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Open Access
Review Article
Journal of Vascular
Medicine & Surgery
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ISSN: 2329-6925
Caprio et al., Vasc Med Surg 2016, 4:2
http://dx.doi.org/10.4172/2329-6925.1000259
Volume 4 • Issue 2 • 1000259
J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
*Corresponding author: Mancini M, Institute of Biostructures and Bioimaging,
National Research Council, via Tommaso De Amicis 95 -80145 Naples, Italy, Tel:
+39 081 2203411; Fax: +39 081 2203498; E-mail: direttore@ibb.cnr.it
Received February 23, 2016; Accepted March 04, 2016; Published March 11,
2016
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016)
Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med Surg
4: 259. doi:10.4172/2329-6925.1000259
Copyright: © 2016 Caprio MG, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Vascular Disease in Patients with Multiple Sclerosis: A Review
Caprio MG1, Russo C2, Giugliano A2, Ragucci M2 and Mancini M1*
1Institute of Biostructures and Bioimaging, National Research Council, Italy
2Department of Advanced Biomedical Sciences, University “Federico II”, Italy
Abstract
Background: despite major advances in immunology and molecular biology, Multiple Sclerosis is poorly
understood with regards to etiology and its immune trigger and causal pathways are substantially unknown. In recent
years, vascular abnormalities associated with Multiple Sclerosis have been investigated, opening the doors to the
hypothesis that in the pathogenesis of multiple sclerosis a vascular component could be important. Different forms of
vascular abnormalities have been associated with MS: increased risk for ischemic disease, cerebral hypoperfusion,
abnormalities of endothelial cells and impaired venous drainage. The aim of this review was to describe literature
evidence concerning the correlation between Multiple Sclerosis and vascular dysfunction, cardiovascular risk factors
and major cardiovascular events.
Methods: A literature review was performed using the following databases and web search engines: PubMed –
US National Library of Medicine; Google Scholar; and Ovid MEDLINE. The search included the following combination
of terms: “multiple sclerosis” and endothelial dysfunction or vascular dysregulation or vascular hypothesis or
risk factors or cardiovascular disease or venous thromboembolism or epidemiology. The selected articles were
divided into six macro-groups according to the topic of the paper: cardiovascular risk; cardiovascular diseases;
microcirculation factors; venous alterations; infectious pathogens; and vascular adverse effects of therapy.
Results: patients with Multiple Sclerosis seem to have more cardiovascular risk factors and an increased risk
for ischemic stroke. Several studies have demonstrated cerebral perfusion abnormalities. The relationship between
the disturbances in cerebral venous outow and neurological disorders remains an open issue that requires further
studies.
Conclusion: Recent evidence suggests that vascular components may be initiating triggers for neuronal
pathology and subsequent neurological manifestations of the disease. The high degree of comorbidity between
vascular disease and Multiple Sclerosis suggests that vascular pathology may be an important factor causing
neuronal dysfunction or degeneration in multiple sclerosis.
Keywords: Multiple sclerosis; Cardiovascular risk factors; Ischemic
stroke; Vascular abnormalities; Cerebral venous outow; Review
Introduction
Multiple sclerosis (MS) is a neurodegenerative disorder that
aects the central nervous system (CNS), sparing the peripheral
nervous system and revealing its rst signs in early adulthood, with a
variable clinical course ranging from a benign condition to a rapidly
evolving disabling disease [1]. MS is the most common disease of the
CNS and the most common cause of neurological disability in young
adults, aecting approximately 2.5 million worldwide, with variable
progression and prognosis [1,2]. e incidence and prevalence rates
of MS vary considerably between regions and populations, showing
a typical latitudinal gradient probably due to genetic and behavioral
variations [3]. Europe is considered a high frequency area for MS
(prevalence ≥ 30/100,000); other high prevalence regions include
the northern USA, Israel, Canada, Southern Australia, New Zealand
and Eastern Russia [4]. Chronic inammation, perivenular cung,
demyelization, gliosis and neuronal loss are hallmarks of the pathology,
producing plaque formation and tissue destruction not only in the
white matter but also in the cerebral cortex. Despite major advances
in immunology and molecular biology, MS is poorly understood with
regards to etiology and its immune trigger and causal pathways are
substantially unknown. Moreover, how etiopathological mechanisms
inuence the course of this disease remains unclear [5-8]. Studies
with magnetic resonance imaging (MRI) have demonstrated that
white matter lesions correlate weakly with neurological disability and
longitudinal studies involving MS patients have shown accelerated
grey matter atrophy as consequence of grey matter lesions. Grey
matter (GM) atrophy correlates with physical and cognitive disability
more strongly than white matter atrophy. Many theories have been
developed, and many potential causes have been identied: genetic
predisposition, environmental factors, infections, vascular risk factors,
and traumatic brain injury. Moreover, it is not known why some
patients develop clinically asymptomatic MS with a benign course,
while other patients experience relapses with permanent neurological
decits or progressive and massive disability. Vascular pathology in
MS patients was investigated by authors and noted by Charcot in his
identication of MS; however, vascular abnormalities associated with
MS have been investigated only in recent years, opening the doors to
the hypothesis that in the pathogenesis of multiple sclerosis a vascular
component could be important [1,9-11]. Assuming that endothelial
dysfunction and chronic inammation play an integral role in CNS
lesions pathogenesis, many authors have decided to elucidate the
primary and secondary eects of these mechanisms regarding the
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
Page 2 of 12
Volume 4 • Issue 2 • 1000259
J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
classical and non-classical cardiovascular risk factors and their
relationship with MS will be considered separately.
