You will have noticed that a lot of discussion on this blog has recently been devoted to the topic of secondary progression or smouldering MS or whatever else you want to call it. At the moment there is no standard terminology for describing the scenario of someone with MS who is NEDA-2 (no relapses and no activity on MRI) who is getting worse. The getting worse could be overt, i.e. worsening EDSS, or a more subtle deterioration, which can only be detected using more sensitive outcome measures, or asymptomatic.
Can you let us know which term you prefer?
Non-relapsing SPMS
Inactive SPMS
Hidden SPMS
Hidden progression
Silent progression
Progression independent of relapses (PIRA)
Smouldering MS
Worsening MS
Festering MS
I personally don’t like the use of secondary progression in the term. This excludes MSers with a primary progressive course who have the same pathology and entrenches the dogma that relapse-onset MS and PPMS are different and separate diseases.
Hidden is another term that I don’t like; what is hidden for some MSers may not be hidden for other MSers. For example, cognitive impairment only becomes a problem when you stress your brain. Some MSers may be in a life stage when cognitive stressors are rare and others may stress or test their cognitive abilities on a daily basis.
The term PIRA seems to have the lead at the moment and is being used more and more in abstracts and meetings. Worsening MS is a catch-all phrase that by definition can occur in the presence or absence of relapses and hence according to the Lublin classification you can have active-worsening and inactive-worsening MS. Please note that according to Lublin the worsening has to be overt, i.e. captured using an objective outcome measure.
I like smouldering MS because it creates a visual analogy of what is happening to the brain and spinal cord of MSers. In other words, the flames or relapses and focal MRI activity have been quelled, but the embers continue to burn. It also implies that the embers can fire-up and reignite the flames at any stage. I have a potential conflict in that the term ‘smouldering MS’ may have been used first on this blog and hence we have a vested interest in this term being selected.
A very common analogy is the comparison of MS to an iceberg. Why?
Only one-eighth of an iceberg is visible above the water; to see what is below the water line requires specialised technology. The MS iceberg analogy refers to several observations:
1. For each clinical relapse, 10 or more MRI visible lesions are seen on MRI. 2. For each visible white matter lesions on MRI, there are at least an equivalent number or more grey matter lesions. In fact, it is now estimated that more than half the MS pathology is in the grey matter. 3. For every visible white matter lesion, either on MRI or with the naked eye, there are 20 or more microscopic lesions present in the white matter. 4. Despite only a relatively small amount of brain or spinal cord atrophy, there is almost three times as much neuronal loss underlying the atrophy. 5. Despite a relatively good recovery of function in a particular pathway, for example, after a relapse, there is a substantial loss of axons and hence reserve capacity in that pathway. 6. People with MS have many more hidden symptoms and disabilities than visible physical disabilities; early MS is often a hidden disease.
When you use newer technologies, for example, a 7 Tesla MRI to look at cortical or grey matter lesions in MS you begin to see how large the iceberg really is. Please remember the vast majority of cortical MS lesions (>90%) or not seen with conventional MRI. The bad news in the study below is that almost all the pwMS studied had cortical lesions and these, not surprisingly, correlated with disability and cognitive impairment. What is interesting is that the lesions on the surface of the brain (subpial), but not those on the grey-white matter interface (leukocortical), correlated better with cortical volume. However, the grey-white matter interface, or leukocortical, lesions correlated most strongly with cognitive impairment.
What is becoming increasingly important is to try and target the grey matter pathology and prevent cognitive impairment in pwMS. The problem is we don’t routinely monitor brain and in particular grey matter atrophy in routine clinical practice; in fact it is largely ignored. If we did we would probably find many more pwMS opting for the higher efficacy treatments that have the greatest impact on brain atrophy (alemtuzumab and HSCT).
It is important for you to realise that you can be NEDA-3, i.e. no clinical attacks and MRI activity, and still have progressive grey matter atrophy. Why this is happening is debatable. Some evidence points to immunoglobulins and complement activation, rather than cytotoxic T-cells, being the major driver of cortical pathology. This why Barts-MS is exploring add-on drugs that will hopefully target the B-cell follicles and plasma cells within the central nervous system to try and slow down this process. We plan to start recruiting for our add-on study later this year.
I have little doubt that slowing down and preventing progressive brain and grey matter atrophy will become one of the treatment targets for the next generation of MSologists. To make this a reality we need to have tools to measure these processes reliably in clinical practice.
IMPORTANCE: Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS.
OBJECTIVE: To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS.
DESIGN, SETTING, AND PARTICIPANTS: An observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and whole-brain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume.
MAIN OUTCOMES AND MEASURES: Physical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery.
RESULTS: Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = -0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10-4 [1.30 × 10-4 to 7.90 × 10-4] vs 1.50 × 10-4 [0 to 1.01 × 10-3]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10-4 [0 to 1.01 × 10-4] vs 1.19 × 10-4 [0 to 7.17 × 10-4]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI, 1.06-192.37; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01).
CONCLUSIONS AND RELEVANCE: This study provides in vivo evidence that CLs are associated with cognitive and physical disability in MS and that leukocortical and subpial lesion subtypes have differing clinical relevance. Quantitative assessments of CL burden on high-field MRI may further our understanding of the development of disability and progression in MS and lead to more effective treatments.
