ABSTRACT
The purpose of the report is to outline the disturbances
of sleep by the circadian rhythm, the master clock of the body. The report is comprised of several articles
published by medical professionals in the field of sleep disorders. The time zones influence the interaction
between the sleep cycle and hormone production activity. Certain hormones peak
in the evening and reach a low level in the morning; others have the reverse
effect.
In view of the fact that I have had sleep apnea problems diagnosed twelve years ago, I decided to write and research the information about the sleep cycle to help others. I have been sleeping well with the bipap machine for eight years. The instrument ascertains that air pressure keeps the airways open preventing an oxygen interruption during the sleep cycle. This report is a collection of different articles found on the internet.
JET LAG:
Most people can feel when they are "not in synch" with their internal clock. Lots of different things can throw you off, like traveling across different time zones. Jet lag is a temporary condition characterized by fatigue and often disorientation which results from the lack of synchronization between the internal circadian rhythm and the external day/night cycle. This sort of mismatch between the body's internal clock and the external day/night cycle can be an outcome of modern, technological lifestyles
An altered sleep pattern manifested by a sleepy feeling
during the day and insomnia during the night is the most common characteristic
of jet lag, but it may also cause indigestion and an inability to
concentrate. Jet lag may last for 25 or
more hours until the circadian rhythm is stabilized.
HISTORICAL
BACKGROUND:
Daily rhythms in plants and animals have been noticed
since early times. As early as the
fourth century BC, Alexander the Great's scribe Androsthenes noted that the
leaves of certain trees opened during the day and closed at night.
In 1729, French astronomer Jean Jacques d'Ortous
deMairan conducted the first known experiment on biological rhythms. He noticed that his heliotrope plant's
leaves opened during the day and folded at night. When he put the plant in total darkness the rhythm continued; it
was not disrupted by the absence of daylight as an environmental cue. Although he was interested in this botanical
phenomenon, deMairan pursued astronomy instead.
Two centuries before modern gardeners noticed that their
day lilies closed at night, the famous taxonomist Carolus Linnaeus discovered
that the petals of many flower species opened and closed at regular times. He even created a garden with flowers which
opened at various times so that he could tell the time of day by looking in his
garden.
Nothing exciting happened for many years... until the
early 1900's, when Karl von Frisch observed that bees visited flowers only at
specific times. He and Ingeborg Beling
trained bees to visit a nectar feeding station between 4 and 6 pm. The bees did not visit at other times, and
they still visited even when the nectar was removed. When outside cues such as light were removed in laboratory
trials, the bees still fed at prescribed times. Although von Frisch did not know it, the bees were operating on
an internal clock.
It wasn't until the 1950's that Gustav Kramer and Klaus
Hoffmann proved the existence of a biological clock. With an ingenious apparatus, Kramer demonstrated that starlings
used the sun as a compass to migrate even though the sun itself moves
throughout the day. That is, the bird's
internal clock reorients it in the direction of the moving sun. Hoffmann showed
that the clock persisted in dim light and thus is endogenous to the
animal. He showed that the animal's
clock was synchronized to local time by the influence of the local environment.
In the 1950's, Colin Pittendrigh demonstrated that
circadian clocks are temperature compensated (have nearly the same period even
when the temperature changes). Most
metabolic activities increase when body temperature increases, but the period
of the biological clock does not.
Pittendrigh placed Drosophila pseudoobscura cultures at different
temperatures and recorded the time of eclosion. Even in constant darkness, the flies emerged on schedule
regardless of the temperature.
Temperature changes thus did not affect the period of the clock [1].
THE
HUMAN CLOCK:
Since the early experiments, chronobiology (the study of
biological rhythms) has become established as an interdisciplinary field within
biology. Most chronobiologists study
circadian rhythms, endogenous cycles of behavior or biological activity with a
period of about 24 hours. In the
example, the human sleep-wake cycle has a period of 1 day, or goes through 1
complete cycle in a day. Circadian
rhythms, like the sleep-wake cycles discussed later, are generated by an
internal clock that is synchronized to light-dark cycles in the environment and
other daily cues. Circadian rhythms are
frequently plotted on an actogram. An
entraining agent (for example, exposure to bright light) can cause a phase shift
(dotted line in the figure) whereby the activity is started earlier or later in
the day.
Like a watch, the circadian clock must be synchronized
to local time. For example, animals
kept in total darkness will show a free running rhythm that is independent of
the local time. A circadian clock is
most useful, however, when it is set to local time; the animal must be in sync
with its prey, pollinators, and other members of its social group in order to
survive. In mammals, the light-dark
cycle is a major synchronizer or entraining agent for circadian rhythms [2].
WHERE
IS THE CLOCK?
The clock in humans is located in the suprachiasmatic
nucleus (SCN); a distinct group of cells found within the hypothalamus. The SCN is only one part of the mechanism by
which the "time" is kept.
There are light receptors found in the retina which have a pathway,
called the retinohypothalamic tract, leading to the SCN. The pineal gland is a pea-like structure
found behind the hypothalamus in humans.
The pineal gland receives information indirectly from the SCN[3]. It appears that the SCN takes the
information on day length from the retina, interprets it, and passes it on to
the pineal gland, which secretes the hormone melatonin in response to this
message. Nighttime causes melatonin
secretion to rise, while daylight inhibits it[3]. Even when light cues are absent, melatonin is still released in a
cyclic manner; yet if the SCN is destroyed, circadian rhythms disappear
entirely[4].
