Dr Lucy Matthews, Dr Jacqueline Palace (Consultant Neurologist John Radcliffe Hospital, Oxford)
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.
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.
Info taken from:
http://www.mstrust.org.uk/information/opendoor/articles/1011_06_07.jsp