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Transcript
CHRONIC FATIGUE SYNDROME
– How to use TCM for accurate diagnosis and effective treatment in your clinic.
Introduction
Chronic fatigue syndrome (CFS) is a relatively common illness, with severely disabling
symptoms. Thus, CFS places a substantial burden on patients, their families and carers,
and hence on society. Estimates of the combined direct costs (for diagnosis and
management) and indirect costs (from lost productivity) to the Australian community are
over $525 million annually. (Loblay et al., 2002) In the absence of effective Western
medical treatments, as well as identifiable causative factors, this paper discusses the
application of specific theories and treatment approaches of traditional Chinese
medicine to this disorder.
CFS IN WESTERN MEDICINE
Definition
‘Fatigue’ is defined as a pervasive sense of tiredness or lack of energy that is not related
exclusively to exertion. It is accompanied by feelings of muscle weakness, slowed
movements and slowed central nervous system reactions. Physical fatigue can also
lead to a sense of mental exhaustion, with reduced cognitive functions (such as memory
and attention). It is a common and usually transitory symptom. (Loblay et al., 2002)
CFS, on the other hand, is defined as unexplained severe chronic or relapsing fatigue
that has persisted for longer than 6 months; it causes impaired overall physical and
mental functioning and is accompanied with other specific mental and physical
symptoms. The accompanying symptoms must either persist or recur during the course
of the illness and do not predate the fatigue. The diagnosis of CFS requires the
presence of four or more of the following symptoms in addition to fatigue:
• Impaired short term memory or concentration
• Sore throat
• Tender cervical or axillary lymph nodes
• Muscle pain
• Multi-joint pain without arthritis
• Headaches of a new type, pattern, or severity
• Unrefreshing sleep
• Post-exertional malaise lasting more than 24 hours
(Fukuda, et al., 1994)
The main differential diagnoses are: neuromuscular disease, cardiac or respiratory
disease, primary sleep disorders, and major depression. Other less common causes of
severe fatigue must also be excluded, e.g. infection, malignancy, thyrotoxicosis, Crohn's
disease, hypothyroidism, sleep apnoea; connective tissue disease, and drug misuse
(prescribed or illicit). (Loblay et al., 2002; Cunha, 2010; Tolan & Stewart, 2011)
Epidemiology
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While prolonged fatigue is a common presentation with a prevalence around 20%
(Loblay et al., 2002), the prevalence of CFS in the community is around 0.2 – 0.4%.
(NICE Guideline Development Group, 2007). CFS predominantly affects young adults
(25 – 45 years), most commonly in females. It occurs in individuals from all
socioeconomic groups. (Straus, 2007)
Clinical Features of CFS
CFS generally arises suddenly in a previously active individual. It begins with a ‘flu-like
illness, or an acute stress which is subsequently followed by a state of unbearable
exhaustion, accompanied by other symptoms, including headache, sore throat, tender
lymph nodes, muscle and joint aches and feverishness. These symptoms are generally
interpreted by the patient as evidence of a persisting infection and medical help is
sought. However, the medical practitioner is unable to find any source of the symptoms
and assures the patient that there is no serious disease present. The symptoms persist
and other features of the syndrome start to manifest, e.g. disturbed sleep, difficulty in
concentration, depressed mood. After 6 months CFS is diagnosed.
Most patients are able to continue their usual family, work and social commitments,
albeit at a substantially reduced level, while substituting increased rest for their normal
leisure and recreational activities. Some will become unable to continue working and a
minority will require assistance with the activities of daily living. A prolonged course of
illness may leave the patient in a state of ‘isolation, frustration, and pathetic resignation’.
(Straus, 2007)
Symptomatology
The major symptom of CFS has the following specific features:
• Lasts longer than six months
• May be either persistent or relapsing.
• Is disabling, leading to a substantial reduction in previous levels of occupational,
educational, social or personal activities.
