We Need a Huge Randomized Controlled Trial by Dr. Manish Mehta
written for the 10th International Symposium of Endovascular Therapeutics in Barcelona, Spain
http://www.sitesymposium.org
Over the past several years tens of thousands of MS patients have undergone percutaneous treatments for CCSVI worldwide, and peer-reviewed journals have reported observational and comparative single and multicenter studies on over 1000 MS patients receiving these treatments for CCSVI indicating these procedures to be relatively safe with minor complications ranging between 1- 2%, and resulting in a vast majority of patients experiencing substantial physical and mental quality of life improvements. (1-4) Well beyond the published data to date, the web- based social networks are overflowing with thousands of patients and patient advocates reporting the substantial physical and mental quality of life improvements that they have witnessed following percutaneous treatments of CCSVI. Although one could argue that anecdotal evidence has little merit when evaluating new treatments particularly for an ailment such as MS that has the potential for having a significant placebo affect, what too is plausible is the notion that thousands of self reporting patients can no longer be perceived as ‘Anecdotal’. Furthermore, CCSVI being an entity of MS, and its treatment resulting in patient symptom improvement is one that has been reported by several independent investigators following Dr. Paolo Zamboni’s invention of this procedure. All such reports to date that have evaluated interventional treatments for CCSVI have reported on significant patient clinical improvements.
So what do we know about MS and CCSVI?
Since the first description of MS in 1886 by a professor of neurology at the University of Paris, Jean- Martin Charcot, there remain more questions than answers regarding the etiology and proposed treatment for this disease that effects over 2 million people worldwide. MS clinical manifestations are inclusive of motor, somatosensory, and cognitive impairment. There is no cure for MS, and the results of lifelong pharmacological immunosuppression are variable and not without its deleterious side effects. Although Chronic cerebrospinal venous insufficiency was first described and treated by Paolo Zamboni, the implications of obstructive venous associations with MS had been described by work by Charcot and Putnam dating back to the 19th and 20th centuries (5-6). Zamboni described CCSVI as outflow obstructions along the extracranial venous system, mainly the Internal Jugular and the Azygous veins that alter the central nervous system venous drainage. (7). He postulated that the chronic venous reflux and the associated physiologic impairment in CNS venous drainage could result in damage to the blood brain barrier leading to red blood cell extravasation and perivenule iron deposition, and the resultant inflammatory and autoimmune response (8-9) The basis of this theory dates back to 1980s when independent investigators published their findings of cadaveric histological evaluation of MS plaques and noted significant iron deposition and vascular damage along the venous vasculature. (10- 11) Advances in 7-Tesla MR susceptibility weighted imaging technology further confirm these findings as several studies have documented perivenule hemosiderin laden macrophages in MS plaques. (12-14). The perivenule topography of MS plaques and the associated histologic as well as MRI findings illuminates a compelling argument in favor of CCSVI. Of course, we fully recognize that the work has just begun and a significant body of scientific evidence will have to emerge to build on these initial findings and that further identify the relationships between iron deposition, inflammation, and the neuro-inflammation and degeneration. (15)
At the epicenter of the debate is confusion and controversy regarding the ideal study methodology for evaluating CCSVI.
While emerging evidence suggests that venous dysfunction might be a critical pathway to our understanding of MS, it might be germane to the pathophysiology of a broader range of neurodegenerative disorders. We all agree in that we need to better understand the spectrum of which MS patients might have CCSVI and ones that would benefit from procedures geared towards diminishing the potential detrimental effects of CCSVI. (16-22) The ideal study design would be inclusive of a multidisciplinary team inclusive of neurologists, vascular surgeons/ interventionists, and radiologists that would construct a well conceived prospective blinded randomized controlled trial with appropriate inclusion and exclusion criteria that would result in meaningful outcomes. We also recognize that in order for the randomized controlled trials to be meaningful, we need to have preliminary pilot studies to better understand and define the endpoints.
In a prospective study of endovascular treatment of CCSVI, Zamboni and colleagues reported their findings of 65 MS patients with CCSVI that underwent PTA of their central extracranial venous stenosis.
