Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, chronic, complex multisystem disease characterized by profound fatigue of new or definite onset, not substantially alleviated by rest, accompanied by post-exertional malaise (PEM)—a hallmark worsening of symptoms following minimal physical or cognitive exertion—and additional core features including unrefreshing sleep and either cognitive impairment or orthostatic intolerance, with symptoms persisting for more than six months and substantially reducing pre-illness activity levels.[1][2] Clinical descriptions emphasize PEM as a cardinal distinguishing symptom, involving a delayed crash in energy production and exacerbation of neurological, autonomic, and immune-related dysfunctions, often triggered by activities well below those tolerated by healthy individuals.[3][4]Diagnostic criteria for ME/CFS have evolved from earlier fatigue-focused definitions, such as the 1994 Fukuda criteria, which required unexplained fatigue plus at least four of eight secondary symptoms but lacked mandatory PEM, to stricter biomedical-oriented frameworks like the 2003 Canadian Consensus Criteria and the 2015 Institute of Medicine (IOM) criteria, which prioritize PEM, systemic exertion intolerance, and exclusion of alternative explanations through clinical evaluation rather than specific biomarkers, as no single diagnostic test exists.[5][6] The IOM criteria, developed via systematic evidence review, identify three obligatory symptoms (activity-limiting fatigue, PEM, unrefreshing sleep) and require at least one of two additional symptoms (cognitive dysfunction or orthostatic intolerance) for diagnosis, aiming to improve clinical utility while acknowledging the illness's heterogeneity and frequent onset following infection or physiological stress.[2][7]Beyond core symptoms, clinical descriptions commonly include orthostatic intolerance (e.g., lightheadedness upon standing), pain (muscle, joint, or headache), sleep disturbances, and neurocognitive issues like memory lapses and concentration deficits, often compounded by immune activation markers, metabolic derangements, and sensory sensitivities, underscoring ME/CFS as a disease of impaired energy metabolism and multisystem failure rather than mere deconditioning.[3] Controversies persist regarding nomenclature and etiology, with historical psychological attributions challenged by empirical evidence of viral triggers, mitochondrial dysfunction, and neuroinflammation, though diagnostic heterogeneity across criteria complicates prevalence estimates and research reproducibility.[8][9] These descriptions guide clinicians toward symptom-based diagnosis of exclusion, emphasizing pacing to avoid PEM crashes, as aggressive exercise therapies have been linked to harm in rigorous patient cohorts.[10]
