Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Interictal dysphoric disorder in people with and without epilepsy.

OBJECTIVE: Interictal dysphoric disorder (IDD) has been regarded as an affective disorder occurring only in people with epilepsy (PWE). Data showing similar characteristics and similar prevalence of IDD in patients with migraine and with psychogenic nonepileptic seizures question the epilepsy-specific nature of IDD. The aim of the study was to investigate the nature of IDD in people with prevalent epilepsy with mood disorders and people with mood disorders who are free of neurological disease. METHODS: This is a case-control study, with 142 patients with a confirmed diagnosis of epilepsy and major depressive disorder (MDD; cases) and 222 patients with MDD only (controls). MDD diagnosis was confirmed by a structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition (SCID-I-RV). We used the Beck Depression Inventory and the Beck Anxiety Inventory to estimate anxiety and depression levels and the Interictal Dysphoric Disorder Inventory (IDDI) to confirm the presence of IDD. Mann-Whitney U test, Pearson chi-squared, Spearman correlation, and logistic regression were used. RESULTS: No differences were found in the prevalence of IDD between PWE with MDD and people with MDD alone (88.73% vs. 85.13%, χ2 = .96, p = .32). There were no differences between the groups overall or for any IDDI subscales (all p > .05). In both groups, IDD symptoms were grouped with the same incidence and had the same duration and periodicity. IDD was not associated with epilepsy (odds ratio = .84, 95% confidence interval = .40-1.98, p = .72). No significant correlation was found between epilepsy, demographic characteristics, and all IDDI subscales (all p > .05). Notably, patients with IDD suffered from affective disorders longer (6.68 ± 6.82 years vs. 3.7 ± 3.97 years, p = .001) and also received higher scores on all psychometric scales (all p < .05). SIGNIFICANCE: This study does not confirm the specificity of IDD for epilepsy. The presence of IDD symptoms may be associated with a more severe course of MDD and significant anxiety distress.

Genetic attribution and perceived impact of epilepsy in multiplex epilepsy families.

OBJECTIVE: Studies have found that affected individuals who believe the cause of their disorder is genetic may react in various ways, including optimism for improved treatments and pessimism due to perceived permanence of the condition. This study assessed the psychosocial impact of genetic attribution among people with epilepsy. METHODS: Study participants were 165 persons with epilepsy from multiplex epilepsy families who completed a self-administered survey. Psychosocial impact of epilepsy was assessed with the Impact of Epilepsy Scale, containing items about relationships, employment, overall health, self-esteem, and standard of living. Genetic attribution was assessed using a scale derived from three items asking about the role of genetics in causing epilepsy in the family, the chance of having an epilepsy-related mutation, and the influence of genetics in causing the participant's epilepsy. We estimated prevalence ratios (PRs) for impact of epilepsy above the median using Poisson regression with robust standard errors, adjusting for number of lifetime seizures and time since last seizure. RESULTS: Participants' age averaged 51 years; 87% were non-Hispanic white, 63% were women, and 54% were college graduates. The genetic attribution scale was significantly associated with having a high impact of epilepsy (adjusted PR = 1.4, 95% confidence interval = 1.07-1.91, P = .02). One of the three genetic attribution questions was also significantly associated with a high impact of epilepsy (belief that genetics had a big role in causing epilepsy in the family, adjusted PR = 1.8). SIGNIFICANCE: These findings reflect an association between the psychosocial impact of epilepsy and the belief that epilepsy has a genetic cause, among people with epilepsy in families containing multiple affected individuals. This association could arise either because belief in a genetic cause leads to increased psychosocial impacts, or because a greater psychosocial impact of epilepsy leads some to believe their epilepsy is genetic.

