MS dementia – Prof G's MS Blog Archive

Barts-MS rose-tinted-odometer: zero-stars

What do you say when I colleague chastises you for stating the fact that MS is potentially a ‘preventable dementia’? This particular colleague was clear that there is no need to draw any parallels between MS and other neurodegenerative diseases because of the negative connations that the term dementia has. I had to remind him that MS ticks all the boxes for being classified as a dementia; i.e. (1) MS is an acquired and not a congenital disorder; (2) MS is a chronic progressive disease; (3) MS impacts on multiple cognitive domains and (4) MS impacts on social and occupational functioning. Have I missed something?

I also had to remind this colleague that almost every neurology or psychiatry textbook included MS on its list of causes of dementia. I am not prepared to peddle alternative facts because pwMS may find it distressing to find out that if MS is left to its own devices it will shred their brains and cause dementia. Please note the rose-tinted-odometer is set to zero for this post.

The small study below reiterates what we already know that both relapsing and progressive patients have cognitive problems that correlate with physical disability. This study also confirms that T1 hypodensities or blackholes on MRI, particular in the thalamus (a deep grey matter structure in the brain) predicts cognition problems. T1 hypodense MS lesions or black holes, or at least a proportion of them, have been shown to be very destructive and include lesions with so-called phase-rims (iron around them) and a subset we call SELs (slowly expanding lesions). Some neuroradiologists often describe an MS brain with a high volume of black holes as being similar to Swiss cheese in reference to Emmental cheese.

Now for the good news is that these studies below are on patients with significant end-organ damage and if we can diagnose and treat MS effectively early on we can prevent or at least delay the end-organ damage and the progressive loss of cognition. This is why we have spent years promoting the concepts of ‘Time-is-Brain’, ‘Treat-2-Target of NEDA’, ‘Rapid escalation’, ‘Flipping-the-Pyramid’, ‘Brain Health’, ‘Beyond-NEDA preventing end-organ damage’, ‘Holistic Management’, ‘Marginal Gains’, etc. Buried in all of these concepts is the use of effective DMTs to prevent end-organ damage and to prevent dementia.

I am very pleased that my pwMS in Australia have taken this one step further and launched their own awareness campaign, albeit sponsored by Biogen, to raise awareness about early effective treatment (www.msmotion.com.au). The campaign is been run by a group of MS social media influencers. I met them all virtually last year and spoke to them about the concepts that underpin our ‘Brain Health: Time Matters’ policy document. It would be great if pwMS across the world could do a similar thing.

Do you agree with my colleague above that we should try and protect pwMS from the harsh realities of MS and what can happen to their brains if we don’t manage their MS appropriately? Or should we peddle false facts and a rose-tinted view of the world?

de Paula Gois et al. Associations between cognitive and clinical disability across MS subtypes: The role of the underlying brain damage. Mult Scler Relat Disord. 2020 Dec 19;48:102701.

Background: Cognitive impairment (CI) is present in all stages and subtypes of multiple sclerosis (MS). However, the majority of studies examined relapsing-remitting (RRMS) patients, and did not address cognitive phenotyping. Is still not clear whether patients with progressive MS (PMS) have a distinct pattern of CI compared to RRMS. In addition, there is conflicting data regarding the correlation between clinical and cognitive disability.

Objective: To investigate the differences of CI between PMS and RRMS patients, evaluating cognitive phenotypes. We also aimed to analyze the association between physical and cognitive disability with MRI measures of grey-matter atrophy and lesion burden.

Methods: Thirty patients with PMS and twenty-four with RRMS underwent neurological, neuropsychological (BRB-N, Boston Naming, and Tower of London), and MRI assessments (3T). Brain volume evaluations were performed using FreeSurfer. Principal Components Analysis on neuropsychological yielded six principal cognitive domains. Cognitive deficits were classified according to three categories: no CI, impairment in isolated cognitive domain, or impairment in combined domains.

Results: In the overall sample, the most frequently impaired cognitive domains were information processing speed (IPS) and visual memory. PMS patients had a higher prevalence of verbal memory and verbal fluency deficits, and more frequent impairment in combined cognitive domains compared to RRMS individuals. After multivariable regression analysis with clinical variables, EDSS was associated with most cognitive domains. Nevertheless, after including T1-lesion volume in the model, it was the most consistent predictor of cognitive performance. To further analyze the interaction between EDSS and T1-lesions, we performed GLM analysis with EDSS and T1-hypointense lesion volume as covariates, and T1-lesion volume adjusted better the model for verbal memory (p = 0.013), IPS (p = 0.021) and total number of impaired cognitive domains (p = 0.021).

Conclusions: RRMS and PMS patients tend to have a similar neuropsychological profile in general, but the extent of CI was greater in PMS patients. Worse cognitive performance was associated with increased physical disability, but this correlation was no longer significant after controlling for T1-lesion volume, suggesting that the underlying MS pathology might be involved in this relationship. Thalamic and T1-lesion volumes were the most consistent MRI predictors associated with cognitive disability.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

How big is your grey matter iceberg?

As you are aware, MS is an iceberg, with most of the MS disease activity and resultant damage being hidden. The study below expands the concept of the MS iceberg to the cerebral cortex or grey matter. Most lesions (~80%) found at post-mortem in the grey matter are not detected using specialised MR imaging. Please note that post-mortem MRI imaging in more standardised than that which happens in clinical practice and I suspect even more lesions will be missed in real-life.

Is this study important? You bet. We know that these grey matter lesions are associated with cognitive impairment, loss of brain volume and in particular progressive grey matter atrophy and are associated with poor longterm outcome and reduced quality of life.

Do you want to know what your true MS disease burden is? Based on this data and other studies it looks as if MRI is not the best way of doing this. I suspect a better marker will be ‘deep phenotyping’, i.e. interrogating the function of your nervous system using stress tests to see how you perform. Knowing you have cognitive impairments, for example, slow cognitive reaction times, difficulty with concentration and attention, poor memory or other specific deficits may be more meaningful to you. Or not? I say ‘or not’ as not all pwMS want to know that have cognitive impairment; they argue if nothing can be done about it is best to ignore it. This is called the ‘ostrich syndrome’.

Knowing you have cognitive deficits will allow you to take specific actions to address the problem and to potentially make important real-life decisions about your future. It also allows your HCP to take action to address some medical issues that are linked to cognitive impairment, i.e. poor adherence to treatments, physical accidents and comorbid depression and anxiety to name a few. One could argue that pwMS who have cognitive impairment should be put on a high-risk register for more proactive management and care.

It is clear that the burden of MS is not only physical but cognitive as well. This is another reason to diagnose, treat and manage MS effectively and as early as possible to prevent end-organ damage and preserve your grey matter. Can I please remind you that no all DMTs are made equal when it comes to preserving brain volume or grey matter.

This post reminds me of an infographic I put together about 5 years ago called ‘Grey Matter, Matters’, which I used to support a campaign I started to redefine MS as a ‘preventable dementia’.

Do you agree with me?

Piet M Bouman et al. Histopathology-validated recommendations for cortical lesion imaging in multiple sclerosis. Brain. 2020 Aug 21;awaa233. doi: 10.1093/brain/awaa233.

Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.

Keywords: cortical lesions; double inversion recovery; multiple sclerosis; phase-sensitive inversion recovery; post-mortem imaging.

CoI: multiple

Tag: MS dementia

Swiss-cheese

Grey matter, matters