#ResearchSpeak: is the answer to MS in the CSF?

Which do you prefer, 'watchful waiting' or 'masterly inactivity'? #MSBlog #ResearchSpeak

The study below from my colleagues at my old Institution, UCL, is really cool; well done! 

Ever since Dawson described the perivenular extension of MS lesions, which are perpendicular to the lateral ventricles, people have been hypothesising that there is something soluble in the cerebrospinal fluid that is causing the MS lesion. The same hypothesis holds for cortical gray matter, optic nerve, brain stem and cervical cord lesions. In other words there is a predilection for MS lesions to occur adjacent to CSF pathways. 

The study below used an imaging technique called MTR that assesses structural integrity of brain tissue. What the UCLers found is that in people presenting with optic neuritis there was a decrease in tissue integrity adjacent to the lateral ventricles and this improved the further into the brain you went. In other words the brain tissue around the ventricles was abnormal. In comparison, in control subjects the opposite was found. The drop in paraventricular tissue integrity, as measured with MTR, was associated with the development of clinically definite MS, or the 2nd attack, and correlated with the development of disability at 5-years. In other words the loss of tissue integrity has something to do with early MS pathology. 

These results support the hypothesis of some soluble factor(s) in the CSF that is damaging the adjacent tissue. Interestingly, previous studies have shown that CSF from pwMS is not healthy CSF, and is toxic to the cells that make myelin (oligodendrocytes). 

This study provides further evidence that even at the earliest clinical stage of MS, i.e. optic neuritis or CIS, there is diffuse sub-clinical pathology or damage in the brain. The million dollar question is what are the factors in CSF of pwMS that is doing this damage? Could it be the oligoclonal IgG bands? A cytokine, or immune messenger? An inflammatory mediator? 

Could this paraventricular MTR technique be used to identify pwMS at greater risk of future disability? It would be interesting to see if the MTR changes are reversible with effective treatment of MS. This has been seen in another context; MTR changes in the normal appearing white matter have been seen to improve after alemtuzumab treatment. 

However, you interpret these data this paper provides food for thought and supports the early-effective treatment paradigm in MS. Despite the mountain of evidence in favour of early effective treatment there are still some people with early MS that are being watched, whilst they are waiting for their disease to become clinically active. Surely its time for passive-waiting to be replaced by active-looking? 

Brown et al. An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis. Brain. 2017 Jan 2. pii: aww296. doi: 10.1093/brain/aww296.

Background: In established multiple sclerosis, tissue abnormality-as assessed using magnetization transfer ratio-increases close to the lateral ventricles. 

Aims: We aimed to determine whether or not (i) these changes are present from the earliest clinical stages of multiple sclerosis; (ii) they occur independent of white matter lesions; and (iii) they are associated with subsequent conversion to clinically definite multiple sclerosis and disability. 

Methods: Seventy-one subjects had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (49 females, mean age 33.5 years) and were followed up clinically 2 and 5 years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter, magnetization transfer ratio gradients were measured 1-5 mm and 6-10 mm from the lateral ventricles. 

Results: In control subjects, magnetization transfer ratio was highest adjacent to the ventricles and decreased with distance from them; in optic neuritis, normal-appearing white matter magnetization transfer ratio was lowest adjacent to the ventricles, increased over the first 5 mm, and then paralleled control values. The magnetization transfer ratio gradient over 1-5 mm differed significantly between the optic neuritis and control groups [+0.059 percentage units/mm (pu/mm) versus -0.033 pu/mm, P = 0.010], and was significantly steeper in those developing clinically definite multiple sclerosis within 2 years compared to those who did not (0.132 pu/mm versus 0.016 pu/mm, P = 0.020). In multivariate binary logistic regression the magnetization transfer ratio gradient was independently associated with the development of clinically definite multiple sclerosis within 2 years (magnetization transfer ratio gradient odds ratio 61.708, P = 0.023; presence of T2 lesions odds ratio 8.500, P = 0.071). At 5 years, lesional measures overtook magnetization transfer ratio gradients as significant predictors of conversion to multiple sclerosis. The magnetization transfer ratio gradient was not significantly affected by the presence of brain lesions [T2 lesions (P = 0.918), periventricular T2 lesions (P = 0.580) or gadolinium-enhancing T1 lesions (P = 0.724)]. The magnetization transfer ratio gradient also correlated with Expanded Disability Status Scale score 5 years later (Spearman r = 0.313, P = 0.027). 

Conclusion: An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis, is clinically relevant, and may arise from one or more mechanisms that are at least partly independent of lesion formation.

CoI: multiple

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