Ana C. Krieger

Delayed diagnosis of narcolepsy: characterization and impact

Narcolepsy, a chronic neurologic condition resulting from dysregulation of the sleep-wake cycle, usually has an onset at an early age. However, a long delay until diagnosis has been consistently reported in the literature across countries and several publications have focused on characterizing this delay. Most studies report a mean delay to diagnosis of up to 15 years, with individual cases of >60 years, although a trend over time toward a shorter diagnostic delay has been suggested. While variables associated with this delay have been identified, a lack of symptom recognition resulting in misdiagnosis prior to reaching the narcolepsy diagnosis is the likely underlying reason. This lack of symptom recognition is especially relevant considering the high comorbidity burden that has been shown in patients with narcolepsy as some disorders manifest with symptoms that overlap with narcolepsy. A consequence of delayed diagnosis is delayed treatment, which affects the burden of disease. Substantial detrimental effects on health-care resource utilization, employment, and quality of life have been described after narcolepsy onset and prior to the diagnosis of narcolepsy. This review highlights the importance of closing the diagnostic gap by expanding awareness of narcolepsy and its symptoms.

A randomised controlled trial on the effect of mask choice on residual respiratory events with continuous positive airway pressure treatment

INTRODUCTION It has been found that mask style can affect the amount of continuous positive airway pressure (CPAP) required to reduce an apnoea/hyponoea index (AHI) to < 5/h on a titration study. However, it was not previously known whether switching from one CPAP mask style to another post titration could affect the residual AHI with CPAP. The purpose of this study was to investigate the differences in residual AHI with CPAP treatment between oronasal and nasal masks. METHODS Twenty-one subjects (age mean (M)=62.9, body mass index (BMI) M=29.6 kg/m2) were randomised (14 subjects completed the protocol) to undergo an in-laboratory CPAP titration with either a nasal mask or an oronasal mask. Subjects were then assigned this mask for 3weeks of at-home CPAP use with the optimal treatment pressure determined on the laboratory study (CPAP M=8.4 cm of H2O). At the end of this 3-week period, data were collected from the CPAP machine and the subject was given the other mask to use with the same CPAP settings for the next 3weeks at home (if the nasal mask was given initially, the oronasal one was given later and vice versa). On completion of the second 3-week period, data on residual AHI were again collected and compared with the first 3-week period on CPAP. RESULTS A Wilcoxon Signed-Rank Test (two-tailed) revealed that residual AHI with CPAP treatment was significantly higher with the oronasal compared with the nasal mask (z = -3.296, p<0.001). All 14 subjects had a higher residual AHI with the oronasal versus nasal mask, and 50% of the subjects had a residual AHI >10/h in the oronasal mask condition, even though all of these subjects were titrated to an AHI of < 5/h in the laboratory. CONCLUSION A higher residual AHI was seen in all patients with the use of an oronasal mask compared with a nasal mask. Switching to an oronasal mask post titration results in an increase in residual AHI with CPAP treatment, and pressure adjustment may be warranted.

Polysomnographic Investigation of Sleep and Respiratory Parameters in Women with Temporomandibular Pain Disorders

STUDY OBJECTIVES Temporomandibular pain disorders (TMD) and myofascial pain were linked to increased prevalence of insomnia and obstructive sleep apnea (OSA) on clinical grounds. However, the literature lacks an accurate polysomnographic (PSG) characterization of sleep abnormalities associated with TMD, given that prior studies included small or uncontrolled samples of TMD patients. The present investigation aims to objectively evaluate measures of sleep and respiratory disturbance in a large representative sample of TMD cases in comparison with matched controls. METHODS Sleep, respiration, and limb movements were measured using a 2-night attended PSG protocol in 170 women-124 TMD cases with myofascial pain and 46 demographically matched controls. The second night data were compared between the groups using ANCOVAs. In TMD cases, the relationship between pain ratings and sleep parameters was analyzed using multiple regressions. RESULTS In comparison to healthy controls, TMD cased evidenced a significant increase in stage N1 sleep (12.2% ± 7.6% vs. 9.2% ± 5.0%, p = 0.03), which was only mild relative to normative values. TMD cases also demonstrated mild but significant elevations in arousals associated with all types of respiratory events (6.0/h ± 6.1 vs. 3.5/h ± 3.3 p = 0.02) and in respiratory effort related arousals (RERAs, 4.3/h ± 4.3 vs. 2.6/h ± 2.7, p = 0.02). Myofascial pain predicted a lower sleep efficiency (p = 0.01), more frequent awakenings (p = 0.04), and higher RERA index (p = 0.04) among TMD cases. CONCLUSIONS Myofascial pain in TMD is associated with mild elevation in sleep fragmentation and increased frequency of RERA events. Further research is required to evaluate the clinical significance of these findings.

