Obstructive Sleep Apnea's Impact on Comorbidities

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic podcast, exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Obstructive sleep apnea is a highly prevalent disorder characterized by repetitive interruptions of breathing during sleep. The role of untreated obstructive sleep apnea in the development and worsening of comorbidities has emerged, with new and emerging research helping clinicians better understand this interplay. In today's episode of Neuro Pathways, we're talking about obstructive sleep apnea's impact on neurological, cardiovascular and metabolic co-morbidities specifically. I'm your host Glen Stevens, neurologist and neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Reena Mehra join me for today's conversation. Dr. Mehra is director of sleep disorders research in the Sleep Disorders Center in Cleveland Clinic's Neurological Institute. Reena, welcome to Neuro Pathways.

Reena Mehra, MD, MS: Wonderful. Thanks so much for having me.

Glen Stevens, DO, PhD: So let's get started. Obstructive sleep apnea may manifest in a number of ways, with subtle intrusions into daily life to profound sleepiness. Can you start today's conversation by educating us on the most common signs and symptoms of obstructive sleep apnea?

Reena Mehra, MD, MS: Well, Glen, you framed that very nicely because there is a wide spectrum in terms of the symptoms of presentation, and some can be subtle. Some can be more obvious. The typical symptoms we will see of patients coming to our clinic include snoring; witnessed apneas, that is, episodes of stopping breathing that have been observed by a bed partner, spouse, if somebody's traveling and their friends noticed that they have episodes of stopping breathing; restlessness of sleep. Those are the predominant nocturnal or nighttime symptoms that people will oftentimes present with, and sometimes it's not the individual themselves, but it's the spouse or significant other that's identifying that these are symptoms that the patient is having, and that's what's driving them to come for evaluation.

There are daytime symptoms as well and sequelae of just these constant interruptions in sleep due to the repetitive upper airway collapse that is characteristic of obstructive sleep apnea. Those daytime symptoms, the most predominant one that we see are daytime sleepiness because of that fragmentation of sleep. The quality of sleep is poor and individuals can present with excessive daytime sleepiness, and perhaps the most concerning manifestation of that is drowsy driving, potential for motor vehicle accidents related to drowsy driving, and also daytime fatigue. And there's a difference with sleepiness being increased dozing propensity, say, during passive situations, versus fatigue, which is more of an overall sense of tiredness. So we usually try to discern between those two symptoms. And in addition, there can be effects on mood with oftentimes increased irritability, sometimes depression-specific symptoms as well, and at times, difficulty with focusing and concentration.

Glen Stevens, DO, PhD: Now I have Zoom fatigue. Does that mean I have obstructive sleep apnea?

Reena Mehra, MD, MS: A lot of us share that Zoom fatigue, yes. But it's a good point. I think this excessive sleepiness fatigue can be somewhat non-specific. So usually if you have these symptoms, but it's in the context of snoring or the context of episodes of stopping breathing that have been observed, then putting it all together, the pretest probability for obstructive sleep apnea can be put together in terms of a conglomerate of those symptoms.

Glen Stevens, DO, PhD: So Reena, once a patient is diagnosed with obstructive sleep apnea, what treatment options are typically prescribed?

Reena Mehra, MD, MS: I typically have a frank conversation with my patients about what are the primary treatment options, and the one that we know is effective is positive airway pressure or continuous positive airway pressure, CPAP, where a device is essentially delivering pressure to the airway to splint the airway open and prevent the collapse of the airway that is characteristic of obstructive sleep apnea. So I usually lay out all of the treatment options with my patients. A lot of it is contingent upon the severity of sleep apnea and also the extent of symptoms and the cardiovascular risk of the patient. So I typically weigh all those things in mind because the reason we treat sleep apnea is, number one, to improve quality of life, and number two, to improve cardiovascular health, although arguably there are other health benefits that are conferred by sleep apnea treatment as well.

So CPAP is the mainstay of treatment because it splints all aspects of the airway, irrespective of where the collapse of the airway's occurring, so if it's behind the tongue, behind the palate or below, so retroglossal, retropalatal or hypopharyngeal, irrespective of where the collapse is occurring, the positive airway pressure is going to splint open the airway. Other treatment options are oral appliances, upper airway surgery, and now most recently we have in our armamentarium hypoglossal nerve stimulation.

