Description:
Chronic cerebrospinal venous insufficiency (CCSVI) may be associated with multiple sclerosis (MS), although this is controversial and an active area of research. Correction of CCSVI in patients with MS has been attempted using percutaneous venoplasty. The intent of this procedure is to relieve MS symptoms by improving venous drainage of the central nervous system.

For individuals who have MS who receive ultrasound with or without magnetic resonance imaging to diagnose CCSVI, the evidence includes systematic reviews and controlled observational studies. Relevant outcomes are test accuracy, test validity and other test performance measures. Systematic reviews have generally found a statistically significant association between CCSVI and MS, but a 2014 meta-analysis that excluded studies by Zamboni (who proposed criteria for defining CCSVI) and associated research groups found no significant association. Moreover, systematic reviews have reported significant heterogeneity among studies. Recent observational studies have not found that Zamboni criteria or updated criteria proposed by the International Society for Neurovascular Disease can discriminate between patients with and without MS. The association between CCSVI and MS, especially as a causative factor, remains unclear. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have MS and CCSVI who receive treatment for CCSVI with percutaneous venoplasty, the evidence includes 1 randomized controlled trial (RCT) and several case series. Relevant outcomes are overall survival, symptoms, quality of life and treatment-related morbidity. The RCT was double-blind and sham-controlled. It found no statistically significant differences in venous outflow characteristics or improvements in clinical disease scores between groups treated with venoplasty and a sham intervention. The results of this RCT are limited by the potential for underpowering, and we did not identify any other RCTs on the efficacy of percutaneous venoplasty. Data on adverse events are available from the Food and Drug Administration (FDA) as well as larger published case series (i.e., with several hundred patients). The case series found that adverse events were uncommon following venoplasty, but serious adverse events have been reported to FDA. FDA issued an alert in May 2012, noting the existence of serious complications, including death, and the need for ongoing monitoring. It is not currently possible from the available literature to estimate with confidence the rate of serious adverse events (e.g., death, major bleeding). The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
Multiple sclerosis (MS) is generally considered a chronic inflammatory demyelinating disease of the central nervous system (brain, spinal cord, optic nerve) believed to be triggered by an autoimmune response to myelin. However, in part due to the periventricular predilection of the lesions of MS, vascular etiologies (chronic cerebrospinal venous insufficiency [CCSVI]) have also been considered. The core foundation of this vascular theory is that venous drainage from the brain is abnormal due to outflow obstruction in the draining jugular vein and/or azygos veins. This abnormal venous drainage, which is characterized by special ultrasound criteria, is said to cause intracerebral flow disturbance or outflow problems that lead to periventricular deposits. In the CCSVI theory, these deposits have a similarity to the iron deposits seen around the leg veins of patients with chronic deep vein thrombosis. Balloon dilatation, with or without stenting, has been proposed to treat the outflow problems, thereby alleviating CCSVI and MS complaints.

The following 5 criteria were defined by Zamboni et al. in 2009 as features of CCSVI.¹ To make the diagnosis of CCSVI, at least 2 of the 5 criteria need to be present:

1. Reflux constantly present (for a duration >0.8 seconds) in the supine and upright positions at the level of an internal jugular or vertebral vein. This parameter was evaluated during a short breath-hold following normal breathing and not under Valsalva maneuver.
2. Reflux at the level of veins of the deep cerebral system (for a duration > 0.5 seconds). This was evaluated with the patient in the sitting and supine positions, and venous flow was enhanced by inviting the patient to breath in.
3. Stenosis (< 0.3 cm), valve abnormalities and septa on B-mode imaging.
4. Absence of flow at the level of the internal jugular or vertebral vein, despite numerous deep inspirations.
5. No increase in the diameter of the internal jugular vein when changing from an upright to a supine position (lack of change in pressure). 

