MYALIC ENCEPHALOMYELITIS
Post-viral Fatigue Syndrome

Guidelines for the care of patients
Introduction

Myalgic encephalomyelitis (ME) is a complex syndrome whose aetiology, pathogenesis and management stimulates intense medical debate. Despite current controversies, the World Health Organisation has now classified ME as a disease of the nervous system (International Classification of Diseases, No 10, ref.G93.3), and the Department of Health has officially recognised it as a "debilitating and distressing condition" (HCDebate, 13/11/91. Hansard col 582W).

Patients are often previously fit adults who have to come to terms with an abrupt onset of severe disability, affecting both mental and physical capacity. Later on, there may be practical difficulties with education, employment, or obtaining DSS benefits, all of which place an increasing strain on both patients and their carers. The aim of these guidelines is to provide up-to-date information on all aspects of management, as well as recommending sensible changes in lifestyle which will form a crucial part in any recovery process.

Generally speaking, management is best co-ordinated by general practitioners, with help from specialists and other health professionals where appropriate. Consultant referral should be reserved for severely affected cases, those where the diagnosis is in doubt, and for patients who are willing to participate in research or treatment trials. Unfortunately, the number of consultants with expert knowledge of this syndrome is extremely limited in some parts of the UK.

Nomenclature

Medical records suggest that a similar post-infectious disorder ("febricula") was first described by Sir Richard Manningham as far back as 1750. Over the past sixty years a number of outbreaks have been reported, sometimes described as atypical polio and often occurring in closed communities or affecting co-workers in hospitals. These have given rise to a variety of confusing names including epidemic neuro-myasthenia (USA), Tapanui flu (New Zealand), Royal Free disease (UK), and even the derogatory media term "Yuppie flu".

The name myalgic encephaiomyelitis was first introduced in 1956 when a leading article in The Lancet reported on an outbreak that had occurred in north-west London during the previous year and later affected staff at the Royal Free Hospital. More recently, in the UK, the term post-viral fatigue syndrome (PVFS) has become synonymous with myalgic encephalomyelitis.

In America, the terms chronic fatigue and immune dysfunction syndrome (CFIDS), and chronic fatigue syndrome with encephalopathy, are also used to describe a similar symptom complex.

Some doctors prefer to use the term chronic fatigue syndrome (CFS) which makes no assumptions about aetiology or pathology. Inevitably, this term includes a wide heterogeneous spectrum of patients whose prominent complaint is undiagnosed fatigue.

International diagnostic criteria

In the UK an attempt at reaching a consensus position on clear diagnostic guidelines, particularly for research purposes, resulted in the so-called Oxford criteria being drawn up (Sharpe et al 1990).

Oxford Criteria

Chronic Fatigue Syndrome (CFS):

• characterised by fatigue as the principal symptom
• of definite onset, i.e. not life-long
• the fatigue is severe, disabling, and affects physical and mental functioning
• the symptom of fatigue should have been present for a minimum of 6 months, during which it was present for more than 50% of the time
• other symptoms may be present, particularly myalgia, mood and sleep disturbance

Certain patients should be excluded from the definition. They include:

• patients with established medical conditions known to produce chronic fatigue (e.g. severe anaemia); such patients should be excluded whether the medical condition is diagnosed at presentation, or only subsequently; all patients should have a history and physical examination performed by a competent physician
• patients with a current diagnosis of schizophrenia, manic depressive illness, substance abuse, eating disorder or proven organic brain disease; other psychiatric disorders (including depressive illness, anxiety disorders, and hyperventilation syndrome) are not necessarily reasons for exclusion.

Post-infectious fatigue syndrome (PIFS)

This is a sub-type of CFS which either follows an infection or is associated with a current infection (although whether such associated infection is of aetiological significance is a topic for research).

To meet research criteria for PIFS patients must fulfil the criteria for CFS as defined above, and also fulfil the following additional criteria:

• there is definite evidence of infection at onset or presentation (a patient's self-report is unlikely to be sufficiently reliable)
• the syndrome is present for a minimum of 6 months after onset of infection
• the infection has been corroborated by laboratory evidence

Although the Oxford criteria clearly emphasise that "in reporting studies it should be clearly stated which of these two syndromes is being studied", this has not always occurred in practice.

