With the growing applications for deep brain stimulators (DBS) in recent years, interest in using DBS as an option for patients with epilepsy has increased. Thalamic DBS appears to be a viable minimally invasive treatment for patients experiencing medically intractable seizures. Thalamic DBS has been associated with significant reduction in seizure frequency and an improvement in overall quality of life, especially in patients who have failed maximal antiepileptic drugs or other surgical alternatives. However, further work is necessary to identify the subgroups of patients experiencing medically intractable seizures who may benefit from DBS, and also to indentify optimal stimulation parameters and mode of stimulation.
Approximately one-third of patients with epilepsies experience persistent seizures despite maximal antiepileptic drug (AED) therapy. Patients with refractory partial seizures may benefit from surgery, which may provide up to 90% reduction in seizure frequencies. The surgical options used for medically refractory epilepsy include (1) lesionectomy: both temporal and extratemporal excisions of seizure focus; (2) lesionectomy with corticectomy: removing both the epileptogenic lesion with the surrounding cortex; (3) disconnection surgery: subpial transections to isolate the seizure focus from the rest of the brain, including corpus callosotomies, and (4) vagus nerve stimulation. However, up to 50% of patients with medically intractable seizures either elect against these resective procedures or are deemed unsuitable candidates.
With the growing number of applications for deep brain stimulation (DBS) in recent years, interest in using it as an option for patients with epilepsy has increased. No consensus exists on the exact target for DBS for epilepsy, and therefore many sites are actively being explored. Candidates include the anterior nucleus of the thalamus (ANT), the centromedian nucleus of the thalamus (CMT), the subthalamic nucleus, and the hippocampus.
Even though the efficacy of DBS is becoming more evident, the exact mechanism through which DBS reduces seizure frequency is not fully understood. In patients with epilepsy, the brain oscillates between a functionally normal state and an abnormal ictal one, implying that the brain in patients with epilepsy is bistable or multistable. DBS for epilepsy generally involves the chronic delivery of high-frequency stimulation, which has been hypothesized to establish or reinforce the functionally normal brain state and block epileptiform activity in the cortex In hippocampal slice model systems, high-frequency stimulation causes increased extracellular potassium accumulation and negative slow potential shifts, resulting in decreased neuronal excitability, and thus suppression of seizures.
The target with the most promise seems to be located within the thalamus. Thalamic DBS has been reported for partial-onset epilepsy with or without secondary generalizations refractory to at least 12 to 18 months of two or more therapeutically dosed AEDs. The benefit of DBS is usually palliative, although certain studies have reported patients to be complete seizure-free post-DBS.
Rationale for stimulation of the ANT
The ANT is a crucial structure in the propagation of limbic epilepsy. In 1937, James W. Papez described for the first time the circuit linking the hippocampal output via the fornix and mamillary nucleus in the posterior hypothalamus to the ANT. The ANT then projects to the cingulum bundle just deep to the cingulated gyrus, which travels around the wall of the lateral ventricle to the parahippocampal cortex. This structure then completes the circuit by returning to the hippocampus. Atrophy or sclerotic changes of any of the structures within this circuit have been noted in known causes of epilepsy, such as mesial temporal sclerosis. Hence, investigators have hypothesized that stimulating targets within this circuit may result in direct anterograde cortical stimulation and concurrent cessation of seizures.
The ANT thus became a natural choice in DBS for epilepsy, especially considering that the ANT was the target for stereotactic lesioning for seizure control for many years. Anatomically, the ANT is also preferred because of its small size but multiple projections into the limbic structures (cingulated cortex, amygdala, hippocampus, orbitofrontal cortex, and caudate) allowing the stimulation of wide regions of the neocortex. Lastly, the ANT is easily accessible through the ventricle and is not as deep or close to the basal vasculature compared with alternative sites, such as the mamillary nuclei.
Evidence for epilepsy treatment
Animal Models
The ANT has been extensively investigated in animal models of epilepsy and in human trials. Mirski and colleagues showed in a rat model that high-frequency stimulation (100 Hz) of the ANT elevated the threshold for pentylenetetrazol-induced seizures. Inversely, low-frequency stimulation (8 Hz) had a converse effect and was even proconvulsant in the absence of pentylenetetrazol. Furthermore, Hamani and colleagues were able to achieve similar results in a rat model with pilocarpine-induced seizures, and showed that 500 μA was the optimal stimulus setting for providing significantly increased latency to seizure onset and status epilepticus. High-frequency stimulation of the ANT or unilateral lesioning of the ANT and blocked with bilateral high-frequency stimulation of the ANT has also been shown to reduce seizure severity and frequency in the kainic acid model. The investigators hypothesized that these effects were secondary to a form of functional, if not structural, microthalamotomy caused by high-frequency ANT stimulation.