The role of melatonin in humans is not clearly
understood and is currently being investigated, but it is thought to play a
role in photoperiodism in seasonally breeding mammals. The SCN is known to have hormone receptors
for melatonin, so there may be a loop from the pineal back to the SCN. Researchers now use melatonin levels as an
accurate marker of the circadian rhythm in humans.
INFLUENCE
ON BODY SYSTEMS:
The SCN also plays a role in the circadian system by
triggering a neuroendocrine response in the hypothalamus, which then acts on
the pituitary. This last pathway
profoundly influences other parts of the body, including the endocrine, immune,
cardiovascular, and urinary systems.
Rhythms in most of these systems have a simple waveform similar to that
of body temperature, which is highest in the early evening and lowest right
before waking in the morning. A plot of
urine volume, for example, shows a cyclic pattern very similar to that of the
body's temperature [4].
Some of the hormones thought to be influenced by the
circadian system are growth hormone, prolactin, thyrotropin, and
testosterone. One endocrine event
clearly under the influence of the clock is the release of the hormone
ACTH. The SCN triggers the
hypothalamus, which activates the anterior pituitary to release ACTH, causing
the adrenal glands to release cortisol and aldosterone. A plot of cortisol concentration in blood
plasma shows a characteristic peak in the very early morning (around 6 AM) with
a trough right before bedtime.
Similarly, the aldosterone level is constantly high throughout the night
and low throughout the day[4].
Activity of the immune system, as represented by the
number of lymphocytes, also seems to peak in the late evening and is lowest a
few hours after the cortisol peak in the morning[5].
The timing of the endocrine and immune systems are
clearly intermeshed. It is known that
aldosteone and cortisol suppress the immune system, while melatonin appears to
enhance it.
CIRCADIAN
RYTHMS:
As living species evolved, their activities aligned to
the day-night cycle caused by the Earth's rotation. Initially, humans also responded to daily light-dark transitions,
which served them well in hunter and agricultural societies.
Like other organisms, they developed real clocks to time
biological processes. These biological
clocks measure events that occur once per day in what are known as
"Circadian" rhythms (from 'circa'-about, 'dies'-a day).
Even in the absence of environmental time cues, such
rhythms maintain a period close to 24 hours.
The circadian clock appears to regulate various aspects of metabolism,
physiology and behavior, in humans as well as in other organisms.
By studying circadian rhythm anomalies in genetically
mutated flies and other organisms, the mechanism has been identified to some
extent.
Molecular and genetic studies indicate that a negative
feedback loop is in order for the group to survive. In mammantrols the transcription is the 24-hour clock genes. While circadian rhythms appear to be similar
in all species, it is unclear if this reflects a common mechanism passed along
from a common evolutionary ancestor, or whether an outwardly similar process
has arisen multiple times in evolution due to the stimulus of nature.
Evidence of circadian rhythms surrounds us. In plants, the daily opening and closing of
petals as well as leaf movements are the most visible, but circadian rhythms
also control the discharge of floral fragrances and other metabolic activities
associated with photosynthesis.
The circadian clock also influences seasonal cycles that
depend on day-length, such as the regulation of flowering. This photoperiodic system is quite likely
dependent on the circadian clock's measurement of the duration of the day or
night, thus monitoring the length and passage of seasons.
YOU'VE
GOT RHYTHM:
A decade ago, the University of Florida Health and Human
Performance newsletter printed a letter in which someone asked if jogging in
the morning was risky because there is more of a chance of dying from a heart
attack at that time of day. The answer
indicated that there was evidence that heart attacks are more likely to happen
in the morning than at other times of day because of our circadian rhythms, our
internal "body clock."
The origins of your body clock in all likelihood date
back to the first living organisms. As
each species evolved, it developed a circadian rhythm that helped it survive
within a specific environment. For some
this meant flying south in the winter.
For others hibernating.
For humans, it meant waking at dawn, hunting, working,
eating, then retiring at dusk. Our
endocrine systems developed to release hormonal secretions that would help us
obtain maximum results under those circumstances. But, my how things have changed. Today some people go to work at
midnight and sleep during the day.
Others awake at dawn and work well beyond dark.
As a society, we are ignoring the survival mechanism of
our body, our own biological rhythms which regulate heart rate, oxygen
consumption, cardio-pulmonary function, and hormone secretions.
Changes in the blood levels of the so-called circadian
hormones (melatonin, cortisol and thyrotropin) as well as levels of growth
hormone and glucose is used to measure our biological rhythms and how various
activities affect these levels. The
release of melatonin is considered a key marker in an individual's body clock. You might think of it as the starting point
of the day, a moment after midnight, but the actual time it occurs in an
individual varies.
The
rhythms in a person's life are:
Ultradian Rhythms - These are shorter cycles,
approximately 90 minutes in length.
Circadian Rhythms - Comprised of about 16 ultradian
rhythms, the circadian rhythm regulates the sleep and awake cycles.
Circaseptan Rhythms – Seven-day cycles that appear to
have been observed as far back in time as the origins of God creating the
world…"on the seventh day he rested."
Infradian (Lunar) Rhythms - Most evident in a woman's
menstrual cycle, this nearly month-long cycle has also been associated with the
cycle of the moon.
