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Chronic Fatigue Syndrome ( CFS/ ME )-Diagnosis

Chronic Fatigue Syndrome ( CFS ) is a complex chronic disorder of unknown etiology 
characterized by the presence of intense and disabling fatigue ( physical and mental ) , with a 
clinical course and without any apparent cause which interferes with daily activities , does not decrease with rest , worsens with exercise and is usually associated to systemic , physical and neurophysiological manifestations 
( Ballester M et al 2002 , Strauss S Harrison’s Principles of Internal Medicine 2006 )
Background –Described in 18th century by Hammurabi ( Babylonian philosopher ) Systemic Exertion Intolerance Disease ( SIED ) proposed by US Institute of Medicine Myalegic encephalopathy/ encephalomyelitis – the terms ME and CFS have been conflated and as of 2016 US Federal health agencies use the combined term ME/ CFS to refer to the disease Immune dysfunction syndrome , Neuroendocrine immune dysfunction syndrome Post-viral syndrome Royal Free Disease ( outbreak in 1955 at Royal Free Hospital in London ) Neurasthenia
Epedmiology –Prevalence is difficult to predict due to
- diagnostic criteria used may vary fundamentally
- depends on the study population / design
- data has started to be available from 1990 only and studies have been carried out mostly in Europe and N America ( data from other countries has started to emerge ) Studies done in the USA and UK show a prevalence between 0.007 % to 2.5 % It is estimated that more than 2 million Americans suffer with CFS , many of whom have not been diagnosed Women seem to suffer more with ratios of up to 4 to 1 It occurs in all ethnic groups and in countries around the world and across all socioeconomic groups ( some evidence that its more prevalent in BME community in UK ) A study in Norway ( Inger Johanne Bakken et al 2014 ) has shown a bimodal peak- with first peak 10-19 yrs and second peak 30-39 yrs ( a large study of 5809 patients ) It is estimated that a large proportion of patients with CFS / ME ( some studies quote numbers as high as 85-90 % ) have not been diagnosed
Causes –WHO ICD-10 now classifies CFS / ME as a neurological illness Pathogenesis is unknown Some patients describe acute onset with associated infection – most patients would recover from such episodes but a sub-group continue to suffer and if the symptoms persist beyond 6 months a diagnosis of CFS/ ME should be considered What causes CFS/ ME is not well understood -multi-system involvement and multiple symptoms of varying intensity Pathophysiological basis of the illness is not clear and further studies are needed to ascertain the basis of ME/ CFS Several triggers and hypothesis have been proposed but no clear mechanism or pathology has been proven yet – the illness is expected to be complex , multisystem , neuroimmune disease
Triggers –Infection – often described as the trigger in up to 80 % of patients , common viral triggers include herpesviruses ( EBV , CMV , HHV6,7 ) and enteroviral infections as Coxsackie B , Physical or emotional trauma – surgery , concussion , RTA ,Genetics-has been observed within some families ,Environmental factors- exposure to toxins or mold
Possible pathological mechanisms – immunological theory , neuroendocrine theory , cellular metabolism abnormalities , blood pressure or heart regulation abnormalities ( POTS and NMH ) , biopsychosocial model , sleep and nutrition
Presentation –Post-exertional malaise is considered to be a hallmark symptom of the disease Onset may be gradual or acute ( for e.g post- infectious ) Most people prior to CFS are healthy and fully functional and have active social lives Fatigue is not due to excessive activity and does not improve with rest , can get worse with stress and leads to persistent disability Fatigue is extreme and disabling and not explained by any other illness and persists for more than 6 months ( NICE suggests 4 months in adults ) Cognitive difficulties , psychiatric problems ( depression or anxiety can be present in up to 28 % of people in the West ) SEID ( systemic exertional intolerance disease ) the name was deduced based on the core symptom of post-exertional malaise which involves the whole body implying the physical aspect of the disease The condition leads to substantial reduction or impairment in the ability to engage in pre-illness activity A delay in diagnosis which can be of few ye
ars duration is common The illness can wax and wane , worse or improve slowly Fatigue is a sensation of exhaustion or difficulty to carry out physical or intellectual activities , without recovery after a period of rest Asthenia -is lack of strength or feeling of inability to carry out daily tasks , it is worse at the end of the day and improves with a period of sleep Weakness is reduction or loss of muscle strength and a key symptom in muscular diseases.

