Ending a "Misadventure"

The following is an open letter to Dr. Dennis Bourdette in response to his editorial in the June 2014 issue of Neurology, entitled Venous Angioplasty for "CCSVI" in multiple sclerosis: ending a therapeutic misadventure.  This open letter has been sent to his university, as well.  I hope to continue a dialogue with the CCSVI advocacy community and neurology.



Dear Dr. Bourdette--


I was disappointed to see that your comments in Neurology only focused on one half of the two phases of the BNAC PREMiSe CCSVI trial.  The first phase, which has been largely ignored by the press and neurology,  was a case controlled study of venoplasty in 15 patients with RRMS.  Eight patients were treated with venoplasty to repair CCSVI, and the other seven had delayed treatment after 6 months.  There was an immediate improvement in cerebrospinal fluid flow in the treated group, a lessening of lesions on MRI, while the delayed treatment group showed continued MS progression, more lesions and altered CSF hemodynamics.  This phase of the study showed venoplasty, when able to restore venous flow to >75% of capacity,  created a measured improvement of CSF flow and better parenchyma venous drainage, which continued on for twelve months after treatment.   It was published in The Journal of Vascular Interventional Radiology.  (1)  Important to note that Phase 2 of PREMiSe DID NOT restore venous flow to >75%.. In fact, it only restored venous flow to 50%, and was a failure of treatment.  There are many more published studies finding a connection of CCSVI and MS and improvements after successful treatment, and they appear mainly in vascular journals and are ignored by neurology. This disconnect has become increasingly frustrating to those of us whose lives depend on the future of MS research.

As a neurologist with an endowed chair from the Swank Family Foundation, I'm sure you are well-versed in the vascular component of multiple sclerosis.  Dr. Roy Swank was documenting  "capillary fragility"  in Neurology's pages in 1958.  He found systemic subcutaneous hemorrhages in his MS patients, decades before the science of the endothelium.(2)  He also noted hypercoagulation, platelet abnormalities, and slowed cerebral blood flow in MS.(3)  Today, we understand much more about how the vasculature is involved in MS. (4)  To label research into CCSVI and the extracranial venous system as a "misadventure" is to do science a great disservice. 

In spite of the accumulating links of MS to cerebral hypoperfusion (5) and recent research as to how the vascular endothelium controls cerebral blood flow and neuronal health (6), neurological researchers remain wedded to Dr. River's EAE murine model of 1935.  This allegiance to EAE is a stranglehold far more damaging than Charcot's harness. (7)  The tragedy of PML occurred in patients receiving Tysabri infusions only because mice cannot be infected by the JC virus.  The murine model testing of Tysabri could not foretell the deadly results in humans. (8)  The mouse model of EAE is not spontaneous nor does not remit, as MS develops, relapses and remits in humans.(9)  It is time to admit that the EAE mouse model, while somewhat effective for testing immune modulating pharmaceuticals, is not helping us understand the disease process we call multiple sclerosis.  Nor is it addressing MS disability progression linked to gray matter atrophy.  

I am married to a man diagnosed with MS in 2007.  Due to his severe presentation, he was told not to expect many more days of mobility.  At the time, I noted vascular issues, including a petechial rash--the same rash Dr. Roy Swank had documented.  My husband also presented with extreme hypercoagulation and high liver enzymes.(10)  By making the connection of his disease to his vascular system, I was able to piece together peer-reviewed and published research to address these factors. Since his diagnosis seven years ago, he follows a diet and active lifestyle based on Dr. Swank's program-- combined with modern research into endothelial health and EDRF (nitric oxide), published by Dr. John Cooke, author of The Cardiovascular Cure. (11) 