Automated detection of sudden unexpected death in epilepsy risk factors in electronic medical records using natural language processing.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an important cause of mortality in epilepsy. However, there is a gap in how often providers counsel patients about SUDEP. One potential solution is to electronically prompt clinicians to provide counseling via automated detection of risk factors in electronic medical records (EMRs). We evaluated (1) the feasibility and generalizability of using regular expressions to identify risk factors in EMRs and (2) barriers to generalizability. METHODS: Data included physician notes for 3000 patients from one medical center (home) and 1000 from five additional centers (away). Through chart review, we identified three SUDEP risk factors: (1) generalized tonic-clonic seizures, (2) refractory epilepsy, and (3) epilepsy surgery candidacy. Regular expressions of risk factors were manually created with home training data, and performance was evaluated with home test and away test data. Performance was evaluated by sensitivity, positive predictive value, and F-measure. Generalizability was defined as an absolute decrease in performance by <0.10 for away versus home test data. To evaluate underlying barriers to generalizability, we identified causes of errors seen more often in away data than home data. To demonstrate how small revisions can improve generalizability, we removed three "boilerplate" standard text phrases from away notes and repeated performance. RESULTS: We observed high performance in home test data (F-measure range = 0.86-0.90), and low to high performance in away test data (F-measure range = 0.53-0.81). After removing three boilerplate phrases, away performance improved (F-measure range = 0.79-0.89) and generalizability was achieved for nearly all measures. The only significant barrier to generalizability was use of boilerplate phrases, causing 104 of 171 errors (61%) in away data. SIGNIFICANCE: Regular expressions are a feasible and probably a generalizable method to identify variables related to SUDEP risk. Our methods may be implemented to create large patient cohorts for research and to generate electronic prompts for SUDEP counseling.

Timing of suicide in people with epilepsy: A population-based study from 18 states of the United States, 2003-2014.

Suicide timing varies across several psychiatric disorders, which may share common underlying pathophysiological mechanisms with epilepsy. We investigated suicide timing in people with epilepsy. Using cross-sectional, population-based U.S. National Violent Death Reporting System data from 2003 through 2014 in 18 States, we identified 1310 suicides with epilepsy and 102,582 suicides without epilepsy among those 10 years and older. We compared patterns of suicide mortality ratios between those with and without epilepsy by month of year, week of month, day of week, time of day, and overall by age, sex, and race/ethnicity. As the suicide patterns seen among persons without epilepsy, suicides in persons with epilepsy occurred significantly more often during the morning, afternoon, and evening hours than at night in all subgroups except females. Compared to Sundays, suicides in persons with epilepsy were only significantly increased on Mondays and Tuesdays in those aged ≥45 years and only on Mondays in men. This pattern differs from persons without epilepsy whose suicides significantly increased on Mondays and significantly decreased on Saturdays in nearly all study subgroups. Suicides in persons with epilepsy did not exhibit the timing patterns of persons without epilepsy by week of month (significant decreases from the third to fifth weeks compared to the first week among those aged ≥45 years, males, and Non-Hispanic whites) and month of year (significant increases from January to November peaking from June to September compared to December in all study groups). Compared to the general population or people without epilepsy, previous and current studies suggest that in people with epilepsy, suicide timing differs from and suicide rates significantly exceed those in people without epilepsy. Preventing suicide in people with epilepsy should focus not only on the peak times of occurrence but also across all time periods.

Migraine comorbidity and cognitive performance in patients with focal epilepsy.

BACKGROUND: Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. METHODS: This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). RESULTS: About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. CONCLUSION: In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.

Comorbidities of Rare Epilepsies: Results from the Rare Epilepsy Network.

OBJECTIVE: To describe the prevalence and characteristics of comorbidities in persons with rare epilepsies. STUDY DESIGN: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities. Comorbidity information was grouped into 15 classes, 12 of which had a stem question followed by detailed branch questions and 3 that were created from a combination of related questions. RESULTS: Of 795 persons with more than 30 different rare epilepsy diagnosis groups, one-half had ≥5 comorbidity classes and 97% were classified as complex chronic disease (C-CD). The highest number of comorbidity classes reported per person were persons with Aicardi syndrome, Phelan-McDermid syndrome (median, 7.0; IQR, 5.0-9.0), and tuberous sclerosis complex (median, 6.0; IQR, 4.0-8.0). The most common comorbidity classes were learning/developmental disability (71%), mental health issues (71%), sleep disorders (60%), brain abnormalities (52%), oral issues (49%), bone-joint issues (42%), hyper/hypotonia (42%), and eye-vision disorders (38%). The prevalence of brain abnormalities, hyper/hypotonia, eye, and cardiac disorders was significantly higher in persons first diagnosed with epilepsy at a younger age (<9 months) than in those first diagnosed at an older age (P < .05 for trend). CONCLUSIONS: Nearly all persons with rare epilepsies are medically complex, with a high prevalence of multiple comorbidities, especially those who were diagnosed with epilepsy in the first year of life. Comorbidities should be carefully considered in the diagnosis and management of persons with rare epilepsies.

