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Treatment Risks

Background

Widespread misinformation has characterized the discussion of CCSVI treatment risks, often confusing and frustrating patients, caregivers, and even some medical professionals.

The aim of CCSVI Alliance’s Treatment Risks section is neither to promote nor denigrate CCSVI treatment – we hope only to inform potential patients, their loved ones, and medical providers with the most accurate information available. We believe that CCSVI treatment decisions are best made by informed patients in conjunction with trusted and knowledgeable medical professionals.
 
Understanding and Discussing Medical Risk

Understanding medical risks is often challenging; information is sometimes scarce, and there may be no clear way to determine how any potential "risk" may affect any given individual. Without this information, patients have no clear way to understand either the general risk of treatment, or how that risk applies specifically to them. Consequently, risks that are extremely uncommon may become blurred together with risks that are minor but much more common, creating an inaccurate risk assessment.

Risk assessment is further complicated for MS patients, who are already exposed to a wide range of risks. Risks for commonly prescribed MS medications already include:
  • PML virus, death, liver dysfunction, glandular dysfunction, etc.
  • Marginal or limited effectiveness (or, for some patients, complete ineffectiveness) with respect to MS progression
Moreover, MS patients must factor in the risk of doing nothing at all (that is, nothing more to inhibit their MS progression), particularly given common medical advice that MS treatment should be aggressive early in order to minimize early deficits.

Ultimately, risk assessment is an individual decision. For MS patients, risk assessment might include questions like:

     "What is the current course of my disease?"
     "How well am I tolerating currently prescribed medications?"
     "Do I know the risks associated with my current medications?"
     "Do I feel comfortable with how I am managing my disease?"
     "What are the known risks of CCSVI treatment, and how do those risks apply to me?"

For further information on potential risks, please see the FDA's Safety Communication on CCSVI Treatment in MS Patients, as well as the Society of Interventional Radiology (SIR)'s response.

CCSVI Treatment Risk Overview

It should be noted that the endovascular procedure upon which CCSVI treatment is based was pioneered in the 1970s and has been in widespread use since the 1990s. Endovascular procedures are non-operative, minimally invasive, and are considered low risk as long as the patient does not have other aggravating conditions (e.g. advanced heart disease).

An exhaustive discussion of every conceivable risk associated with endovascular procedures would be unhelpful. Instead, this risk section will focus on the unique aspects of CCSVI treatment that set it apart from other types of endovascular procedures. However, the most common general risks from endovascular procedures will also be noted.

CCSVI Treatment risks fall into three categories:
  1. Pre-procedure and Diagnostic Risks
  2. Risks common to all forms of endovascular procedures
  3. Risks unique to CCSVI treatment

1.  Pre-Procedure and Diagnostic Risks

The initial imaging technologies used to determine whether a person has CCSVI (MRV, Duplex Ultrasonography, MRI/SWI) are well-established, noninvasive, and carry minimal risk.

The technologies used during CCSVI diagnosis are also used for diagnosing a wide variety of other conditions, and no unique risks are introduced when these technologies are used in CCSVI diagnosis. Hence, we will provide only a basic list of the most common risks/issues associated with these technologies:
  • Possible reaction to or discomfort with imaging contrast dyes
  • Possible problems with accurate scanning for patients with pins, plates, pacemakers, or other metallic objects inside their bodies
  • X-ray exposure (for CT venograms only)