Circannual Rhythms - Summer, fall, winter, spring
demonstrate this cycle externally and it may explain why bears hibernate, birds
migrate and some humans suffer seasonal mood changes.
Seven-year Rhythms - When one looks at childhood,
puberty, adulthood, middle age and retirement, they are close to multiples of 7
years (7, 14, 21, 42, January).
Among the latest findings regarding this various rhythms
are evidence that the body processes medicine better during certain periods of
the day. Pulse rate and blood pressure
vary throughout the day. Exercise is
more beneficial during certain hours.
What you eat may be metabolized quickly at one time of day, but not
another. When you are dieting you
should be more aware of your body clock.
Hormone levels vary throughout the day and month and years affecting
sexuality. Jet lag is caused by a
disruption of our body clock.
Heart attacks and ischemic strokes caused by reduced
blood flow to the brain have also been linked to circadian rhythms with morning
the highest risk time and circannual peaks in March and September.
Ilaria Casetta, MD, from the University of Ferrara,
Ferrara, Italy, and colleagues studied 1656 patients who were hospitalized with
ischemic stroke, found that the strokes were more frequent during the first 2
hours after waking than at other times during the day. This confirmed earlier
research findings that the peak onset of stroke symptoms occurred in the
morning, with a second peak in the evening.
The morning increase is most likely in people 45 to 85.
The phenomenon may be associated with the body clock's
morning rise in blood pressure and increase in the blood's clotting ability,
according to the article Patient Demographic and Clinical Features and
Circadian Variation in Onset of Ischemic Stroke in the January issue of the
Archives of Neurology (2002;59:48-53).
The authors note that this circadian pattern is similar to that of a
heart attack, sudden cardiac death, and other vascular events. They speculate
that an underlying pathophysiological mechanism may be common. This study was supported by a grant from the
Italian Ministry of the University and Scientific and Technological Research,
Rome.
Another pioneering study of a family of people who awake
up to 3 ˝ hours before they want to, suggests that there is a gene that
controls circadian rhythms and the regulation of sleep. This gene may vary in families and thus each
body clock is inherited from our parents.
The study, which was reported in the Archives of Neurology
(2001;58:1089-1094) was conducted by The Departments of Neurobiology and Physiology,
and Molecular Pharmacology and Biological Chemistry, the Transportation Center,
the Center for Circadian Biology and Medicine, and the Howard Hughes Medical
Institute, Northwestern University; and the Department of Neurology,
Northwestern University Medical School, Chicago, Ill.
BIOLOGIC
RHYTHM DISRUPTION:
Ultradian
Rhythms and Insomnia:
Embedded within the daily circadian rhythm are
approximately sixteen 90-minute Ultradian rhythms. Often these go unnoticed due to the pace and schedules in our lives.
One measure of these activities is the Rapid Eye Movements (REM) and Non-REM
periods of sleep. When these get
disrupted people experience insomnia and the resulting fatigue.
Circadian
Rhythms, Metabolism and Eating Disorders:
Circadian rhythms are evident everywhere in nature. In plants, petals open and close as the sun
rises and sets and metabolic activities associated with photosynthesis control
the discharge of floral fragrances and other plant activities. Animals in the wild follow a daily cycle of
awakening, hunting, eating and resting.
Humans on the other hand, tend to ignore their circadian rhythms, which
control all hormonal activity and metabolism.
As a result they feel sluggish when they should be awake and awake when
they should be sleeping. And their
eating habits have made the society as a whole overweight. They feast on a diet of junk food, diet
pills, antidepressants and painkillers to get through the day.
SOLUTIONS
TO BIOLOGIC DISRUPTION:
1. Light therapy
may also be helpful in resetting a person's body clock when sleep cycles have
been disrupted by too much work, partying or jet lag.
2. Some
researchers believe that a combination of light therapy, sauna therapy,
meditation and exercise with restorative recovery are essential for resetting
the body clock.
3. Sauna
Therapy: Some also substitute Sauna
Therapy for a cardiovascular workout since it can burn calories without
muscular and joint stress. In mamleans
clogged pores help to relieve acne, eczema, psoriasis and burns.
4. A cycle of
sauna activity can help mimic the temperature cycles that are part of the
body's natural rhythms. Typically the
highest temperature in the human body occurs around 4 p.m. and the lowest at 4
a.m.
5.
Meditation: One approach to
restoring circadian rhythms is to use the process of meditation to help
eliminate the stress that has disrupted the body clock. Many ancient civilizations have long
recognized that meditation is as effective in restoring energy as a nap can be.
6. When animals
are observed in the wild they tend to exercise in short bursts of activity
followed by a recovery cycle. This is
similar to the wave of activity seen in heart waves and may be the most natural
approach to exercise that maximizes the benefits of innate circadian rhythms.
CIRCADIAN
RYTHM AND INTERACTION WITH JET LAG OR TIME ZONES:
Circaseptan Rhythms, Medical Implications and Sexual
Dysfunction:
The ebb and flow of countless hormones that control
life's processes are intertwined with human biological rhythms. While these secretions occur within
ultradian and circadian time frames, they also appear to fall within a
circaseptan rhythm (the seven-day cycle).
Many physicians believe that transplant patients tend to
have more rejection episodes seven, fourteen, and twenty-one days after
surgery. In western civilizations and
urbanized cultures, heart attacks are most frequent on Monday mornings,
possibly associated with the shift from leisure to work.
