Brain fatigue in Graves' disease: symptoms and presentation of a possible mechanism at the cellular level

Fatigue in patients with Graves' disease (GD) is characterized by a profound lack of mental energy that affects daily functioning, including work. This symptom is particularly prominent in the early stages of the disease, affecting more than 50% of patients, but in some cases, it persists even after successful endocrinological treatment and restoration of euthyroidism. Individuals with persistent fatigue often seek support. Because this tiredness originates in the brain, we refer to it as brain fatigue. It is accompanied by a cluster of interconnected symptoms as cognitive, sensory, and emotional, which we define collectively as brain fatigue syndrome (BFS). BFS is marked by reduced perceived energy levels and associated impairments across multiple domains. The aim of this paper is to improve the understanding and identification of BFS in GD and to propose potential treatment options. We also propose a hypothesis, supported by robust preclinical evidence, that the inflammatory response in this autoimmune disorder may lead to astrocyte dysfunction, impairing neuronal signaling for multiple neurotransmitters. This could reduce the efficiency of brain information processing, increase activation of larger brain areas, and diminish glucose uptake from the bloodstream. Such changes may result in widespread brain dysfunction, culminating in an energy crisis that manifests as profound fatigue and cognitive, sensory, and emotional impairments. However, this hypothesis needs to be tested in humans, particularly regarding the persistence of brain fatigue in GD after normalization of thyroid hormone levels.