Dr. Fisher is Maslah Saul MD Professor and Director of the Stanford Epilepsy Center. He had research awards from the Klingenstein Foundation, EF, CURE and NIH. He published 160 peer-reviewed articles and 4 books. He was named 1996-2020 in Best Doctors in America. He received the Ambassador Award from the International League Against Epilepsy, the 2005 AES Service Award and the 2006 Annual Clinical Research Award. Dr. Fisher is Past-President of the American Epilepsy Society, and has served on the Board of the ILAE and as Editor-in-Chief of the Journal, Epilepsia. He is past Editor-in-Chief of the website His research is on new devices to treat epilepsy.

Clinical Focus

  • Epilepsy
  • EEG
  • Consciousness, Loss of
  • Convulsion, Non-Epileptic
  • Epilepsy, Complex Partial
  • Epilepsy, Generalized
  • Epilepsy, Temporal Lobe
  • Epilepsy, Tonic-Clonic

Academic Appointments

Administrative Appointments

  • Professional Advisory Board, Epilepsy Foundation of America (1990 - 2004)
  • President, Epilepsy Society of Arizona (1997 - 1999)
  • Chair of Neurology, Barrow Neurological Institute, Phoenix, AZ (1998 - 2000)
  • President, American Epilepsy Society (1999 - 2000)
  • Maslah Saul MD Professor of Neurology, Stanford Medical Center (2000 - Present)
  • Director, Epilepsy Center, Stanford (2000 - Present)
  • Professor (by courtesy), Neurosurgery (2000 - Present)
  • Director, Neurology Teaching, Stanford (2000 - Present)
  • Editor-In-Chief, Epilepsia (2000 - 2005)
  • Executive Committee, International League Against Epilepsy (2000 - 2005)

Honors & Awards

  • Member, Marquis' Who's Who in America (2000)
  • Frank Ford Award for Teaching, Johns Hopkins Hospital (1984)
  • Hans Berger Award, American EEG Society (1976)
  • National Service Award, American Epilepsy Society (2004)
  • Ambassador Award, International League Against Epilepsy (2000)
  • President, American Epilepsy Society (2000)
  • Editor-in-Chief, Epilepsia, International League Against Epilepsy (2001-2006)
  • Annual International Clinical Research Award, American Epilepsy Society (2006)
  • Pierre Gloor Award, American Clinical Neurophysiology Society (Annual National EEG Award) (2010)
  • Best Doctors in America, Woodward and White (1998-2020)

Professional Education

  • Medical Education: Stanford University School of Medicine (1977) CA
  • Board Certification: American Board of Psychiatry and Neurology, Neurology (1983)
  • Fellowship: Johns Hopkins Neurology Residency (1983) MD
  • Residency: Stanford University Internal Medicine Residency (1979) CA
  • Board Certification: American Board of Psychiatry and Neurology, Epilepsy (2013)
  • Fellowship: Johns Hopkins University School of Medicine (1982) MD
  • BS, Caltech, Biology (1971)
  • M.D., Stanford, Medicine (1977)
  • Ph.D., Stanford, Neuroscience (1976)

Community and International Work

  • Editor-in-Chief,,


    The World's most visited epilepsy website

    Partnering Organization(s)

    Epilepsy Therapy Project

    Populations Served

    The Epilepsy Community



    Ongoing Project


    Opportunities for Student Involvement


  • Epilepsy Foundation of N. California Board, Oakland, CA


    Epilepsy advocay and education

    Partnering Organization(s)

    Epilepsy Foundation of America

    Populations Served

    N. Calif. Epilepsy Community



    Ongoing Project


    Opportunities for Student Involvement


  • International League Against Epilepsy Board, Brussels, Belgium


    World Epilepsy

    Partnering Organization(s)

    international Bureau for Epilepsy

    Populations Served

    World Epilepsy Community



    Ongoing Project


    Opportunities for Student Involvement


  • The Epilepsy Project Advisory Board, New York


    Funds Innovative Approaches to Epilepsy Therapy

    Partnering Organization(s)

    Epilepsy Foundation, CURE

    Populations Served

    Epilepsy Community



    Ongoing Project


    Opportunities for Student Involvement


  • Epilepsy Foundation, Professional Board, Landover, Maryland


    Epilepsy Research, Education and Advocacy

    Partnering Organization(s)


    Populations Served

    Epilepsy Community



    Ongoing Project


    Opportunities for Student Involvement


  • President, Epilepsy Society of Arizona, Phoenix, AZ


    Epilepsy Education and Advocacy

    Partnering Organization(s)

    Epilepsy Foundation of America

    Populations Served

    People with epilepsy and their families

    Ongoing Project


    Opportunities for Student Involvement


  • Editor-in-Chief


    Epilesia (Journal)

    Partnering Organization(s)

    International League Against Epilepsy

    Populations Served




    Ongoing Project


    Opportunities for Student Involvement


  • Executive Committee


    International Epilepsy Research and Education

    Partnering Organization(s)

    International League Against Epilepsy

    Populations Served

    Epilepsy Professionals



    Ongoing Project


    Opportunities for Student Involvement


Current Research and Scholarly Interests

Dr. Fisher is interested in clincal, laboratory and translational aspects of epilepsy research. Prior work has included: electrical deep brain stimulation for epilepsy, studied in laboratory models and clinical trials; drug delivery directly to a seizure focus in the brain; mechanisms of absence (petit mal) epilepsy and how the physiology and chemistry of brain changes in this disorder; hyperthermic (high-temperature) seizures; diagnosis and treatment of non-epileptic seizures, the post-ictal state (the condition in the aftermath of a seizure); driving and epilepsy; new antiepileptic drugs; surgery for epilepsy.

Clinical Trials

  • Transcranial Magnetic Stimulation for Epilepsy Recruiting

    The goal of the present clinical trial is to determine whether low frequency (0.5 Hz) rTMS can induce long term depression in epileptogenic cortex and thus suppress cortical excitability at the epileptic focus.

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  • Epilepsy Impact Scale Not Recruiting

    The investigators are developing a questionnaire that can quickly measure the impact that epilepsy has on a person's life. This questionnaire will be useful in following whether the impact of epilepsy increases, decreases or stays the same over time. The results also may point out areas that would benefit from discussion or attention in visits with your doctor.

    Stanford is currently not accepting patients for this trial.

    View full details

  • SANTE - Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy Not Recruiting

    The purpose of this research is to study the safety and effectiveness of bilateral stimulation of the anterior nucleus of the thalamus as adjunctive therapy for reducing the frequency of seizures in adults diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to antiepileptic medications.

    Stanford is currently not accepting patients for this trial.

    View full details

  • VNS Therapy Automatic Magnet Mode Outcomes Study in Epilepsy Patients Exhibiting Ictal Tachycardia (E-37) Not Recruiting

    Obtain baseline clinical outcome data (Stage 1) upon which to base a subsequent study (Stage 2) of the Model 106 VNS implantable pulse generator

    Stanford is currently not accepting patients for this trial. For more information, please contact Stanford Department of Neurology , (650) 498-7551.

    View full details

2023-24 Courses

All Publications

  • Neuromodulatory Focused Ultrasound for Epilepsy: Are Animal Models Useful? ACS chemical neuroscience Chu, P., Yu, H., Fisher, R. S., Liu, H. 2024


    Ultrasound neuromodulation is a potential alternative therapy for suppressing epileptic discharges. Recently, several human clinical trials have reported promising results from repeated focused ultrasound (FUS) treatments for temporal lobe epilepsy. In this Viewpoint, we highlight the valuable guidance of preclinical validation methods for choosing the optimal FUS parameters, thus ensuring consistency with the outcomes of clinical trials and leading human trials to the safest and most effective approaches.

    View details for DOI 10.1021/acschemneuro.4c00198

    View details for PubMedID 38634833

  • Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database. Epilepsy research Kan-Tor, Y., Ness, L., Szlak, L., Benninger, F., Ravid, S., Chorev, M., Rosen-Zvi, M., Shimoni, Y., Fisher, R. S. 2024; 201: 107313


    Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.

    View details for DOI 10.1016/j.eplepsyres.2024.107313

    View details for PubMedID 38417192

  • Functional connectomic profile correlates with effective anterior thalamic stimulation for refractory epilepsy. Brain stimulation Xu, C., Qi, L., Wang, X., Schaper, F. L., Wu, D., Yu, T., Yan, X., Jin, G., Wang, Q., Wang, X., Huang, X., Wang, Y., Chen, Y., Liu, J., Wang, Y., Horn, A., Fisher, R. S., Ren, L. 2023


    BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is an effective treatment for refractory epilepsy; however, seizure outcome varies among individuals. Identifying a reliable noninvasive biomarker to predict good responders would be helpful.OBJECTIVES: To test whether the functional connectivity between the ANT-DBS sites and the seizure foci correlates with effective seizure control in refractory epilepsy.METHODS: We performed a proof-of-concept pilot study of patients with focal refractory epilepsy receiving ANT-DBS. Using normative human connectome data derived from 1000 healthy participants, we investigated whether intrinsic functional connectivity between the seizure foci and the DBS site was associated with seizure outcome. We repeated this analysis controlling for the extent of seizure foci, distance between the seizure foci and DBS site, and using functional connectivity of the ANT instead of the DBS site to test the contribution of variance in DBS sites.RESULTS: Eighteen patients with two or more seizure foci were included. Greater functional connectivity between the seizure foci and the DBS site correlated with more favorable outcome. The degree of functional connectivity accounted for significant variance in clinical outcomes (DBS site: |r| = 0.773, p < 0.001 vs ANT-atlas: |r| = 0.715, p = 0.001), which remained significant when controlling for the extent of the seizure foci (|r| = 0.773, p < 0.001) and the distance between the seizure foci and DBS site (|r| = 0.777, p < 0.001). Significant correlations were independent of variance in the DBS sites (|r| = 0.148, p = 0.57).CONCLUSION: These findings suggest that functional connectomic profile is a potential reliable non-invasive biomarker to predict ANT-DBS outcomes. Accordingly, the identification of ANT responders could decrease the surgical risk for patients who may not benefit and optimize the cost-effective allocation of health care resources.

    View details for DOI 10.1016/j.brs.2023.08.020

    View details for PubMedID 37633491

  • Multisite thalamic recordings to characterize seizure propagation in the human brain. Brain : a journal of neurology Wu, T. Q., Kaboodvand, N., McGinn, R. J., Veit, M., Davey, Z., Datta, A., Graber, K. D., Meador, K. J., Fisher, R., Buch, V., Parvizi, J. 2023


    Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

    View details for DOI 10.1093/brain/awad121

    View details for PubMedID 37137813

  • Pulsed Focused Ultrasound Reduces Hippocampal Volume Loss and Improves Behavioral Performance in the Kainic Acid Rat Model of Epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Chu, P., Huang, C., Ing, S., Yu, H., Fisher, R. S., Liu, H. 2023


    Focused ultrasound (FUS) has the potential to modulate regional brain excitability and possibly aid seizure control; however, effects on behavior of FUS used as a seizure therapy are unknown. This study explores behavioral effects and hippocampal restoration induced by pulsed FUS in a kainic acid (KA) animal model of temporal lobe epilepsy. Twenty-nine male Sprague-Dawley rats were observed for 20weeks with anatomical magnetic resonance imaging (MRI) and behavioral performance evaluations, comprising measures of anxiety, limb usage, sociability, and memory. FUS targeted to the right hippocampus was given 9 and 14weeks after KA was delivered to the right amygdala. Ultrasound pulsations were delivered with the acoustic settings of 0.25 of mechanical index, 0.5 W/cm2 of intensity spatial peak temporal average (ISPTA), 100Hz of pulse repetition frequency, and 30% of duty cycle, during three consecutive pulse trains of 10min separated by 5-min rests. Controls included normal animals with sham injections and KA-exposed animals without FUS exposure. Longitudinal MRI observations showed that FUS substantially protected hippocampal and striatal structures from KA-induced atrophy. KA alone increased anxiety, impaired contralateral limb usage, and reduced sociability and learning. Two courses of FUS sonications partially ameliorated these impairments by enhancing exploring and learning, balancing limb usage, and increasing social interaction. The histology results indicated that two sonications enhanced neuroprotection effect and decreased the inflammation markers induced by KA. This study supports existence of both neuroprotective and beneficial behavioral effects from low-intensity pulsed ultrasound in the KA animal model of epilepsy.

    View details for DOI 10.1007/s13311-023-01363-7

    View details for PubMedID 36917440

  • Deep brain stimulation of thalamus for epilepsy. Neurobiology of disease Fisher, R. S. 2023: 106045


    Neuromodulation (neurostimulation) is a relatively new and rapidly growing treatment for refractory epilepsy. Three varieties are approved in the US: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). This article reviews thalamic DBS for epilepsy. Among many thalamic sub-nuclei, DBS for epilepsy has been targeted to the anterior nucleus (ANT), centromedian nucleus (CM), dorsomedial nucleus (DM) and pulvinar (PULV). Only ANT is FDA-approved, based upon a controlled clinical trial. Bilateral stimulation of ANT reduced seizures by 40.5% at three months in the controlled phase (p = .038) and 75% by 5 years in the uncontrolled phase. Side effects related to paresthesias, acute hemorrhage, infection, occasional increased seizures, and usually transient effects on mood and memory. Efficacy was best documented for focal onset seizures in temporal or frontal lobe. CM stimulation may be useful for generalized or multifocal seizures and PULV for posterior limbic seizures. Mechanisms of DBS for epilepsy are largely unknown, but animal work points to changes in receptors, channels, neurotransmitters, synapses, network connectivity and neurogenesis. Personalization of therapies, in terms of connectivity of the seizure onset zone to the thalamic sub- nucleus and individual characteristics of the seizures, might lead to improved efficacy. Many questions remain about DBS, including the best candidates for different types of neuromodulation, the best targets, the best stimulation parameters, how to minimize side effects and how to deliver current noninvasively. Despite the questions, neuromodulation provides useful new opportunities to treat people with refractory seizures not responding to medicines and not amenable to resective surgery.

    View details for DOI 10.1016/j.nbd.2023.106045

    View details for PubMedID 36809846

  • A Phase-1 Open-label Trial Evaluating Focused Ultrasound Unilateral Anterior Thalamotomy for Focal Onset Epilepsy. Epilepsia Krishna, V., Mindel, J., Sammartino, F., Block, C., Dwivedi, A. K., Van Gomple, J. J., Fountain, N., Fisher, R. 2023


    OBJECTIVE: Focused ultrasound ablation (FUSA) is an emerging treatment for neurological and psychiatric diseases. We describe the initial experience from a pilot, open-label, single-center, clinical trial of unilateral anterior nucleus of the thalamus (ANT) FUSA in patients with treatment-refractory epilepsy.METHODS: Two adult subjects with treatment-refractory, focal-onset epilepsy were recruited. The subjects received ANT FUSA using the Exablate Neuro (Insightec, Inc.) system. We determined the safety and feasibility (primary outcomes), and changes in seizure frequency (secondary outcome) at 3, 6 and 12-months. Safety was assessed by the absence of side effects, i.e., new-onset neurological deficits or performance deterioration on neuropsychological testing. Feasibility was defined as the ability to create a lesion within the anterior nucleus. The monthly seizure frequency was compared between baseline and post thalamotomy.RESULTS: The patients tolerated the procedure well without neurological deficits or serious adverse events. One patient experienced a decline in verbal fluency, attention/working memory, and immediate verbal memory. Seizure frequency reduced significantly in both patients: one patient was seizure free at 12-months, and in the second patient, the frequency reduced from 90-100 seizures per month to 3-6 seizures per month.SIGNIFICANCE: This is the first known clinical trial to assess the safety, feasibility, and preliminary efficacy of ANT FUSA in adult patients with treatment-refractory focal-onset epilepsy.

    View details for DOI 10.1111/epi.17535

    View details for PubMedID 36745000

  • Transcranial Direct Current Stimulation for Focal Status Epilepticus or Lateralized Periodic Discharges in Four Patients in a Critical Care Setting. Epilepsia Fisher, R. S., McGinn, R. J., Von Stein, E. L., Wu, T. Q., Qing, K. Y., Fogarty, A., Razavi, B., Venkatasubramanian, C. 2023


    OBJECTIVE: Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4 mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting.METHODS: Patients in the intensive care unit were referred for tDCS treatment when focal status or clinically-relevant lateralized periodic discharges did not resolve with conventional anti-seizure medications and anesthetics. Battery-powered direct cathodal current at 2 mA was delivered by an ActivaDose (Caputron) tDCS device via a saline soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 minutes, repeated twice in a day, then again 1-4 times more over the next few days.RESULTS: Three females and one male, ages 34-68 were treated. Etiologies of status were PRES in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke and CNS lupus. tDCS led to significant reduction of interictal spikes (0.78/s to 0.38/s, p<0.0001) in 3 cases and electrographic seizures (3.83/hr to 0/hr, p<0.001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home and one became fully responsive as seizures were controlled with tDCS.SIGNIFICANCE: Spikes and electrographic seizure frequency significantly improved within a day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.

    View details for DOI 10.1111/epi.17514

    View details for PubMedID 36661376

  • A Robust eLORETA Technique for Localization of Brain Sources in the Presence of Forward Model Uncertainties. IEEE transactions on bio-medical engineering Noroozi, A., Ravan, M., Razavi, B., Fisher, R. S., Law, Y., Hasan, M. S. 2022; PP


    OBJECTIVE: In this paper, we present a robust version of the well-known exact low-resolution electromagnetic tomography (eLORETA) technique, named ReLORETA, to localize brain sources in the presence of different forward model uncertainties.METHODS: We first assume that the true lead field matrix is a transformation of the existing lead field matrix distorted by uncertainties and propose an iterative approach to estimate this transformation accurately. Major sources of the forward model uncertainties, including differences in geometry, conductivity, and source space resolution between the real and simulated head models, and misaligned electrode positions, are then simulated to test the proposed method.RESULTS: ReLORETA and eLORETA are applied to simulated focal sources in different regions of the brain and the presence of various noise levels as well as real data from a patient with focal epilepsy. The results show that ReLORETA is considerably more robust and accurate than eLORETA in all cases.CONCLUSION: Having successfully dealt with the forward model uncertainties, ReLORETA proved to be a promising method for real-world clinical applications.SIGNIFICANCE: eLORETA is one of the localization techniques that could be used to study brain activity for medical applications such as determining the epileptogenic zone in patients with medically refractory epilepsy. However, the major limitation of eLORETA is sensitivity to the uncertainties in the forward model. Since this problem can substantially undermine its performance in real-world applications where the exact lead field matrix is unknown, developing a more robust method capable of dealing with these uncertainties is of significant interest.

    View details for DOI 10.1109/TBME.2022.3202751

    View details for PubMedID 36136923

  • Correction to: Antiseizure Drugs and Movement Disorders. CNS drugs Saenz-Farret, M., Tijssen, M. A., Eliashiv, D., Fisher, R. S., Sethi, K., Fasano, A. 2022

    View details for DOI 10.1007/s40263-022-00947-9

    View details for PubMedID 35976567

  • Antiseizure Drugs and Movement Disorders. CNS drugs Saenz-Farret, M., Tijssen, M. A., Eliashiv, D., Fisher, R. S., Sethi, K., Fasano, A. 2022


    The relationship between antiseizure drugs and movement disorders is complex and not adequately reviewed so far. Antiseizure drugs as a treatment for tremor and other entities such as myoclonus and restless leg syndrome is the most common scenario, although the scientific evidence supporting their use is variable. However, antiseizure drugs also represent a potential cause of iatrogenic movement disorders, with parkinsonism and tremor the most common disorders. Many other antiseizure drug-induced movement disorders are possible and not always correctly identified. This review was conducted by searching for all the possible combinations between 15 movement disorders (excluding ataxia) and 24 antiseizure drugs. The main objective was to describe the movement disorders treated and worsened or induced by antiseizure drugs. We also summarized the proposed mechanisms and risk factors involved in the complex interaction between antiseizure drugs and movement disorders. Antiseizure drugs mainly used to treat movement disorders are clonazepam, gabapentin, lacosamide, levetiracetam, oxcarbazepine, perampanel, phenobarbital, pregabalin, primidone, topiramate, and zonisamide. Antiseizure drugs that worsen or induce movement disorders are cenobamate, ethosuximide, felbamate, lamotrigine, phenytoin, tiagabine, and vigabatrin. Antiseizure drugs with a variable effect on movement disorders are carbamazepine and valproate while no effect on movement disorders has been reported for brivaracetam, eslicarbazepine, lacosamide, and stiripentol. Although little information is available on the adverse effects or benefits on movement disorders of newer antiseizure drugs (such as brivaracetam, cenobamate, eslicarbazepine, lacosamide, and rufinamide), the evidence collected in this review should guide the choice of antiseizure drugs in patients with concomitant epilepsy and movement disorders. Finally, these notions can lead to a better understanding of the mechanisms involved in the pathophysiology and treatments of movement disorders.

    View details for DOI 10.1007/s40263-022-00937-x

    View details for PubMedID 35861924

  • Practical considerations in epilepsy neurostimulation. Epilepsia Simpson, H. D., Schulze-Bonhage, A., Cascino, G. D., Fisher, R. S., Jobst, B. C., Sperling, M. R., Lundstrom, B. N. 2022


    Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death from epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7-10years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with co-morbidities such as severe mood or sleep disorders, may influence choice of modality. Programming has evolved - DBS is typically initiated at lower current/voltage than used in the pivotal trial while charge density is lower with RNS, but generalizable optimal parameters are yet to be defined. Non-invasive brain stimulation is an emerging stimulation modality, although currently not widely used. Clinical practice has evolved from those established in pivotal trials. Guidance is available for clinicians wishing to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

    View details for DOI 10.1111/epi.17329

    View details for PubMedID 35700144

  • Impact of high-density EEG in presurgical evaluation for refractory epilepsy patients. Clinical neurology and neurosurgery Li, Y., Fogarty, A., Razavi, B., Ardestani, P. M., Falco-Walter, J., Werbaneth, K., Graber, K., Meador, K., Fisher, R. S. 2022; 219: 107336


    OBJECTIVE: Electrical source localization (ESI) can help to identify the seizure onset zone or propagation zone, but it is unclear how dipole localization techniques influence surgical planning.METHODS: Patients who received a high density (HD)-EEG from 7/2014-7/2019 at Stanford were included if they met the following inclusion criteria: (1) adequate epileptiform discharges were recorded for source localization analysis, (2) underwent surgical treatment, which was at least 6 months before the survey. Interictal ESI was performed with the LORETA method on age matched MRIs. Six neurophysiologists from the Stanford Epilepsy Program independently reviewed each case through an HIPPA-protected online survey. The same cases were presented again with additional data from the HD-EEG study. Ratings of how much the HD-EEG findings added value and in what way were recorded.RESULTS: Fifty out of 202 patients met the inclusion criteria, providing a total of 276h of HDEEG recordings. All patients had video EEG recordings and at least one brain MRI, 88 % had neuropsychological testing, 78 % had either a PET or SPECT scan. Additional HD-EEG information was rated as helpful in 83.8 %, not useful in 14.4 % and misleading in 1.8 % of cases. In 20.4 % of cases the HD-EEG information altered decision-making in a major way, such as choosing a different surgical procedure, avoidance of invasive recording or suggesting placement of invasive electrodes in a lobe not previously planned. In 21.5 % of cases, HD-EEG changed the plan in a minor way, e.g., extra invasive electrodes near the previously planned sites in the same sub-lobar region. In 42.3 % cases, HD-EEG did not change their plan but provided confirmation. In cases with normal MRI, additional HD-EEG information was more likely to change physicians' decision making during presurgical process when compared to the cases with MRI-visible lesions (53.3 % vs. 34.3 %, p=0.002). Among patients achieving Engel class I/II outcome, the concordance rate of HD-EEG and resection zone was 64.7 % versus 35.3 % with class III/IV (p=0.028).CONCLUSION: HD-EEG assists presurgical planning for refractory epilepsy patients, with a higher yield in patients with non-lesional MRIs. Concordance of HD-EEG dipole analysis localization and resection site is a favorable outcome indicator.

    View details for DOI 10.1016/j.clineuro.2022.107336

    View details for PubMedID 35716454

  • Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Chu, P. C., Yu, H. Y., Lee, C. C., Fisher, R., Liu, H. L. 2022


    Focused ultrasound (FUS) has potential utility for modulating regional brain excitability and possibly aiding seizure control; however, the duration of any beneficial effect is unknown. This study explores the efficacy and time course of a short series of pulsed FUS in suppressing EEG epileptiform spikes/bursts in a kainic acid (KA) animal model of temporal lobe epilepsy. Forty-four male Sprague-Dawley rats were recorded for 14 weeks with EEG while software calculated EEG numbers of epileptiform spikes and bursts (≥ 3 spikes/s). Four regimens of FUS given in a single session at week 7 were evaluated, with mechanical index (MI) ranging from 0.25 to 0.75, intensity spatial peak temporal average (ISPTA) from 0.1 to 2.8 W per cm2, duty cycle from 1 to 30%, and three consecutive pulse trains for 5 or 10 min each. Controls included sham injections in four and KA without FUS in eleven animals. Histological analysis investigated tissue effects. All animals receiving KA evidenced EEG spikes, averaging 10,378 ± 1651 spikes per 8 h and 1255 ± 199 bursts per 8 h by weeks 6-7. The KA-only group showed a 30% of increase in spikes and bursts by week 14. Compared to the KA-only group, spike counts were reduced by about 25%, burst counts by about 33%, and burst durations by about 50% with FUS. Behavioral seizures were not analyzed, but electrographic seizures longer than 10 s declined up to 70% after some FUS regimens. Repeated-measure ANOVA showed a significant effect of higher intensity and longer sonication duration FUS treatment using 0.75-MI, ISPTA 2.8 W/cm2, 30% duty cycle for 10-min sonications (group effect, F (4, 15) = 6.321, p < 0.01; interaction effect, F (44, 165) = 1.726, p < 0.01), with the hippocampal protective effect lasting to week 14, accompanied by decreased inflammation and gliosis effect. In contrast, spike and burst suppression were achieved using an FUS regimen with 0.25-MI ISPTA 0.5 W/cm2, 30% duty cycle for 10-min sonications. This regimen reduced inflammation and gliosis at weeks 8-14 and protected hippocampal tissue. This study demonstrates that low-intensity pulsed ultrasound can modulate epileptiform activity for up to 7 weeks and, if replicated in the clinical setting, might be a practical treatment for epilepsy.

    View details for DOI 10.1007/s13311-022-01250-7

    View details for PubMedID 35581489

  • Minimum clinically important difference (MCID) of the personal impact of epilepsy scale (PIES). Epilepsy & behavior : E&B Martz, G., Fisher, R. S., Folley, B., Panza, G. A., Ando, F., McEachern, C., Blinn, A., Cramer, J. A. 2022; 130: 108691


    INTRODUCTION: The Personal Impact of Epilepsy Scale (PIES) assesses patient functional status in subscales of (1) seizure impact, (2) medication effects, (3) mood & social status, and (4) overall quality of life. This study was designed to determine the Minimal Clinically Important Change (MCID) in PIES subscale and total scores that demonstrate improvement.METHODS: To ascertain the correspondence of PIES score change and clinical status change (improved, same, worse) in each PIES subscale and total score, we used two distinct retrospective anchor-based assessments of clinical status (patient self-assessment and trained rater assessment) across two clinic visits. Mean PIES scores were compared between clinical status groups, controlling for days between visits and initial clinical status. Personal Impact of Epilepsy Scale score change was quantified for each group to determine MCID. A small prospective proof-of-concept study was conducted in a separate subject group.RESULTS: Patient self-report anchor analysis demonstrated lower (better) PIES scores in the "improved" group vs the "worse" group on the mood & social subscale (p < .001) and total score (p = .002), with a similar trend on the seizure subscale (p = 0.056). Clinical rater anchor analysis demonstrated lower PIES scores in the "improved" vs "worse" group in the mood & social subscale (p = .029) and a trend in total score (p = .082). For the "improved" group, the reduction in PIES scores between visits averaged across both anchor analyses was 8.14% for subscales and 8.67% for total score.DISCUSSION/CONCLUSION: Reduction of 8% on a PIES subscale or total score indicates meaningful improvement in patient clinical status, and is designated the MCID for this instrument. Personal Impact of Epilepsy Scale can be useful in day-to-day clinical care and as an outcome metric in clinical research.

    View details for DOI 10.1016/j.yebeh.2022.108691

    View details for PubMedID 35453042

  • Complex negative emotions induced by electrical stimulation of the human hypothalamus. Brain stimulation Parvizi, J., Veit, M. J., Barbosa, D. A., Kucyi, A., Perry, C., Parker, J. J., Shivacharan, R. S., Chen, F., Yih, J., Gross, J. J., Fisher, R., McNab, J. A., Falco-Walter, J., Halpern, C. H. 2022


    Stimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated.To examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions.We examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG).Recordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and tractography.This patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion and the importance of subcortical structures in processing emotions. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus ought to be seen as a causally important functional unit, within a broader human telencephalon, for our human subjective experience.