2.  General Risks associated with an Endovascular Procedure


Note: If you are unfamiliar with endovascular procedures, we suggest you read our CCSVI Treatment section prior to reading the following Risk sections. While endovascular procedures have become routine, they nonetheless introduce a range of patient risks. These risks vary depending on the health of the person undergoing the procedure, and the specifics of the procedure. The most common risks include:
  • Post-procedural bruising or hemorrhaging at the point where the catheter enters the vein
  • Allergy or other reaction to local anesthesia, radiographic contrast dyes, metallic stents, etc.
  • Infection introduced by the catheter or other tools
  • Short-term (1-2 hours) post-procedure dizziness or headache
  • Migration/slippage of inserted devices (e.g. stents)
  • Blood clotting
  • Puncture of a vein wall
  • Serious complications such as abrupt deterioration of neurological status, stroke, or death (all rare, but possible)
Open Surgery for CCSVI Treatment?
To date, all reported cases of CCSVI treatment have been performed using endovascular procedures.
However, several researchers, including  Dr. Zamboni, have suggested that open surgery may become a viable alternative to endovascular treatment.
Because the most common location of stenosis in MS patients is in the jugular vein(s), and because the jugular is near the skin, some researchers believe that a fairly simple incision in the neck could provide surgical access to the jugular.
Once accessed, the stenosis could be cut from the vein, and the vein re-sewn/connected. Alternatively, a vein segment taken from a different part of the body  - e.g. the leg - would be grafted into the jugular, making the vein whole again.
The hope of CCSVI treatment via open surgery is that it would reduce the near 50% restenosis rates found in jugular veins treated by angioplasty, and eliminate any risk of stent migration.
While open surgery is an interesting idea, it would introduce a new set of patient risks. However, until the exact procedure is proposed, a full risk assessment cannot be made.

Anti-platelet and Anti-coagulant Drugs

Following an endovascular procedure, the patient is typically placed on drug therapy, which includes administrating anti-platelet agents or anti-coagulants to prevent blood clotting. In balloon angioplasty, the inflated balloon may cause trauma to the vein, potentially exposing the muscle layer to blood, which can cause clotting. With stents, clotting may occur when blood flow is disrupted or caught in the struts or mesh of the stent.

The anti-coagulants prescribed after endovascular procedures are industry standard (Coumadin, Heparin Arixtra, etc). In general, the effects of anti-coagulants are more robust than those of anti-platelets. However, there is some disagreement about whether anticoagulants or anti-platelets (drugs that prevent platelets from forming into clots; examples include aspirin and Plavix) are preferable, and different physicians may follow different courses, with some recommending both.

Together, anticoagulants and antiplatelets are often referred to as “blood thinners,” and it should be noted that all blood thinners have the potential to cause complications. Because the risks associated with blood thinners are not unique to CCSVI treatment, they will not be discussed at length. Briefly, common risks associated with blood thinners include:
  • Abnormal bleeding or bleeding that resists clotting
  • Intestinal bleeding
  • Bruising (bruises form more easily for those on anti-clotting drugs)
  • Potential interference/interaction with steroids (which are often prescribed during MS relapses)
3.  Risks Unique to CCSVI Treatment

Because CCSVI treatment introduces some unique aspects to common endovascular surgery, it also introduces some unique risks, including:
  • CCSVI Treatment is predominantly performed on MS patients
  • In some cases, CCSVI treatment introduces uncommon use of stents and angioplasty

Risks associated with CCSVI Treatment on MS Patients


The goal of CCSVI treatment is to remove, open, or clear blockages and stenoses in the veins. However, because CCSVI is strongly associated with MS, the majority of patients currently undergoing CCSVI treatment are patients who also have MS. Not surprisingly, there is no data showing that risks from endovascular procedures are either greater or lesser for MS patients. Because MS patients present with a wide variety of health conditions – from essentially healthy to significantly disabled, patient health will likely play a role in overall risk. Beyond this, because CCSVI treatment is a very new procedure, many unknowns remain, both for MS patients and non-MS patients. Until more information is available, a full understanding of all treatment risks and of long-term outcomes is impossible.


Risks associated with Stents and Angioplasty in CCSVI Treatment

CCSVI treatment employs two of the most common types of endovascular procedures: angioplasty and stenting. However, in CCSVI treatment, the locations in the body receiving ballooning or stents can be uncommon.  For MS patients with CCSVI, the highest rates of stenosis are found in the jugular veins, followed closely by the azygos vein. Less common though not infrequent stenoses are also found in the lumbar, vertebral, renal, and deep cerebral veins.

Performing stent placement in the upper jugular has not been widespread and carries some risk (described below). Additionally, there is little data on outcomes for stenting or angioplasty on vertebral and lumbar veins, so long-term patency, particularly for angioplasty, is largely unknown.


