Download Chronic Fatigue Syndrome ME a real disease

Chronic Fatigue Syndrome/ME:
A real disease?
Gavin Spickett
Consultant Clinical Immunologist
Royal Victoria Infirmary
Chronic Fatigue Syndrome
(ME)
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What is it?
Is it a real illness?
What are the
symptoms?
How is it treated?
What is the prognosis?
How will affect
patients?
What is chronic fatigue?
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Fatigue and tiredness
are not the same!
Because there is little to
see and no specific
findings on examination
or routine tests it is
easy to dismiss it as
psychologically based
Good fun for
cartoonists – but not
much fun for patients
What is chronic fatigue?
CFS/ME affects all social classes and all races but healthcare behaviour when ill
biases social analysis limited to clinic referral!
What is CFS(ME)?
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Classified by WHO in ICD-10 as a neurological
disorder G93.3
Medical unexplained
 Physiologically distinct from depression
 Identifiable immunological, neurological,
endocrine abnormalities that are consistent
It is not a somatisation disorder
 Somatisation may present as CFS and forms part
of the differential diagnosis
 Medically unexplained does not equal
somatisation!!
What is CFS/ME?
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Severe debilitating fatigue causing
interference with normal functions.
No evidence for other medical or psychiatric
problems.
Typical history
No pointers on examination to alternative
diagnoses.
Blood tests are normal
What is fatigue
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Fatigue is not the same as tiredness and is
not relieved by sleep or rest.
It is common to a broad range of chronic
medical illnesses.
Our understanding and recognition of the
importance of fatigue in chronic illness is
improving.
Fatigue
Fatigue
Chronic infection
Connective tissue
disease
Autoimmune
disease
Sleep
disturbance
Organic brain
disease
EBV
Toxoplasma
HCV, HIV (AIDS)
Brucella
Lupus
Rheumatoid arthritis
Polymyositis
Coeliac disease
Thyroid disease
Addison’s disease
PBC
Sleep apnoea
Sleep deprivation
narcolepsy
Alzheimer’s
MS
Parkinson’s Disease
Primary psychiatric
Also consider other organ-based disease (lung (COPD), heart, liver, kidney, bowel),
malignancy and chemotherapy/radiotherapy, brain injury, PTSD, diabetes
History of CFS/ME
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Not a new illness!
Almost certain medical descriptions from 1750
onwards
Neurasthenia described in mid 19th Century
1936 – Winsconsin Convent disease
1937-1939 ‘abortive polio’ in Swiss Towns and Army
1938 – polio-like illness in Los Angeles
History of CFS/ME
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Epidemics of polio-like illnesses worldwide
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Iceland – Akureyri disease
Adelaide – 800 people ill from 1949-1951
Other affected Countries included USA.
Denmark, South Africa
Royal Free Disease 1955 (benign myalgic
encephalomyelitis
Lake Tahoe outbreak 1980’s (“Raggedy Anne
syndrome”) – originally thought to be ‘chronic
EBV’ – subsequently refuted
George Miller Beard
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1839-1883
Graduated from Yale
1862
Served as assistant
surgeon US Navy in
American Civil War
Champion of
‘electrotherapy’
First described
Neurasthenia
Neurasthenia
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A condition characterised by
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Fatigue
Anxiety & Depression
Headache
Impotence
Neuralgia
Exhaustion of the nervous system’s energy
resources
Associated with ‘the stress of urbanisation’
Neurasthenia
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Concept remained popular into early 20th
Century
Other synonyms include
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Effort Syndrome
Da Costa’s syndrome
Thought to be behavioural
Now consigned under ICD-10 to classification
F48 – Other Neurotic Disorders!