    View details for DOI 10.1016/j.brs.2022.04.008

    View details for PubMedID 35413481

  • EEG Evoked Potentials to Repetitive Transcranial Magnetic Stimulation in Normal Volunteers: Inhibitory TMS EEG Evoked Potentials. Sensors (Basel, Switzerland) Zhou, J., Fogarty, A., Pfeifer, K., Seliger, J., Fisher, R. S. 2022; 22 (5)


    The impact of repetitive magnetic stimulation (rTMS) on cortex varies with stimulation parameters, so it would be useful to develop a biomarker to rapidly judge effects on cortical activity, including regions other than motor cortex. This study evaluated rTMS-evoked EEG potentials (TEP) after 1 Hz of motor cortex stimulation. New features are controls for baseline amplitude and comparison to control groups of sham stimulation. We delivered 200 test pulses at 0.20 Hz before and after 1500 treatment pulses at 1 Hz. Sequences comprised AAA = active stimulation with the same coil for test-treat-test phases (n = 22); PPP = realistic placebo coil stimulation for all three phases (n = 10); and APA = active coil stimulation for tests and placebo coil stimulation for treatment (n = 15). Signal processing displayed the evoked EEG waveforms, and peaks were measured by software. ANCOVA was used to measure differences in TEP peak amplitudes in post-rTMS trials while controlling for pre-rTMS TEP peak amplitude. Post hoc analysis showed reduced P60 amplitude in the active (AAA) rTMS group versus the placebo (APA) group. The N100 peak showed a treatment effect compared to the placebo groups, but no pairwise post hoc differences. N40 showed a trend toward increase. Changes were seen in widespread EEG leads, mostly ipsilaterally. TMS-evoked EEG potentials showed reduction of the P60 peak and increase of the N100 peak, both possibly reflecting increased slow inhibition after 1 Hz of rTMS. TMS-EEG may be a useful biomarker to assay brain excitability at a seizure focus and elsewhere, but individual responses are highly variable, and the difficulty of distinguishing merged peaks complicates interpretation.

    View details for DOI 10.3390/s22051762

    View details for PubMedID 35270910

  • Visually sensitive seizures: An updated review by the Epilepsy Foundation. Epilepsia Fisher, R. S., Acharya, J. N., Baumer, F. M., French, J. A., Parisi, P., Solodar, J. H., Szaflarski, J. P., Thio, L. L., Tolchin, B., Wilkins, A. J., Kasteleijn-Nolst Trenite, D. 2022


    Light flashes, patterns, or color changes can provoke seizures in up to 1 in 4000 persons. Prevalence may be higher because of selection bias. The Epilepsy Foundation reviewed light-induced seizures in 2005. Since then, images on social media, virtual reality, three-dimensional (3D) movies, and the Internet have proliferated. Hundreds of studies have explored the mechanisms and presentations of photosensitive seizures, justifying an updated review. This literature summary derives from a nonsystematic literature review via PubMed using the terms "photosensitive" and "epilepsy." The photoparoxysmal response (PPR) is an electroencephalography (EEG) phenomenon, and photosensitive seizures (PS) are seizures provoked by visual stimulation. Photosensitivity is more common in the young and in specific forms of generalized epilepsy. PS can coexist with spontaneous seizures. PS are hereditable and linked to recently identified genes. Brain imaging usually is normal, but special studies imaging white matter tracts demonstrate abnormal connectivity. Occipital cortex and connected regions are hyperexcitable in subjects with light-provoked seizures. Mechanisms remain unclear. Video games, social media clips, occasional movies, and natural stimuli can provoke PS. Virtual reality and 3D images so far appear benign unless they contain specific provocative content, for example, flashes. Images with flashes brighter than 20 candelas/m2 at 3-60 (particularly 15-20) Hz occupying at least 10 to 25% of the visual field are a risk, as are red color flashes or oscillating stripes. Equipment to assay for these characteristics is probably underutilized. Prevention of seizures includes avoiding provocative stimuli, covering one eye, wearing dark glasses, sitting at least two meters from screens, reducing contrast, and taking certain antiseizure drugs. Measurement of PPR suppression in a photosensitivity model can screen putative antiseizure drugs. Some countries regulate media to reduce risk. Visually-induced seizures remain significant public health hazards so they warrant ongoing scientific and regulatory efforts and public education.

    View details for DOI 10.1111/epi.17175

    View details for PubMedID 35132632

  • Experience and consensus on stimulation of the anterior nucleus of thalamus for epilepsy. Epilepsia Fasano, A., Eliashiv, D., Herman, S. T., Lundstrom, B. N., Polnerow, D., Henderson, J. M., Fisher, R. S. 2021


    Deep brain stimulation of the anterior nuclei of thalamus (ANT-DBS) is effective for reduction of seizures, but little evidence is available to guide practitioners in the practical use of this therapy. In an attempt to fill this gap, a questionnaire with 37 questions was circulated to 578clinicians who were either engaged in clinical trials of or known users of DBS for epilepsy, with responses from 141, of whom 58.2% were epileptologists and 28.4% neurosurgeons. Multiple regions of the world were represented. The survey found that the best candidates for DBS were considered those with temporal or frontal seizures, refractory to at least two medicines. Motivations for renewing therapy upon battery depletion were reduced convulsive, impaired awareness, and severe seizures and improved quality of life. Targeting of leads mainly was by magnetic resonance imaging, sometimes with intraoperative imaging or microelectrode recording. The majority used transventricular approaches. Stimulation parameters mostly imitated the SANTE study parameters, except for initial stimulation amplitudes in the 2-3-V or -mA range, versus 5V in the SANTE study. Stimulation intensity was most often increased or reduced, respectively, for lack of efficacy or side effects, but changes in active contacts, cycle time, and pulse duration were also employed. Mood or memory problems or paresthesias were the side effects most responsible for adjustments. Off-label sites stimulated included centromedian thalamus, hippocampus, neocortex, and a few others. Several physicians used DBS in conjunction with vagus nerve stimulation or responsive neurostimulation, although our study did not track efficacy for combined use. Experienced users varied more from published parameters than did inexperienced users. In conclusion, surveys of experts can provide Class IV evidence for the most prevalent practical use of ANT-DBS. We present a flowchart for one protocol combining common practices. Controlled comparisons will be needed to choose the best approach.

    View details for DOI 10.1111/epi.17094

    View details for PubMedID 34697794

  • Analysis of Deep Brain Stimulation Lead Targeting in the Stimulation of Anterior Nucleus of the Thalamus for Epilepsy Clinical Trial. Neurosurgery Gross, R. E., Fisher, R. S., Sperling, M. R., Giftakis, J. E., Stypulkowski, P. H. 2021


    BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites.OBJECTIVE: To conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTE pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings.METHODS: Postoperative images from SANTE subjects (n=101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes.RESULTS: Approximately 70% of subjects had "good" bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P<.05).CONCLUSION: Consistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy.

    View details for DOI 10.1093/neuros/nyab186

    View details for PubMedID 34161589

  • The SANTE study at 10 years of follow-up: Effectiveness, safety, and sudden unexpected death in epilepsy. Epilepsia Salanova, V., Sperling, M. R., Gross, R. E., Irwin, C. P., Vollhaber, J. A., Giftakis, J. E., Fisher, R. S., SANTE Study Group 2021


    OBJECTIVE: We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) study.METHODS: After the 3-month blinded and 9-month unblinded phases, subjects continued to be assessed during long-term follow-up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed.RESULTS: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7years, median seizure frequency percent reduction from baseline was 75% (p<.001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTE study experience (two deaths in 938years) and previous pilot studies (0 deaths in 76years), indicated a rate of 2.0 deaths for 1000 person-years. Overall mortality was 6.9 deaths per 1000 person-years.SIGNIFICANCE: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy.

    View details for DOI 10.1111/epi.16895

    View details for PubMedID 33830503

  • Status epilepticus after intracranial neurosurgery: incidence and risk stratification by perioperative clinical features. Journal of neurosurgery Jin, M. C., Parker, J. J., Zhang, M. n., Medress, Z. A., Halpern, C. H., Li, G. n., Ratliff, J. K., Grant, G. A., Fisher, R. S., Skirboll, S. n. 2021: 1–13


    Status epilepticus (SE) is associated with significant mortality, cost, and risk of future seizures. In one of the first studies of SE after neurosurgery, the authors assess the incidence, risk factors, and outcome of postneurosurgical SE (PNSE).Neurosurgical admissions from the MarketScan Claims and Encounters database (2007 through 2015) were assessed in a longitudinal cross-sectional sample of privately insured patients who underwent qualifying cranial procedures in the US and were older than 18 years of age. The incidence of early (in-hospital) and late (postdischarge readmission) SE and associated mortality was assessed. Procedural, pathological, demographic, and anatomical covariates parameterized multivariable logistic regression and Cox models. Multivariable logistic regression and Cox proportional hazards models were used to study the incidence of early and late PNSE. A risk-stratification simulation was performed, combining individual predictors into singular risk estimates.A total of 197,218 admissions (218,217 procedures) were identified. Early PNSE occurred during 637 (0.32%) of 197,218 admissions for cranial neurosurgical procedures. A total of 1045 (0.56%) cases of late PNSE were identified after 187,771 procedure admissions with nonhospice postdischarge follow-up. After correction for comorbidities, craniotomy for trauma, hematoma, or elevated intracranial pressure was associated with increased risk of early PNSE (adjusted OR [aOR] 1.538, 95% CI 1.183-1.999). Craniotomy for meningioma resection was associated with an increased risk of early PNSE compared with resection of metastases and parenchymal primary brain tumors (aOR 2.701, 95% CI 1.388-5.255). Craniotomies for infection or abscess (aHR 1.447, 95% CI 1.016-2.061) and CSF diversion (aHR 1.307, 95% CI 1.076-1.587) were associated with highest risk of late PNSE. Use of continuous electroencephalography in patients with early (p < 0.005) and late (p < 0.001) PNSE rose significantly over the study time period. The simulation regression model predicted that patients at high risk for early PNSE experienced a 1.10% event rate compared with those at low risk (0.07%). Similarly, patients predicted to be at highest risk for late PNSE were significantly more likely to eventually develop late PNSE than those at lowest risk (HR 54.16, 95% CI 24.99-104.80).Occurrence of early and late PNSE was associated with discrete neurosurgical pathologies and increased mortality. These data provide a framework for prospective validation of clinical and perioperative risk factors and indicate patients for heightened diagnostic suspicion of PNSE.

    View details for DOI 10.3171/2020.10.JNS202895

    View details for PubMedID 33990087

  • Identification of seizure clusters using free text notes in an electronic seizure diary. Epilepsy & behavior : E&B Werbaneth, K., Cramer, J. A., Bartfeld, E., Fisher, R. S. 2020; 113: 107498


    SIGNIFICANCE: Online seizure diaries offer a wealth of information regarding real world experience of patients living with epilepsy. Free text notes (FTN) written by patients reflect concerns and priorities of patients and provide supplemental information to structured diary data.OBJECTIVE: This project evaluated feasibility using an automated lexical analysis to identify FTN relevant to seizure clusters (SCs).METHODS: Data were extracted from EpiDiary, a free electronic epilepsy diary with 42,799 unique users, generating 1,096,168 entries and 247,232 FTN. Both structured data as well as FTN were analyzed for presence of SC. A pilot study was conducted to validate an automated lexical analysis algorithm to identify SC in FTN in a sample of 98 diaries. The lexical analysis was then applied to the entire dataset. Outcomes included cluster prevalence and frequency, as well as the types of triggers commonly reported.RESULTS: At least one FTN was found among 13,987 (32.68%) individual diaries. An automated lexical analysis algorithm identified 5797 of FTN as SC. There were 2423 unique patients with SC that were not identified by structured data alone and were identified using lexical analysis of FTN only. Seizure clusters were identified in n = 10,331 (24.1%) of diary users through both structured data and FTN. The median number of SCs days per year was 13.7, (interquartile rank (IQR): 3.2-54.7). The median number of seizures in a cluster day was 3 (IQR 2-4). The most common missed medication linked to patients with SC was levetiracetam (n = 576, 29%) followed by lamotrigine (n = 495, 24%), topiramate (n = 208, 10.5%), carbamazepine (n = 190, 9.6%), and lacosamide (n = 170, 8.6%). These percentages generally reflected prevalence of medication use in this population. The use of rescue medications was documented in 3306 of structured entries and 4305 in FTN.CONCLUSION: This exploratory study demonstrates a novel approach applying lexical analysis to previously untapped FTN in a large electronic seizure diary database. Free text notes captured information about SC not available from the structured diary data. Diary FTN contain information of high importance to people with epilepsy, written in their own words.

    View details for DOI 10.1016/j.yebeh.2020.107498

    View details for PubMedID 33096508

  • Computational analysis of Seizure Clusters in electronic diary free text notes Werbaneth, K., Cramer, J., Bartfeld, E., Fisher, R. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Sounds of seizures. Seizure Shum, J. n., Fogarty, A. n., Dugan, P. n., Holmes, M. G., Leeman-Markowski, B. A., Liu, A. A., Fisher, R. S., Friedman, D. n. 2020; 78: 86–90


    A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings.We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated.The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97).This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.

    View details for DOI 10.1016/j.seizure.2020.03.008

    View details for PubMedID 32276233

  • Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study. EClinicalMedicine Cook, M. n., Murphy, M. n., Bulluss, K. n., D'Souza, W. n., Plummer, C. n., Priest, E. n., Williams, C. n., Sharan, A. n., Fisher, R. n., Pincus, S. n., Distad, E. n., Anchordoquy, T. n., Abrams, D. n. 2020; 22: 100326


    A clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated.In this single arm study, five adult subjects, with 29-234 focal onset seizures per month from a seizure focus involving the mesial temporal lobe were implanted with the system ( identifier NCT02899611). Oral valproic acid (VPA) had previously been ineffective in all subjects. Post-surgery, pharmacokinetic studies of CSF infused VPA were performed. Valproic acid doses were increased stepwise in a standardised protocol.The procedure and implantation were well-tolerated by all subjects. Four subjects responded with > 50% seizure reduction at the highest tested dose of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects reported significant quality of life improvement. No clinical dose limiting side effects were encountered and there was no evidence of local periventricular toxicity in three subjects who were evaluated with imaging (T2 MRI). Side effects included nausea and appetite loss but were not dose-limiting. Mean CSF valproic acid levels were 45 μg per ml (range 20-120 μg per ml), with corresponding serum levels of 4-14 μg per ml.  Subjects have received therapy for up to 2.5 years in total . The efficacy analysis presented focuses on the period of time with the current pump with a mean 12.5 months, range 11.5-15 months. Pump failure requiring reimplantation was a significant initial issue in all subjects but resolved with use of pumps suitably compatible with long-term exposure to valproic acid.The study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well-tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal.The study was funded by Cerebral Therapeutics Inc., Suite 137 12635 East Montview Blvd Aurora CO 80045.

    View details for DOI 10.1016/j.eclinm.2020.100326

    View details for PubMedID 32395709

    View details for PubMedCentralID PMC7205744

  • Epileptogenic network of focal epilepsies mapped with cortico-cortical evoked potentials. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Guo, Z. H., Zhao, B. T., Toprani, S. n., Hu, W. H., Zhang, C. n., Wang, X. n., Sang, L. n., Ma, Y. S., Shao, X. Q., Razavi, B. n., Parvizi, J. n., Fisher, R. n., Zhang, J. G., Zhang, K. n. 2020; 131 (11): 2657–66


    The goal of this study was to investigate the spatial extent and functional organization of the epileptogenic network through cortico-cortical evoked potentials (CCEPs) in patients being evaluated with intracranial stereoelectroencephalography.We retrospectively included 25 patients. We divided the recorded sites into three regions: epileptogenic zone (EZ); propagation zone (PZ); and noninvolved zone (NIZ). The root mean square of the amplitudes was calculated to reconstruct effective connectivity network. We also analyzed the N1/N2 amplitudes to explore the responsiveness influenced by epileptogenicity. Prognostic analysis was performed by comparing intra-region and inter-region connectivity between seizure-free and non-seizure-free groups.Our results confirmed that stimulation of the EZ caused the strongest responses on other sites within and outside the EZ. Moreover, we found a hierarchical connectivity pattern showing the highest connectivity strength within EZ, and decreasing connectivity gradient from EZ, PZ to NIZ. Prognostic analysis indicated a stronger intra-EZ connection in the seizure-free group.The EZ showed highest excitability and dominantly influenced other regions. Quantitative CCEPs can be useful in mapping epileptic networks and predicting surgical outcome.The generated computational connectivity model may enhance our understanding of epileptogenic networks and provide useful information for surgical planning and prognosis prediction.

    View details for DOI 10.1016/j.clinph.2020.08.012

    View details for PubMedID 32957038

  • Cortical Excitability, Synaptic Plasticity, and Cognition in Benign Epilepsy With Centrotemporal Spikes: A Pilot TMS-EMG-EEG Study. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society Baumer, F. M., Pfeifer, K. n., Fogarty, A. n., Pena-Solorzano, D. n., Rolle, C. E., Wallace, J. L., Rotenberg, A. n., Fisher, R. S. 2020; 37 (2): 170–80


    Children with benign epilepsy with centrotemporal spikes have rare seizures emerging from the motor cortex, which they outgrow in adolescence, and additionally may have language deficits of unclear etiology. We piloted the use of transcranial magnetic stimulation paired with EMG and EEG (TMS-EMG, TMS-EEG) to test the hypotheses that net cortical excitability decreases with age and that use-dependent plasticity predicts learning.We assessed language and motor learning in 14 right-handed children with benign epilepsy with centrotemporal spikes. We quantified two TMS metrics of left motor cortex excitability: the resting motor threshold (measure of neuronal membrane excitability) and amplitude of the N100-evoked potential (an EEG measure of GABAergic tone). To test plasticity, we applied 1 Hz repetitive TMS to the motor cortex to induce long-term depression-like changes in EMG- and EEG-evoked potentials.Children with benign epilepsy with centrotemporal spikes tolerate TMS; no seizures were provoked. Resting motor threshold decreases with age but is elevated above maximal stimulator output for half the group. N100 amplitude decreases with age after controlling for resting motor threshold. Motor cortex plasticity correlates significantly with language learning and at a trend level with motor learning.Transcranial magnetic stimulation is safe and feasible for children with benign epilepsy with centrotemporal spikes, and TMS-EEG provides more reliable outcome measures than TMS-EMG in this group because many children have unmeasurably high resting motor thresholds. Net cortical excitability decreases with age, and motor cortex plasticity predicts not only motor learning but also language learning, suggesting a mechanism by which motor cortex seizures may interact with language development.

    View details for DOI 10.1097/WNP.0000000000000662

    View details for PubMedID 32142025

  • Optimized SEEG-guided radiofrequency thermocoagulation for mesial temporal lobe epilepsy with hippocampal sclerosis. Seizure Fan, X., Shan, Y., Lu, C., An, Y., Wang, Y., Du, J., Wang, D., Wei, P., Fisher, R. S., Wang, Y., Ren, L., Zhao, G. 2019; 71: 304–11


    PURPOSE: Concerns about the impact of open surgery for drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) have driven interest in minimally invasive techniques. Stereo-electro-encephalography guided radiofrequency thermocoagulation (SEEG guided RF-TC) offers an alternative choice but with currently limited efficacy. We developed a procedure for optimally extended thermocoagulative lesions and investigated the efficacy and safety for MTLE-HS in a preliminary observational study.METHODS: From June 2016 to August 2017, twenty-two patients were selected for the present study. They met the criteria of unilateral MTLE-HS after noninvasive evaluation and then underwent implantation of a combination of SEEG electrodes to form a high-density focal stereo-array, including one electrode along the long axis of amygdalohippocampal complex and three orthogonal electrodes to widely sample mesial temporal structures. A unilateral epileptogenic zone of mesial temporal structures was confirmed in these 21 patients. SEEG-guided bipolar coagulations were performed between two contiguous contacts of the same electrode, or between two adjacent contacts of different electrodes.RESULTS: Surgical procedures were well tolerated, with no related complications. At the follow-up of 12 months, 20 patients (95.2%) experienced a >90% decrease in seizure frequency and 16 patients (76.2%) were free of disabling seizures (Engel class I). Among them, eight (38.1%) were classified as Engel class Ia and the other eight (38.1%) as Engel class Ib. Four others (19%) had rare disabling seizures (Engel class II). Only one (4.8%) experienced an Engel class III outcome.CONCLUSION: Optimized SEEG-guided RF-TC is a promising complementary option for the treatment of MTLE-HS.

    View details for DOI 10.1016/j.seizure.2019.08.011

    View details for PubMedID 31521052

  • Classification as autonomic versus sensory seizures. Epilepsia Fisher, R. S., Cross, H., D'Souza, C., French, J. A., Haut, S., Higurashi, N., Hirsch, E., Jansen, F. E., Peltola, J., Moshe, S. L., Perucca, E., Lagae, L., Roulet-Perez, E., Schulze-Bonhage, A., Scheffer, I. E., Somerville, E., Sperling, M. R., Wiebe, S., Yacubian, E. M., Zuberi, S. 2019

    View details for DOI 10.1111/epi.16308

    View details for PubMedID 31353460

  • 2017 International League Against Epilepsy classifications of seizures and epilepsy are steps in the right direction EPILEPSIA Fisher, R. S., Cross, H., D'Souza, C., French, J. A., Haut, S., Higurashi, N., Hirsch, E., Jansen, F. E., Peltola, J., Moshe, S. L., Perucca, E., Lagae, L., Roulet-Perez, E., Schulze-Bonhage, A., Scheffer, I. E., Somerville, E., Sperling, M. R., Wiebe, S., Yacubian, E., Zuberi, S. 2019; 60 (6): 1040–44

    View details for DOI 10.1111/epi.15052

    View details for Web of Science ID 000472983800004

  • Adjunctive repetitive transcranial magnetic stimulation delivers superior quality of life for focal epilepsy compared to anti-epileptic drugs: A meta-analytic utility prediction study. Brain stimulation Mahajan, U. V., Parker, J. J., Williams, N. R., Bhati, M. T., Ku, S. n., Grant, G. n., Fisher, R. S., Stein, S. C., Halpern, C. H. 2019

    View details for DOI 10.1016/j.brs.2019.12.006

    View details for PubMedID 31874798

  • Neuromodulation - Science and Practice in Epilepsy: Vagus Nerve Stimulation, Thalamic Deep Brain Stimulation, and Responsive NeuroStimulation EXPERT REVIEW OF NEUROTHERAPEUTICS Markert, M. S., Fisher, R. S. 2019; 19 (1): 17–29
  • 2017 International League Against Epilepsy classifications of seizures and epilepsy are steps in the right direction. Epilepsia Fisher, R. S., Cross, H. n., D'Souza, C. n., French, J. A., Haut, S. n., Higurashi, N. n., Hirsch, E. n., Jansen, F. E., Peltola, J. n., Moshé, S. L., Perucca, E. n., Lagae, L. n., Roulet-Perez, E. n., Schulze-Bonhage, A. n., Scheffer, I. E., Somerville, E. n., Sperling, M. R., Wiebe, S. n., Yacubian, E. M., Zuberi, S. n. 2019

    View details for PubMedID 31074833

  • Tripolar concentric EEG electrodes reduce noise. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Aghaei-Lasboo, A. n., Inoyama, K. n., Fogarty, A. S., Kuo, J. n., Meador, K. J., Walter, J. J., Le, S. T., Graber, K. D., Razavi, B. n., Fisher, R. S. 2019; 131 (1): 193–98


    To assay EEG signal quality recorded with tripolar concentric ring electrodes (TCREs) compared to regular EEG electrodes.EEG segments were recorded simultaneously by TCREs and regular electrodes, low-pass filtered at 35 Hz (REG35) and 70 Hz (REG70). Clips were rated blindly by nine electroencephalographers for presence or absence of key EEG features, relative to the "gold-standard" of the clinical report.TCRE showed less EMG artifact (F = 15.4, p < 0.0001). Overall quality rankings were not significantly different. Focal slowing was better detected by TCRE and spikes were better detected by regular electrodes. Seizures (n = 85) were detected by TCRE in 64 cases (75.3%), by REG70 in 75 (88.2%) and REG35 in 69 (81.2%) electrodes. TCRE detected 9 (10.6%) seizures not detected by one of the other 2 methods. In contrast, 14 seizures (16.5%) were not detected by TCRE, but were by REG35 electrodes. Each electrode detected interictal spikes when the other did not.TCRE produced similar overall quality and confidence ratings versus regular electrodes, but less muscle artifact. TCRE recordings detected seizures in 7% of instances where regular electrodes did not.The combination of the two types increased detection of epileptiform events compared to either alone.

    View details for DOI 10.1016/j.clinph.2019.10.022

    View details for PubMedID 31809982

  • Neuromodulation - science and practice in epilepsy: Vagus nerve stimulation, thalamic deep brain stimulation, and responsive neurostimulation. Expert review of neurotherapeutics Markert, M. S., Fisher, R. S. 2018: 1–13


    INTRODUCTION: Neuromodulation devices can be safe and effective for the treatment of drug-resistant epilepsy. A body of scientific work supports peripheral, subcortical and cortical targets, each with different fundamental methods of action. Areas covered: High-quality evidence is available for vagal nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Mechanistic research in animals and human studies are reviewed, along with key data from VNS, DBS, and RNS clinical trials. Specifically, the authors review some of the science behind the most frequently used medical devices for neuromodulation, the evidence that lead to their adoption, a delineation of the populations that often benefit from these devices, and perspectives on clinical practice to optimize benefit in treatment of seizures. Expert Commentary: Neuromodulation is increasingly used to complement medical management of refractory epilepsy. Device preference will be made on the basis of patient preference, physician familiarity and other individualized factors. Right now, the field is very new and decision-making will improve with experience.

    View details for PubMedID 30526131

  • Intravascular stimulation of the motor cortex NATURE BIOMEDICAL ENGINEERING Fisher, R. S. 2018; 2 (12): 883–84
  • Intravascular stimulation of the motor cortex. Nature biomedical engineering Fisher, R. S. 2018; 2 (12): 883-884

    View details for DOI 10.1038/s41551-018-0330-y

    View details for PubMedID 31015730

  • Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology ZEITSCHRIFT FUR EPILEPTOLOGIE Fisher, R. S., Cross, J., French, J. A., Higurashi, N., Hirsch, E., Jansen, F. E., Lagae, L., Moshe, S. L., Peltola, J., Perez, E., Scheffer, I. E., Zuberi, S. M. 2018; 31 (4): 272–81
  • Instructionmanual for the ILAE 2017 operational classification of seizure types ZEITSCHRIFT FUR EPILEPTOLOGIE Fisher, R. S., Cross, J., D'Souza, C., French, J. A., Haut, S. R., Higurashi, N., Hirsch, E., Jansen, F. E., Lagae, L., Moshe, S. L., Peltola, J., Perez, E., Scheffer, I. E., Schulze-Bonhage, A., Somerville, E., Sperling, M., Yacubian, E., Zuberi, S. M., ILAE Commission Classification 2018; 31 (4): 282–95
  • Laser interstitial thermal therapy (LITT): Seizure outcomes for refractory mesial temporal lobe epilepsy. Epilepsy & behavior : E&B Le, S., Ho, A. L., Fisher, R. S., Miller, K. J., Henderson, J. M., Grant, G. A., Meador, K. J., Halpern, C. H. 2018; 89: 37–41


    BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative with less cognitive risks compared with traditional surgery for focal drug-resistant epilepsy.OBJECTIVE: We describe seizure outcomes and complications after LITT in our cohort with intractable mesial temporal lobe epilepsy (MTLE).MATERIAL AND METHODS: We prospectively tracked Stanford's MTLE cases treated with LITT from October 2014 to October 2017. Primary endpoints were seizure outcomes by (1) Engel classification and (2) reduction in baseline seizure frequency. Secondary outcomes were postablation complications.RESULTS: A total of 30 patients underwent selective amygdalohippocampotomy via LITT. Mesial temporal sclerosis (MTS) was present in 23/30 (77%) patients. Median follow-up was 18 ± 12 months (range: 6-44 months). Almost all 28/29 (97%) patients had >50% reduction, and 22/29 (76%) patients had >90% reduction in seizure frequency. Engel Class I outcome was achieved in 18/29 (62%) patients; with complete seizure freedom in 9/29 (31%) patients (Engel Class IA). Three (10%) patients have had only focal aware seizures (Engel Class 1B). Seizures only occurred with medication withdrawal in 6/29 (21%) patients (Engel Class ID). Class II was achieved by 6/29 (21%) and Class III by 5/29 (17%) patients. Complications included perioperative seizures in 10/29 (34%) and nonseizure complaints in 6/29 (21%) patients. Three (10%) patients had neurological deficits including one permanent superior quadrantanopsia, one transient trochlear, and one transient oculomotor nerve palsy.CONCLUSIONS: Overall, Engel Class I outcome was achieved in 62% of patients with MTLE, and 97% of patients achieved >50% seizure frequency reduction. Complications were largely temporary, though there was one persistent visual field deficit. Laser ablation is well-tolerated and offers marked seizure reduction for the majority of patients.

