Prevalence of Sleep-Disordered Breathing (SDB) in patients with first-ever stroke or TIA is higher than in normal populations [1]. The disturb more frequently recognized in these cases is a ‘mixed’ rather than purely obstructive or central disorder [1,2]. In some cases, what starts as clearly obstructive disease, evolves into predominantly central by the end of the recording [3,4]. This phenomenon has been reported to frequently occur in patients affected by Congestive Heart Failure (CHF) [4,5]; more often it is precipitated by the Continuous Positive Airway Pressure (CPAP) treatment of an obstructive sleep apnea/ hypopnea (OSAH) [6-8]. Characteristics of SDB in patients with stable stroke have not been studied jet.

In order to define the clinical and instrumental profile of patients affected by OSAH and to compare them with the profile of cases affected by a Central Sleep Apnea/Hypopnea (CSAH), we report here data on a series of 34 cases with stable stroke, studied at Sapienza, University of Rome.

Patients

A consecutive series of patients with acute stroke, admitted to the Stroke Unit of Policlinico Umberto I University Hospital, were screened. After the exclusion of patients who did not consent to enter the study, elected cases were submitted to both clinical and instrumental diagnostic tests at 4 months of stroke onset. Stroke risk profile was assessed, and then classified, according to the Italian SPREAD guidelines [9]. Participants were visited firstly at stroke onset and at discharge from the Stroke Unit, and then on the day of the polisomnographic Study (PSG). The severity of neurological deficit was assessed by means of NIH-SS [10,11]. Causes of stroke were classified as to TOAST criteria [12]. Daytime sleepiness was estimated with the Epworth Sleepiness Scale questionnaire (ESS) [13]. The presences of symptoms other than daytime sleepiness have also been investigated, and classified so as: choking, gasping, fragmented sleep, unrefreshing sleeps, reported daytime sleepiness, inattention, accordingly with guidelines [13,14]. In order to identify conditions predisposing to OSAHS, an otorhinolaryngology’s (ORL) evaluation was performed.

Sleep studies and polysomography

The ambulatory PSG study was performed by the hand-held 34 channel Morpheus Ambulatory recorder by Micromed^® S.r.l. Ambulatory 34 Channels PSG was preferred to standard laboratory recording in order to allow the patients to sleep in their home setting, without needs of adaptation. The following parameters were recorded: 1) body position; 2) rib-gage and abdominal respiratory efforts (Dual thoracoabdominal RIP -respiratory inductance Plethysmographybelts by Micromed^® S.r.l. Accessories EPM 915x A); oro-nasal airflow (thermistor transducer by Micromed^® S.r.l. Accessories EPMs 1450-S ); 4) haemoglobin saturation (finger pulse oximeter sensor); 5) 8 EEG channels (2 frontal, 2 central, 2 temporal, 2 occipital); 6) right and left electrooculography, and 7) sub mental electromyography from surface electrodes; 8) Electrocardiogram (EKG). Morpheus was retrieved the following morning the sensors were attached; data were downloaded to the SystemPlus Evolution software, and subsequently analyzed with dedicated software Rembrandt Sleep View, by a sleep expert. Were considered adequate only PSGs with a total recording time >4 hours and a Total Sleep Time (TST) >2 hours, with presence of both NREM and REM sleep episodes. Sleep-stage scoring was done visually according to standard criteria [15].

