Measuring fatigue

Several fatigue scales have been developed. These include the ‘Fatigue Severity Scale’ (FSS), the ‘Fatigue Scale’ (FS), the ‘Energy/Fatigue Scale’ (EFS), ‘Checklist Individual Strength’ (CIS), and ‘Fatigue Impact Scale’. Selection of a fatigue rating score has been reviewed by Friedberg and Jason (2002); within their review several key points are noted from the literature:

Jones et al (2009) have very recently examined the descriptions of fatigue within a range of chronic disease scenarios. In a retrospective review of FIS data 605 chronic disease patients and 45 normal controls were assessed by each of the three domains. The FIS appeared to be a valuable tool for comparing CFS with other disease groups.

Whilst fatigue is understood to be commonly reported in patients with JHS, it has not been examined in detail either epidemiologically or in relation to response to therapy using the validated tools described above. Interestingly, the prevalence of JHS varies in racial groups, and there is evidence to suggest similar variability in CFS (Dinos et al 2009). This is an important area for future research.

Managing fatigue

Identification and management of diseases associated with fatigue is assumed. Thereafter, there is very little published evidence to support the use of the various forms of therapy available for fatigue per se. Much is anecdotal and relates to individual successes. Nevertheless there are reasonable guiding principles. In CFS, FM and JHS, for example, the use of antidepressants, anti-anxiety drugs, sleep aids and analgesics in the general management of the condition might be expected to have some impact on the fatigue be it direct or indirect.

Lifestyle changes including pacing, changing sleep pattern, exercise, and even change of job or hours of work may help, as may behavioural therapy. These are covered in other sections of this book. Complementary therapies such as acupuncture, massage and Reiki may be beneficial.

While there is limited scientific evidence supporting the use of nutritional supplements for CFS, many doctors and patients consider them an important part of treatment. Commonly recommended supplements include Carnitine, Co-enzyme Q10 and 5-HTP. Such agents are considered to be effective in boosting the immune system, raising energy levels, and improving cognitive functioning.

Carnitine, at a dose of 500 mg twice daily, is considered to raise energy levels by increasing fat metabolism. It may also have a function in facilitating the effect of serotonin and glutamate in the central nervous system (Chapter 3). Carnitine is naturally found in red meat and poultry, fish, dairy, wheat, asparagus and avocado. The main side-effects of Carnitine include hypertension, tachycardia and fever. It may also impair thyroid function.

Co-enzyme Q10 is a powerful antioxidant required for the metabolism of adenosine triphosphate (ATP). Typically 30–90 mg is taken in two or three divided doses daily. It is slow-acting and benefit may not be realized for up to 8 weeks. Co-enzyme Q10 is found naturally in oily fish, offal and whole grains. The side effects include nausea and vomiting, diarrhoea, skin irritation, irritability, increased sensitivity to bright light and flu-like symptoms. It may also induce hypoglycaemia and hypotension.

5-HTP is directly converted to serotonin. Low serotonin is a feature of FM (Chapter 5). 5-HTP has been reported to alleviate many of the symptoms of FM. The dose range is from 50 to 500 mg a day starting at a low dose and escalating slowly. 5-HTP should not be taken with other medications that alter serotonin levels. The side effects of 5-HTP include nausea, dizziness and diarrhoea.

With all supplements it is important to remember the potential for negative interactions with other supplements and medication, that there are limited or no data on use in pregnancy and lactation, and that there is no specific dosage recommendation for CFS, FM or JHS.

Symptoms

The three typical findings of cardiovascular autonomic dysfunction (CAD) are orthostatic hypotension (OH), orthostatic intolerance (OI), and postural tachycardia syndrome (POTS). Patients report dizziness, light-headedness, visual blurring, tunnel vision, inattention or poor concentration and a fear of or history of ‘blacking out’ (syncope). In childhood and adolescence typical features include tiring easily, clumsiness and an intolerance of exercise. Because of this, it is important that paediatricians as well as adult physicians are alert to the associations. The reader will recognize that many of these symptoms also describe those reported in association with fatigue (as above) and several of the physical manifestations of JHS (Chapter 2).

Symptoms of autonomic (sympathetic) activation include palpitations, tremor, excessive sweating and anxiety (Chapter 4). Both groups of symptoms may occur transiently and immediately after standing up, and may remit spontaneously without necessarily being considered significant.

There are a number of symptoms that are not restricted to a change in posture. These are shown in Box 6.1.1.