Obesity: Observational studies analyzing the prevalence of
overweight and obesity in MS in comparison with the general
population are inconclusive. Among MS patients, the combined
prevalence of overweight (Body mass index (BMI) ≥ 25 kg/m2) and
obesity (BMI ≥ 30 kg/m2) is approximately between 50% and 65% in
large sample sizes. ese estimates are similar to those of the non-
diseased adult population. Some studies in childhood and adolescence
showed an association between BMI and the risk of developing multiple
sclerosis [16]. Instead this association was not found in adults. ese
data suggest that the prevention of obesity in adolescence may reduce
the risk of MS [17,18].
In other studies a lower prevalence of obesity in MS patients
compared to controls has been reported [19,20]. In contrast, the
prevalence of metabolic syndrome seems similar to that of the general
population and waist circumference seems to increase among disabled
MS patients. e paradox of the discrepancy between the prevalence
of high BMI and metabolic syndrome can be explained by the lower
ratio of muscle to fat in disabled patients. erefore, the use of waist
circumference, instead of BMI, as a cardiovascular risk factor in these
patients could be recommended.
e association between BMI and disability was examined in four
studies. In two of these studies, the BMI, was calculated using weight
and height self-reported. us represents a potential limitation because
overweight patients frequently to under-report their weight [17].
Only one study clearly demonstrated a correlation between BMI
and disability [21]. is study showed a correlation of BMI and
almost all the determinants of serum lipids and Apo lipoproteins with
disability as assessed by Expanded Disability Status Scale (EDSS). Aer
adjusting the analysis for BMI and physical activity the magnitude of
BMI and disability persisted.
Levels of vitamin D: e importance of vitamin D as a risk factor
of MS has been demonstrated in several studies [22-24]. One study
showed that women who took vitamin D supplements had a 40% lower
risk of developing MS [25]. Recent studies also describe a relationship
between low levels of vitamin D and relapses and disease progression
[26]. Moreover, low vitamin D levels are correlated with both MS
and cardiovascular disease [27,28]. e studies are not yet conclusive;
however, a growing body of evidence supports a protective role for
vitamin D in MS development.
vasculature in MS patients compared to that in the healthy population.
Fundamentally, dierent forms of vascular abnormalities have been
associated with MS: increased risk for ischemic disease, arterial cerebral
hypoperfusion, abnormalities of endothelial cells and impaired venous
drainage. e aim of this review is to describe literature evidence
concerning the relationship between MS and vascular dysfunction,
cardiovascular risk factors and major cardiovascular events.
Materials and Methods
A literature review was performed using the following databases
and web search engines: PubMed – US National Library of Medicine;
Google Scholar; and Ovid MEDLINE. A text search was also
performed: “e epidemiology of Neurological Disorders”, Compston
et al. BMJ Books, London, 1998; “Principles of Neurology”, Chapter
36, Multiple Sclerosis and Allied Demyelinating Diseases, Adams
et al., McGraw-Hill, 1997; “Neurological disorders: public health
challenges”, World Health Organization 2006, WHO Library; and
“McAlpine’s Multiple Sclerosis” - Fourth Edition, Alastair Compston,
Churchill Livingstone Elsevier, 2006. In addition, a manual search
of reference lists from original articles was performed. e search
included the following combination of terms: “multiple sclerosis” and
“endothelial dysfunction” or “vascular dysregulation” or “vascular
hypothesis” or “risk factors” or “cardiovascular disease” or “venous
thromboembolism” or “epidemiology”. We considered articles and
publications from 1830 to 2015; the research was limited to texts and
articles published in English or with available translation into English.
We referenced primary sources, using secondary papers exclusively
when the primary sources were not available. Our initial search yielded
3842 articles whose abstracts were reviewed; the selection of the articles
was performed based on the agreement between the authors MGC, CR,
AG and MM. Of the 3842, we excluded dierent studies from the same
research group concerning similar ndings or overlapping populations
with redundant collected data. We also excluded case-reports or
studies with a small sample population size (fewer than 20 patients).
At the end of the selection procedure, 3643 articles had been excluded.
e selected articles were divided into six macro-groups according
to the topic of the paper: cardiovascular risk; cardiovascular diseases;
microcirculation factors in MS; venous alterations; MS and infectious
pathogens; and vascular adverse eects of MS therapy (Figure 1) and
(Table 1 as supplementary material). All the articles mentioned in this
review are included in the nal reference list.
Results
Cardiovascular risk
Many authors have discussed the association between MS and
classical/non-classical cardiovascular (CV) risk factors, analyzing this
issue from dierent points of view and trying to elucidate the impact
of these factors on the underlying disease [10-13]. e most salient
evidence from the literature is the higher prevalence of traditional
risk factors in patients with MS and the change in clinical outcomes
produced by the presence of one or more CV risk factors. e prevalence
increases with age and is higher in man. It was also shown an increased
risk of ischemic heart disease, ischemic stroke and peripheral vascular
disease [14].
e simultaneous presence of individual or multiple CV risk
factors is related to the increased accumulation of white matter
lesions, decreased grey matter and cortical volume and consequential
accelerated brain atrophy [15]. In the subsections below, the various
Figure 1: This owchart describes the systematic literature review, which were
selected papers included in the study.
