CLINICAL STUDY

Internal Jugular Veins Outflow in Patients withMultiple Sclerosis: A Catheter Venography Study

Pierfrancesco Veroux, MD, Alessia Giaquinta, MD, Debora Perricone, MD,Lorenzo Lupo, MD, Flavia Gentile, MD, Carla Virgilio, MD,

Anna Carbonaro, MD, Concetta De Pasquale, MD, andMassimiliano Veroux, MD, PhD

ABSTRACT

Purpose: To investigate an examiner-independent catheter venography protocol that could be used to reliably diagnose venousoutflow abnormalities in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency and to determinewhether venous angioplasty is effective in the treatment of these abnormalities.

Materials and Methods: A total of 313 patients with MS and 12 patients with end-stage renal disease underwent echo-colorDoppler sonography and catheter venography of the internal jugular veins (IJVs) to evaluate contrast medium clearance time. Inpatients with venous outflow anomalies, balloon angioplasty of the IJVs was performed.

Results: A contrast medium clearance time cutoff value of 4 seconds or less provided the maximal combination of sensitivityand specificity for the right IJV (sensitivity, 73.4%; specificity, 100%) and left IJV (sensitivity, 91.4%; specificity, 100%). IJVswith a clearance time between 4.1 and 6 seconds had moderate delayed flow (MDF), and IJVs with a clearance time longer than6 seconds had severe delayed flow (SDF); 89% of patients showed MDF/SDF through at least one IJV, 79% showed MDF/SDFthrough both IJVs, and only 5% showed normal flow in both IJVs. Balloon angioplasty was immediately able to improve flow inat least one IJV in 69% of patients, but venous flow was normalized in both veins in only 37% of patients; SDF persisted afterangioplasty in 32% of patients.

Conclusions: There is a high prevalence of abnormal delayed flow through IJVs in patients with MS. Venous angioplasty waseffective in only a minority of patients with SDF.

ABBREVIATIONS

CCSVI = chronic cerebrospinal venous insufficiency, ESRD = end-stage renal disease, IJV = internal jugular vein, MDF = moderatedelayed flow, MS = multiple sclerosis, PP = primary progressive, PTA = percutaneous transluminal angioplasty, ROC = receiveroperating characteristic, RR = relapsing–remitting, SDF = severe delayed flow, SP = secondary progressive

Venous phlebography is a well recognized diagnostictechnique that is extensively used in the definition oflarge-vein occlusive disease. Large veins of the thorax

and abdomen may be involved in many malignant andbenign diseases, and a variety of clinical syndromes arecaused by their stenosis or occlusion (1).Recently, chronic cerebrospinal venous insufficiency

(CCSVI) was described as characterized by stenosis inthe internal jugular veins (IJVs) and azygos vein, whichtogether provide the venous outflow from the brain andspinal cord (2–9). Various diagnostic modalities havebeen used to evaluate the controversial problem ofquantification of the cerebral venous return, in partic-ular, in patients with chronic neurodegenerative disor-ders, such as multiple sclerosis (MS) (6–10).Because of the high variability of venous drainage

from the central venous system, it is difficult to usecurrent magnetic resonance (MR) imaging (6,11) toaccurately detect the outflow of the IJVs; on the contrary,recent studies (12) have demonstrated that echo-color

& SIR, 2013

J Vasc Interv Radiol 2013; 24:1790–1797

http://dx.doi.org/10.1016/j.jvir.2013.08.024

None of the authors have identified a conflict of interest.

