“Doctor, I’m so tired!” Refining your work-up for chronic fatigue

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Applied Evidence

“Doctor, I’m so tired!” Refining your work-up for chronic fatigue

J Fam Pract. 2015 February;64(2):84-91

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References

1. Nijrolder I, van der Windt DA, van der Horst HE. Prognosis of fatigue and functioning in primary care: a 1-year follow-up study. Ann Fam Med. 2008;6:519-527.

2. Griffith JP, Zarrouf FA. A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Primary Care Companion J Clin Psychiatry. 2008;10:120-128.

3. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-389.

4. Morris G, Maes M. Case definitions and diagnostic criteria for myalgic encephalomyelitis and chronic fatigue syndrome: from clinical consensus to evidence-based case definitions. Neuro Endocrinol Lett. 2013;34:185-199.

5. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.

6. Centers for Disease Control and Prevention. Chronic fatigue syndrome. Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/cfs/diagnosis/index.html. Accessed January 6, 2015.

7. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270:327-338.

8. Johnston SC, Brenu EW, Hardcastle S, et al. A comparison of health status in patients meeting alternative definitions for chronic fatigue syndrome/myalgic encephalomyelitis. Health Qual Life Outcomes. 2014;12:64.

9. Anderson VR, Jason LA, Hlavaty LE, et al. A review and meta-synthesis of qualitative studies on myalgic encephalomyelitis/chronic fatigue syndrome. Patient Educ Couns. 2012;86:147-155.

10. Christley Y, Duffy T, Everall IP, et al. The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: revisiting the enigma. Curr Psychiatry Rep. 2013;15;353.

11. Henningsen P, Zimmermann T, Sattel HH. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003;65:528-533.

12. Nater UM, Jones JF, Lin JM, et al. Personality features and personality disorders in chronic fatigue syndrome: a population-based study. Psychother Psychosom. 2010;79:312-318.

13. Taylor RR, Jason LA, Jahn SC. Chronic fatigue and sociodemographic characteristics as predictors of psychiatric disorders in a community-based sample. Psychosom Med. 2003;65:896-901.

14. Leonard B, Maes M. Mechanistic explanations of how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36:764-785.

15. DeLuca J, Christodoulou C, Diamond BJ, et al. Working memory deficits in chronic fatigue syndrome: differentiating between speed and accuracy of information processing. J Int Neuropsychol Soc. 2004;10:101-109.

16. Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010;40:1253-1267.

17. Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011;31:325-337.

18. Naess H, Sundal E, Myhr KM, et al. Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway. In Vivo. 2010;24:185-188.

19. Hickie I, Davenport T, Wakefield D, et al; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575.

20. Plioplys AV, Plioplys S. Electron-microscopic investigation of muscle mitochondria in chronic fatigue syndrome. Neuropsychobiology. 1995;32:175-181.

21. Vernon SD, Whistler T, Cameron B, et al. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006;6:15.

22. Miwa K, Fujita M. Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010;25:319-323.

23. Rosenblum H, Shoenfeld Y, Amital H. The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome. Infect Dis Clin North Am. 2011;25:851-863.

24. Vincent A, Brimmer DJ, Whipple MO, et al. Prevalence, incidence, and classification of chronic fatigue syndrome in Olmsted County, Minnesota as estimated using the Rochester Epidemiology Project. Mayo Clin Proc. 2012;87:1145-1152.

25. Goroll AH, Mulley AG. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 7th ed. Morrisville, PA: Wolters Kluwer; 2014.

26. Brown RF, Schutte NS. Direct and indirect relationships between emotional intelligence and subjective fatigue in university students. J Psychosom Res. 2006;60:585-593.

27. Pigeon WR, Sateia MJ, Ferguson RJ. Distinguishing between excessive daytime sleepiness and fatigue: toward improved detection and treatment. J Psychosom Res. 2003;54:61-69.

28. Bailes S, Libman E, Baltzan M, et al. Brief and distinct empirical sleepiness and fatigue scales. J Psychosom Res. 2006;60:605-613.

29. National Collaborating Centre for Primary Care (UK). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. London, UK: Royal College of General Practitioners; 2007.

30. Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990;299:313-318.

31. Vaucher P, Druisw PL, Waldvogel S, et al. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012;184:1247-1254.

32. US Preventive Services Task Force. Hepatitis C: Screening. US Preventive Services Task Force Web site. Available at: http://www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm. Accessed January 7, 2015.

33. Rolfe A, Burton C. Reassurance after diagnostic testing with a low pretest probability of serious disease: a systematic review and meta-analysis. JAMA Intern Med. 2013;173:407-416.

34. Smith RC, Lyles JS, Gardiner JC, et al. Primary care clinicians treat patients with medically unexplained symptoms: a randomized controlled trial. J Gen Intern Med. 2006;21:671-677.

35. White PD, Goldsmith KA, Johnson AL, et al; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue (PACE): a randomised trial. Lancet. 2011;377:823-836.