Today's hectic pace also takes its toll on sexual activity. While some studies indicate that the typical
married couple is intimate 2-3 times a week and usually on Tuesday nights,
others studies report a rising number of couples that report no contact for
weeks on end. It may be that their biological rhythms are so out of sync that
"the chemistry" between them has disappeared.
Infradian
(Lunar) Rhythms and Hormones:
The 28-30 day Infradian rhythm has long been recognized
as a phenomenon that not only affects tides, but also hormones. The most obvious is the menstrual cycle in
women with fluctuating levels of estrogen and progesterone. There are some studies that suggest that the
timing of breast cancer surgery within the hormonal cycle of pre-menopausal
women can have a significant impact on the course of the disease.
Circannual
Rhythms and Mood Disorders:
Seasons are part of the circannual rhythm seen in the
blooming of flowers in the spring, the changing of leaves in the fall, the rise
of temperatures in the summer and the winter's cold and snow. These seasonal cycles depend on day-length,
and the shortened days seem to have an effect on people who suffer from a mood
disorder known as Seasonal Affective Disorder (SAD).
It is believed that deep within the brain, two clusters
of cells get information from photoreceptors in the retina, which transmit
signals about light and dark through the optic nerves to the hypothalamus. In response, the pineal gland regulates the
secretion of melatonin, which may result in the production of serotonin. In mamlved, several central psychological
processes occur including pain perception, temperature and blood-pressure
regulation, and several neuropsychological functions such as appetite, memory
and mood. The photoreceptors in some
people require more light to stimulate the hypothalamus than others, without
which they will suffer SAD.
Out beyond the yearly circannual biological rhythm there
appears to be seven-year cycles that have been noted by the seven-year itch in
marriage, but interestingly the typical homeowner also holds onto their first
house for approximately the same period of time. The itch may have less to do
with lust than with a biological rhythm related to wanderlust.
In animals, the circadian clock controls all hormonal
activity-which means that if your circadian clock is off you will feel the
effects in your metabolism, sexual appetite, sleep patterns and tolerance to
stress. Problems with your circadian
clock can cause symptoms in the following systems of your body:
THE
CLOCK IN OTHER ORGANISMS:
Non
Human Animals:
Research in the area of biological clocks did not begin
with humans. Early research was done on
a variety of animals including rats, hamsters, sparrows, lizards, marine
snails, and fruit flies. The choice of
an animal depended on many considerations--size, rate of reproduction, expense
to maintain, and availability--as well as behavioral issues, such as whether it
entrained easily and what environmental factors seemed to affect its behavior.
House sparrows were one of the first animals in which
the biological clock was anatomically localized [23]. The sparrow's clock is believed to consist of the suprachiasmatic
nucleus (SCN), as in humans, and the pineal gland. In this circadian system, photoreceptors are found in the retina
as well as in the pineal gland and in the deep brain. Investigators are clarifying the relationship between the
sparrow's two clocks and its photoreceptors [24].
Although sparrows are similar to humans, how do they
compare with other vertebrates such as reptiles? Reptiles also have photoreceptors in the eye, the pineal and in
the deep brain. Most reptiles and some
amphibians, however, also have photorecptors in the parietal eye, an unseeing
third eye located on the top of the skull with a well-defined retina, lens, and
cornea that is known to play a role in thermoregulation and photoperiodism in
some species [25]. In reptiles and
other lower vertebrates, the pineal gland synthesizes information from the
photoreceptors and in turn secretes melatonin in a rhythm which synchronizes
other parts of the clock system. The
role of the SCN in lower vertebrates is unclear, but it is thought to contain
another part of the clock.
One of the most intensively studied invertebrates is
Drosophila, the familiar fruit fly. This
insect reproduces quickly, is economical to raise, requires very little space,
and has an extensively mapped genome.
Locomotor activity is difficult to observe in individual flies, but the
eclosion rhythm, which is under clock control, can be observed in large numbers
of flies [23]. Mutant strains of flies
are presently being used to discover more about the molecular basis of the
clock.
The biological clock has been found in the optic lobe in
other invertebrates, such as cockroaches, crickets and silkmoths [23]. Mollusks seem to have a clock only in the
eyes. Two types of mollusks, a marine
snail (Bulla gouldiana), pen and ink of
Bulla by Donna Bennet,and the sea hare (Aplysia californica), have large
neurons that can be individually studied [see review by 23]. Furthermore, isolated retinal neurons can
even be placed in vitro, and still exhibit circadian rhythms in their
electrical behavior.
The most widely studied mammals are rats, mice, and
hamsters. All of these rodents have clearly defined circadian rhythms measured
as the onset of their daily locomotor activity. Hamsters, for example, are
nocturnal and will become active at as a group in order to survive. In mamcertain time every night, this rhythm
can be quantified by recording their activity on a running wheel which is
connected to a computer that converts the raw data into an actogram.
The SCN was first identified as a circadian clock in
rats. When Richter lesioned the rat
SCN, the animals' locomotor activity became arrhythmic. This experiment was soon followed by a
series of investigations in other rodents and mammals on how SCN lesions can
affect circadian rhythms [23].
