Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums.

A growing body of evidence has demonstrated a link between Alzheimer disease (AD) and epilepsy. Late-onset epilepsy and epileptiform activity can precede cognitive deterioration in AD by years, and its presence has been shown to predict a faster disease course. In animal models of AD, amyloid and tau pathology are linked to cortical network hyperexcitability that precedes the first signs of memory decline. Thus, detection of epileptiform activity in AD has substantial clinical importance as a potential novel modifiable risk factor for dementia. In this Review, we summarize the epidemiological evidence for the complex bidirectional relationship between AD and epilepsy, examine the effect of epileptiform activity and seizures on cognition in people with AD, and discuss the precision medicine treatment strategies based on the latest research in human and animal models. Finally, we outline some of the unresolved questions of the field that should be addressed by rigorous research, including whether particular clinicopathological subtypes of AD have a stronger association with epilepsy, and the sequence of events between epileptiform activity and amyloid and tau pathology.

Sleep/Wake Disorders After Sports Concussion: Risks, Revelations, and Interventions.

SUMMARY: Sleep-wake disturbances (SWDs) are among the most prevalent, persistent, and often disregarded sequelae of traumatic brain injury. Identification and treatment of SWDs in patients with traumatic brain injury is important and can complement other efforts to promote maximum functional recovery. SWDs can accentuate other consequences of traumatic brain injury, negatively affect mood, exacerbate pain, heighten irritability, and diminish cognitive abilities and the potential for recovery. The risk for sports injuries increases when athletes are sleep deprived. Sleep deprivation increases risk-taking behaviors, predisposing to injuries. SWDs are an independent risk factor for prolonged recovery after sports-related concussion. SWDs following sports-related concussion have been shown to impede recovery, rehabilitation, and return to preinjury activities.

Sleep and Epilepsy: Practical Implications.

Sleep is a restorative balm for many, often less so for people with epilepsy. Complex bidirectional interactions between sleep and epilepsy can be detrimental to sleep, epilepsy and those affected. Sleep is a state of variable activation of the EEG and seizure occurrence in people with epilepsy. Sleep disorders are highly prevalent and portend worse seizure and epilepsy-related outcomes. Randomized clinical trials of sleep interventions in epilepsy populations are few, yet warranted, given the effects of sleep dysfunction on quality of life and the risk of SUDEP in people with epilepsy.

Minimum Technical Requirements for Performing Ambulatory EEG.

SUMMARY: Ambulatory EEG (AEEG) devices offer portable, multichannel, digital EEG recording with or without video in the patient's natural environment. The technology applied for AEEG recording is like the technology for routine EEG and inpatient long-term video-EEG monitoring but designed to be compact and wearable. Computer-based AEEG technology is well-suited to digital recording, signal processing, and visual display. However, acquiring interpretable EEG outside of the hospital setting presents its own technical challenges. Published guidelines have established technical standards for performing routine EEG and inpatient video-EEG monitoring, but technical standards for AEEG are lacking. Therefore, this guideline provides minimal technical standards for the performance of AEEG which are essential to ensure the quality of studies for clinical and research practice. We expect these minimum standards to evolve over time with improved performance and advances in the technology.

Stroke: What's Sleep Got to Do With It?

SUMMARY: Ischemic strokes most often occur between 6 am and 12 am after awakening from sleep but up to 30% occur during sleep. Wake-up strokes (WUS) are new focal neurological deficit(s) persisting for ≥ 24 hours attributable to an ischemic event present on patient awakening. Obstructive sleep apnea (OSA) is a major risk factor for WUS because it compounds the instability of the morning environment and increases the likelihood of cardiovascular events, including hypertension, atrial fibrillation, right-to-left shunts, and stroke. Circadian-driven alterations in structural, homeostatic, and serological factors also predispose to WUS. Also, WUS patients are often not considered candidates for time-dependent intravenous thrombolysis therapy because of an uncertain onset time. However, using the tissue clock (positive diffusion weighted imaging-negative fluid-attenuated inversion recovery mismatch) dates the WUS as 3 to 4.5 hours old and permits consideration for intravenous thrombolysis and if needed mechanical thrombectomy. Given the high prevalence of moderate/severe OSA in stroke patients and its impact on stroke outcomes, screening with overnight pulse oximetry and home sleep apnea test is needed. Treating OSA poststroke remains challenging. Polysomnographic changes in sleep architecture following acute/subacute stroke may also impact upon stroke outcome.

Recognizing New-Onset Sleep Disorders in Autoimmune Encephalitis Often Prompt Earlier Diagnosis.

