Neurostimulation for the Treatment of Epilepsy

About 30% of epilepsy cases are medically intractable and require non-pharmacologic treatment. ^[1] While resective surgery is the treatment of choice in these cases, it is not always feasible. In addition, about 20% of patients treated at the most experienced epilepsy centers are not seizure-free even after surgery. ^[1] Neurostimulation (or neuromodulation) is an acceptable palliative treatment option for both patients who are not surgical candidates and those who do not gain seizure freedom after surgery. It is considered a palliative treatment as the aim is seizure reduction and patients do not generally attain seizure freedom. ^[2]

From 1997 to 2013, the only neurostimulation modality approved in the United States was vagus nerve stimulation (VNS). The brain-responsive neurostimulator (RNS system) was approved in 2013, and the approval of deep brain stimulation (DBS) was approved in May 2018. There are also additional modalities available in other countries, though they are not approved in the United States at this point.

This article will provide a review of the different neurostimulation modalities and compare them with respect to each other and to epilepsy surgery.

In July 1997, the US Food and Drug Administration (FDA) approved the use of VNS as an adjunctive treatment for refractory partial epilepsy in adults and adolescents aged 12 years and older. The approval was mainly based on the results of the E05 study, ^[3] which compared the efficacy and safety of VNS in patients who received high stimulation vs. low stimulation. Subsequently, newer (improved) models have been released, each with enhancement of VNS technology.  

Efficacy

The high-stimulation group in the E05 study had a 28% decrease in mean of seizure frequency, vs.15% decrease in the low-stimulation group. Following the acute phase of the study, longer-term results ^[4] showed a responder rate (50% or more in seizure reduction) of 36.8% of patients after one year, 43.2% at two years, and in 42.7% at three years. Median seizure reductions compared with baseline were 35% at one year, 44.3% at two years, and 44.1% at three years. It was concluded that the long-term, open-label VNS provided seizure reduction similar to or greater than acute studies.

 An 11-year retrospective review of VNS in a consecutive series of 436 adults and children ^[5] found that when used in conjunction with a multidisciplinary and multimodality treatment regimen, more than 60% of patients experienced at least a 50% reduction in seizure burden.

Tolerability and safety

In the E05 study, adverse effects reported by more than 10% of the patients during the peri-operative period were pain (29%), cough (14%), voice change (13%), chest pain (12%), and nausea (10%). In the high-stimulation group, voice alteration/hoarseness, cough, throat pain, nonspecific pain, dyspnea, paresthesia, dyspepsia, vomiting, and infection were increased significantly from baseline. Clinical experience has since showed that the most common effects (hoarseness, cough, shortness of breath, paresthesias) appear during stimulation and tend to diminish over time. ^{[4, 6]} It was concluded that VNS is safe and well tolerated, with nearly three quarters of the patients choosing to continue therapy. VNS is not associated with the usual adverse effects of antiepileptic drugs (AEDs), such as fatigue, dizziness, depression, insomnia, confusion, cognitive impairment, weight gain, and sexual dysfunction. VNS may have deleterious effects on sleep apnea, ^[7] though it is not clear how clinical relevant this is.

Stimulation parameters

Stimulation parameters are many. Output current varies from 0.5 to 3.5 mA, and is typically increased gradually according to efficacy and tolerance. The default parameters are usually 30-Hz signal frequency, 500-microsecond pulse width, 30 seconds of "on" time and 5 minutes of "off" time (10% duty cycle). The optimal range of device duty-cycles and other parameters remain unclear and largely subject to individual preferences. ^{[8, 9]}

The handheld magnet can used on demand to interrupt or reduce the severity of an oncoming seizure. The patient or a companion may activate the generator (triggering an additional stimulation) by swiping the magnet on the generator. Magnet use offers patient and family alike a sense of control or empowerment, and may indeed decrease seizure duration or severity. ^[10] The magnet can also be used to turn off automatic stimulation on demand to restore the voice to its normal level if need be.

Quality of life (QOL)

VNS appears to improve quality of life independent of its effect on seizure control. Subjective improvement in Quality of Life (QoL) occurred in 84% of patients, which is likely attributable to additional factors besides seizure control. ^[11] VNS is in fact FDA-approved for treatment-resistant depression, ^[12] though rarely used due to poor reimbursement.

