Management of epilepsy during pregnancy and lactation.

Epilepsy is a group of neurological diseases characterized by susceptibility to recurrent seizures. Antiseizure medications (ASMs) are the mainstay of treatment, but many antiseizure medications with variable safety profiles have been approved for use. For women with epilepsy in their childbearing years, the safety profile is important for them and their unborn children, because treatment is often required to protect them from seizures during pregnancy and lactation. Since no large randomized controlled trials have investigated safety in this subgroup of people with epilepsy, pregnancy registries, cohort and case-control studies from population registries, and a few large prospective cohort studies have played an important role. Valproate, in monotherapy and polytherapy, has been associated with elevated risk of major congenital malformations and neurodevelopmental disorders in children born to mothers who took it. Topiramate and phenobarbital are also associated with elevated risks of congenital malformations and neurodevelopmental disorders, though the risks are lower than those of valproate. Lamotrigine and levetiracetam are relatively safe. Insufficient data exist to reach strong conclusions about the newest antiseizure medications such as eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Besides antiseizure medications, other treatments such as vagal nerve stimulation, responsive neurostimulation, and deep brain stimulation are likely safe. In general, breastfeeding does not appear to add any additional long term risks to the child. Creative ways of optimizing registry enrollment and data collection are needed to enhance patient safety.

Measuring Ambulatory Racial and Ethnic Neurologic Disparities With the Axon Registry.

Background and Objectives: The primary objective is to examine potential racial and ethnic (R/E) disparities in ambulatory neurology quality measures within the American Academy of Neurology Axon Registry. R/E disparities in neurologic US morbidity and mortality have been clearly documented. Despite these findings, there have been no nationwide examinations of how ambulatory neurologic care affects these negative health outcomes. Methods: This was a retrospective nonrandomized cohort study of patients in the AAN Axon Registry. The Axon Registry is a neurology-specific outpatient quality registry that collects, reports, and analyzes real-world deidentified electronic health record (EHR) data. Patients were included in the study if they contributed toward one of the selected quality measures for multiple sclerosis, epilepsy, Parkinson disease, or headache during the study period of January 1, 2019-December 31, 2019. Descriptive analyses of patient demographics were performed and then stratified by race and ethnicity. Results: There were a total of 633,672 patients included in these analyses. Separate analyses were performed for race (64% White, 8% Black, 1% Asian, and 27% unknown) and ethnicity (52% not Hispanic, 5% Hispanic, and 43% unknown). The mean age ranged from 18 to 55 years, with 61% female and 39% male. Quality measures were chosen based on completeness of R/E data and were either process or outcomes focused. Statistically significant differences were noted after controlling for multiple comparisons. Discussion: The large proportion of missing or unknown R/E data and low overall rate of performance on these quality measures made the relevance of small differences difficult to determine. This analysis demonstrates the feasibility of using the Axon Registry to assess neurologic disparities in outpatient care. More education and training are required on the accurate capture of R/E data in the EHR.

Association Between Migraine Comorbidity and Psychiatric Symptoms Among People With Newly Diagnosed Focal Epilepsy.

OBJECTIVE: Little is known about psychiatric symptoms among patients with migraine and newly diagnosed focal epilepsy. The investigators compared symptoms of depression, anxiety, and suicidality among people with newly diagnosed focal epilepsy with migraine versus without migraine. METHODS: The Human Epilepsy Project is a prospective multicenter study of patients with newly diagnosed focal epilepsy. Depression (measured with the Center for Epidemiologic Studies Depression Scale), anxiety (measured with the 7-item Generalized Anxiety Disorder scale), and suicidality scores (measured with the Columbia-Suicide Severity Rating Scale [C-SSRS]) were compared between participants with versus without migraine. Data analysis was performed with the Kolmogorov-Smirnov test for normality assessment, the Mann-Whitney U test, chi-square test, and linear regression. RESULTS: Of 349 patients with new-onset focal epilepsy, 74 (21.2%) had migraine. There were no differences between the patients without migraine versus those with migraine in terms of age, race, and level of education. There were more women in the group with migraine than in the group without migraine (75.7% vs. 55.6%, p=0.0018). The patients with epilepsy and comorbid migraine had more depressive symptoms than the patients with epilepsy without migraine (35.2% vs. 22.7%, p=0.031). Patients with epilepsy with comorbid migraine had more anxiety symptoms than patients with epilepsy without migraine, but this relation was mediated by age in logistic regression, with younger age being associated with anxiety. Comorbid migraine was not associated with C-SSRS ideation or behavior. CONCLUSIONS: Among a sample of patients with newly diagnosed focal epilepsy, 21.2% had migraine. Migraine comorbidity was associated with higher incidence of depressive symptoms. Future studies should be performed to better assess these relationships and possible treatment implications.

Analysis of Morbidity and Outcomes Associated With Use of Subdural Grids vs Stereoelectroencephalography in Patients With Intractable Epilepsy.

Importance: A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown. Objective: To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center. Design, Setting and Participants: Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy. Procedures were performed from November 1, 2004, through June 30, 2017, and data were analyzed in June 2017 and August 2018. Interventions: Implantation of SDE using standard techniques vs SEEG using a stereotactic robot, followed by resection or laser ablation of the seizure focus. Main Outcomes and Measures: Length of surgical procedure, surgical complications, opiate use, and seizure outcomes using the Engel Epilepsy Surgery Outcome Scale. Results: Of the 260 cases included in the study (54.6% female; mean [SD] age at evaluation, 30.3 [13.1] years), the SEEG (n = 121) and SDE (n = 139) groups were similar in age (mean [SD], 30.1 [12.2] vs 30.6 [13.8] years), sex (47.1% vs 43.9% male), numbers of failed anticonvulsants (mean [SD], 5.7 [2.5] vs 5.6 [2.5]), and duration of epilepsy (mean [SD], 16.4 [12.0] vs17.2 [12.1] years). A much greater proportion of SDE vs SEEG cases were lesional (99 [71.2%] vs 53 [43.8%]; P < .001). Seven symptomatic hemorrhagic sequelae (1 with permanent neurological deficit) and 3 infections occurred in the SDE cohort with no clinically relevant complications in the SEEG cohort, a marked difference in complication rates (P = .003). A greater proportion of SDE cases resulted in resection or ablation compared with SEEG cases (127 [91.4%] vs 90 [74.4%]; P < .001). Favorable epilepsy outcomes (Engel class I [free of disabling seizures] or II [rare disabling seizures]) were observed in 57 of 75 SEEG cases (76.0%) and 59 of 108 SDE cases (54.6%; P = .003) amongst patients undergoing resection or ablation, at 1 year. An analysis of only nonlesional cases revealed good outcomes in 27 of 39 cases (69.2%) vs 9 of 26 cases (34.6%) at 12 months in SEEG and SDE cohorts, respectively (P = .006). When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I or II) for SEEG compared with SDE were similar (57 of 121 [47.1%] vs 59 of 139 [42.4%] at 1 year; P = .45). Conclusions and Relevance: This direct comparison of large matched cohorts undergoing SEEG and SDE implantation reveals distinctly better procedural morbidity favoring SEEG. These modalities intrinsically evaluate somewhat different populations, with SEEG being more versatile and applicable to a range of scenarios, including nonlesional and bilateral cases, than SDE. The significantly favorable adverse effect profile of SEEG should factor into decision making when patients with pharmacoresistant epilepsy are considered for intracranial evaluations.

Reducing neurodisparity: Recommendations of the 2017 AAN Diversity Leadership Program.

Many advances in prevention, diagnosis, and treatment of neurologic disease have emerged in the last few decades, resulting in reduced mortality and decreased disability. However, these advances have not benefitted all populations equally. A growing body of evidence indicates that barriers to care fall along racial and ethnic lines, with persons from minority groups frequently having lower rates of evaluation, diagnosis, and intervention, and consequently experiencing worse neurologic outcomes than their white counterparts. The American Academy of Neurology (AAN) challenged its 2017 Diversity Leadership Program cohort to determine what the AAN can do to improve quality of care for racially and ethnically diverse patients with neurologic disorders. Developing a fuller understanding of the effect of disparities in neurologic care (neurodisparity) on patients is an important prerequisite for creating meaningful change. Clear insight into how bias and trust affect the doctor-patient relationship is also crucial to grasp the complexity of this issue. We propose that the AAN take a vital step toward achieving equity in neurologic care by enhancing health literacy, patient education, and shared decision-making with a focus on internet and social media. Moreover, by further strengthening its focus on health disparities research and training, the AAN can continue to inform the field and aid in the development of current and future leaders who will address neurodisparity. Ultimately, the goal of tackling neurodisparity is perfectly aligned with the mission of the AAN: to promote the highest-quality patient-centered neurologic care and enhance member career satisfaction.

Laser ablation for mesial temporal lobe epilepsy: Surgical and cognitive outcomes with and without mesial temporal sclerosis.

OBJECTIVES: Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique for focal epilepsy. A major appeal of LITT is that it may result in fewer cognitive deficits, especially when targeting dominant hemisphere mesial temporal lobe (MTL) epilepsy. To evaluate this, as well as to determine seizure outcomes following LITT, we evaluated the relationships between ablation volumes and surgical or cognitive outcomes in 43 consecutive patients undergoing LITT for MTL epilepsy. METHODS: All patients underwent unilateral LITT targeting mesial temporal structures. FreeSurfer software was used to derive cortical and subcortical segmentation of the brain (especially subregions of the MTL) using preoperative magnetic resonance imaging (MRI). Ablation volumes were outlined using a postablation T1-contrasted MRI. The percentages of the amygdala, hippocampus, and entorhinal cortex ablated were quantified objectively. The volumetric measures were regressed against changes in neuropsychological performance before and after surgery, RESULTS: A median of 73.7% of amygdala, 70.9% of hippocampus, and 28.3% of entorhinal cortex was ablated. Engel class I surgical outcome was obtained in 79.5% and 67.4% of the 43 patients at 6 and 20.3 months of follow-up, respectively. No significant differences in surgical outcomes were found across patient subgroups (hemispheric dominance, hippocampal sclerosis, or need for intracranial evaluation). Furthermore, no significant differences in volumes ablated were found between patients with Engel class IA vs Engel class II-IV outcomes. In patients undergoing LITT in the dominant hemisphere, a decline in verbal and narrative memory, but not in naming function was noted. SIGNIFICANCE: Seizure-free outcomes following LITT may be comparable in carefully selected patients with and without MTS, and these outcomes are comparable with outcomes following microsurgical resection. Failures may result from non-mesial components of the epileptogenic network that are not affected by LITT. Cognitive declines following MTL-LITT are modest, and principally affect memory processes.

Surgical Resection for Epilepsy Following Cerebral Gunshot Wounds.

OBJECTIVE: The surgical management of epilepsy after penetrating gunshot wounds (GSWs) to the head has not been described in the modern era. Given the extensive damage to the cranium and cortex from such injuries, the safety and efficacy of surgical intervention are unclear. We report surgical strategy and outcomes after resection for medically refractory epilepsy following GSWs in 4 patients. METHODS: A prospectively compiled database of 325 patients with epilepsy was used to identify patients undergoing surgery for medically refractory epilepsy after a GSW to the brain. Seizure frequency, scalp and intracranial electroencephalography evaluation, type of resection, and seizure outcomes were compiled. RESULTS: All 4 patients underwent direct electrocorticography recordings either with implanted electrodes or intraoperatively that were used to drive surgical decision making. All patients had intracranial shrapnel fragments and large areas of encephalomalacia on imaging. Intracranial electrodes were placed in 2 patients to localize seizure onsets. Two patients underwent frontal lobe resections, and the other 2 patients underwent multilobar resections. Latency between injury and epilepsy surgery was 12 years, and mean age at surgery was 28 years. In all cases, epilepsy surgery led to a significant improvement in seizure control (Engel class I, 2 patients; II, 1 patient; and III, 1 patient). CONCLUSIONS: Epilepsy is common after penetrating head injury, and the incidence is likely to increase given the growing numbers of armed conflicts in urban centers worldwide. In selected cases, intracranial monitoring and surgical resections may be safely performed and can lead to favorable seizure outcomes.

Longitudinal feasibility of MINDSET: a clinic decision aid for epilepsy self-management.

The purpose of this paper is to report on the development and feasibility of the longitudinal version of MINDSET, a clinical tool to assist patients and health-care providers in epilepsy self-management. A previous study described the feasibility of using MINDSET to identify and prioritize self-management issues during a clinic visit. This paper describes the development of the longitudinal version of MINDSET and feasibility test over multiple visits with a printed action plan for goal setting and the capacity for monitoring changes in self-management. Feasibility was assessed based on 1) postvisit patient and provider interviews addressing ease of use and usefulness, patient/provider communication, and shared decision-making and 2) the capacity of the tool to monitor epilepsy characteristics and self-management over time. Results indicate MINDSET feasibility for 1) identifying and facilitating discussion of self-management issues during clinic visits, 2) providing a printable list of prioritized issues and tailored self-management goals, and 3) tracking changes in epilepsy characteristics and self-management over time.

Quality assessment of electroencephalography obtained from a "dry electrode" system.

This study examines the difference in application times for routine electroencephalography (EEG) utilizing traditional electrodes and a "dry electrode" headset. The primary outcome measure was the time to interpretable EEG (TIE). A secondary outcome measure of recording quality and interpretability was obtained from EEG sample review by two blinded clinical neurophysiologists. With EEG samples obtained from 10 subjects, the average TIE for the "dry electrode" system was 139s, and for the conventional recording 873s (p<0.001). The results support the hypothesis that such a "dry electrode" system can be applied with more than an 80% reduction in the TIE while still obtaining interpretable EEG.

