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

History, Hysteria and Hope

May 24, 2013

  

In the last two years, the paradigm for treating MS has changed.  Vitamin D supplementation is routinely recommended.  A healthy diet and exercise are encouraged.  Stress reduction and lifestyle changes, like smoking cessation, are encouraged.  

We are seeing a subtle shift in the understanding of MS as a purely autoimmune disease which cannot be modified, to an inflammatory disease which can be addressed with lifestyle changes encouraging cardiovascular health.

This is new.  

We also now understand that the changes which happen to the brain early in the MS disease process create pain, depression and fatigue.  These are not imagined symptoms.  They are real, and linked to atrophy of the hippocampus and thalamus.

Here is some more background about how MS has been viewed and treated throughout history.

You will see, the shift in how neurology considers MS is still evolving.

We're getting there.

The history of MS research is full of assumptions that were once held as fact by neurologists, but were later proven untrue.  It's important to review how multiple sclerosis patients have been described over the course of history, in order to understand the current mindset of neurology.  I hope this opens some eyes.   

Each of these three points were once believed to be factual.  We now know they were wrong, dead wrong. 
But the repercussions of these inaccurate beliefs linger today.

1. MS is related to the patient's psychological condition.

The very beginnings of MS research were dominated by French neurologist Charcot's fascination with hysteria and personality disorders as related to neurological disease.

Hysteria, from the ancient Greek word for uterus, was a nervous illness long associated exclusively with women. Symptoms differed from patient to patient and from one historical period to another, but they always involved both the body and the mind. Some characteristic symptoms included shortness of breath, heaviness in the abdomen, muscular spasms and fainting. Anxiety, irritability and embarrassing or unusual behaviour were also noted.

Hysteria received intense attention during the late 1800s. The French neurologist Jean-Martin Charcot proposed hysteria was an inherited nerve disease, similar to multiple sclerosis...Charcot investigated hysteria using hypnosis. In lectures he invoked characteristic symptoms in male and female hysterics by applying pressure to specific spots on the hypnotised patient’s body. Critics argued these performances testified to Charcot’s powerful influence over his patients, not the nature of hysteria.

http://www.sciencemuseum.org.uk/broughttolife/techniques/hysteria.aspx

This subtle message, which began as an understanding of MS as a disease involving the psyche,  was that MS was somehow initiated by a personality or nervous disorder which could be controlled by the neurologist.  This subtext continued on into the 20th century.  Here is research from the 1950s.

"The personality characteristics associated with multiple sclerosis as revealed by the MMPI profiles are presented and discussed. The personality characteristics revealed are: a reaction of depression, preoccupation and concern about bodily functions, feelings of hopelessness and insecurity, as well as tendencies toward indecisiveness, narrowness of interests, and introversion. Difficulty in accepting the disease, and its progressive limitations, as well as ambivalence and insecurity concerning the future, are often reflected in relatively poor emotional control and social adjustment."

http://psycnet.apa.org/journals/ccp/15/3/253/

2. MS does not cause fatigue.  

In the 20th century it was believed that fatigue was not a symptom of MS.  It was believed that fatigue was what caused MS.

Patients were told to stop exercising and to rest in order to avoid relapses.  The underlying message, again, was that there was a personality type that developed MS--neurotic, stressful, type A personality--hysterics. The message was that if patients could just rest, take it easy, not worry;  they could avoid relapses and disease progression.  This has been proven untrue.  Many different people develop MS: from athletes to academics, from mothers to rock stars, from children to middle aged adults.   And stress and rest are not part of the equation in contracting the disease.  And fatigue is often the presenting symptom before an official MS diagnosis as we learned this week.  And those who are able to exercise do better with symptom management.

3. MS does not cause pain

 When most people think of multiple sclerosis, they think of a disease that causes symptoms of weakness and motor problems -- not pain.

"About 10 or 20 years ago, there was a saying that MS causes all kinds of trouble but doesn't cause pain, which really isn't true," says Francois Bethoux, MD, director of rehabilitation services at the Mellen Center for Multiple Sclerosis Treatment and Research at The Cleveland Clinic.

http://www.medicinenet.com/script/main/art.asp?articlekey=52405

As many with MS can tell you---they feel pain.  Their pain is real, and it is caused by their MS.  Even though patients have been describing their pain to their doctors for over a hundred years, it is only in the last 10 years that this has been taken seriously.

