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Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study

Anthony L Traboulsee, Katherine B Knox, Lindsay Machan, Yinshan  Zhao, Irene Yee, Alexander  Rauscher, Darren Klass, Peter Szkup,  Robert Otani, David Kopriva, Shanti  Lala, David K Li, Dessa Sadovnick

Lancet 2014; 383: 138–45

Published Online October 9, 2013http://dx.doi.org/10.1016/ S0140-6736(13)61747-X

Department of Medicine (A L Traboulsee MD, Y Zhao PhD, Prof D Sadovnick PhD), Department of Radiology (L Machan MD, A Rauscher PhD, D Klass MD, Prof D K Li MD), and Department of Medical Genetics (I Yee MSc, D Sadovnick), University of British Columbia, Vancouver, BC, Canada; Department of Physical Medicine and Rehabilitation (K B Knox MD) and Department of Medical Imaging (P Szkup MD, R Otani MD), College of Medicine, University of Saskatchewan, Saskatoon, Canada; and Department of Surgery, University of Saskatchewan, Regina, Saskatchewan, Canada (D Kopriva MD, S Lala MD)

Correspondence to: Dr Anthony L Traboulsee, University of British Columbia Hospital, University of British Columbia, 2211 Wesbrook Mall, Room s199, Vancouver, BC, V6T 2B5, Canada t.traboulsee@ubc.ca

Summary

Background Chronic  cerebrospinal venous insufficiency  has been proposed as a unique combination  of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. Initial reports indicated that all patients with multiple sclerosis had chronic cerebrospinal venous insufficiency. We aimed to establish the prevalence of venous narrowing in people with multiple sclerosis, unaffected full siblings, and unrelated healthy volunteers.

Methods We did an assessor-blinded, case-control, multicentre study of people with multiple  sclerosis, unaffected siblings, and unrelated healthy volunteers. We enrolled the study participants between January, 2011 and March, 2012, and they comprised  177 adults: 79 with multiple  sclerosis,  55 siblings, and 43 unrelated controls, from three centres in Canada. We assessed narrowing of the internal jugular and azygous veins with catheter venography and ultrasound criteria for chronic cerebrospinal venous insufficiency proposed by Zamboni and colleagues. Catheter venography data were available  for 149 participants and ultrasound data for 171 participants.

Findings Catheter venography criteria for chronic cerebrospinal venous insufficiency  were positive for one of 65 (2%) people with multiple  sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1·0 for all comparisons). Greater than 50% narrowing  of any major vein was present in 48 of 65 (74%) people with multi- ple  sclerosis,  31 of  47 (66%) siblings (p=0·41 for comparison with patients with multiple  sclerosis), and 26 of 37 (70%) unrelated controls  (p=0·82). The ultrasound criteria for chronic cerebrospinal venous insufficiency were fulfilled  in 35 of 79 (44%) participants  with multiple  sclerosis,  17 of 54 (31%) siblings (p=0·15 for comparison with patients with multiple  sclerosis) and 17 of 38 (45%) unrelated controls  (p=0·98). The sensitivity of the ultrasound criteria for detection of greater than 50% narrowing  on catheter venography was 0·406 (95% CI 0·311–0·508), and specificity was 0·643 (0·480–0·780).

Interpretation This study shows that chronic cerebrospinal venous insufficiency  occurs rarely in both patients with multiple  sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple  sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing  on catheter venography. The  significance  of venous narrowing  to multiple sclerosis symptomatology remains unknown.

Funding MS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.

Introduction

Multiple sclerosis is a leading cause of neurological disability and is estimated to affect more than 2 million people worldwide.  The cause of the disease remains uncertain and a vascular mechanism has long been suggested to have a possible role.  Zamboni and colleagues  reported that the presence of multiple stenosis of the extracranial venous drainage system—a disorder they called chronic cerebrospinal venous insufficiency— was significantly associated with multiple sclerosis. The venous blockages  were present in all 65 patients  with multiple sclerosis studied by ultrasound and on catheter venography. These combinations  of blockages were not seen in healthy control participants studied by ultrasound, nor in patients  with other diseases  who underwent catheter   venography.  Zamboni and colleagues  thus speculated that venous blockages have a central role in the pathogenesis of multiple  sclerosis, and that treatment with venoplasty would ameliorate the disease.