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
Page 3 of 12
Volume 4 • Issue 2 • 1000259
J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
In 2012, La Vela and colleagues compared 1,142 male MS veterans
with healthy veterans and with the general population: hypertension
was more frequent in the rst group than in the second group and the
general population (respectively 47.6%, 41.2%, and 20.9%) [48].
Studies that evaluated the relationship between hypertension and
disability reported that the presence of arterial hypertension could
inuence the development of disability in MS patients. e presence
of hypertension at any time in the disease was associated with a 29%
increased risk of early gait disability [45] and a 32% increased risk of
visual disability [46].
Dyslipidemia: Case-control studies reported higher total and
LDL cholesterol in MS patients compared with control subjects
[42,49-51]. A signicant worsening in expanded disability status
scale was concomitant with higher baseline low-density lipoprotein
and total cholesterol levels [52]; a prospective study showed a direct
association between higher ratio of total cholesterol to high-density
lipoprotein and deterioration in EDSS [20]. Higher serum high-density
lipoprotein levels were associated with lower contrast-enhancing T1-
weigthed lesion volume, therefore with a protective eect in the acute
inammatory phase. Contrast enhancement in T1-weighted images
corresponds to focal areas of impairment of the blood-brain barrier
(BBB), associated with acute inammatory inltration [53]. erefore,
these enhancing lesions are a marker of active disease [54]. e
assumption is that apolipoprotein A-1 and paraoxonase anti-oxidant
enzyme associated with high-density lipoprotein may participate to its
anti-oxidant and anti-inammatory activities. [49,50,55-58].
A negative eect of hypercholesterolemia on the development of
disability was demonstrated by Weinstock-Guttman and colleagues in
2011 that reported the relationship between adverse lipid prole and an
increased number of new T2 lesions [59].
Moreover Swank and colleagues found that a diet low in saturated
fats and supplemented with vegetable oils provides benets on the
progression of MS and on disability [60,61].
Cigarette smoking: Compared to non-smokers, the risk of MS in
smokers is about 50% greater and is correlated with the duration and
with the amount of smoking [62-66].
In a study of a large number of nurses [61], the risk of MS is about
twice as high among women who smoked ≥ 25 pack-years (equivalent
to smoking a pack of cigarettes a day for more than 25 years) than non-
smokers. e negative eects of smoking on the risk of MS appear even
higher among men than women, with some studies reporting a nearly
three-fold increased risk in male never smokers compared to male
never smokers [66-68]. It was observed that only the tobacco smoke,
but not the snu, is associated with an increased risk of MS; from this
it follows that the combustion plays an important role for toxicity [66].
Mechanisms underlying the eects of smoking on the risk of MS are
still unknown. Mechanisms hypothesized are: eects on demyelination
[69,70], eects on the breaking of the blood-brain barrier [71],
immunomodulatory eects [72,73] and an increase in nitric oxide
metabolites and nitric oxide [74].
A study conducted on a population of 1465 MS patients showed a
negative inuence of smoking on the progression of the disease [75].
At baseline smokers have a worse disease than non-smokers and ex-
smokers in terms of EDSS and multiple sclerosis severity score (MSSS).
EDSS and MSSS were directly correlated with the number of pack-years
smoked at baseline. A longitudinal analysis reported no relationship
between smoking and progression EDSS at 2 and 5 years. However,
Vitamin D is a potent immunomodulatory [29] and some
studies have shown that administration of the active hormone
1,25-dihydroxyvitamin D prevents the onset and slows the progression
of the disease in mice [30,31].
It is unknown the exact mechanism of this protection; it could be
an indirect eect, possibly mediated by regulatory T cells [32] that are
suppressed in individuals with MS [33].
Serum levels of vitamin D are regulated by exposure to UV radiation
from sunlight. e exposure to UV light whole body suppresses EAE
in mice [34], enhances the function of regulatory T cells and increases
the production of immunosuppressive cytokines interleukin 4 and
interleukin 10 [35].
e risk of developing MS among migrants is higher when
migrations occurs in childhood and tend to decrease with increasing
age [36]. erefore the level of vitamin D in childhood may confer a
protection for the development of MS.
In literature, there are few data on vitamin D levels earlier in
life and risk of MS. At ages 16 and 19 years was demonstrated on
association between the risk of multiple sclerosis and the levels of
25-hydroxyvitamin D.
In conclusion, it is not clear if you can reduce the incidence
of MS in high-risk populations, increasing circulating levels of
25-hydroxyvitamin D. We need more evidence to support the
observational studies alone.
Diabetes: A cohort study [37] including 98% of the pediatric
diabetic population in Austria and Germany below the age of 21 years
analyzed the RR of MS co-occurrence and demonstrated that the RR
for MS in type 1 diabetes was three to almost ve times higher than that
in the healthy population.
is study shows that children and adolescents with diabetes have a
greater risk of developing MS. e risk for the development of MS was
higher in diabetic patients born during spring and summer; therefore
environmental factors can aect the risk for the onset of both diseases.
In studies on the Sardinian population, there was a prevalence of
type 1 diabetes by two to ve times greater in adult patients with MS
than the general population. [38,39].
Studies on the prevalence of type-2 diabetes (T2D) in patients with
MS compared to subjects without MS have contradictory results. e
studies on type -2 diabetes in MS patients are inconclusive. Hospitalized
MS patients showed a lower frequency of T2D compared to healthy
controls [19,40].