To add to the confusion, American researchers use a rather different set of diagnostic criteria which were originally developed at the Centres for Disease Control (CDC) and published in the Annals of Internal Medicine (Holmes et al 1988). CDC criteria recommend the exclusion of a number of specific clinical conditions where chronic fatigue can be an important feature. A major revision of CDC criteria was published in December 1994 (Fakuda et al).

CDC criteria

Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is:

• of new or definite onset (has not been lifelong)
• not the result of ongoing exertion
• not substantially relieved by rest
• results in substantial reduction in previous levels of occupational, educational, social, or personal activities and also concurrently exhibits four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness, and must not have predated the fatigue
• self-reported impairment in short-term memory or concentration severe enough to cause a substantial reduction in previous levels of occupational, educational, social or personal activities.
• sore throat
• tender cervical or axillary lymph nodes
• muscle pain
• headaches of a new type, pattern or severity
• unrefreshing sleep
• post-exertional malaise lasting more than twenty four hours
• multi-joint pain without joint swelling or redness

Australian criteria

Australian researchers tend to use their own case definition, often with an added emphasis on disturbances in cell-mediated immunity (Lloyd et al 1988a), as follows:

• Disabling and prolonged feelings of physical tiredness or fatigue, exacerbated by physical activity
• Present for at least 6 months
• Unexplained by an alternative diagnosis reached by history, laboratory, or physical examination
• Accompanied by the new onset of neuro-psychological symptoms including: impaired short-term memory and concentration, decreased libido, and depressed mood; these symptoms usually have their onset at the same time as the physical fatigue, but are typically less severe, and less persistent than those seen in classic depressive illness

Patients are to be excluded if:

• they have a chronic medical condition that may result in fatigue
• there is a history of schizophrenia, other psychotic illnesses, or bipolar affective disorder

In addition, drug or alcohol dependence makes CFS very unlikely.

Clearly, this is an unsatisfactory situation. Some research groups and clinical trials are being conducted on a heterogeneous group of patients with unexplained fatigue, whereas others stick to a much more rigid case of post-infectious cases. No wonder the ensuing results are often confusing and conflicting.

Prevalence of CFS and ME/PVFS

Although no precise figures are available, it has been suggested in one recent survey (Bates et al 1993) that as many as 8.5% of the adult population attending a primary care centre in the United States have some form of chronic fatigue syndrome.

Many cases of chronic fatigue turn out to be due to a "hidden" primary psychiatric disorder such as depression, somatisation, or anxiety, and will fit the CFS model of depression (inactivity, deconditioning, sick role behaviour). A smaller number will have an underlying physical cause for their fatigue. In others a combination of psychological and social factors may all be interacting.

Large scale epidemiological studies into both CFS and ME/PVFS are desperately required. In the meantime statistical data obtained from a few small studies (Dowsett et at 1990, Hinds and McCluskey 1993, Ho-Yen and McNamara 1991) suggest that as far as ME/PVFS is concerned:

• The prevalence may be around 1-2/1000 of the population
• A peak incidence occurs in the 20-40 age group
• Children as young as seven are affected
• There is a slight female predominance
• All socio-economic groups are involved, although there appears to be strong representation from teachers and health care professionals

Current research

To date no truly consistent findings have been detected which could be considered useful for routine diagnostic purposes in ME/PVFS. However, definite organic abnormalities are being recorded in a significant number of patients which may help to explain the multi-system symptomatology. These include:

• Evidence of persisting or reactivated viral infection
• Disturbances in immune function
• Structural and functional abnormalities in the CFS as detailed below.

Evidence of persisting or reactivated viral infection

PCR (polymerase chain reaction) assays from muscle biopsies showed enteroviral RNA present in 53% of patients compared to 15% of controls (Gow et al 1991). However, a larger and more recent study by the same group (Gow et al 1994), which compared PCR findings from muscle biopsies of patients to those with other types of neuromuscular disorders, found no significant differences (26% positive for patients; 20% positive in controls).

