Central and peripheral fatigue: exemplified by multiple sclerosis and myasthenia gravis

Fatigue is a feature of several chronic diseases of the central and peripheral nervous system. The pathophysiology of central fatigue is complex and often not well-defined. In contrast, peripheral fatigue is more objectively defined and measured. Fatigue can be part of the primary disease process, but there are often contributions from comorbid factors such as depression, sleep disturbance, medication, or deconditioning. Multiple sclerosis (MS) offers an example of central fatigue. More than 40% of MS patients complain of fatigue. Validated questionnaires are used to assess fatigue severity and comorbid factors. Although fatigue is believed to be a primary process in MS, depression and sleep disturbance are often comorbid problems. Magnetic resonance imaging (MRI), positron emission tomography, and functional MRI studies suggest that fatigue is related to gray matter disease, particularly of the cerebral cortex, but also of the thalamus and caudate. Disruption of impulse propagation from demyelination is also a likely factor. It is uncertain if pro-inflammatory cytokines have a specific effect on the genesis of MS fatigue. Several medications have been reported to alleviate fatigue in MS, but controlled studies show contradictory results. Treatment of depression and sleep disturbance, use of exercise programs and rehabilitation therapies as well as treatment of other comorbid conditions is necessary for optimal alleviation of fatigue. Myasthenia gravis (MG) patients exhibit peripheral fatigue. In contrast to MS, the mechanism of weakness and fatigue in MG is well-defined. Antibodies to the postsynaptic acetylcholine receptor at the myoneural junction cause diminution of the force of muscle contractions. This leads to a feeling of fatigue. MG treatments increase the availability of acetylcholine and reduce antibody formation. Evaluation for comorbid conditions, especially thymoma and hyperthyroidism, are mandatory in patients with MG.