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*See post 5 for summary/explanation of these articles*

First the response to the Prineas findings...

Evidence for Pathogenic Heterogeneity in Multiple
Sclerosis
Claudia F. Lucchinetti, MD,1 Wolfgang Bruck, MD,2
and Hans Lassmann, MD3
Barnett and Prineas recently described extensive oligodendrocyte
apoptosis in the absence of inflammation in a pediatric
multiple sclerosis (MS) case, who died 9 months after disease
onset and 17 hours after presenting with acute pulmonary
edema.1 To what extent perimotem hypoxia may in part
have contributed to the pathological observations in this case
is uncertain. The authors confirm our published reports on
aspects of pattern III MS pathology in a subset of MS patients,
2 however, indicate that the coexistence of remyelinating
lesions and complement activation in other lesions from
this and six other patients suggest that all MS lesions begin
with this type of pathology.
In our experience of 201 immunopathologically classified
MS cases to date,2,3 pattern III MS demonstrates inflammatory
lesions with a preferential loss of myelin associated glycoprotein
(MAG), apoptotic oligodendrocytes, limited remyelination,
and ill-defined inflammatory lesion borders. When
analyzing multiple active lesions in pattern III autopsy cases,
we have not found evidence of complement activation by
using the monoclonal antibody against C9neo antigen. Although
apoptosis is occasionally found in pattern II cases,
this is not associated with MAG loss. In addition, the authors
have not stained their cases for MAG. Furthermore, a
subset of pattern III cases in our series also had Balo-type
concentric lesions, with ongoing remyelination, which is
consistent with the presence of remyelination as described by
Barnett and Prineas.
Detailed clinical follow-up of our early MS cohort (n
99 patients) fails to show any correlation between time of
symptom onset, date of biopsy, and pathological pattern,
thus arguing against all MS lesions beginning with pattern
III pathology.4 In addition, we have observed a striking correlation
between therapeutic response to plasma exchange in
MS patients with evidence for antibody and complement activation
(pattern II pathology, n 10) on biopsy, versus no
response in pattern I (n 3) or pattern III (n 6) cases.5
The sharp border at the active plaque edge with accumulating
macrophages in pattern I and II MS lesions is highly
associated with the presence of ring enhancement on Gd-
MRI, and hypointense T2 rims, whereas these imaging features
are not found in pattern III lesions ( p 0.001; 54
cases examined). Furthermore, on follow-up MRI, we have
not observed ring enhancing lesions in any pattern III case
(n 11).6
Our pathological and clinical observations on a large series
of MS cases continue to support pathogenic heterogeneity in
immune effector mechanisms involved in MS lesion formation,
which persist over a period of time, rather than a single
mechanism dominating the formation of all lesions as suggested
by the authors.
1Department of Neurology, Mayo Clinic, Rochester, MN;
2Department of Neuropathology, University of Gottingen,
Gottingen, Germany; and 3Brain Research Institute, University
of Vienna, Austria
References
1. Barnett MH, Prineas JW. Relapsing and remitting multiple
sclerosis: pathology of the newly forming lesion. Ann Neurol
2004;55:458–468.
2. Lucchinetti CF, Bruck W, Parisi J, et al. Heterogeneity of multiple
sclerosis lesions: implications for the pathogenesis of demyelination.
Ann Neurol 2000;47:707–717.
3. Lucchinetti CF. Merging of minds and matter. Multiple Sclerosis
2003;9(suppl 1):8.
4. Pittock SJ, McClelland FL, Achenbach SJ, et al. The clinical
course of biopsy-proven demyelinating disease and comparison
with a population-based multiple sclerosis prevalence cohort.
Platform presentation at the Eighth Annual ACTRIMS Meeting;
2003; San Francisco, CA.
5. Keegan M, Konig F, Bitsch A, et al. Multiple sclerosis pathological
subtype predicts response to therapeutic plasma exchange.
Neurology 2004;62(suppl 5):S29.A259.
6. Lucchinetti CF, Altintas A, Wegner C, et al. Magnetic resonance
imaging correlates of multiple sclerosis pathologic subtypes. Ann
Neurol 2003;54(suppl 7):S37:67.
DOI: 10.1002/ana.20182

Annals of Neurology
Volume 56, Issue 2, Pages 309

Letter
Reply: Pathological heterogeneity in multiple sclerosis: A reflection of lesion stage?
Michael H. Barnett, MBBS, John W. Prineas, MBBS
Institute of Clinical Neurosciences, Department of Medicine, University of Sydney, Australia

Letter

Pathological Heterogeneity in Multiple Sclerosis: A Reflection of Lesion Stage?

