Review: The past, present and future challenges in epilepsy-related and sudden deaths and biobanking.

Awareness and research on epilepsy-related deaths (ERD), in particular Sudden Unexpected Death in Epilepsy (SUDEP), have exponentially increased over the last two decades. Most publications have focused on guidelines that inform clinicians dealing with these deaths, educating patients, potential risk factors and mechanisms. There is a relative paucity of information available for pathologists who conduct these autopsies regarding appropriate post mortem practice and investigations. As we move from recognizing SUDEP as the most common form of ERD toward in-depth investigations into its causes and prevention, health professionals involved with these autopsies and post mortem procedure must remain fully informed. Systematizing a more comprehensive and consistent practice of examining these cases will facilitate (i) more precise determination of cause of death, (ii) identification of SUDEP for improved epidemiological surveillance (the first step for an intervention study), and (iii) biobanking and cell-based research. This article reviews how pathologists and healthcare professionals have approached ERD, current practices, logistical problems and areas to improve and harmonize. The main neuropathology, cardiac and genetic findings in SUDEP are outlined, providing a framework for best practices, integration of clinical, pathological and molecular genetic investigations in SUDEP, and ultimately prevention.

De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X­linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss­of­function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole­exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X­linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.

Abnormalities of cortical thickness in postictal psychosis.

Postictal psychosis (PIP), the occurrence of psychotic episodes following a seizure, is a common and serious comorbidity in patients with epilepsy. Yet, the anatomical correlates remain poorly defined. Here, we used quantitative MRI morphometry to identify structural abnormalities in the cortex of patients with PIP relative to patients with epilepsy without PIP and age- and gender-matched normal healthy controls. Comparison of patients with epilepsy and PIP with patients with epilepsy without PIP revealed increased cortical thickness in the right lateral prefrontal cortex, right anterior cingulate cortex, and right middle temporal gyrus. The PIP group was distinguished from the EC and NC groups by thicker cortex in the right rostral anterior cingulate cortex and thinner cortex in the right angular gyrus and the left middle temporal region. Findings indicate that PIP is associated with thickening of the right anterior cingulate cortex, which may serve as a marker for patients at risk for developing PIP.

Potential of cannabinoids as treatments for autism spectrum disorders.

Current treatments for autism spectrum disorders (ASD) are limited in efficacy and are often associated with substantial side effects. These medications typically ameliorate problem behaviors associated with ASD, but do not target core symptom domains. As a result, there is a significant amount of research underway for development of novel experimental therapeutics. Endocannabinoids are arachidonic acid-derived lipid neuromodulators, which, in combination with their receptors and associated metabolic enzymes, constitute the endocannabinoid (EC) system. Cannabinoid signaling may be involved in the social impairment and repetitive behaviors observed in those with ASD. In this review, we discuss a possible role of the EC system in excitatory-inhibitory (E-I) imbalance and immune dysregulation in ASD. Novel treatments for the core symptom domains of ASD are needed and phytocannabinoids could be useful experimental therapeutics for core symptoms and associated domains.

Cell-mediated immunity: delayed-type hypersensitivity and cytotoxic responses are mediated by different T-cell subclasses.

Cell-mediated immunity includes both the generation of cytotoxic cells and initiation of delayed-type hypersensitivity (DTH). The resting T-cell population, before stimulation by antigen, already contains cells of the Lyl subclass that are programmed to initiate DTH (and helper function) but not cytotoxic responses, as well as Ly23 cells which can generate killer activity (and suppressive function) but not DTH. The central implication of these findings is that the broad division between humoral and cell-mediated immune responses does not precisely correspond to the division of labor among T-cell subclasses. The relative contribution of DTH-competent Lyl cells and cytotoxic Ly23 cells to the classical homograft response remains to be determined.

Historical perspectives and definitions of the postictal state.

The postictal state and its features were recognized by physicians from Babylonian times through to the advent of modern neurology in the late 19th century. Among varied descriptions and definitions lies one of the best known and still used eponyms in medicine, Todd's paralysis. Despite a relative lack of biological insight, many key observations were made in an era mostly devoid of treatments for epilepsy.

Seizure prediction and recall.

