CCSVI RESEARCH here

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Postby eric593 » Fri Aug 19, 2011 9:47 am

http://www.ncbi.nlm.nih.gov/pubmed/21849656


Neurology.

2011 Aug 17. [Epub ahead of print]

Progressive multiple sclerosis is not associated with chronic cerebrospinal venous insufficiency.

Baracchini C, Perini P, Causin F, Calabrese M, Rinaldi F, Gallo P.Source

From the First Neurology Clinic (C.B., P.P., M.C., F.R., P.G.), Multiple Sclerosis Centre of The Veneto Region (P.P., M.C., F.R., P.G.), and Neuroradiology Unit (F.C.), Department of Neurosciences, University Hospital, Padova, Italy.

Abstract

OBJECTIVE:
Chronic cerebrospinal venous insufficiency (CCSVI) had been suggested to play a major pathogenetic role in multiple sclerosis (MS), but recent data on early stages of MS have not confirmed this theory. Nonetheless, CCSVI could represent a late phenomenon of MS or be associated with progression of disability. Thus, we studied CCSVI prevalence in primary progressive (PP) and secondary progressive (SP) MS, to clarify whether CCSVI characterizes the progressive forms of this disease.

METHODS:

A total of 35 patients with SPMS, 25 patients with PPMS, and 60 age- and gender-matched normal controls (NC) were enrolled into a cross-sectional study. Extracranial and transcranial high-resolution venous echo color Doppler sonography (ECDS-TCDS) was performed in all patients and NC. Those patients having any abnormal ultrasound finding were asked to undergo selective venography (VGF).

RESULTS:

Patients with PPMS (11 women, 14 men; mean age 47 ± 11 years) had a disease duration of 11 ± 7 years and Expanded Disability Status Scale (EDSS) score of 6.0 ± 0.5. Patients with SPMS (22 women, 13 men; mean age 45 ± 14.5 years) had a disease duration of 18 ± 14 years and EDSS score of 6.0 ± 0.8. TCDS was normal in all patients. ECDS showed one or more abnormal findings in 9/60 (15.0%) patients (7/35 [20.0%] SPMS, 2/25 [8.0%] PPMS) and in 14/60 (23.3%) NC (p not significant for all comparisons). CCSVI criteria were fulfilled in 0 NC and 4 (6.7%) patients with MS: 3 SPMS and 1 PPMS. VGF, performed in 6/9 patients, was abnormal only in one case who had bilateral internal jugular vein stenosis.

CONCLUSION:

Our findings indicate that CCSVI is not a late secondary phenomenon of MS and is not associated with disability.

PMID: 21849656 [PubMed - as supplied by publisher]
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Postby eric593 » Tue Aug 23, 2011 1:04 pm

http://www.ncbi.nlm.nih.gov/pubmed/21856578


Complications in MS Patients after CCSVI Procedures Abroad

(Calgary, AB).Burton JM, Alikhani K, Goyal M, Costello F, White C, Patry D, Bell R, Hill MD.

Source

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Abstract

Background:
The "chronic cerebrospinal venous insufficiency" or "CCSVI" hypothesis, namely that multiple sclerosis (MS) is caused by abnormalities in the azygous and internal jugular veins with subsequent alterations in venous hemodynamics in the central nervous system, has been a dominant topic in MS care in Canada over the past year. Although there is no methodologically rigorous evidence to support this hypothesis presently, a considerable number of MS patients have undergone endovascular CCSVI procedures. Such procedures include angioplasty or stent placement in jugular and azygous veins. The safety and efficacy of these procedures is unknown, but not without risk.

Methods:
Chart and patient review of five patients with confirmed MS followed in Calgary were undertaken after patients came to medical attention by referral or admission secondary to complications believed to be associated with CCSVI procedures.

Results:
Complications upon investigation and review included internal jugular vein stent thrombosis, cerebral sinovenous thrombosis, stent migration, cranial nerve injury and injury associated with venous catheterization.

Conclusions:
As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer. As increasing numbers of MS patients are seeking such procedures, these five cases represent the beginning of a wave of complications for which standardized care guidelines do not exist.

Our experience and that of our colleagues will be used to develop guidelines and strategies to monitor and manage these patients as their numbers increase.

PMID: 21856578 [PubMed - in process]
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neurology article

Postby jcivetta » Tue Aug 30, 2011 12:29 pm

I haven't seen this mini-review article listed here, though you all must know about it. Just in case: Ref Frontiers in Neurology, published 14 July
Endovascular therapy fro chronic CCSCI in MS
Lazzaro, Zaidat, Mueller-Kronast, Taqu and Woo
www.frontiersin.org July 2011 Volume 2 Article 44.
they are still cautious neurologists but they do acknowledge that 'CCSVI underlies the pathophysiology of MS has emerged with several compelling reports.
As an academic surgeon and intensive care specialist, i agree that multiple large randomized studies are needed to uphold the theory. i also agree that standardization of diagnosis, treatments, long term outcomes are necessary to be scientific evidence.

