Perspectives in Medicine (2012) 1, 371—374

Bartels E, Bartels S, Poppert H (Editors):New Trends in Neurosonology and Cerebral Hemodynamics — an Update.

Perspectives in Medicine (2012) 1, 371—374

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / p e r m e d

Fact or fiction: Chronic cerebro-spinal insufficiency

Claudio Baracchini ∗, Paolo Gallo

Department of Neurological Sciences, University of Padua, Via Giustiniani 5, 35128 Padova, Italy

KEYWORDSCCSVI;Ultrasound;Multiple sclerosis

Summary Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative diseaseof the central nervous system (CNS). Its autoimmune origin has been recently challenged by asubstantially different mechanism termed chronic cerebrospinal venous insufficiency (CCSVI),which has attracted worldwide attention in the scientific community, in the media and amongMS patients. According to this hypothesis, a congestion of cerebrovenous outflow induces anincreased intracranial pressure and a disintegration of the blood—brain barrier in perivenularregions promoting local iron deposition and activation of pro-inflammatory factors, ultimatelyleading to MS. After the initial report of a perfect association between CCSVI and MS, differentindependent groups were not able to replicate these results, casting doubts on the credibilityof the CCSVI concept in MS. In spite of this, interventional procedures like venous angioplastynamed the ‘‘liberation’’ treatment have been claimed as a cure of MS or at least as a major

improvement of MS symptoms. As a result, an increasing number of MS patients are undergoingendovascular treatment, in spite of a lack of an evidenced-based benefit and recent reportsof serious adverse events. This review represents a critical appraisal of the CCSVI hypothesis,discusses its basis, the diagnostic criteria and its relationship with MS.© 2012 Elsevier GmbH.

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Open access under CC BY-NC-ND license.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory, neurode-generative disease of the central nervous system (CNS).Its autoimmune origin is supported by immunological,genetic, histopathological, and therapeutic observations,even though the mechanisms that initiate this autoimmuneattack are still unknown [1—4]. A disorder of cerebrospinalblood flow named ‘‘chronic cerebrospinal venous insuffi-

ciency’’ (CCSVI) has been proposed by Zamboni to play apossible etio-pathogenetic role in multiple sclerosis [5,6].This ‘‘big idea’’, a term used by Zamboni himself to define

∗ Corresponding author. Tel.: +39 049 8213600;fax: +39 049 8751770.

E-mail addresses: claudiobaracchini@tin.it (C. Baracchini),paolo.gallo@unipd.it (P. Gallo).

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2211-968X © 2012 Elsevier GmbH.doi:10.1016/j.permed.2012.01.005

Open access under CC BY-NC-ND license.

is theory, rises from observations on systemic venous dis-ases and the possible parallels between these and brainnflammation [5]. Zamboni’s working hypothesis is thatrain inflammation is iron-dependent [7]: he postulatedhat multiple extracranial venous anomalies of the internalugular and/or azygos veins [8] cause a venous reflux intohe cerebrospinal compartment, determining an increasedntra-venous pressure that disaggregates the blood—brainarrier, thus causing the deposition of iron in brain tis-ue and evoking a local inflammatory response. By applyingve parameters of abnormal venous outflow, indicative ofCSVI, Zamboni and co-workers were able to demonstratestrong relationship between CCSVI and MS. Indeed, in

heir pivotal study, they analyzed 109 patients with clin-

cally definite MS and 177 control subjects by means ofranscranial and extracranial color Doppler sonography andound that all patients with MS had abnormal venous param-ters: the presence of at least 2 of those 5 parameters was

372

Table 1 Ultrasound CCSVI criteria.

1. Reflux (t > 0.88 s) in the IJVs and/or in the VVs in sittingand supine position

2. Reflux (t > 0.5 s) in the DCVs3. High-resolution B-mode evidence of proximal IJV

stenoses (local reduction of CSA ≥ 50% in the recumbentposition or CSA ≤ 0.3 cm2)

4. Flow not Doppler-detectable in the IJVs and/or VVsdespite numerous deep inspirations with the head at 0◦

and +90◦

5. Reverted postural control of the main cerebral venousoutflow pathways: negative �CSA in the IJV

CSA, cross-sectional area of the internal jugular vein; IJV, inter-

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nal jugular vein; VV, vertebral vein; DCVs, deep cerebral veins;�CSA = CSAsitting − CSAsupine.

bserved as being diagnostic of MS with 100% specificity,00% sensitivity, and positive and negative predictive valuesor MS of 100%. Zamboni and co-workers went on to performnblinded selective venography in 65 patients with MS asell as in some control subjects, and reported that patientsith MS had multiple severe extracranial stenoses, while

hese abnormalities were never found in normal controls9]. Furthermore, in a retrospective study, the same authorsound that the distribution of the pathological hemodynamicatterns was highly predictive of the symptoms at onset andf the following clinical course [10]. In this review, we tryo analyze critically the various aspects of Zamboni’s theorynd address several questions not only on the relationshipetween CCSVI and MS, but also on the scientific basis ofCSVI and thus, on its real existence.

