Is polysomnography screening effective for stroke prevention?

KEYWORDS:

• Atrial fibrillation
• cardioembolic stroke
• hypertension
• obstructive sleep apnea
• patent foramen ovale

Stroke ranks as the second most common cause of death worldwide and the leading cause of adult disability [1]. Thus, identification and treatment of modifiable risk factors represent the most effective approach to diminish stroke-related burden. A recent meta-analysis supports existing evidence that obstructive sleep apnea (OSA) represents an independent stroke predictor, showing that cerebrovascular risk increases with OSA severity [2]. Another meta-analysis revealed a high prevalence of sleep-disordered breathing (SDB) in patients with stroke or transient ischemic attack (TIA) (63% of patients with an apnea–hypopnea index more than 10/h); SDB was primarily obstructive in nature (OSA), with only 7% of patients having primarily central apneas [3]. Moreover, SDB seems to be similarly prevalent in stroke and TIA patients, indicating that SDB probably represents a preexisting condition. OSA has been also associated with poor outcomes among patients with stroke, including higher mortality and recurrent vascular events, worse functional status, and longer hospitalization duration [4]. Thus, screening and intervention in OSA patients represent a relevant issue not only for prevention of stroke recurrence but, probably, to facilitate poststroke recovery as well.

The mechanisms underlying the relationship between OSA and stroke are not fully established. Recurrent OSA events lead to different acute adverse consequences: brain arousal, intrathoracic pressure changes, and intermittent episodes of hypoxemia. These events activate pathways such as oxidative stress, sympathetic activation, inflammation, hypercoagulability, endothelial dysfunction, and metabolic dysregulation that, in turn, predispose OSA patients to other main risk factors for stroke: hypertension, atherosclerosis, and atrial fibrillation (AF) [5]. In particular, OSA represents the most common condition associated with resistant hypertension [6]. Moreover, current literature reports a strong association between OSA and AF, with a prevalence of AF in patients with OSA of approximately 5%, which is higher than the prevalence of AF in the general population (1–2%). Conversely, the prevalence of OSA among AF patients ranges between 21% and just over 80% [7]. A retrospective study showed that in a group of AF patients, the occurrence of first-time stroke was more common in patients with OSA compared with patients without; this association remained significant after accounting for cardiovascular risk factors [8].

Besides these long-standing mechanisms, sleep apnea could act as a precipitating, acute factor, favoring a cardio-embolic cerebrovascular ischemic event in patients with patent foramen ovale (PFO). Indeed, a study conducted in 335 patients with mild stroke or TIA found that the association of sleep apnea events with right to left shunt increases the risk of wake-up stroke, suggesting that OSA might provoke paradoxical embolism [9]. Even though studies analyzing the prevalence of SDB in different stroke etiologies obtained discordant results, a recent work revealed a strong association between OSA and cardioembolic stroke [10]. Interestingly, Lipford et al. [10] found that the association between OSA and cardioembolic stroke remains even after adjustment for the presence of known AF. This finding may be explained by a high rate of occult paroxysmal AF in this population but, alternatively, OSA may lead to stroke through mechanisms independent of cardiac arrhythmias. One of this could be represented by a PFO-mediated paradoxic embolism.

Although OSA affects 24% of middle-aged men and 9% of women [11], as many as 70–80% of them are neither diagnosed nor treated [12]. Considering the high prevalence of OSA and its role as an independent risk factor for stroke, the American Heart Association/American Stroke Association (AHA/ASA) recently included recommendations on diagnosis and treatment of SDB for the primary prevention of Stroke (Class IIb; Level of Evidence C) [13]. Recently, a low level of accuracy for the diagnosis of OSA of different clinical prediction algorithms against PSG has been highlighted [14]. For instance, the high number of potential false-negative results using different questionnaires compared to PSG limits their use as instruments to diagnose individual patients with OSA (for the AHI ≥5 cutoff: Berlin Questionnaire sensitivity was 0.76 and specificity was 0.45; Epworth Sleepiness Scale sensitivity was 0.27–0.72 and specificity was 0.50–0.76; STOP-BANG questionnaire sensitivity was 0.93 and specificity was 0.36). For these reasons, the recent guidelines of the American Academy of Sleep Medicine recommend that clinical tools, questionnaires, and prediction algorithms not be used to diagnose OSA in adults, in the absence of polysomnography (PSG) or home sleep apnea testing [14]. Thus, an integration of hypnological anamnesis together with a physical examination (e.g. evaluation of body max index, neck circumference, and oral anatomy according to Mallampati) and sleep screening scales could represent only the first diagnostic step. Patients who are considered to be at high risk on the basis of this screening should be referred for PSG. Moreover, since the recent pathophysiological and clinical evidence demonstrates a strong association of OSA with hypertension and AF, we would recommend a particular consideration to these groups of patients for stroke primary prevention. For instance, a PSG could be suggested in patients with refractory hypertension if all other main causes of secondary hypertension are excluded. Considering AF, different scales have been developed and validated to aid in the decision to prophylactically anticoagulate patients to decrease the risk for stroke but OSA assessment was not included in these risk scoring systems. We could suggest a PSG screening in the group of AF patients not receiving anticoagulation because of a low risk score; the detection of an OSA could change the indication to anticoagulants [8]. Finally, a cautious attention should be reserved to patients with PFO. PFO is rather common in the general population and it is often not clear whether a PFO in a patient with stroke should be considered the primary cause of the event or an incidental finding. However, Ciccone et al. suggested that even a mild OSA might be responsible of paradoxical embolism in presence of PFO [9].

