Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review

Abstract

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS.

Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS.

Conclusions and relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.

Figure 1.. Summary of the MRI features supporting PPMS and SPMS diagnosis.

Features supporting diagnosis for both PPMS and SPMS include: A) PSIR axial sequence of the spinal cord (SC) (top and middle rows), lesions involving the GM and ≥2 WM columns on axial plane. No lesions detected in a RRMS female patient with 4 years of disease duration (left), whereas a lesion affecting the right anterior and posterior column, the left posterior column and the central GM is visible at C3-C4 level in a SPMS female patient with a disease duration of 22 years (right). A schematic representation of spinal cord subdivisions of GM and WM columns is shown in the bottom row. B) atrophy of the lower portion of the cervical SC. On the right, a sagittal 3D T1-weighted sequence reveals atrophy of the lower portion of the cervical SC (C7) (cord surface in blue) in a SPMS male patient with disease duration of 26 years. On the left, a sagittal 3D T1-weighted sequence (cord surface in green) of a RRMS male patient with disease duration of 6 years is shown. SC atrophy was quantified using the cord finder toolbox (Jim 7.0). C) Diffuse signal abnormalities in the SC (orange arrowheads) on a T2-weighted sequence in a patient with PPMS. D) GM atrophy of the SC in SPMS.. Compared to a RRMS female patient with a disease duration of 7 years (left), greater SC GM atrophy at C3/C4 level is visible on PSIR sequence in a SPMS patient with a disease duration of 19 years (right) using a local thresholding segmentation technique (Jim 7.0). Abbreviations: ant=anterior column; GM=gray matter; L=left; mm=millimeter; MS=multiple sclerosis; post=posterior column; PP=primary progressive; PSIR=phase-sensitive inversion recovery; R=right; RR=relapsing-remitting; SC=spinal cord; SP=secondary progressive; WM=white matter.

Figure 2.. Summary of MRI predictors of subsequent disability progression and evolution to SPMS at disease onset.

In PPMS early predictors are A) gadolinium (Gd)-enhancing (orange arrowheads) on post-contrast T1-weighted sequences and B) spinal cord (SC) lesions at baseline (orange arrowheads), STIR sequence. In SPMS early predictors are C) the number and volume of baseline brain lesions (T2-FLAIR sequences); D) increase of brain lesion volume (LV) during the first 5 years (orange arrowheads) (T2-FLAIR sequences); E) ≥2 Gd-enhancing lesions at baseline (orange arrowheads) (post-contrast T1-weighted sequence); F) ≥1 SC lesion at baseline or ≥1 SC lesion within 1–3 years (orange arrowheads) (STIR sequence); G)≥1 infratentorial lesion at baseline or ≥1 infratentorial lesion within 1–3 years (orange arrowheads) (T2-FLAIR sequence); H) ≥1 cortical lesion at baseline (orange arrowheads) (DIR sequence); I) ≥1 new deep WM lesion within 1 year (orange arrowheads) (T2-FLAIR sequence). Relevant OR, HRs or global T2 LV that are associated with disability progression and evolution to SPMS at disease onset and that were derived from the literature and discussed in the text are also reported. Abbreviations: cm=centimeter; DIR=double inversion recovery; FLAIR=fluid-attenuated inversion recovery; Gd=gadolinium; HR=hazard ratio; LV=lesion volume; MRI=magnetic resonance imaging; MS=multiple sclerosis; OR=odds ratio; PP=primary progressive; SC=spinal cord; SP=secondary progressive; STIR=short tau inversion recovery; WM=white matter.

Figure 3.. Summary of the MRI markers to identify disability progression and SPMS evolution during the disease course.

In both PPMS and SPMS MRI markers are A) increase of number or volume of brain T1-hypointense lesions. Baseline and 1-year follow-up T1-weighted sequences of a PPMS patient. At follow-up, three new T1-hypointense lesions are visible (orange arrowheads); B) cortical lesion number and volume. A DIR sequence showing three cortical lesions (orange arrowheads) from a PPMS patient is shown; C) baseline thalamic (blue) and cortical (green) damage and atrophy. Quantification on MT imaging (left) and 3D T1-weighted sequences (right); D) rate of whole brain, brain GM (green) and deep GM (blue) atrophy. Quantification on a 3D T1-weighted sequence using SIENA and FIRST software. In SPMS also E) brain T2-hyperintense lesion volume (LV) (T2-FLAIR sequence) and F) conversion of DAWM (orange arrowheads and dotted orange areas) into focal WM lesions (T2-FLAIR sequence). Further promising MRI markers are G) the presence of ≥4 rim positive lesions on susceptibility-based MRI (orange arrowheads) and H) presence of subpial demyelination (orange arrowheads) on T2* sequence at ultra-high field (i.e., 7 Tesla). Figure 3H is adapted from Kilsdonk et al. with permission. Relevant OR, HRs or global T2 LV that were suggested to identify disability progression and SPMS evolution during the disease course and that were derived from the literature and discussed in the text are also reported. Abbreviations: cm=centimeter; DAWM=dirty-appearing white matter; DIR=double inversion recovery; FLAIR=fluid-attenuated inversion recovery; GM=gray matter; LV=lesion volume; MRI=magnetic resonance imaging; MS=multiple sclerosis; MT=magnetization transfer; MTR=magnetization transfer ratio; OR=odds ratio; PP=primary progressive; SP=secondary progressive; y=year; WM=white matter.