Outpatients with MS showed a higher prevalence of diabetes than
that in the general population [40,41] which was not observed in other
studies [42-44].
Marrie and colleagues using the NARCOMS registry, comparing
MS patients with and without T2D showed in the rst group a 29%
increased risk of early gait disability [43,45]. Furthermore, the
development of T2D during the course of the disease has led to a 35%
increased risk of mild visual impairment, 41% of moderate visual
disability and 54% of visual impairment [46].
Hypertension: e data on the prevalence of hypertension in
MS are contrasting. Some studies have reported no dierences or a
lower prevalence of hypertension in MS cases compared to controls
[13,19,40,44,45,47]. Kang and colleagues observed a higher frequency
of hypertension among MS cases (n = 898) compared to controls [42].
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
Page 4 of 12
Volume 4 • Issue 2 • 1000259
J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
there was an earlier conversion from relapsing remitting multiple
sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) in
smokers than in non-smokers and ex-smokers. MRI showed a greater
increase in the volume of T2 lesions and a greater reduction of brain
parenchymal fraction in smokers than non-smokers and ex-smokers
[62,76].
Hyperhomocysteinemia: Some authors have described
hyperhomocysteinemia (Hcy), a risk factor for thromboembolic
disease [77], in the serum of MS patients and linked this nding to
an increased risk of intercurrent vascular diseases [78-80]. Neurons
may be particularly susceptible to Hcy-induced excitotoxicity, with
the hypomethylation of myelin basic proteins and consequent lack
of myelin structure stability [81]. Signicantly higher serum levels of
homocysteine were found in MS patients compared to healthy controls,
even in the absence of the methylenetetrahydrofolate reductase
(MTHFR) mutation [82-85]. Hyperhomocysteinemia was also related
to cognitive impairment in patients with MS [86], and high levels of
Hcy with low levels of folate/vitamin B12 were associated with higher
EDSS scores [87]. However, the clinical implications of literature
ndings about the relationship between hyperhomocysteinemia and
MS are not completely clear, requiring further studies to elucidate the
prognostic implications of this evidence [82].
Cardiovascular diseases
Several studies have reported an increased cardiovascular
morbidity in MS patients and that the mortality related to stroke and
cardiovascular disease was higher in MS patients compared to the
general population [88,89].
MS patients who reported more than one CV risk factor at the time
of diagnosis had an increased chance of ambulatory disability and this
risk increased with the number of reported CV risk factors [9,45,90].
Although studies do not provide data on the pathogenesis of
cardiovascular disease in MS patients, inammation and autoimmunity
are central to the pathogenesis of MS and endothelial dysfunction,
which is a precursor of atherosclerosis and arterial vascular diseases.
e activated endothelium has pro-coagulant properties and is a
central component of the anti-phospholipid syndrome, associated with
MS and venous thromboembolism [91]. Moreover, platelet activation
in MS could increase thromboembolic events.
Stroke: Patients with chronic inammation of the central nervous
system, have a higher risk of developing cardiovascular disease,
including ischemic stroke [92-95]. e cause may be endothelial
dysfunction, induced by chronic inammation, resulting in progress of
atherosclerosis and cardiovascular disease [96,97] such as stroke.
Few studies have associated MS with the development of ischemic
stroke [11,98]. Allen et al. conducted a cross-sectional study on
hospitalized patients. MS was associated with a higher prevalence of
the concurrent primary diagnosis of ischemic stroke compared to
other inpatients but not with hemorrhagic stroke [19]. In addition,
other authors observed a higher risk of stroke and cerebrovascular
diseases in MS patients compared to the control population [42,98,99].
A large Danish cohort study showed an increased relative risk that
was very pronounced for young patients [11]. Similarly, in a recent
Swedish cohort study MS was associated with signicantly increased
relative risks for cerebrovascular disease. However, in this study, aer
the rst year of follow-up, the overall relative risk of occurrence of
cerebrovascular disease and in particular cerebral infarction was not
statistically signicant. In a recent study in Taiwan, a database of 22
million people, recruited by the National Health Insurance (NHI)
database, was used to evaluate the association between MS and ischemic
stroke in 1174 patients with multiple sclerosis and 4496 controls,
randomly selected and monitored in follow-up for 14 years. Patients
with multiple sclerosis showed an increased risk of stroke compared
to the control population in the rst 5 years of follow-up. Among
participants without comorbidities, multiple sclerosis group shows a
risk of ischemic stroke higher than healthy controls. Also in a subset
of the population aged <40 years, patients with multiple sclerosis had a
signicantly increased risk of stroke. erefore, patients with multiple
sclerosis, in particular young people, should be carefully monitored for
stroke prevention (99).
Ischemic heart disease: In a study by Allen et al. admission with
a principal diagnosis of myocardial infarction was less frequent in MS
patients than in other hospitalized patients [19]. In addition, Fleming
and Blake observed a lower frequency of acute myocardial infarction
and heart failure in MS cases than in matched hospitalized controls
[40]. A Swedish cohort study showed an overall non-statistically
signicant inverse association with ischemic heart disease [100]. In
contrast, many studies showed an increased relative risk for ischemic
heart disease in MS patients. A cross-sectional study by Lindegard
et al. comparing MS patients with the general population showed a
prevalence of myocardial infarction that was four to six times higher
in MS patients [101].
