The perfect crime? CCSVI not leaving a trace in MS

Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 02/2011; 82(4):436-40. DOI: 10.1136/jnnp.2010.231613
Source: PubMed


Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system, believed to be triggered by an autoimmune reaction to myelin. Recently, a fundamentally different pathomechanism termed 'chronic cerebrospinal venous insufficiency' (CCSVI) was proposed, provoking significant attention in the media and scientific community.
Twenty MS patients (mean age 42.2 ± 13.3 years; median Extended Disability Status Scale 3.0, range 0-6.5) were compared with 20 healthy controls. Extra- and intracranial venous flow direction was assessed by colour-coded duplex sonography, and extracranial venous cross-sectional area (VCSA) of the internal jugular and vertebral veins (IJV/VV) was measured in B-mode to assess the five previously proposed CCSVI criteria. IJV-VCSA ≤ 0.3 cm(2) indicated 'stenosis,' and IJV-VCSA decrease from supine to upright position 'reverted postural control.' The sonographer, data analyser and statistician were blinded to the patient/control status of the participants.
No participant showed retrograde flow of cervical or intracranial veins. IJV-VCSA ≤ 0.3 cm(2) was found in 13 MS patients versus 16 controls (p=0.48). A decrease in IJV-VCSA from supine to upright position was observed in all participants, but this denotes a physiological finding. No MS patient and one control had undetectable IJV flow despite deep inspiration (p=0.49). Only one healthy control and no MS patients fulfilled at least two criteria for CCSVI.
This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.

