Treatment Response Assessment Tools for Relapsing Multiple Sclerosis

Relapsing multiple sclerosis (RMS) is the most common form of multiple sclerosis (MS). Early diagnosis and treatment of RMS can reduce relapsing disease activity, lengthen periods of protracted remission, and improve quality of life (QoL). Earlier diagnosis coupled with the use of highly effective disease-modifying therapies (DMTs) and close monitoring contribute to an improved clinical outlook.¹ Various tools have been created to assess treatment response, most of which have been derived from their use in clinical trials. We explore available tools for assessing treatment response in RMS (Table) and provide practical recommendations for their use in clinical practice.

Clinical Tools to Assess Disease Activity

Treatment goals for RMS include reducing relapses, disability progression, and subclinical MRI disease activity, a triad known as “no evidence of disease activity.”² A relapse is defined as appearance of new or previously experienced neurologic symptoms, consistently present for at least 24 hours, in the absence of infection, heat exposure, exhaustion, or significant stress, which may cause a pseudorelapse.^2a Clinical assessment of a relapse can be complemented by findings of new gadolinium-enhancing lesions on MRI. Progression associated with incomplete or lack of recovery from relapses or relapse-associated worsening must be reassessed at 3 and 6 months post-relapse to determine whether the deficits are permanent. A 6-month confirmed disability is unlikely to be reversed.

Disease progression can be assessed with various clinical tools, including the Expanded Disability Status Scale (EDSS), a standardized neurologic examination to monitor disability progression across 8 functional domains commonly affected in MS (vision, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and ambulatory functions).³ The Timed 25-Foot Walk test (T25FW), 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT) are timed tests evaluating ambulation, upper extremity manual dexterity, and cognition, respectively.

The EDSS, T25FW, 9HPT, and SDMT can be assessed during an annual follow-up visit specifically dedicated to obtaining metrics and offer a standardized basis for comparison over time, facilitating the clinician’s decision-making process for DMT escalation.

Imaging Tools: MRI and Volumetric Analysis

Whenever possible, MRI should be performed using the recommended guidelines from the Consortium of Multiple Sclerosis Centers (CMSC; http://www.mscare.org/MRI). The MS-specific protocol improves identification of new or enlarging T2 lesions and new gadolinium-enhancing lesions.⁴

Recommendations for RMS Monitoring

A baseline brain MRI is recommended before starting or switching DMTs. MRI with gadolinium contrast should be considered in the presence of known active disease or if previous MRI study results are not available. A rebaseline MRI is recommended 3 to 6 months after starting any DMT. Spinal cord rebaseline is not needed unless there are clinical concerns of a possible new spinal cord lesion. A new baseline brain MRI is also recommended postpartum.^4a

Annual MRIs are useful for assessing treatment efficacy. In individuals with stable disease with no evidence of clinical or MRI activity in 2 to 3 consecutive years after diagnosis or DMT switch, MRIs can be obtained every other year. To evaluate unexpected clinical worsening, a spinal cord MRI may be considered if brain MRI findings do not align with clinical concerns. Gadolinium-based contrast agents are not required for routine monitoring and should be used judiciously. The use of gadolinium-based contrast agents is not essential for detecting subclinical disease activity because new T2 lesions can be identified on well-performed standardized MRI scans. It can be challenging to detect new or enlarged T2 lesions when comparing MRI scans obtained from different scanners without standardized protocols. Adjustments to differences in technique, especially magnet strength (1.5 vs 3 T) or slice thickness (3 vs 5 mm), can be helpful in avoiding over- or underestimation of lesions. In addition, MRI with gadolinium contrast allows for the detection of new lesions. A review by Ravira et al provides guidelines for cutoff numbers of new T2 lesions or gadolinium-enhancing lesions that warrant consideration of a treatment change.⁵