Two studies demonstrated that patients with multiple sclerosis
have an increased of risk of death from cardiovascular disease by 32-
34% compared to the general population [88-102]. Other studies have
also shown an increased risk of myocardial infarction and heart failure
in the MS group compared to the control group [11,98]. Finally other
studies reported a higher rate of coronary heart disease [42,98] and
ischemic heart disease [103] in MS patients compared to controls.
Venous thromboembolism: Many autoimmune diseases are
associated with an increased risk of venous thromboembolism
(VTE) [104,105]. An increased risk of VTE was observed in MS. An
increased incidence of VTE in patients with MS was reported [106-
107], especially during the rst year aer diagnosis [108]. Peeters et
al reported a risk of venous thromboembolism 2.5 times higher in MS
patients compared with healthy subjects. According to the authors, this
association can be explained by presence in MS patients of disability
and glucocorticoids therapy [109]. Only one study relieved a lower risk
of VTE in MS patients. e authors hypothesized that muscle spasm
could favor the venous return with a non-eective emptying of veins of
lower limb, reduction of venous stasis and consequently lower of risk
of deep venous thrombosis [110].
Microcirculation factors in MS
Endothelial dysfunction: Together with the loss of myelin and
the glial proliferation, perivascular inltration and endothelial damage
have been described as histological ndings in the brain tissue of
patients with MS [111]. is observation has led to the hypothesis
that a possible vascular factor should be involved in the pathogenesis
of multiple sclerosis [112]. In particular, vessels in the pathological
area showed changes that are typical of chronic inammation. Many
factors have been associated with chronic inammation and oxidative
damage in multiple sclerosis lesions [113-117]. Endothelin-1 (ET-
1) is a vasoconstrictor peptide that is regulated by a large number of
vasoactive agents [118] and, should play a role in endothelial damage
and vascular pathological reaction. It has been suggested that ET-1
plasma level dysregulation may lead to excessive vasoconstriction
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
Page 5 of 12
Volume 4 • Issue 2 • 1000259
J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
or insucient vasodilatation, resulting in vasospasm and reduced
cerebral blood ow (CBF) [119]. In some studies, (ET-1) plasma levels
measured in a blood sample taken from one of the main routes of
venous eux from the brain were signicantly elevated in patients with
MS compared to healthy controls; this increase could lead to chronic
cerebral hypoperfusion, especially in the more susceptible white
matter, with resulting myelin damage and progressive neuronal loss
[118]. Moreover, during immunomodulatory treatment MS patients
showed a signicant reduction in ET-1 plasma levels [120]. Other
elements frequently associated with MS lesions include endothelial
micro-particles, endothelial cell adhesion molecules (selectins,
integrins, ICAMs, VCAMs, JAMs, lymphoid chemokines and their
receptors), pro-inammatory cytokines and vascular growth factors.
e overexpression of these molecules should participate in the
vascular remodeling that is typical of multiple sclerosis, in a deleterious
cascade. Over time these elements should lead to cerebral endothelial
junctional disorganization, pathological iron deposition, immune cell
extravasation and metabolic disorders leading to massive apoptosis,
which culminate in the loss rst of neural and then of glial cells [113-
117,121,122] associated with a variable degree of brain atrophy, with
permanent disability and cognitive impairment [123].
In addition, autoimmune mechanisms targeting the central
nervous system myelin have long been proposed, but not proved. 17
cells producing interleukin-17 and 1 cells producing interferon-
gamma are postulated to play major roles in initiating inammation
while regulatory T cell functions are dampened [124].
Alterations in peripheral blood mononuclear cell (PBMC) cytokine
production have been found in patients with MS compared to healthy
controls. Stimulated PBMC-produced TNF-α and IFN-γ modulated
MS relapse risk, such that increased TNF-α was protective, while
increased IFN-γ increased relapse risk. Zhou et al. reported the novel
modulation of TNF-α and IFN-γ associations with relapse by SNPs in
major cytokines [125].
Adult human astrocytes stimulated with interferon-γ, a common
inammatory cytokine that is evidently present in neuropathological
brains, exert potent neurotoxicity in vitro. is interferon- γ-induced
astrocytic neurotoxicity is mediated by the activation of the Janus kinase-
signal transducer and activator of transcription (STAT) 3 pathways in
astrocytes and involves the intracellular phosphorylation of STAT3 at
the tyrosine-705 residue. erefore, the control of STAT3 activation
in human astrocytes may be a promising new therapeutic strategy
for a broad spectrum of neurodegenerative and neuroinammatory
disorders where activated astrocytes may contribute to the pathology
[126].
Platelet abnormalities: In MS, as result of endothelial lesions, can
occur a platelet activation, which markers are Platelet microparticles
and CD62p expression. Sheremata et al showed, in MS patients,
elevated levels of plasmatic endothelial micro particles positive for
platelet endothelial cell adhesion molecule-1(CD31/PECAM). is
may be expression of the interaction of activated T-cells with the
endothelium. is interaction may play a role in the abnormalities
involved in the pathophysiology of MS.
e ndings of this study demonstrate that platelets are signicantly
activated in MS patients. However, their role in the pathogenesis of MS
remains unknown. [127].