    View details for DOI 10.1016/j.yebeh.2018.09.040

    View details for PubMedID 30384097

  • Return of individual results in epilepsy genomic research: A view from the field EPILEPSIA Ottman, R., Freyer, C., Mefford, H. C., Poduri, A., Lowenstein, D. H., Epilepsy Return Results Workshop 2018; 59 (9): 1635-1642


    Genomic findings are emerging rapidly in 2 large, closely related epilepsy research consortia: the Epilepsy Phenome/Genome Project and Epi4K. Disclosure of individual results to participants in genomic research is increasingly viewed as an ethical obligation, but strategies for return of results were not included in the design of these consortia, raising complexities in establishing criteria for which results to offer, determining participant preferences, managing the large number of sites involved, and covering associated costs. Here, we describe the challenges faced, alternative approaches considered, and progress to date. Experience from these 2 consortia illustrates the importance, for genomic research in epilepsy and other disorders, of including a specific plan for return of results in the study design, with financial support for obtaining clinical confirmation and providing ongoing support for participants. Participant preferences for return of results should be established at the time of enrollment, and methods for allowing future contacts with participants should be included. In addition, methods should be developed for summarizing meaningful, comprehensible information about findings in the aggregate that participants can access in an ongoing way.

    View details for DOI 10.1111/epi.14530

    View details for Web of Science ID 000443303400006

    View details for PubMedID 30098010

    View details for PubMedCentralID PMC6119474

  • The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know? EPILEPTIC DISORDERS Brodie, M. J., Zuberi, S. M., Scheffer, I. E., Fisher, R. S. 2018; 20 (2): 77–87


    The International League against Epilepsy (ILAE) published in the April 2017 edition of Epilepsia three companion articles on the classification of seizures and the epilepsies. These represent a long-awaited update on the original 1981 and 1989 publications and provide a modern descriptive template. The new classification presents three levels of terminology, involving seizure types, epilepsy types, and syndromes. In this fourth paper, we present an interpretation of these new concepts for people with epilepsy and those who care for them, as well as for young medical doctors not specialized in epilepsy and nurses. Our goal in writing this paper is to ensure that everyone is speaking and understanding the same language, which is fundamental to the optimal management of people with epilepsy.

    View details for DOI 10.1684/epd.2018.0957

    View details for Web of Science ID 000431251100001

    View details for PubMedID 29620013

  • Repetitive transcranial magnetic stimulation directed to a seizure focus localized by high-density EEG: A case report. Epilepsy & behavior case reports Fisher, R., Zhou, J., Fogarty, A., Joshi, A., Markert, M., Deutsch, G. K., Velez, M. 2018; 10: 47–53


    We demonstrate feasibility of using high-density EEG to map a neocortical seizure focus in conjunction with delivery of magnetic therapy. Our patient had refractory seizures affecting the left leg. A five-day course of placebo stimulation followed a month later by active rTMS was directed to the mapped seizure dipole. Active rTMS resulted in reduced EEG spiking, and shortening of seizure duration compared to placebo. Seizure frequency, however, improved similarly in both placebo and active treatment stages. rTMS-evoked EEG potentials demonstrated that a negative peak at 40 ms - believed to represent GABAergic inhibition - was enhanced by stimulation.

    View details for PubMedID 29984172

  • The Next Paradigm Change in EEG Recording: What Will it Mean for EEG Technologists? The Neurodiagnostic journal Fisher, R. S., Burdelle, M. E. 2018; 58 (3): 140–42


    Several companies are developing an EEG recording system that uses dry, wireless electrodes, and one has recently been approved by the Food and Drug Administration (FDA) for medical use. Today, the quality of EEG signals recorded by these dry systems may not always match those of conventionally applied electrodes, but the gap is closing fast. As dry, wireless EEG systems find their way into hospitals and clinics over the next few years, the job of the EEG technologist will change. Dry systems can be placed on like a cap and, after a few minutes of adjustment, begin broadcasting EEG. No longer will it be as necessary to spend time meticulously measuring, cleaning, affixing, and adjusting electrodes on the scalp. This upcoming time of rapid change can be an opportunity to redefine the role of the EEG technologist.

    View details for DOI 10.1080/21646821.2018.1490105

    View details for PubMedID 30257173

  • The Revised Definition and Classification of Epilepsy for Neurodiagnostic Technologists. The Neurodiagnostic journal Fisher, R. S., Bonner, A. M. 2018; 58 (1): 1–10


    The definition of who has epilepsy, classification of seizure types, and types of epilepsy have all recently been revised. The classical definition of epilepsy as a person having two or more unprovoked seizures more than 24hours apart has been expanded also to include those with one seizure and a high likelihood (more than 60%) of having another. In the new definition, epilepsy is considered to be resolved when a person is seizure-free for 10years, the terminal 5 being off seizure medicines, or when an age-dependent syndrome has been outgrown. The new seizure type classification revises the 1981 system but maintains the primary distinction of focal- versus generalized-onset seizures. Seizures also can be of unknown onset. Focal seizures may demonstrate retention or impairment of awareness, resulting in focal-aware or focal-impaired awareness seizures. Several new focal and generalized seizure types are introduced. Classification of the epilepsies is now by grouping of seizure types, etiologies, comorbidities, and epilepsy syndromes. The goal of the new terminology is greater clarity of communication and more accurate grouping of seizure types for research. Neurodiagnostic technologists can be of great help in observing clinical and electrographic features that will define the type of seizure.

    View details for PubMedID 29562876

  • Repetitive transcranial magnetic stimulation directed to a seizure focus localized by high-density EEG: A case report EPILEPSY & BEHAVIOR CASE REPORTS Fisher, R., Zhou, J., Fogarty, A., Joshi, A., Markert, M., Deutsch, G. K., Velez, M. 2018; 10: 47–53
  • The new definition and classification of seizures and epilepsy. Epilepsy research Falco-Walter, J. J., Scheffer, I. E., Fisher, R. S. 2018; 139: 73–79


    This review discusses the updated classifications of seizures and the epilepsies, which were recently published by the International League Against Epilepsy (ILAE). While it is always a challenge to learn a new classification system, particularly one that has remained essentially unchanged for over three decades, these new classifications allow for the inclusion of some previously unclassifiable seizure types and utilize more intuitive terminology. In this review, we specifically discuss the use of these new classifications for patients, clinicians, and researchers.

    View details for PubMedID 29197668

  • A Comment on Driving and Neurologic Impairment MAYO CLINIC PROCEEDINGS Fisher, R. S., Drazkowski, J. F. 2017; 92 (9): 1326–27

    View details for PubMedID 28870352

  • How long for epilepsy remission in the ILAE definition? EPILEPSIA Fisher, R. S., Acevedo, C., Arzimanoglou, A., Bogacz, A., Cross, J., Elger, C. E., Engel, J., Forsgren, L., French, J. A., Hesdorffer, D. C., Lee, B., Mathern, G. W., Moshe, S. L., Perucca, E., Scheffer, I. E., Tomson, T., Watanabe, M., Wiebe, S. 2017; 58 (8): 1486–87

    View details for PubMedID 28799662

  • Response to the numbering of seizure types EPILEPSIA Fisher, R. S., Cross, J., D'Souza, C., French, J. A., Haut, S., Higurashi, N., Hirsch, E., Jansen, F. E., Lagae, L., Moshe, S. L., Korey, S. R., Purpura, D. P., Peltola, J., Roulet Perez, E., Scheffer, I. E., Schulze-Bonhage, A., Somerville, E., Sperling, M., Yacubian, E., Zuberi, S. M. 2017; 58 (7): 1300–1301

    View details for PubMedID 28677853

  • The New Classification of Seizures by the International League Against Epilepsy 2017 CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Fisher, R. S. 2017; 17 (6)


    This review presents the newly developed International League Against Epilepsy (ILAE) 2017 classification of seizure types.The fundamental distinction is between seizures that begin focally in one hemisphere of the brain, generalized onset seizures that apparently originate in both hemispheres, and seizures of unknown onset. Focal seizures optionally can be subclassified according to whether awareness (a surrogate marker for consciousness) is intact or impaired. The next level of classification for focal seizures is motor (with subgroups automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic), non-motor (with subgroups autonomic, behavior arrest, cognitive, emotional, sensory), and focal to bilateral tonic-clonic. Generalized seizures are categorized as motor (tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms) and non-motor/absence (typical, atypical, myoclonic, eyelid myoclonia). The classification allows new types of focal seizures and a few new generalized seizures, and clarifies terms used to name seizures.

    View details for DOI 10.1007/s11910-017-0758-6

    View details for PubMedID 28425015

  • Instruction manual for the ILAE 2017 operational classification of seizure types EPILEPSIA Fisher, R. S., Cross, J. H., D'Souza, C., French, J. A., Haut, S. R., Higurashi, N., Hirsch, E., Jansen, F. E., Lagae, L., Moshe, S. L., Peltola, J., Perez, E. R., Scheffer, I. E., Schulze-Bonhage, A., Somerville, E., Sperling, M., Yacubian, E. M., Zuberi, S. M. 2017; 58 (4): 531-542


    This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and examples. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor-onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic, or tonic-clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic-clonic, epileptic spasms, or behavior arrest. This "users' manual" for the ILAE 2017 seizure classification will assist the adoption of the new system.

    View details for DOI 10.1111/epi.13671

    View details for Web of Science ID 000398861000009

    View details for PubMedID 28276064

  • Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology EPILEPSIA Fisher, R. S., Cross, J. H., French, J. A., Higurashi, N., Hirsch, E., Jansen, F. E., Lagae, L., Moshe, S. L., Peltola, J., Roulet Perez, E., Scheffer, I. E., Zuberi, S. M. 2017; 58 (4): 522-530


    The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.

    View details for DOI 10.1111/epi.13670

    View details for Web of Science ID 000398861000008

    View details for PubMedID 28276060

  • Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Troester, A. I., Meador, K. J., Irwin, C. P., Fisher, R. S. 2017; 45: 133-141


    Bilateral deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces seizures and is relatively safe but may be accompanied by complaints of memory problems and depression. This study examined incidence of memory and depression adverse events (AE) in the SANTE study blinded phase and their relationship to objective neurobehavioral measures, baseline characteristics, quality of life and long-term neurobehavioral outcome.The neurobehavioral AE and neuropsychological data from a previously reported prospective randomized trial (SANTE) were analyzed. Reliable change indices (RCI) were calculated for memory and mood measures. Analyses examined relationships among AEs, RCIs, demographic and seizure variables, and long-term neurobehavioral outcome.No significant cognitive declines or worsening of depression scores were observed through the blinded phase or in open-label at 7-years. Higher scores were observed at 7 years on measures of executive functions and attention. Depression and memory-related AEs were not associated with reliable change on objective measures or 7-year neurobehavioral outcome. The AEs were without significant impact on life quality. Memory and depression AEs were not related to demographic or seizure characteristics, change in seizure frequency, frequency of AE or depression report.Bilateral ANT DBS was associated with subjective depression and memory AEs during the blinded phase in a minority of patients that were not accompanied by objective, long-term neurobehavioral worsening. Monitoring and neuropsychological assessment of depression and memory are recommended from a theoretical standpoint and because more memory and depression AEs occurred in the active stimulation than control group.

    View details for DOI 10.1016/j.seizure.2016.12.014

    View details for PubMedID 28061418

  • Bad information in epilepsy care EPILEPSY & BEHAVIOR Fisher, R. S. 2017; 67: 133–34

    View details for PubMedID 28034713

  • Vagus Nerve Stimulation: Rapid versus Slow Cycling in a Laboratory Model NEUROTHERAPEUTICS Fisher, R. S. 2016; 13 (3): 590–91

    View details for DOI 10.1007/s13311-016-0441-7

    View details for Web of Science ID 000380679400016

    View details for PubMedID 27185253

    View details for PubMedCentralID PMC4965409

  • Tracking generalized tonic-clonic seizures with a wrist accelerometer linked to an online database SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Velez, M., Fisher, R. S., Bartlett, V., Le, S. 2016; 39: 13-18


    Clinical management of epilepsy and current epilepsy therapy trials rely on paper or electronic diaries often with inaccurate self-reported seizure frequency as the primary outcome. This is the first study addressing the feasibility of detecting and recording generalized tonic-clonic seizures (GTCS) through a biosensor linked to an online seizure database.A prospective trial was conducted with video-EEG (vEEG) in an epilepsy monitoring unit. Patients wore a wristwatch accelerometer that detected shaking and transmitted events via Bluetooth® to a bedside electronic tablet and then via Wi-Fi to an online portal. The watch recorded the date, time, audio, duration, frequency and amplitude of events. Events logged by the watch and recorded in a bedside paper diary were measured against vEEG, the "gold standard."Thirty patients were enrolled and 62 seizures were recorded on vEEG: 31 convulsive and 31 non-convulsive. Twelve patients had a total of 31 convulsive seizures, and of those, 10 patients had 13 GTCS. The watch captured 12/13 (92.3%) GTCS. Watch audio recordings were consistent with seizures in 11/12 (91.6%). Data were successfully transferred to the bedside tablet in 11/12 (91.6%), and to the online database in 10/12 (83.3%) GTCS. The watch recorded 81 false positives, of which 42/81 (51%) were cancelled by the patients. Patients and caregivers verbally reported 15/62 seizures (24.2% sensitivity) but no seizures were recorded on paper logs.Automatic detection and recording of GTCS to an online database is feasible and may be more informative than seizure logging in a paper diary.

    View details for DOI 10.1016/j.seizure.2016.04.009

    View details for PubMedID 27205871

  • Methods for Measuring Seizure Frequency and Severity NEUROLOGIC CLINICS Aghaei-Lasboo, A., Fisher, R. S. 2016; 34 (2): 383-?


    Counting seizures is not simple. Patients may not be aware of their seizures. Adherence to diary entry often is poor. Shake detectors pick up only seizures with rhythmic movements and suffer from false-positive results. Measurement of electrodermal response is a promising technology but sensitivity and specificity for partial seizures are uncertain. Video-electroencephalogram monitoring is accurate but of short duration and performed in an artificial and expensive environment. Invasive electroencephalogram electrodes can detect seizure-like patterns, sometimes of unknown clinical significance. Practical long-term electroencephalogram monitors are under development. Methods to rank seizure severity are subjective. New approaches and solutions are needed.

    View details for DOI 10.1016/j.ncl.2015.11.001

    View details for Web of Science ID 000375503400007

    View details for PubMedID 27086985

  • Serum prolactin in seizure diagnosis Glass half-full or half-empty? NEUROLOGY-CLINICAL PRACTICE Fisher, R. S. 2016; 6 (2): 100–101

    View details for PubMedID 29377043

    View details for PubMedCentralID PMC5720615

  • Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance-The U.S. E-37 Trial. Neuromodulation Fisher, R. S., Afra, P., Macken, M., Minecan, D. N., Bagic, A., Benbadis, S. R., Helmers, S. L., Sinha, S. R., Slater, J., Treiman, D., Begnaud, J., Raman, P., Najimipour, B. 2016; 19 (2): 188-195


    The Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3-5-day Epilepsy Monitoring Unit (EMU) stay and long- term clinical outcomes of the device stimulating in all modes.The E-37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR(®) in subjects with drug-resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events.Twenty implanted subjects (ages 21-69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six-months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3).The Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

    View details for DOI 10.1111/ner.12376

    View details for PubMedID 26663671

  • Stereotactic laser ablation of the splenium for intractable epilepsy. Epilepsy & behavior case reports Ho, A. L., Miller, K. J., Cartmell, S., Inoyama, K., Fisher, R. S., Halpern, C. H. 2016; 5: 23-26


    Partial or complete corpus callosotomies have been applied, traditionally via open surgical or radiosurgical approaches, for the treatment of epilepsy in patients with multifocal tonic, atonic, or myoclonic seizures. Minimally invasive methods, such as MRI-guided laser interstitial thermal ablation (MTLA), are being employed to functionally remove or ablate seizure foci in the treatment of epilepsy. This therapy can achieve effectiveness similar to that of traditional resection, but with reduced morbidity compared with open surgery. Here, we present a patient with a history of prior partial corpus callosotomy who continued to suffer from medically refractory epilepsy with bisynchronous onset. We report on the utilization of laser ablation of the splenium in this patient to achieve full corpus callosotomy. Adequate ablation of the splenial remnant was confirmed by postoperative MRI imaging, and at four-month follow-up, the patient's seizure frequency had dropped more than 50%. This is the first reported instance of laser ablation of the splenium to achieve full corpus callosotomy following a previous unsuccessful anterior callosotomy in a patient with intractable generalized epilepsy.

    View details for DOI 10.1016/j.ebcr.2015.12.003

    View details for PubMedID 26955518

  • Brain stimulation for epilepsy TREATMENT OF EPILEPSY, 4TH EDITION Bergey, G. K., Fisher, R. S., Shorvon, S., Perucca, E., Engel, J. 2016: 967–79
  • Frequency-selective control of cortical and subcortical networks by central thalamus ELIFE Liu, J., Lee, H. J., Weitz, A. J., Fang, Z., Lin, P., Choy, M., Fisher, R., Pinskiy, V., Tolpygo, A., Mitra, P., Schiff, N., Lee, J. H. 2015; 4


    Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation.

    View details for DOI 10.7554/eLife.09215

    View details for Web of Science ID 000367511000001

    View details for PubMedCentralID PMC4721962

  • Frequency-selective control of cortical and subcortical networks by central thalamus. eLife Liu, J., Lee, H. J., Weitz, A. J., Fang, Z., Lin, P., Choy, M., Fisher, R., Pinskiy, V., Tolpygo, A., Mitra, P., Schiff, N., Lee, J. H. 2015; 4: e09215


    Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation.

    View details for DOI 10.7554/eLife.09215

    View details for PubMedID 26652162

    View details for PubMedCentralID PMC4721962

  • Stimulation of the medial septum should benefit patients with temporal lobe epilepsy MEDICAL HYPOTHESES Fisher, R. S. 2015; 84 (6): 543-550


    Electrical stimulation of the septal nuclei via deep brain stimulating electrodes is proposed as a potentially beneficial therapy for medication-resistant temporal lobe epilepsy. In a multicenter study, stimulation of anterior thalamus was shown to reduce numbers of seizures, but decrease was only in the range of 40%. This might be improved with septal stimulation, which has strong and direct reciprocal connections with the hippocampal formation, the structure most involved in temporal lobe epilepsy. Medial septal neurons drive a 3-12Hz theta rhythm in hippocampus of rodents. Theta rhythm is less obvious in human hippocampus, but it is present and it varies with cognitive tasks. The hippocampal theta rhythm is disrupted by seizures. In animal models, restoration of theta by sensory stimulation, septal electrical stimulation or cholinergic drugs infused into septum ameliorates seizures. Seizure activity in hippocampus is faithfully reflected in septal nuclei, and septum sometimes leads the seizure activity. A subset of patients with temporal lobe epilepsy have structural enlargement of their septal nuclei. At high levels of intensity, septal stimulation is subjectively pleasurable and strongly reinforcing. Rats will repeatedly press a bar to stimulate their septum. Initial experience with human septal stimulation in the 1950s was not favorable, with ineffective therapy for schizophrenia and a high rate of surgical complications. Subsequent experience in 50-100 pain patients employing modern neurosurgical techniques was more favorable and demonstrated septal stimulation to be safe and tolerable. The current state of knowledge is sufficient to consider design of a clinical trial of medial septal stimulation in selected patients with medication-resistant temporal lobe epilepsy.

    View details for DOI 10.1016/j.mehy.2015.02.016

    View details for Web of Science ID 000355357600004

    View details for PubMedID 25771138

  • Use of an online epilepsy diary to characterize repetitive seizures EPILEPSY & BEHAVIOR Fisher, R. S., Bartfeld, E., Cramer, J. A. 2015; 47: 66-71


    Little is known about patterns of seizures that occur multiple times a day, sometimes called clusters or serial seizures.The online diary, My Epilepsy Diary (MED), provided self-reported data from community-based patients to describe the characteristics of clusters.We used MED data to define a population of 5098 community outpatients, including 1177 who specified time of multiple seizures in a 24-hour period. Outcomes included cluster prevalence and frequency, distribution of interseizure time intervals, as well as the types of triggers commonly reported.One-fourth of days with any seizures included clusters for these patients. Most days with clusters included 2 seizures, with >5 events occurring in only 10% of days. One-third of seizures occurred within 3h of the initial event and two-thirds within 6h. When more than 2 seizures occurred, the time to the next seizure decreased from an average of over 2h (to the 3rd event) to a quarter-hour (from the 4th to the 5th event).My Epilepsy Diary data have provided the first overview of cluster seizures in a large community-based population. Treatments with less than 3-hour duration of action would be bioavailable at the time of only one-third of subsequent seizures. Although limited by the self-reported and observational nature of the diary data, some general patterns emerge and can help to focus questions for future studies.

    View details for DOI 10.1016/j.yebeh.2015.04.022

    View details for Web of Science ID 000356366900011

    View details for PubMedID 26046724

  • Redefining epilepsy CURRENT OPINION IN NEUROLOGY Fisher, R. S. 2015; 28 (2): 130-135


    In 2014, the definition of epilepsy was revised by the International League Against Epilepsy (ILAE).A conceptual definition of epilepsy was proposed by the ILAE in 2005, as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by its psychosocial consequences. Practical application of the epilepsy definition usually is taken to mean at least two unprovoked seizures more than 24 h apart, but a 2014 practical definition refines the description. With this definition, epilepsy is a disease of the brain with either: (1) at least two unprovoked (or reflex) seizures occurring more than 24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals past the applicable age of an age-dependent epilepsy syndrome or those who have remained seizure-free for the past 10 years, with no seizure medicines for the past 5 years.A consensus process has refined the definition of epilepsy.

    View details for DOI 10.1097/WCO.0000000000000174

    View details for PubMedID 25734953

  • Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology Salanova, V., Witt, T., Worth, R., Henry, T. R., Gross, R. E., Nazzaro, J. M., Labar, D., Sperling, M. R., Sharan, A., Sandok, E., Handforth, A., Stern, J. M., Chung, S., Henderson, J. M., French, J., Baltuch, G., Rosenfeld, W. E., Garcia, P., Barbaro, N. M., Fountain, N. B., Elias, W. J., Goodman, R. R., Pollard, J. R., Tröster, A. I., Irwin, C. P., Lambrecht, K., Graves, N., Fisher, R. 2015; 84 (10): 1017-1025


    To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy.This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries.The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.

    View details for DOI 10.1212/WNL.0000000000001334

    View details for PubMedID 25663221

  • Electroencephalographic features of moyamoya in adults CLINICAL NEUROPHYSIOLOGY Frechette, E. S., Bell-Stephens, T. E., Steinberg, G. K., Fisher, R. S. 2015; 126 (3): 481-485


    Electroencephalography is useful for evaluating transient neurological events in the setting of moyamoya disease.EEG findings of adults with moyamoya seen at a large moyamoya referral center are summarized. Patients were identified by retrospective chart review.EEGs were ordered after cerebral revascularization for altered mental status, aphasia, limb shaking, or facial twitching. Among the study population of 103 patients having EEGs, 24% of adults with moyamoya had a history of clinical seizures. Ischemic or hemorrhagic strokes were associated with a twofold relative risk of seizures. Overall, 90% of EEGs were abnormal, most commonly focally (78%), or diffusely slow (68%). Epileptiform EEG discharges were seen in 24%. Whereas hemispheres with an ischemic stroke had a 19% risk of epileptiform discharges and an 8% risk of seizures on EEG, hemispheres with hemorrhagic stroke had a 35% risk of epileptiform discharges and 19% risk of seizures on EEG. Focal amplitude attenuation was seen in 19%, breach rhythm in 15%, rhythmic delta in 14%, and electrographic seizures in 12%.Seizures and epileptiform EEG changes are common in patients with moyamoya disease.Transient events in patients with moyamoya can result from seizures as well as ischemia.

    View details for DOI 10.1016/j.clinph.2014.06.033

    View details for Web of Science ID 000349616700010

    View details for PubMedID 25065300

  • Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations. NeuroImage Weitz, A. J., Fang, Z., Lee, H. J., Fisher, R. S., Smith, W. C., Choy, M., Liu, J., Lin, P., Rosenberg, M., Lee, J. H. 2015; 107: 229-241


    Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.

    View details for DOI 10.1016/j.neuroimage.2014.10.039

    View details for PubMedID 25462689

  • Vagus nerve stimulation magnet activation for seizures: a critical review. Acta neurologica Scandinavica Fisher, R. S., Eggleston, K. S., Wright, C. W. 2015; 131 (1): 1-8


    Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0-89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15-67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation.

    View details for DOI 10.1111/ane.12288

    View details for PubMedID 25145652

  • The Personal Impact of Epilepsy Scale (PIES) EPILEPSY & BEHAVIOR Fisher, R. S., Nune, G., Roberts, S. E., Cramer, J. A. 2015; 42: 140-146


    The impact of epilepsy is manifest by effects related to seizures and side effects of therapy and comorbidities such as depression. This report describes the development of a brief patient-reported outcome (PRO) instrument, the Personal Impact of Epilepsy Scale (PIES), to measure the influence of epilepsy overall and in each of these domains.Instrument development followed standard procedures and an FDA Guidance. People with epilepsy were surveyed with open-ended questions to derive major themes of their concerns, resulting in 4 key areas: seizures, side effects, comorbidities, and overall quality of life (QOL). A preliminary set of 152 questions was based on these themes and completed by 50 patients, age 42.7 (range: 21-71) years, concurrent with comparator instruments, including the NH Seizure Severity Scale (NHSSS), the Liverpool Adverse Events Profile (LAEP), the Quality of Life in Epilepsy (QOLIE-31) scale, the Beck Depression Inventory, and the Epilepsy Foundation Depression: A Checklist. A multiple regression model indicated which PIES measures were associated with scores from the comparator instruments. Questions in each of the domains were selected for correlations and nonduplication. Test-retest consistency at a 3-day interval was completed by 38 subjects and a final set of questions constructed.The final question set comprised 25 items: 9 about characteristics of seizures, 7 about medication side effects, 8 about comorbidities, and 1 about overall quality of life. All items had 5 response choices (0-4), with higher scores reflecting more negative status. A total of 46 subjects completed the 25 questions. Cronbach's alpha was 0.87, indicating good internal consistency. Each of the three domains correlated well with the overall QOL item. The questions pertaining to seizures correlated with the NHSSS, the side effect questions with the LAEP, and the comorbidity questions with the QOLIE-31.The PIES provides a simple, brief PRO measure as a profile of overall impact of seizures, medication side effects, comorbidities, and overall QOL for people with epilepsy. Further study will explore sensitivity to change quantification of the minimal clinically significant change.

    View details for DOI 10.1016/j.yebeh.2014.09.060

    View details for PubMedID 25450530


    View details for PubMedID 25382823

  • Untitled EPILEPSIA Fisher, R. S. 2014; 55 (8): 1153

    View details for DOI 10.1111/epi.12613

    View details for Web of Science ID 000342236400008

    View details for PubMedID 24981785

  • Ictal tachycardia: The head-heart connection SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Eggleston, K. S., Olin, B. D., Fisher, R. S. 2014; 23 (7): 496-505


    Epileptic seizures can lead to changes in autonomic function affecting the sympathetic, parasympathetic, and enteric nervous systems. Changes in cardiac signals are potential biomarkers that may provide an extra-cerebral indicator of ictal onset in some patients. Heart rate can be measured easily when compared to other biomarkers that are commonly associated with seizures (e.g., long-term EEG), and therefore it has become an interesting parameter to explore for detecting seizures. Understanding the prevalence and magnitude of heart rate changes associated with seizures, as well as the timing of such changes relative to seizure onset, is fundamental to the development and use of cardiac based algorithms for seizure detection. We reviewed 34 articles that reported the prevalence of ictal tachycardia in patients with epilepsy. Scientific literature supports the occurrence of significant increases in heart rate associated with ictal events in a large proportion of patients with epilepsy (82%) using concurrent electroencephalogram (EEG) and electrocardiogram (ECG). The average percentage of seizures associated with significant heart rate changes was similar for generalized (64%) and partial onset seizures (71%). Intra-individual variability was noted in several articles, with the majority of studies reporting significant increase in heart rate during seizures originating from the temporal lobe. Accurate detection of seizures is likely to require an adjustable threshold given the variability in the magnitude of heart rate changes associated with seizures within and across patients.

    View details for DOI 10.1016/j.seizure.2014.02.012

    View details for PubMedID 24698385

  • Electrical brain stimulation for epilepsy NATURE REVIEWS NEUROLOGY Fisher, R. S., Velasco, A. L. 2014; 10 (5): 261-270


    Neurostimulation enables adjustable and reversible modulation of disease symptoms, including those of epilepsy. Two types of brain neuromodulation, comprising anterior thalamic deep brain stimulation and responsive neurostimulation at seizure foci, are supported by Class I evidence of effectiveness, and many other sites in the brain have been targeted in small trials of neurostimulation therapy for seizures. Animal studies have mainly assisted in the identification of potential neurostimulation sites and parameters, but much of the clinical work is only loosely based on fundamental principles derived from the laboratory, and the mechanisms by which brain neurostimulation reduces seizures remain poorly understood. The benefits of stimulation tend to increase over time, with maximal effect seen typically 1-2 years after implantation. Typical reductions of seizure frequency are approximately 40% acutely, and 50-69% after several years. Seizure intensity might also be reduced. Complications from brain neurostimulation are mainly associated with the implantation procedure and hardware, including stimulation-related paraesthesias, stimulation-site infections, electrode mistargeting and, in some patients, triggered seizures or even status epilepticus. Further preclinical and clinical experience with brain stimulation surgery should lead to improved outcomes by increasing our understanding of the optimal surgical candidates, sites and parameters.