Human Trials
The effects of DBS on epilepsy in animal models did not take long to inspire the start of human trials. Upton and colleagues first described improvement in seizure frequencies with chronic bilateral stimulation on the ANT in four of six patients, one of whom was completely seizure-free at follow-up. Again, this effect could have been secondary to a form of functional microthalamotomy of the ANT. In a case series of five patients, Hodaie and colleagues also reported a mean reduction in seizure frequency of greater than 50% after high-frequency stimulation of the ANT. The observed benefits did not differ between stimulation-on and stimulation-off periods. Subsequent studies have shown that electrode implantation itself decreases seizure frequencies (possibly from thalamotomy effect from insertion), and that activation of the implantable pulse generator (IPG) and multiple subsequent adjustments to stimulation parameters may not be directly linked to any further benefit in seizure control. Andrade and colleagues found that ANT DBS electrode implantation in six patients was followed by seizure reduction 1 to 3 months before active stimulation, again raising the possibility of a microthalamotomy effect. Continued improved seizure control in a patient for more than a year after the pulse generators were turned off further suggests the primary role for the microthalamotomy in seizure control. However, Osorio and colleagues were unable to detect any lesion effect with electrode insertion during the immediate postoperative period.
In a pilot study by Kerrigan and colleagues, four of five patients who received intermittent ANT stimulation had a statistically significant reduction in frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency with active stimulation, and discontinuation of DBS stimulation resulted in an immediate increase in seizure frequency and vice versa. These findings also suggested the role of ANT stimulation in the reducing seizure frequency.
Other studies improved on the statistical power of the initial small studies through recruiting multiple health care centers. In a large phase III multicenter trial, the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial (SANTE trial) sponsored by Medtronic (Minneapolis, MN, USA), patients were observed to have a reduction in seizure frequency after ANT DBS implantation and before active stimulation, indicating the presence of microthalamotomy effect. However, a statistically significant reduction in seizure frequency in the stimulation group compared with the control group continued during the blinded phase of the study. Furthermore, continued reduction in seizure frequency occurred over time during long-term follow-up, and improvement in seizure control within the control group was also seen 4 months after initiation of stimulation. These findings clearly suggest an effect of stimulation independent of the microlesion effect of electrode implantation.
During the blinded phase of the study, seizure frequency reduction was significantly greater in the stimulation group (38% reduction) versus the control group (15% reduction). During long-term follow-up and open-label phase of the study, seizure frequency reduction as a function of stimulation was −40% at 13 months, −57% at 25 months, and −67% at 37 months. The 50% responder rate was 41% at 13 months, 54% at 2 years, and 65% at 3 years. Seizure freedom was observed for at least 6 months in 13 patients. In addition, these improvements were seen in some participants who had not previously received multiple AEDs, vagus nerve stimulation, or epilepsy surgery. The SANTE trial also reported an overall improvement of quality of life based on Quality-of-Life-in-Epilepsy (QoLIE-31) scores in the stimulation group. The trial reported an outlier who had 210 seizures corresponding to the 5-minute stimulation cycle when the stimulator was turned on throughout the entire blinded phase of the study. The stimulator was turned off and the new seizures stopped immediately. Subsequently, this patient improved as stimulator parameters were adjusted.
Seizure Type Localization
The localization of seizure focus may also affect the efficacy of ANT stimulation for seizure control. Bitemporal mesial epilepsy in comparison with extratemporal or poorly localized seizures confers different benefits of DBS. Bitemporal mesial seizures seem to be more responsive to ANT stimulation than nonmesial ones. Osorio and colleagues reported up to a 75% reduction in seizure frequency, and even a 93% reduction in seizure frequency in one patient with this type of epilepsy. However, in Osorio’s study, a higher frequency of up to 157 Hz was used, which may partially explain the improved seizure response.
The SANTE trial also reported that the efficacy of ANT stimulation for seizure control depended on the region of seizure origin. A statistically significant benefit in reduction of seizure frequency was reported in patients with seizure origin in one or both temporal regions, with a 44.2% reduction in seizure frequency within the stimulated group versus 21.8% in the control group ( P = .025). Of these patients, 6% had a 100% reduction and approximately 19% had a 90% decrease in seizure frequency. However, among patients with seizure origin within the frontal, parietal, or occipital regions no significant differences in seizure reduction were seen between the stimulated and control groups. The trial also reported a reduction in seizure frequency in patients with multifocal or diffuse seizures, with a 35% reduction in the stimulation group versus 14.1% in the control group. However, because of the small number of patients, the difference was not statistically significant.
Evidence for epilepsy treatment
Animal Models
The ANT has been extensively investigated in animal models of epilepsy and in human trials. Mirski and colleagues showed in a rat model that high-frequency stimulation (100 Hz) of the ANT elevated the threshold for pentylenetetrazol-induced seizures. Inversely, low-frequency stimulation (8 Hz) had a converse effect and was even proconvulsant in the absence of pentylenetetrazol. Furthermore, Hamani and colleagues were able to achieve similar results in a rat model with pilocarpine-induced seizures, and showed that 500 μA was the optimal stimulus setting for providing significantly increased latency to seizure onset and status epilepticus. High-frequency stimulation of the ANT or unilateral lesioning of the ANT and blocked with bilateral high-frequency stimulation of the ANT has also been shown to reduce seizure severity and frequency in the kainic acid model. The investigators hypothesized that these effects were secondary to a form of functional, if not structural, microthalamotomy caused by high-frequency ANT stimulation.
