Abstract
Sisterson ND, Kokkinos V, Urban A, Li N, Richardson RM. J Neurol Neurosurg Psychiatry. 2022: jnnp-2021-327512. doi:10.1136/jnnp-2021-327512. Up to 40% of patients with idiopathic generalised epilepsy (IGE) are drug resistant and potentially could benefit from intracranial neuromodulation of the seizure circuit. We present outcomes following 2 years of thalamic-responsive neurostimulation for IGE. Four patients with pharmacoresistant epilepsy underwent RNS System implantation in the bilateral centromedian (CM) nucleus region. Electrophysiological data were extracted from the clinical patient data management system and analysed using a specialised platform (BRAINStim). Postoperative visualisation of electrode locations was performed using Lead-DBS. Seizure outcomes were reported using the Engel scale. Patients experienced a 75%-99% reduction in seizure frequency with decreased seizure duration and severity (Engel class IB, IC, IIA and IIIA), as well as significant improvements in quality of life. Outcomes were durable through at least 2 years of therapy. Detection accuracy for all patients overall decreased over successive programming epochs from a mean of 96.5% to 88.3%. Most electrodes used to deliver stimulation were located in the CM (7/10) followed by the posterior dorsal ventral lateral (2/2), posterior ventral posterior lateral (3/4) and posterior ventral ventral lateral (2/3). In all patients, stimulation varied from .2 to 2.0 mA and amplitude only increased over successive epochs. The raw percentage of intracranial electroencephalography recordings with stimulations delivered to electrographic seizures was 24.8%, 1.2%, 7.6% and 8.8%. Closed-loop stimulation of the CM region may provide significant improvement in seizure control and quality of life for patients with drug-resistant IGE. Optimal detection and stimulation locations and parameters remain an active area of investigation for accelerating and fine-tuning clinical responses.Objectives:
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Commentary
After more than 20 years of randomized-controlled clinical trials and consensus recommendations by major neurological societies, including the International League Against Epilepsy (ILAE), the message is crystal clear: Patients with drug resistant epilepsy should be promptly referred to a tertiary epilepsy center for surgical evaluation. Surgical resection or ablation can result in seizure freedom in many patients, and several neuromodulation options are now available to reduce seizures in individuals who are not candidates for resection. These guidelines for referral do not distinguish between focal or generalized epilepsies, in part because the diagnosis is often not clear prior to evaluation, but the conventional wisdom is that focal epilepsy is surgically treatable, while primary generalized epilepsy is usually not. Approximately 15-20% of epilepsy patients suffer from idiopathic generalized epilepsy (IGE), and seizures are drug resistant in many of these individuals. There are likely more than 100,000 patients with drug resistant IGE in the US alone. While corpus callosotomy may be considered to reduce atonic seizures in certain IGE patients, these individuals are not candidates for resection or ablation, and there are no neuromodulation options for generalized epilepsy approved by the US Food and Drug Administration (FDA). Many patients with IGE have been treated “off-label” with palliative vagus nerve stimulation (VNS), and there is even retrospective evidence that seizure reduction in patients with primary generalized epilepsy may be greater than with VNS for focal epilepsy. 1 But in focal epilepsy, more data support the long-term efficacy of brain stimulation compared to VNS, as recently described in a systematic review by the ILAE Surgical Therapies Commission. 2 This leads to an important question: can novel brain stimulation therapies break the barrier to surgical treatment of primary generalized epilepsies?
