Narcolepsy and sleep-disordered breathing.

BACKGROUND AND PURPOSE: There is a high incidence of sleep-disordered breathing (SDB) in narcoleptic patients. Some narcoleptics with SDB may benefit from treatment with continuous positive airway pressure therapy (CPAP). The aim of this study was to examine the prevalence of SDB in narcoleptics referred to a tertiary sleep disorders clinic and assess the effectiveness of CPAP as adjunctive therapy. METHODS: A retrospective review of patients meeting ICSD-2 criteria for the diagnosis of narcolepsy from 2000 to 2009. RESULTS: One hundred and two patients (61 women) with narcolepsy were included in the study. Twenty-nine (29) patients (eight women, 21 men) were diagnosed with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) of whom 26 commenced CPAP therapy with 11 patients concurrently treated with stimulants. Patients with narcolepsy and OSAHS were older (P = 0.009) and heavier (BMI, 29.6 ± 4.8 vs. 27.3 ± 6, P = 0.042), but their ESS did not differ from patients with narcolepsy alone. Patients treated with both CPAP and stimulants were younger (P = 0.008) and less obese (BMI, 29.1 ± 4.6 vs. 30.4 ± 5.4, P = 0.044) with higher apnoea-hypopnoea index (36.15 ± 21.9 vs. 31.5 ± 16.7, P = 0.03) than those treated with CPAP alone. The ESS of CPAP-treated patients improved during follow-up (19 ± 3.6 vs. 15.8 ± 4.5, P = 0.006), but BMI increased (30.6 ± 5 vs. 31.7 ± 5.6, P = 0.05). The use of stimulants did not seem to improve on the effectiveness of CPAP. CONCLUSION: Coexisting SDB is common in narcoleptics (28.5%). CPAP therapy in narcoleptics with OSAHS remains a useful second-line adjunct to standard therapy.

Diagnosing narcolepsy with cataplexy on history alone: challenging the International Classification of Sleep Disorders (ICSD-2) criteria.

BACKGROUND AND PURPOSE: The second version of the International Classification of Sleep Disorders suggests narcolepsy with cataplexy can be diagnosed on history alone. PATIENTS: Five patients with a history supportive of narcolepsy/cataplexy. METHOD: Case review following clinical investigation. RESULTS: None of the five patients had a diagnosis of narcolepsy/cataplexy on the basis of objective testing using polysomnography (PSG) and multiple sleep latency testing (MSLT). CONCLUSION: PSG and MSLT should always be used in conjunction with a comprehensive history taken by an experienced sleep physician to support a diagnosis of narcolepsy with cataplexy and to exclude other conditions that may mimic narcolepsy.

Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial.

BACKGROUND: The obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is associated with hypertension and increased cardiovascular risk, particularly when accompanied by marked nocturnal hypoxaemia. The mechanisms of these associations are unclear. We hypothesised that OSAHS combined with severe nocturnal hypoxaemia causes impaired vascular function that can be reversed by continuous positive airways pressure (CPAP) therapy. METHODS: We compared vascular function in two groups of patients with OSAHS: 27 with more than 20 4% desaturations/h (desaturator group) and 19 with no 4% and less than five 3% desaturations/h (non-desaturator group). In a randomised, double blind, placebo controlled, crossover trial, the effect of 6 weeks of CPAP therapy on vascular function was determined in the desaturator group. In all studies, vascular function was assessed invasively by forearm venous occlusion plethysmography during intra-arterial infusion of endothelium dependent (acetylcholine 5-20 microg/min and substance P 2-8 pmol/min) and independent (sodium nitroprusside 2-8 microg/min) vasodilators. RESULTS: Compared with the non-desaturator group, patients with OSAHS and desaturations had reduced vasodilatation to all agonists (p = 0.007 for all). The apnoea/hypopnoea index and desaturation frequency were inversely related to peak vasodilatation with acetylcholine (r = -0.44, p = 0.002 and r = -0.43, p = 0.003) and sodium nitroprusside (r = -0.42, p = 0.009 and r = -0.37, p = 0.02). In comparison with placebo, CPAP therapy improved forearm blood flow to all vasodilators (p = 0.01). CONCLUSIONS: Patients with OSAHS and frequent nocturnal desaturations have impaired endothelial dependent and endothelial independent vasodilatation that is proportional to hypoxaemia and is improved by CPAP therapy. Impaired vascular function establishes an underlying mechanism for the adverse cardiovascular consequences of OSAHS.

Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure.

BACKGROUND: Sleep-disordered breathing (SDB) is common after stroke, but it is unclear whether it should be treated. OBJECTIVE: To conduct a randomised controlled trial of continuous positive airway pressure (CPAP) after stroke. METHODS: Patients with stroke with > or = 30 apnoeas and hypopnoeas per hour ((A+H)/h) with predominant obstructive sleep apnoea or hypopnoea were randomised to either CPAP treatment or conservative treatment for 8 weeks. Outcomes were measured blind to treatment allocation at 8 weeks and 6 months after the stroke. The primary outcome was physical function on the Nottingham Extended Activities of Daily Living Scale. RESULTS: Of 658 patients with stroke screened, only 71 (10.7%) were eligible and consented to a sleep study 14-19 days after stroke. 66 patients completed the sleep study (21 women; mean age 72 years), 33 (50%) had > or = 30 (A+H)/h that were predominantly obstructive. 15 were randomised to CPAP treatment and 15 to conventional treatment. Despite intensive efforts, objective use of CPAP was poor, averaging 1.4 h a night. CPAP treatment resulted in no significant improvements (p>0.1) in the primary outcome or in neurological function or sleepiness, and in poorer health status on some measures. CONCLUSIONS: This trial showed no benefit from CPAP treatment, the relevance of the observed detrimental effects is questionable. Even in our highly selected patients with stroke, use of CPAP was poor. At present, CPAP treatment should be advocated for patients with stroke only if they have symptoms of SDB.

Breathing, sleep, and diabetic autonomic neuropathy.

Sudden, unexplained deaths are relatively common in diabetic autonomic neuropathy. As disturbed autonomic function has been associated with sleep apnea, and sleep apnea with sudden death, we recorded breathing patterns, arterial oxygen saturation, and EEG during sleep in 8 male diabetic subjects with severe autonomic neuropathy and 8 age-matched, male diabetic subjects without autonomic neuropathy. None of the patients with autonomic neuropathy had more than 11 apneic episodes per night, and there were no significant differences between the two groups in the number of sleep apneas, the duration of individual apneic episodes, the total duration of irregular breathing during sleep, or the duration and quality of sleep. The arterial oxygen saturation when awake and the lowest arterial oxygen saturation during sleep were also similar in both groups. Thus, diabetic patients with severe autonomic neuropathy have normal breathing patterns and oxygenation during sleep, and it is unlikely that sleep apnea causes these unexpected deaths.

Factors impairing daytime performance in patients with sleep apnea/hypopnea syndrome.

Patients with sleep apnea/hypopnea syndrome commonly demonstrate impaired daytime performance. In a prospective study, 29 patients with sleep apnea/hypopnea syndrome were assessed polysomnographically to determine the relationship of cognitive performance and daytime sleepiness with sleep disruption, hypoxemia, and mood. Deterioration of cognitive performance correlated significantly with increasing severity of nocturnal breathing irregularity, magnitude of nocturnal hypoxemia, and extent of sleep disruption. Multiple regression analysis identified frequency of apneas plus hypopneas and of arousal and the extent of nocturnal hypoxemia as the variables most strongly associated with cognitive deficits. Anxiety and depression also contributed to this impairment. Objective daytime sleepiness was not significantly associated with nocturnal variables. This study showed that the frequency of breathing irregularities and the extent of both sleep disruption and nocturnal hypoxemia are important in determining daytime function in patients with sleep apnea/hypopnea syndrome. All of these factors should be considered when deciding which patients require treatment.

