Rapid Rescue Treatment with Diazepam Nasal Spray Leads to Faster Seizure Cluster Termination in Epilepsy: An Exploratory Post Hoc Cohort Analysis.

INTRODUCTION: Although prompt treatment of status epilepticus is standard of care, the effect of timing of rescue therapy administration for seizure clusters in epilepsy remains unknown. Seizure clusters are a rare but clinically important condition, and benzodiazepines are the cornerstone rescue therapy for seizure clusters in epilepsy. We characterized temporal patterns from a large dataset of treated seizure clusters in the safety study of diazepam nasal spray. METHODS: This post hoc analysis used timing data of treated seizure clusters recorded by care partners and patients in seizure diaries during a 1-year safety study. Data analysis used time from seizure start to administration of diazepam. RESULTS: From 4466 observations, 3225 had data meeting criteria for analysis. Overall, median times from seizure start to dose administration, dose administration to seizure termination, and total seizure duration were 2, 3, and 7 min, respectively. In seizure clusters treated in < 5 min (median 1.0 min), median time from dose to seizure termination was 2.0 min, and median total seizure duration was 4.0 min. Among seizure clusters treated in ≥ 5 min (median 10.0 min), median time to seizure termination was 10.0 min, and median total seizure duration was 23.0 min. Previously published safety results reported that over a mean participation of 1.5 years, 82.2% of patients had ≥ 1 treatment-emergent adverse events (TEAEs) irrespective of relationship to treatment, including 30.7% with serious TEAEs; 18.4% had TEAEs deemed at least possibly related to the study drug, none of which were serious. There were no events of cardiorespiratory depression. CONCLUSION: Echoing the importance of early use of benzodiazepines in status epilepticus, the findings from this exploratory analysis of patients with refractory epilepsy and frequent seizure clusters identify a potential benefit of early diazepam nasal spray treatment leading to faster seizure resolution within the seizure cluster. Trial Registration Information: ClinicalTrials.gov identifier NCT02721069 ( https://clinicaltrials.gov/ct2/show/NCT02721069 ).

Some people with epilepsy who take daily antiseizure drugs might still have seizures. Some of these seizures may be emergencies that can be treated with rescue medicine. For status epilepticus, rescue treatment should be given as soon as this seizure emergency is recognized. Seizure clusters are rare and might also become emergencies, but until now it had not been clear if earlier treatment would be better. Diazepam nasal spray is a rescue medicine approved to treat seizure clusters. The report used data from a study of the safety of diazepam nasal spray in people needing treatment ≥ 6 times a year. We looked at the time the seizure in a seizure cluster started to the time rescue treatment was given. We also looked at the time from taking rescue treatment to the time when that specific seizure stopped. For some seizure clusters, rescue medicine was given in < 5 min after the seizure started; on average, these seizures stopped within 2 min after rescue treatment. The total time from the start of the seizure in the seizure cluster to when it stopped was 4 min. In contrast, for seizure clusters treated after 5 min, the seizures stopped in an average of 10 min after treatment. Overall, these seizures lasted 23 min. In conclusion, this analysis found that seizures in a seizure cluster ended more quickly when diazepam nasal spray was given sooner. These findings are suggestive that select patients and caregivers should not wait to treat a seizure cluster once it has been identified.

Four State Sleep Staging From a Multilayered Algorithm Using Electrocardiographic and Actigraphic Data.

PURPOSE: Sleep studies are important to evaluate sleep and sleep-related disorders. The standard test for evaluating sleep is polysomnography, during which several physiological signals are recorded separately and simultaneously with specialized equipment that requires a technologist. Simpler recordings that can model the results of a polysomnography would provide the benefit of expanding the possibilities of sleep recordings. METHODS: Using the publicly available sleep data set from the multiethnic study of atherosclerosis and 1769 nights of sleep, we extracted a distinct data subset with engineered features of the biomarkers collected by actigraphic, oxygenation, and electrocardiographic sensors. We then applied scalable models with recurrent neural network and Extreme Gradient Boosting (XGBoost) with a layered approach to produce an algorithm that we then validated with a separate data set of 177 nights. RESULTS: The algorithm achieved an overall performance of 0.833 accuracy and 0.736 kappa in classifying into four states: wake, light sleep, deep sleep, and rapid eye movement (REM). Using feature analysis, we demonstrated that heart rate variability is the most salient feature, which is similar to prior reports. CONCLUSIONS: Our results demonstrate the potential benefit of a multilayered algorithm and achieved higher accuracy and kappa than previously described approaches for staging sleep. The results further the possibility of simple, wearable devices for sleep staging. Code is available at https://github.com/NovelaNeuro/nEureka-SleepStaging.

