Investigation of cerebrovenous haemodynamics by transcranial and extracranial Color-Doppler sonography and MR-venography in patients with multiple sclerosis and healthy controls.

Background:
The sequence of events underlying the development of the inflammatory plaques
in multiple sclerosis (MS) remains still unclear. MR-studies show plaques in MS
are venocentric, MS progresses along the venous vasculature. Histological
studies of plaques in MS reveal aspects of any status of chronic cerebrospinal
venous insufficiency (CCSVI) such as the perivascular fibrin cuffs of
infiltrating cells and the peculiar disposition of perivenous iron stores. It
is known that chronic impaired venous drainage in lower extremities leads to
increased iron stores in affected tissue and chronic infections with poor skin
healing. Clinical investigators have become increasingly aware of the parallels
between iron-dependent inflammation in impaired venous drainage of the lower
extremities and iron deposits near inflammatory areas in MS.
Prevalence estimates of CCSVI in MS range widely. A few studies have attempted
to identify this prevalence in MS patients and healthy controls, with
contradictory results. The prevalence of CCSVI in MS and the association with
its pathogenesis is still unclear.

Also the best technique to assess impaired venous drainage is open for
discussion. Zamboni et al, the group who detected CCSVI, used transcranial and
extracranial Color-Doppler sonography. A recent study by the investigators at
the free University of Amsterdam using magnetic resonance venography (MRV) did
not show a significant increased incidence of CCSVI in 20 patients with MS.
However, a recent study at the Buffalo University, USA, showed that Color
Doppler sonography at the moment is the best technique to assess impaired
venous drainage and that MRV is not suitable to assess CCSVI.

The recent findings of CCVSI in MS and its enormous global impact on the care
for MS patients resulting in unproven treatment of CCSVI with its possible
risks are reasons to perform a study amongst a large group of Dutch patients
with MS and in healthy subjects to assess the prevalence of CCVSI in these
groups.

Hypothesis:
1. CCSVI in MS patients occurs more frequently in comparison to healthy controls
2. CCSVI is more common in MS patients with a longer disease duration of MS
3. CCSVI is more common in MS patients with a progressive clinical course
4. The pattern of CCSVI in the primary progressive course, characterized by MRI
demonstration of MS plaques in the spinal cord, is in particular stenosis of
the azygous vein
5. The use of MRV for diagnosis of CCSVI in MS patients has limited value

The primary objective of this study is to determine the prevalence and degree
of impaired cerebral venous drainage in MS patients in comparison to healthy
subjects.

Secondly, we want to determine a possible relationship between the degree of
impaired cerebral venous drainage and signs of peripheral impaired venous flow,
the haemosiderinuria concentration and serum concentration of soluble
transferrin receptor and serum ferritin levels.

The third objective is to determine a possible relationship between age,
gender, clinical type of the disease, disease progression, and the presence of
impaired cerebral venous drainage.

Observational study

Burden:
One visit to the hospital, one phsyical examination.
One urine sample and one blood sample of 2 ml, for 40 MS patients and 40
healthy controls.
For twenty MS patients intravenous contrast will be given undergoing the
MR-venography.

Risks:
There are no risks associated with participation.

Benefit:
We hope to improve understanding the pathogenesis of the MS plaques by
investigating cerebral venous drainiage as a possible mechanism related to
increased iron deposition in MS plaques.

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