Jonathan C. Edwards

Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Effects of vagus nerve stimulation on respiration during sleep: a pilot study.

Background: Vagus nerve stimulation (VNS) is associated with respiratory effects such as hoarseness, dyspnea, and laryngeal irritation. The effects of VNS on sleep-related breathing in humans have not been reported previously. Methods: Four epilepsy patients underwent polysomnography (PSG) before and after 3 months of treatment with VNS. Two of the four patients also underwent follow-up PSG to assess the effects of changing stimulus parameters on sleep-related breathing. Results: All patients showed consistent sleep-related decreases in airflow and effort coinciding with VNS activation, although most events did not meet laboratory criteria for apneas or hypopneas. Apneas and hypopneas were more frequent during VNS activation than during nonactivation. Apnea–hypopnea index (AHI) for three subjects during VNS treatment PSG was <5 apneas and hypopneas/hour. In one patient with obstructive sleep apnea (OSA) before VNS treatment, AHI rose from 4 (pretreatment) to 11.3 (treatment). In this patient and in another patient without clinically significant OSA, lowering stimulus frequency, but not stimulus intensity, pulse width, or on-time, ameliorated VNS-related apneas and hypopneas. Conclusions: VNS is associated with adverse changes in respiration during sleep. In patients without preexisting OSA, this VNS effect is probably not clinically significant. In patients with preexisting OSA, VNS should be administered with care. Lowering VNS stimulus frequency or prolonging off-time may prevent exacerbation of OSA.

Vagus nerve stimulation reduces daytime sleepiness in epilepsy patients

Background: Given that vagal afferents project to brainstem regions that promote alertness, the authors tested the hypothesis that vagus nerve stimulation (VNS) would improve daytime sleepiness in patients with epilepsy. Methods: Sixteen subjects with medically refractory seizures underwent polysomnography and multiple sleep latency tests (MSLT) and completed the Epworth Sleepiness Scale (ESS), a measure of subjective daytime sleepiness, before and after 3 months of VNS. Most subjects (>80%) were maintained on constant doses of antiepileptic medications. Results: In the 15 subjects who completed baseline and treatment MSLT, the mean sleep latency (MSL) improved from 6.4 ± 4.1 minutes to 9.8 ± 5.8 minutes (± SD; p = 0.033), indicating reduced daytime sleepiness. All subjects with stimulus intensities of ≤1.5 mA showed improved MSL. In the 16 subjects who completed baseline and treatment ESS, the mean ESS score decreased from 7.2 ± 4.4 to 5.6 ± 4.5 points (p = 0.049). Improvements in MSLT and ESS were not correlated with reduction in seizure frequency. Sleep-onset REM periods occurred more frequently in treatment naps as compared to baseline naps (p < 0.008; Cochran-Mantel-Haenszel test). The amount of REM sleep or other sleep stages recorded on overnight polysomnography did not change with VNS treatment. Conclusions: Treatment with VNS at low stimulus intensities improves daytime sleepiness, even in subjects without reductions in seizure frequency. Daytime REM sleep is enhanced with VNS. These findings support the role of VNS in activating cholinergic and other brain regions that promote alertness.

Medial temporal lobe epilepsy is associated with neuronal fibre loss and paradoxical increase in structural connectivity of limbic structures

Background It has been hypothesised that seizure induced neuronal loss and axonal damage in medial temporal lobe epilepsy (MTLE) may lead to the development of aberrant connections between limbic structures and eventually result in the reorganisation of the limbic network. In this study, limbic structural connectivity in patients with MTLE was investigated, using diffusion tensor MRI, probabilistic tractography and graph theory based network analysis. Methods 12 patients with unilateral MTLE and hippocampal sclerosis (five left and seven right MTLE) and 26 healthy controls were studied. The connectivity of 10 bilateral limbic regions of interest was mapped with probabilistic tractography, and the probabilistic fibre density between each pair of regions was used as the measure of their weighted structural connectivity. Binary connectivity matrices were then obtained from the weighted connectivity matrix using a range of fixed density thresholds. Graph theory based properties of nodes (degree, local efficiency, clustering coefficient and betweenness centrality) and the network (global efficiency and average clustering coefficient) were calculated from the weight and binary connectivity matrices of each subject and compared between patients and controls. Results MTLE was associated with a regional reduction in fibre density compared with controls. Paradoxically, patients exhibited (1) increased limbic network clustering and (2) increased nodal efficiency, degree and clustering coefficient in the ipsilateral insula, superior temporal region and thalamus. There was also a significant reduction in clustering coefficient and efficiency of the ipsilateral hippocampus, accompanied by increased nodal degree. Conclusions These results suggest that MTLE is associated with reorganisation of the limbic system. These results corroborate the concept of MTLE as a network disease, and may contribute to the understanding of network excitability dynamics in epilepsy and MTLE.