Volumetric MRI analysis is emerging as an important tool in evaluating treatment response in MS. Some commercial entities use deep learning–based image segmentation to automate volumetric analysis with high precision (eg, icometrix, NeuroQuant, SyntheticMR). These tools streamline brain volume and lesion quantification, potentially providing clinicians with reliable and rapid insights into MS progression. Tracking changes in brain atrophy and lesion volume provides a sensitive indicator of disease stability or progression, reflecting therapeutic efficacy. Challenges such as standardizing protocols across MRI platforms and defining clinically meaningful thresholds remain. Continued improvements in volumetric MRI analysis techniques may lead to their routine use in MS monitoring, which could guide timely therapeutic adjustments and help clinicians assess treatment efficacy.⁶

Optical Coherence Tomography

Optical coherence tomography (OCT) is a useful and sensitive tool for tracking axonal and neuronal loss in the anterior visual pathways in individuals with MS. OCT shows retinal anatomy at high resolution, including the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL).⁷ Loss of RNFL thickness represents axonal loss, because axons are unmyelinated in the human retina. RNFL thinning is seen within 3 to 6 months after acute optic neuritis, and up to 75% of people with MS lose 10 to 40 mm of RNFL after optic neuritis, equal to the average loss over 60 years in healthy individuals.⁷ RNFL thinning is also observed in eyes without previous optic neuritis, indicating subclinical axon loss.Β Increased rates of RNFL thinning are seen in progressive forms of MS, whereas less RNFL thinning has been seen in people with MS who receive immunotherapy within 24 months of disease onset, highlighting the importance of early diagnosis and treatment.⁸

GCL and IPL thickness can represent neuronal loss. Because these measures have been found to mirror cortical and caudate atrophy, cognition, and neurologic disability in MS, they are thought to be useful markers for MS progression.⁷ Thinning in GCL and IPL is also seen within 3 to 6 months after acute optic neuritis, but unlike RNFL, these measures are not affected by edema during acute optic neuritis.

Biomarkers: NfL, GFAP, and the MSDA Composite

Biomarkers are emerging tools for assessing treatment response in RMS. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been studied independently as biomarkers for MS in serum and cerebrospinal fluid (CSF). Neither biomarker is exclusive to MS, and both can also be elevated in other neurologic diseases. NfL, a subunit of neurofilaments, is a neuron-specific intracellular cytoskeletal protein. GFAP is a monomeric intermediate filament protein mostly found in astrocytes. Both are released when neuroaxonal damage occurs. They are reliably measured in serum, plasma, and CSF with a highly sensitive single molecule array assay and slightly less sensitive electrochemiluminescence immunoassay.⁹

Serum NfL (sNfL) and CSF NfL levels can correlate with MRI changes, relapses, and response to DMT. The CMSC published a guide to aid clinicians in the practical application of NfL testing.¹⁰ Recommendations include obtaining baseline sNfL levels in addition to interval monitoring during relapses, new MRI activity, and the evaluation of DMT effects. There are, however, some important caveats to keep in mind when interpreting individual sNfL results. Each assay has its own specific absolute values, and each assay’s reference ranges for normative values and values specific to the MS population may vary depending on the resource (eg, clinical validation studies, laboratory resources) used for its validation. Therefore, results must be interpreted in the context of the assay used with its specific reference ranges. In addition, results may not be reliable in individuals with other conditions that may raise sNfL levels, such as kidney disease and diabetes.¹¹ Both serum and CSF GFAP correlate more closely with MS progression.¹²

The Multiple Sclerosis Disease Activity (MSDA) test (Octave Bioscience, Menlo Park, CA) is a composite biomarker test available for use in clinical practice. This serum-based assay panel measures the levels of 18 proteins, including NfL and GFAP, and provides an overall disease activity score. Validation studies demonstrated a strong association between the MSDA score and MRI findings (eg, gadolinium-enhancing lesions and new and enlarging T2 lesions) and active vs stable disease status.¹³ Determination of disease status is made on the basis of radiologic findings and clinical relapses.¹³ The MSDA test may be particularly valuable in cases where clinical or MRI evidence of disease breakthrough is lacking or inconclusive.

