Martha Morrell, MD

All Publications

• Acute effects of brain-responsive neurostimulation in drug-resistant partial onset epilepsy. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Ronborg, S. N., Esteller, R., Tcheng, T. K., Greene, D. A., Morrell, M. J., Wesenberg Kjaer, T., Arcot Desai, S. 2021

  Abstract

  OBJECTIVE: Understanding the acute effects of responsive stimulation (AERS) based on intracranial EEG (iEEG) recordings in ambulatory patients with drug-resistant partial epilepsy, and correlating these with changes in clinical seizure frequency, may help clinicians more efficiently optimize responsive stimulation settings.METHODS: In patients implanted with the NeuroPace RNS System, acute changes in iEEG spectral power following active and sham stimulation periods were quantified and compared within individual iEEG channels. Additionally, acute stimulation-induced acute iEEG changes were compared within iEEG channels before and after patients experienced substantial reductions in clinical seizure frequency.RESULTS: Responsive stimulation resulted in a 20.7% relative decrease in spectral power in the 2-4 second window following active stimulation, compared to sham stimulation. On several detection channels, the AERS features changed when clinical outcomes improved but were relatively stable otherwise. AERS change direction associated with clinical improvement was generally consistent within detection channels.CONCLUSIONS: In this retrospective analysis, patients with drug-resistant partial epilepsy treated with direct brain-responsive neurostimulation showed an acute stimulation related reduction in iEEG spectral power that was associated with reductions in clinical seizure frequency.SIGNIFICANCE: Identifying favorable stimulation related changes in iEEG activity could help physicians to more rapidly optimize stimulation settings for each patient.

  View details for DOI 10.1016/j.clinph.2021.03.013

  View details for PubMedID 33931295

• Mood and quality of life in patients treated with brain-responsive neurostimulation: The value of earlier intervention. Epilepsy & behavior : E&B Loring, D. W., Jarosiewicz, B. n., Meador, K. J., Kanner, A. M., Skarpaas, T. L., Morrell, M. J. 2021; 117: 107868

  Abstract

  To establish whether earlier treatment using direct brain-responsive neurostimulation for medically intractable focal-onset seizures is associated with better mood and Quality of Life (QoL) compared to later treatment intervention.Data were retrospectively analyzed from prospective clinical trials of a direct brain-responsive neurostimulator (RNS® System) for treatment of adults with medically intractable focal-onset epilepsy. Participants completed the Quality of Life in Epilepsy Inventory (QOLIE-31) yearly through 9 years of follow-up and the Beck Depression Inventory-II (BDI-II) through 2 years of follow-up. Changes in each assessment after treatment with responsive neurostimulation were calculated for patients who began treatment within 10 years of seizure onset (early) and those who began treatment 20 years or more after seizure onset (late).The median duration of epilepsy was 18.3 years at enrollment. At 9 years, both the early (N = 51) and late (N = 109) treatment groups experienced similar and significant reductions in the frequency of disabling seizures (73.4% and 77.8%, respectively). The early treatment patients had significant improvements in QoL and mood. However, the late treatment patients not only failed to show these improvements but also declined in the emotional QoL subscale.Patients treated with brain-responsive neurostimulation earlier in the course of their epilepsy show significant improvements in multiple domains of QoL and mood that are not observed in patients treated later in the course of their epilepsy despite similar efficacy in seizure reduction. Even with similar and substantial reductions in seizure frequency, the comorbidities of uncontrolled epilepsy may be less responsive to treatment when too many years have passed. The results of this study suggest that, as with resective and ablative surgery, treatment with brain-responsive neurostimulation should be delivered as early as possible in the course of medically resistant epilepsy to maximize the opportunity for improvements in mood and QoL.

  View details for DOI 10.1016/j.yebeh.2021.107868

  View details for PubMedID 33684783

• A High Accuracy Electrographic Seizure Classifier Trained Using Semi-Supervised Labeling Applied to a Large Spectrogram Dataset. Frontiers in neuroscience Barry, W., Arcot Desai, S., Tcheng, T. K., Morrell, M. J. 2021; 15: 667373

  Abstract

  The objective of this study was to explore using ECoG spectrogram images for training reliable cross-patient electrographic seizure classifiers, and to characterize the classifiers' test accuracy as a function of amount of training data. ECoG channels in 138,000 time-series ECoG records from 113 patients were converted to RGB spectrogram images. Using an unsupervised spectrogram image clustering technique, manual labeling of 138,000 ECoG records (each with up to 4 ECoG channels) was completed in 320 h, which is an estimated 5 times faster than manual labeling without ECoG clustering. For training supervised classifier models, five random folds of data were created; with each fold containing 72, 18, and 23 patients' data for model training, validation and testing respectively. Five convolutional neural network (CNN) architectures, including two with residual connections, were trained. Cross-patient classification accuracies and F1 scores improved with model complexity, with the shallowest 6-layer model (with 1.5 million trainable parameters) producing a class-balanced seizure/non-seizure classification accuracy of 87.9% on ECoG channels and the deepest ResNet50-based model (with 23.5 million trainable parameters) producing a classification accuracy of 95.7%. The trained ResNet50-based model additionally had 93.5% agreement in scores with an independent expert labeller. Visual inspection of gradient-based saliency maps confirmed that the models' classifications were based on relevant portions of the spectrogram images. Further, by repeating training experiments with data from varying number of patients, it was found that ECoG spectrogram images from just 10 patients were sufficient to train ResNet50-based models with 88% cross-patient accuracy, while at least 30 patients' data was required to produce cross-patient classification accuracies of >90%.

  View details for DOI 10.3389/fnins.2021.667373

  View details for PubMedID 34262426

• Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology Nair, D. R., Laxer, K. D., Weber, P. B., Murro, A. M., Park, Y. D., Barkley, G. L., Smith, B. J., Gwinn, R. P., Doherty, M. J., Noe, K. H., Zimmerman, R. S., Bergey, G. K., Anderson, W. S., Heck, C., Liu, C. Y., Lee, R. W., Sadler, T., Duckrow, R. B., Hirsch, L. J., Wharen, R. E., Tatum, W., Srinivasan, S., McKhann, G. M., Agostini, M. A., Alexopoulos, A. V., Jobst, B. C., Roberts, D. W., Salanova, V., Witt, T. C., Cash, S. S., Cole, A. J., Worrell, G. A., Lundstrom, B. N., Edwards, J. C., Halford, J. J., Spencer, D. C., Ernst, L., Skidmore, C. T., Sperling, M. R., Miller, I., Geller, E. B., Berg, M. J., Fessler, A. J., Rutecki, P., Goldman, A. M., Mizrahi, E. M., Gross, R. E., Shields, D. C., Schwartz, T. H., Labar, D. R., Fountain, N. B., Elias, W. J., Olejniczak, P. W., Villemarette-Pittman, N. R., Eisenschenk, S., Roper, S. N., Boggs, J. G., Courtney, T. A., Sun, F. T., Seale, C. G., Miller, K. L., Skarpaas, T. L., Morrell, M. J. 2020

  Abstract

  OBJECTIVE: Prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.METHODS: Adults treated with brain-responsive neurostimulation within 2 year feasibility or randomized controlled trials enrolled into a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL using the quality of life in epilepsy (QOLIE-89) inventory.RESULTS: 230 of 256 patients treated in the initial trials participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p<0.0001; Wilcoxon Signed Rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. 18.4% (47/256) experienced ≥1 year of seizure freedom with 62% (29/47) seizure free at last follow-up and an average seizure-free period of 3.2 years (range: 1.04 - 9.6 years). Overall QOL, epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p<0.05). There were no serious AEs related to stimulation and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p<0.05; one-tailed Chi Square).CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated, implant related AEs were typical of other neurostimulation devices, and SUDEP rates were low.CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

  View details for DOI 10.1212/WNL.0000000000010154

  View details for PubMedID 32690786

• Mood and Quality of Life in Patients Treated with Brain-responsive Neurostimulation: The Value of Earlier Intervention Loring, D., Jarosiewicz, B., Meador, K., Kanner, A., Skarpaas, T., Morrell, M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058002233

• Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system. Epilepsia Hirsch, L. J., Mirro, E. A., Salanova, V., Witt, T. C., Drees, C. N., Brown, M., Lee, R. W., Sadler, T. L., Felton, E. A., Rutecki, P., Shin, H. W., Hadar, E., Hegde, M., Rao, V. R., Mnatsakanyan, L., Madhavan, D. S., Zakaria, T. J., Liu, A. A., Heck, C. N., Greenwood, J. E., Bigelow, J. K., Nair, D. R., Alexopoulos, A. V., Mackow, M., Edwards, J. C., Sotudeh, N., Kuzniecky, R. I., Gwinn, R. P., Doherty, M. J., Geller, E. B., Morrell, M. J. 2020

  Abstract

  OBJECTIVE: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator(RNS) system.METHODS: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3months before MTL resection.RESULTS: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean=42months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1year of follow-up (N=21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets.SIGNIFICANCE: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

  View details for DOI 10.1111/epi.16442

  View details for PubMedID 32072621

• Brain-Responsive Neurostimulation for Loss of Control Eating: Early Feasibility Study. Neurosurgery Wu, H. n., Adler, S. n., Azagury, D. E., Bohon, C. n., Safer, D. L., Barbosa, D. A., Bhati, M. T., Williams, N. R., Dunn, L. B., Tass, P. A., Knutson, B. D., Yutsis, M. n., Fraser, A. n., Cunningham, T. n., Richardson, K. n., Skarpaas, T. L., Tcheng, T. K., Morrell, M. J., Roberts, L. W., Malenka, R. C., Lock, J. D., Halpern, C. H. 2020

  Abstract

  Loss of control (LOC) is a pervasive feature of binge eating, which contributes significantly to the growing epidemic of obesity; approximately 80 million US adults are obese. Brain-responsive neurostimulation guided by the delta band was previously found to block binge-eating behavior in mice. Following novel preclinical work and a human case study demonstrating an association between the delta band and reward anticipation, the US Food and Drug Administration approved an Investigational Device Exemption for a first-in-human study.To assess feasibility, safety, and nonfutility of brain-responsive neurostimulation for LOC eating in treatment-refractory obesity.This is a single-site, early feasibility study with a randomized, single-blinded, staggered-onset design. Six subjects will undergo bilateral brain-responsive neurostimulation of the nucleus accumbens for LOC eating using the RNS® System (NeuroPace Inc). Eligible participants must have treatment-refractory obesity with body mass index ≥ 45 kg/m2. Electrophysiological signals of LOC will be characterized using real-time recording capabilities coupled with synchronized video monitoring. Effects on other eating disorder pathology, mood, neuropsychological profile, metabolic syndrome, and nutrition will also be assessed.Safety/feasibility of brain-responsive neurostimulation of the nucleus accumbens will be examined. The primary success criterion is a decrease of ≥1 LOC eating episode/week based on a 28-d average in ≥50% of subjects after 6 mo of responsive neurostimulation.This study is the first to use brain-responsive neurostimulation for obesity; this approach represents a paradigm shift for intractable mental health disorders.

  View details for DOI 10.1093/neuros/nyaa300

  View details for PubMedID 32717033

• The RNS System: brain-responsive neurostimulation for the treatment of epilepsy. Expert review of medical devices Jarosiewicz, B. n., Morrell, M. n. 2020: 1–10

  Abstract

  Epilepsy affects more than 1% of the US population, and over 30% of adults with epilepsy do not respond to antiseizure medications without life-impacting medication-related side effects. Resection of the seizure focus is not an option for many patients because it would cause unacceptable neurological or cognitive harm. For these patients, neuromodulation has emerged as a nondestructive, effective, and safe alternative. The NeuroPace® RNS® System, the only brain-responsive neurostimulation device, records neural activity from leads placed at one or two seizure foci. When the neurostimulator detects epileptiform activity, as defined for each patient by his or her physician, brief pulses of electrical stimulation are delivered to normalize the activity.This review describes the RNS System, the results of multi-year clinical trials, and the research discoveries enabled by the chronic ambulatory brain data collected by the RNS System.Brain-responsive neurostimulation could potentially be used to treat any episodic neurological disorder that's accompanied by a neurophysiological biomarker of severity. Combining advanced machine learning approaches with the chronic ambulatory brain data collected by the RNS System could eventually enable automatic fine-tuning of detection and stimulation for each patient, creating a general-purpose neurotechnological platform for precision medicine.

  View details for DOI 10.1080/17434440.2019.1683445

  View details for PubMedID 32936673

• Electrocorticographic events from long-term ambulatory brain recordings can potentially supplement seizure diaries. Epilepsy research Quigg, M. n., Skarpaas, T. L., Spencer, D. C., Fountain, N. B., Jarosiewicz, B. n., Morrell, M. J. 2020; 161: 106302

  Abstract

  To determine the feasibility of using epileptiform events detected by continuous electrocorticographic monitoring via a brain-responsive neurostimulation system to supplement patient-maintained seizure diaries.Data were retrospectively analyzed from a randomized controlled trial of brain-responsive neurostimulation (RNS® System) for adjunctive treatment of medically intractable focal onset seizures in 191 subjects. The long-term (≥3 months) correspondence between daily counts of diary-reported seizures and device-recorded "long epileptiform events" (LEs), a proxy for electrographic seizures (ESs), was assessed using cross-correlation and logistic generalized estimating equation models.Diary-reported seizures and LEs significantly co-varied across days in 124 patients whose detection settings were held constant, with a significantly higher correlation in 54 patients (44 %) whose LEs were usually ESs (high concordance patients). There were more days in which LEs were detected than days in which patients reported a seizure (positive predictive value (PPV): 34 %). On days when there were no LEs, there were typically no diary-reported seizures (negative predictive value (NPV): 90 %). In patients with a high concordance between LEs and ESs, the PPV and NPV were both slightly higher, 43 % (35-52 %) and 93 % (95 % CI: 86-97 %) respectively.Although LEs can substantially outnumber diary reported seizures, the high across-day correlation and strong NPV between LEs and diary seizures suggests that LEs recorded by the RNS® System could potentially supplement seizure diaries by providing an objective biomarker for relative seizure burden.

  View details for DOI 10.1016/j.eplepsyres.2020.106302

  View details for PubMedID 32126490

• Brain-responsive neurostimulation for epilepsy (RNS (R) System) EPILEPSY RESEARCH Skarpaas, T. L., Jarosiewicz, B., Morrell, M. J. 2019; 153: 68–70

  View details for DOI 10.1016/j.eplepsyres.2019.02.003

  View details for Web of Science ID 000468014600011

• Quantitative electrocorticographic biomarkers of clinical outcomes in mesial temporal lobe epileptic patients treated with the RNS system. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Arcot Desai, S., Tcheng, T. K., Morrell, M. J. 2019; 130 (8): 1364–74

  Abstract

  OBJECTIVES: Find interictal electrocorticographic (ECoG) biomarkers of clinical outcomes in mesiotemporal lobe (MTL) epilepsy patients.METHODS: In the NeuroPace RNS System clinical trials with 256 patients, 20 MTL patients with the most reduction in clinical seizures at Year 7 compared to baseline (upper response quartile; -96.5% median change) and 20 with the least reduction in clinical seizures (lower response quartile; -17.4% median change) were evaluated. Clinical and interictal ECoG features from the two response quartiles were compared.RESULTS: Demographic and clinical features were similar in the upper and lower response quartiles. Interictal spike rate (ISR) was substantially lower (p < 0.0001) in the upper quartile patients, while normalized theta (4-8 Hz) and normalized gamma (>25 Hz) were also different (p < 0.05) between the two response quartiles. ISR was positively correlated (p < 0.05) with clinical seizure rates in 71% of the channels analyzed. ECoG records captured during months with no clinical seizures had the lowest ISR.CONCLUSIONS: ISR is a strong differentiator of clinical response in MTL patients. Normalized theta and gamma also differentiates clinical response.SIGNIFICANCE: In MTL patients, the interictal spike rate along with spectral power computed from chronic ambulatory baseline ECoGs may serve as biomarkers of clinical outcomes and maybe used as treatment endpoints.

  View details for DOI 10.1016/j.clinph.2019.05.017

  View details for PubMedID 31212202

• Nine-year Prospective Safety and Effectiveness Outcomes from the Long-Term Treatment Trial of the RNS (R) System Nair, D., Morrell, M. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965906282

• Brain-responsive neurostimulation for epilepsy (RNS System). Epilepsy research Skarpaas, T. L., Jarosiewicz, B., Morrell, M. J. 2019

  Abstract

  Controlled clinical trials in adults with medically intractable focal seizures treated with the RNS System demonstrate that closed-loop responsive neurostimulation to the seizure focus reduces the frequency of disabling seizures, is well tolerated, and is acceptably safe. Seizure reductions begin with initiation of treatment and continue over time, reaching median reductions of 75% after 9 years of treatment. Treatment with responsive cortical stimulation is also associated with improvement in quality of life and cognitive function related to the functional area being treated. In addition, the RNS System's chronic ambulatory electrocorticographic monitoring provides unprecedented insight into each patient's disease management, and into the study of epilepsy itself, in ways that may enhance the treatment of epilepsy in the future.

