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Diagnosis and Treatment of Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis

Policy Number: MP-477

Latest Review Date: July 2023

Category:  Medical                                                                

POLICY:

The identification and subsequent treatment of chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis is considered investigational. 

DESCRIPTION OF PROCEDURE OR SERVICE:

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 has been attempted via percutaneous venoplasty. The intent of this procedure is to relieve MS symptoms by improving venous drainage of the central nervous system.

The foundation of this vascular theory is that there is abnormal venous drainage from the brain due to outflow obstruction in the draining jugular vein and/or azygos veins. This abnormal venous drainage, which is identified 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 veins in the legs in individuals with chronic deep vein thrombosis. Those studying this theory have promoted the idea that balloon dilatation, with or without stenting, will resolve the CCSVI and alleviate MS complaints.

Multiple sclerosis (MS) is generally considered a chronic inflammatory demyelinating disease of the central nervous system (brain, spinal cord, optic nerve) felt to be triggered by an autoimmune response to myelin. However, in part due to the periventricular predilection of the lesions of multiple sclerosis, vascular etiologies (chronic cerebrospinal venous insufficiency [CCSVI]) have also been considered.

The following five criteria were defined by Zamboni et al as features of CCSVI. To make the diagnosis of CCSVI, at least two of the five criteria need to be present:

1. Reflux constantly present (for a duration >0.8 s) 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 s). 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-).

The association of CCSVI with MS is uncertain. The rate of CCSVI in MS patients varies widely in the literature for unclear reasons, from 0% to 100%. Some studies report higher rates of CCSVI in patients with MS compared with Non-MS patients, but others do not. If there is an association between MS and CCSVI, it is not known whether this is a causative factor for MS or a secondary result of the disease. It also appears that CCSVI can occur in other disorders and is not specific for MS.

Treatment of CCSVI with endovascular interventions has been attempted. Some currently available studies report improvement in patient-reported symptoms following treatment, but this evidence is not sufficient to establish efficacy. A prospective, double-blind, sham-controlled randomized controlled trial (RCT) of venous angioplasty in MS patients (N=20) with CCSVI published in 2014 showed no significant differences in venous outflow characteristics between the treated and control groups, nor any significant improvements in clinical disease scores among treated patients compared with controls. The results of three this RCT are limited by the small number of patients. However, the failure to show a beneficial effect of venous angioplasty on blood flow or symptoms supports a lack of efficacy for this treatment.

Adverse events occur at a low overall rate, but serious adverse events can occur, and the U.S. Food and Drug Administration (FDA) issued an alert in 2012 concerning the potential for serious adverse events with treatment of CCSVI.

KEY POINTS:

This policy is based on a PubMed literature search through July 26, 2023.

Summary of Evidence

For individuals who have multiple sclerosis 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 when all studies are included 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 (ISNVD) can discriminate between MS and Non-MS patients. 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 multiple sclerosis and CCSVI who receive percutaneous venoplasty, the evidence includes one 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 the groups treated with venoplasty versus a sham intervention. The small number of patients limits the results of this RCT and no other RCTs on the efficacy of percutaneous venoplasty were identified. Data on adverse events are available from the FDA and 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 the 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 the rate of serious adverse events such as death or major bleeding with confidence. 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). 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

The Cardiovascular and Interventional Radiological Society of Europe (CIRSE) commentary on the treatment of chronic cerebrospinal venous insufficiency notes 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.” 

The Society for Interventional Radiology (SIR)

The Society for Interventional Radiology (SIR) published a position statement on the association of CCSVI with MS and the efficacy of endovascular treatments. Their 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.

The U.K. National Institute for Health and Clinical Excellence (NICE)

The U.K. National Institute for Health and Clinical Excellence (NICE) published a guidance document on the use of percutaneous venoplasty to treat CCSVI in patients with MS. This document 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.

