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Treatment and Efficacy


Treatment
Efficacy

Treatment Overview

CCSVI treatment is a non-operative, minimally invasive intervention usually performed as part of a catheter-based endovascular procedure. CCSVI treatment employs either balloon angioplasty and/or stent placement to open or clear obstructions from the veins that drain the brain and spinal cord.

Patients seeking treatment may have been previously diagnosed with CCSVI, usually through one or more of the current diagnostic methods: duplex ultrasonography, magnetic resonance venography, or selective venography. Alternatively, patients may undergo a single procedure that combines both selective venography for diagnosis and endovascular treatment.

The physician performing the procedure is trained in endovascular surgery. Often, the physician is an interventional radiologist or vascular surgeon, though some neurosurgeons also receive training in vascular procedures.

While some physicians only use angioplasty to treat CCSVI, others may offer a combination of angioplasty and stents. Therefore, it is important to discuss with your physician what type of procedure he or she may perform, and to understand the various risks associated with each option.


Pre-operative procedures

Once the course of the CCSVI treatment has been determined, preparation is generally straightforward. The patient is changed into a surgical garment. To prevent dehydration, an IV is started. Once the patient is on the operating table, the physician will inject local anesthesia in the region near the groin where the catheter will be inserted.

Because CCSVI treatment is minimally invasive, most physicians prefer to conduct treatment with the patient either fully aware or only mildly sedated. However, while general anesthesia is typically not used, it could be required in the event of an emergency. Because of this, physicians may require a pre-procedure anesthesia consultation, and may require the patient to fast prior to the procedure. 



The Procedure  

Once the skin and groin tissue are anesthetized, the femoral vein is punctured with a small needle. A guidewire is advanced through the needle into the vein. The needle is removed and a catheter, which is a small hollow tube, is introduced over the wire. The catheter, which is extremely narrow, is inserted into the vein (which is much wider), and threaded upwards into the right ventricle of the heart, out of the right atrium of the heart, and into the superior vena cava. From the superior vena cava, the physician can access the veins that drain the central nervous system, including the internal jugular veins (IJVs), the azygos vein, vertebral veins, and others.

When the catheter is moved near or into an obstructed area, the physician usually injects a radio-opaque contrast agent (dye) into the blood vessel to verify venous obstructions and/or to observe blood flow characteristics in real-time via an X-ray based technology such as fluoroscopy. This process is called catheter venography. Images acquired through catheter venography can be archived for later analysis.

Some physicians may also use a second tool, intravascular ultrasound (IVUS), to confirm the stenosis. IVUS is particularly useful for identifying problems such as valve abnormalities or septums.  Some physicians also take pressure measurements inside the vein because pressure is related to blood flow.

Typically, treatment is performed immediately following confirmation of each blockage. By coupling diagnostic confirmation and treatment, catheter movement and relocation is minimized, thus reducing risk.

Is CCSVI Treatment a form of surgery?

Through much of the 20th century, the word ‘surgery’ suggested an etherized patient on an operating table partially covered by a white sheet and surrounded by gloved physicians and assistants actively working inside the body with sterilized stainless tools.

This vision, however, captures only a very specific type of "open" surgery. Merriam-Webster more broadly defines surgery as “A branch of medicine concerned with disease or conditions requiring or amenable to operative or manual procedures.” Unfortunately, this broad definition could include everything from chiropractic adjustment to massage therapy.

Surgeons skilled in complex open surgeries may scoff at the notion that comparatively simple endovascular procedures (which don’t even require an incision) are a form of surgery at all. Yet those performing endovascular procedures may refer to themselves as surgeons. Oddly enough, there is no accepted definition of exactly what does and does not constitute surgery. Because of this, CCSVI Alliance will avoid this confusion and refer to the specific technique used, namely, an “endovascular procedure,” or, alternatively, “endovascular surgery.”

Because the patient is awake and aware during the procedure, many physicians will interact with the patient while performing diagnosis and treatment. For example, the physician may ask the patient to "hold your breath now," or "exhale now," in order to help measure blood flow rate or to assess the effects of the treatment. Further, the operating room may have closed-circuit computer or television screens that can show any images the physician has taken from within the vein; patients can sometimes watch the inside of their veins during the procedure.