Other studies which have supported a role for persisting enteroviral infection include Bowles et al 1993 (an enterovirus group-specific probe detected viral RNA in muscle biopsy specimens from 41/158 (26%) in a patient group, compared to only 2/152 in the controls), and Clements et al 1994 (serum screened for enteroviral specific sequences by PCR assay found positive results in 36/88 (41 %) but only in 3/126 healthy controls). For further reviews of the possible role of persistent enteroviral infection see Melchers et al 1994, Muir and Archard 1994, and Swanink et al 1994.

A post-mortem report (McGarry et al 1994) on a thirty-year-old female patient found positive PCR sequences for enterovirus (comparable with Coxsackie B3) in muscle, heart and brain samples from the hypothalamus and brain stem. PCR assays to detect human herpes virus type 6 (HHV-6) nucleic acid, monocional antibodies specific to HHV-6 proteins, and primary cell culture of lymphocytes, demonstrated active replication of HHV-6, a lymphotropic and gliotropic virus (Buchwald et al 1992, Levene and Komaroff 1993). See also Yaicin et al 1994.

Infection of natural killer cells by HHV-6 has been investigated (Lusso et al 1993).

Evidence of possible retroviral involvement (De Freitas et al 1991) has not been replicated (Gow et al 1993, Khan et al 1993, Morbidity and Mortality Weekly Report 1993).

Evidence of Epstein-Barr virus reactivation; see "Investigations" and a study by Nateison et al (1994) which found high titres of anti-Epstein-Barr virus DNA polymerase in some severely affected patients.

Disturbances in immune function

A large number of subtle changes in immune function involving T cell subsets, natural killer (NK) cell activity, auto-antibodies, immunoglobulin patterns, and circulating immune complexes, have now been reported. The published findings are often conflicting and this may be related to the fact that the patients involved were not of comparable severity or duration in the course of their illness. Other variables such as age, sex and coexistent stress or infections, could also be affecting immune status. The abnormalities referred to below are not indicative of clinical immune deficiency, and patients do not go on to develop opportunistic infections as a result.

• evidence of disordered cell-mediated immunity: in vitro by impaired lymphocyte proliferation in response to mitogen stimulation, and in vivo by reduced or absent delayed-type hypersensitivity skin responses (Behan et al 1985, Kiimas et al 1990, Lloyd et al 1989)
• increased state of differentiation of peripheral T cells (Straus et al 1993)
• evidence of immune activation (Landay et al 1991 and Bates et al 1995)
• elevated levels of serum anglotensin-converting enzyme (ACE) in 80% of patients with CFIDS (US definition) compared to 9.4% in non-endemic controls (Lieberman & Bell 1993); elevations in ACE activity are also frequently reported in sarcoidosis, another condition which may involve a hyperactive immune response
• changes in natural killer cell activity, perhaps the most consistent finding to date (Caligiuri et al 1987, Ho-Yen et al 1991, Lusso et al 1993, Morrison et al 1991, Tirelli et al 1993, Tirelli et al 1994)
• raised levels of cytokines as a response to continued antigenic stimulation (Cheney et al 1989, Ho-Yen et al 1988, Lever et al 1988, Lloyd et al 1991, McDonald et al 1987, Straus et al 1989)

Precisely which of these abnormalities in the immune response might be related to symptomatology in ME/PVFS remains the subject of considerable debate. A growing interest in the way that nervous, endocrine and immune systems all interact (neuroendocrinimmunology and psychoneuroimmunology) to adapt to infections may help to provide some of the answers (Reichlin 1993).

On one side of this complex relationship, it has now been established that cytokines can be produced locally within the brain by activated glia and from immune cells which enter via the circulation. Cytokine production can, in turn, produce changes in mood and cognitive function, appetite disturbance, fatigue, increased slow-wave sleep and even the destruction of neurons. Some cytokines, particularly interleukins 1 and 6, have an important role in the control of hormones secreted by the hypothalamic-pituitary-axis. This may help to explain some of the reported abnormalities in cortisol and vasopressin secretion.

