Chronic Fatigue Syndrome/ME – “ not just tired all the time… ”

1. Chronic Fatigue Syndrome/ME – “not just tired all the time…” Alastair Miller MA FRCP FRCP(Ed) DTM&H AHEA Consultant Physician Hon Senior Lecturer Institute of Infection & Global Health University of Liverpool Former Clinical Lead Liverpool CFS Service Principal Medical Adviser Action for ME Chair British Association for CFS/ME (BACME) Deputy Medical Director Joint Royal Colleges of Physicians Training Board

2. First….a few definitions • Symptoms – subjective “complaints” from patient gathered by “taking a history” • (Physical) signs – objective abnormalities identified by an examining clinician Taken together these make up the clinical features of a condition that will lead to a potential diagnosis

3. Diagnosis • After eliciting the clinical features, the diagnosis can be confirmed or alternative diagnoses considered by performing investigations….. • These are “tests” “ordered/requested” by clinicians and will include a wide range of laboratory and imaging evaluations • A diagnosis can then be made at several levels of accuracy/complexity

4. A syndrome • A collection of symptoms and signs that together make up a recognized pattern that may lead to a diagnosis…eg • Headache • Fever • Neck stiffness Make up a syndrome that suggests meningism

5. Management • The overall (medical) care of a patient including establishing diagnosis, communication, drug treatment, surgery, therapy etc… • Aim is to • Improve natural history/prognosis • Relieve symptoms

6. Historical background • Neurasthenia - 19 cent • Royal Free (ME) - 1955 • Tahoe outbreak - “Yuppie flu” – 1988 • CDC definition - 1994 • RCP report -1996 • CMO report – 2002 • NICE 2007 • PACE 2011 • US IOM report 2015

7. How big is the problem? • 1/10 GP appointments are about fatigue • 0.2-2% fatigue persists for 4 months, is disabling and associated with other symptoms • Comorbidity is high with associated depression and anxiety in up to 75% • High health economic costs due to frequent contact with GPs, psychologists and other health professionals

8. BUT NB Chronic fatigue is NOT Chronic Fatigue Syndrome • CFS prevalence 0.2 -0.4%

9. It’s all in the name! • Neurasthenia • Effort/Da Costa/Soldier syndrome • Myalgic encephalomyelitis (ME) • Yuppie flu • Post viral (fatigue) syndrome • Chronic Fatigue Syndrome (CFS) • CFS/ME • CFIDS • Systemic Exertion Intolerance Disease

10. Who looks after CFS? • Mainly GPs • No specific specialist training in CFS for doctors • But BACME trying to rectify this • CFS may present to many different specialist services • Infectious disease • Neurology • Endocrinology • Rheumatology • Mental health • Clinical psychology • Specialist services may be “led” by any of these specialists • Best clinician is the one with the interest and experience

11. Definition of CFS • Fatigue • clinically evaluated • unexplained • lasting more than 6 months, not lifelong • not result of exertion • not relieved by rest • causing significant functional disability Fukuda et al. Ann Int Med 1994;121:953 (Previously Holmes criteria 1988)

12. Accompanying features • At least four of • sore throat • tender swollen glands • cognitive dysfunction • myalgia • arthralgia • new headaches • unrefreshing sleep • post exertion malaise

13. How do we diagnose in practice? • Is it really a “diagnosis of exclusion”? • Yes but only partially • Clearly important to consider other diagnoses that cause fatigue BUT • Fatigue of CFS is very characteristic • Remember other conditions can co-exist • History is crucial • Defined onset • Characteristically associated with infection and/or adverse life event • Often fluctuant pattern • No definite time period (NICE says 4 months) • History often written or • Given by relative • Try not to put words in patients mouth

14. NICE guidelines (CG53 August 2007) • Fatigue • New/specific onset • Persistent and/or recurrent • Unexplained by other conditions • Resulting in substantial reduction in activity level • Characterized by post exertional malaise/fatigue

15. NICE • Fatigue accompanied by one or more of • Sleep disturbance • Myalgia/arthralgia • Headache • Painful lymphadenopathy without pathological enlargement • Sore throat • Payback • Brain fog • “Flu like symptoms” • Dizziness/nausea • Palpitations without cardiac pathology