From the Vascular Surgery and Organ Transplant Unit, Department of Surgery,Transplantation and Advanced Technologies (P.V., A.G., D.P., F.G., C.V., A.C.,C.D.P., M.V.) and Neuropsychiatric Unit, Department of Medical and SurgicalSciences (D.P.C.), University Hospital of Catania and Department “Ingrassia”(L.L.), University of Catania, Catania, Italy. Received April 26, 2013; finalrevision received August 28, 2013; accepted August 29, 2013. Addresscorrespondence to P.V., Vascular Surgery and Organ Transplant Unit,Department of Surgery, Transplantation and Advanced Technologies, Uni-versity Hospital of Catania, Via S. Sofia 84, 95123 Catania, Italy; E-mail:veroux@unict.it

Doppler sonography scan techniques are accurate but arealso technically challenging and examiner-dependent,and require active collaboration from patients, whichleads to highly variable results. Zamboni et al (13)proposed a new cervical plethysmography method thatevaluates the cerebral venous return in relation to thechange in position, and demonstrated that the cerebralvenous return characteristics of patients with CCSVIwere markedly different from those of control subjects.Catheter venography demonstrated a high prevalence

—always greater than 90%—of venous outflow abnor-malities in patients with MS (2,7,14–19). However,despite the use of catheter venography in the diagnosisof CCSVI before treatment, no validated catheter venog-raphy scores are now available to classify the anomalousflow patterns of IJVs in these patients. Given this, thepurpose of the present study was to evaluate an examiner-independent catheter venography protocol that could beused to reliably diagnose venous outflow abnormalities inpatients with MS and to determine if venous angioplastyis effective in the treatment of these abnormalities.

PATIENTS AND METHODSThe study was approved by the ethical committee of theUniversity Hospital of Catania. All patients signed aninformed consent form on which the potential risks andbenefits of the study treatment were detailed.This was a prospective, single-center study of a stand-

ardized, operator-independent catheter venography pro-tocol to evaluate the hemodynamic patterns in IJVs (asdetailed later). The study was unfunded; the ItalianNational Health System covered all the study’s costs,and the patients and investigators were not paid for theirparticipation.

From May 2011 to September 2012, 313 consecutivepatients were referred to our institution with MS. Allpatients underwent echo-color Doppler sonography oftheir IJVs in accordance with the recommendations of theinternational consensus conference on the use of echo-color Doppler sonography in patients with CCSVI (12),followed by catheter venography of their IJVs (Fig 1).An IJV was considered normal if it had no morphologicabnormalities, such as endoluminal defects causingstenosis of the vein (r 50% of vein diameter),hypoplasia, or extrinsic muscular compression, and nohemodynamic alterations of venous flow confirmed bysonographic evaluation.Twelve patients with end-stage renal disease (ESRD;

mean age, 48.4 y; eight women and four men) whounderwent venography of their IJVs and subclavianveins to evaluate the feasibility of vascular access forhemodialysis were included in the study and consideredas control subjects.The same physician performed all echo-color Doppler

sonography evaluations and catheter venography proce-dures. The patient characteristics and the technicalaspects and images from the venography and angio-plasty procedures were saved in a database. An inde-pendent physician reviewed the images.The primary endpoints of the study were to define the

normal flow time through the IJVs, to detect if a delayedflow time in the IJVs was present in patients with MS,and, in patients with abnormal flow, to determine theimmediate efficacy of percutaneous transluminal angio-plasty (PTA) in improving the flow.

PatientsA total of 313 consecutive patients with MS were studied forsuspected anomalies of venous flow in their IJVs (Table 1).

Figure 1. Study design.

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There was a predominance of female patients (63%). Amongthe study population, patients with relapsing–remitting (RR)disease were the most predominant cohort (177 patients),followed by those with secondary progressive (SP) disease(95 patients) and those with primary progressive (PP) disease(31 patients). The mean time since MS diagnosis wassignificantly longer in patients with SP disease (17.8 y vs8.6 y in RR disease and 11.1 y in PP disease; P o .001),whereas the mean age at the time of MS diagnosis was notsignificantly different among the three groups.

