Chronic fatigue syndrome

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Chapter 35 Chronic fatigue syndrome

Gary Deed, MBBS (Hons I)

OVERVIEW

Chronic fatigue syndrome (CFS) is a complex yet defined spectrum disorder. It is characterised by expert consensus to include persistent disabling fatigue lasting more than 6 months with other symptoms as listed in the box below. This definition is based upon the USA’s Centers for Disease Control’s description of this illness.1 Importantly there are medical conditions by their nature that may mimic CFS and need to be excluded prior to making an accurate diagnosis. These include untreated thyroid disease, sleep disorders such as sleep apnoea, alcohol abuse, major depressive disorders and schizophrenia. The presence of past and treated malignancy or unresolved infectious hepatitis is also considered exclusive of CFS.1–4 However, the persistence of symptoms despite adequate treatment of the above conditions, including thyroid conditions or infections such as Lyme disease, fibromyalgia and anxiety disorders, may possibly co-exist with a diagnosis of CFS.2 CFS presents significant difficulties in diagnosis and assessment, as there is no single laboratory or clinically significant specific diagnostic test. Patients often appear

CDC CRITERIA FOR THE DIAGNOSIS OF CFS1,2,3,4

• Patients have severe chronic fatigue of 6 months or longer duration with other known medical conditions excluded by clinical diagnosis.
• Patients concurrently have four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern or severity; unrefreshing sleep; and postexertional malaise lasting more than 24 hours.
• The symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.
• The condition must also be defined by excluding other organic or psychiatric causes including that covered in Chapter 15 on adrenal exhaustion.

clinically well, though express profound deterioration of social and occupational functioning and have significant physical and psychological distress.

AETIOLOGY

Infectious agents

Clinically it is well known that many patients commence their illness after what appears to be an infectious episode. Certainly no single agent has been shown consistently to create all CFS cases; however, the CDC state ‘the possibility remains that CFS may have multiple causes leading to a common endpoint, in which case some viruses or other infectious agents might have a contributory role for a subset of CFS cases, and infection with Epstein-Barr virus, Ross River virus and Coxiella burnetti will lead to a postinfective condition that meets the criteria for CFS in approximately 12% of cases’.4

Further research pointing to an infectious origin include:

• enterovirus in muscle biopsies of 20.8% of CFS patients, but not controls5
• Mycoplasma spp. (52%), Chlamydia pneumoniae (7.5%) and HHV 6 (30.5%)6
• mycoplasma infection7
• multiple active viral infections—HHV6; HHV 7; parvovirus B 198
• tick-borne illnesses and borreliosis9
• gram-negative enterobacteria causing increased intestinal permeability.10

Immunologic abnormalities

CFS quite possibly may be the result of a complex interplay between an infectious insult and/or a disordered immune response in a susceptible individual. This complexity is revealed in research in the area of immunity and CFS; it clearly has not shown any one consistent abnormality (concerning interleukin abnormalities and altered cell-mediated immunity).11–13 Combined with the consistently observed possibility of multiple infectious aetiological agents and the possibility of persistent or relapsing infections, the resulting immunologic disorders such as elevated pro-inflammatory cytokines ‘may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity’.14

Neuroendocrine abnormalities

Hypoactivity of the hypothalamic–pituitary–adrenal (HPA) axis combined with hyperactivity of the serotonergic system has been postulated as a cause of CFS.15,16 Other research suggests that up-regulation of hypothalamic serotonergic receptors may be the cause some of the HPA disorders—distinctly different from depression17 and ‘adrenal exhaustion’. With respect to the HPA axis, lowered levels of dehydroepiandrosterone (DHEA, an adrenal steroidal hormone) have been assessed in CFS patients.18 The interplay of dysfunctional immunity, cytokine imbalances leading to subtle neurotransmitter changes is demonstrated in Figure 35.1. Importantly, as mentioned above, depression and its manifestations are distinctly different from CFS both in psychological distress and in physiological dysfunctioning (see Section 4 on the nervous system for treatment details).19

image

Figure 35.1 Cytokine-induced cell injury as the basis of CFS

Orthostatic intolerance

Patients with CFS have been shown to have abnormal autonomic responses to prolonged standing or even sitting for long periods.20 This ‘orthostatic intolerance’ manifests as fatigue plus elevated pulse rates, often associated with faintness when the above activities occur. The condition is diagnosable with a severe hypotensive response to ‘tilt table’ testing, where a patient is subjected to a head tilt when lying flat.21

