Updated Clinical Guidelines

Support for Severely Affected ME Sufferers
Information for General Practitioners and Clinicians
Greg Crowhurst (Updated Nov 2 2009)

Introduction
There is still much confusion and a lack of accurate knowledge about severe ME/CFS in the medical profession, leaving many patients “dismissed and abandoned without support.” Hooper et al (2005) .

It is a matter of record that “the most severely affected are excluded from study in the UK.” (Hooper, Marshall & Williams 2006) Recent research by the 25% Group uncovers a shocking picture of severely ill ME/CFS sufferers being labelled as psychiatric patients, being treated with contempt by GP’s, doctors and nurses, being locked in secure units and shut in AIDS wards, being refused food and being made to participate in inappropriate graded exercise and behavioural therapy, designed to convince them there is nothing wrong with them. (Crowhurst 2005)

What is ME/CFS?

Variants of the term "M.E." were first used following a series of repeating epidemics starting in May 1955 in the Royal Free Hospital, London (Hyde 1998) . Recognised as a specific disease entity by The Royal Society of Medicine in 1978 and by the World Health Organisation since 1969 as an organic neurological disease, ME/CFS is currently classified under ICD code G93.3. In the USA, ME ranks second only to HIV as the cause of serious, long-term illness (Hooper 2004)

Cycles of severe relapse are common, as are further symptoms developing over time. Around 30% of cases are progressive and degenerative and sometimes ME/CFS is fatal. (National CFIDS Foundation). Two recent reviews have concluded that, “Substantial improvement is uncommon and is less than 6%" (Anderson et al. 2004); and, "Full recovery... is rare" (Cairns & Hotopf, 2005). According to the Chief Medical Officer (DH 2002) people with severe ME/CFS in the UK currently receive "seriously inadequate health care"

ME/CFS is characterized by (Mark 2005 ) : malaise following even modest physical activity; delayed reaction to physical and/or mental activity (up till 24 hours and more); abnormal length of convalescence (out of proportion to level of activity); varying and fluctuating symptoms during the day, but also in the course of days, weeks and months. Above all, the defining characteristic of ME/CFS is cellular metabolic (Sieverling 1999 ) and acquired central nervous system dysfunction ( Hyde 2003 )

There is a significant body of compelling published evidence, demonstrating the involvement of the central nervous system, the autonomic nervous system and the peripheral nervous system in the pathogenesis of ME/CFS, as well as immunological and vascular disruption. (Hooper, Marshall & Williams (2006) Objective evidence of quantifiable organic abnormalities in Myalgic Encephalomyelitis patients has existed since the 1950’s. (Bassett 2006) According to Professor Komaroff, a renowned world expert on ME/CFS, there are more than 2,000 papers which demonstrate that ME/CFS is an organic, not psychiatric, disorder (Hooper et al 2005).

Researchers from the Whittemore -Petersen Institute , the National Cancer Institute and the Cleveland Clinic in the USA, have discovered a significant correlation between an infectious retrovirus called XMRV (xenotropic murine-related retrovirus) and ME/CFS , potentially opening the door to useful treatments and putting an end once and for all to the psychological causation theory. (Science 2009)

A study, published in Science in October 2009 (Lombardi et al 2009), compared blood samples from 101 ME/CFS patients with samples from 218 people without it. It found evidence of the XMRV virus in about two-thirds of the people with ME/CFS and less than 4% of people without the disease. Novel associations of such magnitude are rarely found between long-standing chronic illnesses and infectious agents. (ME Research UK 2009)

This finding potentially has serious health implications not only for patients and those caring for people with ME, but for the entire population.

What ME/CFS is not :

ME/CFS and Chronic Fatigue are not the same. ME is formally classified as a neurological disorder in the International Classification of Diseases (ICD10:G 93.3; WHO 1992), and the ICD separately classifies fatigue syndromes as a behavioural (psychiatric) disorder (ICD 10:F 48) Researchers have failed to distinguish between ME and CFS and/or between subgroups. (Anon 2001) As Carruthers & van de Sande (2005) point out : “ Chronic fatigue must not be confused with ME/CFS because the ‘fatigue’ of ME/CFS represents pathophysiological exhaustion and is only one of many symptoms.