Central sleep apnea. Improvement with acetazolamide therapy.

Respiratory rhythm during sleep may be dependent on blood pH with apneas being associated with alkalosis. Acidification may therefore have therapeutic value in some forms of sleep apnea. We administered acetazolamide to six patients with symptomatic central sleep apnea, a disorder of respiratory rhythm with little or no upper airway obstruction. Sleep studies were carried out before and after one week of drug therapy, during which time the mean arterial pH decreased from 7.42 to 7.34. All six patients had significant improvement, demonstrating a 69% reduction in total apneas. Five of the six patients reported better-quality sleep and decreased daytime hypersomnolence. Subsequent studies in normal subjects showed that acetazolamide, like other agents known to produce a metabolic acidosis, shifted the hypercapnic ventilatory response to the left 5 +/- 0.54 mm Hg. This may be important in mediating the observed decrease in apneas.

Cytokine gene polymorphisms in obstructive sleep apnoea/hypopnoea syndrome.

OBJECTIVE: The pro-inflammatory cytokines, TNF-α, IL-6, and IL-8 are elevated in obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Cytokine gene interactions are complex and haplotype analysis may be more informative. We hypothesized that the effects of TNF-α in OSAHS might be due to linkage disequilibrium of the TNF-α (-308A) single nucleotide polymorphism (SNP) with other polymorphisms within the TNF-α gene, and that predisposition to elevated IL-6 and IL-8 levels in OSAHS might be attributable to pro-inflammatory IL-6 and IL-8 gene promoter polymorphisms. METHOD: 173 subjects were classified as having definite OSAHS or not on the basis of apnoea-hypopnoea frequency, sex, age, and symptoms. Population controls comprised 192 random UK blood donors. Genotyping was undertaken for the TNF-α promoter polymorphisms (-1031, -863, -857, -238), two lymphotoxin-α polymorphisms (intron 1 and Thr60Asn), the pro-inflammatory IL-6 gene promoter polymorphism (-174), and IL-8 gene promoter polymorphisms (-251; -781). RESULTS: There was no significant difference between groups re: genotype/allelic frequency in the genes investigated. Association between disease status and the TNF-α alleles independently (TNF-103, TNF-803, TNF-857, TNF-238) with five haplotypes of TNF-α was not significant (p > 0.05). There was no difference in allelic or genotypic frequencies between obese and non-obese subjects with OSAHS. The TNF-α (-863A) allele alone, was significantly associated with obesity (OR 2.4; CI95% 1.1-5; p = 0.025). CONCLUSION: Only the TNF-α (308A) SNP appears to be significantly associated with OSAHS. The impact of cytokine gene polymorphisms on phenotypic expression of inflammation in OSAHS is likely to be complex.

The psychosocial aspects of narcolepsy.

Although referrals for narcolepsy are increasing, physicians continue to confront obstacles in diagnosing and treating this condition. Patients with narcolepsy also face challenges at work, at school, and at home. One of the more disturbing problems is the lack of public awareness of the disorder and its potential therapy. As a result, patients with narcolepsy are often viewed in the school or work setting as being "lazy." In addition, the psychological and sexual side effects of the medications currently available to treat narcolepsy can lead to marital, family, and work-related problems. Irritability, anxiety, and impotence are common. Of particular concern are the risk for a serious automobile accident when the person with narcolepsy remains untreated and the reluctance of narcoleptic patients to seek treatment for fear of losing their driver's license. This article addresses the health system factors that influence the identification and care of patients with narcolepsy and focuses on the psychosocial impact of the disease.

Peripheral edema in the sleep apnea/hypopnea syndrome.