Diagnostic definitions –CFS is a diagnosis of exclusion based on a number of diagnostic criteria which have been developed over the last 3 decades. More than 20 criteria have been proposed for CFS / ME and they vary in severity of fatigue , presence of post-exertional malaise and ancillary symptoms. Currently there is no consensus on which diagnostic criteria should be used.

Fakuda criteria ( or Centre for Disease Control ) 1994 is one of the most widely mentioned and used criteria for research( see under links for limitations and criticism of CDC criteria ) Canadian Clinical Criteria 2003 ( Carruthers et al 2003 ) London Criteria for ME ( 2014 ) International Consensus Criteria ( ICC ; Carruthers et al 2011 ) Oxford 1991 ( Sharpe ) criteria- The US Institute of Medicine Criteria for SEID 2015 NICE Clinical Guideline for CFS/ ME 2007 ( see below ) Revised Canadian Clinical Case Definition 2010

Tests –Physical examination is usually normal Some patients may have tender lymph nodes , localised tender points in muscles , resting tachycardia , low BP or low body temperature Abnormal findings should prompt the clinician to look for other possible diagnoses
No specific diagnostic biomarker exists for CFS/ ME ie use of criteria for case definitions is the only way to diagnose CFS / ME What kind of blood tests to be done varies between guidelines NICE recommends the following
-urinalysis for protein , blood and glucose
-Us & Es , LFTs , TFTs , 
- random Bl glucose
- coeliac screen
- serum calcium
- creatinine kinase
- ferritin in children and young people only

CFS is a clinical diagnosis which can only be made once other causes of fatigue have been excluded
Most commonly reported symptoms – reduced stamina and / or functional capacity physical fatigue cognitive exhaustion problems thinking unrefreshing sleep muscle pain insomnia muscle weakness / instability temp dysregulation flu-like symptoms
NICE Diagnostic criteria 2007 –new or had a specific onset
( ie its not lifelong ) persistent and or recurrent unexplained by other conditions has resulted in a substantial reduction in activity level characterized by post- exertional malaise and or / fatigue ( typically delayed for e.g by 24 hrs , with slow recovery over several days ) difficulty with sleeping , such as insomnia , hypersomnia , unrefreshing sleep a disturbed sleep-wake cycle muscle and / or joint pain that is multi-site without evidence of inflammation headaches painful lymph nodes without pathological enlargement sore throat cognitive dysfunction such as
- difficulty thinking
- inability to concentrate
- impairment of short-term memory
-difficulties with word-finding , planning / organizing thoughts and information processing physical or mental exertion makes symptoms worse general malaise or flu like symptoms dizziness and / or nausea palpitation in the absence of identified cardiac pathology
localising / focal neurological signs signs or symptoms suggestive of inflammatory arthritis or connective tissue disease signs or symptoms indicating a cardiorespiratory illness significant weight loss sleep apnoea clinically significant lymphadenopathy
NICE guidance suggests that the symptoms should have been present for atleast 4 months in adults and 3 months in a child or young person. This is different to International criteria which suggest that the symptoms should last more than 6 months
Differential diagnosis of CFS / ME is extensive. Consider using self-score questionnaire ( e.g multi dimensional fatigue inventory ) to evaluate symptoms .A diagnosis of CFS/ ME can have a profound implication on patients life, a detailed history , examination over several encounters is advisable before reaching a diagnosis. Few notable conditions to consider in the differentials are
Sleep disorders –sleep apnoea , RLS and circadian sleep disorders.
Ferritin and folate –It is recommended that ferritin should be > 50ng/mL as levels below 50 may be associated with fatigue
Vitamin D deficiency-Deficiency can mimic few features associated with CFS/ ME
Postural orthostatic hypotension syndrome-consider if pulse rate changes from seated to standing by > 30 bpm or when it rises to 120 bpm-fall in bp can be delayed. Autonomic dysfunction is common with CFS/ ME patients
Management –Most CFS/ ME patients can be managed in primary care ( with no cure managing the illness is the only option ) A positive diagnosis , acknowledgment and education are vital steps in helping the patients cope with this difficult and serious illness Despite several approaches with various interventions no definitively effective treatment has been approved for CFS/ ME No FDA approved drug is currently licensed for CFS/ ME Both pharmacological and non-pharmacological measures can be used to alleviate symptoms and improve patients QoL Cognitive therapy protocols are based on 3 key elements
- programmed physical exercises
- control and coping with disease associated stress
- cognitive re-structuring Pharmacological measures involves drugs as
-cortisol medications
- psyciatric drugs
No pharmacotherapy has been found to be effective for CFS/ ME till date RCTs have been more positive for non-pharmacological measures than for medications
Self help information leaflet from Cambridgeshire and Peterborough NHS Foundation Trust 23 pages
A huge patient resource from UK ME Association
Action for ME- a large charity
NRS Healthcare on ME
Diet and Food factsheet from The Association of UK Dietitians
Information for public from NICE
Fakuda Criteria
Multidimensional Fatigue Inventory (MFI)
Modified Fatigue Impact Scale (MFIS)
De Paul Symptom questionnaire