  View details for PubMedID 30850259

• Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: The NEAD prospective observational study. Epilepsy & behavior : E&B Cohen, M. J., Meador, K. J., May, R., Loblein, H., Conrad, T., Baker, G. A., Bromley, R. L., Clayton-Smith, J., Kalayjian, L. A., Kanner, A., Liporace, J. D., Pennell, P. B., Privitera, M., Loring, D. W., NEAD Study Group 2019; 92: 154–64

  Abstract

  The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study was a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on learning and memory functions in 221 six-year-old children (including four sets of twins) whose mothers took one of these AEDs during pregnancy. Their performance was compared with that of a national sample of normally developing six year olds from the standardization sample of the Children's Memory Scale (CMS). The major results of this study indicate that the mean performance levels of children exposed to valproate were significantly below that of the children in the normal comparison group across all seven of the CMS Indexes. With one exception, this finding held up at the subtest level as well. These findings taken together with nonsignificant verbal and nonverbal forgetting scores appear to indicate that, as a group, children exposed to valproate experienced significant difficulty in their ability to process, encode, and learn both auditory/verbal as well as visual/nonverbal material. In addition, they exhibited significant difficulty holding and manipulating information in immediate auditory working memory. However, once the information was learned and stored, the valproate-exposed children appeared to be able to retrieve the information they did learn at normal levels. Finally, the processing, working memory, and learning deficits demonstrated by the valproate-exposed children are dose-related. In contrast to valproate, the findings pertaining to the children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy are less clear. Therefore, further research will be required to delineate the potential risks to learning and memory functions in children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy during pregnancy. Additional research employing larger prospective studies will be required to confirm the long-term cognitive and behavioral risks to children of mothers who are prescribed these four AEDs during pregnancy as well as to delineate any potential risks of newer AEDs and to understand the underlying mechanisms of adverse AED effects on the immature brain.

  View details for PubMedID 30660966

• Treatment of drug-resistant epilepsy in patients with periventricular nodular heterotopia using RNS® System: Efficacy and description of chronic electrophysiological recordings. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Nune, G. n., Arcot Desai, S. n., Razavi, B. n., Agostini, M. A., Bergey, G. K., Herekar, A. A., Hirsch, L. J., Lee, R. W., Rutecki, P. A., Srinivasan, S. n., Van Ness, P. C., Tcheng, T. K., Morrell, M. J. 2019; 130 (8): 1196–1207

  Abstract

  Describe changes in clinical seizure frequency and electrophysiological data recorded in patients with medically-intractable seizures and periventricular nodular heterotopias (PVNH) treated with the RNS® System (NeuroPace, Inc., Mountain View, CA).Clinical seizures from eight patients (mean follow-up of 10.1 years) were analyzed pre- and post-treatment. Chronic ambulatory electrocorticograms (ECoGs) recorded from PVNHs, hippocampus and neocortex were evaluated to identify the earliest electrographic seizure onset type, pattern of spread, and interictal characteristics.Mean reduction in disabling seizures was 85.7 % (n = 8); seven patients had >50% seizure reduction and two were seizure-free in the final year of analysis. Seizure rate showed a progressive reduction over the course of the study with the highest rate of improvement in the first two to three years after implantation. Four of seven patients with one PVNH lead and a second lead in the hippocampus or neocortex had some electrographic seizures first recorded at either lead location, suggesting two foci or seizure propagation patterns. Low voltage fast type activity was the prominent seizure onset pattern. Interictal ECoG power was lower in PVNH than hippocampus.RNS® System treatment substantially reduced clinical seizure frequency in patients with PVNH. Analysis of ictal ECoG records suggests PVNH may be involved in seizure generation.Chronic ECoG recordings suggest PVNH tissue can actively participate in epileptogenic networks. Direct brain-responsive neurostimulation is a safe and effective treatment option in such patients, progressively reducing seizure rate over a period of years.

  View details for DOI 10.1016/j.clinph.2019.04.706

  View details for PubMedID 31163364

• linical and electrocorticographic response to antiepileptic drugs in patients treated with responsive stimulation EPILEPSY & BEHAVIOR Skarpaas, T. L., Tcheng, T. K., Morrell, M. J. 2018; 83: 192–200

  Abstract

  The objective of this study was to explore whether chronic electrocorticographic (ECoG) data recorded by a responsive neurostimulation system could be used to assess clinical responses to antiepileptic drugs (AEDs).Antiepileptic drugs initiated and maintained for ≥3 months by patients participating in clinical trials of the RNS® System were identified. Such "AED Starts" that produced an additional ≥50% reduction in patient-reported clinical seizure frequency were categorized as clinically beneficial, and the remaining as not beneficial. Electrocorticographic features recorded by the RNS® Neurostimulator were analyzed during three periods: 3 months before the AED Start, first month after the AED Start, and the first 3 months after the AED Start.The most commonly added medications were clobazam (n = 41), lacosamide (n = 96), levetiracetam (n = 31), and pregabalin (n = 25). Across all four medications, there were sufficient clinical data for 193 AED Starts to be included in the analyses, and 59 AED Starts were considered clinically beneficial. The proportion of AED Starts that qualified as clinically beneficial was higher for clobazam (53.7%) and levetiracetam (51.6%) than for lacosamide (18.8%) and pregabalin (12%). Across all AED Starts for which RNS ECoG detection settings were held constant, the clinically beneficial AED Starts were associated with a significantly greater reduction in the detection of epileptiform activity (p < 0.001) at 1 (n = 33) and 3 months (n = 30) compared with AED Starts that were not beneficial at 1 (n = 71) and 3 months (n = 60). Furthermore, there was a significant reduction in interictal spike rate and spectral power (1-125 Hz) associated with a clinically beneficial response to an AED Start at 1 (n = 32) and 3 months (n = 35) (p < 0.001). These reductions were not observed at either 1 (n = 59) or 3 months (n = 60) for AED Starts that were not clinically beneficial.Significant quantitative changes in ECoG data recorded by the RNS System were observed in patients who experienced an additional clinical response to a new AED. While there was variability across patients in the changes observed, the results suggest that quantitative ECoG data may provide useful information when assessing whether a patient may have a favorable clinical response to an AED.

  View details for PubMedID 29719278

• Electrographic Correlates of Clinical Seizures Desai, S., Tcheng, T., Morrell, M. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090806062

• Changes in the electrocorticogram after implantation of intracranial electrodes in humans: The implant effect CLINICAL NEUROPHYSIOLOGY Sun, F. T., Desai, S., Tcheng, T. K., Morrell, M. J. 2018; 129 (3): 676–86

  Abstract

  Subacute and long-term electrocorticographic (ECoG) changes in ambulatory patients with depth and cortical strip electrodes were evaluated in order to determine the length of the implant effect.ECoG records were assessed in patients with medically intractable epilepsy who had depth and/or strip leads implanted in order to be treated with brain-responsive stimulation. Changes in total spectral power, band-limited spectral power, and spike rate were assessed.121 patients participating in trials of the RNS® System had a total of 93994 ECoG records analyzed. Significant changes in total spectral power occurred from the first to second months after implantation, involving 55% of all ECoG channels (68% of strip and 47% of depth lead channels). Significant, but less pronounced, changes continued over the 2nd to 5th post-implant months, after which total power became more stable. Similar patterns of changes were observed within frequency bands and spike rate.ECoG spectral power and spike rates are not stable in the first 5 months after implantation, presumably due to neurophysiological and electrode-tissue interface changes.ECoG data collected in the first 5 months after implantation of intracranial electrodes may not be fully representative of chronic cortical electrophysiology.

  View details for PubMedID 29233473

• Response: Therapeutic brain-responsive neurostimulation in eloquent cortex can be delivered without symptoms. Epilepsia Jobst, B. C., Skarpaas, T. L., Morrell, M. J. 2017; 58 (8): 1488

  View details for DOI 10.1111/epi.13844

  View details for PubMedID 28799661

• Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia Jobst, B. C., Kapur, R., Barkley, G. L., Bazil, C. W., Berg, M. J., Bergey, G. K., Boggs, J. G., Cash, S. S., Cole, A. J., Duchowny, M. S., Duckrow, R. B., Edwards, J. C., Eisenschenk, S., Fessler, A. J., Fountain, N. B., Geller, E. B., Goldman, A. M., Goodman, R. R., Gross, R. E., Gwinn, R. P., Heck, C., Herekar, A. A., Hirsch, L. J., King-Stephens, D., Labar, D. R., Marsh, W. R., Meador, K. J., Miller, I., Mizrahi, E. M., Murro, A. M., Nair, D. R., Noe, K. H., Olejniczak, P. W., Park, Y. D., Rutecki, P., Salanova, V., Sheth, R. D., Skidmore, C., Smith, M. C., Spencer, D. C., Srinivasan, S., Tatum, W., Van Ness, P., Vossler, D. G., Wharen, R. E., Worrell, G. A., Yoshor, D., Zimmerman, R. S., Skarpaas, T. L., Morrell, M. J. 2017; 58 (6): 1005-1014

  Abstract

  Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin.Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

  View details for DOI 10.1111/epi.13739

  View details for PubMedID 28387951

• Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia Geller, E. B., Skarpaas, T. L., Gross, R. E., Goodman, R. R., Barkley, G. L., Bazil, C. W., Berg, M. J., Bergey, G. K., Cash, S. S., Cole, A. J., Duckrow, R. B., Edwards, J. C., Eisenschenk, S., Fessler, J., Fountain, N. B., Goldman, A. M., Gwinn, R. P., Heck, C., Herekar, A., Hirsch, L. J., Jobst, B. C., King-Stephens, D., Labar, D. R., Leiphart, J. W., Marsh, W. R., Meador, K. J., Mizrahi, E. M., Murro, A. M., Nair, D. R., Noe, K. H., Park, Y. D., Rutecki, P. A., Salanova, V., Sheth, R. D., Shields, D. C., Skidmore, C., Smith, M. C., Spencer, D. C., Srinivasan, S., Tatum, W., Van Ness, P. C., Vossler, D. G., Wharen, R. E., Worrell, G. A., Yoshor, D., Zimmerman, R. S., Cicora, K., Sun, F. T., Morrell, M. J. 2017; 58 (6): 994-1004

  Abstract

  Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin.Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices).Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

  View details for DOI 10.1111/epi.13740

  View details for PubMedID 28398014

• Infection and Erosion Rates in Trials of a Cranially Implanted Neurostimulator Do Not Increase with Subsequent Neurostimulator Placements STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Weber, P. B., Kapur, R., Gwinn, R. P., Zimmerman, R. S., Courtney, T. A., Morrell, M. J. 2017; 95 (5): 325–29

  Abstract

  The RNS® System utilizes a cranially implanted neurostimulator attached to leads placed at the seizure focus to provide brain responsive stimulation for the treatment of medically intractable partial onset epilepsy. Infection and erosion rates related to the cranial implant site were assessed overall and by neurostimulator procedure to determine whether rates increased with additional procedures.Infection and erosion rates were calculated as (1) chance per neurostimulator procedure, (2) incidence per patient implant year, and (3) rates for initial and each subsequent neurostimulator implant (generalized estimating equation).In 256 patients followed for an average of 7 years, the infection rate was 3.7% per neurostimulator procedure (n = 31/840), and the rate of erosions was 0.8% per neurostimulator procedure (n = 7/840). Rates did not increase with subsequent neurostimulator procedures (p = 0.66, infection; p = 0.70, erosion). A prior infection or erosion at the implant site did not significantly increase the risk at a later procedure (p ≥ 0.05 for all combinations).These data indicate that the risk for infection compares favorably to other neurostimulation devices and suggest that rates of infection and erosion do not increase with subsequent neurostimulator replacements.

  View details for DOI 10.1159/000479288

  View details for Web of Science ID 000415150700005

  View details for PubMedID 28910805

  View details for PubMedCentralID PMC5804848

• Responsive Direct Brain Stimulation for Epilepsy. Neurosurgery clinics of North America Morrell, M. J., Halpern, C. 2016; 27 (1): 111-121

  Abstract

  Closed-loop, responsive focal brain stimulation provides a new treatment option for patients with refractory partial onset seizures who are not good candidates for potentially curative epilepsy surgery. The first responsive brain neurostimulator (RNS® System, NeuroPace), provides stimulation directly to the seizure focus when abnormal electrocorticographic is detected. Seizure reductions of 44% at one year increase to 60 to 66% at years 3 to 6 of treatment. There is no negative impact on cognition and mood. Risks are similar to other implanted medical devices and therapeutic stimulation is not perceived.

  View details for DOI 10.1016/j.nec.2015.08.012

  View details for PubMedID 26615113

• Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy EPILEPSIA Loring, D. W., Kapur, R., Meador, K. J., Morrell, M. J. 2015; 56 (11): 1836-1844

  Abstract

  Responsive neurostimulation decreases the frequency of disabling seizures when used as an adjunctive therapy in patients with medically refractory partial-onset seizures. The effect of long-term responsive neurostimulation on neuropsychological performance has not yet been established.Neuropsychological data were collected from subjects participating in the open-label arm of a randomized controlled trial of responsive neurostimulation with the RNS(®) System. Primary cognitive outcomes were the Boston Naming Test (BNT) and Rey Auditory Verbal Learning (AVLT) test. Neuropsychological performance was evaluated at baseline and again following 1 and 2 years of RNS System treatment. Follow-up analyses were conducted in patients with seizure onset restricted to either the mesial temporal lobe or neocortex.No significant cognitive declines were observed for any neuropsychological measure through 2 years. When examined as a function of seizure onset region, a double dissociation was found, with significant improvement in naming across all patients (p < 0.0001), and for patients with neocortical seizure onsets (p < 0.0001) but not in patients with mesial temporal lobe (MTL) seizure onsets (p = 0.679). In contrast, a significant improvement in verbal learning was observed across all patients (p = 0.03), and for patients with MTL seizure onsets (p = 0.005) but not for patients with neocortical onsets (p = 0.403).Treatment with the RNS System is not associated with cognitive decline when tested through 2 years. In fact, there were small but significant beneficial treatment effects on naming in patients with neocortical onsets and modest improvements in verbal learning for patients with seizure onsets in MTL structures. These results suggest that there are modest cognitive improvements in some domains that vary as a function of the region from which seizures arise.

  View details for DOI 10.1111/epi.13191

  View details for PubMedID 26385758

• Day-Night Patterns of Epileptiform Activity in 65 Patients With Long-Term Ambulatory Electrocorticography JOURNAL OF CLINICAL NEUROPHYSIOLOGY Anderson, C. T., Tcheng, T. K., Sun, F. T., Morrell, M. J. 2015; 32 (5): 406-412

  Abstract

  To characterize cyclic day-night patterns of electrocorticographic epileptiform activity (EA) in patients with focal onset seizures.Epileptiform events as defined by the physician (also termed more generally as "epileptiform activity" or EA) were recorded in 65 patients with partial onset (also referred to as "focal onset") seizures using the RNS System, which includes a cranially implanted neurostimulator connected to 1 or two 4-contact leads placed at the seizure focus. The neurostimulator is programmed to detect specific patterns of electrocorticographic activity and to provide responsive stimulation. The 24-hour periodicity of detections of EA was analyzed for individual patients and for subgroups of patients according to the type of EA, laterality, lobe of onset, and whether the onset was neocortical or hippocampal. The time of day when peaks in EA occurred was also analyzed.There were robust circadian patterns of detections of EA in most patients, with a primary peak in detections at night and a secondary peak in the late afternoon in some cases. Subset analyses were performed by lobe, region of the brain, and type of cortex (neocortical vs. hippocampal); significant circadian rhythmicity was present in all subsets.This is the first report of circadian cycles of EA as assessed through chronic ambulatory electrocorticographic recordings in adults with focal onset seizures. Epileptiform activity displayed circadian patterns in the majority of these patients. These findings suggest that epilepsy therapies might be optimized by adjusting the timing of therapy according to each patient's unique circadian pattern of EA.

  View details for DOI 10.1097/WNP.0000000000000183

  View details for PubMedID 26426769

• Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography EPILEPSIA King-Stephens, D., Mirro, E., Weber, P. B., Laxer, K. D., Van Ness, P. C., Salanova, V., Spencer, D. C., Heck, C. N., Goldman, A., Jobst, B., Shields, D. C., Bergey, G. K., Eisenschenk, S., Worrell, G. A., Rossi, M. A., Gross, R. E., Cole, A. J., Sperling, M. R., Nair, D. R., Gwinn, R. P., Park, Y. D., Rutecki, P. A., Fountain, N. B., Wharen, R. E., Hirsch, L. J., Miller, I. O., Barkley, G. L., Edwards, J. C., Geller, E. B., Berg, M. J., Sadler, T. L., Sun, F. T., Morrell, M. J. 2015; 56 (6): 959-967

  Abstract

  Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions.Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded.Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording.About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

  View details for DOI 10.1111/epi.13010

  View details for PubMedID 25988840

• Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation EPILEPSY & BEHAVIOR Meador, K. J., Kapur, R., Loring, D. W., Kanner, A. M., Morrell, M. J. 2015; 45: 242-247

  Abstract

  The primary efficacy and safety measures from a trial of responsive neurostimulation for focal epilepsy were previously published. In this report, the findings from the same study are presented for quality of life, which was a supportive analysis, and for mood, which was assessed as a secondary safety endpoint.The study was a multicenter randomized controlled double-blinded trial of responsive neurostimulation in 191 patients with medically resistant focal epilepsy. During a 4-month postimplant blinded period, patients were randomized to receive responsive stimulation or sham stimulation, after which all patients received responsive neurostimulation in open label to complete 2years. Quality of life (QOL) and mood surveys were administered during the baseline period, at the end of the blinded period, and at year 1 and year 2 of the open label period.The treatment and sham groups did not differ at baseline. Compared with baseline, QOL improved in both groups at the end of the blinded period and also at 1year and 2years, when all patients were treated. At 2years, 44% of patients reported meaningful improvements in QOL, and 16% reported declines. There were no overall adverse changes in mood or in suicidality across the study. Findings were not related to changes in seizures and antiepileptic drugs, and patients with mesial temporal seizure onsets and those with neocortical seizure onsets both experienced improvements in QOL.Treatment with targeted responsive neurostimulation does not adversely affect QOL or mood and may be associated with improvements in QOL in patients, including those with seizures of either mesial temporal origin or neocortical origin.