BOX 6.1.1 Symptoms associated with autonomic dysfunction that are not specifically associated with postural change

Flushing

Headaches

Muscle and joint pain

Neuropathic pain

Hypervigilance to bodily changes (Chapter 8)

Gastrointestinal dysfunction (Chapter 6.2)

Increased sweating

Symptoms may be worsened by dehydration and other low-volume states such as anaemia (Table 6.1.1), high temperatures, exercise, systemic illness or prolonged bed rest. Symptoms may also fluctuate with the menstrual cycle, being at their worst during bleeding. In general this is likely to be related to blood loss and volume depletion, however in JHS sensitivity to changing levels of progesterone is recognized as a triggering factor for a number of other symptoms including pain and worsening joint stability.

Table 6.1.1 Clinical findings and associations with OH, OI and POTS

As well as syncope being induced by orthostatic stressors, vasovagal syncope (VVS) may be provoked by straining, e.g. when passing urine or stool, or coughing (the Valsalva – see below), or by emotional stress.

It is not the intention of this chapter to explore pure or primary autonomic failure, multiple system atrophy or secondary autonomic failure, for example in diabetes mellitus. These have been recently reviewed in detail by Low and Benarroch (2008). However, it is important to be aware of such conditions when considering the potential cause of autonomic dysfunction in patients with CFS, FM or JHS as co-morbidity. A detailed examination is required to exclude evidence of conditions such as Parkinson disease, multiple sclerosis, syringobulbia, Guillain-Barre syndrome, transverse myelitis, diabetic neuropathy and paraneoplastic syndromes.

Likewise, as shown in Table 6.1.1, a number of medications may precipitate symptoms and a detailed history is therefore necessary.

Postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (defined in Table 6.1.1) typically affects adults between 20–50 years of age. It is 4–5 times more common in women than men. Syncope is common and is usually of the vasovagal type. In POTS, symptoms characteristically occur after a period of standing or sitting. They may also fluctuate between acute episodes lasting just a day and chronic episodes lasting months. In addition, POTS may be accompanied by fatigue whether supine or erect, with significant negative impact on quality of life as described above (Benrud-Larson et al 2002).

The exact mechanism for POTS may remain elusive despite investigation. Low (1993) and colleagues (1995) have suggested three subgroups of the disorder: neuropathic POTS, hyperadrenergic POTS and POTS with deconditioning.

Neuropathic POTS is caused by autonomic neuropathy leading to defective peripheral vasoconstriction and excessive venous pooling in the legs during standing. It can follow a viral infection and have an autoimmune basis, suggested by auto-antibodies to acetylcholine receptors found in some patients. Hyperadrenergic POTS is associated with high plasma catecholamine levels when supine or upright. Typically, standing noradrenaline (norepinephrine) levels rise over 600 pg/ml. There are individual reports of hyperadrenergic POTS associated with genetic abnormalities of catecholamine transporters and mast cell activation causing increased availability of noradrenaline in autonomic synapses (Shannon et al 2000, Robertson et al 2001, Garland et al 2002, Shibao et al 2005). These rare conditions are beyond the scope of this chapter; for a more detailed recent review of POTS and orthostatic syncope the reader is directed to Grubb (2008) and Moya and Wieling (2006) respectively.

POTS with deconditioning can follow prolonged bed rest or prolonged periods of physical inactivity leading to cardiac atrophy, reduced blood volume, and consequently reduced cardiac stroke volume.

There are no epidemiological studies of POTS; estimates of prevalence range between 170–2000/100 000. Perhaps the first descriptions of POTS date back to Beard’s (1869) account of neurasthenia, and the Da Costa syndrome or irritable heart of soldiers (Da Costa 1871). As early as 1918 physicians recognized the dilemmas still present today – the heterogeneity and aetiological uncertainty of OI (Fraser & Wilson 1918, Khurana 1995).

Orthostatic hypotension and intolerance

Clinical examination of patients with OI (defined in Table 6.1.1) will most often reveal no abnormality. After a prolonged period (which may take 30 minutes or more) a patient may begin to hyperventilate, sweat, become pale and anxious. Acrocyanosis, a dusky red/blue discoloration of the lower leg during standing may be seen. This is caused by excessive venous pooling due to increased capacitance. The legs may swell. This may be exacerbated in the collagen disorders given the excessive elasticity of the connective tissues. Orthostatic hypotension may cause considerable disability, with the potential risk of serious injury (Mathias 2007).

