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Vinpocetine, cognition, and epilepsy

Meador, Kimford J; Leeman-Markowski, Beth; Medina, Alexandre E; Illamola, Sílvia M; Seliger, Jordan; Novak, Gloria; Lin, Christine; Ivanisevic, Mirjana; Razavi, Babak; Marino, Susan; Boyd, Alan; Loring, David W
OBJECTIVE:Vinpocetine has been shown to enhance memory in animal models, with possible cognitive benefit in humans. The present study sought to demonstrate if vinpocetine can enhance cognition in healthy volunteers or patients with epilepsy. In addition, we compare blood levels of vinpocetine and its active metabolite (apovincaminic acid; AVA) in humans and animals to further characterize factors related to possible therapeutic benefit. METHODS:The cognitive effects of vinpocetine were assessed in healthy adult volunteers (n = 8) using a double-blind, randomized, crossover design at single doses (placebo, 10, 20, and 60 mg oral). Cognitive effects of vinpocetine in patients with focal epilepsy (n = 8) were tested using a double-blind, randomized, crossover design at single doses (placebo, 20 mg oral) followed by one-month open label at 20 mg oral three times a day. The neuropsychological battery included both computerized and non-computerized tests. Levels of vinpocetine and AVA in the human studies were compared to levels in 45 mice across time dosed at 5-20 mg/kg intraperitoneal of vinpocetine. RESULTS:No significant cognitive benefits were seen in healthy volunteers or patients with epilepsy. No appreciable side effects occurred. Vinpocetine and AVA levels were lower in humans than animals. CONCLUSIONS:Vinpocetine was well tolerated, but was not associated with positive cognitive effects. However, blood levels obtained in humans were substantially less than levels in animals obtained from dosages known to be effective in one model. This suggests that higher dosages are needed in humans to assess vinpocetine's cognitive efficacy.
PMID: 33957389
ISSN: 1525-5069
CID: 4873362

Methylphenidate for attention problems in epilepsy patients: Safety and efficacy

Leeman-Markowski, Beth A; Adams, Jesse; Martin, Samantha P; Devinsky, Orrin; Meador, Kimford J
Children with attention deficit hyperactivity disorder (ADHD) have an increased risk of seizures, and children with epilepsy have an increased prevalence of ADHD. Adults with epilepsy often have varying degrees of attentional dysfunction due to multiple factors, including anti-seizure medications, frequent seizures, interictal discharges, underlying lesions, and psychiatric comorbidities. Currently, there are no approved medications for the treatment of epilepsy-related attentional dysfunction. Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of ADHD, and often used for ADHD in the setting of pediatric epilepsy. Large database and registry studies indicate safety of MPH in children with ADHD and epilepsy, with no significant effect on seizure frequency. Small single-dose and open-label studies suggest efficacy of MPH in adults with epilepsy-related attention deficits. Methylphenidate represents a possible treatment for attentional dysfunction due to epilepsy, but large, randomized, placebo-controlled, double-blinded studies are needed.
PMID: 33360744
ISSN: 1525-5069
CID: 4731392

Sounds of seizures

Shum, Jennifer; Fogarty, Adam; Dugan, Patricia; Holmes, Manisha G; Leeman-Markowski, Beth A; Liu, Anli A; Fisher, Robert S; Friedman, Daniel
PURPOSE/OBJECTIVE:A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings. METHODS:We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated. RESULTS:The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97). CONCLUSION/CONCLUSIONS:This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.
PMID: 32276233
ISSN: 1532-2688
CID: 4374322

Does memantine improve memory in subjects with focal-onset epilepsy and memory dysfunction? A randomized, double-blind, placebo-controlled trial

Leeman-Markowski, Beth A; Meador, Kimford J; Moo, Lauren R; Cole, Andrew J; Hoch, Daniel B; Garcia, Eduardo; Schachter, Steven C
OBJECTIVE:Excitotoxic injury involving N-methyl-d-aspartate (NMDA) receptor hyperactivity contributes to epilepsy-related memory dysfunction (ERMD). Current treatment strategies for ERMD have limited efficacy and fail to target the underlying pathophysiology. The present pilot study evaluated the efficacy of memantine, an NMDA receptor antagonist, for the treatment of ERMD in adults with focal-onset seizures. METHODS:Subjects underwent cognitive testing at baseline, after a 13-week randomized, parallel-group, double-blinded phase (of memantine titrated to 10 mg bid or placebo), and following a 13-week open-label extension phase (of memantine titrated to 10 mg bid). The selective reminding test (SRT) continuous long-term retrieval (CLTR) score and 7/24 Spatial Recall Test learning score served as the primary outcome measures. Secondary measures included tests of attention span, fluency, visual construction, and response inhibition, as well as assessments of quality of life, depression, sleepiness, and side effects. RESULTS:Seventeen subjects contributed data to the blinded phase (n = 8 memantine, n = 9 placebo). No significant differences were seen between groups on the primary or secondary outcome measures. Pooled data at the end of the open-label phase from 10 subjects (initially randomized to memantine n = 3 or placebo n = 7) demonstrated statistically significant improvement from baseline in CLTR score, memory-related quality of life, spatial span, and response inhibition. No significant changes were evident in depression, sleepiness, side effects, or seizure frequency throughout the trial. SIGNIFICANCE/CONCLUSIONS:Results demonstrated no significant effect of memantine on cognition when assessed at the end of the blinded period. Pooled data at the end of the open-label phase showed significant improvement over baseline performance in measures of verbal memory, frontal-executive function, and memory-related quality of life. These improvements, however, may be due to practice effects and should be interpreted cautiously. Findings suggest a favorable safety profile of memantine in the setting of epilepsy.
PMID: 30449328
ISSN: 1525-5069
CID: 3479232

