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What New Understanding of Progressive MS Reveals About Disease Progression

Article In Brief

In a plenary session, a leading researcher in multiple sclerosis described the multiple drivers of disease progression, including so-called smoldering white matter plaques, axonal degeneration, spinal cord lesions, the failure of full remyelination, cortical demyelination, meningeal inflammation, and deep gray matter pathology.

PHILADELPHIA—No area of neurology has seen greater strides in development of new treatments than multiple sclerosis (MS). But until very recently, therapies were effective only for the relapsing-remitting stage of the disease, with no effect on secondary progressive MS. And yet, as Claudia F. Lucchinetti, MD, FAAN, pointed out in her Robert Wartenberg Lecture at the AAN Annual Meeting here in May, “the majority of impact arises in the progressive phase, where disability accumulates inexorably.”

If new therapies are to be developed that can slow or halt worsening disability, it will require better understanding of the process—or, as Dr. Lucchinetti emphasized, the processes—that drive progression.

Even in the preclinical period, before inflammatory responses become clinically apparent, “there is an underlying pathological process at play,” she said, with accumulation of axonal injury and decreasing brain volume. “This gradual worsening differs from relapse worsening, in that it is irreversible and permanent.”

Within 20 years of diagnosis, between 30 and 60 percent of MS patients will convert to a secondary progressive course. Risk factors for earlier conversion include older age at onset, male sex, smoking, and lower vitamin D levels, although the links between any of these and the underlying drivers of progression are not clear. More relapses in the first two to five years increase the probability of worsening and the rate of disability progression, and ongoing relapses during the progressive phase accelerate the time to disability milestones.

Dr. Lucchinetti's specialty is neuropathology, and in her talk she presented news from the cutting edge of MS neuropathology research, much of it from her own lab at Mayo Clinic in Rochester, MN, where she is the Eugene and Marcia Applebaum Professor of Neurosciences and chair of neurology.

There are multiple drivers of progression, she noted, including so-called smoldering white matter plaques, axonal degeneration, spinal cord lesions, the failure of full remyelination, cortical demyelination, meningeal inflammation, and deep gray matter pathology.

Smoldering Plaques

Active lesions are the pathological hallmark of MS, but they are rare in the chronic, progressive stage of the disease. In contrast, smoldering lesions are more commonly seen. These lesions slowly expand, and at the edge of the plaque there is a predominance of microglia and evidence of acute axonal injury, suggesting ongoing damage. “Smoldering plaques are present only in progressive forms of MS,” she said.

Many smoldering plaques are characterized by a paramagnetic rim enriched in iron. Such rim lesions are also found in relapsing patients, but they become more common in progressive disease, and correlate with significantly worse disability scores.

“Iron is a double-edged sword,” Dr. Lucchinetti said. It plays well-known physiological roles in oxygen transport and the mitochondrial respiratory chain, among other processes, “but it is also a potential source of free radicals if it is not tightly controlled. Liberation of iron in MS lesions may amplify demyelination and promote neurodegeneration through oxidative injury.”

“Little is known about metals in MS, due to the inherent limitations of histochemical stains,” she added. To learn more about iron and other metals in MS lesions, Dr. Lucchinetti's group has turned to X-ray fluorescence microscopy, which uses highly energetic photons to produce metal-specific emission spectra in tissue, allowing the detection of multiple individual metals with high spatial resolution independent of their ionic state.


“Remyelination is important for protection of the axon, and is extensive in early MS, but is incomplete in progressive disease. Importantly, areas of previous demyelination and remyelination often become targets of new lesions and neurodegeneration.”


That work has shown that reactive astrocytes accumulate iron in a subset of smoldering and inactive lesions, “where it is safely sheltered,” she said. “We think this may represent a protective barrier,” absorbing iron released by degenerating microglia and macrophages.

Oxidative damage is clearly an important process in progressive MS, “but immunohistochemical analysis of oxidative lesions has its limitations,” Dr. Lucchinetti said.

