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Authors
and
Disclosures

E Mark Haacke
Director, The MRI Institute for Biomedical Research and Director, MR Research Fa
cility, Wayne State University, MI, USA
nmrimaging@aol.com
From
Expert
Review
of
Neurotherapeutics

Chronic Cerebral Spinal Venous Insufficiency in Multiple

Sclerosis
E Mark Haacke
Posted: 12/30/2010; Expert Rev Neurother. 2011;11(1):5-9. © 2011 Expert Reviews Lt
d.

Abstract
and
Introduction

Abstract

"Perhaps it is time to be thinking of a 'vascular immunology' focus in the study

of neurological disease, an interesting marriage
between cardiovascular and neurodegenerative research."
Introduction

At a workshop in Bologna (Italy) in 2009, Professor Paolo Zamboni openly discuss

ed research that he had been pursuing for the
previous few years regarding the role of venous flow abnormalities in multiple s
clerosis (MS). His data demonstrated that there were
major extracranial venous abnormalities in MS patients. He did not claim that th
ese were 'the' etiology of MS, rather he noted that
they were associated with MS and not generally with normal individuals. He refer
red to the resulting condition as chronic
cerebrospinal venous insufficiency, or chronic cerebrospinal venous insufficienc
y.[1] In this brief article, we would like to bring to bear
some of the previous research into the role of the venous vasculature in both MS
 and other diseases, which may shed some light on
the importance of the venous system in neurological diseases.
Historical
Considerations

According to Putnam,[2] who discussed vascular abnormalities in MS in the 1930s,

the first observations related to abnormal
vasculature or effects related to vasculature appeared in the work of Cruveilhie
r in 1839, more than 170 years ago.[3] In 1863,
Rindfleisch noted an engorged vessel in the center of a plaque,[4] and in the sa
me year, Charcot described vascular obstruction in
MS.[5] These observations would be noted many times over the next 135 years. Put
nam himself appeared convinced that the
etiology of MS lay in the venous system. To test his hypothesis, he proceeded to
study the effects of obstructed venous flow in the
cerebral veins of dogs. These animals developed a number of abnormalities (lesio
ns), many of them similar to encephalitis or MS.
He noted at the end of his article: "The similarity between such lesions and man
y of those seen in cases of multiple sclerosis in man
is so striking that the conclusion appears almost inevitable that venular obstru
ction is the essential immediate antecedent to the
formation of typical sclerotic plaques".[6]
The story continues with a reference to Borst, who suggests that vascular obstru
ction occurs to the point of complete obliteration and
hyaline transformation.[7] A similar loss of the venous vasculature has been rep
orted using susceptibility-weighted imaging by Ge et
al. in 2009.[8] Some researchers describe the combination of congestion, perivas
cular hemorrhage and pigments (possibly
hemosiderin or iron-related[2,9]) in encephalitis following measles.[10] In the
1980s, Adams found the presence of hemosiderin in the
form of old hemorrhage in 30% of cadaver brain MS lesions.[11] More recently, a
number of articles on measuring iron using MRI
also found 30% or more of MS lesions appeared to have increased iron content.[12 1
4] Could this hemosiderin correspond, for
example, to cases where we see iron deposition with susceptibility-weighted imag
ing in brain lesions [12]? In another article, iron was
shown to build up backward along the venous system in the basal ganglia in the t
halamostriate region.[15]
In a recent review of the role of venous reflux, Simka stated: "It is hypothesiz
ed that pathological refluxing venous flow in the
cerebral and spinal veins increases the expression of adhesion molecules, partic
ularly ICAM-1, by the cerebrovascular
endothelium".[16] Along these lines, Bergan demonstrated, by occluding a major v
ein in the rat, that the number of leukocytes
migrating across the vessel wall increased progressively during occlusion.[17 19]
Multiple microhemorrhages occurred upstream of
the occlusion (usually 20 30 µm in diameter, but some as large as 200 µm). "The venula
r occlusion experiments showed that
reduced flow can rapidly set in motion an inflammatory cascade, including hallma
rks like leukocyte adhesion to the endothelium,
migration into the interstitium, free radical production and parenchymal cell de
ath that begins soon after occlusion " Bergan goes
on to say: "Elevated pressures can also cause the formation of transcellular gap
s through endothelial cells, which may be related to
the development of microhemorrhages."
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In the 1980s, Schelling believed that there was a significant mechanical nature
related to the fact that the vascular damage follows a
path opposed to the flow.[20] He quotes Carswell as saying: "In inflammation, th
e local congestion commences in the capillaries,
afterwards extends to the small veins, but never to large branches; in mechanica
l congestion (by venous flow inversion) the blood
accumulates first in the venous trunks, which are always conspicuous, and afterw
ards in the branches and capillaries.".[21] Further
evidence of this mechanical effect comes from observations of Allen, who noticed
the widened vascular beds around veins and the
central widening of the venous tree indicative of intermittent increases in cere
bral pressure.[22] It is also worth looking into Fog's
work. He summarizes his results from a series of cadaver brain studies as "thirt
y plaques showed that they definitely followed the
course of the veins, so that course and dimensions of the veins determine the sh
ape, course and dimension of the plaques.".[23] He
also closes his work with the comment: "Consequently, multiple sclerosis, pathol
ogico-anatomically, must be considered a
periphlebitis, as proved by the author in 1948 in the case of plaques of the spi
nal cord.".[24]
In summary, during the last two centuries there has been ample evidence that the
venous system is strongly associated with MS.
Integrating this information together yields a more complete picture of the role
the veins play, from mechanical issues to
immunological issues. As discussed later, this will be complemented by informati
on regarding perfusion deficits, evidence for venous
effects in other diseases and the clinical evidence for major venous insufficien
cy in MS seen with modern imaging technologies
today.
Perfusion
Deficits
in
Multiple
Sclerosis