Royal Free Disease
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1955 outbreak at
RFH in London
affecting staff
Associated with
inflammation of brain
and spinal cord
Neuroimmune
pathogenesis
suggested
Epidemic vs Sporadic Disease
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Epidemic form described by Psychiatrists
McEvedy and Beard as ‘mass hysteria’ in 1970
Findings refuted subsequently (poor descriptions
of patients)
Symposium 1978 at RSM concluded that
epidemic myalgic encephalomyelitis was a
distinct disease entity
Epidemic form not seen now
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Last epidemic at Lake Tahoe mid-1980s
Unclear why
Strongly suggestive of infectious agent
No agent ever identified for main epidemics
Epidemiology
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Prevalence of 0.2-0.4%
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Average GP practice of
10,000 will have up to 40
patients
Estimated annual
prevalence 4000
cases/million population
Recognition of CFS/ME
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Gradual acceptance of reality of the illness at official
levels
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1996 - Kenneth Calman (CMO) commissioned report form
Royal Colleges
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2002 – Report by Liam Donaldson (CMO)
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Royal Colleges of Physicians, Psychiatrists and General
Practitioners. Chronic fatigue syndrome: Report of a joint working
group or the Royal Colleges of Physicians, Psychiatrists and
general Practitioners. London, 1996
CFS/ME Working Group. A report of the CFS/ME working group:
report to the Chief Medical Officer of an independent working
group. DH, 2002
2005-6 DH funded specialist services for CFS/ME in
England (but no funded services in Scotland or N. Ireland)
Is it a real illness?
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Medically unexplained = patient is mad or
bad!
Almost all patients are devastated by their
illness and suffer depression as a result.
Most will suffer severe hardship with loss of
income, job, loss of hobbies, marital
difficulties.
Difficult to conceive that the majority of
patients would wish to continue in this state
CFS/ME as a Psychological
Disease?
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Assumed (by Psychiatrists and
Psychologists) to be:
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Variant of depression/anxiety
Somatisation
Factitious illness
Lack of acceptance in some quarters of
medical profession that this is an illness with
real physiological abnormalities distinct from
those seen secondary to depression
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Many GPs still treat fatigued patients with antidepressants despite the lack of evidence for
depression or benefit from the drugs.
CFS/ME as a Psychological
Disease?
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1997: Elaine Showalter described CFS as a
“hysterical narrative” – a modern
manifestation of hysteria, a self-perpetuating
“cultural symptom of anxiety and stress”
(Hystories: hysterical epidemics and modern
culture)
Is it a real illness?
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Scientific evidence now points to underlying
physiological abnormalities.
Psychiatric symptoms are secondary.
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Anger
Frustration
Reactive depression and anxiety
Aetiology
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Uncertain
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Two presentations:
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Acute, usually following infective sounding illness
Gradual, no obvious predisposing factors
Unclear whether these are the same or separate
illnesses
Infectious Agents
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Through 1960s disease attributed to chronic
EBV (USA rules for benefits suggested patients
must have high antibodies to EBV!!) ; other
Herpes viruses (CMV)
1960s-1970s attributed to chronic Brucellosis
1990s suggestion of association with retrovirus
HTLV-II (later refuted)
1990s association with Coxsackieviruses
popular (based on poor quality test)
Infectious Agents
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2009 – report from
USA associating
CFS/ME with murine
endogenous
retrovirus XMRV
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2010 – 2011: findings
not repeated.
Original Lab confirms
contamination
Aetiology
Genetic
predisposition
Chronic fatigue
syndrome
Intercurrent
infection
Psychosocial
background
Aetiology
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Evidence supporting an organic basis against
a psychological basis
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Neuronal abnormalities
Neurocognitive disorder
Autonomic dysfunction
Functional MRI scanning muscles
Genetic predisposition (multiple genes, immune
system, brain); runs in families
Endocrine abnormalities (adrenocortical axis, sex
hormones)
Genetic predisposition
Psychosocial background
Triggering event (infection)
Dysfunctional immunological response
Chronic cytokine abnormalities
Endocrine disturbance (adrenocortical axis)
Autonomic dysfunction
POTS, postural hypotension,
abnormal muscle and skin blood flow
Mitochondrial abnormality?