Investigation of CAD

Many tests, including ECG, postural blood pressure changes, heart rate variation to deep breathing, the Valsalva manoeuvre and sustained handgrip, can all be done at the bedside or in clinic.

More detailed investigation requires a well-equipped laboratory. The findings may be subtle and dismissed clinically even though the symptoms seem profound and associated with significant morbidity. The exclusion of cardiac disease or hypotension due to drug therapy is essential (Table 6.1.1). Before planning autonomic assessment a detailed history and examination are needed.

Other screening tests

Other autonomic screening tests help determine the site and extent of CAD, be it cardiovagal, adrenergic, or peripheral, post-ganglionic sympathetic sudomotor denervation. These are shown in Box 6.1.2.

BOX 6.1.2 Autonomic tests used to determine the likely neurophysiological trigger of CAD

Responses to the Valsalva manoeuvre assess sympathetic function as well as vagal function.

Cardiac parasympathetic (vagus) activity can be assessed by heart rate responses to:

postural change

deep breathing (sinus arrhythmia)

hyperventilation.

Evaluation of the postganglionic sympathetic sudomotor axon reflex using acetylcholine as a stimulus; for example the quantitative sudomotor axon reflex test (QSART) (Low et al 1983), performed at several sites including the forearm, outer thigh, inner lower leg, or the foot.

Activation of sympathetic outflow (adrenergic function) within different afferent or central pathways is assessed by applying stimuli that raise blood pressure:

isometric exercise (by sustained hand grip for 3 minutes)

the cold pressor test (immersing the hand in ice for 90 seconds)

mental arithmetic (using serial-7 or -17 subtraction), activate different afferent or central pathways.

Factors contributing to orthostatic pathologies and syncope also include the response to food ingestion, exercise and carotid sinus massage.

To assess postprandial hypotension, the cardiovascular responses to a balanced liquid meal containing carbohydrate, protein and fat are measured while supine, with comparisons of the blood pressure response to head-up tilt before the meal and 45 minutes later.

To evaluate exercise-induced hypotension, responses are obtained during graded incremental supine exercise using a bicycle ergometer with measurement of postural responses before and after exercise. Many find that the tachycardia is worse during exercise; deconditioning due to lack of physical activity may complicate the disorder (Chapters 9 and 13); indeed it may be very difficult to isolate POTS as a primary autonomic dysfunction from deconditioning (Joyner & Masuki 2008). In some individuals, as with OI on prolonged standing, hyperventilation and panic attack may occur.

Thermoregulatory sweat test may be helpful in demonstrating sudomotor denervation.

Finally, in order to complete the assessment plasma catecholamine levels may be needed. Measurements are available in specialized laboratories and may be of value in certain disorders such as hyperadrenergic POTS.

Evidence of autonomic dysfunction in CFS

The association of CAD with CFS first appeared in case-reports and epidemiological studies of ME in the late 1970s (Parish 1978, Ramsay 1978). Streeten and Anderson (1992) later suggested that fatigue may be due to an inability to maintain blood pressure when standing. Using tilt-table technology Rowe et al (1995), Bou-Holaigah et al (1995), and Timmers et al (2002) identified a predisposition to CAD in CFS, demonstrating the presence of ‘neurogenic syncope’.

Soetekouw et al (1999), recognizing that the signs of CAD in CFS can be subtle, assessed non-invasive measurements in an unselected group of 37 patients with CFS and 38 healthy controls. Blood pressure and heart rate were recorded continuously before and during forced breathing, standing up, the Valsalva manoeuvre, sustained handgrip exercise and mental arithmetic testing. At rest, there were no significant differences in blood pressure, heart rate or Valsalva ratio between the groups. However, on standing the systolic and diastolic blood pressure responses were significantly larger in CFS patients. Also, the heart rate response to mental arithmetic was found to be significantly less in the CFS group. This suggested impaired cardiac sympathetic responsiveness to mental stress. Finally, the haemodynamic responses to the hand grip exercise were lower in the CFS group than in the control group, but it was considered that this might have been attributable to lower levels of muscle exertion in the CFS patients. The findings of the study were subtle, leading to the suggestion that there were no gross alterations in cardiovascular autonomic function in CFS.

