[Ohio-talk] non-24 trouble sleeping? read this!
Edward Louden
edlouden6485 at gmail.com
Tue Jan 15 14:22:23 UTC 2019
Non-24-hour sleep—wake disorder
>From Wikipedia, the free encyclopedia
Non-24-hour sleep—wake disorder (non-24), is one of several types of chronic
circadian rhythm sleep disorders (CRSDs). It is defined as a "complaint of
insomnia or excessive sleepiness related to abnormal synchronization between
the 24-hour light—dark cycle and the endogenous circadian rhythms of sleep
and wake propensity.'" Symptoms result when the non-entrained (free-running)
endogenous circadian rhythm drifts out of alignment with the desired or
conventional sleep—wake schedule. However, the sleep pattern can be quite
variable; some individuals adopt a sleep pattern that is congruent with
their free-running circadian clock, shifting their sleep times daily,
thereby often obtaining satisfactory sleep but suffering major social and
occupational consequences. People with non-24 "resemble free-running, normal
individuals living in a time-isolation facility with no external time
cues",' while using artificial lighting at will.
The majority of patients with non-24 are totally blind, and the failure of
entrainment is explained by an absence of photic input to the circadian
clock.w However, the disorder can also occur in sighted people for reasons
that are not well understood.
Though often referred to as non-24, for example by the FDA,W it is also
known by the following terms:
· Non-24-hour sleep—wake syndrome
· Non-24-hour sleep-wake disorder
· Non-24-hour sleep-wake rhythm disorder
· Free running disorder (FRD)
· Hypernychthemeral disorder
· Circadian rhythm sleep disorder — free-running type
· Circadian rhythm sleep disorder — nonentrained type
· N24HSWD
· Non-24-hour circadian rhythm disorder
The disorder is an invisible disability that can be "extremely debilitating
in that it is incompatible with most social and professional obligations"
.141
Mechanisms
The internal circadian clock, located in the hypothalamus of the brain,
generates a signal that is slightly longer (occasionally shorter) than 24
hours. Normally, this slight deviation is corrected by exposure to
environmental time cues, especially the solar light-dark cycle, which reset
the clock and synchronize (entrain) it to the 24-hour day. Morning light
exposure resets the clock earlier, and evening exposure resets it later,
thereby bracketing the rhythm to an average 24-hour period. If normal people
are deprived of external time cues (living in a cave or artificial
time-isolated environment with no light), their circadian rhythms will
"free-run" with a cycle of more
(occasionally less) than 24 hours, expressing the intrinsic period of the
circadian clock. The circadian rhythms of individuals with non-24 can
resemble those of experimental subjects living in a time-isolated
environment, even though they are living in normal society.
The circadian clock modulates many physiological rhythms. The most easily
observed of these is the propensity for sleep and wake; thus, patients with
non-24 experience symptoms of insomnia and daytime sleepiness (similar to
"iet lag") when their endogenous circadian rhythms drift out of synchrony
with the social/solar 24-hour day and they attempt to conform to a
conventional schedule. Eventually, their circadian rhythms will drift back
into normal alignment, and symptoms temporarily resolve, only to recur as
their clock drifts out of alignment again. Thus the overall pattern involves
recurring symptoms on a weekly or monthly basis, depending on the length of
the internal circadian cycle. For example, an individual with a circadian
period of 24.5 hours would drift 30 minutes later each day and would be
maximally misaligned every 48 days. If patients set their own schedule for
sleep and wake, aligned to their endogenous non-24 period (as is the case
for most sighted patients with this disorder), symptoms of insomnia and
wake-time sleepiness are much reduced. However, such a schedule is
incompatible with most occupations and social relationships.
