Nancy L. Slocumb

Treatment outcomes in REM sleep behavior disorder

OBJECTIVE 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. METHODS 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. RESULTS 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 two 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 (p(m) = 0.0001, p(c) = 0.0005). Melatonin-treated patients reported significantly reduced injuries (p(m) = 0.001, p(c) = 0.06) 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). CONCLUSIONS 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.

Idiopathic rapid-eye-movement sleep disorder: associations with antidepressants, psychiatric diagnoses, and other factors, in relation to age of onset.

BACKGROUND A retrospective, case-control chart review was performed to examine the relationship between the age of onset of idiopathic RBD and secondary associations. METHODS Forty-eight idiopathic RBD patients were divided into early-onset and late-onset groups, compared to each other, and to their respective non-RBD controls. RESULTS There were more females in the early-onset group as compared to their older counterparts (45% vs. 11%, p=0.007). Early-onset patients also had significantly more past and present psychiatric diagnoses [85% (both categories) vs. 46% and 36%, respectively, p<0.01 for both comparisons] and antidepressant use (80% vs. 46%, p=0.02) than the late-onset group. In comparison to non-RBD controls, early-onset patients again exhibited more psychiatric diagnoses (odds ratio=17.0 [3.5-83.4], equivalent for past and present diagnoses) and antidepressant use (odds ratio=12.0 [2.7-53.3]). Late-onset patients also had a higher frequency of past (odds ratio=7.2 [1.8-29.6]) and present (odds ratio=4.6 [1.1-19.3]) psychiatric diagnoses as compared to their non-RBD controls, but did not demonstrate a statistically significant difference in antidepressant use. There were otherwise no significant intergroup or intragroup differences with respect to the other assessed variables. CONCLUSIONS Although causality cannot be inferred, numerous implications can be entertained, particularly in the early-onset group, including direct or indirect correlations with medication use and/or psychopathology and the development of RBD. The relatively high number of females in the early-onset group suggests a unique clinical profile for a condition typically characterized as male-predominant.

Studies of humoral immunity to preprohypocretin in human leukocyte antigen DQB1*0602-positive narcoleptic subjects with cataplexy

BACKGROUND Canine models for narcolepsy have mutations of the hypocretin receptor 2 gene, and preprohypocretin knockout murine lines exhibit narcoleptic-like behaviors. Human narcolepsy with cataplexy is associated with human leukocyte antigen DQB1*0602 and reduced hypocretin levels in cerebrospinal fluid, suggesting an autoimmune diathesis. We tested the hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have immunoglobulin (Ig)G reactive to human preprohypocretin and its cleavage products. METHODS Serum samples of 41 DQB1*0602-positive narcoleptic subjects with cataplexy and 55 control subjects were studied, as were 19 narcoleptic and 13 control samples of cerebrospinal fluid. We tested for IgG reactive to preprohypocretin and its major cleavage products (including hypocretin 1 and 2), using immunoprecipitation assays (IP), immunofluorescence microscopy (IF) of Chinese hamster ovarian cells expressing preprohypocretin, and Western blots. RESULTS There was no evidence for IgG reactive to preprohypocretin or its cleavage products in CSF of subjects with narcolepsy as measured by IPs, Western blots, and IF. Although the IP with CSF and the C-terminal peptide showed significant differences by two methods of comparison, the control subjects had higher counts per minute than narcoleptic subjects, which was opposite to our hypothesis. CONCLUSIONS The hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have IgG reactive to preprohypocretin or its cleavage products was not supported.

Factors associated with injury in REM sleep behavior disorder

OBJECTIVE As factors associated with injury in rapid eye movement (REM) sleep behavior disorder (RBD) remain largely unknown, we aimed to identify such factors. METHODS We surveyed consecutive idiopathic (iRBD) or symptomatic RBD patients seen between 2008 and 2010 regarding RBD-related injuries. Associations between injuries and clinical variables were determined with odds ratios (OR) and multiple logistic regression analyses. The primary outcome variables were injury and injury severity. RESULTS 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. CONCLUSIONS 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 (DEB)-related falls were associated with more severe injuries. One in nine patients suffered injury requiring medical intervention. The 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.

Characteristics of REM sleep behavior disorder in childhood.

STUDY OBJECTIVE To describe our experience regarding the clinical and polysomnographic features of REM sleep behavior disorder (RBD) in childhood. METHODS This was a retrospective chart review of children and adolescents with RBD and REM sleep without atonia. Demographics, and clinical and polysomnographic information were tabulated. Our findings were compared with those in the existing literature. RESULTS The 15 subjects identified (13 RBD and 2 having REM sleep without atonia) had a mean age at diagnosis of 9.5 years (range 3-17 years); 11/15 (73%) were male. Nightmares were reported in 13/15 and excessive daytime sleepiness in 6/15. Two children had caused bodily harm to bedmate siblings. Comorbidities, which were multiple in some subjects, included anxiety (8/15), attention deficit disorder (10/15), nonspecific developmental delay (6/15), Smith-Magenis syndrome (1/15), pervasive developmental disorder (1/15), narcolepsy (1/15), idiopathic hypersomnia (1/15), and Moebius Syndrome (1/15). Abnormal MRI scans were seen in 5/8 evaluated subjects. Treatments consisted of clonazepam (10/15), melatonin (2/15), and discontinuation of a tricyclic agent (1/15), with a favorable response in 11 of 13. Two of 15 patients with REM sleep without atonia did not require pharmacotherapy. CONCLUSIONS RBD in children may be associated with neurodevelopmental disabilities, narcolepsy, or medication use. It seems to be modestly responsive to benzodiazepines or melatonin. The etiology is distinct from that of common childhood arousal parasomnias and RBD in adults; congenital and neurodevelopmental disorders, medication effect, and narcolepsy coexisted in some, but none had an extrapyramidal neurodegenerative disorder.