• Is unexplained (i.e. not due to a medical or psychiatric condition or over-exertion)
• Is not much relieved by resting and is seriously worsened by physical or mental
exertion
(Fukuda, et al., 1994)
A study of patients diagnosed with CFS gives the approximate frequency of the
following accompanying symptoms:
•
•
•
•
•
•
•
•
•
Difficulty concentrating
Headache
Sore throat
Tender lymph nodes
Muscle aches
Joint aches
Feverishness
Difficulty sleeping
Psychiatric problems
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90%
90%
85%
80%
80%
75%
75%
70%
65%
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• Allergies
• Abdominal cramps
• Weight loss
• Rash
• Rapid pulse
• Weight gain
• Chest pain
• Night sweats
(Straus, 1988)
55%
40%
20%
10%
10%
5%
5%
5%
Theories of causes
While several possible causes for CFS have been proposed, none have been shown to
have a definitive causal relationship to the condition. These include infection due to viral
agents such as EBV, HHV-6, coxsackievirus B, spumaviruses, and human T-cell
leukemia virus strains; or bacteria such as Chlamydia pneumonia. (Cunha, 2010)
Treatments
As there are no effective drugs for the treatment of fatigue, medications are directed at
the management of symptoms (e.g. headache, muscular pain, depression). Drugs such
as analgesics, non-steroidal anti-inflammatory drugs (NSAID’s) and antidepressants are
generally given on a trial basis in order to determine whether the benefits outweigh the
adverse effects. At the time of writing there is no clear evidence to support the
generalized use of antidepressants or corticosteroids. (Reid et al., 2008)
There is evidence that graded exercise therapy and cognitive behavioral therapy are
effective in patients with CSF. (Reid et al., 2008) Patients are advised to continue with
low level activity and to avoid becoming inactive.
Restoration of a normal sleep cycle is an important part of patient management,
although there is no direct evidence of benefit to CSF patients. (Loblay et al., 2002)
As with other chronic and debilitating illnesses, psychological and social support is
required in order to assist the patient in adjusting to the impact of the condition on
physical, mental, financial and social well-being.
Prognosis
In children and adolescents, the vast majority will recover or improve, with a disease
duration of 2-4 years. (Loblay et al., 2002; Tolan & Stewart, 2011) In adults only 20 – 50%
showed improvement in the medium term (12 – 39 months) and only 6% recovered.
(Reid et al., 2008) Adults who have had CFS for more than five years tend to remain
symptomatic. People with CFS are at increased risk of psychological disorders such as
depression and anxiety. Concurrent psychological disorder, somatic symptoms, high
levels of fatigue and a low sense of control over symptoms are associated with poorer
outcomes. (Loblay et al., 2002)
CFS IN TRADITIONAL CHINESE MEDICINE
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As the major symptom is severe and debilitating fatigue, some authors and researchers
focus almost exclusively on deficiency syndromes in CFS. (Flaws & Sionneau, 2001, pp.
141-5; Flaws, 2002; Chen et al., 2010) However, when consideration is given to the
overall symptom picture, together with antecedent history (in most cases) of an acute
infection, it becomes apparent that retained pathogens (e.g. Heat and/or Damp) play a
major role in the pathogenesis of this disorder. Indeed, a careful analysis of the
presenting symptoms, as discussed above, leads to the conclusion that both deficiency,
as well as excess of pathogenic factors underlies most presentations of CFS. (Maciocia,
1991; Maciocia, 2010) Moreover, the mixed results of clinical studies that focus
exclusively on deficiency syndrome-patterns in CSF, with treatments based solely on
tonifying herbs, (Chen et al., 2010) speak against an overly simplistic interpretation of
CSF symptomatology.
Pathogenesis of CSF
Invasion of exogenous pathogens in a patient with some form of deficiency is the
fundamental etiology in this condition. The pathogens may be relatively mild or strong
and they may lodge at various levels in the body. The pre-existing deficiency may take
different forms and it is universally exacerbated by the disease process, beginning with
the pathogenic invasion and continuing with the resultant disruption to normal organ
functions and the generation of internal pathogens (such as Damp, Phlegm and Heat).
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KEY TCM CONCEPTS
Deficiency – Excess
Deficiency refers to an insufficient quantity of something that should normally be present in the
body, or a decline in functional activity. A deficiency condition is one in which the body's vitality
is insufficient to sustain normal functioning and to resist pathogens. ISuch conditions may be
due to lifestyle factors or may arise during or after a systemic illness. Deficiency is generally
described in relation to the Qi, Blood, Body Fluids, the Yin, the Yang or the Zang-fu organs.
The concept of Excess has two aspects:
a) The presence of too much of something that is normally present in the body (both in
terms of substance as well as functional activity)
b) The presence of something that should not be present at all.
