MediTest
27 Apr 2018
Author
paron
Title

Multiple Sclerosis Damage Found In 'Normal' Brain Tissue

Body

I hope this isn't off-topic, and I don't believe I've seen it here before. It's not about C.Pn., specifically, but so many here have MS, that I thought it might be of interest. Multiple Sclerosis Damage Found In 'Normal' Brain Tissue Ron

Comments

Ron, as far as I know this hasn't been posted here before.  Many similar things are posted from time to time on ThisisMS, usually indicating the worthlessness of MRI scans, either because the degree of disability doesn't correlate to the number of lesions or the fact that some lesions can be found in normal brains.  In my scan there is a very old area of damage which must have been there before I started showing visible symptoms.  From scan to scan it doesn't change one iota.  As far as disease processes outside visible lesions, I'm sure they occur because many people report only one or two lesions yet great levels of disability.  This was probably happening with me as well, although there didn't look like there was much room left when I saw my first scan.  I'm glad I didn't see it until it was compared to my second one and could see the improvements.  Then, six months later again, some peripheral lesions had actually disappeared, but a year later things were not much different.  Throughout all this and the following year, I carried on getting slow improvements, so I think all that can be said is that an MRI is a useful tool as an aid to diagnosis and means that many people don't need a lumbar puncture any more.  I never had one because it was so obvious.  I don't think I am going to look at them again, though, so I'll just leave them all in a folder on a shelf in David's study: too much of a reminder of bad times.......Sarah

An itinerary in Light and ShadowStarted the Wheldon regime in August 2003, for very aggressive SPMS.  Moved to intermittent therapy after one year. 2006 still take this, two weeks every two months.  EDSS was about 7, now 2.

Completed Stratton/Wheldon regime for aggressive secondary progressive MS in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

D W

Thanks for posting this, Ron. Very interesting; it has been known for some time that there are functional changes in grey matter in MS which proceed independently of relapses; these can't be accounted for by demyelination. A recently published study showed that changes in the 'normal appearing white matter' were related to distance from established plaques [Vrenken H, Geurts JJ, Knol DL, et al., Normal-appearing white matter changes vary with distance to lesions in multiple sclerosis. Am J Neuroradiol. 2006 Oct;27(9):2005-11.] (Abstract only read) These authors state: 'NAWM disease farther from the lesions may be mainly characterised by subtle blood-brain barrier damage, with leakage of fibrinogen into the parenchyma and microplaque formation.' This supports the idea of spreading infective vasculitis as a precursor of the neuropathology; this idea was first advanced by Rindfleisch in the 1860s. Here's another interesting study (again, abstract only read) which discusses the molecular nature of this disruption of the blood-brain barrier. [Hochmeister S, Grundtner R, Bauer J, Engelhardt B, et al., Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol. 2006 Sep;65(9):855-65.] These authors comment: 'Dysferlin is a muscle protein involved in cell membrane repair. . . In the inflamed CNS of patients with multiple sclerosis (MS) or in animals with experimental autoimmune encephalomyelitis, dysferlin reactivity is induced in endothelial cells and the expression is associated with vascular leakage of serum proteins. In MS, dysferlin expression in endothelial cells is not restricted to vessels with inflammatory cuffs but is also present in noninflamed vessels. In addition, many blood vessels with perivascular inflammatory infiltrates lack dysferlin expression in inactive lesions or in the normal-appearing white matter. In vitro, dysferlin can be induced in endothelial cells by stimulation with tumor necrosis factor-alpha. Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis.' Once the neuropathology starts, though, a lot goes on quietly. A person with MS said to me recently that she thought a lot of serious damage accrued silently between the obvious episodes. A very prescient remark.

D W - [Myalgia and hypertension (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazole. No medication now. Morning BP typically 110/75]

Red

Hi Ron & DW,

Interesting.   I don't think I understood this about MS before.   The leaky blood vessels in the brain in MS sound very similar to the leaky blood vessels in rosacea facial skin.  Under the inflammatory theory of rosacea, from what I understand, much of the edema is caused by an excess of this leaking infiltrate, etc, and much of the tissue destruction is caused by things such as the MMP's (including collagenase), nitric oxide and ROS, that are released by leaked neutrophils into the surrounding tissues.   It's explained fairly clearly in the first part of this short video:

http://rosaceatoday.com/MOA.asp?Display=1&Player=mov

Is this kind of like what's going on with MS too? 

