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One potential explanation for prolonged symptom expression is the concurrent development of a stress\u2010mediated illness or CMI (Chronic Multi\u2010Symptom Illness). In such a scenario, the chronic regional pain and other symptoms that the individual is experiencing would be attributable to the CMI rather than to tissue damage or a biomechanical dysfunction of the upper\u2010extremity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This article critically reviews the case definitions of the new class of CMI disorders and evaluates the existing evidence supporting centrally mediated physiological changes (e.g., sensory hypervigilance, dysautonomia) that manifest as symptoms of pain and fatigue in some individuals experiencing chronic stressors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>While explanations for prolonged pain and fatigue have historically focused on mechanisms involving peripheral pathology or psychiatric explanations, ample evidences support the role of altered Central Nervous System function in accounting for symptom manifestation in CMI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A model is presented that unites seemingly disparate findings across numerous investigations and provides a framework for understanding how genetics, triggering events, stressors, and early life events can affect CNS activity. Resultant symptom expression (e.g., pain and fatigue) from central dysregulation would be expected to occur in a subset of individuals in the population, including a subset of individuals with work\u2010related upper extremity disorders. Thus when symptoms such as pain and fatigue persist beyond a reasonable period, consideration of CMI and associated assessment and interventions focused on central mechanisms may be worthwhile. Am. J. Ind. 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