He had venoplasty at Stanford University over five years ago, to resolve a severe stenosis in his left jugular vein and dural sinus. (12) Since this successful endovascular treatment, which is approved for dural sinus stenosis (13), his gray matter atrophy has reversed, as documented on MRI. This fact makes it difficult to claim his improvements are due to placebo.  He jogs, skis, mountain bikes, hikes and works full days.  Not bad for a 51 year old man with MS.  Since venoplasty, his heat intolerance is gone, his cognitive fog and fatigue hugely reduced.  His bladder issues and spasms have remitted. He no longer has central sleep apnea.  He has had no further lesions or MS progression.  And yes, he is a wonderful anecdote; as are the thousands of other MS patients who have received venoplasty and had benefit.  Or the thousands of other patients, like Dr. Terry Wahls and Dr. George Jelinek, who have changed their diets, increased aerobic exercise, stopped smoking, utilized UV ray therapy, and found hope in "alternative" cardiovascular treatments.

Where is the intellectual curiosity of neurologists?  Why the continued disassociation of the brain with the cardiovascular system and blood vessels?  

It is time to admit---neuroimmunology has failed MS patients.  This is exactly why so many patients and caregivers are turning to treatments outside the EAE autoimmune paradigm.  Neurologists must reach out, across academic silos, to include the new research of the endothelium and the vascular component of MS.  CCSVI investigation is only just beginning.  Neurology has had eighty years of EAE, and many, many failures.  The vascular endothelium and extracranial venous system deserve a bit more time and effort, before you proclaim the exploration over.

I invite a dialogue, Dr. Bourdette-- and would be happy to share your thoughts on this letter- in my blog and with the online CCSVI community.  I also invite you to consider the continuing research of the International Society for Neurovascular Disease. (14)

most sincerely,

Joan Beal

Disclosure:  Joan Beal is not a doctor.  She receives no money for her MS advocacy work.  She funds her own endeavors.  Her personal reward is seeing her husband thriving.  She writes about current MS research on her blog, Multiple Sclerosis-the vascular connection.  Joan's theory of MS is that it is a disease of endothelial dysfunction, cerebral hypoperfusion and reperfusion injury, and she invites researchers to consider the scientific evidence. Multiple Sclerosis--the vascular connection: Multiple Sclerosis -- Hypoperfusion/Reperfusion Theory

References:

1.  Zivadinov R, Magnana C,  Galeotti R, Schirda C, Menegatti E, Weinstock-Guttman B, Marr K, Bartolomei I, Hagemeier J, Maiagoni AM, Hoinacki D, Kennedy C, Beggs C, Salvi F, Zamboni P    Changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: a case-control study.  Journal of Vasc. Interv. Radiology 2013 Jun;24(6):829-38. 

2. Swank RL. Subcutaneous hemorrhages in multiple sclerosis. Neurology. 1958; 8: 497-498. 

3.. Swank RL: Plasma and multiple sclerosis - past and present; in: Multiple Sclerosis: Immunological, Diagnostic and Therapeutic Aspects. London, John Libbey Eurotext, 1987, pp 217-220.

4.. D'haeseleer M., Cambron M., Vanopdembosch L, De Keyser, J.  Vascular aspects of multiple sclerosis.Lancet Neurology. 2011 Jul;10(7):657-66. 

5. Narayan P, Zhou Y, Hasan K, Datta S, Sun X, Wolinsky J.  Hypoperfusion and T1 hypointense lesions in white matter in MS.  Multiple Sclerosis Journal.  March 2014 vol. 20 no. 3365-373

6. Brenda R. Chen, PhD; 

Mariel G. Kozberg, MPhil; 

Matthew B. Bouchard,   PhD;

Mohammed A. Shaik, BS; 

Elizabeth M. C. Hillman, PhD     

Vascular Medicine-A Critical Role for the Vascular Endothelium in Functional Neurovascular Coupling in the Brain.   J Am Heart Assoc. 2014;3:e000787  


7. Behan, P Chaudhuri, A.  EAE in not a useful model for demyelinating disease.   Multiple Sclerosis 

and Related Disorders.   01/2014


    Behan, P Futility of the Autoimmune orthodoxy in MS research.  Expert Rev. Neurother. 10(7), 1023–1025 (2010)  


8. Steinman, L  Zamvil, S  Virtues and Pitfalls of EAE for the development of therapies for multiple sclerosis, TRENDS in Immunology Vol.26 No.11 November 2005

9. Gold, R Linington, C Lassman, H.  Understanding pathogenesis and therapy of MS via animal models: 70 years of merits and culprits in EAE research.  Brain  doi:10.1093  2006.

