Dr Charles Shepherd ROYAL SOCIETY OF MEDICINE WEDNESDAY

Dr Charles Shepherd ROYAL SOCIETY OF MEDICINE WEDNESDAY MARCH 18 th 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, Do. H, 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 20 s to mid 40 s 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

1980 s: 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, Io. M (2015)…… >> Messy compromise of ME/CFS: represents a very heteregenous group of clinical presentations and disease pathways

Io. M Report: February 2015 Lancet editorial: What’s in a name? (2015, v 385, p 663) 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: HHV 6, 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 X 3

Research Inititaives MRC Expert Group on ME/CFS Research Identified research priorities including immune dysfunction and neuroinflammation >> 5 MRC funded studies costing £ 1. 5 m+ UK CFS/ME Research collaborative Annual conference in Newcastle on October 3 rd/4 th £££ 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, p 23 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 9 am 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 B 12 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-CD 20 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 Further Norwegian trial underway but not yet replicated

Key messages >>> Name that doctors and patients agree on Practical simple clinical definition (? Io. M) 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 page