Chronobiology of fatigue disorders

1. Chronobiology of Fatigue
Disorder
Dr. Ghizal Fatima
Assistant Professor
Department of Biochemistry
Era’s Medical College and Hospital,
Lucknow, India

2. For everything there is a season and time for
every matter under heaven: a time to be born
and a time to die; a time to plant and a time
to pluck up what is planted. A time for sleep
and a time for wake up. God has made
everything beautiful in its time.
- Ecclesiastes

3. • Chronobiology is a field of biology that
examines periodic (cyclic) phenomena in living
organisms and their adaptation to solar-
and lunar-related rhythms.
• These cycles are known as biological rhythms.
Chronobiology comes from the ancient
Greek (chrónos, meaning "time"), and biology,
which pertains to the study, or science, of life.

5. • The variations of the timing
and duration of biological
activity in living organisms
occur for many essential
biological processes.
• These occur in animals, in
plants and in microbial
organisms such as fungi and
protozoa.
• They have even been found
in bacteria, especially
among the cyanobacteria.

7. • The most important rhythm in chronobiology
is the circadian rhythm, a roughly 24-hour
cycle shown by physiological processes in all
these organisms.
• The term circadian comes from
the Latin circa, meaning "around" and dies,
"day", meaning "approximately a day." It is
regulated by circadian clocks.

9. The light-entrainable oscillator (LEO) is located in the
suprachiasmatic nucleus (SCN) of the hypothalamus. The LEO is
directly entrained by light-dark cycles in the environment through
intrinsically photoreceptive retinal ganglion cells, and generates
circadian rest-activity rhythms as well as other rhythms that
entrain to the environmental light-dark cycles.

10. Fatigue is a lingering tiredness that is constant and
limiting.
Fatigue patients have unexplained, persistent, and
relapsing exhaustion.
It's similar to how you feel when you have the flu or have
missed a lot of sleep.

11. “Fatigue is here, in my body, in my
legs, in my eyes. Throughout the day
and night, that never goes even by
the name of God that I chant all the
while.
Margaret Atwood, The Handmaid’s
Tale.

12. Fatigue Disorders
• If you have chronic fatigue, or
systemic exertion intolerance
disease (SEID), you may wake in
the morning feeling as though
you've not slept.
• Or you may be unable to
function at work or be
productive at home.

13. • You may be too exhausted
even to manage your daily
affairs.
• In most cases, there's a
reason for the fatigue. It
might be allergic
rhinitis, anemia, depressio
n, FMS, or some other
health condition.

14. • There are multiple types of
Fatigue disorders, they are
debilitating chronic, multi-
systemic neuroimmune
condition, probably of
multifactorial etiology.
• There are no clinically
established diagnostic tests,
nor are any FDA-approved
drugs available for treatment.

15. • CFS or FMS is estimated affects approximately
17 million children/adolescents and adults
worldwide.
• It affects females more than males and causes
high levels of work disability in adults or poor
school performance in adolescents

16. • CFS or FMS is characterized by severe
disabling fatigue.
• lasting more than six months that does not
improve with rest, worsens with minimal
physical and mental exertion and cannot be
explained by any underlying medical
condition.

17. • During the course of the illness, CFS/FMS
patients also experience relapses and partial
remissions of the common features which
include pathological dysregulation of the
neuro-endocrine, immunological,
gastrointestinal, autonomic systems with
cellular energy metabolism/ion transport
impairments of varying onset, duration,
frequency and severity.

18. • Symptoms can persist for
years, and few patients
regain their premorbid
level of health or
functioning .
• The duration of CFS/FMS
and the potentially
debilitating consequences
of its symptoms
significantly increase the
economic burden and
establish the condition as
a top-level health
problem in today’s
society.

20. • The aetiology of fatigue disorders remains
unclear.
• Although muscle function is altered in this
condition there is now a growing body of
literature that associates autonomic
dysfunction with, hypothalamic-pituitary-
adrenal-axis impairment.

21. • Moreover, sleep disturbances and insomnia are
very common, with a pattern of restlessness and
difficulty in falling and remaining sleep.
• A high percentage of naps may also be observed,
related to strategies for mitigating pain or
compensating for the lack of sleep at night.

24. • Circadian rhythms are prominent in the
regulation of many physiological processes
that are crucial to health.
• Patients with CFS may show evidence of
circadian rhythm disturbances, but no clear
results about this subject have yet been
found.

