Solve webinar today, Thurs May 19: Dr Jarred Younger, "CFS & ME: Can we find answers in the brain?"

[mango]

@Scarecrow great work, well done! looks fantastic! thank you so soo much!

i haven't been able to transcribe anything today. will try tomorrow

 

[Sushi]

I've just transcribed the section that @BurnA had asked you about where Younger was describing the hypothesis that there are peripheral immune cells in the brain, akin to MS but non autoimmune.

Great job Scarecrow--thanks! Younger does such a good job of translating complex material into language that most any of us can understand. He is an impressive ally.

 

[BurnA]

Great job Scarecrow--thanks! Younger does such a good job of translating complex material into language that most any of us can understand. He is an impressive ally.

He sure is. I like the fact he said it's time to go after risky hypotheses and not be afraid if they are wrong ( or words to that effect )

 

[JaimeS]

So I think this is why you probably saw recently that rituximab which is a B cell depleter, why it may work in ME/CFS because if you can give rituximab and deplete the B cells in your body, there won't be as many B cells to cross into the brain to cause problems. That's just my guess as to how it works but it all fits together with the hypothesis.

Dicey. If B cells weren't such a big issue, the people who've taken Rituximab might note mild improvement, but they wouldn't be cured. Last I heard, some of them were, like, literally mountain-climbing now, right?

What we expect to see is that in the healthy brain no signal will be detected at all. There'll be no evidence of infiltration of the brain but we think in the ME/CFS individuals, we'll pick up that signal in the brain.

Fantasized briefly that it turned out to be the other way around.

Of course, we can come up with a hypothesis for any outcome, right? Maybe that would imply an unchecked brain infection in PWME, whereas healthy controls can do 'housekeeping' duties with immune cells, even in the brain... that would be cool!

My very general impression of the BBB stuff is that it's not nearly the impenetrable wall we were taught in the recent past.

-J

 

[Jonathan Edwards]

@Jonathan Edwards, I've just transcribed the section that @BurnA had asked you about where Younger was describing the hypothesis that there are peripheral immune cells in the brain, akin to MS but non autoimmune.

Because of the time to response and because he's not just talking about B cells, I'm not convinced about his explanation that this could be why rituximab works in some pwME. If anything, it could explain some of the non responders. But ignoring that, could it be possible that a subset of people with ME have a blood brain barrier that is not intact and letting leukocytes into the brain?

I agree. The time to response does not seem to fit. MS is unusual in that the effect of rituximab is immediate in the sense that new episodes stop occurring straight away, as expected from taking away B cells in blood that might get into brain at a new site. If the person with MS is already in a relapse that relapse will not improve any quicker, as rituximab does not get into the brain well.

The delay in benefit in ME, if the benefit is real, could be due to the time it takes for the changes already present in brain to heal - maybe for microglia to wander away. So it would be consistent with stopping B cell getting into brain. But it seems a coincidence that it should take roughly the same time as we see it takes for autoantibodies to decline.

I think the mechanism he proposes is probably sufficiently plausible on those time scale grounds to be worth testing - and he is not going to be testing whether it is B cells getting in specifically. The limitation I think will be that you may not get enough cells going in to brain in the short period between injection and scan. In MS the cells probably only go into brain intermittently - once every few months or even years.

 

[nandixon]

The delay in benefit in ME, if the benefit is real, could be due to the time it takes for the changes already present in brain to heal - maybe for microglia to wander away.

Since rituximab cannot effectively penetrate an intact blood-brain-barrier, perhaps another possibility (under Younger's theory) is that the multi-month delay in response in ME/CFS is corresponding to the gradual death of B-cells that have already infiltrated the brain.

(In a mouse study, I believe it was shown that B-cells that had infiltrated the brain in response to a CNS infection had a lifespan of at least 6 months. http://jvi.asm.org/content/87/5/2420.full)

Also, cyclophosphamide penetrates the BBB, so the apparently faster response time of that drug compared to rituximab in ME/CFS seems consistent with Younger's idea as well.

 

[Jonathan Edwards]

Since rituximab cannot effectively penetrate an intact blood-brain-barrier, perhaps another possibility (under Younger's theory) is that the multi-month delay in response in ME/CFS is corresponding to the gradual death of the B-cells that have already infiltrated the brain.

(In a mouse study, I believe it was shown that B-cells that had infiltrated the brain in response to a CNS infection had a lifespan of at least 6 months. http://jvi.asm.org/content/87/5/2420.full)

Also, cyclophosphamide penetrates the BBB, so the apparently faster response time of that drug compared to rituximab in ME/CFS seems consistent with Younger's idea as well.

That would be the scenario that probably applies in MS. What makes this seem unlikely in ME is that B cells almost always survive within clusters and clusters are big enough to produce focal clinical signs and lesions on MR (as in MS). Neither of these occur in ME so the mystery would be where the B cells in the brain were.

 

[JaimeS]

and clusters are big enough to produce focal clinical signs and lesions on MR (as in MS). Neither of these occur in ME

@Jonathan Edwards , it seems that you are saying that lesions on MR are not indicative of ME, only MS. Am I misinterpreting you?

