ISNVD Abstract Book

The 2 nd Annual ISNVD Scientific Meeting 

Orlando, Florida USA 

18-22 February 2012 

ABSTRACTS, POSTERS, 

CONSENSUS NOTES 

Conference Chair 

Robert Zivadinov, MD, PhD 

President of ISNVD 

Professor of Neurology, University of Buffalo 

Annual Meeting and Workshop Committee Chairmen 

E. Mark Haacke, PhD and Michael D. Dake, MD

CCSVI IN MS: 

WHY ALL THE CONFUSION? 

CCSVI AND MS: 

(UN-)CONNECTED ENTITIES? 

CCSVI and CDMS: What relates venous to 

neurological anomalies? 

Individual CCSVI findings and 

cerebrospinal MS pathology: Not 

necessarily related? 

Concrete MRI & post mortem evidence in 

MS: The key to understanding CCSVI? 

CCSVI-FINDINGS: INDICATORS OF STASIS 

OR VENOUS REFLUX? 

Stages of stasis: Plethora; edema; 

hemorrhagic infarction 

In MS and CCSVI, both potential stasis and 

reflux appear still staged according to times 

of nervous incapacitations 

Are the neurologist’s criteria for staging MS 

adequate for staging venous stasis in, and 

venous reflux into, brain and spine in CCSVI? 

VENOUS PATHOLOGY IN MS OF THE BRAIN 

Unique at post mortem: Steiner’s 

Wetterwinkel with its Dawson’s fingers; 

Steiner’s splashes and semilunar subcortical 

lesions; Lumsden’s cortical kissing plaques 

Unique in the living: Steiner’s Wetterwinkel 

with its gradually advancing Dawson’s 

fingers; fluctuations in both presence 

and size of central as well as juxtacortical 

lesions. 

Are there plausible ideas or hints for relating 

these findings, via venous stasis or reflux, to 

CCSVI? 

FLANK FIBROSIS IN MS OF THE SPINAL 

CORD 

Post mortem studies for MS typically 

traced fibrous wedges invading the spinal 

cord’s sides 

No MR study seems ever to have focused 

on this point. 

Lateral spinal cord lesions result in front-tobackwards 

or longitudinal displacement of 

the spinal cord. 

Can spinal MS findings be accounted for, 

through either venous stasis or reflux, relative 

to CCSVI? 

HOW TO PUT CCSVI AND CEREBRAL OR 

SPINAL MS FINDINGS IN CONTEXT? 

This might be done by identifying 

in MS of the brain, the 

compartmentalization of venous reflux via 

or from internal jugular and deep cervical 

veins to cerebral lesion veins 

in MS of the spinal cord, the 

compartmentalization of venous reflux 

and resulting subdural displacements 

from engorged prevertebral veins in the 

direction of the specifically damaged parts 

of the spinal cord.

PRINCIPLE CONSIDERATIONS ON 

VENOUS STASIS AND VENOUS 

REFLUX 

COMPARTMENTALIZATION IN VENOUS 

STASIS 

In a vascular compartment affected by 

venous obstruction, pressure rises to that 

level at which (also adaptive enhancement 

in local) arterial inflow is balanced out by 

compensatory rises in collateral venous 

outflow. 

Any rise in pressure in an obstructed venous 

drainage domain depends on limitations 

to collateral venous drainage from the 

affected vascular domain. Owing to the 

rigid channeling of cerebral venous passages 

by dura mater and cranial bones, it is in 

the cranial cavity that critical degrees of 

compartmentalization of venous excess 

pressures to particular cerebral venous 

territories preferably occur. 

COMPARTMENTALIZATION OF VENOUS 

REFLUX 

Tending to arise during even short-lived 

vein compression, reflux works through 

intermittent, at times turbulent, back and 

forth flow. It washes out its passages, strains 

corpuscular vein content and - dependent on 

channeling, speed and massivity - eventually 

affects the venous periphery. 

Peripheral impacts will be harder and tighter, 

the more the veins involved in venous reflux 

are engorged. Crucial importance is thereby 

attained not by the duration or even the 

volume, but by the peak value in the speed of 

venous reflux. 

A vascular compartment affected by venous 

reflux accordingly has its source domain, 

connecting domain and target domain, each 

marked by different venous flow behaviors. 

Apart from transcranial doppler observations 

of exspiratory venous reflux, the findings 

of CCSVI tell little about flow behavior in 

a cerebral or spinal venous reflux‘ source, 

connecting domain or target domain. Eventual 

damaging of cerebral or spinal venous 

structures can be identified either at post 

mortem or, in vivo, on MRI. 

Cerebral angiography, 3D CCT and MRV 

present development potential for mapping out 

pathways of venous reflux. The structure of, and 

short-term flow behavior in, a venous reflux’ 

source and connecting domain can be traced 

in some detail by IVUS, MR flow mapping and 

conventional phlebography. 

SOURCE DOMAIN: THE WAYS IN WHICH 

VENOUS REFLUX EMERGES 

Without at least some transient block in 

normal flow direction, abrupt vein compression 

displaces blood chiefly towards the heart. 

Peripheral vein pressure is hardly ever 

substantially raised. The more pronounced 

a venous stenosis, the more it is apt to boost 

peripheral reflux. 

Any segment of a main venous pathway 

related to brain and spinal canal, by its 

being obstructed heartwards and then 

compressed headwards, may become a 

source of venous reflux. With incompetent 

IJV valves, intracranial reflux may start in a 

brachiocephalic and superior cava vein, right 

atrium, in an incompetent tricuspid valve in the 

heart, or else as far down as the inferior cava 

vein. 

Higher up, any kind of IJV or deep cervical vein 

obstruction is liable to turn such a vein into a 

source of brainwards directed reflux. 

Reflux into the spinal canal tends to emerge, 

especially in the abdomen, during compression 

of engorged prevertebral collecting veins. 

For such a reflux to gain critical momentum,

there must be a lowered resistance against 

abrupt widening of epidural target veins 

and a corresponding emptying of separate 

cerebrospinal veins. 

CONNECTING DOMAIN: SHORT, WIDE, 

SEPARATE 

Abrupt overburdening of a cerebral or 

spinal target domain will changeably be 

counteracted by arterial pulsations or 

venous reflux simultaneously invading the 

craniovertebral space. 

The wider the pathway of venous reflux, the 

stronger and more widespread its peripheral 

impacts can become. 

The most essential property of the 

connecting domain of a venous reflux is the 

noticeable absence of local excess pressure 

diversion, or its dispersion through venous 

collaterals: Here, inside the skull, structure 

and interconnections of the dural sinuses 

approaching the so-called confluence of 

sinuses gain primary importance; inside 

the spinal canal, ease and speed of flow 

distribution within the meshes of epidural 

veins are decisive. 

Gradual washing out of the channels of 

venous reflux as well as of the secondary fluid 

shifts in and out of the craniovertebral space 

promotes a long term enhancement of venous 

reflux activity. 

Thereby white matter is in several respects 

more at risk than grey matter. 

In this context, the ways in which MS affects 

the brain are particularly revealing. Peaked or 

rounded lesion waves surge up along Steiner’s 

Wetterwinkel; Dawson’s fingers emerge from 

subependymal veins, then radiate out along 

particular affluent veins; farther out lengthy 

ovoid Steiner’s splashes embed venous turns 

and branching points; eventually lesions are 

prevented from invading central and cortical 

grey matter, and so expand in between 

two cerebral convolutions or form a “ 

crescent“ around their trough. 

Reflux into the spinal canal dissipates its 

energy by locally engorging epidural veins, 

causing headward displacement of easily 

shifted content of the dural sac. Spinal cord 

and nerve roots are burdened by local venous 

expansions and extensive subdural volume 

shifts. 