Using separate generalized mixed-effects models, we assessed seizure recall and prediction, as well as contributing diagnostic variables, in 83 adult patients with epilepsy undergoing video/EEG monitoring. The model revealed that when participants predicted a seizure, probability equaled 0.320 (95% CI: 0.149-0.558), a significant (P<0.05) increase over negative predictions (0.151, 95% CI: 0.71-0.228]). With no seizure, the rate of remembering was approximately 0.130 (95% CI: 0.73-0.219), increasing significantly to 0.628 (95% CI: 0.439 to 0.784) when a seizure occurred (P<0.001). Of the variables analyzed, only inpatient seizure rate influenced predictability (P<0.001) or recollection (P<0.001). These models reveal that patients were highly aware of their seizures, and in many cases, were able to make accurate predictions, for which seizure rate may be an important factor.

Expectations prior to epilepsy surgery: an exploratory comparison of men and women.

Although the clinical goal of resective epilepsy surgery is seizure freedom, patients have a wide set of expectations for this invasive procedure. The goal of this study was to evaluate potential gender differences in expectations among patients undergoing resective epilepsy surgery. Ratings of the importance of 12 potential impacts ("expectations") of resective surgery were analyzed in a seven-center cohort study including 389 adults aged 16 and older who underwent resective epilepsy surgery. Men and women both ranked anticipated changes in driving and memory as the most important presurgical expectations. Women rated driving, physical activity limitations, and economic worries as less important, and fatigue and pregnancy concerns as more important than did men (p's< or =0.05). Exploratory factor analysis indicated a different pattern of associations among the 12 importance items for men and women. Whether gender differences in presurgical values are associated with outcomes needs exploration.

3T MRI Whole-Brain Microscopy Discrimination of Subcortical Anatomy, Part 1: Brain Stem.

BACKGROUND AND PURPOSE: The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS: We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS: We identified most brain stem structures at 7 canonical axial levels. Multiplanar or oblique planes illustrate the 3D course and spatial relationships of major brain stem white matter pathways. Measurements of the relative position, course, and cross-sectional area of these pathways across multiple samples allow estimation of pathway location in other samples or clinical subjects. Possible structure-function asymmetries in these pathways will require further study-that is, the cross-sectional area of the left corticospinal tract in the midpons appeared 20% larger (n = 13 brains, P < .10). CONCLUSIONS: Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

3T MRI Whole-Brain Microscopy Discrimination of Subcortical Anatomy, Part 2: Basal Forebrain.

BACKGROUND AND PURPOSE: The basal forebrain contains multiple structures of great interest to emerging functional neurosurgery applications, yet many neuroradiologists are unfamiliar with this neuroanatomy because it is not resolved with current clinical MR imaging. MATERIALS AND METHODS: We applied an optimized TSE T2 sequence to washed whole postmortem brain samples (n = 13) to demonstrate and characterize the detailed anatomy of the basal forebrain using a clinical 3T MR imaging scanner. We measured the size of selected internal myelinated pathways and measured subthalamic nucleus size, oblique orientation, and position relative to the intercommissural point. RESULTS: We identified most basal ganglia and diencephalon structures using serial axial, coronal, and sagittal planes relative to the intercommissural plane. Specific oblique image orientations demonstrated the positions and anatomic relationships for selected structures of interest to functional neurosurgery. We observed only 0.2- to 0.3-mm right-left differences in the anteroposterior and superoinferior length of the subthalamic nucleus (P = .084 and .047, respectively). Individual variability for the subthalamic nucleus was greatest for angulation within the sagittal plane (range, 15°-37°), transverse dimension (range, 2-6.7 mm), and most inferior border (range, 4-7 mm below the intercommissural plane). CONCLUSIONS: Direct identification of basal forebrain structures in multiple planes using the TSE T2 sequence makes this challenging neuroanatomy more accessible to practicing neuroradiologists. This protocol can be used to better define individual variations relevant to functional neurosurgical targeting and validate/complement advanced MR imaging methods being developed for direct visualization of these structures in living patients.

Neural correlates of unstructured motor behaviors.