16. Post exertional fatigue or malaise • “Payback”. • Usually delayed and long lived.

17. Cognitive difficulties • “Brain fog” • Poor short term memory, concentration, reasoning. • Unable to read or watch TV. • Dysphasia. • Confused behaviour • Putting washing up in fridge • Often most serious problem that affects ability to work

18. Sleep disturbance • NB fatigue is lassitude/lethargy/exhaustion NOT sleepiness • If daytime somnolence is the issue then consider other diagnoses. • Epworth score may be useful • Often have difficulty getting to sleep but may “sleep in” • Cardinal feature is “unrefreshing sleep”

19. Pain • Often myalgia or arthralgia • Muscles may be tender but no objective evidence of inflammation • May be very generalised • Characteristically does not respond well to paracetamol or anti-inflammatory drugs • May respond better to neuropathic pain type drugs • Drugs are frequently not tolerated well • May be having treatment in pain clinic (which can make CFS treatment complex)

20. Physical examination • Usually normal or • Unrelated pathology • Lymphadnopathy not significant • Check for oral candida • Is full examination essential? • Does patient expect it? • GP or secondary care responsibility?

21. Tests • No single diagnostic test • No consistent abnormal finding/biomarker • Including cytokines etc • NICE recommends • Urinalysis • Full blood count • U&Es, LFTs, Thyroid function, Calcium, Creatinine, CPK, glucose • CRP and ESR or plasma viscosity • Test for gluten sensitivity (coeliac) • Other tests to be carried out for specific indication only

22. No routine testing for • Haematinics (ferritin, B12, folate) • Tilt table • Nerve conduction studies • Evoked responses • Tests for infection • HCV, HBV, HIV, CMV, EBV, toxoplasma, Borrelia (Lyme!) • Routine imaging • CXR, CT, MRI • Auto –antibody testing

23. Review • Reconsider diagnosis and consider alternative OR additional diagnoses if • Atypical history and especially if no payback, brain fog, pain or sleep disturbance • “Red flag” features such as severe weight loss, significant lymphadenopathy, oral candida daytime somnolence, cardiorespiratory symptoms • Significant abnormalities on physical examination • Abnormal investigation results

24. NICE clinical guideline 53. 2007 “…best regarded as a spectrum of illness that is triggered by a variety of factors in people who have an underlying predisposition”

25. Two extreme views • CFS is a pure physical problem and psychological issues and therapy have no role in pathogenesis or management • CFS is psychiatric/psychological condition and there is no disordered physiology

26. A sterile debate “It is puzzling indeed to me to see how the concept of a seperateness of mind and body can have continuing legitimacy in contemporary medicine and science” Tony Pinching. A tale of two syndromes Clinical Medicine 2003

27. Pathogenesis (3 Ps) • Predisposing • Genetic • 20% have family history. Relative risk increases according to closeness • Twin study (55% monzygotes 19% dizygote) • No conclusive gene studies linking to phenotype • Is association genetic or exposure • Precipitating • Infection, vaccination, stress, toxin, life events • Double hit • Perpetuating • Illness beliefs • Law suits • Searching for a cause • Extremes of activity

28. Infections • Non specific viral infection (URI) • EBV (Glandular fever) • HAV (Hepatitis A) • SARS • West Nile Virus • Influenza • Coxiella (Q fever) • Borrelia (Lyme disease) • (XMRV) • Seems rare after bacterial infection

29. Other factors These infections often occur around other adverse life events • working too hard • conflict • divorce • redundancy • overtraining

30. The original Science paper linking XMRV to CFS Virus detected in 67% of those with CFS and 3.7% healthy controls

32. Timelines for XMRV • Original Science paper (WPI – Reno) October 2009 • Judy Mikovits/Dan Petersen(Yuppie flu/ ampligen) • XMRV discovered in 2/3 of CFS patients • Rapidly rebutted by 4 negative studies (Wessley, Weber etc) • Then Lo- Alter paper. MLV associated CFS patients stopped from blood donation • NIH blood working group study ($500K) sent samples to 9 labs. No evidence of XMRV • Original paper retracted by Science