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Available from: Waltraud Pfeilschifter
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    • "In contrast to the previous observations, an Italian study, investigating only MS patients with clinically isolated syndrome, reported a normal ultrasound investigation in 84% of study population (Baracchini et al. 2011). Moreover, CCSVI could not be detected in additional series of MS patients investigated in Greece (Tsivgoulis et al. 2011) and Germany (Frankfurt/Giessen) (Mayer et al. 2011). In addition, the largest to date, methodologically robust (using both local and central blinded readers) ultrasound case–control study involving 1874 subjects from 35 Italian centers reported a similar (very low) prevalence of CCSVI in MS (3%) and HC (2%) (Comi et al. 2013). "
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    ABSTRACT: Background Chronic cerebrospinal venous insufficiency (CCSVI) has recently been introduced as a chronic state of impaired cerebral or cervical venous drainage that may be causally implicated in multiple sclerosis (MS) pathogenesis. Moreover, percutaneous transluminal angioplasty of extracranial veins termed “Liberation treatment” has been proposed (based on nonrandomized data) as an alternative therapy for MS.MethodsA comprehensive literature search was conducted to identify available published, peer-reviewed, clinical studies evaluating (1) the association of CCSVI with MS, (2) the reproducibility of proposed ultrasound criteria for CCSVI detection (3) the safety and efficacy of “Liberation treatment” in open-label and randomized-controlled trial (RCT) settings.ResultsThere is substantial heterogeneity between ultrasound case–control studies investigating the association of CCSVI and MS. The majority of independent investigators failed to reproduce the initially reported high prevalence rates of CCSVI in MS. The prevalence of extracranial venous stenoses evaluated by other neuroimaging modalities (contrast or MR venography) is similarly low in MS patients and healthy individuals. One small RCT failed to document any benefit in MS patients with CCSVI receiving “Liberation treatment”, while an exacerbation of disease activity was observed. “Liberation treatment” has been complicated by serious adverse events (SAEs) in open-label studies (e.g., stroke, internal jugular vein thrombosis, stent migration, hydrocephalus).ConclusionCCSVI appears to be a poorly reproducible and clinically irrelevant sonographic construct. “Liberation treatment” has no proven efficacy, may exacerbate underlying disease activity and has been complicated with SAEs. “Liberation treatment” should stop being offered to MS patients even in the settings of RCTs.
    Full-text · Article · Nov 2014 · Brain and Behavior
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    • "Only 2 subjects in the control group met at least 2 ultrasonographic criteria of chronic cerebrospinal venous insufficiency. The criteria were not met by any MS patient [18]. "
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    ABSTRACT: Though the etiology of multiple sclerosis remains unknown, the widely accepted explanation is that it has an autoimmune inflammatory background. In 2006 Paolo Zamboni renewed the somewhat forgotten vascular theory of the pathogenesis of multiple sclerosis, proposing the new entity of ‘chronic cerebrospinal venous insufficiency’. As a result of this hypothesis, Zamboni suggested an endovascular treatment for multiple sclerosis involving venoplasty of the internal jugular vein and the azygos vein. Unfortunately, several teams have tried to replicate Zamboni’s results without success. In this review, we present a chronological description of the results of the studies conducted by Zamboni and the later attempts to replicate his work. The main conclusion is that, taking into account results that are currently available, we should remain cautious and routine use of this treatment in patients should not be advisable.
    Preview · Article · Jun 2014 · Polski przegla̜d radiologii i medycyny nuklearnej
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    • "Maybe the most important result of the PREMiSe study is that our multimodal imaging findings contradict the number of recent DS studies that reported a prevalence of CCSVI <10% in MS patients [9,11,12,16,17,33,42-44]. In fact, the invasive diagnostic portion of PREMiSe confirmed that 19 of the 20 MS patients screened as CCSVI positive by DS had severe impairment of extracranial venous outflow with significant stenosis in the IJVs and azygos veins. "
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    ABSTRACT: There is no established noninvasive or invasive diagnostic imaging modality at present that can serve as a 'gold standard' or "benchmark" for the detection of the venous anomalies, indicative of chronic cerebrospinal venous insufficiency (CCSVI). We investigated teh sensitivity and specificity of 2 invasive vs. 2 noninvasive imaging techniques for the detection of extracranial venous anomalies in the internal jugular veins (IJVs) and azygos vein/vertebral veins (VVs) in patients with multiple sclerosis (MS). The data for this multimodal imaging comparison pilot study was collected in phase 2 of the "Prospective Randomized Endovascular therapy in Multiple Sclerosis" (PREMiSe) study using standardized imaging techniques. Thirty MS subjects were screened initially with Doppler sonography (DS), out of which 10 did not fulfill noninvasive screening procedure requirements on DS that consisted of >=2 venous hemodynamic extracranial criteria. Accordingly, 20 MS patients with relapsing MS were enrolled into the multimodal diagnostic imaging study. For magnetic resonance venography (MRV), IJVs abnormal findings were considered absent or pinpoint flow, whereas abnormal VVs flow was classified as absent. Abnormalities of the VVs were determined only using non-invasive testing. Catheter venography (CV) was considered abnormal when >=50% lumen restriction was detected, while intravascular ultrasound (IVUS) was considered abnormal when >=50% restriction of the lumen or intra-luminal defects or reduced pulsatility was found. Non-invasive and invasive imaging modality comparisons between left, right and total IJVs and between the VVs and azygos vein were performed. Because there is no reliable way of non-invasively assessing the azygos vein, the VVs abnormalities detected by the non-invasive testing were compared to the azygos abnormalities detected by the invasive testing. All image modalities were analyzed in a blinded manner by more than one viewer, upon which consensus was reached. The sensitivity and specificity were calculated using contingency tables denoting the presence or absence of vein-specific abnormality findings between all imaging modalities used individually as the benchmark. The sensitivity of CV + IVUS was 68.4% for the right and 90% for the left IJV and 85.7% for the azygos vein/VVs, compared to venous anomalies detected on DS. Compared to the venous anomalies detected on MRV, the sensitivity of CV + IVUS was 71.4% in right and 100% in left IJVs and 100% in the azygos vein/VVs; however, the specificity was 38.5%, 38.9% and 11.8%, respectively. The sensitivity between the two invasive imaging techniques, used as benchmarks, ranged from 72.7% for the right IJV to 90% for the azygos vein but the IVUS showed a higher rate of venous anomalies than the CV. There was excellent correspondence between identifying collateral veins on MRV and CV. Noninvasive DS screening for the detection of venous anomalies indicative of CCSVI may be a reliable approach for identifying patients eligible for further multimodal invasive imaging testing of the IJVs. However, the noninvasive screening methods were inadequate to depict the total amount of azygos vein/VVs anomalies identified with invasive testing. This pilot study, with limited sample size, shows that both a non-invasive and invasive multimodal imaging diagnostic approach should be recommended to depict a range of extracranial venous anomalies indicative of CCSVI. However, lack of invasive testing on the study subjects whose results were negative on the DS screening and of healthy controls, limits further generalizibility of our findings. In addition, the findings from the 2 invasive techniques confirmed the existence of severe extracranial venous anomalies that significantly impaired normal blood outflow from the brain in this group of MS patients.
    Full-text · Article · Oct 2013 · BMC Neurology
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