26. • Circadian rhythm regulates the
amount of hormones and
neurotransmitters the body
produces, and by this it creates
circadian rhythm in balance.
• But in FMS/CFS there is
alteration in hormones and
neurotransmitters production.
• FMS/CFS patients have lower
melatonin secretion during
hours of darkness which may
contribute to disturbed sleep at
night, fatigue and
musculoskeletal pain during the
day. (Wikner et al.1998)

27. • Abnormal circadian rhythm of cortisol secretion in reported
in FMS/CFS. (Claw et al 2003)
• Sleep disorder causes a shift in circadian pattern of cytokines
level (IL-6,TNF-alpha) which is produced less at bed time
and more during the day (Salemi et al,2003)
• The study is conducted to study the relationship of
fibromyalgia syndrome and circadian pattern of release of
hormones and cytokines.

28. Our Conclusion
• Our results suggest that the disturbance in the circadian
pattern of cortisol is found in FMS patients.
• Interestingly, this increase in nocturnal serum cortisol in
patients group suggests deregulated circadian patterns which
may explain in part the patient complaint of unrefreshing
sleep.
• In sum, our results showing lower cortisol values in the
morning, support the hypothesis of a circadian dysfunction of
the cortisol among patients group.

29. • Further, our results suggest that there was a weak
circadian pattern of 5-HT in patients with FMS.
• And this decrease in 5-HT levels, might contribute to
the pathogenesis of the disease.
• Interestingly, the decrease in 5-HT in patients group
throughout the day is important because it may explain
in part the patients complaint of unrefreshing sleep.

30. • Low melatonin level during the hours of darkness may
cause disturbed sleep among patients group.
• Due to which patients may complain of increased
lethargy, emotional distress, and cognitive and
performance difficulties that accompany the diffuse
pain, fatigue and stiffness in the morning.
• Furthermore, our results suggest that there were no
perturbations in the circadian pattern of serum levels of
IL-6 and TNF-alpha in patients with FMS.

31. • The sleep disturbance in FMS patients and that
the pain is increased during night-time imply that
the ideal treatment at night hours may promote
restful sleep.
• For treatment to be effective, the
Chronobiological model implies that there must
be a reduction in the sleep -arousal disturbance.

32. • Moreover, the diurnal variation of symptoms
suggests that the optimal midday time for the
least pain and fatigue provides opportunities to
promote and to monitor the response to
treatment programmes.
• For example, excessive physical exertion or
energy-consuming tasks should be discouraged
in the early morning or evening.

33. • On the other hand, any interventional programme would be
more acceptable by the patient during the midday time.
• Therefore, timing may be crucial in treating FMS and this
has important implications for scheduling activities of daily
living and possibly for timing the administration of
medications in FMS patients, and, therefore, these findings
may lead to novel interventions in the treatment of
Fibromyalgia Syndrome.

34. Decreased
Melatonin Level
Maximum Stress
Elevated Cortisol Level
Impaired sleep
Maximum
Numbness
Worst Stiffness
Fatigue
Least stiffness,
Anxiety and
Pain
Worst
Fibromyalgia Syndrome : Circadian
Rhythm of Symptoms
Feel good time
Day time
Sleepiness
Immense Fatigue
minimally Alert
Difficulty in
Concentration.Dizziness
12
Mid night
12
Noon
6 PM
6 AM
Headache onset
Maximum Pain,
stiffness
and Anxiety
Low Cortisol
level, High
stress
12:Midnight
High alertness
12
Noon

36. Harmful Effects of Disrupted Circadian
Rhythms
• The importance of keeping the circadian
system synchronized is illustrated by the
harmful outcomes of disrupted rhythms.
• It is well reported that circadian dysfunction
can have dramatic effects on health in both
animal models and humans.

38. • Disturbances in the circadian system can have
negative effects on cognition, immune
functioning, metabolic processes, and the
cardiovascular system, resulting in fatigue,
disorientation, insomnia, altered hormone
profiles, higher morbidity, and higher
mortality in humans and animal models

39. • In humans, the experience of jet-lag or shift work
represents a state when the circadian system is
out of sync with the environment, and is
associated with damaging effects on health.
• Shift-workers are at a higher risk of harmful
conditions such as metabolic syndrome, obesity,
Fatigue related disorders, which may partly result
from the disrupted rhythmicity of sleep.

40. Driven by the pineal gland and clock genes, cortisol
production is at its peak in the early hours of the morning
and then gradually declines over the course of the day.
During night, cortisol production climbs again to its early
morning diurnal zenith.

41. The circadian rhythmicity of cortisol secretion is important
for our health. Certain processes are linked to this circadian
flow, which is supported by the HPA axis, including
processes such as cell repair, immune restoration, and
repletion of cellular redox potential are linked to the
Circadian rhythm maintained by the HPA axis.