Multiple SclerosisNCT07856485
Bridging Gaps in the Multidimensional Assessment and Management of Overlapping Symptoms in Multiple Sclerosis and Functional Motor Disorders: Prevalence and Rehabilitation Effectiveness
A study testing Functional Motor Disorder-Specific Multidisciplinary Rehabilitation and Conventional Multiple Sclerosis Rehabilitation in people with Multiple Sclerosis and Functional Neurological Disorders, run by IRCCS San Raffaele at 2 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Sclerosis, Functional Neurological Disorders
- What is being tested?
- Functional Motor Disorder-Specific Multidisciplinary Rehabilitation and Conventional Multiple Sclerosis Rehabilitation
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 192 participants
- Where
- 2 sitesItaly
- Study dates
- 1 Oct 2026to 31 Aug 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Inclusion Criteria for Part A - Observational Diagnostic and Prevalence Phase
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.
Additional Inclusion Criteria for Part B - Randomized Interventional Rehabilitation Phase
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.
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:
- 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.
Additional Exclusion Criteria for Part B - Randomized Interventional Rehabilitation Phase
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.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Italy2 sites
IRCCS San Raffaele
Milan, Italy, 20132
Maria A. Rocca, MD, +390226433019, rocca.mara@hsr.it
University of Verona
Verona, Italy, 37134
Michele Tinazzi, MD, +390458124288, michele.tinazzi@univr.it
About this study
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.
Read more
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.
Read the detailed description
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.
- Being tested
- Functional Motor Disorder-Specific Multidisciplinary Rehabilitation, Conventional Multiple Sclerosis Rehabilitation
- Keywords
- Multiple sclerosis, Functional neurological disorder, Multiple sclerosis relapse, Acute neurological symptom worsening, Neurorehabilitation, Functional pseudorelapse
- Medical subject headings
- Multiple Sclerosis, Conversion Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Functional Motor Disorder-Specific Multidisciplinary RehabilitationOther
Also called FMD-specific rehabilitation, Functional movement retraining, FMD-targeted multidisciplinary 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.
Conventional Multiple Sclerosis RehabilitationOther
Also called Standard multiple sclerosis rehabilitation, Conventional neurorehabilitation, Usual rehabilitation care for multiple sclerosis
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Conventional Multiple Sclerosis Rehabilitation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: From Part B baseline before randomization to the 3-month follow-up after randomization, ±14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Oct 2026
- Study start1 Oct 2026 (estimated)
- Primary completion31 May 2029 (estimated)
- Study completion31 Aug 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (35)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 192 participants (estimated)
Sponsor and investigators
- Lead sponsor
- IRCCS San Raffaele
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Maria A. Rocca, IRCCS San Raffaele
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07856485
- Sponsor's protocol ID
- 2025/R-Multi/004
- Other IDs
- FISM 2025/R-Multi/004
- Status last verified
- Oct 2026
- First submitted
- 28 Sep 2026
- Last updated
- 9 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- 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.
Publications
Sandri A, Bonetto C, Fiorio M, Salaorni F, Bonardi G, Geroin C, Smania N, Tinazzi M, Gandolfi M. Unraveling the mechanisms of high-level gait control in functional gait disorders. J Neural Transm (Vienna). 2025 Jan;132(1):95-104. doi: 10.1007/s00702-024-02829-4. Epub 2024 Sep 6.
PubMed 39237791Gandolfi M, Fiorio M, Geroin C, Torneri P, Menaspa Z, Smania N, Giladi N, Tinazzi M. Dual tasking affects gait performance but not automaticity in functional gait disorders: A new diagnostic biomarker. Parkinsonism Relat Disord. 2023 Mar;108:105291. doi: 10.1016/j.parkreldis.2023.105291. Epub 2023 Jan 24.
PubMed 36764083Gandolfi M, Fiorio M, Geroin C, Prior M, De Marchi S, Amboni M, Smania N, Tinazzi M. Motor dual task with eyes closed improves postural control in patients with functional motor disorders: A posturographic study. Gait Posture. 2021 Jul;88:286-291. doi: 10.1016/j.gaitpost.2021.06.011. Epub 2021 Jun 11.
PubMed 34153806Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995 Jun;4(3):187-206. doi: 10.1007/BF02260859.
