On August 8 2011, at 07.45 A.M., was published in this blog an article written by Andres Brakke, who I presumed is not a Doctor and probably is a marketing manager of some kind for the so called “Clinics of the Heart” in Cabo San Lucas, México, about CCSVI and their experience with the so called Liberation Treatment for Multiple Sclerosis ( M S ). We at Excel Medical Center in Tijuana, Baja California, México, found some irregularities and exaggerations on the text of the article and for the benefit of the CCSVI community, we would like to set the record straight.
First we would like to give a bit of history on this disease.
Multiple sclerosis (MS) is a neurodegenerative disorder that affects approximately 350,000 people in the United States and possibly up to 2.5 million people worldwide (Anderson et al., 1992), making it the most common non-traumatic cause of disability among young and middle-aged people in the developed world (Koch-Henriksen and Sorensen, 2010). The pathogenesis is complex with varying associations and is primarily thought to be autoimmune, but a unifying hypothesis has yet to be identified. Compelling reports have recently emerged proposing a link between a recently defined entity named “chronic cerebrospinal venous insufficiency” (CCSVI) and MS.
Anatomy
The cerebro-spinal venous system is a large interconnected network of venous drainage that spans the length of the neuro-axis (Figure 1). The primary intracranial venous drainage can be simplistically divided into deep and superficial systems, while additional drainage occurs through emissary veins. The cortex or brain matter, drains through a series of veins that ultimately form a sort of a dam, called sinus, which in turn drains into a lower level sinus that eventually drains into the Transverse Sinuses in both sides of the head.
Anatomy
Areas of interest in CCSVI
From the transverse sinuses, two outflow systems provide the majority of venous drainage out of the head; the internal jugular veins (IJV) anteriorly right and left, and the vertebral venous system posteriorly (San Millan Ruiz et al., 2002). Each of the paired IJVs receives venous outflow from the transverse sinus, and terminates at the brachiocephalic vein which is formed by the junction of the bilateral IJV and the Subclavian Vein ( which drain blood flow coming from the arms) on each side of the upper chest.
The other system is the posterior vertebral venous system which includes the internal and external vertebral venous plexuses. This system too, eventually drains as well into the brachiocephallic system in the upper chest. (Braun and Tournade, 1977). Finally, there is communication between the vertebral venous system and the Azygos vein via the intercostal veins and other collaterals (Ibukuro et al., 2001
We like to point out that the Azigous system lies in the most posterior aspect of the thorax and joins the Superior Vena cava immediately above the right side of the heart.
The cerebrospinal venous system is a large and complex valveless system governed largely by distensibility and intracranial pressure as well as respiratory pressure changes which together lead to antegrade flow (Eckenhoff, 1970). Most studies of venous blood flow are performed with the patient in a supine position which will often demonstrate preferential IJV outflow, however a postural dependence of cerebral venous outflow has also been described (Valdueza et al., 2000). Encephalic venous drainage predominantly exits through the jugular system in the supine position, in contrast to the upright position where blood flow preferentially exits through the vertebral venous system. This is important because most physiologic studies are performed with the subject in the supine position thereby limiting visualization of the vertebral venous drainage system. These findings suggest that complete evaluation of venous outflow in patients may demand more rigorous study including changing postural position. The hydrodynamics of cerebrospinal venous drainage are complex, relying on interplay between arterial blood flow, intracranial pressure, venous system architecture, and intra-thoracic pressure as dictated by respiration.
The complex pathogenesis of MS partially involves peri-venular regions of inflammatory demyelination which are thought to arise from an autoimmuneattack/process. The trigger for the autoimmune attack has been unclear, and the mechanism of blood brain barrier (BBB) disruption remains poorly understood, although chronic inflammatory damage promoting permeability anderythrocyte passage has been considered. The vascular theory attempts to answer these questions.
The hypothesis that venous obstruction plays an important role in the development of sclerotic plaques of MS was reported as early as the 1930s. A canine model of cerebral venule obstruction demonstrated histological findings of myelin destruction with axonal preservation and localized proliferation of the fibrous glia (Putnam, 1935). The mechanism of venule obstruction in MS was thought to be due to thrombosis ( blood clots) , and this theory was supported by the notion that acute infection and pregnancy alter coagulability and thereby explain the association of these conditions with MS exacerbations.