The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial studied patients with pharmacoresistant focal seizures and divided them into two groups: one received VNS as adjunct to best medical practice (VNS + BMP) and the other received BMP alone. Significant difference was observed in favor of VNS + BMP regarding improvement of seizure frequency and QoL. However, it was noted that more patients in the VNS + BMP group (43%) reported adverse events compared to BMP group (21%) (p = 0.01). adverse events were mostly related to VNS implantation or stimulation. It was concluded that VNS + BMP was superior to BMP alone in improving QoL. ^[13]

Effect on Sudden Unexpected Death in Epilepsy (SUDEP)

The risk of premature death is increased in patients with intractable epilepsy. Sudden Unexpected Death in Epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. The effect of VNS on mortality remains unclear. Earlier studies suggested that VNS may reduce the risk of SUDEP after 2 years of treatment, ^[14]  but other studies did not confirm this. ^[15] In a study ^[16] of T-wave alternans (a cardiac marker for sudden cardiac death associated with SUDEP) and heart rate variability (an indicator of autonomic function), VNS seemed to have a cardio-protective role.

The (USA) FDA indication for VNS use is "adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizure, which are refractory to anti-epileptic medications." Although the FDA indication for VNS is rather narrow, most epileptologists agree that VNS indications are probably broader. For example, VNS is often the best option for intractable generalized epilepsies, ^[17] whether of the Lennox-Gastaut type or idiopathic (genetic) generalized epilepsies. In fact, generalized epilepsies of the Lennox-Gastaut type, even though technically “off label”, may be the most common use of VNS. Appropriately, VNS is approved for all types of refractory epilepsies in Europe.

Evolution and improvements over time

The models and specifications of the generator have evolved and improved since its first release two decades ago. Generally speaking, the device has become smaller, thinner, and its battery life has increased. The latest improvement replaced the blind closed-loop stimulation concept with an open loop therapy. The Aspire device, ^{[18, 19]} in addition to the automatic stimulation, detects any increase in heart rate associated with seizures and delivers an additional stimulation. Detection parameters here include heart rate detection and tachycardia threshold. SenTiva (Model 1000) also detects ictal tachycardia and delivers a therapy dose to prevent seizure progression and abort the seizure. SenTiva additionally has a wireless programming wand, a small tablet for user interface, guided programming, scheduled programming, and day and night programming. ^[20]

A trial by Hamilton et al. studied the efficacy of the Aspire device compared to older models. The trial was retrospective and examined patients over a 3-year period. The cohorts were divided in two and seizure burden was compared in both. The first cohort compared patients with prior VNS models that were replaced with the AspireSR model; the second cohort compared patients before and after AspireSR was implanted, in the setting of no prior VNS use. Out of the patients who had a newly inserted AspireSR VNS model, 59% reported ≥50% reduction in seizure frequency. Out of the patients who had an existing VNS, 53% had reduction in seizure burden when the original VNS was placed, and 71% reported a further seizure reduction of ≥50%. The results suggest that 70% of patients with prior models of VNS insertions could have additional benefit from cardiac-based seizure detection and closed-loop stimulation from the AspireSR device. ^[21]

One limitation of VNS is that it limits the use of later MRIs. MRI of the head and body, including 3T, can be performed (with a send and receive coil and the generator off), but the neck area is not considered safe due to possible heating of the lead.

Since its release, VNS has been reviewed periodically by the American Academy of Neurology (AAN) and American Epilepsy Society. Guidelines and practice parameters ^{[22, 23, 24]} consistently consider VNS standard of care as a non-pharmacologic treatment. AAN Quality Measures ^[25] rightly include VNS as indicated in patients who are refractory to AEDs and not suitable for epilepsy surgery. The AAN ranks VNS as effective and safe based on a preponderance of class I evidence (level Ia).

