Scalp and hippocampal sleep correlates of memory function in drug-resistant temporal lobe epilepsy.

Seminal animal studies demonstrated the role of sleep oscillations such as cortical slow waves, thalamocortical spindles, and hippocampal ripples in memory consolidation. In humans, whether ripples are involved in sleep-related memory processes is less clear. Here, we explored the interactions between sleep oscillations (measured as traits) and general episodic memory abilities in 26 adults with drug-resistant temporal lobe epilepsy who performed scalp-intracranial electroencephalographic recordings and neuropsychological testing, including two analogous hippocampal-dependent verbal and nonverbal memory tasks. We explored the relationships between hemispheric scalp (spindles, slow waves) and hippocampal physiological and pathological oscillations (spindles, slow waves, ripples, and epileptic spikes) and material-specific memory function. To differentiate physiological from pathological ripples, we used multiple unbiased data-driven clustering approaches. At the individual level, we found material-specific cerebral lateralization effects (left-verbal memory, right-nonverbal memory) for all scalp spindles (rs > 0.51, ps < 0.01) and fast spindles (rs > 0.61, ps < 0.002). Hippocampal epileptic spikes and short pathological ripples, but not physiological oscillations, were negatively (rs > -0.59, ps < 0.01) associated with verbal learning and retention scores, with left lateralizing and antero-posterior effects. However, data-driven clustering failed to separate the ripple events into defined clusters. Correlation analyses with the resulting clusters revealed no meaningful or significant associations with the memory scores. Our results corroborate the role of scalp spindles in memory processes in patients with drug-resistant temporal lobe epilepsy. Yet, physiological and pathological ripples were not separable when using data-driven clustering, and thus our findings do not provide support for a role of sleep ripples as trait-like characteristics of general memory abilities in epilepsy.

A Subpopulation of Spikes Predicts Successful Epilepsy Surgery Outcome.

OBJECTIVE: Epileptic spikes are the traditional interictal electroencephalographic (EEG) biomarker for epilepsy. Given their low specificity for identifying the epileptogenic zone (EZ), they are given only moderate attention in presurgical evaluation. This study aims to demonstrate that it is possible to identify specific spike features in intracranial EEG that optimally define the EZ and predict surgical outcome. METHODS: We analyzed spike features on stereo-EEG segments from 83 operated patients from 2 epilepsy centers (37 Engel IA) in wakefulness, non-rapid eye movement sleep, and rapid eye movement sleep. After automated spike detection, we investigated 135 spike features based on rate, morphology, propagation, and energy to determine the best feature or feature combination to discriminate the EZ in seizure-free and non-seizure-free patients by applying 4-fold cross-validation. RESULTS: The rate of spikes with preceding gamma activity in wakefulness performed better for surgical outcome classification (4-fold area under receiver operating characteristics curve [AUC] = 0.755 ± 0.07) than the seizure onset zone, the current gold standard (AUC = 0.563 ± 0.05, p = 0.015) and the ripple rate, an emerging seizure-independent biomarker (AUC = 0.537 ± 0.07, p = 0.006). Channels with a spike-gamma rate exceeding 1.9/min had an 80% probability of being in the EZ. Combining features did not improve the results. INTERPRETATION: Resection of brain regions with high spike-gamma rates in wakefulness is associated with a high probability of achieving seizure freedom. This rate could be applied to determine the minimal number of spiking channels requiring resection. In addition to quantitative analysis, this feature is easily accessible to visual analysis, which could aid clinicians during presurgical evaluation. ANN NEUROL 2023;93:522-535.

Does epileptic activity impair sleep-related memory consolidation in epilepsy? A critical and systematic review.