ME/CFS is not a somatoform disorder. The documented biochemical, metabolic, vascular, neurological and muscle abnormalities in ME/CFS patients (Williams 2004) have led to the WHO classification of ME/CFS as a neurological illness. The UK Department of Health and the WHO Collaborating Centre at the Institute of Psychiatry have agreed that ME/CFS is undoubtedly neurological. There is no published evidence whatsoever, as opposed to opinion, that ME (as distinct from chronic fatigue) is a psychiatric disorder. (Williams 2004). Unlike somatisation disorder, M.E. is not ‘medically unexplained.’ M.E. is a multi-system disease with many organ and bodily systems affected, producing a myriad of symptoms [and] many aspects of the pathophysiology of the disease have, indeed, been medically explained in volumes of research. (ME Society of America )

ME/CFS is not “cured” by Cognitive Behavioural Therapy (CBT) and Graded Exercise (GET). CBT and GET are not accepted in the British Formulary for ME and therefore cannot be considered automatically to be within the legal framework for treatment, especially for the severely affected . (25% Group 2005) CBT and GET are potentially harmful to anyone with neurological ME. The Chief Medical Officer (2002) has warned that exercise-based regimes advocated for less severely affected patients tend not to have been studied among those most severely affected. Shepherd (2001) warns that as much care should be taken in prescribing exercise as in prescribing pharmaceuticals for ME/CFS patients do not respond to exercise in a manner that is expected of healthy people (Streeten et al 2001) A recent study (2009) has found that it is “unethical to treat patients with ME/CFS with ineffective,
non-evidence-based and potentially harmful “rehabilitation therapies”, such as CBT and GET”

It is not 'fatigue' or 'tiredness' that is the one essential characteristic of ME/CFS but central nervous system (CNS) dysfunction (Bassett 2006). As leading M.E. expert Dr Byron Hyde MD (2003 ) explains: 'The one essential characteristic of M.E. is acquired CNS dysfunction, [not] chronic fatigue. A patient with M.E. is a patient whose primary disease is CNS change, and this is measurable. We have excellent tools for measuring these physiological and neuropsychological CNS changes: SPECT, xenon SPECT, PET, and neuropsychological testing.' Drs Cheney and Peterson describe ME/CFS as ‘A global disablement, nearly comparable to paralysis.’ (Johnson 1996 ) Dowsett comments that ‘"Fatigue" is the wrong word. Fatigue is a silly word.’ (Colby 1996 ) Dr David Bell M.D (1995 ) describes the word “fatigue” as: 'A very inappropriate term for what patients experience. It’s not really fatigue at all, which is defined as a normal recovery state from exertion and that is precisely what does NOT happen in this illness. ‘ In 2003 The Canadian Expert Consensus Panel published a medical milestone, the first clinical case definition for the disease known as myalgic encephalomyelitis/chronic fatigue syndrome, making it compulsory that in order to be diagnosed with ME/CFS, a patient must become symptomatically ill after exercise and must also have neurological, neurocognitive, neuroendocrine, dysautonomic, and immune manifestations. In short, symptoms other than fatigue must be present for a patient to meet the criteria. (Carruthers et al 2003 )

ME/CFS is not depression. Research, for example, shows that CFS patients show more alpha electroencephalographic activity during non-REM sleep, but this is not seen in dysthymic or major depressive disorder (Whelton, Salit, & Moldofsky, 1992 ). Cognitive changes are also not due to psychiatric co-morbidity (Vercoulen et al 1998 Backwood et al 1998 ) SPECT cerebral blood flow studies of persons with CFS show decreased blood flow in several key areas such as frontal lobes and brain stem which are different from both healthy controls (Barnden et al, 2001 Costa et al, 1995 ) and depressed subjects (Schwartz et al, 1994 ; Fischler et al, 1996 ). PET scan studies have reached similar conclusions (Tirelli et al, 1998 ). Bakheit, Behan, Dinan, Gray, and O'Keane (1992) found up-regulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. Hickie (1991) found that general characteristics of depression: anhedonia (lack of pleasure in life); weight loss; suicidal ideation; severe psychomotor change; pathological guilt; and severe anxiety, are not typical in ME/CFS.