However, my wife has had MS for 30 years; i started reading this string, called a former resident of mine who is in the Albany Vascular Group. My wife is scheduled as a self-pay patient on Sept 13.

It will be five or more years for rigorous science to be created. That is not in the time frame of a former trauma surgeon and director of a surgical ICU at Jackson Memorial-University of Miami.
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Postby eric593 » Wed Aug 31, 2011 7:07 am

http://www.ncbi.nlm.nih.gov/pubmed/21876515

Neuro Endocrinol Lett. 2011
Aug 30;32(4). [Epub ahead of print]

An endovascular treatment of Chronic Cerebro-Spinal Venous Insufficiency in Multiple Sclerosis patients - 6 month follow-up results.

Kostecki J.

Source
Department of Gynecology Obstetrics, Medical University of Silesia, District Specialist Hospital, Tychy, Poland.

Abstract
OBJECTIVE: In this study, the mid-term results (6 month follow-up) of the endovascular treatment in patients with Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) and multiple sclerosis (MS) were prospectively evaluated.

METHODS: Thirty-six patients with confirmed MS and CCSVI underwent endovascular treatment by the means of the uni- or bilateral jugular vein angioplasty with optional stent placement. All the patients completed 6 month follow-up. Their MS-related disability status and quality of life were evaluated 1, 3 and 6 months postoperatively by means of the following scales: Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS -29), Epworth Sleepiness Scale (ESS), Heat Intolerance scale (HIS) and Fatigue Severity Scale (FSS). For patency and restenosis rate assessment, the control US duplex Doppler examination was used.

RESULTS: Six months after the procedure, restenosis in post-PTA jugular veins was found in 33% of cases. Among 17 patients who underwent stent implantation into the jugular vein, restenosis or partial in-stent thrombosis was identified in 55% of the cases. At the 6 month follow-up appointment, there was no significant improvement in the EDSS or the ESS. The endovascular treatment of the CCSVI improved the quality of life according to the MSIS-29 scale but only up to 3 months after the procedure (with no differences in the 6 month follow-up assessment). Six months after the jugular vein angioplasty (with or without stent placement), a statistically significant improvement was observed only in the FSS and the HIS.

CONCLUSIONS: The endovascular treatment in patients with MS and concomitant CCSVI did not have an influence on the patient's neurological condition; however, in the mid-term follow-up, an improvement in some quality-of-life parameters was observed.

PMID: 21876515 [PubMed - as supplied by publisher]
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Postby cheerleader » Thu Sep 01, 2011 6:40 pm

http://journals.indexcopernicus.com/abs ... cid=935588

Early results of a prospective open-label study on endovascular treatments for chronic cerebrospinal venous insufficiency in the patients with associated multiple sclerosis
Tomasz Ludyga, Marek Kazibudzki, Paweł Latacz, Marcin Świerad, Jacek Piegza, Marcin Hartel, Ewa Kluczewska, Marian Simka
Phlebological Review 2011; 19(1):9-14


The aim of this paper was to document clinical improvements after endovascular treatment for chronic cerebrospinal venous insufficiency in a group of clinically defined multiple sclerosis patients. There were assessed clinical results of the treatment of 94 patients and follow-up was 6 months. We have found statistically significant improvements of clinical symptoms of multiple sclerosis measured with Multiple Sclerosis Impact Scale-29 (MSIS-29) questionnaires: in terms of total MSIS-29 scores, as well as of MSIS-29 physical and psychological domains. Similarly, the patients experienced an improvement of chronic fatigue syndrome measured with Fatigue Severity Scale and Epworth sleepiness questionnaires. On the contrary, no statistically significant improvement of heat intolerance occurred. Our preliminary results confirm the findings of the previous studies that have found positive effect of endovascular treatment for venous pathologies on clinical course of multiple sclerosis. These results are encouraging and warranting further studies on this topic.
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby cheerleader » Thu Sep 01, 2011 6:48 pm

Chronic cerebrospinal venous insufficiency in multiple sclerosis: diagnostic, pathogenetic, clinical and treatment perspectives

Robert Zivadinov†1,2, Murali Ramanathan3, Kresimir Dolic1, Karen Marr1, Yuval Karmon2,4, Adnan H Siddiqui4, Ralph HB Benedict2 and Bianca Weinstock-Guttman2
† Author for correspondence


