Gaps in Sleep Medical Knowledge: Part IX (Miscellaneous Topics)

Biomedical markers

Diabetes is a systemic illness that can wreak havoc on virtually every organ system in the body. When blood sugar levels are abnormally elevated, for example when after eating a meal the sugar rises rapidly to abnormal levels and remains high for longer than in a non-diabetic, this excess glucose attaches itself to blood hemoglobin, the special protein in red blood cells that transports oxygen through the bloodstream. The glucose attachment to hemoglobin is called glycation and can occur in any human, but it occurs more so in diabetics due to the excess glucose in the system. To read a brief and interesting story about the discovery of this biomolecule, now known as Hemoglobin A1C (HbA1c), you can go to this piece in PubMed about Dr. Samuel Rahbar, the man making the discovery in 1968.

The remarkable thing about HbA1c is how closely it correlates with the disease of diabetes. In other words, the higher your A1C levels, the worse the diabetes. The more tightly controlled the A1C, hopefully near levels close to what is measured in normal, nondiabetics individuals, the more likely diabetes will have less impact. Some research predicts diabetic-related kidney or eye diseases are more common in those with A1C levels > 8.0; whereas the more recent recommendations for A1C control indicate levels < 7.0 are protective against damage inflicted by diabetes. Many doctors recommend their patients keep A1C levels in the 6.0 to 6.9 range, but some patients actually achieve levels < 6.0. However, in this latter case, these low HbA1c levels may create new risks in cardiac patients, because this extremely tight control of glucose may herald more hypoglycemic episodes, especially while sleeping, which in turn can trigger serious problems with heart function, including sudden death.

As you might imagine, the HbA1c biomarker has proven exceptionally useful in monitoring and treating diabetic patients. And, the HbA1c biomolecule is one of the most powerful measuring tools in all of medicine. Other markers with which you might be familiar are cardiac enzymes when a person suffers a heart attack, creatinine and blood urea nitrogen levels in kidney failure, and liver enzymes in patients with acute or chronic alcoholism.  

Regrettably, in sleep medicine, there is no biomarker that correlates with the major sleep diseases such as OSA/UARS, insomnia, restless legs syndrome (RLS) and periodic limb movement disorder (PLMD), or even with the main waking complaints of sleepiness or tiredness. The absence of such biomarkers in this developmental phase of sleep medicine clearly hampers our efforts to treat patients, because we are relying exclusively on patients’ self-reports on their improvements in symptoms or lack thereof. While we have access to objective markers of sleep diseases, for example, how many breathing events or leg jerks while sleeping or how much sleep loss in a night of insomnia, these numbers often do not correlate with the severity of the diseases or the intensity and duration of the daytime symptoms. Even notable outcomes such as hypertension or nocturia (bathroom trips during the night), both of which are common in OSA/UARS patients cannot be specifically correlated with the severity of the sleep breathing disorder.

A biomarker for sleep diseases and symptoms due to impaired sleep will represent an enormous scientific breakthrough that will dramatically improve our ability to understand and treat sleep disorders. Some noteworthy articles on this topic include ones that discuss how biomarkers will lead to greater precision in sleep medicine, ones that describe how biomarkers will lead to easier diagnosis of OSA/UARS without relying on PSG, and ones that may demonstrate new treatment approaches to lessen the impact of sleep-breathing disorders on human health.


Root Causes for and Clinical Attention to RLS/PLMD

Although there are troubling signs different types of physicians and medical staff are not paying attention to the epidemic of OSA/UARS in numerous patient cohorts, there are equally bothersome indicators within the sleep medicine community of physicians who are not paying attention to RLS/PLMD. The reason for this oversight seems uncertain, but the main issue tends to be an entrenched conventional wisdom that diminishes the relevance and impact of these leg movement disorders. 

This conventional wisdom dates back several decades where minimizing the consequences of RLS/PLMD was routinely discussed at the annual sleep conferences. At various points in the 1990s, expert researchers in the field declared that leg jerks had no impact whatsoever on sleep quality or daytime symptoms. Even to this day, there are many sleep physicians and researchers who presume leg jerks are unlikely to be a factor in the management of sleep disorders’ patients. 

Some of this perspective is accurate in so far as increasing evidence reveals leg jerks are often a sign of arousal activity caused by the primary condition of sleep-disordered breathing. Nonetheless, there remains a substantial number of patients where leg jerks turn out to be truly independent, meaning the limb movements independently disrupt sleep. The problem arising is the long time it often takes, many months or longer, and the considerable effort to sort out these diagnoses. For example, if the patient’s airflow curve is not normalized, how can the sleep staff figure out whether or not the leg jerks are independent? This factor alone may create long delays in attempting to determine leg movement status. And, many patients are reluctant to try medications for RLS/PLMD until it is clearly proven to them this co-occurring disorder needs its own treatment. Obviously, patients with noticeable RLS are more interested in drug therapy sooner in the course of clinical care, but even some of these cases, remarkably, turn out to be caused by untreated sleep-disordered breathing.

The bottom line is the field of sleep medicine needs research that more accurately defines these movement problems and the actual causes of RLS/PLMD. Knowing such info would go a long way towards expediting care for this disorder in relevant patients. This gap is substantial and severely impacts those patients who suffer from these leg movement disorders and who often experience considerable delays in diagnosis and treatment.