Two CCSVI treatment types are common: balloon angioplasty and stenting.

In balloon angioplasty, the vein is opened or widened by inflating a cylindrically-shaped balloon inside the vein for short period of time. The balloon, which is near the tip of the catheter, is moved into the area of stenosis and inflated. The balloon is often inflated and deflated several times in order to ensure the desired degree of patency. When inflated, the balloon is capable of extreme rigidity, allowing it to open or clear even difficult blockages. Once all stenoses have been cleared (as possible), the balloon is deflated and, together with the catheter, drawn back through the veins and out of the body. 

Stenting is performed in the same manner as angioplasty. However, stenting uses a slightly different catheter (called a “stent-delivery” catheter). A stent is a manufactured metal-mesh tube that is attached near the end of the catheter so that it can be placed inside the vein and opened. Like angioplasty, the stent is used to clear or open blockages. Stent placement is considered a more permanent solution than angioplasty, but it carries some additional risks.

Once the blockages have been opened or cleared (as much as possible), the catheter is removed, and the physician’s primary work is done.


Post-operative Process

To minimize bleeding, the incision point at the femoral vein is treated with pressure for 10 to 20 minutes after the procedure, and then covered with a simple dressing. The patient is kept immobile for approximately one hour in order for the incision point to heal. Some physicians will release the patient immediately following this one hour period, while others prefer to keep patients under observation at the hospital for longer periods, potentially overnight.

Follow-up procedures vary by physician, and follow-up visits may be scheduled as early as several weeks post-procedure, or as late as six or more months post-procedure. This variance may reflect the physician’s original intent in performing the procedure. Some physicians are simply interested in treating the blockage; follow-up procedures with these physicians focus primarily on whether the treated area has remained patent (unblocked). Other physicians, however, may be interested in the relationship between CCSVI treatment and MS. Because these physicians may want to measure changes in the patient’s symptom profile and MS disease progression, they may require more frequent follow-up examinations.  

Patients often benefit by having their neurologist conduct routine MS disease progression tests (e.g. EDSS) both before and after CCSVI treatment. This provides the patient and the patient's neurologist with clear before versus after measures of the impact of the CCSVI treatment. Such information may be useful in determining the best post-treatment program for the patient. Further, this information provides a formal record of CCSVI treatment impact, which may help advance our understanding of CCSVI. Note that patients may benefit from these before and after tests regardless of whether the neurologist supported the decision to have CCSVI treatment, and regardless of whether their CCSVI physician will be conducting his/her own follow-up tests.

Following an endovascular procedure, the patient is typically placed on anticoagulant or anti-platelet drugs 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.) Depending on the physician’s preference, this course may run for days or for a couple of months, and may use any of a variety of commonly prescribed and over the counter medications such as Plavix, Arixtra, aspirin, Coumadin, or others. When taking anti-coagulants or blood thinners (e.g., Coumadin), blood samples must be checked regularly to insure that the level of drug effectiveness is within a desired range that limits the risk of bleeding complications. This typically involves a common blood draw from the arm or a finger prick. Outpatient clinics and medical centers may perform this function, and a revisit with the primary doctor is generally not necessary. Blood checks are not necessary for those patients taking anti-platelet agents (e.g., Plavix, aspirin, etc.) exclusively.

Lastly, while the basic endovascular procedures used in CCSVI treatment are commonplace, they still expose patients to certain types of risk. For details, please read our Treatment Risks page. 



Efficacy

The only currently published data on CCSVI treatment efficacy comes from Dr. Zamboni’s original open label pilot study, which focused first on treatment safety and second on impact to MS symptoms and progression.


Nature of the Study

In 2008-2009, Dr. Zamboni conducted an 18 month open label study measuring the safety and efficacy of balloon angioplasty to treat CCSVI. While the study was quite thorough, it was only performed on 65 patients. Additionally, for obvious ethical reasons, all patients were strongly encouraged to remain on their Disease Modifying Drugs (DMDs) throughout the study, which may have skewed the results (though it’s not clear in what way; see *footnote for a full discussion). Regardless, results from all open label studies must be considered preliminary, and should be viewed as suggestive, but not definitive.