Nutritional causes

As the diagnosis is defined by the absence of other medical conditions, the fatigue that arises from iron deficiency, vitamin B and B12 deficiency is necessarily excluded as a cause. However, lowered levels of essential fatty acids, L-carnitine and magnesium have been assessed in patients with CFS.17 Interestingly, these nutrients give direct support to mitochondrial function—an essential pathway for the production of cellular energy.22 Empiric research has shown that vitamin B12 injections may improve energy and cognitive ability and mood often with normal serum B12 levels.23,24 Serum folic acid levels have been assayed in patients with CFS and 50% of 60 patients have been shown to have lowered levels.25 Oral nicotinamide (NADH) has been shown in a randomised placebo-controlled trial to give benefit to 31% of CFS patients treated.26

RISK FACTORS

No single risk factor has been strongly associated with CFS. With a spectrum disorder with multiple aetiological factors it seems prudent to individually assess the clinical case as it presents. However study has commenced on what makes a person vulnerable to CFS with the general consensus based upon observation that disordered immunity and infectious agents intervene in a susceptible individual. A summary of the recent researched factors is shown in Table 35.1.

Table 35.1 Predictive risks factors for developing CFS27

Older age Female > male (4:1)
Low or middle rather than high educational level The presence of an anxiety disorder
Mood disorder (pre-morbid or 2 months postinfection) Personality trait—emotional instability
Musculoskeletal pain Low fitness 2 months postinfection
Lower physical functioning at baseline assessment The presence of fatigue at time of viral illness
Fatigue severity Other family members with symptoms of CFS

Very recent research has revealed that childhood trauma—abuse of sexual or emotional type—may predispose an individual to developing CFS in the presence of other initiating factors.28 Neuroendocrine dysfunction, as discussed in Chapter 15 on adrenal exhaustion, explains how the combination of these factors develop as a definite risk for CFS.29

CONVENTIONAL TREATMENT

There remains much contention in some medical services about the existence of CFS, let alone its management. Fatigue is a common presentation to general practice; however, CFS is a unique and separate entity that requires understanding and knowledge of the condition itself and those things that may mimic it. Confusion arises because of the lack of a definitive laboratory test, plus uncertainty about management options available to patients.17 Thus much conventional therapy is directed to symptomatic control of distress in the absence of single or definitive interventions. Key areas of conventional therapy that are summarised in one study30 include:

• sedating antidepressants such as tricyclic antidepressants, and serotonergic reuptake inhibitors for sleep disorders31,32
• simple analgesia and non-steroidal anti-inflammatory agents for ongoing pain management
• serotonergic modulators such as fluoxetine or similar agents in this class for psychological support, especially reactive mood disorder with or without anxiety.

Note: It is important the patient has had a careful medical assessment to exclude those conditions that mimic CFS.

KEY TREATMENT PROTOCOLS

The primary clinical protocol is to be supportive and patient, and to address the individual needs of the person with CFS. Negotiate a personalised plan recognising the person knows the effect of their illness better than anyone else. The following discussion provides choices that may be individually assessed as appropriate to the person’s needs.

Decrease suffering

Reduce pain and stiffness

Conventional therapies to reduce pain and suffering include regular doses of paracetamol and the use of a nocturnal dose of a tricyclic anti-depressant such as amitryptylline—10–50 mg at night.31,32 Integrative interventions most favoured by people with CFS include massage and chiropractic therapies.33 Recent research suggests that, in the presence of accompanying myofascial pain, manual therapies such as manipulation and myofascial trigger point therapy may have some benefit.34 Nutritional interventions such as magnesium is a nutrient that is an essential cofactor in enzymes of energy metabolism; it acts on muscle tissue as a relaxant (through its calcium channel blocking actions), and also is an essential cofactor in neurotransmitter regulation of pain.35 In CFS it has been used by injection of either magnesium sulfate or oral chelates (such as citrate) at 500 mg two or three times a day to assist pain management.36

INTEGRATIVE MEDICAL TREATMENT AIMS

• Individualisation of therapies allows a patient centred approach.
• Decrease suffering:

– reduce pain and stiffness
– improve sleep.

• Increase physical condition:

– increase graded physical activity goals
– use nutritional and herbal therapies for fatigue and weakness.

• Improve immune dysfunction:

– assess for infection, allergy and toxicity or deficiency
– use nutrition and phytotherapy.