Another aspect of this bidirectional communication is the possibility that aspects of the patient's emotional state or coping mechanisms may be producing abnormalities in the immune response. One recent review (Stein et al 1991) of 22 studies on the affect of depression on the immune system concluded that there was no significant link between depression and immunosuppression. However, other studies have suggested that a reduction in the number and function of natural killer cells can occur in depressed men (Evans et al 1992), but not in depressed women. Clearly, the extent to which psychological factors can affect the immune response in a whole range of conditions has yet to be established.

Structural and functional abnormalities in the CFS
Neuro-imaging

MRI brain scans showed punctate areas of high signal intensity in the sub-cortical white matter, consistent with CFS demyeiination or oedema, in 78% of one patient group (Buchwald et al 1992). See also Natelson et al 1993 and Schwartz et al 1994a. Data from these studies suggests that some patients have an organic problem manifesting itself on neuro-imaging. However, the discovery of MR abnormalities should alert the physician to the fact that the patient's symptoms may be secondary to some other neurological condition.

SPECT scans (9gmTc HMPAO) have shown hypoperfusion in specific parts of the brain, particularly the hypothalamus and brain stem (Costa et al 1992 & 1994) and frontal or parietal lobes (lchise et al 1992, Troughton et al 1992). This pattern of hypoperfusion differs from that seen in patients with depression. The authors of a further study (Schwartz et al 1994b), which compared SPECT scan findings in CFS, AIDS dementia complex, and major unipolar depression, concluded that the abnormalities observed in the CFS group may have been due to a chronic viral encephalitis. SPECT scan abnormalities could become a useful way of following clinical progression in the disease, as well as assessing the results of treatment trials.

Hypothalamic-pituitary-axis (HPA) studies

Although a great deal of uncertainty and disagreement still surrounds many of the current research findings already described here, there is growing concensus amongst all shades of opinion that there are definite abnormalities in HPA functioning. Furthermore, some of these abnormalities are now starting to be replicated.

Evidence of upregulation of 5-hydroxytryptamine (5HT) receptors has been found (Bakheit et al 1991). These results were found to be significantly different from a control group with primary depression. With 5HT receptors exerting an important influence on corticotrophin releasing hormone (CRH) from the hypothalamus, these findings could also help to explain the abnormalities in cortisol levels described below. In addition, it is worth noting that these receptors play a vital role in temperature regulation by the hypothalamus. Bearn et al (1994) have recently demonstrated impaired prolactin responsiveness to metabolic stress (insulin tolerance test) which cannot be explained by concurrent depression.

Abnormal arginine-vasopressin secretion and control of water metabolism has been investigated (Bakheit et al 1993).

Mild hypocortisolism has been noted, possibly due to a deficit at the level of the hypothalamus or above (Demitrack et al 1991). This study used CRH to stimulate adrenocorticotrophic hormone (ACTH) release from the anterior pituitary. A significant decrease in baseline cortisol levels and an elevation in basal ACTH were found. Overall, the ACTH release in response to CRH was blunted.

This particular disturbance is again very different to that seen in a depressive illness (Ur et al 1992). Additional evidence of impaired adrenal cortical function, as shown by neuroendocrine responses to d-fenfluramine, has recently been demonstrated by Bearn et al (1994).

In studies on growth hormone (GH) release, using a dexamethasone challenge test Majeed et al (1994) showed a blunting of GH release when patients were compared to healthy controls. These results suggest that patients may have resistant type 2 steroid receptors (examethasone is a synthetic type 2 steroid agonist which stimulates GH release, and so provides a useful index of the responsiveness of type 2 steroid receptors).

One recent hypothesis (Task Force Report, page 1021) puts forward the idea that a short-lived infection, with or without the presence of stress, results in a disturbance of the HPA which then persists for a long period after the infection has been eradicated. Persistent dysregulation of the HPA then interferes with normal brain functioning, particularly in those neuronal networks where there are high concentrations of steroid receptors. Altered functioning in these systems could then account for many of the psychological and some of the physical symptoms described by patients. See also editorial by Demitrack (1994) in the Annals of Internal Medicine.