SUMMARY: Sleep/wake disorders are common in patients with autoimmune encephalitis, sometimes the most prominent or sole initial symptom, then delaying diagnosis. Sleep/wake disorders in autoimmune encephalitis vary and include severe sleeplessness, hypersomnia, central and/or obstructive sleep apnea, rapid eye movement sleep behavior disorder, indeterminate sleep/wake states, and loss of circadian sleep/wake rhythms. N-methyl- d aspartate receptor encephalitis (NMDAR) is often associated with insomnia, then hypersomnia and sleep-related central hypoventilation. Profound sleeplessness and rapid eye movement sleep behavior disorder are seen in patients with voltage-gated potassium channel-complex antibodies. Fragmented sleep and hypersomnia are common in paraneoplastic syndromes associated with anti-MA protein encephalitis; rapid eye movement sleep behavior disorder in those with antibodies against leucine-rich glioma inactivated protein (LGI1) or contactin-associated protein 2 (CASPR2) antibodies. Antibodies against a cell adhesion protein IGLON5 may result in obstructive sleep apnea, inspiratory stridor, disorganized nonrapid eye movement sleep, and excessive movements and parasomnias fragmenting nonrapid and rapid eye movement sleep. Recognizing a particular sleep/wake disorder is often a presenting or prominent feature in certain autoimmune encephalitis permit for earlier diagnosis. This is important because reduced morbidity and better short- and long-term outcomes are associated with earlier diagnosis and immunotherapies.

Sleep Biomarkers Help Predict the Development of Alzheimer Disease.

SUMMARY: Middle-aged or older adults who self-report sleep-wake disorders are at an increased risk for incident dementia, mild cognitive impairment, and Alzheimer disease. Dementia in people with mild cognitive impairment and Alzheimer disease who complain of sleep-wake disorders progress faster than those without sleep-wake disorders. Removal of amyloid-beta and tau tangles occurs preferentially in non-rapid eye movement 3 sleep and fragmented or insufficient sleep may lead to accumulation of these neurotoxins even in preclinical stages. Selective atrophy in the medial temporal lobe on brain MRI has been shown to predict impaired coupling of slow oscillations and sleep spindles. Impaired slow wave-spindle coupling has been shown to correlate with impaired overnight memory consolidation. Whereas, a decrease in the amplitude of 0.6 to 1 Hz slow wave activity predicts higher cortical Aß burden on amyloid PET scans. Overexpression of the wake-promoting neurotransmitter orexin may predispose patients with mild cognitive impairment and Alzheimer disease to increased wakefulness, decreasing time they need to clear from the brain the neurotoxic accumulation of amyloid-beta and especially tau. More research exploring these relationships is needed and continuing.

What Is the Prognostic Significance of Rapid Eye Movement Sleep Without Atonia in a Polysomnogram?

SUMMARY: Freud said we are lucky to be paralyzed during sleep, so we cannot act out our dreams. Atonia of skeletal muscles normally present during rapid eye movement sleep prevents us from acting out our dreams. Observing rapid eye movement sleep without atonia in a polysomnogram in older adults first and foremost warrants consideration of rapid eye movement behavior disorder. Seventy-five to 90% of older adults with isolated rapid eye movement behavior disorder will develop a neurodegenerative disease within 15 years, most often a synucleinopathy. Rapid eye movement sleep without atonia in those younger than 50 years is commonly found in individuals with narcolepsy and those taking antidepressant medications.

Sleep Spindles and K-Complexes Are Favorable Prognostic Biomarkers in Critically Ill Patients.

SUMMARY: In this narrative review, we summarize recent research on the prognostic significance of biomarkers of sleep in continuous EEG and polysomnographic recordings in intensive care unit patients. Recent studies show the EEG biosignatures of non-rapid eye movement 2 sleep (sleep spindles and K-complexes) on continuous EEG in critically ill patients better predict functional outcomes and mortality than the ictal-interictal continuum patterns. Emergence of more complex and better organized sleep architecture has been shown to parallel neurocognitive recovery and correlate with functional outcomes in traumatic brain injury and strokes. Particularly interesting are studies which suggest intravenous dexmedetomidine may induce a more biomimetic non-rapid eye movement sleep state than intravenous propofol, potentially providing more restorative sleep and lessening delirium. Protocols to improve intensive care unit sleep and neurophysiological studies evaluating the effect of these on sleep and sleep architecture are here reviewed.

High prevalence of pathological alertness and wakefulness on maintenance of wakefulness test in adults with focal-onset epilepsy.