Recently, it has been demonstrated that there is reduced perfusion and even loss
of small medullary vein visibility in MS.[8] Juurlink
discusses the role of hypoperfusion in MS.[25] He comments that the reduced perf
usion can be detrimental to oligodendrocytes,
preferentially affects white matter, causes demyelination and leads to microglia
l activity. He notes that these can be most marked in
the optic nerve and tract. He then states: "There is now ample evidence that isc
hemic insults of sufficient severity can cause
upregulation of cell adhesion molecules onto the endothelial cells, thus allowin
g infiltration of leukocytes into the brain parenchyma,
resulting in an inflammatory lesion." He goes on to point out that hypertension
of genetically susceptible lesions leads to vascular
damage, which in turn leads to ischemia. There is actually a body of evidence su
ggesting reduced perfusion in MS patients. Back in
the 1980s, Swank et al. found that past the age of 40 years, MS patients had mar
kedly reduced blood flow compared with normal
individuals.[26] Using MRI, there has been a thrust in the last 10 years to stud
y perfusion in MS. The work of Meng Law[27] and others
[28 32] demonstrates that there is reduced perfusion as a function of severity of
disease. Law et al. reported a significant decrease of
cerebral blood flow and a prolongation of mean transit time in the normal-appear
ing white matter (NAWM) at the level of the lateral
ventricles in MS patients.[27] These reductions often appear in the basal gangli
a and thalamus and have been related to fatigue.
[30,31,33] A study of seven patients with relapsing remitting MS revealed decrease
d relative cerebral blood volume (CBV) in chronic
lesions and further reduced relative CBV in one acute lesion in white matter com
pared with that in gray matter.[27] Haselhorst et al.
examined 25 patients with MS and found that acute lesions had significantly high
er relative CBV than NAWM and that chronic
plaques had significantly lower relative CBV than NAWM.[34] Inflammatory activit
y can cause compensative vasodilatation and result
in increased cerebral blood flow and CBV, which is found in enhancing lesions. O
n the other hand, any evidence of increased
perfusion in some chronic nonenhancing lesions can be explained by lesion reacti
vity with new vascular inflammatory changes.
Clinical
Evidence
of
Venous
Abnormalities

