Validation of the RBD Symptom Severity Scale in the North American Prodromal Synucleinopathy Consortium.

BACKGROUND AND OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment. The International RBD Study Group developed the RBD Symptom Severity Scale (RBDSSS) to assess symptom severity for clinical or research use. We assessed the psychometric and clinimetric properties of the RBDSSS in participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium for RBD. METHODS: NAPS participants, who have polysomnogram-confirmed RBD, and their bedpartners completed the RBDSSS (participant and bedpartner versions). The RBDSSS contains 8 questions to assess the frequency and severity/impact of (1) dream content, (2) vocalizations, (3) movements, and (4) injuries associated with RBD. Total scores for participant (maximum score = 54) and bedpartner (maximum score = 38) questionnaires were derived by multiplying frequency and severity scores for each question. The Clinical Global Impression Scale of Severity (CGI-S) and RBD symptom frequency were assessed by a physician during a semistructured clinical interview with participants and, if available, bedpartners. Descriptive analyses, correlations between overall scores, and subitems were assessed, and item response analysis was performed to determine the scale's validity. RESULTS: Among 261 study participants, the median (interquartile range) score for the RBDSSS-PT (participant) was 10 (4-18) and that for the RBDSSS-BP (bedpartner) was 8 (4-15). The median CGI-S was 3 (3-4), indicating moderate severity. RBDSSS-BP scores were significantly lower in women with RBD (6 vs 9, p = 0.02), while there were no sex differences in RBDSSS-PT scores (8 vs 10.5, p = 0.615). Positive correlations were found between RBDSSS-PT vs RBDSSS-BP (Spearman rs = 0.561), RBDSSS-PT vs CGI-S (rs = 0.556), and RBDSSS-BP vs CGI-S (rs = 0.491, all p < 0.0001). Item response analysis showed a high discriminatory value (range 1.40-2.12) for the RBDSSS-PT and RBDSSS-BP (1.29-3.47). DISCUSSION: We describe the RBDSSS with adequate psychometric and clinimetric properties to quantify RBD symptom severity and good concordance between participant and bedpartner questionnaires and between RBDSSS scores and clinician-assessed global severity.

Comorbid neurotrauma increases neurodegenerative-relevant cognitive, motor, and autonomic dysfunction in patients with REM sleep behavior disorder: A substudy of the North American Prodromal Synucleinopathy Consortium.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g., Parkinson's disease (PD), Lewy Body Dementia (LBD), and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) - henceforth "neurotrauma" (NT) - increase the odds of RBD by ~2.5-fold and is associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. METHODS: Participants ≥18 years with overnight-polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy (NAPS) Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory and autonomic function were completed. This cross-sectional analysis compared cases (n=24; RBD+NT) to controls (n=96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). RESULTS: RBD+NT reported earlier RBD symptom onset (37.5±11.9 vs. 52.2±15.1 years of age) and a more severe RBD phenotype. Similarly, RBD+NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. CONCLUSION: This cross-sectional, matched case:control study shows individuals with RBD+NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD+NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.

Increasing access to evidence-based insomnia care in the United States: findings from an American Academy of Sleep Medicine stakeholder summit.

Challenges exist in access to high-quality care for insomnia disorder. After the recent publication of a clinical practice guideline on behavioral and psychological treatments for insomnia in adults, the American Academy of Sleep Medicine (AASM) hosted a 1-day virtual Insomnia Summit in September 2022 to discuss improving care for patients with insomnia disorder. Fifty participants representing a variety of organizations (eg, medical, psychological, and nursing associations; patient advocacy groups; and federal institutions) participated in the event. Videos highlighting patient perspectives on insomnia and an overview of current insomnia disorder treatment guidelines were followed by thematic sessions, each with 3 to 4 brief, topical presentations by content experts. Breakout groups were used to brainstorm and prioritize issues in each thematic area. Top barriers to care for insomnia disorder include limited access, limited awareness of treatment options, low perceived value of insomnia treatment, and an insufficient number of trained clinicians. Top facilitators of high-quality care include education and awareness, novel care models to increase access, expanding the insomnia patient care workforce, incorporating research into practice, and increasing reimbursement for psychotherapies. Priorities for the future include increasing awareness among patients and providers, increasing the number of skilled behavioral sleep medicine providers, increasing advocacy efforts to address insurance issues (eg, billing, reimbursement, and performance measures), and working collaboratively with multidisciplinary organizations to achieve common goals. These priorities highlight that goals set to improve accessible, high-quality care for insomnia disorder will require sustained, coordinated efforts to increase awareness, improve reimbursement, and grow the necessary skilled health care workforce. CITATION: Schotland H, Wickwire E, Aaronson RM, et al. Increasing access to evidence-based insomnia care in the United States: findings from an American Academy of Sleep Medicine stakeholder summit. J Clin Sleep Med. 2024;20(3):455-459.