STUDY OBJECTIVES: People with epilepsy often complain about disturbed sleep and cognitive impairment. Beyond seizures, the occurrence of interictal epileptic activity during sleep is also increasingly recognized to negatively impact cognitive functioning, including memory processes. The aim of this study was to critically review the effect of interictal epileptic activity on sleep-related memory consolidation. METHODS: PubMed and PsychINFO databases were systematically searched to identify experimental studies that investigated sleep-related memory consolidation and the relationships between sleep-related epileptic activity and memory in adults and children with epilepsy. This review also highlights hypotheses regarding the potential pathophysiological mechanisms. RESULTS: A total of 261 studies were identified; 27 of these met selection criteria. Only 13 studies prospectively assessed the effect of sleep on memory in epilepsy. Most studies reported no alteration of sleep-related memory consolidation in patients, with either similar retention levels following a period containing sleep (n = 5) or improved memory performance postsleep (n = 4). Two studies in children with epilepsy found impaired sleep-related memory consolidation. Ten studies, of which 6 were in childhood epilepsy syndromes, reported a debilitating effect of sleep-related epileptic activity on memory functioning. CONCLUSIONS: Conclusions from existing studies were hampered by small sample sizes, heterogeneous patient groups, and variations in memory assessment techniques. Overall, results to date preclude any definitive conclusions on the alteration of sleep-related memory consolidation in epilepsy. We discuss methodological considerations specific to people with epilepsy and provide suggestions on how to best investigate the relationship between epileptic activity, sleep, and memory consolidation in future studies. CITATION: Latreille V, Schiller K, Peter-Derex L, Frauscher B. Does epilepticimpair sleep-related memory consolidation in epilepsy? A critical and systematic review. J Clin Sleep Med. 2022;18(10):2481-2495.

Objectively measured sleep-wake patterns in patients with drug-resistant epilepsy - Interaction with quality of life and antiepileptic treatment.

RATIONALE: Patients with epilepsy experience frequent episodes of fragmented sleep which may contribute to chronic sleep loss. Enhancing sleep patterns might lead to improved quality of life in these patients. Currently, unlike some other antiepileptic drugs (AEDs), there are no data on the effects of clobazam, a novel AED on sleep. Therefore, we tested the hypothesis that patients with epilepsy will have longer, more consolidated sleep after treatment with clobazam. METHODS: In this prospective study, we included adults with drug-resistant epilepsy who were being considered for treatment with clobazam. Patients with known untreated moderate/severe sleep apnea or with major circadian rhythm disorders were excluded. We tested a set of the following subjective sleep measures: Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS), Karolinska Sleepiness Scale (KSS), Insomnia Severity Index (ISI), and Quality of Life in Epilepsy (QOLIE) prior to starting the treatment, as well as after achieving a stable clobazam dose. We also measured sleep pattern using wrist actigraphy - before starting therapy and after achieving stable dose. RESULTS: A total of 12 participants completed all parts of the study. After treatment, a lower number of awakenings and less wake after sleep onset (WASO) were seen, as well as a lower number of seizures. Average pretreatment bedtime was 23:45, and average wake time was 8:24. A higher seizure frequency significantly correlated with all subjective sleep measures, as well as with a higher amount actigraphy measured WASO and less total sleep time (TST) measured both by sleep log and by actigraphy. Those with higher baseline WASO by actigraphy also had more depressive symptoms, worse quality of life, longer duration of epilepsy, and a higher seizure frequency. CONCLUSION: Both objective and subjective sleep metrics correlate with depressive symptoms and quality of life. After treatment, there were fewer awakenings as well as fewer seizures.

Sleep Disruption in Epilepsy: Ictal and Interictal Epileptic Activity Matter.

