Dr Charles Shepherd ROYAL SOCIETY OF MEDICINE WEDNESDAY MARCH 18 th 2015 me/cfs: frontiers in...
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Transcript of Dr Charles Shepherd ROYAL SOCIETY OF MEDICINE WEDNESDAY MARCH 18 th 2015 me/cfs: frontiers in...
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Dr Charles ShepherdROYAL SOCIETY OF MEDICINEWEDNESDAY MARCH 18th 2015
me/cfs: frontiers in research, clinical practice and public perceptionTheories and controversies in ME/CFS
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BioPersonal 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
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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
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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
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Royal Free disease 1955 >> Lancet editorial: ME
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Middlesex Hospital: McEvedy and Beard, BMJ 1970 >> mass hysteria
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Chickenpox
Working in hospital medicine………….
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Personal experienceExtremely 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
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1980s: ME >> CFSUS 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
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IoM Report: February 2015Lancet 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
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(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>>
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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
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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 pro- and anti-inflammatory cytokines. Correlation of cytokine alterations with illness duration suggesting immunopathology of ME/CFS is not static.
Link to neuroinflammation?
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NeuroinflammationPET 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. Journal of Nuclear Medicine, 2014, 55, 945 – 950.
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Dorsal root ganglionitis
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MEA RRF Muscle mitochondria studies X3
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Research InititaivesMRC 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
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(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
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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
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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
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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
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(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
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2007 NICE GuidelineHeavily 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/forward-me-meeting-and-the-nice-guideline-on-mecfs-statement-by-the-me-association-10-july-2014/
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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
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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
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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
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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….
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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 >>
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Rituximab
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RituximabAnti-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
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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
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ME AssociationLiterature 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 page