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1.  Factors Associated with Injury in REM Sleep Behavior Disorder 
Sleep medicine  2014;15(11):1332-1338.
Since factors associated with injury in REM sleep behavior disorder (RBD) remain largely unknown, we aimed to identify such factors.
We surveyed consecutive idiopathic (iRBD) or symptomatic RBD patients seen between 2008-2010 regarding RBD-related injuries. Associations between injuries and clinical variables were determined with odds ratios and multiple logistic regression analyses. The primary outcome variables were injury and injury severity.
Fifty-three patients (40%) responded. Median age was 69 years, and 35 (73.5%) were men. Twenty-eight (55%) had iRBD. Twenty-nine (55%) reported injury, with 37.8% to self and 16.7% to the bed partner. 11.3% had marked injuries requiring medical intervention or hospitalization, including two (4%) subdural hematomas. iRBD diagnosis (OR=6.8, p=0.016) and dream recall (OR=7.5, p=0.03) were associated with injury; and iRBD diagnosis was independently associated with injury and injury severity adjusting for age, gender, DEB frequency and duration. Falls (p=0.03) were also associated with injury severity. DEB frequency was not associated with injury, injury severity, or falls.
Injuries appear to be a frequent complication of RBD, although the relatively low response rate in our survey could have biased results. iRBD patients are more likely to suffer injury—and more severe injuries—than symptomatic RBD patients. In addition, recall of dreams was also associated with injury, and dream enactment behavior-related (DEB) falls were associated with more severe injuries. One in nine patients suffered injury requiring medical intervention. Frequency of DEB did not predict RBD-related injuries, highlighting the importance of timely initiation of treatment for RBD in patients having even rare DEB episodes. Future prospective studies will be necessary to define predictors of injury in RBD.
PMCID: PMC4253642  PMID: 25194585
REM sleep behavior disorder; injury; falls; synucleinopathy; Parkinson’s disease; subdural hematoma
3.  Treatment Outcomes in REM Sleep Behavior Disorder 
Sleep medicine  2013;14(3):237-242.
REM sleep behavior disorder (RBD) is usually characterized by potentially injurious dream enactment behaviors (DEB). RBD treatment aims to reduce DEBs and prevent injury, but outcomes require further elucidation. We surveyed RBD patients to describe longitudinal treatment outcomes with melatonin and clonazepam.
We surveyed and reviewed records of consecutive RBD patients seen at Mayo Clinic between 2008–2010 to describe RBD-related injury frequency/severity as well as RBD Visual Analog Scale (VAS) ratings, medication dosage, and side effects. Statistical analyses were performed with appropriate non-parametric matched pairs tests before and after treatment, and with comparative group analyses for continuous and categorical variables between treatment groups. The primary outcome variables were RBD VAS ratings and injury frequency.
Forty-five (84.9%) of 53 respondent surveys were analyzed. Mean age was 65.8 years and 35 (77.8%) patients were men. Neurodegenerative disorders were seen in 24 (53%) patients, and 25 (56%) received antidepressants. Twenty-five patients received melatonin, 18 received clonazepam, and 2 received both as initial treatment. Before treatment, 27 patients (60%) reported an RBD associated injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS ratings were significantly improved following both treatments (pm=.0001, pc=.0005). Melatonin-treated patients reported significantly reduced injuries (pm=.001, pc=.06) and fewer adverse effects (p=0.07). Mean durations of treatment were no different between groups (for clonazepam 53.9 +/− 29.5 months, and for melatonin 27.4 +/− 24 months, p=0.13) and there were no differences in treatment retention, with 28% of melatonin and 22% of clonazepam-treated patients discontinuing treatment (p=0.43).
Melatonin and clonazepam were each reported to reduce RBD behaviors and injuries and appeared comparably effective in our naturalistic practice experience. Melatonin-treated patients reported less frequent adverse effects than those treated with clonazepam. More effective treatments that would eliminate injury potential and evidence-based treatment outcomes from prospective clinical trials for RBD are needed.
PMCID: PMC3617579  PMID: 23352028
REM sleep behavior disorder; parasomnia; melatonin; clonazepam; treatment; side effects; tolerability; retention; injury; falls; synucleinopathy
4.  Impulse control disorders in patients with dopamine agonist-treated prolactinomas and non-functioning pituitary adenomas: a case-control study 
Clinical endocrinology  2013;80(6):863-868.
We aimed to assess the prevalence of impulse control disorders (ICDs) in patients with prolactin-secreting adenomas treated with dopamine agonists (DAs), to identify associated factors, and compare it with a group of patients with non-functioning pituitary adenoma.
