Multiple sclerosis (MS) is a multifactorial
neurodegenerative disorder with an unknown etiology and elusive pathogenesis,
and within that context it is often not appropriate to seek the discrete cause
or causes of a disease, but rather to identify a complex of interrelated and
interacting factors that influence the risk of disease and subsequently
complicates the assessment of causality1.
Multiple sclerosis was firstly described by Charcot in
1868; since that it was known that plaques in MS are venocentric. Post mortem
studies and magnetic resonance venography demonstrated that veins could also be
dilated and split longitudinally MS lesions. Furthermore the presence of fibrin
cuffs, perivenous iron deposits and iron laden macrophages at histological
examination of involved veins represented the rationale to investigate the
cerebral venous drainage as a possible mechanism related to increased iron
deposition in MS plaques and to the etiology of MS itself. Thus suggesting the
concept that chronic cerebrospinal venous insufficiency (CCSVI) could have a
causative role in MS2,3.
a case-control study conducted on 30 Egyptian subjects divided into two groups,
Group (1): Includes 15 Egyptian MS patients, Group (2): Includes 15 Egyptian
healthy subjects. Healthy control
group was age and sex matched to patients.
Inclusion criteria: Patients with Relapsing
remitting MS (RRMS) and secondary progressive MS (SPMS) fulfilling the revised
McDonald diagnostic criteria for diagnosis of MS4 and
its revision5. We excluded from the study those subjects having, or
showing the potential for developing, a nervous system pathology of a venous
refluxive and/or obstructive nature, including: Patients having thrombosis of
jugular vein(s), giving history of central venous catheter in the internal
jugular vein (IJV) or head and neck surgery; Patients with Chronic venous insufficiency
of the lower limbs, or history of venous thrombosis and/or post-thrombotic
syndrome. Also, Patients with genetic thrombophilia, or congenital vascular
malformations or Budd–Chiari syndrome and Patients with cerebrovascular
diseases; were excluded.
All subjects are subjected to the following battery of assessment:
I. Clinical evaluation:
History taking and Neurological examination: according to the Neurology
assessment sheet currently used in Neurology department, Cairo University.
Expanded Disability Status Scale (EDSS) (for assessment of disease severity):
The Kurtzke Expanded Disability Status Scale is a method of quantifying
disability in multiple sclerosis. EDSS scores less than 4.5 refer to people
with MS who have no impairment to their daily activity and need no or mild
assistance. EDSS scores of 5.0 or more are defined by the disability severe
enough to impair full daily activity.6
Magnetic resonance imaging (MRI) of the brain is performed on a 1.5
Tesla Phillips Intera® scanner at the Magnetic Resonance Unit, Radio diagnosis
Department, Kasr AL Ainy hospital. The following protocol was used: T1 –
weighted axial and sagittal images. T2 – weighted axial and coronal images.
Fluid attenuated inversion recovery (FLAIR) axial images. MRI is used as a part
of the McDonald criteria for diagnosis of MS and to assess the load of MRI by
measuring the number of white matter MRI lesions
Magnetic Resonance Venography (MRV) of the brain and neck veins is done
for the 30 subjects using 2D and 3D time of flight technique, either on an open
sequence magnet 0.23 Tesla machine or a closed 1.5 Tesla magnet according to
availability. The sequences included are: Axial and sagittal T2 brain. Axial 3D
brain. The study includes the neck veins as well as the cerebral sinuses to
detect any stenosis and insufficient flow in internal jugular veins and deep
Data were statistically described in terms of mean ±standard deviation
(SD), median and range, or frequencies (number of cases) and percentages when
appropriate. Comparison of numerical variables between the study groups was
done using Student t test for independent samples in comparing 2 groups when
normally distributed and Mann Whitney U test for independent samples when not
normally distributed. For comparing categorical data, Chi square (χ²) test was performed. Exact test was used instead when
the expected frequency is less than five. P-value less than 0.05 was considered
statistically significant. All statistical calculations were done using
computer programs SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL,
USA) version 15
for Microsoft Windows.
Multiple sclerosis patients included were fifteen,
9 of them were females (60%) and 6 of them were males (40%). The age of MS
patients ranged from 26 to 56 years with the mean age of 37.47±8.14 years,
control group age ranged from 20 to 49 years with the mean age of 35.13±8.94. Healthy control group was age and sex
of MS patients:
Multiple Sclerosis : Among 15 patients with MS, 9 (60%) patients had RRMS and 6
(40%) patients had SPMS
of illness ranged from 3 to 19 years with mean duration
8.43±4.93. The severity of multiple sclerosis was assessed by EDSS,
among 15 MS patients there were 5 patients with EDSS scores between 0-4, 4
patients had EDSS scores between 4.5-5.5, 4 patients had EDSS scores between
6-6.5 and 2 patients had EDSS scores 7-7.5.
