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Endovascular Treatment of Multiple Sclerosis: A Critique

The startling idea that multiple sclerosis is caused not by autoimmunity but by obstruction of the neck veins which drain the brain has drawn extraordinary interest since its reintroduction by Italian vascular surgeon Paolo Zamboni in 2006.  His motivation to study the disease was a severe exacerbation of his wife’s multiple sclerosis.  

In the earlier 1946 edition of A Textbook of Clinical Neurology by JM Nielsen [1], this same theory was presented as the leading hypothesis of the pathogenesis of multiple sclerosis, although the idea was subsequently forgotten.  I value the ideas in old textbooks because, at least in the case of vascular pathology, recent texts are swollen with in vitro observations which have no relevance in vivo

Because I believe blood flow plays a fundamental role in health and disease, I read the modern literature about the role of venous obstruction, or chronic cerebrospinal venous insufficiency (CCSVI), in multiple sclerosis with an open mind.  I am highly critical of the scientific method being trumped by special interests in medicine and am sympathetic to thinking that is outside of the box. 

Pathologically, multiple sclerosis is characterized by “plaques” of demyelinated axons and associated inflammatory cells.  Clinically, the disease is most commonly characterized by a progressive course of unpredictable relapses and remissions.  This makes prospective study of multiple sclerosis difficult:  Is the therapy effective or the disease process remitting spontaneously? 

Endovascular Treatment of Multiple Sclerosis

In 2009, Zamboni reported that endovascular balloon dilatation of stenotic neck veins significantly improved quality of life and function one year following treatment in patients with relapsing remitting and primary progressive multiple sclerosis but not secondary progressive multiple sclerosis [2].    Venous obstruction causes back pressure, called “passive congestion,” and leakage of erythrocytes resulting in accumulation of hemosiderin, an iron-containing breakdown product of hemoglobin. 

Accumulation of hemosiderin is characteristic of congestion, being present in the skin in venous stasis dermatitis, the lungs in congestive heart failure and pulmonary veno-occlusive disease, and the liver in chronic passive congestion due to right heart failure.  In my opinion, a histopathologic diagnosis of these conditions would be questionable in the absence of hemosiderin.   

Zamboni found that Jean-Marie Charcot, the pioneering French neurologist who first described multiple sclerosis, reported iron accumulation in brain lesions in his original description of the disease.  However, we now know that hemosiderin accumulation is not characteristic of the lesions in multiple sclerosis.  In a study aimed at determining the prevalence of hemosiderin in multiple sclerosis, Adams found hemosiderin in only 30% of cases.  Only seventeen percent (n=12) of active cases showed recent hemorrhage [3]. 

Critique of the Endovascular Approach

Hemosiderin accumulation is not mentioned in pathologic descriptions of multiple sclerosis in standard reference texts [4,5].  In my opinion, these data are sufficient to refute the hypothesis that venous obstruction causes multiple sclerosis.  The presence of hemosiderin in Adams’ study could easily be explained by collateral damage of vessels by autoimmune inflammation.      

Like Dr. Charcot’s finding of iron in the lesions of multiple sclerosis, Dr. Zamboni’s finding that CCSVI is strongly and uniquely associated with multiple sclerosis has not been reliably reproducible.  Reporting a negative result in October 2012, Giancarlo Comi, MD, Director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, said, "I do really hope that this is the last time I have to talk about this topic… because there is no rationale for a trial exploring the efficacy of liberation therapy [the name by which proponents refer to endovascular venous angioplasty], I personally think it's absolutely inappropriate that the government finances any type of investigation or research." [6]

Less than a year later in May 2013, Alexander Rae-Grant, MD, neurologist and chair of Neurological Education at the Cleveland Clinic stated, "What if we're missing something? What if there is a vascular piece to this? What if there's a subset in which this means something? What if we're throwing the baby out with the bathwater? And what if, down the road, it becomes clear that we missed it?" [7]    

Perhaps the best study of the role of CCSVI in multiple sclerosis was published online in October 2013.  This study found 1 of 65 (2%) multiple sclerosis patients had CCSVI, compared to 1 of 46 unaffected siblings (2%) and 1 of 32 (3%) of unrelated controls [8].  The editorial accompanying this study was entitled “Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis:  the Final Curtain.” [9] However, the curtain will not fall on CCVSI.  Because of pressure applied by multiple sclerosis patients in Canada, government funded clinical trials of endovascular dilation versus sham treatment will continue.  Early study results are expected to be available in the fall of 2015. 

In 2012, the U.S. FDA issued a warning to MS patients that endovascular surgery poses a risk of serious injury without proven benefit [10].   Possibly as a result of this warning, it was reported in the New York Times that a practice in California which performs only the Zamboni procedure has changed the indication for the procedure from multiple sclerosis to “autonomic dysfunction” [11].

My critique of endovascular venous angioplasty in multiple sclerosis serves as an example of how changes in blood flow cannot serve as a de facto mechanism of action behind disease states or treatment approaches. Only an evidence-based approach permits adherence to the scientific method. As the story of multiple sclerosis, chronic cerebrospinal venous insufficiency, and endovascular surgery amply demonstrates, adherence to the scientific method is not universal.  Science is, as Thomas Kuhn put it, an “arational” process in the short term.  Society should be grateful for those clinical researchers who do adhere to the scientific method.  If not for them, this story would have dragged on for much longer and wasted many more resources. 


References:

1.  A Textbook of Clinical Neurology.  Nielsen, JM.  Paul B Hoeber, Inc.  New York, 1946, p. 529.

2.  A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency.  Zamboni P, et al.  J Vasc Surg 2009; 50(6):  1348-8.

3.  Perivascular iron deposition and other vascular damage in multiple sclerosis.  Adams CWM.  Journal of Neurology, Neurosurgery, and Psychiatry 1988; 51:  260-265.

4.  Robbins & Cotran Pathologic Basis of Disease, Seventh Edition, Kumar, V, Fausto, N. and Abbas, A.  Saunders, 2004.

5.  Practical Surgical Neuropathology: A Diagnostic Approach.  Perry A, Brat, DJ.  Chruchill Livingstone, 2010, p 487-492.

6.  New CCSVI Studies Negative, Procedure Not Without Risk.  Jeffrey, S.  October 26, 2012.  http://www.medscape.com/viewarticle/773381

7. Don’t Dismiss CCVSI Yet, Expert Says.  Anderson, P.  June 10, 2013. http://www.medscape.com/viewarticle/805565

8.  No link between CCSVI and MS using Gold Standard Imaging, Anderson P.  October 8, 2013. http://www.medscape.com/viewarticle/812262

9.  Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis:  the Final Curtain.  Friedemann, P, and Watties MP.  Lancet 2014; 383;9912:  106-108.

10.  FDA Safety Communication:  Chronic Cerebrospinal Venous Insufficiency Treatment in Multiple Sclerosis Patients.  May 10, 2012.  http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm303318.htm

11.  A controversial ‘cure’ for M.S.  Tullis, P.  New York Times October 26, 2012.  

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