Autonomic dysregulation during sleep in Parkinsonian spectrum disorders - A proof of concept.

INTRODUCTION: Autonomic dysfunction is common in α-synucleinopathies such as Lewy Body dementias (LBD), Parkinson's disease (PD), and isolated REM Sleep Behavior Disorder (iRBD). We analyzed pulse-rate changes during sleep to index autonomic nervous system (ANS) dysfunction in patients with α-synucleinopathies vs. non-synucleinopathy groups expected to have normal ANS function. METHODS: Patients with LBD (n = 16), PD (PD, n = 14) or iRBD (n = 12) were compared to the non-synucleinopathy groups Alzheimers disease dementia (ADem, n = 26), mild cognitive impairment (MCI, n = 34) or controls (CG, n = 54). Sleep Profiler was used to derive a sleep autonomic activation index (AAI), i.e., ≥6 beat-per-minute increase/decrease, pulse rate coefficient of variation (PR-CV), and automated sleep staging with sleep-spindles and non-REM hypertonia (NRH). Analysis included statistical group comparisons and receiver operating characteristics curves to determine optimal classification of groups. RESULTS: AAI and PR-CV were moderately correlated across all recordings (rs = 0.58, P < 0.0001), except in the LBD and PD groups. AAI but not PR-CV differentiated the LBD, PD and iRBD from non-Parkinsonian groups. AAI was decreased in LBD and PD patients compared to the CG (p < 0.003) and MCI (p < 0.03). AAI decreased based on age and its receiver operating characteristic area under the curve ranged from 0.63 to 0.75. AAI had a weak negative correlation to NRH (rs ≤ -0.26) but not sleep-spindles. CONCLUSION: Synucleinopathy-related ANS dysfunction can reasonably discriminate prodromal and manifest PD/LBD diseased groups from non-synucleinopathies. Further studies incorporating AAI into a multivariate classifier of neurodegenerative disorders based on sleep characteristics acquired in the patient's home are planned.

Proof-of-concept for characterization of neurodegenerative disorders utilizing two non-REM sleep biomarkers.

Study objective: This proof-of-concept study aimed to determine whether the combined features of two non-rapid eye movement (NREM) sleep biomarkers acquired predominantly in-home could characterize different neurodegenerative disorders. Methods: Sleep spindle duration and non-REM hypertonia (NRH) were evaluated in seven groups including a control group (CG = 61), and participants with isolated REM sleep behavior disorder (iRBD = 19), mild cognitive impairment (MCI = 41), Parkinson disease (PD = 16), Alzheimer disease dementia (ADem = 29), dementia with Lewy Bodies or Parkinson disease dementia (LBD = 19) and progressive supranuclear palsy (PSP = 13). One-way analysis of variance (ANOVA), Mann-Whitney U, intra-class (ICC) and Spearman ranked correlations, Bland-Altman plots and Kappa scores, Chi-square and Fisher exact probability test, and multiple-logistic regression were focused primarily on spindle duration and NRH and the frequencies assigned to the four normal/abnormal spindle duration/NRH combinations. Results: ANOVA identified group differences in age, sleep efficiency, REM, NRH (p < 0.0001) and sleep time (p = 0.015), Spindle duration and NRH each demonstrated good night-to-night reliabilities (ICC = 0.95 and 0.75, Kappa = 0.93 and 0.66, respectively) and together exhibited an association in the PD and LBD groups only (p < 0.01). Abnormal spindle duration was greater in records of PSP (85%) and LBD (84%) patients compared to CG, MCI, PD and ADem (p < 0.025). Abnormal NRH was greater in PSP = 92%, LBD = 79%, and iRBD = 74% compared to MCI = 32%, ADem = 17%, and CG = 16% (p < 0.005).The combination biomarker normal spindle duration/normal NRH was observed most frequently in CG (56%) and MCI (41%). ADem most frequently demonstrated normal spindle duration/normal NRH (45%) and abnormal spindle duration/normal NRH (38%). Normal spindle duration/abnormal NRH was greatest in iRBD = 47%, while abnormal spindle duration/abnormal NRH was predominant in PSP = 85% and LBD = 74%. Conclusion: The NREM sleep biomarkers spindle duration and NRH may be useful in distinguishing patients with different neurodegenerative disorders. Larger prospective cohort studies are needed to determine whether spindle duration and NRH can be combined for prodromal assessment and/or monitoring disease progression.

