Dr Charles ShepherdISLE OF MAN

September 2015ME/CFS: Research, Diagnosis and Management

BioPersonal 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/CFSPrevalence 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

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

>> 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 2015Lancet 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 pro- and 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. Journal of Nuclear Medicine, 2014, 55, 945 – 950.

Ref: Nakatomi et al.JNM , 2014, 55, 945 - 950

Dorsal root ganglionitis

Is there a peripheral 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 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

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 dysfunctionOrthostatic 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 nauseaVery 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 sleepDifferent 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 problemsCan 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

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/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

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