BACKGROUND: Excessive daytime sleepiness (EDS) is a common complaint in adults with epilepsy (AWE), but objective evaluation is lacking. We used the maintenance of wakefulness test (MWT) to objectively measure the ability of adults with focal-onset epilepsy to maintain wakefulness in soporific conditions. METHODS: Adults with epilepsy participating in a study investigating the effects of lacosamide on sleep and wakefulness underwent baseline ambulatory polysomnography (PSG)/EEG followed by MWT. Mean sleep latency (MSL) and mean percent sleep time (MST, mean percentage of non-wake EEG scored in 3-sec bins from lights out to sleep onset averaged over the 4 MWT trials) were quantified. Subjective sleepiness was assessed by the Epworth Sleepiness Scale (ESS). Spearman correlation and linear regression assessed relationships between MWT parameters, ESS and relevant sleep and epilepsy-related variables. RESULTS: Maintenance of wakefulness test MSL in 51 AWE (mean age 43.5 ±â€¯13 years, 69% female, mean BMI 24.6 ±â€¯11.2 kg/m2) was 21.7 ±â€¯11.9 min; 45.1% had an abnormally short MSL <19.4 min and 15.7% <8 min. MST was 9.3% [3.3, 19.1]. Mean ESS score was 8.8 ±â€¯5.7; 39% had elevated ESS (>10). No correlation between subjective ESS and objective MSL (p = 0.67) or MST (p = 0.61) was found. MSL was significantly shorter in subjects with focal to bilateral tonic-clonic seizures (FBTCS; 7.9 min [13.6, 22.3]) compared to those without (27.4 min [21.2, 33.6], p = 0.013). Younger subjects had shorter MSL; MSL increased 3.2 min for every 10-year increase in age. CONCLUSION: We found a high prevalence of objective sleepiness/difficulty maintaining wakefulness on the MWT and subjective sleepiness using the ESS in AWE without a correlation between the two. More severe objective sleepiness was found in subjects with a history of FBTCS and younger age. Further research is needed to determine mechanistic underpinnings and optimal measurements of pathological sleepiness in people with epilepsy given the burden of it on quality of life.

The Epworth Sleepiness Scale in epilepsy: Internal consistency and disease-related associations.

BACKGROUND: The Epworth Sleepiness Scale (ESS) is the most common instrument for measuring subjective sleep propensity in people with epilepsy but has not yet been validated in this population. STUDY OBJECTIVES: We aimed to systematically assess the validity, performance, and internal consistency of the ESS, as well as correlations between the ESS and disease-specific variables and patient-reported outcome measures in a cohort of adults with epilepsy (AWE). METHODS: Ninety-five AWE completed sleep and seizure diaries, in-laboratory polysomnography (PSG) and patient-reported outcome measures, including the ESS, Insomnia Severity Index (ISI), and the Beck Depression Inventory (BDI). Demographic information and data from 95 matched controls referred for PSG for suspected obstructive sleep apnea (OSA) was taken from the electronic medical record. Frequencies of high ESS item ratings (item score ≥2) were calculated for each group. Cronbach's α and factor analysis were performed to assess the internal consistency and validity of the ESS within cases and controls. Multivariable linear models were used to assess the association between ESS and predictors of interest, adjusting for demographic and disease-specific variables, including seizure type, frequency, and anti-seizure medication (ASM) therapy. RESULTS: While suspected OSA controls had significantly greater mean ESS total scores (9.9 vs 7.9, p = 0.004) and proportion with ESS >10 (42% vs 25%, p = 0.014), there were no significant differences in the severity of item responses, with the exception of "lying down to rest in the afternoon when circumstances permit," for which more controls rated as likely/very likely (79% vs 64%), p = 0.024). AWE with ESS >10 had higher mean standardized ASM dose (2.5 vs 1.7, p = 0.026). All ESS items were significantly correlated with the total score within each group. Cronbach's α was 0.75 for cases and 0.85 for controls, indicating good internal consistency of the ESS for both groups. After adjusting for demographic and sleep characteristics, higher ESS scores were associated with greater insomnia scores on the ISI (p = 0.024) and depressive symptoms on the BDI (p = 0.018). CONCLUSIONS: This study provides validity for the use of the ESS in adult populations with epilepsy.

Bidirectional relationships of sleep and epilepsy in adults with epilepsy.

This targeted review addresses the best accepted and most intriguing recent observations on the complex relationships between sleep and epilepsy. Ten to 15% of all epilepsies are sleep-related. Included in these is sleep-related hypermotor epilepsy, renamed from nocturnal frontal lobe epilepsy by a 2016 consensus conference since 30% of cases are extra-frontal, seizures are related to sleep rather than clock time, and the predominant semiology is hypermotor. Stereo-EEG is providing crucial insights into network activation in sleep-related epilepsies and definition of the epileptogenic zone. Pathologic high-frequency oscillations, a promising biomarker for identifying the epileptogenic zone, are most frequent in NREM sleep, lowest in wakefulness and REM sleep, similar to interictal epileptiform discharges (IEDs). Most sleep-related seizures are followed by awakening or arousal and IEDs cause arousals and increase after arousals, likely contributing to sleep/wake complaints. Sleep/wake disorders are 2-3 times more common in adults with epilepsy than the general population; these comorbidities are associated with poorer quality of life and may impact seizure control. Treatment of sleep apnea reduces seizures in many cases. An emerging area of research is in circadian biology and epilepsy. Over 90% of people with epilepsy have seizures with circadian periodicity, in part related to sleep itself, and the majority of SUDEP cases occur in sleep. Recognizing these bidirectional relationships is important for patient and caregiver education and counseling and optimizing epilepsy outcomes.