Dr Charles Shepherd
ISLE OF MAN
September 2015
ME/CFS: Research, Diagnosis and Management
Bio
 Personal experience of PVFS++ following chickenpox +
cerebellar encephalitic component
 PMH in hospital psychiatry
 Medical Adviser, ME Association
 MRC Expert Group on ME/CFS Research
>> UK CMRC
 CMO Working Group
 DWP Fluctuating Conditions Group
Disagreements, uncertainty,
consensus…
 Background: WHO, DoH, DWP, NICE, MRC, Royal Colleges all
accept this is a genuine and disabling illness BUT…
 1 Nomenclature: ME, CFS, PVFS, SEID
 2 Over 20 Clinical and Research definitions: Fukuda, Oxford,
NICE, Canadian…..
 3 Cause: Physical>>P+P> Psychological
 4 Diagnosis: Often a long delay in making a diagnosis
 5 Management: Rituximab >>> CBT and GET
 Result: ME/CFS rather like calling any form of arthritis a chronic
joint pain syndrome and assuming they all have the same
cause/disease pathway and management
What is ME/CFS?

Often fit young adults; children and adolescents as well

Acute onset often following infection or immune system stressor - vaccination

Muscle: exercise-induced fatigue and…..

Post- exertional exacerbation of symptoms

CNS: cognitive dysfunction: memory concentration info processing word finding

Problems with balance, thermoregulation, alcohol intolerance

ANS dysfunction: O intolerance, O hypotension and POTS; Ryynaud’s

Immune system: sore throats and glands

Pain in approx 75%: muscles, joints, neuropathic

Non restorative sleep
Epidemiology of ME/CFS
 Prevalence of 0.2 to 0.4% = ? 250,000 in UK,
 ?200 to 300 in IoM (pop 85,000)
 Commonest cause of long term sickness absence from
school
 Adults onset: early 20s to mid 40s
 All social classes
 Strong female predominance
 Spectrum of severity: 25% severe at some stage >>
severely neglected by the NHS
Royal Free disease 1955 >>
Lancet editorial: ME
and Beard, BMJ 1970 >>
mass hysteria
Working in hospital
medicine………….
Personal experience
 Extremely fit young adult
 Well motivated
 Infection ‘pre spots’ >> 48 hours >> exercise induced
muscle fatigue, brain (balance/OI and cognitive++) and
flu-like: not deconditioning
 Two years to get a diagnosis
 Well meaning but very bad management++
 Work >> off sick >> work
1980s: ME >> CFS
 US and UK decision to rename and redefine ME as CFS
 >> Now over 20 diagnostic criteria for both clinical and
research purposes
 UK: Oxford research (>> 2014 NIH report recommended
removal), NICE clinical guideline (2007)
 US: 1994 Fukuda/CDC research
 Canadian, London (ME), International, IoM (2015)……
 >> Messy compromise of ME/CFS: represents a very
heterogenous group of clinical presentations and disease
pathways
IoM Report: February 2015
 Lancet editorial: What’s in a name? (2015, v385, p663)
 Complex, serious multisystem DISEASE process
 Rename CFS and ME – systemic exertion
intolerance syndrome (SEID)
 Mixed reaction from patient community
 New clinical definition >>
 3 No longer a diagnosis of exclusion
What causes ME/CFS: A
three stage illness?
Consensus: Predisposing factors
Genetic predisposition increases susceptibility >>
Consensus: Precipitating factors
Viral infections++ other immune system stressors,
including vaccinations – hepatitis B+ >> abnormal host
response
Gradual onset in up to 25%
Debate: Perpetuating factors>>
Evidence for cytokine
mediated fatigue??
 Viral infection >> low level immune system activation
 MRC at KCH: what happens to people with hepatitis C who
are treated with interferon alpha and develop ME/CFS
symptoms as a result?
 Hornig/Lipkin: Science Advances, 1 February 2015. Early