Risks associated with Angioplasty in CCSVI Treatment

Angioplasty is generally considered the best initial option for treating CCSVI. With angioplasty, there are no device-specific risks, as nothing is left inside the vein (the vein is simply ballooned open).

What is “Restenosis?”
Restenosis simply means a "re-narrowing" of the vein. However, there has been some confusion because the term does not suggest what part of the vein has become narrowed.
In scientific literature, "restenosis" nearly always refers to a re-narrowing at the point where the vein or artery was treated.
However, in blogs, chat rooms, and other on-line forums, patients often use the term "restenosis" to describe any stenosis that appears post-treatment. Hence, patients may not differentiate between restenosis at the spot of treatment, and a new stenosis that has occurred somewhere else in the vein. From a patient perspective, the result of any new stenosis is the same: additional treatment may be needed.
To avoid confusion, CCSVI Alliance will only use the term "restenosis" to describe a re-narrowing at the point of treatment (that is, we will use the medical standard). To describe additional stenoses that occur post-treatment, we will say “a new stenosis,” or a “previously untreated” stenosis.
However, angioplasty for CCSVI treatment has proven limited, or even ineffective, in some situations. While the effectiveness of a treatment, or “efficacy,” is generally not considered a risk, the odds of restenosis after angioplasty appear sufficiently high to warrant mentioning. Specifically:
  • Relatively high rates of restenosis have been measured after CCSVI treatment via balloon angioplasty in the Jugular veins (nearly 50% in one study1)
Thus, while the procedure is relatively safe, angioplasty is associated with a high risk of restenosis in some veins (while the rate of restenosis in the IJVs was nearly 50%, it was only 4% in the azygos system).

Consequently, those undergoing balloon angioplasty may require repeated procedures, which increase overall risk. Further, preliminary evidence suggests that some types of stenoses are unlikely to remain patent after angioplasty. In these cases, stents may be required to reopen the vein(s). Thus, a potential patient may need to decide whether to undergo repeated attempts with angioplasty, which may ultimately prove futile, or to use stents (or, potentially, open surgery) at the outset.


Risks Associated with Venous Stenting

Venous stenting is neither a new or radical procedure; it has been performed to treat a wide range of medical conditions for nearly 20 years. Examples include:
  1. Treatment for Budd-Chiari syndrome, May-Thurner syndrome, Paget-Schroetter syndrome, and others
  2. Treatment for deep vein thrombosis (DVT)
  3. Vein repair after dialysis
  4. Vein repair after injury/accident
  5. Repair for congenital and/or developmental venous obstructions
Despite this history of use, stents are generally considered higher risk than angioplasty for two important reasons:
  1. Possible movement, or migration, of the stent from its initially placed location inside the vein
  2. Uncertainties about the long term durability of the stents currently used in CCSVI treatment
Additionally, while restenosis is generally much lower for stents than for angioplasty, restenosis can occur even after stent placement.
Stent Migration Risks?
A Vascular Surgeon Responds
“The whole discussion about stent migration is ridiculous. All are saying: 'Don't perform stenting because the risk of migration.'  Nobody is discussing: 'How to perform the procedure to avoid this complication.' In Poland, we have spent hours discussing this issue. And it is only a technical problem that CAN be solved and HAS been solved. It is the problem of proper preop diagnostics, proper intraop tactics and proper choice of the stent. The stent should be tailored to the vein. And such a stent CANNOT migrate. And if you cannot tailor the stent, or stenting is just not necessary - you simply perform ballooning. But Zamboni's statistics show that in 50% of the patients ballooning is not enough. Consequently, either you will require repetitive balloon angioplasty (most likely not very successful)...Or - you should use a stent."                                
                        - Dr. Marian Simka, 20102

Stent Migration

Stents are metal-mesh tubes (sometimes called “scaffolds”) manufactured from state-of-the-art metals in various diameters and lengths. Stents are placed inside the vein to unblock a stenosis or other venous obstruction.

