5. Chronic Cerebrospinal Venous Insufficiency

Chronic Cerebrospinal Venous Insufficiency, more commonly known as CCSVI, is a vascular disease that results from the narrowing of the internal jugular and azygos veins (stenosis). This leads to a disruption to the blood flow from the brain and spinal cord. In 2006, Dr. Zamboni argued that there was an association between CCSVI and Multiple Sclerosis (MS) [1]. He stated that because the blood could not be drained from the brain and spinal cord, this deposits iron in the central nervous system, triggering autoimmunity [1]. He stated that endovascular surgery, also known as liberation therapy, showed dramatic improvements in symptoms within his MS patients. In this therapy, blood was drained from the brain and spinal cord by opening up the internal jugular and azygos veins. However, there has been major controversy to this original paper where many scholars have argued that his study was not blinded and had no control groups. They emphasized that due to these research methodological insufficiencies, a conclusive argument could not be made about the association between CCSVI and MS, and therefore liberation therapy should be approached with caution [2].

5.1 Discovery of CCSVI

5.1a Personal struggle

Figure 1. Interview with Dr. Paolo Zamboni in 2010

Dr. Zamboni’s wife Elena Ravalli was diagnosed with MS, experiencing symptoms such as vertigo, numbness, and vision loss [3]. In 1995, Dr. Zamboni sought out to figure out the mystery behind MS and its causes [3]. He began his research studying early research on MS as well as looking at ultra-modern imaging technologies [3]. He soon realized, from reading early research from a century ago, that there was an access of iron buildup in a lot of MS patients [3]. Furthermore, using ultra-modern imaging technology, he soon discovered that in 90% of MS patients, there was an abnormal drainage of blood from the brain and spinal cord [3]. He thus made the controversial statement claiming that MS was a vascular disease and not one of autoimmune origin[3].

5.1b Stenosis

Chronic Cerebrospinal Venous Insufficiency is characterized by narrowing of the internal jugular and/or azygous veins, otherwise known as stenosis [4]. This leads to the impairment in the draining of blood from the brain and spinal cord [4]. This stenosis is caused and maintained by abnormal accumulation of proteins, such as adhesion molecules, macrophages, T-lymphocyte infiltration, and iron [4]. In a preliminary study, Zamboni found the stenosis and abnormal venous drainage was significantly more prevalent in his 89 MS patients than in the 60 healthy controls [5]. Furthermore, he also found that the severity of the disease was also correlated to the severity of the venous abnormality. In other words, the more severe the disability in the MS patient, the more pronounced the stenosis was. Studies have shown that although stenosis has been hypothesized to be causing MS, blood pressure was not significantly different between MS cohort and controls. However, it has also been shown that a stenosis of 2.2cm/H2O reduced the cross-sectional area of the internal jugular vein by 50% [6].

5.2 Pathology of CCSVI

5.2a Incorporation of iron into ferritin

The abnormal drainage of blood from the brain and spinal cord sets off a cascade of negative effects. The impaired drainage triggers interstitial macrophages in releasing iron from their native red blood cells [1]. The iron is incorporated into ferritin and soon changed into a molecule known as haemosiderin [6]. Zamboni argued that the accumulation of iron deposits in the brain is what triggers autoimmunity in CCSVI and MS[1].

5.2b Chronic inflammatory signal

The accumulation of iron and its associated degradation of red blood cell proteins initiate the chronic inflammatory signal, by acting as chemo-attractants, initiating the chronic inflammatory signal[1]. White blood cells soon enter the inflammatory site, migrating into the subcutaneous matrix. This maintains the chronic inflammatory response [1].

5.2c Role of matrix-metallo-proteases (MMPs)

The last step in the chronic inflammatory process involves increasing the amount of matrix metallo-proteases (MMPs). An accumulation of MMPs is detrimental to the matrix as it breaks it down [1]. Previous studies show that iron accumulation can trigger an even larger expression of MMP, exacerbating the negative effects. It is still unknown why iron and MMP produces MS-related lesions in only some individuals, although a few scholars have hypothesized that this may be due to genetics [1]. For example, mutations in C282Y and H63D within the HFE gene have been shown to cause the cascade effects seen with CCSVI-like symptoms. These mutations have also been shown to release more iron from macrophages, triggering autoimmunity [1].

5.3 Diagnostic technology

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Figure 2. Criteria for the diagnosis of CCSVI. 2 of the 5 criteria must be satisfied for positive diagnosis. Source:http://www.examiner.com/article/liberation-therapy-for-ms-not-very-liberating-it-seems-now

Posture and respiration are two vital characteristics that are needed to direct cerebrospinal venous flow [5]. For example, cerebrospinal venous flow goes through the internal jugular vein in the supine position [5]. To capture cerebrospinal venous flow, echocolour Doppler (ECD) and transcranial colour-coded Doppler sonography (TCCS) is often utilized [5].The following 2 of the 5 criteria must be fulfilled in order to diagnose CCSVI [6]. Zamboni also stated that based on these criteria, only MS patients were diagnosed with CCSVI [6].
1. Internal jugular vein reflex
2. Cerebral vein reflex
3. Presence of Internal jugular vein stenosis
4. Absence of flow in the internal jugular vein
5. Reverse cerebrospinal flow

Doppler utilizes colour and contrast to show cerebrospinal blood flow [6]. Zamboni showed that in the MS cohort, 288 subjects had normal blood flow while 257 had abnormal blood flow [7]. In the control group, 861 had normal blood flow with a non-significant 24 subjects having abnormal blood flow [7]. In a controlled study, ECD and Doppler did not show venous malformations in control, as with the MS cohort [7]. However, in recent studies, it has been shown that ECD cannot be used to diagnose and detect CCSVI due to the high variability in cerebrospinal blood flow that exists [2]

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Treatment of CCSVI. This figure illustrates opening the IJV and asygous vein. Source: http://www.mynewnormals.com/the-ccsvi-option/

5.4 Treatment of CCSVI

The narrowing of veins causes a decrease in resistance, propelling drainage to occur much more fluidly [6]. Venous drainage soon becomes compromised. Balloon angioplasty was first suggested to treat CCSVI in MS patients. Dr. Zamboni describes a procedure where he performed balloon angioplasty in 65 patients with CCSVI, and medically monitored their health for up to 18 months [6]. This procedure is safe with minimal side effects and problems [6].