Clinical, imaging, and biomarker evidence of amyloid- and tau-related neurodegeneration in late-onset epilepsy of unknown etiology.

Accumulating evidence suggests amyloid and tau-related neurodegeneration may play a role in development of late-onset epilepsy of unknown etiology (LOEU). In this article, we review recent evidence that epilepsy may be an initial manifestation of an amyloidopathy or tauopathy that precedes development of Alzheimer's disease (AD). Patients with LOEU demonstrate an increased risk of cognitive decline, and patients with AD have increased prevalence of preceding epilepsy. Moreover, investigations of LOEU that use CSF biomarkers and imaging techniques have identified preclinical neurodegeneration with evidence of amyloid and tau deposition. Overall, findings to date suggest a relationship between acquired, non-lesional late-onset epilepsy and amyloid and tau-related neurodegeneration, which supports that preclinical or prodromal AD is a distinct etiology of late-onset epilepsy. We propose criteria for assessing elevated risk of developing dementia in patients with late-onset epilepsy utilizing clinical features, available imaging techniques, and biomarker measurements. Further research is needed to validate these criteria and assess optimal treatment strategies for patients with probable epileptic preclinical AD and epileptic prodromal AD.

Increasing challenges to trial recruitment and conduct over time.

OBJECTIVE: This study was undertaken to evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal onset epilepsy have changed over time. METHODS: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal onset epilepsy, we evaluated how the numbers of participants, sites, and countries have changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability. RESULTS: The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants/site/year, p < .0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94/year, p = .014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%/year, p = .02; odds ratio of increase in 50% responder rate of 1.03/year, p = .02), which was not directly associated with the number of sites per trial (p > .20). SIGNIFICANCE: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. RESULTS: There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic-clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. RESULTS: There was a strong consensus for valproic acid as the first-line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel-blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

Amygdala subfield and prefrontal cortex abnormalities in patients with functional seizures.

BACKGROUND: Functional seizures (FS) are paroxysmal episodes, resembling epileptic seizures, but without underlying epileptic abnormality. The aetiology and neuroanatomic associations are incompletely understood. Recent brain imaging data indicate cerebral changes, however, without clarifying possible pathophysiology. In the present study, we specifically investigated the neuroanatomic changes in subregions of the amygdala and hippocampus in FS. METHODS: T1 MRI scans of 37 female patients with FS and 37 age-matched female seizure naïve controls (SNC) were analyzed retrospectively in FreeSurfer version 7.1. Seizure naïve controls included patients with depression and anxiety disorders. The analysis included whole-brain cortical thickness, subcortical volumes, and subfields of the amygdala and hippocampus. Group comparisons were carried out using multivariable linear models. RESULTS: The FS and SNC groups did not differ in the whole hippocampus and amygdala volumes. However, patients had a significant reduction of the right lateral amygdala volume (p = 0.00041), an increase of the right central amygdala, (p = 0.037), and thinning of the left superior frontal gyrus (p = 0.024). Additional findings in patients were increased volumes of the right medial amygdala (p = 0.031), left anterior amygdala (p = 0.017), and left dentate gyrus of the hippocampus (p = 0.035). CONCLUSIONS: The observations from the amygdala and hippocampus segmentation affirm that there are neuroanatomic associations of FS. The pattern of these changes aligned with some of the cerebral changes described in chronic stress conditions and depression. The pattern of detected changes further study, and may, after validation, provide biomarkers for diagnosis and treatment.

