Interrelationship of Sleep Disturbances and Cognitive Status on Mortality.

Sleep disturbances may promote the development and advancement of Alzheimer's disease. Our purpose was to determine if sleep disturbances were associated with earlier mortality while accounting for cognition. The National Alzheimer's Coordinating Center database was used to evaluate mortality risk conferred by sleep, and the Montreal Cognitive Assessment score determined cognitive status. Demographics, sleep disturbances, cognitive status, and comorbid/other neuropsychiatric conditions were examined as predictors of survival time via Cox regression. The sample (N = 31,110) had a median age [interquartile range] of 72 [66, 79] years, MoCA score of 23 [16, 26], and survival time of 106.0 months [104.0,108.0]; 10,278 (33%) died during follow-up; 21% (n = 6461) experienced sleep disturbances. Sleep disturbances impacted survival time depending on cognition, with the greatest effect in transition from normal to cognitive impairment (P < .001). Findings support that sleep disturbances negatively impact survival time, and the impact of sleep disturbances on survival time is interrelated with cognition.

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.

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%.

Sleep Disturbances Predict Cognitive Decline in Cognitively Healthy Adults.

BACKGROUND: The effect of nighttime behaviors on cognition has not been studied independently from other neuropsychiatric symptoms. OBJECTIVE: We evaluate the following hypotheses that sleep disturbances bring increased risk of earlier cognitive impairment, and more importantly that the effect of sleep disturbances is independent from other neuropsychiatric symptoms that may herald dementia. METHODS: We used the National Alzheimer's Coordinating Center database to evaluate the relationship between Neuropsychiatric Inventory Questionnaire (NPI-Q) determined nighttime behaviors which served as surrogate for sleep disturbances and cognitive impairment. Montreal Cognitive Assessment scores defined two groups: conversion from 1) normal to mild cognitive impairment (MCI) and 2) MCI to dementia. The effect of nighttime behaviors at initial visit and covariates of age, sex, education, race, and other neuropsychiatric symptoms (NPI-Q), on conversion risk were analyzed using Cox regression. RESULTS: Nighttime behaviors predicted earlier conversion time from normal cognition to MCI (hazard ratio (HR): 1.09; 95% CI: [1.00, 1.48], p = 0.048) but were not associated with MCI to dementia conversion (HR: 1.01; [0.92, 1.10], p = 0.856). In both groups, older age, female sex, lower education, and neuropsychiatric burden increased conversion risk. CONCLUSION: Our findings suggest that sleep disturbances predict earlier cognitive decline independently from other neuropsychiatric symptoms that may herald dementia.

Indications for continuous electroencephalographic (cEEG) monitoring: What do they tell us?

OBJECTIVE: While studies have explored clinical and EEG predictors of seizures on continuous EEG (cEEG), the role of cEEG indications as predictors of seizures has not been studied. Our study aims to fill this knowledge gap. METHODS: We used the prospective cEEG database at Cleveland Clinic for the 2016 calendar year. Patients ≥ 18 years who underwent cEEG for the indication of altered mental status (AMS) and seizure-like events (SLE: motor or patient-reported events) were included. Baseline characteristics and EEG findings were compared between the two groups. Multivariable regression was used to compare the two groups and identify seizure detection risk factors. RESULTS: Of 2227 patients (mean age 59.4 years) who met the inclusion criteria, 882 (50% females) underwent cEEG for AMS and 1345(51% females) for SLE. SLE patients were younger(OR: 0.988, CI: 0.98-0.99, p < 0.001), had longer monitoring(OR:1.04, CI:1.00-1.07, p = 0.033), were more likely to have epilepsy-related-breakthrough seizures(OR:25.9, CI:0.5.89-115, p < 0.001), psychogenic non-epileptic spells (OR:6.85, CI:1.60-29.3, p = 0.008), were more awake (p < 0.001) and more likely to be on anti-seizure medications(OR:1.60, CI:1.29-1.98, p < 0.001). On multivariable analysis, SLE was an independent predictor of seizure detection (OR: 2.60, CI: 1.77-3.88, p < 0.001). SIGNIFICANCE: Our findings highlight the differences in patients undergoing cEEG for AMS vs. SLE. SLE as a cEEG indication represents an independent predictor of seizures on cEEG and, therefore, deserves special attention. Future multicenter studies are needed to validate our findings.

