Natelson, Benjamin H, Lange, Gudrun · Environmental health perspectives · 2002 · DOI
This review examines why people develop ME/CFS, a condition marked by extreme tiredness and other symptoms that doctors struggle to explain. The authors suggest that ME/CFS likely isn't caused by a single thing, but rather by several different problems—including brain issues, difficulty handling stress, and concerns about making symptoms worse through activity. They note that while severe infections can trigger ME/CFS, the condition seems to persist through different biological mechanisms than the original infection itself.
This foundational status report advocates for a heterogeneous disease model of ME/CFS, which has influenced subsequent research strategy and helped legitimize investigation into multiple biological and psychological mechanisms. Recognition that ME/CFS has multiple causes rather than a single etiology has important implications for treatment development and personalized medicine approaches in this population.
This review does not establish which specific pathophysiological mechanisms predominate in individual patients or provide definitive evidence for any single causal pathway. The authors explicitly note they cannot be certain CFS comprises multiple subgroups—this remains a conceptual framework requiring empirical validation. The review also does not provide quantitative meta-analysis of existing data.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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