  View details for DOI 10.1016/j.yebeh.2015.01.012

  View details for Web of Science ID 000353830700047

  View details for PubMedID 25819949

• Long-term treatment with responsive brain stimulation in adults with refractory partial seizures NEUROLOGY Bergey, G. K., Morrell, M. J., Mizrahi, E. M., Goldman, A., King-Stephens, D., Nair, D., Srinivasan, S., Jobst, B., Gross, R. E., Shields, D. C., Barkley, G., Salanova, V., Olejniczak, P., Cole, A., Cash, S. S., Noe, K., Wharen, R., Worrell, G., Murro, A. M., Edwards, J., Duchowny, M., Spencer, D., Smith, M., Geller, E., Gwinn, R., Skidmore, C., Eisenschenk, S., Berg, M., Heck, C., Van Ness, P., Fountain, N., Rutecki, P., Massey, A., O'Donovan, C., Labar, D., Duckrow, R. B., Hirsch, L. J., Courtney, T., Sun, F. T., Seale, C. G. 2015; 84 (8): 810-817

  Abstract

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

  View details for DOI 10.1212/WNL.0000000000001280

  View details for Web of Science ID 000350463800016

  View details for PubMedID 25616485

  View details for PubMedCentralID PMC4339127

• The RNS System: responsive cortical stimulation for the treatment of refractory partial epilepsy EXPERT REVIEW OF MEDICAL DEVICES Sun, F. T., Morrell, M. J. 2014; 11 (6): 563-572

  Abstract

  The RNS(®) System is the first commercially available device to provide closed-loop responsive brain stimulation. The system includes a cranially implanted neurostimulator that continually monitors the electrocorticogram through one or two depth and/or subdural cortical strip leads that are placed at the seizure focus. When abnormal electrographic activity is detected, the neurostimulator delivers brief pulses of electrical stimulation to the seizure focus through the implanted leads. In November 2013, the US FDA approved the RNS System as an adjunctive therapy for patients with drug resistant, partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci. Safety and effectiveness of the RNS System for the indicated patient population was demonstrated in a multicenter, randomized, sham-stimulation controlled 2-year pivotal study. An ongoing, prospective, long-term treatment study is currently gathering an additional 7 years of prospective safety and effectiveness data of the RNS System.

  View details for DOI 10.1586/17434440.2014.947274

  View details for Web of Science ID 000343800200004

  View details for PubMedID 25141960

• In response: The RNS System multicenter randomized double-blinded controlled trial of responsive cortical stimulation for adjunctive treatment of intractable partial epilepsy: Knowledge and insights gained EPILEPSIA Morrell, M. J. 2014; 55 (9): 1470-1471

  View details for DOI 10.1111/epi.12736

  View details for Web of Science ID 000342236600027

  View details for PubMedID 25223509

• Closed-loop Neurostimulation: The Clinical Experience NEUROTHERAPEUTICS Sun, F. T., Morrell, M. J. 2014; 11 (3): 553-563

  Abstract

  Neurostimulation is now an established therapy for the treatment of movement disorders, pain, and epilepsy. While most neurostimulation systems available today provide stimulation in an open-loop manner (i.e., therapy is delivered according to preprogrammed settings and is unaffected by changes in the patient's clinical symptoms or in the underlying disease), closed-loop neurostimulation systems, which modulate or adapt therapy in response to physiological changes, may provide more effective and efficient therapy. At present, few such systems exist owing to the complexities of designing and implementing implantable closed-loop systems. This review focuses on the clinical experience of four implantable closed-loop neurostimulation systems: positional-adaptive spinal cord stimulation for treatment of pain, responsive cortical stimulation for treatment of epilepsy, closed-loop vagus nerve stimulation for treatment of epilepsy, and concurrent sensing and stimulation for treatment of Parkinson disease. The history that led to the development of the closed-loop systems, the sensing, detection, and stimulation technology that closes the loop, and the clinical experiences are presented.

  View details for DOI 10.1007/s13311-014-0280-3

  View details for Web of Science ID 000340372400010

  View details for PubMedID 24850309

• Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial EPILEPSIA Heck, C. N., King-Stephens, D., Massey, A. D., Nair, D. R., Jobst, B. C., Barkley, G. L., Salanova, V., Cole, A. J., Smith, M. C., Gwinn, R. P., Skidmore, C., Van Ness, P. C., Bergey, G. K., Park, Y. D., Miller, I., Geller, E., Rutecki, P. A., Zimmerman, R., Spencer, D. C., Goldman, A., Edwards, J. C., Leiphart, J. W., Wharen, R. E., Fessler, J., Fountain, N. B., Worrell, G. A., Gross, R. E., Eisenschenk, S., Duckrow, R. B., Hirsch, L. J., Bazil, C., O'Donovan, C. A., Sun, F. T., Courtney, T. A., Seale, C. G., Morrell, M. J. 2014; 55 (3): 432-441

  Abstract

  To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up.All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood.Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

  View details for DOI 10.1111/epi.12534

  View details for Web of Science ID 000332685000012

  View details for PubMedID 24621228

• Long-Term Measurement of Impedance in Chronically Implanted Depth and Subdural Electrodes During Responsive Neurostimulation in Humans BRAIN STIMULATION Sillay, K. A., Rutecki, P., Cicora, K., Worrell, G., Drazkowski, J., Shih, J. J., Sharan, A. D., Morrell, M. J., Williams, J., Wingeier, B. 2013; 6 (5): 718-726

  Abstract

  Long-term stability of the electrode-tissue interface may be required to maintain optimal neural recording with subdural and deep brain implants and to permit appropriate delivery of neuromodulation therapy. Although short-term changes in impedance at the electrode-tissue interface are known to occur, long-term changes in impedance have not previously been examined in detail in humans. To provide further information about short- and long-term impedance changes in chronically implanted electrodes, a dataset from 191 persons with medically intractable epilepsy participating in a trial of an investigational responsive neurostimulation device (the RNS(®) System, NeuroPace, Inc.) was reviewed. Monopolar impedance measurements were available for 391 depth and subdural leads containing a total of 1564 electrodes; measurements were available for median 802 days post-implant (range 28-1634). Although there were statistically significant short-term impedance changes, long-term impedance was stable after one year. Impedances for depth electrodes transiently increased during the third week after lead implantation and impedances for subdural electrodes increased over 12 weeks post-implant, then were stable over the subsequent long-term follow-up. Both depth and subdural electrode impedances demonstrated long-term stability, suggesting that the quality of long-term electrographic recordings (the data used to control responsive brain stimulation) can be maintained over time.

  View details for DOI 10.1016/j.brs.2013.02.001

  View details for Web of Science ID 000325046600003

  View details for PubMedID 23538208

• Responsive cortical stimulation for the treatment of medically intractable partial epilepsy NEUROLOGY Morrell, M. J. 2011; 77 (13): 1295-1304

  Abstract

  This multicenter, double-blind, randomized controlled trial assessed the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy.A total of 191 adults with medically intractable partial epilepsy were implanted with a responsive neurostimulator connected to depth or subdural leads placed at 1 or 2 predetermined seizure foci. The neurostimulator was programmed to detect abnormal electrocorticographic activity. One month after implantation, subjects were randomized 1:1 to receive stimulation in response to detections (treatment) or to receive no stimulation (sham). Efficacy and safety were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation.Seizures were significantly reduced in the treatment (-37.9%, n = 97) compared to the sham group (-17.3%, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events. During the open-label period, the seizure reduction was sustained in the treatment group and seizures were significantly reduced in the sham group when stimulation began. There were significant improvements in overall quality of life (p < 0.02) and no deterioration in mood or neuropsychological function.Responsive cortical stimulation reduces the frequency of disabling partial seizures, is associated with improvements in quality of life, and is well-tolerated with no mood or cognitive effects. Responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures. Classification of evidence: This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.

  View details for DOI 10.1212/WNL.0b013e3182302056

  View details for Web of Science ID 000295253800019

  View details for PubMedID 21917777

• Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs EPILEPSY & BEHAVIOR Pack, A. M., Morrell, M. J., McMahon, D. J., Shane, E. 2011; 21 (4): 453-458

  Abstract

  Relationships between reproductive hormone levels, bone turnover marker levels, bone mineral density, and rates of bone loss were evaluated in premenopausal women with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs: phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormone levels, bone turnover marker levels, and bone mineral density were measured at baseline and 1 year. Bone mineral density did not differ between groups. Serum calcium (P<0.001) and estrone (P<0.001) levels were lower in the EIAED group. Sex hormone-binding globulin levels were higher (P<0.001) and percentage free estradiol levels were lower (P<0.001) in the EIAED group. We detected no relationship between bone mineral density change and calciotropic hormone or bone turnover marker levels. Women with higher sex hormone-binding globulin and lower free estradiol levels sustained more bone loss at the total hip (P=0.04 and P=0.02) and a trend toward more bone loss at the lumbar spine (P=0.07 and P=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy.

  View details for DOI 10.1016/j.yebeh.2011.05.001

  View details for Web of Science ID 000294104900024

  View details for PubMedID 21704565

• Closed-Loop Stimulation in the Control of Focal Epilepsy of Insular Origin STEREOTACTIC AND FUNCTIONAL NEUROSURGERY Smith, J. R., Fountas, K. N., Murro, A. M., Park, Y. D., Jenkins, P. D., Morrell, M., Esteller, R., Greene, D. 2010; 88 (5): 281-287

  Abstract

  Previous studies have shown that closed-loop or responsive neurostimulation can abort induced or spontaneous epileptiform discharges.To assess the effectiveness of a programmable cranially implanted closed-loop neurostimulation system in the control of seizures originating from an area relatively inaccessible by open craniotomy.A patient with drug-resistant partial epilepsy had previously undergone open resection of the left frontal opercular cortex and the underlying insular area. Although subdural-depth electrode ictal recordings had been nonlocalizing, depth electrode insular stimulation had produced the patient's habitual aura. Postoperatively, there was a sustained 50% reduction in seizure frequency. The residual seizures were identical to the preoperative seizures. Repeat depth electrode monitoring revealed that the ictal focus was immediately posterior to the previously resected insular area. A closed-loop cranial internal pulse generator system including left anterior insular and posterior orbitofrontal depth electrodes was implanted.There was an additional 60% reduction of seizures.Preliminary observation indicates that responsive neurostimulation may be an effective alternative to higher-risk resective epilepsy surgery.

  View details for DOI 10.1159/000316760

  View details for Web of Science ID 000281966000003

  View details for PubMedID 20588079

• Intracranial Stimulation Therapy for Epilepsy 4th Workshop on New Horizons in the Development of Antiepileptic Drugs Skarpaas, T. L., Morrell, M. J. SPRINGER. 2009: 238–43

  Abstract

  Epilepsy is a common chronic neurological disorder effecting 1 to 2% of the population. Despite advances in anti-epileptic drug therapy, epilepsy surgery, and vagus nerve stimulation, approximately 30% of patients continue to have seizures. Intracranial stimulation is currently under investigation as an adjunctive treatment to anti-epileptic medications in adults with medically intractable epilepsy. Several different approaches are now being investigated. Specifically, acute and long-term clinical studies have delivered stimulation either to inhibitory regions outside the seizure focus or directly to the seizure focus. These studies have demonstrated the safety of intracranial stimulation and proof of principle in epilepsy patients. In addition to the different locations tested, clinical studies have also used different temporal patterns of stimulation. The majority of studies have used open-loop or scheduled stimulation, in which, stimulation is delivered on a fixed schedule and is independent of electrographic activity. In contrast, a number of recent investigations have demonstrated the feasibility of closed-loop or responsive stimulation, which is stimulation that is contingent upon the detection of epileptiform activity. This chapter will review the acute and long-term clinical studies of intracranial stimulation, including focal, and nonfocal, and open-loop and responsive stimulation. We will also discuss the optimization and safety of therapeutic parameters used in neurostimulation for epilepsy.

  View details for Web of Science ID 000264659900004

  View details for PubMedID 19332315

• Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine ANNALS OF NEUROLOGY Morrell, M. J., Hayes, F. J., Sluss, P. M., Adams, J. M., Bhatt, M., Ozkara, C., Warnock, C. R., Isojarvi, J. 2008; 64 (2): 200-211

  Abstract

  To evaluate development of components of polycystic ovary syndrome (PCOS) and PCOS in women with epilepsy initiating valproate or lamotrigine therapy.Female individuals with epilepsy and regular menstrual cycles were eligible for this prospective study. Participants were randomized to 12 months of valproate (n = 225) or lamotrigine (n = 222) therapy. Serum androgen levels were measured every 3 months. Urinary pregnanediol glucuronide levels were measured weekly for two 3-month periods. The primary end point was development of PCOS components (ie, hyperandrogenism or ovulatory dysfunction). A post hoc analysis was conducted in women more than 2 years after menarche (177 lamotrigine, (HA) 186 valproate) to exclude OD the confounding effect of puberty.More women in the valproate group than the lamotrigine group developed (OD) in the prospective (54% valproate, 38% lamotrigine; p = 0.010) and the post hoc (HA) analyses (36% valproate, 23% lamotrigine; p = 0.007). More women in the valproate group than the lamotrigine group developed PCOS (9 vs 2%; p = 0.007). Development of HA was more frequent with OD valproate than lamotrigine among those initiating treatment at age younger than 26 years (44% valproate, 23% lamotrigine; p = 0.002) but was similar if treatment was started at age 26 years or older (24% valproate, 22% lamotrigine).Development of HA occurred more frequently with valproate than lamotrigine, especially if medication was started at age younger than 26 years.

  View details for DOI 10.1002/ana.21411

  View details for Web of Science ID 000258921800011

  View details for PubMedID 18756476

• Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy NEUROLOGY Pack, A. M., Morrell, M. J., Randall, A., McMahon, D. J., Shane, E. 2008; 70 (18): 1586-1593

  Abstract

  Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin.Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year.Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling.In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy.

  View details for Web of Science ID 000256706900003

  View details for PubMedID 18443309

  View details for PubMedCentralID PMC3139539

• Responsive cortical stimulation for the treatment of epilepsy NEUROTHERAPEUTICS Sun, F. T., Morrell, M. J., Wharen, R. E. 2008; 5 (1): 68-74

  Abstract

  Epilepsy is a common chronic neurological disorder affecting approximately 1-2% of the population. Despite the available treatment options (pharmacotherapy, surgery, and vagus nerve stimulation), a large percentage of patients continue to have seizures. With the success of deep brain stimulation for treatment of movement disorders, brain stimulation has received renewed attention as a potential treatment option for epilepsy. Responsive stimulation aims to suppress epileptiform activity by delivering stimulation directly in response to electrographic activity. Animal and human data support the concept that responsive stimulation can abort epileptiform activity, and this modality may be a safe and effective treatment option for epilepsy. Responsive stimulation has the advantage of specificity. In contrast to the typically systemic administration of pharmacotherapy, with the concomitant possibility of side effects, electrical stimulation can be targeted to the specific brain regions involved in the seizure. In addition, responsive stimulation provides temporal specificity. Treatment is provided as needed, potentially reducing the likelihood of functional disruption or habituation due to continuous treatment. Here we review current animal and human research in responsive brain stimulation for epilepsy and then discuss the NeuroPace RNS System, an investigational implantable responsive neurostimulator system that is being evaluated in a multicenter, randomized, double-blinded trial to assess the safety and efficacy of responsive stimulation for the treatment of medically refractory epilepsy.