Lucchinetti and colleagues are correct in their assertion that our findings[1] fail to support the concept of a fundamental dichotomy in multiple sclerosis (MS) pathogenesis. The hypothesis is based on a study that found that most patients with MS examined at autopsy fall into two quite distinct groups: one in which remyelinated lesions are absent and tissue breakdown is accompanied by widespread oligodendrocyte apoptosis (type 3 lesions) and a second group in which remyelinated shadow plaques are common and tissue destruction is associated with the activity of macrophages located at the edges of plaques devoid of myelin (type 1 and 2 lesions).[2] Although we describe features not previously known to accompany oligodendrocyte apoptosis in new lesions (ie, complement activation; microglial activation; and the absence of T cells, MRP-14-positive mononuclear cells and macrophages),[1] we agree with Lucchinetti and colleagues that most active lesions appear at autopsy either as sharp-edged lesions or as areas of palely staining myelin sheaths and apoptotic oligodendrocytes. In contrast, however, we observed, in a study of comparable size, both types of lesions in individual patients, as well as evidence of remyelination in all but one of our seven cases with type 3 lesions.[1]

Although our findings strongly suggest that apoptotic lesions are prephagocytic and probably represent an early stage in the formation of most lesions in patients with relapsing and remitting MS, this is not to say that apoptotic lesions evolve directly into active sharp-edged plaques, the early history of which is unknown. New oligodendrocytes and remyelinated nerves are often observed within such plaques, suggesting that they may, in fact, be pre-existing lesions exhibiting fresh activity.[2-4] In support of this notion, apoptotic lesions were found mainly in patients with disease duration of less than 3 months in both our own study and that of Lucchinetti and colleagues,[2] whereas sharp-edged active lesions occurred at all intervals up to 32 years.

Lucchinetti and colleagues are incorrect in asserting that the only evidence of complement activation we provide is based on a figure showing the presence of the serum protein C3d within macrophages. In fact, we describe and illustrate deposition of C3d (Figs 14 and 15) and C9neo (Figs 13 and 12D) on altered myelin and oligodendrocytes.[1] The monoclonal C9neo antibody (clone B7) used was the same as that used in the study by Lucchinetti and colleagues.[2]

Although the correlation between lesion type, magnetic resonance imaging findings, and therapeutic response to plasma exchange reported by Lucchinetti and colleagues is interesting, we feel that it is premature to conclude that the apparent pathological heterogeneity of MS lesions reflects the existence of distinct pathogenic subtypes of the disease.

References
1 Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004; 55: 458-468. Links
2 Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707-717. Links
3 Prineas JW, Barnard RO, Revesz T, et al. Multiple sclerosis. Pathology of recurrent lesions. Brain 1993; 116: 681-693. Links
4 Raine CS, Scheinberg L, Waltz JM. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest 1981; 45: 534-546. Links


Michael H. Barnett, MBBS, John W. Prineas, MBBS
Institute of Clinical Neurosciences, Department of Medicine, University of Sydney, Australia

Forgot to say if you want to understand the lesion pattern issue a bit more and, therefore ,why this is an important debate then following link to an article about the Lucchinetti findings on MS lesion patterns may help.

http://www.stemcelltherapies.org/ms.htm

F

outstanding post! Thank you for finding and sharing, Felly.

Uh...could someone translate the information and results down to the reading level of a person with only a bachelor's degree?

Ok here goes, English is not my first language,although I am fluent, it is sometimes hard to translate.

These letters in the annals refer to the Australian findings by Prineas and Barnett that put the theory that MS is not an autoimmune condition but that oligodendrocyte cell death occurs prior to the immune reaction.

The article can be found here and also on this site in the MS is not an autoimmune disease thread.

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15048884

Prineas and Barnett found oligodendrocytes (which are glial cells responsible for producing myelin) were undergoing apostopsis with no evidence of inflammation. In essence the myelin producing cells were dying before the immune system got involved so using immune modifiers may now be seen BY SOME as a waste of time.

Further they found no Phagocytes. These are white blood cells that are part of the immune defense system and digest microbes and other foreign matter. This is contrary to what the animal models of MS would suggest would be the picture in a biopsy.