OBJECTIVE: We studied the relationship between uninstructed, unstructured movements and neural activity in three epilepsy patients with intracranial electroencephalographic (iEEG) recordings. APPROACH: We used a custom system to continuously record high definition video precisely time-aligned to clinical iEEG data. From these video recordings, movement periods were annotated via semi-automatic tracking based on dense optical flow. MAIN RESULTS: We found that neural signal features (8-32 Hz and 76-100 Hz power) previously identified from task-based experiments are also modulated before and during a variety of movement behaviors. These movement behaviors are coarsely labeled by time period and movement side (e.g. 'Idle' and 'Move', 'Right' and 'Left'); movements within a label can include a wide variety of uninstructed behaviors. A rigorous nested cross-validation framework was used to classify both movement onset and lateralization with statistical significance for all subjects. SIGNIFICANCE: We demonstrate an evaluation framework to study neural activity related to natural movements not evoked by a task, annotated over hours of video. This work further establishes the feasibility to study neural correlates of unstructured behavior through continuous recording in the epilepsy monitoring unit. The insights gained from such studies may advance our understanding of how the brain naturally controls movement, which may inform the development of more robust and generalizable brain-computer interfaces.

Simulating human sleep spindle MEG and EEG from ion channel and circuit level dynamics.

BACKGROUND: Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain. METHOD: We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors. RESULTS: The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted. COMPARISON WITH EXISTING METHODS: Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales. CONCLUSIONS: This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

Effects of vagus nerve stimulation on cardiovascular regulation in patients with epilepsy.

OBJECTIVE: To evaluate the impact of vagus nerve stimulation (VNS) on heart rate and blood pressure (BP) modulation in epilepsy patients. MATERIAL AND METHODS: Twenty-one epilepsy patients with VNS were tested during on (60 s) and off (5 min) phases. We monitored BP, RR intervals (RRI) and respiration. Spectral analysis was performed in low- (LF: 0.04-0.15 Hz) and high-frequency bands (HF: 0.15-0.5 Hz). For coherences above 0.5, we calculated the LF transfer function between systolic BP and RRI, and the HF transfer function gain and phase between RRI and respiration. Differences between the on and off phases were evaluated using Wilcoxon test. RESULTS: VNS did not change RRI and BP values. The LF power of BP and the LF and HF power of RRI increased significantly. There was a slight change in the RRI/BP LF gain and the RRI/respiration HF gain (ns). The HF phase between RRI and respiration decreased significantly. CONCLUSIONS: Our findings show that VNS influences both sympathetic and parasympathetic cardiovascular modulation. However, our results also show that VNS does not negatively influence autonomic cardiovascular regulation.

Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome.

AIM: The aim of the study was to evaluate the surgical treatment of epilepsy and detection of possible early surgery predictive elements in patients with tuberous sclerosis complex (TSC). MATERIALS AND METHODS: Forty-two TSC patients with epilepsy were selected and divided into two main groups: definite and fruste forms. Definite forms were divided into different groups: patients with pharmacologically controlled epilepsy, patients with pharmacoresistant epilepsy excluded from surgery after an extensive presurgical assessment, and patients with a pharmacoresistant epilepsy who underwent surgery. We compared the definite TSC groups to identify elements that predict surgical candidacy. Second, we compared all operated patients to assess surgical outcome. CONCLUSION: We found several factors that could predict a surgical intervention even if identification of patients with refractory epilepsy who can benefit from surgery is an evolving process. Also, several positive factors for good surgical outcome were identified. Patients with the fruste form had excellent surgical outcome.

Effects of carbamazepine on pituitary-adrenal function in healthy volunteers.