Resolving ambiguities in SUDEP classification.

OBJECTIVE: To examine the consistency of applying the Nashef et al (2012) criteria to classify sudden unexpected death in epilepsy (SUDEP). METHODS: We reviewed cases from the North American SUDEP Registry (n = 250) and Medical Examiner Offices (n = 1301: 698 Maryland, 457 New York City, 146 San Diego). Two epileptologists with expertise in SUDEP and epilepsy-related mortality independently reviewed medical records, scene investigation, autopsy, and toxicology and assigned a SUDEP class. RESULTS: Major areas of disagreement arose between adjudicators concerned differentiating (1) Definite SUDEP Plus Comorbidity from Possible SUDEP and (2) Resuscitated (Near) SUDEP from SUDEP. In many cases, distinguishing between contributing and competing causes of death when trying to classify Definite SUDEP Plus Comorbidity versus Possible SUDEP is ambiguous and relies on judgement. Similarly, determining if an intervention was lifesaving or not (Resuscitated SUDEP or Not SUDEP), or if resuscitation merely delayed SUDEP (Resuscitated SUDEP or SUDEP) is often a judgement call and can differ between experienced adjudicators. Given these persisting ambiguities, we propose more explicit criteria for distinguishing these categories. SIGNIFICANCE: Accurate and consistent classification of cause of death among individuals with epilepsy remains a dire public health concern. SUDEP is likely underestimated in national health statistics. Greater standardization of criteria among epilepsy researchers, medical examiners, and epidemiologists to determine cause and classify death will lead to more accurate tracking of SUDEP and other epilepsy-related mortalities.

Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy.

OBJECTIVE: Limited data are available regarding the evolution over time of the rate of sudden unexpected death in epilepsy patients (SUDEP) in drug-resistant epilepsy. The objective is to analyze a database of 40 443 patients with epilepsy implanted with vagus nerve stimulation (VNS) therapy in the United States (from 1988 to 2012) and assess whether SUDEP rates decrease during the postimplantation follow-up period. METHODS: Patient vital status was ascertained using the Centers for Disease Control and Prevention's National Death Index (NDI). An expert panel adjudicated classification of cause of deaths as SUDEP based on NDI data and available narrative descriptions of deaths. We tested the hypothesis that SUDEP rates decrease with time using the Mann-Kendall nonparametric trend test and by comparing SUDEP rates of the first 2 years of follow-up (years 1-2) to longer follow-up (years 3-10). RESULTS: Our cohort included 277 661 person-years of follow-up and 3689 deaths, including 632 SUDEP. Primary analysis demonstrated a significant decrease in age-adjusted SUDEP rate during follow-up (S = -27 P = .008), with rates of 2.47/1000 for years 1-2 and 1.68/1000 for years 3-10 (rate ratio 0.68; 95% confidence interval [CI] 0.53-0.87; P = .002). Sensitivity analyses confirm these findings. SIGNIFICANCE: Our data suggest that SUDEP risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study.

Dead in the water: Epilepsy-related drowning or sudden unexpected death in epilepsy?