In rosacea we also seem to have some sort of nerve involvement, relating specifically with what has been described a neuropathic pain (or continual burning), that seems to be stimulated via the inflammatory response.   I haven't read much on how this occurs, but could it somehow be related to the nerve damage in MS?

 

 

 

On Combined Antibiotic Protocol for Cpn in Rosacea since 01/06

Treatment for Rosacea

  • CAP:  01/06-07/07
  • High-Dose Vit D3, NAC:  07/07-11/08
  • Intermtnt CAP, HDose Vit D3:  11/08-01/09
  • HDose Vit D3, Mg, Zn: 01/09-
D W

Red, it does seem likely that there's a similar underlying inflammatory pathology in many of these chronic disorders. Elevated MMPs are the rule. The activity of MS is linked to MMP levels [Fainardi E, Castellazzi M, Bellini T, et al., Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis. Mult Scler. 2006 Jun;12(3):294-301.] The route the disease takes, and its appearance within that disease-form is likely to depend on multilayered host factors. Small-vessel disease and nerve injury at a local level seem to be a common pattern, though; it is found in Crohn's disease (mesenteric vasculitis) and in interstitial cystitis, where damage to vessels and nerves in the muscularis and sub-urothelial layers. Giant-cell arteritis is another disease-form in which chronic infection with Chlamydia pneumoniae may be implicated. Many of these conditions can give rise to severe intractible pain, presumably due to nerve involvement. Many associations between different disease forms are not seen because medicine is compartmentalized. There is, for instance, a raised incidence of white-matter MRI abnormalities in people with Crohn's disease. Retinal vasculitis has been known to be associated with MS for about 60 years.

D W - [Myalgia and hypertension (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazole. No medication now. Morning BP typically 110/75]

Red

Interesting.  I've seen terms small vessel disease and vasculitis, etc mentioned on the site before, but not having a medical background myself, I don't think I understood the implications, and didn't realize how closely linked some of these disease pathogenesis are or potentially could be (since I don't know much about these other diseases).

Thanks as always for the added info... 

 

On Combined Antibiotic Protocol for Cpn in Rosacea since 01/06

Treatment for Rosacea

  • CAP:  01/06-07/07
  • High-Dose Vit D3, NAC:  07/07-11/08
  • Intermtnt CAP, HDose Vit D3:  11/08-01/09
  • HDose Vit D3, Mg, Zn: 01/09-

 Exactly, Red. The reason we have kept mentioning small vessel disease and vasculitis is that both David and Chuck (Stratton) have repeatedly drawn the links between these factors and Cpn, as the basis really for a number of the diseases in which Cpn is implicated. It is this inflammatory infiltration which also allows entry into tissues and organs from the circulatory system, for example across the Brain Blood Barrier, or the spreading into microcirculation in the epidermis in rosacea, or the cardiac epithelium in heart disease.

Combined Antibiotic Protocol for Chlamydia pneumonia in Chronic Fatigue Syndrome & Fibromyalgia- Currently: 150mg INH, Doxycycline/Zithromycin, Tinidazole pulses. Northern Ohio, USA

 Linking more on MMPs 7 and 9 in MS.

Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions .

Here is link.

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

Linking more on MMPs 9, Chlamydia Pneumonia and Atherosclerosis.

Matrix metalloproteinase-9 expression is associated with the presence of Chlamydia pneumoniae in human coronary atherosclerotic plaques

Here is link.

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

 Linking more on MMP, Chlamydia (non pneumonia)

A role for matrix metalloproteinase-9 in pathogenesis of urogenital Chlamydia muridarum infection in mice. (Microbes Infection 2007)

Here is the link.

Chlamydia trachomatis enhances the expression of matrix metalloproteinases in an in vitro model of the human fallopian tube infection.

Here is link. 

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

 Linking more on Cpn and MMP

Exposure of human monocytes to Chlamydia pneumoniae resulted in a significant enhancement of matrix metalloproteinase (MMP) 1 and 9 production. 

Here is link.

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

Linking more on MMP and numerous autoimmune diseases. 