  1. Kim, D., Lee, J., Park, S. et al. Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med 18, 7 (2020).
  2. Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey by Carly S. Holtzman, Shaun Bhatia, Joseph Cotler and Leonard A. Jason
    Center for Community Research, Department of Psychology, DePaul University, Chicago, IL 60604, USA 

  3. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10. 3, Current Case Definitions and Diagnostic Criteria, Terminology, and Symptom Constructs and Clusters. Available from:
  4. Chronic fatigue syndrome/myalgic encephalomyelitis ( elitis or encephalopathy or encephalopathy): diagnosis and management diagnosis and management
    Clinical guideline Published: 22 August 2007
  5. ME/CFS Guidelines Myalgic Encephalopathy (ME)/ Chronic Fatigue Syndrome (CFS) Management Guidelines for General Practitioners A guideline for the diagnosis and management of ME/CFS in the community or primary care setting
  6. Are current chronic fatigue syndrome criteria diagnosing different disease phenotypes? Laura Maclachlan, Stuart Watson, Peter Gallagher, Andreas Finkelmeyer, Leonard A. Jason, Madison Sunnquist, Julia L. Newton
  7. Chronic fatigue syndrome
    Rosamund Vallings MB BS (Lond), MRCS, LRCP, Dip Clin Hypnosis J PRIM HEALTH CARE 2019;11(4):295–299. doi:10.1071/HCv11n4_ED2 Published 18 December 2019
  8. Avellaneda Fernández, A., Pérez Martín, A., Izquierdo Martínez, M., Arruti Bustillo, M., Barbado Hernández, F. J., de la Cruz Labrado, J., Díaz-Delgado Peñas, R., Gutiérrez Rivas, E., Palacín Delgado, C., Rivera Redondo, J., & Ramón Giménez, J. R. (2009). Chronic fatigue syndrome: aetiology, diagnosis and treatment. BMC psychiatry, 9 Suppl 1(Suppl 1), S1.
  9. Chronic Fatigue Syndrome: Diagnosis and Treatment
  10. Diagnosing and Treating
  11. Bayliss, K., Riste, L., Fisher, L., Wearden, A., Peters, S., Lovell, K., & Chew-Graham, C. (2014). Diagnosis and management of chronic fatigue syndrome/myalgic encephalitis in black and minority ethnic people: A qualitative study. Primary Health Care Research & Development, 15(2), 143-155. doi:10.1017/S1463423613000145 ( Abstract )
  12. Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) Service
    A guide to the diagnosis and management of CFS/ME in primary care
  13. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 via
  14. Johnston, S., Brenu, E. W., Staines, D., & Marshall-Gradisnik, S. (2013). The prevalence of chronic fatigue syndrome/ myalgic encephalomyelitis: a meta-analysis. Clinical epidemiology, 5, 105–110.
  15. Centers for Disease Control and Prevention Myalgic Encephalomyelitis / Chronic Fatigue Syndrome via
  16. Bakken, I.J., Tveito, K., Gunnes, N. et al. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med 12, 167 (2014).
  17. Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union
    Strand EB, Nacul L, Mengshoel AM, Helland IB, Grabowski P, et al. (2019) Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union. PLOS ONE 14(12): e0225995.
  18. REVIEW ARTICLE Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome
    CorrespondenceJesusCastro-Marrero,Valld’HebronUniversityHospital,CollserolaResearchInstitute,CFS/MEUnit(Lab.145–Floor1), Passeig de Vall d’Hebron 119-129, E-08035 – Barcelona, Spain. E-mail:
    Received 8 June 2016; Revised 25 November 2016; Accepted 14 December 2016
    Jesus Castro-Marrero1, Naia Sáez-Francàs2, Dafna Santillo1 and Jose Alegre1
    1CFS/ME Unit, Vall d’Hebron University Hospital, Collserola Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain, and 2Psychiatry Unit, Sant Rafael Hospital (FIDMAG), Barcelona, Spain British Journal of Pharmacology (2017)


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