Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system that may cause a broad range of motor and non-motor symptoms. New or worsening neurological symptoms in people with MS are frequently interpreted as a possible relapse. However, relapse-like episodes are not always caused by new inflammatory disease activity and may instead reflect infection, fever, comorbidities, fluctuations of pre-existing symptoms, or an overlapping functional neurological disorder. Functional motor disorders (FMDs) are characterized by altered voluntary motor control and may present with weakness, tremor, gait disturbance, postural instability, abnormal movements, or impaired motor performance. These manifestations may resemble MS-related symptoms and may coexist with established structural neurological disease. In people with MS, functional motor symptoms may therefore be misclassified as relapse or disease progression, potentially leading to unnecessary investigations, corticosteroid treatment, inappropriate escalation of disease-modifying therapy, avoidable healthcare use, and delayed access to appropriate rehabilitation. Despite growing recognition of FMD-MS overlap, its prevalence, clinical characteristics, and optimal management remain insufficiently defined. This multicenter prospective study aims to improve the identification, characterization, and management of FMD-MS overlap in people with MS presenting with acute neurological symptom worsening. The study consists of two sequential and interconnected parts.
Part A is an observational, cross-sectional diagnostic and prevalence study. A total of 192 adults with MS according to the 2017 revisions of the McDonald criteria and reporting new or worsening neurological symptoms within the previous 30 days will be enrolled at two tertiary MS centers in Italy. No study-assigned treatment will be administered during Part A. Participants will undergo a standardized multidimensional assessment including demographic and MS-related clinical information, neurological examination, evaluation of positive functional motor signs, disability and functional measures, gait and balance assessments, patient-reported outcome measures, and review of laboratory and magnetic resonance imaging findings obtained as part of routine clinical care when clinically indicated.
The primary aim of Part A is to estimate the prevalence of FMD-MS overlap, also referred to in the protocol as functional pseudorelapse, among people with MS presenting with acute symptom worsening. Additional aims are to distinguish FMD-MS overlap from true MS relapse and other causes of symptom worsening and to identify demographic, clinical, functional, gait, balance, psychological, quality-of-life, and routine-care imaging characteristics associated with each diagnostic category.
Part B is a pilot randomized, assessor-blinded, active-controlled rehabilitation study. Approximately 26 participants with confirmed FMD-MS overlap identified during Part A and meeting the additional rehabilitation eligibility criteria will enter Part B. These 26 participants are included within the overall cohort of 192 participants and are not an additional study population.
Participants entering Part B will be randomized in a 1:1 ratio to either a targeted FMD-specific multidisciplinary rehabilitation programme or conventional MS rehabilitation. The experimental programme will include five consecutive days of in-person rehabilitation focused on education regarding functional symptom mechanisms, movement retraining using attentional-redirection strategies, and development of an individualized self-management plan. This will be followed by a 12-week home-based programme supported by weekly telemedicine sessions. The active comparator will consist of conventional MS rehabilitation addressing mobility, strength, gait, balance, endurance, fatigue management, and functional independence, without protocolized FMD-specific techniques.
Part B aims to assess the feasibility, safety, and preliminary efficacy of the FMD-specific rehabilitation programme compared with conventional MS rehabilitation. Outcomes will be assessed at baseline, immediately after the five-day intervention, and at three months. The main efficacy outcome will be change in functional motor symptom severity, with additional evaluation of disability, functional performance, gait, balance, fatigue, pain, emotional functioning, quality of life, healthcare utilization, and costs.
Overall, the study is expected to provide prospective evidence on the frequency and clinical profile of FMD-MS overlap and preliminary evidence on whether a mechanism-specific rehabilitation approach may improve outcomes in affected people with MS.