EASEE ® and Direct: Direct Cortical Stimulation for Focal Epilepsy

Abstract

Two-Year Outcomes of Epicranial Focal Cortex Stimulation in Pharmacoresistant Focal Epilepsy

Schulze-Bonhage A, Hirsch M, Knake S, Mertens A, Rademacher M, Kaufmann E, Kegele J, Jenkner C, Coenen V, Glaser M, Groppa S, Winter Y; EASEE Study Group. Epilepsia. 2025; doi:10.1111/epi.18448. Epub ahead of print. PMID: 40377414.

Objective: This study was undertaken to report on the long-term safety and efficacy of epicranial focal cortex stimulation (FCS) using the EASEE device as adjunctive neuromodulatory therapy in improving seizure control in adults with pharmacoresistant epilepsy originating from one predominant epileptogenic zone. Methods: Prospective open-label follow-up of patients from the EASEE II and PIMIDES I clinical trials was done for a period of 2 years after the epicranial implantation of the EASEE electrode and stimulator device. Results: Thirty-three patients underwent device implantation, and stimulation was activated in 32 patients. Of these, 26 patients continued stimulation up to 2-year follow-up and provided seizure diary data for efficacy analysis. The 50% responder rate at 2-year follow-up was 65.4% (95% confidence interval = 44.3-82.8), corresponding to a median seizure frequency reduction of 68%. Patients reported improved health-related quality of life. Tolerability was excellent, and there were no severe adverse events considered to be related to implantation or stimulation, nor were adverse effects on mood or cognition reported. Significance: Results of the 2-year follow-up show that epicranial FCS is well tolerated by patients while providing improved seizure control in the long term. It thus offers a minimally invasive treatment option for patients with a predominant epileptic focus.

Epileptogenic Zone Characteristics Determine Effectiveness of Electrical Transcranial Stimulation in Epilepsy Treatment

Daoud M, Medina-Villalon S, Garnier E, Bratu IF, Damiani G, Salvador R, Wendling F, Ruffini G, Bénar C, Pizzo F, Bartolomei F. Brain Commun. 2025;7(1):fcaf012. doi:10.1093/braincomms/fcaf012

Transcranial direct current stimulation shows promise as a non-invasive therapeutic method for patients with focal drug-resistant epilepsy. However, there is considerable variability in individual responses to transcranial direct current stimulation, and the factors influencing treatment effectiveness in targeted regions are not well understood. We aimed to assess how the extent and depth of the epileptogenic zone and associated networks impact patient responses to transcranial direct current stimulation therapy. We conducted a retrospective analysis of stereoelectroencephalography data from 23 patients participating in a personalized multichannel transcranial direct current stimulation protocol. We evaluated the extent and depth of the epileptogenic zone network, propagation zone network, and the combined network of the entire epileptogenic and propagation zones, correlating these factors with clinical response measured by the reduction in seizure frequency following repeated transcranial direct current stimulation sessions. Among the patients, 10 (43.5%) were classified as responders (R), experiencing a significant (>50%) decrease in seizure frequency, while 13 were non-responders, showing minimal improvement or increased seizure frequency. Importantly, we found a significant positive correlation between the extent of the epileptogenic zone network and changes in seizure frequency. A smaller epileptogenic zone network extent was associated with better transcranial direct current stimulation efficacy, with responders demonstrating a significantly smaller epileptogenic and propagation zones compared with non-responders. Additionally, non-responders tended to have a significantly deeper epileptogenic zone network compared with responders. Our results highlight the significant impact of the extent and depth of the epileptogenic zone network on transcranial direct current stimulation efficacy in patients with refractory focal epilepsy. Responders typically exhibited a smaller and shallower epileptogenic zone network compared with non-responders. These findings suggest that utilizing individualized epileptogenic zone network characteristics could help refine patient selection for personalized transcranial direct current stimulation protocols, potentially improving therapeutic outcomes.

