ECTRIMS2018. Hot Topics

Is there a new MS subtype. Nerve loss without Demyelination

Myelocortical multiple sclerosis: cortical neuronal loss in the absence of cerebral white matter demyelination B. Trapp, Cleveland, US
Background: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis (MS). Brain magnetic resonance imaging (MRI) studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. The purpose of this study was to investigate whether post-mortem MS brains show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination. 
Methods: Visual examination of centimeter-thick slices from 97 postmortem MS brains identified 12 without evidence of cerebral white-matter demyelination. Demyelination was quantified histologically in cerebral white matter, cerebral cortex, and spinal cord and compared with demyelination in 12 cases of MS with cerebral white-matter lesions. Atrophy, MRI metrics, cortical neuronal densities, and pathological correlates of MRI abnormalities were compared. 
Results: Cases without cerebral macroscopic lesions had demyelination in spinal cord and cortex, but a paucity of histologic cerebral white-matter demyelination. Despite the lack of cerebral white-matter demyelination, cortical neuronal loss, cortical thinning, and cerebral white-matter MRI abnormalities were significantly increased compared to brains from healthy controls and were similar to those in MS brains with cerebral white-matter demyelination. In the 12 brains without cerebral white-matter demyelination, swollen myelinated axons were the pathological correlate of white-matter regions with MRI abnormalities.
Conclusions: A subtype of MS, which we call myelocortical multiple sclerosis (MCMS), is characterized by demyelination of spinal cord and cerebral cortex, but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and is therefore an independent pathological event in MCMS.

It has been suggested that there is an MS subtype that displays nerve loss without significant demyelination in the outside of the brain, in people with demyelination in the spinal cord.

Pathologists are like detectives and turn up to the crime scene sometimes days after the event, however they so often think that the criminal will still be there (See below).

Lesions with axonal loss in the relative absence of demyelination has been seen before….it’s call mouse EAE. There it is common to see nerve loss without much demyelination. Is this a different type of EAE or part of the spectrum of EAE.

DrK has also seen axonal loss without demyelination (see above). In this case in the spinal cord and they cut sections along the entire length of the cord and they looked above and below a lesion and found axonal loss in the lesion and this was found below the lesion, where there was axonal loss without demyelination (bottom pictures). However in this case DrK would say that the demyelinating lesion is the root cause of the axonal loss without  demyelination lesions.

There may well be different types of lesions and this will be important if it impacts on treatment as there is no point trying to remyelinate a non-demyelinated lesion. However do these lesions have a different route cause, that will determine whether you need a certain type of treatment.

3 - Pathology of radiologically isolated syndrome
C. Lucchinetti, Rochester, US

Ocassionally people destined to be diagnosed with MS have a scan and these see lesions likely to represent early MS. In this case people had a diagnosistic biopsy. The result is they have active demyelinating lesions  typical of MS. In some there is evidence of mild axonal loss and even remyelination. Therefore MS is inflammatory and degenerative from beginning to the end.

This is in part a repost 

Pathology is the study of disease and pathologists often only get to see the MS brain after death. Have you considered donation of your brain to the MS or other Brain Bank?

A pathologist is someone who studies disease and it is their job to find the cause of disease and death, so they hunt for cancers, infections etc. They normally take tissue and stain it with dyes to see different things. They may look for MS lesions.

If you want to look at them click here for a previous post

A pathologist sees the snapshots in the tissues and views it as points on a map that take you from one place to another as they use MSers brains to build pictures of what goes on.

However maybe the pathologists spend too much time looking down microscopes because unbelievably they missed grey matter lesions when you can see them by eye (probably a technician and not the pathologist did the brain dissection). They also forgot that MS is associated with nerve loss until the late 1990's. People complain about animal models but until pathologists agree what should be modelled it is hard to blame the animal modellers. 

However pathologists do not all agree with each other

We can get this right or wrong, but I will give you a a simple analogy, I know some of you don't like these .......others do! So constructive comments only please.

However, if we imagine the spinal cord that can be viewed as a safe. If we open the safe-door we can see that in health it is full of cash (eg. myelinated), but following diease i.e the safe door is opened we can see that the safe is empty (demyelinated). We can see something is wrong and that something has happened, but we have to try and guess what happened using these snap shots. This is what pathologists do.

Maybe the reason the money has gone is because it has been taken by a bank robber, who'll go to jail if caught. However, an alternative explanation is that there was a greedy banker who has taken the cash to invest and has made loads of profits from selling loans to people that can't afford to repay the loan. Therefore, the bank has gone out of business and someone has been to empty the safe to take the cash to the administrators. 

We know the safe is empty so why is important to know who emptied it? It is important because of the solution (treatment) that we need to stop the safe being emptied again in the future. If the cash has gone because of a robber we can deter this from happening by employing more police, using a flash new alarm system or identify and deal with the social reason that led to the person acquiring a thieving behaviour in the first place. However if it is a gambling banker that caused the money to go, the solution may be the (re)introduction of regulation, etc. Therefore if you get it wrong, your treatments don't work.

One way to try and determine what is happening is to use other techniques to monitor the brain. As such magnetic resonance imaging has become very useful tool, because it can be done repeatedly in the living individual and it is very useful in the diagnosis of MS. The problem is that the things that MRI detects (movement of water molecules in magnet planes) are often not the same as any pathological outcome that we can see down a microscope. This is because they work in different ways and detect different things. Importanly the other problem is that the MRI does not have very high resolution like microscopes. So its abit like CCTV-you can see it's a human but the resolution is so low you can't really tell that it's your next door neighbour. Many of my friends say that they often seen me on Tele..........Crime watch. It's abit like you know that the problem is occuring in Brussels but the imaging shows you that the problem is occurring in all of western
So is the image above detecting a robber or a banker?

Well if we had a device and the technology to monitor the living human brain at high resolution, as we do have for imaging technologies for some aspects of disease in mice, we could see that whilst a banker is there, it is really dangermouse who has taken all the money and we didn' t even notice him (bottom of right leg) on the MRI above. He urinated on the lock of the safe and it rusted, so the banker left the safe unlocked and dangermouse then took the cash....Simples

Now hopefully you can see that whilst people may be looking at tissue from pwMS, it is possible that they don't have the same view about what really is happening and hence some of the controversy.