In 2014, the International Society for Neurovascular Disease published modifications to the Zamboni Doppler ultrasound protocol and described protocols for additional imaging using magnetic resonance and intravascular ultrasound to supplement Doppler ultrasound.² The revised ultrasound criteria, originally proposed in 2011, are:

1. Reflux present in the internal jugular or vertebral veins:
   • Bidirectional flow in 1 or both internal jugular veins in both positions (supine or upright) or bidirectional flow in 1 position with absence of flow in the other position;
   • Reversal of flow or bidirectional flow in 1 or both venous veins in both positions.
2. Internal jugular vein stenosis:
   • Reduction of proximal internal jugular vein cross-sectional area in the supine position to no more than 0.3 cm², which does not increase with Valsalva maneuver.
   • Structural abnormalities.
3. Absence of detectable flow in the internal jugular veins or venous veins despite numerous deep inspirations and bidirectional flow detected in the other position on the same side.
4. The cross-sectional area of the internal jugular vein is greater in the seated than supine position or is similar in the 2 positions.
5. Bidirectional flow in the intracranial vein and sinuses (recommended as an additional criterion).

Regulatory Status 
Endovascular correction of chronic cerebrospinal venous insufficiency is a surgical procedure and, as such, is not subject to regulation by the U.S. Food and Drug Administration. 

Policy:
The identification and subsequent treatment of chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis is considered NOT MEDICALLY NECESSARY.    

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices may not be considered investigational, and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
Diagnosis of Chronic Cerebrospinal Venous Insufficiency and Association With Multiple Sclerosis
In 2009, Zamboni et al. used 5 ultrasound criteria (see Background section) to define the condition of chronic cerebrospinal venous insufficiency (CCSVI).¹ In initial research reports, these investigators reported 100% sensitivity and 100% specificity in separating patients with multiple sclerosis (MS) from controls when applying these criteria.³ Since publication of the Zamboni studies, numerous other research studies have attempted to replicate its findings on the association between CCSVI in MS patients (i.e., comparing rates of CCSVI in MS patients and healthy controls and/or patients with other neurologic diagnoses).

Systematic Reviews
In 2014, a meta-analysis on the association between CCSVI and MS was published by Tsivgoulis et al.⁴ Nineteen studies (1,250 MS patients, 899 healthy controls) were included in the meta-analysis. CCSVI was associated with MS in the pooled analysis (odds ratio (OR), 8.35; 95% confidence interval (CI), 3.44 to 20.31; p < 0.001). Heterogeneity across studies was considerable (I² = 80.1%). In additional sensitivity analyses, the odds ratio associating CCSVI and MS decreased. In the most conservative sensitivity analysis, which excluded 8 studies (studies by Zamboni or associated groups and studies conducted in Italy or by advocates of endovascular procedures for CCSVI), MS was not associated with CCSVI (OR = 1.35; 95% CI, 0.62 to 2.93; p = 0.453). Additionally, heterogeneity was not found (I² = 0%).

Zwischenberger et al. in 2013 reported on a meta-analysis of the association between MS and CCSVI diagnosed by ultrasound.⁵ Thirteen studies (1,141 MS patients, 738 healthy controls) were included in the meta-analysis. Initial analysis demonstrated CCSVI was associated with MS (OR = 2.57; p < 0.001), but heterogeneity was significant (I² = 82.7%; p < 0.001). In a subsequent analysis of 9 studies with 4 outliers (studies with disproportionately high ORs) removed, the odds ratio decreased, but still associated CCSVI with MS (OR = 1.885; p < 0.001) and heterogeneity decreased (I² = 18%; p = 0.279).  

A systematic review of the association between CCSVI and MS was published in 2011 by Laupacis et al.⁶ It included 8 studies that used ultrasound to diagnose CCSVI by Zamboni criteria and compared the rate of CCSVI in patients with MS to those without MS. Studies were mostly small, with the median number of patients with MS of 50. A large degree of heterogeneity existed across studies in the rate of CCSVI among MS patients. Two smaller studies reported a rate of 0% for CCSVI (n range, 20 – 56 patients with MS). In contrast, the original study by Zamboni et al. reported a 100% rate of CCSVI in 109 patients with MS. A small study of 25 patients also reported a very high rate of CCSVI at 84% (21/25). No obvious reason was identified for this large discrepancy in CCSVI rates; the authors hypothesized that the most likely reason was variability in ultrasound technique and interpretation. The analysis suggested a significant association between CCSVI and MS in combined analysis, with an odds ratio of 13.5 (95% CI, 2.6 to 71.4). A substantial degree of heterogeneity existed in this measure as well (I² = 89%). Several sensitivity analyses showed marked variability of the odds ratio from a low of 3.7 to more than 58,000. However, in all cases the association between CCSVI and MS remained significant.