An unblinded,  uncontrolled  interventional  treatment trial by Zamboni and colleagues5 of venoplasty in patients with multiple sclerosis showed improvements in disability and quality of life. The procedure was hailed by media outlets as a  “medical  miracle”, and many patients with multiple  sclerosis advocated for treatment before independent  validation  studies had been completed. Thousands of venoplasties, venous stenting procedures, or both, were undertaken outside registered clinical trials, despite expressed safety concerns, contradictory results from imaging studies, and caution recommended by the Society  for Interventional Radiology, patient advocacy societies, the US Food and Drug Administration, and the UK National Institute for Health and Care Excellence.

The inability of independent  research groups to reproduce Zamboni  and colleagues’ findings  regarding the diagnosis of chronic cerebrospinal venous insufficiency in all patients with multiple sclerosis called into question the existence of the disorder and its role in multiple sclerosis  pathogenesis. However, until now, studies have been limited  to the imaging  techniques of ultra- sound and magnetic resonance venography without validation from catheter venography, which has the advantage of direct visualisation  of venous anatomy. Catheter venography is regarded as the gold standard for the assessment of venous stenosis because it details the venous  anatomy with high spatial and temporal resolution and allows imaging  of the azygous  vein. Collateral flow, stasis, and reflux patterns can be assessed in real time. Changes in cerebral venous drainage with posture are profound.20   In the supine position, venous flow occurs mainly through the jugular veins, whereas in the upright position the flow is redirected through the vertebral venous plexus and azygous vein. Changes in intrathoracic or intra-abdominal  pressure (eg, Valsalva manoeuvre)  also affect  drainage.  In this Article, we present a blinded study detailing venous anatomy with catheter venography in patients with multiple sclerosis, their unaffected siblings who are at an increased risk of developing the disease,  and age-matched  and sex- matched  unrelated  healthy  controls.  Genetic factors affect susceptibility  to multiple  sclerosis21   and clinical course.  The risk of multiple sclerosis can be assessed according to the degree of genetic sharing with an affected patient. The overall lifetime risk of multiple sclerosis  in  the white population  is two  in  1000, 35  in 1000 for a sibling of a person with multiple local newspapers. Inclusion criteria  for patients with multiple sclerosis were age 18–65 years, diagnosis  of definite multiple sclerosis (2010 McDonald criteria), and an expanded disability  status score29  between 0 and 6·5. We  excluded patients who had previously  undergone venous procedures or those using vasoactive drugs.

All assessing  study team members  were masked  to participant  status (patient  with multiple  sclerosis, un- affected sibling, or unrelated control). Participants were positioned  and draped (covered with a blanket,  leaving only the head and neck exposed) by the unmasked study coordinator, mobility aids were hidden, and participants were instructed  to not discuss their diagnosis with the study  team.  Blinding was  assessed  by  questionnaire, which asked the study team members whether or not they thought each participant had multiple  sclerosis. Clinical assessments included  expanded disability  status score29 and relapses within the previous 2 years.

The study protocol was approved by clinical  research ethics boards at the three participating Canadian centres (University of British Columbia Hospital,  Vancouver; University of Saskatchewan,  Saskatoon;  and Regina Qu’Appelle Health Region, Regina, Saskatchewan). All participants provided written informed consent.

Procedures

In view of the plastic  nature of veins with postural changes, we did catheter venography on a tilt table in the supine position, with the participants positioned 85° upright to assess venous anatomy in the best possible way. We  standardised  the protocol  across  the three centres, with three training sessions for the performance and interpretation  of venography.  We  introduced   a sheath into the right femoral vein in the supine position with use of local anaesthetic and ultrasound guidance. We advanced a 5 Fr hockey stick or H1 catheter over a guidewire under fluoroscopic  guidance into the right internal jugular vein at the level of the skull base, 5 cm below the mastoid, with the tip directed laterally. We tilted the table  upright and, after  three in-and-out respirations  to enhance  change  in positional cranial venous drainage, we recorded intravenous pressure. We did pump injections  at 2 cm³/s  to assess reflux  and 4 cm³/s  to assess  anatomy  during quiet apnoea and normal exhalation. We returned the table to the supine position and, after three in-and-out respirations, repeated the same procedures with the catheter in the upper and lower jugular vein. We repeated all procedures in the left internal jugular vein and the azygous vein. We recorded the upper,  lower,  and withdrawal  pressures  for the azygous vein relative to the superior vena cava. We defined internal jugular vein stenosis as a narrowing of more than 50%  (valvular or non-valvular  vessel segment) in comparison ith a normal reference segment (widest vessel segment below the mandible) in the supine position. We used the supine position for this assessment because both internal jugular veins usually collapse in the upright position, with blood  redirected to the azygous vein and vertebral  veins.  We  defined  azygous vein stenosis  as more  than 50% narrowing  relative  to the largest normal segment in either the upright or supine position. We judged a haemodynamically  significant narrowing  to be present if at least one of the following was recorded: reflux (persistent retrograde flow of most of the contrast bolus after injection was completed); stasis (contrast was present after the injection);  or abnormal collaterals  (one or more  vessels >50% the size of the adjacent primary vessel, or two or more collateral vessels present at <50% the size of the adjacent primary vessel). We assessed the four patterns  of venous  obstruction described by Zamboni and colleagues, including  stenosis of the proximal azygous vein and complete occlusion of one internal jugular vein (type  A);  stenosis of both internal jugular veins and the proximal  azygous vein (type B); bilateral  stenosis of internal jugular veins only (type C); and azygous vein stenosis (type D).

