Primary Care Corner with Geoffrey Modest MD: Chronic fatigue syndrome

By: Dr. Geoffrey Modest 

The AHRQ (Agency for Healthcare Research and Quality) came out with an evidence report/technology assessment for the diagnosis and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome — ME/CFS (see here), reviewing 71 studies in 81 publications.


–In general, this diagnosis is entertained when there is chronic and disabling fatigue, along with a variety of other symptoms including neurological and cognitive changes, motor impairment, pain, sleep disturbance and altered immune and autonomic responses. The etiology is unknown: it is unclear whether ME and CFS are part of the same illness, or whether this is just a nonspecific set of symptoms shared by other disease entities. The diagnosis of ME/CFS requires exclusion of other possible diagnoses (e.g., rheumatoid arthritis or other immune diseases, etc) and there is considerable overlap with some psych diagnoses (about 2/3 of cases, though hard to tell if these are primary or secondary psych issues — i.e. do they cause the fatigue and other symptoms or result from it). There are 8 different case definitions of ME/CFS, with those just for ME requiring postexertional malaise and having the more symptomatic subset. In this technology assessment they were not able to determine differences in accuracy between these definitions nor a universally accepted reference standard.

–Self-reported symptom scales differentiate ME/CFS from controls, but they are not adequately evaluated to determine validity or generalizability to large populations

–The diagnosis itself has some “harms”: patients may feel stigmatized in terms of financial stability, work opportunities, judgment by others, social isolation (found in several studies), or in misdiagnosis and not having the real issue treated (e.g., depression)

–35 treatment trials, with no medications approved by the FDA for this condition.

–Rintatolimod, an experimental immunomodulator not approved by the FDA, improved exercise performance vs placebo (small studies, low strength of evidence)

​–Other meds were inconclusive (galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, acyclovir). These meds were targeting different potential etiologies: immune dysfunction, viral causes, depression. Insufficient evidence also for rituximab (1 trial, 27 patients, with improved physical health and function, but not other outcomes)

–Complementary and alternative medicine. 7 trials. inconclusive results, though “studies of homeopathy, pollen extracts, and L-carnitine preparations reported benefit for some outcomes”, but small sample sizes, methodologic issues with studies, and no reports of adverse effects

–Counseling and GET (graded exercise treatment) improved function, fatigue and quality of life, with GET having more harms and withdrawal rates than counseling therapies or controls. Counseling improved fatigue (7 of 11 trials), functioning (4 of 11 trials), quality of life (2 of 4 trials) and global improvement (2 of 2 trials).

So, a pretty mixed bag. Uncertainty about diagnosis/case definition (which makes it difficult to conduct effective trials, and, to me, makes it pretty likely that ME/CFS is a hodge-podge of different entities), and it seems that the best treatment is counseling. But a couple of other issues. There may well be a relationship with higher socio-economic status, as found in several studies, and my experience in an inner city health center is that in the past 30 years I have seen approximately 1 person who fit the broad scope of this diagnosis, though I must admit there could have been some ascertainment bias on my part…. also, it is potentially very harmful to give this diagnosis incorrectly and not address the real cause of the fatigue. in the workup of the patient, most of the medical causes have been assessed (though it is certainly possible that some as-of-yet unidentified virus causes a lot of the problems), but my concern is that us medical providers may miss/not treat significant psych issues and thereby do the patient a real disservice ​(e.g., whether the depression or sleep disorder is primary or secondary, it should be treated).

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