Barts-MS rose-tinted-odometer: zero-★s
She was only 26-years and she couldn’t understand why she was falling behind her peers at work. She started working at an ultra-competitive law firm after finishing as one at the top of her peer group at Oxford. She was clearly the best-performing intern in the 2017 intake, which is why she was kept on after her internship. However, things were now going wrong. She was suffering from chronic fatigue, forgetfulness and she simply couldn’t juggle the complex tasks she was being expected to working for more than one client at a time. This job was a high-octane one and you were expected to perform at the level. Her poor performance and increasing list of mistakes had resulted in one performance review already. What should she do?
The back story to this young lawyer is her identical twin sister had been diagnosed with MS at the age of 18, shortly after completing her A-levels. Her sister had decided to delay going to university because of being diagnosed with MS. The odds are this young lawyer had asymptomatic MS and her fatigue and cognition problems are linked to smouldering MS. Do you think she should seek a neurological opinion? She is aware that her lifetime risk of being diagnosed with MS is about 30%.
Do you think she should seek a neurological opinion?
I have made the case that the real MS is not relapses and/or focal MRI activity, but smouldering MS. The real question is when do the pathological processes that drive smouldering MS begin? In this study on asymptomatic MS (radiologically-isolated syndrome or RIS) a third of them already have cognitive impairment and two-thirds had lesions with paramagnetic rims (PRL), i.e. a rim of hot microglia. These so-called PRLs are the precursor to the dreaded SELs (slowly-expanding lesions) that are so unresponsive to our current treatments and responsible for so much damage in MS.
So what are the implications of this study for MS?
- MS begins long before your first attack.
- Smouldering MS, formerly known as progressive MS, also begins long before your first attack.
- PRLs and SELs, one of the substrates for smouldering MS, are part of MS pathology from very early in the disease course; possibly the beginning.
- Cognitive impairment and end-organ damage begin very early in the course of MS.
- We need to change our diagnostic criteria to allow MS to be diagnosed very early on, in this case in the so-called asymptomatic phase of the disease. By using PRLs and the central vein sign (CVS) we are likely to improve the sensitivity and specificity of the diagnostic criteria. So what are we waiting for?
We clearly need a new treatment paradigm to tackle smouldering MS. The current anti-inflammatory monotherapy model of treating MS is unlikely to work. We need combination therapies ASAP. To achieve the latter we are going to have to get Big Pharma and the regulators to innovate quickly and intelligently.
Oh et al. Cognitive impairment, the central vein sign, and paramagnetic rim lesions in RIS. Mult Scler. 2021 Mar 23:13524585211002097.
Objective: The central vein sign (CVS) and “paramagnetic rim lesions” (PRL) are emerging imaging biomarkers in multiple sclerosis (MS) reflecting perivenular demyelination and chronic, smoldering inflammation. The objective of this study was to assess relationships between cognitive impairment (CI) and the CVS and PRL in radiologically isolated syndrome (RIS).
Methods: Twenty-seven adults with RIS underwent 3.0 T MRI of the brain and cervical spinal cord (SC) and cognitive assessment using the minimal assessment of cognitive function in MS battery. The CVS and PRL were assessed in white-matter lesions (WMLs) on T2*-weighted segmented echo-planar magnitude and phase images. Multivariable linear regression evaluated relationships between CI and MRI measures.
Results: Global CI was present in 9 (33%) participants with processing speed and visual memory most frequently affected. Most participants (93%) had ⩾ 40% CVS + WML (a threshold distinguishing MS from other WM disorders); 63% demonstrated PRL. Linear regression revealed that CVS + WML predicted performance on verbal memory(β =-0.024, p = 0.03) while PRL predicted performance on verbal memory (β = -0.040, p = 0.04) and processing speed (β = -0.039, p = 0.03).
Conclusions: CI is common in RIS and is associated with markers of perivenular demyelination and chronic inflammation in WML, such as CVS + WML and PRL. A prospective follow-up of this cohort will ascertain the importance of CI, CVS, and PRL as risk factors for conversion from RIS to MS.