Apoptosis occurs in two ways, either by following a process where the cells swell, the cell contents leak and then comes inflammation of surrounding tissue. Or they commit suicide. It is a complicated process, suffice to say the end point is that phagocytic cells like macrophages will engulf the cell fragments and at some point secrete cytokines which will then inhibit inflammation. In both cases inflammation is involved. But after the fact.

So in the cells were dying before inflammation and that there was no sign of this anyway Prineas and Barnett is questioning much of the basis of MS research over the past 40 odd years.

Lucchinetti et al are arguing that first, it is not known to what extent peri mortem hypoxia may have been responsible for this. Basically around the time of death the brain is starved of oxygen which according to some theories will reduce inflammation. Low oxygen levels have been found to block the development of inflammation in mice. So perhaps this was why Barnett and Prineas found no inflammation?

Ultimately they are disputing the Bartlett theory or at least saying it is only 1/4 of the story and this story is still one of an autoimmune disease. They argue that various lesion patterns in MS show there is no one single cause of MS - the only commanality is an auto immune one.

One lesion pattern (out of 4) reflects the Bartlett study - Pattern 111. In the case of pattern 111 the lesions were not around veins and oligodendrocyte death from apoptosis was prominent. Just like with the Bartlett study. This is extremely interesting and needs more research. Lucchinetti are not disputing this pattern type but do not see if as the answer to why *everyone* that has MS.

Barnett and Prineas to a certain degree then agree with the pattern theory as put forward by Lucchinetti but do not agree that this leads to a conclusion that there are sub types within MS.

I am rather swayed by the Lucchinetti argument. The Lucchinetti study - 'the MS lesion project' (at the Mayo) was and is (still ongoing) pretty rigourous and leads to the conclusion that MS is a syndrome of various diseases with various types of 'immune related causes'

This is not completely an autoimmune disease vs non autoimmune disease argument (though Barnett and Prineas see it more this way).

Whichever way you look at it, the immune system does play a role, at least in RRMS, and it is for the most part destructive. Getting the balance right between too much and too little inflammation, too much of the wrong type and too little of the right type is something that needs more research and ties with the Lucchinetti argument that if you can establish the lesion type then you will have better luck targetting therapy.

And yes this is where the much scorned MRI comes in to the equation. Is there a way to discover the lesion pattern by MRI, so you do not have to wait until someone is dead? This is why much research is going in to MRI technology, if lesion patterns can be shown and the Lucchinetti theory is correct then a much better way of targeting MS is found, she believes the different variations in MS are down to biological variations in individuals and that trying to find a single cause for MS is the wrong way to go.

See the stem cell link above for more explanation. And link below for an update on the Myelin Project led by Lucchinetti
http://www.nationalmssociety.org/Target ... ogress.asp

Felly

Well done! Thanks for taking the time to summarize this article.

Sorry, time to leave the board.

-finn

Finn,

It's too bad that this kind of varied research with MS hasn't been going on for a longer period of time. Personally, I feel that the world of MS research has been "fixated" with the immune system only theory. All the energy and resulting drug therapies from this line of research hasn't provided the MS patient with very much relief from the disease. As you have said in the past, what good is it to have nicer MRI pictures of the brain while your disease and disability level progresses?

At lease now the scientists are looking at other possible areas and who knows, perhaps someone just may accidentally stumble upon something that will give us the long awaited answer.

Harry

Sorry, time to leave the board.

-finn

Finn,

Yes, the MRI is an extremely important tool in tracking what is going on in the person's brain and/or spine. I feel, however, that researchers have placed too much reliance on MRI results as the sole indication of drug trials. Prineas and Barnett have uncovered that there is obviously something else initially going on with MS and hopefully a lot of attention can now be given to this unknown cause of myelin destruction.

The same emphasis on the autoimmune system, while very important, I also feel has detracted from other possible research avenues. We both know that the CRAB drug makers and world of MS researchers have ensured, up to recently, that other theories have received little attention.

I can give one example here. For years, the cause of fatigue in MS patients has been attributed to improper nerve conduction due to damaged myelin. When Elaine Delack, the Prokarin inventor, put forth the theory that the main cause of fatigue had to do with a serious lack of physiological processes in one's system, she was dismissed as a quack and fraud artist. Then, just over a year ago, a neurologist here in London, Canada was presenting at an MS Fatigue Seminar. She made the comment that researchers had now thought that a lack of proper chemical functions in the brain was the culprit. Unfortunately she didn't elaborate due to time constraints and I didn't get a chance afterwards to speak with her. So because Elaine wasn't an accredited researcher, nobody paid attention but the minute a "proper" scientist spoke up, this was now a possibility.