A 2011 systematic review published that included 4 studies found the rate of CCSVI in MS patients ranged from 7% to 100%, while the rate in non-MS patients ranged from 2% to 36%.⁷ A significant association was detected between MS and CCSVI, but with a high degree of heterogeneity (I² = 96%) and an odds ratio for association that varied widely, from approximately 2 to more than 26,000.

Controlled Observational Studies
Observational studies published more recently than the systematic reviews are described next. In 2016, Fox et al. published a study with 61 MS patients and 20 non-MS controls (15 healthy individuals, 5 patients with other neurologic disorders).⁸ Zamboni criteria were used to assess patients. However, investigators used 2 interpretations of the ultrasound data that involved narrow and broad interpretations of criteria 2 and 3. Using the narrow criteria, the incidence of CCSVI (i.e., meeting ≥ 2 of 5 criteria) was 21.3% in MS patients and 20.0% in controls (p = 0.99). Using broad criteria, estimates were 36.1% in MS patients and 40% in controls (p = 0.75). In addition, there were no significant differences in the proportion of MS and control patients who met any single ultrasound criterion.

A 2016 study by Cardaioli et al. included 57 subjects (39 MS patients, 18 healthy individuals).⁹ Study participants were assessed using Zamboni criteria for CCSVI as revised by the International Society for Neurovascular Disease (ISNVD).² Seventeen (43.6%) MS patients and 6 (33.3%) healthy controls met the diagnostic criteria for CCSVI; the difference between groups was not statistically significant (p = 0.4). In addition, there were no statistically significant differences between MS patients and healthy controls on any single CCSVI criterion.

In 2016, Schrauben et al. evaluated 172 subjects (76 MS patients, 53 healthy controls) who were age- and sex-matched to MS patients and 43 patients with other neurologic diseases.¹⁰ Patients were assessed with ultrasound and 4-dimensional (4D) magnetic resonance imaging (MRI) augmented by contrast-enhanced magnetic resonance venography (MRV). Twelve (15.8%) MS patients, 15 (9.3%) patients with other neurologic diseases and 9 (17.0%) healthy controls met ultrasound criteria for CCSVI. The difference between groups was not statistically significant (p value not reported). Moreover, no 4D MRI parameter differed significantly among groups and contrast-enhanced MRV did not identify significant differences in stenosis scores among groups.

Section Summary: Diagnosis of Chronic Cerebrospinal Venous Insufficiency
The relation between CCSVI and MS remains unclear. Initial reports of excellent discrimination of patients with and without MS using CCSVI ultrasound criteria have not been replicated in subsequent studies. Systematic reviews have generally found a statistically significant association between CCSVI and MS, but a 2014 meta-analysis that excluded studies by Zamboni and associated research groups found no significant association. Moreover, systematic reviews have reported significant heterogeneity among studies. Recent observational studies have not found that Zamboni criteria or updated criteria proposed by the ISNVD can discriminate between patients with and without MS. 

TREATMENT OF CCSVI WITH PERCUTANEOUS VENOPLASTY
Initial interest in percutaneous venoplasty to treat patients with MS and CCSVI came after publication of case series by Zamboni et al. For example, in a pilot series of 65 patients with MS and CCSVI, Zamboni et al. reported clinical improvement following catheter-based venoplasty.³ Patients were subdivided by MS clinical course into relapsing-remitting (n = 35), secondary progressive (n = 20) and primary progressive (n=10) MS, and all patients underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months. In this study, outpatient endovascular treatment of CCSVI was noted to be feasible, with a minor complication rate. Postoperative venous pressure was significantly lower. The endovascular treatment was noted to improve MS clinical outcome measures, especially in the relapsing-remitting group: the rate of relapse-free patients changed from 27% to 50% postoperatively (p < 0.001). The Multiple Sclerosis Functional Composite at 1 year improved significantly in relapsing remitting patients (p < 0.008) but not in primary progressive or secondary progressive. Physical quality of life (QOL) improved significantly in relapsing-remitting (p < 0.01) and primary progressive (p < 0.03) patients, with a positive trend in secondary progressive (p < 0.08). The authors concluded that PTA of venous strictures in patients with CCSVI is safe, and especially in patients with relapsing-remitting disease, the clinical course was positively influenced by treatment. The authors also indicated a randomized controlled trial (RCT) is warranted.