Stewart (2000) examined the nature of autonomic and vasomotor changes in symptomatic adolescents. The cohort included 22 cases of POTS, 14 of CFS with a history of orthostatic tachycardia, and ten healthy individuals and 20 cases of simple faint as controls. Stewart showed that the R–R interval on ECG and heart rate variability were decreased in the CFS and POTS patients compared with controls and remained decreased with head-up tilt. Blood pressure variability was increased in the CFS and POTS patients compared with controls and increased further with head-up tilt. Stewart concluded that ‘heart rate and blood pressure regulation in POTS and CFS patients are similar and show an attenuated efferent vagal baroreflex associated with increased vasomotor tone. The loss of beat-to-beat heart rate control may contribute to a destabilized blood pressure resulting in orthostatic intolerance. The dysautonomia of orthostatic intolerance in POTS and in chronic fatigue are similar’.

Peckerman et al (2003) also postulated that altered cardiovascular responses to mental and orthostatic stressors reported in CFS may involve changes in baroreceptor reflex functioning. Their study demonstrated that patients with CFS had a greater decline in baroreceptor reflex sensitivity during standing, although only those with severe CFS were significantly different from the controls, suggesting that classifying patients by illness severity may aid in interpreting response to CAD testing.

More recently the association between CAD and CFS has been reaffirmed (Grubb et al 2005, Newton et al 2007) and the mechanisms further described. Wyller et al (2008) showed that adolescents with CFS have increased sympathetic activity at rest with exaggerated cardiovascular responses to orthostatic stress.

Legge et al (2008) identified fatigue as a significant symptom in the presence of VVS. Fatigue was assessed in 140 sequential cases of VVS with matched controls using the FIS. The severity and type of autonomic symptoms was explored using the composite autonomic symptom scale or COMPASS (Suarez et al 1999). The conclusions were that fatigue is a significant problem in patients with VVS and that, like the observation of Peckerman et al (2003), the severity of autonomic symptoms correlated with the degree of fatigue.

The association between POTS and CFS in adolescence has also been explored by Galland et al (2008). The study concluded that CFS subjects were more susceptible to OI than controls and that the cardiovascular response predominantly manifested as POTS without hypotension. Similarly, Hoad et al (2008) showed that the maximum heart rate on standing was significantly higher in patients with CFS/ME compared with controls. Increasing fatigue was associated with increase in heart rate.

Finally, there has recently been a re-focus on cardiovascular deconditioning. Hurwitz et al (2009) examined the association between cardiac output and blood volume, lifestyle, and illness severity in CFS. Participants were subdivided into two CFS groups based on symptom severity data (severe (N = 30) vs. non-severe (N = 26)). Two healthy control groups were matched to the CFS groups. The controls were also split into subgroups on the basis of reported physical activity (sedentary (N = 58) vs non-sedentary (N = 32)). Echocardiographic measures indicated that the severe CFS participants displayed 10.2% lower cardiac volume and 25.1% lower contractility than the control groups. Deficit in ‘total blood volume’ in CFS explained greater than 90% of the group differences in the cardiac volume indices, and primarily within the group with severe CFS.

Newton et al (2009) examined blood pressure circadian rhythm in patients with CFS (N = 38), normal (N = 120) and fatigue (N = 47) controls. The fatigue controls had primary biliary cirrhosis. The study correlated blood pressure regulation with fatigue using the FIS. Lower blood pressure and exaggerated abnormal diurnal blood pressure regulation occurred in patients with CFS compared to controls.

In response to such findings Stewart (2009) has recently commented that the presence of low blood pressure, whether symptomatic or not, is ‘primarily attributable to a measurable reduction in blood volume … similar findings are observed in microgravity and bed rest de-conditioning, in forms of orthostatic intolerance, and to a lesser extent in sedentary people. The circulatory consequences of reduced cardiac output may help to account for many of the findings of the syndrome’.

Non-pharmacological management of CAD

Non-pharmacological measures are a key component of management, even when drugs are used. As no single drug can effectively mimic the actions of the sympathetic nervous system, a multipronged approach is needed. It is important that patients should be made aware of the many factors, other than postural change, that lower blood pressure (Box 6.1.4).

BOX 6.1.4 Factors that may precipitate OH and OI and therefore to be avoided

Rapid postural change, especially in the morning when getting out of bed

Sitting or standing for too long in one position

Prolonged bed rest

Nocturnal polyuria

Excessive straining during micturition and defaecation

Heat

Alcohol

Large carbohydrate meals

Simple techniques may help reduce symptoms by either (i) increasing fluid volume in the body, or (ii) improving venous return to the heart. Good fluid balance is fundamental (Yunoszai et al 1998, Wieling et al 2002) and intake should be at least 2–2.5 litres a day or more. The simplest way to be sure of adequate fluid intake is the realization that the urine should become pale yellow or preferably colourless with adequate fluid intake, and that on average a person passes urine with a frequency of twice in the morning and twice in the evening. Dark urine is a sign of dehydration.