Results and Discussion

Regarding the impact of CCSVI treatment on MS, Dr. Zamboni’s team reported two distinct types of data:

  • 3, 6, 12, 15, and 18 month patency rates (a measure of whether the stenoses/obstructions receiving balloon angioplasty remained open or cleared.)
  • Impact on MS progression and symptoms. Specific MS measures included:
    1. Disease Severity as measured on the Multiple Sclerosis Functional Composite (MSFC, which yields both cognitive and motor skill results)
    2. Number of gadolinium enhanced lesions on MRI suggesting acute inflammatory or active disease
    3. Number of relapses (in RR patients only)
    4. MS Quality of Life questionnaire (MSQOL – a subjective measure of physical and mental status)


Patency Rates by Stenosis Location

Patency rates, the fundamental measure of whether balloon angioplasty was an effective treatment approach for clearing venous obstructions, varied significantly based on the location of the obstruction. Results are summarized in Table 1 below:

Table 1: Patency by Stenosis Location (Data from Zamboni, 2009)

Location of Stenosis

% Patients with Stenosis

Patency rates after 18 months

 

Internal Jugular Vein(s)

91%

53% (partially effective)

Azygous

86%

96% (extremely effective)

Lumbar, Vertebral, Renal

N/A

N/A

Table 1 indicates that for the most common type of venous obstruction – stenoses in the internal jugular vein(s) – angioplasty is effective about half of the time. In 47% of the cases, re-narrowing or reblockage occurred at the point where treatment was performed (peak restenosis rates occurred between 7 and 9 months post procedure; the majority of restenosis concluded by the 12th month). Hence, restenosis in the jugular veins after angioplasty is a significant problem, and clearly limits the efficacy of using a single balloon angioplasty procedure as the lone approach to CCSVI treatment for many patients.

On the other hand, restenosis of the azygos vein was very low, occurring only 4% of the time. Thus, angioplasty appears to be an excellent treatment option for stenoses in the azygos system.

Given the high rates of restenosis in the IJVs when traditional balloon angioplasty is used, researchers have proposed four options to improve treatment outcomes:

  1. Use stents when balloon angioplasty fails.  To minimize restenosis rates, stenting has been performed by some physicians. However, due to potential risks, CCSVI venous stenting remains relatively uncommon. (Note that there is significant uncertainty about the risks of venous stenting. Please read our Treatment Risks page for a full discussion of these issues.) While restenosis rates in veins treated with stents are typically much lower than in those treated with balloon angioplasty, there is, at present, no published data on restenosis rates for stents used in the IJVs for CCSVI treatment.
  2. Use super-rigid balloons for CCSVI treatment. The balloon typically used in balloon angioplasty, including CCSVI treatment, achieves rigidity equal to 6 atmospheres of pressure. While 6 atmospheres is exceedingly rigid, some researchers believe that even more rigid balloons may be needed to clear some venous obstructions. Use of a 20 atmosphere balloon has been proposed. However, no data has been published demonstrating patency rates using a 20 atm balloon versus a 6 atm balloon, so any increased efficacy due to a 20 atm balloon is purely speculative at this time.
  3. Over-dilating the vein. While in traditional angioplasty the balloon is dilated up to the diameter of the vein being treated, some physicians treating CCSVI are experimenting with inflating the balloon to a slightly larger diameter than the vein (e.g. 2mm larger). It is hoped that this over-dilation may decrease restenosis rates, but no data yet confirms this supposition.
  4. Use open surgery to repair restenosing veins segments in the IJVs. Because the IJVs experience the greatest rates of restenosis, and because the IJVs are located near the skin of the neck, open surgery to repair IJV stenosis has been proposed. However, to date, there are no reported cases of open surgery to repair stenosis of the IJV, and so both the efficacy and risk of this potential treatment remain unknown.

In summary, efficacy of CCSVI treatment varies considerably depending on the location of the venous obstruction being cleared. While obstructions in the azygos vein respond well to balloon angioplasty, obstructions in the IJVs may require repeated attempts, and ultimately may not respond to balloon angioplasty. As a result, patients may need to consider whether to attempt repeated procedures with balloon angioplasty, or look to alternatives if they experience restenosis.  While over-dilating the vein or using super-rigid balloons have been proposed to minimize restenosis rates, these procedures remain largely untested.