  View details for Web of Science ID 000252532300008

  View details for PubMedID 18164485

• Brain stimulation for epilepsy: can scheduled or responsive neurostimulation stop seizures? Current opinion in neurology Morrell, M. 2006; 19 (2): 164-8

  Abstract

  Scheduled and responsive direct brain stimulation may be an effective and safe therapy for medically intractable epilepsy.Scheduled stimulation (open loop) has been provided via electrodes implanted in thalamic nuclei, the cerebellum and the hippocampus using devices commercially available for treatment of tremor and Parkinson's disease. Small pilot trials suggest that seizure frequency is reduced in some patients with intractable epilepsy. Responsive stimulation requires systems that detect abnormal electrographic activity and provide stimulation (closed loop). Studies in inpatients and outpatients suggest that abnormal electrographic discharges can be detected before there is evolution into a clinical seizure, and that focal stimulation of the epileptogenic region terminates electrographic seizures and reduces the frequency of clinically evident seizures.Direct brain stimulation appears to be safe and may be efficacious in treating medically intractable epilepsy. The optimal location (deep brain or cortical) and characteristics of the stimulation (frequency, current, duration), and whether stimulation should be focal or responsive are still to be determined. If ongoing studies of a deep brain stimulator and of a cranially implanted responsive neurostimulator demonstrate effectiveness, then neurostimulation may become available as adjunctive therapy for medically intractable epilepsy.

  View details for DOI 10.1097/01.wco.0000218233.60217.84

  View details for PubMedID 16538091

• Treatment of epilepsy in adults: expert opinion, 2005 EPILEPSY & BEHAVIOR Karceski, S., Morrell, M. J., Carpenter, D. 2005; 7: S1-S64

  Abstract

  Over the past decade, there has been a proliferation of new therapies for the treatment of epilepsy. Faced with this growing list of options, clinicians must decide what therapy, or combination of therapies, is best for a given individual. Although controlled clinical trials exist for each treatment option, the answer to these questions may remain unclear. In 2000, a survey of expert opinion was done to address questions concerning which treatment options might be best in a number of clinical situations. We surveyed a group of US epileptologists again in 2004 and compared the results of the two surveys.We sent a questionnaire on the treatment of adolescent and adult epilepsy syndromes to a group of opinion leaders in the field of epilepsy. The questions were formatted to simulate real-world clinical situations in the treatment of symptomatic localization related epilepsy (SLRE) and idiopathic generalized epilepsy (IGE). The experts were asked to rate treatment options based on a modified RAND 9-point scale (with "9" most appropriate and "1" least appropriate). Statistical analysis of data was performed as defined by the expert consensus method. The results were used to develop user-friendly recommendations concerning overall treatment strategies and choice of specific medications.Of the 48 experts to whom the survey was sent, 43 (90%) responded; 29 (67%) of the respondents had also participated in the first survey. For initial monotherapy for IGE (generalized tonic-clonic [GTC], absence, and myoclonic seizures), valproate was rated as treatment of choice. For IGE-GTC seizures, lamotrigine and topiramate were also identified as usually appropriate for initial monotherapy. For IGE-absence seizures, ethosuximide was also a treatment of choice, and lamotrigine was usually appropriate. For SLRE, the experts were again asked to rate treatment options based on seizure type: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized tonic-clonic seizures (SGTC). In SLRE-SPS and SLRE-SGTC, carbamazepine and oxcarbazepine were treatments of choice, with lamotrigine and levetiracetam also usually appropriate. In SLRE-CPS, carbamazepine, lamotrigine. and oxcarbazepine were treatments of choice, while levetiracetam was also usually appropriate. For women who are pregnant or trying to conceive, lamotrigine was treatment of choice for both syndrome types. In the elderly, whether medically stable or ill, the treatment of choice was lamotrigine, while levetiracetam was also usually appropriate (along with gabapentin for persons with comorbid medical illness). In persons with HIV and epilepsy, lamotrigine and levetiracetam were usually appropriate. In people with both epilepsy syndromes who have depression, lamotrigine was treatment of choice. In a person with seizures and renal disease, lamotrigine was usually appropriate for both syndromes, with valproate also usually appropriate for IGE. In patients with hepatic disease, levetiracetam and lamotrigine were usually appropriate for IGE; in SLRE, levetiracetam was treatment of choice, with gabapentin also usually appropriate.Although the panel of experts reached consensus on many treatment options, there are limitations to these types of data. Despite this, the expert consensus method concisely summarizes expert opinion, and this opinion may be helpful in situations in which the medical literature is scant or lacking. The information in this report should be evaluated in conjunction with evidence-based findings.

  View details for DOI 10.1016/j.yebeh.2005.06.001

  View details for Web of Science ID 000231545500001

  View details for PubMedID 16102515

• Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs EPILEPSY & BEHAVIOR Morrell, M. J., Flynn, K. L., Done, S., Flaster, E., Kalayjian, L., Pack, A. M. 2005; 6 (3): 360-365

  Abstract

  Women with epilepsy are believed to be at risk for sexual dysfunction. Disorders of sexual desire and sexual arousal, including dyspareunia, vaginismus, and lack of lubrication, affect an estimated 30 to 60% of women with epilepsy. In this study, 57 reproductive-aged women with either localization related (LRE) or primary generalized epilepsy (PGE) on antiepileptic drug (AED) monotherapy and 17 nonepileptic controls completed questionnaires examining sexual experience, arousability, anxiety, and symptoms, as well as an inventory of depression. An endocrine assessment was performed during the early follicular phase of the menstrual cycle. Sexual dysfunction was more common in women with LRE, in women receiving phenytoin, in women with low levels of estradiol and dehydroepiandrosterone sulfate, and in women with self-reported symptoms of mild depression. The mechanisms of sexual dysfunction in women with epilepsy are multifactorial, but AED choice appears to be one cause that is modifiable.

  View details for DOI 10.1016/j.yebeh.2005.01.004

  View details for Web of Science ID 000228626300011

  View details for PubMedID 15820344

• Sex-steroid hormones in women with epilepsy. American journal of electroneurodiagnostic technology Jette, N., Morrell, M. J. 2005; 45 (1): 36-48

  Abstract

  Women with epilepsy face unique challenges, in part related to changes in the seizure threshold at various times in the menstrual cycle or during their reproductive life. Ovarian sex-steroid hormones alter the excitability of the central nervous system (CNS) and alter the frequency and severity of seizures. By understanding the effects of hormones on seizures, clinicians are better equipped to treat hormonally mediated epilepsy.

  View details for PubMedID 15832673

• Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy ANNALS OF NEUROLOGY Pack, A. M., Morrell, M. J., Marcus, R., Holloway, L., Flaster, E., Done, S., Randall, A., Seale, C., Shane, E. 2005; 57 (2): 252-257

  Abstract

  Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.

  View details for DOI 10.1002/ana.20378

  View details for Web of Science ID 000226633800013

  View details for PubMedID 15668966

• 2005 update on the treatment of epilepsy: Survey of expert opinion 59th Annual Meeting of the American-Epilepsy-Society/American-Clinical-Neurophysiology-Society Karceski, S. C., Morrell, M. J., Carpenter, D. WILEY-BLACKWELL. 2005: 177–177

  View details for Web of Science ID 000232540100521

• Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy NEUROLOGY Hirsch, L. J., Weintraub, D., Buchsbaum, R., Spencer, H. T., Hager, M., Strake, T., Bazil, C. W., Adams, D. J., Resor, S. R., Morrell, M. J. 2004; 63 (6): 1022-1026

  Abstract

  To correlate lamotrigine (LTG) serum concentrations (levels) with tolerability in patients with epilepsy.The charts of 811 outpatients with epilepsy who had received LTG and were seen at the Columbia Comprehensive Epilepsy Center after January 1, 2000, were reviewed. Data gathered included levels, dosage, duration of use, concomitant antiepileptic drugs (AEDs), clinical toxicity, specific side effects, and efficacy. Rates of toxicity, specific side effects, and efficacy were calculated and correlated with serum levels.In total, 3,731 LTG levels were recorded. A regimen was categorized as toxic if the patient experienced side effects that led to a dosage change or discontinuation of LTG. Of 3,919 AED regimens, 9.4% were toxic and 30.7% of patients had at least one toxic regimen. Toxicity increased with increasing LTG levels (p < 0.0001): With levels <5.0 microg/mL, 7% of patients were toxic; with levels of 5 to 10 microg/mL, 14%; with 10 to 15 microg/mL, 24%; with 15 to 20 microg/mL, 34%; and with >20 microg/mL, 59%. The correlation between levels and tolerability was independent of concurrent medication. Increasing efficacy, as measured by seizure freedom for a 6-month period, occurred up to levels of >20 microg/mL.There is a correlation between LTG serum level and tolerability, independent of the use of other AEDs. Adverse effects requiring a dose change are uncommon with the most frequently encountered LTG concentrations (<10 microg/mL) and occur in only 7.4% of patients at levels obtained during the majority of clinical trials (<5 microg/mL). An initial target range of 1.5 to 10 microg/mL is suggested, though higher levels, up to >20 microg/mL, are often tolerated and can lead to additional efficacy in refractory patients.

  View details for Web of Science ID 000224128500015

  View details for PubMedID 15452293

• Epilepsy and bone health in adults EPILEPSY & BEHAVIOR Pack, A. M., Morrell, M. J. 2004; 5: S24-S29

  Abstract

  Adults taking antiepileptic drugs (AEDs) have an augmented risk for osteopenia and osteoporosis because of abnormalities of bone metabolism associated with AEDs. The increased fracture rates that have been described among patients with epilepsy may be related both to seizures and to AEDs. The hepatic enzyme-inducing AEDs phenytoin, phenobarbital, and primidone have the clearest association with decreased bone mineral density (BMD). Carbamazepine, also an enzyme-inducing drug, and valproate, an enzyme inhibitor, may also adversely affect bone, but further study is needed. Little information is available about specific effects of newer AEDs on bone. Physicians are insufficiently aware of the association between AEDs and bone disease; a survey found that fewer than one-third of neurologists routinely evaluated AED-treated patients for bone disease, and fewer than 10% prescribed prophylactic calcium and vitamin D. Physicians should counsel patients taking AEDs about good bone health practices, and evaluation of bone health by measuring BMD is warranted after 5 years of AED treatment or before treatment in postmenopausal women.

  View details for DOI 10.1016/j.yebeh.2003.11.029

  View details for Web of Science ID 000220350200004

  View details for PubMedID 15123008

• Reproductive disturbances in patients with epilepsy. Cleveland Clinic journal of medicine Morrell, M. J., Montouris, G. D. 2004; 71: S19-24

  Abstract

  In persons with epilepsy, both seizures and antiepileptic drugs can disturb reproductive health. For example, seizures can alter the release of hypothalamic and pituitary hormones, while some antiepileptic drugs alter concentrations of sex steroid hormones. Women with epilepsy are at increased risk for polycystic ovary syndrome and disorders of the menstrual cycle. Studies have found reduced fertility rates among men and women with epilepsy. The reasons for this reduction in fertility are likely to be both psychosocial and physiologic, and again, both epilepsy itself and antiepileptic drugs are implicated. Sexual dysfunction is common among patients with epilepsy and can have a somatic, psychological, or social basis. To provide the best care for patients with epilepsy, particularly women of reproductive age, clinicians must consider both the gender-based biology of epilepsy and the effects of antiepileptic drugs on reproductive health.

  View details for PubMedID 15379296

• Use of levetiracetam in a population of patients aged 65 years and older: a subset analysis of the KEEPER trial EPILEPSY & BEHAVIOR Ferrendelli, J. A., French, J., Leppik, I., Morrell, M. J., Herbeuval, A., Han, J., Magnus, L. 2003; 4 (6): 702-709

  Abstract

  Levetiracetam (Keppra) was evaluated in a subset of patients aged >/=65 years (n=78) enrolled in a large (n=1030) open-label, phase IV trial (the KEEPER trial). A 4-week dose adjustment was followed by a 12-week evaluation period. An overall median reduction in partial seizures of 80.1% (n=65) was observed. Overall, 76.9% of patients were >/=50% responders, 56.9% were >/=75% responders, and 40.0% were 100% responders. Levetiracetam was well tolerated, with 42.3% of patients reporting one or more adverse events. A total of 15 patients (19.2%) experienced an adverse event that led to discontinuation. Somnolence (n=13,16.7%) and dizziness (n=7,9.0%) were the most commonly reported adverse events. Despite the limitations of the open-label study design, these data provide information regarding the use of levetiracetam as add-on therapy for the treatment of partial-onset seizures in patients >/=65 years of age, including those requiring concomitant medications.

  View details for DOI 10.1016/j.yebeh.2003.09.007

  View details for Web of Science ID 000187243300015

  View details for PubMedID 14698704

• Seizure-free days observed in randomized placebo-controlled add-on trials with levetiracetam in partial epilepsy EPILEPSIA Leppik, I., Morrell, M., Godfroid, P., Arrigo, C. 2003; 44 (10): 1350-1352

  Abstract

  We examined the effect of adjunctive levetiracetam (LEV; 1,000 to 3,000 mg/day) on the number of seizure-free days gained per quarter in adult patients with refractory partial-onset epilepsy.The treatment effect was studied in a meta-analysis using individual patient data of a subpopulation of patients (n = 846) emerging from the three randomized, double-blind, placebo-controlled, phase III trials (n = 904).Adding LEV effectively increased the number of days without seizures by 5.19 days per quarter [95% confidence interval (CI), 3.63-6.76; p = 0.0001; titration and stable dose periods].LEV adjunctive treatment shows a clear benefit in terms of seizure-free days gained for patients with refractory epilepsy. This gain is significant for the pooled and for each LEV dose compared with placebo.

  View details for Web of Science ID 000185806700011

  View details for PubMedID 14510829

• Working toward an epilepsy cure. Current neurology and neuroscience reports Morrell, M. J. 2003; 3 (4): 323-324

  View details for PubMedID 12930702

• Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Ferin, M., Morrell, M., Xiao, E. N., Kochan, L., Qian, F., Wright, T., Sauer, M. 2003; 88 (6): 2908-2915

  Abstract

  An association between epilepsy and reproductive disturbances with an apparent increase in a polycystic ovarian syndrome (PCOS) has been reported. Whether this association can be attributed to epilepsy itself or is related to antiepileptic drug therapy, in particular valproate (VPA), remains controversial. We studied effects of a long-term VPA treatment on cycling monkeys, postulating that, if VPA monotherapy were to promote abnormal endocrine and metabolic parameters that are characteristic of PCOS, changes in cyclicity would be readily demonstrated. After a 2-month control, a 12- to 15-month VPA monotherapy was initiated in 7 regularly cycling rhesus monkeys. Overall mean levels of VPA were 88.7 +/- 4.0 (SE) microg/ml. Mean body weight increased progressively during VPA treatment from 8.5 +/- 0.5 kg before treatment to 9.6 +/- 0.7 kg in the last week of treatment (P < 0.05). Monkeys continued to have regular ovulatory menstrual cycles throughout VPA monotherapy. Length of the cycles was 28 +/- 0.58 d in control and 28.4 +/- 1.18 d in the last 3 months of VPA treatment. Follicular and luteal lengths and peak preovulatory estradiol and integrated luteal progesterone levels did not differ between control and treatment. Ovaries from VPA-treated monkeys showed histological evidence of ovulation, and none had characteristic features of PCOS. Endocrine PCOS markers, such as increased early follicular LH/FSH ratio and androgen levels were not different in control and VPA treatment cycles. LH and 17-hydroxyprogesterone responses to GnRH agonist challenges and the insulin response to glucose tolerance tests were similar in control and VPA groups. Lipid profiles were not affected by VPA treatment. The data indicate that a 12- to 15-month therapeutic exposure to VPA does not induce cyclic hormonal or morphological ovarian abnormalities or characteristics of the PCOS when administered to nonepileptic normally cycling nonhuman primates.

  View details for DOI 10.1210/jc.2002-021614

  View details for Web of Science ID 000183318200078

  View details for PubMedID 12788905

• Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy EPILEPSY RESEARCH Morrell, M. J., Isojarvi, J., Taylor, A. E., Dam, M., Ayala, R., Gomez, G., O'Neill, F., Tennis, P., Messenheimer, J. 2003; 54 (2-3): 189-199

  Abstract

  Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain.This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years.Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg.Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.

  View details for DOI 10.1016/S0920-1211(03)00085-8

  View details for Web of Science ID 000184223500012

  View details for PubMedID 12837570

• The KEEPER (TM)(1) trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study EPILEPSY RESEARCH Morrell, M. J., Leppik, I., French, J., Ferrendelli, J., Han, J., Magnus, L. 2003; 54 (2-3): 153-161

  Abstract

  Three randomized, placebo-controlled trials have demonstrated the safety and efficacy of levetiracetam, a new antiepileptic medication, as add-on therapy for partial-onset seizures. The purpose of this study was to gather additional safety and efficacy data on levetiracetam in the real-world setting of community-based practice.This was a phase IV prospective, open-label, multicenter, community-based trial. A total of 1030 patients (intent-to-treat (ITT) population) at least 16 years old (mean, 42.2 years) with partial-onset seizures were enrolled by over 300 investigators. Patients whose partial-onset seizures were inadequately controlled on their current medications had levetiracetam 500 mg bid added to their regimens. The levetiracetam dose was increased by 500 mg bid at the end of weeks 2 and 4 to a maximum dose of 1500 mg bid, unless the patient had been seizure-free during the preceding 2-week period. The dose was then to remain the same for 12 weeks. The main outcome measures were reduction in seizure frequency, global evaluation scale (GES), and adverse events.During the 16 weeks of the trial, 57.9% (542/936) experienced at least a 50% reduction in the frequency of partial-onset seizures, 40.1% (375/936) experienced at least a 75% reduction, and 20% (187/936) demonstrated a 100% seizure reduction. During the last 6 weeks of the study, 66.7% (500/750) experienced at least a 50% reduction in the frequency of partial seizures, 52.4% (393/750) experienced at least a 75% reduction, and 42.1% (316/750) demonstrated a 100% seizure reduction. On the investigator-completed clinical impression rating (GES), 74.3% (734/988) of patients were considered improved, with 37% of patients showing marked improvement. The most common adverse events were somnolence, dizziness, asthenia, and headache; these events were predominantly mild-to-moderate in nature.These results provide further evidence regarding the efficacy and safety of levetiracetam as adjunctive treatment for partial-onset seizures.

