Christopher Kosky

First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias

OBJECTIVES Discrimination between narcolepsy, idiopathic hypersomnia, and behavior-induced inadequate sleep syndrome (BIISS) is based on clinical features and on specific nocturnal polysomnography (NPSG) and multiple sleep latency test (MSLT) results. However, previous studies have cast doubt on the specificity and sensitivity of these diagnostic tools. METHODS Eleven variables of the NPSG were analyzed in 101 patients who were retrospectively diagnosed with narcolepsy with cataplexy (N+C) (n=24), narcolepsy without cataplexy (N-C) (n=38), idiopathic hypersomnia with long sleep period (IHL) (n=21), and BIISS (n=18). RESULTS Fifteen out of 24 N+C and 8 out of 38 N-C entered the first rapid eye movement (REM) sleep period (FREMP) from sleep stage 1 (N1) or wake (W), though this sleep-stage sequence did not arise in the other patient groups. FREMP stage sequence was a function of REM sleep latency (REML) for both N+C and N-C groups. FREMP stage sequence was not associated with mean sleep latency (MSL) in N+C but was associated in N-C, which implies heterogeneity within the N-C group. REML also was a useful discriminator. Depending on the cutoff period, REML had a sensitivity and specificity of up to 85.5% and 97.4%, respectively. CONCLUSIONS The FREMP stage sequence may be a useful tool in the diagnosis of narcolepsy, particularly in conjunction with sleep-stage sequence analysis of sleep-onset REM periods (SOREMPs) in the MSLT; it also may provide a helpful intermediate phenotype in the clarification of heterogeneity in the N-C diagnostic group. However, larger prospective studies are necessary to confirm these findings.

Effect of an Indwelling Pleural Catheter vs Talc Pleurodesis on Hospitalization Days in Patients With Malignant Pleural Effusion: The AMPLE Randomized Clinical Trial

Importance Indwelling pleural catheter and talc pleurodesis are established treatments for malignant pleural effusions among patients with poor prognosis. Objective To determine whether indwelling pleural catheters are more effective than talc pleurodesis in reducing total hospitalization days in the remaining lifespan of patients with malignant pleural effusion. Design, Setting, and Participants This open-label, randomized clinical trial included participants recruited from 9 centers in Australia, New Zealand, Singapore, and Hong Kong between July 2012 and October 2014; they were followed up for 12 months (study end date: October 16, 2015). Patients (n = 146) with symptomatic malignant pleural effusion who had not undergone indwelling pleural catheter or pleurodesis treatment were included. Interventions Participants were randomized (1:1) to indwelling pleural catheter (n = 74) or talc pleurodesis (n = 72), minimized by malignancy (mesothelioma vs others) and trapped lung (vs not), and stratified by region (Australia vs Asia). Main Outcomes and Measures The primary end point was the total number of days spent in hospital from procedure to death or to 12 months. Secondary outcomes included further pleural interventions, patient-reported breathlessness, quality-of-life measures, and adverse events. Results Among the 146 patients who were randomized (median age, 70.5 years; 56.2% male), 2 withdrew before receiving the randomized intervention and were excluded. The indwelling pleural catheter group spent significantly fewer days in hospital than the pleurodesis group (median, 10.0 [interquartile range [IQR], 3-17] vs 12.0 [IQR, 7-21] days; P = .03; Hodges-Lehmann estimate of difference, 2.92 days; 95% CI, 0.43-5.84). The reduction was mainly in effusion-related hospitalization days (median, 1.0 [IQR, 1-3] day with the indwelling pleural catheter vs 4.0 (IQR, 3-6) days with pleurodesis; P < .001; Hodges-Lehmann estimate, 2.06 days; 95% CI, 1.53-2.58). Fewer patients randomized to indwelling pleural catheter required further ipsilateral invasive pleural drainages (4.1% vs 22.5%; difference, 18.4%; 95% CI, 7.7%-29.2%). There were no significant differences in improvements in breathlessness or quality of life offered by indwelling pleural catheter or talc pleurodesis. Adverse events were seen in 22 patients in the indwelling pleural catheter group (30 events) and 13 patients in the pleurodesis group (18 events). Conclusions and Relevance Among patients with malignant pleural effusion, treatment with an indwelling pleural catheter vs talc pleurodesis resulted in fewer hospitalization days from treatment to death, but the magnitude of the difference is of uncertain clinical importance. These findings may help inform patient choice of management for pleural effusion. Trial Registration anzctr.org.au Identifier: ACTRN12611000567921

Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England

STUDY OBJECTIVES An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England. METHODS Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design. RESULTS Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45-12.38) using all cases and 9.06 (1.90-43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses. CONCLUSIONS We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design.