Does Alzheimer's disease with mesial temporal lobe epilepsy represent a distinct disease subtype?

Alzheimer's disease (AD) patients have a high risk of developing mesial temporal lobe epilepsy (MTLE) and subclinical epileptiform activity. MTLE in AD worsens outcomes. Therefore, we need to understand the overlap between these disease processes. We hypothesize that AD with MTLE represents a distinct subtype of AD, with the interplay between tau and epileptiform activity at its core. We discuss shared pathological features including histopathology, an initial mesial temporal lobe (MTL) hyperexcitability followed by MTL dysfunction and involvement of same networks in memory (AD) and seizures (MTLE). We provide evidence that tau accumulation linearly increases neuronal hyperexcitability, neuronal hyper-excitability increases tau secretion, tau can provoke seizures, and tau reduction protects against seizures. We speculate that AD genetic mutations increase tau, which causes proportionate neuronal loss and/or hyperexcitability, leading to seizures. We discuss that tau burden in MTLE predicts cognitive deficits among (1) AD and (2) MTLE without AD. Finally, we explore the possibility that anti-seizure medications improve cognition by reducing neuronal hyper-excitability, which reduces seizures and tau accumulation and spread. HIGHLIGHTS: We hypothesize that patients with Alzheimer's disease (AD) and mesial temporal lobe epilepsy (MTLE) represents a distinct subtype of AD. AD and MTLE share histopathological features and involve overlapping neuronal and cortical networks. Hyper-phosphorylated tau (pTau) increases neuronal excitability and provoke seizures, neuronal excitability increases pTau, and pTau reduction reduces neuronal excitability and protects against seizures. The pTau burden in MTL predicts cognitive deficits among (1) AD and (2) MTLE without AD. We speculate that anti-seizure medications improve cognition by reducing neuronal excitability, which reduces seizures and pTau.

Sleep Disturbances, Cognitive Status, and Biomarkers of Dementia.

BACKGROUND: While sleep disturbances appear to be risk factors in Alzheimer's disease (AD) progression, information such as the prevalence across dementia severity and the influence on the trajectory of cognitive decline is unclear. OBJECTIVE: We evaluate the hypotheses that the prevalence of insomnia differs by cognitive impairment, that sleep disturbances track with AD biomarkers, and that longitudinal changes in sleep disorders affect cognition. METHODS: We used the National Alzheimer's Coordinating Center Database to determine the prevalence of clinician-identified insomnia and nighttime behaviors in normal, mild cognitive impairment (MCI), and demented individuals. We evaluated mean Montreal Cognitive Assessment (MoCA) scores, hippocampal volumes (HV), and CSF phosphorylated tau:amyloid-ß ratios at first visit using analysis of variance with age as a covariate. In longitudinal evaluations, we assessed changes in MoCA scores and HV in insomnia and nighttime behaviors between the first and last visits. RESULTS: Prevalence of insomnia was 14%, 16%, and 11% for normal, MCI, and dementia groups. Prevalence of nighttime behaviors was 14%, 21%, and 29% respectively. Insomnia patients had higher MoCA scores, larger HV, and lower pTauBeta than individuals without insomnia, indicating less neurodegeneration. In contrast, nighttime behaviors were associated with worse cognition, smaller HV, and higher pTauBeta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and HV. CONCLUSION: Our findings suggest that insomnia is unreliably recognized in patients with cognitive impairment. Nighttime behaviors may better indicate the presence of sleep disturbances and have diagnostic specificity in AD over insomnia.

Electrographic Features of Epilepsy With Eyelid Myoclonia With Photoparoxysmal Responses.