  View details for DOI 10.1016/S0920-1211(03)00080-9

  View details for Web of Science ID 000184223500008

  View details for PubMedID 12837566

• Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs EPILEPSY & BEHAVIOR Pack, A. M., Olarte, L. S., Morrell, M. J., Flaster, E., Resor, S. R., Shane, E. 2003; 4 (2): 169-174

  Abstract

  Antiepileptic drug (AED) use is identified as being associated with increased fracture risk. AEDs commonly associated with osteopathies are inducers of the hepatic cytochrome p450 enzyme system (EIAEDs). We performed a retrospective cross-sectional study assessing bone mineral density (BMD) in an adult outpatient population receiving EIAEDs. Patients were routinely referred for dual-energy X-ray absorptiometry to evaluate BMD. BMD was measured at the femoral neck of hip and lumbar spine. Results were presented as absolute BMD (g/cm(2)), T score, and Z score. T and Z scores were used in this analysis. As a group, those with BMD measurements represent people with intractable epilepsy. There were no statistically significant differences found in the T or Z scores by gender; therefore all analyses combined both men and women. Significant reductions in both T and Z scores were present in men and women <50 and >or=50.

  View details for DOI 10.1016/S1525-5050(03)00036-2

  View details for Web of Science ID 000182633900013

  View details for PubMedID 12697142

• Review of lamotrigine and its clinical applications in epilepsy EXPERT OPINION ON PHARMACOTHERAPY Choi, H., Morrell, M. J. 2003; 4 (2): 243-251

  Abstract

  Lamotrigine is an anti-epileptic agent with broad efficacy. Lamotrigine works at voltage-sensitive sodium channels, thereby stabilising the neuronal membrane and inhibiting the release of excitatory neurotransmitters such as glutamate and aspartate. Early preclinical animal studies indicate its broad-spectrum efficacy, which was later confirmed in clinical trials. Multiple randomised, placebo-controlled and comparative trials demonstrate its efficacy against partial and secondarily generalised seizures. Open-label trials show its efficacy against generalised seizures, especially absence seizures of childhood absence epilepsy and generalised seizures of juvenile myoclonic epilepsy. Lamotrigine has a wide clinical dose range and possesses favourable pharmacokinetic properties. It has a good tolerability and safety profile, which enhance compliance. Its small risk of serious skin rash should be weighed against its potential benefits when choosing lamotrigine on an individual basis. Lamotrigine is an excellent therapeutic option in epilepsy.

  View details for Web of Science ID 000183860400013

  View details for PubMedID 12562315

• Reproductive and metabolic disorders in women with epilepsy 5th European Congress on Epileptology Morrell, M. J. WILEY-BLACKWELL PUBLISHING, INC. 2003: 11–20

  Abstract

  Epilepsy is a common neurologic disorder affecting women during the reproductive years. Seizures and some antiepileptic drugs (AEDs) can compromise reproductive health, and some AEDs can adversely affect carbohydrate and bone metabolism. Women with epilepsy have lower birth rates and more frequent anovulatory menstrual cycles. This appears to be related to seizure- and AED-associated reproductive endocrine disturbances. Carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) induce hepatic cytochrome P450 enzymes and lower endogenous estrogens, adrenal and ovarian androgens, and contraceptive steroids. Valproate (VPA) inhibits steroid hormone metabolism, elevates androgens, and predisposes to phenotypic signs of hyperandrogenism-hirsutism, obesity, acne, and frequent anovulatory cycles. VPA is associated with weight gain, probably by altering insulin metabolism. CBZ, PHT, and VPA, but not lamotrigine (LTG), are associated with lower levels of calcium. PHT, but not VPA or LTG, appears to accelerate bone turnover. AED effects on bone mineral metabolism may explain the elevated risk of fracture described in women with epilepsy. Prospective pregnancy registries are beginning to provide information about AED-associated teratogenesis. The North American Antiepileptic Drug Pregnancy Registry reports a 12% rate of major malformations after first trimester exposure to PB and an 8.6% rate after first trimester exposure to VPA. A prospective LTG-specific registry reports a 1.8% chance of major malformations after the first trimester. The registries will continue to release information as data become significant. In the meantime, practitioners can be alert to signs and symptoms of reproductive or metabolic health disturbances and participate in pregnancy registry efforts.

  View details for Web of Science ID 000184150600003

  View details for PubMedID 12823565

• Stigma and epilepsy. Epilepsy & behavior : E&B Morrell, M. J. 2002; 3 (6S2): 21-25

  Abstract

  For individuals with epilepsy in the United States and other countries, stigma can be one of the most distressing consequences of having seizures, along with the unpredictability of future seizures and the inability to drive. The impact of stigma on the lives of epilepsy patients is far reaching, frequently including effects on interpersonal relationships, general health, employment opportunities, and overall quality of life. Education about epilepsy directed at the broader community, as well as at the individual with epilepsy, is the most effective means of addressing misperceptions and fear. Epilepsy advocacy organizations, such as the Epilepsy Foundation, are important allies in this effort.

  View details for PubMedID 12609302

• Predictors of ovulatory failure in women with epilepsy ANNALS OF NEUROLOGY Morrell, M. J., Giudice, L., Flynn, K. L., Seale, C. G., Paulson, A. J., Done, S., Flaster, E., Ferin, M., Sauer, M. V. 2002; 52 (6): 704-711

  Abstract

  Women with epilepsy (WWE) are at increased risk for reproductive disorders. This study was designed to evaluate whether WWE are more likely to have anovulatory cycles and to assess the relative association of the epilepsy syndrome category and antiepileptic drugs (AEDs) to ovulatory dysfunction. Subjects included women aged 18 to 40 years not receiving hormones. Women without epilepsy (23 controls) and women with localization-related epilepsy (LRE, n = 59) or idiopathic (primary) generalized epilepsy (IGE, n = 35) receiving either a cytochrome P450 enzyme (cP450) inducing AED (carbamazepine, phenytoin, and phenobarbital), a cP450 inhibiting AED (valproate), or an AED that does not alter cP450 enzymes (lamotrigine and gabapentin) in monotherapy for 6 months or more were followed for three menstrual cycles. A transvaginal ovarian ultrasound was obtained. Endocrine and metabolic variables were measured and luteinizing hormone sampled over 8 hours on days 2 to 5 of one cycle. Anovulatory cycles occurred in 10.9% of cycles in controls, 14.3% of cycles with LRE, and 27.1% of cycles with IGE. Of women using valproate currently or within the preceding 3 years, 38.1% had at least one anovulatory cycle in contrast with 10.7% of women not using valproate within the preceding 3 years. Predictors of ovulatory failure included IGE syndrome, use of valproate currently or within 3 years, high free testosterone, and fewer numbers of luteinizing hormone pulses, but not polycystic-appearing ovaries. WWE are more likely to experience anovulatory menstrual cycles and the effects of epilepsy syndrome, and AED therapy may be additive. Women with IGE receiving valproate were at highest risk for anovulatory cycles, polycystic-appearing ovaries, elevated body mass index, and hyperandrogynism. WWE with anovulatory cycles may have no other signs of reproductive dysfunction. Therefore, clinicians must be alert to this potential complication of epilepsy.

  View details for DOI 10.1002/ana.10391

  View details for Web of Science ID 000179500500004

  View details for PubMedID 12447923

• Epilepsy in women AMERICAN FAMILY PHYSICIAN Morrell, M. J. 2002; 66 (8): 1489-1494

  Abstract

  Epilepsy in women raises special reproductive and general health concerns. Seizure frequency and severity may change at puberty, over the menstrual cycle, with pregnancy, and at menopause. Estrogen is known to increase the risk of seizures, while progesterone has an inhibitory effect. Many antiepileptic drugs induce liver enzymes and decrease oral contraceptive efficacy. Women with epilepsy also have lower fertility rates and are more likely to have anovulatory menstrual cycles, polycystic ovaries, and sexual dysfunction. Irregular menstrual cycles, hirsutism, acne, and obesity should prompt an evaluation for reproductive dysfunction. Children who are born to women with epilepsy are at greater risk of birth defects, in part related to maternal use of antiepileptic drugs. This risk is reduced by using a single antiepileptic drug at the lowest effective dose and by providing preconceptional folic acid supplementation. Breastfeeding is generally thought to be safe for women using antiepileptic medications.

  View details for Web of Science ID 000178868300012

  View details for PubMedID 12408423

• Women with epilepsy: current treatment strategies. The journal of gender-specific medicine : JGSM : the official journal of the Partnership for Women's Health at Columbia Karceski, S., Morrell, M. J. 2002; 5 (5): 22-26

  Abstract

  Despite an ever-growing body of medical literature on epilepsy and its treatment, there are many clinical situations in which the best approach is unclear. In these situations, physicians may turn to expert opinion for guidance. Several methods exist for summarizing expert opinion. The least biased method is also the newest: the expert consensus method. When this method is used to analyze opinion regarding the treatment of women with epilepsy, it is clear that the selection of therapy is influenced by the sex of the patient.

  View details for PubMedID 12380197

• Treatment of women with epilepsy SEMINARS IN NEUROLOGY Pack, A. M., Morrell, M. J. 2002; 22 (3): 289-297

  Abstract

  Epilepsy is equally prevalent in men and women. However, for women there are unique concerns related to hormone effects on seizures and the effects of seizures and antiepileptic drugs (AEDs) on reproductive health. Steroid hormones affect neuronal excitability and seizure frequency. Some AEDs reduce the efficacy of oral contraceptive agents, increasing the probability of unplanned pregnancies. AEDs affect bone density. AEDs may alter reproductive hormones resulting in polycystic-appearing ovaries, anovulatory cycles, and infertility. Seizure frequency may change during pregnancy, seizures may cause pregnancy complications, some AEDs are teratogenic, and many cross into breast milk. The treatment of a woman with epilepsy must consider all these issues.

  View details for Web of Science ID 000180122600008

  View details for PubMedID 12528054

• Antiepileptic medications for the treatment of epilepsy SEMINARS IN NEUROLOGY Morrell, M. J. 2002; 22 (3): 247-258

  Abstract

  Epilepsy is one of the most common neurological conditions encountered worldwide. The development of newer antiepileptic drugs (AEDs) has expanded over recent years, and the use of such drugs for indications other than epilepsy has also broadened. These factors insure that the majority of health care providers will be using an increasing number of AEDs in the care of their patients. Contained herein is a review of the mechanism of action of AEDs, individual drugs and their potential drug interactions, and general principles to guide the clinician in selection, implementation, and long-term monitoring of AEDs.

  View details for Web of Science ID 000180122600004

  View details for PubMedID 12528050

• Folic Acid and Epilepsy. Epilepsy currents / American Epilepsy Society Morrell, M. J. 2002; 2 (2): 31-34

  Abstract

  Folic acid has been a topic of discussion within the epilepsy community for several decades. Folic acid was initially suspected to be epileptogenic (1), but that concern has been resolved, as research has demonstrated that folic acid in less than supraphysiologic concentrations does not promote seizures. Epileptologists are now concerned that folic acid may be too low in persons with epilepsy taking some antiepileptic drugs (AEDs). Low serum and red blood cell levels of folic acid in women of childbearing potential increase the risk of fetal birth defects. For men and women, low levels of folic acid are associated with elevated homocysteine and an increased risk for cardiovascular disease. A convincing argument now develops that routine folic acid supplementation is important for women and men receiving AEDs.

  View details for DOI 10.1046/j.1535-7597.2002.00017.x

  View details for PubMedID 15309159

  View details for PubMedCentralID PMC320966

• The Expert Consensus Guideline Series Treatment of Epilepsy EPILEPSY & BEHAVIOR Karceski, S., Morrell, M., Carpenter, D. 2001; 2 (6): A1-A50

  View details for DOI 10.1006/ebeh.2001.0283

  View details for Web of Science ID 000208208800028

• Future directions for epilepsy research NEUROLOGY Jacobs, M. P., Fischbach, G. D., Davis, M. R., Dichter, M. A., Dingledine, R., Lowenstein, D. H., Morrell, M. J., Noebels, J. L., Rogawski, M. A., Spencer, S. S., Theodore, W. H. 2001; 57 (9): 1536-1542

  Abstract

  The authors propose that epilepsy research embark on a revitalized effort to move from targeting control of symptoms to strategies for prevention and cure. The recent advances that make this a realistic goal include identification of genes mutated in inherited epilepsy syndromes, molecular characterization of brain networks, better imaging of sites of seizure origin, and developments in seizure prediction by quantitative EEG analysis. Research directions include determination of mechanisms of epilepsy development, identification of genes for common epilepsy syndromes through linkage analysis and gene chip technology, and validation of new models of epilepsy and epileptogenesis. Directions for therapeutics include identification of new molecular targets, focal methods of drug delivery tied to EEG activity, gene and cell therapy, and surgical and nonablative therapies. Integrated approaches, such as coupling imaging with electrophysiology, are central to progress in localizing regions of epilepsy development in people at risk and better seizure prediction and treatment for people with epilepsy.

  View details for Web of Science ID 000172161300004

  View details for PubMedID 11706087

• Structural brain abnormalities in patients with schizophrenia, epilepsy, and epilepsy with chronic interictal psychosis PSYCHIATRY RESEARCH-NEUROIMAGING Marsh, L., SULLIVAN, E. V., Morrell, M., Lim, K. O., Pfefferbaum, A. 2001; 108 (1): 1-15

  Abstract

  Chronic interictal psychotic syndromes, often resembling schizophrenia, develop in some patients with epilepsy. Although widespread brain abnormalities are recognized as characteristic of schizophrenia, prevailing but controversial hypotheses on the co-occurrence of epilepsy and psychosis implicate left temporal lobe pathology. In this study, quantitative MRI methods were used to address the regional specificity of structural brain abnormalities in patients with epilepsy plus chronic interictal psychosis (E+PSY, n=9) relative to three comparison groups: unilateral temporal lobe epilepsy without chronic psychosis (TLE, n=18), schizophrenia (SCZ, n=46), and healthy control subjects (HC, n=57). Brain measures, derived from a coronal spin-echo MRI sequence, were adjusted for age and cerebral volume. Relative to HC, all patient groups had ventricular enlargement and smaller temporal lobe, frontoparietal, and superior temporal gyrus gray matter volumes, with the extent of these abnormalities greatest in E+PSY. Only TLE had temporal lobe white matter deficits, as well as smaller hippocampi, which were ipsilateral to the seizure focus. Structural brain abnormalities in E+PSY are not restricted to the left temporal lobe. The confluence of cortical gray matter deficits in E+PSY and SCZ suggests salience to chronic psychosis.

  View details for Web of Science ID 000172053800001

  View details for PubMedID 11677063

• Reproductive dysfunction in women with epilepsy: antiepileptic drug effects on sex-steroid hormones. CNS spectrums Morrell, M. J., Flynn, K. L., Seale, C. G., Done, S., Paulson, A. J., Flaster, E. R., Ferin, M. 2001; 6 (9): 771-?

  Abstract

  Women with epilepsy are at risk for reproductive health dysfunction. Sex-steroid hormone abnormalities have been reported in women with epilepsy, but it has been difficult to determine whether these abnormalities are due to epilepsy-related hypothalamic-pituitary axis dysfunction, or to pharmacokinetic actions of antiepileptic drugs (AEDs). Sex-steroid hormones were evaluated in 84 reproductive-aged women with epilepsy receiving an AED in monotherapy, and in 20 nonepileptic controls. Estrone, free testosterone, and androstenedione were significantly lower in subjects receiving enzyme-inducing AEDs than in nonepileptic controls. Free testosterone was significantly elevated in subjects receiving valproate compared to nonepileptic controls. Subjects with epilepsy receiving gabapentin or lamotrigine were no different from the nonepileptic controls in any of the endocrine variables. Subjects with epilepsy who are receiving AEDs that alter cytochrome P450 enzymes are at risk for significant abnormalities in sex-steroid hormones. In contrast, subjects receiving AEDs that do not alter cytochrome P450 enzymes show no differences in sex-steroid hormones compared with nonepileptic controls. With new AEDs available that do not alter cytochrome P450 enzymes, physician selection of therapy should consider not only seizure control, but also potential effects on reproductive physiology.

  View details for PubMedID 15492730

• Epilepsy: diagnosis and treatment in the 21st century. CNS spectrums Morrell, M. J. 2001; 6 (9): 749-?