Aetiology
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Genetics
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Evidence for specific patterns of gene
activation/repression in CFS
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Brain – neuronal function
Immune system regulatory genes
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Apoptosis
Cytokines
Endocrine system
Cardiovascular system
Mitochondrial function
Likely to be polygenic
Aetiology
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Infectious triggers
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Any infection
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Viral
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Bacterial
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Herpes viruses (EBV, CMV, HHV6, HHV7
Ross River virus
Borna Disease
Parvovirus
Severe pneumonia
Parasitic
Aetiology
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Psychosocial background
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Increase in major life events in year preceding
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Divorce
Bereavement
Unemployment
High proportion of patients have history of
abuse (sexual, physical, mental)
Autonomic disorder
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Evidence that dysfunction of
autonomic system correlates
with level of fatigue
Associated with
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Heart rate and blood pressure
abnormalities
Disordered blood flow in skin
(temperature dysregulation,
sweating)
Muscle pain (failure to clear
lactate on exercise)
Bowel symptoms
Breathing difficulty (increased
awareness, subjective
shortness of breath)
Aetiology – other factors
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Immunological abnormalities
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Cytokine disorder (excess IL-6)
Altered Th1-Th2 balance
Reduced natural killer cells
Disordered gene activation (over/under)
Endocrine abnormalities
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Hypothalamic-Pituitary axis
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Low cortisol
Enhanced feedback sensitivity
Reduced oestrogen and testosterone
Aetiology – other factors
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Oxidative stress
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Mitochondrial disorder
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Abnormalities of genes involved in control of
oxidative stress
Unproven
Mitochondrial myopathies form part of differential
diagnosis
Toxins
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Organophosphate insecticides - unproven
PET Scan Abnormalities
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Evidence on functional
brain scanning for
reproducible
abnormalities
Abnormalities are
different from those
seen in depression!
Evidence of
neurocognitive disorder
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Short-term memory
Word-finding difficulty
Aetiology
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There is no evidence that CFS(ME) is caused
by:
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Amalgam fillings
Chronic candida overgrowth syndrome
Environmental intolerance
Food allergies (common and occur by chance
together with CFS)
Undiagnosed thyroid disorder (NHS tests ‘no use’)
What are the symptoms?
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Symptoms are very
stereotyped
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However symptoms are
not unique to CFS/ME.
Typical symptoms
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Flu-like malaise
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Muscle, joint pain,
cramp
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Intolerances
Worse after activity
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No joint swelling
Tenderness at FM points
Disturbed body
temperature
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Inappropriate to environment
Inappropriate sweating
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Noise
Light
Touch
Smell
Medications
Dizziness
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Pre-syncope
Blackouts
Postural hypotension
Typical symptoms
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Palpitations
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Anxiety
Postural
Bloating
Diarrhoea/constipation
Food intolerances (NOT
allergy!!)
Headache/migraine
Tinnitus, vertigo
Pins & needles
Neurocognitive
problems
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Irritable bowel (100%!)
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Unrefreshing sleep
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Poor concentration
Poor short term memory
Word-finding difficulty
Sleep disturbance
Worse with over-exertion
Sore throat/swollen
glands
Presentation
Diagnosis of CFS
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Diagnosis is primarily one of exclusion
Diagnosis is therefore difficult and dependent
on the skill of the clinician
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Fatigue is not a unique symptom!
Fatigue is the final common pathway of many
discrete diseases
Fatigue has a complex aetiology and involves
multiple organ systems
Fatigue is NOT the same as tiredness
Chronic Fatigue Syndrome
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Exclusions to diagnosis of CFS (Fukada)
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Organ failure (emphysema, cardiac, liver, kidney)
Chronic infections
Rheumatic/chronic inflammatory conditions
Major neurological disease (MS, Myasthenia)
Systemic treatment for neoplasms
Untreated endocrine disorders
Primary sleep disorders (narcolepsy, sleep apnoea)
Obesity (BMI > 40)
Alcohol/substance abuse
Reversible causes of fatigue (operations, medication)
Psychiatric disorders (depression, bipolar disorder, psychosis,
eating disorders)
Chronic Fatigue Syndromes
Irritable bowel syndrome
CFS
(post-viral fatigue)
Fibromyalgia
POTS
Over-training syndrome
Chronic Fatigue Syndrome
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Referrals from primary care
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Strict referral criteria
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Pre-referral screening bloods
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Duration of fatigue
No identifiable cause
Need to be up-to-date
Screen out many treatable causes so that
inappropriate therapy is not offered
N.B. – there is no single diagnostic test to confirm
or refute the diagnosis
Medical Screening
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Referral from primary care (6 minute
consultations); pathway with pre-screening
Role of experienced physician/paediatrician
Identification of non CFS/ME conditions
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49% of referred patients do NOT have CFS/ME
Identification of important CFS-related conditions
for which specific drug treatment may be required
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Pain
POTS
Sleep disturbance
Secondary depression
Outcome of Clinical
Assessment
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2007 – 49% of patients referred from primary care
do NOT have CFS/ME
2010 – Same figure, also replicated by CFS Service
at St. Bartholomews Hospital, London
Clinicians getting better at identifying other causes
Earlier referral – other diseases may not yet have
fully declared themselves
Refer on to therapy teams for management where
CFS/ME confirmed (CBT therapist, OT, Physio,
Nurse)
Clinical Services
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Set up and funded by DH after CMOs report
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Only for England and Wales
No services in Scotland
£8.5m investment
Requirement on PCTs to fund services (!)