Cognitive enhancement in epilepsy

Chapter by: Leeman-Markowski, Beth A; Meador, Kimford J
in: Cognitive enhancement in CNS disorders and beyond by Keefe, Richard S
New York : Oxford, 2018
pp. 123-150
ISBN: 978-0-19-021440-1
CID: 3274312

Cognitive and Behavioral Interventions in Epilepsy

Leeman-Markowski, Beth A; Schachter, Steven C
PURPOSE OF REVIEW: Cognitive and behavioral treatments for epilepsy offer several advantages, as they are relatively low cost, are non-invasive, lack serious side effects, and facilitate patient participation. Their role in the management of epilepsy, however, is unclear. The following manuscript will critically review the efficacy data regarding psychological treatments for seizure reduction. RECENT FINDINGS: Encouraging results have been found for the cognitive behavioral therapy-based Reiter/Andrews approach and mindfulness or arousal-based programs (e.g., yoga, meditation, relaxation, and biofeedback). Most studies attained responder rates between 45 and 90%. Cognitive and behavioral interventions may be considered as low-risk adjuncts to standard therapies. Efficacy data are limited, however, by small numbers of subjects, inadequate randomization, controls, and blinding, brief trial durations, varying methodologies, and variability in the presentation of results. Additional clinical trials are warranted.
PMID: 28382495
ISSN: 1534-6293
CID: 2519572

Treatment of Cognitive Deficits in Epilepsy

Leeman-Markowski, Beth A; Schachter, Steven C
Cognitive deficits, including attention, language, memory, and executive dysfunction, are common in the setting of epilepsy and can greatly impair quality of life. The etiology is often multifactorial and may be due to the underlying seizure disorder, treatment adverse effects, and psychiatric comorbidities, among other factors. Management of cognitive deficits aims to address these underlying etiologies as well as provide rehabilitative strategies. Several investigational therapies are also currently under study. This article examines current and future treatments for cognitive dysfunction in epilepsy.
PMID: 26613999
ISSN: 1557-9875
CID: 2189712

Cessation of gamma activity in the dorsomedial nucleus associated with loss of consciousness during focal seizures [Case Report]

Leeman-Markowski, B A; Smart, O L; Faught, R E; Gross, R E; Meador, K J
RATIONALE: Impaired consciousness during seizures may be mediated by ictal propagation to the thalamus. Functions of individual thalamic nuclei with respect to consciousness, however, are largely unknown. The dorsomedial (DM) nucleus of the thalamus likely plays a role in arousal and cognition. We propose that alterations of firing patterns within the DM nucleus contribute to impaired arousal during focal seizures. METHODS: Electroencephalograph data were collected from electrodes within the left DM thalamus and midcingulate cortex (MCC) in a patient undergoing seizure monitoring. Spectral power was computed across ictal states (preictal, ictal, and postictal) and level of consciousness (stupor/sleep vs. awake) in the DM nucleus and MCC. RESULTS: Eighty-seven seizures of multifocal left frontal and temporal onsets were analyzed, characterized by loss of consciousness. At baseline, the left DM nucleus demonstrated rhythmic bursts of gamma activity, most frequently and with greatest amplitude during wakefulness. This activity ceased as ictal discharges spread to the MCC, and consciousness was impaired, and it recurred at the end of each seizure as awareness was regained. The analysis of gamma (30-40Hz) power demonstrated that when seizures occurred during wakefulness, there was lower DM ictal power (p<0.0001) and higher DM postictal power (p<0.0001) relative to the preictal epoch. This spectral pattern was not evident within the MCC or when seizures occurred during sleep. CONCLUSIONS: Data revealed a characteristic pattern of DM gamma bursts during wakefulness, which disappeared during partial seizures associated with impaired consciousness. The findings are consistent with studies suggesting that the DM nucleus participates in cognition and arousal.
PMID: 26295448
ISSN: 1525-5069
CID: 2189722

Intra-stimulation discharges: an overlooked cortical electrographic entity triggered by direct electrical stimulation

Karakis, Ioannis; Leeman-Markowski, Beth A; Leveroni, Catherine L; Kilbride, Ronan D; Cash, Sydney S; Eskandar, Emad N; Simon, Mirela V
OBJECTIVE: Intra-stimulation discharges (IDs) can occur during language mapping, are largely unrecognized, and may precede the occurrence of after-discharges (ADs) and seizures. This study aimed to identify predictors of ID occurrence and determine whether IDs increase the probability of triggered ADs. METHODS: A total of 332 stimulation events performed during language mapping were analyzed in 3 patients who underwent intracranial EEG recordings during evaluations for epilepsy surgery. IDs were identified in 76 stimulation events. The relationships between IDs and the stimulus current intensity, stimulation duration, and proximity to regions of abnormal cortical excitability [characterized by the presence of baseline epileptiform discharges (BEDs)] were determined using regression analysis. RESULTS: The presence of BEDs in close proximity to stimulation, an increase in stimulus intensity by 1 mA, and an increase in stimulation duration by 1s independently increased the odds of triggering IDs by 7.40, 1.37, and 1.39 times, respectively. All IDs were triggered during stimulations in the temporal lobe. The occurrence of IDs increased the odds of triggering ADs 5-fold. CONCLUSIONS: Longer stimulations, higher currents, and the presence of BEDs at the stimulation site increase the probability of ID occurrence, which in turn increases the probability of triggering ADs. SIGNIFICANCE: Attention to IDs may improve the safety and precision of neurophysiologic mapping.
PMID: 25266305
ISSN: 1872-8952
CID: 2189742

Fifteen years of Epilepsy & behavior: a hearty congratulations and a heartfelt thank you [Letter]

Leeman-Markowski, Beth A
PMID: 25281296
ISSN: 1525-5069
CID: 2189732