Comparison of 7 versus 14 days wrist actigraphy monitoring in a sleep disorders clinic population.

Wrist actigraphy is a valid measure to assess sleep and circadian rhythm abnormalities. It is listed in the diagnostic criteria for sleep disorders where single night polysomnography is insufficient (ICSD-2). However, an optimal recording time remains unclear. We hypothesised that seven days would provide sufficient data for analysis, similar to recordings for 14 days. We analysed three consecutive years of actigraphy data obtained within a tertiary sleep referral centre. Data were recorded continuously for two weeks using an AW4 actiwatch (Cambridge NeuroTechnology, Cambridge, UK; Mini Mitter Co, Sunriver, OR). Parameters, including sleep efficiency (SE), sleep latency (SL), sleep fragmentation index (SFI), total sleep time (TST) and wake after sleep onset (WASO) were analysed using GraphPad Prism (Version 5.02, GraphPad Software Inc, San Diego, CA) and classified into week one, week two and an overall average for the duration of 14 days. In addition, two experienced consultants working in the sleep laboratory compared the results of week one versus week two independently, visually analysing the data for circadian rhythmicity and fragmentation of the pattern, allowing calculation of the intraclass correlation coefficient (ICC), κ. The actigraphies of 239 patients (51.9% male; age 42 (16) years) were analysed. There was no difference in SE, SL, SFI or WASO between week one, week two and 14 days average recording. A small difference was found between TST week one (399.9 minutes, 95% CI 389.9–409.9 minutes) and TST week two (388.7 minutes, 95% CI 378.3–399.1 minutes), but not between TST for 14 days average recording (394.3 minutes, 95% CI 384.7–403.9 minutes) and either week. Independent scorers achieved a good agreement in the rhythmicity of the sleep pattern (ICC κ 0.734, p < 0.001) and a low agreement for the fragmentation of the pattern (ICC κ 0.380, p < 0.001). One week of wrist actigraphy recording provides similar data to two week actigraphies, despite subtle differences between the weeks. One week wrist actigraphy could be recommended as standard compared to longer recordings to maximise efficiency of the clinical service. Further studies are required to validate our results in specific clinical subgroups.