The specific literature reveals many striking 

resemblances between what is seen in post 

mortem studies of spinal MS and what results 

from different forms of mechanical impacts 

displacing the spinal cord in relation to its 

sheaths. 

TARGET DOMAINS: THERE IS A DIRECT 

AND CAN ALSO BE SOME REMOTE ONES 

In keeping with its speed, massiveness 

and duration, venous reflux may balloon 

or otherwise deform its target vessels, 

depending on local deceleration of rejected 

blood and fluctuations in perivascular 

perfusion and CSF pressure. This endangers 

primarily the most vulnerable structures in 

the burdened venous channels’ surroundings.

CHARCOT‘S FIRST POST MORTEM DRAFTS ON MS: BURIED SINCE JUNE 1866 

Franz Schelling, M.D. 

Fingstr. 32 

6974 Gaißau 

+43 5578 71543 

www.ms-info.net 

The book “Multiple Sclerosis: The Image and 

its Message” offers a 

Synopsis of the historic post mortem evidence 

on MS 

Critique of vague notions which have supplanted 

concrete findings made in MS 

Discussion of the role of veins in cerebral 

and of ligaments in spinal MS.

SATURDAY – FEBRUARY 18, 2012 1:10pm-1:30pm 

Consensus on US CCSVI screening criteria (Sandra Morovic, ITALY-CROATIA) 

CCSVI is a syndrome characterized by stenoses or obstructions of the internal jugular vein (IJV) and/or azygos 

veins (AZV) with disturbed flow and formation of collaterals. Most common venous lesions are truncular 

vascular malformations. Catheter venography is a gold standard for assessment of lesions producing CCSVI, 

but it is invasive and cannot be used as a screening method. Ultrasound is an ideal, non-invasive, bedside, realtime 

screening tool with high sensitivity and specificity. It is a valuable diagnostic test, in presence of which, 

catheter venography will only be needed when a decision has already been made for intervention. 

Recommendations with a protocol, methodology, and criteria on CCSVI screening using ultrasound, have been 

proposed during a 2011 Consensus Conference, at the 1 st ISNVD Meeting. At least two criteria have to be 

positive to consider CCSVI: 1) Bidirectional flow in one or both IJVs in both positions, or bidirectional flow in 

one, with absence of flow in the other position and/or B) reversal or bidirectional flow in one or both vertebral 

veins (VVs) in both positions. 2) Bidirectional flow in intracranial veins and sinuses (additional criteria). 3) 

Reduction of IJV cross sectional area (CSA) in supine position to ≤0.3 cm 2 which does not increase with 

Valsalva manoeuvre, and/or B) Intraluminal defects combined with hemodynamic changes. Valve leaflet/s 

immobility confirmed by M-mode. 4) Absence of detectable flow in IJV and/or VV, in both positions, or B) In 

one posture, absence of detectable flow in IJV and/or VV, and bidirectional flow detected in the other position, 

same side. 5) CSA of IJV is greater in sitting than in lying position or B) Appears almost unchanged despite 

change in posture. 6) Performance of CCSVI screening protocol, on both sides and in both positions, ensures 

high scanning reproducibility with comparable accuracy between centers. 

No financial disclosures to report.


Does thoracic pump influence cerebral venous return? (Erica Menegatti, ITALY) 

The effect of the respiratory pump on cerebral venous return is absolutely well established in human 

physiology. Even though this concept is accepted by everybody, the exact quantification of the effects of the 

respiratory pump on venous hemodynamics are still unknown. We assessed the hemodynamic effects induced 

by the thoracic pump in the intra- and extracranial veins of the cerebral venous system on 44 healthy 

volunteers (21 males, and 23 females; mean age was 27.5 5.0 years). Activation of the thoracic pump was 

standardized among subjects by setting the deep inspiration at 70% of individual vital capacity. Peak velocity 

(PV), time average velocity (TAV), vein area (VA), and flow quantification (Q) were assessed by means of echo 

color Doppler in supine posture. Deep respiration significantly increases PV, TAV, and Q, but it is limited to the 

extracranial veins. To the contrary, no significant hemodynamic changes were recorded at the level of the 

intracranial venous network. Moreover, at rest TAV in the jugular veins was significantly correlated with Q of the 

intracranial veins. We conclude that the modulation of the atmospheric pressure operated by the thoracic 

pump significantly modifies the hemodynamics of the jugular veins and of the reservoir of the neck and facial 

veins, with no effect on the vein network of the intracranial compartment. 



A prospective study comparing ultrasound and angiography (Marian Simka, POLAND) 

This study was aimed at evaluation of diagnostic accuracy of currently used CCSVI sonographic criteria. We also 

tried to identify alternative sonographic parameters associated with impaired outflow in the internal jugular 

veins. Firstly, we compared extracranial Zamboni’s and ISNVD criteria with the results of reference test: catheter 

venography. We evaluated internal jugular and vertebral veins in 58 multiple sclerosis patients. Then, we 

assessed 41 different sonographic variables in 115 patients. We found that although sonographic patterns 

suggesting outflow abnormalities were very common: at least one positive Zamboni’s criterion was found in 

92.2% of assessed veins, their diagnostic accuracy was limited. For example, positive and negative predictive 

values of one positive Zamboni’s criteria were: 79.4% and 33.3%, and of at least two positive criteria: 81.8% and 

21.7%. Accuracy of ISNVD criteria were not much better. Multivariate regression analysis of 41 sonographic 

parameters revealed variables associated with increased prevalence of venographic abnormalities: no flow 

detected in all three segments of internal jugular vein in upright position, peak flow velocity in the upper and 

middle segments in upright position less than 24 cm/s, and in lower segment less than 88 cm/s, peak flow 

velocity in the upper segment in supine position less than 24 cm/s, cross-sectional area of the upper segment 

in the supine position less than 8 cm 2 . However, even using these parameters we were unable to create a 

reliable set of criteria. Of note, many variables used by the current sonographic criteria were not proven to be 

associated with increased prevalence of venographic pathology, for example: reduced or bidirectional flow in 

the vertebral veins. Our research is showing a clear gap in the understanding hemodynamics in this particular 

venous territory. Consequently, more research is needed to improve diagnostic accuracy of Doppler 

sonography for the diagnosis of CCSVI. 

Financial disclosures: American Access Care, Euromedic Specialist Clinics


A Hemodynamic Model for Quantification of Cerebral Venous Return (Sandra Morovic, ITALY-CROATIA) 

Venous outflow depends on arterial inflow, cerebrospinal fluid circulation, and venous drainage. Human studies 

have shown that internal jugular veins (IJV) are the main outflow pattern in upright position, while vertebral 

veins (VV) are the main outflow pattern in supine position. A discrepancy in blood quantification of incoming 

and outgoing blood volume, calculated by previous modelling attempts, created a need for an improved 

hemodynamic model. In addition, it is the amount of blood, flowing into the collaterals. The aim is to build a 

hemodynamic model best describing quantitatively the circulatory pattern of the head and neck. We examined 

5 healthy volunteers. Inflow and outflow of intracranial and extracranial blood was measured. Measurements 

were taken on both sides, in supine and sitting positions, during a 4 second period, at main arterial and venous 

points. Flow volume, time average velocity, and cross sectional area were assessed. Lumped modelling was 

performed to understand the venous recirculation pathway. Preliminary data show a significant difference in 

blood flow volume between J3 point (385±150mL/min), the most distal part of IJV, and J1 point of 

measurement, the most proximal part (732±175mL/min). This difference in blood volumes between these two 

points quantitatively corresponds to the blood volume incoming through the external carotid artery. This 

amount of blood volume reenters into the IJV and VV on each side. The further difference between the inflow 

and the outflow at J3 and vertebral level represents the final amount of the collateral network returning to the 

chest independently (280±85mL/min). The results did not change with change of position. This study enhances 

the importance of collateral circulation network, and flow resistance, in quantification of cerebral venous return. 

