Contemporary Challenges in the Recognition, Diagnosis, and Management of Progressive Multiple Sclerosis

In 1996, Lublin and Reingold¹ proposed definitions for the essential clinical phenotypes of multiple sclerosis (MS) with the goal of improving clinical trial population selection and clinical decision-making. Fundamental to these definitions was the idea that there are 2 distinct clinical courses of the disease (relapsing or progressive), each with differing underlying disease mechanisms. Under this rubric, the main subtypes of disease proposed at that time were relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS.¹

With expanded understanding in the field, definitions of MS phenotypes were updated and revised in 2013 to incorporate concepts of progressive MS that had evolved in the intervening years. In addition to including the pre-MS diagnostic categories of clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS), modifiers were added to incorporate both clinical and imaging indicators of disease activity and progression across the phenotypes. One could now categorize progressive disease as being “with activity” or “without activity,” corresponding to clinical relapses or new MRI lesions, as well as “with progression” or “without progression,” referring to clinical progression of existing symptoms in the absence of new MRI disease activity. As such, “SPMS with activity” effectively became codified as a form of relapsing MS. These changes also eliminated the need for the progressive relapsing MS phenotype, in favor of characterizing PPMS as with or without disease activity.²

In the decade since the revised phenotypes effectively blurred the distinction between RRMS and SPMS, the concept that there is considerable overlap between relapsing and progressive MS has been increasingly investigated and discussed. However, in clinical practice, the categorical distinction between relapsing and progressive disease has persisted, and the original phenotypes have continued to inform eligibility and outcome criteria for MS clinical trials and the language of Food and Drug Administration (FDA) approvals. Nonetheless, the 2019 approvals of siponimod and oral cladribine incorporated this terminology, approving them for an indication of “active SPMS.” This designation was subsequently assigned to other disease-modifying therapies (DMTs) for RRMS. One significant consequence of the 2013 revisions, particularly with the incorporation of this nomenclature, is that regular clinical and imaging evaluation—typically at least annually—is necessary to define a patient’s precise disease phenotype. This level of disease surveillance is implemented in clinical trials, but is less feasible in clinical practice. Thus, a real-world challenge is that precise clinical phenotyping often may not be achieved in routine patient care.³

Ambiguity regarding MS clinical course is not merely an issue of nomenclature. The underlying mechanistic relationship between relapsing and progressive MS, and how and why relapsing disease becomes progressive, has many unanswered questions regarding pathology and causality. One common view is that relapsing disease is the manifestation of repeated, acute bouts of central nervous system (CNS) inflammation, with progressive disease mediated by chronic CNS inflammation and neurodegeneration. In this concept, MS is a single disorder with differing phenotypes reflecting varying stages and manifestations of the disease course.^4,5 Noting the great heterogeneity in the development of progression following a relapsing onset, predictors of progression from a relapsing to a progressive phenotype, in principle, can be identified. However, substantial challenges remain, because even despite the suggestion for annual “time-locked” clinical and imaging assessments,² the transition from RRMS to SPMS is usually gradual, and progression often does not occur in a uniform fashion. Thus, the diagnosis of SPMS must be made retrospectively, and often at a considerable delay after disease progression begins.⁶

Predictors of Progression

Our growing understanding of progressive disease in MS is aided by continual improvements in our tools for detecting and predicting disease progression. This allows for DMT decision-making to be optimized. It also offers the opportunity to personalize therapies for physical and cognitive health. However, no clear objective criteria exist to delineate the point at which the SPMS phenotype should be applied. This is attributable, in part, to the diverse clinical manifestations of disease progression, from an insidious myelopathy with pyramidal dysfunction and gait limitations, to a brainstem/cerebellar syndrome intrinsic to Charcot’s original description of MS, to the more recently recognized MS cognitive syndrome that is overlooked in traditional measures of MS disability like the Expanded Disability Status Scale (EDSS).

Nevertheless, identifying potential predictors of progression does not rely on a clear boundary between RRMS and SPMS phenotypes. Existing predictors of disease progression include both clinical parameters and paraclinical biomarkers. Patients with a history of many early relapses (especially motor relapses) or incomplete recovery from relapses are at higher risk of subsequent progression. Several radiographic features have been associated with increased risk for progression, including lesion location,^7-9 brain or spinal cord atrophy,¹⁰ and early, high lesion burden or disease activity seen on MRI, even in the presence of an initially mild-appearing disease course.¹¹

Clinical Challenges in Progressive Disease

Making the diagnosis of progressive MS can be difficult in practice, particularly if there are atypical clinical or radiographic features that limit one’s ability to apply the McDonald 2017 diagnostic criteria,¹² which require typical clinical syndromes and MRI findings with the caveat of “no better explanation.” In a PPMS phenotype, the initial differential diagnosis may include various other causes of progressive myelopathy, such as other neuroinflammatory (eg, neurosarcoidosis), infectious (eg, human immunodeficiency virus, human T-cell lymphotropic virus myelopathy), metabolic (eg, vitamin B12 or copper deficiency), or genetic (eg, hereditary spastic paraplegia) etiologies. The extent of additional diagnostic workup to rule out “other explanations” depends on how suggestive the overall clinical presentation is of MS.¹³