PubMed 7613530Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001 Jul;33(5):337-43. doi: 10.3109/07853890109002087.
PubMed 11491192Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996 Mar;34(3):220-33. doi: 10.1097/00005650-199603000-00003.
PubMed 8628042Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x.
PubMed 6880820Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3. doi: 10.1001/archneur.1989.00520460115022.
PubMed 2803071Poquet N, Lin C. The Brief Pain Inventory (BPI). J Physiother. 2016 Jan;62(1):52. doi: 10.1016/j.jphys.2015.07.001. Epub 2015 Aug 21. No abstract available.
PubMed 26303366Nielsen G, Ricciardi L, Meppelink AM, Holt K, Teodoro T, Edwards M. A Simplified Version of the Psychogenic Movement Disorders Rating Scale: The Simplified Functional Movement Disorders Rating Scale (S-FMDRS). Mov Disord Clin Pract. 2017 Mar 11;4(5):710-716. doi: 10.1002/mdc3.12475. eCollection 2017 Sep-Oct.
PubMed 30363505Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson A, Willoughby E. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain. 1999 May;122 ( Pt 5):871-82. doi: 10.1093/brain/122.5.871.
PubMed 10355672Tinazzi M, Gandolfi M, Menaspa Z, Sandri A, Landi S, Leardini C. Reducing healthcare costs by timely diagnosis and management in functional motor disorders. Neurol Sci. 2025 Mar;46(3):1191-1200. doi: 10.1007/s10072-024-07865-2. Epub 2024 Nov 13.
PubMed 39532797Tinazzi M, Gandolfi M, Landi S, Leardini C. Economic Costs of Delayed Diagnosis of Functional Motor Disorders: Preliminary Results From a Cohort of Patients of a Specialized Clinic. Front Neurol. 2021 Dec 8;12:786126. doi: 10.3389/fneur.2021.786126. eCollection 2021.
PubMed 34956066Gervasoni E, Torchio A, Bertoni R, Chieffo R, Rocca MA, Pau M, Cocco E, Morozumi T, Filippi M, Cattaneo D, Rovaris M. Beyond EDSS: multidomain impairments are detectable and associated with walking disorders in low-disabled people with multiple sclerosis. J Neurol. 2025 May 18;272(6):404. doi: 10.1007/s00415-025-13128-7.
PubMed 40382461Filippi M, Ceccarelli A, Pagani E, Gatti R, Rossi A, Stefanelli L, Falini A, Comi G, Rocca MA. Motor learning in healthy humans is associated to gray matter changes: a tensor-based morphometry study. PLoS One. 2010 Apr 15;5(4):e10198. doi: 10.1371/journal.pone.0010198.
PubMed 20419166
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Bridging Gaps in the Multidimensional Assessment and Management of Overlapping Symptoms in Multiple Sclerosis and Functional Motor Disorders: Prevalence and Rehabilitation Effectiveness
- ClinicalTrials.gov ID
- NCT07856485
- Acronym / sponsor ID
- 2025/R-Multi/004
- Keywords
- Multiple sclerosis, Functional neurological disorder, Multiple sclerosis relapse, Acute neurological symptom worsening, Neurorehabilitation, Functional pseudorelapse
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 192 participants (estimated)
- Lead sponsor
- IRCCS San RaffaeleUniversity, hospital or other
- Study start
- 1 Oct 2026 (estimated)
- Primary completion
- 31 May 2029 (estimated)
- Study completion
- 31 Aug 2029 (estimated)
- First posted
- 2 Oct 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 3
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| 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 | Other: Functional Motor Disorder-Specific Multidisciplinary RehabilitationParticipants 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. |
| Part B Active Comparator: Conventional Multiple Sclerosis Rehabilitation | Active comparator | Other: Conventional Multiple Sclerosis RehabilitationParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Functional Motor Disorder-Specific Multidisciplinary RehabilitationAlso: FMD-specific rehabilitation, Functional movement retraining, FMD-targeted multidisciplinary rehabilitationA 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. | Other | Part B Experimental: FMD-Specific Multidisciplinary Rehabilitation |
| Conventional Multiple Sclerosis RehabilitationAlso: Standard multiple sclerosis rehabilitation, Conventional neurorehabilitation, Usual rehabilitation care for multiple sclerosisStandard 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. | Other | Part B Active Comparator: Conventional Multiple Sclerosis Rehabilitation |
Primary outcome
Prevalence of Functional Motor Disorder-Multiple Sclerosis Overlap Among Participants Presenting With Acute Neurological Symptom Worsening
Time frame: At Part A enrollment, following completion of the diagnostic assessment and within 30 days of onset of 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.
