Circadian Rhythm Sleep-Wake Disorders (Sleep Neurology August 2020)

Educational Objectives

The goal of this program is to improve diagnosis and management of sleep disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Identify patients with circadian rhythm sleep-wake disorders.
2. Select appropriate zeitgebers when treating patients with circadian rhythm sleep-wake disorders.

Summary

Control of circadian rhythm: Circadian is defined as recurring with a 24-hour period; circadian rhythms are primarily controlled by the suprachiasmatic nucleus (a set of paired nuclei in the hypothalamus); the suprachiasmatic nucleus regulates the sleep-wake cycle, release of hormones, core body temperature, and feeding behavior; circadian rhythms are governed by a set of clock genes that feature a transcription-translation feedback loop (TTFL).

Characteristics of the circadian clock: In each individual, the period of the circadian clock (ie, time to complete the TTFL) is slightly longer or shorter than 24 hours; therefore, an organism makes tiny, daily adjustments to remain aligned with the 24-hour environment; the clock may be reset by signals in the environment; zeitgebers (time givers) are signals that influence the internal clock; light is the strongest signal; other key factors include melatonin, social interaction, activity, and the timing of meals.

Case: A 23-year-old woman presented for evaluation of intermittent difficulty falling asleep and waking up; in high school, she began having difficulty with initiating sleep and could not fall asleep until 2:00 am or 3:00 am; she struggled to awaken in time for school, often missing her morning classes; this became less problematic when the patient entered college and was able to choose her own class schedule; she typically enrolled only in afternoon classes and slept between 4:00 am or 5:00 am and 1:00 pm or 2:00 pm; with this schedule, she slept well and received good grades, allowing her to graduate with honors; following graduation, she had difficulty maintaining steady employment because she was unable to fall asleep at a time that allowed her to arrive at work by 9:00 am.

Approach to case: This history represents a classic example of delayed sleep-wake phase disorder; circadian timing naturally becomes later during adolescence; however, those who already tend toward a delayed sleep-wake phase may struggle as young adults, when they are expected to be in the workplace from 9:00 am to 5:00 pm; to make the diagnosis, ask the patient to complete a sleep log or use actigraphy (ie, wear a wristwatch with an accelerometer); exposure to zeitgebers (including melatonin) is used to treat such patients.

Etiology of delayed sleep-wake phase disorder: Risk factors include genetic mutations that affect the TTFL; for example, the circadian day for an affected patient may be closer to 25 hours than 24 hours; exposure to light j plays a role; patients who tend to stay up late are exposed to more light in the evening, which may further advance their circadian clocks; some of these patients may be overly sensitive to light exposure in the evening and less sensitive to morning light; however, in some patients who appear to have delayed sleep-wake phase disorder, biologic markers of circadian timing (eg, the time when melatonin is produced, the time when core body temperature reaches its nadir) are similar to those of a typical patient (ie, the delay is behavioral rather than circadian).

Management of delayed sleep-wake phase disorder: The clinician should begin by providing validation (ie, the disorder is biologic and not caused by laziness or lack of effort to awaken on time); in some patients, recognizing the problem is sufficient (it allows the patient to adapt his or her schedule); in others, interventions (exposure to light and melatonin) are required to move the cycle earlier.

Light for delayed sleep-wake phase disorder: Exposure to light in the biological morning (just after awakening) tends to move the circadian clock earlier, while light in the biological evening tends to move the clock later; for the patient in the case example, exposure to bright light should be instituted shortly after her natural waking time (ie, early afternoon), using commercially available light boxes; when clinicians mistakenly interpret the recommendation for “light exposure in the morning” as “exposure during typical morning waking times” (eg, 7:00 am), they may cause the patient’s cycle to move in the wrong direction; use of actigraphy and the sleep log allows the clinician to accurately pinpoint biological morning for each patient.

Melatonin for delayed sleep-wake phase disorder: To move the clock earlier, melatonin should be taken in the biological evening; taking melatonin after awakening tends to push the clock later; the patient should take a low dose of melatonin in the evening (the usual dose is approximately 0.5 mg); higher doses of melatonin are used for rapid eye movement (REM) sleep behavior disorder; for circadian disorders, if melatonin is not effective, the clinician should adjust the timing of the dose rather than increasing the dose.

Advanced sleep-wake phase disorder: These patients feel sleepy as early as 6:00 pm or 7:00 pm, then awaken at 2:00 am or 3:00 am; such patients are less likely to present for care.

Management of advanced sleep-wake phase disorder: These patients are treated with exposure to bright light in the evening, beginning at the time when they become tired and wish to sleep.

Irregular sleep-wake rhythm disorder: Patients with this disorder have an irregular pattern of sleep and wakefulness; they sleep at multiple times throughout the day and night (by definition, the patient must have at least three distinct bouts of sleep within 24 hours); the patient’s total sleep time is adequate, but hours of sleep are not consecutive; this pattern is seen in patients with dementia; taking an afternoon nap does not indicate presence of this disorder (the pattern must be more irregular).

Risk factors for irregular sleep-wake rhythm disorder: Include impaired function of the suprachiasmatic nucleus or loss of external zeitgebers in the setting of a weak suprachiasmatic nucleus; patients with dementia may have degeneration of the suprachiasmatic nucleus and may live in an environment with limited time cues (eg, a nursing facility); other neurologic conditions that predispose to irregular sleep-wake rhythm disorder include diseases associated with loss of the optic nerve (these patients may also develop non-24-hour sleep-wake rhythm disorder).

Non-24-hour sleep-wake rhythm disorder: In most individuals, the circadian day is slightly longer than 24 hours; some patients with non-24-hour sleep-wake disorder have no light input to the suprachiasmatic nucleus, so the patient follows the internal clock, and, therefore, goes to sleep slightly later each day; this disorder may be seen in patients with normal vision.

Management of non-24-hour sleep-wake rhythm disorder: For patients with blindness, zeitgebers other than light are used, such as a fixed, low dose of melatonin at the same time each evening; tasimelteon is a melatonin agonist approved for this purpose; tasimelteon has not been compared directly with melatonin.

Other clinical interventions based on circadian rhythms: The future of circadian biology is likely to explore the optimal timing of medications (eg, antihypertensives) and other interventions.

Readings

Zee PC, Abbott SM. Circadian rhythm sleep-wake disorders. Continuum (Minneap Minn) 2020;26(4, Sleep Neurology).

Disclosures

For this program, the following was disclosed: Dr Abbott has received personal compensation for serving as a member of the American Board of Internal Medicine’s Sleep Medicine Exam Writing Committee, research/grant support from the American Sleep Medicine Foundation (155-JF-16), and publishing royalties from UpToDate, Inc.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Abbott discusses the unlabeled/investigational use of melatonin for the treatment of circadian rhythm sleep-wake disorders.

To view disclosures of planning committee members with relevant financial relationships, visit: legacy.audio-digest.org/continuumaudio/committee. All other members of the planning committee report nothing to disclose.

The material presented in Continuum Audio has been made available by the AAN for educational purposes only and is not intended to represent the only method or procedure for the medical situations discussed but rather to present an approach, view, statement, or opinion of the speaker(s), which may be helpful to others who face similar situations. Opinions expressed by the speakers are not necessarily those of the AAN, its affiliates, or the publisher. The AAN, its affiliates, and the publisher disclaim any liability to any party for the accuracy, completeness, efficacy, or availability of the material contained in this program (including drug dosages) or for any damages arising out of the use or nonuse of any of the material contained in this program.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

CA090410

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.