INTRODUCTION

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 MS^2,3.

PATIENTS AND METHODS

This is 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

II.           Neuroimaging:

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 cerebral veins.

Statistical Methods

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.

RESULTS

Demographic Data:

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 matched.

Clinical Characteristics of MS patients:

Type of Multiple Sclerosis : Among 15 patients with MS, 9 (60%) patients had RRMS and 6 (40%) patients had SPMS

Duration 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.

Radiological findings:

The MRI load (number of lesions): The number of lesions in MRI ranged from 7 to 13 with mean number 10.27±1.87.

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 sinuses.

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).

Comparison 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).

Comparison 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 MRV:

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.

Case one:

Thirty years 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

Case two:

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.

Case three:

Twenty 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.

Figure 1. Different patterns of venous insufficiency in MS group.

Table 1. The comparison between age of CCSVI positive and negative patients.

Table 2. The comparison between sex of CCSVI positive and negative patients.

Table 3. The comparison between clinical characteristics of CCSVI positive and negative patients.

Table 4. The comparison between different patterns of venous insufficiency in MS patients.

Figure 2. Imaging of case 1: Left- MRI brain of MS patient. Right- MRV showing left IJV stenosis (white arrow).

Figure 3.  Imaging of case 2: Left - MRI brain of patient. Right- MRV showing bilateral IJV stenosis (white arrow).

Figure 4. Imaging of case 3: Left- MRI brain of patient. Right- MRV showing left

sigmoid (gray arrow) sinus and IJV stenosis (white arrow).

DISCUSSION

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 MS.

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 probably weak.

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.

[Disclosure: Authors report no conflict of interest]

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