Nacul, Luis, O'Boyle, Shennae, Palla, Luigi et al. · Frontiers in neurology · 2020 · DOI
This study proposes a framework for understanding how ME/CFS develops and changes over time, similar to other long-term illnesses. The authors suggest that ME/CFS progresses through stages—starting with genetic and environmental risk factors, moving through an early phase with high energy use and immune system problems, and potentially progressing to a later phase with low energy production and multiple system involvement. They emphasize that ME/CFS is not the same in every person or at every stage of illness, and that some people may improve if their body can restore better balance.
This framework helps explain why ME/CFS presents so differently between patients and why a single set of diagnostic criteria or biomarkers cannot capture everyone's experience. Understanding ME/CFS as a progressive condition with distinct stages may improve diagnosis, guide personalized treatment approaches, and help researchers design better studies that account for where patients are in their disease course.
This is a theoretical model, not a study of actual patient data, so it does not prove that all ME/CFS cases follow this progression pattern or timeline. The framework cannot establish causation for any specific pathophysiological mechanism, nor does it validate the proposed stages in clinical practice. The authors explicitly acknowledge gaps in research evidence underlying the model.
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 →
The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.
Primary citation
Nacul, Luis, O'Boyle, Shennae, Palla, Luigi, Nacul, Flavio E, Mudie, Kathleen, Kingdon, Caroline C, et al. (2020). How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS.. Frontiers in neurology. https://doi.org/10.3389/fneur.2020.00826
BibTeX
@article{mecfsatlas-nacul-2020-how-myalgic,
author = {Nacul, Luis and O'Boyle, Shennae and Palla, Luigi and Nacul, Flavio E and Mudie, Kathleen and Kingdon, Caroline C and Cliff, Jacqueline M and Clark, Taane G and Dockrell, Hazel M and Lacerda, Eliana M},
title = {How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS.},
journal = {Frontiers in neurology},
year = {2020},
doi = {10.3389/fneur.2020.00826},
note = {PubMed: 32849252},
url = {https://www.mecfsatlas.com/evidence/nacul-2020-how-myalgic},
}Atlas snapshot reference
ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-28. https://www.mecfsatlas.com/evidence/nacul-2020-how-myalgic
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