With help of this hemodynamic model we were able to calculate more coherently the amount of blood 

returning to IJV, VV, and the collateral network. 



Magnetic resonance imaging CCSVI protocol (J. Joseph Hewett, USA) 

Much of the attention surrounding CCSVI has centered on the treatment itself. At this time however, some of 

our greatest contributions to the field may be in the diagnostic tools we have developed surrounding the 

diagnosis and monitoring of vascular disease as it relates to neurologic function. The Haacke MRI/MRV 

protocol is a very powerful diagnostic tool for looking for anatomic irregularities of the venous and arterial 

system of the head and neck, for evaluating the state of the CSF flow, for interrogating the status of venous 

flow surrounding the neuro axis, for evaluating the function status of the brain before and after treatment and 

for evaluating possible long term effects of the neurodegenerative etiologies. Current protocols using MRI will 

soon be able to help us stratify prospective patients for symptomatic treatment outcomes, help predict long 

term benefits, synthesize current and prospective theories postulating etiologies for vascular and CSF mediated 

neurologic damage, and guide us toward more effective treatment strategies. 

Financial Disclosures: Synergy Health Concepts


Morphological MRV multimodal studies in CCSVI (Robert Zivadinov, USA) 

Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis 

(MS). CCSVI is diagnosed non-invasively by Doppler sonography (DS) and invasively by catheter venography 

(CV). The role of conventional magnetic resonance venography (MRV) for detection of venous anomalies in 

patients with MS diagnosed with CCSVI, and in healthy controls (HC) was investigated in recent studies. Two 

types of MRV approaches were proposed: conventional and non-conventional. Conventional MRV approaches 

include assessment of venous anomalies on 2D-Time-Of-Flight venography (TOF) and 3D-Time Resolved 

Imaging of Contrast Kinetics angiography (TRICKS), whereas non-conventional MRV approaches include phasecontrast 

MRV with flow quantification and multi-directional TOF sequences. The advantages are driven by MRV 

being a non-invasive technique, less time-consuming and less operator-dependent than DS. MRV can also 

depict, easily and globally, the anatomy and morphology of the head and extra-cranial venous system. Its main 

disadvantages are represented by lack of MRV dynamism in real time, lower resolution compared to DS and CV 

(this is especially true for detection of intra-luminal structural abnormalities that represent major part of the 

CCSVI pathology), and it is affected by the nature of the veins themselves, which are prone to collapse under 

multiple circumstances, as opposed to arteries. Although MRV is not capable of reliably detecting the intraluminal 

structural abnormalities, it has important value in detecting extra-luminal structural abnormalities and 

visualizing the collateral veins. In general, studies using conventional and non-conventional MRV techniques 

found no significant differences between the extra-cranial venous system characteristics of MS patients and HC, 

although more extra-luminal structural abnormalities and collateral veins were detected in progressive MS 

patients. Recent studies showed that MRV can add diagnostic value to DS. Future multimodal non-invasive vs. 

invasive imaging studies are needed to determine sensitivity and specificity of MRV for diagnosis and follow-up 

of subjects presenting with CCSVI. 

Financial Disclosures: Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Bracco, Questcor, Greatbatch


MS, MRI Database (E. Mark Haacke, USA) 

Nowadays, patients with chronic diseases fight against two enemies: the disease and its economy. While the 

disease itself causes both physical and mental burdens, drug prices as well as hospital bills are often too costly 

for those without insurance. It has been estimated for instance that drug costs for multiple sclerosis (MS) 

patients has reached 7.1 billion dollars annually while the cost for traumatic brain injury (TBI) drugs reached 

48.1 billion dollars. While current drug treatments have had some success, new approaches (such as studying 

the vascular aspects of neurological diseases) might lead to a better understanding of the underlying 

mechanisms of the diseases and create new treatment pathways for long term recovery. Recent breakthroughs 

in imaging developed here in Detroit offer a new means by which to study both macro and micro-vascular 

disease. These techniques are built on four main concepts: imaging the arteries, veins, perfusion and flow in the 

brain. We have been using two of these for MS studies in the last two years and during this time have 

collaborated with sites around the world to create a database of more than 1500 cases. The main goal of an 

international collaborative project should be to create a system wide MR database for studying neurovascular 

diseases such as multiple sclerosis for example. This means coming to a consensus on an MRI CCSVI protocol, 

managing the data acquired through a shared database; and analyzing the data seeking vascular MR 

landmarks specific to each disease and understanding its pathophysiology. We believe that the number of 

patients in a clinical database could easily be on the order of tens of thousands if a coordinated effort is made 

and that this could lead to major medical breakthroughs. The key issue is to have a complete picture of the 

vascular system. The successful implementation of this program will undoubtedly attract both patients and 

physicians alike to collaborate. The outcomes of this project will be a state-of-the-art clinical imaging protocol 

that is integrated into the usual MR imaging protocols available to patients. 

Financial Disclosure: MR Innovations, McMaster University

SUNDAY – FEBRUARY 19, 2012 8:30am-10:00am 

Establishing US imaging standards (Nikolaos Liasis, GREECE) 

The 21 st century has brought an innovation to the better understanding of the pathophysiology of venous 

disease based on the duplex findings after the applying of the DUS, at the end of the 20 th century. Chronic 

venous disease (CVD) of the lower extremities is the result of venous hypertension which is primary caused by 

reflux or obstruction and ends up to the development of skin damage or venous ulcer. Venous dysfunction 

develops when venous return is impaired for some reason. Abnormalities within deep veins, superficial veins, or 

both can be the etiology of for this disorder. Chronic Cerebrospinal Venous Insufficiency (CCSVI) is 

characterized by stenoses or obstructions of the internal jugular and / or azygos veins with disturbed venous 

outflow and collateral formation. Considering the fact that venous malfunction results to the aforementioned 

valve disorders of the lower extremities, it is wise to support that the same disorders may be associated with 

damage to the sensitive cerebral tissue. Studies using ultrasound in patients suffering from multiple sclerosis 

(MS) has shown a considerable high prevalence of CCSVI compared to healthy individuals. Duplex ultrasound 

(DUS) can be used as a noninvasive screening method. It provides real time anatomical imaging and venous 

flow information in different postural and respiratory conditions. The proportion rate of existence of CCSVI in 

MS patients varies widely in relation to healthy individuals in relevant studies. This variability could be 

attributed to the different techniques and ultrasound parameters applied the different criteria or the skills and 

experience of the examiner. It is foremost to emphasize the character of the method 

which affects the accuracy and reproducibility. In order to increase the accuracy and reproducibility of the 

method we suggest a detailed ultrasound protocol based on standard methodology and specific criteria. 



Summary of the consensus on US imaging standards (Nikolaos Liasis, GREECE) 

Chronic Cerebrospinal Venous Insufficiency (CCSVI) is characterized by impaired blood outflow from the 

Central Nervous System (CVS) to the periphery, secondary to anatomical abnormalities of the major neck and 

azygos veins. The cerebrospinal venous system is usually asymmetric and has a more variable vessel pattern 

than the arterial system. One of the problems in investigating CCSVI and its potential connection with M.S. is 

lack of well-established standards for diagnosing CCSVI. Catheter venography (C.V.) is considered to be the 

for determing the anatomical site, type and extent of lesions producing cerebrospinal 

venous insufficiency (CCSVI). CV however is an invasive procedure and cannot be used as a screening method. 