Insular seizures causing sleep-related breathlessness

A 52-year-old woman was referred for assessment for sleep apnoea in October, 2010, with excessive daytime sleepiness, loud snoring, and regular waking from sleep with choking and breath lessness. She described regular events—occurring shortly after falling asleep—whereby she would suddenly wake up with a feeling of choking or being strangled for several seconds, accompanied by a sharp, central chest pain. These events were always associated with a feeling of dyspnoea and anxiety, lasting 1–2 min. Rarely she would feel a stiff ening sensation of her right leg as the event subsided. After prompting, she recalled that with more severe events, she may have bitten the lateral margins of her tongue. She remained fully aware of her surroundings throughout, and was able to return to sleep afterwards. These events would happen once, and at most twice, during the night, 5 or 6 nights a week, and would worsen in severity during the late luteal phase of her menstrual cycle. She remembered having very similar, less frequent, and less severe events from the age of 11 years, which had been treated as panic attacks with intermittent oral chlorpromazine. Her birth, childhood, and developmental history were unremarkable. She had a background of mild asthma. There was no family history of epilepsy. Physical examination was normal. Standard overnight poly somnography demonstrated fragmented sleep and an apnoea-hypopnoea index of 5·4/h. An MRI scan of the brain was normal. A further full-montage overnight sleep EEG, and separate sleep-deprived wake EEG, showed brief focal bursts of irregular theta activity over the left temporal area during frequent awakenings from stage N2 sleep. An FDG-PET scan of the brain showed an asymmetrical hypometabolic focus in the region of the left insula extending into the left temporal lobe (fi gure). A diagnosis of sleep-related focal epilepsy, localised to the left insular cortex, was made. Initiation of oral levetiracetam, escalated to a dose of 1500 mg nightly, resulted in suppression of almost all the patient’s seizures, with great improvement in sleep quality and daytime functioning. At last follow-up in September, 2013, she was experiencing only very occasional attacks of much reduced severity, which would occur only in the few days preceding her menses. The insular cortex lies deeply folded within the lateral sulcus of each hemisphere, covered by overlying areas of frontal, temporal, and parietal lobes. Penfi eld and Jasper were the fi rst to report the insular cortex’s prominent roles in viscerosensory, visceromotor, and autonomic control, as well as somatosensory, pain, auditory, and speech processing. With the location of the insula and its functional connectivity with the central autonomic net work, seizures arising from it can mimic temporal and frontal seizures, and may more rarely cause ictal arrhyth mias, including asystole. Scalp EEG may show interictal discharges of value in lateralising the side of the epi lep tic focus, but is otherwise unhelpful at diff erentiating seizures of insular origin from those originating from overlying areas of cortex. Isnard and coworkers directly recorded insular seizures using im planted cortical EEG in six patients, and described key characteristics, thought to be highly specifi c for these attacks. All patients maintained full consciousness and immediately noted laryngeal dis comfort as a choking or strangling sensation that was marked by anxiety and subjective dyspnoea. Perioral or truncal paraesthesiae were described, together with dys phonia and mutism in some patients, lasting up to a minute. The attacks typically ended with a stiff ening sen sation in a limb contralateral to the focus. Nocturnal choking and dyspnoea are frequently described symp toms of common disorders, such as obstructive sleep apnoea, heart failure, gastro-oesophageal refl ux, laryngospasm, and panic disorder. Careful ap praisal of additional symp toms suggestive of seizure activity should be done during the assessment of such patients.

Nocturnal pulse rate and symptomatic response in patients with obstructive sleep apnoea treated with continuous positive airway pressure for one year

BACKGROUND Obstructive sleep apnoea (OSA) is the most common form of sleep-disordered breathing and a known risk factor for cardiovascular disease. We hypothesised that in patients with OSA the characteristics of nocturnal pulse rate (PR) are associated with changes in blood pressure and daytime sleepiness, following commencement of continuous positive airway pressure (CPAP) therapy. METHODS Pulse oximetry data, demographics, daytime sleepiness and blood pressure were recorded at baseline and at one year follow up. Patients with OSA were grouped according to positive and negative changes in the PR (ΔPR) response during the first night of pulse oximetry before commencement of CPAP. RESULTS A total of 115 patients (58 with OSA and 57 matched subjects without OSA) were identified and included in the analysis. The scale of improvement in daytime sleepiness could be predicted by a negative or positive ΔPR, as recorded in the initial screening pulse oximetry [ΔESS -5.8 (5.1) vs. -0.8 (7.2) points, P<0.05]. A negative correlation was observed between mean nocturnal PR and changes in systolic blood pressure (SBP) after one year of CPAP treatment (r=-0.42, P<0.05). CONCLUSIONS Mean nocturnal PR prior to CPAP initiation was associated with changes in SBP at one year follow up. A descending nocturnal PR in patients with OSA, prior to CPAP initiation, might help to identify a symptomatic response from long term CPAP treatment.

The use of an online pictorial Epworth Sleepiness Scale in the assessment of age and gender specific differences in excessive daytime sleepiness

BACKGROUND Excessive daytime sleepiness (EDS) is a non-specific but highly prevalent cardinal symptom of sleep disorders. We hypothesized that with modern media and an online pictorial Epworth Sleepiness Scale (ESS) age and gender specific differences of EDS could be identified on a large scale. This could be helpful in the screening of patients with sleep disorders. PATIENTS AND METHODS In 8,098 subjects, age and gender were recorded in addition to an online pictorial ESS (range 0-24 points). The cut-off for EDS (ESS >10 points) was chosen in line with the traditional ESS. RESULTS The prevalence of EDS was slightly higher in male subjects (45% vs. 43%, P=0.033). When age was considered, female subjects tended to be sleepier in their 3(rd) and 4(th) lifetime decade (P=0.01 and P=0.003, respectively), whilst male subjects scored significantly higher in their 7(th) decade (P<0.0001); there was a trend to more daytime symptoms with higher age (P for trend <0.001). CONCLUSIONS The online pictorial ESS identifies gender differences in EDS and reveals increased levels of sleepiness associated with higher age. The use of modern media facilitates reaching out to the general population to raise awareness of conditions associated with EDS such as sleep apnoea.