    View details for DOI 10.1038/nrneurol.2014.59

    View details for PubMedID 24709892

  • ILAE Official Report: A practical clinical definition of epilepsy EPILEPSIA Fisher, R. S., Acevedo, C., Arzimanoglou, A., Bogacz, A., Cross, J. H., Elger, C. E., Engel, J., Forsgren, L., French, J. A., Glynn, M., Hesdorffer, D. C., Lee, B. I., Mathern, G. W., Moshe, S. L., Perucca, E., Scheffer, I. E., Tomson, T., Watanabe, M., Wiebe, S. 2014; 55 (4): 475-482


    Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

    View details for DOI 10.1111/epi.12550

    View details for PubMedID 24730690

  • Final Comments on the Process: ILAE Definition of Epilepsy EPILEPSIA Fisher, R. S. 2014; 55 (4): 492–93

    View details for DOI 10.1111/epi.12585

    View details for Web of Science ID 000334657000011

    View details for PubMedID 24731068

  • Rehospitalization and emergency department use rates before and after vagus nerve stimulation for epilepsy: use of state databases to provide longitudinal data across multiple clinical settings. Neuromodulation Kalanithi, P. S., Arrigo, R. T., Tran, P., Gephart, M. H., Shuer, L., Fisher, R., Boakye, M. 2014; 17 (1): 60-65

    View details for DOI 10.1111/ner.12051

    View details for PubMedID 23551457

  • High-Frequency Oscillations Recorded on the Scalp of Patients With Epilepsy Using Tripolar Concentric Ring Electrodes. IEEE journal of translational engineering in health and medicine Besio, W. G., Martinez-Juarez, I. E., Makeyev, O., Gaitanis, J. N., Blum, A. S., Fisher, R. S., Medvedev, A. V. 2014; 2: 2000111


    Epilepsy is the second most prevalent neurological disorder ([Formula: see text]% prevalence) affecting [Formula: see text] million people worldwide with up to 75% from developing countries. The conventional electroencephalogram is plagued with artifacts from movements, muscles, and other sources. Tripolar concentric ring electrodes automatically attenuate muscle artifacts and provide improved signal quality. We performed basic experiments in healthy humans to show that tripolar concentric ring electrodes can indeed record the physiological alpha waves while eyes are closed. We then conducted concurrent recordings with conventional disc electrodes and tripolar concentric ring electrodes from patients with epilepsy. We found that we could detect high frequency oscillations, a marker for early seizure development and epileptogenic zone, on the scalp surface that appeared to become more narrow-band just prior to seizures. High frequency oscillations preceding seizures were present in an average of 35.5% of tripolar concentric ring electrode data channels for all the patients with epilepsy whose seizures were recorded and absent in the corresponding conventional disc electrode data. An average of 78.2% of channels that contained high frequency oscillations were within the seizure onset or irritative zones determined independently by three epileptologists based on conventional disc electrode data and videos.

    View details for DOI 10.1109/JTEHM.2014.2332994

    View details for PubMedID 27170874

  • How Can We Identify Ictal and Interictal Abnormal Activity? Workshop on Issues in Clinical Epileptology - A View from the Bench held in honor of Phil Fisher, R. S., Scharfman, H. E., deCurtis, M. SPRINGER. 2014: 3–23


    The International League Against Epilepsy (ILAE) defined a seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain." This definition has been used since the era of Hughlings Jackson, and does not take into account subsequent advances made in epilepsy and neuroscience research. The clinical diagnosis of a seizure is empirical, based upon constellations of certain signs and symptoms, while simultaneously ruling out a list of potential imitators of seizures. Seizures should be delimited in time, but the borders of ictal (during a seizure), interictal (between seizures) and postictal (after a seizure) often are indistinct. EEG recording is potentially very helpful for confirmation, classification and localization. About a half-dozen common EEG patterns are encountered during seizures. Clinicians rely on researchers to answer such questions as why seizures start, spread and stop, whether seizures involve increased synchrony, the extent to which extra-cortical structures are involved, and how to identify the seizure network and at what points interventions are likely to be helpful. Basic scientists have different challenges in use of the word 'seizure,' such as distinguishing seizures from normal behavior, which would seem easy but can be very difficult because some rodents have EEG activity during normal behavior that resembles spike-wave discharge or bursts of rhythmic spiking. It is also important to define when a seizure begins and stops so that seizures can be quantified accurately for pre-clinical studies. When asking what causes seizures, the transition to a seizure and differentiating the pre-ictal, ictal and post-ictal state is also important because what occurs before a seizure could be causal and may warrant further investigation for that reason. These and other issues are discussed by three epilepsy researchers with clinical and basic science expertise.

    View details for PubMedID 25012363

  • Deep brain stimulation for epilepsy. Handbook of clinical neurology Fisher, R. S. 2013; 116: 217-234


    Deep brain stimulation for seizures has been applied to cerebellum, caudate, locus coeruleus, subthalamic nucleus, mammillary bodies, centromedian thalamus, anterior nucleus of thalamus, hippocampus and amygdala, hippocampal commissure, corpus callosum, neocortex, and occasionally to other sites. Animal and clinical studies have primarily investigated seizure prevention and, to a lessersmaller extent, seizure interruption. No studies have yet shown stimulation able to cure epilepsy. A wide variety of stimulation parameters have been employed in multiple different combinations of frequencies, amplitudes, and durations. Literature review identifies at least 52 clinical studies of brain stimulation for epilepsy in 817 patients. Two studies were large, randomized, and controlled, one in the anterior nucleus of thalamus and another at the cortical or hippocampal seizure focus; both of these studies showed efficacy and tolerability of stimulation. Many questions remain. We do not know the mechanisms, the best stimulation parameters, the best patient population, or how to predict benefit in advance. We do not know why benefit of neurostimulation for epilepsy seems to increase over time or whether there are long-term deleterious effects. All of these questions may be answerable with a combination of laboratory research and clinical experience.

    View details for DOI 10.1016/B978-0-444-53497-2.00017-6

    View details for PubMedID 24112896

  • Seizure diaries for clinical research and practice: Limitations and future prospects EPILEPSY & BEHAVIOR Fisher, R. S., Blum, D. E., Diventura, B., Vannest, J., Hixson, J. D., Moss, R., Herman, S. T., Fureman, B. E., French, J. A. 2012; 24 (3): 304-310


    An NINDS-sponsored conference in April of 2011 reviewed issues in epilepsy clinical trials. One goal was to clarify new electronic methods for recording seizure information and other data in clinical trials.This selective literature review and compilation of expert opinion considers advantages and limitations of traditional paper-based seizure diaries in comparison to electronic diaries.Seizure diaries are a type of patient-reported outcome. All seizure diaries depend first on accurate recognition and recording of seizures, which is a problem since about half of seizures recorded during video-EEG monitoring are not known to the patient. Reliability of recording is another key issue. Diaries may not be at hand after a seizure, lost or not brought to clinic visits. On-line electronic diaries have several potential advantages over paper diaries. Smartphones are increasingly accessible as data entry gateways. Data are not easily lost and are accessible from clinic. Entries can be time-stamped and provide immediate feedback, validation or reminders. Data can also can be graphed and pasted into an EMR. Disadvantages include need for digital sophistication, higher cost, increased setup time, and requiring attention to potential privacy issues. The Epilepsy Diary by and Irody, Inc. has over 13,000 registrants and SeizureTracker over 10,000, and both are used for clinical and research purposes. Some studies have documented patient preference and increased compliance for electronic versus paper diaries. Seizure diaries can be challenging in the pediatric population. Children often have multiple seizure types and limited reporting of subjective symptoms. Multiple caregivers during the day require more training to produce reliable and consistent data. Diary-based observational studies have the advantages of low cost, allowing locus-of-control by the patient and testing in a "real-world" environment. Diary-based studies can also be useful as descriptive "snapshots" of a population. However, the type of information available is very different from that obtained by prospective controlled studies. The act of self-recording observations may itself influence the observation, for example, by causing the subject to attend more vigilantly to seizures after changing medication. Pivotal anti-seizure drug or device trials still mostly rely on paper-based seizure diaries. Industry is aware of the potential advantages of electronic diaries, particularly, the promise of real-time transmission of data, time-stamping of entries, reminders to subjects, and potentially automatic interfaces to other devices. However, until diaries are validated as research tools and the regulatory environment becomes clearer, adoption of new types of diaries as markers for a primary study outcome will be cautious.Recommendations from the conference included: further studies of validity of epilepsy diaries and how they can be used to improve adherence; use and further development of core data sets, such as the one recently developed by NINDS; encouraging links of diaries to electronic sensors; development of diary privacy and legal policies; examination of special pediatric diary issues; development of principles for observational research from diaries; and work with the FDA to make electronic diaries more useful in industry-sponsored clinical trials.

    View details for DOI 10.1016/j.yebeh.2012.04.128

    View details for PubMedID 22652423

  • Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy A Randomized Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Engel, J., McDermott, M. P., Wiebe, S., Langfitt, J. T., Stern, J. M., Dewar, S., Sperling, M. R., Gardiner, I., Erba, G., Fried, I., Jacobs, M., Vinters, H. V., Mintzer, S., Kieburtz, K. 2012; 307 (9): 922-930


    Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ≥12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.Receipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation.Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio = ∞; 95% CI, 11.8 to ∞; P < .001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, -1.0 to 18.1; P = .08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect = 9.9; 95% CI, 2.2 to 17.7; P = .01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate Identifier: NCT00040326.

    View details for DOI 10.1001/jama.2012.220

    View details for Web of Science ID 000301172100020

    View details for PubMedID 22396514

  • Therapeutic devices for epilepsy ANNALS OF NEUROLOGY Fisher, R. S. 2012; 71 (2): 157-168


    Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation (VNS), which continues to develop new technology, is approved for use in the United States. Deep brain stimulation of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to 1 or 2 seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS are split on efficacy, which may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of shake detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of electroencephalography (EEG) is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures, and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience.

    View details for DOI 10.1002/ana.22621

    View details for PubMedID 22367987

  • An online diary for tracking epilepsy EPILEPSY & BEHAVIOR Le, S., Shafer, P. O., Bartfeld, E., Fisher, R. S. 2011; 22 (4): 705-709


    My Epilepsy Diary is a free Web-based application on the public website, available for patients to track epilepsy and to aid clinicians with data-based, individualized management. The first aim of this descriptive study was to outline electronic diary functions. Second, the study retrospectively profiled a large cohort of 2010 calendar year diary users including demographics, seizure types, temporal distribution of seizures, triggers, and use and side effects of antiepileptic drugs (AEDs). A total of 1944 users provided demographic information and 1877 recorded seizure data. Most (64%) users were women. Average age was 29.9±16.0 years. A total of 70,990 seizure entries and 15,630 AED entries were logged. Events were apportioned as 79% seizures and 21% seizure clusters. Specific AEDs were detailed in 7331 entries: monotherapy was used in 18% and polytherapy in 82%. Mood-related side effects were most commonly reported in 19% of 1027 users.

    View details for DOI 10.1016/j.yebeh.2011.08.035

    View details for PubMedID 21975298

  • Benefits of trigeminal nerve stimulation EPILEPSY & BEHAVIOR Fisher, R. S. 2011; 22 (4): 615-616

    View details for DOI 10.1016/j.yebeh.2011.09.024

    View details for Web of Science ID 000298067600001

    View details for PubMedID 22019017

  • Neurostimulation for Epilepsy: Do We Know the Best Stimulation Parameters? EPILEPSY CURRENTS Fisher, R. S. 2011; 11 (6): 203-204

    View details for Web of Science ID 000300152600012

    View details for PubMedID 22130194

    View details for PubMedCentralID PMC3220430

  • Direct brain stimulation is an effective therapy for epilepsy NEUROLOGY Fisher, R. S. 2011; 77 (13): 1220-1221

    View details for DOI 10.1212/WNL.0b013e3182312000

    View details for Web of Science ID 000295253800007

    View details for PubMedID 21917779

  • Detection of seizure-like movements using a wrist accelerometer EPILEPSY & BEHAVIOR Lockman, J., Fisher, R. S., Olson, D. M. 2011; 20 (4): 638-641


    Caregivers of people with epilepsy are commonly concerned about unwitnessed seizures causing injury and even death. The goal of this study was to determine if a wrist-worn motion detector could detect tonic-clonic seizures. Individuals admitted for continuous video/EEG monitoring wore a wristwatch-size device that was programmed to detect rhythmic movements such as those that occur during tonic-clonic seizures. When such movement was detected, the device sent a Bluetooth signal to a computer that registered the time and duration of the movements. Recorded detections were compared with the routinely recorded video/EEG data. Six of 40 patients had a total of eight tonic-clonic seizures. Seven of the eight seizures were detected. Nonseizure movements were detected 204 times, with opportunity for canceling transmission by the patient. Only one false detection occurred during sleep. In principle, this device should allow caregivers of people with tonic-clonic seizures to be alerted when a seizure occurs.

    View details for DOI 10.1016/j.yebeh.2011.01.019

    View details for PubMedID 21450533

  • Direct electrical stimulation for epilepsy: The laboratory evidence EPILEPSIA Graber, K. D., Fisher, R. S. 2010; 51: 86-86
  • Definition of the postictal state: When does it start and end? EPILEPSY & BEHAVIOR Fisher, R. S., Engel, J. J. 2010; 19 (2): 100-104


    The postictal state is the abnormal condition occurring between the end of an epileptic seizure and return to baseline condition. Applying this definition operationally can be difficult, especially for complex partial seizures, where cognitive and sensorimotor impairments merge imperceptibly into the postictal state. Many patients are unaware of even having had a seizure. Electroencephalography sometimes helps to distinguish ictal from postictal periods, but may demonstrate focal slowing both during and after a seizure. Epileptiform electroencephalographic changes do not always correspond precisely to behavioral changes, especially with scalp recordings. The postictal state ends at the interictal state, but this too can be ambiguous. Interictal spikes and spike-waves can be associated with cognitive and behavioral impairments, suggesting that they may represent fragments of ictal episodes. Except where boundaries are clear, it is better to describe a sequence of behaviors and electroencephalographic changes, without labeling arbitrary stages as being ictal or postictal.

    View details for DOI 10.1016/j.yebeh.2010.06.038

    View details for PubMedID 20692877

  • Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy EPILEPSIA Engel, J., McDermott, M. P., Wiebe, S., Langfitt, J. T., Erba, G., Gardiner, I., Stern, J., Dewar, S., Sperling, M. R., Jacobs, M., Kieburtz, K., Early Randomized Surgical Epilepsy 2010; 51 (10): 1978-1986


    To describe the trial design for the multicenter Early Randomized Surgical Epilepsy Trial (ERSET). Patients with pharmacoresistant epilepsy are generally referred for surgical treatment an average of two decades after onset of seizures, often too late to avoid irreversible disability. ERSET was designed to assess the safety and efficacy of early surgical intervention compared to continued pharmacotherapy.ERSET is a randomized controlled, parallel group clinical trial with blinded outcome adjudication. Participants are patients with mesial temporal lobe epilepsy (MTLE) older than the age of 12 who have had pharmacoresistant seizures for not >2 years and are determined by detailed evaluation to be surgical candidates prior to randomization. The primary outcome measure is seizure freedom in the second year of a 2-year follow-up period. Health-related quality of life (HRQOL), neurocognitive function, ancillary outcomes, and adverse events were also measured.Significant methodologic problems addressed by the study design included the following: recruitment of participants early in the course of epilepsy; establishment of operational definitions for "pharmacoresistant" and "early"; and standardization of diagnostic testing, medical treatment, and surgical interventions across multiple centers.Rigorous trial designs to assess surgical interventions in epilepsy are necessary to provide evidence to guide treatment. This article is the first of a series; trial results will be reported in subsequent publications.

    View details for DOI 10.1111/j.1528-1167.2010.02641.x

    View details for Web of Science ID 000282639700007

    View details for PubMedID 20550556

    View details for PubMedCentralID PMC2941700

  • Prospective, Double-Blind, Randomized, Placebo-Controlled Comparison of Acetazolamide Versus Ibuprofen for Prophylaxis Against High Altitude Headache: The Headache Evaluation at Altitude Trial (HEAT) WILDERNESS & ENVIRONMENTAL MEDICINE Gertsch, J. H., Lipman, G. S., Holck, P. S., Merritt, A., Mulcahy, A., Fisher, R. S., Basnyat, B., Allison, E., Hanzelka, K., Hazan, A., Meyers, Z., Odegaard, J., Pook, B., Thompson, M., Slomovic, B., Wahlberg, H., Wilshaw, V., Weiss, E. A., Zafren, K. 2010; 21 (3): 236-243


    High altitude headache (HAH) is the most common neurological complaint at altitude and the defining component of acute mountain sickness (AMS). However, there is a paucity of literature concerning its prevention. Toward this end, we initiated a prospective, double-blind, randomized, placebo-controlled trial in the Nepal Himalaya designed to compare the effectiveness of ibuprofen and acetazolamide for the prevention of HAH.Three hundred forty-three healthy western trekkers were recruited at altitudes of 4280 m and 4358 m and assigned to receive ibuprofen 600 mg, acetazolamide 85 mg, or placebo 3 times daily before continued ascent to 4928 m. Outcome measures included headache incidence and severity, AMS incidence and severity on the Lake Louise AMS Questionnaire (LLQ), and visual analog scale (VAS).Two hundred sixty-five of 343 subjects completed the trial. HAH incidence was similar when treated with acetazolamide (27.1%) or ibuprofen (27.5%; P = .95), and both agents were significantly more effective than placebo (45.3%; P = .01). AMS incidence was similar when treated with acetazolamide (18.8%) or ibuprofen (13.7%; P = .34), and both agents were significantly more effective than placebo (28.6%; P = .03). In fully compliant participants, moderate or severe headache incidence was similar when treated with acetazolamide (3.8%) or ibuprofen (4.7%; P = .79), and both agents were significantly more effective than placebo (13.5%; P = .03).Ibuprofen and acetazolamide were similarly effective in preventing HAH. Ibuprofen was similar to acetazolamide in preventing symptoms of AMS, an interesting finding that implies a potentially new approach to prevention of cerebral forms of acute altitude illness.

    View details for Web of Science ID 000282163300007

    View details for PubMedID 20832701

  • Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy EPILEPSIA Fisher, R., Salanova, V., Witt, T., Worth, R., Henry, T., Gross, R., Oommen, K., Osorio, I., Nazzaro, J., Labar, D., Kaplitt, M., Sperling, M., Sandok, E., Neal, J., Handforth, A., Stern, J., DeSalles, A., Chung, S., Shetter, A., Bergen, D., Bakay, R., Henderson, J., French, J., Baltuch, G., Rosenfeld, W., Youkilis, A., Marks, W., Garcia, P., Barbaro, N., Fountain, N., Bazil, C., Goodman, R., McKhann, G., Krishnamurthy, K. B., Papavassiliou, S., Epstein, C., Pollard, J., Tonder, L., Grebin, J., Coffey, R., Graves, N. 2010; 51 (5): 899-908


    We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy.Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation.One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

    View details for DOI 10.1111/j.1528-1167.2010.02536.x

    View details for PubMedID 20331461

  • What is a classification essay? EPILEPSIA Fisher, R. S. 2010; 51 (4): 714-715

    View details for PubMedID 20394643

  • Tracking epilepsy with an electronic diary ACTA PAEDIATRICA Fisher, R. S. 2010; 99 (4): 516-518

    View details for DOI 10.1111/j.1651-2227.2010.01694.x

    View details for PubMedID 20105139

  • Recurrent Seizures Related to Motor Cortex Stimulator Programming NEUROMODULATION Henderson, J. M., Heit, G., Fisher, R. S. 2010; 13 (1): 37-42


    Objective. Motor cortex stimulation (MCS) is increasingly being utilized for the treatment of intractable pain. While the risks of MCS are relatively low, focal or generalized seizures may be produced during programming of MCS systems. Occasionally, patients may experience seizures hours after programming. In order to understand this phenomenon better, we undertook a retrospective analysis of five patients in whom seizures limited the efficacy of MCS. Methods. A retrospective chart review was performed in five patients who underwent MCS between 2002 and 2006 and who had persistent seizures that limited programming. Results. The initial seizure during programming in these patients occurred at amplitudes of between 4.8 and 6.6 V. Four patients experienced generalized tonic-clonic seizures and one patient experienced focal seizures. Subsequent seizures occurred at amplitudes of between 4.4 and 5.5 V, with a tendency for seizure thresholds to progressively decrease. All five patients experienced at least one seizure occurring many minutes to hours after programming, with no side-effects initially observed once the final settings had been programmed. Four out of five patients were programmed with frequencies documented at between 70 and 90 Hz; documentation on frequency was unavailable for the remaining patient. One patient never achieved adequate pain relief and had the MCS system explanted. Conclusions. Despite the overall safety of MCS for the treatment of chronic pain, seizures during and after programming are a serious risk that should be anticipated. In this group of patients, seizures were associated only with stimulus rates between 70 and 90 Hz. No patient developed chronic epilepsy from the stimulation.

    View details for DOI 10.1111/j.1525-1403.2009.00256.x

    View details for Web of Science ID 000273318200016

    View details for PubMedID 21992763

  • Therapeutic Brain Stimulation for Epilepsy NEUROLOGIC CLINICS Lockman, J., Fisher, R. S. 2009; 27 (4): 1031-?


    DBS has been a possible therapy for epilepsy for more than 30 years, and now it is moving to the point of clinical utility. Animal models have shown efficacy of DBS at several brain regions, although not all animal studies have shown efficacy. Clinically, an array of sites have been explored, including the cerebellum, anterior nucleus of the thalamus, CM nucleus, hippocampus, subthalamic nucleus, brainstem, and corpus callosum; direct stimulation of the cortex has also been explored. Interest in evaluating these sites for treatment of epilepsy has been enhanced by the success of vagus nerve stimulation for epilepsy and DBS for movement disorders. Literature consists of mostly small and uncontrolled studies that are subject to limitations in interpretation. A pivotal large, double-blind controlled trial of anterior nucleus of the thalamus has recently been completed, and it showed efficacy for partial seizures with or without secondary generalization.28 A controlled trial for RNS is underway.57 In addition, pilot studies of hippocampal stimulation 41,43 are expected to lead to more definitive trials of this site.Brain stimulation for epilepsy holds several challenges for the future. Mechanisms of DBS are poorly understood, although investigations are actively being pursued. Little is known about optimal stimulation parameters. DBS has been little examined in cases of intractable generalized epilepsy. Because DBS carries some risk, mainly of hemorrhage and infection, clinicians will need to develop an effective method of identifying the best candidates. DBS is palliative rather than curative, but experience suggests that this relatively new therapy may be of benefit to some people with otherwise untreatable epilepsy.

    View details for DOI 10.1016/j.ncl.2009.06.005

    View details for PubMedID 19853222

  • What clinicians want to know from epilepsy researchers EPILEPSIA Fisher, R. S. 2009; 50 (3): 364-367

    View details for DOI 10.1111/j.1528-1167.2009.02026.x

    View details for PubMedID 19317884

  • Group therapy for patients with psychogenic nonepileptic seizures: A pilot study 58th Annual Meeting of the American-Epilepsy-Society Barry, J. J., Wittenberg, D., Bullock, K. D., Michaels, J. B., Classen, C. C., Fisher, R. S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: 624–29


    Great advances have been made in the diagnosis of people with psychogenic nonepileptic seizures (PNES) since the advent of video/EEG monitoring. However, treatment options for this population have lagged significantly. This pilot study was undertaken to evaluate whether group therapy done with a psychodynamic focus would offer a useful intervention. Twelve patients entered the study and seven completed at least 75% of the 32 weekly sessions. The Beck Depression Inventory and the Global Severity Index of the Symptom Checklist-90 showed improvement as well as an overall decrease in PNES frequency. The data suggest that group therapy focusing on interpersonal issues may benefit patients with PNES.

    View details for DOI 10.1016/j.yebeh.2008.06.013

    View details for Web of Science ID 000260701500008

    View details for PubMedID 18621147

  • Sensitivity and specificity of video alone versus electroencephalography alone for the diagnosis of partial seizures EPILEPSY & BEHAVIOR Chen, D. K., Graber, K. D., Anderson, C. T., Fisher, R. S. 2008; 13 (1): 115-118


    We examined the usefulness of video versus EEG in isolation for the differentiation of epileptic seizures (ES) from psychogenic nonepileptic events (PNEE). Video-EEG recordings of 43 events in 43 patients (27 with ES and 16 with PNEE) were analyzed by experienced clinical epileptologists/electroencephalographers blinded to the patients' clinical histories. Both the video and EEG were scored independently by the same reader for each event. Relying on video recordings alone, the readers correctly identified ES with a sensitivity of 93% and specificity of 94%. Based on EEG data alone, the readers correctly identified ES with a sensitivity of 89% and specificity of 94%. Semiologically, a gradual evolving buildup of visible symptoms, reaching maximal behavioral intensity within 70 seconds of event onset, was a reliable indicator of ES. No patient with ES demonstrated eye closure at the time of peak behavioral manifestations. Although several additional semiologic features were statistically associated with either ES or PNEE, they were less reliably present and, hence, less clinically useful. Correct categorization of some neurobehavioral events can be made by experienced epileptologists on the basis of video or EEG recordings during an event, without simultaneous review of both provided that the full event is recorded. Home video recordings may represent a useful screening tool for a subset of patients with neurobehavioral events of unclear etiology.

    View details for DOI 10.1016/j.yebeh.2008.02.018

    View details for Web of Science ID 000257009400020

    View details for PubMedID 18396110

  • Debate: When does a seizure imply epilepsy? EPILEPSIA Fisher, R. S., Leppik, I. 2008; 49: 7-12


    Epilepsy recently has been defined conceptually as a condition of at least one seizure, with an enduring predisposition to have seizures. It is not yet clear how to make this definition operational and practical. A diagnosis of epilepsy has potentially serious consequences for health, psychosocial well-being, and economics, and, therefore, it should be made with a high level of certainty. A definite diagnosis of epilepsy can be made with two unprovoked seizures at least 24 h apart. This method has the benefit of simplicity and consistency with past epidemiologic studies. Nevertheless, certain circumstances suggest a high likelihood of having a second seizure, as evidenced by common clinical practice of considering treatment after a first unprovoked seizure in conjunction with additional risk factors (surrogate markers). One unifying approach is an operational definition of "definite epilepsy" after two unprovoked seizures at least 24 h apart. An operational definition of "probable epilepsy" can be established with one unprovoked seizure and clinical, electroencephalography (EEG), neuroimaging, genetic, or other information to suggest greater than a 50% chance of having another seizure. "Possible epilepsy" operationally would exist with a single unprovoked seizure and insufficient evidence to predict a high likelihood of recurrence. Future clinical and epidemiologic evidence would allow refinements of the operational definitions.

    View details for DOI 10.1111/j.1528-1167.2008.01921.x

    View details for PubMedID 19087112

  • An Unusual Case of Seizures and Violence PUZZLING CASES OF EPILEPSY, 2ND EDITION Fisher, R. S., Schmidt, D., Schachter, S. C. 2008: 309–12
  • Anti-voltage-gated-potassium channel antibodies can be associated with a variant of Rasmussen encephalitis 61st Annual Meeting of the American-Epilepsy-Society Anderson, C. T., Graber, K. D., Fisher, R. S. WILEY-BLACKWELL. 2007: 34–35
  • Subcortical control of cortical excitability Fisher, R. S., Brown, L., Gale, K. BLACKWELL PUBLISHING. 2007: 410
  • How to get the answer to nearly everything: Using the internet for epilepsy research EPILEPSIA Fisher, R. S. 2007; 48 (7): 1421–22
  • Gender and age differences in expression of GABA(A) receptor subunits in rat somatosensory thalamus and cortex in an absence epilepsy model NEUROBIOLOGY OF DISEASE Li, H., Huguenard, J. R., Fisher, R. S. 2007; 25 (3): 623-630


    Absence epilepsy is more prevalent in females, but reasons for this gender asymmetry are unknown. We reported previously that perinatal treatment of Long-Evans Hooded rats with the cholesterol synthesis inhibitor (CSI) AY9944 causes a life-long increase in EEG spike-wave discharges (SWDs), correlated with decreased expression of GABA(A) receptor subunit gamma2 protein levels in thalamic reticular and ventrobasal nuclei (SS thalamus) [Li, H., Kraus, A., Wu, J., Huguenard, J.R., Fisher, R.S., 2006. Selective changes in thalamic and cortical GABA(A) receptor subunits in a model of acquired absence epilepsy in the rat. Neuropharmacology 51, 121-128]. In this study, we explored time course and gender different effects of perinatal AY9944 treatment on expression of GABA(A) receptor alpha1 and gamma2 subunits in SS thalamus and SS cortex. Perinatal AY9944 treatment-induced decreases in GABA(A) gamma2 receptor subunits in rat SS thalamus and increases in SS cortex are gender and age specific. The findings suggest a mechanism for the higher prevalence of absence epilepsy in female patients.

