Dr Charles Shepherd
ROYAL SOCIETY OF MEDICINE
WEDNESDAY MARCH 18th 2015
me/cfs: frontiers in research, clinical practice and public perception
Theories and controversies in ME/CFS
Bio
 Personal experience PVFS++ following chickenpox +
cerebellar encephalitic component
 PMH in hospital psychiatry
 Medical Adviser, ME Association
 MRC Expert Group on ME/CFS Research
>> UK CMRC and CMO Working Group
 DWP Fluctuating Conditions Group
Content: 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: Long delay in making: reluctance >> experience
 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
Consensus +/- Epidemiology
of ME/CFS
 Prevalence of 0.2 to 0.4% = ? 250,000
 Commonest cause of long term sickness absence from
school
 Adults onset: early 20s to mid 40s
 All social classes
 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
 >> Numerous 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
heteregenous 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
 1 Rename CFS and ME – systemic exertion
intolerance syndrome (SEID)
 Mixed reaction from patient community
 2 New clinical definition >>
 3 No longer a diagnosis of exclusion
(3) Cause?? A three stage
illness?
Consensus: Predisposing factors
Genetic predisposition increases susceptibility >>
Consensus: Precipitating factors
Viral infections++ and other immune system stressors,
including vaccinations – hepatitis B+ >> abnormal host
response
Gradual onset in up to 25%
Debate: Perpetuating factors>>
A Neuroimmune Disease….
 (Infection) >> abnormal host response involving >>
 Immune system activation >> pro inflammatory cytokines,
interferon gamma?, and autoantibodies? >> Rituximab
 >> ? Reactivated viral infection: HHV6, EBV
 >> Neuroendocrine dysfunction >> HPA downregulation
and hypocortisolaemia
 Neurotransmitter dysfunction >> ?serotonin
 Autonomic NS dysfunction >> orthostatic intolerance and
POTS/postural orhostatic tachycardia syndrome
Cytokine mediated??
 Viral infection >> low level immune system activation
 MRC: 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. Correlation of cytokine
alterations with illness duration suggesting
immunopathology of ME/CFS is not static.
 Link to neuroinflammation?
Neuroinflammation
 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: neuroinflammation in the
amygdala, which is known to be involved in cognition.
Pain >> thalamuc.
 Ref: Nakatomi et al.
2014, 55, 945 – 950.
Journal of Nuclear Medicine,
Dorsal root ganglionitis
MEA RRF Muscle
mitochondria studies X3
Research Inititaives
 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
 Annual conference in Newcastle on October 3rd/4th
 £££ Charity funding: ME biobank
(4) 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
 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: NAD
 ESR + C reactive ptotein
 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 transgulataminase antibody >> arthralgia,
fatigue, IBS, mouth ulcers
 Urinalysis for protein, blood and glucose
In some circumstances….
 MCV macrocytosis >> folate or B12 deficiency? Coeliac
disease?
 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
(5)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

Role of CBT?

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
 Minutes: http://www.meassociation.org.uk/2014/07/forwardme-meeting-and-the-nice-guideline-on-mecfs-statement-bythe-me-association-10-july-2014/
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
Activity Management (2)
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
PACING
Clinical trial evidence –ve/not there
Patient evidence +++
N = 2137: 72% improved; 24% no change; 4% worse
Debate: Cognitive behaviour
therapy
 Covers approaches based on abnormal illness
beliefs/behaviours >> practical coping strategies
 RCT evidence: some +ve
 PATIENT EVIDENCE (N =998):
 26% improved; 55% no benefit; 19% worse
 MEA Survey: Help people who are having difficulty
coping with ME/CFS and/or mental health problems
Consensus: Drugs for
symptomatic relief
 Pain – overlap with fibromyalgia in some
OTC painkillers >> low dose sedating tricyclic –
amitriptyline >> gabapentin >> opiates?
 Sleep
Short acting hypnotics; sedating tricyclics; melatonin?
Sleep hygiene advice
 ANS dysfunction – tilt table testing – ? midodrine
 IBS, Depression, Psychosocial distress….
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/30treated >> significant
benefits
 Expensive
 Potential to cause serious++ side effects
 Further Norwegian trial underway but not yet replicated
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 services that cater for 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
 ME Connect information and support:
Tel: 0844 576 5326
 Campaigning: benefits, services
 Political: APPG on ME
 Website: www.meassociation.org.uk and Facebook
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