All retained pathogens are regarded as a form of excess.
An excess condition is one in which either: an exogenous pathogen invades the body; there is
over-activity of a body function or an organ system; there is an accumulation of one or more
endogenous pathogens.
Interior – Exterior
This describes the location of the disease process. The Exterior of the body comprises the skin,
subcutaneous tissues, skeletal muscles and the upper respiratory tract. The Interior of the body
comprises the internal organs systems. Exterior diseases are caused primarily by exogenous
pathogens, such as Wind, Cold, Heat or Damp. Interior diseases may be due to emotional
imbalance, lifestyle factors, internally generated pathogens, or pathogens that have come from
the Exterior and moved internally. The clinical features vary greatly depending on which internal
organ system is affected.
Invasion by exogenous pathogens
There are six exogenous pathogens: Wind, Cold, Heat, Damp, Dryness and Fire. They are said
to originate as a result of extreme or untimely climactic conditions, which penetrate the body’s
defenses to lodge in the Exterior of the body. When present in the body they cause Excess type
diseases. The disease process is initially located in the Exterior of the body and is referred to as
an Exterior type of disease. If not properly treated (e.g. with antibiotics) they may penetrate the
Interior of the body and cause an Interior disease.
Developm ent of endogenous pathogens
The endogenous pathogens include Wind, Cold, Heat and Fire, Damp and Dryness, which affect
the Interior of the body. Endogenous pathogens may arise due to the penetration by an
exogenous pathogen into the Interior of the body. They may also arise due to dysfunction of the
internal organs, which leads to disruption to the normal functions of the Qi, Blood or body Fluids.
The clinical manifestations of each of the endogenous pathogens are similar to those of its
exogenous counterpart. In addition, Phlegm, stagnant Qi and stagnant Blood may be generated
internally through impaired function of organs or vital substances (i.e. the Qi, Blood and body
Fluids).
Fever (fa re)
In TCM ‘fever’ refers to subjective sensations of heat that may or may not be accompanied by a
measurable rise in core body temperature.
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Thus, the underlying causes of CSF are twofold, involving retained pathogens on the
one hand, and severe deficiency on the other. The retained pathogens (i.e. pathogenic
factors that the body is unable to expel) originate from outside the body (‘exogenous’
pathogens) in the form of an infection or ‘invasion’ through the body’s defenses by one
or more of Cold, Heat or Damp.
Under normal circumstances the invading pathogens are restricted to the Exterior and
do not affect the internal organs, located on the Interior. However, in patients with preexisting deficiency syndromes, (especially if the Kidney is deficient), the invading
pathogen may penetrate directly to the Interior or ‘get stuck’ midway between the
Exterior and the Interior, giving rise to a specific set of signs and symptoms.
A third possible scenario would be when, during the course of an acute pathogenic
invasion (generally described as a viral infection in Western medicine), the pathogen
has not been completely cleared and works its way into the Interior. Patients with a preexisting deficiency or those who do not take sufficient rest and/or receive inappropriate
care during the acute stage are vulnerable to this process, which eventually leads to
disruption of internal organ function and the subsequent development of endogenous
pathogens (such as Damp, Heat and Phlegm). Moreover, such patients become more
susceptible to further episodes of invasion by exogenous pathogens. Thus a twofold
vicious cycle is generated with repeated low grade infections together with internal
organ disruption by pathogens.
Maciocia describes three main pathogenetic pathways in CSF: Residual Pathogenic
Factor, Latent Heat and Lesser Yang Pattern (Maciocia, 1991; Maciocia, 2010) As an
understanding of each of these pathological processes is necessary for accurate
diagnosis, a brief description follows.
Residual Pathogens
As described above, in some patients who experience an invasion by exogenous
pathogens (such as Wind, Cold, Heat or Damp), the pathogen manifests symptoms of
an Exterior disorder (e.g. acute upper respiratory infection), but is not expelled due to
inappropriate treatment, lack of rest and care, and possibly also a pre-existing
deficiency. Subsequently the pathogen penetrates to the Interior and disrupts normal
organ functioning, generating Damp and possibly also Heat which continue to disrupt
organ function – exacerbating both the deficiency condition as well as the endogenous
pathogens. Additionally, as the Exterior has become weakened in this process, there is
increased susceptibility to further pathogenic invasions. Pathogenic Damp often ‘seeps’
into the muscles, causing the characteristic muscle aches and pains that are
experienced by most CSF patients.