Frequency of Orthostatic Hypotension in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Although orthostatic hypotension (OH) can be an early feature of autonomic dysfunction in isolated REM sleep behavior disorder (iRBD), no large-scale studies have examined the frequency of OH in iRBD. In this study, we prospectively evaluated the frequency of OH in a large multicenter iRBD cohort. METHODS: Participants 18 years or older with video polysomnogram-confirmed iRBD were enrolled through the North American Prodromal Synucleinopathy consortium. All participants underwent 3-minute orthostatic stand testing to assess the frequency of OH, and a Δ heart rate/Δ systolic blood pressure (ΔHR/ΔSBP) ratio <0.5 was used to define reduced HR augmentation, suggestive of neurogenic OH. All participants completed a battery of assessments, including the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction (SCOPA-AUT) and others assessing cognitive, motor, psychiatric, and sensory domains. RESULTS: Of 340 iRBD participants (65 ± 10 years, 82% male), 93 (27%) met criteria for OH (ΔHR/ΔSBP 0.37 ± 0.28; range 0.0-1.57), and of these, 72 (77%) met criteria for OH with reduced HR augmentation (ΔHR/ΔSBP 0.28 ± 0.21; range 0.0-0.5). Supine hypertension (sHTN) was present in 72% of those with OH. Compared with iRBD participants without OH, those with OH were older, reported older age of RBD symptom onset, and had worse olfaction. There was no difference in autonomic symptom scores as measured by SCOPA-AUT. DISCUSSION: OH and sHTN are common in iRBD. However, as patients may have reduced autonomic symptom awareness, orthostatic stand testing should be considered in clinical evaluations. Longitudinal studies are needed to clarify the relationship between OH and phenoconversion risk in iRBD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03623672; North American Prodromal Synucleinopathy Consortium.

Sleep Disorders in Patients with Neurologic Disease.

OBJECTIVE: This article provides an overview of the growing body of evidence showing bidirectional relationships between sleep and various neurologic disorders. LATEST DEVELOPMENTS: Mounting evidence demonstrates that disrupted sleep can negatively impact various neurologic disease processes, including stroke, multiple sclerosis, epilepsy, neuromuscular disorders including amyotrophic lateral sclerosis, and headache syndromes. Abnormal sleep can also be a precursor to Alzheimer disease and neurodegenerative disease states such as Parkinson disease and dementia with Lewy bodies. Interventions to improve sleep and treat obstructive sleep apnea may play a vital role in preventing neurologic disease development and progression. ESSENTIAL POINTS: Sleep disorders are common among patients with neurologic disorders. To provide comprehensive care to patients with neurologic conditions, neurologists must ask patients about sleep issues that may warrant further diagnostic testing, treatment, and sleep medicine referral when indicated.

Long-Term Treatment of Narcolepsy and Idiopathic Hypersomnia with Low-Sodium Oxybate.

Narcolepsy and idiopathic hypersomnia are chronic conditions that negatively affect alertness, mental and physical energy, functioning, and quality of life (QoL). Calcium, magnesium, potassium, and sodium oxybates (low-sodium oxybate; LXB) is an oxybate formulation with 92% less sodium than sodium oxybate (SXB; a treatment for narcolepsy) and the same active moiety. LXB is approved in the US for treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy, and idiopathic hypersomnia in adults. In Phase 3 clinical trials, LXB exhibited a safety profile consistent with that of SXB in narcolepsy. Besides continued efficacy in treating symptoms, potential benefits of long-term LXB treatment include flexible optimization of dosing and regimen, improvement of QoL and functioning, weight loss, and (relative to SXB in narcolepsy) health benefits of reduced sodium content. Dosing of LXB is twice nightly (for narcolepsy) or once or twice nightly (for idiopathic hypersomnia) based on patient characteristics and response, and individualized titration can be leveraged over the long term as a patient's life circumstances change. Patients with narcolepsy transitioning from SXB initiate LXB at the same dose, and most patients require no further changes to achieve similar efficacy and tolerability. Improvements in functioning and QoL with LXB treatment could have cascading positive effects in multiple domains, particularly in younger patients. In clinical trials, LXB was associated with weight loss in both narcolepsy (in which obesity is a well-established comorbidity) and idiopathic hypersomnia, only occasionally leading participants to be underweight. As both narcolepsy and idiopathic hypersomnia are associated with increased risk of cardiometabolic and cardiovascular comorbidities, limiting medication-related sodium intake with LXB may have significant health benefits, although this has not yet been verified prospectively due to the prolonged follow-up required. LXB is a promising long-term treatment for narcolepsy and idiopathic hypersomnia.