Subjects, Design and Measurement
In a postal survey, 77 patients from Group A (patients with prolactinomas and present or past use of DAs) and 70 patients from Group B (patients with non-functioning pituitary adenoma and no history of DA therapy) responded to a questionnaire on compulsive shopping, pathologic gambling, hypersexuality and punding. Associated clinical information was obtained through the survey and review of medical electronic records.
The total ICD prevalence was 24.68% in Group A and 17.1% in Group B (p=0.31). Group A had an increased rate of hypersexuality (p=0.03). Subgroup analysis revealed that men in Group A had a significantly increased frequency of total ICDs when compared to men in Group B (27.7% versus 3.7%, p=0.01). No differences in rates of total ICDs were found between women of Groups A and B (20% versus 25.6%, p=0.78). No association with type, dose, or duration of treatment with DA was noted.
Males with prolactinomas treated with DAs were 9.9 times more likely to develop an ICD than their counterparts with non-functioning pituitary adenomas. Until prospective studies on the relationship of DA use in prolactinoma patients and ICDs are available, the authors propose that prolactinoma patients be forewarned of possible ICD development with DA therapy.
PMCID: PMC4136510  PMID: 24274365
ICD; prolactinoma; dopamine agonist
5.  Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer’s disease using the Multiple Sleep Latency Test 
Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer’s disease (AD) dementia.
A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out.
Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 ± 5 minutes vs 11 ± 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables.
Daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep–wake physiology, and further work is needed to better understand the underlying mechanisms.
PMCID: PMC4266572  PMID: 25512763
6.  Chiari 1 Malformation Presenting as Central Sleep Apnea during Pregnancy: A Case Report, Treatment Considerations, and Review of the Literature 
Purpose: Chiari malformation (CM) type-1 frequently causes obstructive or central sleep-disordered breathing (SDB) in both adults and children, although SDB is relatively rare as a presenting manifestation in the absence of other neurological symptoms. The definitive treatment of symptomatic CM is surgical decompression. We report a case that is, to our knowledge, a novel manifestation of central sleep apnea (CSA) due to CM type-1 with severe exacerbation and initial clinical presentation during pregnancy.
Methods: Case report from tertiary care comprehensive sleep medicine center with literature review of SDB manifestations associated with CM type-1. PubMed search was conducted between January 1982 and October 2013.
Results: We report a 25-year-old woman with severe CSA initially presenting during her first pregnancy that eventually proved to be caused by CM type-1. The patient was successfully treated preoperatively by adaptive servoventilation (ASV), with effective resolution of SDB following surgical decompression, and without recurrence in a subsequent pregnancy. Our literature review found that 58% of CM patients with SDB had OSA alone, 28% had CSA alone, 8 (10%) had mixed OSA/CSA, and 6 (8%) had hypoventilation. Of CM patients presenting with SDB, 50% had OSA, 42% had CSA, 8% had mixed OSA/CSA, and 10.4% had hypoventilation. We speculate that CSA may develop in CM patients in whom brainstem compression results in excessive central chemoreflex sensitivity with consequent hypocapnic CSA.
Conclusion: Chiari malformation type-1 may present with a diversity of SDB manifestations, and timely recognition and surgical referral are necessary to prevent further neurological deficits. ASV therapy can effectively manage CSA caused by CM type-1, which may initially present during pregnancy.
PMCID: PMC4208407  PMID: 25386156
Chiari malformation; central sleep apnea; pregnancy; presentation; adaptive servoventilation
7.  Greatest rapid eye movement sleep atonia loss in men and older age 
To determine quantitative REM sleep muscle tone in men and women without REM sleep behavior disorder, we quantitatively analyzed REM sleep phasic and tonic muscle activity, phasic muscle burst duration, and automated REM atonia index in submentalis and anterior tibialis muscles in 25 men and 25 women without REM sleep behavior disorder. Men showed significantly higher anterior tibialis phasic muscle activity. Higher phasic muscle activity was independently associated with male sex and older age in multivariate analysis. Men and the elderly may be biologically predisposed to altered REM sleep muscle atonia control, and/or some may have occult neurodegenerative disease, possibly underlying the predominance of older men with REM sleep behavior disorder.
PMCID: PMC4241799  PMID: 25493286
8.  Restless legs syndrome and daytime sleepiness are prominent in myotonic dystrophy type 2 
Neurology  2013;81(2):157-164.
Although sleep disturbances are common in myotonic dystrophy type 1 (DM1), sleep disturbances in myotonic dystrophy type 2 (DM2) have not been well-characterized. We aimed to determine the frequency of sleep disturbances in DM2.
