Abstract
Deep Brain Stimulation of the Centromedian Thalamic Nucleus for the Treatment of Generalized and Frontal Epilepsies
Valentín A, García Navarrete E, Chelvarajah R, Torres C, Navas M, Vico L, Torres N, Pastor J, Selway R, Sola RG, Alarcon G. Epilepsia 2013;54:1823–1833.
PURPOSE: Deep brain stimulation (DBS) of the thalamus is an emerging surgical option for people with medically refractory epilepsy that is not suitable for resective surgery, or in whom surgery has failed. Our main aim was to evaluate the efficacy of bilateral centromedian thalamic nucleus (CMN) DBS for seizure control in generalized epilepsy and frontal lobe epilepsy with a two-center, single-blind, controlled trial. METHODS: Participants were adults with refractory generalized or frontal lobe epilepsy. Seizure diaries were kept by patients/carers prospectively from enrollment. The baseline preimplantation period was followed by a control period consisting of a blind stimulation-OFF phase of at least 3 months, a 3-month blind stimulation-ON phase, and a 6-month unblinded stimulation-ON phase. The control period was followed by an unblinded long-term extension phase with stimulation-ON in those patients in whom stimulation was thought to be effective. KEY FINDINGS: Eleven patients were recruited at King's College Hospital (London, U.K.) and at University Hospital La Princesa (Madrid, Spain). Among the five patients with frontal lobe epilepsy, only one patient had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, two patients with frontal lobe epilepsy had >50% improvement in seizure frequency. All six patients with generalized epilepsy had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, five of the six patients showed >50% improvement in the frequency of major seizures (one became seizure free, one had >99% improvement, and three had 60–95% reduction in seizure frequency). Among patients with generalized epilepsy, the DBS implantation itself appears to be effective, as two patients remained seizure free during 12 and 50 months with DBS OFF, and the remaining four had 50–91% improvement in the initial 3 months with DBS OFF. SIGNIFICANCE: DBS implantation and stimulation of the CMN appears to be a safe and efficacious treatment, particularly in patients with refractory generalized epilepsy. CMN stimulation was not as effective in frontal lobe epilepsy, which requires further studies. DBS of the CMN should be considered as a treatment option, particularly in patients with refractory generalized epilepsy syndromes.
Commentary
Idiopathic generalized epilepsies (IGE) represent around 20% of all new-onset epilepsy and are controlled with various antiepileptic drugs in up to 80% of the cases. For the remaining 20% with intractable IGE, treatment options are limited. Most new AED clinical trials evaluate cohorts with partial epilepsy. The ketogenic diet has helped many children with catastrophic symptomatic generalized epilepsy, but its applicability as a viable, long-term, treatment option in adults is questionable (1). Some uncontrolled series suggest a benefit of vagus nerve stimulation in reducing the frequency of convulsions in generalized epilepsy (GE), but the extent and “longevity” of this success remains to be proven in controlled randomized prospective evaluations (2). Resective epilepsy surgery is simply not an option for patients with GE or rapidly synchronizing bihemispheric epileptic networks. In this “lay of the land,” any attempt to bring an intractable GE treatment closer to the therapeutic armamentarium is hugely welcome, and the work highlighted in this commentary is very timely.
In this study, Valentin et al. report a single-blind, controlled trial evaluating the efficacy of bilateral centromedian thalamic nucleus (CMN) stimulation for seizure control in generalized epilepsy and frontal lobe epilepsy. Electrode placement was stereotactically guided and confirmed by intraoperative EEG recordings. A postoperative 1-week period of scalp video-EEG with externalized electrodes allowed for optimization of the stimulation settings, and patients were then followed for at least 6 months. Stimulation was continuous, at a frequency at 60 HZ with pulse width of 90 μs, and up to 5V. Although the number of patients studied is small (11 total, including six with GE), the results are very encouraging, with >50% improvement in seizure frequency seen in all patients with GE, including two patients who were completely seizure free for 12 and 50 months, respectively. Considering that study patients had at least 10 seizures/month prior to implantation, the benefit is noticeable, and not necessarily surprising considering the long record of basic and human research involving deep brain stimulation of the CMN of the thalamus.
Mechanisms of the Antiepileptic Effect of CMN Stimulation
Animal studies of the CMN are scarce (3) but do suggest that the corticoreticular system, including the CMN and the reticular thalamic nucleus, are clearly involved in the genesis of generalized epileptic activity. A recent EEG-fMRI study of 10 patients with IGE found that while both the CMN and anterior nucleus of the thalamus are activated during generalized spike-and-wave discharges, earlier activation occurred in the CMN, suggesting that it may be involved in epileptic discharge initiation or early propagation, while the anterior nucleus may only play a role in the maintenance of this epileptic activity (4). These results provide a “functional” equivalent of earlier human depth recordings documenting that fast 3/sec spike-wave complex discharges from the right CMN anticipated those recorded from the contralateral CMN, the scalp, and the appearance of clinical symptoms during the development of a typical absence seizure, further implying that this type of epileptic seizure may originate in the CMN (5). The CMN is indeed very strategically placed within the ascending subcortical system arising from the brain stem and diencephalon and projecting diffusely to the cerebral cortex, particularly to the motor systems, allowing it to crucially participate in the modulation of both the conscious state, and cortical motor hyperexcitability with implications then for the control of both absence seizures and convulsions. Hypothesized alterations in this modulation have gained further support from recent in vitro experiments assessing the synaptic field potential changes in thalamocortical slices obtained from a new genetic mouse model of absence epilepsy (6). All these observations help us understand the clinical effect of deep brain stimulation within thalamic nuclei in intractable GE patients. However, the lack of connectivity between the CMN and the temporal lobes may account for the lack of treatment response with CMN stimulation in patients with intractable temporal lobe epilepsy (7, 8).
Current Data on the Effectiveness of CMN Stimulation
Velasco et al. have pioneered therapeutic trials of CMN stimulation for the treatment of intractable epilepsy (5, 7, 8). Over more than 20 years, Velasco's group has stimulated close to 60 patients with various generalized epilepsy syndromes and reported up to 87% reduction in seizures while stimulation is on, with a residual benefit lasting months after stimulation is off. Their stimulation paradigm was somewhat different from the study at hand by Valentin et al.: They used a higher frequency (130 Hz), 0.45 msec, 400–600 mA alternating in left/right 1-min trains with a 4-min quiescent interval phase (8). The best treatment responses were observed in patients with Lennox–Gastaut syndrome, those where the localization of the stimulating electrodes was confirmed upon placement, and their reliability periodically assessed (5, 7–9). A recurrent theme in almost all CMN stimulation study is a reduction in seizure frequency observed solely after implantation and prior to turning the stimulation ON, suggesting a potential lesion effect or yet another unknown mechanism of inducing benefit (8).
A placebo-controlled pilot study (10) using similar stimulation parameters to those used here by Valentin et al. did not reproduce a statistically significant reduction in seizures: Close to half the patients in that study (3/7), however, did not have GE and may actually have had temporal lobe epilepsy. The lack of direct connectivity between the CMN and the mesial temporal structures may account for this lack of therapeutic benefit. Studies using a low-frequency stimulation paradigm of the CMN actually worsened seizure control with high-intensity 3-Hz stimulation actually triggering clinical seizures mimicking those seen in absence epilepsy (9).
Future Questions
Whether centromedian thalamic stimulation is the long-awaited answer for intractable GE remains to be seen. Work still needs to be done to define the ideal patient population and the ideal stimulation parameters, as alluded to earlier. What is clear though is that this work needs to be done as we face the tremendous unmet need of our patients with intractable GE.