ANZSVS Information Sheet / position Statement Chronic Cerebrospinal Venous Insufficiency (CCSVI)
Chronic Cerebrospinal Venous Insufficiency is a condition named to describe the concept of impaired Cerebrovascular Venous Drainage which could contribute to adverse physiological conditions of raised cerebral venous pressure, a postulated mechanism in the development of Multiple Sclerosis (and some other neurological conditions).
The original pathological description by Zamboni (Zamboni, 2006), was based upon the concept of chronic lower limb ambulatory venous hypertension (although lower limb venous pressures are significantly greater due to gravitational effects). Vascular clinicians are well aware of the detrimental effects of venous hypertension on the skin of the lower limbs and postulated that the delicate neural tissue might be susceptible to such physiological forces. Zamboni’s second article (Zamboni, 2009) described procedures to treat CCSVI (sometimes referred to as “liberation therapy”) with a balloon angioplasty procedure or inserting a stent in order to open blocked or narrowed veins thereby achieving better blood flow and improved drainage of blood from the brain. This publication gained an initial optimistic response due to reported benefits in a cohort of sufferers of Multiple Sclerosis. This sparked optimism amongst thousands of MS sufferers and their carers worldwide.
The evidence expanded on the prevalence of CCSVI among people living with MS and people who do not have MS suggest that CCSVI is not specifically linked with MS. Researchers found discrepancies in results and felt these may be attributed to inconsistencies in imaging techniques, training of personnel, the interpretation of results, and even on the hydration status of people undergoing testing. There is some doubt as to the validity of the diagnostic criteria used to make the diagnosis CCSVI.
Venous angioplasty CCVSI found enthusiasm among many procedural specialists worldwide who were willing to perform a relatively simple procedure with purported benefits for longstanding sufferers of a devastating chronic neurological illness.
As with most new procedures and technologies, there was a corresponding reserved response from the cardiovascular scientific community. Was high cerebrospinal venous pressure ever documented? Was a post-treatment reduction in pressure ever documented in each case? The early critiques of the initial two Zamboni publications focused on the low-level of scientific evidence that its conclusions were based on. There were calls for a randomised controlled trial (RCT) with the control arm being subjected to a “sham” venous angioplasty.
The venous angioplasty procedure was the subject of an initial Cochrane review in 2012 but there were no publications that met the suitable inclusion criteria due to their poor methodology (non-randomised nature of those reports).
Following the publication of more up-to-date research a subsequent Cochrane review was commissioned and undertaken in 2018. This systematic review identified “moderate‐quality” evidence, comprised of 238 patients from 3 publications (Siddiqui, 2014; Traboulsee, 2018 & Zamboni, 2018), that compared the venous angioplasty intervention with a “sham” procedure. This important study-design feature ensures that the recipients, carers and their managing clinicians remain “blinded” to the randomised treatment they have received. In this meta-analysis, there was no benefit documented based on analysis of patient‐centred outcomes (disability, physical or cognitive functions, relapse, quality of life). Moreover, the fact that results for restored blood flow were similar for treated and sham groups suggested that PTA was not effective in restoring venous outflow. In the discussion of the paper authored by Dr. Zamboni and his co-authors they conclude that “Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.”).
The conclusion of the latest Cochrane review was that although venous angioplasty was proven to be a safe technique (without any serious adverse outcomes in the 3 publications included) it was concluded that the intervention was ineffective and could not be recommended in people with MS. Furthermore, the Cochrane reviewers felt that there was no requirement for further randomised clinical studies on this procedure.
The U.S. FDA had initially issued a safety communication in May 2012, in regard to interventional management of CCVSI. It explained that virtually all FDA-approved disease-modifying therapies for MS have their own risk/benefit profiles. The difference was that those therapies have been shown, through large-scale, controlled clinical trials, to significantly reduce MS disease activity in certain individuals. So far angioplasty for CCVSI has not been shown to have any benefit. Furthermore, they advised that CCSVI procedures have been associated with serious, even fatal, complications. The FDA has received reports of one patient who died from bleeding in the brain and one patient who suffered permanent paralysis from a stroke after CCSVI treatment. The FDA’s advice for future research is that any trial would have “significant-risk” status for ethics approval.
The ANZSVS cannot recommend or support the conduct of such procedures (nor utilisation of significant Medicare or Health Department funding) that are not scientifically supported. Any patients who may subsequently request or be offered such a procedure should be recruited into an ethically designed and rigorously conducted therapeutic trial (at a minimum) and funded via alternative mechanisms.