Definitions

Apnea was defined as the cessation of airflow for at least 10 seconds. Hypopnea was defined a reduction less than a 50% from baseline of a valid measure of breathing during sleep, associated with an arousal or with an oxygen desaturation of >3%. Apnoea-Hypopnoea Index (AHI) was the sum of all apneas and hypopneas occurring per hour of sleep. Sleep Disordered Breathing (SDB), either central or obstructive, was diagnosed in presence of an Apnea/Hypopnea Index (AHI) value>5 [13]. Three different degrees of severity were outlined: Mild SDB: AHI value > 5 ≤ 15; Moderate SDB: AHI value >15 ≤ 30; Severe SB: AHI value >30 [16]. Each event without associated chest wall movement was considered as central in origin (CSAH). A diagnosis of OSAHS was set in cases in whom at least 50% of the total respiratory events showed a clear dissociation between preserved chest wall movement and airflow pattern with a decrease in the amplitude >50% from baseline, and lasting at least 10 seconds (pOSAH). A CSAHS was instead diagnosed when at least 50% of the total respiratory events were central in origin (pCSAH). Central Periodic Breathing (CPB) was defined so as recommended [17]. Arousals were defined as “an abrupt change from a “deeper” stage of non-REM (NREM) sleep to a “lighter” stage, or from REM sleep toward wakefulness, with the possibility of awakening as the final outcome” [18]. Arrhythmias were defined as any disturbances of the normal rhythmic beating of the heart.

Statistical analysis

On the bases of PSG study, 3 groups were identified: patients with normal sleep study, cases with predominantly OSAHS (pOSAH), and cases with predominantly CSAHS (pCSAH). Groups were compared in terms of: age, sex, time from stroke to PSG evaluation (days); NIH-SS at entry and at discharge from Stroke Unit; Body Mass Index (BMI), ESS, TST; Total Sleep Period (TSP); Sleep Efficiency Index; arousal /h sleep; sleep phases; number and type of apneas and hypopneas; arrhythmias of sleep; total number of central apneas-hypopneas per hour of sleep; total number of obstructive apneas-hypopneas per hour of sleep; and Oxygen Desaturation Index (ODI). Patient‘s demographic data, risk factors for stroke, and sleep study data are expressed as mean and SD or percentages. Statistical comparisons between groups were made using ANOVA, χ² or Fisher exact test, depending on which was more appropriate. Correlation analyses were done with non-parametric tests (Spearman’s rho). Statistical significance was set at p<0.05. Statistical analysis was performed with Statistical Package of Social Sciences (SPSS) version 18.0 for Windows.

After the exclusion of patients who did not consent, 34 cases entered the study. All had an ischemic stroke. The 55% (n=18) were embolic in nature, the 32% (n=11) were lacunar, in the 9 % (n=3) of cases the cause of stroke was undetermined, and in 6% (n=2) a large artery cause was revealed. Patients’ mean age was 62.4 ± 14.6. Sixteen cases had a mild (AHI value>5 ≤ 15), 8 had a moderate (AHI value>15 ≤ 30) and 2 cases a severe SDB (AHI value > 30). Sixteen out of the 26 cases with an AHI ≥ 5 (61.5%) had a predominantly OSAH (pOSAH), and 10 cases (38.5%) had a predominantly CSAH (pCSAH). None of the patients affected by pCSAH presented central periodic breathings during sleep (CPBS). The BMI was 28 ± 6 kg/m2 (range 21 to 47; median 26.5). The mean AHI was 12 ± 9 (range 1 to 35; median 10.5). The PSG study was performed 126.4 ± 49 days after stroke onset (range: 66-282; median 113,5 days). The ORL evaluation was performed in 32 cases and was abnormal in 15 of them. Fourteen cases had an obstruction of the upper airways and in 8 of them the obstruction was combined with an increase in pharyngeal tissue. Eight patients with positive ORL evaluation had a pOSAH at the PSG and 4 were affected by pCSAHS. All these 4 cases who presented at PSG a pCSAH had an obstruction of the upper airways combined with an increase in pharyngeal tissue; two of them had a BMI>30.

The profile of cases respectively affected by pOSAH and pCSAH are reported in table 1.

Table 1: Patients demographic data, clinical characteristics, risk factors for stroke, PSG data, and comparisons respectively between OSAHs, CSAHs, and controls.