Furthermore it provides little or no data about the vessel wall or intraluminal defects. The most important 

disadvantages of ultrasound imaging are the artifacts and the subjectivity of the method. To overcome these 

shortcomings we should use the right ultrasound equipments with proper adjustment of preset – settings. In 

an effort to ensure high reproducibility and accuracy of the method we suggest a detailed US protocol with 

standard methodology and five ultrasound criteria. Besides the parameters that might improve the accuracy 

and reproducibility of the method such as range of velocity, presence and duration of reflux, volume flow in 

normal individuals and patients with specific lesion of CCSVI, require further research. Combined thranscranial 

and extracranial Doppler US allows for noninvasive assessment of venous hemodynamic parameters indicative 

of CCSVI. Finally, it seems that DUS in properly trained hands could become the most reliable and cost effective 

diagnostic tool for noninvasive screening for CCSVI. Multicenter prospective studies need to be done in 

combination with DUS, MRV, CV and intravascular US. It is of great importance to elucidate the impact of 

CCSVI to MS to the medical community as well as to thousands of people in agonized appeal. 



Advancing a CCSVI Research Agenda Focused on Care (Kirsty Duncan, CANADA) 

Since Zamboni’s initial description of chronic cerebrospinal venous insufficiency (CCSVI), patients, practitioners, 

scientists, and decision-makers have been left with numerous questions regarding the condition, the 

procedure, and its impacts on the quality of life for patients diagnosed with multiple sclerosis (MS). In general, 

questions have focused on the venous system and CCSVI and how these relate to MS, CCSVI diagnosis and 

treatment, the benefits and adverse effects of CCSVI treatment, re-stenosis and its diagnosis, and secondary 

procedures. Several questions have received much less attention: namely, combined therapies, follow-up care, 

supportive care for recovering patients, and prevention in the next generation. In terms of combination 

therapies, questions should include: "Is CCSVI treatment along with pharmacological agents more efficacious 

than just the CCSVI procedure? and "Is CCSVI treatment more efficacious with mesenchymal- or adiposederived 

stem-cell infusion than just the CCSVI procedure alone?" Follow-up care has centered primarily on 

when re-imaging should be done. However, important questions are: what is the optimal environment for 

recovery, and what are the best supportive care therapies following the procedure, including, brain plasticity 

exercises, drugs, nutrition, osteopathy, physiotherapy, speech therapy, supplements, etc., and which therapies 

have the best outcomes? After treatment, many MS patients want to know how CCSVI can be prevented in the 

next generation. What would be the best method to discover and treat vascular problems at the earliest time 

possible to avoid possible health impacts at a later date? Will giving children and adolescents vitamin D reduce 

the risk of their developing vein inflammation and venous hypertesion? This paper will first present a 

comprehensive set of questions related to the above issues and recommend a consultative process to develop 

a research agenda focused on patient care. 


SUNDAY – FEBRUARY 19, 2012 11:45am-12:00pm 

Bringing neurologists into the CCSVI arena (Jack Burks, USA) 

Why are many neurologists so resistant to CCSVI? They believe the theoretical basis of CCSVI is flawed. The 

diagnostic test results are not consistent. One study says CCSVI is correlated 100% to MS while another study 

says no correlation to MS. “Should we fund studies to get rid of flying saucers?” The clinical trials are not 

scientifically meaningful and do not have acceptable “follow-up” which leads to patients’ false hopes, financial 

hardship and serious adverse events, including death. Interventionalists are “getting rich” from desperately ill, 

financially strapped patients who may become disenfranchised from their neurologists for not supporting 

CCSVI. Many neurologists believe CCSVI is touted to MS patients as providing “liberation” from MS. While that 

is unrealistic, angioplasty may be helpful to some patients. If CCSVI exists, treating the vascular factor may 

improve MS symptoms and Quality of Life. In early RRMS, it may help more. On the other hand, the positive 

reports may represent a placebo response. Scientific data through collaboratively planned and implemented 

research will provide many answers and put CCSVI into better perspective. Working in isolation will prolong 

the “battle”. If collaborative research projects are positive, the procedure will gain wide acceptance and 

insurance funding. If negative, we have saved patients from the medical disappointments and financial drain. 

Specific ideas will be presented Wednesday. 

Financial Disclosure: Accorda, Allergan, Avanir, Bayer, Novartis, Serono, Sanofi-Aventis

SUNDAY – FEBRUARY 19, 2012 1:20pm-2:00pm 

Remodeling the Brain after Stroke and Neural Injury (Michael Chopp, USA) 

Historically, the focus of the treatment of stroke and neurological injury and disease has been neuroprotection, 

i.e., reduction of damage to brain. However, a more fruitful approach which may permit the efficacious 

treatment of all patients is to treat, not the injured tissue, but the intact brain, in order to stimulate and amplify 

endogenous restorative mechanisms which promote neurological recovery. In this presentation, I will describe 

our work on cell-based and pharmacological-based therapies for the treatment of stroke and demonstrate that 

a major neurorestorative pathway is via the vascular system. Effective treatment of neurological diseases 

stimulates vascular changes which in-turn amplify and couple with other restorative events, such as 

neurogenesis, to promote neurological recovery post stroke. 



Venous outflow abnormalities in neurological disease (Han-Hwa Hu, TAIWAN) 

Over the past decade, many neurological diseases/disorders, of which the etiologies remain elusive, have been 

linked to the venous outflow abnormalities. In addition to the well-known relationship between the chronic 

cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis, the venous abnormalities have been 

identified as an attribute in various neurological illnesses: 1. Intracranial dural sinus or vein stenosis/occlusion 

have been reported to be an attribute (disease-attribute association) for benign intracranial hypertension 

(pseudotumor cerebri), dural A-V malformation, cerebral venous infarction/hemorrhage, and brain white matter 

disease; 2. Internal jugular venous valve incompetence (IJVVI) has been reported having disease-attribute 

association with transient global amnesia (TGA), transient monocular blindness (TMB), cough headache, normal 

pressure hydrocephalus, benign intracranial hypertension and brain white matter disease; 3. Extracranial venous 

stenosis/occlusion has been reported in acute intracranial hypertension, ophthalmoplegia, and normal pressure 

hydrocephalus. Our recent works found that patients of TMB and TGA have significantly higher frequencies of 

internal jugular vein stenosis/compression at C 1 level and left brachiocephalic vein stenosis/compression 

between the sternum and aorta than the age and sex-matched controls. Moreover, a phenomenon of internal 

jugular vein, we call it “functional stenosis/occlusion” maybe a contributing factor in the orthostatic intolerance, 

panic disorder and gravity-induced loss of consciousness. 



Venous involvement in neurological disorders (Robert Zivadinov, USA) 

The hypothesis that central nervous system (CNS) disorders might be related to venous pathology has been 

considered in the past. Recently, a condition called chronic cerebrospinal venous insufficiency (CCSVI) has been 

proposed and reported with high frequency in patients with multiple sclerosis (MS), although the condition was 

also found in patients with other CNS diseases and subjects without known CNS pathology. More recent 

reports suggest that some non-CNS diseases (especially of the bowel system) may be associated with CCSVI. 

Risk factors for development of CCSVI need to be determined. CCSVI is described as a vascular condition 

characterized by anomalies of the main extra-cranial cerebrospinal venous routes that possibly interferes with 

normal blood outflow of brain parenchyma. It has been hypothesized that an excessive amount of iron, due to 

altered cerebrospinal venous return (reflux) present in CCSVI positive subjects, may cause damage to the 

blood-brain-barrier and consequent disturbed microcirculation, leading to erythrocyte extravasation as a 

primary source of iron deposition in the form of micro bleeds. Histopathological studies have confirmed the 

association between venous cerebral microvasculature and number of inflammatory and neurodegenerative 

CNS disorders. Therefore, a close relationship may exist between cerebrospinal venous reflux, damage of the 

cerebrovascular endothelium, iron overload, downregulation of matrix metalloproteinases and over-expression 

of adhesion molecules. Other mechanisms may be involved. This initial damage at the endothelial level may 

result in a powerful chemotactic stimulus that attracts microglia and macrophages contributing to activation of 

autoimmunity of neurodegenerative mechanisms in CNS disorders. The regional predilection of this process 

may be essential in determining the disease phenotype. For example, high-field and ultra-high field imaging 

studies showed that a majority of MS lesions are associated with centrally coursing veins. Iron imaging studies 

showed a predilection for iron accumulation in Parkinson's and Alzheimer's diseases. 

