Monitoring Disease Course and Treatment Response in Various Populations With Multiple Sclerosis

Monitoring for signs of disease activity or progression in multiple sclerosis (MS) is a crucial component of effective disease management. Detection of disease activity can influence clinical decision-making regarding the initiation, escalation, or withdrawal of disease-modifying therapies (DMTs). Treatment decisions and response assessments for MS may vary as the biology of the disease changes across the lifespan. Specific life events or clinical settings may restrict access to or utilization of certain monitoring modalities. We review the evidence for monitoring of disease and treatment in different populations with MS. Key points are summarized in the Table.

Pediatric Populations

Most children with MS experience a relapsing-remitting course of illness, with higher annualized relapse rates than in adult-onset disease.^1,2 Recovery tends to be substantial, and chronic disability (as defined by clinical scores such as the Expanded Disability Status Scale [EDSS]) is rare during childhood.³ Comorbid mood disorder and cognitive impairment are frequent in children with MS and may affect social and academic functioning.^4,5 Childhood MS is associated with reduced brain volume and brain growth failure,⁶ which may not be observed until adulthood when compensatory mechanisms lessen.

Because of the active nature of the disease in childhood, close monitoring is imperative to detect clinical or radiographic signs of activity, facilitate DMT modification, and mitigate the risk of poor outcomes. As with the adult population, clinical assessment of relapse activity and regular MRI scan assessment remain the mainstay of disease and treatment monitoring in pediatric MS. Because of the more rapid development of new lesions and greater white matter lesion burden in pediatric MS, the International Pediatric MS Study Group recommends surveillance MRI every 6 months.⁷

Disability worsening can be assessed clinically with similar tools that are used in the adult population, such as the EDSS.⁸ In addition, the widespread familiarity with the Symbol Digit Modalities Test (SDMT) and its recommended use in the adult population has led to its adoption as a screening tool in children aged >8 years.⁹ Paramagnetic rim lesions (PRLs) on MRI can be identified in a large proportion of demyelinating lesions in pediatric-onset MS. In addition to aiding the diagnosis of MS, these lesions are associated with higher risk of cognitive impairment.⁵ As such, detection of PRLs, particularly multiple PRLs, can trigger the consideration of high-efficacy therapy even early in the disease course. High-efficacy therapy (eg, B-cell depletion) has demonstrated effective disease modification, including in cases of highly active pediatric-onset MS¹⁰ and has been associated with better disease control (ie, reduced relapse rates over time) than moderate-efficacy treatments.¹¹

Serum neurofilament light chain (sNfL) biomarkers have demonstrated utility for monitoring disease activity and treatment response in the pediatric MS population and are positively associated with new MRI lesions, recent relapses, and higher EDSS scores.¹² Treatment with DMT is associated with a reduction in sNFL levels in both children¹² and adults.¹³ Furthermore, persistent sNfl elevation with lower efficacy therapies (such as interferons or glatiramer acetate) is associated suboptimal disease control, with subsequent improvement in disease control and sNfl levels after switching to higher-efficacy therapy.¹²

Pregnancy and Postpartum

For women with MS who are planning to conceive, maintaining disease stability is essential. Experts recommend at least 1 year of disease control with the use of DMTs before pregnancy is attempted, as disease stability in the year before conception is associated with reduced risk of disease activity during pregnancy and postpartum.¹⁴ A study by Confavreux et al¹⁵ demonstrated that pregnancy provided a natural protective effect (ie, a decreased rate of relapse), but the rate of relapse increased significantly during the first 3 months postpartum and returned to the pre-pregnancy relapse rate.¹⁵ Most DMTs are discontinued before or upon confirmation of pregnancy because of the risks these drugs to the fetus. The lack of placental transfer of IgG-based monoclonal antibodies (eg, natalizumab [Tysabri; Biogen, Cambridge, MA], rituximab, ocrelizumab [Ocrevus; Genentech, South San Francisco, CA], ofatumumab [Kesimpta; Novartis, East Hanover, NJ], ublituximab [Briumvi; TG Therapeutics, Morrisville, NC]) in the first trimester suggests limited fetal risks if administered during this period, though utilization during pregnancy is not recommended unless potential benefits outweigh risks.^14,16

Cessation of treatment with fingolimod and natalizumab is associated with increased relapse activity.¹⁷ Fingolimod treatment should be stopped before conception, but treatment with natalizumab up until 34 weeks of pregnancy may be considered to prevent disease rebound during pregnancy.¹⁸ For additional information regarding individual DMT use and recommendations for DMT use during pregnancy, the reader is referred to a previously published article on this topic: https://practicalneurology.com/articles/2024-jan-feb/practical-considerations-for-family-planning-in-multiple-sclerosis.