In a 2012 Cochrane review, van Zuuren et al. found no RCTs on the treatment of CCSVI in MS patients.¹¹ Reviewers concluded the efficacy or safety of PTA for CCSVI treatment in MS patients could not be determined. A 2014 update of this Cochrane review also did not identify any RCTs.¹² 

An RCT was published in 2014, after the literature search date cutoff for the Cochrane review. The RCT, by Siddiqui et al., was double-blind, sham-controlled and evaluated venous angioplasty in MS patients with CCSVI.¹³ This trial enrolled 9 patients in intervention group and 10 in the sham-controlled group. All patients met the criteria for diagnosis of CCSVI.¹⁴ The primary end points of the trial included safety at 24 hours and 30 days after angioplasty; greater than 75% restoration of venous outflow at 30 days; the presence of new MS lesions; and relapse rate over 6 months. Secondary end points included changes in disability scores, brain volume, cognitive test scores and QOL measures. All patients tolerated the procedures well; no operative or postoperative complications were identified. One patient in the angioplasty group experienced an episode of symptomatic bradycardia. No significant differences were observed in venous outflow characteristics between the treated and control groups, nor were any significant improvements observed in clinical disease scores among treated patients compared with controls. The results of this RCT are limited by the small number of patients. However, the failure to show a beneficial effect of venous angioplasty on MS activity supports a lack of efficacy for this treatment.

The authors of a 2015 comprehensive literature review of venous angioplasty as treatment for CCSVI in MS concurred, concluding that venous angioplasty has no proven efficacy for treating CCSVI in MS, may exacerbate underlying disease activity and suggesting that the treatment should no longer be offered, even in clinical trials.¹⁵ 

Adverse Events
A Food and Drug Administration (FDA) alert issued in May 2012 reported the potential for adverse events following endovascular interventions for MS.¹⁶ Reports of adverse events obtained by FDA included death, stroke, detachment and/or migration of stents, vein damage, thrombosis, cranial nerve damage and abdominal bleeding. This alert included the caveat that clinical trials of this procedure require FDA approval and an investigational device exemption because of the potential for harms.

Petrov et al. reported on the safety profile of 495 venoplasty procedures performed in 461 patients with MS, including 98 stent implantations.¹⁷ There were no deaths, major bleeding events or acute exacerbations of MS. The most common procedure-related complication was vein dissection, which occurred in 3.0% of cases. Other complications included cardiac arrhythmias (1.2%), groin hematoma (1.0%), vein rupture (0.4%) and acute stent thrombosis (1.6%).

Mandato et al. reported on adverse events within 30 days of an endovascular intervention for 240 patients with MS over an 8-month period.¹⁸ Neck pain occurred in 15.6% of patients, most commonly following stent implantation. Headache occurred in 8.2% of patients and persisted more than 30 days in 1 (0.4%) patient. Intraprocedural arrhythmias occurred in 1.3%, and 1 patient was diagnosed with a stress-induced cardiomyopathy following the procedure.

Section Summary: Treatment of CCSVI With Percutaneous Venoplasty
A 2014 prospective, double-blind, sham-controlled RCT of venous angioplasty in MS patients with CCSVI showed no significant differences in venous outflow characteristics between the treatment and control groups, nor any significant improvements in clinical disease scores among treated patients and controls. The results of this RCT are limited by the small number of patients. A few case series of several hundred patients have reported on adverse events. They have established that adverse events are uncommon following venoplasty, but serious adverse events do occur. FDA issued an alert in 2012, noting the existence of serious reported complications, including death, and the need for ongoing monitoring. The published literature does not currently allow accurate estimates of rates of serious adverse events.

