No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset

Abstract

Objective

An impaired cerebrospinal venous drainage, defined as chronic cerebrospinal venous insufficiency (CCSVI), has been recently hypothesized to be the possible cause of multiple sclerosis (MS). We investigated this hypothesis by studying the occurrence of CCSVI in clinically isolated syndromes (CISs) suggestive of MS.

Methods

Fifty consecutive patients presenting with a CIS and evidence of dissemination in space of the inflammatory lesions (ie, possible MS [pMS]) underwent a detailed diagnostic workup, including extracranial and transcranial venous echo-color Doppler sonography (ECDS-TCDS). Those with CCSVI underwent selective venography. Fifty healthy subjects (HCs) age-matched and gender-matched with pMS patients (HC1); 60 patients with transient global amnesia (TGA); and 60 healthy subjects age-matched and gender-matched with TGA patients (HC2) constituted the control groups and underwent ECDS-TCDS.

Results

Mean age of pMS patients was 33.0 ± 8.5 years (range, 14–50); 35 (70%) were female (female:male ratio, 2.3). TCDS was normal in all pMS patients. One or more abnormal ECDS findings were observed in 26 of 50 (52.0%) pMS patients, in 35 of 110 (31·8%) HCs (HC1+HC2), and in 41 of 60 (68.3%) TGA patients. Eight (16%) pMS patients fulfilled the diagnosis of CCSVI. Selective phlebography performed in 7 of these patients (1 denied consent) did not show venous anomalies.

Interpretation

Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS. Ann Neurol 2011;69:90–99.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS).1, 2 Perivenular cuffing of lymphocytes, microglia activation and proliferation, axonal damage, and neuronal apoptosis are the major aspects of white matter (WM) and gray matter MS pathology.3, 4 The autoimmune origin of MS is supported by immunological, genetic, histopathological, and therapeutic observations. However, the mechanism(s) that initiates the autoimmune attack on the CNS is still speculative, and all hypotheses remain open.

Chronic cerebrospinal venous insufficiency (CCSVI) syndrome was defined as a condition characterized by an “anomalous venous outflow from brain and spinal cord,” determined by obstruction at different levels of the internal jugular veins (IJVs), vertebral veins (VV), azygous system, and lumbar venous plexus.5 Four CCSVI types (A, B, C, and D) resulting from the association of various venous flow and/or structural anomalies have been proposed by Zamboni and colleagues6 (Table 1), who found an impressive association between CCSVI and MS, inasmuch as 100% of MS patients were also affected by CCSVI vs 0% of controls.6 Moreover, in a retrospective study, the authors found that the distribution of the pathological hemodynamic patterns was highly predictive of the symptoms at onset and of the following clinical course.7

Table 1. Description of the Four CCSVI Types

Other groups have published similar data. Simka and colleagues8 found sonographic signs of abnormal venous outflow in 64 of 70 (91.4%) MS patients, and in 63 (90.0%) patients a CCSVI condition was demonstrated. Al-Omari and Rousan9 observed that 23 of 25 (92%) MS patients and 6 of 25 (24%) controls had abnormal extracranial venous findings, but evidence of CCSVI was found in 84% MS and 0% controls. All these observations, obtained in independent laboratories using the same methodology, suggest that MS is strongly associated with CCSVI. A new pathogenetic hypothesis for MS10 postulates that obstructions of the cervical venous system may cause an increased intracranial venous pressure that disintegrates the blood-brain barrier (BBB) integrity, promoting iron deposition within the brain parenchyma, and thus initiating a local inflammatory response. Therefore, CCSVI, being of a malformed nature, would be the cause of MS.