10. Tremlett H, Seemüller S, Zhao Y, Yoshida EM, Oger JD, Petkau J.    Liver test abnormalities in multiple sclerosis: findings from placebo-treated patients.  Neurology. 2006 Oct 10;67(7):1291-3.  

11. Cooke, JP. Therapeutic interventions in Endothelial Dysfunction.  Clin. Cardiol. Vol. 20 (Suppl. II), II-45–II-51 (1997)

12. Dake MD,  Dantzer N, Bennett WL, Cooke, JP.   Endovascular correction of cerebrovenous anomalies in multiple sclerosis: a retrospective review of an uncontrolled case series.   Vascular Medicine 2012 Jun;17(3):131-7. doi: 10.1177/1358863X12440125. E2012

13. Arac, A  Lee, M  Steinberg, G   Efficacy of endovascular stenting in dural venous sinus stenosis   Neurosurg Focus 27 (5):E14, 2009 

14.  www.isnvd.org

The Endothelium

Update  APRIL 2019
More research continues to come in, linking endothelial dysfunction to multiple sclerosis.  Pub med has hundreds of new papers. 
https://www.ncbi.nlm.nih.gov/pubmed/?term=multiple+sclerosis+endothelial+dysfunction

++++++++++++++++++++++++++++++++++++++++++++

When I first began looking into how Jeff's MS was related to his vascular system in 2007,  I read many papers on pubmed which discussed the "endothelium."  A dysfunction in the lining of our blood vessels was implicated in chronic diseases of inflammation and hypoperfusion, such as MS.  I noticed that there were many modern day environmental factors that caused problems with endothelial health and blood flow.  Endothelial dysfunction was linked to diabetes, cardiovascular disease, autoimmune disease and neurodegenerative disease.  

Fast-forward seven years, and there are health stories on the endothelium in the mainstream press every day.  Here's a sampling from just last week----

Tomato Sauce helps fight heart disease   Of 36 patients with heart disease, those taking the pill every day for two months saw their blood vessels widen by 53 per cent.  This was due to improved functioning of the endothelium, the inner wall cell lining of blood vessels, scientists believe. link

How the brain regulates blood flow   Hillman found that the vascular endothelium, the inner layer of blood vessels, plays a critical role in propagating and shaping the blood flow response to local neuronal activity. While the vascular endothelium is known to do this in other areas of the body, until now the brain was thought to use a different, more specialized mechanism and researchers in the field were focused on the cells surrounding the vessels in the brain.link

Eating Strawberries may lower blood pressure   Strawberries are rich in antioxidants, which may lower blood pressure by relaxing the endothelium, the lining inside blood vessels.  Relaxing the endothelium widens the arteries, reducing pressure.link

So, now that we know the endothelium is truly important---how is our current environment impacting our health?   And what can we do about it?
Here's what I wrote in 2007:

                                                            

I truly believe endothelial dysfunction is the disease of modern man, and is responsible for the increasing rates of chronic disease in industrialized nations.

To provide a contrast and by means of example, I present a day in the life of two women, separated by only 200 years in time.

19th Century- Life as it been lived for thousands of years-

You and your husband get up from bed as the sun rises and the rooster crows. You both get dressed and head outside together to milk the cows and feed the livestock. You work the pump at the well, get a drink of water, which comes from a fresh spring underground. The physical exertion of pumping water and carrying it, lifting the feed and milking the cows has worked up a good sweat. You gather some fresh eggs from the henhouse, and head inside to cook breakfast. The meal includes coffee or tea made with spring water, fresh milk from the cow, eggs and toast with apple preserves, jarred last fall.