So oral appliances are really indicated for those with mild, maybe moderate obstructive sleep apnea. And then for those who have more of a positional component, so if there's more of a positional relationship such that the sleep apnea is worsened in the laying on the back position, then there's some data to suggest the oral appliance, which essentially moves the mandible or jaw forward, will be effective in those situations. So that's an alternative for those with mild to moderate sleep apnea.

Upper airway surgery, the typical upper airway intervention that we consider is uvulopalatopharyngoplasty where the uvula and the palate is removed. And that really is not a surgery that's conducted that often, because outcomes with it are essentially not very good. It's a coin flip as to whether it's effective in treating the sleep apnea, and sleep apnea can recur down the line even if it is effective.

And then finally, hypoglossal nerve stimulation. This is a treatment that has come into play in terms of an option within the last several years. And it is certainly an option for those who are recalcitrant to CPAP, who cannot tolerate any other therapies, who have severe sleep apnea. This is an implantable device that can stimulate the hypoglossal nerve, which innervates the tongue, to maintain patency of the upper airway. There are certain characteristics that have to be met in terms of the type of upper airway collapse: the body mass index, age of the patient and so forth. And those things are evaluated, and there are some individuals who respond very well to hypoglossal nerve stimulation.

Glen Stevens, DO, PhD: Great. And before we jump into the comorbidities, I'll just ask you one question about weight loss. Is there a percentage of weight that an individual needs to lose or is it variable? Or if I can lose 10% of my body mass, it will have a 50% chance of assisting with my sleep apnea?

Reena Mehra, MD, MS: Thank you for bringing that up, because actually, I should have mentioned the benefits of weight loss. So in terms of risk factors, obesity, overweight is one of the major risk factors. And this is a question we get from our patients. "Well, you're telling me I have obstructive sleep apnea. If I lose weight, will my sleep apnea be cured?" This is a very common question.

The best data that we have to look towards to answer that question is from the Wisconsin cohort study, which is an epidemiologic study, which showed that over time, a 10% weight loss confers about a 30% improvement in the degree of sleep apnea, as defined by the number of times somebody stops breathing during sleep, and conversely a 10% weight gain, 30% worsening in the degree of sleep apnea. So in general terms from epidemiologic data, those are some numbers that help to guide us. However, each person presenting to us in clinic has different risk factor profiles, and sometimes it's more craniofacial or soft tissue upper airway. So it may not pertain to every single individual sitting in front of us in clinic, but in general terms, those are some data that we have to go by.

Glen Stevens, DO, PhD: Great. So let's dive into the topic of obstructive sleep apnea's impact on these other comorbidities that we've hinted about with obstructive sleep apnea, such as neurological, cardiovascular, metabolic. Help us understand the interplay.

Reena Mehra, MD, MS: Obstructive sleep apnea is characterized by upper airway collapse, and when the airway collapses or obstructs, this leads to cessation of breathing. When there's cessation of breathing, then oxygen levels decline. With the apneas and partial upper airway closure as well, the hypopneas, there is sympathetic nervous system activation that happens, alterations in autonomic nervous system. So during the event, actually there's enhanced parasympathetic tone, and then subsequent to the event, there is sympathetic surge. So there's this juxtaposition of parasympathetic and sympathetic activation that's occurring, and there are rises in carbon dioxide. And during the hypoxia, and during the resaturation, this is a time of vulnerability to oxidative stress and also increased systemic inflammation.

So taken together, these pathophysiologic consequences of obstructive sleep apnea confer risk, not only immediately during sleep, but also confer risk that then leads to daytime consequences as well in terms of cardiovascular risk and otherwise. There are data to show that not only do you have sympathetic surges that are occurring during sleep, but in those with severe sleep apnea in particular over time, there's this vascular remodeling that happens, and that enhanced sympathetic activation actually is persisting to the daytime period in addition to the nighttime period compared to those without obstructive sleep apnea.

So this all sets the stage, then, for increased cardiovascular consequences, because these alterations in the autonomic nervous system, the hypoxia, the hypercapnia, the increased systemic inflammation, oxidative stress, the prothrombotic state actually that can be increased in the setting of sleep apnea, the vascular remodeling, and I should say metabolic consequences as well with insulin resistance. So all of these taken together can increase the risk for cardiovascular events, meaning myocardial infarction, meaning stroke, meaning even heart failure, and something our group has been very interested in, cardiac arrhythmia. So it increases arrhythmogenesis as well, likely in part due to remodeling of the heart structurally and also electrically.