Outcome of stereo-electroencephalography with single-unit recording in drug-refractory epilepsy.

OBJECTIVE: The aim of this study was to evaluate the utility and safety of "hybrid" stereo-electroencephalography (SEEG) in guiding epilepsy surgery and in providing information at single-neuron levels (i.e., single-unit recording) to further the understanding of the mechanisms of epilepsy and the neurocognitive processes unique to humans. METHODS: The authors evaluated 218 consecutive patients undergoing SEEG procedures from 1993 through 2018 at a single academic medical center to assess the utility and safety of this technique in both guiding epilepsy surgery and providing single-unit recordings. The hybrid electrodes used in this study contained macrocontacts and microwires to simultaneously record intracranial EEG and single-unit activity (hybrid SEEG). The outcomes of SEEG-guided surgical interventions were examined, as well as the yield and scientific utility of single-unit recordings in 213 patients who participated in the research involving single-unit recordings. RESULTS: All patients underwent SEEG implantation by a single surgeon and subsequent video-EEG monitoring (mean of 10.2 electrodes per patient and 12.0 monitored days). Epilepsy networks were localized in 191 (87.6%) patients. Two clinically significant procedural complications (one hemorrhage and one infection) were noted. Of 130 patients who underwent subsequent focal epilepsy surgery with a minimum 12-month follow-up, 102 (78.5%) underwent resective surgery and 28 (21.5%) underwent closed-loop responsive neurostimulation (RNS) with or without resection. Seizure freedom was achieved in 65 (63.7%) patients in the resective group. In the RNS group, 21 (75.0%) patients achieved 50% or greater seizure reduction. When the initial period of 1993 through 2013 before responsive neurostimulator implantation in 2014 was compared with the subsequent period of 2014 through 2018, the proportion of SEEG patients undergoing focal epilepsy surgery grew from 57.9% to 79.7% due to the advent of RNS, despite a decline in focal resective surgery from 55.3% to 35.6%. A total of 18,680 microwires were implanted in 213 patients, resulting in numerous significant scientific findings. Recent recordings from 35 patients showed a yield of 1813 neurons, with a mean yield of 51.8 neurons per patient. CONCLUSIONS: Hybrid SEEG enables safe and effective localization of epileptogenic zones to guide epilepsy surgery and provides unique scientific opportunities to investigate neurons from various brain regions in conscious patients. This technique will be increasingly utilized due to the advent of RNS and may prove a useful approach to probe neuronal networks in other brain disorders.

A comprehensive narrative review of epilepsy with eyelid myoclonia.

Epilepsy with eyelid myoclonia (EEM) is a generalized epilepsy syndrome with childhood-onset and 2:1 female predominance that consists of: 1. eyelid myoclonia with or without absence seizures, 2. eye closure induced seizures or EEG paroxysms, 3. clinical or EEG photosensitivity. While eyelid myoclonia is the disease hallmark, other seizure types, including absence seizures and generalized tonic-clonic seizures, may be present. It is thought to have a genetic etiology, and around one-third of patients may have a positive family history of epilepsy. Recently, specific genetic mutations have been recognized in a minority patients, including in SYNGAP1, NEXMIF, RORB, and CHD2 genes. There are no randomized controlled trials in EEM, and the management literature is largely restricted to small retrospective studies. Broad-spectrum antiseizure medications such as valproate, levetiracetam, lamotrigine, and benzodiazepines are typically used. Seizures typically persist into adulthood, and drug-resistant epilepsy is reported in over 50%.

Written seizure action plans for adult patients with epilepsy: Distilling insights from emergency action plans for other chronic conditions.