Perfusion abnormalities: Perfusion-weighted MRI was used to
demonstrate abnormalities of regional cerebral hemodynamics in MS,
by using both exogenous tracers (eg, gadolinium-based contrast agents)
and endogenous arterial water (arterial spin labeling). It was found
that, while enhancing lesions showed increased perfusion, chronic MS
lesions showed reduced perfusion. In particular, disruption of the blood-
brain barrier was described before and during the development of focal
MS lesions and it is represented by a local gadolinium-enhancing area
on T1w MR imaging [128]. Diuse enhancing areas were characterized
by increased CBF and CBV [129]; while ring-enhancing areas CBF and
CBV were increased in the ring tissue, CBF was reduced inside the ring.
Because of the similarity with acute ischemia, this nding is evocative
for a focal central ischemic zone and it suggests that focal ischemia
should play a crucial role in the development of some type of focal MS
lesions [129,130]. Law et al, using dynamic susceptibility contrast MR
(DSC-MR) imaging, demonstrate a decreased cerebral blood ow and
a prolonged mean transit time in periventricular regions of normal
appearing white matter (NAWM) in MS patients compared with
controls [131]. Other studies showed diuse hypoperfusion in various
regions (NAWM, cortex and deep GM) independently of the clinical
MS variant of the patient [132,133]. ese changes in brain tissue
perfusion were correlated to clinical disability and neuropsychological
impairment [134]. One study [135] reported a correlation between
decreased perfusion and decreased mean diusivity in the corpus
callosum of patients with RRMS, a nding more consistent with what
is seen in primary ischemia than in secondary hypoperfusion. e data
of perfusion-weighted MR imaging were conrmed by a study in which
the spatial distribution of the MS lesions were compared with images
of a SPECT (Single-Proton Emission-Computed Tomography) atlas of
healthy individuals. Lesions were localized in relatively lower normal
perfusion areas than normal appearing white matter areas [136].
Venous alterations
Over a century ago, researchers were considering the role of
abnormal venous in MS. Subsequently, more recently a small but
important body of research, including Zamboni’s work, contributed to
extend early observations.
e rst observations on vascular anomalies were documented by
French anatomist Cruveilhier [137] in 1839, who studied the dierences
between areas of sclerosis and results of embolic events. In 1863,
Rindeisch [138] described an engorged blood vessel in the center of
the plaques in autopsy specimens of MS brains and in the same period,
Charcot [5] noted the constant presence of vascular obstruction in MS.
Further evidence of the vascular mechanical eect comes from the
observations of Putnam that studied the eects of obstructed venous
ow in the brain of dogs and recorded the development in these
animals of various abnormalities similar to encephalitis or multiple
sclerosis. Fog stated that MS lesions typically developed around small
veins [139,140]. Further evidence of the vascular mechanical eect
comes from Allen’s observations, who noticed the wide vascular beds
around veins and the central widening of the venous tree that testies
an intermittent increase in cerebral pressure [141]. During 1980’s,
studying MS plaque development, Adams conrmed the crucial
contribution of vascular anomalies [121].
In 2006 [142], Dr. Zamboni presented a paper recorded some
similarities between Chronic Venous Disease and MS, including
presence of iron/brinogen deposition. From the rst observation of
MS up to modern MRI studies, a possible connection between MS and
vascular system is evident.
In MS the visibility of small medullary vein is reduced [143], and the
cerebral circulation time is increased [144]. All these results demonstrate
that hemodynamic abnormalities and a vascular compromise are
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
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J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
associated with MS. Zamboni and colleagues proposed that chronic
cerebrospinal venous insuciency (CCSVI) and secondarily venous
hypertension can lead to increase iron deposition along venous
pathway. e iron deposition within the brain parenchyma leads to the
inammation and tissue injury seen in MS [145]. Whether observed
increase in iron in the central nervous system is etiologic to MS or
the result of MS is a fundamental and yet unanswered question in the
debate of CCSVI and MS. e morphological basis of the abnormalities
in venous return are intraluminal defects as septa, membranes and
anomalies of valves in the internal jugular vein (IJV) and azygos vein,
compression muscle, hypoplasia or agenesis.
In 2009 [146], Dr. Zamboni using duplex ultrasonography
identied CCSVI as a vascular condition characterized by anatomical
and functional abnormalities of the intra- and extra-cranial veins
with ow anomalies and presence of collateral venous channels and
demonstrated a correlation between CCSVI and MS.
e outow anomaly focused in particular on 5 anomalous
parameters of cerebral venous drainage:
1. Reux constantly present in IJV and/or Vertebral Veins (VVs)
with the head at 0° and 90° assessed as ow reversal from
physiologic direction for a duration of >0.88 s.
2. Bidirectional ow (or reux) in the intracranial veins and
sinuses.
3. High-resolution B-mode ultrasound evidence of proximal
stenosis of the IJV (Cross sectional area (CSA) < 0.3 cm2).
4. Absence of detectable ow in the IJV and/or VVs despite
numerous deep inspirations with the head positioned at 0° and
90°.
5. Abnormal change of the IJV CSA with change in position
(negative ∆ CSA).
In the study of Zamboni the presence of at least two of these
parameters in a single subject was dened as abnormality. Heterogeneity
among studies investigating chronic cerebrospinal venous insuciency
detected by duplex sonography for the diagnosis of MS has been wide,
with reported sensitivity ranging from 0% to 100%. [146-154].
