Stephan Eisenschenk

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.

Effectiveness of vagus nerve stimulation in epilepsy patients A 12-year observation

A retrospective review of the safety, tolerability, and efficacy of vagus nerve stimulation (VNS) in 48 patients with intractable partial epilepsy was performed. Side effects were few and mild to moderate. Mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment.

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.

Reduced density of parvalbumin- and calbindin D28k-immunoreactive neurons in experimental cortical dysplasia

Cortical dysplasia (CD) is a congenital brain malformation in humans that is closely associated with intractable epilepsy. This study utilized an animal model of CD, in utero irradiation in rats, to determine if experimental dysplastic cortex demonstrates a reduction in the density of inhibitory interneurons. Fetal rats were exposed to external irradiation on gestational day 17 to produce diffuse CD and heterotopic grey matter. As adults, these rats were processed for immunohistochemistry using primary antibodies for parvalbumin (PA), calbindin D28k (CA), the 67 kD subunit of glutamic acid decarboxylase (GAD67), and cresyl violet staining. Quantitative methods were used to determine the density of immunoreactive neurons and cresyl violet-stained neurons in the neocortex at the rostro-caudal level of the anterior commissure. Compared to control values, the density of PA- and CA-immunoreactive neurons was reduced in dysplastic cortex. Density of glutamic acic decarboxylase-immunoreactive neurons was not different between control and dysplastic cortex. Overall neuronal density, measured in cresyl violet-stained sections, was not significantly different between control and dysplastic cortex. These data suggest a selective reduction in inhibitory interneurons in experimental CD cortex or an impaired ability for these neurons to produce PA and CA.

Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinical-polysomnography study.

Polysomnographic studies of Parkinsons disease (PD) patients with visual hallucinations (VH) usually reveal short, fragmented rapid eye movement (REM) sleep, with lower sleep efficiency and reduced total REM sleep. Quetiapine has been demonstrated in open-label trials to be effective for the treatment of insomnia and VH in PD. To confirm quetiapines efficacy in improving VH, and to determine whether the mechanism was due to its effect on REM sleep architecture, we performed a pilot, double-blind, placebo-controlled study. Sixteen PD patients experiencing VH were recruited. Eight patients were randomized to quetiapine and eight patients to placebo. Patients underwent pre- and post-treatment polysomnography. The Clinical Global Impression Scale (CGIS), Brief Psychiatric Rating Scale (BPRS), and Unified Parkinson Disease Rating Scale (UPDRS) motor subscale were obtained. There were no differences in baseline characteristics between the treatment arms except that the placebo group had more sleep in stage REM (74.7 min vs. 40.1 min; p < .001). Data were imputed for all patients who prematurely discontinued (four quetiapine and one placebo) in an intention-to-treat analysis. The average quetiapine dose was 58.3 mg/day. While there was no significant difference in the change in REM duration pre- vs. post-treatment in either arm, patients randomized to quetiapine improved on the CGIS (p = .03) and the hallucination item of the BPRS (p = .02). No difference was noted in the UPDRS motor scores. Despite the small sample, this is the first double-blind trial to show quetiapines efficacy over placebo in controlling VH in the PD population. However, normalization of sleep architecture was not supported as the mechanism.

The Effect of LINAC Stereotactic Radiosurgery on Epilepsy Associated with Arteriovenous Malformations

Reduction of seizures associated with arteriovenous malformations (AVMs) following radiosurgery has been reported. This investigation assessed the effect of LINAC radiosurgical treatment of AVMs on the associated epilepsies correlated to AVM location, size, seizure type, and postradiosurgical thrombosis. Of 100 patients with AVMs, 33 presented with seizures (11 generalized tonic-clonic seizures, 8 simple partial seizures, and 14 complex partial seizures with or without secondary generalization). Patients with AVMs ≥25.0 mm were more likely to have seizures. Patients with frontal lobe AVMs were the most likely to have associated epilepsy (72.7%). Following radiosurgery, 59% were seizure-free and 19% had marked reduction of seizure frequency. Seizure remission was most frequent for AVMs of the centrum (83.3%). Of 14 patients with 2-year follow-up angiography, 9 had complete thrombosis and 6 became seizure-free. Four of 5 patients without thrombosis also became seizure-free. We conclude that LINAC radiosurgery is effective for epilepsies associated with AVMs. Radiosurgery was most effective for generalized tonic-clonic and complex partial seizures. There was no statistically significant correlation between reduction in epilepsy and original AVM size. Four of 5 patients without thrombosis became seizure-free, suggesting that structural or biochemical alterations of epileptogenic neurons following radiosurgery may reduce epileptogenicity.