Catheter Venography of IJVsAll procedures were performed under local anesthesia:because it was necessary for the patient to be consciousand cooperative during the procedure, no furthergeneral sedation was used. Access to the venous systemwas achieved through a percutaneous anterogradeapproach of the right common femoral vein undersonographic guidance to avoid pain and accidentalarterial puncture.After placement of an 8-F sheath introducer (Boston

Scientific, Natick, Massachusetts), an intravenous bolusof 5,000 U of heparin was administered. The right IJVwas first cannulated with the use of a 0.035-inch short-angle regular hydrophilic guide wire 260 cm in length(AQUATRACK; Cordis, Bridgewater, New Jersey)supported by a BER II diagnostic catheter (4 F, 100cm; Cordis). The BER II catheter, a straight catheterwith a short distal angulation of the tip, was preferred inview of the goal to minimize possible interference withany endoluminal defects of the IJVs. Before the frameacquisition, for all cases, the BER II catheter waspositioned at the level of the jaw angle.Selective venography of the IJVs was performed by

automatic injection of a low-viscosity contrast medium

(Iomeron 150; Bracco Imaging, Milano, Italy) in ante-rior–posterior projection. A low pressure (100 psi) wasused to avoid induced reflux. The rate of contrast mediuminjection was 4 mL/s for 2 seconds (a total of 8 mL foreach acquisition). The frame rates were as follows: threeframes per second for the first 4 seconds and then twoframes per second for 8 seconds, for a total of 28 framesin 12 seconds. The long acquisition time was used todetect a delay of contrast medium clearance through theIJVs. All patients were asked to maintain a straight headand neck position and regular breathing during the frameacquisitions to minimize the venous flow alteration thatoccurs when a patient holds his/her breath. The sameprocedure was used for the left IJVs (Fig 2).Clearance of contrast medium was evaluated before

and after percutaneous transluminal angioplasty (PTA)and analyzed prospectively on the basis of cathetervenography frames by independent physicians. Thecontrast medium clearance time was evaluated foranalysis in patients with MS and in those with ESRD.

Venous AngioplastyIJV angioplasty was performed only in the presence ofmoderate delayed flow (MDF) or severe delayed flow(SDF) at catheter venography. If endoluminal defectswere observed in the presence of a normal clearancetime, the vein was not dilated. Compliant balloons ofvariable diameters (10–18 mm) were chosen to beapproximately 10% larger than the native vein diameter.Noncompliant balloons were used only in cases ofunsatisfactory results. The balloons were inflated at 8–12 atm to avoid vein damage or rupture for 30 seconds(Fig 3).The balloon angioplasty was considered effective

when it reduced the abnormal delayed flow by at least

Table 1 . Baseline Characteristics of the Study Cohort (N ! 311)

Characteristic

MS Type

P ValuePP (n ! 31) SP (n ! 95) RR (n ! 177)Sex (M/F) 19/12 36/58 55/122Age (y) 40.9 ! 13.4 44.2 ! 14.8 39.8 ! 13.7 .322Mean time from diagnosis (y) 11.1 ! 7.1 17.8 ! 9.1 8.6 ! 6.4 o .001Contrast medium clearance timeRight IJV .28r 4 s 1 11 404–6 s 10 31 41Z 6 s 20 52 96

Left IJV .27r 4 s 2 9 184–6 s 13 25 48Z 6 s 16 60 111

Values presented as means ! standard deviation where applicable.IJV ! internal jugular vein, MS ! multiple sclerosis, PP ! primary progressive, RR ! relapsing–remitting, SP ! secondaryprogressive.

Veroux et al ’ JVIR1792 ’ Catheter Venography of IJV Outflow in Multiple Sclerosis

2 seconds. After venous angioplasty, all patients receiveda fluid load of 1,500 mL overnight to minimize the riskof contrast medium–induced nephropathy.

Statistical AnalysisData are expressed as means ! standard deviation. TheFisher exact test was used for analysis of categoricvariables. Differences between means were tested withthe two-sided t test or the Wilcoxon rank-sum test. A Pvalue of less than .05 was used to determine statisticalsignificance.