33. CFS – a medically unexplained syndrome (MUS)? • Parallel (and frequent co-existence) with other MUS • Underlying mechanism not understood • Irritable bowel syndrome • Tension headache • Fibro myalgia syndrome (FMS) • Chronic pain syndromes

34. Differential diagnosis • Infection • TB, endocarditis, HIV, hepatitis, brucella (NOT Lyme) • Neoplasia • lymphoma, cancer • Neurological • myaesthenia, MS, PD • Endocrine • DM, thyroid, adrenal, pituitary, calcium disorders • Mental Health Conditions • Others • SLE, narcolepsy, sleep apnoea, alcohol, drugs, obesity • Difficult to assess contribution of drugs (eg beta blockers)

35. Co-existing mental health issues • Degree of depression is common • Severe mental health issues such as psychotic depression would exclude • Is depression a “normal” reaction to the chronic symptoms of CFS • Can we view depression as a symptom of CFS and treat with pharmacological agents to break the vicious cycle • 1/3 on anti-depressants at time of assessment • 1/3 have been on anti depressants • 1/3 have never been on anti-depressants

36. Diagnosis and assessment • Often made in primary care • Many services have assessment/review by non doctor prior to therapy • Does this matter? • Some just want a diagnostic label • Work/pension • Permanent health insurance • Litigation • Diagnosis needs to be made definitively

37. NICE guidlelines: Mild • Mobile, can care for themselves and do light domestic tasks with difficulty • May still be in work or education but has probably stopped all leisure and social pursuits • Often takes days off or uses the weekend to cope with the rest of the week

38. Moderate • Reduced mobility and is restricted in all activities of daily living • Has probably stopped work, school or college and needs rest periods • Sleep is generally poor quality and disturbed

39. Severe • Unable to do any activity, or minimal daily tasks only • Severe cognitive difficulties and depends on a wheelchair for mobility • Unable/barely able to leave the house • May spend most of their time in bed • Often extremely sensitive to light and noise

40. Phenotyping - ?the way ahead • Probable that several different conditions with different aetiologies will come under the umbrella diagnosis of CFS • Distinguishing between these different pheotypes will be key to designing clinical trials BUT • Without good biomarkers, phenotyping will need to be done on a clinical basis… • And this will be problematic

41. Management • Sympathetic, open approach • Mainly in primary care • Referral • establish diagnosis • exclude other possibilities • access multi disciplinary management • legitimise - formally/informal • CBT, graded exercise, antidepressants • Symptom control

42. Drugs affecting natural history • “There is no known pharmacological treatment or cure for CFS/ME. However, symptoms of CFS/ME should be managed as in usual clinical practice.” • None confirmed as providing benefit • None recommended by NICE

43. York CRD 2007 • 70 studies included (out of 10768!) • 59 were RCTs • “ GET and CBT appeared to reduce symptoms and improve function based on evidence from RCTs. For most other interventions, evidence of effectiveness was inconclusive and some interventions were associated with significant adverse events” www.york.ac.uk/inst/crd/pdf/crdreport35.pdf

44. PACE Design • Parallel group RCT • Four arms (SMC, APT, CBT, GET) • March 2005-Nov 2008 • 6 UK centres • No previous treatment

45. Conclusions • CBT and GET are better than SMC alone or SMC + APT • No serious deteriorations during GET • No obvious interaction by diagnostic subgroups • Lack of blinding • Multiple endpoints but consistent effects

46. Summary • The strict definition of CFS remains controversial and • Is linked with the mind/body debate over pathogenesis • Most definitions more needed for research projects rather than clinical management • There is no biomarker/diagnostic test • Diagnosis is a positive one made on the basis of a good history • Commonly no alternative diagnosis seems feasible based on duration • Pattern of fatigue differs from other conditions but they still need to be considered and excluded

47. Summary 2 • Other conditions may co-exist • Any new symptoms require clear evaluation • Medical review may be important • Needs an open mind about pathogenesis and aetiology • Diagnosis is start of management

49. Questions?