Her lab has pioneered the use of another type of microscopy for examining MS lesions, called Fourier-transmission infrared microscopy. In this technique, infrared light is used to probe unlabeled tissue, which is differentially absorbed by different types of organic molecules, including lipids, proteins, and nucleic acids.

Axonal damage produces changes in the emission spectra, which can be used to create high spatial resolution images offering complementary information to traditional histologic approaches.

“There is a great deal of information about the plaque region versus the peri-plaque region,” she said. Using this technique, Dr. Lucchinetti's lab has found evidence for oxidation of lipids, proteins, and nucleic acids within lesions.

Other pathological processes contribute to progression as well, Dr. Lucchinetti stressed. “Remyelination is important for protection of the axon, and is extensive in early MS, but is incomplete in progressive disease. Importantly, areas of previous demyelination and remyelination often become targets of new lesions and neurodegeneration.”

Axonal injury is common in MS lesions, and both clinical and imaging metrics correlate with the extent of axonal transection. “Motor disability correlates with axonal density, not white matter lesions,” she said. Neurofilament is a marker for axonal injury in MS and other diseases, and the potential to use either serum or cerebrospinal fluid neurofilament levels as a biomarker for progression is a subject of intense research.

Axonal density is also reduced in the spinal cord, and to a greater degree than the overall volume reduction. “This is important, because MRI indices of spinal cord volume likely underestimate the degree of axonal damage, which may limit the role of such indices as an outcome measure in clinical trials. New techniques that are more specific for underlying tissue damage are needed.”

Cortical demyelination is extensive in MS, and cortical atrophy is a better predictor of future disability than whole-brain atrophy, she said. Cortical lesions can be challenging to detect with conventional MRI, but specific pulse sequences and ultra-high field magnets can improve on this.

“These plaques are often associated with meningeal inflammation, and this inflammation predicts a more aggressive progressive course,” she said. Gray matter lesions are also important contributors to disease progression, particularly in the caudate, where involvement is associated with cognitive decline, motor decline, fatigue, and pain.

And finally, Dr. Lucchinetti pointed out, age at onset negatively affects many aspects of MS disease history, including the probability of and time to conversion to progressive MS. “This tells us that the perfect control of inflammatory processes in relapsing MS is likely insufficient to prevent conversion to progressive MS, or to slow disease progression once it begins.”

Despite the complexity of the pathogenesis of progressive MS, some progress has been made in developing treatments. New agents, including cladribine, fingolimod, siponimod, and ocrelizumab, have been approved for treatment of secondary progressive disease, and evidence is accumulating that early aggressive therapy, rather than escalation, may delay the conversion from relapsing-remitting to progressive MS.

Expert Commentary

“Dr. Lucchinetti's work emphasizes that there are multiple different aspects to progressive MS, and that there is not one pathological cause for progression of disability. This complexity illustrates why it is so difficult to have a therapeutic impact on delaying progression of disability,” commented Eric Klawiter, MD, director of the Multiple Sclerosis and Neuromyelitis Optica Unit at Massachusetts General Hospital in Boston, and assistant professor of neurology at Harvard Medical School.

“This complexity has also been a huge challenge for clinical trials,” he pointed out, since the most important driver of progression may vary from patient to patient, making a single therapy less effective across a large group of patients. Nonetheless, progress in understanding pathogenesis is likely to bring new and more promising agents to trial.

“I think in the next five years we will have new candidate treatments based on our current understanding of progressive MS. But ultimately one of the best ways to treat progressive MS is to prevent it from occurring in the first place,” Dr. Klawiter said, perhaps through more aggressive early treatment, a hypothesis currently being tested.


Drs. Lucchinetti and Klawiter had no disclosures.

Link Up for More Information

• Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis N Engl J Med 2018:378:169–180.
• Popescu BF, Frischer JM, Webb SM, et al. Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions Acta Neuropathol 2017; 134(1):45–64.
• Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque Ann Neurol 2015; 78(5): 710–721.
• Tillema JM, Weigand SD, Dayan M, et al. Dark rims: Novel sequence enhances diagnostic specificity in multiple sclerosis Am J Neuroradiol 2018; 39 (6):1052–1058.