16
free-running rhythm in sighted people
By Regina Patrick, RST, RPSGT
A
free-running rhythm – also called non-24-hour sleepwake syndrome or hypernychthemeral syndrome – is
a circadian rhythm sleep disorder in which the onset of a
person’s biological sleep phase occurs about an hour later each
day. This results in the person’s sleep phase slowly drifting
around the clock over a period of several days. A person
with a free-running rhythm has no difficulty in initiating
sleep or maintaining wakefulness when following his or her
biological rhythm. However, when attempting to adhere to
a 24-hour schedule, the person with a free-running rhythm
will experience alternating periods of insomnia (i.e., difficulty
initiating and maintaining sleep) and excessive daytime
sleepiness. This alternation occurs because sleep phase delays
during the solar night result in the person having difficulty
initiating sleep at a desired time, and sleep phase delays during
the solar day result in the person having difficulty awakening
and remaining awake at a desired time. A person with a freerunning rhythm typically has a circadian period that is greater
than 24 hours.
A free-running rhythm affects a greater number of males
than females, and approximately 25 percent of sighted people
with a free-running rhythm have a coexisting psychiatric disorder such as depression.1 Approximately 50 percent of blind
people have a free-running rhythm,2 but it is rare in sighted
people. As a result, a sighted person with symptoms of a freerunning rhythm may be misdiagnosed as having a psychiatric
disorder or some other disorder.
In 1971, Ann Elliott and colleagues were the first scientists
to describe a free-running rhythm in a patient, who was a
sighted male.3 He had difficulty trying to function socially on
a 24-hour schedule. Elliott measured the rhythmicity of his
sleep/wake cycles and the rise and fall of his body temperature
while he was in an environment free of time cues. The results
of these measurements revealed that the patient had a circadian
period that was about 26 hours long. After the Elliott study,
other researchers also noted a prolonged circadian period in
people with a free-running rhythm, and by 1978 the term “hypernychthemeral syndrome” had been introduced to describe
the phenomenon.4 (Hypernychthemeral is from three Greek
words: “hyper” meaning “above”; “nyx” meaning “night”; and
“hemera” meaning “day.”)
Regina Patrick, RST, RPSGT
Regina Patrick, RST, RPSGT, has been in
sleep field for more than 20 years and
works as a sleep technologist at the
Wolverine Sleep Disorders Center in
Tecumseh, Mich.
The first attempt to treat a free-running rhythm in a patient was reported by Behrooz Kamgar-Parsi and colleagues
in 1983.5 In their case report, the patient (a sighted male)
developed sleep problems after undergoing several stressful
life events. In an effort to improve his sleep, he began going
to bed in the late evening and awakening late in the morning.
With this regimen, he had hoped to increase his drowsiness
to fall asleep more easily at night and to awaken more refreshed. However, the regimen resulted in delayed sleep phase
syndrome (DSPS, a circadian rhythm sleep disorder in which
the biological onset of a person’s sleep and wake cycles are
delayed). His sleep quality continued to deteriorate, and after
several years he developed a free-running rhythm. He also had
borderline hypothyroidism. (Hypothyroidism can cause vitamin B-12 deficiency6; some studies indicate that a low vitamin
B-12 level may alter the circadian rhythm.6,7) The researchers prescribed the thyroid hormone thyroxine to improve his
thyroid function. This was followed by treatment with flurazepam (to treat insomnia) and vitamin B-12 (to advance his
circadian phases). After vitamin B-12 treatment, the patient’s
sleep period advanced to a more desirable time. The patient was
subsequently able to maintain a normal 24-hour sleep-wake
cycle.
An undiagnosed free-running rhythm may be mistaken for
an endocrine disorder since it alters the rhythmicity of biological processes such as the production of endocrine hormones.
For example, Dan Oren and colleagues noted multiple endocrine abnormalities in a patient whom they later diagnosed as
having a free-running rhythm.8 The patient was a 37-year-old
sighted man. Since his early teens, he had experienced difficulty going to sleep until late into the night. By the time he
was in college, he had developed DSPS. At 28 years old, he
initiated chronotherapy on his own in an effort to shift his
sleep/wake cycles to a more desired time. For chronotherapy, a
person progressively delays the bedtime later each day to shift
the sleep phase to a more “normal” time; once the sleep phase
is at the desired time, the person stops shifting the bedtime. In
this case, however, once the patient’s sleep phase was at the desired time, he found that strictly adhering to the new schedule
resulted in his struggling with daytime sleepiness – indicating
that his sleep phase was continuing to delay progressively every
day.