    View details for DOI 10.1016/j.nbd.2006.11.004

    View details for PubMedID 17208003

  • Intraventricular administration of gabapentin in the rat increases flurothyl seizure threshold. Neurosci Lett Oommen J, Kraus AC, Fisher RS. 2007; 417 (3): 308-11
  • Brain stimulation for epilepsy. Acta neurochirurgica. Supplement Theodore, W. H., Fisher, R. 2007; 97: 261-272


    Brain stimulation has been receiving increasing attention as an alternative therapy for epilepsy that cannot be treated by either antiepileptic medication or surgical resection of the epileptogenic focus. The stimulation methods include transcranial magnetic stimulation (TMS) or electrical stimulation by implanted devices of the vagus nerve (VNS), deep brain structures (DBS) (thalamic or hippocampal), cerebellar or cortical areas. TMS is the simplest and least invasive approach. However, the most common epileptogenic areas (mesial temporal structures) probably lie too deep beneath the surface of the skull for effective TMS. The efficacy of VNS in reducing the frequency or severity of seizures is quite variable and depends on many factors which are currently investigated. VNS is well-tolerated and approved in many countries. DBS is much more invasive than either TMS or VNS. Currently, a number of targets for DBS are investigated including caudate, centromedian or anterior thalamic nuclei, and subthalamic nucleus. Direct stimulation of the epileptic cortical focus is another approach to the neuromodulation in epilepsy. Finally, another line of research investigates the usefulness of implantable seizure detection devices. The current chapter presents the most important evidence on the above methods. Furthermore, other important issues are reviewed such as the selection criteria of patients for brain stimulation and the potential role of brain stimulation in the treatment of depression in epileptic patients.

    View details for PubMedID 17691312

  • New routes for delivery of anti-epileptic medications. Acta neurologica Taiwanica Fisher, R. S., Chen, D. K. 2006; 15 (4): 225-231


    Use of novel drug delivery methods might enhance efficacy and reduce toxicity, in comparison with currently existing oral anti-epileptic drugs (AEDs). Novel methods aim to deliver optimal drug concentration more specifically to the seizure focus or foci. In this review, we first consider unconventional routes of drug delivery to the peripheral system, then potential new methods of targeted CNS drug delivery. Intrathecal or intraventricular AEDs might circumvent systemic toxicity. Drug-eluting wafers could be surgically positioned over an epileptogenic region of brain. Drug can be delivered to a seizure focus by an implanted catheter and subcutaneous pump. Inactive prodrugs, given systemically, can be made active only at the seizure focus, by interaction with locally-released substances. Liposomes and polysomes are engineered slow-release storage vehicles for drugs. Targeting components can hold liposomes near a region of interest, provided that they can penetrate the blood brain barrier. Lastly, we discuss future prospects for the use of transplanted cells and genes as potential vehicles for local delivery of renewable anti-epileptic regimen.

    View details for PubMedID 17214084

  • Conversion disorder AMERICAN JOURNAL OF PSYCHIATRY Stonnington, C. M., Barry, J. J., Fisher, R. S. 2006; 163 (9): 1510-1517

    View details for Web of Science ID 000240205100009

    View details for PubMedID 16946174

  • Selective changes in thalamic and cortical GABA(A) receptor subunits in a model of acquired absence epilepsy in the rat NEUROPHARMACOLOGY Li, H., Kraus, A., Wu, J., Huguenard, J. R., Fisher, R. S. 2006; 51 (1): 121-128


    Neonatal treatment of Long-Evans Hooded rats with the cholesterol synthesis inhibitor (CSI) AY9944 has been shown to increase occurrence of spike-waves in EEG recordings and decrease benzodiazepines sensitivity of GABA(A) receptor-mediated responses in neurons from the thalamic reticular nuclei (nRt, Wu et al., 2004). The present experiments were designed to investigate the changes in the gamma2 and alpha1 subunits of the GABA(A) receptor in CSI model rats as possible mechanisms of these changes. Western blot, immunohistochemistry and real-time PCR techniques were performed to measure the levels of GABA(A) receptor gamma2 and alpha1 subunit transcripts and protein in the nRt and ventrobasal (VB) relay nuclei of thalamus and in somatosensory cortex. In CSI model animals, Western blot results showed that gamma2 subunit expression significantly decreased in thalamus (control, n=6: 0.17+/-0.02 relative to actin vs. CSI model, n=6: 0.11+/-0.01, P<0.05) but neither in cortex nor in hippocampal tissues. Conversely, alpha1 subunit expression decreased in CSI model somatosensory cortex, but not in nRt and VB. The present results demonstrate that neonatal block of cholesterol synthesis produces region- and subunit-specific decreases in GABA(A) receptor subunits in thalamus and cortex. Selective reductions in GABA(A) receptor subunits in thalamus may play a role in pathophysiology of absence epilepsy.

    View details for DOI 10.1016/j.neuropharm.2006.03.003

    View details for PubMedID 16678865

  • Nonepileptic seizures: Clinical case conference: Conversion disorder American Journal of Psychiatry Stonnington CM, Barry JJ, Fisher RS 2006; 163: 1510-1517
  • SANTE (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy) interim report Fisher, R. S., SANTE Study Grp BLACKWELL PUBLISHING. 2006: 332
  • Measuring effects of antiepileptic medication on balance in older people Epilepsy Research Fife TD, Fisher RS, Blum DE 2006; 70: 103-109
  • Use of serum prolactin in diagnosing epileptic seizures - Report of the therapeutics and technology assessment subcommittee of the American academy of neurology NEUROLOGY Chen, D. K., So, Y. T., Fisher, R. S. 2005; 65 (5): 668-675


    The purpose of this article is to review the use of serum prolactin assay in epileptic seizure diagnosis.The authors identified relevant studies in multiple databases and reference lists. Studies that met inclusion criteria were summarized and rated for quality of evidence, and the results were analyzed and pooled where appropriate.Most studies used a serum prolactin of at least twice baseline value as abnormal. For the differentiation of epileptic seizures from psychogenic nonepileptic seizures, one Class I and seven Class II studies showed that elevated serum prolactin was highly predictive of either generalized tonic-clonic or complex partial seizures. Pooled sensitivity was higher for generalized tonic-clonic seizures (60.0%) than for complex partial seizures (46.1%), while the pooled specificity was similar for both (approximately 96%). Data were insufficient to establish validity for simple partial seizures. Two Class II studies were consistent in showing prolactin elevation after tilt-test-induced syncope. Inconclusive data exist regarding the value of serum prolactin following status epilepticus, repetitive seizures, and neonatal seizures.Elevated serum prolactin assay, when measured in the appropriate clinical setting at 10 to 20 minutes after a suspected event, is a useful adjunct for the differentiation of generalized tonic-clonic or complex partial seizure from psychogenic nonepileptic seizure among adults and older children (Level B). Serum prolactin assay does not distinguish epileptic seizures from syncope (Level B). The use of serum PRL assay has not been established in the evaluation of status epilepticus, repetitive seizures, and neonatal seizures (Level U).

    View details for PubMedID 16157897

  • Epileptic seizures and epilepsy: Definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) AKTUELLE NEUROLOGIE Fisher, R. S., Boas, W. V., Blume, W., Elger, C., Genton, P., Lee, P., Engel, J. 2005; 32 (5): 249-252
  • Epileptic seizures and epilepsy: Definitions proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) EPILEPSIA Fisher, R. S., BOAS, W. V., Blume, W., Elger, C., Genton, P., Lee, P., Engel, J. 2005; 46 (4): 470-472


    The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have come to consensus definitions for the terms epileptic seizure and epilepsy. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.

    View details for PubMedID 15816939

  • A blinded pilot study of artwork in a comprehensive epilepsy center population EPILEPSY & BEHAVIOR Anschel, D. J., Dolce, S., Schwartzman, A., Fisher, R. S. 2005; 6 (2): 196-202


    The production of artwork is a complex neurological task. A controlled study of artwork produced by people with epilepsy has not previously been performed. The present report details the results of a three-part study involving 60 subjects from a comprehensive epilepsy center population. Subjects were grouped by the following diagnoses: seizures, partial seizures, complex partial seizures with temporal focus, and nonepileptic events. Data were collected in a blinded fashion. The Formal Elements Art Therapy Scale task showed significant effects in patients with epileptic seizures. The Free Drawing was most sensitive to complex partial seizures with temporal focus, while the Outline was most predictive of nonepileptic events. In addition to giving some insight into the neurological functioning of these subjects, this pilot study provides a basis for the future development of diagnostic tests to be used within this patient group.

    View details for DOI 10.1016/j.yebeh.2004.12.004

    View details for Web of Science ID 000227219000011

    View details for PubMedID 15710304

  • Experimental Electrical Stimulation Therapy for Epilepsy. Current treatment options in neurology Oommen, J. n., Morrell, M. n., Fisher, R. S. 2005; 7 (4): 261–71


    Electrical stimulation of the nervous system is an attractive possible therapy for intractable epilepsy, but only stimulation of the vagus nerve has been subjected to large, controlled, and completed clinical trials. Controlled trials are in progress for intermittent cycling stimulation of the anterior nuclei of the thalamus, and for cortical stimulation at a seizure focus, responsive to detection of seizure onset. Anecdotal experience has been gathered with stimulation of cerebellum, centromedian thalamus, subthalamus, caudate, hippocampus, and brainstem. All stimulation of the central nervous system for epilepsy must be considered experimental.

    View details for PubMedID 15967089

  • Neurostimulation for epilepsy, including a pilot study of anterior nucleus stimulation Clinical Neurosurgery Graves NM, Fisher RS 2005; 52: 1-8
  • Photic- and pattern-induced seizures: expert consensus of the Epilepsy Foundation of America Working Group Epilepsia Harding G, Wilkins AJ, Erba G, Barkley GL, Fisher RS 2005; 46: 1423-5
  • Photic- and pattern-induced seizures: a report by the Epilepsy Foundation of America Working Group Epilepsia Fisher RS, Harding G, Wilkins AJ, Erba G, Barkley G 2005; 46: 1426-1441
  • Neurostimulation for epilepsy, including a pilot study of anterior nucleus stimulation Clinical Neurosurgery Graves NM, Fisher RS 2005; 52: 1-8
  • Focally injected adenosine prevents seizures in the rat EXPERIMENTAL NEUROLOGY Anschel, D. J., Ortega, E. L., Kraus, A. C., Fisher, R. S. 2004; 190 (2): 544-547


    Prophylactic drug injection directly onto a seizure focus has the potential to improve seizure control with fewer side effects than is produced by systemic therapy. Using a dose-response model, we evaluated the effectiveness of adenosine application for focal seizure prophylaxis in 12 rats. Total spikes and electroencephalographic ictal events were reduced significantly by treatment with adenosine compared to control (P < 0.0001). This study demonstrates effectiveness and feasibility in a model system using intracranial injection of adenosine to prevent epileptiform events.

    View details for DOI 10.1016/j.expneurol.2004.07.017

    View details for PubMedID 15530893

  • Peer-reviewed publication: A view from inside EPILEPSIA Fisher, R. S., Powers, L. E. 2004; 45 (8): 889-894

    View details for Web of Science ID 000223212100001

    View details for PubMedID 15270753

  • Abnormal benzodiazepine and zinc modulation of GABA(A) receptors in an acquired absence epilepsy model BRAIN RESEARCH Wu, J., Ellsworth, K., Ellsworth, M., Schroeder, K. M., Smith, K., Fisher, R. S. 2004; 1013 (2): 230-240


    Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been shown to be a faithful model of acquired absence epilepsy, a devastating condition for which few therapies or models exist. We employed the CSI model to study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats. Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated from the nucleus reticularis of thalamus (nRt) treated and untreated with a cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs). Patchclamp results revealed that although there was no remarkable change in GABAA receptor affinity, both a loss of ability of benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+ inhibition of GABAA-receptor responses of nRt neurons occurred in Long-Evans Hooded rats previously administered U18666A. This change was specific, since no significant changes were found in neurons exposed to the GABA allosteric modulator, pentobarbital. Taken collectively, these findings provide evidence for abnormalities in benzodiazepine and Zn2+ modulation of GABAA receptors in the CSI model, and suggest that decreased gamma2 subunit expression may underlie important aspects of generation of thalamocortical SWs in atypical absence seizures. The present results are also consistent with recent findings that mutation of the gamma2 subunit of the GABAA receptor changes benzodiazepine modulation in families with generalized epilepsy syndromes.

    View details for DOI 10.1016/j.brainres.2004.03.075

    View details for Web of Science ID 000222257600012

    View details for PubMedID 15193533

  • Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy EPILEPSIA Kerrigan, J. F., Litt, B., Fisher, R. S., Cranstoun, S., French, J. A., Blum, D. E., Dichter, M., Shetter, A., Baltuch, G., Jaggi, J., Krone, S., Brodie, M., Rise, M., Graves, N. 2004; 45 (4): 346-354


    Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open-label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data.We report an open-label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range, 24-47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline.Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters.Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.

    View details for Web of Science ID 000220796800007

    View details for PubMedID 15030497

  • Diazepam prophylaxis for bicuculline-induced seizures: a rat dose-response model NEUROSCIENCE LETTERS Anschel, D. J., Ortega, E., Fisher, R. S. 2004; 356 (1): 66-68


    We developed a screening methodology to test the ability of putative antiepileptic drugs delivered directly to a seizure focus to prevent epileptiform activity. The left hippocampi of 15 rats were implanted with an injection cannula and bipolar recording electrodes. Bone screws were used to record neocortical EEG activity. Diazepam (DZP) at one of four possible concentrations or control solution was injected into the hippocampus, followed 5 min later by bicuculline methiodide. DZP suppressed spikes and ictal events in a dose-dependent manner (P<0.0001). At 100 mM, DZP reduced spikes from 678+/-128 to 87+/-35 for a 15 min segment. Numbers of ictal events (seizure) and latency to the first event were reduced by prophylactic DZP. The study establishes a protocol for testing of intracranially-injected drugs to prevent focal seizures.

    View details for DOI 10.1016/j.neulet.2003.10.082

    View details for PubMedID 14746903

  • Brain stimulation for epilepsy LANCET NEUROLOGY Theodore, W. H., Fisher, R. S. 2004; 3 (2): 111-118


    Neural stimulation is a promising new technology for the treatment of medically-intractable seizures. Vagus-nerve stimulation (VNS) is licensed in several countries as an adjunctive therapy. VNS is as effective as antiepileptic drug therapy, and serious complications are rare. Transcranial magnetic stimulation is simple, non-invasive, and widely used in neurophysiology. Therapeutic results in a few studies are equivocal at best. Deep brain stimulation, although experimental, has been applied to the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, hippocampus, and neocortical seizure foci. Preliminary results are encouraging, but not conclusive. Electrode implantation in the brain for indications other than seizures has been associated with a 5% risk for intracranial haemorrhage and 5% for infection. A controlled study of anterior thalamic stimulation in patients with intractable partial and secondarily generalised seizures has been started. Future investigations are likely to study extrathalamic sites of stimulation, and effects of stimulation contingent upon detection of or prediction of EEG patterns of epileptiform activity.

    View details for Web of Science ID 000188818500021

    View details for PubMedID 14747003

  • Brain stimulation for epilepsy: Pilot patient results and implementation of a controlled clinical trial Graves, N. M., Lozano, A. M., Wennberg, R. A., Osorio, Wilkinson, S., Baluch, G., French, J. A., Kerrigan, J. F., Shetter, A., Fisher, R. S. BLACKWELL PUBLISHING INC. 2004: 148
  • Intracellular energy failure does not underlie hyperthermic spreading depressions in immature rat hippocampal slice BRAIN RESEARCH Wu, H., Takeo, T., Wakui, M., Ellsworth, K., Fisher, R. S. 2003; 987 (2): 240-243


    Hyperthermic spreading depression (HSD) in immature rat hippocampal slices is mediated by Na+/K(+)-ATPase failure. Here, we test whether depleting intracellular ATP serves as a possible mechanism for HSD genesis. Results indicate that (1) pre-incubation with 3 mM creatine for 3 h failed to prevent hyperthermic spreading depression occurrence; and (2) intracellular ATP concentration doubled during experimental hyperthermia. This study suggests that HSD is not be mediated by depletion of intracellular ATP during hyperthermia.

    View details for DOI 10.1016/S0006-8993(03)03355-9

    View details for Web of Science ID 000185945900013

    View details for PubMedID 14499969

  • Seizure-related motor vehicle crashes in Arizona before and after reducing the driving restriction from 12 to 3 months MAYO CLINIC PROCEEDINGS Drazkowski, J. F., Fisher, R. S., Sirven, J. I., Demaerschalk, B. M., Uber-Zak, L., Hentz, J. G., Labiner, D. 2003; 78 (7): 819-825


    To evaluate whether changing the seizure-free interval in Arizona from 12 months to 3 months affected the number of seizure-related motor vehicle crashes.We performed a time trend study with analysis of motor vehicle crash reports in the state of Arizona 3 years before (1991-1993) and 3 years after (1994-1996) the seizure-free interval was decreased from 12 to 3 months. The number of motor vehicle crashes related to seizures, other medical conditions, and other nonmedical crashes was compared before and after the law changed. Other population trends, including population growth, registered vehicles, and registered drivers, are also reported.Seizure-related crashes increased from 125 to 136 for the 3 years before and 3 years after the law changed, respectively. The total rate of seizure-related crashes did not increase on the basis of an incidence rate difference of -0.03/10(9) miles (95% confidence interval [CI], -0.30 to 0.24) and a relative risk of 0.98 (95% CI, 0.77 to 1.24). Over the same time interval, crashes related to other medical conditions increased from 288 to 310, respectively, for an incidence rate difference of -0.09/10(9) miles (95% CI, -0.51 to 033) and a relative risk of 0.97 (95% CI, 0.82 to 1.13). Fatalities due to seizure-related crashes decreased during the same period, whereas the number of multiple vehicle crashes increased.The rate of seizure-related crashes did not significantly increase in the state of Arizona after the seizure-free interval was reduced from 12 to 3 months.

    View details for Web of Science ID 000183848100003

    View details for PubMedID 12839076

  • Psychological factors in the genesis and management of nonepileptic seizures: clinical observations. Epilepsy & behavior : E&B Prigatano, G. P., Stonnington, C. M., Fisher, R. S. 2002; 3 (4): 343-349


    Nonepileptic seizures (NES) are frequently thought to have a "psychogenic" basis. Two 6-month group psychotherapy programs were provided for patients diagnosed as having NES [eight patients were treated during the first program, seven during the second (N=15)] to explore the potential role of psychological factors in the genesis of NES and to determine if psychotherapeutic interventions reduced the frequency of NES. Of the 15 patients, 9 (60%) completed at least 58% of the treatment sessions. Of those 9 patients, 6 (66%) reported a decline in "seizure frequency." One reported an increase (11%). Self-reported frequency highly correlated with paranoid ideation. Dissociative phenomena were common as was a history of sexual abuse. Each patient reported being in an adult situation that they found unacceptable or intolerable. None perceived a solution to their situation. Reports by health care providers that their seizures were not "real" (i.e., true epilepsy) restimulated feelings associated with their not being believed when they reported being sexually abused as children. The psychological genesis of NES in this sample of patients appears rooted in the recurrent experience of being in abusive or exploited relationships for which they perceived no solution.

    View details for PubMedID 12609332

  • Psychological factors in the genesis and management of nonepileptic seizures: clinical observations EPILEPSY & BEHAVIOR Prigatano, G. P., Stonnington, C. M., Fisher, R. S. 2002; 3 (4): 343-349


    Nonepileptic seizures (NES) are frequently thought to have a "psychogenic" basis. Two 6-month group psychotherapy programs were provided for patients diagnosed as having NES [eight patients were treated during the first program, seven during the second (N=15)] to explore the potential role of psychological factors in the genesis of NES and to determine if psychotherapeutic interventions reduced the frequency of NES. Of the 15 patients, 9 (60%) completed at least 58% of the treatment sessions. Of those 9 patients, 6 (66%) reported a decline in "seizure frequency." One reported an increase (11%). Self-reported frequency highly correlated with paranoid ideation. Dissociative phenomena were common as was a history of sexual abuse. Each patient reported being in an adult situation that they found unacceptable or intolerable. None perceived a solution to their situation. Reports by health care providers that their seizures were not "real" (i.e., true epilepsy) restimulated feelings associated with their not being believed when they reported being sexually abused as children. The psychological genesis of NES in this sample of patients appears rooted in the recurrent experience of being in abusive or exploited relationships for which they perceived no solution.

    View details for Web of Science ID 000178784900008

  • Cooling abolishes neuronal network synchronization in rat hippocampal slices EPILEPSIA Javedan, S. P., Fisher, R. S., Eder, H. G., Smith, K., Wu, J. 2002; 43 (6): 574-580


    We sought to determine whether cooling brain tissue from 34 to 21 degrees C could abolish tetany-induced neuronal network synchronization (gamma oscillations) without blocking normal synaptic transmission.Intracellular and extracellular electrodes recorded activity in transverse hippocampal slices (450-500 microm) from Sprague-Dawley male rats, maintained in an air-fluid interface chamber. Gamma oscillations were evoked by afferent stimulation at 100 Hz for 200 ms. Baseline temperature in the recording chamber was 34 degrees C, reduced to 21 degrees C within 20 min.Suprathreshold tetanic stimuli evoked membrane potential oscillations in the 40-Hz frequency range (n = 21). Gamma oscillations induced by tetanic stimulation were blocked by bicuculline, a gamma-aminobutyric acid (GABA)A-receptor antagonist. Cooling from 34 to 21 degrees C reversibly abolished gamma oscillations in all slices tested. Short, low-frequency discharges persisted after cooling in six of 14 slices. Single-pulse-evoked potentials, however, were preserved after cooling in all cases. Latency between stimulus and onset of gamma oscillation was increased with cooling. Frequency of oscillation was correlated with chamber cooling temperature (r = 0.77). Tetanic stimulation at high intensity elicited not only gamma oscillation, but also epileptiform bursts. Cooling dramatically attenuated gamma oscillation and abolished epileptiform bursts in a reversible manner.Tetany-induced neuronal network synchronization by GABAA-sensitive gamma oscillations is abolished reversibly by cooling to temperatures that do not block excitatory synaptic transmission. Cooling also suppresses transition from gamma oscillation to ictal bursting at higher stimulus intensities. These findings suggest that cooling may disrupt network synchrony necessary for epileptiform activity.

    View details for Web of Science ID 000176828400002

    View details for PubMedID 12060015

  • Employment for People with Epilepsy. To the Editor. Epilepsy & behavior : E&B Fisher, R. S., Callanan, M. n. 2002; 3 (2): 203

    View details for PubMedID 12609432

  • Potential new methods for antiepileptic drug delivery CNS DRUGS Fisher, R. S., Ho, J. 2002; 16 (9): 579-593


    Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option. Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus. Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier. In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated in the clinical setting. Gene therapy also may play a role in local drug delivery with the use of adenovirus, adeno-associated virus, herpesvirus or other delivery vectors to induce brain cells to produce local modulatory substances. New delivery systems should significantly improve the therapeutic/toxic ratio of AEDs.

    View details for PubMedID 12153331

  • Gamma oscillation underlies hyperthermia-induced epileptiform-like spikes in immature rat hippocampal slices BMC NEUROSCIENCE Wu, J., Javedan, S. P., Ellsworth, K., Smith, K., Fisher, R. S. 2001; 2


    Recently a hyperthermic rat hippocampal slice model system has been used to investigate febrile seizure pathophysiology. Our previous data indicates that heating immature rat hippocampal slices from 34 to 41 degrees C in an interface chamber induced epileptiform-like population spikes accompanied by a spreading depression (SD). This may serve as an in vitro model of febrile seizures.In this study, we further investigate cellular mechanisms of hyperthermia-induced initial population spike activity. We hypothesized that GABA(A) receptor-mediated 30-100 Hz gamma oscillations underlie some aspects of the hyperthermic population spike activity. In 24 rat hippocampal slices, the hyperthermic population spike activity occurred at an average frequency of 45.9 +/- 14.9 Hz (Mean +/- SE, range = 21-79 Hz, n = 24), which does not differ significantly from the frequency of post-tetanic gamma oscillations (47.1 +/- 14.9 Hz, n = 34) in the same system. High intensity tetanic stimulation induces hippocampal neuronal discharges followed by a slow SD that has the magnitude and time course of the SD, which resembles hyperthermic responses. Both post-tetanic gamma oscillations and hyperthermic population spike activity can be blocked completely by a specific GABA(A) receptor blocker, bicuculline (5-20 microM). Bath-apply kynurenic acid (7 mM) blocks synaptic transmission, but fails to prevent hyperthermic population spikes, while intracellular diffusion of QX-314 (30 mM) abolishes spikes and produces a smooth depolarization in intracellular recording.These results suggest that the GABA(A) receptor-governed gamma oscillations underlie the hyperthermic population spike activity in immature hippocampal slices.

    View details for Web of Science ID 000207529000001

    View details for PubMedID 11747470

    View details for PubMedCentralID PMC61040

  • A pilot study of donepezil for memory problems in epilepsy. Epilepsy & behavior Fisher, R. S., Bortz, J. J., Blum, D. E., Duncan, B., Burke, H. 2001; 2 (4): 330-334


    We performed a pilot 3-month, open-label study of 5-10 mg donepezil, an anticholinesterase inhibitor, as treatment for memory problems in people with epilepsy. The Buschke Selective Reminding Test was administered at baseline and after 3 months of donepezil. In 18 completing patients, the total number of words recalled across learning trials was greater on donepezil (P = 0.4). No change was noted in attention, visual sequencing, mental flexibility, psychomotor speed, or reported quality-of-life scores. Mean 3-month seizure frequency at baseline was 2.70 ± 4.60, and during treatment, 3.06 ± 4.52 (P = 0.19, not significant). Two patients experienced increased tonic-clonic seizures. Side effects included diarrhea, stomach cramps, insomnia, depression, and blurred vision. Cholinergic medication is worthy of investigation as treatment for memory problems in people with epilepsy, but attention must be paid to possible exacerbation of seizures.

    View details for PubMedID 12609209

  • A Pilot Study of Donepezil for Memory Problems in Epilepsy EPILEPSY & BEHAVIOR Fisher, R. S., Bortz, J. J., Blum, D. E., Duncan, B., Burke, H. 2001; 2 (4): 330-334


    We performed a pilot 3-month, open-label study of 5-10 mg donepezil, an anticholinesterase inhibitor, as treatment for memory problems in people with epilepsy. The Buschke Selective Reminding Test was administered at baseline and after 3 months of donepezil. In 18 completing patients, the total number of words recalled across learning trials was greater on donepezil (P = 0.4). No change was noted in attention, visual sequencing, mental flexibility, psychomotor speed, or reported quality-of-life scores. Mean 3-month seizure frequency at baseline was 2.70 ± 4.60, and during treatment, 3.06 ± 4.52 (P = 0.19, not significant). Two patients experienced increased tonic-clonic seizures. Side effects included diarrhea, stomach cramps, insomnia, depression, and blurred vision. Cholinergic medication is worthy of investigation as treatment for memory problems in people with epilepsy, but attention must be paid to possible exacerbation of seizures.

    View details for DOI 10.1006/ebeh.2001.0221

    View details for Web of Science ID 000208208600008

  • Rapid initiation of gabapentin - A randomized, controlled trial NEUROLOGY Fisher, R. S., Sachdeo, R. C., Pellock, J., Penovich, P. E., Magnus, L., Bernstein, P. 2001; 56 (6): 743-748


    To compare the tolerability of two different dose-initiation regimens of gabapentin for the adjunctive treatment of partial seizures.Patient compliance is a key feature of successful outpatient pharmacologic therapy for epilepsy, and one aspect of compliance is simplicity of initiation. By using a rapid titration rate, leading to a rapid therapeutic gabapentin dose, perhaps there could be an improvement with compliance.Male or female patients, at least 12 years old, with a recent history of partial seizures with or without secondary generalization, were randomized to receive gabapentin (following a blinded placebo period of an undisclosed number of days) as either a Slow initiation (300 mg day 1, 600 mg day 2, then 900 mg/day) or a Rapid initiation (900 mg/day immediately following the placebo lead-in).Starting gabapentin therapy at an initial therapeutic dosage of 900 mg/day is well tolerated by patients with epilepsy and is as safe as initiating with a titration schedule over 3 days. Of the four most common adverse events (somnolence, dizziness, ataxia, fatigue), only one, dizziness, occurred more often in the nontitrated (Rapid initiation) group than in the titrated (Slow initiation) group.Initiation of gabapentin at 900 mg/day is as well tolerated as is a 3-day titration, except for a higher incidence of dizziness.