OBJECTIVE: Both drowning and sudden unexpected death in epilepsy (SUDEP) are diagnoses of exclusion with predominantly nonspecific autopsy findings. We hypothesized that people with epilepsy found dead in water with no clear sign of submersion could be misdiagnosed as SUDEP. METHODS: All reported seizure-related deaths undergoing medicolegal investigation in three medical examiner's offices (New York City, Maryland, San Diego County) over different time periods were reviewed to identify epilepsy-related drownings and SUDEPs. Drowning cases that fulfilled inclusion criteria were divided into two groups according to the circumstances of death: definite drowning and possible drowning. The SUDEP group included two sex- and age (±2 years)-matched definite SUDEP/definite SUDEP plus cases for each drowning case. RESULTS: Of 1346 deaths reviewed, we identified 36 definite (76.6%) and 11 possible drowning deaths (23.4%), most of which occurred in a bathtub (72.3%). There were drowning-related findings, including fluid within the sphenoid sinuses, foam in the airways, clear fluid in the stomach content, and lung hyperinflation in 58.3% (21/36) of the definite drowning group, 45.5% (5/11) of the possible drowning group, and 4.3% of the SUDEP group (4/92). There was no difference in the presence of pulmonary edema/congestion between the definite drowning group, possible drowning group, and SUDEP group. The definite drowning group had a higher mean combined lung weight than the SUDEP group, but there was no difference in mean lung weights between the possible drowning and SUDEP groups or between the possible drowning and definite drowning groups. SIGNIFICANCE: No distinguishable autopsy finding could be found between SUDEPs and epilepsy-related drownings when there were no drowning-related signs and no clear evidence of submersion. SUDEP could be the cause of death in such possible drowning cases. As most drowning cases occurred in the bathtub, supervision and specific bathing precautions could be effective prevention strategies.

The primary prevention of epilepsy: A report of the Prevention Task Force of the International League Against Epilepsy.

Among the causes of epilepsy are several that are currently preventable. In this review, we summarize the public health burden of epilepsy arising from such causes and suggest priorities for primary epilepsy prevention. We conducted a systematic review of published epidemiologic studies of epilepsy of 4 preventable etiologic categories-perinatal insults, traumatic brain injury (TBI), central nervous system (CNS) infection, and stroke. Applying consistent criteria, we assessed the quality of each study and extracted data on measures of risk from those with adequate quality ratings, summarizing findings across studies as medians and interquartile ranges. Among higher-quality population-based studies, the median prevalence of active epilepsy across all ages was 11.1 per 1000 population in lower- and middle-income countries (LMIC) and 7.0 per 1000 in high-income countries (HIC). Perinatal brain insults were the largest attributable fraction of preventable etiologies in children, with median estimated fractions of 17% in LMIC and 15% in HIC. Stroke was the most common preventable etiology among older adults with epilepsy, both in LMIC and in HIC, accounting for half or more of all new onset cases. TBI was the attributed cause in nearly 5% of epilepsy cases in HIC and LMIC. CNS infections were a more common attributed cause in LMIC, accounting for about 5% of all epilepsy cases. Among some rural LMIC communities, the median proportion of epilepsy cases attributable to endemic neurocysticercosis was 34%. A large proportion of the overall public health burden of epilepsy is attributable to preventable causes. The attributable fraction for perinatal causes, infections, TBI, and stroke in sum reaches nearly 25% in both LMIC and HIC. Public health interventions addressing maternal and child health care, immunizations, public sanitation, brain injury prevention, and stroke prevention have the potential to significantly reduce the burden of epilepsy.

National Association of Medical Examiners position paper: Recommendations for the investigation and certification of deaths in people with epilepsy.

Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor. To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths. The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered.

Pharmacotherapy in patients with epilepsy and psychosis.

The recognition and treatment of psychosis in persons with epilepsy (PWE) is recommended with the apparent dilemma between treating psychosis and opening the possibility of exacerbating seizures. The pooled prevalence estimate of psychosis in PWE is 5.6%. It has been proposed that a 'two hit' model, requiring both aberrant limbic activity and impaired frontal control, may account for the wide range of clinical phenotypes. The role of antiepileptic drugs in psychosis in PWE remains unclear. Alternating psychosis, the clinical phenomenon of a reciprocal relationship between psychosis and seizures, is unlikely to be an exclusively antiepileptic drug-specific phenomenon but rather, linked to the neurobiological mechanisms underlying seizure control. Reevaluation of antiepileptic treatment, including the agent/s being used and degree of epileptic seizure control is recommended. The authors found very few controlled studies to inform evidence-based treatment of psychosis in PWE. However, antipsychotics and benzodiazepines are recommended as the symptomatic clinical treatments of choice for postictal and brief interictal psychoses. The general principle of early symptomatic treatment of psychotic symptoms applies in epilepsy-related psychoses, as for primary psychotic disorders. In the authors' experience, low doses of antipsychotic medications do not significantly increase clinical risk of seizures in PWE being concurrently treated with an efficacious antiepileptic regimen.