However, if a cause-effect relationship between CCSVI and MS exists, this should be observed at disease onset. None of the above mentioned studies have analyzed the occurrence of CCSVI at MS clinical onset (clinically isolated syndromes [CISs]). Therefore, we studied the occurrence of CCSVI in 50 consecutive patients presenting with a CIS suggestive of MS and having evidence of dissemination in space (DIS) of WM lesions (ie, possible MS [pMS]).11, 12

Patients and Methods

Patients and Controls

Fifty consecutive patients presenting with pMS11, 12 over a period of 1 year were enrolled in this study. The diagnostic workup included: (1) cerebrospinal fluid (CSF) analysis; (2) brain and spinal cord magnetic resonance imaging (MRI); (3) biochemical and immunological blood tests; and (4) transcranial and extracranial high-resolution color-coded Doppler sonography (ECDS-TCDS). CIS patients missing the DIS criterion were excluded from the study to limit CIS patients that would never convert into definite MS. Clinical evaluation was done by applying the Expanded Disability Status Scale (EDSS).

Control groups were as follows: (1) 50 healthy individuals (HC1) matched for age and gender with the pMS patients; (2) 60 patients with transient global amnesia (TGA), which is known to occur in association with venous anomalies, represented positive controls; and (3) 60 healthy subjects (HC2) matched for age and gender with the TGA patients (Table 2). All controls underwent ECDS-TCCS.

Table 2. Demographic Data of the pMS Patients and Controls Included in the Study

CSF Examination

CSF examination included: cell count and differentiation, calculation of the CSF/serum albumin ratio and the immunoglobulin G (IgG) index, and the demonstration of IgG oligoclonal bands (IgGOBs).

MRI Acquisition and Examination

A 1.5T machine (Achieva; Philips Medical Systems) was used and the following images were acquired: (1) fast fluid attenuated inversion recovery (FLAIR); (2) 3D fast field echo; (3) post-contrast T1-weighted spin echo; (4) cervical/dorsal short time inversion recovery; (5) cervical turbo spin echo (TSE) T2-weighted; and (6) dorsal TSE-T2-weighted. On FLAIR images, total WM lesion volume (T2-WMLV) was quantified, after lesion identification, using a semiautomated local thresholding technique based on a fuzzy C-mean algorithm, part of the Medical Images Processing, Analysis and Visualization (MIPAV) software (http://mipav.cit.nih.gov).

Venous Ultrasound Examination

Patients and controls underwent a complete extracranial and intracranial venous ultrasound assessment with a high-resolution color-coded duplex sonography scanner (Philips iU22) using a high frequency (5–10MHz) linear probe for the cervical veins and a low frequency (1–3MHz) phased-array probe for the intracranial veins. The examination was performed by an experienced neurosonographer (C.B.) blinded to the patient's diagnosis and was always done in the same room, in a quiet atmosphere, with the subjects lying first in a sitting position and then in a supine position. In contrast with Zamboni's method,6 for a more comprehensive (deep and superficial) intracranial venous evaluation, we extended our study to the transverse sinuses. Venous flow was enhanced by asking the patient to breathe in: this is the most favorable condition for venous emptying, because of activation of the thoracic aspiration.

Extracranial Examination.13

The patient was asked to place his head in a straight position in order to avoid flow alterations caused by unilateral or bilateral venous outflow obstruction. Great care was taken not to compress the cervical veins when the probe was applied over the neck, in order to obtain reliable velocity or cross-sectional area (CSA) measurements. Before recording the hemodynamic data, the patient was asked to rest in that position (sitting or supine) for at least 2 minutes and take several deep breaths to allow blood redistribution in the venous system. The internal jugular veins (IJVs) and the vertebral veins (VVs) were examined by using either the transverse or the longitudinal cervical insonation planes: the direction of flow was analyzed by comparing the color of the flow and the direction of the pulsed wave in the IJV or VV with that of the satellite carotid or vertebral artery. Longitudinal B-mode insonation of the IJV in its caudal segment was performed to visualize the inferior jugular bulb and the jugular valve. We looked for the presence of malformations in the IJVs (septum, valve malformation) that might reduce or block venous outflow, even during inspiration. We assessed the presence of proximal IJV stenoses by measuring the CSA of the IJV: a local reduction of the CSA ≥50% or a CSA ≤ 0.3cm² in the recumbent position was defined as a stenosis. The lack of a Doppler signal in a vein despite several deep inspirations defined an outflow occlusion. In case of valve incompetence, flow reversal was documented during a Valsalva maneuver. Reflux was defined as a reverse flow assessed in the respiratory pause for a duration >0.88 seconds. Reverted postural control of the main cerebral outflow pathway was assessed in the IJVs: in the normal subject, the CSA of the IJV is greater in the supine position because the IJV represents the predominant outflow route; the occurrence of a negative ΔCSA value (ie, greater value in the sitting position) was defined as a loss of postural control (Fig 1).