At least we are now seeing a variety of other possibilities being explored in MS research. Hopefully these newly discovered paths won't take nearly the length of time in coming up with some new answers as past research efforts have taken.

Harry

Sorry, time to leave the board.

-finn

Finn,

Along the lines of what we have been discussing re: MRI's, I received this information today from a MS Info newsletter. Think you may find it interesting.

Harry

___________________________________________

MRI CHANGES MAY NOT INDICATE DISEASE PROGRESSION
Neurologists often monitor MS patients using periodic MRIs to evaluate disease activity and progression in terms of new lesions, brain atrophy, and lesion volume. Although MRIs can be helpful in determining status and course of action, there are sources of variability and error, as with any measurement technique. Therefore, some of the change between any two sequential MRIs may not be due to disease progression, but to variability in the MRI process.

In an attempt to estimate this built-in variability, a group of radiologists recruited 20 subjects with MS and scanned each twice within 30 minutes. To simulate normal circumstances, each subject got up after the first scan, left the room, and re-entered it, and a different technician did the positioning for the second scan. For each scan, an automated image analysis technique was used to measure brain atrophy (brain parenchymal fraction or BPF) and T2 lesion volume.

Researchers determined a BPF variation of 0.0056 and a T2 lesion volume variation of 0.65 mL could safely be attributed to variation in the scanning and measurement process. T2 variation of 0.65 mL, the authors note, is about half of the average yearly change for people with relapsing-remitting MS and is nearly equal to the average yearly change in people with secondary-progressive MS.

These figures are likely a conservative estimate of MRI variability because other factors (such as using different scanners, upgraded software, or non-automated or semi-automated analysis methods) may increase the level of variability.

MRI can be a powerful tool in the diagnosis and follow-up of the person with MS. However, it must be put into the context of clinical history and examination. Some MRI findings have little correlation with disability in MS, and the potential for technical variations does exist.

Several years ago my wife was having back troubles and I suggested she go see my Chiropractor....so we went. That particular day, we 3 had a fairly lengthy discussion about "advanced medical diagnostics" particularly MRI's and other imaging options. My wife had had an MRI of her lower back which showed what would look like some relatively serious problems. Chiro. seems to be a smart man but tends to keep it simple...if you know what I mean.

His comment " sometimes technology tells you more than you want to know" has proven to be oh so true.

Does anyone really know EXACTLY what an MRI is showing you within the brain? I would argue "NO", not exactly what changes have occurred. With reference to my wifes' back, an MRI is a very detailed picture of placements of structures and relationships to other structures. Also, in her case, stressing of discs and vertebrae.

Bottom line, she had a few adjustments occasionally has some MINOR back pain but certainly isn't in as bad of shape as the MRI might suggest. Yes, it told her more than she needed....or wanted to know.

If MRI's where done of say........1000 seemingly healthy people's brains, how many would have indications of neuro. disease? I'd bet more than one would expect. How many of these people would actually go on to develop clinical disease?

I just realized..............boy am I rambling!!


Treez

P.S. perhaps this piece was better suited in a different topic?
Sorry

Treez,

Researchers have done comparison MRIs of health university students and have found "lesions" on their brains. These students did not have any health issues.

What they have stressed repeatedly is the requirement of an expert to read the MRI properly in relationship to the disease being investigated.
I have read posts on the net from various MS patients whose doctors have sometimes tried to read these scans and they have had some terrible misreads as a result.

Diagnostic imaging of any kind always has a possible error factor and this must be taken into account...especially with MS. That is why the MRI, which is an very important tool in treating MS, must be used in conjunction with other various tests for the proper diagnosis.

Harry

Yep, I couldn't agree more, MRI is just one piece to the puzzle. My wife and I have both said " maybe I shouldn't have had an MRI or Lumbar" although we don't really mean it, it told me more than I wanted to know!

I too have heard "healthy" individuals many times do have "spots". I was hoping that was my case but........Lumbar results misread too? I could only hope huh?

I guess my next question would be..what other conditions can mimic those results?

Treez