Commentary

Direct cortical stimulation (DCS) is an emerging neuromodulatory therapy for focal epilepsy. Forms of DCS are approved and are in use in Europe, the UK, and Australia, although are not yet FDA approved. Which patients with epilepsy would benefit from DCS? This is explored by the two studies in this commentary, the first a clinical trial of an epicranial DCS device, ¹ and the second on transcutaneous DCS to understand patient selection for optimal outcomes. ²

In these studies, DCS involved the application of a cathodal DC (direct current) or AC (alternating current) electrode on the skin (transcutaneous) or inserted subcutaneously (epicranial) depending on the device used.

DCS has also been used to treat depression and has been used in research settings to modulate brain activity in scenarios such as dystonia and post-stroke by modifying (motor) cortex excitability through changes in transmembrane potential and in the longer term by changes in synaptic plasticity. ³

In general, cathodal (−) stimulation inhibits cortical activity by inducing hyperpolarization and anodal (+) stimulation can excite cortical activity by depolarization. Animal models have shown anti-seizure effects with cathodal stimulation. ⁴

DC or “DC-like” currents are favored as they apply a consistent polarity stimulus and have longer lasting effects as opposed to AC which switches polarity, with current only flowing at the peak. Batteries typically supply DC current, hence most neuromodulatory devices such as vagus nerve stimulation (VNS) and responsive neurostimulation (RNS) for epilepsy utilize DC current. Deep brain stimulation (DBS) uses AC current to facilitate use of variable oscillatory frequencies for its effect.

From the EASEE (epicranial application of stimulation electrodes for epilepsy) studies, the authors present 2-year follow-up data of 2 prospective non-randomized trials of epicranial DCS (Precisis, Germany). ⁵

A central cathodal electrode surrounded by four evenly spaced anodal electrodes in a “pseudo-Laplacian” pattern is placed under the skin with a tunnelled lead to a pulse generator in the chest wall. The design allows adaption of the resulting electric field to target deeper brain structures. Battery life is estimated to be 3 to 5 years. The device is CE marked (Conformité Européenne) in Europe but not yet FDA approved.

The stimulator paradigm was a “DC-like” stimulation for 20 minutes per day up to 2 mA (20 ms pulses). In addition, there was 100 Hz AC high frequency stimulation (HFS) of up to 4 mA for 500 ms every 2 minutes over the day, with a subgroup using low frequency stimulation (LFS) 0.5 to 1 Hz. A handheld device to trigger ictal stimulation was available for some patients.

In the original studies over half of adult patients with focal single-focus medication-resistant seizures were responders over 6 months, with adverse events only related to implant and not to stimulation.

Thirty-three subjects were then followed over 2 years with 26 completing follow-up for a total of 55.8 device implant years. Patient age was between 18 and 75 years. Four patients had prior but not active VNS.

No serious adverse events were directly related to the device or stimulation. There was one local infection of the device pocket after a second generator replacement surgery.

Adverse device effects were reported in 18 patients, most in the first month after implantation such as postoperative pain, hematoma, headache, discomfort at device site, and paresthesias. There were no stimulation related adverse effects over eloquent cortex. Mood was stable and there was minor improvement in neurocognition, and in quality-of-life measures such as seizure worry and daily activities.

The median seizure frequency was reduced from a baseline of 12 per month to 5 per month. Responder rate increased from 55% at month 15% to 65% at month 23. In the last month of the 2-year follow-up, 42% had over 75% reduction, 31% over 90% reduction, and 23% reported no seizures. One patient had a >50% increase in seizures. These responder rates compare favorably to responder rates in the 2-year data for RNS and DBS.

There was some missing data and dropouts but by intention to treat analysis the responder rate was still 52% at 23 months. Responder rates were similar across seizure types (focal aware, focal impaired aware, focal to bilateral tonic–clonic) and across etiologies.

Eight non-responders were switched from HFS to LFS by the treating physician with two subsequent responders.