Late in the 1980's a spontaneous mutation, later named
the tau mutant, was discovered in a colony of golden hamsters. The period of the mutant's rhythm was
noticeably shorter than the 24-hour norm: heterozygous tau mutants had
approximately 22-hour periods, and homozygous ones had a 20-hour cycle. When normal hamsters who had been made
arrhythmic by a SCN lesion were given a transplanted tau SCN, they resumed a
circadian rhythmicity that matched that of the donor. This experiment was also repeated in reverse, with the tau
hamster showing a normal hamster's 24-hour rhythm after receiving a normal
hamster's SCN. These experiments
provided the final proof that the SCN is the site of a clock in mammals [26].
July
26, 2002:
Center researcher Mike Menaker observes the behavior of
a tau mutant. A similar mutant gene
(clock) that causes a longer than normal period of running wheel behavior was
recently found in mice. This discovery
is exciting because mice have a well-mapped genome. Investigators hope to use hamster and mouse mutants to identify the
clock's internal mechanisms and determine at the genetic level what makes it "tick."
PLANTS:
Charles Darwin is probably most famous for his ideas on
evolution through natural selection. In
his later years, he became fascinated with plant movements while trying to find
an evolutionary relationship among them.
He did hundreds of experiments to keep track of the movements of the
different varieties of plant leaves.
After experimenting, Darwin concluded that the plants were moving their
leaves so as to expose the smallest possible leaf surface to the night
temperatures. His book, The Power of
Movements in Plants,details the years of work.
In the years following, scientists would debate whether the rhythm arose
from forces external to the plant or was endogenous.
In 1920, a landmark paper was written by W.W. Garner and
H.A. Allard in which they showed that tobacco plants would flower only if
exposed to a certain number of hours of light.
The term "photoperiodism" was used to designate the response
of the organisms to relative length of day and night. Garner and Allard showed that plants could tell time! The ability
to sense day length is an important ability for plants so that they grow,
reproduce and develop during favorable time of the year. The changing times of dawn and dusk contain
seasonal information as well as time of day information so that the organisms
have, in effect, an internal clock and calendar[23].
In plants, a photoperiodic clock not only controls
flowering, but also induction and termination of dormancy in buds and bulbs,
seed germination, and daily rhythms such as leaf movements, petal movements,
and nectar secretion.
In more recent experiments with plants, Steve Kay et al
has developed an interesting technique to measure rhythms in Arabodopsis
thaliana. The researchers chose this
plant for many reasons including its small size, short life cycle, and number
of chromosomes (n=5). As a way to
measure rhythmic gene expression in vivo in these plants, they transplanted
firefly luciferase gene (which is responsible for the insect's glow) into the
plants. The plants exhibited rhythms in
bioluminescense when their CAB genes (CAB is a light harvesting protein) were
being "turned on" rhythmically. In other words, the luciferase gene
was used as an intra-cellular marker to detect the plants' own gene activity rhythms[27]. In other experiments, they isolated and cloned a photoreceptor
gene from rice. Multiple copies of this
ps group are needed in order to survive.
In mamhytochrome, genes were transplanted to tobacco
with the result that the tobacco plants became hypersensitive to light because
of the higher than normal number of photoreceptors[28]. Scientists are attempting to do a similar
experiment with rice in the hope that they will be able to grow rice under
low-light conditions and produce more crops per year.
The
Restless Legs Syndrome:
By: Richard P. Allen, Ph.D.
Outline
General Description
Daily Cycle of Symptoms and the Relation to Sleep
Symptoms in Relation to Activity
Diagnosis
Medical Conditions Associated with RLS
Treatment Approaches
Support Group and the RLS Foundation
Recommended Articles in Medical Journals
General Description
The Restless Legs Syndrome (RLS) is a fairly common
sleep-related neurological disorder affecting, in some form, about five percent
of the adult population. It is one of
the older recognized sleep disturbances, first described over 300 years ago.
Frequently seen with greater frequency in particular families, it is often
reported to be a genetic disorder, although this has yet to be confirmed. RLS
causes disturbing sensations and it leads to a need for excessive amounts of
movement. When the strange sensations,
or sensory symptoms, are clearly present, the diagnosis is fairly easy. The RLS
patients describe peculiar, very disturbing sensations localized in the limbs,
usually the legs.
The abnormal sensations are often hard for patients to
describe since they have no reference in normal life experience. They are commonly described as: "Pepsi
in the veins," "worms under the skin," "crawly feelings in
the legs," "electricity running through the legs," etc. The sensations are painful for about 30% of
the RLS patients, but they are almost always compelling.
There is a wide variation in severity. Some patients experience the sensations only
occasionally at night, while others have intense feelings every day leaving
them almost frantic to find relief even when they are not associated with
pain. It is the compulsion to remove
the feelings that leads to excessive movements, since the best form of relief
is walking or any large body movement.
Sometimes the compulsion to remove the sensation becomes
the dominant feeling, and the patient reports primarily this irresistible urge
to move the legs. The feelings generally wax and wane occurring about once
every 5 to 20 seconds. When the patient
gets up and walks around, these feelings generally go away, but they quickly
return when the patient stops walking.
Fortunately some reasonable treatments are now available for RLS.
Daily
Cycle of Symptoms and the Relation to Sleep:
The symptoms have a marked circadian (daily) pattern
becoming much worse in the evening to early morning and often completely
abating in the later morning. When
severe, the symptoms will start in the afternoon or even shortly before
noon. In some very extreme cases the
symptoms occur 24 hours a day, but even then are generally less severe in the
morning. In almost all cases, however,
there is a relative sparing of the early morning hours from about 7-10 AM, when
there are virtually no symptoms. Patients nonetheless live in dread of the next
bedtime when they will again be struggling with these feelings. Nighttime brings not rest but suffering.