Restless legs syndrome and daytime sleepiness are prominent in myotonic dystrophy type 2

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

LIGHT EXPOSURE AMONG ADOLESCENTS WITH DELAYED SLEEP PHASE DISORDER: A PROSPECTIVE COHORT STUDY

The objective of this study was to compare light exposure and sleep parameters between adolescents with delayed sleep phase disorder (DSPD; n = 16, 15.3 ± 1.8 yrs) and unaffected controls (n = 22, 13.7 ± 2.4 yrs) using a prospective cohort design. Participants wore wrist actigraphs with photosensors for 14 days. Mean hourly lux levels from 20:00 to 05:00 h and 05:00 to 14:00 h were examined, in addition to the 9-h intervals prior to sleep onset and after sleep offset. Sleep parameters were compared separately, and were also included as covariates within models that analyzed associations with specified light intervals. Additional covariates included group and school night status. Adolescent delayed sleep phase subjects received more evening (p < .02, 22:00–02:00 h) and less morning (p < .05, 08:00–09:00 h and 10:00–12:00 h) light than controls, but had less pre-sleep exposure with adjustments for the time of sleep onset (p < .03, 5–7 h prior to onset hour). No differences were identified with respect to the sleep offset interval. Increased total sleep time and later sleep offset times were associated with decreased evening (p < .001 and p = .02, respectively) and morning (p = .01 and p < .001, respectively) light exposure, and later sleep onset times were associated with increased evening exposure (p < .001). Increased total sleep time also correlated with increased exposure during the 9 h before sleep onset (p = .01), and a later sleep onset time corresponded with decreased light exposure during the same interval (p < .001). Outcomes persisted regardless of school night status. In conclusion, light exposure interpretation requires adjustments for sleep timing among adolescents with DSPD. Pre- and post-sleep light exposures do not appear to contribute directly to phase delays. Sensitivity to morning light may be reduced among adolescents with DSPD. (Author correspondence: auger.raymond1@mayo.edu)

Maxillomandibular advancement in the management of obstructive sleep apnea.

Maxillomandibular advancement (MMA) is a surgical option for obstructive sleep apnea (OSA). MMA involves forward-fixing the maxilla and mandible approximately 10  mm via Le Fort I maxillary and sagittal split mandibular osteotomies. We retrospectively reviewed outcomes from 24 consecutive OSA patients who underwent MMA at our institution. MMA resulted in an 83% reduction in the group mean apnea-hypopnea index (AHI) per polysomnography an average of 6.7 months after surgery. Forty-two percent of patients achieved a post-MMA AHI of less than 5 events/hour sleep and 71% achieved an AHI less than or equal to 10 events/hour sleep. The Epworth Sleepiness Scale score decreased by an average of 5 post-surgery. No parameters predictive of cure for OSA by MMA were identified.

The role of nocturnal polysomnography in assessing children with Chiari type I malformation

OBJECTIVE To evaluate nocturnal polysomnogram findings in children with suspected symptomatic Chiari type I malformation, correlate them with clinical and magnetic resonance imaging data and to determine if this information has value in clinical decision making process. METHODS A retrospective review identified 24 children with type I Chiari malformation, presumed symptomatic who had undergone neurological assessment, cranial magnetic resonance imaging and nocturnal polysomnography. Perimedullary subarachnoid space effacement on the magnetic resonance studies and the magnitude of cerebellar tonsillar descent in relation to the McRae line were correlated with frequency of obstructive or central sleep apnea, number of cortical arousals and evidence of impaired vocal mobility on laryngoscopy. The Wilcoxon rank sum test was applied for continuous variables and the Fisher exact test for categorical variables. RESULTS The median age of the subjects was 6 years. The findings from 16/24 subjects with perimedullary subarachnoid space effacement (effaced group) were compared with those of 8/24 in the non-effaced group. The central apnea index [1.5 (IQR 1-3.5) versus 0.5 (IQR 0-1.5)] and cortical arousal index [12 (IQR 10-19) versus 8 (IQR 6.5-9)] were significantly higher in the effaced group than in the non-effaced group (p=0.0376 and 0.0036 respectively). Greater descent of tonsils as measured by distance from the McRae line to the tonsil tip was associated with significantly higher central apnea index, total arousal index and respiratory event related arousals. Measurements of clivus-canal angle, Klauss index and pB-C2 line did not correlate with abnormalities on polysomnography. CONCLUSION The central apnea and arousal indices derived from the nocturnal polysomnogram correlate well with magnetic resonance imaging findings of subarachnoid space effacement and degree of tonsillar herniation. In children with Chiari type I malformation, the nocturnal polysomnogram findings provides important information that aids in the decision making process about proceeding with surgical decompression.

Total sleep time obtained from actigraphy versus sleep logs in an academic sleep center and impact on further sleep testing.

Background 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. Methods 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. Results 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%). Conclusion 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.