Figure 1. ECDS in a “jugular drainer.” (A) IJV (in blue) and CCA (in red). (B) VV (in blue) and VA (in red). (C, D) CSA of IJV in supine and in sitting position, respectively. (a–c) Serial B-mode image of a jugular valve: a, open valve; b,c, closing valve. CCA = common carotid artery; ECDS = extracranial echo-color Doppler sonography; IJV = internal jugular vein; VA = vertebral artery; VV = vertebral vein.

Transcranial Examination.14

The system settings were adjusted for the analysis of low-velocity signals; therefore, the filters were switched off and the pulse repetition frequency was reduced for better venous vessel detection. The patient was examined both in a sitting and in a supine position through the transtemporal bone window. We assessed the paired basal veins of Rosenthal (BV), the unpaired vein of Galen (VG), and the 2 transverse sinuses (TSs). Most important, we collected hemodynamic data from cerebral veins only after having identified them correctly.

The BV was insonated in its middle segment using the axial midbrain plane, whereas more distal parts were seen in the thalamic plane. In its proximal segment the BV Doppler signal is usually found lateral of the P2 segment of the posterior cerebral artery (P2-PCA) with a flow direction toward the probe, while in its distal segments it lies medial and superior to the P2-PCA and P3-PCA segments with a flow direction away from the transducer. The VG was visualized in an axial thalamic plane posterior to the hyperechogenic pineal gland; its flow direction is away from the probe. By following the signal of the BV to its junction with the VG, the contralateral BV is found; its flow direction is toward the transducer. In the same plane, but more lateral and deeper, along the contralateral hyperechogenic skull, the TS is insonated: its flow direction is away from the probe (Fig 2). Blood flow direction and velocity in all these veins were recorded, taking great care not to measure at junctions with other vessels, since at those points venous flow velocities could vary greatly. A reflux was defined as a reverse flow with a duration >0.5 seconds.

Figure 2. (A–C) TCDS, transtemporal approach, midbrain to thalamic axial plane. Color-mode imaging and Doppler spectrum of the ipsilateral BV (in blue), contralateral BV (in red), and VG (in blue). (D) TCDS, transtemporal approach, midbrain to lower pontine oblique axial plane. Color-mode imaging and Doppler spectrum of the TS (in blue). BV = basal vein of Rosenthal; BVc = contralateral BV; TCDS = transcranial echo-color Doppler sonography; TS = contralateral transverse sinus; VG = vein of Galen.

The neurosonographer specifically searched for 1 or more CCSVI criteria.5, 6 (1) Reflux (t > 0.88 seconds) in the IJVs and/or in the VVs in sitting and supine position. (2) Reflux (t > 0.5 seconds) in the deep cerebral veins. (3) High-resolution B-mode evidence of proximal IJV stenoses (local reduction of CSA ≥ 50% in the recumbent position or CSA ≤ 0.3cm²). (4) Flow not detected by Doppler in IJVs and/or VVs. (5) Reverted postural control of the main cerebral venous outflow pathways: a missing increase of IJV diameter in the supine position.