    View details for Web of Science ID 000167697100010

    View details for PubMedID 11274308

  • The etiology and mechanisms of symptomatic acute seizures. Neurologia Fisher RS 2001; 16 (Suppl 2)
  • Hyperthermic spreading depressions in the immature rat hippocampal slice JOURNAL OF NEUROPHYSIOLOGY Wu, J., Fisher, R. S. 2000; 84 (3): 1355-1360


    Febrile seizures are the most common seizure type in children (6 mo to 5 yr). The pathophysiology of febrile seizures is unknown. Current genetic studies show that some febrile seizures result from channelopathies. We have performed electrophysiological experiments in in vitro hippocampal slices to test a novel hypothesis that a disordered regulation of ionic homeostasis underlies the genesis of febrile seizures. In transverse hippocampal CA1 slices from 104 rats, temperature increase from 34 degrees to 40 degrees C produced a series of spreading depressions (SDs), called hyperthermic SDs. The hyperthermic SDs were age-dependent, occurring in only 1/17 8-16 day-old animals, 44/49 17-60 day-old animals, and 11/20 rats older than than 60 days. The hyperthermic SDs usually occurred on the rising phase of the temperature. The mean temperature to trigger a first hyperthermic SD was 38.8 +/- 1.3 degrees C (mean +/- SD, n = 44). The hyperthermic SDs induced a reversible loss of evoked synaptic potentials and a dramatic decrease of input resistance. Neuronal and field epileptiform bursting occurred in the early phases of the hyperthermic SD. During hyperthermic SDs, pyramidal cell membrane potential depolarized by 38.3 +/- 4.9 mV (n = 20), extracellular field shifted negative 18.5 +/- 3.9 mV (n = 44), and extracellular K(+) rose reversibly to 43.8 +/- 10.9 mM (n = 6). Similar SDs could be evoked by ouabain or transient hypoxia with normal temperature. Tetrodotoxin could block initial epileptiform bursting, without blocking SDs. Hyperthermia-induced SDs should be investigated as possible contributing factors to febrile seizures.

    View details for Web of Science ID 000089185200021

    View details for PubMedID 10980008

  • The impact of epilepsy from the patient's perspective II: views about therapy and health care EPILEPSY RESEARCH Fisher, R. S., Vickrey, B. G., Gibson, P., Hermann, B., Penovich, P., Scherer, A., Walker, S. 2000; 41 (1): 53-61


    A national survey of 1023 people with epilepsy in the US assessed their attitudes about their therapies. Subjects were drawn from responders to a previous national survey of US households or from those who phoned the Epilepsy Foundation. Overall response rate was 49%. Approximately 90% of the respondents were taking medications for their epilepsy. Only 56% were on monotherapy, while 26% were taking two, 6% three, and 2% four medications. Only 68% of respondents were very satisfied with their current seizure medications. When asked to rank five areas of importance regarding their seizure medication, the rank order (highest to lowest) was seizure control, fewer side effects, convenient dosing regimens and cost. Adverse medication events were listed in descending rank order as problems with cognition, energy level, school performance, childbearing, coordination, and sexual function. Inter-individual differences in side effects of concern were listed, suggesting medication choices should be individualized according to potential side effects. Twenty percent of 920 respondents adjusted their medications on their own, by adjusting amount (62%), dosing schedule (31%), or both (3%). Eighty percent of respondents were satisfied with their medical care systems. In this group, 82% had health insurance that covered epilepsy. The large majority (94%) of respondents had seen a neurologist. Subjects expressed dissatisfaction about time limits and lack of accessible information about epilepsy. People with epilepsy are generally satisfied with efforts to treat their disorder, but adverse events are of concern. Many patients requested more information about epilepsy.

    View details for Web of Science ID 000088290800006

    View details for PubMedID 10924868

  • The impact of epilepsy from the patient's perspective I. Descriptions and subjective perceptions EPILEPSY RESEARCH Fisher, R. S., Vickrey, B. G., Gibson, P., Hermann, B., Penovich, P., Scherer, A., Walker, S. 2000; 41 (1): 39-51


    This study surveyed the perceptions about and subjective experience of 1023 people with epilepsy in two community-based samples: one from a national postal survey; the other callers to the Epilepsy Foundation. Response to a mail survey was 49%. In comparison with US Census Bureau norms, respondents had received less education, were less likely to be employed or married, and came from lower income households. Complex partial seizures were the most prevalent seizure type, but a convulsion had occurred in 61%. Fifty percent of respondents reported incomplete control of their seizure disorder, although 25% of these had a seizure in the prior year. Thirteen percent had a longest inter-seizure interval of a year or greater, 37% of 3 months, 22% of 1 month, 10% of 1 week and 4% of 1 day. Respondents listed uncertainty and fear of having a seizure as the worst thing about having epilepsy. Lifestyle, school, driving, and employment limits were also listed as major problems. When asked to rank a list of potential problems, cognitive impairment was ranked highest. These data indicate that ongoing medical and psychosocial problems continue for those with epilepsy in the view of those questioned and their families, even in a sample where the majority report good control of their epilepsy.

    View details for Web of Science ID 000088290800005

    View details for PubMedID 10924867

  • Epilepsy from the Patient's Perspective: Review of Results of a Community-Based Survey. Epilepsy & behavior : E&B Fisher, R. S. 2000; 1 (4): S9-S14


    A total of 1023 individuals with epilepsy responded to a community-based questionnaire survey. Relative to U.S. population norms, respondents had lower household incomes and lesser levels of educational and vocational attainment. Although 89% of respondents reported that their seizures were, in their estimation, at least somewhat controlled, 57% reported having suffered at least one seizure in the preceding year. Of the many concerns that accompanied life with epilepsy, fear (of a seizure, of embarrassment, even of death) was the issue most frequently reported. Eighty-eight percent of respondents reported having health insurance, and this insurance covered epilepsy treatment in 93% of cases. The majority of respondents said that they were satisfied with the medical care they were receiving but wished for more information about epilepsy. Despite advances in epilepsy therapy, freedom from seizures and optimal quality of life eludes many.

    View details for DOI 10.1006/ebeh.2000.0107

    View details for PubMedID 12609456

  • The Postictal State: A Neglected Entity in the Management of Epilepsy EPILEPSY & BEHAVIOR Fisher, R. S., Schachter, S. C. 2000; 1 (1): 52-59


    Some of the disability deriving from epilepsy derives from the postictal state (PS). The PS may be complicated by impaired cognition, headache, injuries, or secondary medical conditions. Postictal depression is common, postictal psychosis relatively rare, but both add to the morbidity of seizures. The mechanisms of the PS are poorly understood. Alteration of cerebral blood flow both results from and contributes to the PS. Many neurotransmitters or neuromodulators are involved in the physiology of the PS. Response to glutamate may partially desensitize after a seizure. Endogenous opiates and adenosine serve as natural antiepileptic medications in some circumstances. Nitric oxide has numerous effects on brain excitability, and may be particularly important in regulating postictal cerebral blood flow. Just as the pathophysiology of seizures is complicated, so is that of the PS multifactorial. As a practical issue, it would be very useful to have medications that reduce the morbidity of the PS.

    View details for DOI 10.1006/ebeh.2000.0023

    View details for Web of Science ID 000208203300013

    View details for PubMedID 12609127

  • Epilepsy from the patient?s perspective: Review of results of a community-based survey Epilepsy and Behavior Fisher RS 2000; 1: S9-S14
  • The postictal state: a neglected entity in the management of epilepsy Epilepsy and Behavior Fisher RS, Schachter SC 2000; 1: 52-59
  • The potential for vigabatrin-induced intramyelinic edema in humans: a review Epilepsia Cohen JA, Fisher RS, Brigell MG, Peyster RG, Sze G 2000; 41: 148-157
  • Raising the Bar on Seizure Control. Epilepsy & behavior : E&B Fisher, R. S. 2000; 1 (4): 212–14

    View details for DOI 10.1006/ebeh.2000.0096

    View details for PubMedID 12609435

  • An automated drug delivery system for the treatment of intractable focal epilepsy. Epilepsy Research Stein A, Eder HG, Jones D, Drachev A, Blum DE, Fisher RS 2000; 39: 103-114
  • Reassessment: Vagus nerve stimulation for epilepsy - A report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology NEUROLOGY Fisher, R. S., Handforth, A. 1999; 53 (4): 666-669

    View details for Web of Science ID 000082518300003

    View details for PubMedID 10489023

  • Epilepsy surgery where there is dual pathology LANCET Fisher, R. S., Blum, D. 1999; 354 (9175): 267-268

    View details for Web of Science ID 000081646000003

    View details for PubMedID 10440297

  • Can patients perform volitional motor acts at the start of a seizure? JOURNAL OF CLINICAL NEUROPHYSIOLOGY Block, A., Fisher, R. S. 1999; 16 (2): 141-145


    A seizure warning device might allow some individuals with partial seizures to protect themselves against consequences of seizures, but a prerequisite is the ability to take volitional action in response to a warning. The authors reviewed consecutive seizures in their epilepsy monitoring unit to determine whether patients could squeeze an event bulb, as instructed, at the start of their seizure. Only complex partial seizures with EEG changes and with the patient on camera were analyzed. Data were obtained from 77 patients, 42 with scalp monitoring and 35 with depth electrodes. Forty-seven percent had a left-hemisphere focus, 42% a right-hemisphere focus, and 11% multifocal seizures. The seizure focus was temporal in 68%. A magnetic resonance imaging consistent with mesial temporal sclerosis was seen in 29% of patients. Overall, 44% of the patients made at least one attempt to reach for the event bulb at the start of their seizures. Among the 72% of patients who gave a history of auras, 53% were able to press the event bulb compared to 20% with no history of auras (P = 0.016). EEG changes occurred a mean of 2.9+/-30.5 seconds after reaching for the bulb for scalp-recorded seizures (n = 20), and 16.2+/-13.7 seconds before behavior for depth-recorded seizures (n = 14, difference significant at P = 0.02). Neither seizure focus nor seizure laterality influenced the ability to press the event bulb. The authors conclude that nearly half of individuals with complex partial seizures can take volitional motor action at the start of their seizure. A method to enhance the intensity and timeliness of a seizure warning would not be wasted.

    View details for Web of Science ID 000080527800006

    View details for PubMedID 10359499

  • Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures Neurology Schachter SC, Vazquez B, Fisher RS, Laxer KD, Montouris GD, Combs-Cantrell DT, Faught E, Willmore LJ, Morris GL, Ojemann L, Bennett D, Mesenbrink P, DSouza J, Kramer L 1999; 52: 732-7
  • New antiepileptic drugs: Comparison of key clinical trials Epilepsia Cramer JA, Fisher R, Ben Menachem E, French J, Mattson RH 1999; 40: 590-600
  • Neurology Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Fisher RS, Handforth A 1999; 53: 666-9
  • Bilateral temporal hypometabolism in epilepsy EPILEPSIA Blum, D. E., Ehsan, T., Dungan, D., Karis, J. P., Fisher, R. S. 1998; 39 (6): 651-659


    Positron emission tomography (PET) has proven useful in epilepsy surgery for its ability to identify unilateral temporal hypometabolism (UTH), which is predictive of good surgical outcome. The significance of bilateral temporal hypometabolism (BTH) is not known.We identified all patients who had marked bilateral reduction in temporal lobe metabolism relative to the cerebellar hemispheres and compared their clinical features and treatment outcomes with those of control patients with UTH.BTH was evident in 10% of PET scans for epilepsy at our institution. We compared these patients with age-matched controls with UTH. The BTH patients had a higher percentage of generalized seizures; were more likely to have bilateral, diffuse or extratemporal seizure onsets; and had bilateral or diffuse magnetic resonance imaging (MRI) findings. UTH patients were more likely to have unilateral mesial temporal atrophy on MRI. Even when electrical seizure onsets were well localized, surgical outcomes were markedly worse in these patients than in controls. Medical treatment was also less successful. Social and cognitive functioning was worse in the BTH group. The only death occurred in the group with BTH.Patients with BTH have features distinct from those with UTH and have a worse prognosis for seizure remission after surgery.

    View details for Web of Science ID 000073983500012

    View details for PubMedID 9637608

  • Open label pilot study of oxcarbazepine for inpatients under evaluation for epilepsy surgery Drug Development research Fisher RS, Eskola J, Blum D, Kerrigan JF III, Drazkowski J, M.D., Duncan B 1998; 38: 43-49
  • Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat EPILEPSY RESEARCH Mirski, M. A., Rossell, L. A., Terry, J. B., Fisher, R. S. 1997; 28 (2): 89-100


    Evidence suggests that a specific subcortical pathway synaptically linking the anterior thalamic nuclear complex (AN) to the hypothalamus and midbrain is important in the expression of pentylenetetrazol (PTZ) seizures. Perturbation of neuronal activity along this path via focal disruption or chemical inhibition significantly raises seizure threshold. Recent data has demonstrated that focal electrical stimulation within the hypothalamic component of this pathway inhibited seizure expression in a current and frequency dependent fashion. Similar experiments were conducted in the AN to investigate the hypothesis that stimulation of this thalamic nuclear region can prevent the propagation of PTZ seizures between cortical and subcortical regions. Our results indicate that high frequency (100 Hz) stimulation of AN did not alter the expression of low dose PTZ induced cortical bursting but did raise the clonic seizure threshold compared to naive animals or those stimulated at sites near, but not in AN (P < 0.01). Low frequency stimulation (8 Hz) was in contrast, proconvulsant and could induce behavioral arrest responses accompanied by rhythmic high voltage EEG even without PTZ challenge. This data further highlights the role of AN in mediating the expression of seizures and provides experimental support for the concept that this thalamic region may be a promising target for focal stimulation to treat intractable seizures in humans.

    View details for Web of Science ID A1997XQ95600001

    View details for PubMedID 9267773

  • Assessment of vagus nerve stimulation for epilepsy: Report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology NEUROLOGY Fisher, R. S., Krauss, G. L., Ramsay, E., Laxer, K., Gates, J. 1997; 49 (1): 293-297

    View details for Web of Science ID A1997XK35300050

    View details for PubMedID 9222210

  • Local perfusion of diazepam attenuates interictal and ictal events in the bicuculline model of epilepsy in rats EPILEPSIA Eder, H. G., Jones, D. B., Fisher, R. S. 1997; 38 (5): 516-521


    We evaluated the efficacy of local perfusion of diazepam (DZP) in suppression of EEG spikes and behavioral seizures produced by bicuculline methiodide (BMI) applied to rat sensory motor cortex and hippocampus.Data were obtained from 37 rats implanted with EEG head plugs and perfusion cannulas. BMI 4 mM, 5 microliters was infused on neocortex through the epidural space in 23 rats. BMI 0.1 mM, 2 microliters was infused into the left hippocampus in 14 rats.DZP 0.75-1.0 mg markedly reduced the spiking to a level of 9.9 +/- 15.8% of baseline for DZP as compared with 90.2 +/- 57.9% of baseline for vehicle-treated rats. DZP reduced spiking in a hippocampal BMI focus to 1.9 +/- 2.4% of baseline spiking, as compared with 98.0 +/- 95.6% of that in vehicle-treated animals. The amount of spread of solution was estimated with methylene blue (MB) injections. Ictal events also were attenuated. In most of the animals, systemic levels of DZP were unmeasurable and injection on the contralateral side did not reduce spiking.These findings suggest that focal application of antiepileptic drugs (AEDs) in brain may be a useful new avenue for therapy of intractable partial seizures.

    View details for Web of Science ID A1997WX71900002

    View details for PubMedID 9184595

  • Epilepsy for the neuroradiologist AMERICAN JOURNAL OF NEURORADIOLOGY Fisher, R. S., Stein, A., Karis, J. 1997; 18 (5): 851-863

    View details for Web of Science ID A1997WZ04600007

    View details for PubMedID 9159362

  • Interictal and ictal activity in the rat cobalt/pilocarpine model of epilepsy decreased by local perfusion of diazepam Epilepsy Research Eder HG, Stein A, Fisher RS 1997; 29: 17-24
  • The selective GABA(B) antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model BRAIN RESEARCH Smith, K. A., Fisher, R. S. 1996; 729 (2): 147-150


    Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.

    View details for Web of Science ID A1996VE64400001

    View details for PubMedID 8876982

  • Newer antiepileptic drugs as monotherapy: Data on vigabatrin NEUROLOGY Fisher, R., Kalviainen, R., Tanganelli, P., Regesta, G. 1996; 47 (1): S2-S5


    Studies examining the use of vigabatrin as monotherapy for the treatment of epilepsy are relatively scarce, and of the few that have been reported, only two were of sufficient size to provide definitive data. In both trials, vigabatrin was compared with carbamazepine for efficacy and safety. In one of these studies, carbamasepine was found to be more effective than vigabatrin in reducing seizure frequency, and the two were found to be comparably efficacious in the other study. What differed significantly, however, was vigabatrin's favorable safety profile. Vigabatrin appears to be a reasonable choice for single-drug therapy in the treatment of certain types of seizures. In other patients, it remains useful as an adjunct to other antiepileptic drugs.

    View details for Web of Science ID A1996UX77000002

    View details for PubMedID 8677032

  • Patient awareness of seizures NEUROLOGY Blum, D. E., ESKOLA, J., Bortz, J. J., Fisher, R. S. 1996; 47 (1): 260-264


    In 31 consecutive patients who were admitted to an epilepsy monitoring unit, we prospectively determined whether the patients were aware of having seizures. On admission, all patients stated that they knew of at least some of their seizures. Eight of 23 with classifiable epileptic seizures recognized that they were occasionally unaware of their seizures. During telemetry, following full recovery of consciousness after each seizure, we asked the patients whether they had recently had a seizure. For control purposes, we asked the patients the same question at random times. Among patients with seizures, there were no false-positive answers. Only 6 of 23 (26%) of the patients with epilepsy were always aware of their seizures, including complex partial and secondarily generalized events, and 7 of 23 (30%) were never aware of any seizures. Self-reporting of seizures was unreliable: Patients reporting the lowest baseline frequency of seizures had the highest fraction of unrecognized seizures. Seizure awareness was lowest for patients with temporal lobe foci, especially on the left side. Patients with primarily generalized epilepsy were more likely to be aware of tonic-clonic seizures than were patients with secondarily generalized partial seizures. All four patients with nonepileptic attacks believed that they always knew of their seizures, but only three of the four patients actually did always know. Unrecognized seizures are frequent and should be considered in patient management and in studies.

    View details for Web of Science ID A1996UX18800047

    View details for PubMedID 8710091

  • Titanium aneurysm clips .2. Seizure and electroencephalographic studies in implanted rabbits NEUROSURGERY Fisher, R. S., Ehsan, T., Smith, K., Lawton, M. T., Bichard, W. D., Spetzler, R. F. 1996; 38 (6): 1165-1169


    Because titanium is widely used in neurosurgical procedures, we compared spontaneous and induced epileptiform activity in 12 rabbits with titanium clips implanted in the subarachnoid space with 12 rabbits with cobalt alloy clips and 6 rabbits that were not operated on that served as controls. Beginning 1 week after surgery, 30-minute electroencephalographic recordings were made at monthly intervals for 6 months. Recordings were scored by an electroencephalographer unaware of which treatment group was being recorded. In 48 recordings made during 6 months, no epileptiform activity was observed in any animal. Seizure threshold was evaluated by continuous intravenous injection of the convulsant drug, pentylenetetrazole (2 mg/kg/min), with continuous electroencephalographic recording. Time to spiking for the nonsurgical control group was 327 mean seconds +/- 181 standard deviation (SD), 216 mean seconds +/- 135 SD for the titanium group, and 389 mean seconds +/- 290 SD for the cobalt group. There were no significant differences among the groups (P = 0.17). Latency to behavioral tonicoclonic seizure was 1031 seconds +/- 537 SD for the group not operated on, 875 seconds +/- 334 SD for the titanium group, and 1267 seconds +/- 764 SD for the cobalt group. This study suggests that titanium clips are well tolerated within the brain and will not induce seizures.

    View details for Web of Science ID A1996UM76300046

    View details for PubMedID 8727148

  • Sensitivity and specificity of paired capillary prolactin measurement in diagnosis of seizures JOURNAL OF EPILEPSY Ehsan, T., Fisher, R. S., Johns, D., Lukas, R. J., Blum, D., ESKOLA, J. 1996; 9 (2): 101-105
  • Open label pilot study of oxcarbazepine for inpatients under evaluation for epilepsy surgery DRUG DEVELOPMENT RESEARCH Fisher, R. S., ESKOLA, J., Blum, D., Kerrigan, J. F., Drazkowski, J., Duncan, B. 1996; 38 (1): 43-49
  • Cognitive effects of resecting basal temporal language areas EPILEPSIA Krauss, G. L., Fisher, R., Plate, C., Hart, J., Uematsu, S., GORDON, B., Lesser, R. P. 1996; 37 (5): 476-483


    Electrical stimulation of the basal temporal region of the dominant hemisphere before partial temporal lobectomy for epilepsy sometimes produces temporary interruption of language function, but the significance of removal of this area is unknown. We evaluated the correlation between resection of the basal temporal language areas (BTLA) and certain types of postoperative language deficits. In a population of 25 patients, we mapped the inferolateral temporal lobe with cortical electrical stimulation, verifying the positions of the stimulating electrodes with three-dimensional computed tomography (CT). Eighty percent of the patients developed transient language deficits with stimulation, particularly with tests of confrontation naming and comprehension. BTLA was primarily located in the fusiform gyrus, from 1 to 9 cm from the temporal tip. At testing 6-12 months after operation, patients with BTLA resection performed worse (mean 9% decrease) than those with no BTLA resection (mean 4% improvement) on tests of confrontation naming (p = 0.03). Resection size accounted for less of the variance in decrease in confrontation naming than did resection of the BTLA. Tests of performance I.Q. (PIQ), verbal I.Q. (VIQ), or recognition memory for word and verbal learning showed no significant difference between these groups. Most patients do not have language decrease with removal of basal temporal lobe 5-6 cm from the tip, even with removal of BTLA. Some patients, however, have persistent decrease in naming.

    View details for Web of Science ID A1996UJ86700009

    View details for PubMedID 8617177

  • Titanium aneurysm clips: part II - seizure and electroencephalographic studies in implanted rabbits Neurosurgery Fisher RS, T, Smith K, Lawton MT, Bichard WD, Spetzler RF 1996; 38: 1165-9
  • A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures NEUROLOGY French, J. A., Mosier, M., Walker, S., Sommerville, K., Sussman, N., Barry, E., Bell, W., Bergen, D., Browne, T., Ferrendelli, J., Fisher, R., Fromm, G., Homan, R., Krauss, G., Lai, C. W., Leppik, I., Leroy, R., Pellock, J., Penovich, P., Ramsay, R. E., Shinnar, S. 1996; 46 (1): 54-61
  • Sensitivity and specificity of paired capillary prolactin measurement in diagnosis of seizures Journal of Epilepsy Ehsan T, RS, Johns D, Lukas RJ, Blum D, Eskola J 1996; 9: 101-105
  • Ethical use of placebos and provocative testing in diagnosis of epilepsy Neurology Devinsky O, Fisher RS 1996; 47: 866-870


    Investigators have found it difficult to separate patients with nonepileptic seizures (NES) from those with true epileptic seizures (ES) using quantitative measures of neuropsychological test performance. We examined qualitative response characteristics on the California Verbal Learning Test of 41 patients undergoing continuous video/audio-EEG monitoring in an effort to distinguish these patient groups (12 patients with left temporal [LT] foci, 11 with right temporal [RT] foci, and 18 with NES). NES patients explicitly recognized fewer target words compared with ES patients. In addition, NES patients rarely made false-positive errors, which resulted in failure to endorse a significant number of items on the recognition list. This response tendency is called a negative response bias. In contrast, LT patients endorsed a high number of items on the recognition test, which resulted in a positive response bias. RT patients demonstrated no consistent response tendency. In our sample, a negative response bias index (ie, a cutoff score < 0) showed a sensitivity of 61% and a specificity of 91%. We propose that failure to explicitly recognize words following repeated exposure may reflect aspects of psychological denial in NES patients. Response bias indices may thus help identify patients with NES and may begin to explain the psychological mechanisms underlying this complex disorder.

    View details for Web of Science ID A1995TG31200016

    View details for PubMedID 7501154

  • DOUBLE-BLIND CROSSOVER COMPARISON OF TEGRETOL-XR AND TEGRETOL IN PATIENTS WITH EPILEPSY NEUROLOGY Browne, T. R., MORRIS, H. H., Bourgeois, B., Erenberg, G., VanNess, P. C., Wyllie, E., Rothner, A. D., Cruse, R., Cohen, B. H., Ramsay, R. E., Katz, D., Curless, R., Guterman, A., Curtis, V., Slater, J., Grosz, R., Avery, A., WILDER, B. J., Uthman, B. M., Fisher, R. S., Lesser, R. P. 1995; 45 (9): 1703-1707
  • COMPLEX PARTIAL STATUS EPILEPTICUS ACCOMPANIED BY SERIOUS MORBIDITY AND MORTALITY NEUROLOGY Krumholz, A., Sung, G. Y., Fisher, R. S., Barry, E., Bergey, G. K., Grattan, L. M. 1995; 45 (8): 1499-1504


    Nonconvulsive status epilepticus (NCSE) accounts for approximately 20% of all status epilepticus (SE). Although convulsive SE is recognized as a medical emergency, prompt diagnosis and treatment of patients with NCSE is often not emphasized because its consequences are thought to be benign. We report 10 patients with persistent neurologic deficits or death after well-documented NCSE in the form of complex partial status epilepticus (CPSE). All patients had prolonged CPSE lasting 36 hours or longer, as documented by clinical and EEG findings. Causes for CPSE were preexisting epilepsy with partial and secondarily generalized seizures (3 patients), vascular disease (2 patients), encephalitis (2 patients), and metabolic disease (1 patient); causes were unknown for two patients. Poor outcomes identified included persistent (lasting at least 3 months) or permanent cognitive or memory loss (5 patients), cognitive or memory loss plus motor and sensory dysfunction (3 patients), and death (3 patients). NCSE in the form of CPSE is not a benign entity. Serious morbidity and mortality may occur due to the adverse effects of prolonged seizures and as a result of acute brain disorders that precipitate the seizures.

    View details for Web of Science ID A1995RP30400013

    View details for PubMedID 7644048

  • CLOBAZAM, OXCARBAZEPINE, TIAGABINE, TOPIRAMATE, AND OTHER NEW ANTIEPILEPTIC DRUGS American-Epilepsy-Society Annual Course: New Developments in Antiepileptic Drug Therapy Fisher, R., Blum, D. LIPPINCOTT-RAVEN PUBL. 1995: S105–S114


    Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbamazepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.

    View details for Web of Science ID A1995RD91100011

    View details for PubMedID 8784219

  • PING-PONG SEIZURES JOURNAL OF EPILEPSY Fisher, R. S., Blum, D. E., Shetter, A., Ledin, K., Archibald, J. 1995; 8 (1): 29-32


    High-frequency electrical stimulation of mammillary nuclei (MN) of rat posterior hypothalamus resulted in a significant increase in seizure threshold induced by pentylenetetrazol (PTZ). The anticonvulsant effect was frequency and intensity specific. Stimulation at 100 Hz (1-5 V, 30-200 microA) afforded protection against EEG and behavioral manifestations of PTZ seizures. Stimulation of either low frequency (5 Hz), high intensities (8-20 V, 300-800 microA), or outside the histologically verified MN target region did not increase seizure threshold. In some instances, high-intensity stimulation of MN alone elicited spike-wave epileptiform EEG activity accompanied by either arrest of behavior or myoclonic seizures. In animals with ongoing seizure activity, electrical stimulation of MN disrupted the high-voltage synchronous wave forms on cortical EEG. These data support the concept that electrical perturbation of MN in hypothalamus may functionally inhibit generalization of paroxysmal activity required for expression of the EEG and, in particular, the behavioral component of PTZ seizures. These studies provide additional insight into forebrain-brainstem interactions mediating generalized seizure expression.

    View details for Web of Science ID A1994PX21600028

    View details for PubMedID 7988525



    A diffuse electrodecremental ictal pattern (DEP) has been associated with tonic seizures and, less often, with other forms of epilepsy and has been considered to reflect a generalized seizure disorder of diffuse cortical or subcortical (brainstem) origin. In some seizures associated with DEP, however, focal ictal manifestations have been observed. We reviewed the records of all patients admitted to our seizure monitoring unit for 3 years and detected 39 patients with seizures associated with DEP. In 23 of 39 patients, clinical ictal behaviors resembled seizures of unilateral supero/mesiofrontal lobe origin and interictal EEG showed a prominent unilateral frontal component. Nine of 39 had complex absences (CA)/complex partial seizures (CPS); 4 of them were of unilateral frontal lobe origin. Seven of 39 patients had tonic or atonic seizures. Seven patients were studied further with subdural electrodes. Ictal onsets showed a high-frequency frontal lobe discharge. We conclude that in a subgroup of patients a generalized electrodecremental pattern on scalp EEG results from a regional cortical high-frequency ictal discharge originating in a single frontal lobe.

    View details for Web of Science ID A1994PP61200010

    View details for PubMedID 7925169



    We analyzed retrospectively the clinical and EEG data in 13 patients with simple partial seizures (SPS). All EEGs were recorded with surface electrodes with the standard 10-20 system and additional closely spaced scalp and subfrontotemporal skin electrodes. Seventy-seven seizures were recorded. We detected electrographic correlates with SPS in 10 of 13 patients (77%) and in 47 of 77 seizures (61%). The most common ictal correlates were rhythmic theta waves or spikes. Of the SPS with EEG changes, 58% were motor, 14% were sensory, and 28% were psychic seizures. Use of additional electrodes and recording channels may account for the higher incidence of EEG changes in this study than has been reported previously in the literature.