Diagnosis of PLMD from increased pulse rate variability on overnight oximetry.

Study objective This study was undertaken in a group of patients with periodic limb movement disorder (PLMD) to assess whether the presence of increased pulse rate variability (PRV) without desaturation on overnight oximetry was suggestive of the occurrence of periodic limb movements (PLMs). Methods Seventy sleepy patients with a polysomnographic diagnosis of PLMD and 25 controls with obstructive sleep apnea were included in this retrospective study. All patients had undergone initial domiciliary oximetry and subsequent polysomnography (PSG). The oximetry tracings were independently interpreted by five sleep unit personnel for the presence of increased PRV. Further, the association between increased PRV and PLMs was evaluated in the summary graph of the PSG. Results Fifty seven (81.4%) patients had definite evidence of increased PRV without episodes of desaturation on initial oximetry, which was later confirmed to be due to PLMs on PSG. 13 (18.6%) patients had no PRV on oximetry and PSG but had PLMD. The inter-interpreter concurrence in suspecting a diagnosis of PLMD based on oximetry alone was more than 80% in 64 (91%) patients. Conclusion The presence of isolated increased PRV on overnight oximetry is a valuable tool in suspecting nonsleep apnea disorders like PLMD.

Aggressive versus symptom-guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE-2): an open-label randomised trial

BACKGROUND Indwelling pleural catheters are an established management option for malignant pleural effusion and have advantages over talc slurry pleurodesis. The optimal regimen of drainage after indwelling pleural catheter insertion is debated and ranges from aggressive (daily) drainage to drainage only when symptomatic. METHODS AMPLE-2 was an open-label randomised trial involving 11 centres in Australia, New Zealand, Hong Kong, and Malaysia. Patients with symptomatic malignant pleural effusions were randomly assigned (1:1) to the aggressive (daily) or symptom-guided drainage groups for 60 days and minimised by cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group [ECOG] score 0-1 vs ≥2), presence of trapped lung, and prior pleurodesis. Patients were followed up for 6 months. The primary outcome was mean daily breathlessness score, measured by use of a 100 mm visual analogue scale during the first 60 days. Secondary outcomes included rates of spontaneous pleurodesis and self-reported quality-of-life measures. Results were analysed by an intention-to-treat approach. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000963527. FINDINGS Between July 20, 2015, and Jan 26, 2017, 87 patients were recruited and randomly assigned to the aggressive (n=43) or symptom-guided (n=44) drainage groups. The mean daily breathlessness scores did not differ significantly between the aggressive and symptom-guided drainage groups (geometric means 13·1 mm [95% CI 9·8-17·4] vs 17·3 mm [13·0-22·0]; ratio of geometric means 1·32 [95% CI 0·88-1·97]; p=0·18). More patients in the aggressive group developed spontaneous pleurodesis than in the symptom-guided group in the first 60 days (16 [37·2%] of 43 vs five [11·4%] of 44, p=0·0049) and at 6 months (19 [44·2%] vs seven [15·9%], p=0·004; hazard ratio 3·287 [95% CI 1·396-7·740]; p=0·0065). Patient-reported quality-of-life measures, assessed with EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L), were better in the aggressive group than in the symptom-guided group (estimated means 0·713 [95% CI 0·647-0·779] vs 0·601 [0·536-0·667]). The estimated difference in means was 0·112 (95% CI 0·0198-0·204; p=0·0174). Pain scores, total days spent in hospital, and mortality did not differ significantly between groups. Serious adverse events occurred in 11 (25·6%) of 43 patients in the aggressive drainage group and in 12 (27·3%) of 44 patients in the symptom-guided drainage group, including 11 episodes of pleural infection in nine patients (five in the aggressive group and six in the symptom-guided drainage group). INTERPRETATION We found no differences between the aggressive (daily) and the symptom-guided drainage regimens for indwelling pleural catheters in providing breathlessness control. These data indicate that daily indwelling pleural catheter drainage is more effective in promoting spontaneous pleurodesis and might improve quality of life. FUNDING Cancer Council of Western Australia and the Sir Charles Gairdner Research Advisory Group.