Understanding the Role of Sleeping Pills and Their Sub-optimal Results

As the pharmaceutical industry continues its never ending quest to find the perfect sleeping pill, a number of trends in both the fields of sleep medicine and psychiatry are moving in opposite directions. Although not a groundswell by any means, it is very clear more and more physicians in sleep and mental health practices are recognizing the limited roles and value of sleeping pills. And, this vanguard of physicians are now educating their patients on why they should forego this approach to insomnia. 

In mental health circles, the same phenomenon is occurring regarding the over-use of psychotropic medications, among which are frequently prescribed sedating antidepressants, anxiolytics, or antipsychotics. While a conventional wisdom favoring sleep aids still holds sway in many practices, for the first time in my career as a physician dating back to 1979 I am routinely hearing from mental health providers of all types, including psychiatrists and psychologists who express the opinion that enough is enough when it comes to sleep and psychotropic drug prescriptions. To these professionals, the complexity of mental health disorders and sleep disorders just cannot be cured with meds in the majority of cases. Rather, they want to see patients exposed to more sophisticated forms of psychotherapy that go well beyond the conventional and largely discredited “talk therapy” model.

Also, many of these practitioners are taking the same stance as sleep physicians in rejecting the value of chronic use of sleep aids. While nearly everyone accepts the potential role for acute use of sleep aids to treat acute or transient bouts of insomnia, more providers now recognize a patient’s demand for regular use of sleep aids is not in his or her best interest. Instead, these professionals are increasingly aware of the importance for comprehensive sleep evaluations or the implementation of newer psychological therapies, either of which can lead to curative results.

Many of these patients suffer from complex mental disorders that frequently fail medication approaches because the underlying problems may be psychological conditions described as personality disorders or dimensions. Such patients need highly specialized psychotherapies such as dialectical behavioral therapy (DBT), acceptance and commitment therapy (ACT) or a variety of therapies to treat emotional dysregulation such as emotion-focused therapy (EFT) or somatic experiencing (SE). Often, these patients are medicated for years for their supposed anxiety and depression and their intractable insomnia. These examples are just some of the specific problems the fields of psychiatry and psychology are coming to grips with due to the failure of medication approaches in mental disorders and sleep disorders.

This gap is very large and likely to remain unaddressed due to the long-standing entrenched ideas about the role and value of psychotropic medicines to treat mental health patients and their sleep disorders.


Changing Our Reliance on the AHI and RDI Metrics

Many OSA/UARS patients are harmed by the inadequacies of these metrics. In the most glaring example of the problem, hundreds of thousands of patients undergo upper airway and nasal surgeries for sleep-related breathing conditions, and yet the follow-up evaluations post-surgery often reveal at best only qualitative corroboration of the surgical treatment effects; whereas the AHI/RDI quantitative information frequently proves most unreliable and misleading. 

As discussed at the outset of this lengthy series on gaps in sleep medical knowledge, the current use of AHI/RDI metrics do not help us understand the nature of normal sleep, and they do not assist us in appreciating the severity of sleep breathing disorders. Even when the flow limitations are accurately scored and counted in the RDI, we still do not have a clear picture on the severity or intensity of sleep breathing disorders.

Just recently the American Thoracic Society published a study on the problem of interpreting mild OSA, and one of their first results after reviewing numerous articles on this topic was: ‘Studies were incongruent in their definitions of "mild" OSA.’ (1) In other words, to this day there remains no clarity on how to measure this allegedly low severity level of OSA and what exactly would be defined by a low AHI. The paper purports mild OSA is highly prevalent in adults, which means tens of millions of people suffer from this condition, yet the gap in sleep medical knowledge is huge in this area, because so little can be explained to a patient in this situation, at least according to the ATS review of the literature.

Thus, in attempting to help patients undergoing nose and throat surgeries or patients who are recommended for various sleep breathing treatments, the field of sleep medicine’s failure to pin down exact clinical meaning to our current breathing metrics greatly confuses our efforts to diagnose and treat these patients. And, this confusion adds to the mistrust patients may develop about the field of sleep medicine. Astonishingly, this gap appears to be growing not shrinking in size.



  1. ATS Ad Hoc Committee on Mild Obstructive Sleep Apnea. An Official American Thoracic Society Research Statement: Impact of Mild Obstructive Sleep Apnea in Adults. Am J Respir Crit Care Med. 2016 May 1;193(9):e37-54. doi: 10.1164/rccm.201602-0361ST.


Read more from this series:

Gaps in Sleep Medical Knowledge: Part I (Normal Sleep)
Gaps in Sleep Medical Knowledge: Part II (Normal Breathing)
Gaps in Sleep Medical Knowledge: Part III (The Medicare Hypopnea Scoring Maze)
Gaps in Sleep Medical Knowledge: Part IV (The Unsolved Puzzle of UARS)
Gaps in Sleep Medical Knowledge: Part V (Coding Issues for Billing and Reimbursement)
Gaps in Sleep Medical Knowledge: Part VI (Prior Authorizations and Atypical Patients)
Gaps in Sleep Medical Knowledge: Part VII (Confusing Compliance with Outcomes)
Gaps in Sleep Medical Knowledge: Part VIII (Comorbid Sleep Disorders)
Gaps in Sleep Medical Knowledge: Part IX (Miscellaneous Topics)


Barry Krakow MD


Dr Krakow’s 27 years of sleep research have focused on the complex relationship between physiological and psychological sleep disorders. Dr Krakow currently operates private sleep medical center, Maimonides Sleep Arts & Sciences, Ltd., and serves as Classic SleepCare’s paid Medical Director.

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