Unfortunately, B-mode anomalies of veins (intraluminal defects
such as aps, septa, membranes and valve defects) are dicult to
detect with ultrasound. Several potential factors, both physiologic
and technical, may aect the acquisition and interpretation of duplex
sonograms (respiratory variability, heart rate cardiac rhythm, the
hydration status of the patient, eects of head positioning, degree
of external compression, pulse repetition frequency setting, cross-
sectional area measurement by B-mode versus color Doppler imaging,
and sample volume placement during Doppler imaging).
Moreover, the innovation work of Zamboni is limited by the
absence of a reference standard for intracranial evaluation, and they
used a technology called Quality Doppler Proles (QDP) that is not
available on all ultrasonic scanning systems.
e dierence in CCSVI prevalence between dierent published
studies that use noninvasive or invasive imaging techniques
underscored the central importance of a multimodal imaging approach
for an optimal understanding of venous abnormalities indicative of
CCSVI [155]. At the current state, researchers have been unable to
dene if CCSVI has a crucial role in multiple sclerosis pathogenesis
and this point has raised serious objections to accept the hypothesis of
CCSVI as mechanism originating MS. Actually, additional researches
on the subject are in progress and the results are still not determining.
A 2013 study found out that CCSVI is uncommon both in MS patients
and healthy controls, while narrowing of the cervical veins is equally
common [156].
Lanzillo et al. observed a positive correlation between presence
of CCSVI and the patients’ age. However, no correlation was seen
between CCSVI and clinical forms of MS, except for IJVs blocked ow
that was more prevalent in progressive forms than in non-progressive
forms [157]. Other authors also observed a positive correlation between
age, disease duration and outow block in the cervical veins [158]. e
observation seems to conrm the hypothesis that venous abnormalities
detectable in patients with MS, and in particular the ow block, may be
a secondary and progressive impairment of the veins and not a primary
causal factor.
Valvular IJV abnormalities are strongly associated with venous
blood reux in the intracranial veins, are more frequent in SP form
and related to the EDSS class [159]. Pathologic studies identied
vascular pathology in any layer of the jugular wall. Intraluminal defects
are considered one the mechanisms causing a delay of jugular ow in
patients with CCSVI.
In recent years, some authors have tried to study the ultra structure
of extra cranial veins in patients with MS. e authors evaluated
the expression of collagen type I and III, cytoskeletal protein and
inammatory markers (CD3 and CD8), in patients with CCSVI
who underwent IJV reconstruction for restenosis aer percutaneous
transluminal angioplasty and in individuals without MS or other
neurological diseases who underwent carotid endarterectomy with
autologous external JV patch because of high-grade carotid stenosis.
Collagen deposition was assessed by polarized light examination. e
extra cranial veins of MS patients showed focal thickenings of the wall,
with an altereted proportion of collagen I and III within the adventitia,
due to a relative increase in type III collagen deposition. No dierences
in cytoscheletal protein and inammatory marker expression were
observed [160]. Pascolo et al. evaluated jugular tissue samples by both
advanced synchrotron X-Ray Fluorescence (XRF) microscopy, and
histological examination in two MS patients with CCSVI and in two
control subjects. XRF analyses showed an increased Ca presence in
the pathological samples, corresponding to rare and small basophilic
bodies suggestive of micro calcications. e samples of healthy
controls showed no structural alterations at histological examination
at XRF [161]. Recently Zamboni et al. studied the ultrastructure of IJV
using a scanning electron microscopy (SEM) in 7 patients with CCSVI,
underwent to vein open surgery and in 3 healthy controls who underwent
to vein repair for traumatic causes. e veins of CCSVI patients
showed partially detached endothelial cells, while the veins of healthy
controls showed an intact endothelium, with regular arrangement
of cells [162]. In conclusions, the IJVs of MS patients demonstrated
changes in collagen and increased calcium content in adventitia, and
disruption of endothelial layer, without coexistent inammation. ese
alterations could be due to endothelial chronic stress secondary to
altered hemodynamic. Moreover, the venous alterations as obstruction
and/or reux determine stasis and increased permeability to red blood
cells and brinogen. e brinogen extravagated out of micro vessels
polymerize to brin that, deposited outside the vessel, reduces tissue
oxygenation. e brinogen can also induce local activation of myelin
antigen-specic T-cells, and macrophage recruitment [163].
erefore the link between venous circulation and immune response
could be the extravasation of macromolecules into the interstitium
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
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J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
of brain that can induce neuroinammation, autoimmunity and
demyelization and macrophage recruitment (Figure 2).
MS and infectious pathogens
Over the years, many studies have been published about
MS geographical distribution and about the consistency of the
hypothesis that environmental determinants should play a role in
MS pathogenesis [3,4,164-168]. Among environmental factors,
epidemiologic evidence and biochemical and immunological data from
dierent populations suggest the involvement of an infective agent. e
hypothesized mechanism is that an infectious pathogen, possibly with
the concurrence of other inducing agents, causes a deregulation of
lymphocyte function that leads to an uncontrolled immune reaction
in the CNS, resulting; in early histological changes with an alteration of
the blood-brain barrier that gradually evolve into the more typical CNS
lesions [111,168-170]. Molecular mimicry between protein sequences
from a particular microorganism and structural proteins present in the
normal CNS is a possible explanation for autoimmune reactions in MS
[171]. Many potential infective agents have been indicated as possible
etiologic candidates, but no common interpretation of literature
evidence has emerged [172,173]; the strongest associations are those
with the gut microbiome [174-176], Rickettsia [177] and Chlamydia
[178-180] among bacteria and the Epstein-Barr [181,182] and herpes
viruses among viruses [183-185]. Recently a chronic persisting
venulitis aecting the cerebrospinal venous system, determined by
Chlamydophila pneumonia respiratory infection observed in certain
patients with MS, was hypothesized to lead to typical neural damage
[186,187].