Regional Networks and Area Teams
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Varying structures, pathways and models of care!
Varying effectiveness
Clinical Services
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NICE Guidelines introduced in August 2007
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Recommendations for referral and management
Recommendations regarding appropriate and
inappropriate treatments
Although these are ‘Guidelines’, clinicians are
‘expected’ to use them and PCTs are ‘expected’ to
fund the services!
Recognised that “CFS/ME should be considered
as disabling a condition as multiple sclerosis or
rheumatoid arthritis”
NICE Guidelines
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Judicial Review granted in June 2008
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2 patients challenged the Guidelines on the basis
that NICE recommended only treatments (GET
and CBT) that in their view would be harmful to
their health
Witness statements for the appellants attacked
both the process, including selection of experts,
and the individuals involved in the process directly
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Irrationality of decision to recommend CBT & GET
Pre-determination (i.e. selection bias in evidence and
members of panel)
NICE Guidelines
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Judicial Review under Justice Simon reported on
13th March 2009 ([2009] EWHC 452 (Admin))
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Dismissed the irrationality argument
Concluded on the issue of pre-determination that
appellants allegations against the individuals were
unfounded and biased by the use highly selective
quotations taken out of context
Concluded that the selection process by NICE was
appropriate
Concluded that the appellants could not be held to
represent the CFS/ME community
Drew attention to the damage that the personal attacks on
individual members would have on recruitment to NICE
panels and on scientific enquiry
Therapy Interventions
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Therapy interventions based around models
used for chronic pain team (biopsychosocial
model). Time limited.
Combination of approaches from MDT
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Activity- based
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Pacing, graded exercise, avoidance of ‘boom-and-bust’
Sleep hygiene
General advice (diet, deconditioning, benefits, employment etc)
Lifestyle management
CBT; mindfulness; Lightning therapy
Physiotherapy & OT support
Individual and Group based
Use of drugs only for symptom management
Therapy Interventions
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No curative therapies (orthodox!)
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Small Norwegian study reported significnat
improvement in small number of patients
receiving rituximab (an anti-cancer drug)
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Alternative sector offers many unproven
therapies.
This study needs to be repeated in blinded
fashion with larger study group
MRC Study did not show benefit from Pacing
What are the outcomes?
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There is no curative therapy.
NICE approved therapies are supportive not
curative
Chance of spontaneous recovery is
dependent on duration of illness.
Early signs of improvement are a positive
prognostic indicator.
Lack of improvement by 2 years is a poor
prognostic indicator
Outcomes
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CDC Review of published date identified:
 8-63% showed evidence of recovery (mean 43%)
 5-10% only showed full recovery
Local surveys (Therapy Teams & ME Northeast)
 10% +/- 2% not improved/worse after therapeutic
intervention
 Current scoring systems do not reflect benefit
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Increased anxiety related to developing understanding of
chronic disabling nature of illness
Fatigue may not change
Improvement from increased activity?