Response from the authors to the letter "Pulse rate trends in obstructive sleep apnoea: a reliable tool to predict long term response to CPAP?".

To the editor, We appreciate the interest of Dr. Navarro-Esteva in our study (1). We are well aware of the contributions of previous studies within the field by Kufoy et al. (2) and Kawano et al. (3), which described the changes in physiological parameters but no symptomatic response to continuous positive airway pressure (CPAP) in patients with obstructive sleep apnoea (OSA). We believe we have explicitly acknowledged the methodological limitations of pulse oximetries pointed out by Dr. Navarro-Esteva in our paper. However, nocturnal pulse oximetries are easily available, often used in clinical settings and comply with evidence-based guidance to diagnose OSA (4). In addition, in a randomised controlled trial they were found to be non-inferior when compared to inpatient polysomnography (5). Obese patients with lower oxygen saturations are more likely to suffer not only from OSA but also from obesity hypoventilation syndrome (6). This can only be confirmed by nocturnal carbon dioxide measurements, a measurement that is not included in a standard polysomnography setup. Hence, we argue that the contention by Dr. Navarro-Esteva that “for research purposes, diagnosis should be confirmed by polygraphy or polysomnography” is hardly feasible in practice, as the best approach to diagnose OSA remains a controversial issue. The decision over which overnight investigation to employ is influenced by the available resources in the respective health care system. Moreover, in our study any decision to offer treatment was derived from evidence-based guidelines (4) and only 6 out of 58 (10%) patients with mild OSA were offered CPAP following physicians’ review. Dr. Navarro-Esteva is correct in stating that the symptom of hypersomnolence is of multi-factorial aetiological origin (7). Although OSA has got a high prevalence in the general population (8), hypersomnolence affects a larger group of people than those who suffer with sleep-disordered breathing. The main inclusion criteria in our study was a 4% oxygen desaturation index (ODI) greater than 5/h. We added the pulse rise index (PRI) as additional inclusion criteria for the control group to exclude patients with additional conditions which could lead to autonomic arousals from sleep and affect pulse rate variability. Zamarron et al. studied the approximate entropy (ApEn) analysis of heart rate data derived from nocturnal pulse oximetries in OSA. They concluded that ‘(…) the results presented prove that this method is very well suited to recognize the sleep-apnoea-specific cyclic variability of heart rate’. They also postulated that studying the heart rate signal was an effective tool to understand how brain, sleep and autonomic nervous system interact (9). As regards the definition of PR trend that left Dr. Navarro-Esteva uncertain, in the method section of our paper we have defined ‘PR trend’ as the difference between the average pulse rate of the first and the last hour of sleep. We hypothesised that an increase in ‘PR trend’ reflected an increased sympathetic activation throughout the night and that ‘PR trend’ could be a predictor of treatment success in a group of OSA patients treated with CPAP. In our study, there was no significant difference in CPAP compliance between groups. The observed trend towards a longer use in the group with a negative ‘PR trend’ is consistent with the clinical observation that patients who respond better to CPAP treatment are more likely to use it longer. Heart rate variability, pulse rate and the change in nocturnal pulse rate are important markers of autonomic nervous activity in OSA. Combined with the Epworth Sleepiness Scale (ESS), a patient-based symptoms score, and the response to CPAP therapy they are crucial markers to identify patients who are at an increased risk of cardiovascular events. In conclusion, our data support the usefulness of nocturnal pulse oximetry recordings in a clinical setting of a sleep centre. Although polysomnography remains the Gold-standard for the diagnosis of sleep disorders, nocturnal pulse oximetry has been shown to provide reliable results (10). Indeed, pulse oximetry data convey not only data on ventilation and oxygen saturation, but they also provide an insight into autonomic nervous activity at-a-glance with the potential to identify elevated cardiovascular risks. This finding is not negated by the aforementioned methodological limitations.