cases (< 3 years) had a prominent activation in both proand anti-inflammatory cytokines (IL17a+). Correlation of
cytokine alterations with illness duration suggesting
immunopathology of ME/CFS is not static.
 Link to neuroinflammation through activated microglia?
Is ME/CFS a Neuroimmune
Disease??
 >> Neuroendocrine dysfunction >> HPA
downregulation and hypocortisolaemia
 Neurotransmitter dysfunction >> ?serotonin
 Autonomic NS dysfunction >> orthostatic intolerance
and POTS/postural orthostatic tachycardia syndrome
 Low level neuroinflammation
Neuroinflammation: Japanese
group
 PET scans: neuroinflammation is higher in CFS/ME
patients than in healthy people.
 Inflammation
in cingulate cortex, hippocampus,
amygdala, thalamus, midbrain, and pons elevated in a
way that correlates with symptoms >>
 Impaired cognition>> amygdala
 Pain >> thalamic.
 Ref: Nakatomi et al.
2014, 55, 945 – 950.
Journal of Nuclear Medicine,
Ref: Nakatomi et al.JNM ,
2014, 55, 945 - 950
Dorsal root ganglionitis
Mitochondrial component to
peripheral fatigue??
Prof Anne McArdle, University
of Liverpool
 Arnold DL et al. Lancet, 1984, 1367 – 1369: Excessive
intracellular acidosis of skeletal muscle on exercise in a
patient with post viral fatigue syndrome (CS)
 Defect in energy producing component leads to
fatigue….
 But does the presence of dysfunctional mitochondria
then activate a process that leads to chronic low grade
inflammation?
Research Initiatives……
 MRC Expert Group on ME/CFS Research
 Identified research priorities including immune
dysfunction and neuroinflammation
 >> 5 MRC funded studies costing £1.5m+
 >>UK CFS/ME Research collaborative
 2015 conference in Newcastle in October
 £££ Charity funding: ME biobank
Diagnosis
Consensus: Early and
accurate diagnosis
 Timescale for diagnosis and management:
 First three months of post viral fatigue >> PVFS, which is
often self resolving but can >> ME/CFS
 NICE and CMO WG: Working diagnosis of ME/CFS if
symptoms persist beyond 3 to 4 months and no other
explanation found. Don’t wait 6 months!
 Referral to hospital based services >> CMO report
>>postcode lottery
 High rate of late diagnosis and misdiagnosis >>Newton et al,
p23 MEA purple booklet
Consensus: Routine
investigations for TATT: NAD
 ESR + CRP/C reactive protein
 FBC +/- serum ferritin in adolescents
 Biochemistry: urea, electrolytes, calcium, creatinine, random blood sugar
 Liver function tests > ?PBC, ?hepatitis C ?NAFLD – raised transaminases,
link to Gilbert’s syndrome
 Creatine kinase – ?hypothyroid myopathy
 Thyroid function tests and 9am cortisol
 Screen for coeliac disease - tissue transglutaminase antibody >> arthralgia,
fatigue, IBS, mouth ulcers
 Urinalysis for protein, blood and glucose
In some circumstances….
 Pursue abnormal LFTSs: primary biliary cirrhosis (anti
mitochondrial antibodies); Gilbert’s syndrome, NAFLD
 Raised calcium: ? sarcoidosis
 Joint pain+ Autoantibody screen for ? SLE (anti nuclear
antibodies, anti DNA antibodies, complement)
 Infectious diseases: hep C (blood transfusion), Lyme; HIV,
Q fever (contact with sheep), toxoplasmosis
In some circumstances….
 Dry eyes and dry mouth > ? Sjogren’s syndrome
(Schirmer’s test for dry eyes)
 Low cortisol and suggestion of Addison’s
(hypotension; low sodium; raised potassium) >>
synacthen test
 Autonomic function tests >> tilt table test for POTS
 Muscle biopsy or MRS?
 Serum 25-hydroxyvitamin D (25-OHD) if at risk:
restrictive diet; lack of sunlight; severe condition
Debate: How should we
manage ME/CFS patients
 Correct diagnosis > label > validation > uncertainties
 Specialist referral +/
2007 NICE guideline on ME/CFS