OBJECTIVE: Disturbed sleep is common in epilepsy. The direct influence of nocturnal epileptic activity on sleep fragmentation remains poorly understood. Stereo-electroencephalography paired with polysomnography is the ideal tool to study this relationship. We investigated whether sleep-related epileptic activity is associated with sleep disruption. METHODS: We visually marked sleep stages, arousals, seizures, and epileptic bursts in 36 patients with focal drug-resistant epilepsy who underwent combined stereo-electroencephalography/polysomnography during presurgical evaluation. Epileptic spikes were detected automatically. Spike and burst indices (n/sec/channel) were computed across four 3-second time windows (baseline sleep, pre-arousal, arousal, and post-arousal). Sleep stage and anatomic localization were tested as modulating factors. We assessed the intra-arousal dynamics of spikes and their relationship with the slow wave component of non-rapid eye-movement sleep (NR) arousals. RESULTS: The vast majority of sleep-related seizures (82.4%; 76.5% asymptomatic) were followed by awakenings or arousals. The epileptic burst index increased significantly before arousals as compared to baseline and postarousal, irrespective of sleep stage or brain area. A similar pre-arousal increase was observed for the spike index in NR stage 2 and rapid eye-movement sleep. In addition, the spike index increased during the arousal itself in neocortical channels, and was strongly correlated with the slow wave component of NR arousals (r = 0.99, p < 0.0001). INTERPRETATION: Sleep fragmentation in focal drug-resistant epilepsy is associated with ictal and interictal epileptic activity. The increase in interictal epileptic activity before arousals suggests its participation in sleep disruption. An additional increase in the spike rate during arousals may result from a sleep-wake boundary instability, suggesting a bidirectional relationship. ANN NEUROL 2020;88:907-920.

The human K-complex: Insights from combined scalp-intracranial EEG recordings.

Sleep spindles and K-complexes (KCs) are a hallmark of N2 sleep. While the functional significance of spindles is comparatively well investigated, there is still ongoing debate about the role of the KC: it is unclear whether it is a cortical response to an arousing stimulus (either external or internal) or whether it has sleep-promoting properties. Invasive intracranial EEG recordings from individuals with drug-resistant epilepsy offer a unique opportunity to study in-situ human brain physiology. To better understand the function of the KC, we aimed to (i) investigate the intracranial correlates of spontaneous scalp KCs, and (ii) compare the intracranial activity of scalp KCs associated or not with arousals. Whole-night recordings from adults with drug-resistant focal epilepsy who underwent combined intracranial-scalp EEG for pre-surgical evaluation at the Montreal Neurological Institute between 2010 and 2018 were selected. KCs were visually marked in the scalp and categorized according to the presence of microarousals: (i) Pre-microarousal KCs; (ii) KCs during an ongoing microarousal; and (iii) KCs without microarousal. Power in different spectral bands was computed to compare physiological intracranial EEG activity at the time of scalp KCs relative to the background, as well as to compare microarousal subcategories. A total of 1198 scalp KCs selected from 40 subjects were analyzed, resulting in 32,504 intracranial KC segments across 992 channels. Forty-seven percent of KCs were without microarousal, 30% were pre-microarousal, and 23% occurred during microarousals. All scalp KCs were accompanied by widespread cortical increases in delta band power (0.3-4 â€‹Hz) relative to the background: the highest percentages were observed in the parietal (60-65%) and frontal cortices (52-58%). Compared to KCs without microarousal, pre-microarousal KCs were accompanied by increases (66%) in beta band power (16-30 â€‹Hz) in the motor cortex, which was present before the peak of the KC. In addition, spatial distribution of spectral power changes following each KC without microarousal revealed that certain brain regions were associated with increases in delta power (25-62%) or decreases in alpha/beta power (11-24%), suggesting a sleep-promoting pattern, whereas others were accompanied by increases of higher frequencies (12-27%), suggesting an arousal-related pattern. This study shows that KCs can be generated across widespread cortical areas. Interestingly, the motor cortex shows awake-like EEG activity before the onset of KCs followed by microarousals. Our findings also highlight region-specific sleep- or arousal-promoting responses following KCs, suggesting a dual role for the human KC.

Novel non-pharmacological insomnia treatment - a pilot study.