Financial Disclosure: Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Bracco, Questcor, Greatbatch


Effect of hemodynamics on endothelial adhesion and permeability (John P. Cooke, USA) 

Alterations in shear stress and cyclic strain induce the expression of endothelial adhesion molecules and 

chemokines that participate in vascular inflammation. Accordingly, it is possible that alterations in venous 

hemodynamics in chronic cerebrospinal venous insufficiency (CCSVI) might alter endothelial adhesiveness and 

permeability. These alterations in vascular homeostasis might facilitate the adherence and infiltration of 

immune cells into the surrounding tissue. A predisposition to autoimmunity against an antigen in the brain 

parenchyma could thus be facilitated by obstruction to venous flow. Thus the altered venous hemodynamics in 

CCSVI may be relevant to the inflammatory pathophysiology of multiple sclerosis (MS). We speculate that 

chronic venous diseases (CVD) of the lower extremities, and CCSVI associated with MS, have many similarities 

in their molecular and physiological mechanisms. This speculation is supported by the fact that perivenular 

inflammation is a common histopathological finding in patients with CVD, as well as those with MS. In the leg 

veins, disturbed venous flow increases endothelial adhesion molecules (eg. ICAM-1), vascular permeability, 

edema, infiltration of inflammatory cells, insudation of plasma proteins, and causes hemosiderin deposition. 

The latter is due to erythrocyte extravasation. Iron overload promotes oxidative stress, which further increases 

endothelial adhesiveness and inflammation. Whereas normal levels of blood flow provide for endothelial shear 

stress that reduces the expression of adhesion molecules and chemokines, disturbed flow increases endothelial 

adhesiveness and interaction with immune cells. The role of inflammation in CVD is consistent with the clinical 

observation that individuals with this condition may obtain partial relief of their symptoms with antiinflammatory 

agents. However in patients with CVD, complete relief of symptoms, and modification of the 

progression of disease, requires treatment of the underlying venous insufficiency. To summarize, it is possible 

that changes in venous hemodynamics (as in CCSVI) may cause alterations in endothelial biology that favor 

local tissue inflammation. 


MONDAY – FEBRUARY 20, 2012 8:30am-8:50am 

Stroke and Brain Perfusion (Vida Demarin, CROATIA) 

Stroke is the second most common cause of death and major cause of disability, thus representing enormous 

burden on global health. Cerebral ischemia, or restricted blood flow, is the main cause of stroke, typically due 

to occlusion of a cerebral artery as a result of progressive atherosclerosis or an embolus from the heart or neck 

vessels. Anatomical features and functional responses-cerebral autoregulation-allow high cerebral blood flow 

and provide protection against ischemia. Cerebral autoregulation is impaired in ischaemic stroke and this may 

result in an already damaged brain being excessively sensitive to fluctuations in perfusion pressure. Irrespective 

of cause or mechanism of ischemia, collateral flow might compensate potential injury to the brain. 

Physiologically effective collateral perfusion is evident when cerebral blood flow and cerebral blood volume are 

maintained within the territory of the occluded artery. In acute stroke, ischemia is more often incomplete, with 

the injured area of the brain receiving a collateral blood supply from uninjured arterial and leptomeningeal 

territories. Acute cerebral ischemia may result in a central irreversibly infarcted tissue core surrounded by a 

peripheral region of stunned cells that is called a penumbra. The penumbra is a dynamic entity that exists 

within a narrow range of perfusion pressures, and the duration of the delay in recanalization is inversely related 

to the size of the penumbra. Penumbra has important implications for selection of the appropriate therapy and 

prediction of the clinical outcome. Results of recent studies have demonstrated that intravenous thrombolytic 

therapy may benefit patients who are carefully selected according to findings of a penumbra at neuroimaging. 

Important advances in the imaging of collateral blood vessels and collateral blood flow will need to be 

followed by a rigorous assessment of the therapeutic value of techniques aimed at improving or maintaining 

collateral flow in patients with acute ischemic stroke. 



Technology Insights of Oxygen Metabolic Abnormalities in MS (Yulin Ge, USA) 

The role of vascular pathology in multiple sclerosis (MS) was suggested long ago by Ribbert (1882) and Putnam 

(1933). With the invention and advances of imaging technology, now there is accumulating evidence in vivo of 

primary vascular pathogenesis and hemodynamic impairment in MS. In particular, there is cerebral blood 

perfusion changes in lesions and normal appearing brain tissues, suggesting there might be an ischemic and/or 

hypoxic origin of MS disease. In this presentation, I am going to discuss the hemodynamic perfusion changes 

and vascular abnormalities measured with several advanced MRI techniques and their pathophysiological 

significance in MS. First, the close perivenous relationship of MS lesions associated with the underlying 

vascular inflammatory changes can be evaluated with high resolution susceptibility-weighted imaging. Second, 

cerebral blood perfusion changes including cerebral blood volume (CBV) and flow (CBF) have been evaluated 

with dynamic susceptibility contrast-enhanced (DSC) and arterial spin labeling (ASL) MRI techniques. The 

lesions showed different patterns of perfusion change despite that hypoperfusion is a general feature seen in 

MS tissues. The perfusion changes in MS may provide additional information of microvascular abnormalities. 

Third, the recent promising vascular ischemic / hypoxic hypothesis can be evaluated in vivo with several 

techniques including perfusion- and diffusion- weighted imaging during the acute phase and oxygen 

metabolic measures as well as functional MRI techniques. In summary, there is increased awareness from both 

histopathologic and imaging studies of the role of microvascular and hemodynamic impairment in tissue injury 

in MS; therefore, targeting hypoxic injury may be indicated in the new therapeutic strategy. 



Perfusion changes in CCSVI (Robert Zivadinov, USA) 

A hypoxia-like condition has been evidenced in patients with multiple sclerosis (MS). Perfusion MRI is 

particularly relevant to studying MS pathogenesis because it has been shown that hypoperfusion of the brain 

parenchyma in MS patients may precede disease onset. MS patients show abnormal blood flow perfusion 

patterns, such as increased mean transit time (MTT), and decreased cerebral blood flow (CBF) and cerebral 

blood volume (CBV) within normal appearing white matter (WM) and gray matter (GM). Perfusion MRI 

abnormalities are present from the earliest stages of the disease in normal appearing WM, while GM perfusion 

changes were evidenced at later disease stages. In fact progressive MS patients show more severe perfusion 

changes compared to relapsing MS. Chronic inflammatory events related to local blood congestion and 

secondary hyperemia of the brain parenchyma are proposed as a cause of these hemodynamic abnormalities 

detected on perfusion MRI in patients with MS. The hemodynamic abnormalities detected on perfusion MRI in 

patients with MS are currently interpreted as being a consequence of chronic inflammatory events related to 

local blood congestion and secondary hyperemia of the brain parenchyma. Furthermore, at this time it is not 

clear whether reduced perfusion of the brain parenchyma in MS patients is a sign of vascular pathology or 

decreased metabolic demand. Alternatively, it can be hypothesized as a disorder that involves the major 

vasoactive substances. Increased perfusion in the area of lesion formation could be a sign of vessel dilation 

mediated by pro-inflammatory cytokines. Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular 

condition described in MS patients, characterized by multiple intra- and extra-luminal stenosing malformations 

of the principal pathways of extra-cranial venous drainage. An altered perfusion pattern may not only be a 

consequence of local circulatory disturbances due to inflammatory mechanisms in acute or chronic phases, but 

rather could result from an outflow blockage situated far away from the lesions. CCSVI may impact local 

hemodynamics at places distant from the location of the mechanical stenosis, as in any condition of venous 

obstruction of the major trunks. Such a mechanism may lead to capillary hypertension and leakage, 

consistently contributing to inflammation. Preliminary findings are presented from a pilot study investigating 

the relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. 