We conducted a case-control study of 54 genetically confirmed DM2 subjects and 104 medical controls without DM1 or DM2, and surveyed common sleep disturbances, including symptoms of probable restless legs syndrome (RLS), excessive daytime sleepiness (EDS), sleep quality, fatigue, obstructive sleep apnea (OSA), probable REM sleep behavior disorder (pRBD), and pain. Thirty patients with DM2 and 43 controls responded to the survey. Group comparisons with parametric statistical tests and multiple linear and logistic regression analyses were conducted for the dependent variables of EDS and poor sleep quality.
The mean ages of patients with DM2 and controls were 63.8 and 64.5 years, respectively. Significant sleep disturbances in patients with DM2 compared to controls included probable RLS (60.0% vs 14.0%, p < 0.0001), EDS (p < 0.001), sleep quality (p = 0.02), and fatigue (p < 0.0001). EDS and fatigue symptoms were independently associated with DM2 diagnosis (p < 0.01) after controlling for age, sex, RLS, and pain scores. There were no group differences in OSA (p = 0.87) or pRBD (p = 0.12) scores.
RLS, EDS, and fatigue are frequent sleep disturbances in patients with DM2, while OSA and pRBD symptoms are not. EDS was independently associated with DM2 diagnosis, suggesting possible primary CNS hypersomnia mechanisms. Further studies utilizing objective sleep measures are needed to better characterize sleep comorbidities in DM2.
PMCID: PMC3770170  PMID: 23749798
9.  Polysomnographic Findings in Dementia With Lewy Bodies 
The neurologist  2013;19(1):1-6.
The clinical features of dementia with Lewy bodies (DLB) during wakefulness are well known. Other than REM sleep behavior disorder (RBD), only limited data exists on other sleep disturbances and disorders in DLB. We sought to characterize the polysomnographic (PSG) findings in a series of DLB patients with sleep-related complaints.
Retrospective study of patients with DLB who underwent clinical PSG at Mayo Clinic Rochester or Mayo Clinic Jacksonville over an almost 11 year span for evaluation of dream enactment behavior, excessive nocturnal movements, sleep apnea, hypersomnolence, or insomnia. The following variables were analyzed: respiratory disturbance index (RDI) in disordered breathing events/hour, periodic limb movement arousal index (PLMAI), arousals for no apparent reason (AFNAR), total arousal index (TAI), presence of REM sleep without atonia (RSWA), and percent sleep efficiency (SE).
Data on 78 patients (71M, 7F) were analyzed. The mean age was 71 ± 8 years. Seventy-five (96%) patients had histories of recurrent dream enactment during sleep with 83% showing confirmation of RSWA +/- dream enactment during PSG. Mean RDI = 11.9 ± 5.8, PLMAI = 5.9 ± 8.5, AFNARI = 10.7 ± 12.0, and TAI = 26.6 ± 17.4. SE was <80% in 72% of the sample, <70% in 49%, and <60% in 24%. In patients who did not show evidence of significant disordered breathing (23 with RDI<5), 62% of arousals were AFNARs. In those patients who had significant disordered breathing (55 with RDI ≥ 5), 36% of arousals were AFNARs. Six patients underwent evaluations with PSG plus MSLT. Two patients had mean initial sleep latencies less than five minutes, and both had RDI<5. No patient had any sleep onset rapid eye movement periods. Nineteen patients have undergone neuropathologic examination, and 18 have had limbic- or neocortical-predominant Lewy body pathology. One had progressive supranuclear palsy, but no REM sleep was recorded in prior PSG.
In patients with DLB and sleep-related complaints, several sleep disturbances in addition to RBD are frequently present. In this sample, about three quarters had a significant number of arousals not accounted for by a movement or breathing disturbance, and the primary sleep disorders do not appear to entirely account for the poor sleep efficiency in DLB, especially in those without a significant breathing disorder. Further studies are warranted to better understand the relationship between disturbed sleep, arousal and DLB; such characterization may provide insights into potential avenues of treatment of symptoms which could impact quality of life.
PMCID: PMC3587292  PMID: 23269098
Sleep disorders; REM sleep behavior disorder; dementia with Lewy bodies; synucleinopathy
10.  Total sleep time obtained from actigraphy versus sleep logs in an academic sleep center and impact on further sleep testing 
Nature and Science of Sleep  2013;5:125-131.
