An interventional study of Functional Motor Disorder-Specific Multidisciplinary Rehabilitation and Conventional Multiple Sclerosis Rehabilitation in Multiple Sclerosis and Functional Neurological Disorders, sponsored by IRCCS San Raffaele. Not yet recruiting at 2 sites in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-02.
Sponsored by IRCCS San Raffaele · Not applicable, Interventional, and Treatment
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.
This multicenter prospective study is conducted at two tertiary multiple sclerosis (MS) centers in Italy and uses a sequential design combining an observational diagnostic phase with a nested randomized rehabilitation trial. The study addresses the clinical difficulty of distinguishing inflammatory MS relapse from functional motor symptoms in people with established MS. Functional motor disorder (FMD) may coexist with MS and produce weakness, tremor, gait disturbance, postural instability, or other motor manifestations that resemble relapse or progression. Misclassification may result in unnecessary investigations or anti-inflammatory treatment and may delay access to mechanism-specific rehabilitation.
In Part A, 192 consecutive adults with MS presenting with self-reported acute neurological symptom worsening within the previous 30 days will undergo a standardized, cross-sectional multidimensional assessment. Part A is observational, and no study intervention will be assigned. The assessment will integrate neurological examination, positive clinical signs of FMD, functional and patient-reported evaluations, gait and balance measures, and laboratory or magnetic resonance imaging findings obtained as part of routine clinical care when clinically indicated.
Participants will be classified as having a true MS relapse, FMD-MS overlap or functional pseudorelapse, or another clinically relevant explanation for symptom worsening. A true relapse will be defined according to the occurrence of new or worsening neurological symptoms lasting at least 24 hours in the absence of fever, active infection, trauma, or another acute medical cause. FMD-MS overlap will be established using positive signs of functional motor dysfunction together with applicable DSM-5 and Gupta-Lang criteria. Complex or borderline cases may undergo central diagnostic review to improve consistency between centers. Routine clinical decisions regarding investigations and management of the presenting episode will remain under the responsibility of the treating physician.
Part A will estimate the prevalence of FMD-MS overlap in this clinical population and characterize the multidimensional features associated with the different diagnostic classifications. The planned sample of 192 participants allows for incomplete assessments while providing approximately ±5% precision around an expected prevalence of 13%.
In Part B, participants identified during Part A as having confirmed FMD-MS overlap will be evaluated for suitability for the rehabilitation trial. Approximately 26 participants are expected to proceed to Part B. These participants form a subgroup of the 192 participants enrolled in Part A and are therefore not additional to the overall study enrollment. Participants who do not proceed to Part B will complete their study participation after Part A, while their data will remain included in the observational analyses.
Part B is a pilot, randomized, assessor-blinded, parallel-group, active-controlled trial. After confirmation of eligibility and completion of baseline assessments, participants will be randomized in a 1:1 ratio to targeted FMD-specific multidisciplinary rehabilitation or conventional MS rehabilitation. The allocation sequence will be computer-generated and concealed until treatment assignment. Participants and treating therapists cannot be blinded because of the nature of the interventions; however, outcome assessments will be conducted by evaluators unaware of treatment allocation.
The experimental programme combines a short, intensive in-person intervention with continued home-based self-management and structured telemedicine support. It is based on FMD-specific principles, including explanation of functional symptom mechanisms, identification and therapeutic use of positive functional signs, movement retraining through attentional redirection, and restoration of more automatic motor control. The active comparator consists of conventional MS neurorehabilitation addressing mobility, strength, gait, balance, endurance, fatigue management, and functional independence, without protocolized FMD-specific techniques.
Part B is intended to evaluate the feasibility, safety, and preliminary clinical effects of the targeted programme rather than provide definitive confirmatory evidence of efficacy. Analyses will primarily follow the intention-to-treat principle, with complementary per-protocol analyses where appropriate. Given the pilot sample size, interpretation will emphasize recruitment, adherence, retention, data completeness, outcome variability, effect estimates, and confidence intervals. Together, the two study parts are designed to establish the clinical relevance of FMD-MS overlap and generate evidence needed to plan a larger definitive rehabilitation trial.
3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.
This study's planned enrollment of 192 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.
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Inclusion Criteria for Part A - Observational Diagnostic and Prevalence Phase
Participants must meet all of the following criteria:
Additional Inclusion Criteria for Part B - Randomized Interventional Rehabilitation Phase
To proceed to Part B, participants must additionally meet all of the following criteria:
Exclusion Criteria Exclusion Criteria for Part A - Observational Diagnostic and Prevalence Phase
Participants meeting any of the following criteria will be excluded from Part A:
Additional Exclusion Criteria for Part B - Randomized Interventional Rehabilitation Phase
Participants meeting any of the following criteria will not proceed to Part B:
All enrolled participants will initially undergo the Part A observational diagnostic and prevalence assessment. This group comprises participants who complete Part A but do not proceed to Part B because FMD-MS overlap is not confirmed, the additional Part B eligibility criteria are not met, or the participant does not enter the randomized rehabilitation phase. No study rehabilitation intervention will be assigned. Study participation will end after completion of the Part A assessment.
