I wanted to put together the research I've compiled for the cause of multiple sclerosis as a disease of primary neurodegeneration due to hypoperfusion created by CCSVI with secondary reperfusion injuries.  I felt it was important to document this research into a possible cause of MS.  I also want your input and thoughts.

The reason why MS relapses and remits during the onset of the disease has been difficult to understand, and impossible to replicate in animal models of MS.  EAE, the current model for MS, is not like MS.  EAE is more akin to ADEM, in that it does not relapse and remit.  It's a constant immune reaction.   I believe stroke and cardiovascular researchers, like Dr. John Cooke at Stanford, will be better able to create animal models of MS using perfusion--or bloodflow.   Immunology departments have had 60 years to model MS, and they still don't have it right.

The following information is only a theory. It was first proposed by researchers in the 1980s and now relates to the vascular theory of MS and Dr. Zamboni's discovery of CCSVI. 

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What's reperfusion?  Most of us know the word hypoperfusion---meaning the slowed or less than normal blood flow we see in the MS brain.  Reperfusion simply means to perfuse again, or redeliver blood. Reperfusion is a good thing and a bad thing.  Reperfusion is a natural occurrence; it returns blood to tissue after there is an event which stops or slows blood flow, like a stroke or ischemia.  Reperfusion brings essential O2 and glucose to cells after such an event, but it also brings inflammation and the immune system with it.  Blood returns to the area of tissue where it had been absent, at a cost.

Dr. Dake mentioned in a presentation at ISNVD how hyperperfusion (otherwise known as reperfusion injury) occurs BEFORE an MS lesion forms.   He referenced this paper, which discusses how this perfusion change happens before the break in the blood brain barrier, before the immune system entry, before demyelination. The very first step is a change in perfusion.  I wanted to know--why?

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I believe reperfusion injury explains the relapsing remitting course of early MS and ties together Dr. Zamboni's research into CCSVI and hypoperfusion in the MS brain. There will be an explanation as to how this theory functions in progressive MS at the end of this note. 

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We are learning more and more that gray matter loss, or brain atrophy,  is a reliable method for monitoring the neurodegenerative process in MS.  Gray matter loss and death of neurons begins from the inception of the disease and continues with increasing disability.  It is linked, only modestly, with white matter lesions. This is why the current medications which suppress the immune system do not stop MS.

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We already know that pwMS have lower levels of glucose and O2 being delivered to their brain and spinal tissue, due to hypoperfusion, which can cause neurodegeneration and mitochondrial dysfunction.

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Right now, the debate as to whether this hypoperfusion is caused by CCSVI, or hypoperfusion is simply a result of an unknown disease process we call "MS".  I always refer to Ockham's razor in these instances...'when you have two competing theories that make exactly the same predictions, the simpler one is the better."  On that note, here is research stating the hypoperfusion seen in the MS brains looks like primary ischemia, or low oxygen.

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Lower levels of O2 and glucose can be correlated to slowed blood flow, or hypoperfusion, created by CCSVI.  

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I think that on top of this ongoing process of neurodegeneration,  there are intermittent ischemic events which take these glucose and O2 levels dipping even lower--events like an illness, a trip to high altitude, stress, an injury, giving birth, a bacterial infection--and when the event is over, the reperfusion cycle begins--what we call an exacerbation or "MS flare."  

I believe this is why many pwMS can directly tie their relapses to times after viruses, stress, lack of sleep, etc. These events become the straw that break the camel's back.  And once these events end, reperfusion injury happens. It's a damaging one/two punch.

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Reperfusion injury is NOT the complete disease.  It is a reaction to an event.  I believe MS relapses are not MS. Relapses are a reaction to an event.  The MS neurodegenerative proces continues underneath.  Let's look at how an MS relapse is like reperfusion injury.

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Reperfusion Injury and Multiple Sclerosis relapses share:

1.  Demyelination -- Loss of myelin occurs after nerves have blocked bloodflow, low O2 and glucose, and then a return of bloodflow.  Reperfusion causes demyelination of nerves-

Perivascular demyelination and intramyelinic oedema in reperfusion nerve injury.

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Acute inflammatory demyelination in reperfusion nerve injury

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2.  Blood brain barrier disruption--the blood brain barrier becomes permeable, and endothelial tight junctions are altered in reperfusion injury.

Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats.

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Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats.

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3. An excessive innate immune response--immune cells are called in 

Association of immune responses and ischemic brain infarction in rat.

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Naturally Occurring Autoantibodies Mediate Ischemia/Reperfusion-Induced Tissue Injury

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4. An excess of free radicals, oxidative stress and partially reduced oxygen species are found in both reperfusion injury and Multiple Sclerosis

Oxidative Stress in Multiple Sclerosis

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Mechanisms of Oxidative Damage in Multiple Sclerosis 

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The role of oxidants and free radicals in reperfusion injury

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5. Endothelial Dysfunction as evidenced by elevated levels of endothelin-1 in plasma 

Increased endothelin-1 plasma levels in patients with multiple sclerosis.

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Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis.