PURPOSE: Epilepsy with eyelid myoclonia (EMA) is characterized by eyelid myoclonia, eyelid closure sensitivity, and photosensitivity. EEG may manifest with frontal-predominant (FPEDs) or occipital-predominant epileptiform discharges (OPEDs). Data on clinical and electrographic features of these two subtypes are lacking. The purpose of our research was to look at baseline electroclinical features of EMA subtypes and to study electrographic findings of patients with EMA during intermittent photic stimulation (IPS). METHODS: We retrospectively identified all patients who had photoparoxysmal responses on EEGs performed at Cleveland clinic between January 01, 2012, and December 31, 2019. Patients who met diagnostic criteria for EMA were studied further. RESULTS: Of the 249 patients with photoparoxysmal responses, 70 (28.1%) had EMA (62 [88.6%] female; the mean age of epilepsy onset: 7.0 ± 7.9 years). Patients with EMA had either FPEDs or OPEDs. Eleven patients with EMA (15.7%) had seizures (4 absence, 5 myoclonic and 2 bilateral tonic-clonic) during IPS. Patients with OPEDs were more likely to have drug-resistant epilepsy; occipital focal IEDs and other focal IEDs (other than frontal/occipital) on baseline EEG; and generalized IEDs with occipital predominance, generalized IEDs with no predominance, or focal IEDs during IPS. Predictors of seizure occurrence during photic stimulation included the presence of focal occipital IEDs on baseline EEG, generalized IEDs with frontal predominance during IPS, and photoparoxysmal response outlasting the stimulus. CONCLUSIONS: Our study provides evidence that EMA has two distinct subtypes, which differ in clinical characteristics, baseline EEG, and EEG during photic stimulation. We highlight diagnostic and prognostic implications of these findings. Our study also details EEG characteristics of patients with EMA during IPS.

Epilepsy with Eyelid myoclonias - A diagnosis concealed in other genetic generalized epilepsies with photoparoxysmal response.

OBJECTIVE: Epilepsy with eyelid myoclonias(EMA) is a genetic generalized epilepsy (GGE) characterized by eyelid myoclonia, eye-closure sensitivity and photosensitivity. Data on EMA patients who specifically present with photoparoxysmal response on EEG is lacking. EMA is an under-recognized syndrome which is frequently misclassified as another GGE. The main objective of our research is to describe the occurrence of EMA versus other GGEs among patients with photoparoxysmal response and evaluate their distinguishing features. METHODS: We retrospectively identified all patients who had photoparoxysmal response on EEGs performed at Cleveland clinic between 01/01/2012 and 12/31/2019. Initial epilepsy diagnosis and clinical data were collected. EEGs were reviewed for eyelid myoclonia and eye-closure-sensitivity which were used as main diagnostic clues for EMA. If clinical criteria was met, diagnosis was revised as EMA. RESULTS: Of 249 patients with photoparoxysmal response, 70(28.1%) met EMA criteria. Sixty-two (88.6%) were females. Mean age of onset of epilepsy was 7 years (+7.9) and 120(48.2%) had other GGEs. Fifty-four (77.1%) patients with EMA were initially classified as another epilepsy. Initial diagnosis included CAE or JME in 40(57.1%) patients with EMA so we compared EMA with these syndromes. Female preponderance, drug refractoriness, older age of onset and generalized myoclonia were more common in EMA than CAE. Earlier age of onset, absence seizures, and lack of generalized myoclonic jerks were more common EMA than JME. SIGNIFICANCE: Our study demonstrates that EMA is under-recognized among GGE patients with photoparoxysmal response. It highlights distinguishing clinical and electrographic features which separate EMA from other GGEs. It emphasizes the diverse treatments utilized and the need for therapeutic options for patients with refractory EMA.

Risk factors that predict delayed seizure detection on continuous electroencephalogram (cEEG) in a large sample size of critically ill patients.