Patient-Reported Outcomes

A patient-reported outcome (PRO) represents a perception of health status by the patient “without interpretation or modification by healthcare providers or anyone else.”¹⁴ The Patient-Determined Disease Steps scale, which measures disability by metrics important to QoL, can be used in the investigation of PROs.¹³ Collection of patient-centric data and incorporation of this data into biologic data gathered from neuroligic exams by clinicians is a fundamental shift in assessment and is becoming increasingly relevant in the final analysis of risk vs benefit of a new intervention. Regulatory agencies are paying considerable attention to such reports, and every phase 3 clinical trial now requires collection of such information. Beyond regulatory approval, PROs will become routinely used in quality development plans that support merit-based incentive payment systems for clinicians, such as pay for performance.¹⁵

The National Institutes of Health supported the creation of 2 standard sets of PRO measures: one appropriate for use across neurologic disorders, including MS (Neuro-QoL), and another that is useful across a broad range of chronic health conditions (Patient-Reported Outcome Measurement Information Systems).¹⁶ These instruments are not without limitations, because they do not cover all domains. Furthermore, sensitivity to change and the relevant degree of change that is clinically significant needs to be established. A review by Nowinski et al¹⁷ describes the evolution and expanded use of PROs.

Technology: Wearable Devices and Smartphone Applications

Recent studies investigating the use of wearable devices and smartphone-based applications (SPBAs) to log MS symptoms reveal their potential use in clinical settings. “Invisible” symptoms such as fatigue and cognition are not easy to track in a follow-up clinic visit. Data from wearable devices can provide additional information that helps clinicians monitor DMT responses and symptoms over time.¹⁸

Smartphone apps (eg, Floodlight) are available to measure dexterity, cognition, and mobility through smartphone-based tests.¹⁹ Some of the data from these devices and apps are useful because they align with the EDSS. For example, trackable symptoms through wristwatches include physiologic changes associated with fatigue (eg, heart rate, reduced heart rate variability, sleep behavior). Inertial sensor and global positioning system data using a watch have been used to estimate EDSS data that aligned with neurologists’ assessments.²⁰ Wake-up patterns, circadian cycle, and work–rest patterns can be used to extrapolate data on fatigue.¹⁸ Motor performance outcomes can also be tracked using SPBAs to assess and track symptoms including walking ability, balance, and dexterity. The Cognitive Fatigability Assessment Test, a smartphone-based tool, has been utilized to quantify cognitive fatigue.¹⁹ For this test, the wearer is told to respond to a prompt on their screen and tapping frequency is utilized as an objective measurement for motor fatigability.¹⁹

Although no standardized SPBA or wearable device can be used to assess MS, the clinical utility of these wearable devices is promising. Further research is needed to evaluate the use of these applications to assess DMT response and disease progression outside of the clinic. 

Conclusion

Tools available for assessing treatment response in people with MS were originally used mainly in clinical trials for Food and Drug Administration approval of DMTs. Many of these tools have been incorporated successfully in clinical practice and are important for assessment of treatment response, including clinical evaluations to confirm bona fide relapses, EDSS to establish disability progression, T25FW to assess change in walking ability, 9HPT to assess manual dexterity, and SDMT to screen cognitive function. In addition, MRI enables assessment of clinically silent breakthrough disease, and OCT can be used to monitor RNFL and macular GCL thinning.²¹ Artificial intelligence–driven brain volumetric analysis further enhances MRI data precision. Emerging biomarkers, such as sNfL and GFAP, show promise as indicators of disease activity, progression, and treatment efficacy, but these biomarker test results should be interpreted cautiously.²² Advancements in wearable technologies, such as smartwatches, offer new ways to track physical activity, gait, balance, QoL, and sleep. Despite these advances, no single tool provides a complete assessment of treatment response, emphasizing the need for integrating multiple approaches, including PROs, to enhance accuracy and guide therapeutic decisions.