CCSVI Patient Teaching Sheet

What is CCSVI?

Chronic cerebro-spinal venous insufficiency (CCSVI)
Zamboni Procedure, Liberation Procedure

This is a theory that multiple sclerosis is due to blockage in the veins that drain the nervous system. Arteries take blood from the heart to the brain, and veins return that blood from the brain back to the heart. This theory states that narrowing of these veins blocks the normal flow of blood out of the brain and spinal cord. This blockage increases the pressure in the veins and this backpressure causes damage either by:

• pressing on the brain/spinal cord, or
• causing blood to leak out of the vessel, carrying iron into the tissues leading to damage.

Has CCSVI been proven to cause MS?

No. Much more work will need to be done to prove or disprove this theory.

What must be done before CCSVI can be considered proven?

Three steps are needed to prove that CCSVI is the cause of multiple sclerosis.

1. Blockage of the veins must be present in MS patients, but not healthy people or people with other neurological diseases. This would prove that CCSVI was related to multiple sclerosis, but not prove that it was the cause.
2. Treatment of these blockages must stop the progression of multiple sclerosis, and this must be shown in a placebo-controlled, blinded study conducted at several different research centers. This would prove that CCSVI was contributing to the symptoms of multiple sclerosis, but not prove that it was the cause of the disease.
3. Multiple sclerosis must develop in humans that have diseases that lead to blockage of the veins, or animals must develop a disease similar to multiple sclerosis when their veins are blocked experimentally.

Note that if step 2 was proven correct, treatment of CCSVI could be strongly encouraged for multiple sclerosis.

What research is being done to pursue this?

The scientific community is taking the question of CCSVI very seriously. Currently, most studies are directed towards answering the question of whether multiple sclerosis patients have blockage of the veins or not.

The National MS Society funded seven studies in June 2010, totaling $2,000,000. These are:

• University of Wisconsin: Comparing ultrasound with MRI techniques
• Cleveland Clinic: Comparing ultrasound and MRI in people with multiple sclerosis controls and Alzheimer’s patients to determine whether changes in venous bloodflow are specific for multiple sclerosis, or nonspecific.
• University of Texas Health Science Center at Houston: Comparing ultrasound and MRI in people with multiple sclerosis and various control populations.
• Hospital for Sick Children, Toronto, Ontario: Investigating CCSVI in children with multiple sclerosis to determine if the changes are present early in the disease course.
• Foothills Medical Centre, Calgary, Alberta: Using ultrasound and MRI to determine whether CCSVI is more common in multiple sclerosis patients than in controls, and whether this correlates to the severity of the disease.
• Ottawa Hospital, Ontario: Using ultrasound and MRI to determine whether CCSVI is more common in multiple sclerosis than in controls, and using MRI to investigate the presence of iron in the brain in those with and without vein blockage.
• University of British Columbia Hospital MS Clinic, UBC Faculty of Medicine and Saskatoon MS Clinic, University of Saskatchewan: Comparing catheter venography, ultrasound and MRI in patients with multiple sclerosis and controls.

The MS Society of Italy is contributing €900,000 to a study of the frequency of CCSVI in the population.

Dr. Zivadinov at the Buffalo Neuroimaging Analysis Center is also conducting a study of ultrasound and MRI imaging in multiple sclerosis patients and controls.

Several Canadian Provinces are considering studies as well.

What do the current studies show?

To date, studies have not been adequate to answer the question of whether CCSVI is associated with multiple sclerosis. These studies have either been too small, or have had inadequate blinding or inadequate controls.

In 2009, Dr. Paolo Zamboni (65 MS patients, 235 healthy controls) initially reported that 91% of multiple sclerosis patients had abnormalities in the jugular veins, and 86% in the azygous veins, with virtually 100% showing an abnormality in one of these vein systems. None of the control patients had abnormalities. 47% of veins had recurrence of abnormalities within one year of treatment with angioplasty.

In 2010, preliminary results from the Buffalo Neuroimaging Analysis Center (289 multiple sclerosis patients, 163 healthy controls, 21 clinically isolated syndrome, 26 other neurological disease) found 56.1% of multiple sclerosis patients met criteria for CCSVI, 42.5% of those with other neurological diseases, and 22.7% of controls. Furthermore, this group found a decrease in the volume of veins in the brain of multiple sclerosis patients (the opposite of what would be expected behind a block in vein flow).

In August 2010, a group from Umeå University, Sweden (21 multiple sclerosis patients, 20 healthy controls) found no difference in venous bloodflow between multiple sclerosis patients and controls using MRI. In addition, only 14% of multiple sclerosis patients had jugular vein narrowing by venograms (control group not studied with this technique).

