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

Condition(s) studied

Investigational drug(s) / intervention(s)

Functional Motor Disorder-Specific 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 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.

Study 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.

Eligibility

Primary outcome measure(s)

• Prevalence of Functional Motor Disorder-Multiple Sclerosis Overlap Among Participants Presenting With Acute Neurological Symptom Worsening — 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 — 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 — 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.

Trial sites (2)

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