The predominant psychiatric paradigm, still seems to be that patients have medically unexplained chronic fatigue, and that their problems derive from deconditioning consequent on physical inactivity at best, and simple avoidance behaviour (underpinned by abnormal illness beliefs) at worst.. (Scottish Cross Party Submission 2005 ). What happens in ME/CFS, however, has little to do with cardiovascular deconditioning (Spence & Stewart 2004) and is more related to chronic orthostatic intolerance/postural tachycardia syndrome (POTS), caused by vascular dysfunction. Goudsmit (2005) points out that studies have shown that most patients do not avoid minimal activity and that lack of fitness is not related to the fatigue in CFS (Bazelmans et al 2001 ) . Moreover, deconditioning cannot explain the documented delay between the end of exertion and the exacerbation of symptoms, the upregulated immune system etc. (De Merlier et al 2000 )

DIAGNOSIS & TREATMENT

Although , as with lupus, multiple sclerosis and ovarian cancer for example, there is no medical test available to confirm a diagnosis of M.E, it is absurd to claim no objective or quantifiable abnormalities can be found in patients with severe M.E. (Bassett 2006 ) “Tests will only all be normal in M.E. patients – as with all illnesses – if completely the wrong tests are done, or if those tested do not in fact have M.E. in the first place.” (Bassett 2006) . Tests which can aid diagnosis include :

• SPECT and xenon SPECT scans of the brain : to measure decrease in cerebral blood flow, especially 24-48 hours after exertion. Recent studies have shown that 80% of ME/ICD-CFS patients will have abnormal SPECT scans. These abnormalities have also been shown to correlate with clinical status. (Carruthers et al. 2003)

• MRI scans of the brain : Punctate, subcortical areas of high signal intensity consistent with edema or demyelination were identified by MRI in 78% of ME/CFS patients (similar to those seen in MS). The abnormalities in M.E. patients most closely resemble those seen in AIDS encephalopathy. Research has shown that 50% - 80% of ME/CFS patients will have abnormal MRI scans. (Hyde, 2003) (Carruthers et al. 2003)

• PET scans of the brain. PET scans have shown decreased metabolism of glucose in the right mediofrontal cortex. PET scans have also shown generalised hypoperfusion of the brain with a particular pattern of decreased neuronal metabolism in the brain stem. (Carruthers et al. 2003)

• Neuropsychological testing : to measure cognitive function. Bastein (1992) states : “ Deterioration of IQ levels, as well as cognitive and motor dysfunction in these patients, suggest a pathological process in the brain. The pattern of focal and lateral impairments is consistent with patients who have this particular neurologic dysfunction. The impairment pattern is consistent across the study group [of M.E. patients] although impairment levels vary. This pattern is not seen in other diseases or injuries.”

• EEG brain maps and QEEG brain maps 95% of ME/ICD-CFS patients have been found to have abnormal cognitive-evoked EEG brain maps (Hooper, 2001 ) An (astonishing) degree of cerebral hypoperfusion, hypometabolism in the right mediofrontal cortex and brainstem; damage to the endothelium in blood vessels supplying the brain, spinal cord and nerves; bacterial infection of the brain, decrease in cerebral blood flow, punctate, subcortical areas of high signal intensity consistent with edema or demyelination and significant cognitive impairment, a significant decline in grey matter volume – a reduction of 8% on average in ME patients, altered permeability of the blood-brain barrier; all of these neurological defects are well documented in ME .

• Romberg or tandem Romberg test : ‘In his 1995 Australian Workshop, [ME/ICD-CFS expert Dr Paul] Cheney said that more than 90% of patients have an abnormal Romberg versus 0% of controls.’ (Hooper et al. 2001)