Even in a patient with a well-established diagnosis of RRMS, there frequently are challenges in defining the point of transition to SPMS. In a study of 123 patients from the Corinne Goldsmith Dickinson Center for MS, the average period of diagnostic uncertainty (ie, from the first clinic visit suggesting a component of progression to the visit where the patient was definitively diagnosed with SPMS) was nearly 3 years¹⁴ (Figure 1). This diagnostic delay that exists in practice stems from the indistinct border and increasing evidence for a continuum between RRMS and SPMS. The initial signs of SPMS are subtle and often below the threshold of detection by our neurologic examination, a phenomenon termed “silent progression.”¹⁵

Given the heterogeneity in SPMS onset and variability in how this diagnostic category is applied, there have been attempts to standardize the definition of SPMS and provide more objective measures by which this diagnosis can be recognized. One large study using data from the MSBase registry¹⁶ (a worldwide MS observational cohort) found that the most accurate definition consists of the following: a minimum EDSS score of 4; a minimum pyramidal functional system score of 2; and disability progression by a score of 1 EDSS step in patients with EDSS ≤ 5.5 or by 0.5 in patients with EDSS ≥6.0 occurring in the absence of relapse, with confirmed progression over at least 3 months. The proposed definition also allowed for more timely diagnosis, decreasing the period of diagnostic uncertainty by >3 years compared with neurologists’ assessments.¹⁶ Neurologist-defined SPMS remains the standard in clinical practice, but multiple studies have shown that the use of a data-driven diagnostic definition of SPMS, such as the criteria published by the MSBase collaboration, potentially aids in more timely and accurate identification of the transition to SPMS.^17,18 However, these types of definitions could misclassify patients who exhibit slower progression and lower EDSS scores as having RRMS, particularly when ambulatory function remains ostensibly intact.⁶

A contemporary view of MS acknowledges that, biologically, it is not a strictly 2-phase disease but rather consists of both activity and progression layered together to yield a disease spectrum. Numerous pathologic and imaging studies have shown that neurodegeneration and axonal loss (hallmarks of progression) exist even in the earliest phases of the disease, when inflammation predominates. In later stages of disease, ongoing active inflammation also has been demonstrated.⁴ From both a pathologic and radiologic standpoint, there are no significant qualitative differences between relapsing and progressive MS phenotypes. They cannot be distinguished by MRI measures of lesion morphology or brain volume alone. Pathophysiologically, relapsing and progressive MS are also thought to be on a continuum.⁵ The clinical manifestations of MS are largely driven by the reserve capacity of the CNS: its ability to compensate for the effects of focal inflammatory activity superimposed on damage from underlying neurodegenerative processes. As brain reserve (often approximated by brain volume) declines because of aging and the cumulative effects of MS, disability begins to accrue once a critical threshold is reached, denoted clinically as signs of progression. Therefore, promoting brain health and neurologic reserve are important overall therapeutic strategies in MS. Encouraging positive lifestyle habits, including diet, exercise, and smoking cessation, as well as addressing medical comorbidities, such as diabetes, hyperlipidemia, and hypertension, are favorable in attenuating disease progression.^4,5

The Topographical Model of MS

The topographical model of MS provides a unified concept of disease course and a context for depicting the interplay between multifocal lesions and the loss of brain reserve¹⁹ (Figure 2). This model proposes that there is a clinical threshold below which there are no neurologic deficits because of compensatory mechanisms by neurologic reserve. As reserve decreases over time and lesion burden exceeds the threshold, clinical symptoms manifest and are related to lesion topography. Fundamental to this model is the idea that progression recapitulates and localizes to previous clinical symptoms from multifocal lesions and relapses (the “recapitulation hypothesis”). This recapitulation hypothesis is predicated on the observation that the clinical signs of a particular individual’s progression manifest as an incremental recapitulation of previous relapse symptoms and a cumulative unmasking of previously clinically silent lesions. It helps to underscore the clinical heterogeneity of progression as being referable to an individual’s pattern and burden of lesions. In principle, an individual’s lesion localization and signs or symptoms of previous relapses could portend their pattern of disease progression and disability accumulation as the neurologic reserve gradually declines. Using this framework to identify the leading indicators of progression can facilitate earlier recognition of SPMS.²⁰

