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
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- Patients and Methods
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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.
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- Patients and Methods
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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.