Abstract--
Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in multiple sclerosis patients. CCSVI is characterized by impaired brain venous drainage due to outflow obstruction in the extracranial venous system, mostly related to anomalies in the internal jugular and azygos veins. The current CCSVI diagnosis is based on Doppler sonography of extracranial and transcranial venous hemodynamics criteria. To date, prevalence estimates of CCSVI, provided by different groups using various imaging methods of assessment, vary widely from none to 100%. There is an urgent need to define and validate the spectrum of cranial/extracranial venous anomalies and to establish reliable, diagnostic gold-standard test(s).The potential usefulness of endovascular treatment for CCSVI in multiple sclerosis patients is still unknown.

http://www.expert-reviews.com/doi/abs/1 ... ern.11.117
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Zamboni calls CCSVI a syndrome

Postby MarkW » Sat Sep 03, 2011 6:20 am

Many researchers have not appreciated the statement in this recent paper, in which Prof Paolo Zamboni describes 'The CCSVI Syndrome'.
http://phleb.rsmjournals.com/cgi/reprint/25/6/269.

I am trying to get the message across to pwMS in:
http://www.thisisms.com/ftopicp-173119.html#173119

MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: CCSVI RESEARCH here

Postby jcivetta » Sun Sep 04, 2011 1:11 pm

i've observed that more than a link is usually posted and i am sorry that the one i posted didn't even bring you to the right page. as this is a review by neurologists, i thought i'd print all of it. the link below is correct
http://www.frontiersin.org/endovascular ... 4/abstract

Endovascular therapy for chronic cerebrospinal venous insufficiency in multiple sclerosis
Marc A. Lazzaro1*, Osama O. Zaidat1,2,3, Nils Mueller-Kronast4*, Muhammad A. Taqi1 and Douglas Woo1
*

1 Department of Neurology, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Neurosurgery, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Radiology, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI, USA
4 Department of Neurology, Delray Medical Center, Delray Beach, FL, USA

Recent reports have emerged suggesting that multiple sclerosis (MS) may be due to abnormal venous outflow from the central nervous system, termed chronic cerebrospinal venous insufficiency (CCSVI). These reports have generated strong interest and controversy over the prospect of a treatable cause of this chronic debilitating disease. This review aims to describe the proposed association between CCSVI and MS, summarize the current data, and discuss the role of endovascular therapy and the need for rigorous randomized clinical trials to evaluate this association and treatment.
Introduction

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.
The Cerebrospinal Venous System in Relation to CCSVI

A brief overview of the cerebrospinal venous system anatomy and physiology is important to understand the potential role of a vascular model in the pathogenesis of MS.
Anatomy

The cerebrospinal venous system is a large interconnected network of venous drainage that spans the length of the neuraxis (Figure 1). The primary intracranial venous drainage can be simplistically divided into deep and superficial systems, while additional drainage occurs through emissary veins. The deep system involves tributaries to the vein of Galen from the internal cerebral veins and the basal veins of Rosenthal. The vein of Galen in turn drains into the straight sinus, confluence of sinuses, and into the transverse sinuses. The superficial system provides cortical drainage into the superior sagittal sinus as well as several large channels that provide lateral cortical drainage. The cortical drainage ultimately passes into the dural sinuses before leaving the head through the transverse sinuses. The two systems communicate by shared outflow through the transverse sinuses.
FIGURE 1
http://www.frontiersin.org

Figure 1. Illustration depicting the predominant veins and sinuses involved in the craniocervical venous outflow. Venous narrowing is depicted at locations of interest in chronic cerebrospinal venous insufficiency.

From the transverse sinuses, two outflow systems provide the majority of venous drainage, the internal jugular veins (IJV) anteriorly, and the vertebral venous system posteriorly (San Millan Ruiz et al., 2002). Each of the paired IJVs receives venous outflow from the transverse sinus, as well as superior and inferior petrosal sinuses, and terminates at the brachiocephalic vein. The vertebral venous system includes the internal and external vertebral venous plexuses. The cervical vertebral veins receive drainage from the internal vertebral venous plexus, condylar veins, and emissary veins (Braun and Tournade, 1977). The vertebral vein forms a plexus around the vertebral artery and courses inferiorly and forms a trunk before draining into the brachiocephalic vein. Communication is present between the vertebral venous system and the azygos vein via the epidural venous plexus and intercostal vein communication (Ibukuro et al., 2001).

The first set of valves encountered in the course of craniocervical venous drainage is at the junction with the brachiocephalic veins. A valve is present in the IJV at the junction with the subclavian vein. This valve may be bicuspid or tricuspid and is commonly located approximately 2 cm above the junction with the brachiocephalic vein (Sanchez-Hanke et al., 2000). A study of the IJV valve in cadaveric and live human subjects demonstrated the same valve location, mostly bicuspid, and also reported that only 7% of valves were incompetent out of 41 valves tested (Silva et al., 2002). A similar bicuspid valve is present at the junction of the vertebral vein with the brachiocephalic vein on each side (Chou et al., 2002).