RESULTS

IJV Clearance TimeTo determine a threshold value for the clearance time ofcontrast medium that corresponds to normal flow, areceiver operating characteristic (ROC) analysis wasperformed for catheter venography of the right and leftIJVs in patients with MS or ESRD. A clearance timecutoff value of 4 seconds or less provided the maximalcombination of sensitivity and specificity for the rightIJV (sensitivity, 73.4%; specificity, 100%) and left IJV(sensitivity, 91.4%; specificity, 100%). The completeresults of the ROC analysis for catheter venography of

jugular veins are displayed in Figure 4. The ROCanalysis revealed that left IJVs were more frequentlyaffected by CCSVI than right IJVs (P o .001).The mean contrast medium clearance times in the 12

patients with ESRD and with no signs of IJV stenosis orocclusion was 3.1 seconds ! 0.4, compared with 3.3seconds ! 0.4 in the 69 IJVs without abnormalities in 57patients with MS.Because of the great number of variables that could

have influenced flow velocity (systolic pressure, cardiacrate, length and diameter of the IJV, breathing, reducedrespiratory capacity in MS, and collateral pathways), toavoid including patients with normal flow occurringbetween instances of abnormal flow, and based on theresults of the ROC analysis, IJVs with a clearance time of4 seconds or less (ie, frames 7–11) were considered normal.As a consequence, IJVs with a clearance time of

contrast medium between 12 and 15 frames (ie, 4.1–6s) were considered to have MDF, and IJVs with aclearance time greater than 16 frames (ie, 4 6.1 s) wereconsidered to have SDF.Among the study cohort (313 patients), catheter veno-

graphy demonstrated a venous outflow abnormality inboth IJVs in 73% of patients. For the right IJVs, MDFand SDF were demonstrated in 27.7% and 54.9% ofpatients, respectively, whereas venous flow was normal

Figure 2. Catheter venography of IJVs. (a) Normal left IJV with visible brachiocephalic trunk. (b) Near-total occlusion of left IJV causedby abnormal valve apparatus. (c) Hemodynamic occlusion of left IJV caused by omohyoid muscle entrapment with retrograde flow andcollateral pathways toward the contralateral brachiocephalic trunk.

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in only 17.2% of patients. For the left IJVs, MDF andSDF were demonstrated in 29% and 61% of patients,respectively, but only 9.9% of patients had normal flow.Normal flow in both IJVs was reported in only 5% ofpatients (Table 2).The mean time since MS diagnosis was significantly

longer in patients with SP (17.8 y vs 8.6 y in RR and 11.1y in PPl P o .001), whereas the mean age at the time ofMS diagnosis was not significantly different among thethree groups.There was no correlation between time since MS

diagnosis and SDF rate (P ! .823), suggesting thatMS most likely does not influence the progression ofCCSVI (Table 3). Again, there was no correlationbetween SDF and patient age (P ! .854) or betweenSDF and type of MS (P ! .732).

Angioplasty of IJVsBalloon angioplasty was immediately able to improveflow in at least one IJV in 69% of patients, but venous

flow was normalized in both IJVs in only 37% of patients;SDF was persistent in 32% of patients (Table 4). Theobservation of SDF by catheter venography waspredictive of poorer results of angioplasty (P o .01).Among subjects with SDF of the right IJV (188 patients),venous angioplasty determined normal flow in 26.7% andMDF in 29.5% of patients, whereas delayed flowremained unchanged in 43.8% of patients; in left IJVswith SDF (216 patients), after venous angioplasty, 47% ofpatients had persistent SDF, 29.4% had MDF, and 23.6%had normal flow. Among patients with MDF of the rightIJV (68 patients), venous angioplasty established normalflow or MDF in 73% and 27% of patients, respectively; inpatients with MDF of the left IJV (62 patients), aftervenous angioplasty, 66.7% had normal flow and residualMDF was present in 33.3%.Among the 28 patients with MDF in both IJVs,

venous angioplasty normalized flow in both veins in39.2% of patients; however, venous angioplasty normal-ized venous flow in only 3.7% of 108 patients withbilateral SDF.

Figure 3. Catheter venography of left IJV in a patient with MS. (a) SDF caused by occlusive transversal septa. (b) Excellentmorphologic results after angioplasty.

Veroux et al ’ JVIR1794 ’ Catheter Venography of IJV Outflow in Multiple Sclerosis

Four patients (1.2%) experienced an inguinal hema-toma, which was treated conservatively in each case.

