Which Imaging Criteria Identify Progressive Forms of MS?

December 30, 2020

The role of imaging in diagnosing progressive multiple sclerosis (MS) and in assessing prognosis is the subject of a new review.

MRI is central in the diagnostic workup of patients suspected of having MS, given its high sensitivity in detecting disease dissemination in space and over time and its notable ability to exclude mimics of MS, the authors note. However, diagnosis of primary progressive MS remains challenging and is only possible retrospectively on the basis of clinical assessment.

Identification of imaging features associated with primary progressive MS and features that predict evolution from relapsing-remitting MS to secondary progressive MS is an important, unmet need, they write.

Diagnosis of progressive MS is limited by difficulties in distinguishing accumulating disability caused by inflammatory disease activity from that attributable to degenerative processes associated with secondary progressive MS. Moreover, there are no accepted clinical criteria for diagnosing secondary progressive MS, the authors explain.

This need has promoted extensive research in the field of imaging, facilitated by definition of novel MRI sequences, to identify imaging features reflecting pathophysiologic mechanisms relevant to the pathobiology of progressive MS, the authors say.

The current review reports the conclusions of a workshop held in Milan, Italy, in November 2019, at which an expert panel of neurologists and neuroradiologists addressed the role of MRI in progressive MS.

The review, with lead author Massimo Filippi, MD, Istituto di Ricovero e di Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy, was published online in JAMA Neurology on December 14.

The authors conclude that no definitive, qualitative clinical, immunologic, histopathologic, or neuroimaging features differentiate primary progressive and secondary progressive forms of MS; both are characterized by neurodegenerative phenomena and a gradual and irreversible accumulation of clinical disability, which is also affected by aging and comorbidities.

A definitive diagnosis of primary progressive MS is more difficult than a diagnosis of relapsing-remitting MS; in part, primary progressive MS is a diagnosis of exclusion because it can be mimicked by other conditions clinically and radiologically, the authors note.

The writers do report that although nonspecific, some spinal cord imaging features are typical of primary progressive MS. These include diffuse abnormalities and lesions involving gray matter and two or more white matter columns, but confirmation of this is required.

In patients with primary progressive MS and those with relapse-onset MS, MRI features at disease onset predict long-term disability and a progressive disease course. These features include lesions in critical central nervous system regions (ie, spinal cord, infratentorial regions, and gray matter) and high inflammatory activity in the first years after disease onset. These measures are evaluable in clinical practice, the authors say.

In patients with established MS, gray matter involvement and neurodegeneration are associated with accelerated clinical worsening; however, detection validation and standardization need to be implemented at the individual patient level, they comment.

Novel candidate imaging biomarkers, such as subpial demyelination, and the presence of slowly expanding lesions or paramagnetic rim lesions may identify progressive MS but should be further investigated, they add.

Discovery of MRI markers capable of detecting evolution from relapsing-remitting to secondary progressive MS remains an unmet need that will probably require multiparametric MRI studies, because it is unlikely that a single MRI method will be able to allow clinicians to optimally distinguish among these stages, the authors say.

The contribution of these promising MRI measures combined with other biomarkers, such as quantification of serum neurofilament light chain levels or optical coherence tomography assessment, should be explored to improve the identification of patients with progressive MS, they conclude.

"A Comprehensive Review"

Commenting for Medscape Medical News, Jeffrey A. Cohen, MD, director of the Cleveland Clinic's Mellen Center for MS Treatment and Research, Cleveland, Ohio, said the article is a comprehensive review of the pathologic mechanisms that underlie progression in MS and the proxy measures of those processes (brain and spinal cord MRI, positron-emission tomography, optical coherence tomography, and biomarkers).

"The paper reports there is no qualitative difference between relapsing-remitting and progressive MS; rather, the difference is quantitative," Cohen noted. "In other words, the processes that underlie progression are present from the earliest stages of MS, becoming more prominent over time."

The apparent transition to progressive MS, he added, "rather than representing a 'transition,' instead results from the accumulation of pathology over time, a shift from focal lesions to diffuse inflammation and damage, and unmasking of the damage due to decreased resiliency due to aging and failure of compensatory mechanisms (neuroplasticity and remyelination)."

Also commenting, Edward Fox, MD, director, MS Clinic of Central Texas and clinical associate professor, University of Texas Dell Medical School, Round Rock, Texas, explained that loss of tissue is the main driver of progressive MS.

"We all look at imaging to confirm that the progressive symptoms expressed by the patient are related to demyelinating disease," he told Medscape Medical News. "When I see MRI of the spinal cord showing multifocal lesions, especially if localized atrophy is seen in a region of the cord, I expect to hear a history of progressive deficits in gait and other signs of disability."

Fox noted that on MRI of the brain, gray matter atrophy both cortically and in the deep gray structures usually manifests as cognitive slowing and poorer performance in work and social situations.

"We hope that other biomarkers, such as neurofilament light chain, will add to this body of knowledge and give us a better grasp of the definition of neurodegeneration to confirm the clinical and radiographic findings," he added.

Filippi has received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi, Genzyme, Takeda, and Teva Pharmaceutical Industries; and research support from ARiSLA (Fondazione Italiana di Ricerca per la SLA), Biogen Idec, Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Merck Serono, Novartis, Roche, and Teva Pharmaceutical Industries.

JAMA Neurol. Published online December 14, 2020. Abstract

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