Mapping anterior temporal lobe language areas with fMRI: A multicenter normative study

Removal of the anterior temporal lobe (ATL) is an effective surgical treatment for intractable temporal lobe epilepsy but carries a risk of language and verbal memory deficits. Preoperative localization of functional zones in the ATL might help reduce these risks, yet fMRI protocols in current widespread use produce very little activation in this region. Based on recent evidence suggesting a role for the ATL in semantic integration, we designed an fMRI protocol comparing comprehension of brief narratives (Story task) with a semantically shallow control task involving serial arithmetic (Math task). The Story > Math contrast elicited strong activation throughout the ATL, lateral temporal lobe, and medial temporal lobe bilaterally in an initial cohort of 18 healthy participants. The task protocol was then implemented at 6 other imaging centers using identical methods. Data from a second cohort of participants scanned at these centers closely replicated the results from the initial cohort. The Story-Math protocol provides a reliable method for activation of surgical regions of interest in the ATL. The bilateral activation supports previous claims that conceptual processing involves both temporal lobes. Used in combination with language lateralization measures, reliable ATL activation maps may be useful for predicting cognitive outcome in ATL surgery, though the validity of this approach needs to be established in a prospective surgical series.

Effects of Vagus Nerve Stimulation on Sleep-related Breathing in Epilepsy Patients

Summary:  Purpose: To describe the effects of vagus nerve stimulation (VNS) on sleep‐related breathing in a sample of 16 epilepsy patients.

Extrahippocampal gray matter loss and hippocampal deafferentation in patients with temporal lobe epilepsy

Purpose:  Medial temporal epilepsy (MTLE) is associated with extrahippocampal brain atrophy. The mechanisms underlying brain damage in MTLE are unknown. Seizures may lead to neuronal damage, but another possible explanation is deafferentation from loss of hippocampal connections. This study aimed to investigate the relationship between hippocampal deafferentation and brain atrophy in MTLE.

Presurgical connectome and postsurgical seizure control in temporal lobe epilepsy

Objectives: The objective of this study was to evaluate whether patients with surgically refractory medial temporal lobe epilepsy (MTLE) exhibit a distinct pattern of structural network organization involving the temporal lobes and extratemporal regions. Methods: We retrospectively studied 18 healthy controls and 20 patients with medication refractory unilateral MTLE who underwent anterior temporal lobectomy for treatment of seizures. Patients were classified as seizure-free or not seizure-free at least 1 year after surgery. The presurgical brain connectome was calculated through probabilistic connectivity from MRI–diffusion tensor imaging from 83 anatomically defined regions of interest encompassing the whole brain. The connectivity patterns were analyzed regarding group differences in regional connectivity and network graph properties. Results: Compared with controls, patients exhibited a decrease in connectivity involving ipsilateral thalamocortical regions, with a pathologic increase in ipsilateral medial temporal lobe, insular, and frontal connectivity. Among patients, those not seizure-free exhibited a higher connectivity between structures in 1) the ipsilateral medial and lateral temporal lobe, 2) the ipsilateral medial temporal and parietal lobe, and 3) the contralateral temporal pole and parietal lobe. Patients not seizure-free also exhibited lower small-worldness in the subnetwork within the ipsilateral temporal lobe, with higher subnetwork integration at the expense of segregation. Conclusions: MTLE is associated with network rearrangement within, but not restricted to, the temporal lobe ipsilateral to the onset of seizures. Networks involving key components of the medial temporal lobe and structures traditionally not removed during surgery may be associated with seizure control after surgical treatment of MTLE.

Subtypes of medial temporal lobe epilepsy: Influence on temporal lobectomy outcomes?

Surgical resection of the hippocampus is the most successful treatment for medication‐refractory medial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis. Unfortunately, at least one of four operated patients continue to have disabling seizures after surgery, and there is no existing method to predict individual surgical outcome. Prior to surgery, patients who become seizure free appear identical to those who continue to have seizures after surgery. Interestingly, newly converging presurgical data from magnetic resonance imaging (MRI) and intracranial electroencephalography (EEG) suggest that the entorhinal and perirhinal cortices may play an important role in seizure generation. These areas are not consistently resected with surgery and it is possible that they continue to generate seizures after surgery in some patients. Therefore, subtypes of MTLE patients can be considered according to the degree of extrahippocampal damage and epileptogenicity of the medial temporal cortex. The identification of these subtypes has the potential to drastically improve surgical results via optimized presurgical planning. In this review, we discuss the current data that suggests neural network damage in MTLE, focusing on the medial temporal cortex. We explore how this evidence may be applied to presurgical planning and suggest approaches for future investigation.