Social and psychological consequences of not crying: possible associations with psychopathology and therapeutic relevance.

OBJECTIVE: Emotional crying is hypothesized to serve intra- and interpersonal functions. Intrapersonal functions are assumed to facilitate the capacity to recover from emotional distress, thus promoting well-being. Interpersonal functions are postulated to have a major impact on social functioning. We hypothesized that non-criers would have lower well-being and poorer social functioning than criers. METHODS: Study participants included 475 people who reportedly lost the capacity to cry and 179 "normal" control criers. Applied measures assessed crying, well-being, empathy, attachment, social support, and connection with others. Prevalence estimates of not crying by gender were obtained from a panel survey of 2,000 Dutch households. RESULTS: In the main survey, tearless cases had less connection with others, less empathy, and experienced less social support, but were equal in terms of well-being. They also reported being less moved by emotional stimuli and had a more avoidant and less anxious attachment style. In multivariate analyses, being male, having an avoidant attachment style, and lacking empathy were independent predictors of tearlessness. Some 46.1% felt that not being able to cry affected them negatively; however, despite these findings, only 2.9% had sought any kind of professional help. Loss of the capacity to cry occurred in 8.6% of the men and 6.5% of the women in the large panel survey. CONCLUSIONS: Despite reduced empathy, less connection with others, and a more avoidant/less anxious attachment type, well-being is maintained in tearless people. Additional clinical and therapeutic investigations of tearlessness may lead to clarification of bidirectional associations between psychiatric disorders (e.g., alexithymia, posttraumatic stress disorder, psychopathy) and tearlessness.

Stress is associated with an increased risk of recurrent seizures in adults.

OBJECTIVE: The literature is sparse on the complex interrelationships between stressors, depression, anxiety disorders, and epilepsy. We hypothesized that a relationship exists between stress and epilepsy. We evaluated whether markers of stress are associated with seizure recurrence in a low income community-based cohort of adults with single unprovoked seizure or newly diagnosed epilepsy. METHODS: We ascertained adult residents of Northern Manhattan and Harlem, New York City, with a first unprovoked seizure or newly diagnosed epilepsy, between December 2010 and January 2013. At enrollment, we collected information about seizure phenomenology, demographics, clinical information, and measures of stress (environmental stress, stressful life events, facets of allostatic load-i.e., the cumulative effect of adaptation to stress, psychiatric disorders, and low collective efficacy). Collective efficacy assesses neighborhood characteristics and incorporates social cohesion and informal social control. All subjects were followed for 2 years for further seizures. Cox proportional hazard regression models were used to estimate the hazard ratios of seizure recurrence during the 2 years of follow-up. RESULTS: We identified 52 subjects (64.2%) with a single unprovoked seizure and 29 (35.9%) with newly diagnosed epilepsy. Seizure recurrence was recorded in 38.5% (N = 20) of subjects with a single unprovoked seizure and in 69% of those with epilepsy (N = 20) (p = 0.01). In the overall sample, the hazard of seizure recurrence was increased by lifetime generalized anxiety disorder (3.0-fold) and by low collective efficacy (2.7-fold). In a second model, the hazard was increased by lifetime mood disorder (2.1-fold) and low collective efficacy (2.5-fold). SIGNIFICANCE: Markers of stress (i.e., low collective efficacy, lifetime mood disorder, and lifetime generalized anxiety disorder) were associated with an increased risk for seizure recurrence in adults with a single unprovoked seizure or newly diagnosed epilepsy. Stress-reducing interventions, such as mindfulness, may be a useful, safe, and inexpensive adjunctive treatment for epilepsy.

An evaluation of national birth certificate data for neonatal seizure epidemiology.