The primary alternative to balloon angioplasty is stent placement, but stenting carries additional risks, and thus has not been performed as widely as balloon angioplasty. Lastly, open surgery to repair stenoses in the IJVs has been proposed, but such a procedure is untested and must be considered both highly experimental and potentially risky at this time.

Of note, there is no published information on specific patency rates for balloon angioplasty performed in the lumbar, vertebral, renal, or other veins (all of which are generally considered part of the azygos system).


Efficacy by Clinical Type

In Dr. Zamboni’s study, treatment impact on MS varied considerably across MS clinical type. RRMS patients showed by far the most significant improvements, while SPMS and PPMS patients showed limited to no improvement.


Results for RRMS Patients

RRMS patient results are summarized in Table 2 below.

Table2: RRMS Treatment Results (Data from Zamboni, 2009)

Measure

Pre-treatment

18 month post-treatment

Statistical Significance

Comments and Caveats

Yearly Relapse Rate

.9  ( ± .8)

.7 ( ±1)

No significant difference

For patients who relapsed, there were no differences in relapse rates before or after treatment. However, many fewer patients actually relapsed, so this result applies only to those who did).

Number of Patients remaining Relapse Free

27 during year before treatment

50 during year after treatment

.0014 (very significant)

An impressive reduction in relapse rates, but it must be noted that the study does not account for the placebo effect, and thus these numbers, while strongly suggestive, should not be considered definitive until replicated in a blinded study.

% Patients with new GAD+ Lesions

50%

12%

.0001 (extremely significant)

Reduction in lesion count is encouraging, but again, placebo was not controlled for. Moreover, MRI protocols were not consistent across patient measures. Lastly, patients remained on DMDs throughout the study, which may have influenced GAD+ counts. Thus, lesion count information must only be considered suggestive, not definitive.

MSQOL – Physical

Higher scores are better)

66 (± 18)

strong>84   (± 16)

.009 (very significant)

Subjectively, patients report improved physical function/feelings

MSQOL – Mental

61 (± 22)

82 (± 13) 

.003 (very significant)

Subjectively, patients report improved cognitive function, outlook

MSFC (mean)

Baseline

.65

.008 (very significant)

Objectively, patients improved. Quantitative composite of motor and cognitive function relative to baseline showed clear improvement.

Per Table 2, the most significant outcome for RR patients (together with improved MSFC scores), is the notable reduction in the number of relapses. Perhaps equally important, it was reported that only patients who restenosed had relapses – no patient whose treatment remained patent had a single relapse in the 18 month measured time-period after treatment. This finding suggests that neither the presence of Disease Modifying Drugs (DMDs) nor the placebo effect is entirely accounting for the decrease in relapses for RRMS patients: if the placebo effect and DMDs were responsible for decreases in relapse numbers, then there would be no difference in relapse numbers between patients who did and did not restenose.

However, for PPMS and SPMS patients the results were not nearly so encouraging.

Results for PPMS Patients

PPMS patients reported modest, though not statistically significant, improvement on the MSQOLs (subjective measures of cognitive and motor function), but no improvements were found in the quantitative motility or cognitive function scores on the MSFCC (objective measures of cognitive and motor function).

Importantly, it must be pointed out that only 10 of the 65 patients in Dr. Zamboni’s study were PPMS patients. Because the number of PPMS patients was so small, results reported for PPMS patients must be considered no more than initial trends, and not indicative of long-term outcomes (10 is too small a number to run statistical analysis). Additionally, outcome measures for PPMS patients were not necessarily ideal - improvement in cognitive and motor function may not be an appropriate measure of success for PPMS patients. Cessation of disease progression, or even slowing of disease progression, could also be considered a successful outcome, but these were not evaluated in this initial study.

Finally, several factors may account for the limited results for PPMS patients.  Specifically, research linking CCSVI and MS clinical types indicates that clinical type is associated with stenoses/blockages in specific locations1 and with different hemodynamic patterns2, and that these differences may affect treatment outcomes. While RRMS and SPMS clinical types tend to share an overlapping set of stenoses1,2 (typically in the Jugular and Azygos veins), PPMS patients more often present with fairly unique patterns of stenosis, centering mainly on azygos and vertebral veins, and accompanied by higher incidence of reflux in the deep cerebral veins (DCV).

