Keywords
Multiple Sclerosis - Magnetic Resonance Imaging - Middle Cerebral Artery - Transverse
Sinuses
Palavras-chave
Esclerose Múltipla - Imagem de Ressonância Magnética - Artéria Cerebral Média - Seios
Transversos
INTRODUCTION
Multiple sclerosis (MS) is a chronic demyelinating and degenerative disease of the
central nervous system (CNS).[1] The pathogenesis of MS remains unknown; however, multiple factors have been implicated
in its etiology, and it is widely accepted that an autoimmune mechanism plays an essential
role in the disease.[2] A close relation between MS lesions and the cerebral vasculature has long been recognized;
autoreactive lymphocytes cross the blood-brain barrier to initiate an autoimmune response,
which eventually leads to neuronal degeneration and tissue damage.[3]
[4]
[5]
Recently, an alternative hypothesis related to the pathogenesis of MS has been proposed,
with some authors claiming there is a strong relationship between venous flow abnormalities
and MS. A study examining whether cerebrospinal fluid (CSF) flow dynamics are affected
in MS patients has been reported; however, there is little evidence supporting venous
insufficiency in patients with MS.[6]
The chronic cerebrospinal venous insufficiency (CCSVI) hypothesis introduced by Zamboni
et al. suggests that MS is triggered by CCSVI.[4] Zivadinov et al., however, put forward a different hypothesis, suggesting that chronic
venous insufficiency is a clinical condition that occurs as a result of MS rather
than being its cause.[7] Comparisons of MS patients and healthy controls have revealed that the prevalence
of CCSVI varies from 0 to 100% in patients with MS.[8]
[9]
[10]
Studies in literature investigating the relationship between CCSVI and MS report complicated
and conflicting results. The CCSVI hypothesis has spurred passionate discussion in
the scientific community and has led to an increase in invasive endovascular therapy.
The importance of this discussion and its potential impact on treatment strategies
necessitates the resolution of the question of whether CCSVI exists in patients with
MS.
There are limited studies that have measured cerebral volumes of the artery, vein,
and CSF flow in MS patients. The aim of the present study was to evaluate the flow
volumes of the middle cerebral artery (MCA), transverse sinus (TS), and cerebral aqueduct,
using phase contrast magnetic resonance imaging in relapsing-remitting multiple sclerosis
(RRMS) patients and a control group.
METHODS
MS patients and controls
We included 34 patients (aged 18–61, mean: 37.1 years) diagnosed by clinically defined
RRMS fulfilling the McDonald criteria, revised in 2017, as well as 15 healthy controls
(aged 19–49, mean: 33.2 years) matched by age and sex.
This study was approved by the Firat University's Ethics Committee. The patients were
recruited from the neurology department of our hospital, and the control group consisted
of neurologically normal participants with no other known diseases. The inclusion
criteria for the MS patients were a current remission status of the disease and no
history of any other neurological disease. All patients and the control group were
informed of the study procedures and gave their informed consent.
MRI technique
The MRI scans was performed using a 1.5-T superconducting scanner (Signa Excite, GE
Healthcare, Milwaukee, WI, USA) equipped with high-speed gradient with an 8-channel
head coil. Axial T1-weighted and T2-weighted sequences were performed in all cases
for evaluation of the brain.
Phase-contrast (PC) MRI was performed for quantitative investigation of flow volume
measurements. For the CSF flow, PC-MRI was performed in the axial plane, which was
perpendicular to the cerebral aqueduct ([Figure 1]). The following parameters were used: TR 16 milliseconds; TE minimum ms; slice thickness
4 mm; flip angle 20°; field of view (FOV) 18 × 18 cm; spacing 1; frequency 256 × 256;
velocity encoding (VE) 15 cm/s.
Figure 1 The CSF flow was performed in the axial plane, which was perpendicular to the cerebral
aqueduct.
The MCA and TS were quantitatively investigated for arterial and venous flows, respectively.
All PC-MRI scans were performed in the axial plane, which was perpendicular to the
courses of the MCA and TS. The flow measurements of the MCA and TS were obtained from
oblique-sagittal images ([Figures 2] and [3]). The following parameters were used for the MCA and TS: TR 7.6 and 11.4 milliseconds;
TE minimum ms; slice thickness 4 mm; flip angle 20°; FOV 18 × 18 cm; spacing 1; frequency
256 × 256; velocity encoding (VE) 20 and 50 cm/s, respectively. Cardiac triggering
was performed using finger plethysmography.
Figure 2 The flow measurement of the MCA, from oblique-sagittal image.