Seizure emergencies and potential emergencies, ranging from seizure clusters to prolonged seizure and status epilepticus, may affect adults with epilepsy despite stable antiseizure therapy. Seizure action plans (SAPs) are designed for patients and their caregivers/care partners to provide guidance on the individualized treatment plan, including response to potential seizure emergencies and appropriate use of rescue therapy. The use of pediatric SAPs is common (typically required by schools), however, most adults with epilepsy do not have a plan. Patient-centered action plans are integral to care for other chronic conditions and may offer insights applicable to the care of adults with epilepsy. This review analyzes the potential benefits of action plans for medical conditions by exploring their utility in conditions such as asthma, diabetes, chronic obstructive pulmonary disease, heart disease, and opioid overdose. Evidence across these conditions substantiates the value of action plans for patients, and the benefits of adult SAPs in epilepsy are emerging. Because wide implementation of SAPs has faced barriers, other conditions may provide insights that are relevant to implementing SAPs in epilepsy. Based on these analyses, we propose concrete steps to improve the use of SAPs among adults. A recent consensus statement promoting the use of formal SAPs in epilepsy and advances in rescue therapy delivery methods provides support to engage patients around the value of SAPs. The precedent for use of SAPs for pediatric epilepsy patients serves as the foundation to support increased usage in adults. Seizure action plans in the context of improved clinical outcomes are expected to reduce healthcare utilization, improve patient quality of life, and optimize epilepsy management.

Development of a core outcome set for quality of life for adults with drug-resistant epilepsy: A multistakeholder Delphi consensus study.

OBJECTIVE: In 2017, the American Academy of Neurology (AAN) convened the AAN Quality Measurement Set working group to define the improvement and maintenance of quality of life (QOL) as a key outcome measure in epilepsy clinical practice. A core outcome set (COS), defined as an accepted, standardized set of outcomes that should be minimally measured and reported in an area of health care research and practice, has not previously been defined for QOL in adult epilepsy. METHODS: A cross-sectional Delphi consensus study was employed to attain consensus from patients and caregivers on the QOL outcomes that should be minimally measured and reported in epilepsy clinical practice. Candidate items were compiled from QOL scales recommended by the AAN 2017 Quality Measurement Set. Inclusion criteria to participate in the Delphi study were adults with drug-resistant epilepsy diagnosed by a physician, no prior diagnosis of psychogenic nonepileptic seizures or a cognitive and/or developmental disability, or caregivers of patients meeting these criteria. RESULTS: A total of 109 people satisfied inclusion/exclusion criteria and took part in Delphi Round 1 (patients, n = 95, 87.2%; caregivers, n = 14, 12.8%), and 55 people from Round 1 completed Round 2 (patients, n = 43, 78.2%; caregivers, n = 12, 21.8%). One hundred three people took part in the final consensus round. Consensus was attained by patients/caregivers on a set of 36 outcomes that should minimally be included in the QOL COS. Of these, 32 of the 36 outcomes (88.8%) pertained to areas outside of seizure frequency and severity. SIGNIFICANCE: Using patient-centered Delphi methodology, this study defines the first COS for QOL measurement in clinical practice for adults with drug-resistant epilepsy. This set highlights the diversity of factors beyond seizure frequency and severity that impact QOL in epilepsy.

Self-Reported Severity and Causes of Traumatic Brain Injury in Patients With Epileptic or Functional Seizures.

Background and Objectives: Although moderate and severe traumatic brain injury (TBI) can cause posttraumatic epilepsy (PTE), many patients with functional seizures (FS) also report a history of mild TBI. To determine whether features of TBI history differ between patients with epileptic seizures (ES) and FS, we compared patient reports of TBI severity, symptoms, and causes of injury. Methods: We recruited patients undergoing video-EEG evaluation for the diagnosis of ES, FS, mixed ES and FS, or physiologic seizure-like events at an academic, tertiary referral center. Patients and their caregivers were interviewed before final video-EEG diagnosis regarding their TBI histories, including concussive symptoms and causes of injury. Results: Of 506 patients, a greater percentage of patients with FS reported a history of TBI than patients with ES (70% vs 59%, aOR = 1.75 [95% CI: 1.00-3.05], p = 0.047). TBI with loss of consciousness (LOC) lasting less than 30 minutes was more frequently reported among patients with FS than with ES (27% vs 13%, aOR = 2.38 [1.26-4.47], p < 0.01). The proportion of patients reporting other neurologic symptoms immediately after TBI was not significantly different between FS and ES (40% vs 29%, p = 0.08). Causes of TBI were found to differ, with TBIs caused by falls from a height (17% vs 10%, aOR = 2.24 [1.06-4.70], p = 0.03) or motor vehicle collisions (27% vs 11%, aOR = 2.96 [1.54-5.67], p < 0.01) reported more frequently in FS than ES. Discussion: Our findings further the association of mild TBI with FS and prompt reconsideration of typical assumptions regarding the significance of a reported TBI history in patients with previously undifferentiated seizures. Although common in both groups, TBI with LOC less than 30 minutes and causes of injury that are commonly believed to be more severe were reported more frequently in FS than ES. This suggests that a patient or caregiver reporting of these features does not imply that PTE is a more probable diagnosis than FS. Although a history of TBI with LOC and presumed high-risk causes of injury intuitively raises suspicion for PTE, clinicians should be cautioned that these historical factors also were a frequent finding in patients with FS.