OBJECTIVE: The objective of this prospective pilot study was to examine the effects of a novel non-pharmacological device (BioBoosti) on insomnia symptoms in adults. METHODS: Subjects with chronic insomnia were instructed to hold the device in each hand for 8 mins for 6 cycles on a nightly basis for 2 weeks. Outcomes tested included standardized subjective sleep measures assessing sleep quality, insomnia symptoms, and daytime sleepiness. Sleep was objectively quantified using electroencephalogram (EEG) before and after 2 weeks of treatment with BioBoosti, and wrist actigraphy throughout the study. RESULTS: Twenty adults (mean age: 45.6±17.1 y/o; range 18-74 y/o) were enrolled in the study. No significant side effects were noted by any of the subjects. After 2 weeks of BioBoosti use, subjects reported improved sleep quality (Pittsburgh Sleep Quality Index: 12.6±3.3 versus 8.5±3.7, p=0.001) and reduced insomnia symptoms (Insomnia Severity Index: 18.2±5.2 versus 12.8±7.0, p<0.001). Sleepiness, as assessed by a visual analog scale, was significantly reduced after treatment (5.7±2.8 versus 4.0±3.3, p=0.03). CONCLUSION: BioBoosti use yielded an improvement in insomnia symptoms. Larger placebo-controlled studies are needed to fully assess efficacy.

Age-related cortical signatures of human sleep electroencephalography.

Accumulating evidence demonstrates a direct relationship between impaired neural integrity and disrupted sleep physiology in normal and pathological aging. However, previous work has focus almost exclusively on nonrapid eye movement sleep electroencephalography as a proxy of cortical integrity with aging. Whether this relationship holds true for rapid eye movement sleep electroencephalography is unknown. Our results show that age-related reduction in low-frequency delta activity during both rapid eye movement and nonrapid eye movement sleep was statistically mediated by the thinning of the medial frontal and anterior cingulate cortices. These findings (1) support the potential role of the medial frontal and cingulate cortices, major hubs of the human brain, in synchronizing neuronal assemblies during sleep, and (2) suggest that, with age, a reduction in cortical integrity within this frontal network mediates the loss of delta power during sleep. Further work will determine whether cortical thinning and delta loss may interact and contribute to cognitive decline with aging.

Neuropsychological correlates of obstructive sleep apnea severity in patients with epilepsy.

Obstructive sleep apnea affects up to 30% of patients with epilepsy. As obstructive sleep apnea represents a clinical risk factor for cognitive deficits, its occurrence in epilepsy patients may exacerbate cognitive deficits associated with this condition. However, the cognitive burden of obstructive sleep apnea in epilepsy remains poorly understood. We conducted a retrospective record review of adults with epilepsy who underwent a polysomnography and a neuropsychological assessment at Brigham and Women's Hospital. We examined the relationship between obstructive sleep apnea severity and cognitive functioning, particularly attention/executive functions, memory, and processing speed in untreated obstructive sleep apnea patients with epilepsy. Twenty patients with epilepsy and mild-to-severe obstructive sleep apnea were included in the analyses. We found significant positive correlations between the oxygen saturation levels during rapid-eye-movement sleep and attention/executive tests (p<0.05), as well as time spent with saturation levels ≤90% and executive functioning (p=0.008). Similarly, worse verbal memory performances were associated with lower oxygen levels (p=0.003). In addition, more severe respiratory events during rapid-eye-movement sleep were associated with worse performances on attention tests (p=0.03). Our findings indicate that more severe obstructive sleep apnea-related hypoxemia during sleep is associated with poorer cognitive performances on tests that assess attention/executive functions and verbal memory in patients with epilepsy. Overall, these results are consistent with the sleep apnea literature, and suggest that patients with epilepsy are also vulnerable to the effects of obstructive sleep apnea. Future prospective studies will help in determining whether treatment of obstructive sleep apnea may help improve cognitive functioning in patients with epilepsy.

Sleep disturbances in patients with psychogenic non-epileptic seizures: Is it all subjective? A prospective pilot study of sleep-wake patterns.