The children rise, get dressed, eat and are soon out the door to walk to school. Your husband heads off to his work in the barn. There is laundry to be washed and hung on the line and gardening to do. You spend over two hours out doors, in the sunshine.  Again, hard work and more exercise. This is not a life of leisure!

Fresh fruits and vegetables are eaten in season and canned and jarred for off season.  There isnʼt much meat, but an occasional fish from the stream or chicken from the henhouse. Grains are whole, and you add flaxseed to the bread. Root vegetables and greens are plentiful. Mealtime is spent together as a family. After dinner, and after the dishes pots and pans are cleaned, the family sits together and reads or plays board games. Soon the sun sets and itʼs time for bed. Everyone is tired from the dayʼs activities and ready to sleep.

21st Century--Our Modern Life

You rise in the dark to the incessant buzz of the alarm clock. Itʼs a quick shower in chlorinated and fluoridated city water and blow dry before heading to the kitchen to make a pot of coffee. You get your water from the tap and microwave a breakfast sandwich of processed ham and cheese to go. You check your e-mail on the laptop and holler to wake your husband and the kids and hurry them up- thereʼs no time to waste! They get dressed, grab their backpacks and eat their microwaved breakfasts as everyone piles into the van.

Itʼs off to school where you drop them at the door. Then you get back on the freeway to sit in traffic. Love those fumes! Youʼre starting to get a headache. Trapped on the road, you try to make good use the time by calling clients and checking your phone. Your stress levels are now through the roof of the van. You get to the office late and have to deal with everything that has been piled on your desk. No time for the gym, and lunch is going to be a bag of peanut M&Ms and a can of Coke. You never see the light of day, except through your office windows. By the time you get home, itʼs dark and the kids are fighting over the Playstation.

You still need to make dinner. Your husband has texted you, heʼs running late and will miss dinner...again.

You pile the kids back in the van and head to a fast food place. Itʼs drive through and the kids donʼt mind. Youʼre famished and get a double cheeseburger, since you skipped lunch, how could it hurt? You get everyone home and get the kids doing their homework. Itʼs nine pm before you know it, and your husband finally gets home. He walks in and just wants to sit in front of the TV, heʼs exhausted. You get the kids bathed and into bed. Itʼs 11pm before you fall into bed, head pounding. You have trouble sleeping, and it seems like by the time you finally drift off, the damn alarm is ringing again!

I do not mean to over-romaticize or idealize the lives of men and women from centuries ago. Theirs was a very different experience, and it was physically and emotional demanding. People got sick then, very sick, and many died premature deaths. But not many suffered from chronic diseases. Our modern lifestyle is much easier in many ways-- we have automated appliances to do our labor, vehicles to transport us, and conveniences our great, great grandparents could only have dreamed of. 

Our modern lifestyle has disrupted many natural and hormonal patterns; such as the circadian rhythm. We no longer use the sun to tell us when to rise and set. And doctors are seeing a deficiency of vitamin D (the sunshine vitamin made by our skin when exposed to sunlight) linked to many diseases. Not coincidentally, lack of vitamin D is one of the causes of endothelial dysfunction.

                                                                        +++++++++++

More science continues to come in, and we've learned how endothelial dysfunction is linked to slowed cerebral blood flow and inflammation. Some of the modern lifestyle/environmental factors which have been linked to endothelial dysfunction are:

1. Lack of UV rays, low nitric oxide and low Vitamin D

2. Lack of exercise and sedentary living

3. Higher stress and cortisol release

4. Lack of REM sleep and regular circadian rhythms

5. Too much glucose and refined sugar

6. Eating transfats and processed foods

7. Toxins, pesticides and heavy metals in air and food

8. Lower intake of whole foods, fruits and vegetables

And not coincidentally, when countries become industrialized or "westernized", rates of chronic diseases rise. 