• Improve psychological symptoms:

– cognitive behavioural therapy
– nutrition and phytotherapy.

Herbal interventions may include combinations of Curcuma longa, Boswellia serrata, Zingiber officinale and Apium graveolens41 with an emphasis on management of pain and stiffness.

Improve sleep

Conventional therapies aimed at managing sleep include hypnotic agents such as low-dose benzodiazepines or selective serotonin reuptake inhibitors, and melatonin, a naturally produced sleep hormone 5 mg 1–2 in evening.

Nutritional interventions include the use of 5-hydroxytryptophan, which may increase serotonin production and melatonin production, at a dose of 50–100 mg at night, increasing to a maximum of 250 mg, being careful of nausea and also interactions with conventional antidepressants,

Herbal interventions include:

• Withania somnifera, an adaptogen that may also promote sleep normalisation, 600 mg of dry root extract up to four times a day38
• Valeriana officinalis, which may assist in management of insomnia, irritability and restlessness, 700 mg of the dry root and rhizome three times a day39
• Zizyphus jujuba, synergistic with Valeriana officinalis in helping nocturnal irritability and anxiety, 900 mg of the dry seed up to three times a day39
• Passiflora incarnata, synergistic with Valeriana officinalis to assist sleep and nervous agitation, 500 mg of the dry herb up to three times a day.39

Increase physical conditioning

Graded physical activity

Negotiate a balanced and achievable exercise plan with the patient (after a medical check-up). A graded exercise program supervised by a qualified Health professional e.g. exercise physiologist or equivalent. Two reviews40,42 of research show that, after 3 months of exercise intervention, physical function improved and less fatigue was experienced by those who participated. However improved responses were seen when education was combined with exercise therapy but not when anti-depressants were also used in combination.40 Additionally the exercise intervention may be less palatable to some groups of patients than other interventions.40

Nutritional interventions

• Acetyl carnitine 500 mg three times a day has been shown to improve energy especially mental fatigue in an open labelled randomised trial.43
• In orthostatic intolerance and neurally mediated hypotension, increased intake of salt (sodium chloride) 600 mg twice to three times a day with increased water intake may assist the control of this syndrome.21
• Magnesium citrate 500 mg three times a day may assist energy metabolism.36
• Nicotinamide (NADH) 10 mg a day may assist energy metabolism.26
• Essential fatty acids have been trialled, with reported benefit in patients treated with high dose 1000 mg omega-3 marine oil four times a day.44,45
• Other interventions used with less evidence in CFS include Co Q10, with anecdotal evidence of improved exercise tolerance at 100 mg a day.46

Herbal interventions

• Eleutherococcus senticosus has been shown to assist physical labour and mental tasks, and reduces sick days in workers studied. It has been studied in a randomised controlled trial in CFS with improvements shown in treated, moderately fatigued CFS patients.37
• Panax ginseng is an adaptogenic (improves adaptation to stress) and tonic herb that increases stamina and helps normalise the hypothalamic–pituitary–adrenal axis.47
• Withania somnifera is adaptogenic but a non-stimulant and helps normalise sleep.48
• Rhodiola rosea is a tonic herb, improving cognitive performance, stamina and recall. The dose is 600 mg of the dry root up to four times a day or 3–4 mL of the alcoholic extract twice a day.49

Herbal treatments for orthostatic intolerance

• Glycyrrhiza glabra contains glycyrrhizin and glycyrrhetinic acid, which have adrenal steroidal anti-inflammatory effects, plus elevation of blood pressure due to the promotion of sodium retention from the kidney.22 The dose is 1–2 mL of the 1:1 alcoholic extract up to three times a day.
• Rehmannia glutinosa supports the adrenal gland and acts in a similar way to liquorice without the potential for hypertensive effect. It is traditionally used for fatigue in traditional Chinese medicine.50,51 The dose is 350 mg of the dry root up to four times a day.
• Ruscus aculeatus has been shown to assist the management of orthostatic hypotension.52 Dose is 800 mg of the dry herb up to three times a day. It may be more effective when combined with Aesculus hippocastanum.

Improve immune dysfunction

Assess first for allergy and environmental toxicity (see Table 35.2).45,46,54 Dysfunctional immunity has been demonstrated in CFS;55,56 this may manifest as sensitivity to environmental agents such as foods, pollens, dust mites and other agents. Assessment may range from skin prick/patch testing for inhalant allergens, foods and mites to immunoglobulin G testing for food sensitivity.