Spinal venous drainage is characterized by a similar large continuous valveless system of veins with comparable complexity and redundancy as is found in the cerebral venous system. The spinal venous drainage shares the cervical outflow with the cranial venous system. Throughout the spinal cord, intrinsic veins drain the parenchyma in a radial pattern into two longitudinal venous trunks, the anterior and posterior median spinal veins (Hurst, 2008). These superficial veins course along the pia mater with segmental drainage via radicular veins to the internal vertebral plexus, or epidural plexus. This multichannel network surrounds the spinal cord in a sleeve-like distribution and extends from the skull base to the sacrum. An external venous system consists of an anterior and posterior plexus that courses along the anterior and posterior aspects of the vertebral bodies, respectively. The external system anastomoses with the internal system via intervertebral veins. The spinal venous system drains through deep cervical and vertebral veins at the cervical level and through intercostal and segmental veins into the azygos and hemiazygos veins which drain into the superior vena cava.

The azygos arch courses anteriorly at the level of the fourth and fifth thoracic vertebral bodies to drain into the superior vena cava. A valve is commonly present in the azygos arch, located within 4 cm of the junction with the superior vena cava, and present in about 65–70% of cases studied by computerized tomography, which is likely an underestimate due to the study design (Yeh et al., 2004; Steinke and Moghaddam, 2009). In one study, contrast material was visualized posterior to the azygos valve in 53% of cases suggesting frequent valve insufficiency, but the study was not designed to evaluate competence (Steinke and Moghaddam, 2009).

Embryological development of the venous system involves various stages of growth and invagination that ultimately leads to the complex and variable network forming the cerebrospinal venous system. This intricate series of events leads to variability and can also lead to abnormalities such as focal regions of webbing, stenosis, and valve malformation leading to venous outflow obstruction (Lee et al., 2010).
Physiology

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. Corrosion cast studies of the vertebral venous system demonstrate posterior fossa dural venous sinus connections with the vertebral venous system through lateral, posterior, and anterior condylar veins and mastoid and occipital emissary veins (San Millan Ruiz et al., 2002). 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 intrathoracic pressure as dictated by respiration.
CCSVI in MS: Proposed Association

The complex pathogenesis of MS partially involves perivenular regions of inflammatory demyelination which are thought to arise from an autoimmune 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 and erythrocyte 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, 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 neurodegeneration by an inflammatory response, which may be exacerbated by venous hypertension induced upregulation 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 transcranial color-coded Doppler sonography and high-resolution echocolor 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.
TABLE 1
http://www.frontiersin.org

Table 1. Proposed parameters for anomalous venous outflow (Zamboni et al., 2009a).
TABLE 2
http://www.frontiersin.org

Table 2. Four proposed principle patterns of venous rerouting in CCSVI in MS (Zamboni et al., 2009a).

The vascular model for MS and several compelling reports have generated considerable enthusiasm for investigation of the role of venous obstruction in the pathogenesis of MS. Furthermore, interest has emerged for endovascular therapies including angioplasty and stent implantation for venous stenosis. However, rigorous data demonstrating safety and efficacy are lacking and considerable controversy remains.
Findings Supportive of a Link between CCSVI and MS

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. 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 deposition. This may be due to hemosiderin accumulation from microhemorrhages. A recent study of susceptibility weighted imaging found that 12 of 14 MS patients imaged had evidence of increased iron deposition in the medial venous drainage system (Haacke et al., 2010). The pattern of iron accumulation could be considered consistent with the vascular model. The basal ganglia, midbrain, and thalamostriate regions are all drained by the medial venous drainage and all demonstrate increased iron content on MRI. The authors suggest that the iron accumulates in a pattern tracking backward through the venous outflow system.

Results from a human genetic study have been proposed to also link MS and venous malformations. A small investigation of copy number variations (CNVs) in 15 patients with MS and CCSVI did not show association between CNVs and patient phenotype, however the number of CNVs correlated with the number of stenosing malformations in the extracranial cerebrospinal veins (Ferlini et al., 2010). Although the series was small, the authors postulate that CNVs in the HLA region, a region associated with MS, may suggest a common genetic location responsible for venous formation and MS.

Multiple sclerosis commonly involves the cerebral white matter with less involvement of the spinal cord. Following the vascular model, spinal involvement may be spared due to a reflux-impeding mechanism within the dural sleeves that limit retrograde flow into radicular or perimedullary veins (Krings et al., 2006). Although no valves have been demonstrated within the spinal venous system, the venous architecture including the hairpin turn of the radicular veins has been thought to impede retrograde flow. Studies of contrast injection have demonstrated impeded retrograde opacification of the spinal cord veins.