Because the stent is a foreign object placed inside the vein, it must subsequently become integrated with the vein, or “endothelialized.” Until the stent is established in the vein, a process generally taking 48 hours or less, there is some risk that the stent may drift, or migrate, from its initial position.

While uncommon, stent migration is potentially more dangerous when the stent is placed in the venous system (as with CCSVI treatment), than in the arterial system. In the venous system, blood is moving toward the heart, and the diameter of the vessels generally widen toward the heart. As a result, a freely migrating stent, particularly one initially placed in a location that has a relatively direct path toward the heart (e.g. the jugular veins), may actually travel down and into the outer chambers of the heart. Such a migration could result in the need for emergency procedures to remove or re-place the stent.

At present, the risk of stent migration cannot be quantified, as there is no study aggregating the number of venous stents placed and the number of stent migrations.


Stents designed for veins?
Some CCSVI researchers, including Dr. Zamboni and Dr. Michael Dake, have suggested that a stent specifically designed for a vein could reduce stent migration.
While most current stents are tubular, CCSVI researchers have suggested that a tapered stent would be preferable. A tapered stent would subtly increase in diameter in one direction, thus mimicking the shape of the vein, which often increases in diameter toward the heart. Being "vein-shaped," the stent might better adhere to the vein walls during placement, thus decreasing the chance of migration risks.
While the need for a tapered stent seems compelling, creating such a stent is not necessarily simple. Even subtle variations from a tubular structure could change the stress and torque on the stent, potentially requiring important redesign, materials evaluation, and testing. To date, no device manufacturers have formally announced plans to market a stent designed for veins.

In CCSVI treatments at Stanford University and at Dr. Simka’s research facility in Poland, a total of about 280 stents were placed as of spring, 2010. In Poland, no stents migrated. At Stanford, one stent migrated and resulted in an emergency open heart surgery to remove it.

Note, however, that once the stent is endothelialized, migration is extremely unlikely, if possible at all. Further, migration risk is thought to be different depending on the vein in which the stent is placed. For example, Dr. Zamboni used stents in two patients undergoing CCSVI treatment. However, Dr. Zamboni chose only to place stents in the azygos system, where he believes migration risks are lower than for stents placed in the jugular veins. However, other vascular surgeons believe that with proper preparation, placement technique, and stent selection, migration risks become insignificant. Moreover, these physicians believe that to counter the near 50% rate of restenosis occurring after angioplasty in jugular veins, stenting is a safe and effective option (see sidebar).


Stent Durability

Currently, no stents have been formally FDA tested and approved for CCSVI treatment. (Note, however, that extending the use of FDA approved medical devices for a similar but unapproved function – called "off-label" use – is commonplace and, generally, legal if it is a decision made between a patient and their doctor, and that an adequate and accurate explanation of off-label use and the associated risks are first discussed.)

The risk in off-label use of stents is that most stents are tested and approved for arteries, which are both functionally and physically different from veins. Specifically, the tissue types are different: arteries tend to be stiff while veins are more pliable and elastic. Additionally, the stresses, torques, and tensions in some veins are different from those in most arteries. The effect of these differences on stent longevity, however, is unknown.

Additionally, because CCSVI stenting is a new procedure, there is no research-based consensus on which types of stents should be used in which locations. Many stents are designed and rated for 10 or more years, but again, testing typically reflects arterial placement as opposed to venous placement.

Regardless of stent type, placement, and rated longevity, patients must expect that a stent could eventually fail. While failure rates and timeframes cannot be reliably predicted – a stent may last many years or even decades – stent stresses may eventually cause one of following failure types:3
  • Deformation (buckling, bending)
  • Fracture
  • Corrosion
  • Wear caused by metal-on-metal movement
  • Erosion caused by fluid flowing across the stent
Precisely what will happen when venous stents used in CCSVI treatment fail is unknown. Generally, when arterial stents fail, restenosis occurs. Because stents quickly become endothelialized and are thus well integrated into the body, it is extremely unlikely that stent failure would result in stent fragments or particles traveling freely in the veins, as has sometimes been suggested. However, at present, there are no studies documenting long-term stent failure outcomes in CCSVI treatment.