__________________________________________________________

I believe that the distance between the multiple sclerosis patient and the neurologist was allowed to persist through the historical characterization of the MS patient as hysteric, emotionally labile, neurotic or mentally unbalanced.  These false depictions were created by a group of doctors who were threatened by their own personal lack of understanding of the disease and inability to change its course.    It was too difficult to confront the ravages of MS and not be able to cure the disease.  It was easier to portray the patient as defective and the source of their malady.   This provided a comfortable distance between doctor and patient.

Neurology so distanced itself from the patient, that THEY DIDN'T EVEN BELIEVE THE MS PATIENT WAS IN ACTUAL PAIN.  It took over one hundred years for neurologists to admit that there might be pain, or fatigue, or depression caused by multiple sclerosis.  This is absurd.

Since the advent of MRI technology, doctors have concrete evidence of the degredation of gray matter, atrophy of the hippocampus, and demyelination in areas of the brain responsible for emotion, pain and cognition.  All of these changes to the brain are linked to depression, pain and fatigue.  
http://ccsviinms.blogspot.com/2010/07/study-on-brain-changes-in-ms-and.html

These changes to the brain occur early in MS.  Researchers can see the slowed blood flow and hypoperfusion.  They can study fMRI images. 7Tesla imaging (Ge, et al) has allowed researchers to see the microscopic vascular changes that happen to the veins in the MS brain. 
http://ccsviinms.blogspot.com/2009/12/hypoperfusion-decreased-blood-flow-in.html

The physical changes to the brain are caused by a disease process.  They are not psychological or imagined.   The disease comes first, and the brain damage follows.

If there are any young neurologists reading this, I implore you, bridge the gap between patient and doctor.

Look at your patients as family members, friends, siblings, loved ones, human beings. 

Study their MRI images, work with vascular doctors and look at their cerebral blood flow, specifically, the venous return.  Don't be afraid of collaboration between disciplines.  For this is the future of medicine.

Talk to your patients, but most importantly, listen to them.  When they tell you they are in pain, or exhausted or depressed--believe them.  Try to help them.  And try to learn WHY this is happening.

It's time to say goodbye to the era of Charcot and hysteria.  It's time for science.

Joan

Charcot demonstrating hypnosis on an "hysterical" Salpêtrière patient, "Blanche" 

A painting by Pierre Brouillet

Medical Hierarchies

February 2,  2013  

We are beginning to see how the hierarchical power structure at universities and in medical journals is impacting research into CCSVI. Negative studies are picked up time and time again in the press and regurgitated ad infinitum,  while positive and corroborative CCSVI research from vascular specialists is ignored. 

Why?

Aside from corporate conspiracy theories (which may be true, but near impossible to prove)---there is another force which comes into play in research.

The hierarchies of medical disciplines.

Here is a paper written in the 1980s, regarding the favoring of the immunologists' explanation of MS over the vascular paradigm. 

Yes, this debate has been waging for many, many years-it is not new.

http://onlinelibrary.wiley.com/doi/10.1111/1467-9566.ep11340153/pdf

From the paper on Social Constructionism and medical sociology: a study of the vascular theory of MS--

"A recent debate surrounding the pathogenesis of multiple sclerosis is analysed in terms of the skills, interests and backgrounds of the medical personnel involved. It is noted that the proponents of the vascular theory possess developed expertises in interpreting disease in

structural, vascular terms, whereas their opponents' skills lie in immunology or neurology. Different observers have produced different conceptions of the disease because modes of

observation, and the points from which observation takes place, differ. 

It is also noted that the debate over the causation and treatment of MS has occurred between a large and powerful social group and a weak and marginal one. The effects of this power inequality on the production and assessment of knowledge about MS are investigated."

The authors go on to explain how the "large and powerful group" of more highly paid and trained neurologists got to "own" MS. Because of this, any other theories or modalities of MS diagnosis or treatment from weaker and less powerful medical groups or patients are shot down, called quack theories and easily discounted.

This is a very important paper for us to understand.  It reviews Dr. Philip James' studies in Scotland in the 80's. He likened the MS disease process to decompression sickness and oxygen deprivation he found in divers. James, like Dr. Roy Swank, thought this might be due to blockages in the vascular system, and he had much success treating MS patients with hyperbaric oxygen. 

This paper helps us understand what we've always been up against- and why the internet is a democratizing power in this "social constructivism" and how we can change the dialogue, and insist on more vascular research.  We can lend our voices to help the "marginalized" vascular profession.

We may not be able to control what the mainstream/corporate press publishes in terms of research results, BUT we can inform one another, and help the vascular doctors have a platform for their research.

Spread the word.

Joan