PURPOSE: Patients with psychogenic non-epileptic seizures (PNES) frequently complain of poor sleep, yet there are few and inconsistent data supporting objective sleep disturbances in this population. In this prospective observational study, we aimed to compare objective and subjective sleep-wake patterns in patients with PNES with those with epilepsy. METHODS: Subjects were recruited through the Brigham and Women's Epilepsy Monitoring Unit (EMU) over a 6-month period, and were diagnosed as having PNES or epilepsy by experts using video-electroencephalography (v-EEG). Sleep-wake patterns were objectively examined using EEG and actigraphy during EMU admission. Subjects also completed several validated questionnaires on sleep. RESULTS: Twenty-seven subjects, including 17 with PNES and 10 with epilepsy were enrolled in the study. Compared to controls with epilepsy, PNES subjects showed greater sleep onset latency (48.7 ± 47.5 min vs 14.0 ± 13.4 min; p = 0.02). Otherwise, sleep architecture was similar between the groups. However, subjectively, PNES subjects reported worse sleep quality (10.8 ± 5.1 vs 5.8 ± 2.9; p = 0.01) and were more likely to meet clinical criteria for insomnia relative to epilepsy subjects (50% vs 10%, p = 0.05). Moreover, a higher proportion of PNES subjects reported taking medications for sleep (44% vs 0%, p = 0.01). CONCLUSION: Overall, we found more evidence for a subjective basis rather than a pathophysiological nature for the reported sleep disturbances in PNES subjects. In addition to educating PNES patients on the importance of maintaining good sleep habits, clinicians should address sleep complaints and screen for insomnia, as effective treatments are available and may improve overall health.

Sleep Disorders.

Sleep disorders are frequent and can have serious consequences on patients' health and quality of life. While some sleep disorders are more challenging to treat, most can be easily managed with adequate interventions. We review the main diagnostic features of 6 major sleep disorders (insomnia, circadian rhythm disorders, sleep-disordered breathing, hypersomnia/narcolepsy, parasomnias, and restless legs syndrome/periodic limb movement disorder) to aid medical practitioners in screening and treating sleep disorders as part of clinical practice.

Sleep in psychogenic nonepileptic seizures: Time to raise a red flag.

Poor sleep is a frequent complaint in patients with psychogenic nonepileptic seizures (PNES). However, few studies have examined sleep problems in this population. We aimed to compare sleep complaints in patients with PNES with those with epilepsy. Subjects diagnosed as having PNES by experts using video-electroencephalography (vEEG) were recruited through the Brigham and Women's Hospital epilepsy monitoring unit (EMU) between 3/25/2013 and 3/29/2018. Controls were patients with epilepsy recruited through the EMU and subspecialty clinics. All subjects were given the Beck Depression Inventory, 2nd Edition (BDI-II) and the Quality of Life in Epilepsy Inventory-10 (QOLIE-10). Subjective sleep problems were identified from item 16 (changes in sleep patterns) of the BDI-II. Independent sample t-test, chi-square test, and Spearman correlation were used. A total of 149 patients with PNES and 82 patients with epilepsy completed the BDI-II and QOLIE-10. Compared with control subjects with epilepsy, patients with PNES more frequently reported moderate-severe changes in sleep patterns, notably sleeping less than usual, waking up 1-2 h too early, and having trouble returning to sleep. These changes in sleep patterns were associated with worse quality of life. Our findings suggest that sleep is more commonly reported as a problem in PNES compared with epilepsy. Because sleep plays a major role in good health, understanding the specific sleep problem in PNES may provide insight for improving quality of life for this challenging disorder.

Positive Airway Pressure Therapy Is Challenging for Patients With Epilepsy.