Stroke and Obstructive Sleep Apnea: A Review

Obstructive sleep apnea (OSA) has been found to be an independent risk factor for stroke in large epidemiological studies. The mechanisms underlying this relationship have been investigated over the past 2–3 decades, with a particular focus on identifying pathophysiological pathways and risk modification strategies. Despite the advancements made, the specific understanding of the implicated mechanisms is still limited. This brief review focuses on presenting some of the epidemiological evidence of the linkage between OSA and stroke, discussing mechanistic pathways and the potential effect of OSA treatment in modulating the risk for stroke in these patients. Future directions for research in this field are also discussed.

REM behavior disorder associated with familial amyotrophic lateral sclerosis

Abstract The association between RBD and synucleinopathies is well known. However, the association between RBD and other neuromuscular diseases has not been as well described. Our case study describes two siblings with familial ALS, confirmed by the identification of the L84F mutation in the SOD1 gene, and RDB. We hope this case study will promote future studies on the prevalence of this association and will stimulate research in identifying the underlying pathogenic mechanism.

Effects of laparoscopic adjustable gastric banding on sleep and metabolism: a 12-month follow-up study

Background Obstructive sleep apnea is commonly associated with metabolic changes and obesity, and changes in body weight by either medical or surgical approaches have been considered to affect the severity of sleep apnea and appetite-controlling hormones. This prospective study evaluated the effect of weight loss induced by laparoscopic adjustable gastric banding (LAGB) surgery on respiratory disturbance during sleep, oxygen saturation levels, sleep architecture, and leptin and ghrelin levels. Methods Participants were patients at a university-based medical center surgical weight loss program. All participants with a body mass index > 30 kg/m2 undergoing LAGB surgery for weight reduction were offered the opportunity to participate in the study. Procedures included overnight polysomnography followed by fasting hormone levels at baseline and 12 months postoperatively. Results Thirty subjects (10 men, 20 women) of mean age 44.0 ± 12.5 years were recruited. At 12 months postoperatively, mean excess weight loss was 44.4% ± 14%. The apnea-hypopnea index decreased from 34.2 ± 35 to 19.0 ± 21.7 events per hour (P < 0.0001), while leptin levels decreased from 24.5 ± 17.42 pg/mL to 11.6 ± 10.6 pg/mL (P = 0.02). Ghrelin levels did not change substantially. Nadir oxygen saturation levels increased from 81% to 84% at 12 months (P = 0.03). Mean oxygen saturation improved and was positively correlated with ghrelin levels at both time points (r = 0.39, P = 0.07, and r = 0.60, P = 0.01). Conclusion LAGB surgery was associated with 44.4% excess weight loss at 12 months, accompanied by a 33.7% improvement in apnea-hypopnea index as well as a reduction in leptin levels by 31.7% in this group. An association between ghrelin and mean oxygen saturation was seen and deserves further investigation.

Unmasking of periodic limb movements with the resolution of obstructive sleep apnea during continuous positive airway pressure application.

Purpose: Periodic limb movements (PLMs) and obstructive sleep apnea (OSA) may present as overlapping conditions. This study investigated the occurrence of PLM during continuous positive airway pressure (CPAP) titration, with the hypothesis that the presence of PLM during CPAP represented “unmasking” of a coexisting sleep disorder. Methods: A total of 78 polysomnographic recordings in 39 OSA subjects with an hourly PLM index ≥5 during CPAP application were evaluated. Results: Application of CPAP significantly improved sleep architecture without change in the PLM index when compared with baseline. The PLM indices and PLM arousal indices were linearly correlated during both nights (r = 0.553, P < 0.01; r = 0.548, P < 0.01, respectively). Eleven subjects with low PLM indices at baseline had greater changes in the PLM index as compared with the sample remainder (P = 0.004). Sixteen subjects with significantly lower PLM indices at baseline required optimal CPAP levels higher than the sample average of 8.2 cm H2O (P = 0.032). These subjects also showed significantly higher median apnea–hypopnea index (AHI) at baseline than the sample remainder (74.4 events per hour [range: 24.2–124.4 events per hour] vs. 22.7 events per hour [range: 8.6–77.4 events per hour], respectively, P < 0.001). Conclusions: These findings suggest that PLM seen during CPAP titration may be related to a concurrent sleep disorder because of “unmasking” in patients with treated OSA.