Optical neuritis is another common condition for MS patients. Evaluating periphl

ebitis retinae involves detecting sheathing and
hemorrhage in veins in the retina. Lightman et al. demonstrated that 3.5 years a
fter initial onset of acute idiopathic optic neuritis,
eight out of 14 patients who had vascular abnormalities in a first episode of op
tic neuritis went on to develop MS, while only five out
of 32 patients without vascular abnormalities went on to develop MS.[35] The ove
rall incidence of patients with optic neuritis going on
to be diagnosed as clinically definite was 13 out of 46 subjects, or 28%. The au
thors go on to draw the following conclusion: "We
therefore suggest that the sheathing of retinal vessels that we observed opthalm
oscopically is the visible clinical sign of the
perivascular lymphocytic infiltration and accompanying oedema which characterize
s the lesions of MS."
Venous abnormalities might best be viewed from an embryological background when
trying to understand the presence of truncular
venous malformations.[36] The development of the venous system begins in the ear
ly stages of the fetus and has a well-known
developmental etiology. An example of abnormal venous development occurs in the
case of primary Budd Chiari syndrome, which
can lead to severe portal hypertension. For jugular veins, development occurs as
the neck lengthens and its drainage level shifts
toward the cephalad part of the precardinal vein, which later develops into the
internal jugular vein.
There is a very timely review of the importance of jugular venous reflux.[37] In
this article, the authors note that without a competent
jugular valve, and with prolonged venous reflux, the individual may develop veno
us hypertension or occlusion.[38] Several disorders
are now associated with internal jugular vein incompetence, including: transient
global ischemia;[39] transient blindness;[40] cough
headache;[41] and primary exertional headache.[42] Many other conditions can als
o generate some level of this elevated venous
pressure, such as congestive heart disease, tricuspid valve regurgitation, prima
ry pulmonary hypertension and chronic obstructive
pulmonary disease. Valves can also tend to breakdown with age. In veins without
valves, simply reversing the pressure gradient can
produce reflux. This condition "might impede cerebral venous outflow and induce
neurologic dysfunction," according to Chung and
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Hu.[37] These conditions can occur during Valsalva-like activities, such as coug
hing, heavy lifting and other strenuous activities.
Of significance to MS patients currently undergoing treatment with balloon angio
plasty are studies of idiopathic intracranial
hypertension. In a group of MS patients, it has been demonstrated using 3D magne
tic resonance venography that in the order of
90% of these patients have sinovenous stenoses.[43] There are a variety of diffe
rent methods used to image these abnormalities
(including computer tomography angiography), but magnetic resonance venography a
ppears to be the safest and provides sufficient
information to make the diagnosis.[44]
Zamboni et al. assessed the venous system using transcranial color-coded duplex
sonography.[45] They comment that venous reflux
overloads the microcirculation, leading to the activation of MMPs that in turn d
igest basement membrane-type IV collagen and
fibronectin, allowing migration of cells and proteins into the CNS. Venous reflu
x also facilitates erythrocyte diapedesis, leading to
perivenous iron deposits. Pericapillary fibrin cuff and vessel thickening are ma
rkers of venous insufficiency. "In our study, the
involvement of the veins of the gray matter was significantly associated with th
e worse disability scores of our MS population."
Ludyga et al. report on their first 330 cases.[46] Apart from minor problems wit
h difficulty removing the angioplastic balloon, occlusion
of stent or local bleeding from the groin, there were no major complications (se
vere bleeding, venous thrombosis, stent migration or
injury to the nerves) related to the procedure. They reported that approximately
60% had bilateral stenoses of a jugular vein and
40% had unilateral stenoses. Balloon angioplasty alone was performed in approxim
ately 55% of cases, whereas the stenting of at
least one vein was required in approximately 45%. Surgical interventions were pl
anned in 330 patients. In 11 cases (3%), no obvious
pathology was found, despite signs of chronic cerebrospinal venous insufficiency
on color Doppler sonography and/or MR
venography.
Zamboni thought outside the box by looking for extracranial vascular abnormaliti
es to understand MS. His focus was using
ultrasound as a biomarker for stenoses and flow changes. His gold standard was t
he angiographic scanning carried out during
treatment. Our own work in this area has focused on using MR angiographic method
s to collect time-resolved data post-contrast to
image the arterial and venous phases. With appropriate post-processing, we can t
hen separate 3D images of both arteries and
veins. Figure 1 shows an example of an MR venogram revealing a tight stenosis in
the left internal jugular vein. This is the type of
venous malformation that would have served as a candidate for percutaneous trans
luminal angioplasty in their study. Currently,
there are a number of ongoing studies around the world set in motion to try and
validate the findings of Zamboni et al. and quantify
both the frequency of stenoses and the flow abnormalities in both MS patients an
d in normal volunteers.
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Figure 1. A magnetic resonance venogram from a multiple sclerosis patient showin
g a tight stenosis (long, thin arrow) of the
left internal jugular vein in the region of the confluence of a vertebral vein (
short, thick arrow) into the trunk of the left internal
jugular vein.
Conclusion

The above discussions provide varied evidence that the venous system plays a maj
or role, or in the least is associated with, MS.
Past efforts in immunology have been impressive. More recent efforts in understa
nding how vascular abnormalities lead to
immunological effects are suggestive. Perhaps it is time to be thinking of a 'va
scular immunology' focus in the study of neurological
disease, an interesting marriage between cardiovascular and neurodegenerative re
search. A recent review has promoted this
concept as it relates to vascular endothelial health[47] and is written focusing
on MS as a vascular disease. It behooves us to follow
this advice, especially in light of the work of Zamboni and now many others foll
owing in his footsteps worldwide that suggest the
venous vascular system may be strongly associated with MS.
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Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organi
zation or entity with a financial interest in or financial conflict with the sub
ject
matter or materials discussed in the manuscript. This includes employment, consu
ltancies, honoraria, stock ownership or options, expert testimony, grants
or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Expert Rev Neurother. 2011;11(1):5-9. © 2011 Expert Reviews Ltd.

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