ME/CFS in the 21st Century.

[Guest guest]

ME/CFS in the 21st Century.

By Dr Abhijit Chaudhuri

(Dr Chaudhuri is clinical senior lecturer in neurology at

the University of Glasgow and consultant neurologist in the

Institute of Neurological Sciences, South Glasgow

University Hospitals NHS Trusts. He co-authored The ME

Association booklet ME/CFS/PVFS: An exploration of the key

clinical

issues.)

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Chronic fatigue syndrome (CFS) is characterised by

otherwise unexplained, overwhelming, persistent, relapsing

fatigue of new onset in variable combination with post

exertional malaise, unrefreshing sleep, self reported

impairment in short-term memory, headache, muscle and joint

pain.

CFS is recognised worldwide and in all age groups, usually

affecting more women than men. As yet, there is no specific

or sensitive laboratory test for CFS and the diagnosis is

made by exclusion of known disorders of chronic fatigue

(symptomatic chronic fatigue). Because of its chronicity,

lack of effective therapy and consequent disability in

adults, a diagnosis of CFS has significant socio-economic

impact.

Full recovery is unlikely in the majority of adults who

have been symptomatic for over four years. In a number of

cases, initial periods of remission and stability are

followed by rather unpredictable relapses and subsequent

deterioration. Paediatric CFS is generally believed to have

a better outcome, although there have been few systematic

studies to confirm this impression. Atopic symptoms

(asthma, eczema or allergy) have been frequently noted in

children who develop CFS after a viral infection.

CFS, in reality, is an umbrella term. Together with

patients having characteristic symptoms of ME (myalgic

encephalopathy/encephalomyelitis) or PVFS (post viral

fatigue syndrome), a diagnosis of CFS may also be applied

to patients with depressive or somatising fatigue.

One set of clinical diagnostic criteria (the Oxford

Criteria) is far too imprecise to be clinically useful but

has been widely used in the epidemiologic studies and

intervention trials of CFS. Since patients with

neurogenic chronic fatigue (ICD G93.3) are sufficiently

distinct from somatising or psychogenic chronic fatigue

(ICD F48.0), it is difficult to see how the proposed

interventions in CFS (graded exercise therapy and

cognitive behavioural therapy) might equally apply to the

ME/PVFS subgroup especially when these interventions were

based on the psychogenic paradigm of chronic fatigue.

Unfortunately, the traditional medical establishment

refuses to acknowledge this point of difference dismissing

the lack of efficacy of GET and CBT in many ME/CFS patients

as anecdotal and the reluctance to accept these

interventions as irrational.

There is also a recurrent theme in many quarters that

ME/CFS patients wilfully impose on themselves a level of

physical rest that is far greater than indicated. An

extrapolation of this is the view that these patients show

avoidance behaviour to physical activities and that fatigue

in these

cases is due to physical deconditioning and somatisation.

The failure to segregate neurogenic and somatising

subgroups of chronic fatigue lies at the heart of the

controversies surrounding ME/CFS at present. This is

unfortunate and, to an extent, artificially imposed by the

use of the broad diagnostic term, " CFS " .

The challenge of segregating neurogenic and somatising

symptoms in clinical practice, however, is neither new nor

uncommon. As an example, it would be imperative to

clinically distinguish epileptic seizures from

pseudoseizures because management will substantially differ

with very different implications on life-style (e.g.

driving). Similarly, a patient with common migraine will be

approached rather differently from a patient with headache

due to anxiety or headaches of non specific cause.

Nevertheless, there is a fairly widespread belief that the

MC/CFS patients are " depressed " or simply " unable to get

along with their lives " , based essentially on the

psychiatric data and some may even record ME/CFS as a

" non disease " . There are few examples in the history of

medicine where an unproven hypothesis has been so

retrogressive.

The international criteria for CFS introduced in December

1994 (the CDC criteria) emphasises exclusion of all

diseases that could explain fatigue. However, there is

little doubt that the current diagnosis of CFS still

selects a heterogeneous population. ME/CFS patients can be

reliably

distinguished from those with depression and fatigue in

these cases does not respond to antidepressant therapy.

Despite suggestions that CFS may be due to somatisation, no

more than 5% of CDC-defined CFS patients fulfil the

diagnostic criteria for somatisation disorder. Present

clinical data indicate that psychological co morbidity in

CFS is modest and has been over-emphasised in the

psychiatric literature probably as a result of selection

bias.

It has also been shown in a recent study that pre morbid

psychiatric history did not predict future development of

CFS after infectious mononucleosis. Finally, the results of

the intervention studies in CFS using graded exercise and

CBT provide no information on the underlying

pathophysiology

that may apply to ME/CFS.

Typically, community acquired common viral infections

trigger ME/CFS symptoms in previously healthy and often

physically active individuals. In the past century,

epidemic outbreaks of CFS type symptoms were recognised

after viral infections and were variously termed

neuromyasthenia or atypical poliomyelitis. ME/CFS type

fatigue is also common in other post-viral neurologic

disorders like post-polio syndrome (PPS), Guillain Barre

syndrome (GBS) and multiple sclerosis (MS).