Neurotransmitter abnormalities

Significant reductions in the basal plasma levels of MHPG (3-methoxy-4-hydroxyphenyiglycol) along with increased levels of 5-HIAA (5-hydroxyindoiaecetic acid), both of which are monoamine metabolises, have been noted (Demitrack et ai 1992). The elevation in 5-HIAA is consistent with the abnormal neuroendocrine findings already referred to.

Neuropsychology performance testing
Cognitive function

Both ME and MS (multiple sclerosis) patients experience similar difficulties when required to simultaneously process complex cognitive information (De Luca et al 1993). Krupp et al (1994), however, found that cognitive defects in MS patients were more widespread than in CFS patients. Cognitive difficulties may be directly related to certain specific immunological abnormalities (Lutgendorf et al 1993).

Abnormalities in cognitive evoked potentials, particularly P3, have been noted (Prasher et al 1990), but these findings were not replicated in a further study (Scheffers et al 1992).

For further information on cognitive function research see De Luca et al 1995, Grafman et al 1993, Riccio et al 1992, Sandman et al 1993, Smith 1991, Smith et al 1993 and page 52 of the Task Force Report.

Muscle pathology

Histology, with diffuse or focal atrophy of type II fibres and mitochondrial degeneration (e.g. swelling, vacuolation, and compartmentalisation of cristae) was found in 80% of patients in one study (Behan WMH et al 1991). See also Wassif et al 1994.

Single-fibre electromyographic studies have shown very high jitter values which are not associated with impulse or concomitant blocking. Results suggest a muscle membrane disorder (Jamai and Hansen 1989). See also Connolly et al 1993; Roberts and Byrne 1994.

In the area of cellular protein synthesis, a reduction in both muscle protein synthesis as measured by 3C-leucine incorporation techniques (Pacy et al 1988) and mean muscle RNA composition (Preedy et al 1993) has been observed.

In one UK study using 31P nuclear magnetic resonance spectroscopy (Barnes et al 1993), 6 patients out of 46 showed increased acidification relative to phosphocreatine depletion, whereas 6 had decreased acidification during an exercise protocol.

However, a Canadian group (Wong et al 1992) found the same metabolic patterns in both patients and controls. These latter patients reached the point of biochemical exhaustion far more rapidly, at which point they had reduced intracellular concentrations of ATP. The latter findings suggest a defect in oxidative metabolism, possibly related to an acceleration of normal glycolysis in the working skeletal muscles of patients.

Lane et al (1994) have described a group of patients undergoing sub-anaerobic threshold exercise testing who showed abnormal lactate accumulation which correlated with the detection of enterovirus RNA sequences in muscle biopsies. These patients had normal heart rate responses to exercise and normal muscle morphometry, discounting physical deconditioning, and significantly less psychiatric morbidity than similar patients with a normal exercise test.

A small study (Brouwer and Packer 1994) has examined the characteristics of the responses evoked by transcranial magnetic stimulation in relaxed and voluntarily active muscle as a way of assessing corticospinal excitability in patients.

Other research on the strength and fatiguability of skeletal muscle has questioned whether there is any significant peripheral neuromuscular component (Lloyd et al 1988, Stokes et al 1988, Gibson et al 1993, Kent-Braun et al 1993). However, some of this research has been conducted on a very heterogeneous group of fatigued patients.

These abnormalities in skeletal muscle structure and function continue to be the subject of considerable disagreement. Although most observers would now accept that ME/PVFS is not a primary disorder of muscle, the abnormal mitochondria findings, in particular, do indicate that there could be important (and possibly treatable) biochemical problems at a cellular level.

Role of depression and psychological disorders

A number of studies have now been carried out which examine the incidence of associated depression in patients with chronic fatigue. Not surprisingly, in view of the fact that differing case definitions have been employed, there are wide variations in the extent to which a psychiatric disorder is found to co-exist. Ho-Yen and Shanks, for example, found that the presence of psychiatric disorder was very similar to that seen in various other chronic medical conditions, whereas others have described much higher (and sometimes lower) levels of depression.

