Wednesday, 7 May 2014

Vivens mortua est certiores now the living can inform the living

vivens mortua est certiores"the dead can inform the living" in Latin

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
Europe.


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 MSers, it is possible that they don't have the same view about what really is happening and hence some of the controversy.

Now the problem with understanding pathology in MS, is that it sadly occurs after the death. Therefore you only see a snap shoot in time and it is impossible to know what has come before and what may of occurred later. However, in cases where the lesions have looked like tumours then biopsies have been taken and when the biospies were looked at under the microscope, it has been proposed that there are 4 different types of white matter lesion.

Pattern I (~15% Lesions)
-Centered around venule (vein) with sharp, demarcated edges
-T-cell/macrophage associated
-extensive remyelination
-oliogodendrocytes in lesion centre

Pattern II (~58% lesions)
-Antibody/complement associated, lesions contain large quantities of immunoglobulin proteins
-Centered around venule, with sharp demarcated edges
-Deposition of immunoglobins and activated complement at site of demyelination
-Resembles an antibody mediated process
-No defects in mitochondrail respiratory chain detected

Pattern III(~26% Lesions)
-Distal oligodendrogliopathy, diffuse lesions with variable inflammation and pronounced microglial activations
-Indistinct border
-Not centered around venule
-Striking loss of myelin associated glycoprotein
-No complement activation
-Pattern associated with hypoxia
-Dying back of oligodendrocyte
-Looks like white matter stroke
-Defects in mitochondrial respitory chain

Pattern IV(~1% of Lesions)
-sharp macrophage borders
-Degeneration and oligodendrocyte death in white matter
-inactive plaque and no remyelination 


Myelin Stain Myelin Stain Myelin Stain Macrophage
(LFB) MOG MAG stain (CD68)
* = loss of MAG compared to LFB and MOG. 

Is this astericks not remyelination, which it looks like it to me?

Patterns 1 and 2 may suggest that myelin/oligodendrocyte is the target, while patterns 3 and 4 suggest the oligodendrocyte may be the target. In pattern 1, macrophages likely mediate demyelination, whereas in pattern 2, antibody and complement may contribute to demyelination and is more similar to the autoimmune models, whilst patterns 3 and 4 resemble viral, toxic, stroke models. However these latter two lesions are not common in people with SPMS, where the lesions are typically pattern 1 and pattern 2, Pattern III was detected in people with relapsing MS, but this stage responds to immunosuppression, so how do you reconcile this?. However, many pathologists do not agree with these classifications.


So it tells us that the disease process(es) in MS is/are complex.

Do these lesion types persist over time?




Objective: Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immuno patterns of demyelination were identical among multiple active

demyelinating lesions from the same individual, but differed between individuals,leading to the hypothesis of intra-individual pathological homogeneity and inter-individual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue

samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient.

Methods: Archival tissue samples derived from patients with pathologically confirmed CNS inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy, were analyzed immunohistochemically. Inclusion criteria was the presence of early active demyelinating lesions - required for immunopattern classification - obtained from
the same patient at two or more time points.

Results: Among 1321 surgical biopsies consistent with MS, 22 cases met study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This
persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy,but only pattern II among all active lesions examined at autopsy.

Interpretation: These findings continue to support the concept of patient dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized
therapeutic approaches. 

In this study they looked at biopsies and after subsequent death looked at the brain of the MSer and found similar lesions over time in a sample of 22 MSers who had Type I-III lesion types. 
It has been suggested that MS lesions begin a pattern III-like lesion with oligodendrocyte apoptosis, followed by superimposed pattern II-like demyelination and complement activation, which are common in post-mortem tissue

However in this study when the same lesion was sampled it showed the same subtype and type II lesion was the most common. 

However in some instances death was not that much (days) later and so the same type III lesion may have been resampled in a not too distinct state and also as these were active lesions sampled because they looked like tumours, it is strange that a long time later they would not be inactive as lesions often only enhance for a short time (a month).

Will pathologists agree?

What does it say about MRI is it cannot distinguish the different lesions?



Does the type III lesion need a different therapy?

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