Additional studies

A review of the VNS Patient Outcome Registry (5554 patients) evaluating rates and predictors of seizure freedom with VNS therapy showed that 49% of patients responded to VNS therapy from 0 to 4 months with ≥50% reduction in seizure frequency, with 5.1% of patients becoming seizure free. In comparison, 63% of patients were responders at 24 to 48 months, with 8.2% achieving seizure freedom. The factors that predicted seizure freedom were age of epilepsy onset >12 years and principally generalized seizure type. The most significant factor that predicted overall response to VNS was nonlesional epilepsy. The literature review data was consistent with trends found in the registry data; from 0 to 4 months, 40% of patients responded and 2.6% achieved seizure freedom; at last follow-up, 60.1% of patients were responders and 8.0% became seizure free. The data revealed that patient response and seizure freedom continues to increase over time with VNS therapy, although only a small percentage of patients reach seizure freedom. ^[26]

Responsive neurostimulation (RNS) involves one or more implantable electrical leads that are placed over seizure foci. It is a closed-loop circuit; the leads detect the electrocorticography (ECOG) patterns and produce electrical cortical stimulation on demand. It is activated by patterns that indicate seizure activity and then delivers an electrical stimulation with the goal of terminating the seizure (brain response). RNS also offers unprecedented amounts of electrographic monitoring as it records electrocorticogram (eCoG) data, which can be uploaded to a program daily for later review. This has allowed deeper understanding of epilepsy. ^[27] It also offers the benefit of occasionally assisting in resection planning in patients with bilateral mesial temporal lobe epilepsy, as it provides continuous ECOG recordings and can identify the more severely affected side. ^[2]

The brain-responsive RNS system was approved by the FDA in 2013 for medically refractory focal epilepsy. The pivotal multicenter, double blind, randomized controlled study ^[28] observed 191 subjects with medically refractory focal epilepsy. Subjects were randomized into two groups; one received stimulation in response to detections (treatment), and the other received no stimulation (sham).

Efficacy

Groups were assessed over a 12-week blinded period, during which it was found that treatment group had significant reduction in seizures (37.9%) compared to 17.3% in the sham group (p = 0.012) without differences in adverse events. They were assessed again over an 84-week open-label period, during which all subjects received stimulation. This resulted in a sustained reduction in the treatment group and a significant reduction in the sham group. The study concluded that patients who received RNS exhibited a significant reduction in seizure frequency, with an associated improvement in overall QoL (p< 0.02), and with no mood and cognitive changes. This study led to FDA’s approval of RNS for adults who average three or more seizures per month, have failed two or more AEDs, and have one or two seizure foci.

A subsequent study on the longer-term effects of RNS ^[29] found a median percent reduction in seizures in the open labeled period of 44% at 1 year and 53% at 2 years, representing a significant improvement over time. No significant difference in adverse event rate was noted between the treatment and sham stimulation groups. It was concluded that, similar to VNS, the efficacy of RNS tends to improve over time.

Tolerability and safety

Complications such as infection and skull osteomyelitis can occur but are rare. ^{[30, 31]}

The Pivotal Trial Open Label Period also showed improvements in naming and verbal memory, and in visual memory and executive function. No cognitive adverse effects were seen. ^[32]

Quality of life (QOL)

The Pivotal Trial Open Label Period showed significant long term improvements in quality of life in all domains (Overall QOL, Epilepsy-targeted, Mental Health, and Physical Health) at one and two years, in both neocortical and mesiotemporal scenarios. A modest improvement in mood was also noted. ^[33]

Like VNS, RNS is palliative, and therefore is appropriate for patients who are not candidate for, or have failed, resective epilepsy surgery. The most common indications for RNS are true bitemporal epilepsy, and focal epilepsy, where the focus is in an eloquent cortex that cannot be resected. The average follow up was between 4 and 8 years. The median percent seizure reduction was 70%.

MRI of the brain is contra-indicated with the RNS system.

