Chronic lesion activity in MS as seen on MRI

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If you’d asked an year ago on whether I though MRI had a role beyond diagnosis in MS? My answer would have been an emphatic ‘NO’. The Achilles heel of MRI has always been the difficulty of standardizing scanning techniques to a large scale population level and adapting these accurately to work seamlessly during the day-to-day shortcomings of clinical imaging facilities within busy hospitals. Then, there is the saturation index to consider; the same research being published again and again, with little in the way of new developments. Maybe, I’m being too harsh, but very few would disagree with me when I say a new lease of life in MRI physics is long overdue.

This month, after what seems a decade of sameness, the development of high-field (7 Tesla) MRI has led to the visualization of the smouldering MS lesion (in fact, it seems you can even use a 3T scanner for this). MS researchers have always known of their existence, but in autopsy brain tissues – not very useful if your goal is to discover what they mean in real life! And so, in this instance, the availability of imaging these smouldering lesions and monitoring their evolution is a critical step taken in our understanding of MS.

Inflammation per se is invariably present in all stages in MS, however chronic active lesions or smoldering lesions are more commonly seen than active lesions in those with progressive MS (accounting for ~12-28% MS lesions). They are characterized by a slow expanding rim of activated microglia/macrophages (few of which contain broken down myelin) surrounding an inactive center. The activated cells sit behind a partially or non-disrupted blood-brain barrier with the chronic inflammation contributing to chronic myelin and axonal loss (see Figure 1 for the different types of MS lesions or plaques)

Figure 1 (from Frischer et al., Ann Neurol 2015): (A, B) Early active plaques (EAL) were defined by macrophages immunoreactive for minor myelin proteins (MOG positive macrophages right insert in A) as well as major myelin proteins (PLP positive macrophages left insert in A).
(C, D) Smoldering plaques (also called slowly expanding plaques) typically showed a rather inactive centre with no or few macrophages, surrounded by a rim of activated microglia. Only few of these macrophages or microglia cells contained early myelin degradation products. Inserts depict plaque edge.
(E, F) Inactive plaques revealed a sharp plaque border without or only few macrophages or activated microglia (insert).
(G, H) Completely remyelinated plaques typically containing few macrophages without early myelin degradation products were classified as shadow plaques. Shadow plaques presented with a sharp plaque edge and were associated with fibrillary gliosis.

These activated microglia/macrophages are iron-laden and on imaging appear as lesions with paramagnetic rims (see Figure 2 below).

In a study of 209 PwMS Absinta et al. found that 56% of them had at least 1 chronic lesion with a paramagnetic rim. When cases were classified based on the number of rims, those with 4 or more had 1.6x chance of having progressive MS, and reached disability milestones and decline in cognition at a younger age. Moreover, the overall area of brain involved by lesions was also the greatest in those with 4 or more rims; with rim lesions accounting for ~a third of of the total brain lesion volume (26% in individuals with 1-3 rims and 36% in those with 4 or more rims).

Figure 2: A and B, Cumulative distribution and histogram of the frequency of chronic nonenhancing lesions with paramagnetic rims. C, Group 1 (no detectable rims) is a woman in her mid-20s with relapsing multiple sclerosis (MS). D, Group 2 (detection of 1–3 rims) is a man in his late 50s with relapsing MS and 2 rim lesions. E, Group 3 (detection of ≥4 rims) is a man in his early 30s with relapsing MS and 16 rim lesions. Rim lesions are indicated with arrowheads, and the insets show representative magnified views.

Moreover, although the occurrence of rims were less in those on treatment, they still occurred on those taking the most current DMTs, including ocrelizumab. This maybe due to a lack of direct targeted activity on microglia/macrophages; although, there does appear to be some indirect of bystander effect from suppression of the adaptive immune system (i.e. T and B cells) by these treatments.

Abstract

JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2399. [Epub ahead of print]

Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo.

Absinta M, Sati P, Masuzzo F, Nair G, Sethi V, Kolb H, Ohayon J, Wu T, Cortese ICM, Reich DS.

Importance:

In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target.

Objective:

To assess whether rim lesions are associated with patient disability and long-term lesion outcomes.

Design, Setting, Participants:

We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992).

Main Outcomes and Measures:

(1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions.

Results:

Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation.

Conclusions and Relevance:

Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.

About the author

Neuro Doc Gnanapavan

7 comments

  • Re: whether MRI had a role beyond diagnosis in MS? An emphatic no? Surely, MRI is useful for new lesions as well as brain atrophy. Maybe you meant whether MRI had a role in further differentiating lesion phenotypes. Anyway, this imaging seems to reinforce the microglial role in chronic lesions and hopefully will be a treatment target.

    • In clinical practice the application of other measures reliably have been tricky, this hopefully will provide more info. Targeting macrophages/microglia is one with potentially very bad adverse events though.

  • Is it fair to assume that potent immunosuppressive agents may prevent these rimmed lesions from forming but once they form then immunosuppressant agents are useless?

    Again, we can diagnose chronic progressive disease but cannot in any way, shape or form treat it in the foreseeable future.

    Neurology in a nutshell.

  • Are these types of lesions ever seen in lesions inside of the spinal cord or are they only present in the brain?

    • You will see these lesions in spinal cord too and spinal cord lesions correspond even more strongly to disability.

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