While actigraphy has been deemed ideal for the longitudinal assessment of total sleep time (TST) by select groups, endorsement has not been universal and reimbursement is lacking, preventing its widespread use in clinical practice. This study compares longitudinal TST data obtained by actigraphy and logs preceding a clinical evaluation, and secondarily ascertains whether longitudinal TST impacts clinicians’ decisions to proceed with further sleep testing.
This was a retrospective, consecutive chart review spanning about 4 months in an academic sleep center. Eighty-four patients wore actigraphs in anticipation of clinical evaluations. Concomitant completion of sleep logs is routinely requested in this setting. Longitudinal TST data available in complete form was reviewed in a blinded fashion among a subset of these patients. A review of text from clinical notes of an expanded cohort with complete actigraphy data (regardless of the degree of completion of logs) enabled determination of the frequency and rationale for cancellation of prescheduled sleep testing.
Of 84 actigraphy recordings, 90% produced complete data, and 30% produced fully completed logs. Among the subset with both available in complete form, significant mean TST differences were observed on weekends (7.06 ± 2.18 hours versus 8.30 ± 1.93 hours, P = 0.009), but not on weekdays (7.38 ± 1.97 hours versus 7.72 ± 1.62 hours, P = 0.450) for actigraphy and logs, respectively. Further analyses revealed poor agreement between the two measures, with predominantly increased TST estimation with logs. Among those with complete actigraphy data (±logs), testing was cancelled in 11 (15%), eight of whom (73%) presented with hypersomnia and three of whom (27%) presented with insomnia. Determination of insufficient sleep time was cited as the primary reason for cancellation (64%).
Actigraphy and sleep logs provided discrepant mean TST data on weekends only, and the latter predominantly estimated increased TST. Actigraphy was completed more reliably than logs. Longitudinal TST information influenced clinicians’ decisions to proceed with further testing, particularly among patients presenting with hypersomnia.
PMCID: PMC3794964  PMID: 24124399
sleep diaries; polysomnography; multiple sleep latency testing
11.  Probable REM Sleep Behavior Disorder Increases Risk for Mild Cognitive Impairment and Parkinson’s Disease: A Population-Based Study 
Annals of Neurology  2012;71(1):49-56.
REM sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.
Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.
Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
PMCID: PMC3270692  PMID: 22275251
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
12.  Validation of the Mayo Sleep Questionnaire to Screen for REM Sleep Behavior Disorder in an Aging and Dementia Cohort 
Sleep medicine  2011;12(5):445-453.
To validate a questionnaire focused on REM sleep behavior disorder (RBD) among participants in an aging and dementia cohort.
RBD is a parasomnia that can develop in otherwise neurologically-normal adults as well as in those with a neurodegenerative disease. Confirmation of RBD requires polysomnography (PSG). A simple screening measure for RBD would be desirable for clinical and research purposes.
We had previously developed the Mayo Sleep Questionnaire (MSQ), a 16 item measure, to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of patients’ bed partners with the findings on PSG. All subjects recruited in the Mayo Alzheimer’s Disease Research Center at Mayo Clinic Rochester and Mayo Clinic Jacksonville from 1/00 to 7/08 who had also undergone a PSG were the focus of this analysis.
The study sample was comprised of 176 subjects [150 male; median age 71 years (range 39–90)], with the following clinical diagnoses: normal (n=8), mild cognitive impairment (n=44), Alzheimer’s disease (n=23), dementia with Lewy bodies (n=74), as well as other dementia and/or parkinsonian syndromes (n=27). The core question on recurrent dream enactment behavior yielded a sensitivity (SN) of 98% and specificity (SP) of 74% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD and one on obstructive sleep apnea improved specificity.
These data suggest that among aged subjects with cognitive impairment and/or parkinsonism, the MSQ has adequate SN and SP for the diagnosis of RBD. The utility of this scale in other patient populations will require further study.
PMCID: PMC3083495  PMID: 21349763
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism
13.  History of the Development of Sleep Medicine in the United States 
Sleep Medicine has only recently been recognized as a specialty of medicine. Its development is based on an increasing amount of knowledge concerning the physiology of sleep, circadian biology and the pathophysiology of sleep disorders. This review chronicles the major advances in sleep science over the past 70 years and the development of the primary organizations responsible for the emergence of Sleep Medicine as a specialty, sleep disorders as a public health concern and sleep science as an important area of research.
PMCID: PMC2413168  PMID: 17561617
Sleep medicine; history; sleep disorders; sleep research
14.  MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies 
Neurology  2013;81(19):1681-1689.
To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.
Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.
pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.
Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
PMCID: PMC3812105  PMID: 24107861

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