Vascular adverse eects of MS therapy
e impact of the more-or-less recently introduced disease-
modifying drugs (DMDs) has changed patients ‘outcome [188] but
in some cases has shown negative eects at the cardiovascular level
in various ways, whether directly or indirectly [44,189]. Systemic
glucocorticoids have been associated with an increased risk of
cardiovascular diseases including stroke, myocardial infarction, and
atrial brillation [190,191]. Congestive heart failure was reported for
both interferons and mitoxantrone, but data are scarce and causality
is doubtful [192,193]. Mitoxantrone induces congestive heart failure,
although it is usually asymptomatic [193]. Fingolimod has been
associated with hypertension, bradycardia and atrioventricular blocks
[194,195] and, in a case report with ischemia of ngers, arterial
vasospasm [196]. In contrast, the use of natalizumab was associated
with lower cardiovascular risk factors [44].
Figure 2: The immunological factors and vascular factors are connected. The scheme depicts the possible interplay between changes in macro and microcirculation
and immunological factors. An altered macro-and microcirculation induces changes in endothelial cells that may determine cell-mediated immunity reactions:
presenting antigens to lymphocytes, promoting inammation in response to cytokines, and responding to oxidant injury. The autoimmune inammation can
determine iron deposition and increased leukocyte inltration. In turn the vascular mediators released by immune cells, and the activated endothelium can cause
neovascularization, lead to changes in microcirculation and recruitment of further effector cells. Venous alterations as obstruction and/or reux determine stasis
and increased permeability to red blood cells and brinogen. The brinogen extravasation reduce tissue oxygenation and induce macrophage recruitment and local
activation of myelin antigen-specic T-cells. All factors affect the neurovascular unit.
Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016) Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
Page 8 of 12
Volume 4 • Issue 2 • 1000259
J Vasc Med Surg
ISSN: 2329-6925 JVMS, an open access journal
Interferon beta-1b is an immunomodulatory drug used for a
treatment of several diseases including MS. In 1993 recombinant
interferon beta-1b (Betaseron) was approved for the treatment of
exacerbations of multiple sclerosis. e drug’s eectiveness was
modest, with 30% of relapses and the appearance of side eects such as
local irritation, and a u-like syndrome [197,198].
Conclusions
e etiology of MS and neurologic involvement are still unknown
and the clinical course extremely variable. It can take various forms,
including those relapsing and progressive ones. Each of these
forms involves numerous disease mechanisms, and as such, MS is a
multifactorial disease.
e typical characteristics of MS pathophysiology include
inammatory and vascular factors that lead to the molecular
interactions between cellular components (brain endothelial cells,
astrocytes, pericytes, inammatory cells, and neurons) and myelin
components, resulting in increased blood-brain barrier permeability,
neurovascular uncoupling and dysfunction and neuronal damage.
is review focuses on vascular abnormalities that have been
described in MS. Recent hypotheses and evidence suggest that vascular
components may be initiating triggers for neuronal pathology and
subsequent neurological manifestations of the disease.
Patients with MS have more cardiovascular risk factors, an
increased risk for ischemic stroke and an increased risk of venous
thrombosis and pulmonary embolism. Vascular comorbidities are
common in MS and adversely inuence disability. ere is evidence
suggesting that MS patients are more susceptible to cardiovascular risk
factors than healthy controls.
Several studies have demonstrated regional cerebral perfusion
abnormalities in MS compared to controls. e relationship between
the disturbances in cerebral venous outow and neurological disorders
remains an open issue that requires further studies.
e debate on whether vascular events are the primary cause of
neurological diseases or rather a mere participant recruited from a
primary neuronal origin of pathology is still open.
e high degree of comorbidity between vascular disease and MS
suggests that vascular pathology may be an important factor causing
neuronal dysfunction or degeneration in multiple sclerosis.
In our opinion, this review is useful to shed light on a hot topic in
which literature is still lacking.
e results in literature are not always consistent, both for the
frequency of association between vascular disease and neurological
disease, both for the relationship between vascular disease, cerebral
damage and clinical disability. Several studies are mostly “case-control”
and studies on population are few. Furthermore, the authors of studies
do not always come from centers with expertise in epidemiological
assessment. It is possible that many of the changes reported in the
literature are a result of bias in the interpretation or eects of the
disease itself, or activation of the immune system or of drug treatment.
erefore, more rigorous epidemiological and pathophysiological
studies are needed to verify the biological plausibility between vascular
damage and demyelinating-neurodegenerative diseases.
Acknowledgement
This work was supported by a research grant from the Italian Ministry for
Education University and Research in the framework of PRIN (2010XE5L2R_004).
The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript. The authors thank Dr. Marianna Malgieri
for the editing of the manuscript.
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Citation: Caprio MG, Russo C, Giugliano A, Ragucci M, Mancini M (2016)
Vascular Disease in Patients with Multiple Sclerosis: A Review. J Vasc Med
Surg 4: 259. doi:10.4172/2329-6925.1000259
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