RESUMO
Background: Epilepsy is a widespread neurologic disorder and almost one-third of patients suffer from drug-resistant epilepsy (DRE). Neuromodulation targeting the centromediannucleus of the thalamus (CM) has been showing promising results for patients with generalized DRE who are not surgical candidates. Recently, the effect of CM- deep brain stimulation (DBS) in DRE patients was investigated in the Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype (ESTEL) trial, a monocentric randomized-controlled study. The same authors described a 'cold-spot' and a 'sweet-spot', which are defined as the volume of stimulation in the thalamus yielding the least and the best clinical response, respectively. However, it remains unclear which structural connections may contribute to the anti-seizure effect of the stimulation. Objective: We investigated the differences in structural connectivity among CM, the sweet-spot and the cold-spot. Furthermore, we tried to validate our results in a cohort of DRE patients who underwent CM-DBS or CM-RNS (responsive neurostimulation). We hypothesized that the sweet-spot would share similar structural connectivity with responder patients. Methods: By using the software FMRIB Software Library (FSL), probabilistic tractography was performed on 100 subjects from the Human Connectome Project to calculate the probability of connectivity of the whole CM, the sweet-spot and the cold-spot to 45 cortical and subcortical areas. Results among the three seeds were compared with multivariate analysis of variance (MANOVA). Similarly, the structural connectivity of volumes of tissue activated (VTAs) from eight DRE patients was investigated. Patients were divided into responders and non-responders based on the degree of reduction in seizure frequency, and the mean probabilities of connectivity were similarly compared between the two groups. Results: The sweet-spot demonstrated a significantly higher probability of connectivity (p < 0.001) with the precentral gyrus, superior frontal gyrus, and the cerebellum than the whole CM and the cold-spot. Responder patients displayed a higher probability of connectivity with both ipsilateral (p = 0.011) and contralateral cerebellum (p = 0.04) than the non-responders. Conclusion: Cerebellar connections seem to contribute to the beneficial effects of CM-neuromodulation in patients with drug-resistant generalized epilepsy.
RESUMO
Deep brain stimulation (DBS) of the thalamic nuclei for the treatment of drug-resistant epilepsy (DRE) has been investigated for decades. In recent years, DBS targeting the anterior nucleus of the thalamus (ANT) was approved by CE and FDA for the treatment of focal-onset DRE in light of the results from the multicentric randomized controlled SANTE trial. However, stereotactic targeting of thalamic nuclei is not straightforward because of the low contrast definition among thalamic nuclei on the current MRI sequences. When the FGATIR sequence is added to the preoperative MRI protocol, the mammillothalamic tract can be identified and used as a visible landmark to directly target ANT. According to the current evidence, the trans-ventricular trajectory allows the placement of stimulating contact into the nucleus more frequently than the trans-cortical trajectory. Another thalamic nucleus whose stimulation for the treatment of generalized DRE is receiving increasing attention is the centromedian nucleus (CM). CM-DBS seems to be particularly efficacious in patients suffering from Lennox-Gastault syndrome (LGS) and the recent monocentric randomized controlled ESTEL trial also described a beneficial "sweet-spot". However, CM targeting is still based on indirect stereotactic coordinates, since acquisition times and post-processing techniques of the actual MRI sequences are not applicable in clinical practice. Moreover, the results of the ESTEL trial await confirmation from similar studies accounting for epileptic syndromes other than LGS. Therefore, novel neuroimaging approaches are advisable to improve the surgical targeting of CM and potentially tailor the stimulation based on the patient's specific epileptic phenotype.