Venous doppler ultrasound equipment was identical to that used in Zamboni and colleagues’  study4   (MyLab Vinco, Esaote,  Genoa,  Italy [Health Canada,  Health Products  and Food Branch medical   device  #79702]). Experienced ultrasonographers were trained by Zamboni in Ferrara, Italy. We used a 7 MHz transducer capable of grey scale (for  venous  stenosis  and loss of postural control of venous outflow) and duplex (for reflux) to study the internal jugular vein from the skull base to as far centrally as was visible.

Table 1: Baseline demographics and clinical characteristics

Participants with multiple sclerosis Healthy controls (n=98)

                                                                          

Sex

Female                                       67 (85%)                  71 (72%)

Male                                       12 (15%)                    27 (28%)

Study site

British Columbia                        42 (53%)                   63 (64%)

Saskatchewan                             37 (47%)                   35 (36%)

Age, years

Mean (SD)                                     47·8 (10·1)               48·7 (10·7)

Median (range)                            48·0 (22·0–68·0)     49·0 (27·0–72·0)

Expanded disability status score

Mean (SD)                                       2·7 (1·6)                NA

Median (range)                              2·0 (0–6·5)            NA

Multiple sclerosis duration, years

Mean (SD)                                    16·1 (9·3)                NA

Median (range)                            13·0 (2·0–41·0)       NA

Disease course, n

Relapsing–remitting                    67 (85%)                 NA

Secondary progressive                   8 (10%)                 NA

Primary progressive                       4 (5%)                    NA

Data are n (%), unless otherwise indicated. NA=not applicable.

 …cont’d from above

We measured the internal jugular vein cross-sectional area in both the supine and upright positions during a short period of apnoea after a normal exhalation. A cross-sectional area smaller than 0·3 cm² was judged to be a positive result. Loss of postural control of cerebral venous outflow was established by subtraction of the cross-sectional area of the internal jugular vein in the upright position from that in the supine position measured during a short period of apnoea after a normal exhalation. Normal response is an increased diameter of the internal jugular vein in the supine position compared with the upright position. Normal direction of flow is towards the chest in both positions  recorded during  a short period of apnoea  after  exhalation.  Reflux was present when a cranially directed flow of 0·88 s or longer was identified. We recorded the direction of flow in the internal cerebral vein, basal vein of Rosenthal, and great vein of Galen in quiet respiration in both positions with a 2 MHz transcranial Doppler transducer. Reversal of flow for longer than 0·5 s was viewed as abnormal. At least two  positive  ultrasound  criteria were  diagnostic  for chronic cerebrospinal venous insufficiency.4

Data forms were reviewed and double entered into an electronic database at the University of British Columbia Coordinating  Centre.  Missing data  fields or logical queries corrections occurred before final database lock (on Oct 29, 2012) and statistical analyses. In the analyses, Sonographers correctly identified multiple sclerosis status in 37 of these 82 cases (45%) and responded with “no idea” in 16 (20%).  Blinding  was assessed after catheter venography in 78 of 149 (52%) cases. Radiologists selected “no idea” regarding multiple sclerosis status in all cases.