When interpreting the results of these studies it should be noted that:

• depression may well be a natural reaction to both the physical symptoms and the many limitations on lifestyle imposed by the illness
• there may be active pathology within the central nervous system (e.g. persisting viral infection, immune system activation, hypoperfusion, HPA disturbance) leading to neurotransmitter and mood disturbances
• there are special difficulties in situations where key symptoms (e.g. fatigue, cognitive dysfunction and sleep disturbance) are common to both disorders.

For a detailed review of current findings in this area, please refer to the Task Force Report.

Other research findings

These have covered the following areas:

• reduced aerobic work capacity (Riley et al 1990)
• cardiac dysfunction; repetitively negative to flat T waves, alternating with normal upright T waves in a 24 hour ECG (Lerner et al 1993), and a markedly abbreviated exercise capacity characterised by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved (Montague et al 1989) - a finding which may be comparable with the effects of latent viral infection on the cardiac electrical and skeletal muscle tissues; Dworkin et al (1994) have described abnormal left ventricular myocardial dynamics; Rowe et al (1995) have studied a group of adolescents (using tilt-table testing) in whom clinically significant neurally mediated hypotension was present
• hyperventilation; no evidence that this forms part of the syndrome (Riley et al 1990); see also Saisch et al 1994
• red blood cell morphology changes; see Simpson et al 1993 and Lloyd et al 1989
• sleep disturbances are extremely common in these patients; even those who report no obvious disturbance in normal sleep patterns frequently say they are "unrefreshed" or "sleep deprived" the following morning; lack of deep restorative sleep obviously has important implications for subsequent daytime functioning, and this type of abnormality has now been linked to fibromyalgia, a condition which has several clinical similarities with ME/PVFS; abnormalities in sleep-wake rhythms may also be contributing to some of the changes in immune system function described previously; sleep disturbances which have been reported include prominent alpha electroencephalographic non rapid eye movement sleep anomaly (Moidofsky et al 1989) and a generalised decrease in sleep efficiency (Morriss et al 1993); see also Krupp et al 1993
• upregulation of the 2-5A synthetase/RNase L antiviral pathway (Suhadolinik et al 1994), a finding which is consistent with the hypothesis that an activated immune response and persistent viral infection may be playing a role in the pathogenesis; see also Matsuda et al 1994
• post-viral fatigue in athletes; a longitudinal study by Maffulli et al (1994) found that both aerobic and anaerobic exercise variables were seriously affected, and may remain so for a considerable period of time
• links between ME/PVFS and organophosphate pesticide toxicity (Corrigan et al 1994, Shepherd 1993), the post-polio syndrome (Bruno et al 1991, Dalakas et al 1986) and hepatitis B vaccination (acting as a precipitating factor) are currently being investigated

Copies of the 1994 Report of the National Task Force on ME and other Chronic Fatigue Syndromes can be obtained from Westcare.

ME/PVFS - A possible pathoaetiology

Which of the research findings already quoted are truly relevant and how they might be related to symptomatology remains uncertain. However, a hypothesis is emerging of factors which both precipitate and perpetuate ME/PVFS.

Precipitating factors include a number of common viral infections along with other agents, including immunisations and neurotoxins, which produce a significant challenge to the normal immune response. Co-factors at the onset appear to include undue physical and/or mental stress, along with the possibility of hormonal and genetic influences.

What then perpetuates the syndrome is far more speculative. The above hypothesis, which takes into account current research findings, looks at the possibility of a complex interaction between persisting and/or reactivated viral infection, immune system disturbance, and consequent abnormalities in brain and muscle function. The fact that persisting viral infection can interfere with a number of key intracellular functions without causing obvious cell damage has been well described by Oldstone (1989).

However, viruses and other trigger factors could simply be lighting the blue "touchpaper" of ME/PVFS and then having no further active involvement in the pathology. Their principle effect may well be the production of a permanent disturbance in hypothalamic-pituitary-axis function. Findings of mild hypocortisolaemia and an upregulation of 5HT receptors are certainly consistent with this theory. Disturbances in the production of cortisol could also be affecting serotonergic and noradrenergic neurotransmitter systems in the brain, which both have a high concentration of steriod receptors present.