Carbamazepine (CBZ) is a widely used therapeutic agent in seizure, pain, and mood disorders. Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro, limited data suggest that systemic CBZ induces pituitary-adrenal activation. Few data are available to reconcile these effects or clarify their mechanism(s), particularly in healthy human subjects. We report here a study of basal ACTH and cortisol secretion and their responses to ovine CRH administration in nine healthy volunteers, studied both during repeated (2-3 weeks) administration of CBZ and while medication free. CBZ significantly increased mean 24-h urinary free cortisol (mean +/- SE, 197 +/- 17 vs. 137 +/- 24 nmol/day; P less than 0.02) and evening basal total plasma cortisol (113 +/- 17 vs. 83 +/- 14 nmol/L; P less than 0.05) as well as cortisol-binding globulin-binding capacity (497 +/- 36 vs. 433 +/- 28 nmol/L; P less than 0.01). Despite the CBZ-induced hypercortisolism, plasma ACTH responses to CRH during CBZ treatment remained robust, rather than being suppressed by basal hypercortisolism. In fact, during CBZ treatment, we noted a positive correlation between the increase in basal plasma cortisol and the increase in the plasma ACTH response to CRH (r = 0.65; P less than 0.05). We also observed a reduction in cortisol-binding globulin-binding capacity after CRH administration (315 +/- 25 vs. 433 +/- 28 nmol/L; P less than 0.001), which was accentuated by CBZ treatment (342 +/- 19 vs. 497 +/- 36 nmol/L; P less than 0.001; magnitude of fall, -155 +/- 22 nmol/L on CBZ vs. -118 +/- 11 nmol/L off CBZ; P less than 0.05). We conclude that CBZ increases plasma cortisol secretion in healthy volunteers independent of its effect on plasma cortisol-binding capacity. This pituitary-adrenal activation seems to reflect a pituitary, rather than a hypothalamic, effect of CBZ. Hence, despite CBZ-induced hypercortisolism, the ACTH response to CRH remained robust in direct proportion to the CBZ-induced rise in basal plasma cortisol. Thus, we propose that the increased cortisol secretion observed during CBZ treatment reflects a relative inefficacy of glucocorticoid negative feedback at the pituitary. This pituitary-driven increase in cortisol secretion combined with the expected reduction in centrally directed CRH secretion could contribute to the anticonvulsant properties of CBZ.

Varieties of aggressive behavior in temporal lobe epilepsy.

While an increase in aggression has frequently been reported in association with temporal lobe epilepsy, the validity of this behavioral observation and the relationship of specific aggressive behavior to electrophysiologic abnormality in the human limbic system remain unclear. Case reports of five patients document the clinical importance of aggressive behavior, especially during the interictal period, in patients with temporal lobe epilepsy. Aggressiveness was often encountered together with other deepened emotions and changes in behavior previously described as an interictal behavior syndrome. Variations among the individual patients may clarify the neuroanatomical mechanisms leading to aggression and suggest specific therapeutic interventions.

Neuroanatomy of Gilles de la Tourette's syndrome. Possible midbrain involvement.

Alterations of the dopaminergic system are well documented in Gilles de la Tourette's syndrome (TS). Dopamine (DA)-receptor blockers often relieve symptoms, whereas DA agonists acutely exacerbate them. The cluster of symptoms and known localization of lesions in encephalitis lethargica (EL), together with studies on the anatomy of vocalization, suggest that damage to the periaqueductal gray and midbrain tegmentum may be involved in TS. Pharmacologic findings in patients with TS and EL suggest that oculogyric crises and obsessions are associated with diminished DA levels and the development of supersensitive DA receptors, and that tics occur when these receptors are stimulated.

J. Russell Reynolds and the study of interictal symptoms in epilepsy.

Sir John Russell Reynolds (1828-1896) was a prominent English neurologist who was among the first to carefully study interictal behavior in patients with epilepsy. He challenged the prevailing dogma that severe mental illness was nearly always concomitant of epilepsy. Studying the cognitive and emotional functions of 62 patients with essential (idiopathic) epilepsy, he found that 39% of the patients were normal, 32% had only mild impairment of recent memory, and 29% had moderate to severe psychopathologic findings. His study of interictal behavior in epilepsy is one of the earliest attempts to avoid selection bias and represents an important contribution to the study of this problem.

Autoscopic phenomena with seizures.

We report the cases of 10 patients with seizures and autoscopic phenomena, which include seeing one's double and out-of-body experiences, and review 33 additional cases of autoscopic seizures from the literature. Autoscopic phenomena may be symptoms of simple partial, complex partial, or generalized tonoclonic seizures. Autoscopic seizures may be more common than is recognized; we found a 6.3% incidence in the patients we interviewed. The temporal lobe was involved in 18 (86%) of the 21 patients in whom the seizure focus could be identified. There was no clear lateralization of lesions in patients with ictal autoscopy. The response of autoscopic episodes to treatment usually paralleled that of the underlying seizure disorder. Autoscopic phenomena are likely to be discovered only on specific questioning of patients with epilepsy and may be an important, distressing feature of a chronic seizure disorder.