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

INTRODUCTION: Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. METHODS: A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. RESULTS: We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. CONCLUSION: The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Some people with epilepsy need to take more than one seizure medicine as part of their treatment. Taking more than one seizure medicine, however, can increase the risk of unwanted side effects. One approach to preventing side effects when adding a new seizure medicine is to lower the amount (dose) of existing seizure medicines. Cenobamate is a newer seizure medicine available in the USA for adults with focal seizures (also referred to as partial-onset seizures). Cenobamate, like many seizure medicines, must be titrated over time to a target dose. A group of epilepsy specialists met and developed recommendations for when and how to change the doses of existing seizure medicines when adding cenobamate. The goal of these recommendations is to prevent or reduce side effects like sleepiness or dizziness. The authors recommend that the dose of specific seizure medicines, including clobazam, lacosamide, phenytoin, and phenobarbital, be lowered as cenobamate is started or as cenobamate's dose is being increased (but before side effects occur). Regular doses of other seizure medicines can be lowered if a side effect occurs because reducing the dose of the other seizure medications can often stop the side effect. These recommendations may help patients successfully reach their optimal dose of cenobamate with fewer side effects, potentially improving their seizure control. Video Abstract: Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Regional variation in brain tissue texture in patients with tonic-clonic seizures.

Patients with epilepsy, who later succumb to sudden unexpected death, show altered brain tissue volumes in selected regions. It is unclear whether the alterations in brain tissue volume represent changes in neurons or glial properties, since volumetric procedures have limited sensitivity to assess the source of volume changes (e.g., neuronal loss or glial cell swelling). We assessed a measure, entropy, which can determine tissue homogeneity by evaluating tissue randomness, and thus, shows tissue integrity; the measure is easily calculated from T1-weighted images. T1-weighted images were collected with a 3.0-Tesla MRI from 53 patients with tonic-clonic (TC) seizures and 53 healthy controls; images were bias-corrected, entropy maps calculated, normalized to a common space, smoothed, and compared between groups (TC patients and controls using ANCOVA; covariates, age and sex; SPM12, family-wise error correction for multiple comparisons, p<0.01). Decreased entropy, indicative of increased tissue homogeneity, appeared in major autonomic (ventromedial prefrontal cortex, hippocampus, dorsal and ventral medulla, deep cerebellar nuclei), motor (sensory and motor cortex), or both motor and autonomic regulatory sites (basal-ganglia, ventral-basal cerebellum), and external surfaces of the pons. The anterior and posterior thalamus and midbrain also showed entropy declines. Only a few isolated regions showed increased entropy. Among the spared autonomic regions was the anterior cingulate and anterior insula; the posterior insula and cingulate were, however, affected. The entropy alterations overlapped areas of tissue changes found earlier with volumetric measures, but were more extensive, and indicate widespread injury to tissue within critical autonomic and breathing regulatory areas, as well as prominent damage to more-rostral sites that exert influences on both breathing and cardiovascular regulation. The entropy measures provide easily-collected supplementary information using only T1-weighted images, showing aspects of tissue integrity other than volume change that are important for assessing function.

Clinical MRI morphological analysis of functional seizures compared to seizure-naïve and psychiatric controls.