Changes in venous anatomy associated with sustained venous insufficiency in Sturge-Weber disease 

(Csaba Juhasz, USA) 

Sturge-Weber syndrome is a sporadic neuro-cutaneous disease defined by a facial capillary malformation in 

the ophthalmic distribution of the trigeminal nerve (“port-wine stain”), a leptomeningeal “angioma” (which is 

also a vascular malformation), and ipsilateral vascular glaucoma. The conventional radiologic hallmarks of brain 

involvement include the contrast-enhancing pial vascular malformation, enlarged transmedullary and 

subependymal veins, enlarged choroid plexus, as well as signs of variable brain tissue damage including 

atrophy and perivascular calcifications. The pial vascular abnormality, which is unilateral in 85% of the cases 

and most commonly involves the parieto-occipital region, likely results from an early embryologic 

malformation of the vascular system due to a failure of the primitive cephalous venous plexus to regress and 

properly mature in the first trimester. The concomitant vascular involvement of the face and eye is commonly 

explained by the embryologic proximity of the ectoderm forming the upper portion of the facial skin to the 

neural tube that forms the parietal occipital areas of the brain. An alternative hypothesis suggests that the 

facial and ocular vascular abnormalities are mostly secondary to intracranial venous stasis, with venous 

hypertension transmitted to nearby areas via persisting communicating and collateral venous channels. In case 

of inadequate compensation, impaired cortical and subcortical white matter perfusion may lead to chronic 

hypoxia triggering early-onset seizures, stroke-like episodes and other neuro-cognitive complications. Cerebral 

venous and parenchymal abnormalities in Sturge-Weber syndrome are best studied by multimodal 

neuroimaging incorporating susceptibility weighted imaging that often shows a variable network of enlarged 

transmedullary veins, bridging the venous watershed area between the subcortical and periventricular white 

matter. In some patients extensive collateral venous drainage appears to salvage cortical function; in other 

cases, deep transmedullary veins are poorly developed or obliterated, and poor cortical and subcortical blood 

flow leads to severe damage of the affected brain regions. 



Venous and CSF flow in brain parenchyma of MS patients (Robert Zivadinov, USA) 

The role of cerebrospinal fluid (CSF) dynamics in relation to multiple sclerosis (MS) clinical and MRI outcomes 

has not been previously investigated. It could be hypothesized that impaired CSF flow dynamics may interplay 

with the enlargement of the third, fourth and lateral ventricles, all of which are MRI signatures of central 

atrophy in MS that appear from the earliest disease stages. The association of CSF dynamics and clinical 

outcomes in MS is also unknown. The Monro-Kellie doctrine postulates that the sum of the brain, CSF, and 

intracranial blood volumes must remain constant at all times throughout the cardiac cycle when the skull is 

intact. Therefore, normal CSF circulation, in which homeostasis is maintained between ultra-filtration of CSF (in 

the veins of the lateral ventricles) and clearance into the venous system at the level of the dural sinuses, 

depends on efficient venous drainage. Chronic cerebrospinal venous insufficiency (CCSVI) is described as a 

vascular condition characterized by anomalies of the main extra-cranial cerebrospinal venous routes that 

possibly interferes with normal blood outflow of brain parenchyma. Any occlusion of the extra-cranial venous 

pathways is likely to induce hypertension in the venous sinuses. Increased pressure in the superior sagittalsinus 

(SSS) can inhibit the absorption of CSF through the arachnoid villi, decrease CSF brain parenchyma 

drainage and induce hypoxic stress in the endothelia. Findings from our pilot study in 16 MS patients and 8 

healthy subjects suggest that changes in the cerebral hydraulic regulatory mechanism may occur in patients 

with MS. In that study, MS patients with CCSVI showed significantly lower net CSF flow which was highly 

associated with the severity of CCSVI, compared to healthy controls. In a recent study, we investigated CSF 

dynamics in the aqueduct of Sylvius in 67 MS patients, 9 patients with clinically isolated syndrome (CIS), and 35 

age- and sex- matched healthy subjects on a 3T MRI using cine phase contrast imaging over 32 phases of the 

cardiac cycle. It was found that CSF flow dynamic is altered in MS patients. More severe clinical and MRI 

outcomes in relapsing MS and CIS patients are related to altered CSF flow and velocity measures. 



Cranial Instability and CCSVI (David Williams, CANADA) 

CCSVI is a complex condition that has a clear association with several clinical illnesses. It has been shown 

repeatedly that, by itself, CCSVI is not the primary cause of these illnesses but appears to be present in 

association with other, as yet, unknown factors. CCSVI shares clinical features with the Central Venous 

Stenosis which is a complication of hemodialysis. The relationship of altered venous pressure and cellular 

responses on the endothelial wall are well documented. The discovery of a mechanism by which intracranial 

pressure and exit venous pressure may be subject to paroxismal changes during sleep cycles may contribute 

one such factor worthy of closer examination. Jaw clenching in the form of nocturnal bruxism occurs during the 

REM phase of sleep. The forces involved can exceed conscious clenching forces by several times. The muscle 

groups that are activated in this scenario are closely associated with cranial structures and may have a 

profound impact on venous pressure directly and indirectly. The discovery of sutural instability during jaw 

clenching in a group of multiple sclerosis patients could lead to fluid trauma to the contents of the skull and 

the endothelium of the extracranial venous system. This mechanical trauma could be expected to precipitate 

microbleeds, accumulation of iron, axonal death, blood brain barrier disruption, amyloid accumulations 

and other processes that are found in post traumatic brain injury. If this phenomenon is present prior to the 

deterioration of the venous system as found in CCSVI, it may be a significant factor in the treatment of 

neurological illness and may enhance the outcome of venous angioplasy. 


MONDAY – FEBRUARY 20, 2012 1:20pm-1:40pm 

Postmortem assessment of jugular and azygos vein pathology (Robert Fox, USA) 

The venous changes of chronic cerebrospinal venous insufficiency (CCSVI) are typically assessed by ultrasound 

or MRV, but no gross anatomical description of venous outflow in MS has been reported to date. We harvested 

bilateral internal jugular (IJV), subclavian, brachiocephalic, and azygous (AZY) veins from 7 deceased MS 

patients and 6 non-MS controls. Veins were injected with silicone, dissected en bloc, incised longitudinally to 

expose the luminal surface, and fixed. All valves and structural abnormalities were characterized and 

photographed using a stereomicroscope. Vein wall stenosis was defined as a >= 50% reduction in crosssectional 

area, defined from vein wall circumference and compared to a normal appearing region in the same 

vein. A variety of vein abnormalities were identified. The incidence of vein wall stenoses was similar in MS and 

controls. Valvular and other intraluminal abnormalities with potential hemodynamic consequences were 

identified in 5 of 7 MS patients (7 abnormalities) and in 1 of 6 controls (1 abnormality). These abnormalities 

included circumferential membranous structures (1 MS and 1 control), longitudinally-oriented membranous 

structures (3 MS), single valve flap replacing IJV valve (2 MS), and enlarged and malpositioned valve leaflets (1 

MS). In addition, many minor anatomic variations without expected hemodynamic consequences were 

observed similarly in both MS and controls. These included valves with >2 leaflets, the presence of valves in the 

AZY, additional (duplicate) normal-appearing IJV valves, and small membranous septa. In conclusion, post 

mortem examination of the IJV and AZY veins of MS patients and non-MS controls demonstrated a variety of 

structural abnormalities and anatomic variations. Although vein wall stenosis occurred at similar frequency in 

MS and non-MS controls, the frequency of intraluminal abnormalities with possible hemodynamic 

consequences was higher in MS patients compared to healthy controls. Histologic analysis is underway. These 

results provide a pathologic explanation for the intraluminal abnormalities observed in ultrasound studies and 

emphasize the importance of detailed intraluminal assessment. 