Hence the traditional mandate to rest (and avoid over-exertion), consume a light, easily
digestible diet and refrain from sexual activity during and immediately subsequent to an
acute pathogenic attack. With these simple steps, together with timely treatment, we can
assist our patients to avoid the above scenario.
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It should be noted that a common cause of residual pathogens is the routine use of
antibiotics by general practitioners in the ‘treatment’ of acute viral infections.
Latent Heat
In some patients, specifically those with a deep level deficiency, such as Kidney
deficiency, the pathogen is able to penetrate directly to the Interior, without resistance
and without any manifest symptoms. Here it incubates, transforming into Heat and
appearing several months later when, due to some sort of stress on the body (such as
overwork, lack of sleep, emotional strain, or a subsequent invasion by exogenous
pathogens) it becomes active both in the Exterior as well as the Interior. These patients
have the characteristic signs of feverishness and irritability.
Lesser Yang (shao yang) Stage Disorder
In this scenario the pathogen lodges in the body at a level that is midway between
Exterior and Interior. As in the Latent Heat pattern, the underlying cause is deficiency,
which compromises the body’s ability to resist and expel pathogens. The characteristic
symptom is alternating sensations of heat and cold. When the pathogen moves towards
the Exterior the patient feels cold and when it moves towards the Interior the patient
feels hot. Other typical clinical signs are the enlarged lymph nodes and a wiry pulse.
Deficiency Syndrome-Patterns
In CSF the following deficiency syndrome-patterns are commonly seen:
• Qi deficiency
• Blood deficiency
• Yin deficiency
• Yang deficiency
Deficiency patterns generally occur in combinations and often present with empty Heat
signs, that is to say signs that are suggestive of the presence of a Heat pathogen, but
which are solely due to deficiency. Such signs include fever, dry mouth and throat and a
red tongue. It is important to distinguish this type of Heat presentation from that due to
the presence of pathogenic Heat, which is a type of excess (as opposed to deficiency).
The key distinguishing features of deficiency Heat are:
• The presence of clear signs of deficiency
• Relatively mild signs of Heat
• Absence of a pathological tongue coat (i.e. it is not thick or greasy)
• Pulse is very thin and/or weak
The Treatment Plan
During the course of treatment, after the pathogens have been cleared, the patient will
manifest signs of deficiency. At this time it is important to commence more intensive
treatment with tonifying herbal medicines. One major clinical difficulty that is frequently
encountered is to know when this point has been reached. Because symptoms are often
vague and intermittent, and because the desire for relief from fatigue is universally
expressed by patients, many of whom have heard stories of ‘miraculous’ Chinese tonic
herbs (such as Ginseng, Astragalus and He Shou Wu), it is very tempting to give strong
tonics too early.
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The nature of the pathogen is generally latent, hidden or moving between body levels.
This is why patients may appear to be deceptively better, while still harboring
pathogenic factors. Therefore it is best to continue giving treatment aimed
predominantly at clearing the pathogens for 10 to 20 days after the excess pathogenic
factors appear to have been completely resolved. If any signs indicatinmg the presence
of pathogens return during treatment with tonifying medicines, they should be
discontinued and replaced with the appropriate clearing herbal formulas.
To summarize the important points relevant to planning treatment:
• Every case is characterized by both a deficiency (of Qi, Yang, or Yin) and an excess
(usually Damp or Damp-Heat).
• The deficiency and the excess are never equal, one always predominates.
• If deficiency predominates, treat with tonification
• If excess predominates, treat by expelling Damp or Damp-Heat.
• Key symptoms of excess pathogenic factors are muscle aches, swollen lymph
glands, a thick tongue coating and a full and/or slippery pulse.
• Key symptoms of deficiency are a weak or fine pulse and the tongue with a thin or
absent coating (i.e. without a thick coating).
TREATMENT PROTOCOLS
Damp (or Damp-Heat) in the Muscles
Key clinical features: Muscle aches and heaviness, nausea, bloating, vaginal discharge,
loose stools, thick tongue coat.
