Bridging Gaps in the Multidimensional Assessment and Management of Overlapping Symptoms in Multiple Sclerosis and Functional Motor Disorders: Prevalence and Rehabilitation Effectiveness

NCT07856485 | Not Yet Recruiting

• 2 other identifiers: 2025/R-Multi/004FISM 2025/R-Multi/004
• Study Type: interventional
• Target: 192
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Multiple Sclerosis; Functional Neurological Disorders

Keywords

Multiple sclerosis; Functional neurological disorder; Multiple sclerosis relapse; Acute neurological symptom worsening; Neurorehabilitation; Functional pseudorelapse

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  From Part B baseline before randomization to the 3-month follow-up after randomization, ±14 days

Study Arms (3)

Part A Only: Observational Diagnostic/Prevalence Assessment

NO INTERVENTION

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.

Part B Experimental: FMD-Specific Multidisciplinary Rehabilitation

EXPERIMENTAL

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

Part B Active Comparator: Conventional Multiple Sclerosis Rehabilitation

ACTIVE COMPARATOR

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

Interventions

Functional Motor Disorder-Specific Multidisciplinary Rehabilitation OTHER

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

Part B Experimental: FMD-Specific Multidisciplinary Rehabilitation

Conventional Multiple Sclerosis Rehabilitation OTHER

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

Part B Active Comparator: Conventional Multiple Sclerosis Rehabilitation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all of the following criteria:
• Age 18 years or older.
• Diagnosis of multiple sclerosis (MS) according to the 2017 revisions of the McDonald criteria.
• Self-reported acute neurological symptom worsening, defined as new neurological symptoms or worsening of pre-existing neurological symptoms, with onset within 30 days before enrollment.
• Ability to understand the study information and provide written informed consent.
• Willingness and ability to complete the planned diagnostic, clinical, functional, gait, balance, and patient-reported assessments.
• To proceed to Part B, participants must additionally meet all of the following criteria:
• Completion of the Part A diagnostic and multidimensional assessments.
• Confirmed diagnosis of Functional Motor Disorder-Multiple Sclerosis (FMD-MS) overlap, based on the presence of at least one positive clinical sign of Functional Motor Disorder (FMD) consistent with the Gupta and Lang criteria and fulfillment of the applicable criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
• Presence of functional motor symptoms considered suitable for rehabilitation.
• Clinical suitability to participate in the 5-day rehabilitation programme and subsequent follow-up assessments.
• Willingness to undergo randomization to either FMD-specific multidisciplinary rehabilitation or conventional MS rehabilitation.
• Ability and willingness to participate in the assigned rehabilitation programme and complete the scheduled follow-up procedures, including home-based rehabilitation and telemedicine-supported follow-up when applicable.

You may not qualify if:

• Participants meeting any of the following criteria will be excluded from Part A:
• Inability to provide written informed consent.
• Inability to complete the core diagnostic or prevalence assessments.
• Any acute medical, neurological, or psychiatric condition that, in the Investigator's judgment, prevents reliable diagnostic assessment or safe participation in Part A.
• Participants meeting any of the following criteria will not proceed to Part B:
• Absence of confirmed FMD-MS overlap after completion of the Part A assessment.
• Any medical, neurological, psychiatric, cognitive, cardiovascular, respiratory, musculoskeletal, or other condition that, in the Investigator's judgment, contraindicates participation in the rehabilitation programme or increases the risks associated with physical exercise.
• Participation in another interventional rehabilitation study or intensive rehabilitation programme that could interfere with the assigned intervention or the assessment of study outcomes.
• Inability to attend or complete the 5-day rehabilitation programme.
• Inability or unwillingness to complete the 3-month follow-up assessments.
• Pregnancy, when, in the Investigator's clinical judgment, it contraindicates participation in the planned rehabilitation procedures.

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (2)

IRCCS San Raffaele

Milan, Italy, 20132, Italy

Location

University of Verona

Verona, Italy, 37134, Italy

Location

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MeSH Terms

Conditions

Multiple Sclerosis; Conversion Disorder

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Somatoform Disorders; Mental Disorders

Central Study Contacts

Maria A. Rocca, MD

CONTACT

+390226433019; rocca.mara@hsr.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Participants and treating therapists cannot be blinded because of the nature of the rehabilitation procedures. Outcome assessors will remain blinded to treatment allocation. Participants will be instructed not to disclose their assigned rehabilitation strategy during assessment visits. Any accidental disclosure of allocation to an outcome assessor will be documented.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: All 192 participants will first enter Part A, a prospective observational diagnostic and prevalence phase in which no study intervention is assigned. After completion of the Part A assessment, 26 participants with confirmed FMD-MS overlap who meet the additional rehabilitation eligibility criteria will proceed to Part B. These 26 participants are included within the overall enrollment of 192 and do not represent an additional population. In Part B, participants will be randomized 1:1 in a parallel-group design to either FMD-specific multidisciplinary rehabilitation or conventional MS rehabilitation. Participants not entering Part B will complete the study after Part A. Masking applies only to Part B, in which outcome assessors will remain blinded to treatment allocation.

Study Record Dates

• First Submitted: September 28, 2026
• First Posted: October 2, 2026
• Study Start: September 1, 2026
• Primary Completion (Estimated): May 31, 2029
• Study Completion (Estimated): August 31, 2029
• Last Updated: October 2, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)