Narcolepsy and idiopathic hypersomnia are disorders that make people feel very sleepy. Low-sodium oxybate (LXB) is a medicine for these disorders. Doctors think LXB works on parts of the brain that keep people awake. LXB may quiet those brain parts down at night by reducing their electrical activity, which helps people sleep better. LXB wears off by the morning, so people can wake up normally and feel more alert the next day. LXB has less sodium (which is part of salt) than a medicine called sodium oxybate. Sodium oxybate has been used for narcolepsy for more than 20 years. LXB has several benefits. First, LXB may be healthier than medicines that contain a lot of sodium, such as a high-sodium oxybate. This is because sodium can increase blood pressure and risk of heart disease. Second, LXB can be taken twice each night for narcolepsy, or once or twice each night for idiopathic hypersomnia. This depends on a person's lifestyle, how well the medicine is working, and side effects. Third, people taking LXB are more able to work and do other activities and have better quality of life. Finally, people taking LXB may lose weight. This can help overweight or obese people.

The Accuracy and Reliability of Sleep Staging and Sleep Biomarkers in Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder.

Purpose: This study aimed to establish the diagnostic accuracy of a previously validated sleep staging system in patients with probable isolated REM sleep behavior disorder (iRBD), and to compare physicians' diagnoses of iRBD based on REM sleep without atonia (RSWA) to non-REM hypertonia (NRH), a sleep measure independently associated with Parkinsonian spectrum disorders. Patients and Methods: Twenty-six patients with a history of dream enactment behavior underwent a diagnostic PSG with simultaneous Sleep Profiler (SP) acquisition at two sites. PSG and SP records were sleep staged, and two sleep neurologists independently diagnosed iRBD based on the presence or absence of polysomnographic identified RSWA. Comparisons for PSG vs SP sleep staging and the qualitative presence or absence of PSG-based RSWA vs automated SP-detected NRH was performed using kappa coefficients (k), positive and negative percent agreements (PPA and NPA), and chi-square tests. Results: The kappa scores from Sites-1 and -2 for PSG vs SP staging were different for Wake (k=0.82 vs 0.65), N2 (k=0.63 vs 0.72) and REM (k=0.83 vs.0.72). The by-site kappa values for stage N3 increased from 0.72 and 0.37 to 0.88 and 0.74 after PSG records were reedited. The kappa values for between-physician agreement in iRBD diagnoses were fair (k = 0.22). The agreement between each physician's iRBD diagnoses and NRH were also fair (k=0.29 and 0.22). Abnormal NRH agreed with at least one physician's iRBD diagnosis in 83% of the records. The PPA resulting from between-physician iRBD agreement was stronger and the NPA weaker than the values obtained from comparison of each physician's iRBD diagnosis and abnormal NRH. Conclusion: The potential utility of RSWA and stage N3 as neurodegenerative disorder biomarkers was influenced by between-site variability in visual scoring. The degree to which NRH was associated with iRBD was similar to the between-physician agreement in their diagnosis of iRBD using RSWA.

Baseline characteristics of the North American prodromal Synucleinopathy cohort.

OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment. METHODS: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function. RESULTS: Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use (n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden (n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ-9; 39.3% and 31%, respectively). INTERPRETATION: These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

Non-REM sleep with hypertonia in Parkinsonian Spectrum Disorders: A pilot investigation.

