by
Christianne N. Heck;
David King-Stephens;
Andrew D. Massey;
Dileep R. Nair;
Barbara C. Jobst;
Gregory L. Barkley;
Vicenta Salanova;
Andrew J. Cole;
Michael C. Smith;
Ryder P. Gwinn;
Christopher Skidmore;
Paul C. Van Ness;
Gregory K. Bergey;
Yong D. Park;
Ian Miller;
Eric Geller;
Paul A. Rutecki;
Richard Zimmerman;
David C. Spencer;
Alica Goldman;
Jonathan C. Edwards;
James W. Leiphart;
Robert E. Wharen;
James Fessler;
Nathan B. Fountain;
Gregory A. Worrell;
Robert Gross;
Stephan Eisenschenk;
Robert B. Duckrow;
Lawrence J. Hirsch;
Carl Bazil;
Cormac A. O'Donovan;
Felice T. Sun;
Tracy A. Courtney;
Caim G. Seale;
Martha J. Morrell
Objective 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. Methods Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. Results All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. Significance Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.
Epilepsy is a network disorder and each type of seizure involves distinct cortical and subcortical network, differently implicated in the control and propagation of the ictal activity. The role of the basal ganglia has been revealed in several cases of focal and generalized seizures. Here, we review the data that show the implication of the basal ganglia in absence, temporal lobe, and neocortical seizures in animal models (rodent, cat, and non-human primate) and in human. Based on these results and the advancement of deep brain stimulation for Parkinson’s disease, basal ganglia neuromodulation has been tested with some success that can be equally seen as promising or disappointing. The effect of deep brain stimulation can be considered promising with a 76% in seizure reduction in temporal lobe epilepsy patients, but also disappointing, since only few patients have become seizure free and the antiepileptic effects have been highly variable among patients. This variability could probably be explained by the heterogeneity among the patients included in these clinical studies. To illustrate the importance of specific network identification, electrophysiological activity of the putamen and caudate nucleus has been recorded during penicillin-induced pre-frontal and motor seizures in one monkey. While an increase of the firing rate was found in putamen and caudate nucleus during pre-frontal seizures, only the activity of the putamen cells was increased during motor seizures. These preliminary results demonstrate the implication of the basal ganglia in two types of neocortical seizures and the necessity of studying the network to identify the important nodes implicated in the propagation and control of each type of seizure.
Optogenetics, a technique that utilizes light-sensitive ion channels or pumps to activate or inhibit neurons, has allowed scientists unprecedented precision and control for manipulating neuronal activity. With the clinical need to develop more precise and effective therapies for patients with drug-resistant epilepsy, these tools have recently been explored as a novel treatment for halting seizure activity in various animal models. In this review, we provide a detailed and current summary of these optogenetic approaches and provide a perspective on their future clinical application as a potential neuromodulatory therapy.
BACKGROUND: Patients with hippocampal epileptogenic foci may benefit from targeted intracranial monitoring of seizures and treatments such as hippocampal electrical stimulation, closed-loop stimulation, and stereotactic laser ablation. Each may benefit from a greater volume of hippocampal coverage with long-axis cannulation. Furthermore, an extraventricular trajectory avoids brain shift and reduces the risk of hemorrhage from ependymal breach. Unfortunately, detailed descriptions of the technical aspects of longitudinal cannulation of the hippocampus remain sparse.
OBJECTIVE: To develop a standard protocol for extraventricular longitudinal hippocampal cannulation.
METHODS: Images from 25 patients stereotactically implanted with 27 longitudinal hippocampal devices were retrospectively reviewed to determine the location of the burr hole or twist drill craniostomy. Simulated planning for bilateral occipital trajectories was then performed on a second cohort of 25 patients (50 trajectories) with mesial temporal sclerosis. An entry point derived from these 77 trajectories was subsequently validated on a third cohort of 25 patients (50 trajectories).
RESULTS: Extraventricular long-axis hippocampal implantation necessitates a lateral-to-medial and cephalad-to-caudal trajectory that skirts the inferomedial border of the temporal horn. Measurements from 64 trajectories suggested a consensus entry point that successfully facilitated 50 test trajectories as well as frame placement on four patients requiring long-axis hippocampal cannulation.
CONCLUSION: Although trajectories must be individually tailored for each patient, we recommend a starting entry point approximately 5.5cm superior to the external occipital protuberance and 5.5cm lateral to midline for extraventricular long-axis hippocampal cannulation in adult patients. Identification of this point is particularly important when positioning the stereotactic frame.
Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. genetically epilepsy-prone rats (GEPRs), genetic absence epilepsy rat from Strasbourg (GAERS), WAG/Rij rats, swim lo-active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders.
When drug-resistant epilepsy is poorly localized or surgical resection is contraindicated, current neurostimulation strategies such as deep brain stimulation and vagal nerve stimulation can palliate the frequency or severity of seizures. However, despite medical and neuromodulatory therapy, a significant proportion of patients continue to experience disabling seizures that impair awareness, causing disability and risking injury or sudden unexplained death. We propose a novel strategy in which neuromodulation is used not only to reduce seizures but also to ameliorate impaired consciousness when the patient is in the ictal and postictal states. Improving or preventing alterations in level of consciousness may have an effect on morbidity (e.g., accidents, drownings, falls), risk for death, and quality of life. Recent studies may have elucidated underlying networks and mechanisms of impaired consciousness and yield potential novel targets for neuromodulation. The feasibility, benefits, and pitfalls of potential deep brain stimulation targets are illustrated in human and animal studies involving minimally conscious/vegetative states, movement disorders, depth of anesthesia, sleep-wake regulation, and epilepsy. We review evidence that viable therapeutic targets for impaired consciousness associated with seizures may be provided by key nodes of the consciousness system in the brainstem reticular activating system, hypothalamus, basal ganglia, thalamus, and basal forebrain.
Localizing an epileptic network is essential for guiding neurosurgery and antiepileptic medical devices as well as elucidating mechanisms that may explain seizure-generation and epilepsy. There is increasing evidence that pathological oscillations may be specific to diseased networks in patients with epilepsy and that these oscillations may be a key biomarker for generating and indentifying epileptic networks. We present a semi-automated method that detects, maps, and mines pathological gamma (30-100 Hz) oscillations (PGOs) in human epileptic brain to possibly localize epileptic networks. We apply the method to standard clinical iEEG ( < 100 Hz) with interictal PGOs and seizures from six patients with medically refractory epilepsy. We demonstrate that electrodes with consistent PGO discharges do not always coincide with clinically determined seizure onset zone (SOZ) electrodes but at times PGO-dense electrodes include secondary seizure-areas (SS) or even areas without seizures (NS). In 4/5 patients with epilepsy surgery, we observe poor (Engel Class 4) postsurgical outcomes and identify more PGO-activity in SS or NS than in SOZ. Additional studies are needed to further clarify the role of PGOs in epileptic brain.
Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised.