Migraine with prolonged aphasic aura associated with a CACNA1A mutation: A case report and narrative review.

OBJECTIVE: To demonstrate that a known CACNA1A variant is associated with a phenotype of prolonged aphasic aura without hemiparesis. BACKGROUND: The usual differential diagnosis of prolonged aphasia without hemiparesis includes vascular disease, seizure, metabolic derangements, and migraine. Genetic mutations in the CACNA1A gene can lead to a myriad of phenotypes, including familial hemiplegic migraine (FHM) type 1, an autosomal dominant disorder characterized by an aura of unilateral, sometimes prolonged weakness. Though aphasia is a common feature of migraine aura, with or without hemiparesis, aphasia without hemiparesis has not been reported with CACNA1A mutations. METHODS: We report the case of a 51-year-old male who presented with a history of recurrent episodes of aphasia without hemiparesis lasting days to weeks. His headache was left sided and was heralded by what his family described as "confusion." On examination, he had global aphasia without other focal findings. Family history revealed several relatives with a history of severe headaches with neurologic deficits including aphasia and/or weakness. Imaging revealed T2 hyperintensities in the left parietal/temporal/occipital regions on MRI scan with corresponding hyperperfusion on SPECT. Genetic testing revealed a missense mutation in the CACNA1A gene. CONCLUSIONS: This case expands the phenotypic spectrum of the CACNA1A mutation and FHM to include prolonged aphasic aura without hemiparesis. Our patient's SPECT imaging demonstrated hyperperfusion in areas correlating with aura symptoms which can occur in prolonged aura.

Recognizing seizure clusters in the community: The path to uniformity and individualization in nomenclature and definition.

Seizure emergencies experienced by patients with epilepsy include status epilepticus and seizure clusters. Although an accepted definition of status epilepticus exists, no clear consensus definition of seizure clusters has emerged; this is further complicated by the appearance in the literature of various empirically based definitions that have been developed for clinical trial study designs. In general, patients with intractable epilepsy have been shown to have a significant risk for acute episodes of increased seizure activity called seizure clusters (also referred to as acute repetitive seizures, among other terms) that differ from their usual seizure pattern. Duration (e.g., number of hours or days) is often included in the definition of a seizure cluster; however, the duration may vary among patients, with some seizure clusters lasting ≥24 h and requiring long-acting treatment for this period. In addition to seizure cluster duration, the time between seizures and possible acceleration in seizure frequency during the cluster may be important variables. The recognition and treatment of seizure clusters require urgent action because episodes that are not quickly and appropriately treated may lead to injury or progress to status epilepticus or potentially death. Most seizure clusters occur outside a medical facility (in the community) and treatment is usually administered by nonmedical individuals; therefore, health care providers may benefit from a clear description of these potential seizure emergencies that they can then use to educate patients and caregivers on the prompt and appropriate identification of seizure clusters and administration of rescue therapy. Here we explore why greater uniformity is needed in the discussion of seizure clusters. This exploration examines epidemiologic studies of seizure clusters and status epilepticus, inconsistencies in nomenclature and definitions for seizure clusters, practical application of seizure cluster terminology, and the potential use of acute seizure action plans and patient-specific individualized definitions in the clinical setting.

Epilepsy-related stigma and attitudes: Systematic review of screening instruments and interventions - Report by the International League Against Epilepsy Task Force on Stigma in Epilepsy.

OBJECTIVE: This is a systematic review aimed at summarizing the evidence related to instruments that have been developed to measure stigma or attitudes toward epilepsy and on stigma-reducing interventions. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. A broad literature search (1985-2019) was performed in 13 databases. Articles were included if they described the development and testing of psychometric properties of an epilepsy-related stigma or attitude scale or stigma-reducing interventions. Two reviewers independently screened abstracts, reviewed full-text articles, and extracted data. Basic descriptive statistics are reported. RESULTS: We identified 4234 abstracts, of which 893 were reviewed as full-text articles. Of these, 38 met inclusion criteria for an instrument development study and 30 as a stigma-reduction intervention study. Most instruments were initially developed using well-established methods and were tested in relatively large samples. Most intervention studies involved educational programs for adults with pre- and post-evaluations of attitudes toward people with epilepsy. Intervention studies often failed to use standardized instruments to quantify stigmatizing attitudes, were generally underpowered, and often found no evidence of benefit or the benefit was not sustained. Six intervention studies with stigma as the primary outcome had fewer design flaws and showed benefit. Very few or no instruments were validated for regional languages or culture, and there were very few interventions tested in some regions. SIGNIFICANCE: Investigators in regions without instruments should consider translating and further developing existing instruments rather than initiating the development of new instruments. Very few stigma-reduction intervention studies for epilepsy have been conducted, study methodology in general was poor, and standardized instruments were rarely used to measure outcomes. To accelerate the development of effective epilepsy stigma-reduction interventions, a paradigm shift from disease-specific, siloed trials to collaborative, cross-disciplinary platforms based upon unified theories of stigma transcending individual conditions will be needed.

Psychogenic nonepileptic seizures during the COVID-19 pandemic in New York City - A distinct response from the epilepsy experience.

Although psychogenic nonepileptic seizures (PNES) are a common neurologic condition, there remains a paucity of literature on the COVID-19 pandemic's effect on these patients. Using a cross-sectional questionnaire study, our group examined the experience of patients with PNES at a single Comprehensive Epilepsy Center in New York City, the epicenter of the initial COVID-19 outbreak in the United States. Among our cohort of 18 subjects with PNES, 22.2% reported an improvement in seizure control during the peak of the COVID-19 pandemic in New York City. Compared to the cohort of subjects with epilepsy without PNES, subjects with PNES were significantly more likely to report an improvement (p = 0.033). Our findings signal that sleep and stress may be relevant variables in both conditions that should be further investigated and potentially intervened upon. Larger dedicated studies of patients with PNES are needed to understand the impact of the pandemic's widespread societal effects on these patients.

Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors.

ARFGEF1 encodes a guanine exchange factor involved in intracellular vesicle trafficking, and is a candidate gene for childhood genetic epilepsies. To model ARFGEF1 haploinsufficiency observed in a recent Lennox Gastaut Syndrome patient, we studied a frameshift mutation (Arfgef1fs) in mice. Arfgef1fs/+ pups exhibit signs of developmental delay, and Arfgef1fs/+ adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the Arfgef1fs/+ brain exhibits a disruption in the apical lining of the dentate gyrus and altered spine morphology of deep layer neurons. In primary hippocampal neuron culture, dendritic surface and synaptic but not total GABAA receptors (GABAAR) are reduced in Arfgef1fs/+ neurons with an accompanying decrease in the number of GABAAR-containing recycling endosomes in cell body. Arfgef1fs/+ neurons also display differences in the relative ratio of Arf6+:Rab11+:TrfR+ recycling endosomes. Although the GABAAR-containing early endosomes in Arfgef1fs/+ neurons are comparable to wildtype, Arfgef1fs/+ neurons show an increase in the number of GABAAR-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABAAR results suggests a mechanism whereby impaired neuronal inhibition leads to seizure susceptibility.

Behavioral interventions in epilepsy.

PURPOSE OF REVIEW: Behavioral intervention describes multiple modalities of treatments which are of increasing interest in epilepsy. This review addresses recent behavioral clinical trials in epilepsy including cognitive behavioral therapy (CBT), mindfulness, progressive muscle relaxation (PMR), and self-management. Results and conclusions from updated Cochrane reviews and the recent International League Against Epilepsy Psychology task force are presented. RECENT FINDINGS: Two recent large randomized controlled trials (mindfulness and progressive muscle relaxation) reported improved seizure frequency with behavioral treatments. In both studies, participants in both the active and the attentional control arms showed significant seizure reduction, whereas quality of life and stress reduction were better noted in the active arms. Additional behavioral modalities have reported improved seizure control including yoga, bio/neurofeedback, and music therapy.Significant improvements in multiple quality of life, cognitive domains, and medication adherence have been reported from randomized and open label trials of cognitive behavioral therapy, and self-management programs. Multiple promising self-management programs have been recently reported, often utilizing the power of web-based apps, and digitally delivered group therapy. In 2018, the International League Against Epilepsy Psychology task force recommended that 'psychological interventions should be incorporated into comprehensive epilepsy care.' SUMMARY: Behavioral treatments are successful and likely underutilized in the treatment of epilepsy. Given the challenge of conducting randomized clinical trials of behavioral therapy, much remains to be studied. However, for motivated and interested patients, appropriately chosen behavioral therapies appear to be important adjuncts to standard therapy. The timing is currently optimal to take best advantage of smartphone apps and web-based delivery systems, both for research and therapeutic purposes.

De novo mutations in epileptic encephalopathies.

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

Instruction manual for the ILAE 2017 operational classification of seizure types.

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

Clinical characterization of the pre-ictal state in the pediatric population: A caretaker's perspective.

The unpredictability of seizures causes distress to patients with epilepsy and their caretakers. To date, no studies have explored seizure prediction specifically in the pediatric population. If the period of time preceding a seizure can be reliably identified, either by child or caretaker, there may be a role for pre-emptive interventions. The aim of this study was to investigate caretaker seizure prediction. A questionnaire was distributed to caretakers of patients with epilepsy. The patients were 0-21years old and experienced ≥1 seizure within the past year. We excluded patients with non-epileptic seizures or daily seizures. One hundred and fifty of 240 questionnaires met criteria. Of these, 32 (21.6%) caretakers indicated a positive report of seizure prediction. Age of seizure onset was earlier in the positive predictive group (3.3±3.3years) than in the non-predictor group (5.3±4.8years) (p=0.01). The most common pre-ictal symptoms reported were being tired, hazy look, and sleepiness. A total of 76.6% of caretakers reported at least one seizure precipitant. The prevalence of positive caretaker seizure prediction in this study is similar to that of seizure self-prediction in adult studies. These findings will be used to design prospective online or electronic diary studies to further investigate the caretaker's, as well as children's, perspectives on seizure prediction. We anticipate that this investigation may lead to novel treatments during times of high seizure risk.

Termination of seizure clusters is related to the duration of focal seizures.

OBJECTIVE: Clustered seizures are characterized by shorter than usual interseizure intervals and pose increased morbidity risk. This study examines the characteristics of seizures that cluster, with special attention to the final seizure in a cluster. METHODS: This is a retrospective analysis of long-term inpatient monitoring data from the EPILEPSIAE project. Patients underwent presurgical evaluation from 2002 to 2009. Seizure clusters were defined by the occurrence of at least two consecutive seizures with interseizure intervals of <4 h. Other definitions of seizure clustering were examined in a sensitivity analysis. Seizures were classified into three contextually defined groups: isolated seizures (not meeting clustering criteria), terminal seizure (last seizure in a cluster), and intracluster seizures (any other seizures within a cluster). Seizure characteristics were compared among the three groups in terms of duration, type (focal seizures remaining restricted to one hemisphere vs. evolving bilaterally), seizure origin, and localization concordance among pairs of consecutive seizures. RESULTS: Among 92 subjects, 77 (83%) had at least one seizure cluster. The intracluster seizures were significantly shorter than the last seizure in a cluster (p = 0.011), whereas the last seizure in a cluster resembled the isolated seizures in terms of duration. Although focal only (unilateral), seizures were shorter than seizures that evolved bilaterally and there was no correlation between the seizure type and the seizure position in relation to a cluster (p = 0.762). Frontal and temporal lobe seizures were more likely to cluster compared with other localizations (p = 0.009). Seizure pairs that are part of a cluster were more likely to have a concordant origin than were isolated seizures. Results were similar for the 2 h definition of clustering, but not for the 8 h definition of clustering. SIGNIFICANCE: We demonstrated that intracluster seizures are short relative to isolated seizures and terminal seizures. Frontal and temporal lobe seizures are more likely to cluster.

Benzodiazepine use in seizure emergencies: A systematic review.

PURPOSE: The aim of this review was to systematically examine safety and efficacy outcomes, as well as patient/caregiver satisfaction, from clinical studies in pediatric and adult patients treated with benzodiazepines (BZDs) through various administration routes in response to seizure emergencies. METHODS: A literature search was conducted to identify articles describing the use of various routes of administration (RoAs) of BZDs for the treatment of seizure emergencies through April 21, 2015, using Embase™ and PubMed®. Eligible studies included (a) randomized controlled trials or (b) controlled nonrandomized clinical trials, either retrospective or prospective. Outcome assessments reviewed were 1) time to administration, 2) time to seizure termination, 3) rate of treatment failure, 4) prevention of seizure recurrence, 5) patient and caregiver treatment satisfaction, 6) adverse events related to BDZ treatment or RoA, and 7) respiratory adverse events. RESULTS: Seventy-five studies evaluated safety and efficacy using individual or comparator BDZs of various RoAs for treating seizure emergencies in all-aged patients with epilepsy. Buccal, intranasal (IN), or intramuscular (IM) BZDs were often more rapidly administered compared with rectal and intravenous (IV) formulations. Time to seizure termination, seizure recurrence rates, and adverse events were generally similar among RoAs, whereas nonrectal RoAs resulted in greater patient and caregiver satisfaction compared with rectal RoA. SIGNIFICANCE: Results of this systematic literature review suggest that nonrectal and non-IV BZD formulations provide equal or improved efficacy and safety outcomes compared with rectal and IV formulations for the treatment of seizure emergencies.

Seizure clusters: characteristics and treatment.

PURPOSE OF REVIEW: Many patients with epilepsy experience 'clusters' or flurries of seizures, also termed acute repetitive seizures (ARS). Seizure clustering has a significant impact on health and quality of life. This review summarizes recent advances in the definition and neurophysiologic understanding of clustering, the epidemiology and risk factors for clustering and both inpatient and outpatient clinical implications. New treatments for seizure clustering/ARS are perhaps the area of greatest recent progress. RECENT FINDINGS: Efforts have focused on creating a uniform definition of a seizure cluster. In neurophysiologic studies of refractory epilepsy, seizures within a cluster appear to be self-triggering. Clinical progress has been achieved towards a more precise prevalence of clustering, and consensus guidelines for epilepsy monitoring unit safety. The greatest recent advances are in the study of nonintravenous route of benzodiazepines as rescue medications for seizure clusters/ARS. Rectal benzodiazepines have been very effective but barriers to use exist. New data on buccal, intramuscular and intranasal preparations are anticipated to lead to a greater number of approved treatments. Progesterone may be effective for women who experience catamenial clusters. SUMMARY: Seizure clustering is common, particularly in the setting of medically refractory epilepsy. Clustering worsens health and quality of life, and the field requires greater focus on clarifying of definition and clinical implications. Progress towards the development of nonintravenous routes of benzodiazepines has the potential to improve care in this area.

Childhood trauma in patients with self-reported stress-precipitated seizures.

OBJECTIVE: Stress is the most commonly reported precipitant of epileptic seizures, but the mechanism by which stress precipitates seizures and the risk factors for stress as a seizure precipitant are poorly understood. Previously, we observed higher levels of anxiety symptoms in patients with epilepsy who reported stress as a seizure precipitant. Given that childhood trauma increases the risk of general psychiatric symptom burden, including anxiety symptoms, we sought to examine the relationship between childhood adversity and stress as a seizure precipitant. METHODS: Sequential outpatients (N=236) evaluated at the Epilepsy Center of the University of Cincinnati Neuroscience Institute who had previously enrolled in an earlier study of stress and seizures were enrolled. Subjects either endorsed stress as a seizure precipitant [Stress (+)] or not [Stress (-)]. The Childhood Trauma Questionnaire Short Form (CTQ-SF), a 28-question scale that evaluates 5 domains of childhood adversity (physical abuse, physical neglect, emotional abuse, emotional neglect, and sexual abuse) was sent via mail and returned on paper or electronically from participants. Total CTQ-SF score and CTQ-SF domain scores were compared between Stress (+) and Stress (-) groups using Wilcoxon rank sum test. Spearman's rank correlation between CTQ-SF scores with depression and anxiety was also determined, and these analyses were followed by a multivariate analysis to identify the association of childhood trauma with other factors including anxiety and depression. RESULTS: A total of 119 out of 236 CTQ-SFs that were sent out were completed. Response rates were 91/195 for Stress (+) and 28/41 for Stress (-). The Stress (+) group reported higher scores in emotional abuse compared with the Stress (-) group (p=0.029); CTQ-SF total scores were higher in the Stress (+) group compared with the Stress (-) group (p=0.08), and sexual abuse scores were higher in Stress (+) group (p=0.07), but there were no statistically significant differences for other types of trauma. Depression and anxiety scores were higher in the Stress (+) group, but anxiety was the only independent factor associated with the Stress (+) group in the multivariate analysis (p=0.0021). CONCLUSION: Patients with epilepsy who report stress as a seizure precipitant are more likely to endorse a history of childhood traumatic experiences, particularly emotional abuse, compared with those who do not perceive stress as a precipitant. Further study is needed to identify how childhood trauma interacts with anxiety in modulating stress response in patients with epilepsy.

Methodological issues in studying trigger factors and premonitory features of migraine.

OBJECTIVE: In this review, we focus on migraine as a chronic disorder with episodic attacks (CDEA). We aim to review methodological approaches to studying trigger factors and premonitory features that often precede a migraine attack. BACKGROUND: Migraine attacks are sometimes initiated by trigger factors, exposures which increase the probability of an attack. They are heralded by premonitory features, symptoms which warn of an impending attack. DESIGN/METHODS: We review candidate predictors of migraine attack and discuss the methodological issues and approaches to studying attack prediction and suggest that electronic diaries may be the method of choice. CONCLUSION: Establishing the relationship between antecedent events and headaches is a formidable challenge. Successfully addressing this challenge should provide insights into disease mechanisms and lead to new strategies for treatment. In the second paper in this series, we review the available literature on trigger factors and premonitory features.

Characteristics of people with self-reported stress-precipitated seizures.

OBJECTIVE: Stress is the most common patient-reported seizure precipitant. We aimed to determine mood and epilepsy characteristics of people who report stress-precipitated seizures. METHODS: Sequential patients at a tertiary epilepsy center were surveyed about stress as a seizure precipitant. We asked whether acute (lasting minutes-hours) or chronic (lasting days-months) stress was a seizure precipitant, whether stress reduction had been tried, and what effect stress reduction had on seizure frequency. We collected information on antiepileptic drugs, history of depression and anxiety disorder, prior or current treatment for depression or anxiety, and scores on the Neurological Disorders Depression Inventory (NDDI-E) and Generalized Anxiety Disorders-7 (GAD-7) instruments, which are administered at every visit in our Epilepsy Center. We also asked whether respondents thought that they could predict their seizures to determine if stress as a seizure precipitant was correlated with seizure self-prediction. RESULTS: Two hundred sixty-six subjects were included: 219 endorsed stress as a seizure precipitant [STRESS (+)] and 47 did not [STRESS (-)]. Among STRESS (+) subjects, 85% endorsed chronic stress as a seizure precipitant, and 68% endorsed acute stress as a seizure precipitant. In STRESS (+) subjects, 57% had used some type of relaxation or stress reduction method (most commonly yoga, exercise and meditation), and, of those who tried, 88% thought that these methods improved seizures. Among STRESS (-) subjects, 25% had tried relaxation or stress reduction, and 71% thought that seizures improved. Although univariate analysis showed multiple associations with stress as a seizure precipitant, in the multivariable logistic regression, only the GAD-7 score was associated with STRESS (+) (OR = 1.18 [1.03-1.35], p = 0.017). Subjects who reported stress as a seizure precipitant were more likely to report an ability to self-predict seizures (p < 0.001). CONCLUSION: Stress-precipitated seizures are commonly reported by patients, may be associated with either acute stress or chronic stress, and are associated with higher scores on anxiety tests. Patients frequently use stress reduction methods to self-treat and report high success rates. A prospective, randomized trial of stress reduction for seizures is indicated.

Modeling seizure self-prediction: an e-diary study.

PURPOSE: A subset of patients with epilepsy successfully self-predicted seizures in a paper diary study. We conducted an e-diary study to ensure that prediction precedes seizures, and to characterize the prodromal features and time windows that underlie self-prediction. METHODS: Subjects 18 or older with localization-related epilepsy (LRE) and ≥3 seizures per month maintained an e-diary, reporting a.m./p.m. data daily, including mood, premonitory symptoms, and all seizures. Self-prediction was rated by, "How likely are you to experience a seizure (time frame)?" Five choices ranged from almost certain (>95% chance) to very unlikely. Relative odds of seizure (odds ratio, OR) within time frames was examined using Poisson models with log normal random effects to adjust for multiple observations. KEY FINDINGS: Nineteen subjects reported 244 eligible seizures. OR for prediction choices within 6 h was as high as 9.31 (CI 1.92-45.23) for "almost certain." Prediction was most robust within 6 h of diary entry, and remained significant up to 12 h. For nine best predictors, average sensitivity was 50%. Older age contributed to successful self-prediction, and self-prediction appeared to be driven by mood and premonitory symptoms. In multivariate modeling of seizure occurrence, self-prediction (2.84; CI 1.68-4.81), favorable change in mood (0.82; CI 0.67-0.99), and number of premonitory symptoms (1.11; CI 1.00-1.24) were significant. SIGNIFICANCE: Some persons with epilepsy can self-predict seizures. In these individuals, the odds of a seizure following a positive prediction are high. Predictions were robust, not attributable to recall bias, and were related to self-awareness of mood and premonitory features. The 6-h prediction window is suitable for the development of preemptive therapy.

Toward new paradigms of seizure detection.

