Gregory A. Worrell

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.

Graph analysis of epileptogenic networks in human partial epilepsy

Purpose:  The current gold standard for the localization of the cortical regions responsible for the initiation and propagation of the ictal activity is through the use of invasive electrocorticography (ECoG). This method is utilized to guide surgical intervention in cases of medically intractable epilepsy by identifying the location and extent of the epileptogenic focus. Recent studies have proposed mechanisms in which the activity of epileptogenic cortical networks, rather than discrete focal sources, contributes to the generation of the ictal state. If true, selective modulation of key network components could be employed for the prevention and termination of the ictal state.

Epilepsy surgery outcomes in temporal lobe epilepsy with a normal MRI.

Purpose:  To determine the long‐term efficacy of anterior temporal lobectomy for medically refractory temporal lobe epilepsy in patients with nonlesional magnetic resonance imaging (MRI).

Ictal Source Analysis: Localization and Imaging of Causal Interactions in Humans

We propose a new integrative approach to characterize the structure of seizures in the space, time, and frequency domains. Such characterization leads to a new technical development of ictal source analysis for the presurgical evaluation of epilepsy patients. The present new ictal source analysis method consists of three parts. First, a three-dimensional source scanning procedure is performed by a spatio-temporal FINE source localization method to locate the multiple sources responsible for the time evolving ictal rhythms at their onsets. Next, the dynamic behavior of the sources is modeled by a multivariate autoregressive process (MVAR). Lastly, the causal interaction patterns among the sources as a function of frequency are estimated from the MVAR modeling of the source temporal dynamics. The causal interaction patterns indicate the dynamic communications between sources, which are useful in distinguishing the primary sources responsible for the ictal onset from the secondary sources caused by the ictal propagation. The present ictal analysis strategy has been applied to a number of seizures from five epilepsy patients, and their results are consistent with observations from either MRI lesions or SPECT scans, which indicate its effectiveness. Each step of the ictal source analysis is statistically evaluated in order to guarantee the confidence in the results.

Recording and analysis techniques for high-frequency oscillations

In recent years, new recording technologies have advanced such that, at high temporal and spatial resolutions, high-frequency oscillations (HFO) can be recorded in human partial epilepsy. However, because of the deluge of multichannel data generated by these experiments, achieving the full potential of parallel neuronal recordings depends on the development of new data mining techniques to extract meaningful information relating to time, frequency and space. Here, we aim to bridge this gap by focusing on up-to-date recording techniques for measurement of HFO and new analysis tools for their quantitative assessment. In particular, we emphasize how these methods can be applied, what property might be inferred from neuronal signals, and potentially productive future directions.

Intracranial electroencephalography seizure onset patterns and surgical outcomes in nonlesional extratemporal epilepsy

OBJECT Patients with normal MR imaging (nonlesional) findings and medically refractory extratemporal epilepsy make up a disproportionate number of nonexcellent outcomes after epilepsy surgery. In this paper, the authors investigated the usefulness of intracranial electroencephalography (iEEG) in the identification of surgical candidates. METHODS Between 1992 and 2002, 51 consecutive patients with normal MR imaging findings and extratemporal epilepsy underwent intracranial electrode monitoring. The implantation of intracranial electrodes was determined by seizure semiology, interictal and ictal scalp EEG, SPECT, and in some patients PET studies. The demographics of patients at the time of surgery, lobar localization of electrode implantation, duration of follow-up, and Engel outcome score were abstracted from the Mayo Rochester Epilepsy Surgery Database. A blinded independent review of the iEEG records was conducted for this study. RESULTS Thirty-one (61%) of the 51 patients who underwent iEEG ultimately underwent resection for their epilepsy. For 28 (90.3%) of the 31 patients who had epilepsy surgery, adequate information regarding follow-up (> 1 year), seizure frequency, and iEEG recordings was available. Twenty-six (92.9%) of 28 patients had frontal lobe resections, and 2 had parietal lobe resections. The most common iEEG pattern at seizure onset in the surgically treated group was a focal high-frequency discharge (in 15 [53.6%] of 28 patients). Ten (35.7%) of the 28 surgically treated patients were seizure free. Fourteen (50%) had Engel Class I outcomes, and overall, 17 (60.7%) had significant improvement (Engel Class I and IIAB with > or =80% seizure reduction). Focal high-frequency oscillation at seizure onset was associated with Engel Class I surgical outcome (12 [85.7%] of 14 patients, p = 0.02), and it was uncommon in the nonexcellent outcome group (3 [21.4%] of 14 patients). CONCLUSIONS A focal high-frequency oscillation (> 20 Hz) at seizure onset on iEEG may identify patients with nonlesional extratemporal epilepsy who are likely to have an Engel Class I outcome after epilepsy surgery. The prospect of excellent outcome in nonlesional extratemporal lobe epilepsy prior to intracranial monitoring is poor (14 [27.5%] of 51 patients). However, iEEG can further stratify patients and help identify those with a greater likelihood of Engel Class I outcome after surgery.

Data mining neocortical high-frequency oscillations in epilepsy and controls.

Transient high-frequency (100-500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100-250 Hz) and fast ripple (250-500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100-500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.

Evidence for self-organized criticality in human epileptic hippocampus

Self-organized criticality (SOC) is a property of complex dynamic systems that evolve to a critical state, capable of producing scale-free energy fluctuations. A characteristic feature of dynamical systems exhibiting SOC is the power-law probability distributions that describe the dynamics of energy release. We show experimental evidence for SOC in the epileptic focus of seven patients with medication-resistant temporal lobe epilepsy. In the epileptic focus the probability density of pathological energy fluctuations and the time between these energy fluctuations scale as (energy)−&dgr; and (time)−&ggr;, respectively. The power-laws characterizing the probability distributions from these patients are consistent with computer simulations of integrate-and-fire oscillator networks that have been reported recently. These findings provide insight into the neuronal dynamics of epileptic hippocampus and suggest a mechanism for interictal epileptiform fluctuations. The presence of SOC in human epileptic hippocampus may provide a method for identifying the network involved in seizure generation.

Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.

Objective: To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. Method: We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. Results: Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). Conclusions: These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. Classification of evidence: This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.