I am a medical doctor with multiple sclerosis and would like to propose a theory that ties together MS and CCSVI. I did this in point form. I tried to keep it simple but still used medical terminology in an effort to get this out soon. Much of what I have written requires a certain base knowledge but I know many of you on the site possess this base. Please excuse any grammatical or spelling errors as this was written with cognitive deficits during my most severe MS exacerbation. Here it goes:
1) MS is a disease of hypercoagulability that is manifest predominantly at the micro-vascular level (capillaries and post capillary venules) of central nervous system tissue.
2) This local hypercoagulability in the MS population can be a result of numerous factors. The predominant factor is likely venous outflow obstruction from the larger veins that drain the central nervous system.
3) This outflow obstruction of the larger veins results in reduced blood flow and stasis at the microvascular level.
4) Stasis in turn triggers an environment of hypercoagulability and reduced blood flow at the mircovascular level through the resultant activation of the coagulation cascade and though related local cell adhesion factors.
5) Stasis in turn results in local ischemia of the CNS tissue and impaired functioning of this tissue resulting in a number of central nervous system deficits.
6) Certain deficits related to ischemia may rapidly reversible if the if the axons and myelin sheaths are still intact. Deficits that result in myelin breakdown but not cell death will improve at the rate of myelin repair. Deficits that result from cell death will be permanent and may explain stepwise deterioration following exacerbations in relapsing remitting MS.
7) I suspect that stepwise deterioration in some patients may be a result of thrombosed collateral veins as well.
Stasis can be worsened by a number of factors that can result in multiple sclerosis exacerbations, pseudo-exacerbation of or just temporary worsening of symptoms.
9) Infections can precipitate exacerbations by creating an environment or hypercoagulabilty that is manifest predominantly at the microvascular level. Numerous viruses are known to create states of hypercoagulabilty and many virus may be associated with or implicated in the pathophysiology of MS. Examples of such pathogens include herpes virus 6, epstein barr virus, chalamydia pneumonia.
10) Certain antibiotics such as minocycline and antivirals such as valacyclovir have been shown to reduce exacerbations. This is likely a result of suppressing replication of these viruses and reducing microvascular hypercoagulability.
11) Heat, either through fever or external sources worsens MS symptoms by increasing coagulability. It is common knowledge that heat can increase coagulability. This in turn results in reduced blood flow and increased symptoms though worsened ischemia.
12) Hypercoagulability in MS is not detectable using traditional methods because it is present only at the microvascular level.
13) Anecdotally, angioplasty patients have experienced rapid and dramatic improvement following the procedure. This is likely a result elimination of stasis at the microvascular level by the improvement of macrovascular venous blood flow.
14) One must keep in mind that sudden improvements may also be a result of the use of heparins both during and post procedure. Heparins may have the ability to increase flow even in the presence of venous outflow obstruction.
15) Vitamin D likely exerts its beneficial effects by maintaining endothelial health. An important part of endothelial health is the endothelium’s ability to activate cell surface heparins which will decrease blood cell adhesion and maintain blood flow and prevent stasis at the microvascular level.
16) Vascular comorbidity has been shown recently to correlate very well with MS progression. This is likely though the same mechanism of maintenance of endothelial health.
17) Natalizuamab (Tysabri) likely exerts its beneficial effects by activating and maintaining activation of endothelial cell heparans. Nathalizuamab binds to alpha-4-integrin a molecule and receptor that mediates attachment between the endothelial cell and lymphocytes and likely other blood cells. Alpha-4-integrin is intimately involved with endothelial heparans. Once endothelial heparans are activated, stasis of blood in the microvasculature is reduced because passage of these cells though the very narrow endothelium (about the width of a blood cell) is facilitated.
18) Rapid removal of natalizumab from the blood stream as occurs with plasmapheresis has been shown to result in severe progression and even death. This likely occurs because the removal of natalizumab results in a marked decrease in the cell,s ability to produce heparin, inducing a severe hypercoagulable state at the microvascular level.
19) Severe MS exacerbations that occur following nathalizumab drug holidays likely operate through the same mechanism. I would suggest extreme caution in anyone considering a drug holiday if my proposed theories are correct.
20) Administering natalizumab during an exacerbation may result in cessation of progression of the exacerbation and rapid reversal of certain symptoms. This was my experience. On October 3rd during my worst ever exacerbation my symptoms rapidly improved over the next 4-5 hours.