PURPOSE: Functional seizures (FS), also known as psychogenic nonepileptic seizures (PNES), are physical manifestations of acute or chronic psychological distress. Functional and structural neuroimaging have identified objective signs of this disorder. We evaluated whether magnetic resonance imaging (MRI) morphometry differed between patients with FS and clinically relevant comparison populations. METHODS: Quality-screened clinical-grade MRIs were acquired from 666 patients from 2006 to 2020. Morphometric features were quantified with FreeSurfer v6. Mixed-effects linear regression compared the volume, thickness, and surface area within 201 regions-of-interest for 90 patients with FS, compared to seizure-naïve patients with depression (n = 243), anxiety (n = 68), and obsessive-compulsive disorder (OCD, n = 41), respectively, and to other seizure-naïve controls with similar quality MRIs, accounting for the influence of multiple confounds including depression and anxiety based on chart review. These comparison populations were obtained through review of clinical records plus research studies obtained on similar scanners. RESULTS: After Bonferroni-Holm correction, patients with FS compared with seizure-naïve controls exhibited thinner bilateral superior temporal cortex (left 0.053 mm, p = 0.014; right 0.071 mm, p = 0.00006), thicker left lateral occipital cortex (0.052 mm, p = 0.0035), and greater left cerebellar white-matter volume (1085 mm3, p = 0.0065). These findings were not accounted for by lower MRI quality in patients with FS. CONCLUSIONS: These results reinforce prior indications of structural neuroimaging correlates of FS and, in particular, distinguish brain morphology in FS from that in depression, anxiety, and OCD. Future work may entail comparisons with other psychiatric disorders including bipolar and schizophrenia, as well as exploration of brain structural heterogeneity within FS.

Phenotyping of Review-of-Systems Responses to Differentiate Functional Seizures From Epilepsy.

Objective: Although the populations of patients with functional seizures (FS) and epileptic seizures (ES) are extremely heterogeneous with multiple etiologies and phenotypes, patients with FS have increased somatic sensitivity and report more positive complaints on review-of-systems questionnaires (ROSQs). We evaluated if data-driven clustering and projection analysis could identify symptom phenotypes that could differentiate between patients with FS and ES.Methods: The dataset included all adult patients admitted from January 2006 to March 2020 for video-electroencephalography with available ROSQs (N = 877). Latent clusters and axes of variation in ROSQ responses were evaluated using multiple well-established methods. Leave-one-out cross-validation was used to evaluate if logistic regression using information could differentiate patients with FS from ES.Results: When evaluating individual symptom response and proportion of positive responses, the area under the receiver operating curve (AUC) was 62% (95% CI, 53%-69%) and 72% (CI, 65%-78%), respectively. The best AUC achieved by phenotyping methods was 74%. The patterns of clusters and components reflected properties of each analysis and did not correlate with assigned "system" from the ROSQ or other interpretations.Discussion: The overall proportion of positive responses was the most informative metric to differentiate patients with FS compared to ES. While both FS and ES are heterogeneous populations with multiple subgroups, these subgroups were not meaningfully identified based on ROSQ symptoms. The limited overall predictive accuracy and AUC suggests that, in absence of other supporting data, ROSQ responses in patients with FS and ES were not clinically useful for screening.

Epilepsy Treatment Complacency in Patients, Caregivers, and Health Care Professionals.