To clarify the roles of lung function, nocturnal hypoxemia and obesity in the development of peripheral edema in patients with the sleep apnea/hypopnea syndrome (SAHS), 65 consecutive SAHS patients had diagnostic sleep studies and respiratory function testing. Eighteen patients (27%) had peripheral edema without other explanation. Their sleep apnea/hypopnea index was similar to those without edema, but they were more obese (p less than 0.01) and had worse lung function (p less than 0.01) and lower oxygen saturation (SaO2) awake (p less than 0.01). These 18 became more hypoxemic during sleep than predicted from their awake SaO2 (p less than 0.005). Eleven patients with edema had evidence of pulmonary hypertension on cardiac catheterization, chest radiograph, or electrocardiograph and could be weight matched to 11 SAHS patients without edema. Those with right heart failure were more hypoxic (p less than 0.01) when awake, desaturated more frequently during sleep (p less than 0.01), and had lower FEV1% predicted (p less than 0.01). Thus, extent of both daytime and nighttime hypoxemia are important in the development of right heart failure in patients with SAHS.

Frequency of EEG arousals from nocturnal sleep in normal subjects.

Brief arousals are clinically important and increasingly scored during polysomnography. However, the frequency of arousals during routine polysomnography in the normal population is unknown. We performed overnight polysomnography in the 55 of 59 control subjects from a family practice list who were approached and agreed to undergo polysomnography. Awakenings were scored according to the criteria of Rechtschaffen and Kales and briefer arousals according to three different criteria, including the American Sleep Disorders Association (ASDA) definition. There was a mean of 4 [95% confidence interval (CI), 1-15) Rechtschaffen and Kales awakenings per hour, whereas the ASDA definition gave 21 (95% CI, 7-56) per hour slept. Arousal frequencies increased significantly (p < 0.001) with age in our subjects, who ranged from the late teens to early 70s. The high upper limit of the frequency of brief arousals was not altered by exclusion of patients who snored or had witnessed apneas or daytime sleepiness. It is important that those scoring arousals on routine polysomnography recognize that high arousal frequencies occur in the normal population on 1-night polysomnography.

The effect of in-laboratory polysomnography on sleep and objective daytime sleepiness.

MSLT guidelines recommend performing MSLTs following polysomnography (PSG) to document the preceding night's sleep. We tested the hypothesis that patients are objectively sleepier after in-laboratory full diagnostic PSG than after a sleep recording at home. Sixteen patients with the sleep apnea/hypopnea syndrome (SAHS; AHI 35+/-SD 28 per hour slept) were recruited into a randomized crossover study. To monitor sleep with minimal disruption at home, only sleep was recorded on 2 consecutive nights, the first for acclimatization. The laboratory limb followed standard PSG. Both study nights were followed next day by MSLT and MWT. There were no differences in MSLT (12.0 SD 5.1 home, 11.6+/-4.7 min laboratory; p=0.7), MWT (32.7+/-8.7, 31.6+/-9.3 min; p=0.6) or total sleep time (362+/-53, 343+/-51 min; p=0.15) between home and laboratory limbs. However, on the home night, fewer microarousals (31+/-14, 54+/-25/hr slept; p<0.0001) and less % wake (15+/-10, 24+/-11; p=0.006) were found. On the home study night, patients had greater % REM sleep, slow-wave sleep and sleep efficiency (all p<0.009). This study does not support the hypothesis that patients are sleepier after laboratory PSG compared to home study night. However, the improved sleep at home raises the question whether laboratory-based polysomnography is always required prior to MSLT/MWT testing or whether less obtrusive monitoring of sleep duration at home would sometimes suffice.

Arousals and the sleep apnea/hypopnea syndrome.

As daytime deficits in sleep apnea/hypopnea syndrome (SAHS) correlate poorly with earlier definitions of arousals, we investigated the relationship between microarousals and sleepiness in 63 patients with SAHS. There was a poor correlation between mean sleep latency and microarousal frequency. To determine whether arousals not detected by current definitions could account for some of the residual variance in normal subjects we used sound to induce "arousals" that were detected by rises in blood pressure but produced no visible EEG change. Such autonomic arousals produced an increase in sleepiness. We conclude that arousals not scored currently on polysomnography may contribute to the sleepiness of patients with SAHS.

Effects of CPAP on vigilance and related functions in patients with the sleep apnea/hypopnea syndrome.