Herbal treatments:
a) With Heat (dry or normal stools, yellow tongue coat):
Classic formulas: Lian Po Yin (Coptis and Magnolia Decoction); Zhi Shi Dao Zhi
Wan (Citrus Pill to Eliminate Stagnation)
Prepared formulas: Bowel Detox Formula + Ping Wei San (Magnolia & Ginger
Combination)
b) No Heat, preponderance of Damp (loose stool, white or cream colored tongue
coat):
Classic formulas: Huo Po Xia Ling Tang (Agastache, Magnolia, Pinellia & Poria
Decoction)
Prepared formulas: Gastro-Aid Formula + Wu Ling San (Hoelen Five Formula)
c) Predominance of GIT symptoms (bloating, belching, nausea):
Combine one of the above protocols with:
Prepared formulas: Xiang Sha Yang Wei Wan (Cyperus & Cardamon Formula)
d) With pronounced deficiency (emaciation, weak and thin pulse):
Combine one of the above protocols with:
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Prepared formulas: Yu Ping Feng San (Jade Screen Formula)
e) Follow up (select one of the following tonifying formulas, also see below):
Prepared formulas: Energy Tonic Formula; Qi & Blood Tonic Formula
Acupuncture: SP-9; SP-6; BL-22; REN-12; REN-9; LI-11 (Damp-Heat); SP-3; ST-8.
(Even or reducing method)
Lesser Yang Stage Disorder
Key clinical features: Alternating fever and chills (sometimes feeling hot and sometimes
feeling cold), enlarged lymph nodes, redness on the tongue, wiry pulse.
Herbal treatments:
a) Initial treatment – until there are no signs of Lesser Yang stage disorder present:
Classic formulas: Xiao Chai Hu Tang (Minor Bupleurum Decocotion) + Bu Zhong
Yi Qi Tang (Tonify the Middle Qi Decocotion)
Prepared formulas: Resistance 2 Formula + Energy Tonic Formula
b) Follow up (prepared formulas):
Energy Tonic Formula (general use)
or
Resistance Formula (frequent infections)
or
Hair Growth Formula (with signs of premature ageing)
Acupuncture: TB-5; DU-14 (even method); ST-12; TB-13 (reducing method)
Deficiency of the Qi with ‘empty’ Heat
Key clinical features: Subjective feelings of heat or low-grade fever; pale tongue with a
thin white coat, weak pulse (not rapid). Relatively short history of CFS.
Herbal treatments:
a) General use:
Classic formulas: Xiao Chai Hu Tang (Minor Bupleurum Decocotion) + Bu Zhong
Yi Qi Tang (Tonify the Middle Qi Decocotion)
Prepared formulas: Resistance 2 Formula + Energy Tonic Formula
b) Combinations:
With frequent infections (add one of the following to the above protocol):
Classic formulas: Yu Ping Feng San (Jade Wind Screen Powder)
Prepared formulas: Yu Ping Feng San (Jade Screen Formula) OR Resistance 1
Formula
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Acupuncture: ST-36; LI-10; SP-6; BL-20; BL-21; REN-6; LU-9; DU-12; BL-13; DU-20;
HE-5. (reinforcing method); PC-5; DU-14 (for empty Heat; use even or reducing
method)
Deficiency of the Qi and the Blood
Key clinical features: Fatigue, poor memory and concentration, poor appetite and
digestion, palpitations, poor sleep, mild anxiety, dull headaches that are worse when
tired, pale tongue, weak and thin pulse. No history of viral infection, no signs of Heat.
Relatively short history of CFS.
Herbal treatments:
a) Younger patient:
Classic formulas: Ren Shen Yang Rong Tang (Ginseng Formula to Nourish the Qi &
Blood)
Prepared formulas: Qi & Blood Tonic 1 Formula
b) Middle aged to elderly patient
Classic formulas: Qi Bao Mei Ran Dan (Seven Treasures Elixir for Beautiful
Whiskers) + Si Jun Zi Tang (Four Gentleman Decoction)
Prepared formulas: Hair Growth Formula + Si Jun Zi Tang (Four Major Herbs
Combination)
Acupuncture: ST-36; LI-10; SP-6; BL-20; BL-21; BL-15; BL-18; REN-6; DU-20; HE-7;
REN-4; KI-3 (reinforcing method).
Deficiency of the Qi and the Yin
Key clinical features: Feelings of heat in the afternoon or early evening, night sweats,
hot sensations in palms, soles and centre of the chest, red tongue that may have cracks,
little or no tongue coat.