Selective Venography

Selective venography (VGF) of the azygous and IJV system was performed via the transfemoral route in pMS patients fulfilling the ECDS-TCDS screening criteria for CCSVI. The radiologist was aware of the clinical diagnosis of the patients, but unaware of the ultrasound findings. The standard exam was performed by asking the patient to hold his breath during dye injection. The selective access was achieved by means of a 5F Cobra-shaped catheter and 5F vertebral-shaped catheter depending on the anatomic district. From 6 to 8ml of nonionic contrast medium were injected at a flow rate of 3ml/minute. The iliolumbar veins, the paravertebral venous plexus, the left renal vein, the azygos vein outlet and the ascending tract, and both IJVs were studied. In the supine position, venous pressures were recorded in the inferior and superior vena cava, inferior and superior azygos vein, and in the IJVs. The morphology and pressure of the IJVs were also studied with the patient in a 45-degree anti-Trendelenburg position. Whenever a stenosis or an atypical aspect of the IJV was observed, VGF was also performed with the patient breathing out or during a Valsalva maneuver.

Statistical Analysis

Clinical, paraclinical, and demographic data are expressed as the mean ± standard deviation (SD). Differences among groups were tested for significance with the 1-way analysis of variance (ANOVA) and, when necessary, with the 2-sided Fisher's exact test. Values of p < 0.05 were considered to be significant.

Results

Clinical Data

The mean age of pMS patients was 33.0 ± 8.5 years (median: 33.0; range: 14–50); 35 (70%) were female, 15 (30%) were male (female:male [F/M] ratio: 2.3); EDSS at onset was 1.6 ± 0.5 (median: 1.5; range: 1.0–3.0). The type of presentation was monosymptomatic in 27 (54%) patients. Ten patients presented with monolateral optic neuritis, 10 with brainstem symptoms, and 11 with a spinal cord syndrome. The remaining patients had symptoms due to supratentorial lesions (Table 3). The DIS criterion of lesions was achieved by combining MRI and CSF findings (McDonald/Polman criteria). Sixteen patients met Barkhof's MRI criteria for DIS, while 32 patients achieved the criterion thanks to the presence of IgGOB in the CSF. Only 2 patients had a normal brain MRI, but they had 2 lesions in the spinal cord and the presence of IgGOB in the CSF. During the study period, 14 patients converted to MS and initiated immunomodulatory therapy (8 interferon-beta, 3 natalizumab, and 3 glatiramer acetate).

Table 3. Clinical and Instrumental Data of the pMS Patients Included in the Study

CSF Data

Forty-two (84%) patients had IgGOB in the CSF, but not in the corresponding serum, while 32 (64%) had increased IgG index. All patients with increased IgG index also had IgGOB; thus, 84% of the patients had evidence of intrathecally synthesized IgG.

MRI Data

In the entire group of patients, the mean ± SD number of brain T2 lesions was 9.50 ± 9.24 (median: 6.5; range: 0–38). T2-WMLV was 1.5 ± 2.0cm³ (median: 0.5; range: 0–7.2). As mentioned above, 2 patients had no T2 lesion in the brain at onset, but both had spinal cord lesions and the presence of IgGOB in the CSF. During the follow-up, 1 of these patients had a clinical relapse and brain MRI disclosed 2 periventricular brain lesions. In the other patient, although asymptomatic, brain MRI performed at 6 months after clinical onset disclosed the appearance of 1 periventricular T2 lesion.

Gadolinium–ethylene diamine tetraacetic acid (EDTA)–enhancing (Gad+) lesions were observed in 22 of 50 (44%) patients. All these patients also had 1 or more T2 inactive lesions. In 18 patients, the Gad+ lesions were asymptomatic, and thus, according to the recently published Magnetic Imaging in Multiple Sclerosis (MAGNIMS) MRI Criteria for MS in patients with CIS, these patients could be considered to have MS.15 However, since the MAGNIMS criteria were published after the initiation of this study, the diagnosis of pMS and the criteria for dissemination in space and time were achieved according to the McDonald/Polmann diagnostic criteria.

No statistically significant difference in clinical, demographic, CSF, and MRI parameters was observed between patients with or without venous flow abnormalities.