Great effort has been made toward defining and characterizing the pre-ictal state. Many studies have pursued the idea that there are recognizable electrographic (EEG-based) features which occur before overt clinical seizure activity. However, development of reliable EEG-based seizure detection and prediction algorithms has been difficult. In this review, we discuss the concepts of seizure detection vs. prediction and the pre-ictal "clinical milieu" and "EEG milieu". We proceed to discuss novel concepts of seizure detection based on the pre-ictal "physiological milieu"; in particular, we indicate some early evidence for the hypothesis that pre-ictal cell swelling/extracellular space constriction can be detected with novel optical methods. Development and validation of optical seizure detection technology could provide an entirely new translational approach for the many patients with intractable epilepsy.

Clinical features of the pre-ictal state: mood changes and premonitory symptoms.

Identifying the pre-ictal state clinically would improve our understanding of seizure onset and suggest opportunities for new treatments. In our previous paper-diary study, increased stress and less sleep predicted seizures. Utilizing electronic diaries, we expanded this investigation. Variables were identified by their association with subsequent seizure using logit-normal random effects models fit by maximum likelihood. Nineteen subjects with localization-related epilepsy kept e-diaries for 12-14 weeks and reported 244 eligible seizures. In univariate models, several mood items and ten premonitory features were associated with increased odds of seizure over 12h. In multivariate models, a 10-point improvement in total mood decreased seizure risk by 25% (OR 0.75, CI 0.61-0.91, p=004) while each additional significant premonitory feature increased seizure risk by nearly 25% (OR 1.24, CI 1.13-1.35, p<001) over 12h. Pre-ictal changes in mood and premonitory features may predict seizure occurrence and suggest a role for behavioral intervention and pre-emptive therapy in epilepsy.

Behavioral intervention as an add-on therapy in epilepsy: designing a clinical trial.

Many patients with epilepsy continue to experience seizures despite taking medication, and stress is a commonly reported trigger for seizures in these individuals. Therefore, a behavioral therapy proven to be effective in epilepsy could be a valuable adjunct to current pharmacotherapy. The challenges in testing such a behavioral intervention for epilepsy are numerous, including lack of consensus about sham designs, maintaining the blind, and powering the study absent known effect sizes. Herein, we present the design of a randomized, controlled, double-blind trial of progressive muscle relaxation as an add-on therapy for refractory epilepsy. Progressive muscle relaxation, which involves the tensing and releasing of muscle groups one at a time, is a well-established technique that relaxes the body and mind, reduces stress, and may improve seizure control. Study design issues discussed may provide insights that will inform future behavioral research in epilepsy.

Factors associated with patients not proceeding with proposed resective epilepsy surgery.

BACKGROUND: This study evaluated the association between eligible patients not proceeding with resective epilepsy surgery and various demographic, disease-specific, and epilepsy-evaluation variables. METHODS: This retrospective case-control study included patients identified as candidates for resective epilepsy surgery at the Montefiore Medical Center between January 1, 2009 and June 30, 2017. Chi-squared, two-tailed, independent sample t-test, Mann-Whitney U test and logistic regression were utilized to identify variables associated with patients not proceeding with surgery. RESULTS: Among the 159 potential surgical candidates reviewed over the 8.5-year study period, only 53 ultimately proceeded with surgery (33%). Eighty-seven (55%) out of these 159 patients were identified as appropriate for resective epilepsy surgery during the study period. Thirty-four (39%) of these 87 patients did not proceed with surgery. Variables independently correlated (either positively or negatively) with the patient not proceeding with surgery were: being employed [Odds Ratio (OR) 4.2, 95% confidence interval (CI) 1.12-15.73], temporal lobe lesion on MRI (OR 0.35, 95% CI 0.14-0.84), temporal lobe EEG ictal onsets (OR 0.21, 95% CI 0.07-0.62), and temporal lobe epileptogenic zone (OR 0.19, 95% CI 0.07-0.55). CONCLUSION: The novel finding in this study is the association between employment status and whether the patient had epilepsy surgery: employed patients were 4.2 times more likely to not proceed with surgery compared to unemployed patients. In addition, patients with a temporal lobe lesion on MRI, temporal lobe EEG ictal onsets, and/or a temporal epileptogenic zone were more likely to proceed with surgery. Future work will be needed to evaluate these findings prospectively, determine if they generalize to other patient populations, explore the decision whether or not to proceed with epilepsy surgery from a patient-centered perspective, and suggest strategies to reduce barriers to this underutilized treatment.