  View details for PubMedID 15489823

• Pregnancy and antiepileptic drugs. Current neurology and neuroscience reports Morrell, M. J. 2001; 1 (4): 359-360

  View details for PubMedID 11898542

• Adverse effects of antiepileptic drugs on bone structure - Epidemiology, mechanisms and therapeutic implications CNS DRUGS Pack, A. M., Morrell, M. J. 2001; 15 (8): 633-642

  Abstract

  Antiepileptic drugs (AEDs) were first associated with disorders of bone in both adults and children in the late 1960s. The most severe manifestations of these disorders are osteopenia/osteoporosis, osteomalacia and fractures. Bone disease has been described in several groups of patients receiving AEDs. Groups identified as being more vulnerable to AED-associated bone disease include institutionalised patients, postmenopausal women, older men and children. Radiological and histological evidence of bone disease is found in patients taking AEDs. Numerous biochemical abnormalities of bone metabolism have also been described. The severity of bone and biochemical abnormalities is thought to correlate with the duration of AED exposure and the number of AEDs used. In monotherapy, the AEDs most commonly associated with altered bone metabolism are phenytoin, primidone and phenobarbital (phenobarbitone). To date there have been no reports of altered bone metabolism in individuals receiving the newer anticonvulsants (specifically lamotrigine, topiramate, vigabatrin and gabapentin). The mechanisms of AED-associated bone disease are not clearly elucidated; however, several theories have been proposed to explain the link. No definitive guidelines for evaluation or treatment have yet been determined.

  View details for Web of Science ID 000171163600006

  View details for PubMedID 11524035

• Fenfluramine-Phentermine (Fen-Phen) and Seizures: Evidence for an Association. Epilepsy & behavior : E&B Spencer, D. C., Hwang, J., Morrell, M. J. 2000; 1 (6): 448-452

  Abstract

  Fenfluramine-phentermine combination therapy ("fen-phen") became a popular treatment for obesity in the 1990s. Although this treatment causes cardiac toxicity, use of these medications has not previously been associated with seizures. We report five cases with apparent association between use of fenfluramine-phentermine and occurrence of seizures. Three patients with a history of childhood-onset idiopathic generalized epilepsy in remission experienced a recrudescence of seizures following treatment with fenfluramine-phentermine. Two patients presented with new-onset seizures in midlife following use of fenfluramine-phentermine, and seizures persisted following discontinuation of this therapy. One of these patients restarted fenfluramine-phentermine months later, and experienced recurrent seizures. The nature of the association between fenfluramine-phentermine and seizures is uncertain from this preliminary report. There may be a specific association with idiopathic generalized epilepsies, which appeared to be overrepresented in this case series. An effect of fen-phen on seizure threshold appears most likely; however, an epileptogenic effect cannot be excluded.

  View details for DOI 10.1006/ebeh.2000.0132

  View details for PubMedID 12737835

• Fenfluramine-Phentermine (Fen-Phen) and Seizures: Evidence for an Association EPILEPSY & BEHAVIOR Spencer, D. C., Hwang, J., Morrell, M. J. 2000; 1 (6): 448-452

  View details for DOI 10.1006/ebeh.2000.0132

  View details for Web of Science ID 000208204400011

• Health issues for women with epilepsy: A descriptive survey to assess knowledge and awareness among healthcare providers JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE Morrell, M. J., Sarto, G. E., Shafer, P. O., Borda, E. A., Herzog, A., Callanan, M. 2000; 9 (9): 959-965

  Abstract

  The American Academy of Neurology and the American College of Obstetricians and Gynecologists recently issued practice parameters for women with epilepsy. These parameters suggest optimal care practices. To assess knowledge of the issues covered in the parameters and to facilitate educational efforts to promote best care, the Epilepsy Foundation conducted a survey of healthcare professionals likely to provide care to women with epilepsy. The survey sampled 3535 healthcare professionals across a wide range of specialties. Most respondents did not know the specific effects of estrogen and progesterone on the seizure threshold, were not aware of menstrual-associated seizure patterns, and could not identify which antiepileptic drugs interfere with oral contraceptives. The majority of respondents did not know that women with epilepsy have higher rates of infertility, reproductive endocrine disorders, and sexual dysfunction. Most respondents did not know the frequency of birth defects in children born to women with epilepsy. Providers seeing the largest number of persons with epilepsy were more likely to have correct answers. By specialty, neurologists provided the highest number of correct responses, followed (in descending order) by endocrinologists, obstetricians/gynecologists, internal medicine physicians, family practice physicians, and pediatricians. These results suggest that women with epilepsy are not receiving adequate counseling and that care practices may not conform to those recommended.

  View details for Web of Science ID 000165592300006

  View details for PubMedID 11103095

• Achieving best care for women with epilepsy. Epilepsy & behavior Morrell, M. J. 2000; 1 (5): 299-300

  View details for PubMedID 12609160

• Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design EPILEPSIA Laxer, K., Blum, D., Abou-Khalil, B. W., Morrell, M. J., Lee, D. A., Data, J. L., Monaghan, E. P. 2000; 41 (9): 1187-1194

  Abstract

  A double-blind, randomized, placebo-controlled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed.Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner.The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. Kaplan-Meier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc chi2 probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group.Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity.

  View details for Web of Science ID 000089128200013

  View details for PubMedID 10999558

• Caring for People with Epilepsy: Resources for the Healthcare Provider. Epilepsy & behavior : E&B Morrell, M. J. 2000; 1 (4): S21-S24

  Abstract

  Epilepsy, a condition that affects all age groups, can have life-altering effects. The psychosocial effects of epilepsy are often as detrimental as the seizures themselves. Unfortunately, healthcare professionals often find themselves providing more care in less time and may be unable to thoroughly address these psychosocial needs. Therefore, national organizations and electronic media resources are prepared to provide information and support. For example, the Epilepsy Foundation has a broad range of educational materials available on the Internet and provides patient-to-patient support through on-line chat rooms and through a new initiative entitled the HOPE (Helping Other People with Epilepsy) Mentor Program, a program that trains individuals with epilepsy and their family members to provide education and support. Directing patients toward available reliable resources can help the time-constrained professional ensure that patients' needs for education and psychosocial support are met.

  View details for DOI 10.1006/ebeh.2000.0106

  View details for PubMedID 12609458

• Efficacy of gabapentin as adjunctive therapy in a large, multicenter study SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Morrell, M. J., McLean, M. J., Willmore, L. J., Privitera, M. D., Faught, R. E., Holmes, G. L., Magnus, L., Bernstein, P., Rose-Legatt, A. 2000; 9 (4): 241-248

  Abstract

  The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.

  View details for Web of Science ID 000087953900001

  View details for PubMedID 10880282

• "The Scarlet E" - Epilepsy is still a burden NEUROLOGY Morrell, M. J., Pedley, T. A. 2000; 54 (10): 1882-1883

  View details for Web of Science ID 000087088000001

  View details for PubMedID 10822421

• The role of the intracarotid amobarbital procedure in evaluation of patients for epilepsy surgery EPILEPSIA Spencer, D. C., Morrell, M. J., Risinger, M. W. 2000; 41 (3): 320-325

  Abstract

  To examine the role of the intracarotid amobarbital procedure (IAP) in the presurgical evaluation of patients with medically refractory localization-related epilepsy.We retrospectively studied 111 patients who underwent cortical resective surgery at our center between 1991 and 1996. In patients with mesial temporal lobe epilepsy (mTLE), a presurgical determination of the epileptogenic zone was compared with localization based on IAP memory asymmetry scores, and with ultimate localization after resective surgery. In patients with neocortical or mesial frontal epilepsy, the IAP was evaluated for evidence of unilateral or bilateral poor memory performance.Of 68 patients with mTLE localized by noninvasive tests, 60 had concordant lateralized memory deficits on IAP. Eight patients had lateralized memory deficits on IAP that were discordant with noninvasive tests and with localization as determined by surgical outcome. All 11 mTLE patients requiring invasive EEG monitoring were correctly lateralized by IAP, including one patient in whom the noninvasive evaluation otherwise provided false lateralization. Of 32 patients with neocortical or mesial frontal lobe epilepsy, 21 displayed memory deficits on IAP. Of 10 patients with bilateral deficits, five had mesial frontal lobe epilepsy. In 13 patients with lateralized memory deficits, seven underwent electrode implantation in the mesial temporal lobe, and four ultimately underwent resection of an epileptogenic mesial temporal lobe in addition to a neocortical resection.In patients with mTLE, lateralized memory deficits on IAP usually confirm localization provided by noninvasive tests. However, in mTLE not well lateralized by the noninvasive evaluation, and in neocortical or mesial frontal epilepsy, the IAP may provide information regarding localization that ultimately alters surgical management.

  View details for PubMedID 10714404

• Qualitative block design performance in epilepsy patients ARCHIVES OF CLINICAL NEUROPSYCHOLOGY Zipf-Williams, E. M., Shear, P. K., Strongin, D., Winegarden, B. J., Morrell, M. J. 2000; 15 (2): 149-157

  Abstract

  Broken configuration errors on the WAIS-R Block Design subtest have been associated with right hemisphere brain damage. This study examined whether pre-surgical epilepsy patients with seizure foci restricted to the right hemisphere would break configuration more frequently than those with left hemisphere foci. Subjects included 38 patients with unilateral right or left hemisphere epilepsy of frontal or temporal lobe origin. The left and right hemisphere groups did not differ significantly in demographic or disease variables, IQ, or Block Design standard scores. Right hemisphere patients made more broken configurations than did those with left hemisphere foci. In the right hemisphere group, more broken configurations were associated with a lower Block Design Scaled Score and Full Scale IQ. These results suggest that the observation of broken configurations in the Block Design can assist in corroborating the seizure focus and highlight the importance of qualitative Block Design analysis.

  View details for Web of Science ID 000084900600005

  View details for PubMedID 14590558

• Discriminating between epileptic and nonepileptic events: The utility of hypnotic seizure induction EPILEPSIA Barry, J. J., Atzman, O., Morrell, M. J. 2000; 41 (1): 81-84

  Abstract

  To determine the validity of the Hypnotic Induction Profile (HIP) followed by seizure induction during continuous video-electroencephalographic (EEG) monitoring to discriminate between epileptic (EE) and nonepileptic events (NEE).Eighty-two patients admitted to the Stanford Comprehensive Epilepsy Center for differential diagnosis of seizure-like events were evaluated. Exclusion criteria included inability or refusal to complete the HIP, lack of a "typical" event, an IQ <70, present evidence of psychosis, or a physiological cause for NEE. Sixty-nine patients met these criteria. While undergoing continuous video-EEG monitoring, the patient completed an HIP, an inventory designed to measure the degree of hypnotizability. An attempt was then made to induce the patient's typical events under hypnosis by using a split-screen technique. An event without an EEG correlate was thought to represent an NEE. A diagnosis of NEE was made independently by the neurology team and was compared with results obtained with the hypnotic evaluation.Results for patients with EE were compared with those with NEE and a group consisting of both EE/NEE. All patients with NEE were then contrasted with the EE group. HIP scores for the EE patients indicated lower hypnotizability than the NEE group and were statistically significant when NEE patients and those with NEE/EE were combined. The sensitivity of seizure induction in the diagnosis of NEE was 77%, with a specificity of 95%.The HIP coupled with seizure induction is a useful technique to aid in the diagnosis of patients with NEE. It is sensitive and specific, and it may provide the patient with a useful behavioral tool to control NEEs. It may also furnish a conduit for long-term treatment.

  View details for Web of Science ID 000084703400014

  View details for PubMedID 10643928

• Epilepsy in women: the science of why it is special Symposium on Womens Health Initiatives - Management of Migraine and Epilepsy Throughout the Reproductive Cycle Morrell, M. J. LIPPINCOTT WILLIAMS & WILKINS. 1999: S42–S48

  Abstract

  Epilepsy is a common neurological disorder that may be affected by reproductive hormones and may complicate reproductive health. Many women with epilepsy experience changes in seizure frequency and severity with changes in reproductive cycles, including at puberty, over the menstrual cycle, with pregnancy and at menopause. Ovarian steroids alter neuronal excitability at the membrane and in the genome. Altered protein synthesis as a consequence of changes in RNA mediated gene transcription is one mechanism for steroid mediated effects on excitability. These genomic effects are delayed and sustained. In contrast, membrane effects are immediate and short duration. These effects are mediated at both the GABA-A and NMDA receptors. Estrogen also dynamically alters synaptic connectivity. Estrogen enhances excitability and lowers the seizure threshold, whereas progesterone enhances inhibition and increases the seizure threshold. In experimental models of epilepsy, estrogen is proconvulsant and progesterone is anticonvulsant. The net effect of these steroid actions is to alter neuronal excitability over physiological cycles. Some epilepsy syndromes are expressed or worsened at puberty. One third to one half of women with epilepsy have catamenial seizure patterns, with seizures most likely to occur in the perimenstrual period and at ovulation. More research is needed to understand the effects of menopause on epilepsy. Antiepileptic drugs may exacerbate the risk of reproductive endocrine disorders in women with epilepsy. Fertility rates are lower for women with epilepsy. Women with epilepsy are more likely to have anovulatory menstrual cycles, abnormal pituitary LH release and altered ovarian steroid concentrations. Polycystic ovaries are detected more often in women with epilepsy, particularly those on valproate. Treatment of hormone sensitive seizures relies on standard AEDs. Small trials suggest that adjunctive progesterone therapy is sometimes helpful. The newer AEDs, gabapentin and lamotrigine may have some advantages for women with epilepsy. These drugs do not alter levels of steroid hormones and do not interfere with effectiveness of hormonal contraception. Experience in pregnancy is limited. The dynamic effects of hormones on seizure expression and of seizures on reproductive health complicate the management of epilepsy in women. Newer AEDs may offer advantages for women with epilepsy in the reproductive years.

  View details for Web of Science ID 000082545600010

  View details for PubMedID 10487515

• Safety and tolerability of gabapentin as adjunctive therapy in a large, multicenter study EPILEPSIA McLean, M. J., Morrell, M. J., Willmore, L. J., Privitera, M. D., Faught, R. E., Holmes, G. L., Magnus-Miller, L., Bernstein, P., Rose-Legatt, A. 1999; 40 (7): 965-972

  Abstract

  To evaluate the tolerability and safety of gabapentin (GBP) as add-on therapy for seizure control.Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages < or = 1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP < or =1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow-up contact.A total of 2,216 patients enrolled in this open-label, 16-week study and were evaluable for safety. Of these, 74.0% completed the 16-week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only < or =1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at < or = 1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients.Gabapentin doses >1,800 mg/day were as well tolerated as doses < or =1,800 mg/day and were not associated with more adverse events.

  View details for Web of Science ID 000081247200019

  View details for PubMedID 10403221

• Sensitivity of verbal paired associates learning to mesial temporal sclerosis Thomander, D., Shear, P. K., Zeifert, P., Riley, N., Karzmark, P., Hostetter, G., Risinger, M., Morrell, M. J. WILEY-BLACKWELL. 1999: 175–175

  View details for Web of Science ID 000082947600702

• Dosing to efficacy with neurontin: The STEPS trial Symposium on Neurontin - Expanding the Clinical Experience Morrell, M. J. BLACKWELL PUBLISHING. 1999: S23–S26

  Abstract

  The STEPS (Study of Titration to Effect Profile of Safety) trial, a 16-week, open-label, postmarketing multicenter study, assessed the efficacy of gabapentin as adjunctive therapy in patients with inadequately controlled partial seizures. Inclusion criteria were less restrictive than for Phase III studies, to include a population more representative of the patient population treated in clinical practice. Gabapentin was titrated up to a maximal dosage of 3600 mg/day to achieve seizure control or to tolerability. The efficacy analysis included compliant patients who had completed approximately 16 weeks of therapy (n = 1055); 573 received < or = 1800 mg/day and 482 received > or = 1800 mg/day. The average decrease in seizure frequency was 61%, the percentage of seizure-free patients was 46.35%, and the percentage of patients with a > or = 50% decrease in seizure frequency was 76.05%. The cumulative percentage of responders and of patients who were seizure free increased with each dosage increase. The results confirm that titration to efficacy is appropriate for adjunctive therapy with gabapentin in patients with partial epilepsy treated in clinical practice.

  View details for Web of Science ID 000083169700006

  View details for PubMedID 10530679

• Guidelines for the care of women with epilepsy Consensus Conference on Current Clinical Practice at the 25th Annual Meeting of the Southern-Clinical-Neurological-Society Morrell, M. J. LIPPINCOTT WILLIAMS & WILKINS. 1998: S21–S27

  Abstract

  Antiepileptic drug (AED) selection in women of reproductive age should consider efficacy, tolerability, interactions with contraceptive medications, and teratogenicity. Women planning a pregnancy should be counseled regarding the need for compliance with therapy and the risk for birth defects. All women with epilepsy who are of childbearing potential should receive folate supplementation. Vitamin K supplementation is recommended during the final month of pregnancy. Withdrawal of AED therapy in seizure-free women can be considered before conception. Women who require AED therapy should receive AED monotherapy rather than polytherapy when at all possible. Medication changes post conception do not significantly reduce the risk for major fetal malformations and may compromise seizure control. Breastfeeding is generally safe for women taking AEDs. Menstrual disorders, reproductive endocrine disorders, ovulatory dysfunction, and infertility appear to be relatively common in women with epilepsy.