Table 35.2 Tests for infection, allergy and environmental toxicity45,46

TESTS FUNCTIONAL OUTCOME MANAGEMENT RECOMMENDATION
Assess for infection Detect any ‘occult’ or latent infections, e.g. Mycoplasma, Chlamydia, Rickettsia, virus or parasites Requires specialised assessment and advice, but nutritional and herbal immune support can be used as a basis of management
Heavy metal assessment
Tests to consider:

• hair analysis
• chelation challenge
• porphyrin assessment

Elevated heavy metals
• Stabilise metal detoxification—improve digestion, antioxidants, replace displaced minerals—zinc, selenium etc.
• Specific chelation agents

Liver detoxification profile
• Impaired phase 1 and/or phase 2 detoxification
• Uncoupled phase 1 to phase 2
Enhance appropriate detoxification through nutritional support:

• phase 1—vitamin B, phase 2—amino acid support
• antioxidants
Food allergy assessment:

• skin/patch test
• IgG4 blood test for food
• digestive stool analysis or faecal bacterial DNA assessment
Identification of possible triggers for persistent immune dysfunction
• Elimination diet and challenge after exclusion
• Digestive support through probiotic supplementation, digestive enzymes

Toxicity may involve allergy as mentioned above, but also the possibility of immunological or metabolic injury from heavy metals and chemicals. The effects may range from displacement of energy cofactors such as copper antagonising zinc bioavailability, or mercury displacing selenium. Other effects may be from enzyme induction or inhibition, leading to altered metabolic clearance or the production of physiological energy cofactors. An example of the latter is alteration of liver detoxification pathways.

Nutritional interventions

• Omega-3 fatty acids 1000 mg three times a day may rebalance eicosanoid pathways.44,52
• Zinc chelate 220 mg at night may have direct effects on immune cell proliferation and function. An observational study54 found that serum zinc levels correlated with fatigue in 18 patients with CFS compared with 18 controls. The higher the zinc level, the less the fatigue.
• Glutamine 500 mg three times a day has been shown to modulate lymphocyte proliferation and assist immune outcomes.57
• Digestive enzymes may assist the reduction in ability to digest protein and complex carbohydrates (see Chapter 5 on food intolerances).
• Probiotics may be needed if there are significant abnormalities on digestive bacterial analysis (see Chapter 3 on irritable bowel syndrome).

Herbal interventions

• Astragalus membranaceus contains polysaccharides and saponins that may be indicated for chronic immune enhancement and recurrent viral illness. A recent study of 6 weeks found that its effects in CFS involved its ability to balance abnormal cytokine levels.41 The dose is 4–5 mL t.d.s. of 1:2 alcoholic extract.
• Hemidesmus indicus contains essential oils and triterpenoid saponins, which are indicated for immune system suppression in cases of auto immune conditions. The dose is 3–6 mL a day of 1:2 alcoholic extract or 500 mg up to four times a day of the dry root.
• Echinacea spp. is immunomodulatory for viral illness and immune disorders. The dose is 3–5 mL twice daily of the 1:2 alcoholic extract (mixed augustifolia/purpurea) or 600 mg of the tablets containing dried herbs of mixed species up to three times a day.58
• Rehmannia glutinosa supports the adrenal gland and acts in a similar way to liquorice without the potential for hypertensive effect. The dose is 350 mg of the dry root up to four times a day.51
• Hypericum perforatum assists mild mood disorders and depression. It may have activity against encapsulated viruses such as Epstein Barr. In a randomised controlled trial in 1994 39 patients treated with St John’s wort showed significant improvement in symptoms after 4 weeks.59 The dose is 1.8 g of the dry herb (standardised to 990 μg of hypericin) up to 3 times a day or 2.5 mL up to twice daily of the 1:2 alcoholic extract.59

Improve psychological symptoms

Conventional therapies

• Short-term studies have shown that cognitive behavioural therapy (CBT) is effective in reducing fatigue compared with other psychological therapies including relaxation, counselling and education/support.60 This intervention has also shown benefit in randomised controlled studies in children and young adults. The long-term follow-up of CBT has shown benefits in fatigue, symptom reduction, physical functioning and school and work absences. It warrants further research.27,30,31,60
• Antidepressants may help regulate pain, sleep disorders (tricyclic antidepressants) or severe reactive depression. Possible side effects may limit their use and individual variations may occur in response. Research has failed, however, to show a consistent effect in most patients with CFS.32,61