Characteristics
Sighted
In people with non-24, the body essentially insists that the length of a day
(and night) is appreciably longer (or, very rarely, shorter) than 24 hours
and refuses to adjust to the external light—dark cycle. This makes it
impossible to sleep at normal times and also causes daily shifts in other
aspects of the circadian rhythms such as peak time of alertness, body
temperature minimum, metabolism and hormone secretion. Non-24-hour
sleep—wake disorder causes a person's sleep—wake cycle to move around the
clock every day, to a degree dependent on the length of the cycle,
eventually returning to "normal" for one or two days before "going off'
again. This is known as free-running sleep.
People with the disorder may have an especially hard time adjusting to
changes in "regular" sleep—wake cycles, such as vacations, stress, evening
activities, time changes like daylight saving time, travel to different time
zones, illness, medications (especially stimulants or sedatives), changes in
daylight hours in different seasons, and growth spurts, which are typically
known to cause fatigue. They also show lower sleep propensity after total
sleep deprivation than do normal sleepers.'
Non-24 can begin at any age, not uncommonly in childhood. It is sometimes
preceded by delayed sleep phase disorder.141
Most people with this disorder find that it severely impairs their ability
to function in school, in employment and in their social lives. Typically,
they are "partially or totally unable to function in scheduled activities on
a daily basis, and most cannot work at conventional jobs".11-1Attempts to
keep conventional hours by people with the disorder generally result in
insomnia (which is not a normal feature of the disorder itself) and
excessive sleepiness,w to the point of falling into
microsleeps, as well as myriad effects associated with acute and chronic
sleep deprivation. Sighted people with non-24 who force themselves to live
on a normal workday "are not often successful and may develop physical and
psychological complaints during waking hours, i.e. sleepiness, fatigue,
headache, decreased appetite, or depressed mood. Patients often have
difficulty maintaining ordinary social lives, and some of them lose their
jobs or fail to attend school."151
Blind
It has been estimated that non-24 occurs in more than half of all people who
are totally blind.16171 The disorder can occur at any age, from birth
onwards. It generally follows shortly after loss or removal of a person's
eyes,'sias the photosensitive ganglion cells in the retina are also removed.
Without light to the retina, the suprachiasmatic nucleus (SCN), located in
the hypothalamus, is not cued each day to synchronize the circadian rhythm
to the 24-hour social day, resulting in non-24 for many totally blind
individuals.w Non-24 is rare among visually impaired patients who retain at
least some light perception. Researchers have found that even minimal light
exposure at night can affect the body clock.'91
Symptoms
Symptoms reported by patients forced into a 24-hour schedule are similar to
those of sleep deprivation and can include:
•
Apraxia including Ideational
•
Impaired balance
apraxia, Ideomotor apraxia,
•
•
Photosensitivity"°'1'
Kinetic apraxia, Limb
Joint pain
apraxia, Verbal apraxia
•
Loss of muscle
•
Cognitive dysfunction
coordination (ataxia)
•
Difficulties concentratine
•
Menstrual irregularities
•
Confusion
•
Muscle pain
•
Depressed mood'`'
•
Suicidal thoughts
•
Diarrhea
•
Weight gain
•
Extreme nausea
•
Hallucinations"
•
Extreme fatigue
•
Hair loss
•
Headaches'"
Prevalence
There are an estimated 140,000 people with N24 - both sighted and blind - in
the European Union, a total prevalence of approximately 3 per 10,000, or
0.03%.' It is unknown how many individuals with this disorder do not seek
medical attention, so incidence may be higher. The
European portal for rare diseases, Orphanet, lists Non-24 as a rare disease
by their definition: fewer than 1 affected person for every 2000
population?'
Sighted
As of 2005, there had been fewer than 100 cases of sighted people with
non-24 reported in the scientific literature."