With Zamboni and colleagues’ catheter venography classification  of chronic cerebrospinal venous  insufficiency,4 we identified one of 65 (2%) patients  with multiple sclerosis, one of 46 (2%) unaffected siblings, and one of 32 (3%) unrelated  controls  who met the criteria  (table 2). 48 of 65 (74%) people  with multiple sclerosis,  31 of 47 (66%) siblings, and 26 of 37 (70%) unrelated controls met the criterion of more than 50% narrowing on venography in any major extracranial vein. When evidence of physiological flow alterations was added to narrowing, 33 of 65 (51%) people with multiple sclerosis, 21 of 47 (45%) siblings, and  20 of 37 (54%) unrelated controls met the criteria. On the basis of the multivariate logistic regression, the odds of participants

Participants with multiple sclerosis

48/65 (74%)          20/27 (74%)           28/38 (74%)           1·06 (0·35–3·19)  0·92

Participants without multiple sclerosis

53/78 (68%)         21/29 (72%)           32/49 (65%)          1·50 (0·50–4·46) 0·66

meeting the criterion of more than 50% narrowing were higher at University  of British Columbia Hospital than in Saskatchewan (OR 2·78, 95% CI 1·35–5·88, p=0·006). We recorded the same trend in patients with multiple laboratories, four exclusionary medications, two cases of orthostatic hypotension, one previous vascular procedure, one claustrophobia, one history of head injury, and one contrast allergy) and 17 people  withdrew  before  either procedure  was done. Of the 177 participants included, 171 had ultrasound, 149 catheter venography, and 143 both procedures. The reason for missing an ultrasound (six healthy controls) was travel distance (inability to schedule tests on the same day). Reasons for incomplete  catheter venography  studies  (n=12) were the inability  to tolerate the full protocol because of vasovagal symptoms or dis- comfort;  one patient had an asymptomatic  venous dissection.  Reasons  for missing catheter  venography studies  (n=16) included change in blood work (liver or renal function) and participant choice.

79 patients with multiple  sclerosis, 55 unaffected siblings,  and 43 unrelated healthy controls participated in the study, with a similar mean age and proportion of women in each  group  (table  1). The participants included 12 twin pairs (three monozygotic  and nine dizygotic), one pair from a triplet, and 30 additional  sibling  pairs. Of these pairs, 19 were HLA identical. Two full sets of triplets also took part, one of which was HLA identical.  30 patients with multiple sclerosis without a sibling participated.

67  (85%)  of the patients  with multiple sclerosis  had relapsing–remitting  disease. The median expanded disability  status score was 2·0 (range 0–6·5) and median disease duration was 13·0 years (2·0–41·0 years). Blinding was assessed after ultrasound in  82 of 171 cases. We  recorded  similar results with use of the catheter venography criteria of greater than 50% stenosis with evidence of flow abnormalities with sensitivity 0·400 (95% CI 0·287–0·524), specificity  0·616 (0·495–0·726), positive predictive   value 0·500 (0·373–0·627),   and negative predictive value 0·517 (0·408–0·625). When we considered sibling  pairs only, we noted no significant difference in rates of participants who met ultrasound  criteria (40 pairs) for chronic cerebrospinal venous insufficiency  or any of the catheter criteria for narrowing (27 pairs; data not shown).

Discussion

We present the first study to use catheter venography systematically in patients with multiple sclerosis, their unaffected siblings,  and unrelated healthy volunteers, with careful  attention  to  standardisation  of imaging protocols and blinding (panel). The results provide no evidence that extracranial venous anatomy differs between patients with multiple sclerosis, their unaffected siblings (including monozygotic twin pairs), and unrelated  healthy controls. Catheter venography findings of chronic  cerebrospinal venous insufficiency as described by Zamboni and colleagues are therefore rare findings and do not distinguish  patients with multiple sclerosis from healthy controls. Almost 75% of the total study sample  had venous narrowing of more than 50% on catheter venography, with little difference recorded between patients with multiple sclerosis and controls.  This high rate  of narrowing in a healthy control group has not previously been reported. Moreover, with ultrasound, we did not find differences in the rates of  Zamboni-defined chronic cerebrospinal  venous  insufficiency (two or more positive criteria of five) or valvular abnormalities between healthy controls and participants with multiple sclerosis. A meta-analysis of published studies of ultrasound diagnosis of chronic cerebrospinal venous insufficiency suggests an association between  this disorder and multiple sclerosis  (OR 3·5, 95%  CI 0·8–15·8).  In our study, the agreement between ultrasound and catheter venography for the detection of venous narrowing  was very poor. Moreover, chronic cerebrospinal venous insufficiency  was rarely detected by catheter venography despite the higher prevalence of cases meeting criteria for chronic cerebrospinal venous insufficiency on ultrasound. Our results also challenge both the validity  of ultrasound  for the purpose  of detecting chronic cerebrospinal  venous insufficiency and its existence as a disorder. Few studies of chronic  cerebrospinal venous insufficiency in multiple  sclerosis have included  the gold standard method of catheter venography, despite the fact that this procedure has been proposed as a guide for decision making in endovascular treatment. Scalise and colleagues did a small study in patients with multiple sclerosis to  show the advantages  of  intravascular ultrasound. In a smaller study of ten patients with multi- ple sclerosis, Zivadinov and colleagues compared magnetic resonance venography techniques  with catheter venography. Both studies did not have  controls  or blinding, and they did not address the original descriptions of chronic cerebrospinal venous insufficiency.