The MRI load (number of
lesions): The number of lesions in MRI ranged from 7 to 13 with mean
The prevalence of CCSVI: Among group 1 (MS patients) six patients
(40%) had abnormal MRV (CCSVI) compared to healthy controls in which only one
patient (6%) had abnormal MRV. There was statistically significant difference
between prevalence of venous insufficiency in multiple sclerosis compared to
healthy control subjects (P-value=0.02)
Distribution of patterns
of CCSVI: Among six MS
patients who had an abnormal MRV, three patients had stenosis of internal
jugular vein (IJV) on both sides, two patients had unilateral stenosis of IJV
and only one patient had unilateral IJV stenosis associated with sigmoid and
transverse sinuses (Figure 1). While in healthy controls the patient with
abnormal MRV had unilateral IJV stenosis associated with sigmoid and transverse
Comparison of demographic data in CCSVI positive and
negative MS patients:
No statistically significant difference was found
between CCSVI positive and CCSVI negative groups regarding age of the patients
or gender of patients (Tables 1 & 2).
between clinical characteristics of CCSVI positive and negative MS patients:
No statistically significant difference was found
between CCSVI positive and CCSVI negative groups regarding age of onset of the
disease, duration of illness, type of MS, severity of disease (measured by
EDSS, or number of relapses (Table 3).
between MRI load in CCSVI
positive and negative MS patients:
No statistically significant difference was found
between CCSVI positive and CCSVI negative groups regarding the number of
lesions found in brain MRI (Table 4). In MS patients the number of lesions in
MRI in patients with abnormal venous system ranged from 7 to 12 with mean
10.33±2.16 compared to patients with normal venous system in which the number
of MRI lesions range was 7 to 13 with mean number 10.22±1.78.
Comparison between different patterns of abnormal
No statistically significant difference was found
between patients with different patterns venous insufficiency regarding age of
onset, disease duration, EDSS, relapse rate or number of lesions in the brain
MRI (Table 4).
Cases discussed below show clinical characteristics
and MRI picture of patients with different patterns of venous insufficiency.
old female patient, diagnosed with RRMS for 5 years now, her age at the disease
onset was 25 years, she developed three attacks; at time of assessment her EDSS
score was 2.5. MRI and MRV were done results shown in (Figure 2). Diagnosis: CCSVI
+ve MS patient with unilateral IJV stenosis
Thirty four years old female patient, diagnosed with RRMS
for 3 years now, her age at the disease onset was 31 years, she developed she
developed two attacks at time of assessment her EDSS score was 2.5. MRI and MRV
were done results shown in (Figure 3). Diagnosis: CCSVI +ve MS patient with
bilateral IJV stenosis.
eight years old female patient, diagnosed with RRMS for 7years now, her age at
the disease onset was 21 years, she developed four attacks; first attack was in
the form of right sided weakness, second attack was in the form of urine
hesitancy and unsteady gait, third attack was in the form of right sided
weakness and in fourth attack she experienced left optic neuritis and unsteady gait,
at time of assessment her EDSS score was 4. MRI and MRV were done results shown
in (Figure 4). Diagnosis: CCSVI +ve MS patient with unilateral IJV and
sigmoid sinus stenosis.
The very recent claims that CCSVI could be a variable combination of
vascular abnormalities playing a role in MS has opened a completely new
perspective in the pathogenesis of the disease, with potential therapeutic
implications. The topic of CCSVI and MS has gained widespread attention that is
ultimately due to unclear and uncontrolled results. Epidemiological studies
produced quite variable results, from a very strict association between CCSVI
and MS7 to the complete absence of association8. According
to a recent systematic review the average prevalence of CCSVI is 55.6% among MS
patients (ranging from 0% to 100%) and 11.4% among the control subjects
(ranging from 0 to 35.7%)9.
Magnetic resonance venography (MRV) is a
well-established and robust method for the evaluation of the intracranial and
extracranial (neck) venous system in vivo. This study aimed to find prevalence of
CCSVI in Egyptian MS patients using MR venography.
In this study there was
a significant association between CCSVI and MS. Differences are evident among
the groups studied: MS patients show the higher CCSVI prevalence, among 15
patients with MS six of them had abnormal MRV (40%) compared to healthy control group in which the
prevalence is (6.7%). Among six CCSVI positive MS patients, three patients
(50%) showed stenosis of IJV on both sides, two patients (33.3%) had stenosis
affecting unilateral IJV and only one patient (16.6%) showed stenosis of
unilateral IJV associated with sigmoid and transverse sinuses affection. This
come in agreement with Yamout et al. (2010) who reported CCSVI in (45%) of MS
patients10, and also with Zaharchuck et al. (2011) who found that
CCSVI was associated with (54%) of MS patients11. Nevertheless the
prevalence of CCSVI found in this sample is far less than that initially
reported by Zamboni and his colleagues; as they found venous outflow
abnormalities in 100% of 65 examined MS
patients. While none of the 235 examined controls were positive for more than one
of the CCSVI criteria (7). Other published data tried to reproduce
these results; Simka et al. (2010) found that CCSVI criteria were fulfilled in
90% of 63 MS patients12. Al-Omari and Rousan (2010) found that 84%
of 25 MS patients and none of 25 controls showed evidence for CCSVI13.