Nutritional interventions

• B12 replenishes CNS methylation imbalance. Improved cognitive function at doses of 1000 μg intramuscularly, titrated to patient response (weekly to monthly).23,24
• S-adenosylmethionine may relieve mood disorder plus joint pains, 200 mg three times a day.22

Herbal Interventions

Hypericum perforatum improves mild depressive symptoms. It has been postulated to have antiviral activity as well. It may be helpful for reactive depression. Care should be taken with possible interactions with prescription antidepressants.53,59

Case Study

A 25-year-old male presents with a 5-year history of developing recurrent and relapsing severe fatigue, muscle aches with morning stiffness worsening after any physical exertion. His fatigue escalates for about 48 hours after simple activity such as a brisk prolonged walk. He has difficulty with concentration and memory at tasks over 30 minutes. His illness initially commenced after a viral episode of high fevers, glandular swelling, headache. He feels he has never fully recovered from it with his energy levels being rated at 4–5/10 every day.

SUGGESTIVE SYMPTOMS

• Fatigue worsening after activity lasting more than 6 continual months
• Muscle ache and pains
• Headache
• Poor concentration and memory

image

Figure 35.2 Integrative treatment decision tree—chronic fatigue syndrome (CFS)

Example treatment

Prescription

The patient with CFS was assisted to develop a plan for the next 3 months of management, to be reviewed every 4 weeks:

• psychological supportive sessions with cognitive behavioural therapy (CBT), supervised by a psychologist
• a graded exercise program to improve fitness and his physical stamina, supervised by an exercise physiologist or physiotherapist
• two herbal formulas—see the treatment box for immunological support and sleep stabilisation and stamina
• acetyl carnitine 500 mg three times a day for stamina and energy.

Herbal prescription

Rhodiola rosea 1:1 20 mL
Rehmannia glutinosa 1:2 30 mL
Astragalus membranaceus 1:2 35 mL
Glycyrrhiza glabra 1:1 15 mL
5 mL t.d.s. 100 mL
Withania somnifera 600 mg
Panax ginseng 125 mg 2 tablets b.d.

Nutritional prescription

Acetylcarnitine—500 mg t.d.s. before meals

CoQ10—100 mg per/day

Note: Create a plan. Negotiate this with the patient.

Be flexible—people with CFS have fluctuating symptoms and needs.

Review the patient for not just physical symptoms but also psychological distress, social isolation and financial stress. Nutritional intervention may require follow-up to assess their response and adjustment.

Expected outcomes and follow-up protocols

CFS is a chronic condition that may take months to resolve, so patience is required. The patient with CFS has a spectrum of needs. Management of such a spectrum disorder may necessitate different team members at different times in the illness. Such team members may be a psychologist, exercise physiologist, dietician, physiotherapist and massage therapist, even a physician. Note that consideration of orthostatic intolerance may necessitate earlier assessment via tilt table testing. If a positive result is obtained, then additional assessment to exclude hypoadrenal function (fasting salivary cortisol) may be necessary with the addition of salt and fluid loading. Conventional therapy may include the use of a low dose beta-blocker. Interventions that may assist are liquorice, Rehmannia glutinosa and Ruscus aculeatus (see above). Fluctuations may occur with immunological symptoms (fluctuating fevers or glandular swelling, inflammatory symptoms such as joint pains and regional or diffuse muscle pain) require careful assessment. Exclusion of persistent infection through specific assessment for infectious agents and immunological disorders may be required. Exclusion of toxic exposure or persistent toxins such as heavy metals needs to be considered. In addition the possibility of detoxification disorders of the liver may be excluded through appropriate functional liver detoxification studies.

Table 35.3 Review of the major evidence

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KEY POINTS

• Chronic fatigue syndrome is a complex disorder distinctive from depression and fatigue or other causes including ‘adrenal exhaustion’.
• A spectrum of causes and symptom manifestations may require individualised management.
• Management should engage the patient through the use of a negotiated plan to address their physical and psychological needs while accepting that the patient is in charge of their health.
• Always observe and treat comorbid health conditions.
• An integrative approach using psychological, herbal, nutritional and lifestyle therapies should benefit the treatment of CFS, though pharmacotherapies may also be advised.

Further reading

Bruce M., Carruthers A., Kumar J., De Meirleir K.L., et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue. 2003;11(1):7-116.

Shomon M.J. Living well with chronic fatigue syndrome and fibromyalgia. New York: HarperCollins; 2004.

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