OBJECTIVE: Seizures are a common manifestation of neurologic dysfunction in neonates and carry a high risk for mortality and adverse long-term outcomes. U.S. birth certificates are a potentially valuable source for studying the epidemiology of neonatal seizures. However, the quality of the data is understudied. METHODS: We reviewed all U.S. birth records from 2003 to 2013 to describe the following: (1) rates of missing data, (2) evidence of underreporting, and (3) effect of the 2003 revision of the birth certificate form. We evaluated missingness by state, year, demographic, infant health, and medical care factors using bivariate analyses. To measure potential underreporting, we compared estimates to a published reference (0.95 per 1,000 term births). We developed criteria for data plausibility, and reported which states met these criteria. RESULTS: Of 22,834,395 live term births (≥36 weeks of gestation) recorded using the revised form from 2005 to 2015, there were 5,875 with neonatal seizures, suggesting an incidence of 0.26 per 1,000 term births, one fourth of the expected incidence. Although the overall degree of missing seizure data was low (0.5%), missingness varied significantly by state, year, demographic, infant health, and medical care factors. After the 2003 birth certificate form revision, missing data and evidence of potential underreporting increased. Nine states met criteria for plausibility. SIGNIFICANCE: The value of U.S. birth certificate data for neonatal seizure epidemiology is limited by biased missingness, evidence suggestive of underreporting, and changes in reporting subsequent to the 2003 revision. There are plausible data from nine states, which merit investigation for further research.

Premature mortality of epilepsy in low- and middle-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy.

To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low- and middle-income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank-defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7-45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3-7.2) among higher-quality population-based studies. Clinical cohort studies yielded 7.1 (range 1.6-25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5-75.5%) derived from population-based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high-income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.

The burden of premature mortality of epilepsy in high-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy.

Since previous reviews of epidemiologic studies of premature mortality among people with epilepsy were completed several years ago, a large body of new evidence about this subject has been published. We aim to update prior reviews of mortality in epilepsy and to reevaluate and quantify the risks, potential risk factors, and causes of these deaths. We systematically searched the Medline and Embase databases to identify published reports describing mortality risks in cohorts and populations of people with epilepsy. We reviewed relevant reports and applied criteria to identify those studies likely to accurately quantify these risks in representative populations. From these we extracted and summarized the reported data. All population-based studies reported an increased risk of premature mortality among people with epilepsy compared to general populations. Standard mortality ratios are especially high among people with epilepsy aged <50 years, among those whose epilepsy is categorized as structural/metabolic, those whose seizures do not fully remit under treatment, and those with convulsive seizures. Among deaths directly attributable to epilepsy or seizures, important immediate causes include sudden unexpected death in epilepsy (SUDEP), status epilepticus, unintentional injuries, and suicide. Epilepsy-associated premature mortality imposes a significant public health burden, and many of the specific causes of death are potentially preventable. These require increased attention from healthcare providers, researchers, and public health professionals.

Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury.

OBJECTIVE: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. METHODS: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. RESULTS: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1ß levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1ß and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1ß, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1ß or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17-393) of hippocampal T2 hyperintensity after FSE. SIGNIFICANCE: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

Experiences with premorbid SUDEP discussion among participants in the North American SUDEP Registry (NASR).

The North American SUDEP Registry (NASR) is a repository of clinical data and biospecimens in cases of sudden unexpected death in epilepsy (SUDEP), a leading cause of epilepsy-related deaths. We assessed whether bereaved families were aware of SUDEP before their family member's death and their preferences for SUDEP disclosure. At enrollment, next-of-kin of SUDEP cases completed an intake interview, including questions assessing premorbid SUDEP discussions. Only 18.1% of the 138 next-of-kin recalled a previous discussion of SUDEP with a healthcare provider or support resource. Of the 112 who did not recall such a discussion, 72.3% wished it was discussed, 10.7% were satisfied it was not discussed, and 17% were unsure. A history of status epilepticus predicted SUDEP discussion. Rates of SUDEP discussion were not significantly higher among SUDEPs after 2013 (the approximate study midpoint) compared with those before then. Our study suggests that SUDEP remains infrequently discussed with family members of persons with epilepsy. Nearly three-quarters of family members wished they had known of SUDEP before the death. However, some were indifferent or were satisfied that this discussion had not occurred. We must balance more systematic education of patients and families about SUDEP while respecting individual preferences about having this discussion.