Venous drainage is thought to play an important role in cerebral thermoregulation through countercurrent heat exchange (Zhu, 2000). At the base of the skull, both the carotid and vertebral arteries are encased by a cavernous sinus, which may in part serve as a countercurrent heat exchanger, thereby cooling the brain. In the setting of impaired venous outflow, the mechanism of counter current cooling may be impaired. For over a century, Uhthoff’s phenomenon has been recognized as a temperature dependent neuronal conduction dysfunction in demyelinated fibers (Humm et al., 2004). The impaired venous outflow described in the vascular model may further compromise central nervous system temperature regulation and contribute to heat intolerance among MS patients.
Findings Unsupportive of a Link between CCSVI and MS

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 and TCCS evaluation. Basing the theory of CCSVI and MS on this measurement modality has drawn criticism 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) 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 and 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.

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.

Other conditions of venous rerouting including cerebral venous thrombosis and venous embolization in treatment of vascular abnormalities such as arteriovenous malformations have not been reported to be associated with the development of MS type plaques. More recently, idiopathic intracranial hypertension (IIH) has been considered to arise from dural sinus narrowing and venous outflow obstruction. This also may result in a more restricted region of venous congestion that causes no evidence of MS type plaques due to compensation by collateral venous outflow. Additionally, venous outflow obstruction from IJV incompetence has been associated with transient global amnesia (Lewis, 1998), however this has not been associated with MS.

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, there is often considerable pressure on the vena cava. 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 rerouting and possibly congestion, would develop sclerotic plaques. However, interpretation of this finding differently may in fact support the theory that the vascular model contributes to MS and that venous rerouting in pregnancy explains MS exacerbations.
Unifying the Vascular Model with Current Understanding of MS

The absence of a unifying theory to explain the heterogeneous disease process of MS continues to invite new hypotheses. Integration of the vascular model into the pathogenesis of MS will likely be as an adjunctive role in patients who have an underlying autoimmune susceptibility that could be enabled by venous congestion. The current understanding of the pathophysiology of MS has been an autoimmune process, however the etiology remains poorly understood. It is plausible that the vascular model offers an additional explanation to the heterogeneity of the disease and compliments the well-established role of autoimmunity. The inconsistent representation of CCSVI in the reported studies may be representative of differences in technique using a highly operator-dependent measurement tool that lacks reference values in small non-randomized patient populations with differing disease profiles. The vascular model demands the presence of multiple factors to allow for a role in the disease process. It is possible that a subset of MS patients harbor several specific characteristics. Unifying the current understanding of MS pathogenesis with the hypothesis of a vascular model may be best explained with the patient meeting several criteria including a propensity to be sensitized to myelin, and a venous drainage architecture that results in congestion.
Diagnosis

If indeed a link between venous outflow obstruction and MS is established, diagnosis will likely remain challenging. The cerebrospinal venous outflow is complex and dynamic making evaluation with any single modality challenging. Sonography is heavily operator dependent with no standardized criteria, MR flow quantification has not been validated (Wattjes et al., 2011), and catheter angiography is largely limited to supine studies neglecting the potential role of postural dependence. The considerable limitations to transcranial Doppler evaluation include velocity measurement and insonation angle as well as operator variability. The IJV is a thin-walled compressible structure susceptible to changes from sonography probe pressure and adjacent structures. The extracranial venous system is susceptible to morphology changes resulting from hydration, body position, compression, and intrathoracic pressure changes. Furthermore, standard values for venous sonography will have to be established.

Although a multitude of magnetic resonance imaging sequences exist, MRV is inferior to Doppler sonography and selective venography in identifying cervical venous abnormalities (Hojnacki et al., 2010). Limitations of MRV are likely related to the static nature of the modality as well as the morphological venous changes due to body position and compression.

Catheter venogram remains the gold standard for venous system evaluation, however no reference data are available. Additionally, the postural dependence of the venous outflow system may introduce an additional challenge in accurate evaluation.
Treatment

A discussion on treatment may be premature, however it should be noted that if indeed a link is demonstrated, 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 restenosis 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).