DISCUSSIONWe have demonstrated, by using a standardized cathetervenography protocol, that MS is associated with aquantifiable prolonged clearance time of contrastmedium in the IJVs.CCSVI was first described by Zamboni et al in 2009

(2) as abnormal outflow from the central nervous systemto the heart as a result of different anomalies in the maingreat veins of the neck (ie, IJVs) and chest (ie, azygosvein) (2). CCSVI has been linked to MS, with conflictingresults (7,8,20,21).

Figure 4. ROC curve depicts sensitivity versus specificity of clearance time of contrast medium during catheter venography of right IJV(a) and left IJV (b). (Available in color online at www.jvir.org.)

Table 2 . Hemodynamic Patterns of IJVs in Patients with MSBased on Contrast Medium Clearance Time (N ! 313)

Characteristic No. of Pts.

Flow

Normal MDF SDFIJVRight 313 54 (17.2) 87 (27.7) 172 (54.9)Left 313 31 (9.9) 91 (29) 313 (61)

Age at diagnosisr 30 y 30 2 (6.6) 12 (40) 16 (53.3)31–40 y 83 5 (6.1) 36 (43.3) 42 (50.6)41–50 y 127 4 (4.6) 59 (46.4) 64 (50.4)4 51 y 73 4 (3.3) 32 (43.8) 37 (50.6)

Values in parentheses are percentages.IJV ! internal jugular vein, MDF ! moderate delayed flow,MS ! multiple sclerosis, SDF ! severe delayed flow.

Table 3 . Patients with SDF in IJV Based on Time since MSDiagnosis

Time since Diagnosis One IJV (%) Two IJVs (%)o 5 y 48 365–10 y 56 3910–15 y 57 4315–20 y 57 374 20 y 55 41

IJV ! internal jugular vein, MS ! multiple sclerosis, SDF !severe delayed flow.

Table 4 . Immediate Results of PTA of IJV Compared withPreoperative Hemodynamic Flow

Vessel

Flow (%)

Normal MDF SDFRight IJVBefore PTA Control 26 74After PTA 40 30 30

Left IJVBefore PTA Control 21 79After PTA 35 30 35

IJV ! internal jugular vein, MDF ! moderate delayed flow,PTA ! percutaneous transluminal angioplasty, SDF ! severedelayed flow.

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One of the major concerns regarding the diagnosis ofCCSVI and its association with MS is the accuratequantification of cerebral venous return as a result of theinherent variability and complexity of the cerebralvenous system. This has generated an increasing interestin the determination of an imaging gold standard for thedetection of extracranial venous anomalies.Echo-color Doppler sonographic evaluation of IJVs

requires careful interpretation and is operator-depend-ent; therefore, to improve the reproducibility of echo-color Doppler sonographic evaluation, a consensusconference defined five criteria for the diagnosis ofCCSVI (12). However, this created great variability ofprevalence of CCSVI in patients with MS, ranging from3% to 100% (2,4–8,12,22,23), and the European Societyof Neurosonology and Cerebral Hemodynamicsexpressed considerable concerns regarding the accuracyof these proposed criteria for CCSVI in MS (8).MR imaging may be useful in the observation of

potential CCSVI risk factors (11), but the data regardingthis are conflicting, and MR of the venous system haslimited value in the assessment of IJV anomalies fordiagnostic and post-PTA purposes (5,11,24). Moreover,MR is less sensitive than echo-color Doppler in thedefinition of intraluminal structural and functionalvenous abnormalities in patients with MS (12).Although it is invasive and cannot be used as a screening

tool, catheter venography is considered the gold standardfor determining the anatomic site, type, and extent of lesionsproducing CCSVI (2). Membranes, valve malformations,and septa in IJVs are frequently encountered duringcatheter venography in patients with CCSVI (2–5,10).Catheter venography alone (19,25–28) or in combinationwith intravascular ultrasound (29) has been used to evaluatethe morphological alterations of IJVs in patients with MS.Currently, the role of catheter venography in the