Majority of the MS patients were relapse remitting and CCSVI-PTA in these patients resulted in a significant improvement in MS clinical outcome measures at 1 year including the Multiple Sclerosis Functional Composite (p
The findings of the largest prospective blinded study evaluating patients with MS as well as other neurological disorders with healthy matched controls that set out to determine the prevalence of CCSVI in patients with MS using transcranial and extracranial color- duplex ultrasound indicated a significantly higher prevalence of CCSVI in MS patients when compared to the healthy controls (56% vs. 22% p
Relationships between CCSVI and iron deposition in MS patients have been evaluated by correlating venous hemodynamic parameters and iron concentration in deep-gray matter and lesions measured by MR susceptibility-weighted imaging in 24 patients (16 MS patients vs. 8 age and gender matched healthy controls). Initial findings indicated that all 16 MS patients and none of the healthy controls fulfilled the diagnosis of CCSVI. They also noted a significant association between the venous hemodynamic parameters and higher iron concentrations, as well as a relationship between iron concentration and longer disease duration and increased disability. These findings suggest that CCSVI might play an important role in iron deposition in the MS patient’s brain parenchyma. (24)
The first report of histological analysis of venous structures associates with chronic cerebrospinal venous insufficiency was reported at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). They harvested and analyzed bilateral IJV, Subclavian, Brachiocephalic, and the Azygous veins from 7 deceased MS patients and 6 non-MS controls. Marked valve and other intraluminal abnormalities with potential hemodynamic consequences were identified in 5 of 7 (71%) patients (7 abnormalities) and in only 1 of 6 (17%) controls (1 abnormality). These abnormalities included circumferential and longitudinal membranous structures, single valve flap replacing IJV valve, and enlarged and malpositioned valve leaflets. This postmortem examination demonstrates that a vast majority of MS patients have a variety of structural abnormalities and anatomic variations with possible hemodynamic consequences when compared to the non-MS population. (25)
The Albany Vascular Group Experience:
At the Society for Vascular Surgery meeting in 2011 we presented our initial experience of percutaneous balloon angioplasty of the extracranial central venous system including the internal jugular and the Azygous veins in MS patients with CCSVI. (26) Our goal was to evaluate the safety, feasibility, and efficacy of PTA for extracranial venous stenosis and valve abnormalities in MS patients with CCSVI and its influence on the clinical outcomes of MS. One hundred relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP) MS patients underwent a detailed evaluation of the bilateral internal jugular and Azygous veins via selective venography, and patients with angiographic evidence of >50% stenosis, valve abnormality, and reflux underwent PTA. Clinical evaluation included a timed 25-foot walk, MS Quality of Life (MSQOL), and Modified Fatigue Impact Scale (MFIS) at 3, 6, and 12 months. The study was conducted with IRB approval and statistical analysis was performed using two-tailed Student’s t-test. Venography in 100 MS patients identified 178 central veins with >50% stenosis & valve abnormalities in the IJV (n=160/178, 90%) and AV (n=18/178, 10%), (1.8 lesions/patient (mean)). In treating IJV and AV lesions, PTA was technical feasible in 97%, technical successful in 77% (
In another study, we wanted to quantitatively analyze the impact of internal jugular vein (IJV) PTA on the flow dynamics across these lesions. Fifty IJV form MS patients with CCSVI and 12 IJV from healthy volunteers (Vascular surgeons from the Albany Vascular Group) underwent detailed angiographic evaluation. Technical components of all venograms were standardized. Quantitative analysis included the contrast time of flight (TOF) from the mid IJV to the superior vena cava, and the primary venous emptying time (PVET), quantified as >50% of venous emptying, from the IJV. The TOF and PVET were recorded in patients with CCSVI prior and subsequent to balloon angioplasty, as well in normal healthy subjects. All data was prospectively collected, and statistical analysis was performed using two-tailed Student’s test. Of the 50 CCSVI-MS patients with IJV stenosis >70% and reflux underwent balloon angioplasty, technical success defined as
Prior to intervention, when compared to the healthy controls, the MS patients had significantly longer mean TOF (5.28 sec. vs. 2.33 sec, p
Following IJV-PTA, CCSVI patients were noted to have a significantly improvement in flow dynamics resulting in comparable mean TOC (2.45 sec. vs. 2.33 sec., p
So back to the question at hand, is CCSVI an entity and a subset of MS? On the basis of the significant body of evidence generated from multispecialties across the globe, the answer to that question would be YES. From its initial description, over the past several years, many investigators have continued to add to rapidly evolving scientific evidence that identifies CCSVI association with MS and maybe even other neurodegenerative disorders. As with any new therapy and particularly with MS, the initial learning curve is steep, and many of the publications have emerged without a standardized approach to the diagnosis, intervention, adjunctive treatments, and critical endpoint analysis. It would have been impossible for any single individual, institution, or specialty to discover a phenomenon, invent a procedure, and identify all of its perceived benefits, particularly in a disease state as elusive as MS. Our understanding of CCSVI and its implications in MS patients has evolved significantly over the past several years and today MS societies worldwide are committing millions of dollars to CCSVI related research projects. The ongoing collaborative efforts among national and international multidisciplinary research teams to better understand the implications of CCSVI in MS is underway, and it is likely that this evidence will help shape the future treatment strategies for not just MS patients but also those with a variety of other neurodegenerative disorders.