Herbal treatments:
a) General use:
Classic formulas: Liu Wei Di Huang Wan (Rehmannia Six Ingredients Pill) + Bu
Zhong Yi Qi Tang (Tonify the Middle Qi Decocotion)
Prepared formulas: Yin Tonic Formula + Energy Tonic Formula
Combinations
i)
With Dryness (dry mouth, eyes, skin, throat, nose, etc.)
Prepared formulas: + Zhi Yin Gan Lu Yin (Rehmannia & Asparagus Formula)
ii)
With pronounced or stubborn Heat signs
Prepared formulas: Use Empty Heat Formula instead of Yin Tonic Formula
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Acupuncture: LU-9; Ren-17; BL-43; BL-13; Du-12; REN-12; ST-36; SP-6; KI-3; KI-6;
LU-7; REN-4; BL-23; BL-52 (reinforcing method).
Deficiency of the Yang
Key clinical features: Feelings of cold, increased sensitivity to the cold, low back pain,
polyuria, nocturia, pale and swollen tongue with an overly wet appearance. Long history
of CFS.
Herbal treatments:
a) General use:
Classic formulas: Fu Gui Ba Wei Wan (Aconite, Cinnamon and Rehmannia Pill) +
+ Bu Zhong Yi Qi Tang (Tonify the Middle Qi Decocotion)
Prepared formulas: Rehmannia Eight Vitality Formula + Energy Tonic Formula
b) With slow metabolism and/or pronounced edema
Prepared formulas: Thyrotone Formula + Rehmannia Eight Vitality Formula
c) Follow up:
Classic formulas: You Gui Wan (Right Restoring Pill) + Yu Ping Feng San (Jade
Wind-Screen Powder)
Prepared formulas: Yu Ping Feng San (Jade Screen Formula) + Zhuang Yang Yi
Jing Wan (Epimedium & Ginseng Formula)
Acupuncture: Du-4; REN-4; ST-36; BL-23; BL-52; LI-3; KI-7 (reinforcing method with
moxa).
CONCLUSION
A recent systematic review concluded that there is no evidence supporting the use of
Chinese herbal medicines in the treatment of CSF. (Adams et al., 2009) This was based
on the fact that none of the studies published up until 2008 met the inclusion criteria,
due to the presence of ‘serious flaws in the conduct and reporting of clinical studies
conducted in China …. both for conventional medicine and TCM’. This situation is slowly
being rectified, and two newly published Chinese studies provide some evidence that
various combinations of Chinese herbal medicines may indeed be effective in the
treatment of CFS. (Zhang et al., 2009; Cho et al., 2009) However, much of the research
fails to clearly address the issues discussed above, in that treatments need to be
specifically staged and also tailored to the individual patient, both in terms of the initial
condition as well as response to treatment. It is difficult to imagine how such a study
could be designed so as to satisfy the stringent and restricting criteria of evidence based
(Western) medicine. Thus, we need to rely on the current best available evidence: the
opinions of experts based upon their clinical experience. In this article I have attempted
to bring together the works of eminent Western TCM authorities, together with the
clinical experience of my own colleagues and mentors.
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CLINICAL COMMENTARY
In assessing patients with CFS it is most important to recognize that, although the main
symptom is severe fatigue, this does not always mean that the main problem is one of
deficiency, to be treated with tonic herbal formulations.
In most cases there is the presence of one or more pathogenic factors, that must be
cleared before intensive treatment with tonics can be successfully given. The key
diagnostic features, which should alert the practitioner to the presence of pathogens are:
muscle aches, swollen lymph nodes, a thick coating on the tongue, full and/or slippery
pulse. In addition, if the symptoms immediately worsen when tonifying medicines are
given, it is safe to assume that pathogens are still present, and treatment should be
directed at resolving them.
Patients who are impatient and want quick relief from the fatigue should be encouraged
to ‘stick with the program’ and wait until it is appropriate for them to take tonifying herbal
medicines. Obviously there is no ‘quick fix’ for CFS, and Chinese herbal treatments
together with acupuncture are time tested therapies that offer a good chance for
improvement or recovery in the long term.
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Cho, J., Cho, C., Shin, J., Son, J., Kang, W., Son, C. (2009). Myelophil, an extract mix of
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