Autonomic dysfunction in isolated rapid eye movement sleep without atonia

OBJECTIVES Autonomic dysfunction has been demonstrated in patients with rapid eye movement sleep behavior disorder utilizing heart rate variability parameters. We hypothesized that isolated rapid eye movement sleep without atonia is similarly associated with autonomic dysfunction as demonstrated by a reduction in heart rate variability. METHODS An evaluation of 120 records demonstrating rapid eye movement sleep without atonia during polysomnography was performed. Many (n=99) were discarded owing to factors potentially affecting heart rate variability. The remaining 21 records were matched with 21 records of patients demonstrating normal REM atonia, and subjected to electrocardiogram analysis. The parameters measured included R to R interval (RR) length, RR standard deviation, heart rate variability power, and very low frequency, low frequency, and high frequency bands. RESULTS Autonomic dysfunction was seen in patients with isolated rapid eye movement sleep without atonia as denoted by a reduction in heart rate variability compared to those with normal REM atonia. Significant differences between the groups were demonstrated in RR standard deviation (mean difference=0.1502 ± 0.317, 95% confidence interval [95% CI]=0.006, 0.295, p=0.042), heart rate variability power (mean difference=0.3005 ± 0.635, 95% CI=0.011, 0.589, p=0.042), and the low frequency band (mean difference=0.3166 ± 0.616 ms(2), 95% CI=0.036, 0.597, p=0.029), and a borderline significant reduction in the high frequency band (mean difference=0.3121 ± 0.686 ms(2), 95% CI=0.000, 0.624, p=0.050). CONCLUSIONS Our data confirms the hypothesis that heart rate variability is reduced in patients with isolated rapid eye movement sleep without atonia. The values obtained are consistent with previous findings in rapid eye movement behavior sleep disorder patients. SIGNIFICANCE This is the first report of autonomic dysfunction in isolated rapid eye movement sleep without atonia, revealing the need for further evaluation of the clinical significance and potential implications of this finding.

Narcolepsy with cataplexy masked by the use of nicotine.

This report describes a case of narcolepsy with cataplexy masked by the chronic use of cigarettes and nicotine patches. It has been described that narcoleptic smokers report relief of symptoms by smoking tobacco cigarettes. In addition, a case describing partial treatment of sleepiness using a nicotine patch in an adolescent with narcolepsy was recently reported in this journal. Our case adds to the growing literature that nicotine may be used to manage symptoms associated with narcolepsy.

Dorsolateral prefrontal cortex GABA deficit in older adults with sleep-disordered breathing

Significance Sleep-disordered breathing (SDB), characterized by intermittent hypoxia and sleep fragmentation during sleep, is common in the elderly and can contribute to cognitive decline, with significant impairment of executive function, including mental flexibility, problem solving, and working memory, which are under dorsolateral prefrontal cortex (DLPFC) control. The results of the present study suggest a potential mechanism of SDB in which a hypoxia-driven deficit of DLPFC γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter, disrupts the neural excitation/inhibition balance which could lead to hyperexcitability, and potentially neuronal damage and cognitive decline. If validated, these findings, along with the proposed model, would represent a significant advance toward achieving a better understanding of the neurobiology of SDB and novel targets for interventions for the disorder. Sleep-disordered breathing (SDB) is a common disorder in aging that is associated with cognitive decline, including significant executive dysfunction, for which the neurobiological underpinnings remain poorly understood. Using proton magnetic resonance spectroscopy (1H MRS), this study assessed whether dysregulation of the homeostatic balance of the major inhibitory and excitatory amino acid neurotransmitter systems of γ-aminobutyric acid (GABA) and glutamate, respectively, play a role in SDB. Levels of GABA and those of the combined resonances of glutamate and glutamine (Glx), were measured by 1H MRS in the left dorsolateral prefrontal cortex (l-DLPFC) and bilateral hippocampal regions of 19 older adults (age ± SD: 66.1 ± 1.9 years) with moderate to severe SDB, defined as having an Apnea–Hypopnea Index (AHI) greater than 15 as assessed by polysomnography, and in 14 older adults (age ± SD: 62.3 ± 1.3 years) without SDB (AHI < 5). In subjects with SDB, levels of l-DLPFC GABA, but not Glx, were significantly lower than in control subjects (P < 0.0002). Additionally, there was a negative correlation between l-DLPFC GABA levels, but not Glx, and SDB severity by AHI (r = -0.68, P < 0.0001), and a positive correlation between l-DLPFC GABA levels, but not Glx, and minimal oxygen saturation during sleep (r = 0.62, P = 0.0005). By contrast, no group differences or oxygenation associations were found for levels of GABA or Glx in right or left hippocampal region. These findings are interpreted in terms of a pathophysiological model of SDB in which hypoxia-mediated inhibitory neurotransmission deficit in DLPFC could lead to hyperexcitability and, potentially neuronal dysfunction and cognitive decline.