Human Trials
The effects of DBS on epilepsy in animal models did not take long to inspire the start of human trials. Upton and colleagues first described improvement in seizure frequencies with chronic bilateral stimulation on the ANT in four of six patients, one of whom was completely seizure-free at follow-up. Again, this effect could have been secondary to a form of functional microthalamotomy of the ANT. In a case series of five patients, Hodaie and colleagues also reported a mean reduction in seizure frequency of greater than 50% after high-frequency stimulation of the ANT. The observed benefits did not differ between stimulation-on and stimulation-off periods. Subsequent studies have shown that electrode implantation itself decreases seizure frequencies (possibly from thalamotomy effect from insertion), and that activation of the implantable pulse generator (IPG) and multiple subsequent adjustments to stimulation parameters may not be directly linked to any further benefit in seizure control. Andrade and colleagues found that ANT DBS electrode implantation in six patients was followed by seizure reduction 1 to 3 months before active stimulation, again raising the possibility of a microthalamotomy effect. Continued improved seizure control in a patient for more than a year after the pulse generators were turned off further suggests the primary role for the microthalamotomy in seizure control. However, Osorio and colleagues were unable to detect any lesion effect with electrode insertion during the immediate postoperative period.
In a pilot study by Kerrigan and colleagues, four of five patients who received intermittent ANT stimulation had a statistically significant reduction in frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency with active stimulation, and discontinuation of DBS stimulation resulted in an immediate increase in seizure frequency and vice versa. These findings also suggested the role of ANT stimulation in the reducing seizure frequency.
Other studies improved on the statistical power of the initial small studies through recruiting multiple health care centers. In a large phase III multicenter trial, the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial (SANTE trial) sponsored by Medtronic (Minneapolis, MN, USA), patients were observed to have a reduction in seizure frequency after ANT DBS implantation and before active stimulation, indicating the presence of microthalamotomy effect. However, a statistically significant reduction in seizure frequency in the stimulation group compared with the control group continued during the blinded phase of the study. Furthermore, continued reduction in seizure frequency occurred over time during long-term follow-up, and improvement in seizure control within the control group was also seen 4 months after initiation of stimulation. These findings clearly suggest an effect of stimulation independent of the microlesion effect of electrode implantation.
During the blinded phase of the study, seizure frequency reduction was significantly greater in the stimulation group (38% reduction) versus the control group (15% reduction). During long-term follow-up and open-label phase of the study, seizure frequency reduction as a function of stimulation was −40% at 13 months, −57% at 25 months, and −67% at 37 months. The 50% responder rate was 41% at 13 months, 54% at 2 years, and 65% at 3 years. Seizure freedom was observed for at least 6 months in 13 patients. In addition, these improvements were seen in some participants who had not previously received multiple AEDs, vagus nerve stimulation, or epilepsy surgery. The SANTE trial also reported an overall improvement of quality of life based on Quality-of-Life-in-Epilepsy (QoLIE-31) scores in the stimulation group. The trial reported an outlier who had 210 seizures corresponding to the 5-minute stimulation cycle when the stimulator was turned on throughout the entire blinded phase of the study. The stimulator was turned off and the new seizures stopped immediately. Subsequently, this patient improved as stimulator parameters were adjusted.
Seizure Type Localization
The localization of seizure focus may also affect the efficacy of ANT stimulation for seizure control. Bitemporal mesial epilepsy in comparison with extratemporal or poorly localized seizures confers different benefits of DBS. Bitemporal mesial seizures seem to be more responsive to ANT stimulation than nonmesial ones. Osorio and colleagues reported up to a 75% reduction in seizure frequency, and even a 93% reduction in seizure frequency in one patient with this type of epilepsy. However, in Osorio’s study, a higher frequency of up to 157 Hz was used, which may partially explain the improved seizure response.
The SANTE trial also reported that the efficacy of ANT stimulation for seizure control depended on the region of seizure origin. A statistically significant benefit in reduction of seizure frequency was reported in patients with seizure origin in one or both temporal regions, with a 44.2% reduction in seizure frequency within the stimulated group versus 21.8% in the control group ( P = .025). Of these patients, 6% had a 100% reduction and approximately 19% had a 90% decrease in seizure frequency. However, among patients with seizure origin within the frontal, parietal, or occipital regions no significant differences in seizure reduction were seen between the stimulated and control groups. The trial also reported a reduction in seizure frequency in patients with multifocal or diffuse seizures, with a 35% reduction in the stimulation group versus 14.1% in the control group. However, because of the small number of patients, the difference was not statistically significant.
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