It may be necessary to increase salt intake. Studies show that salt supplementation increase plasma volume (El-Sayed & Hainsworth 1996, Claydon & Hainsworth 2004). Patients need reassurance that it is okay to increase their salt intake, as so much publicity exists around reducing salt intake for well-being and reduction of hypertension, that the message may be confusing. Isotonic drinks are recommended.

Various physical manoeuvres (Wieling et al 1993, Brignole et al 2002, Krediet et al 2002), such as leg crossing, squatting, sitting in the knee-chest position, and abdominal compression, are of value in reducing OH, as may be ‘tilt training therapy’ for syncope (Reybrouck et al 2002, Gajek et al 2006, Ector & Reybrouck 2007). Exercise for muscle re-conditioning is important and is the subject of much of Section 2 of this book in relation to managing the patient with JHS. Consideration should also be given to garments aimed at preventing venous pooling. These include intermittent use of lower limb elastic stockings and abdominal binders.

Pharmacological management of CAD

The aim is to either increase blood volume (fludrocortisone, EPO), increase vasoconstriction (midodrine, etilefrine, SSRIs), or block the effect of (nor)epinephrine (beta-blockers, disopyramide, ACE-I).

Fludrocortisone is a potent synthetic mineralocorticoid with minimal glucocorticoid effect. It encourages an increase in intra- and extravascular fluid, sensitizes vascular receptors to pressor amines, and reduces vascular wall elasticity making blood vessels more resistant to stretch. A dose of 0.1 mg daily is effective for more than 24 hours, and for this reason is useful in adolescents, because it is taken once a day and if the tablet is missed one day there is no problem. The half-life elimination in plasma is 30–35 minutes. The biological half life is 18–36 hours. Dietary salt intake must be adequate and occasionally potassium supplements are needed to counteract the side effect of hypokalaemia. Electrolyte balance should be checked before starting the drug, in a month and then once a year. It should be noted that there are no specific trials for Fludrocortisone, or indeed any of the other agents used in management of CAD, in patients with JHS.

Midodrine is an alpha-adrenoreceptor agonist. It has an effect on arterial resistance and venous capacitance, through its active metabolite desglymidodrine. Several studies have shown it to be efficacious (Low et al 1997, Ward et al 1998, Perez-Lugones et al 2001). Midodrine is given as 2.5–10 mg 3–4 times daily and is licensed for recurrent neurogenic syncope. It is effective, but the problem is that the action lasts only 4 hours and needs to be taken several times a day. The side effects include supine hypertension, scalp tingling and urinary retention.

Selective beta-blockade with, for example bisoprolol, metoprolol or propranolol may be of value in reducing the frequency of POTS. In a recent study by Lai et al (2009) of adolescents attending the Mayo Clinic, USA, midodrine was compared to beta-blocker therapy. More patients treated with a beta-blocker reported improvement in symptoms and more attributed their improvement to their medication compared to those taking midodrine. This was in contrast to an earlier study from the Mayo Clinic in which Thieben et al (2007), reporting on 152 cases of POTS, found no differences in the symptomatic response to beta-blockers, fludrocortisone, midodrine and SSRIs, with all class of agents inducing partial symptom relief in 40–60% of patients.

Whatever the combination of the above medication required to produce the desired effect, selective targeting is often needed and is best determined under the guidance of a specialist unit. Orthostatic and postprandial hypotension may respond to L-theo-dihydroxyphenylserine (Droxidopa) (Freeman et al 1996, Mathias et al 2001, Goldstein 2006, Mathias 2008); acarbose also showing efficacy in postprandial hypotension (Jian & Zhou 2008), octreotide is also useful in postprandial hypotension. Orthostatic hypotension might also respond to pyridostigmine (Singer et al 2006), nocturnal polyuria and morning hypotension to desmopressin (Mathias et al 1986, Mathias & Young 2003) and POTS and hypotension to the somatostatin analogue, octreotide (Hoeldtke & Davis 1991, Smith et al 1995). Erythropoietin (Grubb & Karas 1999) may also improve blood pressure. The drawback with erythropoietin is its cost, the need to administer by subcutaneous injection, and the need to closely monitor the red cell count.