The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH)

The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) issued a statement on CCSVI and MS in 2012. The ESNCH statement indicates the proposed criteria for the diagnosis of CCSVI is questionable due to methodological and technological errors, and lack of validation. The statement strongly discourages 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.

KEY WORDS:

Chronic cerebrospinal venous insufficiency, CCSVI, Liberation Procedure, CCSVI interventions, balloon venoplasty, catheter-based venoplasty, PTA of venous strictures in patients with CCSVI

APPROVED BY GOVERNING BODIES:

Endovascular correction of CCSVI is a surgical procedure and as such is not subject to FDA approval. However, in 2012, FDA issued an alert concerning the potential for serious adverse events with the treatment for CCSVI.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply.  Refer to member’s benefit plan.

CURRENT CODING: 

There is no specific code CPT for this test.

CPT Codes:

37248

Transluminal balloon angioplasty (except dialysis circuit), open or percutaneous, including all imaging and radiological supervision and interpretation necessary to perform the angioplasty within the same vein; initial vein

37249

Transluminal balloon angioplasty (except dialysis circuit), open or percutaneous, including all imaging and radiological supervision and interpretation necessary to perform the angioplasty within the same vein; each additional vein

REFERENCES:

  1. 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 2012; 259(12):2585-2589.
  2. Barreto AD, Brod SA, Bui TT et al. Chronic cerebrospinal venous insufficiency: Case-control neurosonography results. Ann Neurol. Dec 2012.
  3. Bourdette DN, Cohen JA. Venous angioplasty for "CCSVI" in multiple sclerosis: ending a therapeutic misadventure. Neurology. Jul 29 2014; 83(5):388-389.
  4. Burton JM, Alikhani K, Goyal M et al. Complications in MS patients after CCSVI procedures abroad (Calgary, AB). Can. J. Neurol. Sci. 2011; 38(5):741-746.
  5. Centonze D, Floris R, Stefanini M et al. Proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity. Ann. Neurol. 2011; 70(1):51-58.
  6. Costello, F., Modi, J., Lautner, D., Bhayana, D., Scott, J., Davenport, W., et al. (2014). Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with multiple sclerosis. Canadian Medical Association Journal, 186 (11), E418-E426.
  7. Doepp F, Paul F, Valdueza JM et al.  No cerebrospinal venous congestion in patients with multiple sclerosis.  Ann Neurol 2010; 68(2):155-159.
  8. FDA News Release: FDA issues alert on potential dangers of unproven treatment for multiple sclerosis. Available online at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm303538.htm?source=govdeli very
  9. Floris R, Centonze D, Fabiano S et al. Prevalence study of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: preliminary data. Radiol Med 2012.
  10. 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.
  11. Fox RJ, Rae-Grant A.  Chronic cerebrospinal venous insufficiency: have we found the cause and cure of MS?  Neurology. Jul 12 2011; 77(2):98-100.
  12. Hubbard D, Ponec D, Gooding J et al. Clinical improvement after extracranial venoplasty in multiple sclerosis. J Vasc Interv Radiol 2012; 23(10):1302-1308.
  13. Jagannath, V., Pucci, E., Asokan, G.V., & Robak, E.W. (2019). Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in people with multiple sclerosis. Cochrane Database of Systematic Reviews, 5 (5), CD009903. 
  14. Kugler, N., Patel, P., & Lee, C. (2015). Chronic cerebrospinal venous insufficiency in multiple sclerosis: a failed concept. Vascular Specialist International, 31 (1), 11-14.
  15. 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.
  16. 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.
  17. Mayer CA, Pfeilschifter W, Lorenz MW et al.  The perfect crime?  CCSVI not leaving a trace in MS.  J Neurol Neurosurg Psychiatry 2011; 82(4):436-440.
  18. Napoli, V., Berchiolli, R., Carboncini, M.C., Sartucci, F., Marconi, M., Bocci, T., et al. (2019). Percutaneous venous angioplasty in patients with multiple sclerosis and chronic cerebrospinal venous insufficiency: A randomized wait list control study. Annals of Vascular Surgery, 62, 275-286.
  19. National Institute for Health and Clinical Excellence (NICE). Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis. March 2012. http://www.nice.org.uk/ipg420.
  20. National Institute for Health and Clinical Excellence (NICE). (2019). Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis.
  21. Olek, Michael J, DO, Mowry, Ellen, MD, MCR. Pathogenesis and epidemiology of multiple sclerosis In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.  Topic last updated April 19, 2023.
  22. Paul F, Wattjes MP. Chronic cerebrospinal venous insufficiency in multiple sclerosis: the final curtain. Lancet 2014; 383:106.
  23. 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.
  24. 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 2011;34(1):1-2.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. U.S. Food and Drug Administration (FDA). FDA News Release: FDA issues alert on potential dangers of unproven treatment for multiple sclerosis. Available online at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm303538.htm?source=govdelivery 
  31. 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.
  32. 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.
  33. Weinstock-Guttman B, Ramanathan M, Marr K et al. Clinical correlates of chronic cerebrospinal venous insufficiency in multiple sclerosis. BMC Neurol 2012; 12:26.
  34. 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.
  35. Zamboni P, Galeotti R, Weinstock-Guttman B et al. Venous angioplasty in patients with multiple sclerosis: results of a pilot study. Eur. J. Vasc. Endovasc. Surg. 2012; 43(1):116-122.
  36. Zamboni R, 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.
  37. Zamboni, P., Tesio, L., Galimberti, S., Massacesi, L., Salvi, F., D’Alessandro, R., et al. (2018). Efficacy and safety of extracranial vein angioplasty in multiple sclerosis. JAMA Neurology, 75 (1), 35-43. 
  38. 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.
  39. Zivadinov R, Cutter G, Marr K et al. No association between conventional brain MR imaging and chronic cerebrospinal venous insufficiency in multiple sclerosis. AJNR Am J Neuroradiol 2012; 33(10):1913-1917.
  40. Zivadinov R, Mar K, Cutter G et al.  Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. Jul 12 2011; 77(2):138-144.
  41. 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.