    View details for Web of Science ID A1994PF80800002

    View details for PubMedID 8082613

  • EPILEPSY AND DRIVING - AN INTERNATIONAL PERSPECTIVE Consensus Conference on Driver Licensing and Epilepsy Fisher, R. S., PARSONAGE, M., Beaussart, M., Bladin, P., MASLAND, R., Sonnen, A. E., Remillard, G. LIPPINCOTT-RAVEN PUBL. 1994: 675–84


    Individuals with a history of seizures may be granted driving privileges if the risks of future seizure while driving are relatively low. Different nations have defined these risks in a wide variety of ways. Some countries, e.g., Japan, Greece, Brazil, India, and Russia, preclude driving after a single seizure. Other countries, such as Canada and the United States, allow driving < or = 3 months after certain types of seizures. A Joint Commission of the International Bureau for Epilepsy/International League Against Epilepsy has summarized regulations in several countries. From a consideration of medical literature and existing practices, a series of proposed guidelines for driving and epilepsy is recommended. In general, these guidelines suggest use of a seizure-free interval, generally 1-2 years but less in particular instances, to determine fitness to drive. Required physician reporting is discouraged, but physicians should report patients whom they believe pose a danger to themselves and to public safety. Individualized consideration should be given to special circumstances that may modify a general driving prohibition. Education and information programs are necessary for medical and regulatory authorities to develop a rational approach to driving and epilepsy worldwide.

    View details for Web of Science ID A1994NW29100028

    View details for PubMedID 8026417

  • THE LONG-TERM SAFETY AND EFFICACY OF GABAPENTIN (NEURONTIN(R)) AS ADD-ON THERAPY IN DRUG-RESISTANT PARTIAL EPILEPSY EPILEPSY RESEARCH Oommen, K., Penry, J., Riela, A., Rowan, A., Rosenbaum, D., Schear, M., Sivak, M., Wiener, J., Sauermann, W., WIBBERG, M., Smith, D., Kramer, R., Yerby, M., Lesser, R., Fisher, R., Sanders, P., North, R., Homan, R., Hayes, A., Shellenberger, M. K., Trudeau, V., Wallace, J., Sackellares, J., AASVED, K., Hirschorn, K., Olson, L., Leppik, I., Rask, C., Rosenfeld, W., FROMM, G. H., Nagel, N., Dreifuss, F., Bertram, E., Cooper, G., Lee, S. I., Ojemann, L., Wilensky, A., ABOUKHALIL, B., COURVILLE, K., McLean, M., Ramsay, R., Guterman, A., MCJILTON, J., Sanchez, R., Slater, J., Mattson, R., Scheyer, R., Treiman, D., Handforth, A. 1994; 18 (1): 67-73
  • ADVANCES IN EPILEPSY CURRENT OPINION IN NEUROLOGY Blum, D., Fisher, R. S. 1994; 7 (2): 96-101


    Recent advances in clinical epilepsy have included improved systems for classifying seizures and epileptic syndromes, better definition of nontemporal seizures, improved methods for distinguishing syncope and pseudoseizures from epilepsy, and new approaches in the management of pregnant women with epilepsy. There has been continued development of the concept that epilepsy is a heterogeneous disorder with many imitators. Treatment is most successful when tailored to the particular seizure type, epileptic syndrome, and special needs of the individual patient.

    View details for Web of Science ID A1994ND72400002

    View details for PubMedID 8019668



    We conducted a study to explore how electroencephalographers (EEGers) read EEGs and reach clinical impressions based upon them. Eight EEGers and a rule-based computerized "spike" detector marked epileptiform discharges ("EDs") in 12 test records. Of all marked events, 18% were marked by all readers and 38% were marked by only one reader. Readers agreed on basic clinical features of the records, such as whether a record demonstrated EDs, the rank order of ED sources by location, and the ranking of test records in order of the number of EDs detected. Readers marked records in a consistent pattern that was independent of an objective measure of expertise and experience. Our computerized ED detector had lower sensitivity and selectivity than human readers, but either parameter could be adjusted to be comparable to human EEGers at the expense of the other. We propose that EEGers employ reproducible, quantitatively different styles of reading EEG tracings to reach qualitatively similar clinical impressions. In practice, EDs are not absolutely defined, but appear to represent a continuum of activity which lends itself better to description and rank ordering than to absolute quantitation. More than just counting EDs, a successful computerized ED detector should be adaptable to the style of individual readers in order to help them efficiently formulate their clinical impressions.

    View details for Web of Science ID A1993MR14000003

    View details for PubMedID 7508368



    The introduction of several new antiepileptic drugs in the United States is likely in 1993. Many new drugs have undergone testing, but the four currently considered the most important are felbamate, gabapentin, lamotrigine, and vigabatrin. When these drugs are used as add-on therapy for patients with intractable epilepsy, 20 to 60% of patients show at least a 50% improvement in seizure frequency and 7% become seizure free. An overview of these agents is presented.

    View details for Web of Science ID A1993MJ68300004

    View details for PubMedID 8232982

  • GABAPENTIN AS ADD-ON THERAPY IN REFRACTORY PARTIAL EPILEPSY - A DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY NEUROLOGY Oommen, K., Penry, J., Riela, A., Rowan, A. J., Rosenbaum, D., Schear, M., Sivak, M., Wiener, J., Sauermann, W., WIBBERG, M., Smith, D., Kramer, R., Yerby, M., Lesser, R., Fisher, R., Sanders, P., North, R., Homan, R., Alexander, J., Shellenberger, M. K., Wallace, J., Sackellares, J., AASVED, K., Hirschorn, K., Olson, L., Leppik, I., Rask, C., Rosenfeld, W., FROMM, G. H., Nagel, N., Dreifuss, F., Bertram, E., Cooper, G., Lee, S. I., Ojemann, L., Wilensky, A., ABOUKHALIL, B., COURVILLE, K., McLean, M., Ramsay, R. E., Guterman, A., MCJILTON, J., Sanchez, R., Slater, J., Mattson, R., Scheyer, R., Treiman, D., Handforth, A. 1993; 43 (11): 2292-2298
  • MIRTH, LAUGHTER AND GELASTIC SEIZURES BRAIN Arroyo, S., Lesser, R. P., GORDON, B., Uematsu, S., Hart, J., SCHWERDT, P., Andreasson, K., Fisher, R. S. 1993; 116: 757-780


    Little is known about what pathways subserve mirth and its expression laughter. We present three patients with gelastic seizures and laughter elicited by electrical stimulation of the cortex who provide some insight into the mechanisms of laughter and its emotional concomitants. The first patient had seizures manifested by laughter without a subjective feeling of mirth. Magnetic resonance imaging showed a cavernous haemangioma in the left superior mesial frontal region. Ictal subdural electrode recording showed the seizure onset to be in the left anterior cingulate gyrus. Removal of the lesion and of the seizure focus rendered the patient virtually seizure free over 16 months of follow-up. The other two patients had complex partial seizures of temporal lobe origin. Electrical stimulation of the fusiform gyrus and parahippocampal gyrus produced bursts of laughter accompanied by a feeling of mirth. These cases reveal a high likelihood of cingulate and basal temporal cortex contribution to laughter and mirth in humans, and suggest the possibility that the anterior cingulate region is involved in the motor act of laughter, while the basal temporal cortex is involved in processing of laughter's emotional content in man.

    View details for Web of Science ID A1993LT17900001

    View details for PubMedID 8353707



    Regional binding of 123I-iododexetimide, a muscarinic acetylcholine receptor antagonist, was measured in vivo in the temporal lobes of 4 patients with complex partial seizures using single-photon emission computed tomography. In the anterior hippocampus ipsilateral to the electrical focus, 123I-iododexetimide binding was decreased by 40 +/- 9% (mean +/- SD, p < 0.01) compared with the contralateral hippocampus; 123I-iododexetimide binding in other temporal lobe regions was symmetrical. The data indicate a regionally specific change of muscarinic acetylcholine receptor in anterior hippocampus in complex partial seizures of temporal lobe origin.

    View details for Web of Science ID A1993LR02400019

    View details for PubMedID 8338348

  • Cerebellar and thalamic stimulation for epilepsy. Advances in neurology Krauss, G. L., Fisher, R. S. 1993; 63: 231-245

    View details for PubMedID 8279308

  • MANIA IN TEMPORAL-LOBE EPILEPSY NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY Lyketsos, C. G., Stoline, A. M., LONGSTREET, P., Ranen, N. G., Lesser, R., Fisher, R., Folstein, M. 1993; 6 (1): 19-25


    Sphenoidal electrodes are used to localize epileptiform activity originating in the temporal lobe during complex partial seizures. Sphenoidal electrodes, however, are semi-invasive and uncomfortable to the patient. We compared skin electrodes placed on the cheek ("cheek electrodes") with sphenoidal electrodes for the detection of the side and site of complex partial seizure onset. In a masked, randomized comparison of single ictal recordings in 22 patients, there were no significant differences between sphenoidal and cheek electrode montages in detecting the side or site of ictal onset (P < 0.01). Signal/noise ratios for interictal spikes were a mean 16.5% greater at sphenoidal sites compared to cheek sites (paired t test, t = 2.4, P < 0.05). This difference, however, did not influence the detection of rhythmical ictal activity in cheek and sphenoidal montages in our study, nor the assignment of side, site or time of seizure onset by unbiased readers. Recordings from cheek electrodes are comparable to those from sphenoidal electrodes and are useful for localizing ictal activity.

    View details for Web of Science ID A1992KD27800001

    View details for PubMedID 1281078



    Stimulation of centromedian (CM) thalamic nuclei has been proposed as a treatment for seizures. We implanted programmable subcutaneous (s.c.) stimulators into CM bilaterally in 7 patients with intractable epilepsy to test feasibility and safety. Stimulation was on or off in 3-month blocks, with a 3-month washout period in a double-blind, cross-over protocol. Stimuli were delivered as 90-microseconds pulses at 65 pulses/s, 1 min of each 5 min for 2 h/day, with voltage set to half the sensory threshold. Stimulation was safe and well-tolerated, with a mean reduction of tonic-clonic seizure frequency of 30% with respect to baseline when stimulator was on versus a decrease of 8% when the stimulator was off. There was no improvement in total number of generalized seizures with stimulation, and treatment differences were not statistically significant. Stimulation at low intensity did not alter the EEG acutely, but high-intensity stimulation induced slow waves or 2-3 Hz spike-waves with ipsilateral frontal maximum. In an open-label follow-up segment with stimulator trains continuing for 24 h/day, 3 of 6 patients reported at least a 50% decrease in seizure frequency. There were no side effects. This pilot project demonstrated the feasibility of controlled study of thalamic stimulation in epilepsy, but further study will be needed to demonstrate efficacy.

    View details for Web of Science ID A1992JR40200012

    View details for PubMedID 1396427

  • HIGH-FREQUENCY EEG ACTIVITY AT THE START OF SEIZURES JOURNAL OF CLINICAL NEUROPHYSIOLOGY Fisher, R. S., Webber, W. R., Lesser, R. P., Arroyo, S., Uematsu, S. 1992; 9 (3): 441-448


    Frequencies above 35-40 Hz are poorly visualized on conventional EEG scalp recordings. We investigated frequency components up to 150 Hz in digitally recorded EEGs of seizures in five patients with implanted subdural grids, as part of their evaluation for epilepsy surgery. Amplifier bandpass was set from 0.1 to 300 Hz, and EEG was digitized at 2,000 samples per second. Seizures with electrodecremental patterns at the start showed a significant increase in spectral power above 35 Hz, with a twofold increase in the 40-50-Hz range, and up to a fivefold increase in the 80-120-Hz portion of the spectrum. Activity above 40 Hz could represent summed action potentials, harmonics of synaptic potentials or transient sharp components of synaptic potentials. High-frequency increases were largely localized to the region of the seizure focus. Grid sites remote from the focus did not show significant energy in the EEG band above 40 Hz at baseline, nor at time of seizure onset. Our findings suggest that high-frequency recordings may be of use in localizing seizure foci.

    View details for Web of Science ID A1992JJ42200012

    View details for PubMedID 1517412

  • MOTOR AND SENSORY CORTEX IN HUMANS - TOPOGRAPHY STUDIED WITH CHRONIC SUBDURAL STIMULATION NEUROSURGERY Uematsu, S., Roberts, D. W., Lesser, R., Fisher, R. S., GORDON, B., Hara, K., Krauss, G. L., Vining, E. P., WEBBER, R. W. 1992; 31 (1): 59-72


    Classic neurosurgical teaching holds that once the Rolandic fissure (Rf) has been located, there are distinct differentiated primary motor and sensory functional units confined within a narrow cortical strip: Brodmann's Areas 4 and 6 for primary motor units in front of the Rf and 3, 1, and 2 for sensory units behind the Rf. To test this assumption, we examined in detail the records of cortical mapping done by electrical stimulation of the cerebral cortex via implanted subdural electrode grids in 35 patients with seizure disorders. Of 1381 stimulations of the electrode sites, 346 (25.1%) produced primary motor or motor-arrest and sensory responses in contralateral body parts: 56.8% were primary motor responses; 16.2% were motor-arrest; 22.5% were sensory; and the remaining 4.5% were mixed motor and sensory responses. Two-thirds (65.9%) of the primary motor responses were located within 10 mm of the Rf, and the remaining one-third (34.1%) were more than 10 mm anterior to the Rf or were posterior to the Rf. Furthermore, in the patient group with brain lesions, fewer than one-third (28.1%) of the responses were within the 10-mm narrow anterior strip. Our study reconfirmed that a significant number--at least one-third--of motor responses are distributed outside the classic narrow cortical strip. In patients with brain lesions, the motor representation is further displaced outside the narrow strip. This finding indicates that primary motor cortex may extend beyond the gyrus immediately anterior to the Rf.

    View details for Web of Science ID A1992JC69900009

    View details for PubMedID 1641111


    View details for Web of Science ID A1992HN08800001

    View details for PubMedID 1372545


    View details for Web of Science ID A1992KH38100036

    View details for PubMedID 1337449

  • ASSESSMENT OF SURGICAL OUTCOME EPILEPSY RESEARCH Lesser, R. P., Fisher, R. S., Uematsu, S. 1992: 217-229


    Evaluation of outcome of epilepsy surgery is complex because of several factors. Epilepsy is itself a heterogeneous disorder. Different epilepsy centers encounter different referral mixes of patients. Institutions employ various methods for pre-operative evaluation and widely varying surgical techniques. Clear definitions of surgical success and reliable scales for its measurement are lacking. Few data are acquired prospectively and maintained in a format allowing inter-institutional collation of results. A better representation of surgical outcome could in the future be served by adherence to 4 principles: collection of common data in standard formats; comparison of like, rather than disparate, populations; maintenance of quantitative data in raw form; and measurement of outcome along several dimensions or scales. Psychosocial issues have been underemphasized in most prior analyses of outcome.

    View details for Web of Science ID A1992JY99700027

    View details for PubMedID 1418453


    View details for Web of Science ID A1992KA43400026

    View details for PubMedID 1358098

  • Positron emission and single photon emission computed tomographic studies in the frontal lobe with emphasis on the relationship to seizure foci. Advances in neurology Swartz, B. E., Theodore, W. H., Sanabria, E., Fisher, R. S. 1992; 57: 487-497

    View details for PubMedID 1311896


    View details for Web of Science ID A1991GT66900012

    View details for PubMedID 1790776


    View details for Web of Science ID A1991GT66900002

    View details for PubMedID 1686427

  • QUANTIFICATION OF MU-OPIATE AND NON-MU-OPIATE RECEPTORS IN TEMPORAL-LOBE EPILEPSY USING POSITRON EMISSION TOMOGRAPHY ANNALS OF NEUROLOGY Mayberg, H. S., SADZOT, B., Meltzer, C. C., Fisher, R. S., Lesser, R. P., Dannals, R. F., Lever, J. R., Wilson, A. A., Ravert, H. T., WAGNER, H. N., Bryan, R. N., Cromwell, C. C., Frost, J. J. 1991; 30 (1): 3-11


    Alterations in a variety of neurotransmitter systems have been identified in experimental models of epilepsy and in brain tissue from patients with intractable temporal lobe seizures. The availability of new high-affinity radioligands permits the study of some neuroreceptors in vivo with positron emission tomography (PET). We previously characterized the in vivo binding of 11C-carfentanil, a potent and selective mu opiate receptor agonist, and described increases in 11C-carfentanil binding in the temporal neocortex of patients with unilateral temporal lobe epilepsy. These studies have been extended to 11C-diprenorphine, which labels mu, kappa, and delta opiate receptor subtypes. Paired measurements of opiate receptor binding were performed with PET using 11C-carfentanil and 11C-diprenorphine in patients with unilateral temporal lobe seizures. Carfentanil binding, reflecting changes in mu opiate receptors, was increased in the temporal neocortex and decreased in the amygdala on the side of the epileptic focus. Diprenorphine binding, reflecting mu as well as non-mu opiate subtypes, was not significantly different among regions in the focus and nonfocus temporal lobes. Regional glucose metabolism, measured using 18F-2-fluoro-2-deoxyglucose, was decreased in the mesial and lateral aspects of the temporal lobe ipsilateral to the epileptogenic focus. The variation in pattern of carfentanil and diprenorphine binding supports a differential regulation of opiate subtypes in unilateral temporal lobe epilepsy.

    View details for Web of Science ID A1991FV10200001

  • EPILEPSY JOURNAL OF NUCLEAR MEDICINE Fisher, R. S., Frost, J. J. 1991; 32 (4): 651-659


    As surgical treatments for adult and pediatric forms of epilepsy have become more refined, methods for noninvasive localization of epileptogenic foci have become increasingly important. Detection of focal brain metabolic or flow abnormalities is now well recognized as an essential step in the presurgical evaluation of many patients with epilepsy. Positron emission tomography (PET) scanning is most beneficial when used in the context of the total clinical evaluation of patients, including scalp EEG, invasive EEG, neuropsychologic testing, etc. Metabolic PET studies also give insight into pathophysiologic mechanisms of epilepsy. The dynamic nature of the interictal hypometabolism observed with 18[F]FDG in some patients suggests that excitatory or inhibitory neurotransmitters and their receptors may be involved. An exciting current application of PET scanning is the use of tracers for neurotransmitter receptors in the study of epilepsy patients. Mu and non-mu opiate receptors have been extensively studied and are beginning to give new insights into this disorder. Increased labeling of mu receptors in temporal neocortex using 11C-carfentanil has been demonstrated and, in some patients, supplements the clinical localization information from 18[F]FDG studies. Increased mu opiate receptor number or affinity is thought to play a role in anticonvulsant mechanisms. Specificity of increased mu receptors is supported by the absence of significant changes in non-mu opiate receptors. Other brain receptors are also of interest for future studies, particularly those for excitatory neurotransmitters. Combined studies of flow, metabolism, and neuroreceptors may elucidate the factors responsible for initiation and termination of seizures, thus improving patient treatment.

    View details for Web of Science ID A1991FG79700018

    View details for PubMedID 1849558

  • MAPPING THE DISTRIBUTION OF AMOBARBITAL SODIUM IN THE INTRACAROTID WADA TEST BY USE OF TC-99M HMPAO WITH SPECT RADIOLOGY Jeffery, P. J., Monsein, L. H., Szabo, Z., Hart, J., Fisher, R. S., Lesser, R. P., Debrun, G. M., GORDON, B., WAGNER, H. N., Camargo, E. E. 1991; 178 (3): 847-850


    The intracarotid amobarbital sodium, or Wada, test has been used to localize speech and memory function prior to surgical treatment of temporal lobe seizures. The authors mixed technetium-99m hexamethyl-propyleneamine oxime (HMPAO) with amobarbital sodium and injected the mixture in 25 patients with epilepsy. Single photon emission computed tomography (SPECT) of the brain was then performed to determine intracerebral distribution of the amobarbital sodium. Results of SPECT were compared with those of conventional and digital subtraction angiography (DSA). The distribution of Tc-99m HMPAO and, presumably, amobarbital sodium varied from patient to patient. SPECT revealed a statistically different distribution from that predicted with conventional angiography. The distribution also often differed from that of DSA, although the difference was not significant. SPECT revealed infrequent delivery to mesial temporal lobe structures. This emphasizes the need for caution in the use of the intracarotid amobarbital sodium test to predict the outcome of removal of these areas.

    View details for Web of Science ID A1991EY09700048

    View details for PubMedID 1994430



    Driving and epilepsy is a problem that involves physicians as both care providers to patients and consultants to regulatory authorities. Driving restrictions for people with seizure disorders are intended to ensure the public's safety, but such restrictions may unduly harm the welfare of many people with seizures. In the United States, all states now permit some people with epilepsy to drive. In general, only people whose seizures are adequately controlled are licensed to drive. Adequate control has been judged principally by the seizure-free interval, but individual state standards widely vary. There is a trend toward greater liberalization of driving standards for people with seizure disorders, but the appropriateness and application of these standards continue to raise questions, as does the role physicians should have in the licensing process. Our responsibilities to persons with disabilities and advances in our understanding of seizures and the nature of driving risks warrant a reappraisal of the current medical, legal, and social implications of driving and epilepsy.

    View details for Web of Science ID A1991EV71800020

    View details for PubMedID 1987412



    Measurement of serum prolactin levels can be useful in the diagnosis of epilepsy, since prolactin levels often rise after seizures, but not after most imitators of epilepsy. Utility of the test is limited by the need to obtain blood 10 to 20 minutes after the episode. The present study documents the validity of prolactin measurements using capillary blood, which was obtained by the finger-stick method after a possible seizure and then applied to filter paper. Venous and capillary prolactin levels were determined 10 to 20 minutes after seizure-like episodes in 20 patients who were studied in an epilepsy monitoring unit. Venous and capillary prolactin values correlated, with a Pearson coefficient of 0.90. Using a criteria of any elevation above the laboratory upper limit of normal, capillary prolactin values correctly identified seizure versus pseudoseizure in 9 (100%) of 9 patients with generalized tonic-clonic seizures, in 5 (71%) of 7 patients with complex partial seizures, and 4 (100%) of 4 patients with pseudoseizures. Prolactin values were unaffected by leaving filter paper samples at room temperature for up to 1 week. This study suggests the utility of diagnostic capillary blood collection kits to assist in the diagnosis of epilepsy in outpatients.

    View details for Web of Science ID A1991EW93900011

    View details for PubMedID 2012387



    Abolition of speech production after intracarotid amobarbital injection is generally considered evidence for language laterality. However, complex auditory comprehension may be preserved after injection of the dominant (left) side. The possibility that this sparing may be due to the intracarotid amobarbital injection not adequately deactivating some of the areas responsible for speech comprehension in the posterior part of the hemisphere was tested with a task known to be critically dependent on the left posterotemporal-inferoparietal region, one assessing visuo-verbal semantic relatedness. Even when the intracarotid injection of the left side produced marked deficits of speech production, comprehension of semantic relations was still intact in eight of 15 patients. Ten of these 15 patients also received right carotid injections, none of which affected comprehension of semantic relatedness. These data indicate that the intracarotid amobarbital injection cannot always specify the laterality of all language functions, an important concern when considering surgical procedures in the dominant posterotemporal-inferoparietal region.

    View details for Web of Science ID A1991ET98800017

    View details for PubMedID 1986727



    It would appear from the above that Pritchard agrees with the use of some agents other than magnesium sulfate that have known anticonvulsant properties. We believe that the subject at issue is whether magnesium sulfate should be used in treating the seizures of eclampsia. In our "Controversies" article, we do not address the issue of whether magnesium sulfate modifies pathophysiological factors leading to preeclampsia, but restrict ourselves to the treatment of the seizure per se, once seizures supervene, and the avoidance of their recurrence. The pathophysiological mechanisms and optimal treatment of preeclampsia and of eclampsia (excepting seizures) remain to be determined, as does the use of magnesium sulfate in this condition. Eclamptic seizures are clinically and electroencephalographically indistinguishable from generalized tonic-clonic seizures. Whether seizures arise in or out of the setting of preeclampsia, they should be treated as are other seizures, with known anticonvulsants. Controlled clinical trials are needed to address the effectiveness of alternative antiseizure regimens.

    View details for Web of Science ID A1990DX86100019

    View details for PubMedID 2204330



    Effects of dextrorphan (DX), a metabolite of the over-the-counter antitussive, dextromethorphan, were investigated in rat hippocampal slices exposed to the epileptogenic agent penicillin. At 50 microM and 100 microM concentrations dextrorphan suppressed late components of the epileptiform CA1 field potential elicited by afferent electrical stimulation, and partially suppressed the intracellularly recorded paroxysmal depolarization shift. These effects were not due to non-specific changes in cell excitability, since resting cell membrane potential, input resistance, and the ability of cells to fire action potentials in response to direct depolarizing current were unaffected. The depressant effect of 100 microM dextrorphan was probably due to actions at the NMDA receptor, since pretreatment with the competitive NMDA antagonist D-APV prevented any further depressant effects of dextrorphan in this model. In contrast, at a 10 microM concentration DX enhanced the amplitude of evoked epileptiform field potentials and intracellularly recorded EPSPs. These findings support a role for dextrorphan and similar agents as anticonvulsants at high concentrations, but raise a caution regarding possible excitatory actions of dextrorphan at low concentrations.

    View details for Web of Science ID A1990DP31200009

    View details for PubMedID 1975767

  • CHARACTERIZATION OF THE BASAL TEMPORAL LANGUAGE AREA IN PATIENTS WITH LEFT TEMPORAL-LOBE EPILEPSY NEUROLOGY BURNSTINE, T. H., Lesser, R. P., Hart, J., Uematsu, S., Zinreich, S. J., Krauss, G. L., Fisher, R. S., Vining, E. P., GORDON, B. 1990; 40 (6): 966-970


    We evaluated 5 consecutive patients with subdural grid electrodes (including placement over the left basal temporal region) for focal resections for control of intractable epilepsy. All 5 had language dysfunction when we performed cortical stimulation over the basal temporal region (the inferior temporal gyrus, the parahippocampal gyrus) using a systematic battery of language tests. The area in which language interference could be produced began from at least 11 to 35 mm posterior to the temporal tip and ended at least 39 to 74 mm posterior to the temporal tip. The most consistently impaired language tasks were spontaneous speech and passage reading, but there was impairment of all language functions tested in some patients. Language deficits after dominant temporal lobectomy may result from resection of this area.

    View details for Web of Science ID A1990DG80000020

    View details for PubMedID 2345619



    Safe parameters for electrical cortical stimulation in humans are difficult to estimate from the animal experimental literature. We therefore examined the light microscopic histology at a total of 11 sites of direct subdural electrical stimulation, taken as part of anterior temporal lobectomies in 3 patients. Stimulations had been done through 3.175 mm diameter electrodes, with 0.3 msec square wave pulses of alternating polarity at 50 pulses/sec. In 2 patients, one site each had been used as a common reference for stimulation, receiving over 251 stimulation trials, most of 2-5 sec duration, at currents of 12.5-15.0 mA, 1 day prior to resection. The maximum charge per phase was 4.0-4.4 microC; the maximum charge density was 52-57 microC per geometric cm2 per pulse at the electrode surfaces. Comparison of hematoxylin and eosin, periodic acid-Schiff, and cresyl violet-stained material from the electrode sites with that from other regions did not show any histologic abnormalities attributable to the electrical stimulation. The relatively brief and intermittent periods utilized for human stimulation testing do not appear to cause structural damage at the light microscopic level at charge densities that exceed the threshold for damage established in animal studies with more continuous, chronic stimulation schedules.

    View details for Web of Science ID A1990DD09300002

    View details for PubMedID 1692272

  • DEXTROMETHORPHAN FOR TREATMENT OF COMPLEX PARTIAL SEIZURES NEUROLOGY Fisher, R. S., CYSYK, B. J., Lesser, R. P., Pontecorvo, M. J., FERKANY, J. T., Schwerdt, P. R., Hart, J., GORDON, B. 1990; 40 (3): 547-549


    We performed a double-blind, crossover, add-on study of the antitussive agent dextromethorphan (DM 120 mg/d) as therapy for seizures on 9 patients suffering from severe complex partial seizures. DM had no significant influence on key laboratory values, nor on anticonvulsant drug levels. Side effects were negligible. Complex partial seizure frequency increased 25% during the DM arm of the study, although this increase was not clinically significant.