Effect on Sudden Unexpected Death in Epilepsy (SUDEP)

In a separate trial, Devinsky et al. studied the incidence of SUDEP in patients treated with RNS. They evaluated all deaths in patients treated in both the clinical traiils (N=256) and in patients who received it after FDA approval (N=451). The SUDEP rate was 2.0/1000 patient stimulation years. SUDEP rate in patients with treatment-resistant epilepsy is 3.2–5.9.  The SUDEP rate in patients after resective surgeries is 6.3–9.3. The study concludes that RNS is favorable for preventing SUDEP relative to treatment-resistant epilepsy and seizures after resective surgeries. ^[34]

Additional studies

Ongoing research continues to evaluate the effectiveness of RNS and its different applications. In a prospective clinical trial, Geller et al. evaluated the seizure reduction and safety in patients with mesial temporal lobe epilepsy (MTLE). There were 111 patients; 72% had bilateral MTLE, while 28% had unilateral MTLE. The subjects had 1 to 4 leads placed, but only two leads could be connected to a live device. The seizure reduction was calculated by comparing the baseline seizure frequency to 2–6 years after implantation. The median seizure reduction was 70%. The conclusion of the study is that RNS is a safe and effective treatment option for medical intractable epilepsy in patients with unilateral or bilateral MTLE, including those who have failed prior mesial temporal lobe resection. ^[35]

Deep brain stimulation (DBS) was approved in May 2018 by the FDA as adjunctive therapy for adults with medically refractory localization-related epilepsy. The critical trial that supported the use of DBS in patients with refractory epilepsy is called the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE). ^[36] This was a multicenter, randomized, double-blind, prospective trial.

Efficacy

The SANTE study included 110 adults who were divided into two cohorts; one received stimulation and the other did not over a three-month blinded phase, then all received open-label stimulation. Baseline median seizure frequency was 19.5 per month. DBS involved implanting electrodes in the bilateral anterior nucleus of the thalamus. There was a 40.4% median reduction in total seizure frequency in patients that received DBS implantation compared to14.5% reduction in the placebo group at 4 months. At the 5-year point, patients who had DBS had 69% seizure reduction. ^[37]

The FDA indication for DBS is as follows: “indicated as adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to three or more antiepileptic medications.”

Tolerability and safety

Salanova et al. evaluated the long-term safety of the SANTE trial. They found that many areas in the cognitive functioning and psychological domains improved, as measured by gains on neuropsychological testing scores. The specific areas included improved attention, executive function, depression, anxiety, mood disturbances, and subjective cognitive functioning. The most common reported adverse events were depression and memory impairment, but a majority of patients already had a history of these, respectively, prior to the surgery. Additionally, the events were not deemed to be severe. ^[37]

Quality of life (QOL)

A trial by Fisher et al. used the Quality of Life in Epilepsy Inventory (QOLIE-31) score, which measures emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, medication effects, and overall quality of life. They conducted baseline surveys and follow-up surveys at 13 and 25 months. The scores improved from baseline by 5.0 ±9.2 and 4.8 ± 9.3 at 13 and 25 months. ^[36]   

Effect on Sudden Unexpected Death in Epilepsy (SUDEP)

The rate of SUDEP in patient who received DBS was 2.9 per 1000 patients per year, which is significantly lower when compared to the epilepsy surgical candidates at 9.3 per 1,000 patients per year. ^[36]

Transcutaneous Vagus Nerve Stimulation (t-VNS)

Non-invasive t-VNS is a device that stimulates the afferent auricular branch of the vagus nerve located medial to the tragus of the left ear. It may be a useful, safe and well tolerated alternative treatment option. In a pilot-study by Stefan et al, ^[38] t-VNS was applied to 10 patients with pharmaco-resistant epilepsy where they received stimulation 3 times/day for 9 months. Three patients aborted the study. Five out of the remaining seven patients had overall reduction of seizure frequency after 9 months. T-VNS is not approved by the FDA due to minimal research. 

External Trigeminal Nerve Stimulation

External trigeminal nerve stimulator (eTNS) is another non-invasive neuromodulation therapy that is not approved in the US. A double-blind randomized controlled study of 50 subjects ^[39] concluded that eTNS is associated with significant within-group improvement in the responder rate, which increased to 40.5% at the conclusion of the double blind period (p =0.01). It is also associated with a significant improvement in mood. Given promising results of phase 2 trial providing class II evidence that eTNS may be safe and effective, it was approved in Europe and Canada. It is still under investigation with larger multicenter phase 3 clinical trials.