This 2006 Bayer patent has a very comprehensive explanation of MMP and it's association with nearly every disease

" The invention provides a human MMP9 which is associated with the infections, cardiovacular diseases, dermatological diseases, endocrinological diseases, metabolic diseases, cancer, inflammation, gastroenterological diseases, hematological diseases, respiratory diseases, muscle skeleton diseases, neurological diseases, urological diseases, reproduction diseases."

So let's see - CPN causes significant enhancement of MMP 9 - hmmmm.     

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

Red

Hi Daisy,

Add MMP-1, -3 and -9 in Rosacea:

http://rosaceatoday.com/TheoriesofRosacea.asp

On Combined Antibiotic Protocol for Cpn in Rosacea 01/06 - 07/07, On Vit D3 + NAC since 07/07 and daily FIR Sauna since 08/07

Treatment for Rosacea

  • CAP:  01/06-07/07
  • High-Dose Vit D3, NAC:  07/07-11/08
  • Intermtnt CAP, HDose Vit D3:  11/08-01/09
  • HDose Vit D3, Mg, Zn: 01/09-

 January 2008, Respiratory Research Article on persistence of other forms of chlamydia (and association with COPD).  Here is article.

"The release of matrix metalloproteinases (MMP-9) is shown to be stimulated by chlamydial heat shock protein 60. Release of MMPs is also crucial for tissue destruction by macrophages in human emphysema"

Yes the article is on horses but it's pretty cool they are proving persistence of infection in other strains of Chlamydia.

"For the first time persistence of CPP and CPA in the lungs of clinically healthy horses and acute (possibly reactivated) chlamydial infections in those with obvious disease is demonstrated. Respiratory chlamydial infection probably becomes clinically relevant only in animals affected by additional pathogenic factors. In this context, inflammation seems to be associated with the activation of chlamydiae. Furthermore, the high prevalence of these chlamydial agents in horse lungs deserves further attention as a reservoir, especially in the light of recent studies,...."

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

And just to keep it all in one thread for inquiring minds that may want to know in the future, MMP9 is suppressed by tetracyclines see it HERE

This protocol is really a multi factorial benefit for the person with these diseases. Yet another reason for people to consider it...even if they feel the connection between MS and CPn is not as solid as they'd like.
marie

On CAP since Sept '05 for MS, RA, Asthma, sciatica. EDSS at start 5.5.(early cane) Now 6 (cane full time) Currently on: Doxy 200, Azith 3x week, Tini cont. over summer '07, back to pulses of flagyl winter '08 all supplements.
"Color out side the lines

On CAP since Sept '05 for MS, RA, Asthma, sciatica. EDSS at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxy 200, Azith 3x week, Tini cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

 Marie - I agree !  The protocol is really a multi factorial benefit for the person with these diseases. 

There are loads of studies on the use of doxycycline and minocycline suppressing MMP9 in stroke, MS, diabetes, asthma, COPD, uterine fibroids, etc....  with the spam catcher it would take hours to post them all. 

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

I had lost this thread completely, because I really couldn't follow some of the discussion easily. So, I am getting better; today I read it like a newpaper.

The connections to MMP-9 are very interesting, Daisy. I wonder what other bacteria can cause elevated MMP's?  I did a (very) little checking, just for curiosity's sake. Borrelia burgdorferi looked interesting; Toxoplasma gondii less so. HIV is another henchman in the destruction of the BBB by MMP-9.

At any rate, thanks for digging out this old thread. I'd forgotten all about it, partly because I couldn't really follow the discussion very well. 

I wonder when the MRI for T1 changes will be available outside the lab? It could perhaps flag individuals whose MS is worsening despite the lack of change in the lesions.

It seems that traditional MRIs (like Sarah's old ones) are like trying to judge the health of a plant by looking at holes in the leaves. I mean: a leaf can have a fairly chewed-up appearance (lesions) but still be functioning pretty well (nice and green); another leaf may have only a couple of small holes, but be all yellow and wilty.

Counting the holes just wouldn't tell the story. It seems the T1 MRI looks more at  "yellow wilty"  generalized damage. or is that a bad analogy?

 Ron

On CAP for CFS starting 01/06 (NE Ohio, USA)

Currently: doxy & zith -- continuous; metronidazole -- 5 days on, 9 days off.