    View details for Web of Science ID A1990CU48500036

    View details for PubMedID 2314601



    Electrode grids were implanted subdurally in 28 patients with epilepsy. In 16 of the 28 patients, an epileptogenic area was located in the speech-dominant left temporal lobe. Recordings made with the grid revealed that the epileptogenic areas in the patients varied widely in extent: the area was confined within the first 10 mm of the temporal lobe in some patients or it was scattered throughout the entire anterior to posterior 80-mm extend in others. Resection of the epileptogenic area was adjusted accordingly in each case. In 6 of 16 patients who were left-hemisphere-dominant for language, up to 55-80 mm from the tip of the temporal lobe was removed, a measure that exceeds the conventional limit of 50 mm from the tip of the dominant hemisphere. In the remaining 12 of the 28 patients, epileptogenic areas were located in a combination of several lobes. In 7 of these 12 patients, the epileptogenic area encompassed the rolandic area; it was removed without deficit in 4 patients and with expected deficit in 3. Of the latter 3 patients, 1 patient underwent hemispherectomy, and a large portion of the epileptogenic rolandic cortex in the frontal and parietal lobes was removed from the other 2. There were 2 cases of grid-related infection, which cleared with antibiotic treatment; there were no lasting complications of grid implantation in any patient. There was no mortality. Electroencephalographic recording and functional mapping using subdural electrode grids allow a tailored, maximal resection of epileptogenic tissue with minimal injury to critical cortex.

    View details for Web of Science ID A1990EL27800004



    We have developed a model of cyclosporin A (CsA) central nervous system toxicity in the Munich-Wistar rat in which CsA, 20 mg/kg/day i.p., produces significant EEG abnormalities and mortality. In the present study we used cohorts of Munich-Wistar rats to assess effects of CsA on the threshold for tonic-clonic electroshock-induced seizures. Rat cohorts were begun on cremephore, CsA-10 mg/kg/day, or CsA-20 mg/kg/day. On day 7 and day 14 of the dosing protocol, cohorts of animals were exposed to maximal electroshock (MES) using a minimal staircase method within each cohort. Multiple logistic regression models were used to determine differences between groups on the relative odds of producing a MES-induced seizure while controlling for other variables. Seizure threshold was significantly affected by shock amperage and body weight, but not by SUN, creatinine, bilirubin, sodium, potassium, weight loss or day the shock was delivered. The odds ratios of seizure induction in the CsA-treated groups versus placebo group were 1.91 for CsA-10 mg/kg/day and 3.63 for CsA 20-mg/kg/d, both statistically significant. These results suggest that cyclosporine lowers seizure threshold and probably increases susceptibility to seizures, the etiology of which may be multifactorial clinically.

    View details for Web of Science ID A1990CV68600007

    View details for PubMedID 2325502



    Conceptual advantages, together with advances in both technique and technology, have considerably altered the approach to intractable epilepsy over the past two decades. Appropriate utilization of these advances allows our evaluation of patients with intractable seizures to be much more precise and specific than was once the case and allows us to improve considerably our ability to treat patients with intractable epilepsy. We propose an algorithm for the evaluation and treatment of patients with intractable complex partial seizures. Other forms of intractable epilepsy may benefit from similar diagnostic and therapeutic approaches.

    View details for Web of Science ID A1989CA70100004

    View details for PubMedID 2479516



    Magnesium sulfate has been used as an anticonvulsant in the treatment of eclampsia, but efficacy of magnesium in other types of seizure disorders is poorly documented. We examined the effects of magnesium sulfate (MgSO4) on seizures produced in mice by maximal electroshock (MES) and pentylenetetrazol (PTZ), MgSO4 injection (6.7 mEq/kg i.p.) caused weakness in all animals. With suprathreshold electroshock, 10/10 controls and 11/12 treated animals had seizures with tonic hind limb extension (P = NS). Electroshock threshold was unaltered by magnesium treatment (n = 48; P = 0.47). PTZ induced clonic seizures in 12/12 controls and 5/14 treated animals (P less than 0.05). This difference was likely due to muscular weakness because frequency of EEG spikes was the same in PTZ and PTZ + MgSO4 groups. Mean serum magnesium levels were 2.3 +/- 0.3 mEq/l in animals not given MgSO4; 10.9 +/- 1.4 mEq/l and 12.8 +/- 2.2 mEq/l in treated animals with and without seizures (P = NS). We conclude that magnesium sulfate had no significant anticonvulsant activity in mouse MES and PTZ models for epilepsy. The relevance of these findings to the possible efficacy of magnesium sulfate in eclamptic seizures and other types of epilepsy remains to be determined.

    View details for Web of Science ID A1989CB17300004

    View details for PubMedID 2612492

  • CENTRAL NERVOUS-SYSTEM TOXICITY OF CYCLOSPORINE IN A RAT MODEL TRANSPLANTATION Famiglio, L., Racusen, L., Fivush, B., SOLEZ, K., Fisher, R. 1989; 48 (2): 316-321


    The central nervous system toxicity of cyclosporine, which is known to be neurotoxic clinically, was investigated in a rat model. Munich-Wistar rats were divided into 3 groups for a 2-week protocol. After baseline EEG and behavioral testing, group 1 (control) received a weight-adjusted volume of parenteral cyclosporine vehicle i.p., group 2 (low-dose) received 5 or 10 mg/kg/day i.p., and group 3 (high-dose) received 20 mg/kg/day i.p. Spontaneous behavior was observed, simple sensorimotor testing performed daily, and awake EEG's recorded 3 times per week. Four of 12 high-dose animals died during study, one after a witnessed tonic-clonic seizure, and two after recording of frankly epileptiform EEG's; there were no deaths in control or low-dose animals. Significant EEG abnormalities developed only at high-dose, with frankly epileptiform EEG's and/or seizures seen in 58 +/- 15% of these rats (P = 0.005, different from controls by life-table analysis). Although some high-dose animals demonstrated hyperirritability and dystonic posturing, behavioral changes were subtle, and animals were often still or rocking slightly during recording of frankly epileptiform EEG's. Walking latency and alley escape behaviors were delayed in high-dose rats, the latter correlating with abnormal EEG's. Serum urea nitrogens were mildly elevated in high-dose animals, but serum creatinine, electrolytes, bilirubin, body magnesium stores, and blood pressure remained normal in all groups. Kidneys showed only mild vacuolation histologically. The brain showed only very focal cortical injury sites related to electrode placement, which did not correlate with EEG changes or mortality. These results suggest that there may be a direct effect of cyclosporine on the central nervous system. This model system should prove useful in defining mechanisms of cyclosporine-related neurotoxicity.

    View details for Web of Science ID A1989AM05700025

    View details for PubMedID 2756557



    The study of mechanisms of the epilepsies requires employment of animal models. Choice of a model system depends upon several factors, including the question to be studied, the type of epilepsy to be modelled, familiarity and convenience. Over 50 models are reviewed. Major categories of models are those for simple partial seizures: topical convulsants, acute electrical stimulation, cortically implanted metals, cryogenic injury; for complex partial seizures: kainic acid, tetanus toxin, injections into area tempesta, kindling, rodent hippocampal slice, isolated cell preparations, human neurosurgical tissue; for generalized tonic-clonic seizures: genetically seizure-prone strains of mouse, rat, gerbil, fruitfly and baboon, maximal electroshock seizures, systemic chemical convulsants, metabolic derangements; and for generalized absence seizures: thalamic stimulation, bilateral cortical foci, systemic penicillin, gamma-hydroxy-butyrate, intraventricular opiates, genetic rat models. The lithium-pilocarpine, homocysteine and rapid repetitive stimulation models are most useful in studies of status epilepticus. Key findings learned from each of the models, the model's strengths and weaknesses are detailed. Interpretation of findings from each of these models can be difficult. Do results pertain to the epilepsies or to the particular model under study? How important are species differences? Which clinical seizure type is really being modelled? In a model are behavior or EEG findings only similar superficially to epilepsy, or are the mechanisms comparable? The wealth of preparations available to model the epilepsies underscores the need for unifying themes, and for better understanding of basic mechanisms of the epilepsies.

    View details for Web of Science ID A1989AX19100003

    View details for PubMedID 2679941



    The effects of dextrorphan (DX) and dextromethorphan (DM) on responses to excitatory amino acids in the CA1 region of the hippocampus of the rat were studied using extracellular and intracellular recording in in vitro slices of brain. Dextrorphan selectively and non-competitively blocked depolarizations evoked by focally-applied N-methyl-D,L-aspartate (NMA), recorded by both extracellular and intracellular techniques. Quisqualate (QUIS) responses and evoked field potentials were not affected by DX. Epileptiform activity elicited in Mg2+-free solution was suppressed by DX. Dextrorphan had no effect on resting membrane potential or input resistance. The antagonism of NMA by DX was dose-dependent with an EC50 of 0.65 microM; DM was also effective but considerably less potent. In the paradigm used in the present study, DX did not produce the clear use-dependent block observed in the presence of MK-801. These data suggest that DX, the metabolite of the widely used antitussive DM, is a potent NMDA antagonist with a potential role as an anticonvulsant and neuroprotective agent.

    View details for Web of Science ID A1989T616800008

    View details for PubMedID 2657479



    The effect of prolonged glutamate (GLU) application was examined on 60 CA1 pyramidal neurons in the in vitro rat hippocampal slice preparation. Continuous application of L-GLU, either by bath perfusion (0.5-2 mM) of the slices or iontophoresis (200 mM) into the dendritic region of the neurons, elicited a transient depolarization which faded to a mean of 53% of the initial peak amplitude despite continued exposure to the agonist. Membrane depolarization to aspartate (ASP) and the d-isomer of GLU also faded with time. In contrast, the depolarizing response to the excitatory amino acid agonists N-methyl-D,L-aspartate (NMA), quisqualate (QUIS), and kainate (KA) did not fade significantly during continuous application. The fade of the GLU depolarization was not affected by the NMDA antagonist D-2-amino-5-phosphonovalerate (APV) or by blocking synaptic transmission with tetrodotoxin. At the time of maximum fade of the GLU depolarization, there was no change in input resistance or GLU reversal potential. In addition, fade of the response was not a consequence of changes in extracellular potassium concentration, GLU uptake mechanisms, or the electrogenic pump. The most likely explanation for fade is postsynaptic receptor desensitization.

    View details for Web of Science ID A1989AG53600002

    View details for PubMedID 2570466

  • NO, MAGNESIUM-SULFATE SHOULD NOT BE USED IN TREATING ECLAMPTIC SEIZURES ARCHIVES OF NEUROLOGY Kaplan, P. W., Lesser, R. P., Fisher, R. S., Repke, J. T., Hanley, D. F. 1988; 45 (12): 1361-1364

    View details for Web of Science ID A1988R130000017

    View details for PubMedID 3058097



    An unsuccessful attempt to terminate myoclonic status epilepticus with elevation of serum magnesium levels is described. During 3 days, serum magnesium was increased from 1.5 mEq/L to 14.2 mEq/L by continuous i.v. infusion of 3-6 g/h of magnesium sulfate. Other anticonvulsants were maintained at nearly constant levels. Cerebrospinal fluid magnesium was 3.5 mEq/L during the infusion. Despite magnesium-related neuromuscular blockade and accompanying cessation of visible myoclonus, the electroencephalogram revealed ongoing blunted sharp-wave activity at the baseline frequency. Transient complications of the infusion included prolongation of the PR interval on the electrocardiogram, hypomotility of the gastrointestinal tract, and peripheral muscle flaccidity, all of which resolved within 24 h of return to normal serum magnesium levels. These results suggest that the therapeutic role of magnesium in myoclonic status epilepticus is limited.

    View details for Web of Science ID A1988R210600007

    View details for PubMedID 3148367

  • Driving and epilepsy. Maryland medical journal (Baltimore, Md. : 1985) Fisher, R. S., Krumholz, A. 1988; 37 (10): 795-798

    View details for PubMedID 3185150



    The time course of recovery in the Guillain-Barré syndrome is known to vary widely, but factors associated with differences have not been previously defined. In this study we used multivariate analysis to identify such factors and to determine whether the presence or absence of specific factors would influence treatment decisions, particularly the use of plasmapheresis. Data from 245 patients randomized into conventional and plasmapheresis arms were used to assess the time to walk independently (Grade 2), the time to improve one grade, and the percentage improved at 4 weeks. Individually, many factors were associated with outcome. In the multivariate analysis, four factors correlate with poorer outcomes: mean amplitude of compound muscle action potential on stimulating distally of 20% of normal or less, older age, time from onset of disease of 7 days or less, and need for ventilatory support. The most powerful predictor of outcome was the abnormal mean amplitude of compound muscle action potential on stimulating distally. Plasmapheresis, the only variable the physician can influence, has a beneficial effect over and above any or all of these factors. The plasmapheresis patients on continuous flow machines had better outcomes than those on intermittent flow machines. From these data, tables of expected outcome probabilities have been developed.

    View details for Web of Science ID A1988M851200005

    View details for PubMedID 3382169

  • MU-OPIATE RECEPTORS MEASURED BY POSITRON EMISSION TOMOGRAPHY ARE INCREASED IN TEMPORAL-LOBE EPILEPSY ANNALS OF NEUROLOGY Frost, J. J., Mayberg, H. S., Fisher, R. S., DOUGLASS, K. H., Dannals, R. F., Links, J. M., Wilson, A. A., Ravert, H. T., Rosenbaum, A. E., Snyder, S. H., WAGNER, H. N. 1988; 23 (3): 231-237


    Neurochemical studies in animal models of epilepsy have demonstrated the importance of multiple neurotransmitters and their receptors in mediating seizures. The role of opiate receptors and endogenous opioid peptides in seizure mechanisms is well developed and is the basis for measuring opiate receptors in patients with epilepsy. Patients with complex partial seizures due to unilateral temporal seizure foci were studied by positron emission tomography using 11C-carfentanil to measure mu-opiate receptors and 18F-fluoro-deoxy-D-glucose to measure glucose utilization. Opiate receptor binding is greater in the temporal neocortex on the side of the electrical focus than on the opposite side. Modeling studies indicate that the increase in binding is due to an increase in affinity or the number of unoccupied receptors. No significant asymmetry of 11C-carfentanil binding was detected in the amygdala or hippocampus. Glucose utilization correlated inversely with 11C-carfentanil binding in the temporal neocortex. Increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.

    View details for Web of Science ID A1988M500100003

    View details for PubMedID 2837132



    Carbamazepine is a drug of choice for partial epilepsies, certain affective disorders and neuralgic pain syndromes. It has an excellent safety record; however, overdose can be dangerous. This article reports one of the very few fatalities from carbamazepine overdosage, in an individual with a peak carbamazepine level of 54 mg/L. Manifestations of this and other major carbamazepine overdoses reviewed from the literature were similar to those of tricyclic - anticholinergic overdose, with coma, hypotension, respiratory depression, cardiac arrhythmias, abnormal movements and seizures. Fatality from cardiovascular causes occurred despite decline of serum carbamazepine levels to the putatively non-toxic range, emphasizing the potential for delayed consequences of carbamazepine overdosage. Management should consist of vigorous gastric lavage and installation of activated charcoal, full supportive care in a monitored setting and consideration of early charcoal hemoperfusion, before the patient becomes hypotensive.

    View details for Web of Science ID A1988T671600005

    View details for PubMedID 3068370



    A technique of locating current dipoles in spherical conducting volumes by determining the location of the magnetic field maximum and inverting the magnetic field equations was developed and the expected localisation errors were predicted. AC current dipoles were placed in spheres of uniform conductivity. Each dipole's magnetic field was measured and its location was calculated by determining the angle between the magnetic field null and maximum and using an iterative inverse solution to the magnetic field equations. Absolute agreement between predicted magnetic field strengths and actual magnetic field measurements was within 5%. A study of the effect of signal to noise ratio and number of data points in the analysis indicates that dipole localisation of approximately 1 mm is achievable for a signal to noise ratio greater than 10 decibels (S/N greater than 10 db).

    View details for Web of Science ID A1988L933100010

    View details for PubMedID 3353445



    N-methyl-D,L-aspartate (NMA) antagonists are of potential value in the treatment of epilepsy and ischemia, but commonly utilized compounds are of low potency and poorly penetrate the brain. Tiletamine hydrochloride is a lipophilic and potent veterinary anesthetic. This study shows tiletamine to be similar to ketamine and to phencyclidine, agents known to interact with the NMA receptor. Effects of tiletamine on synaptic transmission and on direct excitatory responses to exogenous amino acids were examined in rat hippocampal and striatal slices. In striatal slices, tiletamine inhibited the NMA-mediated, but not the spontaneous, release of [3H]acetylcholine, with an IC50 of 70 nM. In hippocampal CA1 cells, 3 microM tiletamine in the perfusate reversibly blocked the intracellularly recorded responses to ionophoretically applied NMA, but not to glutamate, quisqualate and kainate. Tiletamine, 3 to 100 microM, had no effect on the orthodromically elicited excitatory postsynaptic potential, action potential amplitude or duration, resting membrane potential, or input resistance. In Mg++-free perfusate, the excitatory postsynaptic potential was greatly augmented to give a paroxysmal depolarization shift and was reversibly blocked by 10 microM tiletamine. Our results show that tiletamine is a potent and reversible antagonist of NMA-mediated responses without itself having major effects in low concentrations on normal membrane and synaptic pyramidal cell properties.

    View details for Web of Science ID A1987L418400018

    View details for PubMedID 3320347


    View details for Web of Science ID A1987K636400018

    View details for PubMedID 3675252



    Depth EEG recordings were carried out in 16 patients with clinical and EEG evidence of the Lennox-Gastaut syndrome (LGS), in attempts to identify a surgically-resectable focus. Structures explored included the mesial temporal (amygdaloid) areas, the orbito-frontal cortex, the superior parasagittal cortex, and in three cases deep cerebellar nuclei. All patients showed disordered and slow background activity in depth leads. Slow spike-waves were prominent in orbito-frontal and parasagittal frontal areas, but were generally reflected as well in surface frontal leads. Runs of rapid spikes were recorded in 7 patients, again mainly in deep frontal leads. Independent interictal spikes were observed in 9 patients, chiefly from one or both amygdaloid areas. Ictal events were recorded in 9 patients. Frontal lobes were most often involved at the start, and a few cases showed origin of apparently generalized surface activity beginning unilaterally in deep frontal lobe. None of the identified interictal nor ictal foci were sufficiently dominant to justify local surgical resection. Frontal bilateral synchrony, when present, was adequately visualized by noninvasive surface EEG recording. Depth electroencephalography in our hands therefore has a very limited role in evaluation of patients with LGS.

    View details for Web of Science ID A1987M434900006

    View details for PubMedID 3117442



    Effects of prolonged (5-10 min) continuous perfusion of excitatory amino acids on penicillin (PEN)-evoked epileptiform activity in hippocampal slices were examined with extracellular and intracellular recordings. L-glutamate (GLU), L-aspartate (ASP), quisqualate (QUIS), and N-methyl-D,L-aspartate reversibly depressed multiple (epileptiform) population spikes elicited by PEN (1.7 mM). Intracellularly recorded, PEN-evoked paroxysmal depolarization shifts (PDS) were partially blocked by 1 mM GLU and largely eliminated by 2 mM GLU or ASP. In the presence of PEN, perfusion with both GLU and ASP induced a transient 4 to 6-mV depolarization, usually followed by spontaneous return of membrane potential to control levels. During the amino acid (AA)-induced block of epileptiform activity, there was no significant change in resting membrane potential, input resistance, or the ability to fire action potentials in response to depolarization, indicating that the decreased responsiveness is not a consequence of nonspecific pyramidal cell overdepolarization. The observed depression of epileptiform activity by continued exposure to GLU and its analogues may reflect desensitization or another regulatory mechanism to limit overexcitation.

    View details for Web of Science ID A1986F304700004

    View details for PubMedID 2877868



    There has been considerable progress in various segments of epileptology over the past two to three decades. The diagnostic sector has benefited from more advanced and sophisticated EEG-related techniques. The advent of computerized tomography has expedited the clinical evaluation of epileptic patients and new high-technology methods have been introduced. A new type of diagnostic subdivision (based on age-determined epileptic conditions and certain epileptic syndromes) is of great practical significance because of its prognostic implications (distinction of basically benign and severe forms of epileptic seizure disorders). The therapeutic sector has been stimulated by the introduction of new antiepileptic medications and particularly by profound insights into metabolic and pharmacokinetic characteristics of anticonvulsants; this has resulted in the introduction of techniques for serum level determinations. There have been new developments in the field of neurosurgical treatment of epileptic seizure disorders.

    View details for Web of Science ID A1985AFZ0400001

    View details for PubMedID 3998768



    The dipeptide N-acetylaspartylglutamate (NAAG), and possibly the related dipeptide aspartylglutamate (AG), have been found in high concentrations in rat brain, and have been shown to bind avidly and selectively to a subset of glutamate (GLUT) receptors. Certain observations regarding GLUT and aspartate might be explained if the endogenous transmitter were a compound composed of both amino acids. We therefore examined the electrophysiological actions of NAAG and AG in the rat in vitro rat hippocampal slice model. NAAG or AG and GLUT were applied locally to cells by a dual-barrel pressure technique. Intracellular recordings from 34 CA1 pyramidal neurons showed depolarizations and conductance increases resembling evoked excitatory postsynaptic potential in 15 of 20 cells exposed to NAAG, and 14 of 14 exposed to AG. Many GLUT-responsive sites did not respond to AG, and most did not respond to NAAG. Responses to NAAG were usually too small to induce cell firing; they were best detected, therefore, by intracellular recording. With extracellular unit recordings, GLUT was equally excitatory in stratum radiatum and pyramidale of CA1 (N = 19; p greater than 0.10, one-way analysis of variance). In contrast, AG was considerably more potent (N = 21; p less than 0.01) in stratum radiatum. NAAG was not noted to excite cells when applied to stratum pyramidale. The region of maximal responsiveness to AG in CA1 coincided with the area of the dendritic tree receiving Schaffer collateral-commissural afferents. This spatial profile, together with other neuropharmacological evidence, support the candidacy of glutamate-containing peptides as endogenous excitatory compounds in certain pathways of hippocampus.

    View details for Web of Science ID A1985AKC7400006

    View details for PubMedID 2989450



    Exposure of rat hippocampal slices to perfusate containing 1-2 mM glutamate (GLU) induces reversible and relatively selective blockade of excitatory transmission. Intracellular recordings from 20 region CA1 hippocampal cells demonstrated only transient and mild effects on resting membrane properties and action potentials. In contrast, in 2 mM GLU excitatory postsynaptic potentials declined to 28% of control (P less than 0.001); inhibitory postsynaptic potentials remained robust at 88% of control. This suggests that excess exposure to GLU may result in a selective 'down-regulation' of excitatory synaptic transmission, while preserving inhibitory pathways. These observations may have practical implications for development of new anticonvulsant drugs.

    View details for Web of Science ID A1985AVF4200004

    View details for PubMedID 2867502



    Depression of GABA-mediated IPSPs has been proposed to be a crucial factor in the onset of epileptiform activity in most models of epilepsy. To test this idea, we studied epileptiform activity induced by bath application of the excitatory neurotoxin kainic acid (KA) in the rat hippocampal slice. Repetitive field potential firing, spontaneous or evoked, occurred during exposure to KA. Intracellular records from 52 CA1 pyramidal cells during changes from control saline to saline containing 1 microM KA indicated that KA depolarized cells an average of about 5 mV and caused a 15% decrease in input resistance. Action potentials and current-induced burst afterhyperpolarizations did not change significantly. In several cells the tonic effects of KA were preceded by a transient phase of sporadic, spontaneous depolarizations of 2 to 10 mV and 50 to 200 msec duration. These phasic depolarizations were blocked by hyperpolarization. The major effect of 1 microM KA was a depression of synaptic potentials. Initially, KA depressed fast GABA-mediated IPSPs and slow, non-GABA-mediated late hyperpolarizing potentials to 23% and 40% of control values, respectively. IPSP depression correlated closely with onset of burst potential firing in response to synaptic stimulation. Similar observations were made on six cells from the CA2/3 region, although these cells were affected by lower doses of KA. The mechanism of IPSP depression was studied by using KCl-filled electrodes to invert spontaneous IPSPs and make them readily visible. In nine CA1 cells the rate and amplitude of spontaneous IPSPs transiently increased but then decreased in conjunction with evoked IPSP depression. Possible KA effects on postsynaptic GABA responses were investigated by applying GABA locally to cells. KA did not significantly affect GABA responses. Prolonged exposure of CA1 cells to KA in doses of 1 microM or higher depressed intracellularly and extracellularly recorded EPSPs and all field potential activity. This depression was not apparently due to depolarization block in CA1, however. We conclude that KA induces epileptiform activity in hippocampus principally by a presynaptic block of IPSP pathways.

    View details for Web of Science ID A1984ST87900016

    View details for PubMedID 6726334



    Neuropathological findings in a patient with fatal neurological complications due to infection with Mycoplasma pneumoniae were similar to those seen in postinfectious encephalitis and acute hemorrhagic leukoencephalitis. This case supports the hypothesis that immune mechanisms play a role in the pathogenesis of neurological symptoms during mycoplasmal infections.

    View details for DOI 10.1001/archneur.1983.04050020071016

    View details for Web of Science ID A1983QA65500013

    View details for PubMedID 6824440


    View details for Web of Science ID A1982PW66500010

    View details for PubMedID 7176293



    Surface and depth recordings were made in 21 cats with generalized, parenteral penicillin induced epileptiform activity often assuming spike-wave forms, to obtain information on the structural substrate of "spontaneous" spike-wave rhythms. Recordings were made from neocortex, medial and lateral thalamus, hippocampus and brainstem reticular formation. Epileptiform activity first appeared in cortex and subsequently projected to depth structures. Occasionally, focal discharges could be seen in subcortical structures, but these generally did not spread to cortex. No consistent "pacemaker" was identified in cortex or depth. Bilateral applications of penicillin to cortex produced synchronous spike-wave bursts. In contrast, ventriculocisternal perfusion of penicillin solutions yielded synchronous cortical potentials which differed clearly in morphology and frequency from parenterally induced spike-wave bursts. During generalized activity, transcortical, intrahemispheric lesions interfered with ipsilateral synchrony. After transcortical section, projection of localized cortical bursts to thalamus did not necessarily result in "recruitment" of diffuse cortical regions into epileptiform activity. These results emphasize the importance of cortical circuitry and corticocortical connections in the genesis and synchronization of spike-wave rhythms.

    View details for Web of Science ID A1977DF15300002

    View details for PubMedID 67022



    Epileptiform potentials, consisting of spontaneous, generalized bursts frequently assuming a 3/sec spike-wave form and tonic clonic electrographic seizures were produced in 32 lightly anesthetized cats by parenteral injections of penicillin. The activity of 83 identified pyramidal tract cells and 207 cortical non-pyramidal tract cells was correlated with the surface EEG. The majority of both cell types generated depolarizations and action potentials with the EEG spike. Hyperpolarizations, during which cells were inhibited, followed the depolarizations. The depolarizations responded to injected current as if they were generated by excitatory synapses; and hyperpolarizations to injected current and chloride ions as if generated by proximal inhibitory synapses. Attempts to identify a class of neurons firing during the surface-negative wave (presumed inhibitory interneurons) were unsuccessful. Forty-two units were recorded during tonic-clonic seizures. Intracellular records disclosed tonic oscillations of membrane potential, phased bursting with "depolarization shifts", abortive action potentials and post-ictal hyperpolarizations. Cell somata often depolarized to the point of inactivation, but axons continued to fire at high rates. These results emphasize the role of EPSP-IPSP sequences in the generation of spike-wave rhythms.

    View details for Web of Science ID A1977DF15300003

    View details for PubMedID 67023



    Characteristic elevations in the brain's extracellular potassium concentration [K+]0 occur during focal epileptogenesis. These changes have particular spatial and temporal profiles that are different in hippocampus and neocortex, and in mature and immature animals. Increases in [K+]0 cannot be the sole explanation for regional variations in seizure susceptibility, interictal-ictal transitions, or termination of ictal episodes. Excess [K+]0 is cleared primarily by passive diffusion with a small amount taken up into cells and blood vessels. Cortical neuroglia have sensitivities to changes in [K+]0 similar to that observed in glial cells in invertebrates and amphibia. However, discrepancies in the expected relationship between [K+]o and glial membrane potential Vm suggest either a heterogeneous population of glial cell types and/or the presence of a glial syncytium which acts as a spatial buffer to increases in [K+]0.

    View details for Web of Science ID A1976BR08700005

    View details for PubMedID 816678



    It has been proposed that the notable capacity for epileptogenesis in the hippocampus may be related to potassium accumulation in extracellular spaces. To investigate this hypothesis more directly, we measured changes in extracellular potassium concentration ([K+]o) during focal hippocampal epilepsy using potassium-sensitive microelectrodes. Interictal and ictal electroencephalographic events were accompanied by increases in [K+]o that varied systematically with depth from the ependymal surface and lateral distance from the focus. Maximal [K+]o changes during interictal and ictal discharges occurred in the stratum pyramidale. Initiation of ictal activity did not correlate with a particular "threshold" [K+]o. Comparing these results with similar data from neocortex, we observed that interictal K+ responses in hippocampus lasted longer and had slower rise times, and that peak interictal and ictal [K+]o values were consistently lower. Increases in [K+]o cannot be the sole explanation for regional variations in seizure susceptibility, interictal-ictal transitions, or termination of ictal episodes.

    View details for Web of Science ID A1976BD60300002

    View details for PubMedID 1252153

  • Extracellular potassium activity during epileptogenesis: a comparison between neocortex and hippocampus. Transactions of the American Neurological Association Pedley, T. A., Fisher, R. S., Moody, W. J., Futamachi, K. J., Prince, D. A. 1974; 99: 41-5

    View details for PubMedID 4463561