Cerebellar stimulation

Research in cerebellar stimulation for cortically or hippocampal induced epilepsy has been conducted since 1941 on animal models and in small clinical trials, resulting in mixed results. In 2005, bilateral cerebellar stimulation for intractable motor seizures was re-evaluated ^[40] in a small randomized double-blind study of 5 patients. Four-contact plate electrodes were placed on the cerebellar superomedial surface through two suboccipital burr holes. In the first month post-placement, none of the patient received stimulation, then patients were randomized into two groups: three received stimulation and two didn’t. After 4 months, all five patients received stimulation. No change was found in the mean tonic clonic seizure rate in the two patients who did not receive stimulation in the initial 3-month double blind phase whereas the three patients who received stimulation had a 33% seizure reduction (p = 0.023). A 41% seizure reduction was achieved in all five patients after 6 months of stimulation. At 24 months, tonic seizure reduction in all four patients who had them was 43%. The statistical analysis showed a significant reduction in tonic-clonic seizures (p < 0.001), and tonic seizures (p < 0.05). Complications included migration in three patients and wound infection in one patient.

When patients have drug-resistant epilepsy and fail to have seizure control after more than 2 appropriate AEDs, the next step should be to consider nonpharmacological treatments. The only curative measure available for epilepsy is resective surgery. Therefore, surgical consideration should be considered next.

Surgical evaluation is multi-disciplinary and evaluates many factors. However, being a surgical candidate is not a binary (yes/no) proposition. It can be viewed as a continuum. At one extreme, idiopathic (genetic) generalized epilepsies and symptomatic generalized epilepsies of the Lennox-Gastaut type are never treated with focal resections. At the other extreme, because the likelihood of seizure freedom is high, clear-cut unilateral mesiotemporal epilepsy or straightforward focal lesional epilepsy should be treated with focal resections. Several scenarios fall somewhere in between, such as bitemporal epilepsy (although it depends how bitemporal is defined), extratemporal non-lesional epilepsy, and lastly, extratemporal, non-lesion, poorly localized epilepsy.

The steps for evaluating patients for epilepsy surgery are multi-layered. EEG video monitoring and MRI localization are the initial indispensable methods. If generalized or multifocal epilepsy is found, one can proceed to considering the neurostimmulation options. Multiple seizures are ideally captured during EEG video monitoring. The events captured should be typical for the patient to ensure the right seizure is being captured. If the patient has focal seizures, then one can proceed with further seizure work-up, including MRI of the brain, if not already obtained, neuropsychological testing, the Wada test, and in some cases functional imaging such as PET or SPECT.

In comparing VNS to RNS to DBS, there are several relevant factors to consider. RNS is more invasive than VNS and requires seizure localization to be effective. VNS is less invasive and does not require localization, thus may be used (and often is) in truly multifocal or generalized epilepsies of the Lennox-Gastaut type, or in focal epilepsy that is completely unlocalizable. DBS is also more invasive than VNS, although localization of seizures is not required. At this point, the efficacy of VNS and RNS appears roughly comparable, ^{[17, 41]} so that it would seem logical to try VNS first as it is less invasive. However, the 3-year seizure reduction of 44% for VNS ^[4] and 60% for RNS ^[30] , and possibly longer-term data would seem to favor RNS in terms of efficacy. In addition, the new DBS trial demonstrated a seizure reduction rate as high as 69%. ^[42]

Overall, one needs to compare the benefits and features of the neurostimulation devices to decide which treatment would be best for the patient. One advantage of RNS is the capability to use it as a recording device, and especially for bitemporal epilepsy the ability to record for weeks to months or years, while providing treatment, which may allow lateralization and an eventual resection. ^{[43, 44, 45]}  However, if a patient would like the least invasive option, then VNS could be a good choice. Additionally, VNS, DBS, and RNS can be used after failed epilepsy surgery. ^{[46, 47]}

As can be seen with the above discussion, deciding surgery vs neurostimulation, then which neurostimulation device to choose, is a complicated decision. Every patient’s situation is different and patient preference always sways the final decision. Due to this complexity, it is vital to refer patients for evaluation to level-4 (surgical) epilepsy centers where a multidisciplinary team and management conference can review cases and find the best options. There is certainly room for centers' preferences and differences in opinion, but within reason. ^{[17, 2]}