Through various tests, Oren found that the patient had a
normal sensitivity to light and a normal vitamin B-12 level.
However, he was exposed throughout the day to a very low
level of light with an intensity of only 43 lux. (For comparison,
500 lux is the intensity of light on a bright sunny day.) He
also had a small calcified pineal gland and asymmetric optic
nerves. The extent to which the low level of light exposure and
the small pineal gland (which produces melatonin) may have
contributed to the patient’s impaired circadian rhythm was
unclear to Oren.
In two experimental conditions, Oren then measured the
levels of the endocrine hormones melatonin, prolactin, luteinizing hormone, cortisol, testosterone, and thyroid-stimulating
A2 Zzz 20.4 | December 2011
17
Behaviorally, he was able to maintain a consistent sleep/wake
schedule. However, alternating periods of severe insomnia
and excessive daytime sleepiness indicated that his sleep/wake
phases were not entrained (i.e., occurring in association with
external cues such as light and darkness) and that his symptoms were the consequence of a free-running rhythm.
How to best treat a free-running rhythm in a sighted person
has not been definitively determined since most reports in the
medical literature are case reports involving few people. For
example, the finding that vitamin B-12 improves entrainment
in some people with a free-running rhythm is based on two
case reports,6,7 and no research has focused on its efficacy in
entrainment.2
However, the results of various reports indicate that bright
light therapy and the administration of melatonin effectively
improve entrainment in some people with a free-running
rhythm. Mark Brown and colleagues prescribed melatonin
to advance the sleep phase in a 67-year-old sighted man who
had a free-running rhythm that was coexistent with severe
depression, anxiety, obsessive-compulsive disorder (OCD), and
agoraphobia.11 The patient described having had problems for
22 years with “sleep cycling,” by which he meant that his sleep
was progressively delayed by about one-half hour each day
(i.e., free-running rhythm). For treatment, Brown prescribed
melatonin (to advance the sleep phase), which the patient took
one hour before going to bed. Each week, he took melatonin
one-half hour earlier. Once the sleep phase was advanced to
the desired time, he continued to take the dose of melatonin
at the same time. He also underwent bright light therapy for
one hour just after awakening to advance his wake phase. By
maintaining this regimen, he was able to maintain a stable
sleep/wake schedule.
Angela McArthur and colleagues found that their patient
was less sensitive than normal to the melatonin-suppressant
effect of bright light.3 For example, at 2500 lux, his melatonin
production was only reduced by 78 percent after two hours;
in most people, melatonin production would be reduced by
this much in one hour. Rather than using bright light therapy
to shift the patient’s sleep/wake phases, McArthur prescribed
melatonin. The patient took the medication daily, and by four
weeks of treatment, his sleep/wake rhythms had stabilized.
A physician may not think to assess a patient presenting
with abnormal endocrine function or alternating periods of
insomnia and excessive sleepiness for a free-running rhythm
since it is rare in sighted people. The physician may instead
treat the patient for another disorder such as depression, which
may worsen the free-running rhythm. For example, certain
serotonin reuptake inhibitor drugs used to treat depression may
aggravate the free-running rhythm by decreasing a person’s
response to light cues.3 An untreated free-running rhythm can
be debilitating for a sufferer since alternating periods of insomnia and sleepiness hinder the person’s ability to effectively
function socially, at work, or at school. Therefore, recognizing
symptoms of a free-running rhythm in a sighted person may
prevent the person from being misdiagnosed and suffering the
consequences of improper treatment.
A2 Zzz 20.4 | December 2011
 Continued on Page 18
hormone (TSH). In the first condition, blood and urine
samples were obtained to measure the level of melatonin when
his biological “night” coincided with the solar night (i.e., when
the patient was “in phase”). In the second experimental condition, blood samples were drawn when his biological “night”
coincided with the solar day (i.e., when the patient was “out of
phase”); his melatonin, thyroid-stimulating hormone (TSH),
and testosterone levels were measured.
The results showed that the patient had no detectable serum
melatonin, although his urine had a lower-than-normal level of
melatonin. When he was in phase, he lacked the normal surge
of TSH production during sleep. When he was out of phase, he
had an exaggerated TSH surge during sleep. Other endocrine
hormones such as prolactin, luteinizing hormone (LH), and
testosterone were at lower-than-normal levels. These abnormal
findings indicated that the patient had an abnormal endocrine
function.