Current device technology and interventional skill is available to afford endovascular remodeling, however further understanding of the pathophysiology is needed. The overall restenosis rate of 47% suggests balloon angioplasty may be insufficient and that stent implantation may be necessary for durable revascularization. Balloon angioplasty and stent implantation in the arterial system has been well-described and utilized for many years with an adequate understanding of feasibility, safety, and long-term effects. 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 hyperplasia, webbing, trabeculation, or fenestration and therefore respond differently to varying treatment modalities. The long-term effects of endoluminal scaffold implantation with stents in the venous system is not as well understood and will need further investigation of host response, such as endothelialization, and the appropriate subsequent antithrombotic regimen. Stent design will also likely be important in achieving safety, durability, and efficacy, however this will only follow a better understanding of the lesion pathology. Although endovascular technique and device technology are available to implement invasive treatment, data on safety and efficacy are lacking.
Future

Grants for research investigating CCSVI have thus far been awarded for seven projects by the National MS Society and the MS Society of Canada (FAQs About New CCSVI Grants, 2011). Intentional cerebral venous obstruction in an animal model of MS could also further elucidate the role of a vascular model in MS by testing the hypothesis that venous congestion leads to BBB disruption and enables the autoimmune response. Additionally, review of MS registries for an association between IIH and severity of MS disease may also be helpful in better understanding the role of venous obstruction.
Summary

The association between MS and venous system pathology is compelling given the perivenule topography of plaques that has been demonstrated both histologically and with MR imaging, however the fundamental mechanism of venous dysfunction is less clear. Venous outflow obstruction leading to venous congestion and BBB dysfunction is conceivable, however the redundancy of the venous anatomy would seem to demand venous obstruction at numerous places to exhaust collateral pathways. Explaining MS by a vascular model is further challenged by an incomplete understanding of venous system physiology, which is highlighted by the postural dependence of venous outflow. The vascular model may relate to only a portion of those patients with MS, in which particular patient selection would be needed to demonstrate reproducibility.
Conclusion

The incomplete understanding of the pathophysiology and effective treatment in a chronic and debilitating disease that affects up to 2.5 million people worldwide is the foundation of the enthusiasm for a proposed treatable vascular model such as CCSVI. If confirmed, the vascular model would change understanding of the pathophysiology of MS considerably. The proposal that CCSVI underlies the pathophysiology of MS has emerged with several compelling reports, however a careful understanding of several elements is needed. A better understanding of the pathophysiology, standardized diagnostic criteria, and rigorous randomized evaluation of intervention with long-term outcomes are needed before widespread adoption of endovascular therapies. Further endovascular technique and device developments will then be needed to ensure durable efficacy. Endovascular therapy for MS remains investigational and should remain limited to multicenter, blinded, randomized, controlled clinical trials.
Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: angioplasty, stent, jugular, azygos, stenosis, CCSVI, MS

Citation: Lazzaro MA, Zaidat OO, Mueller-Kronast N, Taqi MA and Woo D (2011) Endovascular therapy for chronic cerebrospinal venous insufficiency in multiple sclerosis. Front. Neur. 2:44. doi: 10.3389/fneur.2011.00044

Received: 03 May 2011; Accepted: 28 June 2011;
Published online: 14 July 2011.

Edited by:
Randall Edgell, Saint Louis University, USA

Reviewed by:
Ashish Nanda, University of Missouri, USA
Edgard Pereira, JFK Medical Center, USA

Copyright: © 2011 Lazzaro, Zaidat, Mueller-Kronast, Taqi and Woo. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

*Correspondence: Marc A. Lazzaro and Douglas Woo, Department of Neurology, Froedtert Hospital and Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA. e-mail: mlazzaro2@gmail.com; dwoo@mcw.edu; Nils Mueller-Kronast, Department of Neurology, Delray Medical Center, 5162 Linton Boulevard 106, Delray Beach, FL 33484, USA. e-mail: muellerkronast@gmail.com


Isn't it crazy that by the time these studies have entered sufficient patients, followed them long enough, the statistics done by an outside organization, submitted them either to a meeting or a journal and have the results come out in an acceptable scientific manner, they will be of historical interest only. in those 5 years or more, manufacturers even now must be anxious to design new catheters, investigators will have designed better criteria [already primary progressive disease seems likely to be excluded], technical improvements, interchange among doctors to standards at a different level and more contributions from interventional radiologists. I just told the interventional radiologist, who has been treating my low back pain for years about what's happening now in CCSVI [my wife is the one with MS]. He was very skeptical for about 5 min. after 30 minutes he wanted to join a trial. i hope he does because he is one of the truly gifted people i've known in my pretty long experience as a trauma surgeon and surgical intensivists [these specialties have need of interventional radiologists in numerous ways during the evaluation and treatment of patients.