Even if PSG could represent a useful tool to identify a possible relevant risk factor for cerebrovascular disease, the main issue consists in the potential efficacy of OSA therapy in stroke prevention. No prospective, randomized trial has evaluated the efficacy of continuous positive airway pressure (CPAP) treatment to reduce the risk of a first cerebrovascular event in patients with OSA. Therefore, the effectiveness of OSA treatment for primary stroke prevention has not been yet demonstrated. Concerning secondary stroke prevention, study results are controversial: few randomized studies investigating effects of CPAP poststroke seem to report beneficial associations of CPAP use with neurologic recovery and low recurrent vascular event rates [4] whilst a very recent secondary prevention trial in adults with coronary or cerebrovascular disease and OSA has shown that therapy with CPAP plus usual care, as compared with usual care alone, does not prevent serious cardiovascular events [15]. However, it would be necessary to clarify if negative results from this latter study derive from the inadequate adherence to CPAP therapy of patients enrolled (mean duration of treatment: 3.3 h per night). Hopefully, ongoing multicenter studies will provide further results on possible efficacy of CPAP treatment for stroke prevention. For instance, the ‘Sleep Disordered Breathing in Transient Ischemic Attack/Ischemic Stroke and Continuous Positive Airway Pressure Treatment Efficacy, SAS-CARE’ is an open, observational multicenter study in patients with acute cerebrovascular event designed to assess the effects of SDB on clinical evolution, vascular functions, and markers within the first three months after the event and the effect of CPAP on clinical evolution, cardiovascular events, mortality, vascular functions, and markers at 12 and 24 months after a stroke or TIA [16].

Furthermore, taking into account the negative results from the recent CPAP trial [15], other possible treatment strategies should be considered, such as oral device, weigh loss, or preventing supine sleeping position. However, none of these alternative therapies has been already systematically examined in stroke patients [4].

At the moment, the identification of OSA is considered essential in the clinical management of stroke patients, in accordance with the updated AHA/ASA stroke guidelines (Class IIb; Level of Evidence B) [17]. Moreover, new guidelines of the American Academy of Sleep Medicine recommend the use of PSG, rather than cardiopulmonary sleep testing (CST), for the diagnosis of OSA in patients with history of stroke [14]. However, considering that standard PSG is not always feasible and readily available to hospitalized patients, some pilot studies demonstrated also the feasibility of early sleep apnea screening with CST and the reliability of this approach in the diagnosis of sleep apnea when compared with the gold standard PSG [18]. If some evidence is available regarding ‘how’ to obtain a diagnosis of sleep apnea, there are no indications regarding ‘when’ this screening should be performed in patients with stroke. Indeed, considering that SDB seems to be most severe in acute stroke and often improve spontaneously during stroke recovery [4], a PSG immediately following a cerebrovascular event could over-estimate the severity of the disease. In patients with a confirmed OSA during the stroke acute phase, a further PSG should be recommended within 1–2 months from the discharge.

OSA is a stroke risk factor often neglected, and among stroke medical professionals, there is frequently a lack of education about the importance of OSA management. Further efforts are needed to increase the awareness about the importance of OSA as a risk factor for stroke and to improve screening practices for OSA in national and international stroke medical communities. OSA management should be regarded as an important issue in stroke prevention. PSG screening could represent an effective tool for stroke prevention especially if the ongoing and future studies will demonstrate the efficacy of OSA treatment to reduce the risk of a first or a recurrent cerebrovascular event.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.