Ongoing monitoring of MS during pregnancy is important particularly in women at increased risk of disease activity due to an aggressive disease course or discontinuation of DMT.

Clinical assessment is the primary modality for tracking disease activity in pregnant women with MS. Although MRI can be conducted safely during pregnancy, noncontrast studies are generally recommended unless presence of abnormal enhancement would affect immediate clinical decision-making (eg, evaluation of possible progressive multifocal leukoencephalopathy or detection of acute disease activity).¹⁴ sNfL may be useful to monitor MS activity during pregnancy,¹⁹ but larger studies are needed to further inform best practices.

Monitoring of MS during the postpartum period is essential. More than half of women with MS may experience disease activity within the first 6 months postpartum.²⁰ Although women who breastfeed exclusively have a 37% lower likelihood of experiencing a postpartum relapse compared with those who do not,²¹ this is not sufficient protection from relapses and reintroduction of DMT should still be considered in these individuals. There is growing evidence that resumption of high-efficacy therapies as early as feasible after childbirth reduces the risk of postpartum relapses.²² Furthermore, B-cell depleting monoclonal antibody therapies have been reported to be safe to use while breastfeeding because of minimal breastmilk transfer.²³ For these reasons, early reintroduction of DMT after childbirth should be considered, particularly in high-risk patients.

Contrast-enhanced postpartum MRI is recommended for disease monitoring during the early (3 to 6 months) postpartum period and can reveal radiographic evidence of breakthrough disease activity before clinically evident relapses, defined as acute or subacute neurologic symptoms lasting more than 24 hours not attributed to fever or infection.²⁰ Such findings are important when counseling individuals regarding the risks and benefits of restarting DMT during the postpartum period. Because only miniscule amounts of gadolinium-based contrast are expressed in breastmilk and absorbed by the infant’s gastrointestinal tract (estimated <.0004%), American College of Radiology Guidelines do not recommend interruption of breastfeeding after gadolinium contrast for MRI.²⁴

Older Populations

In individuals with MS, a decrease in inflammatory disease activity (ie, annualized relapse rates and inflammatory MRI activity) is associated with increased age. While there is no discrete age cut-off for these effects, studies have identified this trend in people with MS aged >40 years.^25,26 In addition, DMT-related adverse outcomes appear to increase with advancing age due to age-related decline in immune system function which leads to higher rates of infections.²⁷ These age-related factors influence DMT de-escalation and discontinuation decisions. In the absence of large studies with long-term follow-up, no definite best practices have been developed regarding DMT management in this population. Personalization of treatment decisions in older adults with MS is complicated by the lack of efficacy and safety data in most randomized clinical trials for individuals aged >55 years and the absence of validated tools for predicting individualized disease course in this age group.

Monitoring treatment response in older adults is important, particularly in the context of treatment de-escalation or discontinuation. Clinical assessment for relapses should consider the possibility of isolated cognitive relapses (ICRs) in addition to more typical presentations of MS relapse involving optic nerve, brainstem, cerebellum, or spinal cord. ICR is defined as a transient and significant decline in cognitive function without other new neurologic findings associated with new lesions on brain MRI, and SDMT monitoring is used to detect ICRs.²⁸ Although ICRs are not unique to older adults, distinguishing them from alternative causes of transient cognitive impairment presents unique challenges in the older population because of higher rates of comorbid confounders that can also influence cognition, such as polypharmacy, underlying cognitive impairment, depression, and other neurologic conditions.