Geriatric epilepsy: research and clinical directions for the future.

There is a growing awareness of the need for improved treatment and care of older adults with epilepsy. The present review article highlights key clinical and research issues in the emerging field of geriatric epilepsy. Drs. Martin and Schmidt explore the scope of the problems in the field, outline topic areas including cognitive health/dementia, and diagnostic challenges, and also present important research questions that should be considered for the future. As part of this presentation, we will highlight the work of two promising young investigators whose work holds great promise for the field of geriatric epilepsy. Dr. Roberson will discuss his work focusing on the relationship of epilepsy and cognitive impairment, particularly as it relates to Alzheimer's disease pathology including tau and its role in epileptiform activity. Dr. Hope will outline key issues, as well as her work, relating to defining and measuring quality care in geriatric epilepsy.

New-onset geriatric epilepsy care: Race, setting of diagnosis, and choice of antiepileptic drug.

PURPOSE: There is a growing movement to assess the quality of care provided to patients in the US, but few studies have examined initial care for epilepsy patients. We examined the relationships among patient race, setting of initial diagnosis, and initial treatment for older veterans newly diagnosed with epilepsy. METHODS: We used Department of Veterans Affairs (VA) inpatient, outpatient, pharmacy and Medicare data (1999-2004) to identify patients 66 years and older with new-onset epilepsy. High quality care was defined as avoiding a suboptimal agent (phenytoin, phenobarbital, primidone) as defined by experts. Predictors included demographic and clinical characteristics, and the context of the initial seizure diagnosis including the setting (e.g. emergency, neurology, hospital, primary care). We used mixed-effects multivariable logistic regression modeling to identify predictors of initial seizure diagnosis in a neurology setting, and receipt of a suboptimal AED. RESULTS: Of 9,682 patients, 27% were initially diagnosed in neurology and 70% received a suboptimal AED. Blacks and Hispanics were less likely to be diagnosed in neurology clinics (black OR = 0.7 95% CI 0.6-0.8; Hispanic OR = 0.6 95% CI 0.5-0.9). Diagnosis in a non-neurology setting increased the likelihood of receiving a suboptimal agent (e.g. Emergency Department OR = 2.3 95% CI 2.0-2.7). After controlling for neurology diagnosis, black race was independently associated with an increased risk of receiving a suboptimal agent. DISCUSSION: We demonstrated that differences in quality of care exist for both clinical setting of initial diagnosis and race. We discussed possible causes and implications of these findings.

Monoamine and motor responses to cocaine are co-deficient in the Fawn-Hooded depressed animal model.

The Fawn-Hooded (FH) genetic animal model of depression continues to be of interest because the FH model has limited biochemical and immune function. The FH animal has an inherited trait, platelet storage pool deficiency (PSPD), an hemorrhagic disorder that is also a component of Chediak-Higashi syndrome (CHS). CHS is a pyrogenic infectious childhood disease; few patients live past the age of 20. Our hypothesis was that FH animals may exhibit different monoamine and motor responses to cocaine versus the Sprague-Dawley (SD) "normal" animal strain, which does not have the FH trait. Therefore, selective neuromolecular imaging (NMI) of the monoamines, dopamine (DA) and 5-HT within nucleus accumbens (NAcc) of behaving male FH versus SD rats was performed in vivo with BRODERICK PROBE sensors and a semiderivative voltammetric circuit. Each animal was placed in a faraday chamber and electrochemical signals were detected via a mercury commutator and flexible cable. Baseline values for neurotransmitters and behavior were derived during the last half-hour of habituation behavior. Release of DA and 5-HT was detected selectively, at separate oxidation potentials, within seconds, before and after intraperitoneal administration of the psychostimulant, cocaine (10 mg/kg). At the same time, frequencies of ambulations and central ambulations were separately monitored with infrared photobeams, which surrounded the faraday chamber. Data were compared by ANOVA analysis followed by Tukey's post hoc test. The data showed that (1) DA release in NAcc of behaving FH animals did not respond to cocaine; neither first hour nor second hour values significantly differed from baseline (both hours, p>0.05), whereas SD animals exhibited a significant increase in cocaine-induced DA release in NAcc (both hours, p<0.001). The ability for acute cocaine to increase DA release in NAcc was significantly greater in SD than in FH animals (p<0.001). (2) 5-HT release in NAcc of behaving FH animals was not significantly increased by cocaine (both hours, p>0.05), whereas 5-HT release in NAcc of SD animals was significantly increased after cocaine (both hours, p<0.001). The ability for acute cocaine to increase 5-HT release was significantly greater in SD than in FH animals (p<0.001). (3) Ambulations in the FH strain were modestly, yet significantly, enhanced after cocaine during both hours of study (p<0.05, p<0.001, respectively) as were ambulations in the SD strain. Nonetheless, the ability for acute cocaine to increase ambulations was significantly greater in SD than in FH animals in the first hour (p<0.001). (4) Central ambulations in the FH strain was not affected by cocaine (both hours, p>0.05), whereas SD animals showed a significant increase in central ambulatory activity in both hours of the cocaine study (p<0.001). The ability for acute cocaine to increase central ambulations was significantly greater in SD than in FH animals (p<0.001). Thus, this is the first study to determine in vivo the neurochemical response to acute cocaine in the behaving FH animal. Moreover, this is the first study to determine in vivo and simultaneously the neurochemical and behavioral response to acute cocaine in the FH strain in comparison with SD animals, a "normal" strain. Remarkable deficiencies in the ability for acute cocaine to alter neurochemistry and behavior in animals with the FH trait are shown. These studies emphasize the need to look differentially at cocaine effects in biochemically and immune-compromised subjects versus "normal" subjects.

Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal.

There is an increasing awareness that a psychosis, similar to that of schizophrenic psychosis, can be derived from cocaine addiction. Thus, the prototypical atypical antipsychotic medication, clozapine, a 5-HT(2)/DA(2) antagonist, was studied for its effects on cocaine-induced dopamine (DA) and serotonin (5-HT) release in nucleus accumbens (NAcc) of behaving male Sprague-Dawley laboratory rats with In Vivo Microvoltammetry, while animals' locomotor (forward ambulations), an A(10) behavior, was monitored at the same time with infrared photobeams. Release mechanisms for monoamines were determined by using a depolarization blocker, gamma-butyrolactone (gammaBL). BRODERICK PROBE microelectrodes selectively detected release of DA and 5-HT within seconds and sequentially in A(10) nerve terminals, NAcc. Acute and subacute studies were performed for each treatment group. Acute studies are defined as single injection of drug(s) after a stable baseline of each monoamine and locomotor behavior has been achieved. Subacute studies are defined as 24-h follow-up studies on each monoamine and locomotor behavior, in the same animal at which time, no further drug was administered. Results showed that (1) acute administration of cocaine (10 mg/kg ip) (n=5) significantly increased both DA and 5-HT release above baseline (P<.001) while locomotion was also significantly increased above baseline (P<.001). In subacute studies, DA release decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at the 15-min mark and at each time point during the second part of the hour (P<.05); the maximum decrease in 5-HT was 40% below baseline. Locomotor behavior, on the other hand, increased significantly above baseline (P<.05). (2) Acute administration of clozapine/cocaine (20 and 10 mg/kg ip, respectively; n=6) produced a significant block of the cocaine-induced increase in DA (P<.001) and 5-HT release (P<.001). Cocaine-induced locomotion was blocked simultaneously with each monoamine by clozapine as well (P<.001). In subacute studies, DA release continued to be blocked presumably via clozapine by exhibiting a statistically significant decrease (P<.001), but 5-HT release increased significantly (P<.001), while cocaine-induced locomotor activity also continued to be antagonized by clozapine, i.e., locomotor activity exhibited no difference from baseline (P>.05). In summary, acute studies (a) support previous data from this laboratory and others that cocaine acts as a stimulant on the monoamines, DA and 5-HT and on locomotor behavior as well and (b) show that clozapine, 5-HT(2)/DA(2) antagonist, blocked enhanced DA, 5-HT and psychomotor stimulant behavior induced by cocaine. Subacute studies (a) suggest that withdrawal responses occurred in the cocaine group, based on recorded deficiencies in monoamine neurotransmitters (b) show that withdrawal effects in the cocaine group likely presynaptic, were distinguished from locomotor behavior, classically known to be mediated postsynaptically, and finally, (c) suggest that clozapine, with longer lived pharmacokinetic properties, reversed 5-HT cocaine-related withdrawal effects, but was unable to reverse DA cocaine-related withdrawal responses. Taken together with data from this laboratory, in which the 5-HT(2A/2C) antagonist, ketanserin, affected cocaine neurochemistry in much the same way as did clozapine, a mediation by either separate or combined 5-HT(2A/2C) receptors for these clozapine/cocaine interactions, is suggested. Further studies, designed to tease out the responses of selective 5-HT(2A) and 5-HT(2C) receptor compounds to cocaine and clozapine/cocaine, are underway.