he ultrasound puzzle

he diagnosis of CCSVI is based on five ultrasonographic cri-eria (Table 1), four extracranial and one intracranial [11].ccording to Zamboni’s initial findings the presence of at

east two of these criteria provides indirect evidence ofmpaired cerebral venous drainage and should be consistentith the diagnosis of MS. Several independent investiga-

ors have tried to reproduce — with various methodologicalpproaches — the striking results obtained by Zamboni, butone have succeeded [12—19]. In particular, we performedwo large studies. In the first study, we aimed at analyz-ng the occurrence of CCSVI at MS onset, to elucidate theossible causative role of CCSVI in MS as suggested by Zam-oni, who surprisingly did not study these patients. Fiftyatients presenting a clinically isolated syndrome (CIS) andaving evidence of dissemination in space of the inflamma-ory lesions underwent a comprehensive diagnostic workup,ncluding extracranial and transcranial venous echo-coloroppler sonography. Patients who showed evidence of CCSVIere further evaluated by selective venography. Fifty MS-atched normal controls (NC), 60 patients with transient

lobal amnesia (TGA), and 60 TGA-matched NC were stud-

ed. Transcranial venous echo-color Doppler was normal inll patients with CIS. One or more abnormal extracranialenous echo-color Doppler findings were observed in 26 of0 (52.0%) of the patients with CIS, 35 of 110 (31.8%)

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C. Baracchini, P. Gallo

f the controls and 41 of 60 (68.3%) of the patients with TGA.he eight (16%) patients with CIS who fulfilled the diagnosisf CCSVI were further evaluated blindly by selective venog-aphy, which did not disclose any venous anomalies. Thus,e could not demonstrate any causative effect of CCSVI onS [14]. The second study was focused on the progressive

orms of MS, to investigate whether CCSVI could play a rolen determining disease progression. We analyzed 60 patientsith chronic progressive forms of MS (35 SP, 25 PP) and 60ge-/gender-matched NC. TCDS was normal in all patients.CDS showed one or more abnormal findings in 9/60 (15.0%)atients [7/35 (20.0%) SPMS, 2/25 (8.0%) PPMS] and in 14/6023.3%) NC (p not significant for all comparisons). CCSVIriteria were fulfilled in 0 NC and 4 (6.7%) MS patients: 3PMS and 1 PPMS. VGF, performed blindly in 6/9 patients,as abnormal only in one case that had bilateral internal

ugular vein (IJV) stenosis [17]. These findings indicate thatCSVI is not a late secondary phenomenon of MS and is notesponsible for disability progression.

he ultrasound method

n the basis of these contradictory results, it is absolutelyecessary to question the validity of the five ultrasound cri-eria proposed by Zamboni for the diagnosis of CCSVI. In therst criterion, Zamboni et al. used the threshold value of.88 s to discriminate IJV and vertebral vein (VV) physiolog-cal back flow due to valve closure from pathological refluxithout performing the Valsalva maneuver (VM) [8] and they

ound that 71% of MS patients had a pathological reflux vs. 0%f controls. This threshold value comes from a totally dif-erent study on IJV valve insufficiency during a controlledM [20] where it was chosen to differentiate VM-induced

nsufficiency through insufficient valves lasting >1.23 s, fromhysiological backward flows during normal valve closure,asting 0.22—0.78 s. In this study it was found that about0% of normal subjects have a physiological (t < 0.88 s) backow during normal valve closure. Furthermore, the utiliza-ion of this threshold by Zamboni for assessing reflux in otheressels (i.e. VVs) other than IJV valve insufficiency is alsocientifically incorrect.

For the second criterion, the intracranial veins andinuses were not examined through the transtemporal boneindow for which there are published ultrasound crite-

ia and velocity data [21,22]. Zamboni et al. used aew bone window (supracondylar) for which there areeither accepted published criteria nor normative data,nd the figures published are not compatible with normalnatomy [8,11]. With regard to venous reflux, this eval-ation requires a Doppler spectrum analysis, because aolor-based approach is inadequate and can easily lead tohe misinterpretation of flow direction. More importantly,he rationale of adopting a threshold value of 0.5 s to dis-riminate pathological reflux in the deep cerebral veins isnclear. This value was derived from studies in the veinsf the leg where it served to quantify venous valve insuf-ciency following deflation of a tourniquet [23,24]. The

ationale for transferring this value from the legs to the brains very questionable since it has never been validated foreep cerebral veins. The validity and significance of dataollected by this method are therefore unclear especially

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[3] Lassmann H, Bruck W, Lucchinetti CF. The immunopathology ofmultiple sclerosis: an overview. Brain Pathol 2007;17:210—8.

CCSVI: fact or fiction?

if it is used to diagnose CCSVI, where cerebral reflux isnot described by the same author as associated with valveincompetence.

