Blood starved MS

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There is mounting evidence that the brain blood supply is affected in MS. Perfusion MRI studies have found that blood flow is globally impaired in the normal appearing brain of both relapsing and progressive forms of MS. Interestingly, there appears to be an association between this and cognitive (memory and intelligence) dysfunction in MS. In animal models, chronic hypoperfusion of the brain appears to lead to energy failure in the mitochondrion (the power house of every cell) through oxygen starvation, releasing free radicals and finally resulting in axonal degeneration. This theory is further backed up by the fact that there is a predilection for MS lesions in the anterior and occipital horns of the lateral ventricles, in the so-called watershed regions of the arterial circulation susceptible to hypoperfusion (see figure below).

Energy failure caused by mitochondrial dysfunction is therefore thought to be a major contributor in axonal degeneration in MS. N-acetylaspartate or NAA synthesized in the mitochondria, is both a marker of neuro-axonal mitochondrial function and integrity. Studies looking at NAA in normal appearing brain tissue in MS have found that NAA is more likely to be reduced in progressive MS compared to RRMS and those without MS.

So, what if you can reverse both at the source by increasing cerebral perfusion?

That is exactly what one group are trying to achieve (see abstract below). It is too early to say what the outcome will be as they have just started the work; but I thought it would be useful to look at their strategy in greater detail.

The ROCHIMS (Role Of Cerebral Hypoperfusion In MS) study will be using the vasoactive agent bosentan (endothelin-1 blocker) to explore whether prolonged treatment can restore cerebral blood and enhance NAA levels, reflecting improved mitochondrial function and axonal integrity. The underlying hypothesis is that reduced blood flow in MS is mediated by endothelin-1 in the brain circulation.

Bosentan is already licensed for pulmonary arterial hypertension (Actelion Pharmaceuticals) and has been shown to reduce the number of ulcers in the fingers in those with scleroderma (10% develop pulmonary arterial hypertension). It can cause liver damage and is category X for pregnancy (studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience) meaning that women must not become pregnant whilst taking it.

In cerebral malaria, endothelin-1 induced vasculopathy has been demonstrated to contribute to the evolution of cerebral malaria. Reduced brain endothelial activation in a mouse model of cerebral malaria prevented blood-brain barrier disruption, cerebral vasconstriction, that eventually lead to improved cognitive function and improved survival in the infected mice.

The ROCHIMS study commenced recruitment in Sep 2017 and is expected to end recruitment in Apr 2019; so watch this space!

ABSTRACT
Trials. 2019 Mar 14;20(1):164. doi: 10.1186/s13063-019-3252-4.

Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan.

Hostenbach S, Pauwels A, Michiels V, Raeymaekers H, Van Binst AM, Van Merhaeghen-Wieleman A, Van Schuerbeek P, De Keyser J, D’Haeseleer M.

Background: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS.

Methods: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.

Discussion: We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest.

About the author

Neuro Doc Gnanapavan

18 comments

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  • Is this possible redemption for the CCSVI contingent? Granted, the problem may not lie in venous obstructions or blood outflow, but this certainly lends credence to the idea that reduced perfusion in the brain is directly linked to the nerve damage seen in MS.

    Should be very interesting to see where this leads. Perhaps the baby was indeed thrown out with the bathwater when CCSVI was so thoroughly disavowed by the neurologic community back around 2010. The original hypothesis may turn out to have been relevant, but it’s presentation flawed. Then again, maybe not…

    In any event, cue the onslaught of the CCSVI aficionados… There are still quite a few out there, who have refused to let the embers of Zamboni’s original idea be thoroughly extinguished. To their credit or detriment, it now seems, may soon be determined…

    • Uhm…No!!! Arteries not veins, and in particular not about the large vessels. The science behind this is more solid and has been reproduced by many groups. There have been a resurgence of hyperbaric O2 supporters when this theory was put forward, but no controlled trials as yet.

      • I certainly feel much, much better when working outside in fresh air in the garden, my fatigue is reduced. (Would find sitting in a hyperbaric O2 chamber too claustrophobic, boring…)

      • “Anyone know what he’s doing now?”