Activity management >> time and expertise
 Symptomatic relief

Drugs aimed at underlying disease process
 Help with education, employment
 DWP benefits: ESA
 Information and support: MEA Management Report
2007 NICE Guideline
 Heavily criticised by patients for ‘one size fits all’
recommendations re CBT and GET
 Place on ‘static list’ in 2014
 June 2014: Professor Mark Baker acknowledged that the
guideline did need to be revised
 >> decision rests with NHS England
 NIH report 2015: ….behaviour therapy or graded exercise
are not a primary treatment strategy and should only be
used as a component of multimodal therapy
Debate + Pacing vs GET
 Aim: balance rest with activity = Pacing
 Depends on Stage, Severity, Variability and symptoms such
as autonomic and cognitive dysfunction
 Establish a comfortable baseline: physical and cognitive
 May involve increase/decrease in overall activity
 Gradual and flexible increases
 [Rest] >>> [Activity] >> [Rest]
 Accept progress may be slow and erratic
Pacing vs GET – patient
evidence
GRADED EXERCISE THERAPY > More structured and progressive increase
Clinical trial evidence +ve, including PACE trial
MEA Management Report: N = 906
22% improved; 22% no change; 56% worse
MEA: Abandon as a primary intervention
PACING
Clinical trial evidence –ve/not there
Patient evidence +++
N = 2137: 72% improved; 24% no change; 4% worse
Cognitive behaviour therapy
 Covers approaches based on abnormal illness
beliefs/behaviours >> practical coping strategies
 RCT evidence: some +ve
 MEA Patient Evidence (N =998):
 26% improved; 55% no benefit; 19% worse
 MEA Report: Help people who are having difficulty
coping with ME/CFS and/or mental health problems
Consensus: Drugs for
symptomatic relief
 ANS dysfunction and POTS
 IBS symptomatology
 Nausea
 Pain
 Non restorative sleep
 NOT for fatigue, cognitive dysfunction
 Depression, Psychosocial distress….
ANS dysfunction
 Orthostatic intolerance very common
 POTS may occur: rise in pulse to over 120/min or 30
bpm on supine to standing
 Referral for tilt table testing?
 Self-help measures >>
 Increase hydration
 Salt where low blood pressure
 Drugs?? Midodrine??
IBS and nausea
 Very common overlap
 Exclude other explanations of fatigue + IBS:– coeliac;
ovarian malignancy
 IBS-C; IBS-D and IBS mixed
 Drug approaches depending on type
 Dietary approaches
 FODMAP diet:
Pain management
 Spectrum of severity
 Muscular, arthralgic and neuropathic
 OTC analgesics often of limited value
 Low dose sedating tricyclic >> ? liquid prep (25mg/5ml)
 Duloxetine/Cymbalta >> fibromyalgic component
 Anticonvulsants: Gabapentin and Pregabalin
 Opiates? Tramadol
 Non-drug options: acupuncture; TENS machine; relaxation
 Referral to pain clinic?
Non restorative sleep
 Different types of sleep disturbance
 Sleep hygiene
 Short-acting hypnotics
 Low dose sedating tricyclic – eg amitriptyline 10mg to
30mg
 Melatonin??
 MRC clinical trial of sodium oxybate
Mental health problems
 Can co-exist
 Depression > psychological approaches first
 Drugs: commence with low dose and increase slowly
 Tricyclics – limited role due to sedation/side-effects
 SSRIs – with care as some very sensitive to low doses
 No evidence from RCTs that antidepressants are an
effective form of treatment for ME/CFS
Some problems with RCTs in
relation to ME/CFS
 Not blinded
 Often rely of self-reported outcome measures
 Often fail to include objective outcome measures such
as actographs, disability benefit and employment status
 Specialist centre treatment is not the same as what
happens out in the real world
 Results do not match consistent patient evidence
Can we treat underlying
disease process? Not yet!
 Antiviral medication: valganciclovir?
 Immunotherapy: cytokine inhibition/Etanercept?
 Neuroendocrine: cortisone? thyroxine NO!
 Central fatigue: modafinil?
Recent clinical trials:
 Ampligen – antiviral and immunomodulatory
 Rituximab >>
Rituximab
Rituximab
 Anti-CD20 antibody >> B cell depletion
 Used to treat lymphoma
 Significant response in 3 lymphoma cases with ME/CFS
 MOA? removal autoantibodies or reactivated infection
 Norwegian RCT 30 placebo/30 treated >> significant
benefits
 Expensive
 Potential to cause serious++ side effects
 Norwegian phase 3 trial underway but not yet replicated
Other key aspects of
management
 DWP Benefits – ESA, PIP
 Education
 Employment and occupational health
Key messages >>>
 Name that doctors and patients agree on
 Practical simple clinical definition (?IoM)
 Early and accurate diagnosis + proper investigation
 Pragmatic management guidance that is not based on the
‘one size fits all’ hypothesis
 NHS in patient and domiciliary services that cater for the
severe end of the spectrum
 Research definition that recognises the heterogeneity of
disease pathways involved and facilitates sub-grouping
ME Association
 Literature pdf order form on the MEA website
 Online shop on the website
 ME Connect information and support:
Tel: 0844 576 5326
 Campaigning: benefits, services
 Political: APPG on ME
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