Science News: Fatigue: A Common but Poorly Understood Symptom in Neurological and Non-neurological Diseases

Submitted by: Christine Meadows, MD
Edited by: Rebecca O'Bryan, MD

Citation: Penner IK, Grothe M, Chan A. Fatigue: a common but poorly understood symptom in neurological and non-neurological diseases. Nat Rev Neurol. 2025;21(12):706-720. doi:10.1038/s41582-025-01153-z

Summary:
This article proposes a novel approach to addressing fatigue in neurological and non-neurological diseases. Three categories are proposed based on origin: neurogenic (from the central nervous system), myogenic (from muscle or neuromuscular junction weakness), and systemic (from immune-mediated, inflammatory, or other systemic processes).

Each cluster comprises five distinct concepts describing phenotypic expression of fatigue. The authors emphasize that fatigue results from complex interactions between genetics, epigenetics, immunological changes, structural and functional brain abnormalities, and behavioral alterations, with mechanisms varying between diseases and over time. There is still a lack of a unified definition and understanding of fatigue.

The proposed taxonomy directly addresses a fundamental challenge in neuromuscular practice: distinguishing peripheral fatigue (muscle fatigability from neuromuscular junction or muscle pathology) from central fatigue (subjective sense of exhaustion perceived at the CNS level). In myasthenia gravis, for example, patients experience both peripheral fatigability from acetylcholine receptor dysfunction and central fatigue that persists even in remission (10% of patients with resolved symptoms still have central fatigue). The article's framework helps clinicians systematically evaluate whether fatigue originates from myogenic mechanisms (the "myogenic cluster"), neurogenic mechanisms affecting central motor drive, or systemic factors like inflammation.

Comments:
Fatigue affects approximately 60% of patients diagnosed with neuromuscular disorders and is often underrecognized. Patients suffering from severe fatigue have significantly decreased quality of life. Socioeconomic consequences are far-reaching. The article's integrative model has direct therapeutic implications. While treating the underlying neuromuscular disease is the first step, when fatigue persists, non-pharmacological interventions such as exercise programs, cognitive behavioral therapy, and treatment of comorbid conditions (depression, sleep disorders) are essential.