Zamboni P. The Big Idea: iron‐dependent inflammation in venous disease and proposed parallels in multiple sclerosis. Journal of the Royal Society of Medicine 2006;99(11):589‐93. [PUBMED: PMID: 18045150]
Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, et al. A prospective open‐label study of endovascular treatment of chronic cerebrospinal venous insufficiency. Journal of Vascular Surgery 2009;50(6):1348‐58. [PUBMED: PMID: 19958985]
Siddiqui AH, Zivadinov R, Benedict RH, Karmon Y, Yu J, Hartney ML, et al. Prospective randomized trial of venous angioplasty in MS (PREMiSe). Neurology 2014;83(5):441‐9. [PUBMED: 24975855]
Traboulsee AL, Machan L, Girard JM, Raymond J, Vosoughi R, Hardy BW, et al. Safety and efficacy of venoplasty in MS: A randomized, double‐blind, sham‐controlled phase II trial. Neurology 2018;91(18):e1660‐8. [PUBMED: 30266886]
Zamboni P, Tesio L, Galimberti S, Massacesi L, Salvi F, D’Alessandro R, et al. Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial. JAMA Neurology 2018;75(1):35‐43. [PUBMED: 29150995]
Summary of FDA Recommendations (2012):
For People with Multiple Sclerosis:
- Be aware that there is lack of clear evidence of the existence of CCSVI. Furthermore, the link between CCSVI and MS and the safety and effectiveness of the CCSVI treatment procedure in MS patients has not been established.
- You should know that serious complications can occur as a result of CCSVI treatment procedures. Before you have any CCSVI procedure, discuss with your physician or other health care provider the signs and symptoms of such complications. If you have the procedure and you develop any of the signs or symptoms of a complication, contact your health care provider immediately.
- Before considering CCSVI treatment, discuss the potential risks and benefits with a neurologist or other health care provider who is familiar with MS and CCSVI (including the CCSVI procedures and their outcomes).
- If you decide to undergo diagnostic and/or treatment procedures for CCSVI, continue to follow the MS treatment plan outlined by your neurologist or the provider caring for your MS.
- If you are considering participating in a clinical trial for CCSVI, learn as much as possible about the clinical trial and ask questions of the health care team conducting the trial. Read the informed consent document carefully, and ask for an explanation of anything you do not understand. You can find additional information and recommended questions to ask your health care team on the Understanding Clinical Trials page of www.clinicaltrials.gov.
- If you undergo treatment for CCSVI and experience a complication, we encourage you to file a report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.
For Physicians and Care Providers:
- Inform patients of the following concerns:
- there is conflicting evidence about CCSVI as a clinical entity;
- CCSVI’s relationship to MS is scientifically unproven; and
- consensus on the diagnostic criteria of CCSVI has not been reached.
- You should be aware the FDA has not cleared or approved any angioplasty device or stents for the treatment of CCSVI and use of such devices in treating CCSVI are considered off-label at this time. While the FDA does not regulate the practice of medicine and health care practitioners may choose to use a legally marketed device, based on their clinical assessment, for purposes other than the cleared or approved use, the FDA believes the safety issues observed to date warrant a communication on the subject.
- Discuss the risks of CCSVI treatment with potential patients, including both the adverse events generally associated with catheter-guided endovascular intervention and those related specifically to use of balloon angioplasty devices or venous stenting for CCSVI.
- If your patient experiences a complication following CCSVI treatment, please file a report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.
For Clinical Investigators and Institutional Review Boards (IRBs):
- The FDA has determined that investigations of medical devices for use in CCSVI treatment are significant risk studies. Clinical studies of significant risk medical devices, such as in the case of balloon angioplasty devices and stents to treat CCSVI, require approval through an IRB and the FDA’s Investigational Device Exemption (IDE) program. The IDE regulations help ensure the rights, safety and welfare of patients are protected during these studies and that the risks are as low as possible and are balanced by any potential benefits.
- The FDA encourages clinical investigators to discuss trial design with the FDA in the early planning phase, through both the formal pre-IDE process and less formal meetings and conferences.
- If a patient in an IDE study experiences a complication related to the CCSVI treatment, sponsors and clinical investigators must comply with applicable adverse event recordkeeping and reporting requirements under the FDA’s IDE regulations.
The FDA sent a warning letter to a sponsor/investigator who was conducting a clinical study of CCSVI treatment without an approved IDE. Because the FDA currently considers clinical studies evaluating CCSVI treatment with balloon angioplasty devices and/or stents to be significant risk, this study was in violation of the FDA’s regulations. The sponsor/investigator has reported the study has been voluntarily closed.
The FDA will continue to monitor for adverse events related to medical devices commonly used in CCSVI treatment (e.g. angioplasty devices and stents) and take action when appropriate.
The FDA will continue to monitor this situation and keep the public informed as new information becomes available.
If you have questions about this communication, please contact the Division of Industry and Consumer Education (DICE) at DICE@FDA.HHS.GOV, 800-638-2041 or 301-796-7100.