Mortality
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Retrospective study 2006 using memorial list of CFS
Support Group (difficulties in accessing accurate
data)
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Increased likelihood of death from heart failure, suicide and
cancer
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NB – separate studies have shown sub-population with
progressive heart muscle disease
Ages of death younger than general population
Larger 14 year retrospective study in 2006
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All-cause mortality and suicide rates not significantly
different from standardised mortality rates
Assisted Suicide
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Gilderdale case 2009
 Kay Gilderdale found not
guilty of murder for
assisting the suicide of
her daughter who was
said to have ME for 17
years
 Assisted daughter to
administer morphine
overdose and air via
Hickman line
 Judge Richard Brown
had questioned the
decision by the CPS to
proceed with charges
Economic Cost of CFS/ME
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UK 1998
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Cost per patient £5,095 (20% attributable to
medical costs, remainder to benefits, lost
productivity and tax revenue)
Estimated cost to community of £1 billion
USA 2004
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Cost of $20,000 per patient with CFS in lost
productivity
Total lost productivity $9.1 billion
How does CFS/ME affect
patients?
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Major issues are:
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Neurocognitive problems
Delayed response to activity (boom-and-bust)
Many patients will become:
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Agarophobic/social phobic (negative peer
feedback (especially teenagers)
Trapped in negative feedback loop
Secondary depression/anxiety
Bed-bound = disaster!
Problems for patients with
CFS/ME
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Lack of recognition of
the illness
Lack of empathy from
healthcare
professionals
Discrimination
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Medical
Employers/education
Friends and family
Benefits
Insurance
Problems for patients with
CFS/ME
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Neurocognitive difficulties make work
difficult/impossible and make it hard for
patients to fill in forms.
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Some patients are unsafe left unsupervised (fire
risk, flood risk, falls)
Benefit forms do not reflect the type of
disability that the patients’ suffer
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e.g. delayed deterioration: they can walk today
but if they do they won’t be able to tomorrow.
Benefits
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Pensions
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Difficulties in determining long-term outcomes
Acceptance of the illness by pension providers
Incapacity Benefit/Employment Support
Allowance
Disability Living Allowance and Attendance
Allowance
Permanent Health Insurance
Benefits
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Many occupational health, benefits and
pensions medical specialists, psychologists and
psychiatrists believe that seeking benefits leads
to persistence of symptoms and exaggeration of
disability
This is a gross misperception
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Most patients are devastated by their illness and would give
anything they have to get better (hence expenditure on
alternative therapies)
Most have suffered substantial financial and physical loss
Most have no plausible reason not to get better
Most become depressed because of their illness
Many have given up because of the negativity of the medical
profession
Fights over benefits, pensions and insurance are difficult and
actually prevent the patients getting better
Benefits
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2006 Report by UK Parliamentary Group on
Scientific Research into Myalgic
Encephalomyelitis noted that:
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“CFS/ME is defined as a psychosocial illness by
DWP and Medical Insurance Companies.
Therefore claimants are not entitled to the higher
level of benefits payments. We recognise that if
CFS/ME remains as one illness and/or both
remain defined as psychosocial then it would be
in the financial interest of both the DWP and the
medical insurance companies.”
Benefits
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Advisers to DWP have also had consultancy
roles in medical insurance companies
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Perpetuates misbeliefs about CFS/ME
Not in keeping with CMO’s report, best current
research or with the NICE Guidelines!
Viewed as conflict of interest and not in
patients’ interests?
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Contributes to adversarial approach to
benefits/insurance claims
Causes immense difficulty for patients
Appeals and Tribunals
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CFS/ME patients rarely get benefits on first
application
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This is despite the fact that the NICE Guidelines says that it
is a disabling condition as severe as MS and Rheumatoid
Arthritis!
Appealing decision is time-consuming and a
struggle
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Many patients have difficulty accessing experienced
benefits advisers to represent them
Many CABs do not understand CFS/ME and therefore do
not represent clients adequately
Conclusions
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CFS/ME is a chronic disabling disease with a
genetic background, triggered by infection and with
a link to psychosocial stressors
There is increasing evidence of very specific
physiological abnormalities that deny that the illness
is just a psychological illness
There are still no curative treatments
Patients have major problems with disbelief within
medical and benefits/insurance/pensions systems
Thank you for your attention