Imaging and diagnosis of CCSVI in the deep cerebral veins is more difficult than imaging other veins, and many physicians are unable to accurately diagnose DCV stenosis, let alone provide treatment. Compounding this, some vertebral veins (where PPMS patients have a higher incidence of stenosis than either RRMS or SPMS patients) can be too narrow to treat with angioplasty or stents.

Moreover, certain types of venous obstructions (especially some cases of agenesis and hypoplasia) simply cannot be treated via any current endovascular procedure. 18% of Dr. Zamboni’s patients presented with untreatable obstructions in the azygos system (including the vertebral and lumbar veins). Notably, these untreatable obstructions were significantly associated with PPMS clinical type, and occurred in the veins draining the spinal column. The inability to treat these cases may have contributed to the relatively negligible post-treatment improvement seen by PPMS patients.


Results for SPMS Patients

SPMS patient results were similar to PPMS results: minor short-term improvements in subjective cognitive and motor function (MSQOLs), but no improvements in longer-term subjective measures or in objective measures (MSFCC).

Oddly, while many PPMS patients had untreatable types of stenosis, this was less true for SPMS patients, leaving the underlying causes of the relatively marginal outcomes for SPMS patients unclear. Unfortunately, no detailed discussion of the SPMS outcomes is provided by Dr. Zamboni in his initial paper. Clearly, additional research is needed.


Summary 

The only published data for CCSVI treatment outcomes comes from Dr. Zamboni’s Open Label Study. Because open label studies are, by definition, not blinded or controlled, the results must be viewed as preliminary. Moreover, too few PPMS patients were included to provide reliable data. However, within these limitations, Dr. Zamboni’s team was thorough, and followed appropriate protocols.  Significant findings include:

  • CCSVI treatment via balloon angioplasty was safe and well tolerated for all 65 patients in the study (no significant medical side-effects occurre d).
  • The 18 month patency rates (ability to keep the vein open) for treatment varied substantially based on the location of the stenosis being treated: azygos veins remained open 96% of the time, but IJVs remained open only 53% of the time. No specific details about patency rates for lumbar, renal or vertebral veins were given.
  • Some types of venous obstructions (some instances of agenesis and hypoplasia) cannot be treated by current forms of CCSVI treatment. These types of stenosis are most frequent in PPMS patients.
  • Treatment effect on MS symptoms and relapses varied significantly depending on clinical type: RRMS patients showed significant improvements in the number of relapses, and in both objective and subjective measures of mental and physical function. SPMS and PPMS patients showed marginal but not statistically significant improvements in subjective measures, and no improvement in objective measures.

Lastly, we urge caution in interpreting all results. As Dr. Zamboni writes in the conclusion of the study: “The major shortcoming of our study is that is [sic] not a blinded study. There is a great possibility that bias could be playing an important role in trying to find hope for the treatment of this chronic disease. However, these data will be fundamental in planning a multicenter randomized controlled trial...” 

Indeed, while these initial results are intriguing, more study is required before any conclusions can be reached.


Footnotes 

*About DMDs: At first glance, the use of DMDs throughout the study may seem unimportant because it could be considered a controlled variable (that is, because there were no changes in this variable, the results before, during, and after the study should not be altered by their use). However, this may not hold true. First, DMDs may operate differently over time (that is, perform better/worse over time), and thus the effect of a DMD prior to the study may have been different from its effect during the study, even if dosage amounts and rates were the same. Further, because DMDs were not tracked and reported in the study, it is not clear if patients changed DMDs, or changed dosages, at any point during the study. Thus, the use of DMDs may have skewed the data/results, but it’s not clear in what direction (for better or worse).

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. Bartolomei I, Salvi F, Galeotti R, Salviato E, Alcanterini M, Menegatti E, Mascalchi M, Zamboni P.  Hemodynamic patterns of chronic cerebrospinal venous insufficiency in multiple sclerosis. Correlation with symptoms at onset and clinical course. International Angiology. 2010 Apr;29(2):183-8

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