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CCSVI theory: an update

Dr Lucy Matthews, MRC Clinical Research Training Fellow, Dr Jacqueline Palace, Consultant Neurologist
John Radcliffe Hospital, Oxford

Open Door - November 2010 pages 6-7


We previously covered CCSVI in the February 2010 issue of Open Door. In light of continuing interest, we approached Drs Matthews and Palace for their views on this topic.

scan of blood vessels in the head Picture: Reigh LeBlanc

Multiple sclerosis causes inflammation and damage to myelin, the insulating layer that coats the nerve cells in the brain and spinal cord. The fundamental cause of this is currently unknown, although many theories have been proposed, and it is likely to be a combination of genetic and environmental factors. In 2009, Professor Paolo Zamboni, a vascular surgeon, published research suggesting an association between abnormalities (including narrowing) of the veins draining the brain and spinal cord, and MS.1, 2 This led to a theory that chronic cerebrospinal venous insufficiency (CCSVI) could be a cause of MS, sparking much media interest and controversy over whether there is sufficient evidence to support surgery. Recent independent research has challenged the findings of Zamboni.3, 4


What is the evidence?

It has been well described in post-mortem and MRI studies that MS lesions are often centred around a small vein and it is thought that the inflammatory cells that are found in the lesions enter the brain from the blood. It is also documented that MS lesions contain iron deposits. Traditionally this has been thought to be due to the inflammation causing iron to leak from blood vessels. Prof Zamboni has proposed that alternatively the iron deposition could be caused by back-pressure in the venous system due to restricted outflow through the large draining veins. He theorises that this iron attracts the inflammation and subsequent loss of myelin seen in MS.5 These two contrasting theories are summarised in the diagram.


Alternative theories of iron deposition in multiple sclerosis

Alternative theories of iron deposition
in multiple sclerosis

Prof Zamboni undertook Doppler ultrasound studies to measure the direction and speed of flow through the internal jugular veins that drain blood from the brain and the azygos veins in the spinal cord.1, 2

Of the 65 people with MS investigated, he reported that 37% had evidence of narrowing of the internal jugular vein and 71% had reflux (ie blood flowing in the wrong direction) in either the internal jugular vein or the spinal veins. In the control group of 190 healthy people and 45 people with other neurological conditions, no significant abnormalities were found. Using venography, where dye is injected directly into the vein, Zamboni found a narrowing in either one or both of the internal jugular veins in 91% of the people with MS.

The interim results of a larger study conducted by the University of Buffalo were published in February 2010.6 Of 280 people with MS, 56.4% showed an abnormality in the venous flow within one or both internal jugular veins when examined using Doppler ultrasound. This compared to 22.4% of a healthy control group.

Recently German researchers undertook an extended Doppler study of the internal jugular veins and the vertebral veins, examining 56 people with MS (41 with a relapsing remitting course and 15 with secondary progressive MS) and 20 controls.3 None of the people with MS or healthy controls fulfilled the diagnostic criteria proposed by Prof Zamboni for CCSVI, and in none of the subjects was narrowing of the internal jugular vein detected.

Another recent German Doppler ultrasound study reported that only 20% of 65 patients with MS fulfilled the diagnostic criteria for CCSVI.4


Our comments

Although the early findings may suggest an association between MS and abnormalities of the venous system, it is important to test this theory further in independent studies. The first of these independent studies have not reproduced Zamboni's results. Furthermore, if a valid link is found, it will need to be established whether the narrowing is a cause of MS, or alternatively due to the effect of MS.

It should be noted when interpreting the findings of these studies that it is very difficult to blind the investigators carrying out the ultrasounds to whether the subject has MS or not, and this could influence and bias the results.

Certain conditions can obstruct the draining veins of the brain (eg a clot or a tumour). The symptoms caused by this obstruction include headache (a specific type related to raised pressure), raised pressure in the spinal fluid and haemorrhage associated strokes. These symptoms are not seen in MS, and conversely conditions that obstruct the draining veins in the brain do not to our knowledge produce symptoms typical of MS.

The MS science community has however realised the importance of pursuing this novel theory, and trying to establish its relevance to people living with MS.


Is investigation and treatment currently being offered?

There currently isn't sufficient evidence to support CCSVI as the cause of MS. Several centres around the world, however, are already offering Doppler ultrasound examinations and the option to undergo surgery. This operation involves feeding a catheter from a vein in the groin, through the heart, to the veins in the neck. Here, either a balloon would be inflated to dilate the vein or a stent (wire mesh tube) would be placed. Complications of this procedure have been reported, and it was announced in February 2010 that this procedure was stopped in Stanford University due to two serious complications including one death.

The long-term outcome for people with MS who have undergone this procedure is as yet unknown. Prof Zamboni published the results of this surgery at an average follow up of 18 months in his group of 65 people with MS.7 In people with relapsing remitting MS, the proportion who were relapse free at one year was reported to increase from 27% to 50% post treatment, and there was also some improvement in a functional score (MSFC). There was no improvement in those with secondary and primary progressive MS. The people who underwent the treatment were not compared to a group who did not, and therefore it is very hard to assess the significance of the results. People with MS who have had recent relapses are often recruited to clinical trials, and will usually spontaneously improve with or without intervention. In addition, there was a high rate of the abnormality recurring post surgery (47% of participants).


What is the next step?

CCSVI is an interesting theory, but has been challenged by independent research. The surgical procedure currently on offer in some private clinics is not without risk, and at present not funded by the NHS because it is not clear that it has any positive effect on MS. It is important to await the results of further independent research studies that test the association of venous insufficiency with MS; and if a true relationship is found to investigate whether it is the cause or the effect of the disease process. The true benefits of invasive intervention would then need testing in regulated controlled trials.

References

  1. Zamboni P, et al.
    The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis.
    Journal of Neurological Sciences 2009;282:21-27.
    abstract
  2. Zamboni P, et al.
    Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
    Journal of Neurology, Neurosurgery & Psychiatry 2009;80(4):392-399.
    read online
  3. Doepp F, et al.
    No cerebrocervical venous congestion in patients with multiple sclerosis.
    Annals of Neurology 2010;68:173-183.
    abstract
  4. Krogias C, et al.
    Chronic cerebrospinal venous insufficiency and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients.
    Nervenarzt 2010;81(6):740-746.
    abstract
  5. Singh AV, Zamboni P.
    Anomalous venous blood flow and iron deposition in multiple sclerosis.
    Journal of Cerebral Blood Flow and Metabolism 2009;29:1867-1878.
    abstract
  6. First blinded study of venous insufficiency prevalence in MS shows promising results. University of Buffalo press release - 10 February 2010.
    read online
  7. Zamboni P, et al.
    A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency.
    Journal of Vascular Surgery 2009;50:1348-1358.
    abstract