Blind
While both sighted and blind people are diagnosed with non-24, the disorder
is believed to affect more totally blind individuals than sighted. It has
been estimated by researchers that of the 1.3 million blind people in the
U.S.," 10% have no light perception at all.'"' Of that group, it is
estimated that approximately half to three-quarters, or 65,000 to 95,000
Americans, suffer from non-24.E1
Causes
Sighted
Sighted people with non-24 appear to be more rare than blind people with the
disorder and the etiology of their circadian disorder is less well
understood i2' At least one case of a sighted person developing non-24 was
preceded by head injury;" another patient diagnosed with the disorder was
later found to have a "large pituitary adenoma that involved the optic
chiasma".in Thus the problem appears to be neurological. Specifically, it is
thought to involve abnormal functioning of the suprachiasmatic nucleus (SCN)
in the hypothalamus.u9' Several other cases have been preceded by
chronotherapy, a prescribed treatment for delayed sleep phase disorder.14
"Studies in animals suggest that a hypernyctohemeral syndrome could occur as
a physiologic aftereffect of lengthening the sleep—wake cycle with
chronotherapy".huAccording to the American Academy of Sleep Medicine (AASM):
"Patients with free-running (FRD) rhythms are thought to reflect a failure
of entrainment".'2Q1
There have been several experimental studies of sighted people with the
disorder. McArthur et al. reported treating a sighted patient who "appeared
to be subsensitive to bright light"." In other words, the brain (or the
retina) does not react normally to light (people with the disorder may or
may not, however, be unusually subjectively sensitive to light; one study
found that they were more sensitive than the control group.) In 2002
Uchiyama et al. examined five sighted non-24 patients who showed, during the
study, a sleep—wake cycle averaging 25.12 hours." That is appreciably longer
than the 24.02-hour average shown by the control subjects in that study,
which was near the average innate cycle for healthy adults of all ages: the
24.18 hours found by Charles Czeisler." The literature usually refers to a
"one to two hour" delay per 24-hour day (i.e. a 25-26 hour cycle).
Uchiyama et al. had earlier determined that sighted non-24 patients' minimum
core body temperature occurs much earlier in the sleep episode than the
normal two hours before
Sightedawakening. They suggest that the long interval between the
temperature trough and awakening makes illumination upon awakening virtually
ineffective,(;' as per the phase response curve (PRC) for light.
In their clinical review in 2007, Okawa and Uchiyama reported that people
with Non-24 have a mean habitual sleep duration of nine to ten hours and
that their circadian periods average 24.8 hours.'5-1
Blind
As stated above, the majority of patients with Non-24 are totally blind, and
the failure of entrainment is explained by the loss of photic input to the
circadian clock. Non-24 is rare among visually impaired patients who retain
at least some light perception; even minimal light exposure can synchronize
the body clock. A few cases have been described in which patients are
subjectively blind, but are normally entrained and have an intact response
to the suppressing effects of light on melatonin secretion, indicating
preserved neural pathways between the retina and hypothalamus 212251
Diagnosis
Sighted
The diagnosis is typically made based on a history of persistently delayed
sleep onset that follows a non-24-hour pattern. In their large series,
Hayakawa reported the average day length was 24.9 ± 0.4 hours (range
24A-26.5).1-wThere may be evidence of "relative coordination" with the sleep
schedule becoming more normal as it coincides with the conventional timing
for sleep. Most reported cases have documented a non-24-hour sleep schedule
with a sleep diary (see below)J=6i or actigraphy." In addition to the sleep
diary, the timing of melatonin secretion" or core body temperature
rhythrij27t23' has been measured in a few patients who were enrolled in
research studies, confirming the endogenous generation of the non-24-hour
circadian rhythm.
Blind
The disorder can be considered very likely in a totally blind person with
periodic insomnia and daytime sleepiness, although other causes for these
common symptoms need to be ruled out. In the research setting, the diagnosis
can be confirmed, and the length of the free-running circadian cycle can be
ascertained, by periodic assessment of circadian marker rhythms, such as the
core body temperature rhythm,ll'i the timing of melatonin secretionP"" or by
analyzing the pattern of the sleep—wake schedule using actigraphy." Most
recent research has used serial measurements of melatonin metabolites in
urine or melatonin concentrations in saliva. These assays are not
currently available for routine clinical use.