        Oh..just worked with NASA on a brain drain project on the ISS…seems in zero gravity the blood doesn’t drain…and astronauts are reporting neurological/vision symptoms.
        https://www.nasa.gov/mission_pages/station/research/experiments/1278.html

        Strain-gauge Plethysmographic Analysis of the CErebral DRainage Experimented and Assessed in the Micro-gravitational Setting (Drain Brain) – 11.22.16
        Experiment Details OpNom: Drain Brain
        Principal Investigator(s)
        Paolo Zamboni, MD, Centro Malattie Vascolari,Italy
        Sponsoring Space Agency:
        National Aeronautics and Space Administration (NASA)

        _____________

        Joan the blogger is best source for Zamboni info.

        http://ccsviinms.blogspot.com/2014/11/nasa-drain-brain-and-astro-samantha.html

        “NASA, the Drain Brain and Astro Samantha”

        Right now, on the International Space Station, the first female Italian astronaut, Samantha Cristoforetti, is settling into her new home. Over the weekend, Cristoforetti left the earth’s orbit from a rocket launch in Kazakhstan. As she joins other international astronauts as part of Expedition 42/43, Cristoforetti will be conducting a major research experiment, using the technology developed by Dr. Paolo Zamboni. This study, called Drain Brain, is a collaboration between NASA and the Italian Space Agency. It will be using strain-gauge plethysmography (a neck collar which measures blood flow) as well as doppler ultrasound technology to analyze cerebral drainage in space. ”

        https://www.google.com/search?q=Astro+Samantha+ISS&client=firefox-b-1-d&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjBx7Pv_I7hAhWS-lQKHajIBwEQ_AUIDigB&biw=1525&bih=674&dpr=0.9
        ____________

        “And ‘an evolution of my studies on CCSVI and relationships with multiple sclerosis; is investigated blood flow in microgravity. The US space agency asked to investigate the consequences for astronauts, the hypothesis is that the cerebral circulation is slow as cerebrospinal venous insufficiency in patients. ”

        In this case there have been disputes with other scientists.

        “I Have Not. I participated to ten conference cardiofisiology Americans, I have studded questions. When I convinced them of the goodness of my hypotheses, have voted in favor of this trial. ”

        https://www.thisisms.com/forum/viewtopic.php?f=40&t=24902&sid=a120f433e9973abab38ded0621b22b9e

        • Why the hell is my message being run right off the page..?

          “bout now the old site seems heaven
          2019 and can’t get a readable page

  • The whole anti-CCSVI movement was a little too dismissive (partly right so as it claimed a cause and a cure, while being a dangerous procedure). But if taken as another symptom of MS degeneration, it can have some reason…maybe. Still, this is a much preferable way to target blood flow disruptions. Thanks!

    • Let’s wait and see, the hypothesis has been set and their is precedence for the drugs efficacy in other disorders.

  • Is it too late to apply for inclusion onto the ROCHIMS trail. If it’s not , can you point me in the righ5 direction.
    Thanks

  • Could this be a reason why aspirin works on MS fatigue? By increasing blood flow to the brain? I remember CCSVI patients reporting this improvement too (of course is the most subjective symptom).

  • As some one who had treatment to dilate stenos-ed jugular vein valves and found a massive benefit which unfortunately lasted only 6 months. (I say worth it.)
    I have also experimented on myself since when finally diagnosed tin 1995 there was no treatment.
    Since then I have taken gingko biloba slept propped up (to improve blood circulation in brain and avoiding waking up with head aches) and coenzyme Q10 to reduce/ameliorate fatigue. Also massive doses of Vitamin D.
    I am in pretty good nick for a 72 year old woman, (3 business friends dead of breast cancer so I count being alive as a win.)
    I walk using an FES device still practice as an Architect and buy into your EBV theory so now I am taking natural anti-virals.
    This really really matters my daughter has been diagnosed with Lupus Ms queried and I have a grand daughter who has been bred for MS viz both grand mothers have it.

  • Exercise! This is the single best way we have to increase blood flow to our brains today. I find this article interesting but not too surprising. Regardless of how terrible I’m feeling I get out and exercise and I never regret it. It is like I’m wiping away cobwebs in my brain when I do so.

    • Charcot who first identified MS believed it to be a disease of circulation.
      I have a power pressure plate machine (momma’s twerking machine) which I use in the morning and evening after using it I feel buzzy (like after a sauna)

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