The vascular model for MS has evolved to the recent theory that chronic venous reflux causes an increase in trans-mural pressure in the microcirculation leading to separation of the tight junctions that form the BBB. Dysfunction of the BBB may then allow erythrocyte and inflammatory cell influx into the extracellular space (Zamboni et al., 2007). These changes could contribute to neuro-degeneration by an inflammatory response, which may be exacerbated by venous hypertension induced up-regulation of BBB adhesion molecules, facilitating macrophage and T-cell adhesion, migration, and infiltration, and ultimately leading to iron deposition. Alternatively, the BBB incompetence may not lead to cell migration, but other plasma components such as colloids that would result in osmotic changes leading to cell injury and an inflammatory response (Talbert, 2008).
A recent study investigated the association between abnormalities of the cerebral venous outflow and clinically defined MS (Zamboni et al., 2009a). This study included 65 patients with MS and 235 healthy subjects. All patients underwent screening with trans-cranial color-coded Doppler sonography and high-resolution echo-color Doppler (TCCS–ECD). Those patients identified to have two or more of five previously defined venous outflow abnormalities (Table 1) subsequently underwent catheter venography. Venography showed no abnormalities in control patients, however those patients with MS had multiple areas of venous stenoses and four distinct patterns of central nervous system venous outflow rerouting (Table 2). Additionally, those patients with relapsing–remitting and secondary progressive MS showed venous outflow rerouting patterns significantly different from those with primary progressive MS.
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A canine model of venous obstruction was developed in the 1930s by embolizing part of the longitudinal sinus and adjacent cortical veins (Putnam, 1935). Fourteen dogs survived for varying times that ranged up to 1 year. Histology demonstrated later stages of the lesions having plaques of demyelination with axonal preservation and local dense fibrous gliosis, similar to the findings in M. S.. These findings led the author to conclude that venular obstruction is the immediate antecedent to the formation of typical sclerotic plaques.
Early studies of MS plaques in humans suggested a venocentric pattern of focal inflammatory demyelination, a pattern attributed to an autoimmune process (Fog, 1965; Barnett and Sutton, 2006). Plaque venocentricity has also been demonstrated radiographically using high-resolution magnetic resonance venography (MRV; Tan et al., 2000). Among 95 MS lesions studied, all but one demonstrated a perivenous distribution.
Iron accumulation at sites of MS plaques has been recognized and attributed to the presence of iron-rich macrophages. Iron accumulation may be self-perpetuating by leading to venous endothelial damage and inflammatory response at sites of deposition. In an autopsy study, the incidence of hemosiderin deposition was 30% in brains of patients with MS, in contrast to only 6% in brains of normal control patients (Adams, 1988). Furthermore, iron deposition was restricted to regions of plaques in MS patients compared to diffuse deposition seen in normal control brains. Although iron accumulation may result from chronic inflammation and hemosiderin extravasation through a dysfunctional BBB, the severity of venule injury has been considered greater than would be expected from chronic inflammation (Adams, 1988). The vascular model proposes that venous congestion leads to BBB incompetence and perivenule iron, similar to what happens in varicose veins in the legs of patients, whereby the area around the ankles turn bluish dark due to deposition of the hemosiderin or iron from the red cells.
The initial study by Zamboni et al. (2009a) proposing the entity of CCSVI and the relationship of it to the pathogenesis of MS is based on ECD ( echo doppler) and TCCS ( trans cranial color doppler sonography ) evaluation. Basing the theory of CCSVI and MS on this measurement modality has drawncriticism due to several limitations including the ability to measure intracranial venous blood flow, operator dependence, and a lack of standardized values for diagnostic criteria (Doepp et al., 2010; Wattjes et al., 2011).
The theory of CCSVI in relation to MS holds that venous outflow is obstructed leading to venous congestion with the goal of endovascular therapy to alleviate the stenosis and thus the congestion. The proposed treatment for CCSVI is percutaneous transluminal angioplasty (PTA) of the jugular and azygous veins, as described by Zamboni et al. (2009b) in a subsequent series of endovascular treatment for CCSVI in MS patients. In their series, they defined six different malformation morphologies, including “septum/valve malformation” which indicated an anomalous valve apparatus causing flow obstruction. This was the most common type of malformation and was present in 30 right IJVs and 28 left IJVs. Angioplasty of a stenotic valve would seem to alleviate obstruction of flow, however it would also seem to induce valve incompetence that would result in reflux and thus retrograde flow and venous congestion. Whether this result is present was not described, and evaluation with selected angiography post-procedure and subsequent sonographic evaluation may provide clarification.