Limitations were common to long-term follow-up studies including responder enrichment bias, continuing placebo effect, and underreporting of seizures by diaries, as well as the small number of patients. Anti-seizure medications were mostly stable during follow-up.

The second study also used DCS but with a different device (StarStim ^® , Neuroelectrics) using transcutaneous electrodes worn in a scalp cap. Selected cathodal and anodal electrodes convey an individualized DC current to the scalp.

In the United States, this device has a breakthrough device designation, and is CE marked in Europe. Battery life is about 5 hours, so it needs to be performed under supervision.

The authors aimed to use information from patients prior stereoelectroencephalography (SEEG) studies to find factors associated with a limited response to DCS, in particular the relationship with the extent and depth of the epileptogenic network (EZN)—DC current needs to be strong enough to reach target tissue to induce a therapeutic effect, but not strong enough to cause unintended excitation of other areas.

The authors looked retrospectively at 23 SEEG evaluations in patients over 12 years old with a unifocal epileptogenic zone who had undergone a clinical trial of transcutaneous DCS therapy. ⁶ The stimulation paradigm was daily DC stimulation up to 2 mA for 5 days in 2 × 20-minute sessions separated by 20 minutes, a total of three times every 2 months.

Personalized electrode cathodal and anodal electric field parameters were based on the SEEG localization using an optimization algorithm to determine the best sites for stimulation.

Responder rates 2 months after the third DCS cycle were compared with the extent of the EZN and the propagation zone network (PZN) defined by SEEG epileptogenicity index (EI) in each brain region. In addition, the depth of the EZN was calculated using Euclidean distance from center of virtual epileptic patient (VEP) brain atlas EZN region to the skull surface.

There were 10 responders, and 13 non-responders. Two patients had an increase in seizure frequency after 2 cycles of DCS and did not undergo a third cycle.

Seizure frequency improvement correlated positively with a smaller network and more superficial EZN. A broader network led to increased seizures where nodes were exposed to excitation by the anodal stimulation.

Reduced current density with increasing distance from the scalp, along with more difficulty controlling the direction of current in deeper structures, and evidence of a wider network were felt to limit the beneficial effects of DCS.

While the study provides insight into which patient may benefit, the study was retrospective and numbers were small, and limitations exist as to the ability of SEEG to completely define the EZN.

DCS seems to be a safe and well tolerated addition to our arsenal of treatments for focal epilepsy. It is not for everyone however, with evidence from these studies pointing to its use in a focal superficial EZN that can be accurately targeted by the cathode field, and where surgical resection is not an option due to eloquent cortex or other reasons such as patient preference. Subjects were up to the age of 75 years, so this could be a less-invasive option in patients with higher surgical risks.

Confirmation of the site of the EZN by intracranial EEG is favored. A well-defined lesion such as a focal cortical dysplasia in eloquent cortex with concordant scalp EEG would also be a good candidate. The need for SEEG guidance may limit where SEEG is not available. Concerns about seizure exacerbation did not seem to bear out in the clinical studies in most patients, but care must be taken not to induce inadvertent anodal stimulation. The ability for longer term modulation of neuronal plasticity in the EZN is appealing, as seen in longer term improvements in other neuromodulatory therapies. The surgical procedure should be easy to learn by an epilepsy neurosurgeon familiar with devices such as VNS.

Further elucidation of optimal stimulation paradigms is needed. In the EASEE trial it is unclear which worked, HFS or DC. Studies in adolescents 12-17 years old and long-term follow-up registries are ongoing, as well as steps towards FDA approval.

Epicranial placement has the advantage of enhancing the stimulation effect by a factor of 4 compared to transcutaneous stimulation. Responder rates for epicranial stimulation were better than transcutanous (65.4% vs 43% responders, comparability limited by differing stimulation protocols). However, epicranial stimulation it is more invasive and may be less available in resource limited centers. Careful selection of patients for DCS via an epilepsy surgery multidisciplinary discussion is recommended.