Ultrasound Data

One or more abnormal extracranial venous ultrasound findings were observed in 26 of 50 (52.0%) pMS patients, in 35 of 110 (31.8%) healthy controls (HCs) (HC1+HC2), and in 41 of 60 (68.3%) TGA patients. Pathologic structures (septa, malformed valves) in the IJV were found in 12 pMS patients (24.0%): the malformation was monolateral in 9 (18.0%) patients and bilateral in 3 patients. Reflux in the IJV was present in 15 cases (30.0%), and in 12 (24.0%) it was present in both the supine and sitting position. Stenosis of IJV was observed in 8 cases (16.0%), but the stenosis was bilateral in only 2 cases. In 9 (18%) patients, the flow was not Doppler detectable in 1 IJV only in the sitting position, while in 3 cases (6%) the absence of IJV flow was observed in both the sitting and supine position. We never documented an absence of flow in VVs.

The most frequent abnormal ECDS finding in the control groups was IJV valve incompetence: 12 of 50 (24%) in HC1 (vs pMS, χ²: p = 1.0); 38 of 60 (63.3%) in TGA (vs pMS, χ²: p = 0.00008); and 16 of 60 (26.7%) in HC2.

TCDS of intracranial veins and sinuses was normal in all pMS patients: namely, reflux was not found in patients or controls, and velocity values were within a normal range in all study groups.14

The frequency of CCSVI criteria in patients and controls is reported in Table 4. Overall, CCSVI criteria were fulfilled in only 8 of 50 (16.0%) pMS patients: in particular, according to clinical onset, we observed a Type A pattern in 1 patient with supratentorial symptoms, a Type B pattern in 1 patient with supratentorial symptoms, and 6 Type C patterns: optic neuritis (2), brainstem/cerebellum symptoms (2), and supratentorial symptoms (1), respectively.

Table 4. Frequency of CCSVI Criteria in Patients and Control Groups

VGF Data

Selective VGF was performed in 7 of these 8 patients (1 patient did not give consent); in 6 patients we found regular drainage of IJVs in the supine or 45-degree tilt position and normal azygos system, while in 1 a hypoplasia of the right IJV was observed. VGF was also performed upon specific request by 3 other pMS patients with some ultrasound anomalies that did not satisfy the CCSVI criteria: the findings were normal in 2 cases, while in 1 patient the examination was interrupted because of a paroxysmal supraventricular tachycardia that regressed a few hours later. Figure 3 shows a representative case of pMS having a CCSVI pattern but normal VGF.

Figure 3. (A) ECDS in pMS patient in the supine position: IJV stenosis with septum. (B) Venography in the same patient, supine position: no lumen irregularities. (C) Venography, 45-degree tilt: normal drainage. ECDS = extracranial echo-color Doppler sonography; IJV = internal jugular vein; pMS = possible MS.

Discussion

We studied the possible causative association between CCSVI5–7 and MS. CIS patients having evidence of DIS of lesions, ie, pMS, were analyzed. Our pMS population was very similar to that of the Benefit study16 in terms of mean age (33 years in our study, 30 years in Benefit), percentage of females (70% vs 71%), monofocal onset (54% vs 53%), steroid therapy after the first event (70% vs 72%), and EDSS (1.6 vs 2.0). Therefore, our pMS patients were highly representative of CIS that will develop definite MS within a relatively short period of time. Notably, the conversion rate to clinically definite MS observed in the Benefit study over a 2-year follow-up was 45%.The conversion rate observed in our pMS patients during the study period (11/50, 22%) is in line with the expected value.