A sleep diary with nighttime in the middle and the weekend in the middle, to
better notice trends
Enforcing a 24-hour sleep—wake schedule using alarm clocks or family
interventions is often tried but usually unsuccessful. Bright light exposure
on awakening to counteract the tendency for circadian rhythms to delay,
similar to the treatment for delayed sleep phase disorder,'-' and seasonal
affective disorder (SAD) has been found to be effective in some
cases,'32"3334' as has melatonin administration in the subjective late
afternoon or evening."1-'6'L"ILight therapy involves at least 20 minutes of
exposure to 3000 to 10000 lux light intensity. Going outside on a bright
sunny day can accomplish the same benefit as special light fixtures (light
boxes). Bright light therapy combined with the use of melatonin as a
chronobiotic and avoidance of light before bedtime may be the most effective
treatment. Melatonin administration shifts circadian rhythms according to a
phase response curve (PRC) that is essentially the inverse of the light PRC.
When taken in the late afternoon or evening, it resets the clock earlier;
when taken in the morning, it shifts the clock later. Therefore, successful
entrainment depends on the appropriate timing of melatonin administration.
The accuracy needed for successfully timing the administration of melatonin
requires a period of trial and error, as does the dosage. In addition to
natural fluctuations within the circadian rhythm, seasonal changes including
temperature, hours of daylight, light intensity and diet are likely to
affect the efficacy of melatonin and light therapies since these exogenous
zeitgebers would compete for hormonal homoeostasis. Further to this there
are unforeseen disruptions to contend with even when a stabilised cycle is
achieved; such as travel, exercise, stress, alcohol or even the use of light
emitting technology close to a subjective evening/night.
Hypnotics and/or stimulants (to promote sleep and wakefulness, respectively)
have sometimes been used. Typically a sleep diary is requested to aid in
evaluation of treatment, though the emergence of modern actigraphy devices
can also assist in the logging of sleep data. Additionally, graphs can now
be generated using mobile phone applications, utilising internal
accelerometers which are present in most smartphones in use today. The
graphs and basic sleep diary records can be shared with a physician.
However, due to the lack of clinical accuracy they should not be used for
diagnosis, but instead to monitor the cycle and general progress of any
medications in use.
Blind
In the 1980s and 1990s, several trials of melatonin administration to
totally blind individuals without light perception produced improvement in
sleep patterns, but it was unclear at that time if the benefits were due to
entrainment from light cues.138113911401f4IIThen, using endogenous melatonin
as a marker for circadian rhythms, several research groups showed that
appropriately timed melatonin administration could entrain free-running
rhythms in the totally blind.mwl For example, Sack et al. 4' found that 6
out of 7 patients treated with 10 mg melatonin at bedtime were normally
entrained. When the dose was gradually reduced to 0.5 mg in three of the
subjects, entrainment persisted. Subsequently, it was shown that treatment
initiated with the 0.5 mg dose produced entrainment.L4-4' ' One subject who
failed to entrain at a higher dose was successfully entrained at a lower
dose.'-4 A low dose produces melatonin blood levels that are similar to the
concentrations naturally produced by nightly pineal secretion.L5i
Products containing melatonin are available as dietary supplements in the
United States 47 and Canada, available over the counter. These "supplements"
do not require FDA approval. As
prescription drugs may be prescribed off-label, treatment recommendations
for non-24 in the blind may vary.
There has been a constant growth in the field of melatonin and melatonin
receptor agonists since the 1980s." In 2005 Ramelteon (Rozerem®) was the
first melatonin agonist to be approved in the United States (US), indicated
for insomnia treatment in adults." Melatonin in the form of prolonged
release (trade name Circadin®) was approved in 2007 in Europe (EU) for use
as a short-term treatment, in patients 55 years and older, for primary
insomnia." Tasimelteon (trade name Hetlioz®) received FDA-approval in
January 2014 solely for completely blind persons diagnosed with non-24.'=''
TIK-301 (Tikvah Therapeutics, Atlanta, USA) has been in phase II clinical
trial in the United States since 2002 and the FDA granted it orphan drug
designation in May 2004, for use as a treatment for circadian rhythm sleep
disorder in blind individuals without light perception as well as
individuals with tardive dyskinesie-1
History
The ability of melatonin administration to entrain free-running rhythms was
first demonstrated by Redman, et al. in 1983 in rats who were maintained in
a time-free environment."