21) It would seem logical to administer heparin to reverse this hypercoagulable state, but I have concerns that this may not be possible as nathalizumab may bind to exogenously administered heparin. This observation is based on personal experience. I am on natalizumab. Following balloon angioplasty of my azygous, I was started on enoxaparin (Lovenox). After about nine days on enoxaparin I developed a pruritic drug rash of my arms, legs and trunk that was typical of a serum sickness rash (aka immune complex rash), which would indicate that the natalizumab binds to enoxaparin and would limit its use in this setting.
22) I suspect that other MS disease modifying drugs work though the optimization or activation of endogenous heparans. In my brief research, I identified studies that link the interferons and copaxone to the functioning and possibly increased expression of heparans.
23) Although the evidence for this is weak, I suspect high dose IV methylprednisolone (IVMP), may create a markedly hypo-coagulable (blood thinning) state and be effective for this reason. I came across a case report of three MS patients on Coumadin and high dose IVMP who developed dangerously high INRs. My assumption here is also based an event that recently occurred to me on high dose IVMP. Ten days ago, in the morning, while receiving the 7th last dose of IVMP 1 gram/day, I stumbled while going down stairs and injured the left lateral aspect of my left shin. I got up and thought everything was fine. I had no pain and felt like I had just bumped my knee. Later, in the evening, I noticed that my left shin felt tight. There was a huge hematoma over it. I went to the emergency room of the hospital that I work at and got an xray which was normal. The doctor suggested I do a coagulation profile, but I brushed this suggestion off as I thought I had no reason believe that I had a coagulation disorder. I had normal coagulation tests a few months ago for my angioplasty procedure. I did not understand it at the time, but I suspect my INR and aPTT were likely extremely high. If what I am saying is true, then steroids used in many conditions for their antiinflammatory/immunosuppressive effect, may in fact work by thinning the blood. One example is its use to decrease brain edema in cancer patients. Perhaps its mechanism of acton is by increasing flow through the venous system. One last observation here. When I started IVMP the nurse inserted a very small 24 gauge needle. Small needles like this tend to clot quickly. Mine lasted the full seven days. I have no expertise here, but I suspect this is unusual.
24) I also suspect that stopping IVMP may result in a severe rebound hypercoabulable state that may result in large vessel thrombosis. This happens when such medication such as Coumadin are stopped. There are case reports of patients developing internal jugular vein thrombosis following cessation of high dose IVMP. This assumption is also based on a personal experience. Five days after stopping the IVMP I decided to do an INR/aPTT. They were low and unmeasureably low, which would imply a severely hypercoagulable state. I had a blood test drawn three time to verify the result and the tests were the same each time.
25) Post angioplasty there have been anecdotal reports of patients deriving significant improvement in some symptoms and either worsening of certain symptom or the creation of new symptoms. This type of phenomenon can be explained if one analyses the fluid dynamics of the arterial and venous systems. If a venous obstruction is relieved on one side, this will result in increased blood flow on the affected side, but it will result in reduced blood flow on the other side. The side with sudden reduced flow will experience either new or worsened symptoms.
26) I suspect that heparin may be the drug of choice to treat MS exacerbations. I also suspect it may also be useful more long term as a disease modifying agent.
27) I suspect fatigue in MS may be a result of overall low flow in the brain but I wonder if another mechanism may be responsible. When a vein is stenosed or blocked it dilates upstream or collapses downstream. Large veins possess baroreceptors that sense stretch of the vein so that it can send signals that regulate overall blood volume. If the vein is inappropriately stretched or collapsed, the body will regulate blood volume inappropriately. Fatigue may be secondary to inappropriately low blood volume. I myself have very low blood pressure and have noticed many patients on the forum seem to have the same.
28) The mechanism of disease theory I am proposing for MS very possibly applies to numerous other autoimmune diseases.
After months of reading and research and perusing Thisisms.com, I was suddenly able to connect the dots three days ago. Much of what I have written about was precipitated by the most severe exacerbation I had (and am still having) in my 10 years with MS. I have been desperately trying to find a way to prevent paralysis. This exacerbation is likely a result of having gone on a Tysabri drug holiday. I hope my theory is correct.