Our patients differed significantly in age and gender from those studied by Zamboni and colleagues5 and Bartolomei and colleagues,7 whose F/M ratio was 1.1, not representative of the MS gender distribution in Northern Italy, where Ferrara and Padova are geographically located, which is characterized by a F/M ratio of 2.4.17, 18 Moreover, the mean age of the MS patients (relapsing/remitting multiple sclerosis [RRMS], secondary progressive multiple sclerosis [SPMS], primary progressive multiple sclerosis [PPMS]) studied by Zamboni and colleagues5 was inevitably higher compared to that of our pMS patients. Although both age and gender should not have constituted a significant bias, especially considering that Zamboni and colleagues5 found CCSVI in 100% of MS patients and 0% in HC, it has to be pointed out that in a large study on healthy volunteers, a retrograde venous flow (demonstrated in 55/125, 44.4%, of subjects) was significantly more frequent in men and at older ages (≥50 years).19

The high prevalence of CCSVI in MS patients observed by Zamboni and colleagues5 has been recently confirmed by other independent groups, using the same methodology and the same terminology. In 70 patients having different clinical forms of MS (49 RRMS, 16 SPMS, 5 PPMS), Simka and colleagues8 found a CCSVI condition in 63 cases (90.0%). Reflux in IJV and/or VV was present in 31 (42.8%) cases, stenosis of IJV in 61 (87.1%), undetectable flow in IJV and/or VV in 37 (52.9%), and negative difference in CSA of the IJV assessed in the supine versus sitting position in 28 (40.0%). Flow abnormalities in the VV were found in 8 patients (11.4%) and pathologic structures (septa or inverted valves) were also frequently observed (58.6%).8 Al-Omari and Rousan found a CCSVI in 21/25 (84%) MS and never in controls.9 A high prevalence of CCSVI in RRMS and SPMS was also reported by Zivadinov and colleagues.20 All these observations suggest that MS is strongly associated with CCSVI.

Our data, however, do not confirm a cause-effect relationship between CCVSI and MS. Although 52% of our pMS patients had various types of extracranial venous anomalies at ECDS examination, only 8 (16%) had a venous pattern suggestive of CCSVI. This significant difference with the findings of Zamboni and colleagues5, 6 could be partly explained by the limitations of the method used to define the criteria for CCSVI: (1) In about 70% of MS patients, Zamboni and colleagues5, 6 found a reflux > 0.88 seconds in the IJVs and/or VVs in any body position, whereas in our study we observed the same result in 24% of pMS and 10% of TGA patients. This could be explained by the fact that we assessed reflux along the entire IJV, avoiding false-positive results due to a pulsation artifact from the adjacent carotid artery; moreover, we used a Valsalva maneuver, which is a more adequate method to test venous reflux, otherwise someone might misinterpret a reflux due to IJV valve incompetence for a reflux due to IJV stenosis. (2) Of Zamboni and colleagues'5 MS patients, 37% had a proximal IJV stenosis, compared to 16% of the pMS patients of our study. This could be due to several factors leading to false-positive results: external compression (by the ultrasound probe, surrounding anatomic structures such as the carotid artery, or muscles of the neck) or anatomical and physiological variations of IJV diameter. For these reasons, we made particular efforts to avoid compression by the transducer and by neck muscles. (3) In 52% of MS patients, Bartolomei and colleagues7 did not find blood flow in the IJVs and/or VVs compared to 6% of our pMS patients. Our findings are in line with previous ultrasound studies reporting that in a small percentage of subjects venous blood mainly drains via extrajugular vessels even in a supine position. (4) Zamboni and colleagues5, 6 reported that 55% to 58% of their MS patients had a reverted postural control of the main cerebral venous outflow pathways compared to 16% of pMS patients in our study with no significance difference with regard to TGA patients (10%) and normal subjects (6%). We believe that an analysis of blood flow volume change as reported by Doepp and colleagues21 would avoid most of the limits found in Zamboni and colleagues6 method and might explain the discrepancies found in our study between venous ultrasound and selective venous angiography.