In August 2010, a group from Humboldt University, Berlin (56 multiple sclerosis patients, 20 healthy controls) reported that no multiple sclerosis patients nor controls met criteria for CCSVI using ultrasound.

Though there are many reports of individual patients responding to treatment for CCSVI, the studies do not have control groups making it impossible to determine the effectiveness of the treatment.

What are the problems with the current theory of CCSVI?

Arguments about the theory of CCSVI can only be answered by well-designed studies. There are several questions that must be addressed in considering CCSVI, but ultimately studies will have to be done to prove or disprove the theory.

Criteria for diagnosis: The method of diagnosing CCSVI has not been agreed upon. Experts have not agreed on which findings on ultrasound indicate a significant blockage to bloodflow. The technique (ultrasound, MRI, Xrays) that is best for measuring this has not been determined.

Anatomy: The veins are very redundant and blood can flow through a number of different pathways back to the heart. The jugular veins drain the brain, but there are several other veins that can take this blood back if these are blocked. Likewise, there are at least 12 pathways by which blood from the spinal cord can return to the heart. These venous systems are interconnected so that a blockage is one results in blood immediately flowing through one of the other pathways. Blockage of the jugular system does not account for changes in the spinal cord or optic nerves.

Timing and distribution: CCSVI has not been able to account for the multiple small areas of damage done to the nervous system, nor the relapsing/remitting course of the disease.

Pathology: The pathology of multiple sclerosis is one of inflammation, with the immune system rushing into areas of damage during acute attacks of the disease. CCSVI has not been able to explain how an increase in vein pressure behind a block in the vein can cause inflammation.

Iron: The CCSVI theory has attempted to explain inflammation through iron being pushed through the vein wall, causing damage to the tissues and inflammation. However, the iron in the brain of multiple sclerosis patients is not in red blood cells, nor free in the tissue. Rather, it is in macrophages. Macrophages are a key component of inflammation and are not expected to be seen as an effect of increased vein pressure.

Other diseases with increased vein pressure: There are several other diseases that affect the veins draining the brain. These diseases do not have changes that even remotely look like multiple sclerosis. These include:

• Idiopathic intracranial hypertension (benign intracranial hypertension, pseudotumor cerebri)
• Normal pressure hydrocephalus
• Diseases of decreased venous return to the heart (veno-occlusive disease, post-radiation changes, severe obesity)
• Vein inflammation (Tolosa Hunt, transverse/sigmoid sinus occlusion)
• Surgery – Jugular veins are routinely removed with surgery for head and neck cancer.

Effects of changes in posture and muscle tone: Veins are very low pressure vessels and are easily blocked. The blood vessels in the neck are regularly blocked with changes in posture or tightening of neck muscles. If there are changes in bloodflow through veins (this has not yet been demonstrated) then it will need to be shown whether this is the cause of multiple sclerosis or whether changes in muscle tone or neck posture are responsible. The high rate of CCSVI reported in other neurologic diseases by the group in Buffalo suggests that muscle tone and neck posture may play a role in explaining the blockage of flow in the veins.

Decreased bloodflow with brain injury: Bloodflow to and from the brain varies depending on how much energy and oxygen the brain needs. With brain injury, bloodflow to and from the brain falls because the brain does not need as much energy or oxygen. If decreased flow in the veins of multiple sclerosis patients is proven (it has not been proven yet) then it will need to be determined whether this is due to disease in the veins or due to the injury to the brain. The decrease in volume of the veins in the brain shown by the group in Buffalo suggests that this is due to the brain injury.

Risks/Complications: The risks of procedures used to treat CCSVI are not entirely understood. There are two procedures that have been used: angioplasty and stenting.

Angioplasty involves placing a tube inside the vein under Xray guidance, then blowing up a balloon on the tip of the tube in order to stretch the vein. This may rarely lead to rupture of the vein with bleeding. The acute changes in pressure during the procedure may temporarily impair bloodflow upstream from the angioplasty. The study by Dr. Zamboni found that 47% of veins treated with angioplasty had recurrence of the blockage within one year.

Because of the recurrence of blockage, some recommend that stents be used instead of angioplasty. Stents are wire cages inserted inside the vein to prop it open. These are put in place under Xray guidance. Similar to angioplasty, the vein may rupture on rare occasion leading to bleeding. In addition, the stents can become clotted, or they can occasionally come loose and migrate to other veins or the heart.

Only controlled studies will teach us what the true complication rate of these procedures is.