NEW ORLEANS—Which comes first: sleep apnea or stroke?” asked Mark Eric Dyken, MD, during a presentation at the International Stroke Conference 2005. He then went on to explain that the conventional wisdom on this topic—that stroke causes sleep apnea—may not be a universal truth.

The association between sleep apnea and stroke dates back to animal and human stroke studies, beginning in the 1970s, that established that there are two medullary neuronal centers primarily associated with respiration, Dr. Dyken elaborated. If an individual has a stroke in the nucleus ambiguus, it can cause obstructive apnea; and if a cerebrovascular event affects the solitary tract nucleus—an area of the brain that helps with diaphragmatic function—it can produce, in some cases, a central apnea. In fact, the single proven cause-and-effect relationship between stroke and obstructive sleep apnea occurs when a stroke affects such respiratory centers, he observed.

“Nevertheless, in regard to this cause-and-effect relationship between obstructive sleep apnea and stroke, there have been no large, well-run, prospective, double-blind studies comparing stroke risk in treated versus nontreated, polysomnographically diagnosed apneics,” he remarked. “[Yet,] through small case studies, laboratory investigations, small population and mortality studies … we might hypothesize, in some cases, that obstructive sleep apnea may predispose some people to stroke.” Dr. Dyken is the Director of the Sleep Disorders Center at the University of Iowa in Iowa City.

ELEVATED PREVALENCE

Dr. Dyken’s interest in this association began in the late 1980s, with a 34-year-old, morbidly obese patient who woke up one morning with a right triple-capsular, parietal stroke. “We thought, ‘Huh—this reeks of hypertension,’” he recalled. “Could obstructive sleep apnea in this young fellow have precipitated a hypertensive stroke?”

The case led to work Virend K. Somers, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, who was able to document sympathetic and parasympathetic activation during obstructive apnea using microneurography. In one small study, Dr. Somers documented mean arterial pressures of 240/120 to 240/140 mm Hg during apneic events, which occurred simultaneously with heart block, blood pressure instability, and increased waking sympathetic tone.

Work done by Dr. Dyken and his research group with critically ill patients helped provide evidence for some of the things Dr. Somers found in the laboratory. For example, in a study published in 2003, Dr. Dyken and colleagues showed that obstructive sleep apnea can result in repeated asystolic episodes necessitating emergent care in critically ill patient populations.

In an earlier study of an unselected, consecutively studied stroke population, his research team found that obstructive sleep apnea occurred in 71% of strokes versus only 19% of gender-, age-, and body-mass-index–matched controls. “Even when we took out the potential risk factors of hypertension and cardiac disease, the prevalence [of obstructive sleep apnea] was still elevated in the stroke population,” Dr. Dyken said.

CIRCADIAN RHYTHMICITY

The investigators also studied circadian rhythms in this same group of patients, to determine whether there was an equal probability of an individual having a stroke at any time over a 24-hour period. Given an eight-hour period of sleep, 33% of all strokes should occur then, the investigators hypothesized. However, they found that 54% of strokes occurred during sleep, which was a statistically significant finding.

REM PARESIS

That there is a circadian rhythmicity to ischemic stroke is rather old news; in fact, it was another University of Iowa research team, led by Harold Adams, MD, that demonstrated in the early 1990s that there is an increased risk of ischemic stroke in the early morning hours due to normal elevation of catecholamines, blood viscosity, and platelet aggregation. The research conducted by Dr. Dyken’s group added one more element: REM paresis. During the deepest phase of sleep, when the body is essentially paralyzed, REM is associated with hypertonia and, in the sleep apneic population, generally more severe obstructive events. “Of course, REM sleep occurs mostly in the early morning hours, before rousing,” Dr. Dyken emphasized.

INCREASED MORTALITY

Dr. Dyken and his coauthors subsequently looked at mortality in the group of patients from the 1996 study. Over a four-year follow-up, the only patients who died were those who had obstructive sleep apnea. Of these, only one was being treated for their apnea with continuous positive airway pressure (CPAP), the best overall therapy for apnea in general, according to Dr. Dyken. This patient died of urosepsis.

Additionally, the apnea/hypopnea index, which charts the average number of times a patient stops breathing in a one-hour period throughout the night, was 41.3 in the patients who died and only 22.1 in the survivors. “This suggests that in acute ischemic stroke, the presence of obstructive sleep apnea—severe apnea—portends poorly for mortality,” Dr. Dyken said.

He added that, in a more recent study in which obstructive sleep apnea was associated with cerebral hypoxemia and death, his investigative group demonstrated one-to-one relationships between obstructive sleep apnea and cerebral and cardiovascular catastrophe and death.

CLINICAL RELEVANCE

Such studies enable Dr. Dyken and his colleagues to make important observations, but in the end they aren’t enough. “I need larger studies; I need better clinical trials,” he declared. “But [because of] the ethics … I cannot force myself to do a large, well-run, prospective, double-blind study using polysomnography prior to and after stroke, comparing untreated and treated patients—[yet] that’s what needs to be done.”

NR

—Fred Balzac

Suggested Reading
Dyken ME, Somers VK, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea. Stroke. 1996;27:401-407.
Dyken ME, Yamada T, Berger HA. Transient obstructive sleep apnea and asystole in association with presumed viral encephalopathy. Neurology. 2003;60:1692-1694.
Dyken ME, Yamada T, Glenn CL, Berger HA. Obstructive sleep apnea associated with cerebral hypoxemia and death. Neurology. 2004;62:491-493.
Marsh EE 3rd, Biller J, Adams HP Jr, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol. 1990;47:1178-1180.

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