STUDY OBJECTIVES: To investigate whether patients with epilepsy and comorbid obstructive sleep apnea (OSA) are more likely to be nonadherent to positive airway pressure (PAP) therapy than adults with OSA but without epilepsy. METHODS: This retrospective study included patients with epilepsy diagnosed with OSA and age-, sex-, and apnea-hypopnea index (AHI)-matched controls with OSA but without epilepsy who started PAP treatment between February 2014 and August 2017. Subjects' adherence to PAP therapy was continuously recorded electronically, and comparisons were made at 1 month, 3 months, and 1 year following PAP initiation. Predictors to poor adherence were also evaluated. RESULTS: Patients with epilepsy (n = 23) were less adherent to PAP than controls (n = 23) during the first month of treatment (13% versus 78%, P = .03). During this first month, average PAP use was lower in patients with epilepsy (4.7 ± 2.1 hours) relative to controls (6.1 ± 1.2 hours, P = .03). Despite sustained PAP treatment, patients with epilepsy had a greater residual AHI and were five times more likely than controls to have residual apnea events above normal range at 3-month and 1-year follow-up. However, no clinical characteristics could significantly predict poor adherence in patients. CONCLUSIONS: Patients with epilepsy are less likely to be adherent to PAP therapy during the first month of treatment, as compared to adults with OSA but no epilepsy. Moreover, PAP therapy could not sufficiently reduce AHI in up to 72% of patients. These findings highlight the need for careful monitoring of PAP treatment in patients with epilepsy, as untreated OSA may worsen seizure burden.

Co-morbid sleep disorders and epilepsy: A narrative review and case examples.

Co-morbid sleep disorders, including sleep apnea, insomnia, restless legs syndrome, and the parasomnias, occur frequently in people with epilepsy. This article reviews the cardinal presenting symptoms and diagnostic features of each of these disorders to enable epileptologists to readily screen and identify sleep co-morbidities in their patients. It summarizes current evidence concerning the reciprocal relationship between sleep disturbances and epilepsy and available treatment options for common sleep disorders in people with epilepsy. Several illustrative cases demonstrate the practical consequences of co-morbid sleep disorders in epilepsy patients and suggest diagnostic and treatment approaches that may improve daytime functioning, alertness, quality of life, and seizure burden.

Nocturnal seizures are associated with more severe hypoxemia and increased risk of postictal generalized EEG suppression.

Patients with epilepsy have 20-fold risk of sudden death when compared to the general population. Uncontrolled seizures is the most consistent risk factor, and death often occurs at night or in relation to sleep. We examined seizure-related respiratory disturbances in sleep versus wakefulness, focusing on periictal oxygen saturation. Respiratory measures were examined in 48 recorded seizures (sleep, n = 23, wake, n = 25) from 20 adult patients with epilepsy. Seizures from sleep were associated with lower saturation, as compared to seizures from wakefulness, both during ictal (sleep median = 90.8, wake median = 95.5; p < 0.01) and postictal periods (sleep median = 94.3, wake median = 96.9; p = 0.05). Compared to wake-related seizures, seizures from sleep were also associated with a larger desaturation drop (sleep median = -4.2, wake median = -1.2; p = 0.01). Postictal generalized electroencephalography (EEG) suppression (PGES) occurred more frequently after seizures from sleep (39%), as compared to wake-related seizures (8%, p = 0.01). Our findings suggest that nocturnal seizures may entail a higher sudden unexpected death in epilepsy (SUDEP) severity burden, as they are associated with more severe and longer hypoxemia events, and more frequently followed by PGES, both factors implicated in sudden death.

REM Sleep Behavior Disorder and Cognitive Impairment in Parkinson's Disease.

Study Objectives: REM sleep behavior disorder (RBD) is a parasomnia affecting 33% to 46% of patients with Parkinson's disease (PD). The existence of a unique and specific impaired cognitive profile in PD patients with RBD is still controversial. We extensively assessed cognitive functions to identify whether RBD is associated with more severe cognitive deficits in nondemented patients with PD. Methods: One hundred sixty-two participants, including 53 PD patients with RBD, 40 PD patients without RBD, and 69 healthy subjects, underwent polysomnography, a neurological assessment and an extensive neuropsychological exam to assess attention, executive functions, episodic learning and memory, visuospatial abilities, and language. Results: PD patients with RBD had poorer and clinically impaired performance in several cognitive tests compared to PD patients without RBD and healthy subjects. These two latter groups were similar on all cognitive measures. Mild cognitive impairment (MCI) diagnosis frequency was almost threefold higher in PD patients with RBD compared to PD patients without RBD (66% vs. 23%, p < .001). Moreover, subjective cognitive decline was reported in 89% of PD patients with RBD compared to 58% of PD patients without RBD (p = .024). Conclusions: RBD in PD is associated with a more impaired cognitive profile and higher MCI diagnosis frequency, suggesting more severe and widespread neurodegeneration. This patient subgroup and their caregivers should receive targeted medical attention to better detect and monitor impairment and to enable the development of management interventions for cognitive decline and its consequences.

