title: Multimodal noninvasive and invasive imaging of extracranial venous abnormalities indicative of CCSVI: results of the PREMiSe pilot study.
abstract: BACKGROUND
  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 the 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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Buffalo Neuroimaging Analysis Center, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA. rzivadinov@bnac.net.
authors.forename: Robert
authors.initials: R
authors.lastname: Zivadinov
authors.forename: Yuval
authors.initials: Y
authors.lastname: Karmon
authors.forename: Kresimir
authors.initials: K
authors.lastname: Dolic
authors.forename: Jesper
authors.initials: J
authors.lastname: Hagemeier
authors.forename: Karen
authors.initials: K
authors.lastname: Marr
authors.forename: Vesela
authors.initials: V
authors.lastname: Valnarov
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Kennedy
authors.forename: David
authors.initials: D
authors.lastname: Hojnacki
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Carl
authors.forename: L Nelson
authors.initials: LN
authors.lastname: Hopkins
authors.forename: Elad I
authors.initials: EI
authors.lastname: Levy
authors.forename: Bianca
authors.initials: B
authors.lastname: Weinstock-Guttman
authors.forename: Adnan H
authors.initials: AH
authors.lastname: Siddiqui
mesh_terms: D000328:Adult; D002561:Cerebrovascular Disorders / Q000000981:diagnostic imaging*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods; D010690:Phlebography / Q000379:methods; D010865:Pilot Projects; D011446:Prospective Studies; D018084:Ultrasonography, Interventional / Q000379:methods; D014689:Venous Insufficiency / Q000000981:diagnostic imaging*