The third criterion defines a stenosis of the IJV as a localreduction of the cross sectional area (CSA) ≥50% in therecumbent position or CSA ≤ 0.3 cm2 [8]. This latter cut-offvalue was derived from a study on intensive care patients[25], with possible confounders such as mechanical venti-lation and hypovolemia. It can, therefore, not be used asa reference point in healthy subjects. Furthermore, it isdifficult to decide where to measure the diameter of thevein since IJVs are normally tortuous and the most proxi-mal and distal parts near the superior and inferior bulb arephysiologically dilated more than others. It is important tostress that even mild pressure exerted by the ultrasoundprobe or by a contraction of the cervical musculature itselfcan alter the diameter of the vein leading to false-positiveresults.

The fourth criterion, which is the inability to detect flowin the IJVs and/or in the VVs during deep inspiration, accord-ing to Zamboni et al., provides indirect evidence of venousobstruction [8]. This criterion has never been validated. Alack of flow is not necessarily due to obstruction since it canoccur, e.g. at 15◦ in both IJVs in healthy subjects [22]. Inthe upright position, there is a dramatic reduction and fre-quently a complete cessation of blood flow in the IJV. In thesupine position there may also be no flow in the VVs [26].Furthermore, an inadequate setting of ultrasound indicessuch as pulse repetition frequency might lead to an appar-ent absence of color-coded signal and a misinterpretationof no-flow.

The fifth criterion examines the presence of a physio-logical shift of cerebral venous drainage from the jugularvenous system to the vertebral plexus with postural change:from the supine to the sitting position. In normal subjects,subtracting the CSA measured in the supine position fromthat in a sitting position (�CSA) is usually negative [22].Instead, Zamboni wrongly considered that a negative �CSAvalue would represent a reverted postural control of themain cerebral venous outflow pathways [8]. Furthermore,similarly to criterion three, a mild pressure exerted by theultrasound probe or by a contraction of the cervical mus-cles may alter the diameter of the vein possibly leading tofalse-positive results. A more correct method would be tocalculate the difference of blood flow (CSA × velocity) in thetwo positions (supine and sitting) as has been recently per-formed [12], not confirming the hypothesis of Zamboni andco-workers.

A very important issue is the cut-off point of these cri-teria to diagnose CCSVI. In fact, it is unclear how Zambonidecided that two or more of the five ultrasound criteria maybe used to diagnose CCSVI. Diagnostic criteria using a newalternative method (i.e. ultrasound) are usually comparedwith a validated gold-standard investigation (venographyaccording to Zamboni et al.). However, Zamboni et al.’scomparison of venography in 65 CCSVI ultrasound-positiveMS patients was not blinded and is therefore open tobias. There was also no validation of the CCSVI-criteria bydifferent and independent observers. Finally, subsequentstudies using MR-venography could not confirm differences

regarding cerebrospinal drainage in MS patients and controls[27—30].

373

onclusions

ltrasound investigation of intracranial and cervical veins isighly operator dependent owing to the wide anatomic andhysiological variability of these vessels. Therefore a studyf cerebral venous drainage requires very experienced neu-osonographers, but most importantly, blinding algorithmsre mandatory in assessing MS patients especially duringenographic verification of ultrasound findings; these wereompletely omitted in Zamboni’s studies. To this day, acientifically sound validation of each of the five criteriaroposed by Zamboni for the diagnosis of CCSVI is missing,ot to mention their combined application. Concurrently,here is growing evidence which rejects the role of CCSVIn the pathogenesis of MS and which suggests that the pro-osed CCSVI criteria are questionable due to miscitation,anipulation of known data and methodological flaws. Thus,

ny potentially harmful interventional treatment such asransluminal angioplasty and/or stenting should be stronglyiscouraged, not only for the lack of any evidence, but alsoor the risk of serious peri-procedural complications.

uthor contributions

laudio Baracchini: Conception, organisation and execu-ion of the research project; writing and review of theanuscript.Paolo Gallo: Conception, organisation and execution of

he research project; writing and review of the manuscript.

isclosures

r. Baracchini serves on the executive committee of theuropean Society of Neurosonology and Cerebral Hemo-ynamics; has received funding for travel and speakeronoraria from Pfizer, Sanofi-Aventis, Laboratori Guidottind Novartis; serves as Associate Editor for BMC Neurology;nd has given expert testimony in a medico-legal case.

Dr. Gallo serves on scientific advisory boards, as a con-ultant, and on speakers’ bureaus for and has receivedunding for travel and speaker honoraria from Novartis, Bio-en Idec/Elan Corporation, Merck Serono, Sanofi-Aventis,nd Bayer Schering Pharma; and receives research sup-ort from Novartis, Biogen Idec/Elan Corporation, Merckerono, Sanofi-Aventis, and Bayer Schering Pharma, theeneto Region of Italy, the University of Padova, and theinistry of Public Health of Italy.

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