-J

 

[Jonathan Edwards]

@Jonathan Edwards , it seems that you are saying that lesions on MR are not indicative of ME, only MS. Am I misinterpreting you?

-J

I am not aware of any lesions on MR thought to signify ME. Some changes in blood flow and white matter volumes show statistical differences in some studies, without any clear evidence of cause and effect, but I don't think anyone has found focal inflammatory lesions.

 

[JaimeS]

I am not aware of any lesions on MR thought to signify ME. Some changes in blood flow and white matter volumes show statistical differences in some studies, without any clear evidence of cause and effect, but I don't think anyone has found focal inflammatory lesions.

"White matter lesions" are in the CCC -- I only know because I have them!

[Edit: should add that I visited an MS specialist who did not believe I had MS.]

-J

 

[Jonathan Edwards]

"White matter lesions" are in the CCC -- I only know because I have them!

[Edit: should add that I visited an MS specialist who did not believe I had MS.]

-J

Yes, I do not know quite what to make of that. The trouble with some of these criteria is that they throw in anything that they think might be supportive evidence, without being specific enough to know whether they are really relevant. 'White matter lesions' on its own is too vague to indicate much. A proportion of healthy people have blobs in white matter. And as far as I know there are no cases of ME where white matter lesions relate to any specific focal signs - i.e. that you can relate the MRI appearance to clinical disease.

 

[Sidereal]

Big difference in clinical presentation between white matter lesions in MS and white matter hyperintensities which you often see in ME and all sorts of other conditions including old age.

 

[JaimeS]

Big difference in clinical presentation between white matter lesions in MS and white matter hyperintensities which you often see in ME and all sorts of other conditions including old age.

You're right; in the CCC it says 'white matter hyperintensities'. My doc said 'white matter lesions' though.

-J

 

[Forbin]

"White matter lesions" are in the CCC -- I only know because I have them!

I believe this is where the CCC reference is coming from (at least in part):

Ann Intern Med. 1992 Jan 15;116(2):103-13.
A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection.
Buchwald D1, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al.

MAIN RESULTS: ... Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients (95% CI, 72% to 86%) and in 21% of controls (CI, 11% to 36%) (P less than 10(-9))...

http://www.ncbi.nlm.nih.gov/pubmed/1309285

Such findings are extensively discussed in Osler's Web where they are described as "multiple punctate lesions" or "unidentified bright objects" on MRI scans. When Dr. Cheney showed a stack of CFS patient MRI's with such findings to a pair of neurologists at the University of California at San Diego, they showed him a stack of their own MRI images from AIDS patients - which looked identical.

 

[JaimeS]

Fascinating, @Forbin !

-J

 

[viggster]

"Punctate lesions" - exact words spoken by my first neurologist on my first brain MRI. They seemed to have disappeared but they were there 3 months after acute onset. He pointed out a few of these in my Brocca's area (speech part of the brain)...I was having moderate aphasia and those lesions explained that.

 

[Kati]

"Punctate lesions" - exact words spoken by my first neurologist on my first brain MRI. They seemed to have disappeared but they were there 3 months after acute onset. He pointed out a few of these in my Brocca's area (speech part of the brain)...I was having moderate aphasia and those lesions explained that.

Here in Canada, there is no way we could possibly have a MRI if you have a ME/cfs diagnosis. We are undeserving of any kind of testing, except perhaps a CBC and a TSH. It's quite lame.

 

[JaimeS]

"Punctate lesions" - exact words spoken by my first neurologist on my first brain MRI. They seemed to have disappeared but they were there 3 months after acute onset. He pointed out a few of these in my Brocca's area (speech part of the brain)...I was having moderate aphasia and those lesions explained that.

Ditto -- terrible speech problems. Word-retrieval mostly, but the day I stopped recognizing letters briefly was the day I quit my FT job.

Coincidentally, that was when my guilty-pleasure show, Teen Wolf (yes you can laugh) had an amazing and incredibly creepy possession story as its main plot, and one of the main characters began losing time and had aphasia. He was normally the comic relief, so seeing him suffering and then as the villain could have been a bad move, but instead the actor was by turns pathetic and phenomenally villainous.

There was a scene where the words on the page he's reading slide back into ink and fall off the page to the floor, while he's standing in front of a classroom full of people. Of course, that wasn't literally the way it happened for me, but the visual -- and the metaphor -- has stuck with me.

My punctate lesions were only measured during acute stage, though three times in quick succession -- no one liked the looks of them. Haven't had a scan since I became more 'minor' and less 'moderate'. It would be nice to think that they've gone away.

-J

 

[JaimeS]

Here in Canada, there is no way we could possibly have a MRI if you have a ME/cfs diagnosis. We are undeserving of any kind of testing, except perhaps a CBC and a TSH. It's quite lame.

Sucks, Kati. Participate in the Canadian virtual protest on the 25th, if you can!

-J

 

[Kati]

Sucks, Kati. Participate in the Canadian virtual protest on the 25th, if you can!

-J

Will do