Regarding venous TCDS, we used a high-performance sonograph to avoid inaccurate assessment and found no patient with intracranial venous abnormalities. We believe that this discrepancy with Zamboni and colleagues,6 who found a pathological cerebral venous reflux in 50% of their MS patients, is related to substantial instrumental and methodological differences. Namely, with suboptimal equipment, the detection rate of cerebral veins and sinuses is low, and when these are detected they cannot be visualized over a long distance, rather they are often depicted as merely color speckles; this could lead to misinterpretation of the blood flow direction. Furthermore, if cerebral venous reflux is evaluated using only the color-coded duplex technique, disregarding blood flow analysis using the Doppler spectrum, this again would lead to misinterpretation of findings.

Moreover, no association between symptoms at onset and CCSVI type was observed. Our findings do not exclude that CCSVI is associated with more advanced disease stages, in particular with SPMS and PPMS, and thus we cannot exclude that CCSVI might be a consequence of MS pathology. Recently, however, 2 independent German studies did not confirm Zamboni and colleagues'5, 6 observations: in 20 and 56 unselected RRMS and SPMS patients, respectively, the percentage of patients who fulfilled the required criteria of CCSVI was 20%22 and 0%,21 respectively; another independent case-control study confirmed these results, as no CCSVI was found in 21 RRMS patients.23 Taking into account all of these findings, and the urgent need of independent assessment of CCSVI in MS patients,24 further studies in large cohorts of patients with progressive MS are warranted to elucidate whether MS-associated pathology may contribute to determine a CCSVI condition.

High percentages of venous abnormalities have also been described in normal subjects19 and in other neurological disorders, such as transient global amnesia,25, 26 exertional headache,27 and transient monocular blindness,28 and it has been hypothesized that incompetence of IJV valves may be associated with respiratory brain syndrome.29 Our finding in HC and TGA are in line with previous reports. The clinical importance of these venous abnormalities remains unclear.

In conclusion, CCSVI is an infrequent condition in pMS; indeed, 84% of the patients with pMS did not have it. Moreover, a perfectly normal venous TCDS in all our pMS patients strongly indicates that even in those few patients with a CCSVI pattern the extracranial venous anomalies do not influence cerebral venous hemodynamics. But most importantly, all pMS patients who underwent selective VGF had substantially normal findings. Therefore, the results of our study strongly challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Consequently, any invasive endovascular therapeutic procedure, including angioplasty and venous stent placement, is not only dangereous30 but presently unjustified in MS.

Potential Conflicts of Interest:

C.B. has received compensation for being a board member, expert testimony, payment for development of educational presentations including service on speakers' bureaus, and has had travel/accommodations expenses covered or reimbursed by Pfizer, Guidotti, Sanofi-Aventis, Novartis. M.C. has been a member of the board of Merk-Serono, Sanofi-Aventis, and Bayer-Shering; a consultant for Merk-Serono and Sanofi-Aventis; given expert testimony for Biogen-Dompé Italy and Bayer-Shering; received honoraria from Merk-Serono, Sanofi-Aventis, and Bayer-Shering; and had travel/accommodations expenses covered or reimbursed by Biogen-Dompé Italy, Merk-Serono, Sanofi-Aventis, and Bayer-Shering. P.G. has been a member of the board of Novartis, Biogen-Elan, Merk-Serono, Sanofi-Aventis, and Bayer-Shering; has been a consultant for Biogen-Elan, Sanofi-Aventis, and Bayer-Shering; has given expert testimony for Biogen-Dompé Italy, Sanofi-Aventis, and Merk-Serono; has received honoraria from Novartis Farma, Biogen-Elan, Sanofi-Aventis, Merk-Serono, and Bayer-Shering; and has had travel/accommodations expenses covered or reimbursed by University of Padova, Novartis Farma, Sanofi-Aventis, Biogen-Dompé Italy, Merk-Serono, and Bayer-Shering. P.P. has received honoraria from Biogen-Dompé Italy, Sanofi-Aventis, and Merk-Serono; and has had travel/accommodations expenses covered or reimbursed by Sanofi-Aventis, Biogen-Dompé Italy, and Merk-Serono.