  View details for Web of Science ID 000076957500005

  View details for PubMedID 9818920

• Analysis of prenatal and gestational care given to women with epilepsy NEUROLOGY Seale, C. G., Morrell, M. J., Nelson, L., Druzin, M. L. 1998; 51 (4): 1039-1045

  Abstract

  To assess past care practices of neurologists and obstetricians to identify areas in which practice patterns differ from currently accepted optimal care.Retrospective chart review of 155 women identified as having a diagnosis of epilepsy (or seizure disorder) who had been pregnant any time between January 1988 and December 1995 and were admitted to Stanford University Hospital for delivery. A total of 161 pregnancies (132 women) were selected for study.An obstetrician was seen at some point during the pregnancy in 99% of the pregnancies, whereas a neurologist was seen at least once in only 64% of the pregnancies. In the 3 months before conception, an obstetrician was seen in 5% of the pregnancies and a neurologist was seen in 15%. Seventy-five percent of the patients taking antiepileptic medication and 65% of the untreated patients had documentation of folate supplementation at any time during pregnancy. Vitamin K supplementation in the final month of pregnancy was documented for only 41% of those receiving antiepileptic drugs. In over one-third of the pregnancies the mother did not have a maternal serum alpha-fetoprotein measure documented and a similar percentage did not receive genetic counseling. Monitoring of the maternal serum concentration of the non-protein-bound fraction of the prescribed antiepileptic drugs was not documented.We identified specific omissions of appropriate vitamin supplementation, genetic counseling, and drug level monitoring. Educational efforts should be targeted to improve the management of pregnancy in women with epilepsy.

  View details for Web of Science ID 000076399100024

  View details for PubMedID 9781526

• Management issues for women with epilepsy - A review of the literature NEUROLOGY Zahn, C. A., Morrell, M. J., Collins, S. D., Labiner, D. M., Yerby, M. S. 1998; 51 (4): 949-956

  Abstract

  A review of literature referable to management issues for women with epilepsy (WWE) was undertaken for the development of a practice parameter.Epilepsy is a common neurologic condition with gender-related management implications. Although reviews of this topic often focus on pregnancy-related issues for WWE, specific health concerns for WWE are present throughout all phases of reproductive life.An OVID MEDLINE literature search was conducted for 1965 to 1997 using the following key words/phrases and cross referencing: epilepsy/ seizures and pregnancy, anticonvulsants, antiepileptic drugs (AEDs), teratogenesis, oral contraceptives, birth defects, folate/folic acid, vitamin K, metabolic bone disease, and breast-feeding.Pregnancy outcome literature for WWE spans several decades. Methodology varies and interpretation is complicated by modern management strategies. Contributions of socioeconomic factors, AEDs, maternal epilepsy, and seizures during pregnancy to adverse pregnancy outcomes have not been clearly delineated. There is a biologic basis for recommendations concerning contraception, folate supplementation, vitamin K use in pregnancy, breast-feeding, metabolic bone disease, catamenial epilepsy, and reproductive endocrine disorders, but no outcome studies afford a strong evidence base for practice recommendation.WWE face health issues for which there is no available outcome literature to guide decision making. The urgent need for studies in many of these areas is highlighted by expanded treatment options with new AEDs and epilepsy surgery.

  View details for Web of Science ID 000076399100009

  View details for PubMedID 9781511

• Issues for women with epilepsy WESTERN JOURNAL OF MEDICINE Morrell, M. J. 1998; 168 (4): 266-267

  View details for Web of Science ID 000073259300011

  View details for PubMedID 9584670

• Issues for women in antiepileptic drug development. Advances in neurology Morrell, M. J. 1998; 76: 149-159

  View details for PubMedID 9408472

• Effects of epilepsy on women's reproductive health EPILEPSIA Morrell, M. J. 1998; 39: S32-S37

  Abstract

  Reproductive dysfunctions are common and wide-ranging in women with epilepsy. Menstrual cycle disruption, anovulatory cycles, disturbances in hypothalamic and/or pituitary hormones, and disturbances in gonadal steroids are more common among women with epilepsy. Sexual dysfunction can present as either disorders of desire or physiologic arousal, but the most common dysfunction appears to be an inadequate initial physiologic arousal response. Reproductive dysfunctions may be due to psychologic, pharmacologic, or physiologic factors. Physicians should routinely question all women with epilepsy regarding their reproductive and sexual health. A full history, a complete physical, and laboratory evaluations with endocrinologic work-up should be performed in any woman who reports a reproductive dysfunction. Treatment and/or referral to a gynecologist or endocrinologist should be initiated as appropriate.

  View details for Web of Science ID 000078030000006

  View details for PubMedID 9915618

• Intracranial ictal recordings in mesial frontal lobe epilepsy JOURNAL OF CLINICAL NEUROPHYSIOLOGY Toczek, M. T., Morrell, M. J., Risinger, M. W., Shuer, L. 1997; 14 (6): 499-506

  Abstract

  Localization of ictal onset in patients with medically refractory frontal lobe epilepsy is challenging even with intracranial monitoring. We present a series of nine patients with presumed mesial frontal lobe epilepsy in whom successful localization of ictal onset was achieved in most cases. Intracranial electrodes were placed over cingulate and supplementary motor cortex bilaterally, with additional electrodes placed over lateral and inferior frontal lobes as part of an evaluation for epilepsy surgery. Localization of the ictal onset was clearly defined in seven of nine patients and was characterized by a pattern of lower amplitude beta/gamma range frequencies noted in one to four adjacent electrodes arising from cingulate cortex or supplementary motor cortex in six patients. In the remaining patient, ictal onset was characterized by periodic high amplitude spike and slow-wave discharges evolving into a higher voltage faster rhythm. Electrographic onset occurred coincident with or preceded clinical findings. Ictal pattern also did not demonstrate a widespread propagation pattern in most of the recordings in which ictal onset was well localized. Precise localization of ictal onset within the mesial frontal lobe is possible. Rapid propagation to regions within and outside the frontal lobe does not always occur.

  View details for Web of Science ID 000077365900006

  View details for PubMedID 9458056

• Gabapentin monotherapy .1. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures NEUROLOGY Bergey, G. K., MORRIS, H. H., Rosenfeld, W., Blume, W. T., Penovich, P. E., Morrell, M. J., Leiderman, D. B., Crockatt, J. G., Lamoreaux, L., Garofalo, E., Pierce, M. 1997; 49 (3): 739-745

  Abstract

  We evaluated the efficacy and safety of gabapentin administered as monotherapy in an 8-day, randomized, double-blind, dose-controlled, parallel-group, multicenter study comparing dosages of 300 and 3,600 mg/d gabapentin in 82 hospitalized patients whose antiepileptic medications had been discontinued for seizure monitoring. Seizures under study were complex partial seizures with or without secondary generalization. Patients exited the study if they experienced a protocol-defined exit event indicating lack of efficacy. Time to exit was significantly longer (p = 0.0001) and completion rate was significantly higher (53% versus 17%; p = 0.002) for patients receiving 3,600 mg/d gabapentin. Gabapentin was well tolerated by patients in both dosage groups, and no patients exited the study due to adverse events, despite rapid initiation of full dose within 24 hours. These results demonstrate that gabapentin has anticonvulsant activity and is well tolerated when administered as monotherapy in patients with refractory partial seizures.

  View details for Web of Science ID A1997XX77400019

  View details for PubMedID 9305334

• Cortical and hippocampal volume deficits in temporal lobe epilepsy EPILEPSIA Marsh, L., Morrell, M. J., Shear, P. K., SULLIVAN, E. V., Freeman, H., Marie, A., Lim, K. O., Pfefferbaum, A. 1997; 38 (5): 576-587

  Abstract

  To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE).Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA).As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe.Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.

  View details for Web of Science ID A1997WX71900011

  View details for PubMedID 9184604

• Clinical symptoms and mri abnormalities in schizophrenia and in epilepsy Marsh, L., Sullivan, E., Spears, S., Sung, T., Lim, K., Morrell, M., Pfefferbaum, A. ELSEVIER SCIENCE BV. 1997: 151–52

  View details for Web of Science ID A1997WP19600426

• Maximizing the health of women with epilepsy: Science and ethics in new drug development EPILEPSIA Morrell, M. J. 1997; 38: S32-S41

  Abstract

  Issues of unique concern to women with epilepsy largely arise from gender-based physiological differences. Female sex steroid hormones may alter the expression of epilepsy and the efficacy of antiepileptic drugs (AEDs). Seizures and AEDs in turn affect the hypothalamic-pituitary axis and can adversely impact reproductive function and bone health. Maternal seizures and exposure to AEDs may compromise fetal development. At this time, women with epilepsy and their medical caretakers do not have access to all the information necessary to formulate a treatment plan that will have the least impact on reproductive and general health. In part, this is because reproductive aged women are excluded from the earliest phases of drug testing and pregnant and lactating women are excluded from all aspects of new drug development. Therefore, as new AEDs enter the marketplace, women with epilepsy must decide whether a new AED is appropriate for therapy based on very limited information. Postmarketing surveillance of gender-specific adverse effects, as with all adverse effects, depends on voluntary reporting. Only a small percentage of significant adverse events are believed to be captured by the present system. Consumers, ethicists, and some physician groups are now arguing that women should be included in all aspects of the development of drugs they will ultimately use-even pregnant and lactating women. Some of the issues of concern for women with epilepsy regarding epilepsy treatment, reproductive function and general health will be reviewed, followed by a discussion of the drug development process and how it does, and could better, address the concerns of women.

  View details for Web of Science ID A1997XM93100007

  View details for PubMedID 9240239

• Self-reported sexual function and sexual arousability in women with epilepsy EPILEPSIA Morrell, M. J., Guldner, G. T. 1996; 37 (12): 1204-1210

  Abstract

  Women with epilepsy are at risk for sexual dysfunction but the frequency and types of dysfunction have not been well characterized.Self-reported sexual function was evaluated in 116 women aged 18-65 years with epilepsy and no concomitant medical or psychiatric illness, including 99 with localization-related epilepsy (LRE) and 17 with primary generalized epilepsy (PGE). Variables evaluated included seizure frequency, age of seizure onset, and antiepileptic drug (AED) exposure. Standardized inventories assessed sexual functioning, sexual arousability and anxiety, sexual behavior, and depression.Although sexual experience was not reduced, women with PGE and LRE reported significantly less sexual arousability and women with LRE reported significantly more sexual anxiety. Women with LRE experienced significantly more dyspareunia, vaginismus, arousal insufficiency, and sexual dissatisfaction, whereas women with PGE experienced anorgasmia and sexual dissatisfaction. Sexual symptoms were not associated with seizure frequency, AED exposure, sexual experience, depression, or prepubertal seizure onset.In contrast to subjects of previous research, the women in our study did not have a disorder of sexual desire, but more than one third experienced disorders of sexual arousal, implying a physiological deficit. Although the etiology for these arousal phase dysfunctions has not been defined, such conditions are treatable and warrant referral to a gynecologist versed in the treatment of sexual disorders.

  View details for Web of Science ID A1996VW83000009

  View details for PubMedID 8956853

• Nocturnal penile tumescence and rigidity evaluation in men with epilepsy EPILEPSIA Guldner, G. T., Morrell, M. J. 1996; 37 (12): 1211-1214

  Abstract

  Men with epilepsy appear to have an approximately fivefold increase in risk of erectile dysfunction (ED). We attempted to determine whether ED in men with epilepsy was due to a physiological basis and whether erectile function could be adequately evaluated with an ambulatory nocturnal penile tumescence and rigidity monitor.The physiologic integrity of the sexual response in men with epilepsy and ED was assessed with an ambulatory nocturnal penile tumescence and rigidity monitor (NPTR). Six men with localization-related epilepsy of temporal lobe origin (TLE) and ED, 2 men with TLE and normal sexual function, and 1 man with nonepileptic seizures (NES) and ED underwent evaluation of nocturnal erections for at least 2 nights.Five of 6 men with TLE and complaints of ED had abnormal ambulatory NPTR evaluations. All others had normal ambulatory NPTR. All abnormal evaluations showed reduced levels of rigidity, often with normal levels of tumescence.Previous studies have shown this abnormal ambulatory NPTR pattern to be associated with neurogenic rather than vasogenic ED. Therefore, epilepsy-related ED may have a substantial neurophysiologic component.

  View details for Web of Science ID A1996VW83000010

  View details for PubMedID 8956854

• Cerebellar hemorrhage complicating temporal lobectomy - Report of four cases JOURNAL OF NEUROSURGERY Toczek, M. T., Morrell, M. J., Silverberg, G. A., Lowe, G. M. 1996; 85 (4): 718-722

  Abstract

  Four cases of cerebellar hemorrhage complicating temporal lobectomy are presented. A case of postoperative hemorrhage located remote from the operative site as a complication of intracranial surgery is rare, especially when it involves the cerebellum after supratentorial craniotomy. In a review of the literature, the authors identified only 12 such cases, none of which was described in the setting of a temporal lobectomy. The possible etiologies for cerebellar hemorrhage in the four cases presented are examined, including the role of epidural suction drains and the position of the head during surgery. The mechanism of cerebellar hemorrhage in this series of patients is probably multifactorial. Special attention throughout the perioperative course must be given to hemodynamic, anatomical, and physiological factors that together can affect the patient negatively.

  View details for Web of Science ID A1996VJ24700033

  View details for PubMedID 8814184

• Linear scleroderma and intractable epilepsy: Neuropathologic evidence for a chronic inflammatory process - Reply ANNALS OF NEUROLOGY Horoupian, D. S., Morrell, M., Chung, M., Sum, J. 1996; 39 (2): 278-278

  View details for Web of Science ID A1996TY53300023

• The new antiepileptic drugs and women: Efficacy, reproductive health, pregnancy, and fetal outcome 3rd International Merritt-Putnam Symposium on New Antiepileptic Drugs - From Discovery to Practical Use: Clinical Directions for the Future Morrell, M. J. BLACKWELL PUBLISHING. 1996: S34–S44

  Abstract

  As new antiepileptic drugs (AEDs) become available, physicians will define their appropriate use in particular patient populations. For women, the issues include gender-specific efficacy and tolerability, including the impact of the AED on reproductive health. Women with epilepsy who are treated with established AEDs appear to be at risk for compromised bone health, for disturbances in fertility, menstrual cyclicity, ovulatory function, and sexuality and, with some AEDs, for failure of hormonal contraception. Finally, pregnancy outcome may be adversely affected by the established AEDs, all of which are human teratogens. Felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were reviewed. The preclinical development process had not addressed all the issues of concern to women. Although gender-specific efficacy is routinely evaluated, impact on reproductive health is not. FBM, GBP, LTG, TGB, TPM, and VGB have similar efficacy in women and men. It is not known whether the new AEDs will affect bone health, fertility, the menstrual cycle, and sexuality. FBM, GBP, LTG, TGB, and probably VGB do not interfere with hormonal contraception. Whether these new AEDs are good choices for the pregnant woman with epilepsy awaits further experience in human pregnancy. However, animal reproductive toxicology studies appear promising. The limited number of human pregnancy exposures do not, thus far, signal a significant number or particular type of adverse outcomes. However, only with improved postmarketing surveillance can essential information about teratogenic effects by acquired in an acceptably short time.

  View details for Web of Science ID A1996VU00200006

  View details for PubMedID 8941040

• Functional MRI measurement of language lateralization in Wada-tested patients BRAIN Desmond, J. E., Sum, J. M., Wagner, A. D., Demb, J. B., Shear, P. K., Glover, G. H., Gabrieli, J. D., Morrell, M. J. 1995; 118: 1411-1419

  Abstract

  In this study the use of functional MRI (fMRI) for measuring language lateralization non-invasively was examined. The subjects were seven patients with histories of temporal lobe epilepsy who had undergone Wada testing for pre-surgical evaluation. Four patients were left-hemisphere-dominant and three were right-hemisphere-dominant for language. They received fMRI scans while they made semantic or perceptual judgments about visually presented words. Regions of the inferior frontal gyrus (pars triangularis and pars orbitalis) and neighbouring orbital cortex, corresponding to portions of Brodmann areas 45, 46 and 47, exhibited significant increases in activation during semantic relative to perceptual judgments. Lateralization of the increases in activation were consistent with the Wada test assessments of hemispheric language dominance in each of the seven patients. These results suggest that, in addition to providing a tool for investigating human cognitive processes, fMRI has significant clinical potential as a non-invasive measure of language lateralization.

  View details for Web of Science ID A1995TQ33300004

  View details for PubMedID 8595473

• PREDICTIVE VALUE OF THE FIRST ICTAL RECORDING IN DETERMINING LOCALIZATION OF THE EPILEPTOGENIC REGION BY SCALP SPHENOIDAL EEG EPILEPSIA Sum, J. M., Morrell, M. J. 1995; 36 (10): 1033-1040

  Abstract

  The number of seizures recorded during a noninvasive evaluation for epilepsy surgery varies across centers. We retrospectively studied the accuracy of the first recorded seizure in predicting the final localization of the epileptogenic region. Sixty-six consecutive patients undergoing continuous EEG monitoring with scalp and sphenoidal electrodes were studied. The first recorded seizure was determined to be either well localized or nonlocalized and was compared with the ultimate localization after multiple seizures were recorded. The first seizure was well localized in 28 and nonlocalized in 38 patients. In the localized group, the first seizure correctly predicted the final localization of the EEG monitoring study in 26 patients, whereas 2 patients had bilateral independent temporal seizures. In the nonlocalized group, ictal onset remained nonlocalized in 34 patients despite recording of multiple (median of five) seizures. This gave a sensitivity of 87% and specificity of 94% for the first recorded seizure to predict the final results of noninvasive EEG monitoring. We conclude that the first recorded seizure is highly predictive of the final results of prolonged noninvasive ictal EEG recordings but it cannot exclude the possibility of multiple epileptogenic foci.