Participants will first complete the Part A observational assessment. Participants with confirmed FMD-MS overlap who meet the additional Part B eligibility criteria and are randomized to the experimental arm will receive five consecutive days of in-person FMD-specific multidisciplinary rehabilitation, approximately two hours per day. This will be followed by a 12-week home-based self-management programme, approximately one hour per day, three days per week, and one weekly 30-minute telemedicine session.
Other: Functional Motor Disorder-Specific Multidisciplinary Rehabilitation
Participants will first complete the Part A observational assessment. Participants with confirmed FMD-MS overlap who meet the additional Part B eligibility criteria and are randomized to the active comparator will receive conventional multiple sclerosis rehabilitation representing current standard rehabilitative care. Treatment will address mobility, muscle strength, gait, balance, endurance, fatigue management, and functional independence.
Other: Conventional Multiple Sclerosis Rehabilitation
A mechanism-based multidisciplinary rehabilitation programme adapted for people with multiple sclerosis and overlapping functional motor symptoms. The programme includes education regarding functional symptom mechanisms; exploration of the influence of symptoms on posture and movement; demonstration of positive functional motor signs where clinically appropriate; movement retraining using attentional redirection, graded functional exercises, external cues, dual-task or distraction strategies, visual or video feedback, and task-oriented activities; and development of an individualized self-management plan. The intervention comprises five consecutive days of supervised in-person rehabilitation, approximately two hours per day, followed by 12 weeks of home-based exercises and weekly telemedicine support.
Also known as: FMD-specific rehabilitation, Functional movement retraining, FMD-targeted multidisciplinary rehabilitation
Standard neurorehabilitation for people with multiple sclerosis, individualized according to clinical needs and usual practice. Treatment may include strengthening, mobility exercises, gait and balance training, graded exercise, endurance training, fatigue-management strategies, and activities intended to improve functional independence. The programme will not include protocolized education regarding functional symptom mechanisms, therapeutic demonstration of positive functional motor signs, attentional-redirection-based movement retraining, or a formal FMD-specific self-management programme.
Also known as: Standard multiple sclerosis rehabilitation, Conventional neurorehabilitation, Usual rehabilitation care for multiple sclerosis
Prevalence of Functional Motor Disorder-Multiple Sclerosis Overlap Among Participants Presenting With Acute Neurological Symptom Worsening
The number and percentage of evaluable participants in Part A who are classified as having Functional Motor Disorder-Multiple Sclerosis overlap, also referred to in the protocol as functional pseudorelapse. Classification will be based on the prespecified multidimensional diagnostic algorithm, including neurological examination, positive clinical signs of functional motor disorder, applicable DSM-5 and Gupta-Lang diagnostic criteria, and routine-care investigations when clinically indicated. Prevalence will be calculated as the number of participants meeting the diagnostic criteria for FMD-MS overlap divided by the total number of evaluable participants enrolled in Part A and will be reported with a 95% confidence interval.
Time frame: At Part A enrollment, following completion of the diagnostic assessment and within 30 days of onset of acute neurological symptom worsening
Change From Baseline in Simplified Functional Movement Disorders Rating Scale Score Immediately After the 5-Day Rehabilitation Program
Change in functional motor symptom burden measured using the Simplified Functional Movement Disorders Rating Scale (S-FMDRS). The scale provides a clinician-rated assessment of the anatomical distribution, severity, duration, and functional impact of functional motor symptoms, with higher scores indicating a greater functional motor symptom burden. Change will be calculated as the post-intervention score minus the Part B baseline score; a negative change indicates improvement. The change from baseline will be compared between the FMD-specific multidisciplinary rehabilitation arm and the conventional MS rehabilitation arm.
Time frame: From Part B baseline before randomization to immediately after completion of the 5-day rehabilitation program, at Day 5/6 ±2 days
Change From Baseline in Simplified Functional Movement Disorders Rating Scale Score at 3 Months
Change in functional motor symptom burden measured using the S-FMDRS. Change will be calculated as the 3-month score minus the Part B baseline score; a negative change indicates improvement. The change from baseline will be compared between the FMD-specific multidisciplinary rehabilitation arm and the conventional MS rehabilitation arm.
Time frame: From Part B baseline before randomization to the 3-month follow-up after randomization, ±14 days
Plan to share: No — No individual participant data-sharing plan has been finalized for this pilot multicenter study. Study results will be disseminated in aggregate or anonymized form in accordance with participant consent, Ethics Committee approval, applicable data-protection requirements, and institutional and interinstitutional agreements.
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