Change From Baseline in Simplified Functional Movement Disorders Rating Scale Score Immediately After the 5-Day Rehabilitation Program
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 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.
Change From Baseline in Simplified Functional Movement Disorders Rating Scale Score at 3 Months
Time frame: From Part B baseline before randomization to the 3-month follow-up after randomization, ±14 days
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.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2026.
- Background: PubMed 39237791Sandri A, Bonetto C, Fiorio M, Salaorni F, Bonardi G, Geroin C, Smania N, Tinazzi M, Gandolfi M. Unraveling the mechanisms of high-level gait control in functional gait disorders. J Neural Transm (Vienna). 2025 Jan;132(1):95-104. doi: 10.1007/s00702-024-02829-4. Epub 2024 Sep 6.
- Background: PubMed 36764083Gandolfi M, Fiorio M, Geroin C, Torneri P, Menaspa Z, Smania N, Giladi N, Tinazzi M. Dual tasking affects gait performance but not automaticity in functional gait disorders: A new diagnostic biomarker. Parkinsonism Relat Disord. 2023 Mar;108:105291. doi: 10.1016/j.parkreldis.2023.105291. Epub 2023 Jan 24.
- Background: PubMed 34153806Gandolfi M, Fiorio M, Geroin C, Prior M, De Marchi S, Amboni M, Smania N, Tinazzi M. Motor dual task with eyes closed improves postural control in patients with functional motor disorders: A posturographic study. Gait Posture. 2021 Jul;88:286-291. doi: 10.1016/j.gaitpost.2021.06.011. Epub 2021 Jun 11.
- Background: PubMed 7613530Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995 Jun;4(3):187-206. doi: 10.1007/BF02260859.
- Background: PubMed 11491192Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001 Jul;33(5):337-43. doi: 10.3109/07853890109002087.
- Background: PubMed 8628042Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996 Mar;34(3):220-33. doi: 10.1097/00005650-199603000-00003.
- Background: PubMed 6880820Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x.
- Background: PubMed 2803071Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3. doi: 10.1001/archneur.1989.00520460115022.
- Background: PubMed 26303366Poquet N, Lin C. The Brief Pain Inventory (BPI). J Physiother. 2016 Jan;62(1):52. doi: 10.1016/j.jphys.2015.07.001. Epub 2015 Aug 21. No abstract available.
- Background: PubMed 30363505Nielsen G, Ricciardi L, Meppelink AM, Holt K, Teodoro T, Edwards M. A Simplified Version of the Psychogenic Movement Disorders Rating Scale: The Simplified Functional Movement Disorders Rating Scale (S-FMDRS). Mov Disord Clin Pract. 2017 Mar 11;4(5):710-716. doi: 10.1002/mdc3.12475. eCollection 2017 Sep-Oct.
- Background: PubMed 10355672Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson A, Willoughby E. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain. 1999 May;122 ( Pt 5):871-82. doi: 10.1093/brain/122.5.871.
- Background: PubMed 39532797Tinazzi M, Gandolfi M, Menaspa Z, Sandri A, Landi S, Leardini C. Reducing healthcare costs by timely diagnosis and management in functional motor disorders. Neurol Sci. 2025 Mar;46(3):1191-1200. doi: 10.1007/s10072-024-07865-2. Epub 2024 Nov 13.
- Individual participant dataSharing planned: 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Functional Motor Disorder-Specific Multidisciplinary Rehabilitation and Conventional Multiple Sclerosis Rehabilitation in people with Multiple Sclerosis and Functional Neurological Disorders, run by IRCCS San Raffaele at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 9 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Maria A. Rocca, MD (+390226433019, rocca.mara@hsr.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Prevalence of Functional Motor Disorder-Multiple Sclerosis Overlap Among Participants Presenting With Acute Neurological Symptom Worsening (time frame: At Part A enrollment, following completion of the diagnostic assessment and within 30 days of onset of acute neurological symptom worsening). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07856485, which also lists 35 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2026; AzTrials last refreshed its copy on 31 Oct 2026.