So in terms of the neurologic aspects, in addition to stroke, which is in the realm of cardiovascular consequences, there are relationships not only of sleep apnea, I would say, but also of sleep disruption and sleep deprivation as it relates to neurodegeneration and Alzheimer's dementia in particular. And some really compelling data has emerged over the last several years, which has shown that in experimental models, when there's curtailment of sleep, that this then impairs beta synuclein clearance and therefore causes buildup of this pathology and therefore can contribute to neurodegeneration, so simply not getting sufficient sleep. And superimposed on that, there are data also to suggest that there are relationships with sleep apnea and progression of neurodegeneration over time that may be mediated by, in particular, the nocturnal hypoxia that is associated with the sleep apnea.

Glen Stevens, DO, PhD: So what insights can you give providers who don't typically treat patients with obstructive sleep apnea, but may suspect they have a patient with this condition, or who manage patients with the condition but haven't addressed the possibility of co-morbidities associated with the patients' obstructive sleep apnea?

Reena Mehra, MD, MS: Obstructive sleep apnea is so widely prevalent, so providers are going to encounter patients in their clinics who have symptoms. They may be forthcoming with these symptoms, and sometimes they're not forthcoming with the symptoms. And so if there is suspicion of obstructive sleep apnea... And sometimes what can be used are screening tools such as the STOP-BANG instrument, which basically incorporates common symptoms as well as individual characteristics to create a pretest probability sense of whether the patient has obstructive sleep apnea.

So STOP-BANG, for instance, is something that we oftentimes will use. And the S is for snoring, T tiredness, O observed apneas, P high blood pressure, the B body mass index of greater than 35, A is age for greater than 50, N is neck circumference greater than 17 inches in men, 16 inches in women, and G is gender. So if three or more of those points are positive, then that is consistent with a high pre-test probability for obstructive sleep apnea with about a 90% sensitivity.

So if that is the case, then that helps in terms of where to go next in terms of the diagnostic testing. So if there's high pretest probability for obstructive sleep apnea then a home sleep apnea test may be an acceptable next step, provided that the patient doesn't have considerable cardiopulmonary disease or neurologic disease for which you would want more careful testing done in the laboratory.

So the home sleep apnea test is really a more abbreviated test than we do in the lab, because it allows the ability to monitor the respiratory channels in terms of thoracoabdominal efforts, sensing airflow, oximetry, to really just get a sense in a more crude way as to whether there are apneas and hypopneas that are occurring during sleep. So if there's high pretest probability, you can usually glean the diagnosis from a home sleep apnea test, recognizing that there are inherent limitations and typically an underestimation of the true degree of sleep apnea.

So if there is not a high pre-test probability of sleep apnea, but you're suspecting it, or if there's presence of cardiopulmonary disease or neurologic disease for which you would like a more careful evaluation, then an in-lab polysomnography would be acceptable. And that involves a more in-depth testing with EEG, electrooculogram, electromyogram, which helps to differentiate sleep, wake and the type of stage that the patient is in, and also the respiratory channels, as I mentioned, in addition to EKG, EMG on the limbs to look for limb movements and a position sensor to examine for if there's more of a positional predominant sleep apnea versus not. So in that case, then a diagnostic polysomnogram in the lab would be a reasonable next step.

Glen Stevens, DO, PhD: Great. Reena, your team and others have done a lot of work to get us to our current understanding of these disease interrelationships. What is your research team currently working on that may take our understanding to the next level?

Reena Mehra, MD, MS: There are many areas that we're working on. An interest of mine, historically, has really been on sleep apnea and cardiac arrhythmia relationships. Perhaps of all the cardiovascular outcomes, the relationships with sleep apnea and atrial fibrillation and ventricular arrhythmias are perhaps the strongest in terms of the magnitude of association that have been observed in these epidemiologic studies. So we are basically trying to better understand the mechanisms that underlie and drive that association, and also embarking on some data that can help inform us in terms of performing a clinical trial and identifying those who we can treat for their sleep apnea and have improvement in atrial fibrillation and stroke outcomes as well. And so our team is generating some data in terms of mechanism. We're looking at proteomics and some of the underlying protein biomarkers that may be differentially up-regulated in those who have increasing severity of sleep apnea and atrial fibrillation, and trying to phenotype these individuals more carefully and understand what drivers there are in terms of mechanism.

