dr charles shepherd
DESCRIPTION
Dr Charles Shepherd. Presentation to Newry International C onference on ME/CFS Sunday November 11 th 2012. Chickenpox. CV. Personal experience Medical Adviser, MEA Member MRC Expert Group on ME/CFS Research Member (DWP) Fluctuating Conditions Group - PowerPoint PPT PresentationTRANSCRIPT
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Dr Charles ShepherdPresentation to Newry International Conference on ME/CFS
Sunday November 11th 2012
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Chickenpox
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CVPersonal experienceMedical Adviser, MEAMember MRC Expert Group on ME/CFS ResearchMember (DWP) Fluctuating Conditions GroupMember CMO Working Group on ME/CFS‘ME/CFS/PVFS – An Exploration of the Key Clinical
Issues’‘Living with ME’
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Where I live > Chalford Hill donkey delivery ….
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Research: the UK situationHistorical background >> challengesSymptom based research >>Different names and definitionsResearch fundersMRC strategyBiobank and post-mortem studiesClinical trials: Rituximab
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Royal Free disease 1955 and the Lancet editorial:
ME
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Middlesex Hospital: McEvedy and Beard, BMJ 1970 >> mass hysteria
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Names and definitionsME – Lancet editorial 1955CFS – renamed and redefined in the 1980sPVFS – definite viral onsetCFS: Covers a wide spectrum of chronic fatigue
clinical presentations and causations – similar to placing all types of arthritis under chronic joint pain syndrome and saying they all have the same cause and treatment
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Biomedical research >> symptom based
1 Infection and immune dysfunction2 Muscle 3 Brain
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Core SymptomsCore symptoms: Fit young adults >> viral illness++ >> do not recover >> Exercise induced muscle fatigue Post-exertional malaise Pain (75%) musculoskeletal, arthralgic (not inflammatory),
neuropathic Cognitive dysfunction affecting short term memory, concentration,
attention span, information processing ANS: Orthostatic intolerance, postural hypotension, POTS Sleep disturbance: hypersomnia >> unrefreshing sleep >> SUBSTANTIAL (50%>) reduction in activity levels
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Secondary symptomsAlcohol intoleranceBalance/dysequilibriumSore throats and tender glandsSensory disturbances: paraesthesiae, numbnessThermoregulation upset - ?hypothalamic(Depression)Symptoms fluctuate – ‘good days and bad days’ -
and change over time
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Research funding in the UK
Government funding via MRC (previous bias towards the psychosocial mode) and NIHR
Research funding charities: MEA RRF, AfME, CFSRF, MERUK, Linbury Trust
Other: private donorsDrug companiesResearch is very expensive and cannot be left to
the charity and private sector!
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RESEARCH: What do we know so far? 3Ps
PredisposingGenetic predispostionPrecipitatingViral infections++ and other immune system stressors, including vaccinations – hepatitis B+ >> abnormal host responseGradual onset in up to 25%Perpetuating >>
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PerpetuatingFactors:
Infection?
Neuro-immune+
Neuro-Endocrine+
Muscle+
Brain++
AutonomicNervousSystem
Pain
Sleep
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MRC Expert GroupEstablished in 2009 in response to criticism of failure to
fund biomedical researchChaired by Prof Stephen HolgateProduced a list of biomedical research prioritiesSecured £1.5 million ring fenced fundingDec 2011 >> 5 grants awardedOctober 2012 >> UK Research CollaborativeWebsite:
http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm
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MRC Research Priorities *Autonomic dysfunction Cognitive symptoms *Fatigue – central and peripheral, including mitochondrial function
and energy metabolism *Immune dysregulation: NK cells, cytokines Neuroinflammation Pain *Sleep *Developing interventions: cytokine inhibition and treatment of
symptoms Access to blood and tissues for research
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1. Autonomic nervous system
Nerves from the brain that control body functions that are not under conscious control: rather like a complex electrical circuit
Controls heart (pulse rate and blood vessel diameter) bowels, bladder
>> symptoms: orthostatic intolerance/POTS, bladder and bowel symptoms
Also controls blood flow to brain (?>>cognitive dysfunction and central fatigue) and skeletal muscle (?>peripheral fatigue)
Large amount of consistent research involving autonomic dysfunction from both UK (Newton et al) and USA
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Autonomic nervous system
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Autonomic nervous system
Professor Julia Newton, University of Newcastle‘Upstream’ >> ANS control centres in the brain‘Downstream’>> ANS control of cardiac and
vascular responses that may be involved in orthostatic intolerance and hypotension
Plus >> role of cerbral hypoperfusion in cognitive dysfunction
ME/CFS with ANS dysfunction and those without and sedentary controls
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2. Fatigue: Brain and Muscle
Brain > nerves > muscleCentral (brain) fatigue – seen in a wide range of neuro,
immune and infectious diseases: MS and PD, RhA, HIV and HCV
Peripheral (muscle) fatigue due to abnormalities in muscle >> exercise induced fatigue
Central: immune/infection mediatedPeripheral: mitochondrial dysfunction?Previous muscle research: early and excessive acid
production in muscle in response to exercise and structural abnormalities in the mitochondria
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Central fatigue: biomarker?