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Endothelin-1 is involved in the pathogenesis of ischemia/reperfusion liver injury

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Reperfusion has been studied extensively on the arterial side.  Like most medical research, the study of the veins and venous return is lacking.  But I did find one interesting study that showed how reperfusion injury happens after rats' intestinal veins were blocked and venous hypertension above the blockage occured--

Elevated venous pressure can be associated with severe tissue injury. Few links, however, between venous hypertension and tissue damage have been established. We examined here the effects of micropressure elevation on the outcome of venular occlusion/reperfusion in the mesenteric microvasculature of male Wistar rats. One hour of venular occlusion (diameter approximately 50 microm) by micropipette occlusion followed by reperfusion were carried out with sham surgery without occlusion as control. Leukocyte rolling, adhesion, and migration, oxygen radicals detected by dichlorofluorescein (DCF), and parenchymal cell death detected by propidium iodide (PI) were recorded simultaneously in the same vessel at a location upstream of the occlusion site with elevated micropressure and at a downstream location with low micropressure.

The number of rolling, adhering, and migrating leukocytes increased on the upstream side of the occlusion to a higher level than downstream of the occlusion site.

Microhemorrhages of blood cells into the mesentery interstitium were observed only on the upstream side of the occlusion. These results indicate that an elevation of the venular blood pressure during occlusion/reperfusion exacerbates the inflammatory cascade and tissue injury. Venous occlusion may constitute an important mechanism for tissue injury.

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(note the upstream microhemorrhages caused by venous hypertension in this study.  These tiny, pinpoint spots of blood escaping into tissue might be linked to the iron deposition and hemosiderin we find in the MS brain...but that's just a guess.)

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This theory continues--when MS becomes progressive and relapses no longer occur,  it is because the body has been conditioned--- trained from years of hypoxia and low levels of O2 and the recurrent reperfusion. Eventually, this reperfusion response no longer happens.  It burns out.  There is no more inflammation, no more immune system activation---but the low levels of O2 and glucose are still causing mitochondrial dysfunction, neuronal and axonal death.

Hypoperfusion becomes worse, as the body ages and becomes more inactive.  MS continues to progress, even without the reperfusion injury seen during the RRMS days.  Gray matter continues to atrophy- even if there is no demylination, inflammation or damage to white matter. 

The underlying disease process---low levels of O2 and glucose to CNS tissue, causing neurodegeneration--has remained the same.  MS progresses.  Gray matter atrophies.   But the period of reperfusion injury eventually stops happening, due to conditioning.  There are no more relapses.  The disease moves into the progressive phase.

In the past, MS has largely been considered a chronic inflammatory and demyelinating disease, driving most of the research and treatment development towards targeting the immune system. As of now, disease modifying therapies for MS are limited to various anti-inflammatory agents that reduce acute inflammatory lesions, clinical relapses and disability progression in RRMS. These anti-inflammatory agents, however, do not completely prevent axonal injury and are largely ineffective in treating progressive MS.

The recent resurgence of MS research focused on axonal degeneration mechanisms has resulted in convincing experimental evidence and potential treatment targets. As reviewed above, mitochondrial function is crucial in preserving axonal integrity in both acute inflammatory and progressive stages of MS. Therefore, therapies that protect mitochondria and enhance their functioning warrant investigation.

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The current drugs are treating the body's natural response to reperfusion injury.  But they do not address the diffuse cerebral hypoxia and lowered glucose transport which remain.  And that's why MS continues to progress.  

Dr. Zamboni sought to treat this hypoperfusion caused by venous malformations and collateral circulation.  He uses venoplasty to increase perfusion and bloodflow by allowing the body to use the jugular veins, rather than less efficient collaterals.  It's worked for many people, but not all---we need more research.  

This theory also explains why HBOT treatment, nutrition, antioxidants,  smoking cessation, exercise, stress reduction and vascular approaches help those with MS to receive stability and remission.  These measures provide balance to the body, enable more energy and O2 to be delivered to the central nervous system and help the body avoid these ischemic events which call in the reperfusion response.

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A brief recap:

Venous insufficiency and collateral circulation caused by CCSVI causes hypoperfusion.  This leads to hypoxia and lowered glucose delivery to the CNS.  Cells die.  During the RRMS stage of the disease, the body responds to events which lower levels of O2 with reperfusion. This creates venous hypertension and reperfusion injury. The immune system becomes activated. Lesions form. MS progresses.  As the body slows down with increasing disability and age, hypoperfusion worsens, axons and neurons continue to die.  Gray matter atrophies.  It's a vicious cycle.

How to stop the cycle?  Venoplasty to repair venous malformations and restore blood flow through major veins rather than collaterals.  A whole food diet full of nutrients and plant-derived antioxidents.  Regular exercise. Lifestyle modifications including stress reduction, meditation, smoking cessation.  Potential immuno therapy (like LDN, copaxone, beta interferon) to avoid reperfusion injury during RRMS stage.

But, as you all know by now...I'm not a doctor.  I just hate MS.  And I want more answers.

Please, let me know your thoughts, and please share with medical people and researchers you may know...what part of this theory is lacking?  Does this make any sense?  How should research move forward?

Marie talks about hypoperfusion and slowed bloodflow in her book, "CCSVI as the Cause of MS; The Science Behind the Controversial Theory."  Do you have your copy yet?  It's available on Kindle and here    It's fantastic summer reading---

Joan