INTRODUCTION: From an ongoing multicenter effort toward differentiation of Parkinsonian spectrum disorders (PSD) from other types of neurodegenerative disorders, the sleep biomarker non-rapid-eye-movement sleep with hypertonia (NRH) emerged. METHODS: This study included in the PSD group patients with dementia with Lewy bodies/Parkinson disease dementia (DLB/PDD = 16), Parkinson disease (PD = 16), and progressive supranuclear palsy (PSP = 13). The non-PSD group included patients with Alzheimer disease dementia (AD = 24), mild cognitive impairment (MCI = 35), and a control group with normal cognition (CG = 61). In-home, multi-night Sleep Profiler studies were conducted in all participants. Automated algorithms detected NRH, characterized by elevated frontopolar electromyographic power. Between-group differences in NRH were evaluated using Logistic regression, Mann-Whitney U and Chi-squared tests. RESULTS: NRH was greater in the PSD group compared to non-PSD (13.9 ± 11.0% vs. 3.1 ± 4.7%, P < 0.0001). The threshold NRH≥5% provided the optimal between-group differentiation (AUC = 0.78, P < 0.001). NRH was independently associated with the PSD group after controlling for age, sex, and SSRI/SNRI use (P < 0.0001). The frequencies of abnormal NRH by subgroup were PSP = 92%, DLB/PDD = 81%, PD = 56%, MCI = 26%, AD = 17%, and CG = 16%. The odds of abnormal NRH in each PSD subgroup ranged from 3.7 to 61.2 compared to each non-PSD subgroup. The night-to-night and test-retest intraclass correlations were excellent (0.78 and 0.84, both P < 0.0001). CONCLUSIONS: In this pilot study, NRH appeared to be a novel candidate sleep biomarker for PSD-related neurodegeneration. Future studies in larger cohorts are needed to confirm these findings, understand the etiology of NRH magnitude/duration, and determine whether it is an independent prodromal marker for specific neurodegenerative pathologies.

Suvorexant: a promising, novel treatment for insomnia.

Suvorexant a novel, orexin receptor antagonist was recently approved by the US Food and Drug Administration for the treatment of sleep onset and sleep maintenance insomnia in August 2014. Multiple animal and human studies support the efficacy, safety, and tolerability of suvorexant for patients of various profiles. Current recommendations advocate for a starting dose of 10 mg and a maximum dose of 20 mg, with cautious use in women, obese patients, and patients taking other CYP3A4 inhibitors. More head-to-head studies comparing suvorexant to other sedative-hypnotic therapies are needed to further delineate which patients will benefit the most from this medication over others.

Teleneurosonology: a novel application of transcranial and carotid ultrasound.

BACKGROUND: To demonstrate the technical feasibility of interfacing transcranial Doppler (TCD) and carotid "duplex" ultrasonography (CUS) peripherals with telemedicine end points to provide real-time spectral waveform and duplex imaging data for remote review and interpretation. METHODS: We performed remote TCD and CUS examinations on a healthy, volunteer employee from our institution without known cerebrovascular disease. The telemedicine end point was stationed in our institution's hospital where the neurosonology examinations took place and the control station was in a dedicated telemedicine room in a separate building. The examinations were performed by a postgraduate level neurohospitalist trainee (M.N.R.) and interpreted by an attending vascular neurologist, both with experience in the performance and interpretation of TCD and CUS. RESULTS: Spectral waveform and duplex ultrasound data were successfully transmitted from TCD and CUS instruments through a telemedicine end point to a remote reviewer at a control station. Image quality was preserved in all cases, and technical failures were not encountered. CONCLUSIONS: This proof-of-concept study demonstrates the technical feasibility of interfacing TCD and CUS peripherals with a telemedicine end point to provide real-time spectral waveform and duplex imaging data for remote review and interpretation. Medical diagnostic and telemedicine devices should be equipped with interfaces that allow simple transmission of high-quality audio and video information from the medical devices to the telemedicine technology. Further study is encouraged to determine the clinical impact of teleneurosonology.

Reversible cerebral vasoconstriction syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular disorder with a clinical picture that continues to be refined. It has presented to multiple subspecialties over the past several decades, bringing with it many questions regarding risk factors, diagnosis, and management. Answers have been forthcoming but many questions remain. RCVS presents with recurrent, secondary thunderclap headaches and predominantly affects young women. The mechanism of vasoconstriction is unclear, but there has been speculation regarding a hyperadrenergic state. Diagnosis requires physician awareness, vascular imaging, and knowledge of the differential. The hallmark of its diagnosis is reversibility. Management is empiric, usually with calcium-channel blockers, as there are no controlled treatment trials for RCVS. Randomized controlled trials are needed.

Disrupted daytime activity and altered sleep-wake patterns may predict transition to mild cognitive impairment or dementia: a critically appraised topic.

