillary bodies, enabling safer targeting. Stereotactic ablation of the target demonstrated seizure reduction four decades ago,⁴³ motivating its intensive experimental and clinical study.

Centromedian Thalamic Stimulation

Wilder Penfield first postulated that the centromedian thalamic nucleus could be modulated to ameliorate seizures, noting its diffuse projections from the brain stem to the cerebral cortex.⁴⁴ Targeting the parvocellular division of the centromedian nucleus bilaterally, Velasco and colleagues have found seizure frequency reduction in 13 patients with Lennox-Gastaut syndrome.⁴⁵ Low-frequency (6–8 Hz) bipolar stimulation was delivered through pairs of adjacent quadripolar electrode contacts while assessing responses in concomitant scalp EEG. Implanted DBS settings were low frequency or high (130 Hz), pulse width 450 μs and amplitude of 6 to 10 volts. Their results from unblinded case series showed significant improvements in generalized seizures, less so in complex partial seizures, and seizure frequency increases with depleted battery life of implantable pulse generators.⁴⁶ The results have, however, not yet been replicated by others for this brain target. A double-blinded, crossover design, trial in seven patients by Fisher et al. revealed no clinical improvement in seizure frequency with centromedian thalamic stimulation,⁴⁷ nor did a recent report of two patients with longer-term follow-up.³⁸

Subthalamic Nucleus Stimulation

The subthalamic nucleus has been established of late as the surgical target of choice in DBS for Parkinson’s disease, and is therefore appealing, as functional neurosurgeons should have most experience with it. A mechanistic rationale for its stimulation has arisen from observations that the substantia nigra pars reticulara may gate seizures through inhibitory nigrotectal projections to the superior colliculi, its inhibition suppressing seizures in animal models.⁴⁸ Subthalamic nucleus inhibition has also been shown to suppress seizures in animals.⁴⁹ Clinically, Chabardès et al. demonstrated mean 64% seizure frequency reduction in four of five patients.⁵⁰ Other small studies have also shown improvements, two of five patients reported by Loddenkemper et al. as having 80% improvement in their partial seizures and two patients having their seizures mildly reduced according to Handforth et al.^51,52 Despite this evidence and Benabid’s promising case report of a child showing 81% seizure improvement at 30 months,⁵³ larger, blinded trials are required to demonstrate efficacy.

Other Deep Brain Targets

The posterior hypothalamus has been targeted by DBS based on observations that the mammillary bodies show epileptiform activity with depth electrode recording.⁵⁴ A report of two patients by Franzini et al. showed seizure frequency reduced by up to 80% from baseline after 9 months follow-up.⁵⁵ The mammillothalamic tract has also been stimulated to relieve gelastic seizures secondary to hypothalamic hamartomas with improvements in seizure frequency.⁵⁶