For treatment, the patient adhered to a strict sleep/wake
schedule while undergoing bright light therapy (at 2500 lux)
for two hours after awakening, and wearing dark goggles in
the evening to minimize light exposure. After eight weeks of
this regimen, the patient’s serum melatonin level returned to
normal. Based on these findings, Oren suggests that a circadian
rhythm sleep disorder such as a free-running rhythm should be
part of a physician’s differential diagnosis in a person presenting with abnormal levels of endocrine hormones.
In children, symptoms of a free-running rhythm may be
mistaken for a learning disorder (since excessive sleepiness may
cause problems with concentration) or mistaken for a psychological or psychiatric disorder (because of the alternating
periods of insomnia and excessive sleepiness). In 2001, Dagan
and Ayalon reported their experience with a 14-year-old male
who had been diagnosed as having depression, schizotypal
personality disorder, and learning disabilities.9 The researchers
assessed the patient’s sleep with an overnight polysomnographic study because the patient had excessive sleepiness. The
polysomnographic results were negative for any sleep disorders.
The patient’s circadian rhythm was assessed by wrist actigraphy,
which involves wearing a watch-like instrument that records
the frequency of a person’s movements during wake and sleep.
The results of wrist actigraphy showed he had a non-24-hour
circadian period. Measurements of melatonin showed that his
melatonin production was altered. They treated him with oral
melatonin, which restored a normal sleep-wake schedule. A
follow-up psychiatric evaluation found that he no longer suffered from any of his previous diagnoses.
Delayed sleep phase syndrome may be a prodromal (i.e.,
forerunning) symptom in people who have a free-running
rhythm since many people diagnosed with a free-running
rhythm have struggled with DSPS for years before being diagnosed. Several researchers suspect that treating delayed sleep
phase syndrome with chronotherapy later induces a free-running rhythm in some people. For example, it was after Oren’s
patient had treated himself with chronotherapy that he noted
that his sleep phase continued to delay about an hour later each
day.8 In another report, Oren and his colleague Thomas Wehr
described their experience with two patients who developed
a free-running rhythm after undergoing chronotherapy.10
Angela McArthur and colleagues described a patient who had
treated himself with chronotherapy for five years for DSPS.3
 Continued from Page 17
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REFERENCES
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2.
3.
4.
Sack RL, Auckley D, Auger RR, et al. Circadian rhythm
sleep disorders: part II, advanced sleep phase disorder,
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irregular sleep-wake rhythm. Sleep. 2007;30(11):14841501.
Morgenthaler TI, Lee-Chiong T, Alessi C, et al.
Practice parameters for the clinical evaluation and
treatment of circadian rhythm sleep disorders. Sleep.
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McArthur AJ, Lewy AJ, Sack RL. Non-24-hour sleepwake syndrome in a sighted man: circadian rhythm
studies and efficacy of melatonin treatment. Sleep. Sep
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Kokkoris CP, Weitzman ED, Pollak CP, et al. Long-term
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hypernychthemeral sleep--wake cycle disturbance. Sleep.
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Kamgar-Parsi B, Wehr TA, Gillin JC. Successful
treatment of human non-24-hour sleep-wake syndrome.
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Ohta T, Ando K, Iwata T, et al. Treatment of
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1991;14(5):414-418.
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Okawa M, Mishima K, Nanami T, et al. Vitamin B12
treatment for sleep-wake rhythm disorders. Sleep. 1990
Feb;13(1):15-23.
8.
Oren DA, Giesen HA, Wehr TA. Restoration
of detectable melatonin after entrainment to
a 24-hour schedule in a ‘free-running’ man.
Psychoneuroendocrinology. 1997 Jan;22(1):39-52.
9.
Dagan Y, Ayalon L. Case study: psychiatric misdiagnosis
of non-24-hours sleep-wake schedule disorder resolved
by melatonin. J Am Acad Child Adolesc Psychiatry. Dec
2005;44(12):1271-1275.
10. Oren DA, Wehr TA. Hypernyctohemeral syndrome after
chronotherapy for delayed sleep phase syndrome. N Engl
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11. Brown MA, Quan SF, Eichling PS. Circadian rhythm
sleep disorder, free-running type in a sighted male with
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Med Feb 15 2011;7(1):93-94. 
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