Electroencephalographic prodromal markers of dementia across conscious states in Parkinson's disease.

In Parkinson's disease, electroencephalographic abnormalities during wakefulness and non-rapid eye movement sleep (spindles) were found to be predictive biomarkers of dementia. Because rapid eye movement sleep is regulated by the cholinergic system, which shows early degeneration in Parkinson's disease with cognitive impairment, anomalies during this sleep stage might mirror dementia development. In this prospective study, we examined baseline electroencephalographic absolute spectral power across three states of consciousness (non-rapid eye movement sleep, rapid eye movement sleep, and wakefulness) in 68 non-demented patients with Parkinson's disease and 44 healthy controls. All participants underwent baseline polysomnographic recordings and a comprehensive neuropsychological assessment. Power spectral analyses were performed on standard frequency bands. Dominant occipital frequency during wakefulness and ratios of slow-to-fast frequencies during rapid eye movement sleep and wakefulness were also computed. At follow-up (an average 4.5 years after baseline), 18 patients with Parkinson's disease had developed dementia and 50 patients remained dementia-free. In rapid eye movement sleep, patients with Parkinson's disease who later developed dementia showed, at baseline, higher absolute power in delta and theta bands and a higher slowing ratio, especially in temporal, parietal, and occipital regions, compared to patients who remained dementia-free and controls. In non-rapid eye movement sleep, lower baseline sigma power in parietal cortical regions also predicted development of dementia. During wakefulness, patients with Parkinson's disease who later developed dementia showed lower dominant occipital frequency as well as higher delta and slowing ratio compared to patients who remained dementia-free and controls. At baseline, higher slowing ratios in temporo-occipital regions during rapid eye movement sleep were associated with poor performance on visuospatial tests in patients with Parkinson's disease. Using receiver operating characteristic curves, we found that best predictors of dementia in Parkinson's disease were rapid eye movement sleep slowing ratios in posterior regions, wakefulness slowing ratios in temporal areas, and lower dominant occipital frequency. These results suggest that electroencephalographic slowing during sleep is a new promising predictive biomarker for Parkinson's disease dementia, perhaps as a marker of cholinergic denervation.

Brain Connectivity Alterations Are Associated with the Development of Dementia in Parkinson's Disease.

Dementia affects a high proportion of Parkinson's disease (PD) patients and poses a burden on caregivers and healthcare services. Electroencephalography (EEG) is a common nonevasive and nonexpensive technique that can easily be used in clinical settings to identify brain functional abnormalities. Only few studies had identified EEG abnormalities that can predict PD patients at higher risk for dementia. Brain connectivity EEG measures, such as multiscale entropy (MSE) and phase-locking value (PLV) analyses, may be more informative and sensitive to brain alterations leading to dementia than previously used methods. This study followed 62 dementia-free PD patients for a mean of 3.4 years to identify cerebral alterations that are associated with dementia. Baseline resting state EEG of patients who developed dementia (N = 18) was compared to those of patients who remained dementia-free (N = 44) and of 37 healthy subjects. MSE and PLV analyses were performed. Partial least squares statistical analysis revealed group differences associated with the development of dementia. Patients who developed dementia showed higher signal complexity and lower PLVs in low frequencies (mainly in delta frequency) than patients who remained dementia-free and controls. Conversely, both patient groups showed lower signal variability and higher PLVs in high frequencies (mainly in gamma frequency) compared to controls, with the strongest effect in patients who developed dementia. These findings suggest that specific disruptions of brain communication can be measured before PD patients develop dementia, providing a new potential marker to identify patients at highest risk of developing dementia and who are the best candidates for neuroprotective trials.

Observational Study of the Relation between Parkinson's Disease and Sleep Apnea.