Oh, here is a list of NIH clinical trials as of today.

http://clinicaltrials.gov/ct2/results?t ... ufficiency
Rank Status Study
1 Recruiting Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
Conditions: Ehlers-Danlos Syndrome; Multiple Sclerosis
Intervention:
2 Recruiting Study To Evaluate Treating Chronic Cerebrospinal Venous Insufficiency (CCSVI) in Multiple Sclerosis Patients
Condition: Multiple Sclerosis
Interventions: Procedure: Venoplasty; Procedure: Sham procedure (non-treatment)
3 Recruiting Evaluation of Angioplasty in the Treatment of Chronic Cerebrospinal Venous Insufficiency (CCSVI) in Multiple Sclerosis
Condition: Multiple Sclerosis
Interventions: Procedure: Angioplasty; Other: Observation
4 Active, not recruiting Endovascular Treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI)
Condition: Multiple Sclerosis
Intervention: Procedure: balloon angioplasty and/or stenting
5 Recruiting Doppler Sonography, MR Venography, Plethysmography for the Diagnosis of CCSVI
Condition: Chronic Cerebrospinal Venous Insufficiency
Interventions: Other: Doppler sonography of internal jugular veins; Other: Magnetic resonance venography of internal jugular veins; Other: Air-plethysmography of the neck; Other: Catheter venography of internal jugular veins
6 Recruiting Multi-center Registry for CCSVI Testing and Treatment
Conditions: CCSVI; Chronic Cerebrospinal Venous Insufficiency; Venous Malformations of CNS Draining Veinus; Multiple Sclerosis
Intervention: Procedure: venous angioplasty
7 Not yet recruiting BRAVE-DREAMS (BRAin VEnous DRainage Exploited Against Multiple Sclerosis)
Conditions: Multiple Sclerosis; Venous Insufficiency
Interventions: Procedure: Venous PTA; Other: Catheter Venography
8 Recruiting Observational Study of the Prevalence of CCSVI in Multiple Sclerosis and in Other Neurodegenerative Diseases
Conditions: Multiple Sclerosis; Neurodegenerative Diseases
Intervention:
9 Recruiting Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
Conditions: Ehlers Danlos Syndrome; External Hydrocephalus; Dysautonomia; Postural Orthostatic Tachycardia Syndrome; Venous Insufficiency


I compiled the list for my skeptical interventional radiologist
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Re: neurology article

Postby Cece » Wed Sep 07, 2011 7:19 pm

jcivetta wrote:I haven't seen this mini-review article listed here, though you all must know about it. Just in case: Ref Frontiers in Neurology, published 14 July
Endovascular therapy fro chronic CCSCI in MS
Lazzaro, Zaidat, Mueller-Kronast, Taqu and Woo
http://www.frontiersin.org July 2011 Volume 2 Article 44.
they are still cautious neurologists but they do acknowledge that 'CCSVI underlies the pathophysiology of MS has emerged with several compelling reports.
As an academic surgeon and intensive care specialist, i agree that multiple large randomized studies are needed to uphold the theory. i also agree that standardization of diagnosis, treatments, long term outcomes are necessary to be scientific evidence.

However, my wife has had MS for 30 years; i started reading this string, called a former resident of mine who is in the Albany Vascular Group. My wife is scheduled as a self-pay patient on Sept 13.

It will be five or more years for rigorous science to be created. That is not in the time frame of a former trauma surgeon and director of a surgical ICU at Jackson Memorial-University of Miami.

All best wishes to your wife next week.

It is good to hear that someone with a background such as yours agrees that this is an appropriate avenue to explore for treatment. More science is needed but I too chose not to wait.
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Re: CCSVI RESEARCH here

Postby jcivetta » Wed Sep 07, 2011 7:59 pm

thank you very much.
with regard to the science, too much will be changing over the next decade for a 'definitive' study to be done. i believe Robert Loeb, Co-author of Cecil and Loeb textbook of medicine, which was THE textbook of medicine from the late 40s onward, said it best. Loeb's Laws of Medicine state: 1. if it works, keep doing it. 2. if it doesn't work, stop doing it.
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Re: CCSVI RESEARCH here

Postby CD » Wed Sep 07, 2011 9:27 pm

Hi jcivetta and welcome,
Thank you for those very informative links and posts.

My up-to-date Neurologist thinks that CCSVI is, "Cool." Her words, not mine.

I will be at the Albany Vascular group on Sept 13 also. I have a MS Dx for 30 years. I am due my Doppler Ultrasound again. This is my scan after my CCSVI procedure 9 months ago. I hope I am still seeing some venous flow.

Perhaps we will be there at the same time. I wish the very, very, best for your wife. They do have a great team in Albany, the weather, not always so good. Are you going to the hospital or clinic?

When you have had MS for 30 years, why wait for any approval? If it were a blockage in my leg it would be done ASAP, right?
Take care,
CD
Where there is a will, there is a way. "HOPE"

CCSVI Procedure December 2010
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Re: CCSVI RESEARCH here

Postby jcivetta » Thu Sep 08, 2011 6:44 am

talk about small world! you shudda been a surgeon, i remember a Time magazine cover years ago with Michael DeBakey on the cover. His quote was underneath "If they can operate, you're lucky." we sure feel lucky right now.
what time is your appt? we don't know the schedule yet but it would be great to meet you.
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Re: CCSVI RESEARCH here

Postby cheerleader » Mon Sep 12, 2011 4:41 pm

A new paper was recently published in Phlebology, Sept. 2011 issue.