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography

Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions.

Group-Wise Point-Set Registration Using a Novel CDF-Based Havrda-Charvát Divergence

This paper presents a novel and robust technique for group-wise registration of point sets with unknown correspondence. We begin by defining a Havrda-Charvát (HC) entropy valid for cumulative distribution functions (CDFs) which we dub the HC Cumulative Residual Entropy (HC-CRE). Based on this definition, we propose a new measure called the CDF-HC divergence which is used to quantify the dis-similarity between CDFs estimated from each point-set in the given population of point sets. This CDF-HC divergence generalizes the CDF Jensen-Shannon (CDF-JS) divergence introduced earlier in the literature, but is much simpler in implementation and computationally more efficient.A closed-form formula for the analytic gradient of the cost function with respect to the non-rigid registration parameters has been derived, which is conducive for efficient quasi-Newton optimization. Our CDF-HC algorithm is especially useful for unbiased point-set atlas construction and can do so without the need to establish correspondences. Mathematical analysis and experimental results indicate that this CDF-HC registration algorithm outperforms the previous group-wise point-set registration algorithms in terms of efficiency, accuracy and robustness.

Evidence-based review on epilepsy and driving.

OBJECTIVE The aim of this study was to synopsize the evidence on predictors of crashes and driving status in people with epilepsy (PWE). METHODS Evidence-based review of the published English literature was the method used. We searched various databases and extracted data from 16 (of 77) primary studies. On the basis of American Academy of Neurology criteria, we assigned each study a class of evidence (I-IV, where I indicates the highest level of evidence) and made recommendations (Level A: predictive or not; Level B: probably predictive or not; Level C: possibly predictive or not; Level U: no recommendations). RESULTS For PWE, the following characteristics are considered useful: For identifying crash risk, epilepsy (level B) and short seizure-free intervals (≥3 months) (Level C) are not predictive of motor vehicle crash (MVC). For self/proxy-reported crash risk, epilepsy surgery (Level B), seizure-free intervals (6-12 months) (Level B), few prior non-seizure-related crashes (Level B), and regular antiepileptic drug adjustments (Level B) are protective against crashes; seizures contribute to MVCs (Level C); mandatory reporting does not contribute to reduced crashes (Level C). No recommendations for reliable auras, age, and gender (Level U), as data are inadequate to make determinations. For self-reported driving or licensure status, employment and epilepsy surgery are predictive of driving (Level C); there are no recommendations for antiepileptic drug use, self-reported driving, gender, age, receiving employment benefits, or having reduced seizure frequency (Level U). CONCLUSION Limitations, that is, heterogeneity among studies, examining the English literature from 1994 to 2010, must be considered. Yet, this is the first evidence-based review to synopsize the current PWE and driving literature and to provide recommendation(s) to clinicians and policy makers. Class I studies, matched for age and gender, yielding Level A recommendations are urgently needed to define the risks, benefits, and causal factors underlying driving performance issues in PWE.

Kernel Fisher Discriminant for Shape-based Classification in Epilepsy

In this paper, we present the application of kernel Fisher discriminant in the statistical analysis of shape deformations that indicate the hemispheric location of an epileptic focus. The scans of two classes of patients with epilepsy, those with a right and those with a left anterior medial temporal lobe focus (RATL and LATL), as validated by clinical consensus and subsequent surgery, were compared to a set of age and sex matched healthy volunteers using both volume and shape based features. Shape-based features are derived from the displacement field characterizing the non-rigid deformation between the left and right hippocampi of a control or a patient as the case may be. Using the shape-based features, the results show a significant improvement in distinguishing between the controls and the rest (RATL and LATL) vis-a-vis volume-based features. Using a novel feature, namely, the normalized histogram of the 3D displacement field, we also achieved significant improvement over the volume-based feature in classifying the patients as belonging to either of the two classes LATL or RATL, respectively. It should be noted that automated identification of hemispherical foci of epilepsy has not been previously reported.