This daily cycle expresses itself in the nature of the
sleep disturbances with RLS. The
symptoms make it very hard to fall asleep.
To make matters worse, once asleep, repeated periodic leg movements
usually occur throughout the first several hours of sleep. Even in sleep, the legs cannot be still.
These movements occur about once ever 5-to-40 seconds. Many movements cause
brief arousal, disrupting sleep without awakening the patient. Some actually
cause awakening, with return of the wake-time urge to get up and walk. The
sleep itself is of poor quality that does not fully restore alertness for the
next day. When mild, RLS disturbs mainly sleep onset and the first hour or two
of sleep, with better, even normal, sleep occurring later in the morning. When severe, RLS disturbs sleep most of the
night with only some partial relief in the very last part of the morning.
The more severe RLS patient may be getting no more than
4 hours of sleep a night. The rest of
the night the patient is up wandering around with intermittent and only
partially effective attempts to sleep.
The symptoms sometimes appear to come on in bouts with temporary relief
after some walking around. The patient
can then get some restless sleep before the next bout of the distressing
sensations. The bouts finally may abate
two to four hours before the time to wake up.
This profound sleep deprivation increases sleepiness the next afternoon
and evening and appears to make the disturbing sensations worse.
Symptoms
in Relation to Activity:
Another of the peculiar diagnostic features of this
disorder is the onset during rest. Symptoms start when the patient has been
sitting or reclining for a while. Symptoms are also exacerbated by any
sedentary or resting activity. The most
common activities reported to bring out symptoms include: sitting in a movie or
lecture; riding in a plane or car; and, of course, lying down to rest or
sleep. The longer the period of
inactivity the more pronounced the symptoms may become.
Conversely, motor activity, particularly walking,
provides almost immediate relief of symptoms that lasts as long as the walking
continues. It is probably not the
movement itself that produces the relief but rather the alerting effects of the
movement. Other activities reported to
produce relief are those that produce profound alertness such as: inflicting
mild discomfort by hard rubbing or very hot baths, engaging in active social
interaction such as in an emotional argument and becoming totally engrossed in
needle arts or a computer game. It is
interesting that standing still does not produce much relief, but standing on
one leg is generally as effective as walking.
Standing on one leg requires alert focused attention.
The overall picture is of a disorder gated by time of
day but triggered by activities that lead to sleepiness and relieved by doing
something to become fully awake.
Patients tend to develop an RLS life style characterized by lots of
motor activity and little 'down time' particularly after noontime.
Diagnosis:
A recently formed International Restless Legs Study
group developed the currently accepted diagnostic criteria for RLS. ALL of the following four criteria are
necessary and sufficient for the diagnosis:
1. Urges to move the legs usually associated with
abnormal sensations (paresthesias).
2. Motor restlessness, including one or both of two
types: a) voluntary movements to reduce symptoms, and b) smooth, short (0.5-10
second) bursts of involuntary, usually periodic, limb movements occurring
mostly when the patient is reclining.
3. Onset or exacerbation of symptoms by rest and marked
relief by activity, particularly walking.
4. A pronounced circadian (daily) pattern with symptoms
significantly greater in the evening during the sleep time (maximal between 10
PM and 2 AM) and much less later in the morning.
Medical
Conditions Associated with RLS:
RLS appears to occur secondary to the development of four other recognized medical conditions: iron deficiency, later stage kidney disease, pregnancy and peripheral neuropathy (abnormal sensations in the hands or feet) and radiculopathy (pain which occurs over the distribution of spinal nerves). Cases where RLS occurs after the development of one of these conditions are usually considered to be "secondary RLS," but it should be noted that not all patients with these conditions develop RLS. In other words, RLS occurs for a large number of patients after one of these conditions develops, but the conditions themselves do not suffice to produce RLS. Moreover, these conditions also exacerbate the severity of RLS for patients who have RLS before developing the condition.
Treatment
Approaches:
Evaluation of medication treatment for RLS is
complicated by the marked daily variation observed in the severity of these
symptoms and the different way each person experiences the symptoms. In general, treatments must be tailored to
the severity of the disorder. The
following approaches should be considered.
Iron
Treatment:
Our work at Johns Hopkins has clearly identified a
problem with low iron levels for RLS patients.
The iron measurement that we are most interested in is called ferritin. The level of ferritin in the blood is
critical in RLS and as a conservative rule should be kept above 50 mcg/l. When ferritin is low an iron supplement
should be given. Tablets of 325 mg of
iron sulfate can be obtained from the pharmacist. The dose should be adjusted in consultation with a doctor. Commonly, one iron tablet is taken 3 times a
day with a 500 mg tab of vitamin C to help the body absorb the iron. Iron has the usual side effect of
constipation that should be conservatively managed.
Behavioral
Management:
RLS symptoms can be reduced somewhat by the behavioral
techniques described above: walking, hard rubbing of the legs, very hot baths,
arguments, and engrossing needle work or video games. Patients commonly report that if they become active when they
first feel the onset of the symptoms, they can prevent the development of the
symptoms and later return to being inactive.
If, however, they attempt to delay activity as long as possible, the
symptoms become more pronounced and then reoccur whenever they return to
inactivity.