SUMMARY OF EVIDENCE
For individuals who have multiple sclerosis (MS) who receive ultrasound with or without magnetic resonance imaging to diagnose chronic cerebrospinal venous insufficiency (CCSVI), the evidence includes systematic reviews and controlled observational studies. Relevant outcomes are test accuracy, test validity and other test performance measures. Systematic reviews have generally found a statistically significant association between CCSVI and MS, but a 2014 meta-analysis that excluded studies by Zamboni (who proposed criteria for defining CCSVI) and associated research groups found no significant association. Moreover, systematic reviews have reported significant heterogeneity among studies. Recent observational studies have not found that Zamboni criteria or updated criteria proposed by the International Society for Neurovascular Disease can discriminate between patients with and without MS. The association between CCSVI and MS, especially as a causative factor, remains unclear. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have MS and CCSVI who receive treatment for CCSVI with percutaneous venoplasty, the evidence includes 1 randomized controlled trial (RCT) and several case series. Relevant outcomes are overall survival, symptoms, quality of life and treatment-related morbidity. The RCT was double-blind and sham-controlled. It found no statistically significant differences in venous outflow characteristics or improvements in clinical disease scores between groups treated with venoplasty and a sham intervention. The results of this RCT are limited by the potential for underpowering, and we did not identify any other RCTs on the efficacy of percutaneous venoplasty. Data on adverse events are available from the Food and Drug Administration (FDA) as well as larger published case series (i.e., with several hundred patients). The case series found that adverse events were uncommon following venoplasty, but serious adverse events have been reported to FDA. FDA issued an alert in May 2012, noting the existence of serious complications, including death, and the need for ongoing monitoring. It is not currently possible from the available literature to estimate with confidence the rate of serious adverse events (e.g., death, major bleeding). The evidence is insufficient to determine the effects of the technology on health outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS
International Society for Neurovascular Disease
In 2014, the International Society for Neurovascular Disease published a position statement on detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency (CCSVI).²
The document concluded:

"Although some CNS [central nervous system] disorders have been linked to the presence and severity of CCSVI, the ultimate cause-consequence relationship has not been firmly established. Therefore, it is not clear at this time which patient population should undergo the noninvasive and invasive studies for detection of extracranial venous abnormalities." 

Cardiovascular and Interventional Radiological Society of Europe
A 2011 Cardiovascular and Interventional Radiological Society of Europe (CIRSE) commentary on the treatment of CCSVI noted that:

"Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in progress. Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population."¹⁹  

Society for Interventional Radiology
In 2010, the Society for Interventional Radiology (SIR) published a position statement on the association between CCSVI and multiple sclerosis (MS) and on the efficacy of endovascular treatments.²⁰ Its recommendations included the following statements:

"At present, SIR considers the published literature to be inconclusive on whether CCSVI is a clinically important factor in the development and/or progression of MS, and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS."

SIR strongly supports the urgent performance of high-quality clinical research to determine the safety and efficacy of interventional MS therapies, and is actively working to promote and expedite the completion of the needed studies." 

National Institute for Health and Clinical Excellence
In 2012, the U.K.’s National Institute for Health and Clinical Excellence (NICE) published guidance on the use of percutaneous venoplasty to treat CCSVI in patients with MS.²¹ This guidance contained the following statements on the diagnosis and treatment of CCSVI:

"Current evidence on the efficacy of percutaneous venoplasty for chronic cerebrospinal venous insufficiency (CCSVI) for multiple sclerosis (MS) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. 

NICE encourages further research on percutaneous venoplasty for CCSVI for MS, in the form of robust controlled clinical trials. Studies should clearly define selection criteria and patient characteristics. They should also clearly define technical success which may include measurement of pressure gradients across treated vein segments before and after venoplasty. Outcomes should include clinical and quality of life measures." 

European Society of Neurosonology and Cerebral Hemodynamics
The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) issued a statement on CCSVI and MS in 2012.²² The ESNCH statement indicated that the proposed criteria for the diagnosis of CCSVI were questionable because of methodologic and technologic errors as well as lack of validation. The statement strongly discouraged any interventional treatment for CCSVI in MS, such as transluminal angioplasty and/or stenting, due to lack of evidence and risk of serious complications.  

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT: national clinical trial. 

