Fatigue and impaired balance frequently affect patients with Multiple Sclerosis (MS). This is an open, prospective randomised crossover trial aimed at clarifying whether an improvement in balance control after balance training would also improve fatigue in patients with MS. Balance training will be compared to aerobic training, which is known to be effective on fatigue.

Fatigue is known to affect patients with Multiple Sclerosis (MS), with a prevalence ranging from 55% to 83%, thus contributing to the level of disability, compromising the Quality of Life, and increasing the overall treatment costs. For these reasons, fatigue is considered a main target for pharmacological and non-pharmacological therapies for MS.

The physiopathology of fatigue in MS is still not completely understood, and previous research has shown correlations with reduced motor performance, disease progression and depression. Some possible mechanisms of fatigue in MS have been hypothesised but not yet proven, such as structural alterations in the central nervous system, altered immune function in the brain, impaired pituitary gland function, and changes in cardiac or muscle activity.

Patients with MS also frequently show balance impairments, with prevalence peaking at 87.9%, and previous studies have suggested a causal relationship between fatigue and balance deficits.

Therapeutic exercise has shown a key role in contrasting the functional decline and disability secondary to MS. Several studies have evaluated the effects of different types of training, such as balance training and aerobic training, on balance impairment and the overall patient's functional performance.

In the literature, it is not uncommon to observe improvements in fatigue after the administration of exercise therapy targeted at the balance impairment. However, the literature has not yet clarified whether an improvement in balance control after balance training would also result in an improvement in the scales used to measure fatigue.

The aim of this open prospective randomised crossover trial is to compare the effects of two different types of therapeutic exercise, aerobic training (AT) and balance training (BT), in modifying the intensity of fatigue in patients with MS. AT and BT will be administered at different times to the same patients (crossover trial). Both AT and BT will consist of 15 treatment sessions (5 sessions per week). Patients with MS will be randomly assigned to AT or BT in the first treatment period and then switched to the other type of training in the second treatment period. The time interval between the two time periods will last 60 days, during which the patients will not perform any physical exercise.

In each treatment period, the participants will perform three measurement sessions: before intervention (T0), at the end of intervention (T1), and 30 days after the end of intervention (T2).

Inclusion criteria:

• MS diagnosis according to the revised McDonalds criteria. Relapsing-remitting, primary and secondary progressive MS forms are allowed;
• Expanded Disability Status Scale (EDSS) between 2 and 6, included;
• Fatigue as indicated by a total score of mFIS ≥ 20/84;
• Balance impairment as indicated by a performance at the Equitest Sensory Organisation Test below age-matched normal values (95th percentile of control values).

Exclusion criteria:

• Any of the following in the month before enrolment: an MS relapse; current corticosteroids therapy because of MS; change in medicines prescribed against fatigue; attending an intensive physical therapy program;
• New or active lesions on a brain or spinal cord MRI scan in the 12 months before the study enrolment;
• Angioplasty for chronic cerebrospinal venous insufficiency in the six months before enrolment;
• Any musculoskeletal disease or any additional neurological disorder which causes by itself a balance or gait impairment;
• Any other condition causing fatigue by itself;
• Any unstable cardiological disease.