OBJECTIVE: To explore the perspectives of adult patients with epilepsy, caregivers, and health care professionals (HCPs) on treatment for seizures and treatment decisions, we developed and administered the STEP Survey (Seize the Truth of Epilepsy Perceptions). METHODS: Participants were recruited from online panel M3 and by Rare Patient Voice and completed the self-administered online STEP Survey. Analysis of variance and chi-square tests were used for group comparisons. RESULTS: The STEP Survey was completed by 400 adult patients, 201 caregivers, and 258 HCPs. Patients estimated reporting 45% of their seizures to their HCP, whereas caregivers estimated 83% and HCPs estimated 73% were reported. The most common reason for not reporting seizures was that the seizures were not serious enough to mention (patients 57%; caregivers 66%). A minority of patients (25%) and caregivers (30%) were very or extremely likely to ask their HCP about changing antiseizure medication (ASM) in the next 12 months. The HCP was most frequently selected by patients, caregivers, and HCPs as the person who initiates discussion of changing ASMs (patients 73%/caregivers 66%/HCPs 75%) and increasing ASM dosage (patients 77%/caregivers 68%/HCPs 81%). A majority of patients (65%) and caregivers (68%) somewhat or strongly agreed that they do not change ASMs due to fear of getting worse. HCPs perceive this fear less often, stating that 50% of their patients feel afraid when a second ASM was added. CONCLUSIONS: Improved reporting of all seizures, discussion of treatment changes, and the impact of fear on treatment decisions provide opportunities to reduce complacency and optimize patient outcomes.

Title: Functional seizures across the adult lifespan: female sex, delay to diagnosis and disability.

OBJECTIVE: The clinical characteristics of functional seizures may vary based on age-of-onset or age-of-presentation. Description of age-related differences has focused on three categories: pediatric, young-adult, and older-adult. We evaluated how factors continuously varied based on age-of-presentation across the adult lifespan. METHODS: Based on cross-sectional data from 365 adult (18 to 88 years old) patients with documented diagnoses of functional seizures, we evaluated how the quantity and prevalence of specific ictal behaviors, historical factors, and comorbidities varied based on patient age-of-presentation using sequential weighted averages. RESULTS: Four factors changed prominently with age-of-presentation: female predominance decreased at two inflection points - ages 35 and 62; the prevalence of work disability was higher until age-of-presentation 30 then plateaued at 80%; there was greater delay to diagnosis in older patients; and comorbidities was higher with age-of-presentation, starting from early adulthood. The proportion of patients who presented with functional seizures decreased after 50. Ictal behavior did not substantially vary with age-of-presentation. CONCLUSION: The time from onset to diagnosis increased with age-of-presentation, which may be related to increased comorbidities and the misconception that FS do not start in older age. The female predominance decreased nonlinearly with age. By age 30, most patients' seizures already had substantial association with unemployment. These findings emphasize that patients can develop functional seizures at any age. The rapid development of disability relatively early in life, which then stays at a high prevalence rate, demonstrates the need for prompt referral for definitive diagnosis and treatment.

A minority of patients with functional seizures have abnormalities on neuroimaging.

OBJECTIVE: Functional seizures often are managed incorrectly as a diagnosis of exclusion. However, a significant minority of patients with functional seizures may have abnormalities on neuroimaging that typically are associated with epilepsy, leading to diagnostic confusion. We evaluated the rate of epilepsy-associated findings on MRI, FDG-PET, and CT in patients with functional seizures. METHODS: We studied radiologists' reports from neuroimages at our comprehensive epilepsy center from a consecutive series of patients diagnosed with functional seizures without comorbid epilepsy from 2006 to 2019. We summarized the MRI, FDG-PET, and CT results as follows: within normal limits, incidental findings, unrelated findings, non-specific abnormalities, post-operative study, epilepsy risk factors (ERF), borderline epilepsy-associated findings (EAF), and definitive EAF. RESULTS: Of the 256 MRIs, 23% demonstrated ERF (5%), borderline EAF (8%), or definitive EAF (10%). The most common EAF was hippocampal sclerosis, with the majority of borderline EAF comprising hippocampal atrophy without T2 hyperintensity or vice versa. Of the 87 FDG-PETs, 26% demonstrated borderline EAF (17%) or definitive EAF (8%). Epilepsy-associated findings primarily included focal hypometabolism, especially of the temporal lobes, with borderline findings including subtle or questionable hypometabolism. Of the 51 CTs, only 2% had definitive EAF. SIGNIFICANCE: This large case series provides further evidence that, while uncommon, EAF are seen in patients with functional seizures. A significant portion of these abnormal findings are borderline. The moderately high rate of these abnormalities may represent framing bias from the indication of the study being "seizures," the relative subtlety of EAF, or effects of antiseizure medications.