The Sleep-Stroke Connection: An Under-recognized Entity Simin Khavandgar MD UPMC Neurology Department
Sleep Disordered Breathing (SDB) Obstructive Sleep Apnea (OSA): -Transient cessation of airflow, duration > 10 sec -Apnea: airflow < 10% -Hypopnea: airflow 10-70%, + O 2 desaturation > 4% Central Apnea (CSA): -Caused by marked decrease in respiratory drive
OSA Classification Polysomnography Apnea hypopnea index (AHI) < 5 normal 5-14 mild OSA 15-30 moderate OSA > 30 Severe OSA Medicare guidelines Mild OSA (AHI 5-14) with at least 1 co-morbidity (EDS, cognitive deficit, stroke, cardiac dis, HTN, depression) Moderate or severe OSA does not require comorbidity
OSA Diagnosis Panossian et al., Continuum, 2013, Vol 19, 86-103.
OSA Epidemiology 4% of males, 2% of females If sleepiness criteria not considered: 24% males, 9% females in middle-age range 80% of OSA pts are undiagnosed or untreated
OSA Symptoms and Risk Factors OSA Symptoms: snoring, gasping or choking from sleep, excessive daytime sleepiness, non-refreshing sleep, morning H/A, fatigue, cognitive dysfunction OSA Risk factors shared with stroke: -Weight, age, male sex, family history, smoking Risk factors specific to OSA: -Neck circumference, Craniofacial anatomy Nasal septal deviation, Retrognathia, Incisor overjet, High arched palate, Tonsillar hypertrophy
OSA Screening: Facial Anatomy Panossian et al., Continuum, 2013, Vol 19, 86-103.
OSA Treatment: CPAP Very effective, resolves OSA in 95% of treated A pneumatic splint for airways Reduces upper airway tone & minute ventilation Improves quality of life, cognition, glucose control, heart function & decreases HTN, arrhythmias, & excessive daytime sleepiness
OSA and Stroke Epidemiology OSA is associated with higher risk for multiple stroke risk factors: HTN (mild OSA, OR = 2.3, mod-severe OSA, OR = 6.8) A.Fib. (OR = 4) CHF (OR = 2.4), Coronary artery disease (OR = 1.3) Carotid Atherosclerosis (severe OSA, OR = 2) Insulin Resistance Pro-thrombotic state OSA is also an independent risk factor for stroke
OSA and Risk of Incident Stroke Meta-analysis 11 prospective studies included After adjustment for known CV risk factors Pooled RR 2.1 Li et al., Int. J. Cardiol, 2014, 466-9.
OSA severity correlates with Incident Stroke 20-year follow up study (Australia) 397 subjects dx at baseline with OSA After adjustment for known CV risk factors Moderate-severe OSA (based on AHI) associated with large increased risk of incident stroke (above) and death (not shown) Marshall et al., J Clin. Sleep Med., 2014, 355-362.
OSA is an Independent Risk Factor for Stroke correlates with Incident Stroke 6 year prospective cohort, 1022 subjects Yaggi e t al., NEMJ, 2005, 2034-2041
OSA Severity Correlates w/ Survival Long term Sleep Heart Health Study cohort 5422 subjects w/ sleep study and w/o hx of stroke at baseline OSA severity (AHI quartile) correlates with long-term survival 1 unit increase in AHI %6 increase in stroke risk (in males) Men Women Redline et al., Am. J. Respir. Crit. Care Med., 2010, 269-277.
SDB in patients with stroke and TIA SDB is highly prevalent in patients with: Ischemic CVA Hemorrhagic CVA TIA 50-75% in various studies Both OSA and CSA common post-stroke Prevalence of OSA is NOT affected by: Stroke etiology Stroke topography Co-morbid risk factors
OSA in patient with Ischemic Stroke Pt with L MCA stroke Obstructive AHI = 80 Kryger et al., Principles & Practice of Sleep Medicine, 2011
OSA frequency in patients with stroke / TIA Meta-analysis 29 studies and 2343 subjects included Only 7% CSA, rest OSA No difference in SDB prevalence by event type (TIA vs ischemic vs. ICH) timing after stroke or type of monitoring Recurrent stroke / TIA was associated with higher rate of OSA vs. new strokes (74% vs. 57%, AHI> 5) Rate of SDB improves few months after stroke but remains high Johnson & Johnson, J Clin Sleep Med, 2010, 131-137.
CSA in patients with stroke More with medullary, Ponto-medullary, bilateral thalamic strokes Cheyne-Stokes breathing / periodic central apnea-hyponea Crescendo-decrescendo cycles, > 50% drop in nasal airflow, > 10sec Thomas & Chokroverty, Atlas of Sleep Medicine, 2014
Pathophysiology of SBD in Stroke A. SDB caused or worsened by stroke Hemispheric/ brainstem stroke impaired coordination of respiratory muscles Bulbar weakness reduced nasopharyngeal patency CSA caused by strategic stroke Lat. Med. Stroke central hypoventilation Thalamic/ brainstem stroke, co-morbid CHF Cheyne-Stokes B. SDB as a risk factor for stroke Chronic effects on vascular risk factors Acute effects of apnea / hypoxia Risk applies to both incident and recurrent strokes
Chronic Effects of OSA on Vascular Risk HTN Systemic HTN BP non-dipping at night (5 mm Hg higher BP-> 80% higher stroke risk) A.Fib CAD, MI, CHF Insulin & leptin resistance DM Atherosclerosis Carotid artery disease Coagulopathy Increased platelet aggregation Reduced fibrinolysis Increased endothelial damage Increased inflammatory markers
Acute Effects of Apnea on Vascular Risk Apnea episodes are associated with: Reduced cardiac output Increased negative intrathoracic pressure Impaired hemodynamic autoregulation Leading to reduced cerebral blood flow during apnea episode Worse with longer apnea episodes & apnea during REM Davis et al., Neurol. Clin. Prac., 2013
Acute Effect of Apnea on MCA blood flow Nikolaus Netzer et al., Stroke, 1998, 87-93
Acute Effect of Apnea on MCA blood flow Frequency of reduced blood flow of the MCA during 123 obstructive apneas (OA), 223 obstructive hypopneas (OH), and 96 central apneas (CA) in relation to the duration (in seconds) of apneas. Nikolaus Netzer et al.,stroke, 1998, 87-93.