POLICY HISTORY:

Medical Policy Panel, June 2011

Medical Policy Group, June 2011 (2)

Medical Policy Administration Committee, July 2011

Available for comment July 6 through August 22, 2011

Medical Policy Panel, June 2012

Medical Policy Group, July 2012 (2): Updated Description, Key Points, References

Medical Policy Group, June 2013 (2): Update to Key Points and References

Medical Policy Group, October 2013 (2): Removed ICD-9 Diagnosis codes; no change to policy statement.

Medical Policy Panel, June 2014

Medical Policy Group, June 2014 (4): Updated Key Points and References.  No change to the policy statement.

Medical Policy Panel, May 2015

Medical Policy Group, June 2015 (2): 2015 Updates to Key Points, Approved by Governing Bodies, and Reference; no change to policy statement.

Medical Policy Panel, November 2016

Medical Policy Group, November 2016 (7): Updated Description, Key Points, and References. No changes to policy statement. Retiring policy effective November 28, 2016.

Medical Policy Group, December 2016: 2017 Annual Coding Update.  Created Previous Coding section and moved deleted codes 35460, 35476, and 75978 to this section.  Added new CPT codes 37248 and 37249 to Current coding.

Medical Policy Group, October 2019 (3): 2019 Updates to Key Points. A peer-reviewed literature analysis was completed and no new information was identified that would alter the coverage statement of this policy.

Medical Policy Group, August 2021 (6): Updates to Description, Key Points and References.

Medical Policy Group, August 2022 (3): 2022 Updates to Key Points and References. A peer-reviewed literature analysis was completed and no new information was identified that would alter the coverage statement of this policy.

Medical Policy Group, July 2023 (3): 2023 Updates to Key Points, Benefit Applications, and References. A peer-reviewed literature analysis was completed, and no new information was identified that would alter the coverage statement of this policy.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.