Financial Disclosure: Biogen Idec, Avanir, Novartis, Questcor, Genetech


We can now select ACS patients who require carotid endarterectomy or stenting (Andrew Nicolaides, UK) 

Until recently our current practice has been based on the results of the ACAS and ACST 2 randomized controlled 

trials (RCT), which provided the first scientific evidence that in patients with asymptomatic carotid stenosis 

(ACS) > 60-70% can reduce the annual risk of stroke from 2% to 1%. In these trials the perioperative stroke was 

2.3% and the number needed to treat (NNT) to prevent one stroke per year was 83. Modern medical 

intervention includes life style changes and aggressive risk factor modification such as treating hypertension 

and hypercholesterolemia to predetermined targets, achieved by appropriate adjustment of drug dosages. This 

aggressive medical therapy was not applied to the patients in the ACAS or ACST trials. Observational studies 

published after 1995 show that in patients with moderate to severe ACS the annual stroke risk is not 2.5-2% 

but closer to 1.0-0.5% with the authors suggesting a 70% reduction in stroke rates as a result of modern 

medical therapy. 

However, information from observational studies is level III and any recommendations based on the findings 

are grade C. This is because in such observational studies, bias from patient selection based on the ACAS and 

ACST results and the publications between 1995 and 2000 that echolucent plaques are unstable and dangerous 

cannot be excluded. Only RCT can produce level I evidence and grade A recommendations. In addition, the 

suggestion that the risk of ischemic stroke has been reduced by 70% as a result of modern medical therapy is 

not compatible with the actual results of RCT in asymptomatic and symptomatic patients showing that statins 

can reduce stroke by 20-27%. Assuming optimal medical therapy can reduce the overall ischemic stroke rate by 

30%, there will still be patients with ACS >70% with an annual stroke rate >2% that may require surgery. 

Several methods are now available that can identify high risk patients or even stratify patients according to risk. 

They consist of (a) methods that identify the ulcerated plaque or the plaque with an intraluminal thrombus 

producing microemboli and (b) methods that identify the unstable plaque. They are summarised below. The 

presence of microembolic signals on transcranial Doppler (TCD) can identify a high risk group as demonstrated 

by several studies 7-8 and a meta-analysis of 6 studies. In the ACES study 8 the risk of ipsilateral stroke was 7% 

at one year. In the meta-analysis, microembolic signals were present in 195(17%) of 1144 patients with ACS and 

this group contained 17(57%) of the 30 strokes that occurred during follow-up. A more recent study 9 has 

demonstrated that the combination of microembolic signals and presence of a hypoechoic plaque identify a 

subgroup with even a higher risk. The method of recording microembolic signals is now well established and 

equipment is commercially available. The presence of silent embolic infarcts on CT-Brain scans (discrete 

subcortical, small cortical and non-lacunar basal ganglia infarcts) identify a high risk subgroup as shown by the 

ACSRS prospective natural history study with 1121 patients with a 6 month to 8 year follow-up (mean 4 years) 

10 . In the 60-99% stenosis group the presence of embolic infarcts identified a group of 61(11%) of 572 patients 

that had an annual stroke rate of 4.4%. Future prospective studies should use MRI-Brain scans which are more 

sensitive than CT in identifying such lesions. 

In the ACSRS study, the combination of plaque features (% stenosis, low GSM indicating a hypoechoic plaque, 

plaque area, presence of discrete white areas without acoustic shadow indicating neovascularisation) could 

stratify patients according to stroke risk. 11 This risk varied from 0.5% per year to 10% per year. Of the 923 

patients with >70% stenosis, the annual ipsilateral stroke rate was 6% in 34. The predicted risk correlated well with the observed risk. Patients ≥2% annual stroke risk 

consisted of a group of 250(27%) of the 923. This group contained 36(63%) of the 54 strokes. This method is 

practical provided ultrasonographers are trained on equipment settings and image capture. Such training can 

be done in one day. In addition, semi-automated user friendly software is now commercially available that can 

do the image analysis and calculate the annual stroke risk adding only 10 minutes to the ultrasound 

examination. In conclusion, identification of high risk subgroups and stroke risk stratification is now possible

using several methods. These methods need to be validated in the medical arm of RCT of medical therapy vs 

combined medical plus surgical therapy. Data from such studies will provide us with appropriate cut-off points 

that can be applied to routine clinical practice. 

In the mean time many patients can be spared from an unnecessary operation using the following criteria for 

considering patients with ACS for carotid endarterectomy: 1) ACS patients with two or more microemboli in 

one hour of TCD monitoring. 2) ACS patients with one or more microemboli at baseline, and echolucent plaque 

or 3) ACS patients with annual stroke risk >2% according to risk stratification based on plaque texture analysis. 

Stenting for asymptomatic stenosis carries a nearly double risk of stroke than CE. Thus, it should only be 

considered for patients who meet one of the above criteria, and have lesions unsuitable for surgery, such as a 

high carotid bifurcation, restenosis following prior endarterectomy, or radiation fibrosis. 



MRV Consensus (E. Mark Haacke, USA) 

With the advent of CCSVI, there has been a major thrust to be able to non-invasively image vascular 

abnormalities in multiple sclerosis. Several groups are now doing MR imaging studies that include conventional 

anatomical imaging, vascular imaging, flow quantification, and iron imaging. The last three are over and above 

the usual anatomic imaging protocol requested by neurologists. There are several levels of these so-called 

CCSVI MRI protocols. Each uses a conventional neuroimaging protocol for MS with additional specialized 

sequences to study one or more of the vasculature in the brain, neck and spine as well as the iron content in 

the brain. On the vascular side, both anatomic and flow information is collected. A major benefit of using MRI is 

that it provides the neurologist with what he needs for assessing MS, it provides the interventionalist 3D 

planning and it provides all parties with critical flow information which may well become a key marker for 

deciding when or when not to treat a patient. MRI is also operator independent for the most part and the same 

protocols can be run on most manufacturers’ systems. These protocols should be designed to be viable on all 

manufacturer’s systems for 1.5T and higher field strengths. The data should be easily reproduced when run on 

the same equipment from site to site. Potential biomarkers for CCSVI and MS can be identified from this type 

of data acquisition. MRI can also longitudinally track the progress of the disease over time via lesion counts 

and type, physiologic changes like blood flow and cerebrospinal fluid (CSF) dynamics, and provide a baseline 

for future scans. This protocol should make it possible to collect data from different sites around the world so 

that it can be used in a collaborative research database to evaluate our knowledge of the role of the vascular 

system in multiple sclerosis. There are several versions of this CCSVI protocol, some being as short as roughly 

half an hour and others as long as one and a half hours. The more advanced protocols include imaging the 

brain, spine and azygous with the use of a contrast agent. Such protocols may also have different levels, the 

more research oriented including susceptibility weighted imaging and perfusion weighted imaging to monitor 

changes before and after treatment. 


TUESDAY – FEBRUARY 21, 2012 8:30am-9:00am 

The effects of jugular venous reflux in aging (Chih-Ping Chung, TAIWAN) 

Decreased cerebral perfusion and increased cerebral white matter changes have been found in the elderly. 