Sighted
The first report and description of a case of non-24, a man living on
26-hour days, was "A man with too long a day" by Ann L. Eliott et al. in
November 1970." The related and more common delayed sleep phase disorder was
not described until 1981.
Blind
In the first detailed study of non-24 in a blind subject, researchers
reported on a 28-year-old male who had a 24.9-hour rhythm in sleep, plasma
cortisol, and other parameters. Even while adhering to a typical 24-hour
schedule for bedtime, rise time, work, and meals, the man's body rhythms
continued to shift.u5-1
Research directions
Not all totally blind individuals have free-running rhythms, and those that
do often show relative coordination as their endogenous rhythms approximate
normal timing 1'G' It has been suggested that there are non-photic time cues
that are important for maintaining entrainment, but these cues await to be
characterized.
Classifications
Since 1979, the disorder has been recognized by the American Academy of
Sleep Medicine:
· Diagnostic Classification of Sleep and Arousal Disorders (DCSAD),
1979: Non-24-Hour Sleep—Wake Syndrome; code C.2.dal
· The International Classification of Sleep Disorders, 1st & Revised
eds. (ICSD), 1990, 1997: Non-24-Hour Sleep—Wake Syndrome (or Non-24-Hour
Sleep—Wake Disorder); code 780.55-2w
· The International Classification of Sleep Disorders, 2nd ed.
(ICSD-2), 2005: Non-24Hour Sleep—Wake Syndrome (alternatively, Non-24-Hour
Sleep—Wake Disorder); code 780.55-2w
Since 2005, the disorder has been recognized by name in the U.S. National
Center for Health Statistics and the U.S. Centers for Medicare and Medicaid
Services in their adaptation and extension of the WHO's International
Statistical Classification of Diseases and Related Health Problems (ICD):
· ICD-9-CM: Circadian rhythm sleep disorder, free-running type;
code 327.34 became effective in October 2005. Prior to the introduction of
this code, the nonspecific code 307.45, Circadian rhythm sleep disorder of
nonorganic origin, was available, and as of 2014 remains the code
recommended by the DSM-5.
· ICD-10-CM: Circadian rhythm sleep disorder, free running type;
code G47.24 is due to take effect October 1, 2014.
Since 2013, the disorder has been recognized by the American Psychiatric
Association:
· DSM-5, 2013: Circadian rhythm sleep—wake disorders, Non-24-hour
sleep—wake type; ICD-9-CM code 307.45 is recommended (no acknowledgment of
327.34 is made), and ICD-10-CM code G47.24 is recommended when it goes into
effectPl
See also edit]
· Delayed sleep phase disorder
· Advanced sleep phase disorder
· Irregular sleep—wake rhythm
· Circadian rhythm sleep disorder
· Seasonal affective disorder (SAD)
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External links [edit]
· Circadian Sleep Disorders Organization
· An active mailing list for peer support and information
· DeRoshia, Charles W; Colletti, Laura C.; Mallis, Melissa M (2008).
"The Effects of the Mars Exploration Rovers (MER) Work Schedule Regime on
Locomotor Activity Circadian Rhythms, Sleep and Fatigue" (PDF 10.85MB). NASA
Ames Research Center. NASA/TM-2008-214560.
· "Improving Sleep in the Blind: It's Not Just Insomnia". Matilda
Ziegler Magazine for the Blind October 5, 2011.
· National Organization for Rare Disorders (NORD): Non-24-Hour
Sleep-wake Disorder
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