No significant difference was found between pOSAH and pCSAH cases (Table 1). In the group of cases with pOSAH the PSG study was performed 147.1 ± 63,2 days after stroke onset (range: 92-282; median 124,5 days). Correlation analysis highlighted that the time interval from stroke to PSG (Δ t) was inversely correlated with both TST (p=0.017) and TSP (p 0.039); the NIH-SS score at entry significantly correlated to the number of arousals /h of sleep (p=0.044); finally, the more severe AHI the higher is ODI (p=0.000). In the group of cases with pCSAH the PSG study was performed 113.5 ± 18,5 days after stroke onset (range: 87-140; median 110,5 days). In this group the only significant correlations found were between Δ t and SE Index (inverse correlation; p 0.021) and between Δ t and both arrhythmias/h sleep (p=0.016) and ODI (direct correlation; p=0.033). No significant correlation was found between the number of arrhythmias/h sleep and causes of stroke as to the TOAST criteria (p=0.164) either in the group of cases with pOSAH and pCSAH.

In our series of cases, nearly the 76% of patients had an abnormal breathing during sleep; the 61% of them were predominantly obstructive, and the 39% were predominantly central events.

Patients with predominantly CSAH did not differ significantly to OSAH in demographic characteristics, stroke risk profile, and sleep study parameters. Paradoxically, some of cases with predominantly CSAH are affected also by conditions that would better explain a severe OSAH. In fact, 4 out of 10 cases with pCSAH had an obstruction of the upper airways combined with an increase in pharyngeal tissue; in two of them also a BMI higher than 30 was documented. This result may indicate that the predominance of CSAH over OSAH is just phenotypical and that in certain cases, stroke itself is responsible for the new onset of an OSAH (or of the worsening of a pre-existing one); in a group of those cases, cause of complex, and only partially understood pathophysiological mechanism (loop gain >1, altered chemo sensitivity), the central drive to breathe may be altered so as to result in the absence of efforts to breath, i.e. central sleep apnea [19,20]. In pOSAH cases, the NIH-SS score at entry significantly correlated to the number of arousals of sleep. Given that one of the most significant indicators of sleep efficiency is the number of arousals per hour of sleep, it seems as if the more severe the neurological deficit at the onset of stroke, the less efficient the breathing at the long term. One possible explanation of this phenomenon is that stroke affects airways anatomy or function proportionally to the severity of neurological deficit. The tendency toward a significant correlation between stroke severity at entry and the total number of OSAH events (p 0.080), allows not deny this hypothesis. In the group of cases with pOSAH, the more severe AHI the higher is ODI; not the same in pCSAH. Actually cases affected by central apnea are able to maintain the O2 saturation within normal values more easily than pOSAHs. Nonetheless, this datum conflicts with interpreting pCSAHs as more severe pOSAHs with altered loop gain, and goes instead in the direction of a role of stroke on patients’ CAP (Cycling Alternating Patterns). In this case, the lack of differences between pOSAH and pCSAH events may consist in the fact that stroke causes the fragmentation of sleep and of altered CAP; in order to elucidate differences in pOSAH and pCSAH CAP’s, more insights into the relationship between the microstructure of sleep and the sleep disordered breathing after stroke are required [21].

Correlation analysis highlighted that the longer the time interval from stroke to PSG the higher AHI and ODI, the shorter both the TST and TSP, the lower the Sleep Efficiency index, as if time has a negative influence both on the quality of sleep and on its duration. Also this result goes in the direction of SDB as a consequence of stroke on the microstructure of sleep [22]. Given the influence of depression on CAP, of great interest would be to elucidate its role on stroke patients’ CAP, either affected by pOSAH or pCSAH.

Sleep studies on stroke populations demonstrate they are affected by some mix of OSAH and CSAH, as if these disturbances are the result of an interaction between the patients’ primary breathing condition and some of the long term consequences of stroke on the breathing system (altered loop gain), or on the microstructure of sleep (i.e. CAP system) [1,2,23-25].

The presence of patients affected by obstruction of the upper airways combined with an increase in pharyngeal tissue and a higher than 30 BMI, among cases with predominantly central sleep apnea, goes in the direction of an altered loop gain, probably in cases with severe OSA. This might explain the higher rates of predominantly central sleep apnoea-hypopneas of our series.

Many questions about the SDB profile after stroke are unanswered. Multicenter clinical sleep studied, properly designed to answer these questions are needed.

Funded by Sapienza, University of Rome on year 2010. Grant n. C26A10E3ST.