Get the research results you paid for: support Open Access

RonOn CAP for CFS starting 01/06 (NE Ohio, USA)Began rifampin trial 1/14/09Currently: on intermittent

 Ron - Definitely other bacteria  (and virii) induce elevations in MMP9. 

Strep, borrelia, h.pylori, mycoplasma, HPV, hepatitis, HSV, etc... 

To me it's a bit of a chicken or the egg situation.  MMP's are involved in "good" normal biological processes and "bad" pathological processes. 

It's theorized that MMP9's (matrix degrading) are induced by neutrophils responding to the site of infection.  Once there it is believed MMP9 induce inflammatory angiogenesis.

Some days I am dazzled by the good quality clinical science that has been reproduced indicating various pathogens as "present" in various "auto-immune" diseases and the associated mechanisms of fall out like MMP9.

It further makes me queazy when I think of how much research in MS is focused on EAE model.  I want to stand up to the herd and say - whoa - Wrong Way.  Stop and look at the ICAAC and Antimicrobial journals - it's all there.  Free your minds and the rest will follow...

Re the MRI's.  Good point.  I imagine that a high enough TESLA machine will show the lesions that don't show on the MRI equipment used by most. 

Also, think that even though MRI's can show no new enhancing or current lesion changes in the face of clear disease progression you must also consider brain size (lack of shrinkage), midline shift, sulcus patterns etc... 

It's always been interesting to me that many "healthy" people will show some sort of brain lesions on MRI later in life.  Of couse cognitive decline also shows in many too. Correlation?   Slow growing infections gaining ground as the immune system ages or is overwhelmed?  Maybe?

It's ALL - already in the literature.  The benchwork and proof of concepts are there.  The left and right hands just aren't talking. 

Well - at Vanderbilt they are. 

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

Red

More good stuff: 

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?

 

On Combined Antibiotic Protocol for Cpn in Rosacea 01/06 - 07/07, On Vit D3 + NAC since 07/07 and daily FIR Sauna since 08/07

Treatment for Rosacea

  • CAP:  01/06-07/07
  • High-Dose Vit D3, NAC:  07/07-11/08
  • Intermtnt CAP, HDose Vit D3:  11/08-01/09
  • HDose Vit D3, Mg, Zn: 01/09-

Red -

Genius article on Vita D and MMP !  Thanks!

Here's one on pycogenol and MMP9. 

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

Alpha Lipoic reduce MMP9's. 

"also inhibited high-glucose- and TNF-alpha-induced increases in MMP-9 expression."  Here's link.

And from another article.  "ALA and DHLA reduced matrix metalloproteinase-9 (MMP-9) activity by 18-90% in Jurkat cell supernatants"  Here's link.

Alpha Lipoic in MS.  Reducing MMP9.  Here's link.

Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

 NAC reduces MMP9's.   FC below equals macrophage induced foam cell. 

"We further examined whether FC gelatinolytic activity is dependent on the presence of reactive oxygen species (ROS). We found that treatment (1 to 5 days) with 1 to 10 mmol/L N-acetyl-L-cysteine (NAC), an ROS scavenger, decreased not only gelatinolytic activity but also gelatinase expression by FCs. Similarly, NAC treatment of explanted lesions abolished in situ gelatinolytic activity and MMP-9 expression."   Here is link.

Curiously, my husband's pathology report from his Sept 2006 crainotomy showed a preponderance of "foamy macrophages".

 Daisy - Husband on CAP 5/07.   Roxithromycin, Minocycline, Rifampin, Bactrim DS, Mepron, Prednisone, Novantrone, Doxy, Azithromycin, Flagyl, Diflucan

Daisy - Husband on CAP 5/07.  Husband died from Acute Myelogenous Leukemia Secondary to the Infusion of Novantrone.  Ie - the treatment with the conventional MS drugs killed him. Daisy on her own CAP 11/2012. 

Red

Good stuff, Daisy.   Thanks! 

On Combined Antibiotic Protocol for Cpn in Rosacea 01/06 - 07/07, On Vit D3 + NAC since 07/07 and daily FIR Sauna since 08/07

Treatment for Rosacea

  • CAP:  01/06-07/07
  • High-Dose Vit D3, NAC:  07/07-11/08
  • Intermtnt CAP, HDose Vit D3:  11/08-01/09
  • HDose Vit D3, Mg, Zn: 01/09-