Morphological and haemodynamic abnormalities in the jugular veins of patients with multiple sclerosis
D Radak, J Kolar, S Tanaskovic, D Sagic, Z Antonic, A Mitrasinovic, S Babic, D Nenezic and N Ilijevski Vascular Surgery Clinic, Dedinje Cardiovascular Institute, School of Medicine, Belgrade University, Heroja Milana Tepic ́a 1 Street, Belgrade, Serbia


This study was not conducted by neurologists, nor was it funded with pharmaceutical monies. These are vascular doctors and
this study was partly funded by the Serbian Ministry of Science and Techonological Development – Project No. 41002.

I have the full paper, and will break down what the researchers discovered.

First, it is important to note that they only looked at the jugular veins with doppler. No transcranial doppler, per the Zamboni criteria, and no venography or azygous. These researchers wanted to see if they could find "morphological and haemodynamic abnormalities" in the jugular veins. This means they were looking for physical irregularities and flow distubances in pwMS. Not completely CCSVI, per Dr. Zamboni's definition.

The limitation of our study is that we did not examine the CCSVI prevalence in patients with MS because we did not investigate the intracranial and vertebral veins. The aim of our study was to evaluate morphological and haemodynamic IJV abnormalities in patients with MS and compare it with healthy controls. For morphological and haemodynamic abnormalities assessment of the IJVs, we used some of Zamboni’s criteria and two other parameters (parameters 1 and 2), which in our practice proved to be a good indicator of IJV flow disorder.


What they were surprised to discover was that the IJV flow was very different in pwMS, and that they could pick this up with doppler ultrasound.

All these might result in IJV haemodynamics changes that could be assessed by non-invasive and cost-effective colour duplex sonography.6 The main finding of this study was to demonstrate a significantly higher prevalence of morphological and Doppler haemodynamics abnormalities in patients with MS in relation to healthy subjects.
Our study showed that 42% of the patients with MS had Doppler haemodynamic evidence of venous flow abnormalities as compared with 8.1% of the healthy controls. These data not only indicate that venous flow abnormalities were significantly associated with the presence of MS but also indicate that it can be seen in the population not suffering from MS, yet the difference remains statistically significant (P , 0.001).


Also interesting was that they found faulty valves and stenosing lesions in some of the normal controls, but these irregularities didn't affect the blood flow as much as they did in pwMS....

Although no statistically significant differences in the frequency of stenosing lesion was observed between patients with MS and healthy controls, adding haemodynamic Doppler information in the IJV venous outflow was significantly different in 42% of MS patients showing flow abnormalities (27/64), as compared with 8.1% of the controls (3/ 37), P , 0.001.


Even with incomplete data, these researchers noted how venous malformations were affecting the blood flow in pwMS.

I often restate Dr. Zamboni's most important quote to me...when I met him Bologna at his first worldwide conference in September, 2009.

"CCSVI is not about architecture, it is about the flow!"
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: CCSVI RESEARCH here

Postby jcivetta » Wed Sep 14, 2011 2:35 pm

Hi cheerleader,
Is it a coincidence that you post that article and our story yesterday? we've just returned from Albany where my wife underwent venography and subsequently venoplasty on Sept 13, 2011. Dr. Mehta showed me the films, which showed stenosis at the L IJ junction with the Subclavian and thick, non-compliant, stiff valve leaflets. The 'after' pictures showed wider vein and free flow. He commented to me that the flow was markedly improved after dilatation and that increase was more impressive/important in his mind than widening the stenosis.

I recalled that the first cardiac surgery [before cardiopulmonary bypass] was introducing the surgeon's finger into the left atrium and splitting the stenosed leaflets of the mitral valve scarred by rheumatic heart disease. So much followed that initial cardiac operation that i hope the parallel continues!

In the recovery room, she got out of bed and started walking with her walker. You shudda been there! she started laughing and then laughing/crying with relief and happiness. Immediately she was walking better because her left knee and ankle WORKED again. She also has noticed lots of little improvements in balance and fine movements of her left hand on her first post op day. It seems miraculous, truly, to have problems that we expected to get worse to suddenly change for the better. We think/hope that, loosened from the shackles of disease, she can work on the treadmill and with PT exercises and weights to retrain those long unused muscles. i have to search this site to see what others have seen and recommended for post op patients to enhance the benefit.
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Re: CCSVI RESEARCH here

Postby Cece » Wed Sep 14, 2011 5:57 pm

Really great to hear that, jcivetta. So immediate and after so many years with the disease!
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