An important character of a novel scientific finding is reproducibility. Several investigators have unsuccessfully attempted to reproduce the findings of Zamboni’s group. An independent group was unable to reproduce an association between venous outflow obstruction and MS using sonography (Doepp et al., 2010). This group performed transcranial color-coded sonography on 56 patients with MS and 20 control patients and found only a single patient with abnormal blood flow direction, and none of the patients fulfilled more than one criteria for CCSVI. Differences in studies including an unblinded design, a different profile of MS patients, and different sonography techniques may have contributed to the discrepancy to the findings of Zamboni et al. (2009a). A recent report using MRV to evaluate the craniocervical venous anatomy, drainage pattern, and flow, found anomalies present in MS patients and healthy controls without abnormal flow (Wattjes et al., 2011). Although limited by a small number of subjects (20 MS patients and 20 healthy controls), this also challenges the hypothesis that CCSVI is important in MS. Another study compared 21 patients with MS and 20 healthy control patients who underwent contrast enhanced MRI found no difference regarding internal jugular venous outflow (Sundstrom et al., 2010). Additionally, early results from a study looking at prevalence of CCSVI in MS with venous Doppler identified the entity in 63% of MS patients, 26% of healthy controls, and 45% of patients with other neurological disorders (Zivadinov et al., 2010). While variability is inherently present in study designs and the technique-dependent nature of sonography, the lack of reproducibility of Zamboni’s original findings remains a criticism of the hypothesis.
Finally, radical neck dissection is performed in patients with extensive head and neck cancer and has been reported with bilateral jugular vein ligations (Ensari et al., 2008). Additionally, a small series of patients with an IJV obstruction due to various causes were studied angiographically and showed prominent channels from the sigmoidal, jugular, and vertebral systems (Cook et al., 1958). Following the vascular model of MS, this would seem to cause venous congestion resulting in the proposed inflammatory response and demyelination, but this has not been reported. An alternative explanation may be that an autoimmune predisposition or propensity to be sensitized to myelin is also needed and was not present in these patients. Furthermore, preferential cranial venous outflow may be dependent on posture, with preferential flow through the jugular system in the supine position and through the vertebral system in the erect position (Valdueza et al., 2000). If venous outflow patterns are dependent on posture in this way, then congestion from jugular obstruction may be most relevant in the supine position.
The venous outflow from the head may in fact be predominantly through the vertebral venous system. A postural dependence on venous outflow has been demonstrated (Valdueza et al., 2000). In healthy subjects, ultrasonography demonstrated vertebral venous outflow to be the dominant system in the erect position, while jugular venous drainage was more predominant in the supine position. The diagnostic criteria for CCSVI relies more on anterior venous outflow, which may be only partially involved in cranial venous drainage.
A comparable physiologic model may also be considered in pregnancy. Near the end of pregnancy, the enlarging uterus displace and compress all abdominal organs, specially the vena cava that lies in the back of the abdomen. Venous blood is likely then shunted into the vertebral plexus, which would translate to increased cerebral venous pressure as well. Following the vascular model of pathogenesis in MS, it would seem that pregnant women exposed to extended venous outflow re-routing and possibly congestion, would develop sclerotic plaques. However, interpretation of this finding differently may in factsupport the theory that the vascular model contributes to MS and that venous rerouting in pregnancy explains MS exacerbations.
Treatment
A discussion on treatment of this disease, may be premature, however it should be noted that if indeed a link is demonstrated between M S and the vasculat theory of Zamboni, considerable challenges must be overcome to optimize treatment. In the prospective endovascular treatment pilot trial by Zamboni et al. (2009a) PTA was performed on 65 patients and 18-month follow-up was described. They reported improvement in venous pressure, MS clinical outcome measures, and quality of life assessments (Zamboni et al., 2009b). This was an unblinded pilot series showing that endovascular therapy is feasible with low complications, however this study was small, had no control subjects, and demonstrated a re-stenosis rate of 47%. Although complications were minimal in this initial study, a subsequent report of intracranial hemorrhage was reported as well as a case with stent migration requiring open-heart surgery (Qui, 2010).