BACKGROUND: There is a well-known relationship between neurodegenerative disease, disrupted sleep, and cognition. Pathologic and imaging studies have shown that regions in the brain shown to regulate sleep and circadian rhythm are abnormal in Alzheimer disease. Most of these studies have been cross-sectional, and often look at patients already with dementia. This leaves uncertainty with regard to the temporal relationship of circadian disruption and cognitive decline. OBJECTIVE: To determine whether disrupted daytime activity and altered sleep patterns predict development of mild cognitive impairment (MCI) or dementia. METHODS: The objective was addressed through the development of a structured, critically-appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, and behavioral neurology and sleep medicine content experts. RESULTS: A prospective cohort study of 1282 cognitively normal women demonstrated that when peak circadian activity, as measured by wrist actigraphy, occurred later than average, there was an increased risk of MCI or dementia [odds ratio (OR), 1.83; 95% confidence interval (CI), 1.29-2.61]. Increased odds for dementia or MCI also existed for those with decreased circadian rhythm amplitude (OR, 1.57; 95% CI, 1.09-2.25) and robustness (OR, 1.57; 95% CI, 1.29-2.61). CONCLUSIONS: Disrupted circadian rhythm measures, including lower amplitude, a less robust rhythm, and delayed timing of peak activity on wrist actigraphy, were predictive of future development of MCI or dementia in cognitively normal women.

New-onset atrial fibrillation in severe sepsis and risk of stroke and death: a critically appraised topic.

BACKGROUND: Severe sepsis has been associated with an increased risk of new-onset arrhythmias, namely atrial fibrillation (AF). Single-center and small-center studies suggest that new-onset AF is associated with higher mortality and prolonged hospitalization during severe sepsis. However, the relationship between new-onset AF in severe sepsis to prognosis is unknown. OBJECTIVE: To determine whether new-onset AF increases the risk of stroke and death in severe sepsis. METHODS: The objective was addressed through the development of a structured, critically appraised topic. This incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and fellow-level neurologists, a medical librarian, clinical epidemiologists, and context experts in the fields of vascular neurology, hospital neurology, critical care medicine, and cardiovascular medicine. RESULTS: A recent retrospective, population-based cohort study was selected and appraised to address this prognostic question. Patients were obtained from the California State Inpatient Database administrative claims data from nonfederal acute care hospitals from January 1 through December 31, 2007. Of the 3,144,787 patients, 49,082 (1.56%) had severe sepsis, defined by the validated International Classification of Disease, 9th Revision, Clinical Modification code 995.92. The a priori outcome measures included in-hospital ischemic stroke and mortality. New-onset AF occurred in 5.9% of patients with severe sepsis versus 0.65% of patients without severe sepsis [odds ratio, 6.82; 95% confidence interval (CI), 6.52-7.11; P<0.001]. Compared with severe sepsis patients without new-onset AF, patients with new-onset AF during severe sepsis had greater risks of in-hospital ischemic stroke (2.6% vs. 0.6% strokes; adjusted odds ratio, 2.70; 95% CI, 2.05-3.57; P<0.001) and in-hospital mortality (56% vs. 39% deaths; adjusted relative risk, 1.07; 95% CI, 1.04-1.11; P<0.001). Findings were robust across 2 separate definitions of severe sepsis and multiple sensitivity analyses. CONCLUSIONS: In patients with severe sepsis, new-onset AF seems to increase the risk of in-hospital stroke and mortality compared with patients with no or preexisting AF.

Is dabigatran cost effective compared with warfarin for stroke prevention in atrial fibrillation? A critically appraised topic.

BACKGROUND: Warfarin has provided protection against cardioembolic stroke in the setting of nonvalvular atrial fibrillation (NVAF) for the past 60 years. Dabigatran, the first oral direct thrombin inhibitor to be approved in the United States, promises to provide the same or better stroke protection with reduced risk of intracranial hemorrhage. However, it remains to be seen whether grand-scale adoption of dabigatran will be cost effective. OBJECTIVE: To critically assess current evidence regarding the cost effectiveness of dabigatran for preventing stroke in patients with NVAF compared with warfarin. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular neurology. RESULTS: A cost-effectiveness analysis (CEA) that followed a hypothetical cohort of NVAF patients 65 years of age or older and CHADS2≥1 over their lifetime comparing dabigatran with adjusted-dose warfarin was reviewed. Assuming a willingness to pay a threshold of $50,000 per quality-adjusted life year (QALY), base case results favored high-dose (150 mg bid) dabigatran as a cost-effective alternative to warfarin. Sensitivity analysis asserted that the cost effectiveness of dabigatran improved if it could be obtained for ≤$13/d or if it was used in populations with high risk of stroke or intracranial hemorrhage. CONCLUSIONS: Dabigatran 150 mg bid ($12,286 per QALY) is a cost-effective alternative to International Normalized Ratio-adjusted warfarin for the prevention of ischemic stroke in patients 65 years of age or older with NVAF.