OBJECTIVE: Majority of seizures are detected within 24 hours on continuous EEG (cEEG). Some patients have delayed seizure detection after 24 hours. The purpose of this research was to identify risk factors that predict delayed seizure detection and to determine optimal cEEG duration for various patient subpopulations. METHODS: We retrospectively identified all patients ≥18 years of age who underwent cEEG at Cleveland clinic during calendar year 2016. Clinical and EEG data for all patients and time to seizure detection for seizure patients were collected. RESULTS: Twenty-four hundred and two patients met inclusion criteria. Of these, 316 (13.2%) had subclinical seizures. Sixty-five (20.6%) patients had delayed seizures detection after 24 hours. Seizure detection increased linearly till 36 hours of monitoring, and odds of seizure detection increased by 46% for every additional day of monitoring. Delayed seizure risk factors included stupor (13.2% after 48 hours, P = .031), lethargy (25.9%, P = .013), lateralized (LPDs) (27.7%, P = .029) or generalized periodic discharges (GPDs) (33.3%, P = .022), acute brain insults (25.5%, P = .036), brain bleeds (32.8%, P = .014), especially multiple concomitant bleeds (61.1%, P < .001), altered mental status (34.7%, P = .001) as primary cEEG indication, and use of antiseizure medications (27.8%, P < .001) at cEEG initiation. SIGNIFICANCE: Given the linear seizure detection trend, 36 hours of standard monitoring appears more optimal than 24 hours especially for high-risk patients. For awake patients without epileptiform discharges, <24 hours of monitoring appears sufficient. Previous studies have shown that coma and LPDs predict delayed seizure detection. We found that stupor and lethargy were also associated with delayed seizure detection. LPDs and GPDs were associated with delayed seizures. Other delayed seizure risk factors included acute brain insults, brain bleeds especially multiple concomitant bleeds, altered mental status as primary cEEG indication, and use of ASMs at cEEG initiation. Longer cEEG (≥48 hours) is suggested for these high-risk patients.

Exacerbation of eyelid myoclonia in patients with epilepsy and eyelid myoclonia receiving cannabidiol.

Epilepsy with eyelid myoclonia or Jeavons Syndrome (JS) is a childhood genetic generalized epilepsy. Its clinical features include eyelid myoclonia (hallmark) with or without brief absences, eyelid closure-induced seizures and/or electroencephalographic (EEG) paroxysms (generalized polyspikes and/or generalized spike-wave activity at 3-6 Hz, elicited by closure of eyelid) and photosensitivity. Broad-spectrum anti-seizure medications are often utilized for the management of JS patients. A wide variety of medications may be utilized especially in refractory cases. Efficacy or safety of cannabidiol (CBD) for JS has not been studied. We describe two cases of exacerbation of eyelid myoclonia in JS which correlated with CBD use and resolved after CBD discontinuation. These cases highlight that caution should be practiced when using CBD for JS as it can potentially worsen eyelid myoclonia.

The Efficacy, Safety, and Outcomes of Brain-responsive Neurostimulation (RNS® System) therapy in older adults.

OBJECTIVES: The gold standard for the management of drug-resistant focal epilepsy (DRE) is resection of epileptogenic zone. However, some patients may not be candidates for resection. Responsive neurostimulation is approved in patients above 18 years of age for such patients. We aimed to investigate whether RNS outcomes and safety varied based on age. METHODS: We performed a single-center retrospective cohort study of patients with DRE who were treated with RNS between May 2008 and February 2020. We included patients who had been implanted with RNS for >6 months (N = 55), dividing them into older (N = 11) and younger adults (N = 44) depending on implantation age (≥50 and <50 years, respectively). RESULTS: Mean age at implantation in older adults was 54.9 ± 3.5 years. Seizure onset age, epilepsy duration, and comorbidities were significantly higher in older adults ( P < .01). Stimulation parameters, treatment duration, and median seizure frequency reduction (76% in older vs 50% in younger adults) were statistically comparable between the two cohorts. Posttreatment, antiseizure medication burden was significantly decreased in older compared with younger adults (P = .048). Postoperative and delayed adverse events among older adults were mild. Compared with three younger adults, none of the older adults required device explantation due to surgical site infection. CONCLUSION: Our study suggests that older adults treated with the RNS System achieve seizure outcomes comparable to younger adults with the additional benefit of a significant postimplantation medication reduction. With efficacy and safety similar to younger adults, brain-responsive neurostimulation was well-tolerated in older adults.