Endovascular technology has advanced in meteoric form, as well as Interventional skills to afford endovascular remodeling with balloons and occasionally when required the deployment of stents. However further understanding of the patho-physiology is needed. The overall re-stenosis rate of 47% suggests, that balloon angioplasty by itself may be insufficient in a large density of patients, and may require stent implantation for a more durable revascularization. Balloon angioplasty and stent implantation in the arterial system is time honored and has changed the course of Coronary disease in terms of mortality and morbidity, allowing patients to obtain a very functional life style and in a vast majority of them a cure for their disease. But, we must bear in mind that unlike the arterial system, the venous system lacks a supportive multilayered architecture, theoretically posing a greater risk of vessel rupture. Additionally, the venous wall characteristics leading to the described obstructions are not well understood and may involve webbing, trabeculation, valves etc. and therefore respond differently to endovascular treatment. Furthermore, as of this moment there aren’t stents specifically design for veins and consequently, the long-term effects of endo-vascular scaffolding with stents in the venous system needs further investigation of host response for endothelialization ( deposition of tissue over the metal stent). Finally, anti-clotting therapy needs to be clarify in terms of medication and time of treatment.
The use of Medicated Balloons were originally designed for Coronary interventions in the 90’s, because of the high re-stenoses rates present after coronary angioplasty in patients with coronary artery disease. After several trials where this new modality of endovascular treatment was implemented, it was discontinued because of poor or lack of effect on the mechanism that ultimately leads to 30 or 50 % of the re-stenoses rate following coronary angioplasty.
The reason why Medicated Balloons were not effective in the treatment of these blockages , was related to several factors: a) -first of all, the short permanency time within the lumen of the vessel, did not allow for the medication on the balloon to be absorbed in sufficient quantity to provide the inhibitory effect on cell multiplication once the injury to the vessel wall was accomplished by the dilating balloon.
b)- the amount of medication on the balloon was insufficient to cover all the damaged area while the balloon was inflated delivering the medication. Additionally, once the balloon was deflated the blood flow washed away the medication from the site of delivery depriving the area injured of sufficient drug to avert the normal reparative process that leads to the scar formation and at times exaggerated scar which made the treatment worse than the disease itself.
c)- the size of the vessels in question, were markedly different in caliber; since the coronary arteries fluctuate between 2 to 4 millimeters maximum, with the exception of the main trunk, that at times may be a little bit larger. On the other hand, the Jugular veins are between 12 and 26 millimeters in diameter, making them drastically different than the brothers in the coronary system. The Azygous veins are usually between 8 and 16 millimeters in diameter, once again pointing at structures that will respond differently to the dilating process implemented by the Liberation Treatment. Furthermore, as explained previously, the multilayered architecture of the veins differ with respect to the arteries and we do not know their healing behavior and reparative process once the injury to the vessel is done.
d)- Finally, Brakke boasts their success in the treatment of CCSVI with the use of the so called Dior Freeway catheter, which has a mixture of Shellac a hydrophilic substance, this being the carrier of the anti-proliferative drug, and Paclitaxel the drug that exerts its effects by limiting the multiplication of smooth muscle cells in the damaged artery, that once the Shellac swells in contact with the blood, releases the drug under pressure by the inflating balloon on to the artery wall.
The problem is that, there are two types of Freeway catheters. The Dior Freeway 014 and the Dior Freeway 035. The first comes in sizes of 2 to 4 millimeters in diameter and the Freeway 035 comes in sizes of 4 to 8 millimeters in diameter as well. How can they expect to have surface contact with the injured Vein, when the balloons are UNDERSIZED with respect to the vein, especially after they have been dilated and stretched to even bigger sizes than the original.
One final point regarding Brakke’s comment, is the fact that there is nothing in the literature that tells us that this is a proven modality of treatment for M S on one hand, and the other is that the cost of this modality is quite expensive and the results are unknown.
For all these reasons, we differ with Brakke and his doctors and suggest to use caution, should you decide to undergo this questionable procedure and at least do the most reasonable thing, that is TAKE A SECOND OPINION!!!!.