There have been relatively few robust studies of the effects of CPAP therapy on vigilance and daytime function. This article will use all known published and unpublished randomized clinical trials on this area. There is good evidence that CPAP helps subjective sleepiness, objective sleepiness, quality of life, mood and driving performance. However, CPAP does not appear to normalize objective sleepiness. Many of the improvements are directly related to the nightly use of CPAP. Recent data suggest that increasing CPAP usage improves outcomes.

Do patients with the sleep apnea/hypopnea syndrome drink more alcohol?

As alcohol ingestion may worsen the sleep apnea/hypopnea syndrome, we have investigated the alcohol consumption of patients with the sleep apnea/hypopnea syndrome in comparison to control subjects to determine whether patients with the sleep apnea/hypopnea syndrome drink excessively. A lifetime alcohol history was taken from each. There was no significant difference between the 50 patients with the sleep apnea/hypopnea syndrome and 95 age-matched controls in either the lifetime (patients 27, SEM 5 x 10(3); controls 26, SEM 4 x 10(3) units) or current (12, SEM 2; 12, SEM 2 units per week) alcohol consumption. There was no evidence that alcohol consumption was related to the development of arterial carbon dioxide retention or peripheral edema in such individuals.

Night sleep of patients with chronic ventilatory failure and age matched controls: number and duration of the EEG episodes of intervening wakefulness and drowsiness.

Characteristics of the episodes of wakefulness and drowsiness (stage 0 + 1) intervening in a night of electrophysiologically monitored sleep were compared in a homogeneous group of 13 patients (mean age 57 years) with severe hypoxic chronic bronchitis and emphysema (blue and bloated variety) and 8 age matched control subjects. The total amounts of stage 0 + 1 accumulated over one night (preceded by one night of adaptation) were high in both groups (28% in the patients, 22% in the control subjects). A significant difference was found in the number of brief arousals (episodes of stage 0 + 1 lasting for less than 1 min), which averaged 10/h of sleep in the patients, and 6/h of sleep in the control subjects (p less than 0.05, two tailed). The numbers of longer episodes of stage 0 + 1 were not significantly different and varied independently from the numbers of brief arousals in the individuals. Only a small proportion (8 %) of brief arousals was linked to episodes of hypopnea or apnea in the bronchitic patients. Large numbers of brief arousals/h of non rapid eye movement sleep inthe bronchitic patients correlated significantly with small percentages of stage 3 + 4 sleep (p less than 0.05), and were associated with smell numbers of hypoxemic episodes occurring predominantly in rapid eye movement sleep. The findings indicate a more fractionated sleep in the patients with chronic hypoxic bronchitis, and suggest that the brief arousals represent a limiting factor rather than a result of the nocturnal hypoxemic episodes occurring in these patients.

Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome.

The role of drug therapy in the treatment of the sleep apnea/hypopnea syndrome is unclear. In a randomised, double-blind, placebo-controlled study, we investigated the value of 14-day therapy with protriptyline (20 mg daily) or acetazolamide (250 mg 4 times per day) on symptoms and on the frequency of apneas, hypopneas, arousals, and 4% desaturations in 10 patients with obstructive sleep apnea/hypopnea syndrome. Overall, protriptyline did not have a significant effect either on symptoms or on any of the above polysomnographic criteria. Acetazolamide reduced the apnea/hypopnea frequency [placebo 50 +/- 26 (SD); acetazolamide 26 +/- 20/h of sleep, p less than 0.03] and tended to decrease the frequency of 4% desaturations (placebo 29 +/- 20; acetazolamide 19 +/- 16/h of sleep, p = 0.06). Despite these physiological improvements, acetazolamide did not significantly improve symptoms and paraesthesiae were common. Contrary to earlier studies, we conclude that protriptyline may have a limited role in the treatment of the sleep apnea syndrome. The reason why acetazolamide produced a physiological, but not a symptomatic, response requires further investigation.

Accuracy and significance of scoring hypopneas.

