Neurostimulation for Epileptic Seizures: Who, When, and Where?

For most patients with epilepsy, antiepileptic drugs successfully eliminate seizures. For about 30% of patients, however, medications do not achieve seizure control, requiring an additional or alternative approach. These patients are termed “drug resistant,” “intractable,” or “refractory.” Therapies for drug resistant epilepsy include diet, neurostimulation, and surgery.

The International League Against Epilepsy (ILAE) developed a working definition to standardize the categorization of patients with drug resistant epilepsy. According to the ILAE, “drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.”¹

The journal Neurology recently featured a discussion among epileptologists regarding the appropriate roles of various forms of neurostimulation.^2-5 Although the experts did not agree on all points, their discussion offers a balanced review of the emerging role of neurostimulation for the treatment of drug resistant epilepsy.

Neurostimulation Options

Neurostimulation devices approved by the FDA include the vagus nerve stimulator (VNS), approved in 1997, and responsive neurostimulation (RNS), approved in 2013. Although both devices decrease seizure frequency by repetitive electrical stimulation, their designs differ radically.

• Vagus nerve stimulation. The VNS is a pacemaker-like device implanted in the chest wall. It stimulates the brain via an electrode tunneled under the skin and attached to the left vagus nerve in the neck. The VNS stimulates the vagus nerve with an adjustable preprogrammed frequency. Additional stimulation can be triggered by waving a magnet over the device. There is no implant in the brain.

In double blind trials, seizure reduction ranged from 24.5% to 28%.⁴ In a meta-analysis of 2634 patients, 4.6% became seizure free. Rare adverse events include wound infections and electrode breakage. More frequently, patients experience a hoarse voice and cough during vagus nerve stimulation.

• Responsive neurostimulation. RNS has 2 electrodes implanted in the brain in the region of the seizure foci, which must be pre-identified during in-hospital monitoring. A battery pack and microcomputer triggered by abnormal electrical brain activity is implanted in the skull and delivers an electrical pulse that can abort incipient seizures. In this respect, RNS resembles an implantable cardiac defibrillator.

In the lone double blind, sham stimulation controlled trial of 191 patients, mean seizure reduction was 37.9% in the active stimulation group vs 17.3% in the sham group.⁴ Seizure freedom was achieved by as many as 9%. Intracranial hemorrhage occurred in 4.7% and wound or device infections in 5.2%.

Other neurostimulation techniques (not FDA approved) include the following:

• Anterior thalamus stimulation. This approach has been approved in Europe but not in the United States. In a double blind, randomized, sham stimulation controlled trial of 110 patients, seizure reduction was 40.4% in the active arm vs 14.5% in the control arm.⁶ Fourteen patients were seizure free for at least 6 months. Asymptomatic brain hemorrhages occurred in 4.5% of patients, but there were no symptomatic brain hemorrhages or infections.

• Trigeminal nerve stimulation. This device relies on external stimulation of the trigeminal nerve as a conduit to the brain. (In this respect, it is similar to VNS, which uses the vagus nerve as a route to the brain.) A double blind, randomized, controlled trial of 50 patients demonstrated a responder rate of 30.2% for the treatment group vs 21.1% for the active control group, which was not significantly different (p=0.31).⁷ However, there was a within-group increase in responder rate from 17.8% at 6 weeks to 40.5% at 18 weeks (p=0.01). There also was improvement in mood as measured by the Beck Depression Inventory (p=0.02). Adverse events included anxiety, headache, and skin irritation.

Treatment Algorithm

All experts agree that drug resistant patients should be evaluated at a tertiary epilepsy center. Drug resistant patients should have EEG/video monitoring and be offered resective epilepsy surgery if that is a practical option based on the location of their seizure focus (foci) and other variables. Surgery offers a much higher rate of seizure freedom than neurostimulation and is the treatment of choice for drug resistant mesial temporal lobe epilepsy.⁸ If surgery is not feasible, or the patient refuses, then neurostimulation options come into play. Although diet is an available alternative, diet therapy usually is reserved for intractable childhood epilepsy.

Whether to choose VNS or RNS for a particular drug resistant patient is a judgment call based on the results of the patient’s monitoring, clinician experience, and many other factors.

Conclusions

Treatment options for patients with drug resistant epilepsy include diet, neurostimulation, and epilepsy surgery. Currently, there are 2 FDA-approved neurostimulation devices, VNS and RNS. These should be considered when medications fail and surgery is not an option. Other neurostimulation approaches are under development and may become additional options for epilepsy treatment.

References:

1. 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. [Erratum in Epilepsia. 2010;51:1922.] Epilepsia. 2010;51:1069-1077.

2. Benbadis S, Helmers S, Hirsch L, et al. Yes, neurostimulation has a role in the management of epilepsy. Neurology. 2014;83:845-847.

3. Cole AJ, So NK, Tandon N, et al. Judgment is not ignorance. Neurology. 2014;83:847.

4. So NK, Cole AJ, Tandon N, et al. Neurostimulation for the treatment of epilepsy: the skeptical view. Neurology. 2014;83:847-849.

5. Benbadis S, Helmers S, Hirsch L et al. Skepticism should not result in ignoring a treatment option. Neurology. 2014;83:849-850.

6. Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51:899-908.

7. DeGiorgio CM, Soss J, Cook IA, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology. 2013;80:786-791.

8. Kieling RR, Palmini A, Paglioli E. Treatment of refractory mesial temporal lobe epilepsy. JAMA. 2012;307:2483-2485.