assessment of the hemodynamic patterns of IJVsdetected on echo-color Doppler sonography in patientswith CCSVI is uncertain (2–4,10), and no validatedcatheter venography scores are available for the classi-fication of flow patterns of IJVs. Four years since itsdiscovery, the presence of CCSVI as a clinical entity isstill controversial: in other words, the challenges at thismoment are in defining (i) a definitive diagnostictechnique that is able to detect flow anomalies andvariants of IJVs in patients with CCSVI and (ii) thecriteria on which to base subsequent treatment decisions.The present study evaluated a standardized protocol

of catheter venography of IJVs in patients with MS byusing the clearance time of contrast medium to define thedegree of venous flow abnormality. The ROC analysisdemonstrated that a venous outflow through the IJVscould be considered normal if the clearance time of thecontrast medium was less than 4 seconds. Basing onthese findings, the present study found a high prevalence(79%) of venous flow abnormalities of both IJVs, asexpressed by a clearance time greater than 4 seconds, in

patients with MS, whereas only 5% of patients with MSshowed normal venous outflow. The presence of SDFwas unrelated to time since diagnosis of MS, suggestingthat hemodynamic abnormalities of IJVs are not influ-enced by the clinical progression of MS.The increased prevalence of extracranial venous flow

anomalies has encouraged the use of angioplasty to treatIJV stenosis with the aim of producing a clinical benefit.Overall, results have not been conclusive (25,30), but, inrecent studies, angioplasty was able to reduce the rate ofrelapse and improve the physical and mental quality of lifeof patients with MS (10,19,26–28). Angioplasty is a safeprocedure (14), but its efficacy in randomized, double-blindtrials in patients with MS has not been definitivelydemonstrated (31). This is partly related to the inabilityof catheter venography to serve as a gold standard for thedetection and monitoring of the extracranial anomaliesbecause there are no hemodynamic parameters that canpredict the success of that treatment.In the present study, angioplasty was able to immedi-

ately improve flow in one IJV in 69% of patients, butonly in 37% of patients did the venous angioplastysignificantly improve the venous flow in both IJVs.Again, in 32% of patients, SDF was persistent afterangioplasty, and the presence of SDF was predictive of aworse result after angioplasty.Most studies have reported early restenosis after balloon

angioplasty of IJVs, most likely caused by ineffectivetreatment, in as many as 45% of cases (19,25–28).Although the results of the present study are promising,we are conscious of its limitations. First, the mainchallenge of this study was to define what is “normal”by evaluating 12 patients with ESRD and 313 patientswith MS without any other venographic alterations. Thehemodynamic abnormalities of venous flow in patientswith MS were related to the time it took for contrast mediato empty from the vein, and this allowed for the strat-ification of the degree of venous outflow abnormality.Future studies with catheter venography in healthy indi-viduals over a wide range of ages are warranted, althoughthis may be not ethically feasible. Although the presentstudy was not randomized and included a relatively smallcohort, it analyzed a homogenous group of patients withsimilar characteristics, and all the procedures were per-formed by a single physician with a standardized, non–operator-dependent protocol, which reduced the confound-ing factors related to the methodology of the procedure.Finally, the endpoint of the study was to evaluate only theimmediate efficacy of angioplasty in the treatment of IJVstenosis; therefore, data about the rate of recurrence of IJVdelayed flow and data on the clinical course of patientswith MS after angioplasty were not included.In conclusion, by using a non–operator-dependent

catheter venography examination, the present study dem-onstrated a high prevalence of anomalous delayed flowthrough IJVs in patients with MS. In addition, when SDFwas present, the clinical course of MS in those patients did

Veroux et al ’ JVIR1796 ’ Catheter Venography of IJV Outflow in Multiple Sclerosis

not interfere with the severity of flow patterns. These datasuggest that the anomalous delayed flow of IJVs is anindependent factor. The present study showed that venousangioplasty is immediately effective in patients with mod-erate alterations of venous flow, but, in patients with SDF,the efficacy of PTA was clearly evident in only a minorityof patients. Ongoing clinical and experimental studiesshould address the development of new and dedicateddevices with the aim of treating all different types of venousanomalies and preventing early recurrences of CCSVI.

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