36. van Weert E, Hoekstra-Weebers J, Otter R, et al. Cancer-related fatigue: predictors and effects of rehabilitation. Oncologist. 2006;11:184-196.

There are several possible explanations for CFS and MDD comorbidity, which are not necessarily mutually exclusive.¹⁰ One theory is that CFS is an atypical form of depression; another holds that the disability associated with CFS leads to depression, as is the case with many other chronic illnesses; and a third points to overlapping pathophysiology.¹⁰

An emerging body of evidence suggests that CFS and MDD have some common oxidative and nitrosative biochemical pathways. Activated by infection, psychological stress, and immune disorders, they are believed to have damaging free radical and nitric oxide effects at the cellular level.¹⁴ The cellular effects can result in fatigue, muscle pain, and flu-like malaise.

Cortisol response differs

The majority of patients with CFS report symptoms of cognitive decline, with the acquisition of new verbal learning and information-processing speed particularly likely to be impaired.CFS and MDD might be distinguishable by another pathway—the hypothalamic-pituitary-adrenal (HPA) axis. MDD is classically associated with activation and raised cortisol levels, while CFS is consistently associated with impaired HPA axis functioning and reduced cortisol levels.¹⁰ The majority of patients with CFS report symptoms of cognitive decline, with the acquisition of new verbal learning and information-processing speed particularly likely to be impaired.¹⁵

A meta-analysis of 50 studies of patients with CFS showed deficits in attention, memory, and reaction time, but not in fine motor speed, vocabulary, or reasoning.¹⁶ Autonomic dysfunction has also been observed, including disordered sympathetic activity. The most frequently observed abnormalities on autonomic testing are postural hypotension, tachycardia syndrome, neurally mediated hypotension, and heart rate variability during tilt table testing.¹⁶

The link between infection and CFS

Several infectious agents have been associated with ME/CFS, including the Epstein-Barr virus (EBV), herpes simplex virus 6, parvovirus, Q fever, and Lyme disease.^8,17,18 Most agents that have been linked to ME/CFS are associated with persistent infection and thus incitement of the immune system.

Numerous observational studies^17,18 have documented postinfectious fatigue syndromes after acute viral and bacterial infections and symptoms suggestive of infection, such as fever, myalgias, and respiratory and gastrointestinal distress. In one prospective Australian study,¹⁹ investigators identified 253 cases of acute EBV, Ross River virus, and Q fever. Of those 253 patients, 12% went on to develop CFS, with a higher likelihood among those with more severe acute symptoms. No correlation with preexisting psychiatric disorders was found.

Several infectious agents have been associated with ME/CFS, including the Epstein-Barr virus, herpes simplex virus 6, parvovirus, Q fever, and Lyme disease.Muscle mitochondria studies have demonstrated what appear to be acquired abnormalities in those with CFS.^20,21 Signs of increased oxidative stress have been found in both blood and muscle samples from patients with CFS, and longitudinal studies suggest that oxidative stress is greatest during periods of clinical exacerbation.²² Increased lactate levels suggest increased anaerobic metabolism in the central nervous system consistent with mitochondrial dysfunction. Several studies have demonstrated that exercise can precipitate oxidative stress in patients with CFS, in contrast with healthy controls and controls with other chronic illnesses, suggesting a physiologic basis for their postexertional symptoms.¹⁷

Autoinflammatory syndrome induced by adjuvants, a rare syndrome associated with vaccine administration, has been linked to postvaccination adverse events, exposure to silicone implants, Gulf War syndrome (related to multiple vaccinations), and macrophagic myofasciitis. All involve exposure to immune adjuvants and have similar clinical manifestations. The corresponding exposures appear to trigger an autoimmune response in susceptible individuals. The hepatitis B vaccine is most often associated with CFS, with symptoms occurring within 90 days of administration.²³

The clinical work-up: Putting knowledge into practice

Familiarity with potential causes of and connections with ME/CFS will help you ensure that patients who say they’re always tired receive a thorough work-up. Start with a medical history, inquiring directly about medical and psychiatric disorders that may contribute to fatigue (TABLE 3).^5,24,25 Include a medication history, as well, to help determine whether the fatigue is drug-related (TABLE 4).^5,25

What to ask. Determine the onset, course, duration, daily pattern, and impact of fatigue on the patient’s daily life. Inquire, too, about related symptoms of daytime sleepiness, dyspnea on exertion, generalized weakness, and depressed mood. The prominence of any of these rather than fatigue, per se, point to a diagnosis of a chronic illness other than ME/CFS.

Keep in mind, too, that patients with an organ-based medical illness tend to associate their fatigue with activities that they are unable to complete, such as shopping or light housework. In contrast, those with fatigue that is not organ-based typically say that they’re tired all the time. Their fatigue is not necessarily related to exertion, nor does it improve with rest.²⁶