Dr Wan Ng, University of NewcastleSjogren’s Syndrome biobank: 550 samplesClinical and pathological overlap with ME/CFSWhole blood gene expression for markers of
immune system dysregulation in relation to fatigue
>> Biomarker for fatigue?Repeat in ME/CFS group
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3. Infection >> Immune dysfunction >> fatigue
Immune system orchestra: antibodies, autoantibodies, cytokines, NK cells, T cells…
Range of abnormalities in ME/CFS – not always consistent or robust for either diagnosis or management
Balance of evidence >> low level immune system activation
Role of cytokines? >> on going flu like illness and effect on CNS
Role of cytokine inhibition - ?Etanercept
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Role ofCytokines??
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Immune system activationRole of pro-inflammatory
cytokines?Dr Carmine Paiante, King’s College Hospital 100 patients with hepatitis C infection treated with
interferon alpha – an immune system activator – which often leads to fatigue and flu like symptoms
Follow course of potential biomarkers pre during and post treatment – cytokine and HPA profiles – in those who do/do not develop an ME/CFS like illness
Role of drugs that dampen down immune system activation: Etanercept >> Norwegian trial
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4 Muscle:mitochondrialdysfunction
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4. Muscle mitochondria
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Muscle MitochondriaProfessor Anne McArdle et al, University of
LiverpoolBuilding on previous muscle research >> fatigue
not due to deconditioningMuscle can become a source of pro-inflammatory
cytokinesPossible therapeutic interventions using
inflammatory mediatorsNewcastle research >>
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Sleep…..
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5: Sleep disturbanceAll need 4 – 5 hours solid sleep each nightSleep disturbance is an integral part of ME/CFSHypersomnia (infection) >> fragmented sleep >>
unrefeshing sleepGold standard investigation: polysomnography measures
brain activity, muscle and eye movementsPoor understanding from current published research of
sleep physiology and circadian rhythms in ME/CFSLimited role for drug interventions: short acting
hypnotics, amitriptyline and melatonin
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Sleep Studies and treatment
Professor David Nutt et al, Imperial College Relationship between disturbed sleep and fatigue Slow wave sleep disturbance = deep restorative sleep Role of sodium oxybate in enhancing slow wave sleep. CFS vs
Placebo Expensive drug with potential to cause side effects+ Sodium oxybate improves function in fibromyalgia syndrome: a
randomized, double blind, placebo-controlled, multicentre trial. Russell IJ et al. Arthritis Rheum 2009, 60, 299 - 309
Belgian trial: University Hospital Ghent (Mariman A et al) due to start in June
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MEA Biobank and Post mortems
MEA Biobank at Royal Free Hospital, UCLUpdate on the MEA website:
www.meassociation.org.ukPost-mortem studies >>Dorsal root ganglionitis – dorsal root ganglion are
bundles of neurons on the sensory nerve roots that pass to the spinal cord. DRG has also been fund in Sjogren’s syndrome with a sensory neuropathy
Neuropathology of post-infectious chronic fatigue syndrome. Journal of the Neurological Sciences 2009 (S60-
S61) Cader S., O'Donovan D.G., Shepherd C., Chaudhuri A.