After treatment changes are initiated, MRI of the brain and spinal cord should be performed at regular intervals until long-term disease stability occurs. Although MRI of the spinal cord is not universally recommended in MS monitoring,²⁹ studies showed that new or active lesions may occur only in the spinal cord without concurrent disease activity in the brain and that these spinal cord lesions can be clinically asymptomatic.³⁰

Serial measurements (eg, every 6 months) of serum biomarkers can aid in monitoring for reemerging MS disease activity after DMT discontinuation and can help clinicians determine whether or not to reintroduce DMT. It is important to note that sNfL levels increase with age, and interpretation of sNfl levels in older adults requires comparison with normalized control values. When utilizing patient sNfl levels to determine whether or not to continue DMT, it is valuable to establish baseline sNfl values while the patient is still on DMT. After discontinuation of DMT, serial detection of low sNfl levels represents a reassuring finding. By contrast, elevations in sNfl might represent re-emergence of MS disease activity and should prompt a thorough evaluation to determine the likely cause of elevation of sNfl levels. If it is determined that elevated sNfl are the result of MS disease activity, this might influence frequency of clinical examination, MRI surveillance, or resumption of DMT. It is important for MS disease activity to be distinguished from other causes of sNfL elevation, such as other neurodegenerative diseases.³¹

In addition to the detection of new disease activity with treatment changes, treatment monitoring should also allow for the detection of slow, progressive worsening, which may warrant therapeutic adjustments in some cases. In older adults, disability accrual is more likely to occur independently of relapse activity, a phenomenon called “progression independent of relapse activity (PIRA)”.³² Clinical assessment should include mobility end points, and cognition should be monitored regularly to detect cognitive decline that may be secondary to MS or caused by other reversible or irreversible causes. At a minimum, baseline screening using the SDMT with annual reassessment is recommended to monitor the progression of cognitive impairment and assess treatment effects.³³ Patient-reported outcomes may offer additional insights by reflecting the individual’s own experience of their health and daily challenges. In the future, passive monitoring with wearables may provide a more accurate real-world assessment of the functioning of older adults in their communities.

Underserved and Minority Populations

Although MS affects people of all races and ethnicities,³⁴ there are special considerations for underserved and minority populations which impact the evaluation of DMT efficacy. For instance, Black and Hispanic people with MS may experience a more aggressive disease course³⁵ with lower cognitive performance measured by the SDMT,³⁶ higher lesion load and rate of brain atrophy on MRI, and higher rates of retinal atrophy on optical coherence tomography.³⁷ Biologic differences among populations have been identified, such as the overrepresentation of B-lineage cells in the cerebrospinal fluid of Black people with MS compared with White people, suggesting possible variations in immune system polarization across populations.³⁸ In addition, structural and social determinants of health, which affect non-White populations disproportionately, remain a central contributor to disparities in MS outcomes between non-White and White people with MS globally.

In the United States, a longitudinal study of 2156 individuals with MS showed that those with lower income, residing in rural areas, lacking health insurance, or of Black race were less likely to receive specialized MS care.³⁹ Globally, a recent cross-sectional survey conducted by the Multiple Sclerosis International Federation across 107 countries revealed that the most commonly reported obstacles to MS care in low- and middle-income countries were the lack of health care professionals within close proximity and the limited availability of specialist medical equipment and diagnostic tests.⁴⁰ Structural and social determinants of health are also linked to many vascular comorbidities,⁴¹ which in turn have been shown to substantially increase the risk of disability progression in MS⁴² and to contribute to racial differences in outcomes.⁴³ An understanding of the response to DMT across diverse populations has been hindered by the underrepresentation of non-White participants in MS trials,⁴⁴ although more recent initiatives, such as the Characterization of Ocrelizumab in Minorities With Multiple Sclerosis (CHIMES) trial (NCT04377555), have been recognized for their innovative design and outreach to help bridge this gap.⁴⁵

Individuals with MS who reside in low-resource settings may have limited access to MS imaging tools. As such, serial neurologic examination may constitute the primary modality of monitoring for disease activity. Frequency of clinic follow up encounters can also be limited due to cost burdens or transportation challenges. People with MS should be actively educated to recognize new symptoms suggestive of a relapse and empowered to contact their clinicians if they experience any neurologic changes. Resources such as the Multiple Sclerosis Association of America’s “MS Relapse Toolkit”⁴⁶ can aid patients in identifying and managing relapses. Remote and passive monitoring using patient-reported outcomes or wearable devices may provide additional data regarding daily function and relevant indicators of disease activity. Although MRI is one of the primary tools for assessing the efficacy of DMTs, its use may be limited for underserved populations because of financial and accessibility constraints. In the future, access to new portable, low-field-strength MRI scanners, which have lower financial and technical barriers, may offer promising solutions for underserved populations.⁴⁷