This large variability
is probably related to the diagnosis of CCSVI, which may be due to variability
in patients' selection, variable diagnostic technique used and the lack of
standardized diagnostic guidelines related to the evaluation of the intra- and
extra-cranial cerebrospinal venous system and the different definitions of
pathology related to those anomalies9. A number of other
studies have attempted to reproduce or expand upon the findings of Zamboni and
colleagues7; they concluded that the threshold Zamboni used to
discriminate IJV reflux was not scientifically chosen because of the omission
of measurements during Valsalva maneuver. Furthermore, the threshold used to
identify deep cortical vein reflux was taken from a study that validated the
measure for assessment of the posterior tibial vein exclusively14.
We tried to demonstrate
the relation of the presence of CCSVI in MS to patient charteristics, disease
severity, and MR imaging outcomes. And, we found no significant difference
between subjects with CCSVI and those without CCSVI regarding mean age (35.5
versus 38.7 years respectively) or sex ratio (66.7% versus 55.6% females and
33.3% versus 44.4% males respectively). This comes in agreement with Zivadinov
et al. (2012) who found also no significant difference between both groups in
mean age (46.3 versus 44.8 years) or sex ratio (77.8% versus 78.4% female).
The other variable
associated with CCSVI was clinical charateristics of patient. In this study the
patients with CCSVI had the same range of age of disease onset as patients without CCSVI (28.7 versus 29.2
years respectively). Unlike Bastianello et al. (2011), who found that the CCSVI-positive patients were
about five years older than the CCSVI-negative ones at disease onset15.
Yet, The association of older age at onset with CCSVI should be well studied
and verified as there is a study on the clustering of multiple sclerosis
highlighted the possible effect of ‘exogenous’ factors as determinants of a
higher age at onset16.
Also CCSVI was not found
to be significantly more frequent among MS patients with a longer disease
duration in respect to those with shorter disease duration (6.83 versus 9.5
years respectively). This is differing from results of Zivadinov et al. (2011)
who supported a higher frequency of CCSVI among patients with a longer disease
duration, they found that the frequency of chronic cerebrospinal venous
insufficiency was roughly inversely correlated to the duration of the of
multiple sclerosis and also showing higher prevalence in progressive MS as
compared to relapsing remitting MS17. Also results reported by
Yamout et al. (2010) who performed MRV on 42 MS patients, he concluded that
disease duration was greater in patients with venous insufficiency and it is
likely to be a late secondary phenomenon10. These observations are
not definitive and further research examining the link between chronic
cerebrospinal venous insufficiency and duration of the disease and type
multiple sclerosis is needed9.
Higher frequencies of CCSVI were recorded in the more severely affected
patients15. But in our study did not report higher EDSS score
in patients with venous insufficiency compared to those without (mean EDSS 4.75
versus 5.28 respectively) and CCSVI wasn't also associated with increased
relapse rate compared to patients without CCSVI (2.83 versus 3.67
respectively). The frequency of CCSVI was not also affected by the severity of
No significant differences were found between CCSVI-positive and
CCSVI-negative subjects for MRI lesions load (mean number of lesions was 10.33
versus 10.22) this comes in agreement with Zivadinov et al.17. These
findings warrant further investigation but firmly suggest that if CCSVI
contributes to higher lesion burden in patients with MS, then this effect is
Accordingly, If a "causative relationship" between CCSVI and
MS has been suggested, it should be underlined that association not necessary
imply causation and that observational study alone does not allow us to establish
a cause effect relationship. All the data available in literature concerning
the relationship between CCSVI and MS come from retrospective case-control
studies that are unable to determine whether the exposure precede the outcome.
It cannot be excluded, in fact, either the possibility that CCSVI is in the
causal pathway of MS, or a possible indirect association between CCSVI and MS18.
To date, no scientific evidence is available that fulfills the nine
causality criteria (strength, consistency, specificity, temporality, biological
gradient, plausibility, coherence, experiment, analogy) universally accepted
and considered essential by the scientific community to causally correlate a
condition with a given disease19.
The present study demonstrated that there is higher incidence of CCSVI
in MS. But it showed that CCSVI has no effect on neurologic function and
disability progression in Therefore, these results favor that it is
questionable whether the presence of CCSVI has a role in MS pathogenesis. It has
not been possible to determine whether venous abnormalities are related to MS,
a consequence of MS or there is a possible indirect association between CCSVI
and MS because both share the same risk factors.
Treatments for MS should be evidence-based and be able to have
reproducible results in clinical trials. Although CCSVI and iron deposition may
play a role in MS, patients should be discouraged from seeking such treatment
outside of a clinical trial until the results are verified in other studies.
Authors report no conflict of interest]
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