Dr Charles ShepherdROYAL SOCIETY OF MEDICINEWEDNESDAY MARCH 18th 2015

me/cfs: frontiers in research, clinical practice and public perceptionTheories and controversies in ME/CFS

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

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

Middlesex Hospital: McEvedy and Beard, BMJ 1970 >> mass hysteria

Chickenpox

Working in hospital medicine………….

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

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

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

(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 pro- and anti-inflammatory cytokines. Correlation of cytokine alterations with illness duration suggesting immunopathology of ME/CFS is not static.

Link to neuroinflammation?

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.

Dorsal root ganglionitis

MEA RRF Muscle mitochondria studies X3

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

(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 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/

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

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

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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