There is little evidence to suggest that fatigue symptoms

in GBS, MS or PPS are caused by depression or persistent

infection due to the offending viruses. Thus the paradigm

of chronic fatigue in ME/CFS is likely to follow comparable

paradigms associated with fatigue and neurological

dysfunction in PPS, GBS and MS. There have been sufficient

clues for research in this direction in the 21st Century

beyond the simplistic model of functional somatic syndrome

propagated in the past decade. Already, there exists a

substantial body of research on the neuroendocrine

dysfunction, dysregulated hypothalamic pituitary adrenal

axis, skeletal muscle bioenergetics and subtle

immunological dysfunction in CFS.

It has been recently pointed out that acquired defect in

the norepinephrine inactivation may lead to symptoms of

orthostatic intolerance and postural tachycardia that are

common in young women who may also experience chronic

fatigue. Indeed, younger CFS patients are highly sensitive

to orthostatic challenge, often have marked postural

tachycardia and may lose significant amount of body weight

consequent to ME/CFS, presumably in response to the

exaggerated norepinephrine-effect that may be overlooked as

chronic anxiety. There is an emerging view that the

clinical diagnostic criteria must be amended to recognise

the common autonomic symptoms in ME/CFS. A modified set of

diagnostic criteria for research definition of ME/CFS has

been recently

proposed for wider consultation (see Table).

Based on the observation that there is an undisputed link

between an antecendent viral infection and subsequent

dyresregulation in the neurotransmitter and/or

neuro-hormone functions in a significant proportion of

ME/CFS cases, how can one explain the development of

neurogenic chronic

fatigue?

It is long recognised from the laboratory experiments that

viruses can affect more differentiated ( " luxury " ) functions

of the cells without causing cell death. These specialised

functions may involve neurotransmitters and pituitary

hormones. In the peripheral nervous system, acquired

deficiency of muscle metabolic enzyme (e.g. myoadenylate

deaminase deficiency) may be seen after systemic viral

infections. It is widely known that sustained changes

in cell membrane function may follow viral infections and

after exposure to specific neurotoxins (e.g. ciguatera

toxin).

The time has now come to research how chronic adaptation of

the host cells to residual viral proteins and toxins might

modify cell functions that may persist long after

symptomatic recovery in a proportion of cases and lead to

the spectrum of post-viral neurological syndromes. Early

data from our laboratory indicate that the glial cells in

the central nervous systems are particularly vulnerable to

postviral modifications in function. This is not surprising

since in MS, which often follows viral infections and where

chronic fatigue is common, demyelination results from the

oligodendroglial injury in the central nervous system.

Subjective fatigue is a complex symptom and is probably

best understood as the outcome of a variable combination of

physiological and neuropsychological changes induced by the

primary disease process. Downstream links between brain,

neuro-muscular and the cardio-respiratory functions are

implicated in the neural control of force output during

exercises in health and disease.

Higher perceived effort in neurogenic fatigue is caused by

the central mechanisms while the sensory input to these

neural regulatory mechanisms may limit endurance to maximal

and sub-maximal exercises. It needs to be explored whether

individual predispositions to the host viral interaction

may determine the consequent change in the functions of

specific neurotransmitters, receptors, ion channels and/or

enzymes at the different neuro anatomic levels that may

lead to the development of the ME/CFS symptoms.

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Table:

Proposed diagnostic criteria for CFS for consultation:

Essential criteria (all must be fulfilled)

1. New onset, persistent or relapsing fatigue lasting for

more than six months

2. Failure of rest to improve symptoms

3. Post-exertional malaise lasting for >24 hours

4. Reduced attention span and/or concentration.

5. Significant reduction in all levels of activity

(personal activities of daily living, professional, social

and occupational)

6. Lack of clinical evidence of any concurrent medical or

psychiatric disease; side-effects due to drugs or their

withdrawal

7. No past history of somatisation disorder

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Supportive criteria

(patients must fulfil at least five criteria):

1. Dysautonomic symptoms (orthostatic intolerance and/or

hypotension, dry mouth, temperature changes, fainting and

seating attacks)

2. Vertigo or dysequilibrium (in the absence of orthostatic

changes)

3. Unrefreshing sleep or altered sleeping pattern

4. New onset alcohol intolerance

5. Muscle pain or cramp affecting two or more limbs

6. Any or all of (new onset): daily headache, chest pain

(SyndromeX), asthma/atopy, recurrent attacks of sore

throat, worsening premenstrual symptoms in women of

reproductive age

7. Physical evidence of any or all of: abnormal orthostatic

changes in heart rate and/or blood pressure, altered

sensory threshold to cutaneous sensations, fine distal

tremors.

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Acknowledgement

Abhijit Chaudhuri is supported by the Barclay Research

Trust held at the University of Glasgow.

Reference

Chaudhuri A, Gow J, Behan PO, Chronic fatigue syndrome and

systemic viral infections: current evidence and recent

advances. In Abramsky O. Compston DAS, A, Said

G(eds). Brain disease: therapeutic strategies and

repair. London: Dunitz 2001; pp127-135.

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