Figure 3 The flow measurement of the TS, from oblique-sagittal image.
MRI analysis
Quantitative analyses of flows were performed using the flow analyses program PC-MRI
angiography software, and PC images were transferred to the Advantage Workstation
(GE Healthcare, Milwaukee, WI, USA), software version 2.0. A circular region of interest
(ROI) was placed manually in the cerebral aqueduct for measurement of the CSF flow
volume (expressed as ml/min). We also placed ROIs into the bilateral MCA and TS for
all cases. Thereafter, we measured flow volumes of the MCA and TS. The data of the
patient and control groups were recorded and statistically compared.
Statistical analyses
The Statistical Package for the Social Sciences (SPSS, IBM Corp. Armonk, NY, USA)
software, version 22.0, was used to evaluate the data. The Kolmogorov-Smirnov test
was used to the test the equality of the distribution of variables. Because the age
and CSF flow data are normally distributed, the Student t-test was performed to evaluate these variables. We also used the Mann-Whitney U-test
to compare MCA and TS data because the variables did not show a normal distribution.
A p-value < 0.05 was accepted as statistically significant.
RESULTS
We included 34 patients with MS (22 female, 12 male) and 15 normal controls (4 female,
11 male) in the study. The mean ages of the patient group and control group were 37.15 ± 10.89
years and 33.20 ± 10.94 years, respectively. This was not significant (p > 0.05).
The mean CSF flow volumes of the cerebral aqueduct for MS patients and controls were
0.26 ± 0.16 ml/min and 0.32 ± 0.25 ml/min, respectively, and this difference was not
significant (p > 0.05). The mean flow volume of the TS was 34.65 ± 20.98 ml/min in the MS patient
group, and 53.95 ± 29.27 ml/min in the control group, and this difference was statistically
significant (p < 0.05). The mean flow volumes of the MCA in the MS patient group and the control
group were 19.01 ± 10.67 and 24.09 ± 13.86, respectively, but this difference was
not significant (p > 0.05). The data are summarized in [Table 1].
Table 1
Mean ages and mean flow volumes of the patient and control groups
|
Group
|
Age (years)
|
FVOAq (ml/min)
|
FVOS (ml/min)
|
FVOA (ml/min)
|
|
MS
|
Mean
|
37.15
|
0.26
|
34.65*
|
19.01
|
|
N
|
38
|
31
|
59
|
59
|
|
SD
|
10.89
|
0.16
|
20.98
|
10.67
|
|
Range
|
43.00
|
0.65
|
89.62
|
59.52
|
|
Median
|
39.00
|
0.22
|
31.80
|
16.90
|
|
Control
|
Mean
|
33.20
|
0.32
|
53.95*
|
24.09
|
|
N
|
15
|
15
|
25
|
24
|
|
SD
|
10.94
|
0.25
|
29.27
|
13.86
|
|
Range
|
33.00
|
0.90
|
101.50
|
44.31
|
|
Median
|
33.00
|
0.29
|
51.80
|
26.05
|
Abbreviations: FVOAq, flow volume of aquaductus of cerebri; FVOS, flow volume of transverse sinus;
FVOA, flow volume of middle cerebral artery; SD: standard deviation.
Notes: *p < 0.05.
DISCUSSION
As in other chronic inflammatory diseases of the CNS, vascular pathology is profound
in patients with MS.[11] In chronic MS lesions, extensive enlargement of the perivascular space and vascular
fibrosis is common.[12] However, the relation between the blood-brain barrier damage, inflammation, and
structural vascular pathology is complex.[13] It is assumed that a chain of events, such as inflammation, demyelination, ischemia,
and tissue necrosis following abnormal vascular flow and vasculitis, plays a role
in the pathology of MS.[14] Contrasting the hypothesis suggesting that CCSVI triggers the pathology of MS, there
have been studies concluding that vascular pathology does not trigger MS.[15]
[16]
[17] A meta-analysis established a strong association between CCSVI and multiple sclerosis,
while two recent, large case-control studies could identify no such association.[18]
[19]
[20]
The PC-MRI has a variety of established applications in quantifying blood flow and
velocity;[21] it generates a signal contrast between flowing and stationary nuclei by sensitizing
the phase of the transverse magnetization to the velocity of motion.[22] Before PC-MRI data are acquired, the anticipated maximum flow velocity must be inserted
in the pulse sequence protocol velocity encoding (VENC). To obtain the optimal signal,
the flow velocity should be the same as or slightly less than the selected VENC.[23] Velocity and flow are measured with a commercial software that allows users to define
the ROI around the vessel lumen.[24]
The cerebrovascular perfusion can be potentially altered due to the close relationship
between MS lesions and vascular pathology.[25] Hypoxia-like tissue injury was identified with a suggestion of hemodynamic impairment
in relation to lesion pathogenesis of MS. Brain perfusion in vivo can be assessed
with MRI. Whereas enhancing lesions show increased perfusion, chronic MS lesions show
decreased perfusion. Ge et al. investigated the perfusion characteristics in MS lesions
using dynamic susceptibility contrast MRI (DSC-MRI). They observed reduced blood flow
in all MS lesions, prolonged mean transit time, and decreased cerebral blood flow
compared with the control group. They concluded that DSC-MRI measurements demonstrate
potential for investigating hemodynamic abnormalities in MS lesions.[26] We investigated the flow volume of the MCA using PC-MRI (velocity encoding accepted
as 50 cm/s), but we found no statistically significant differences in the MCA flow
volumes between the patient group and the control group.