  View details for Web of Science ID A1995RW17400012

  View details for PubMedID 7555954

• INTRACEREBRAL INVOLVEMENT IN SCLERODERMA EN COUP DE SABRE - REPORT OF A CASE WITH NEUROPATHOLOGIC FINDINGS ANNALS OF NEUROLOGY Chung, M. H., Sum, J., Morrell, M. J., Horoupian, D. S. 1995; 37 (5): 679-681

  Abstract

  Linear scleroderma en coup de sabre (LScs) is a rare disorder not infrequently associated with neurologic symptoms, notably epilepsy. However, histopathologic documentation of intracerebral lesions in LScs is very limited and the etiology of the central nervous system symptoms has therefore never been convincingly established. We describe a 27-year-old woman with LScs and a longstanding history of epilepsy. Radiographic studies demonstrated a focal, intraparenchymal lesion in the left frontal lobe directly subjacent to the area of scleroderma on the forehead and scalp. The resected cerebral lesion revealed localized band-like sclerosis of the leptomeninges and associated vessels, as well as intraparenchymal calcifications and anomalous, ectatic vessels. These findings suggest that LScs may represent a neurocutaneous syndrome of vascular dysplasia similar to the Sturge-Weber syndrome, rather than a localized form of collagen vascular disease, as suggested by some.

  View details for Web of Science ID A1995RF06900018

  View details for PubMedID 7755364

• OVULATORY FUNCTION IN EPILEPSY EPILEPSIA CUMMINGS, L. N., Giudice, L., Morrell, M. J. 1995; 36 (4): 355-359

  Abstract

  Women with epilepsy have lower fertility rates than women without epilepsy. We hypothesized that limbic dysfunction in temporal lobe epilepsy (TLE) alters the release of hypothalamic trophic hormones that secondarily affect release of the pituitary gonadotropins, causing ovulatory failure. We assessed ovulatory function over three consecutive menstrual cycles in 17 women with partial seizures arising from the temporal lobe (TLE), 7 women with primary generalized epilepsy (PGE), and 12 controls. We devised scores to reflect ovulatory function that were based on daily basal body temperature and monthly serum progesterone levels. Seizure frequency, antiepileptic drugs (AEDs), and depressive symptomatology were also evaluated. Anovulation was more frequent in subjects with TLE (35.3%) than in subjects with PGE (0%) or in controls (8.3%). Anovulatory cycles tended to occur more frequently in subjects with TLE who were treated with polytherapy than in those receiving monotherapy, but this result was not statistically significant. Seizure frequency and symptoms of depression did not affect ovulatory function. Although AED polytherapy may increase the likelihood of anovulation, our results suggest a mechanism of infertility related to temporal lobe dysfunction.

  View details for Web of Science ID A1995QQ26400006

  View details for PubMedID 7607113

• CONTRIBUTIONS OF ANTERIOR CINGULATE CORTEX TO BEHAVIOUR BRAIN Devinsky, O., Morrell, M. J., Vogt, B. A. 1995; 118: 279-306

  Abstract

  Assessments of anterior cingulate cortex in experimental animals and humans have led to unifying theories of its structural organization and contributions to mammalian behaviour. The anterior cingulate cortex forms a large region around the rostrum of the corpus callosum that is termed the anterior executive region. This region has numerous projections into motor systems, however, since these projections originate from different parts of anterior cingulate cortex and because functional studies have shown that it does not have a uniform contribution to brain functions, the anterior executive region is further subdivided into 'affect' and 'cognition' components. The affect division includes areas 25, 33 and rostral area 24, and has extensive connections with the amygdala and periaqueductal grey, and parts of it project to autonomic brainstem motor nuclei. In addition to regulating autonomic and endocrine functions, it is involved in conditioned emotional learning, vocalizations associated with expressing internal states, assessments of motivational content and assigning emotional valence to internal and external stimuli, and maternal-infant interactions. The cognition division includes caudal areas 24' and 32', the cingulate motor areas in the cingulate sulcus and nociceptive cortex. The cingulate motor areas project to the spinal cord and red nucleus and have premotor functions, while the nociceptive area is engaged in both response selection and cognitively demanding information processing. The cingulate epilepsy syndrome provides important support of experimental animal and human functional imaging studies for the role of anterior cingulate cortex in movement, affect and social behaviours. Excessive cingulate activity in cases with seizures confirmed in anterior cingulate cortex with subdural electrode recordings, can impair consciousness, alter affective state and expression, and influence skeletomotor and autonomic activity. Interictally, patients with anterior cingulate cortex epilepsy often display psychopathic or sociopathic behaviours. In other clinical examples of elevated anterior cingulate cortex activity it may contribute to tics, obsessive-compulsive behaviours, and aberrent social behaviour. Conversely, reduced cingulate activity following infarcts or surgery can contribute to behavioural disorders including akinetic mutism, diminished self-awareness and depression, motor neglect and impaired motor initiation, reduced responses to pain, and aberrent social behaviour. The role of anterior cingulate cortex in pain responsiveness is suggested by cingulumotomy results and functional imaging studies during noxious somatic stimulation. The affect division of anterior cingulate cortex modulates autonomic activity and internal emotional responses, while the cognition division is engaged in response selection associated with skeletomotor activity and responses to noxious stimuli. Overall, anterior cingulate cortex appears to play a crucial role in initiation, motivation, and goal-directed behaviours.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for Web of Science ID A1995QP97200022

  View details for PubMedID 7895011

• MEMORY DURING INTRACAROTID SODIUM AMYTAL TESTING RELATES TO HIPPOCAMPAL BUT NOT EXTRAHIPPOCAMPAL VOLUMES IN TEMPORAL-LOBE EPILEPSY Shear, P. K., Marsh, L., Morrell, M. J., SULLIVAN, E. V. WILEY-BLACKWELL PUBLISHING, INC. 1995: 551–551

  View details for Web of Science ID A1995TD34700515

• THE USE OF HYPNOSIS FOR DIFFERENTIATING EPILEPTIC FROM NONEPILEPTIC EVENTS Barry, J. J., Morrell, M. J., Atzmon, O. WILEY-BLACKWELL PUBLISHING, INC. 1995: L12–L12

  View details for Web of Science ID A1995TD34700595

• NEOCORTICAL GRAY-MATTER DEFICITS IN PATIENTS WITH EPILEPSY AND SCHIZOPHRENIA-LIKE SYNDROMES Marsh, L., SULLIVAN, E. V., Sung, T., Morrell, M. J., Pfefferbaum, A. WILEY-BLACKWELL PUBLISHING, INC. 1995: 681–681

  View details for Web of Science ID A1995TD34700676

• INTERPERSONAL RELATIONSHIPS FOLLOWING TEMPORAL LOBECTOMY CALLANAN, M. A., Barry, J. J., Morrell, M. J. WILEY-BLACKWELL PUBLISHING, INC. 1995: H3–H3

  View details for Web of Science ID A1995TD34700364

• SEXUAL DYSFUNCTION IN PARTIAL EPILEPSY - A DEFICIT IN PHYSIOLOGICAL SEXUAL AROUSAL NEUROLOGY Morrell, M. J., Sperling, M. R., Stecker, M., Dichter, M. A. 1994; 44 (2): 243-247

  Abstract

  Men and women with epilepsy frequently complain of sexual dysfunction. We studied the sexual response in men and women with partial epilepsy of temporal lobe origin (TLE) by measuring genital blood flow (GBF) during sexual arousal. Nine women and eight men with TLE and 12 women and seven men as controls completed inventories for symptoms of depression, sexual experience, and sexual attitude and underwent measurement of digital pulse and GBF during alternating segments of sexually neutral and erotic videotape. Subjective ratings of arousal to the videotape were obtained. We calculated digital pulse and GBF response as the percentage increase in pulse amplitude during the erotic compared with the preceding sexually neutral film. No subject group reported symptoms of significant depression on the inventory. However, men and women with epilepsy had fewer sexual experiences than subjects without epilepsy, and women with epilepsy imagined specific sexual activities to be more anxiety-producing and less arousing than did women without epilepsy. Men and women with TLE had a diminished GBF response. The mean increase in GBF in men with TLE was 184% versus 660% for controls (p = 0.01). Women with TLE had a mean increase of 117% versus 161% for controls (p < 0.01). Digital pulse did not vary across stimulus conditions. Subjective ratings for all groups indicated moderate sexual arousal. We conclude that there is a diminution in one aspect of physiologic sexual arousal in some men and women with TLE.

  View details for Web of Science ID A1994MW89000009

  View details for PubMedID 8309566

• DIFFERENTIAL-DIAGNOSIS OF SEIZURES NEUROLOGIC CLINICS Morrell, M. J. 1993; 11 (4): 737-754

  Abstract

  Distinguishing epileptic events from nonepileptic paroxysmal neurologic events represents a common diagnostic challenge. Syncope, either cardiac or noncardiac, can appear similar to atonic and even convulsive seizures. Breath holding and benign paroxysmal vertigo in children may be confused with epilepsy. Classic migraine, transient global amnesia, and transient ischemic attacks may resemble epileptic seizures. Sleep disorders, including nocturnal movements, parasomnias, and narcolepsy also may resemble epileptic seizures. Most movement disorders are distinguished easily from epilepsy; however, paroxysmal dyskinesias may resemble atonic or reflex seizures. The correct diagnosis can be established and appropriate treatment can be instituted by relying on routine and prolonged EEG, EKG, and sleep studies, when appropriate.

  View details for Web of Science ID A1993MG91400002

  View details for PubMedID 8272029

• A NONINVASIVE PROTOCOL FOR ANTERIOR TEMPORAL LOBECTOMY NEUROLOGY Sperling, M. R., OCONNOR, M. J., Saykin, A. J., Phillips, C. A., Morrell, M. J., BRIDGMAN, P. A., French, J. A., GONATAS, N. 1992; 42 (2): 416-422

  Abstract

  We report the results of a protocol for choosing candidates for temporal lobectomy using a standard battery of objective tests without intracranial electrodes. We assigned each test a level of importance, and an algorithm was used to determine whether temporal lobectomy could be performed. Fifty-one patients (total pool, 103 patients) met protocol requirements and had an anterior temporal lobectomy with a mean follow-up of 39.4 months (range, 21 to 64 months), most remaining on anticonvulsant therapy. Eighty percent are seizure free, 12% have less than 3 seizures per year or only nocturnal seizures, and 8% have greater than 80% reduction in seizure frequency. One-third of patients who failed protocol criteria did not have temporal lobe seizures when studied with intracranial electrodes. We analyzed and modified the algorithm after comparing these patients with others who were poor candidates for temporal lobectomy. We conclude that this protocol is effective and recommend using such an objective algorithm.

  View details for Web of Science ID A1992HD79200028

  View details for PubMedID 1736176

• HORMONES AND EPILEPSY THROUGH THE LIFETIME 11TH ANNUAL MERRITT-PUTNAM SYMP ON EPILEPSY THROUGH LIFE : RECENT ADVANCES IN UNDERSTANDING AND TREATING EPILEPSY DURING PREGNANCY, CHILDHOOD, ADULTHOOD, AND OLD AGE Morrell, M. J. LIPPINCOTT-RAVEN PUBL. 1992: S49–S61

  Abstract

  Hormones influence brain function from gestation throughout life and may affect the seizure threshold by altering neuronal excitability. Estrogen enhances and progesterone diminishes neuronal excitability experimentally, whereas testosterone and corticosteroids have less consistent effects. Hormonal effects in the CNS also depend on the region of brain in which the hormone acts. Sites of action for most steroid hormones include the hypothalamus and limbic cortex, providing a mechanism for modulating behavior and endocrine function. Seizure patterns may change at certain life stages, perhaps as a result of alterations in hormones. At puberty, epilepsy and benign rolandic epilepsy often remit, while juvenile myoclonic and photosensitive epilepsy may arise. Other types of epilepsy do not respond predictably to events in the reproductive life or to advancing age. In some women, fluctuations in hormones over the menstrual cycle appear to increase seizure vulnerability, probably reflecting changes in relative amounts of estrogen and progesterone. Seizure patterns can be altered, for better or worse, during pregnancy. Whether this reflects the effects of hormones or changes in levels of antiepileptic drugs is not resolved. More information is needed about changes in established epilepsy at menopause and in the elderly. Better understanding of endocrine effects on seizures over a lifetime should lead to more effective epilepsy therapies.

  View details for Web of Science ID A1992KA42800008

  View details for PubMedID 1425494

• 11TH ANNUAL MERRITT-PUTNAM SYMPOSIUM - EPILEPSY THROUGH LIFE - RECENT ADVANCES IN UNDERSTANDING AND TREATING EPILEPSY DURING PREGNANCY, CHILDHOOD, ADULTHOOD, AND OLD-AGE EPILEPSIA Leppik, I. E., Shields, W. D., Lindhout, D., Morrell, M. J. 1992; 33: S62-S67

  View details for Web of Science ID A1992KA42800009

• SPEECH DURING PARTIAL SEIZURES - INTRACRANIAL EEG CORRELATES EPILEPSIA Morrell, M. J., Phillips, C. A., OCONNOR, M. J., Sperling, M. R. 1991; 32 (6): 886-889

  Abstract

  Vocalization during a seizure may help predict the location of seizure onset or identify structures ultimately involved in the seizure. Spontaneous vocalization during seizures was studied retrospectively in 22 patients with refractory complex partial seizures evaluated with bilateral intracranial electrodes. Of 22 patients, 12 vocalized during seizures. Seizures were as likely to originate from language-dominant (6/12) as from language-nondominant mesial temporal cortex (6/12). Fluent speech frequently occurred as seizure activity was recorded from language-dominant temporal lobe neocortex (6/12 seizures). Of the patients with well-localized seizure onsets who did not speak (6/10), seizures arose from both language-dominant and -nondominant mesial temporal cortex. We conclude that the presence or absence of vocalizations during a seizure does not reliably indicate the anatomic regions in which the seizure begins or spreads.

  View details for Web of Science ID A1991GU51700018

  View details for PubMedID 1743161

• SEXUAL DYSFUNCTION IN EPILEPSY EPILEPSIA Morrell, M. J. 1991; 32: S38-S45

  Abstract

  Sexual dysfunction may arise more frequently in men and women with epilepsy than with other chronic illnesses, manifesting primarily as diminished sexual desire and potency. Studies using retrospective self-report of sexual attitude and behavior find an incidence of sexual dysfunction ranging from 14-66%. Sexual dysfunction may be more common in partial than in generalized epilepsies. Sexual dysfunction in epilepsy may result from a disturbance in social or psychological factors affecting sexual responsiveness. Alternatively, epileptiform discharges may disrupt the function of structures mediating sexual behavior, particularly the limbic cortex, or alter the release of hypothalamic or pituitary hormones. Antiepileptic drugs modulate hormone release from the hypothalamic-pituitary-gonadal axis and may have direct inhibitory effects on sexual behavior. Evidence both supports and refutes each of these etiologies in the sexual dysfunction seen with epilepsy. Specific evaluation and treatment protocols for patients with sexual dysfunction are available.

  View details for Web of Science ID A1991GU43200007

  View details for PubMedID 1959511

• THE INFLUENCE OF AGE AND CYCLING STATUS ON SEXUAL AROUSABILITY IN WOMEN AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Morrell, M. J., DIXEN, J. M., Carter, C. S., DAVIDSON, J. M. 1984; 148 (1): 66-71

  Abstract

  The effects of age and hormonal status on sexual response were quantitatively assessed by the use of a vaginal photoplethysmograph to measure changes in pulse amplitude in response to erotic film and fantasy. In young, regularly cycling women (mean age, 31 years) there were no significant differences in sexual response between the follicular, ovulatory, and luteal phases. The older premenopausal women (mean age, 51 years) showed responses not significantly different from those of the young cycling women. However, both the younger cycling women and older premenopausal women had significantly higher responses to erotic film than the postmenopausal women (mean age, 57 years). It was concluded that the menopause does result in a decrease in sexual response as assessed by vaginal pulse amplitude. However, it was not established that the magnitude of change noted is sufficient to cause any sexual dysfunction.

  View details for Web of Science ID A1984RZ07900013

  View details for PubMedID 6691383

• THE INFLUENCE OF AGE AND OVULATORY STATUS ON SEXUAL AROUSAL IN WOMEN Morrell, M. J., DIXEN, J. M., CARTERPORGES, S., DAVIDSON, J. M. SLACK INC. 1983: A1–A1

  View details for Web of Science ID A1983PU88600009