RLS patients also often develop very poor sleeping
habits. As a result of many nights with
very disturbed sleep onset, some patients develop a physiologic insomnia
complicating their RLS problems. Then,
when the leg movements are reasonably well managed with medications, they will
have a persisting physiologic insomnia that may require behavioral treatment.
Please see our article, "Insomnia," for a full
discussion of the treatment of physiologic insomnia.
Medications
to Avoid:
Before starting medications to treat RLS, it is often
useful to ensure that the patient is not taking any medication that exacerbates
RLS. Patients generally report that all
of the drugs in the "dopamine antagonist" family (drugs which decrease
the effect of the chemical, dopamine, in the brain) exacerbate their RLS. Thus, certain antipsychotic drugs and drugs
for nausea should generally be avoided or used only in lower doses.
Most anti-depressants exacerbate RLS. The one exception
is buproprion (Wellbutrin) which as a dopamine agonist (a drug which increases
the effect of dopamine in the brain) could possible have some mild benefit for
RLS. Some patients also report that the
sleep benefit of trazadone (Desyrel) outweighs its exacerbation of RLS.
Medications:
For very mild RLS, one option is to use a hypnotic agent
(sleeping pill) to promote sleep. The hypnotics that have been shown to work
include Klonopin (clonazepam), Restoril (temazepam), and Halcion
(triazolam). Ambien (zolpidem) is likely
to work, but has not been adequately studied.
Klonopin is the most studied of these medications, but it also is very
long acting and likely to produce daytime sedation and should therefore be used
with caution.
The most effective drugs for RLS are the drugs that
affect the "dopaminergic" nervous system by increasing the amount or
effect of the chemical dopamine in the brain.
One of these drugs, a combination of levodopa with carbidopa called
Sinemet, remains the most effective drug for immediate relief of symptoms. A very low dose (1/2 to 1 tab of Sinemet
25/100) can provide virtually complete relief from symptoms. This medication is usually effective within
30 minutes and lasts about 3 hours. It
can be used during the day when RLS symptoms occur during sedentary activities
and is particularly helpful for long plane rides or car trips. For those patients who don't experience
symptoms every night, it can be used on an "as needed" basis, on
nights when a patient is experiencing symptoms.
Unfortunately the medication does not last long enough
to give relief for the full sleep period and is rarely adequate to manage any
other then mild RLS symptoms. The major
problem with treating RLS with Sinemet is that, over time, the symptoms of RLS
become more severe. This is referred to
as "augmentation." Therefore,
what was once a mild-to-moderate case now gradually becomes a severe case. symptoms that were once limited to the
evening start occurring during the afternoon and even the morning. To avoid this problem, it has been
recommended that the use of this medication be limited to no more than 2 tabs
of Sinemet 25/100 a day.
A number of other drugs which mimic the action of
dopamine in the brain (dopamine agonists) are also considered excellent medications
for treatment of all but the most mild RLS.
Pergolide (Permax) is well studied and commonly used in divided doses in
the evening, starting at a very low dose (1/2 tab 0.05 mg at each dose time)
with very gradual dose increases until symptoms are relieved or significant
adverse effects occur. Augmentation occurs for about 15% of the treated
patients, but is usually mild. It may
again be dose related, so total daily doses above 0.75 mg should be used with
caution. Two newer dopamine agonists, Mirapex and Requip, seem likely to work
with RLS, but at this time they have not been as well evaluated as
pergolide. The major side effects of
this type of medications are nausea, vomiting, stuffy nose and dizziness on standing.
The second line of medications that help RLS include
drugs that are used to treat pain, known as the opiates. Oxazepam has been found effective in
clinical studies, but it is likely that all of the drugs in the opiate family
will have some benefit. They are often
used in combination with dopamine agonists.
They are also used in cases where dopamine agonists fail, either because
of adverse effects or augmentation.
For special cases, particularly those involving RLS
symptoms that are reported to be painful, the use of the anticonvulsant
Neurontin (gabapentin) has also been used successfully.
There are a number of other medications that have been
used with mixed success, but none have the demonstrated effectiveness of those
mentioned above.
Given the wide range of medication alternatives, it is
recommended that if a patient does not experience improvement with one of the
standard single drug therapies (with either a hypnotic or a dopaminergic
medication), consultation be obtained from an expert in RLS. Accredited sleep
disorder centers are required to have expertise in treatment of this disorder
and are likely to be the one good source of quality care for this condition.
Support
Groups and the Restless Legs Syndrome Foundation:
The patients with RLS have formed the RLS foundation, which
is very active in providing education about RLS and supportive services for
patients. They publish a newsletter
called Nightwalkers, available by subscription. The RLS Foundation can be contacted at 4410 19th St. NW,
Rochester, MN 55901-6624.
Light
Therapy:
For people with Seasonal Affective Disorders (SAD) many people are experimenting with Light Therapy. This approach helps stimulate the brain's photoreceptors, which for some people, seem to crave the light stimulation that is at its maximum in the summer. Light therapy may also be helpful in resetting a person's body clock when sleep cycles have been disrupted by too much work, partying or jet lag. Some researchers believe that a combination of light therapy, sauna therapy, meditation and exercise with restorative recovery are essential for resetting the body clock.
Aging alters sleep and hormone levels sooner than
expected.
Contact: John
Easton , 773-702-6241
Embargoed Until:
3 p.m. CT, Tuesday, August 15, 2000
Researchers from the University of Chicago report in the
August 16 issue of JAMA that age-related deterioration of sleep quality occurs
in at least two stages, and that, for men, the first stage occurs sooner than
expected -- between the ages of 25 and 45.