In the presently highlighted study, Sisterson and colleagues report the first case series of four patients with drug-resistant IGE treated with closed-loop responsive neurostimulation (RNS) using bilateral electrodes in the centromedian thalamic nucleus (CM). 3 While neurostimulation of the anterior thalamic nucleus within the limbic circuits is an efficacious treatment for focal epilepsy, 4 CM is a more attractive target for generalized epilepsies due to its broad neocortical projections as the largest member of the caudal intralaminar thalamic nuclei. 5 In this study, patient age at implant ranged from teens to thirties, with epilepsy duration between 5 and 14 years, and individuals suffered from multiple tonic-clonic and/or absence seizures weekly. It was demonstrated that ictal activity could be recorded from the thalamic electrodes, and on average devices delivered 60-450 therapies and detected 3-16 long episodes daily, the latter often presumed to approximate electrographic seizures. Detection accuracy decreased over time from mean 97 to 88% as detectors were programmed to be less specific and more sensitive. After 2 years of treatment, large decreases in overall seizure frequency were observed: >90% in three patients and 75-89% in the fourth individual. Piecewise linear regression showed that long episodes decreased in three of four patients, consistent with their reported outcomes, while a small increase in long episodes in one individual was attributed to missing patient downloads. Subjectively, the patients reported improvements in quality of life, and 2 individuals were essentially free of disabling tonic-clonic seizures and able to maintain full-time employment, long-term relationships, and obtain a driver’s license.
A clear limitation of the highlighted study is that it is an uncontrolled, retrospective investigation of only four patients, so the potential efficacy of CM RNS in the larger IGE patient population is not yet known. Nevertheless, it is promising that favorable outcomes were observed in each of the individuals, and it opens the door to a new potential therapy in a patient population where there are few surgical options. These preliminary findings warrant more rigorous examination in a multi-center randomized clinical trial examining CM RNS for IGE, and such a trial is beginning enrollment in the US this year (ClinicalTrials.gov Identifier: NCT05147571). It is also notable that Sisterson et al utilized indirect targeting guided by previously described standard CM coordinates, and analysis of post-operative images using a thalamic atlas suggested some variability in lead contact location within the CM nucleus itself and immediately adjacent nuclei. The authors indicate they have now incorporated direct anatomical targeting using magnetization-prepared 2 rapid acquisition gradient-echo (MP2RAGE) MRI sequences into their surgical planning, and it is likely that direct anatomical visualization and/or atlas-based predictions will complement coordinate-based targeting and improve consistent CM implantations. Of note, most contacts used for stimulation in the study were within CM proper. Finally, the authors use percent seizure decrease and the Engel scale to report seizure outcomes, noting that a neuromodulation-specific surgical outcome scale has not yet been developed but would be of value.
While Sisterson and colleagues report the first series of closed-loop CM stimulation for IGE using RNS, several studies have examined open-loop cycling CM stimulation using deep brain stimulation (DBS) in generalized epilepsies. A prospective, randomized study of CM DBS in 20 patients with Lennox-Gastaut syndrome was recently reported, with 50% of the stimulation group achieving ≥50% seizure reduction, compared with 22% of controls. 6 In a recent retrospective case series of bilateral CM DBS in 12 patients with symptomatic generalized epilepsy (including Lennox-Gastaut syndrome) or IGE, 10 individuals achieved at least 50% decrease in seizure frequency at last follow-up. 7 Moving forward, it will be worthwhile to compare results with closed-loop responsive vs open-loop cycling CM stimulation in generalized epilepsies, although there is likely significant overlap in the mechanistic effects of these 2 stimulation paradigms. In a study of RNS for focal epilepsy by the authors highlighted here, it was suggested that long-term, indirect neuromodulatory effects may play a larger role than direct ictal abortive effects in contributing to seizure reduction. 8 Importantly, the clinical value that is provided by intracranial recordings with RNS must also be considered when choosing a brain stimulation strategy.
In addition to examining the efficacy of CM stimulation, future brain network studies should explore potential predictors of response and patient-specific targeting. For example, electrographic connectivity biomarkers have recently been shown to predict outcome in RNS for focal epilepsy, 9 and CM connectivity patterns have been demonstrated to be altered in IGE. 10 Identifying patient-specific thalamic connectivity fingerprints may help optimize individualized targeting strategies and outcome prediction. The field of brain stimulation for uncontrolled primary generalized epilepsies is in its infancy, but the potential implications are significant given the lack of surgical options for patients suffering with disabling and often uncontrolled generalized seizures.
