Loss of Neurologic Reserve in Progressive Multiple Sclerosis

Phenotypic variability in multiple sclerosis (MS) remains poorly understood. At disease onset, the majority of patients with MS exhibit a relapsing-remitting MS (RRMS) disease course, and despite the availability of effective anti-inflammatory disease-modifying therapies (DMTs), a substantial proportion of patients will eventually evolve into a secondary progressive MS (SPMS) phase.¹ Apart from SPMS, about 15% of patients with MS show clinical progression from onset without clear remissions, i.e., primary progressive MS (PPMS). The Lublin panel revising the definitions of the clinical course of MS in 2013 acknowledged that some evidence supports PPMS representing a distinct, noninflammatory or at least less inflammatory form of MS.² The panel emphasized that a spectrum of progressive MS phenotypes exists and that any differences between a secondary and primary progressive course are relative rather than absolute.² There are data to suggest that in MS, the acute inflammatory phase is followed by a chronic state that may include a smoldering condition in which inflammation as well as myelin and axonal degeneration may coexist.¹ The transition of RRMS into SPMS is characterized by gradual worsening of neurologic disability independently of the occurrence of superimposed relapses.^1,2 Currently available therapeutic options in both SP and PPMS are only modestly effective, and the approved DMT mainly targets the inflammatory component of the disease.¹

Neurodegeneration includes both white matter tissue damage and pathologic processes in the gray matter.³ There is quite some evidence to suggest that the amount of cortical pathology, including gray matter volume loss, correlates better with clinical disability than the extent of white matter tissue damage.³ Lack of more successful DMT for both SPMS and PPMS can be largely attributed to our incomplete understanding of the mechanisms behind neurodegeneration.³ MS pathologic features, especially those responsible for disease progression in MS, can be only partially explained by a primary autoimmune attack.⁴ One important aspect of our understanding of the neurodegenerative processes may be better insight into the sequence of early events in MS disease.⁴ However, despite numerous efforts and diverse approaches, a lot of the underlying degenerative processes in progressive MS remain to be unraveled.

In this issue of Neurology® Clinical Practice, Vollmer et al.⁵ address the interesting hypothesis that loss of neurologic reserve explains the inception of progressive MS. They propose the wording neurologic reserve in MS to expand the concept as used in other neurodegenerative diseases focusing on cognition. In their opinion, neurologic reserve reflects a broader range of functions apart from cognitive reserve, including motor tasks and sensory symptoms. The authors accentuate that no genetic, pathologic, or immunologic differences convincingly differentiate relapsing forms from progressive MS, nor SP from PPMS. They emphasize the involvement of disease duration and age in progressive disease as determinants of the observed radiologic and pathologic differences between the subtypes. The authors believe that the extent of neurologic reserve explains the moment at which disease progression becomes perceptible and determines the differences in severity over time.⁵

Whether emphasizing the importance of neurologic reserve will result in a paradigm shift in MS research will depend on some key issues that will have to be addressed. One important question is how to accurately quantify and monitor neurologic reserve? The authors propose that assessment of cognitive reserve and its effects on outcomes in patients with MS will provide a good starting point.⁵ The authors refer to cognitive reserve as applied in neurodegenerative diseases like Alzheimer disease (AD).⁵ However, even in AD, cognitive reserve seems to correlate paradoxically with clinical progression during different stages of the disease.⁶ Thus, quantifying neurologic reserve including several other than cognitive domains of MS disease progression will probably be challenging. Timely methods of measuring MS-specific neurologic reserve will have to be defined and validated. Integration with blood (e.g., neurofilament light chain) and MRI (e.g., cortical lesions and atrophy) biomarkers may help monitoring at-risk subjects, as they proved to predict clinical worsening earlier than clinical assessment alone.⁷ Indeed, the concept of neurologic reserve may apply to the very first signs and symptoms of MS. If we believe that the disease is the result of the interplay between genes, lifestyle, and environmental factors, it is reasonable to hypothesize that protective and disease-triggering factors are balanced in the subclinical phase of MS.⁸

The factors that cause exhaustion of the reserve including the preponderance of negative prognostic factors are under discussion. However, because age at onset has been considered one of the reliable and confirmed prognostic variables in MS progression, the impact of genetic/epigenetic variants should still be taken into account.^8,9 Immunologic and genetic studies planned to disentangle the pathogenic issue of the different MS phenotypes still need to reach definitive conclusions (mostly because of lack of power). Nevertheless, increasing evidence points at distinct molecular signatures that underline the differences in disease expression.^8,9 Among others, a recent international whole genome sequencing study revealed that mutations in genes involved in monogenic disorders that share clinicopathologic features with MS (e.g., hereditary spastic paraparesis) seem to contribute to a progressive course, and this effect is independent of the common MS susceptibility risk variants.⁹

Vollmer et al. underscore reducing comorbidities and to promote lifestyle interventions to protect neurologic reserve. Their plea also confirms that interventions and preventive measures need to start as soon as possible to protect neurologic reserve early. Fortunately, MS neurologists increasingly recognize the importance of starting high-efficacy DMT promptly to avoid disease activity and prevent at least some of the subsequent CNS volume loss.¹⁰ We feel, however, that in addition to lifestyle interventions, taking care of comorbidities and timely DMT initiation, a shift toward early pharmacologic interventions enhancing neuroprotective mechanisms is warranted.

Study Funding

No targeted funding reported.

Disclosure

J. Killestein has speaking and consulting relationships with Biogen, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. Amsterdam UMC, location VUmc, MS Center Amsterdam, has received financial support for research activities from Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. M. Liguori reports no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.