Acute Effects of Apnea on Vascular Risk Apnea Hypoxia Arousals Intrathoracic pressure Sympathetic activation with arousals -> BP peak, Arrhythmia Intrathoraic pressure change -> R to L shunt -> paradoxical embolization (in presence of PFO) Thomas & Chokroverty, Atlas of Sleep Medicine, 2014
Acute Effects of Apnea on Vascular Risk OSA increases complex nocturnal arrhythmias (by 2-4 times) Transient tachycardia triggered by apnea --> Thomas & Chokroverty, Atlas of Sleep Medicine, 2014
Circadian impact of OSA on Stroke / Death OSA increases risk of stroke & sudden death at sleep (12AM-6 AM) OSA severity correlates with risk of nocturnal sudden death OSA increases risk of wake-up stroke Gami et al., NEJM, 2005, 1206-1214.
Pathophysiology of OSA Effects on Stroke IH: Intermittent Hypoxia, ITP: Intra-thoracic pressure, SNA: Sympathetic activation, IPC: Ischemic pre-conditioning Lyons et al., Can. J. Cardiol., 2015, 918-927.
Effects of SDB in Acute Stroke Setting Reverse Robin Hood syndrome Apnea autoregulation breakdown vasodilation blood flow steal from ischemic penumbra Rationale for studies of early PAP therapy after acute stroke Presence of SDB in acute stroke setting correlates with: Higher rates of HTN (nocturnal & diurnal) Higher rates of early neurologic worsening Longer hospitalization Higher mortality post-stroke Higher risk of subsequent stroke Rationale for studies of PAP therapy effect on neurologic recovery and secondary stroke and mortality prevention
Screening for SDB in Acute Stroke Setting Diagnostic challenges Typical screening tools not reliable in stroke / TIA patients Screening questionnaires (Epworth, Berlin, etc.) poor predictors Also poor predictors of sleep apnea in stroke pt: -Hx of excessive daytime sleepiness, snoring poor precidtors -Stroke etiology, stroke topography Better predictors of OSA post-stroke: male, obese (BMI> 30), HTN, DM, sleep-onset stroke Polysomnography is the gold standard But difficult to administer in acute stroke setting Early Suspicion, Early confirmation by unattended inpatient sleep study
Screening for SDB in Acute Stroke Setting All patients with stroke / TIA should be screened for SDB 2009 Sleep Medicine Guideline If symptomatic for OSA 2014 American Heart Association / American Stroke Association Guideline Regardless of symptoms
Treatment of SDB in Acute Stroke Setting Therapeutic challenges Neurological deficits: Bulbar weakness: Tolerance of mask, air leakage Limb weakness: Difficulty in removing mask Aphasia, neglect, delirium: Unfamiliarity, lack of understanding Poor tolerance of CPAP, risk of aspiration Auto-PAP better tolerated than CPAP Acute stroke setting: Dynamic clinical setting Nursing training Early nursing application of CPAP increases longterm compliance, does not increase nursing workload much
Treatment of OSA after Acute Stroke Treatment of OSA after stroke clearly reduces HTN, A.Fib., coagulation dysregulation & long term mortality Does OSA improve subacute neurologic recovery and rate of recurrent stroke? Limited studies with mixed results so far Some early studies indicate improved neurologic outcome Other studies failed to show neurologic improvement However, these studies have not accounted for usually low-rate of compliance Short duration of follow up: Longer treatment duration likely needed to affect CV risk factors Severity of OSA is likely to affect treatment benefit Larger and better designed studies are needed
Treatment of SDB in Acute Stroke Setting A number of prospective studies underway to assess benefit of immediate PAP therapy in acute stroke Kepplinger et al., BMC, 2013, 14: 252.
Treatment of SDB in Acute Stroke Setting Kepplinger et al., BMC, 2013, 14: 252.
Treatment of OSA after Acute Stroke SAVE study: Ongoing large multi-center, randomized, controlled trial to assess benefit of CPAP in preventing serious CV events in pts with established CV disease
CPAP Treatment after Acute Stroke Use of CPAP in patients after acute stroke reduces 5 year mortality (Martinez-Garcia, 2009) 96 pts, post-stroke, AHI > 20, CPAP therapy, 5 yr follow up 5 yr mortality 50% (CPAP-treated) vs. 68% (untreated) Improvement in neurological outcome (Parra, 2011) 140 randomized pts, AHI > 20, 24 month post-stroke f/u Improved Rankin Scale and delayed first CV event Other reported positive outcome with CPAP therapy in stroke patients Improved motor recovery Improved depression, subjective well-being Reduced hospitalization time Accelerated rehabilitation These results need verification through randomized studies
Alternative OSA therapies Panossian & Daley, Continnum, 2013, 86-103.
Alternative OSA therapies Strollo et al., NEJM, 2014, 139-149.
Conclusion Sleep disorders, specially OSA, are underrecognized in patients with Stroke / TIA OSA is a modifiable risk factor that increases both primary and secondary risk of stroke independent of other vascular risk factors Treatment of severe OSA after stroke is a plausible strategy to potentially improve ischemic burden, neurologic recovery and long term mortality