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Dorsal root ganglionitis
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>> slides 46 to 48
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MANAGEMENTTimescale for diagnosis and management:First three months of post viral fatigue >> PVFS,
which is often self resolving but can >> ME/CFSNICE and CMO WG: Working diagnosis of ME/CFS
if symptoms persist beyond 3 to 4 months and no other explanation found
Primary careReferral to hospital based services >> CMO
report >>postcode lottery
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Differential diagnosis of chronic fatigue/TATT
HaematologicalInfectiveNeurologicalMuscularPsychiatricRheumatological>> p18 purple booklet
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How do we diagnose ME/CFS/PVFS?
History +++ Needs more than 10 minutes!Examination: ‘Hard’ neuro signs >> referRoutine investigations to exclude other causes
of ME/CFS-like symptoms >>p16Additional investigations where clinical
judgement deems appropriate >>p17Misdiagnosis Self-diagnosis
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Routine investigations ESR + C rective ptotein FBC +/- serum ferritin in adolescents Biochemistry: urea, electrolytes, + calcium Random blood glucose Liver function tests >> ?PBC, ?hepatitis C ?NAFLD – raised transaminases, link to
Gilbert’s syndrome Creatinine Creatine kinase – ?hypothyroid myopathy TFTs Screen for coeliac disease - tissue transgulataminase antibody >> arthralgia,
fatigue, IBS, mouth ulcers Morning cortisol 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 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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How do we manage patients with ME/CFS
Correct diagnosis Specialist referral +/- 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
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Activity management: GET vs Pacing
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Activity Management: Balancing rest and activity Depends on stage, severity and fluctuation of symptoms Graded exercise therapyClinical trial evidence +ve, including PACE trialPatient evidence –veMEA Management Report: N = 906 22% improved; 22% no change; 56% worse PacingClinical trial evidence –ve/not therePatient evidence +++N = 2137: 72% improved; 24% no change; 4% worse
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Cognitive behaviour therapy
Covers abnormal illness beliefs/behaviours >> Practical coping strategies
RCT evidence +vePATIENT EVIDENCE (N =998):26% improved55% no benefit19% worse
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Symptomatic relief Pain – overlap with fibromyalgia in someOTC painkillers >> low dose sedating tricyclic – amitriptyline >> gabapentin >> opiates? SleepShort acting hypnotics; sedating tricyclics; melatonin?Sleep hygiene advice ANS dysfunction (IBS) (Depression) (Psychosocial distress >>CBT)
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Can we treat the underlying disease process? Not yet!
Antiviral medication: valganciclovir?Immunotherapy: cytokine inhibition/Etanercept?Neuroendocrine: cortisone? thyroxine NO!Central fatigue: modafinil?Recent clinical trials:AmpligenRituximab
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Rituximab
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RituximabAnti-CD20 antibody >> B cell depletionUsed to treat lymphomaSignificant response in 3 lymphoma cases with ME/CFSMOA? removal autoantibodies or reactivated infectionNorwegian RCT 30 placebo/30treated >> significant
benefitsExpensivePotential to cause serious++ side effectsFurther Norwegian trial underway but not yet replicated
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DWP
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Benefits: ESA and WCA Major problems for fluctuating conditions ‘Snapshot’ questions >> reliably, repeatedly, safely and in a
timely manner Professor Harrington’s FCG: Arthritis, HIV/AIDS, IBS – Crohns and
UC, ME/CFS, Parkinsons FCG Report available on-line FCG >> reworded WCA descriptors to make them multidensional
to cover both frequency and severity FCG >> New descriptor covering fatigue and pain Recommendations about to be tested by the DWP in a EBR….
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ESA – the claimants journey
ESA50 FormInitial screeningAtos medical assessment>> Support Group>> Work related activity group >> WI>> Claim fails>> Going to appeal
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Atos medical assessment: tips!
Providing additional medical evidenceAsking for a recordingTaking a companionObtaining a copy of your report from DWPMaking a complaint if you are not happy with the way
you were assessed If you have to appeal turn up in personTribunal service video by Dr Jane Rayner – on the MEA
website
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ME AssociationInformation: literature pdf order form on the
MEA websiteSupport: ME Connect information and support:Tel: 0844 576 5326Campaigning: benefits, servicesPolitical: APPG on MEWebsite: www.meassociation.org.uk and
Facebook page
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Questions after the break…