We previously reported that the best definition of hypopneas in the sleep apnea/hypopnea syndrome (SAHS) is based on reduction in thoracoabdominal movement. However, the repeatability of scoring hypopneas from thoracoabdominal movement has not been assessed, nor has the need to record flow as well as thoracoabdominal movement. Thus, two polysomnographers independently scored both apneas and hypopneas on all-night polysomnograms of patients with SAHS. There was close agreement between the polysomnographers for the number of hypopneas (r = 0.98; mean difference 11%) and for the number of apneas (r = 0.99; mean difference 8%). The agreement was similar for the durations of both hypopneas (r = 0.99; mean difference 13%) and apneas (r = 0.99; mean difference 11%). There was also close agreement between the total number of respiratory events scored with and without reference to the flow signal (r = 0.99; mean difference 1.4%) with a maximum under-recognition of 18 events per night in a subject with 237 apneas per night. Thus, hypopneas can be scored reproducibly. In addition, the value of always recording and scoring flow as well as thoracoabdominal signals is questioned.

Cognitive function in the sleep apnea/hypopnea syndrome (SAHS).

The magnitude, determinants and reversibility of cognitive deficits associated with the sleep apnea/hypopnea syndrome (SAHS) are of clinical and research interest. A quantitative overview of impairment effect sizes (ESs) from case-control studies of cognitive performance in SAHS suggests that deficits broadly worsen with disease severity, with large average values for attentional (ES approximately 1.0 SD units) and executive (ES approximately 0.9 SD units) cognitive scores, and moderate values for memory-related (ES approximately 0.6 SD units) performance scores. A study of determinants of cognitive outcomes conducted in 150 patients with SAHS (AHI 5+ and > or =2 symptoms) showed significant but weak associations between a cognitive 'intellectual ability' component score (CS) and both AHI (r=-0.14) and minimum oxygen saturation (r = 0.15), linking increasing disease severity with poorer performance. A somewhat stronger correlation between a cognitive 'response slowing' CS and a 'wakefulness' CS was observed (r=-0.34). That sleepiness as well as hypoxemia might contribute to cognitive deficit has also been suggested by experimental sleep fragmentation in normals, producing small to moderate impairments (average ES approximately 0.3 SD units) in attention-biased scores. The reversibility of attentional cognitive deficits has been investigated through a meta-analysis of randomized placebo-controlled crossover studies of CPAP treatment, involving 98 SAHS patients (AHI 5+ and > or =2 symptoms). While cognitive outcomes showed at least trends towards better performance on CPAP than on placebo (p< or =0.1), the ESs of cognitive enhancements following CPAP were small (average ES approximately 0.2 SD units). This may be due either to the relatively mild study population, suboptimal CPAP use or to an irreversible component in cognitive impairment in SAHS.

Ambulatory blood pressure on and off continuous positive airway pressure therapy for the sleep apnea/hypopnea syndrome: effects in "non-dippers".

Ambulatory blood pressure (BP) monitoring was performed in 13 patients with the sleep apnea/ hypopnea syndrome (SAHS) during a randomized, placebo controlled crossover trial of the effects of continuous positive airway pressure (CPAP) therapy. BP was monitored at half-hourly intervals for a 24-hour period both on CPAP and on an oral placebo, each given for a minimum of 3 weeks. Objective effective CPAP use averaged 4.3 hours per night. Weight and anti-hypertensive medications remained stable over the study period. Systolic, diastolic and mean arterial BP for 24-hour, daytime and nighttime periods were not significantly different on placebo compared to CPAP. Those patients with no significant overnight fall in BP on placebo ("non-dippers") showed a significant improvement in daytime mean arterial BP on CPAP (98 +/- 4 mm Hg) compared to placebo (102 +/- 4 mm Hg; p = 0.01). These findings, in a well-controlled trial, suggest that BP is not reduced by CPAP in a heterogeneous group of SAHS patients, but it may be selectively improved in those patients most at risk for cardiovascular morbidity and mortality.