REFERENCES
1. Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009; 50:1348-1358
2. Ludyga T, Kazibudzki M, Smika M, Hartel M, Swierad M, Piegza J, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology 2010 Dec; 25(6): 286-95
3. Mehta M. A prospective analysis of endovascular treatments of CCSVI in MS. Presented at: the International Society for Neurovascular Disease Annual Meeting; March 14, 2011; Bologna, Italy.
4. Mandato K, Hegener P, Siskin GP, et al. Safety of outpatient endovascular treatment of the IJ and azygos veins for chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (abstract 3). J Vasc Interv Radiol. 2011;22:S4
5. Charcot JM. Histology of “sclerose en plaque” (in French). Gazette Hosp (Paris) 1868; 41:554-566.
6. Putnam TJ. Lesions of encephalomyelitis and multiple sclerosis: venous thrombosis as the primary alteration. JAMA.1937;108:1477-1480
7. Zamboni P, Galeotti R, Menegatti E, Malagoni A M, Tacconi G, Dall'Ara S, Bartolomei I, Salvi F. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80(4):392–399
8. Zamboni P. The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med. 2006;99:589-593.
9. Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab. 2009;29(12): 1867–1878.
10. Craelius W, Migdal MW, Luessenhop CP, Sugar A, Mihalakis I. Iron deposits surrounding multiple sclerosis plaques. Archives of pathology & laboratory medicine. 1982; 106(8): 397.
11. Adams CW. Perivascular iron deposition and other vascular damage in multiple sclerosis. British Medical Journal. 1988; 51(2): 260.
12. Haacke EM, Garbern J, Miao Y, Habib C, Liu M. Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol. 2010; 29(2): 149–157
13. Tallantyre EC, Brookes MJ, Dixon JE, Morgan PS, Evangelou N, Morris PG. Demonstrating the perivascular distribution of MS lesions in vivo with 7-Tesla MRI. Neurology.
14. Tallantyre EC, Morgan PS, Dixon JE, Al-Radaideh A, Brookes MJ, Evangelou N, Morris PG. A comparison of 3T and 7T in the detection of small parenchymal veins within MS lesions. Invest Radiol. 2009; 44(9): 491–494
15. Williams R, Rohr AM, Wang W, Choi I, Lee P, Berman N, Lynch S, LeVine SM. Iron deposition is independent of cellular inflammation and vascular changes in a cerebral model of multiple sclerosis. BMC Neuroscience. 2011; 12:59.
16. Al-Omari MH, Rousan LA. Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int Angiol. 2010 Apr; 29(2): 115- 20.
17. Simka M, Kostecki J, Zaniewski M, Majewski E, Hartel M, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology. 2010 Dec; 25(6): 286-95.
18. Zivadinov R, Marr K, Cutter G, Ramanathan M, Benedict RH, Kennedy C, Elfadil M, Yeh AE, Reuther J, Brooks C, Hunt K, Andrews M, Carl E, Dwyer MG, Hojnacki D, Weinstock-Guttman B. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. 2011 Jul 12; 77(2): 138- 44.
19. Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010 Aug; 68(2): 173-83.
20. Baracchini C, Perini P, Calabrese M, Causin F, Rinaldi F, Gallo P. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol. 2011 Jan; 69(1): 90-9
21. Zivadinov R, Galeotti R, Hojnacki D, Menegatti E, Dwyer MG, Schirda C, Malagoni AM, Marr K, Kennedy C, Bartolomei I, Magnano C, Salvi F, Weinstock-Guttman B, Zamboni P. Value of MR venography for detection of internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal study. AJNR Am J Neuroradiol. 2011 May; 32(5): 938-46
22. Zamboni P, Galeotti R, Menegatti E, Malagoni A M, Tacconi G, Dall'Ara S, Bartolomei I, Salvi F. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009; 80(4): 392–399
23. Zivadinov R, Marr K, Cutter G, Ramanathan M, Benedict RH, Kennedy C, et al. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology 2011 Jul 12; 77(2): 138-44
24. Zivadinov R, Schirda C, Dwyer MG, Haacke ME, Weinstock-Guttman B, Menegatti E at al. Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case- control study. Int Angiol 2010 Apr; 29(2): 158-75
25. Diaconu C, Staugaitis S, McBride J, Schwanger C, Rae-Grant R, Fox R. Anatomical and histological analysis of venous structures associated with CCSVI. Presented at ECTRIMS, October 2011, Amsterdam