Stents have also been used as a treatment option for CCSVI and MS [7]. Placed in the internal jugular vein, this procedure has been argued by few other scholars to be dangerous [7]. Some have shown that in rare cases, these stents can be carried with the blood flow towards the heart [7]. Due to the controversy of CCSVI not being accurately correlated with MS in controlled, blinded studies, the use of the balloon angioplasty and stents as treatments for MS has been discouraged [7].

5.5 Controversial Arguments

There is major controversy to Zamboni’s original study. Scholars claim that it was not blinded and had no control, and therefore any conclusive association between CCSVI and MS cannot be made [2]. Due to these arguments, they claim liberation therapy are solely “research endeavors” that have not been based on the assumed scientific association between MS and CCSVI [7]. Chafe and colleagues also expressed concern over public funding of liberation therapy when this scientific association has yet to be proven [8].

Due to the lack of sufficient control in Zamboni’s original study, Reekers and colleagues performed a similar study, only with randomized trials and adequate control groups [9]. They found that there was no significant difference in stenosis between the MS cohort and health controls [9]. Doepp also found that there was no significant difference in the prevalence of CCSVI between the MS cohort and healthy controls [10].

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Figure 4. Laupacis et al. (2011) meta-analysis of the positive association between CCSVI and MS. [11].

In 2011, Dr. Laupacis and colleagues performed a meta-analysis, looking at all studies that examined the association between CCSVI and MS from 2005 till 2011 [11]. This meta-analysis showed that there was a significant positive association between CCSVI and MS [11]. To account for Zamboni’s original study potentially creating a biased hypothesis, they also performed a meta-analysis excluding Zamboni’s original study [11]. Even, a positive association between CCSVI and MS resulted. However, despite these results, Laupacis et al. concluded that many of these studies that were included were not patient blinded [11]. Hence, there needs to be more future studies that are randomized and blinded in order to make an conclusive argument about the association of CCSVI and MS.

Dr. Zivadinov also publighed in Neurology showing that CCSVI was found in the MS cohort in his study but at a much lower prevalence than what was reported in Zamboni’s original paper [12]. Furthermore, Dr. Zivadinov also reported that CCSVI was present in his healthy controls and in individuals who had other non-MS related neurological disorders [12]. He concluded that CCSVI does not cause MS like Zamboni reported [12].

Bibliography
1. Zamboni, P. (2006). The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. Journal of the Royal Society of Medicine, 99: 589-593.
2. Morovic, S., & Zamboni, P. (2012). CCSVI is associated with multiple sclerosis. Neurological Research, 34(8): 770-779.
3. Picard, A., & Favaro, A. (2009, Nov 20). Researcher’s labour of love leads to MS breakthrough. The Globe and Mail. Retrieved from http://www.theglobeandmail.com/news/national/researchers-labour-of-love-leads-to-ms-breakthrough/article1372414/
4. Ghezzi, A., Comi, G., & Federico, A. (2011). Chronic cerebro-spinal venous insufficiency (CCSVI) and multiple sclerosis. Neurological Science, 32: 17-21.
5. Zamboni, P., Galeotti, R., Menegatti, E., Malagoni, A.M., Tacconi, G., Dall’Ara, S., Bartolomei, I., & Salvi, F. (2009). Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. Journal of Neurological Neurosurgical Psychiatry, 80: 392-399.
6. Zamboni, P., Galeotti, R., Menegatti, E. Malagoni, A.M., Gianesini, S., Bartolomei, I., Mascoli, F., & Salvi, F. (2009). A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. Journal of Vascular Surgery, 50: 1348-1358.
7. Khan, O., Filippi, M., Freedman, M.S., Barkhof, F., Dore-Duffy, P., Lassman, H., Trapp, B., Bar-Or, A., Zak, I., Siegel, M.J., & Lisak, R. (2010). Chronic cerebrospinal venous insufficiency and multiple sclerosis. Annual Neurology, 67 (3): 286-290.
8. Chafe, R., Born, K.B., Slutsky, A.S., et al. (2011). The rise of people power. Nature, 472: 410-411.
9. Reekers, J.A., Lee, M.J., Belli, A.M., et al. (2011). Cardiovascular and interventional radiological society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Cardiovascular Intervention Radiology, 34(1): 1-2.
10. Doepp, F., Paul, F., Valdueza, J.M., Schmierer, K., & Schreiber, S.J. (2010). No cerebrocervical venous congestion in patients with multiple sclerosis. Annual Neurology,68: 173-183.
11. Laupacis, A., Lillie, E., Dueck, A., Straus, S., Perrier, L., Burton, J.M., Aviv, R., Thorpe, K., Feasby, T., & Spears, Julian. (2011). Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ, 183(16): 1203- 1211.:
12. Zivadinov, R., Marr, K., Cutter, G., Ramanathan, M., Benedict, R.H.B., Kennedy, C., Elfadil, M., Yeh, A.E., Reuther, J., Brooks, C., Hunt, K., Andrews, M., Carl, E., Dwyer, M.G., Hoknacki, D., & Weinstock-Guttman, B. (2011). Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology, 77: 138-144.

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