Assessing Subthreshold Progression: Earlier Recognition

Several recent studies support the concept of the topographical model, the importance of subthreshold disease burden, and the notion of MS as a continuum rather than distinct phenotypes. People with RRMS can have gradual and insidious worsening independent of relapse and MRI activity that often goes unrecognized initially (silent progression). In a large prospective cohort of people with RRMS during the era of DMTs, more than half accrued significant new disability at 10 years of follow-up, while still being classified as having relapsing disease. This silent progression was notably associated with accelerated brain atrophy.¹⁵ A recent large study examining the mechanisms by which people with MS develop disability also found that a significant driver of disability was progression independent of relapse activity. Progression independent of relapse activity accounted for up to half of disability accumulation in RRMS and became regarded as the principal way by which the disease worsened over time.²¹ Even in people with RIS, a preclinical stage of MS, there is evidence of thalamic atrophy, suggesting the presence of subthreshold progression even from the earliest biologic manifestations of the disease.²² Cognitive dysfunction has been observed repeatedly in patients with RIS.^23,24 As a thought experiment, if one defines SPMS as predicated on the insidious development of disability, and cognitive dysfunction essentially always manifests gradually, should every person with RIS, CIS, or RRMS with cognitive dysfunction be classified as having SPMS? The mandate for clinicians, irrespective of MS phenotype, is to look more closely and more carefully for evidence of disease progression.

Tools that are commonly used in clinical practice and research settings to assess for disease progression include the EDSS, the timed 25-foot walk (T25FW), the 9-hole peg test (9HPT), and measures of cognitive function such as the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). However, these methods have limitations and may be too insensitive to recognize more subtle worsening. EDSS scores emphasize motor and ambulatory function and can therefore miss progression occurring in other physical or cognitive domains.⁶ Use of high-challenge tasks to assess balance and manual dexterity can improve the ability to detect subtle disability, even in people with an EDSS of 0 who would otherwise be regarded as neurologically normal on traditional measures of function.²⁵ This underscores the importance of incorporating more sensitive measurements to discern the emergence of functional decline, even in early MS. Using patient-reported outcomes (PROs) and continuous measures of function and activity—such as wearable devices or digital trackers—may facilitate earlier detection of progression. One study found a significant correlation among PROs, decline in step count, and worsening performance on the T25FW and Timed Up and Go tests. Step counts decreased even when EDSS scores remained stable, highlighting the potential utility of wearable devices in providing more sensitive measures of worsening disability than EDSS alone.²⁶ New screening methods that are being developed, such as the MS Prediction Score, MS Progression Discussion Tool, or SPMS nomogram, can assess the effect of disease progression on daily activities.²⁷

Whereas the emphasis on assessing progression traditionally has focused on clinical measures, biomarkers and paraclinical tests are likely to play an increasingly important role. Quantitative MRI techniques, which can better capture changes in overall brain volume and gray matter volume, are commercially available and becoming increasingly used in clinical practice. Laboratory biomarkers such as neurofilament light chain and glial fibrillary acidic protein also show some potential in identifying progressive disease, although substantial work in this area remains to be done in order to untangle disease progression from disease activity.²⁷

Treatment Implications for Progressive MS

In the US, only ocrelizumab is approved for PPMS²⁸ and only siponimod is approved for SPMS after a successful clinical trial.²⁹ In the case of siponimod, the primary end point for the phase 3 trial including 1645 people with SPMS was reached; however, the FDA approved it only for active SPMS (along with RRMS, which was not investigated in a phase 3 trial), based on a post hoc analysis. Although the distinction was made by the FDA to approve siponimod only for active SPMS, the time frame for active disease was not defined clearly. (In principle, any individual with SPMS has a history of previous disease activity during the RRMS phase.) In contrast to siponimod’s narrower indication, ocrelizumab was approved for PPMS with or without disease activity, despite evidence of greater efficacy in “active” PPMS.³

Whether SPMS and PPMS are indeed distinct entities remains a subject of debate; there is no clear clinical, imaging, biomarker, or prognostic difference between them in practice. In the phase 2 trial for ibudilast in progressive MS, people with PPMS and SPMS were enrolled in a combined population.³⁰ A post hoc analysis demonstrated a difference in rates of brain atrophy between PPMS and SPMS, raising the question of whether these entities really are distinct.³¹ Additional light may be shed on this question when the results are available from 2 ongoing identical parallel trials assessing tolebrutinib, an oral CNS-penetrant Bruton tyrosine kinase inhibitor, for PPMS and SPMS. These studies have the potential to unify or distinguish the clinical course of progressive MS, as well as to establish the efficacy of this emerging class of treatment for these challenging forms of the disease.³²

Summary

MS classically has been subdivided into RRMS, SPMS, and PPMS phenotypes, but the current classifications invoke the need to surveil for both disease activity and progression in all people with MS across phenotypes. The field has moved toward conceptualizing MS as a disease continuum, with both relapsing and progressive features starting early in the disease course, as depicted in the topographical model of MS. Early recognition of subtle progression and using detailed clinical assessments—as well as annual, ideally quantified MRI measures—can establish more thoroughly the full burden of disease, particularly that of early progressive MS. Lifestyle modifications to optimize brain health may boost CNS reserve and mitigate against progressive decline. Only siponimod and ocrelizumab are FDA-approved on the basis of successful clinical trials in SPMS and PPMS, respectively; however, next-generation therapeutics such as CNS-penetrant Bruton tyrosine kinase inhibitors are in phase 3 trials.