Nevertheless it was the Industrial Revolution (with the widespread use of refined vegetable oils, refined cereal grains, and refined sugars)14,65 and the Modern Age (with the advent of the “junk food” industry, generalized physical inactivity, introduction of various pollutants, avoidance of sun exposure, and reduction in sleep time and quality coupled with increased chronic psychological stress)14,38,65,146,152,153,160 that brought about the most disruptive and maladaptive changes, which may have serious pathophysiological consequences.  link

Take care of your endothelium and it will take care of you.

For more information:

http://ccsvi.org/index.php/helping-myself/endothelial-health

Joan

Vascular aspects of multiple sclerosis

June 21, 2011 at 1:35pm

I have the complete review paper from Lancet Neurology.  It is a review of recent research in MS and is a compilation of the many studies we've linked on this page.  The endothelium, hypoperfusion, ischemia , CCSVI and the many terms we've learned over the past two years are all mentioned.  I do not want to violate copyright laws,  and can't copy and paste the full paper, but I'll give a brief breakdown.  You'll see text from the paper in italics, and then my comments.  

Note the word "might" is used extensively.  They review the research connecting the vascular system to MS.  While this is not earth-shattering to those of us who know CCSVI, up close and personal--it is encouraging to see this review in a neurological journal.  

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(11)70105-3/abstract

Abstract:

Vascular aspects of multiple sclerosis

Miguel D’haeseleer, Melissa Cambron, Ludo Vanopdenbosch, Jacques De Keyser

Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals.

#1   People with MS have ischemic stroke more often than healthy people.

Inflammation is widely accepted to play an integral part in the pathogenesis of atherosclerosis.18,19 Endothelial dysfunction is an early step towards overt atherosclerosis and the immune system seems to be highly involved in both processes.20 Endothelial dysfunction has been described in the very early stage of rheumatoid arthritis, probably as a result of inflammatory disease activity.21 Rheumatoid arthritis is an autoimmune disease22 in which increased cardiovascular morbidity and mortality has been noted.23 Alterations in endothelial function, as well as platelet activation and thrombophilia, have been reported in MS.24–26 Moreover, oxidative stress contributes to the development of endothelial dysfunction.27 Higher amounts of systemic and CNS oxidative stress have been reported in patients with MS than in healthy controls.28–30

The concentration of plasma homocysteine, which is believed to be an independent cardiovascular risk factor,31 is also raised in patients with MS.32,33 The cause of the increase in homocysteine concentration is unknown, but it occurs independently of serum concentrations of vitamin B12, vitamin B6, or folate.34 There is evidence that hyperhomocysteinaemia can cause endothelial dysfunction, even at moderately increased concentrations of homocysteine.35,36

The above evidence suggests that the increased frequency of ischaemic stroke in MS might be mediated through converging inflammatory pathways, oxidative stress, and raised homocysteine concentrations leading to endothelial dysfunction.

What this section is saying is that oxidative stress, endothelial dysfunction, endothelin-1 levels and homocysteine levels are higher in pwMS, and may contribute to higher stroke levels.  (We've talked about this on here for awhile, it's why I created the endothelial health program for Jeff--I noted this connection in his serum numbers, and tried to help him thru diet, supplements, exercise and lifestyle.)

The researchers are positing that this is all due to inflammation and the immune system in MS. They believe it all begins there.   But they have no proof of this.  It's just their theory--their way of looking at the evidence thru their prism of MS as immune.  But what we've discussed on here is that all of these factors are also found in diffuse cerebral hypoxia, or low levels of O2 in the brain.   We don't need to involve the immune system in this theory if we look at it thru the prism of reduced oxygenation in the brain due to slowed blood flow.