BACKGROUND: Parkinson's disease is characterized by numerous non-motor symptoms, including sleep disorders. Sleep apnea has been reported in a substantial proportion of patients with Parkinson's disease, but it is unclear whether it has significant consequences for the quality of life of those affected or whether it is associated with other manifestations of the disease. OBJECTIVE: To verify whether sleep apnea is associated with more severe motor and non-motor clinical features in Parkinson's disease. METHODS: Parkinson's disease patients underwent polysomnography to diagnose the presence of sleep apnea (apnea-hypopnoea index >10). Participants also underwent an extensive assessment, blinded to sleep apnea status, to determine disease severity, quantitative motor indices, motor subtypes, treatment complications, and sleep, autonomic, psychiatric, and sensory dysfunctions. Cognitive status was also determined with a complete neuropsychological assessment. Results were assessed using regression analysis adjusted for age, sex, and disease duration. RESULTS: Of 92 patients examined, 19 had sleep apnea (21%) and 73 did not. We found no significant differences in motor and non-motor symptoms or signs between apneic and non-apneic Parkinson's disease patients. The use of different apnea-hypopnoea index cut-offs (>5 and >15) produced similar results. CONCLUSIONS: Our results show that sleep apnea is not associated with more severe motor or non-motor manifestations in Parkinson's disease. More studies including control groups are needed to confirm the implications of those results.

New Clinical Subtypes of Parkinson Disease and Their Longitudinal Progression: A Prospective Cohort Comparison With Other Phenotypes.

IMPORTANCE: There is increasing evidence that Parkinson disease (PD) is heterogeneous in its clinical presentation and prognosis. Defining subtypes of PD is needed to better understand underlying mechanisms, predict disease course, and eventually design more efficient personalized management strategies. OBJECTIVES: To identify clinical subtypes of PD, compare the prognosis and progression rate between PD phenotypes, and compare the ability to predict prognosis in our subtypes and those from previously published clustering solutions. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study. The cohorts were from 2 movement disorders clinics in Montreal, Quebec, Canada (patients were enrolled during the period from 2005 to 2013). A total of 113 patients with idiopathic PD were enrolled. A comprehensive spectrum of motor and nonmotor features (motor severity, motor complications, motor subtypes, quantitative motor tests, autonomic and psychiatric manifestations, olfaction, color vision, sleep parameters, and neurocognitive testing) were assessed at baseline. After a mean follow-up time of 4.5 years, 76 patients were reassessed. In addition to reanalysis of baseline variables, a global composite outcome was created by merging standardized scores for motor symptoms, motor signs, cognitive function, and other nonmotor manifestations. MAIN OUTCOMES AND MEASURES: Changes in the quintiles of the global composite outcome and its components were compared between different subtypes. RESULTS: The best cluster solution found was based on orthostatic hypotension, mild cognitive impairment, rapid eye movement sleep behavior disorder (RBD), depression, anxiety, and Unified Parkinson's Disease Rating Scale Part II and Part III scores at baseline. Three subtypes were defined as mainly motor/slow progression, diffuse/malignant, and intermediate. Despite similar age and disease duration, patients with the diffuse/malignant phenotype were more likely to have mild cognitive impairment, orthostatic hypotension, and RBD at baseline, and at prospective follow-up, they showed a more rapid progression in cognition (odds ratio [OR], 8.7 [95% CI, 4.0-18.7]; P < .001), other nonmotor symptoms (OR, 10.0 [95% CI, 4.3-23.2]; P < .001), motor signs (OR, 4.1 [95% CI, 1.8-9.1]; P = .001), motor symptoms (OR, 2.9 [95% CI, 1.3-6.2]; P < .01), and the global composite outcome (OR, 8.0 [95% CI, 3.7-17.7]; P < .001). CONCLUSIONS AND RELEVANCE: It is recommended to screen patients with PD for mild cognitive impairment, orthostatic hypotension, and RBD even at baseline visits. These nonmotor features identify a diffuse/malignant subgroup of patients with PD for whom the most rapid progression rate could be expected.