Responsive Neurostimulation of the Thalamus for the Treatment of Refractory Epilepsy.

Introduction: One-third of patients with epilepsy continue to have seizures despite antiepileptic medications. Some of these refractory patients may not be candidates for surgical resection primarily because the seizure onset zones (SOZs) involve both hemispheres or are located in eloquent areas. The NeuroPace Responsive Neurostimulation System (RNS) is a closed-loop device that uses programmable detection and stimulation to tailor therapy to a patient's individual neurophysiology. Here, we present our single-center experience with the use of RNS in thalamic nuclei to provide long-term seizure control in patients with refractory epilepsy. Methods: We performed a prospective single-center study of consecutive refractory epilepsy patients who underwent RNS system implantation in the anterior (ANT) and centromedian (CM) thalamic nuclei from September 2015 to December 2020. Patients were followed postoperatively to evaluate seizure freedom and complications. Results: Twenty-three patients underwent placement of 36 RNS thalamic leads (CM = 27 leads, ANT = 9 leads). Mean age at implant was 18.8 ± 11.2 years (range 7.8-62 years-old). Two patients (8.7%) developed infections: 1 improved with antibiotic treatments alone, and 1 required removal with eventual replacement of the system to recover the therapeutic benefit. Mean time from RNS implantation to last follow-up was 22.3 months. Based on overall reduction of seizure frequency, 2 patients (8.7%) had no- to <25% improvement, 6 patients (26.1%) had 25-49% improvement, 14 patients (60.9%) had 50-99% improvement, and 1 patient (4.3%) became seizure-free. All patients reported significant improvement in seizure duration and severity, and 17 patients (74%) reported improved post-ictal state. There was a trend for subjects with SOZs located in the temporal lobe to achieve better outcomes after thalamic RNS compared to those with extratemporal SOZs. Of note, seizure etiology was syndromic in 12 cases (52.2%), and 7 patients (30.4%) had undergone resection/disconnection surgery prior to thalamic RNS therapy. Conclusion: Thalamic RNS achieved ≥50% seizure control in ~65% of patients. Infections were the most common complication. This therapeutic modality may be particularly useful for patients affected by aggressive epilepsy syndromes since a young age, those whose seizure foci are located in the mesial temporal lobe, and those who have failed prior surgical interventions.

High-resolution transcriptomics informs glial pathology in human temporal lobe epilepsy.

The pathophysiology of epilepsy underlies a complex network dysfunction between neurons and glia, the molecular cell type-specific contributions of which remain poorly defined in the human disease. In this study, we validated a method that simultaneously isolates neuronal (NEUN +), astrocyte (PAX6 + NEUN-), and oligodendroglial progenitor (OPC) (OLIG2 + NEUN-) enriched nuclei populations from non-diseased, fresh-frozen human neocortex and then applied it to characterize the distinct transcriptomes of such populations isolated from electrode-mapped temporal lobe epilepsy (TLE) surgical samples. Nuclear RNA-seq confirmed cell type specificity and informed both common and distinct pathways associated with TLE in astrocytes, OPCs, and neurons. Compared to postmortem control, the transcriptome of epilepsy astrocytes showed downregulation of mature astrocyte functions and upregulation of development-related genes. To gain further insight into glial heterogeneity in TLE, we performed single cell transcriptomics (scRNA-seq) on four additional human TLE samples. Analysis of the integrated TLE dataset uncovered a prominent subpopulation of glia that express a hybrid signature of both reactive astrocyte and OPC markers, including many cells with a mixed GFAP + OLIG2 + phenotype. A further integrated analysis of this TLE scRNA-seq dataset and a previously published normal human temporal lobe scRNA-seq dataset confirmed the unique presence of hybrid glia only in TLE. Pseudotime analysis revealed cell transition trajectories stemming from this hybrid population towards both OPCs and reactive astrocytes. Immunofluorescence studies in human TLE samples confirmed the rare presence of GFAP + OLIG2 + glia, including some cells with proliferative activity, and functional analysis of cells isolated directly from these samples disclosed abnormal neurosphere formation in vitro. Overall, cell type-specific isolation of glia from surgical epilepsy samples combined with transcriptomic analyses uncovered abnormal glial subpopulations with de-differentiated phenotype, motivating further studies into the dysfunctional role of reactive glia in temporal lobe epilepsy.

7T MRI in epilepsy patients with previously normal clinical MRI exams compared against healthy controls.

OBJECTIVE: To compare by 7 Tesla (7T) magnetic resonance imaging (MRI) in patients with focal epilepsy who have non-lesional clinical MRI scans with healthy controls. METHODS: 37 patients with focal epilepsy, based on clinical and electroencephalogram (EEG) data, with non-lesional MRIs at clinical field strengths and 21 healthy controls were recruited for the 7T imaging study. The MRI protocol consisted of high resolution T1-weighted, T2-weighted and susceptibility weighted imaging sequences of the entire cortex. The images were read by two neuroradiologists, who were initially blind to clinical data, and then reviewed a second time with knowledge of the seizure onset zone. RESULTS: A total of 25 patients had findings with epileptogenic potential. In five patients these were definitely related to their epilepsy, confirmed through surgical intervention, in three they co-localized to the suspected seizure onset zone and likely caused the seizures. In seven patients the imaging findings co-localized to the suspected seizure onset zone but were not the definitive cause, and ten had cortical lesions with epileptogenic potential that did not localize to the suspected seizure onset zone. There were multiple other findings of uncertain significance found in both epilepsy patients and healthy controls. The susceptibility weighted imaging sequence was instrumental in guiding more targeted inspection of the other structural images and aiding in the identification of cortical lesions. SIGNIFICANCE: Information revealed by the improved resolution and enhanced contrast provided by 7T imaging is valuable in noninvasive identification of lesions in epilepsy patients who are non-lesional at clinical field strengths.

Palinacousis, Palinacousis: Seven New Cases.

PURPOSE: Palinacousis is an auditory illusion of sound persisting or repeating after the cessation of an auditory stimulation. Up until now, approximately 32 cases have been reported. The purpose of this study is to describe an additional seven cases of palinacousis and review our understanding of audition and palinacousis. METHODS: Patients seen in the epilepsy clinic or admitted to the Epilepsy Monitoring Unit (EMU) at The Mount Sinai Hospital who experienced palinacousis were included. In all these patients, an EEG and MRI were performed at some point during their clinical course. RESULTS: In one case, palinacousis occurred with stimulation of the superior temporal gyrus during brain mapping after a spoken word as well as after the thought of a word. Two people experienced palinacousis during a seizure captured on video EEG. The remaining four cases had palinacousis in the peri- or post-ictal period. CONCLUSIONS: We propose that palinacousis may be coming from the superior temporal gyrus secondary to seizure activity, either onset or spread, or dysfunction of the area in a postictal state. The existence of palinacousis in these pathologic states can help us to understand how we process auditory information.