The rate of CSF formation in humans is approximately 0.3 to 0.4 ml/min. It originates
from the choroid plexus, ependymal lining of the ventricles, parenchyma of the brain,
and the spinal cord.[27] The absorption of the CSF happens through the arachnoid villi into the great dural
sinuses and true lymphatic vessels;[28] its flow is pulsatile and synchronous with the cardiac cycle, so using cardiac gating
can provide increased sensitivity of the image.[29] Because very little CSF liquid truly circulates, pulsatile flow can be measured
by PC-MRI.[30] Reliable flow quantification is reported to be feasible if the diameter of the aqueduct
lumen is greater than 1.5 mm.[2]
[31] Zamboni et al. found a net CSF flow in the cerebral aqueduct to be reduced in MS
patients with CCSVI. They concluded that a significant relationship exists between
the decline in net CSF flow and CCSVI severity.[32] In a study of 40 patients with MS and 40 healthy controls, Gorucu et al. found significantly
higher CSF flow volumes in the MS patients compared with the controls.[5] In contrast, Sunderström et al. incorporated both contrast-enhanced MRI venography
and PC-MRI venography and found no statistically significant difference in the CSF
flow parameters between patients with MS and the normal control group.[33] We also found no statistically significant difference in the CSF flow parameters
between patients with and without MS. Beggs et al. investigated the CSF dynamics in
the cerebral aqueduct in CCSVI-positive and negative healthy individuals, and concluded
that CSF flow was increased in the CCSVI-positive group compared with the negative
group.[34]
The idea of a vascular etiology can be traced back to the original description of
a perivenular predilection of MS lesions, based on observations in dogs, in whom the
injection of obstructing agents into the venous sinuses caused an MS-like condition.[35] Putnam et al. also claimed that using anticoagulant dicumarol produced favorable
results in RRMS patients.[36] Blinkenberg et al., however, found little evidence for anatomic or hemodynamic abnormalities
of cervical venous drainage in patients with MS when compared with healthy controls,
and claimed that CCSVI-like changes were not a pathological condition.[6] Jurkiewicz et al. evaluated the prevalence of extracranial venous system anomalies
in MS patients and found anomalies of the extracranial venous system in 10 MS patients
(47.6%) and 13 controls (68.4%). These measurements were not statistically significant.[37] McTaggart et al. evaluated the possible differences in the extracranial venous drainage
of MS and healthy individuals. They concluded that patients with MS have a greater
internal jugular vein (IJV) flattening, and a trend toward more non-IJV collaterals
than control groups.[38] Our study differed from other studies in the literature by the following points:
we conducted our measurements at the intracranial levels and flow volumes were measured
from the cerebral aqueduct, MCA, and TS using PC-MRI.
In the present study, the flow volume of TS was significantly lower in MS patients
than in the control group. It has been suggested that hemodynamic changes in the venous
system of MS patients may be a functional epiphenomenon of microvascular disorder.[39] Although there have been studies that do not show vascular pathology to be the cause
of MS, the possibility that venous pathologies are a cofactor in the development of
MS cannot be excluded. For people with susceptibility to MS, CCSVI is likely to promote
the development of the disease.[40]
In conclusion, complicated and conflicting results have been recorded in literature
regarding the relationship between CCSVI and MS. A reduced TS flow volume in MS patients
was noted in the present study when compared with the control group, suggesting a
relationship between venous pathologies and MS. Further studies are needed to understand
whether the relationship between venous pathologies and MS is causal or epiphenomenal.