They also found that changes in sleep were mirrored by changes in
hormone secretion.
This was the first study to examine sleep quality and
hormones influenced by sleep throughout adulthood, rather than comparing the
sleep patterns and hormones of young versus old. The researchers collected data from sleep studies conducted
between 1985 and 1999 on 149 healthy men aged 16 to 83.
"Our study maps out the chronology of age-related changes in sleep duration and quality and suggests that altered levels of certain hormones may be a consequence of sleep decay," said Eve Van Cauter, Ph.D., professor of medicine at the University of Chicago and director of the study. "These changes in sleep quality provide an early biological marker of aging in men."
The first stage of deterioration of sleep due to aging
occurs between young adulthood (ages 16 to 25) and mid-life (35-50). Although total sleep remained constant as
young adults moved into mid-life, the proportion of slow wave or deep sleep
decreased from nearly 20 percent of a normal night's sleep for those under 25
to less than five percent for those over 35.
Growth hormone secretion, which occurs primarily during deep sleep, also
declined by about 75 percent.
By the age of 45, note the authors, most men have almost
entirely lost the ability to generate significant amounts of deep sleep. This study suggests that, as a consequence,
most middle-aged men have very low levels of growth hormone.
Growth hormone deficiency has been studied extensively
in the elderly, where it is associated with increased obesity, loss of muscle
mass and reduced exercise capacity.
This study suggests that clinical trials of growth-hormone replacement therapy, which have previously been conducted in older men and women, might better target individuals in early mid-life. People over 65, who have already lived without the hormone for decades, may be less likely to respond and more likely to suffer adverse side effects.
"We begin estrogen replacement as soon as women
enter menopause, not 20 years later," said Van Cauter. "If men go through 'somatopause' -- a
loss of growth hormone -- between 25 and 45, why should we wait another 20
years to initiate treatment?
Another option is an indirect form of hormonal therapy, supported by recent studies in the Van Cauter lab and elsewhere, that involves using investigational drugs to stimulate increases in deep sleep. Increasing deep sleep triggers a proportional increase in growth hormone secretion.
The second stage of deterioration of sleep due to aging
occurs after age 50, during the transition from mid-life to late life. It includes decreased total sleep -- which
declines by about 27 minutes per decade – more frequent and longer night-time
awakenings, and a significant reduction in REM or dream sleep, to about 50 percent
of young-adult levels. The loss of REM sleep appears to be associated with
elevated evening levels of the stress-related hormone cortisol.
Cortisol is a 'fight or flight' hormone that heightens
attention and alertness. Levels
normally peak in the morning and decline during the day to very low levels in
the evening, giving the system time to recover. Subjects with decreased REM sleep, however, had "an impaired
ability to achieve evening quiescence," note the authors.
This lack of hormonal "down time," a recovery period for the stress-response system, has been linked to memory deficits and insulin resistance, a risk factor for diabetes. Elevated evening cortisol levels could also cause additional sleep loss. "Our data support the concept that decreased sleep quality contributes to the wear and tear resulting from overactivity of the stress-responsive systems," said Van Cauter.
By mapping out the effects of aging on sleep quality and
hormone production, this study suggests new ways to intervene in the aging
process.
"It is a tantalizing concept," said Van
Cauter. "We are developing medications that can, in part, restore the
capacity for deep sleep. If we could slow down the age-related changes in sleep
quality, would that delay some of the many hormonal consequences of growing
older?"
Additional authors of the paper were Rachel Leproult,
M.S., and Laurence Plat, M.D., both from the Van Cauter laboratory. The data were collected from a series of
sleep studies; 109 subjects were studied at the University of Chicago and 40
were studied at the University of Pittsburgh, UCLA, or Pennsylvania State.
This
research was supported by grants from the National Institute on Aging, the
National Institute of Diabetes and Digestive and Kidney Diseases, and by the
Mind-Body Network of the MacArthur Foundation.
Summary: University of Chicago researchers report that age-related deterioration of sleep quality occurs in at least two stages. For men, the first stage occurs between the ages of 25 and 45. Changes in sleep are mirrored by changes in hormone secretion. This finding suggests new approaches to hormone replacement for men.
Recommended
Articles in Medical Journals:
Allen, RP, Earley, CJ (1996a). Augmentation of the
Restless Legs Syndrome with Carbidopa/Levodopa. Sleep, 19: 205-213.
Kaplan, P., Allen, R., Buchholz, D., & Walters, J.
(1993). A double-blind, placebo-controlled study of the treatment of periodic
limb movements in sleep using Carbidopa/Levodopa and Propoxyphene. Sleep, 16:
717-723.
Earley, C., Yaffee, J., & Allen, R. (1999).
Double-blind, placebo-controlled assessment of Pergolide treatment of the
restless legs syndrome. Neurology.
Sun, E., Chen, C., Ho, G., Earley, C., & Allen, R.
(1998). Iron and the Restless Legs Syndrome. Sleep 21:381-387.
Walters, A., Aldrich, M., Allen, R., Ancoli-Israel, S.,
& al., e. (1995). Towards a Better Definition of the Restless Legs
Syndrome. Movement Disorders, 10: 634-642.
Several publications from the Sleep Apnea Association
(APA) on Sleep Apnea and Sleep Disorders.