• Tests of the immune system : The immune system abnormalities in M.E. patients mimic the immune pattern seen in viral infections. (McLaughlin ,) (Carruthers et al. 2003) (Hooper et al. 2001) Increased numbers of activated cytotoxic T cells (most patients have evidence of T-cell activation) Reduced T-Cell count , Low natural killer cell numbers/percentage and function (cytotoxicity) , Elevated immune complexes , Atypical lymphocyte count , Significantly reduced CD8 suppressor cell population and increased activation marker (CD38, HLA-DR) on CD8 cells, Abnormal CD4/CD8 ratio ANA , Elevations of circulating cytokines (including IL-6) particularly after exertion (there is an inappropriate and negative immune response to exertion) , Immunoglobulin deficiencies (most often IgG 1 and IgG 3) , Th1/Th2 Imbalance (some patients appear to have an over activation of the anti-inflammatory (Th2) branch and an under activation of the pro-inflammatory (Th1) branch of the immune system. This would explain increased rates of allergies and sensitivities, and conversely, difficulty fighting off pathogens), Th1 –Th2 response to mitogen stimulation (high levels of Th2 indicate autoimmunity) ,Antilamin antibodies (indicate autoimmunity and brain cell damage. Lamin B antibodies are evidence of autoimmunity) , Apoptosis is often raised (this is programmed cell death: known to be raised in infection) , Monocytosis (raised monocytes are suggestive of infection); these are all common findings in ME patients and are well documented.

• Physical Examination : In a recent 25% Group survey of the most severely affected (Crowhurst 2005 ) 71% of respondents reported that they experience 20 or more severe autonomic, endocrine, neurological and immune system manifestations each. Physical signs of illness commonly observed in ME/ICD-CFS patients include: Nystagmus; nystagmus is jelly-like and variable (15% of M.E. patients will have nystagmus) , Sluggish visual accommodation , Unequal pupils and contrary pupil reaction to light; A labile blood pressure (sometimes as low as 84/48 in an adult at rest) ; Shortness of breath (particularly on exertion) ; Sometimes marked falling pulse pressure in arterial pressures taken first when prone, then sitting, then standing ; Rapid heart rate on minor activity such as standing; Subnormal temperature ; Patients show significant reduction in all lung function parameters tested; Liver involvement (an enlarged liver or spleen) ; Abnormal tandem or augmented tandem stance; Abnormal gait ; Hand tremor ; Incoordination; Cogwheel movement of the leg on testing ; Muscular twitching or fasciculation ; Hyper-reflexia without clonus ; Facial vasculoid rash; Vascular demarcation which can cross dermatomes with evidence of Raynaud's syndrome and / or vasculitis and spontaneous periarticular bleeds in the digits ; Mouth ulcers ; Hair loss ; Atrophy of fingerprints is due to perilymphocytic vasculitis and vacuolisation of fibroblasts ; Ghastly pallor of face with frequent lupus-like submaxillary mask ; Parkinsonian rigidity of facial expression; Scanning, disjointed speech, or speech reversals ; Nasal passage obstruction and inflamed areas around tonsillar pillars ; Sicca syndrome of conjunctiva and mucous membranes ; Frequent equivocal Babinski/plantar reflex on one side ; Unusual sensitivity of cervical vertebrae area; (Hooper et al. 2001) (Hyde, 2003)

It is very important that a diagnosis is reached as early as possible (ie. within a period of between 3 – 6 months) so that appropriate advice and treatment can be started as early as possible. Doctors and clinicians can help by: (extract from CMO Report Annex p.12)

• listening to the patient, recognising and believing his or her individual experience
• acknowledging uncertainty and the impact that this has on the patient, family, and carers
• providing support and encouragement – e.g. during setbacks
• providing information on and discussing the nature of the condition, approaches to self management, helpful therapies, and how to access other agencies and services
• agreeing upon a name for the condition
• giving advice on symptomatic treatment

Treatments

There are no known appropriate treatments available at this time and it has been found that some of the so-called mainstream therapies applied to ME sufferers have been unhelpful or harmful on many occasions (especially treatments such as Cognitive Behavioural Therapy and Graded Exercise Therapy). Of those who tried Graded Exercise, 95% of Respondents, in the latest 25% Group survey, reported that it had a negative impact on them and 96% reported that Cognitive Behaviour Therapy had a negative impact. (Crowhurst 2005)

Probably the most beneficial approaches to take with ME Sufferers (especially at the early, acute stage) is rest the ongoing process of learning : “when you can, when you can’t and when you might” (Crowhurst L 2004 )

It is essential to adopt a positive outlook and to work constructively and creatively with patients who have severe ME/CFS. The doctor who is willing to work in partnership and communicate sensitively with patients, developing a trusting, caring and professional relationship can make a real difference to the quality of life of these patients.


References available upon request

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