Standardised testing protocols, blinding, and the inclusion of controls are essential for the scientific exploration of the theory of chronic cerebrospinal venous insufficiency. The highly dynamic and variable nature of venous anatomy in particular calls for a rigorous study design. The interobserver variability noted between our participating sites shows how crucial blinding is for studies of venous anatomy in which technical variability can occur. The subjective interpretation by unmasked observers of venography data could lead to biased results. Although we noted differences in the prevalence of narrowing between sites, these differences were recorded equally across all study groups, which supports the maintenance of blinding. The hypothesis that venous narrowings have a role in the cause of multiple sclerosis is unlikely, since the prevalence of venous narrowings is similar in people with the disease, unaffected siblings, and unrelated healthy controls on catheter venography. Narrowing of more than 50% was recorded in almost 75% of the study population (cases and controls) on catheter venography, which supports the contention that venous narrowing is a common anatomical variant. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown.

Interpretation

Our results confirm that venous narrowing is a frequent finding in the general population and is not a unique anatomical feature associated with multiple sclerosis. We show that the proposed disorder of chronic cerebrospinal venous insufficiency defined by ultrasound criteria is an insensitive screening test for venous narrowing present on catheter venography. Our results call into question the basis for the term chronic cerebrospinal venous insufficiency and its putative role in the pathogenesis of multiple sclerosis.

Panel: Research in context

Systematic review

We searched PubMed with combinations of the keywords “ccsvi”, “multiple sclerosis”, healthy controls”, “validation”, “ultrasound”, and/or “catheter venography”, and identified four original research articles that included results of both ultrasound or magnetic resonance venography and catheter venography. None of these reports were blinded studies that compared catheter venography results in patients with multiple sclerosis versus healthy controls. Three articles showed poor agreement with ultrasound and catheter venography, and a fourth reported poor agreement with magnetic resonance venography and catheter venography. None of the studies included a control group undergoing catheter venography.

Contributors

ALT was the principal  investigator of the study, and KBK (Saskatoon) and Fog T. On the vessel–plaque relations in brain in multiple sclerosis. Acta Neurol Scand 1963; 39: 258–62. DKo (Regina) were the site-specific principal investigators. ALT wrote the first draft. All authors reviewed the report, and LM, KBK, DKL, DS, YZ, and IY provided input toward the final version, which was prepared by ALT. ALT, LM, KBK, DKL, DS, YZ, IY, and PS designed the study. LM, SL, PS, RO, and DKL developed the procedures. RO refined the study hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated?

Med Hypotheses 1998; 51: 299–303.

Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal

protocol. DS was responsible for participant selection. DKo undertookvenous insufficiency in patients with multiple sclerosis.

safety monitoring and recruitment. ALT, LM, KBK, DKL, DS, SL, PS,

RO, and DKo reviewed and analysed the data. YZ and IY did statistical J Neurol Neurosurg Psychiatry 2009; 80: 392–99.

Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label analysis, and ALT, LM, KBK, and DS did the literature searches. Study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009; 50: 1348–58.

Conflicts of interest W5’s ground-breaking investigation of CCSVI. http://www.ctvnews.

 

 

 

 

 

 

 

Written by Doug Broeska

Doug Broeska is a PhD Medical Researcher and CEO of Regenetek Inc, a Canadian Biotech Research firm working with several hospitals and clinics world-wide to develop medical procedural protocols for neurodegenerative disease management.