MS pathology detailed Flashcards
Macroscopy pathology analysis
Macroscopy: making an eye examination. If you have enough samples, you can sort them in a timely manner (what occurs when), and how it develops.
Typical and diagnostic gray lesions can be seen, they are sunken due to tissue loss / hard when touched.
Why we call the disease Multiple Sclerosis = sclerosis means hard.
Lesions can be found everywhere but usually they are periventricular. If you have U-fibers around the lesions, lesions become U shaped, or they follow the pattern of vessels if there’s vessels around, and become elongated.
Less obvious leisures are soft and difficult to see- sometimes there’s no lesions at all in brain. might be wrong diagnosis, or most lesions can be in spinal cord.
Hard to take samples from spinal cord, but might miss lesions.
Microscopy shows most abnormalities.
Types of lesions
1)Large gray lesions:
Shows complete myelin loss
Loss of oligodendrocytes: oligodendrocytes form myelin
Few/no inflammatory cells
Gliotic / scarlike lesions
Surrounded by white matter
Hypocellular lesions: only few cells left. No macrophage, no lymphocyte.
Easy to see in MRI, clearly scarlike - big.
Some lesions show empty center, but show hypercellular outer rim w/ foamy macrophages. Inside macrophages eaten myelin seen.
Astrocytes found
Oligodendrocytes numbers can differ. No mitosis of cells are observed though, so cells come from somewhere else.
Vessels next to the lesions have lymphocytes sometimes.
2) Granular lesions Less frequently found Smaller than gray lesions Often solid and look like hypercellular rim of large gray lesions Have foamy macrophages everywhere digesting myelin Myelin loss Astrocytes observed Oligodendrocyte levels differ Difficult to see in MRI.
3) Other lesions, macroscopically invisible
- Visible in LFB staining: Shadow plaques, look like lesions with decreased staining. They are lesions that remyelinated.
- Visible in IHC
Preactive lesions: Before lesion formation! - but there’s something wrong in tissue, no demyelination yet
Frequently found
Found anytime during disease
Not all preactive lesions advance to active lesions, otherwise you’d have no brain left in months. So in some places it somehow regresses.
-clusters of microglial cells are really packed, and their expression of HLA-DR is clearly more than the surrounding cells.
-Have foamy macrophages rarely = transforming /few lymphocytes
3) Spinal cord lesions
Patients with MS, around 10-15 years later, majority of them are in wheelchair, mostly because of
spinal cord. = very important for quality of life.
Also demyelination and inflammation is seen
All lesions that are found in spinal cord are old and inactive.
Differences with brain lesions:
Active/chronic active lesions are unusual - they tend to be less compact if found
Gray matter is always involved since spinal cord is really small, so if there’s a lesion, it’s almost always running to the gray matter.
So it shows that there’s regional differences = there’s less pre-active/active lesions here. Also it shows that there’s less regenerative capability in spinal cord.
4) Gray matter lesions are even reported in 1900s but completely forgotten - MS was described as white matter disease and it’s wrong.
Unlike white matter lesions, there’s no inflammation on gray matter! The lesions are described depending on their activity: 4 classes.
Type I: combined white and gray
Type II: intracortical
Type III: Subpial demyelination
demyelination occurring under the surface of the brain
Type IV: transcortical
There’s demyelination but no inflammation! - no macrophage-lymphocyte.
If there’s a type I lesion, loads of inflammation is in white matter, no inflammation in gray!
They are almost impossible to find with MRI - if really experienced you can find only %30 of them
Timetable of lesions. - Stages
First a lesion starts in a dot, and that area cleared out, then it becomes hypo-cellular, where the areas that it is slowly expanding (outer edges – rims) are still hyper-cellular, and later they die too.
All stages are morphologically differentiated.
So there’s 4 stages:
Preactive lesion
Active lesion: still macrophages are found, solid lesion
2nd stage: Chronic active, center died, outside still has cells
3rd stage: no cell left - Chronic inactive - scarlike
How to take samples: Blocker Solution
MRI guided sampling:
Small plate, raised edges for 1 cm. Put the brain there and slice it to have 1 cm thick slice. Bring it for MRI Scan. Then you prepare another plate with half a cm edges, and cut the same slice in half, and you can open it like a book, two slides are mirror image, and lesions can be seen. Compare it to MRI results, and pick the lesions that you are interested in = do whatever you want. You have reference of 1 lesion on the other slice.
MRI guided sampling is very efficient - finds lesions that aren’t visible
Finds much more early lesions like preactive ones.
What causes MS? MS is viral/autoimmune - arguments against autoimmune with pathology - EAE
MS is a viral disease: It’s not really believed much. There’s EBV though. = %95 in Western world is EBV infected, so it’s difficult to find a direct relation. But there’s not a single patient that’s EBV negative! = So it definitely has something to do with it in triggering.
MS is an autoimmune disease: Epidemiology shows it: 3:1 Female to male ratio.
There’s HLA DR restriction
Pathology of T lymphocytes and APCs observed
EAE: You inject myelin to mice and they develop a disease that’s very similar to MS.
Arguments against:
EAE looks like MS: isn’t a good argument since it’s actually a model of another disease: ADEM. (Acute demyelinating encephomyelitis, triggered with a virus, and it has only one phase) Can be a model of some of the processes observed in MS only.
Autoreactive T cells against myelin + Abs against them can be found in %5-10 of perfectly healthy people. And they don’t necessarily get MS later, they don’t get it at all – so it doesn’t mean that much.
T cells are only found outside the parenchyma. Inside = only oligodendrocytes
Gray matter lesions argument: Difficult to prove but they are there, and they have huge correlation with atrophy + cognitive dysfunctions
! Gray matter lesions show demyelination, but they don’t show any BBB leakage, Inflammatory cells (T-cells or macrophages) or complement
How there’s no macrophage and demyelination?
It might be we don’t see any of them because they are old? It’s also possible that you don’t need many of them. Because after all there’s not that much myelin there. It might be so subtle, and since there’s so many myelin in white matter its crazy.
All the signs that show autoimmunity doesn’t exist in Gray matter lesions, even though there’s demyelination. If white matter and gray matter lesions are related: Then demyelination is the first step, but not the autoimmunity?
Looks like demyelination isn’t caused by inflammation! Not because of recognizing foreign antigens and cumulating there. Demyelination is primary.
Maybe you see inflammation since there’s too much myelin in white matter? Some people believe that immune cells are only innocent bystanders, they can promote disease progression = but they don’t cause it themselves. So it’s a 2nd response to whatever is happening inside the brain itself. Inflammatory cells are just there to clean up a mess. It’s important to clean them if you want to trigger remyelination, because debris won’t allow it.
Maybe there’s an intrinsic defect that causes demyelination?
The immunity in brain is downregulated as much as possible, since you really don’t want to hurt the brain. Maybe MS occurs since immune system doesn’t work that much, or it’s completely a neurodegenerative disease?
Theory: MS attacks comes and goes, but underneath there might be a continuously progressive line of neurodegeneration! Also at the end, there’s no doubt that there’s a neurodegeneration = Secondary progressive MS