In summary, the long term durability of stents used in CCSVI testing is unknown. Further, stent durability cannot be reliably predicted because 1) different types of stents are being used, and 2) stents are being used in untested locations and thus being exposed to unknown types of wear, and 3) the consequences of stent failure (in CCSVI treatment) are unknown, though restenosis is considered the most likely outcome.


Restenosis

In venous stents, restenosis typically occurs when scar tissue grows beneath, through, or around the stent, blocking blood flow. (Note that while arterial stents may restenose due to plaque or other types of calcification, this is not considered a serious problem for venous stents). Restenosis rates for venous stents are generally not well documented, particularly in some of the locations (vertebral veins, lumbar veins) relevant to CCSVI treatment. It should be noted, however, that restenosis of stents is expected to be significantly lower than restenosis after angioplasty, and that stents can be used to treat particularly difficult occlusions that are not responsive to angioplasty.

When stents stenose, angioplasty may be required to clear the blockage. Alternatively, in some cases, a second, narrower, stent may be placed inside the occluded stent, thus reopening the vein.


CCSVI Stenting – Side Effects

The side effects of CCSVI treatment with stents have not been formally studied, but available evidence suggests that some patients receiving jugular stents experienced temporary pain in muscles near the repaired vein segment (e.g. the levator muscle, which runs down the side of the neck). This is likely due to an effect on the accessory nerve—cranial nerve XI (the accessory nerve serves the trapezius/shoulder area) that runs within the same larger cord of tissues with the jugular vein. When the jugular is expanded with the stent, the nerve may be impinged upon. In all known cases, nerve injury has subsided, though it can be sore and disruptive for several months.


Risk Summary

General risks from CCSVI treatment include:
  • Risks associated with common endovascular procedures
  • Risk associated with anti-clotting drugs
  • Risks associated with overall patient health prior to a procedure
Risks more specific to CCSVI treatment include:
  • High incidence of restenosis after angioplasty
  • Stent migration
  • Stent failure
  • Short term nerve injury, usually around the shoulder
Additionally, CCSVI treatment may not be equally effective for all MS patients. For any given person, a confluence of factors may limit treatment effectiveness, including:
  • Types of stenosis that currently cannot be treated (e.g. agenesis, hypoplasia)
  • The venous obstruction(s) associated with CCSVI may be caused by different factors. The narrowing may be due to disease within the wall of the vein, malfunctioning of the valve, external compression of the vein by adjacent structure outside the vein, etc. It is likely that the relative effectiveness of endovascular treatments for CCSVI will vary depending on the underlying cause
  • Stenosis in locations that cannot be reached via endovascular procedures (e.g. some vertebral veins, potentially some deep cerebral veins)
  • Repeated restenosis of treated vein segments (when stenting is not available)
Lastly, when considering CCSVI treatment risk, patients and caregivers should be equally cognizant of the wide range of risks from currently available disease modifying pharmaceuticals, including:
  • PML/brain viruses, death, liver dysfunction, glandular dysfunction, etc.
  • The marginal or limited efficacy of current medications with respect to MS progression for some patients
  • The risk of doing nothing (attempting nothing new) to inhibit MS progression; risk of relapse
Those considering CCSVI treatment may also want to read our Patient Perspectives section for first-hand accounts of CCSVI treatment experiences.

References: 
  1. Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, Mascoli F, Salvi F. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. Journal of Vascular Surgery 2009; 50: 1349-1358
  2. Dr. Marian Simka responding to a debate held by Alberta Prime Time between neurologist Brad Stewart and False Creek Surgical Center's Clinic Director, Mark Godley. Internet excerpt from http://for-greet.squarespace.com/journal/tag/dr-marian-simka, taken 31 May, 2010
  3. Robertson SW. Stent Failures: Investigation, Research, and Fracture Mechanics. Materials Sciences Division, Lawrence Berkeley National Laboratory. Presented April 4, 2006. Department of Materials Science and Engineering, University of California, Berkeley.

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