References: 

1. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. Apr 2009;80(4):392-399. PMID 19060024
2. Zivadinov R, Bastianello S, Dake MD, et al. Recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the International Society for Neurovascular Disease. J Vasc Interv Radiol. Nov 2014;25(11):1785-1794 e1717. PMID 25255703
3. Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. Dec 2009;50(6):1348-1358 e1341-1343. PMID 19958985
4. Tsivgoulis G, Sergentanis TN, Chan A, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies. Ther Adv Neurol Disord. Mar 2014;7(2):114-136. PMID 24587827
5. Zwischenberger BA, Beasley MM, Davenport DL, et al. Meta-analysis of the correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis. Vasc Endovascular Surg. Nov 2013;47(8):620-624. PMID 24005191
6. Laupacis A, Lillie E, Dueck A, et al. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ. Nov 8 2011;183(16):E1203-1212. PMID 21969411
7. Thapar A, Lane T, Nicholas R, et al. Systematic review of sonographic chronic cerebrospinal venous insufficiency findings in multiple sclerosis. Phlebology. Dec 2011;26(8):319-325. PMID 22021635
8. Fox RJ, Diaconu C, Baus L, et al. No association of chronic cerebrospinal venous insufficiency with multiple sclerosis. Can J Neurol Sci. Jan 2016;43(1):195-197. PMID 26194114
9. Cardaioli G, Di Filippo M, Bianchi A, et al. Extracranial venous drainage pattern in multiple sclerosis and healthy controls: application of the 2011 diagnostic criteria for chronic cerebrospinal venous insufficiency. Eur Neurol. 2016;76(1-2):62-68. PMID 27384420
10. Schrauben EM, Kohn S, Macdonald J, et al. Four-dimensional flow magnetic resonance imaging and ultrasound assessment of cerebrospinal venous flow in multiple sclerosis patients and controls. J Cereb Blood Flow Metab. Jun 30 2016. PMID 27364001
11. van Zuuren EJ, Fedorowicz Z, Pucci E, et al. Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients. Cochrane Database Syst Rev. 2012;12:CD009903. PMID 23235683
12. van Zuuren EJ, Fedorowicz Z, Pucci E, et al. Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency in people with multiple sclerosis: a summary of a Cochrane systematic review. J Neurol Neurosurg Psychiatry. Apr 2014;85(4):405-410. PMID 23781006
13. Siddiqui AH, Zivadinov R, Benedict RH, et al. Prospective randomized trial of venous angioplasty in MS (PREMiSe). Neurology. Jul 29 2014;83(5):441-449. PMID 24975855
14. Zivadinov R, Marr K, Cutter G, et al. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. Jul 12 2011;77(2):138-144. PMID 21490322
15. Tsivgoulis G, Faissner S, Voumvourakis K, et al. "Liberation treatment" for chronic cerebrospinal venous insufficiency in multiple sclerosis: the truth will set you free. Brain Behav. Jan 2015;5(1):3-12. PMID 25722945
16. FDA News Release: FDA issues alert on potential dangers of unproven treatment for multiple sclerosis. 2012, May 10; http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm303538.htm?source=govdelivery. Accessed October 31, 2016.
17. Petrov I, Grozdinski L, Kaninski G, et al. Safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Endovasc Ther. Jun 2011;18(3):314-323. PMID 21679067
18. Mandato KD, Hegener PF, Siskin GP, et al. Safety of endovascular treatment of chronic cerebrospinal venous insufficiency: a report of 240 patients with multiple sclerosis. J Vasc Interv Radiol. Jan 2012;23(1):55-59. PMID 22088659
19. Reekers JA, Lee MJ, Belli AM, et al. Cardiovascular and Interventional Radiological Society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Cardiovasc Intervent Radiol. Feb 2011;34(1):1-2. PMID 21136256 
20. Vedantham S, Benenati JF, Kundu S, et al. Interventional endovascular management of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association. J Vasc Interv Radiol. Sep 2010;21(9):1335-1337. PMID 20800776
21. National Institute for Health and Clinical Excellence (NICE). Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis [IPG420]. March 2012; www.nice.org.uk/ipg420. Accessed October, 2016.
22. Baracchini C, Valdueza JM, Del Sette M, et al. CCSVI and MS: a statement from the European Society of Neurosonology and Cerebral Hemodynamics. J Neurol. Dec 2012;259(12):2585-2589. PMID 22648477

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