There are many other areas that we're also looking at. We are involved with an NIH study looking at pulmonary hypertension and sleep apnea in an effort to try to phenotype patients with pulmonary hypertension in a more novel way by using cluster analysis and incorporating therefore sleep apnea, nocturnal hypoxia in that cluster analysis. We are also looking at sleep and circadian rhythm disruption in neurodegeneration. So with our colleagues in the Center for Brain Health, we are examining sleep and circadian rhythm phenotyping, and even molecular biomarkers of transcriptomics and DNA methylation in those with Alzheimer's who have mild cognitive impairment compared to those who are genetically at risk for Alzheimer's in an effort again, to better understand what are the mechanisms at play, and even with circadian biology, which there are some data to suggest circadian dysfunction can also contribute to neurodegeneration.

We are also collaborating on novel therapeutics for sleep apnea, novel devices, a hypoglossal nerve stimulation device to treat sleep apnea, a novel upper airway negative external pressure device to treat sleep apnea. And also sleep apnea as it relates to patient reported outcomes, sleep dysfunction and seizure disorders and sudden unexpected death during epilepsy. So there are many multi-faceted areas that our group is investigating.

Glen Stevens, DO, PhD: Great. So in closing, just from a clinical perspective, I think that the most common concern that I see with our OSA patients is they'll say to me, "I don't like the mask. The mask doesn't fit. I can't use it." Any words of encouragement? How do we help these people?

Reena Mehra, MD, MS: Excellent point. So the adherence to positive airway pressure has been much discussed, and when we look at the data in general, it appears that adherence is about 60-70% in terms of those that are reliably using their positive airway pressure. If you look at medication adherence, that's pretty much the same, actually. It's pretty comparable. Not to minimize or dismiss the adherence to positive airway pressure and the challenges that it poses, but keeping that in mind, I think, is important.

As we look at adherence with positive airway pressure, there are many things that we can do and many tricks up our sleeve that we can use to help, really, with folks that are having problems with the interface of the mask and challenges therein with pressure intolerance, feeling like the pressure's too high, too low, with nasal congestion... A lot of it is honing in on the specific issue that the individual is having in terms of being able to tolerate that device. And we know we should do this early on. So early adherence predicts later adherence. So the sooner we delve into and identify these issues and act upon them and address them for our patients, the more likely they are to continue to use treatment for the long term.

So if it's an issue in terms of the mask interface, technology is very much advanced so that we have many different masks that are available. So for instance, if folks are claustrophobic, then using a nasal pillows mask may be more comfortable for the patient. If they feel that they're opening their mouth and therefore having dry mouth, sometimes a chin-strap or a full-face mask may be helpful. So there are ways to overcome those mask challenges. If the pressure is too high, then we can try auto-titrating positive airway pressure devices that may be more physiologic and comfortable. We can also try bi-level positive airway pressure if there's nasal congestion issues using the heated humidification on the device. So again, usually we can overcome the issue at hand.

There are other strategies that are unique that we have here at the Cleveland Clinic to really help optimize adherence with positive airway pressure. One is basically the daytime PAP Nap study, which is a daytime sleep study where the patient can come in with a one-on-one with a sleep technologist to essentially identify and troubleshoot the specific mask issues. It offers desensitization and acclimation to the positive airway pressure, and that we have found anecdotally to be pretty successful in our program, and there are evidence-based data as well to show that this technique be effective in improving adherence.

The other approach that can be helpful are the SAM Clinics, so the Sleep Apnea Management Clinics, which really operates to leverage the group dynamic to improve adherence to CPAP, where individuals can learn from one another in terms of the challenges that each has and know that they're not alone, that there are others in there that are also struggling and having challenges. And we are now transitioning to more of a virtual format for the sleep apnea management clinic, and we are actually also conducting a clinical trial, a randomized clinical trial called the SAM PAP clinical trial to understand better whether the SAM approach and intervention really helps to improve adherence in our patients.

Glen Stevens, DO, PhD: Well, Reena, thank you very much for joining us today. This has been a very insightful conversation. I appreciate your time. Thank you.

Reena Mehra, MD, MS: Thank you so much for having me.

Glen Stevens, DO, PhD: I'm going to go home, lose 10% body mass, get more sleep and get my wife to check my snoring.

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