Chronic fatigue syndrome. 1: Etiology and pathogenesis.
Farrar, D J, Locke, S E, Kantrowitz, F G · Behavioral medicine (Washington, D.C.) · 1995 · DOI
Quick Summary
ME/CFS is a serious illness that causes extreme tiredness and many other symptoms, but doctors don't yet fully understand what causes it or how to treat it best. This review looks at research about what might be happening in the body—including problems with the immune system and stress hormone regulation—but notes that no single explanation has been proven. Right now, treatment approaches are based on guesses rather than solid evidence, and we need better ways to identify which patients have which type of ME/CFS.
Why It Matters
This systematic review highlights a fundamental gap in ME/CFS medicine: despite decades of research, the underlying cause remains unknown, leaving patients without evidence-based treatments. By documenting the scientific uncertainty while pointing toward immune and neurological dysfunction as promising areas, this work underscores why continued research investment is critical and why patients may experience variable responses to different treatments.
Observed Findings
Heterogeneous clinical and laboratory findings reported across CFS patient populations
Evidence of immunologic dysfunction in some patient subsets
Neuroendocrine changes documented in CFS cohorts
Variable responses to existing management approaches
Lack of consistent case definitions across studies
Inferred Conclusions
Dysregulation of nervous system and immune system interactions may underlie CFS pathophysiology
Without clear etiologic understanding, current treatment approaches remain speculative rather than evidence-based
Homogeneous patient subtyping is essential for advancing both research and clinical care
Integrated biomedical and psychologic approaches are needed to develop effective treatments
Remaining Questions
What is the primary etiology of ME/CFS, and are there distinct disease subtypes with different underlying mechanisms?
How do immune system dysfunction and neuroendocrine abnormalities mechanistically contribute to symptom generation?
What This Study Does Not Prove
This review does not prove that any single cause or mechanism explains ME/CFS, nor does it validate any specific treatment as effective. It reflects 1995-era understanding and does not establish whether observed immunologic or neuroendocrine changes are primary causes, secondary effects, or correlates of the disease. The inclusive nature of early research meant it did not yet distinguish between heterogeneous patient subgroups, limiting the strength of conclusions.