These age-related cerebral hypoperfusion would result in dementia, gait disturbance, and disables. However, its 

pathophysiologies have not elucidated yet. The internal jugular venous hemodynamic profiles in our 

ultrasonographic registry suggest an increase in internal jugular venous outflow impedance with aging. We 

proposed the hypothesis that jugular venous reflux plays a role in age-related white matter changes. In the 

present talk, I will provide data suggesting that retrogradely-transmitted venous pressure of jugular venous 

reflux could reach cerebral venous system and influent cerebral blood flow in our clinical Doppler 

ultrasonographic studies. The results of studying the relationship between jugular venous reflux and agerelated 

white matter changes will also be demonstrated. At last, I will talk about some preliminary data about 

our animal model of jugular venous reflux. 



Flow effects and brain function in aging (Richard Hoge, CANADA) 

It is well known that vascular endothelial function changes during an individual's lifespan. Functional MRI 

methods have created new challenges and new opportunities related to this evolution. The challenges are 

associated with the widespread use of blood oxygenation level-dependent (BOLD) MRI contrast to characterize 

changing cognitive function in the aging brain. The behaviour of BOLD contrast in the presence of 

compromised vascular function is poorly understood, hindering the physiological interpretation of altered 

BOLD responses in aged cohorts as well as those presenting vascular pathology. The opportunities arise from 

emerging methods for quantitative functional imaging with MRI that provide an integrated picture of vascular 

and metabolic function. This presentation will review issues related to the use of BOLD contrast in altered 

vascular states, and present new quantitative imaging data allowing improved characterization of brain 

physiology under such conditions. 



High resolution imaging of the brain’s vasculature (E. Mark Haacke, USA) 

Magnetic resonance imaging offers a means by which to image both arteries and veins with and without the 

use of a T1 reducing contrast agent such as GdDTPA. In this presentation, we will review some of the early 

concepts in high resolution gradient echo imaging with a particular emphasis on susceptibility weighted 

imaging (SWI), imaging veins and imaging arteries. As consideration for future directions, we discuss the role of 

SWI and susceptibility mapping (SWIM) in estimating changes in oxygen saturation and in absolute 

quantification of oxygen saturation. In vivo high resolution angiographic imaging at 3T has the potential to 

reveal vessels easily on the order of 250 microns if not much smaller. Many approaches can be taken to 

increase both signal-to-noise (SNR) and resolution. In the former case, using high field, multi-channel coils, 

segmented echo planar imaging and a T1 reducing contrast agent make it possible to push resolution and yet 

still have sufficient SNR to see smaller vessels. In the latter case, using high bandwidth, long sampling times, 

and asymmetric echoes along with partial Fourier reconstruction can also lead to better resolution (potentially 

down to 100 microns). High resolution is important to visualize abnormal flow, abnormally vasculature, stroke, 

and vessel wall disease. We will present results from a state-of-the-art double echo SWI sequence that shows 

the potential for simultaneous imaging of both arteries and veins using IDEAS (interleaved double-echo 

acquisition sequence). We show that this type of imaging can reveal microvascular damage in both arteries and 

veins with applications to dementia, multiple sclerosis, stroke and traumatic brain injury. 



Neurovascular coupling and cerebral vascular organization (Kamil Ugurbil, USA) 

In the last two decades, magnetic resonance imaging (MRI) has evolved as a powerful tool capable of imaging 

processes such as organ function, intracellular chemistry, tissue perfusion, oxygen utilization, and enzyme activity 

in intact animals and humans. Most notable among these capabilities is functional magnetic resonance imaging 

(fMRI), which, in 2012, celebrates its twentieth year since its discovery. During these two decades, we have 

systematically pursued studies underlying functional imaging signals, which are mediated by the coupling of 

cerebral blood flow to alterations in neuronal activity. These studies demonstrated presence of flow regulation 

at the level of capillaries, leading to the ability to control flow specifically for neuronal clusters that form 

cortical columns, and across cortical layers. These fundamental discoveries on blood flow regulations have 

ultimately resulted in unique applications such as functional mapping of elementary computational units in the 

human brain (orientation domains in V1 and direction selective organizations in human MT), and visualization 

of functional brain networks with unprecedented spatial and temporal detail. The technological developments 

needed to achieve this required development of ultrahigh magnetic fields (7 Tesla and above). When technical 

challenges posed such ultrahigh magnetic fields are solved, such high fields have also provided the opportunity 

to image the human vascular system with greater resolution and contrast then previously available. 

Financial Disclosure: Agilent, Siemens


The Role of Brain Iron in Neurovascular Disease (James R. Connor, USA) 

A number of devastating neurological disorders are associated with either too much or too little iron in the 

brain. For example, excessive brain iron accumulation is reported in Parkinson’s and Alzheimer’s Diseases, 

amyotrophic lateral sclerosis, neurodegeneration with brain iron accumulation and Huntington’s Disease. On 

the other hand, iron deficiency remains the most prevalent micronutrient problem in the world and it is known 

that too little brain iron during development results in significant cognitive and performance deficits reflecting 

impairments in myelination and neurotransmitter production. Brain iron deficiency during adulthood also 

appears to underlie the pathobiology of a common neurological disorder known as Restless Legs Syndrome. 

Although brain iron concentrations are currently considered static, the maintenance of brain iron homeostasis 

appears much more dynamic than previously thought, particularly given a recent report of cyclical day/night 

variation in brain iron levels. In addition, genetics also play a role in brain iron levels as has been shown in both 

in-bred strains of mice and humans. In humans, both HFE gene variants (the most common polymorphism in 

Caucasians) as variants of the transferrin gene are associated with differences in brain iron status and those 

changes in brain iron concentrations are associated with cognitive performance. Moreover, mutations in the 

HFE protein are associated with a four-fold increase in risk of amyotrophic lateral sclerosis. Thus, elucidation of 

the mechanism(s) by which the brain acquires iron and, equally important, the regulation of brain iron 

transport, can provide insights into the adaptive responses involved in maintaining brain iron homeostasis and 

those that contribute to the maladaptive responses emergent with neurobiological disease. In this talk we will 

review the data on changes in brain iron with aging and disease and discuss novel concepts on regulation of 

brain iron uptake. 



Hepcidin and Ferroportin Genetic Variants in MS susceptibility and progression (Donato Gemmati, ITALY) 

Iron involvement and unbalancing are strongly suspected in multiple sclerosis (MS) etiopathogenesis, but their 

roles are quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal 

concentrations in parenchymal as documented by MR and histochemics. Conversely, systemic iron overload is 

not always observed. We explored in MS patients the role of two common single nucleotide polymorphisms 

(SNPs) in the promoter of the genes of two strongly related iron homeostasis molecules: Hepcidin and 

Ferroportin. By the DNA-pyrosequencing technique, we investigated in 414 MS cases (Relapse Remitting (RR), 

n=273; Secondary Progressive (SP), n=103; Primary Progressive (PP), n=38), and in 414 matched healthy 

controls, the following two SNPs: hepcidin (HEPC, -582AG) and ferroportin (FPN1, -8CG). 

FPN1-8GG homozygotes were overrepresented in the whole population (OR=4.38; 95%CI, 1.89-10.1; P


Iron in MS: Insights from MRI (Stefan Ropele, AUSTRIA) 

There is strong evidence for increased iron deposition in the brain of patients suffering from Multiple Sclerosis 

(MS) which is commonly considered as a consequence of inflammatory and neurodegenerative processes. The 

mechanism(s) behind this phenomenon are not yet fully clear but a better understanding can only be achieved 

with reliable and precise techniques for iron mapping. MRI is the only method that allows to assess the iron 

content non invasively. So far, MRI has been mainly used to assess disease related iron accumulation in the 

basal ganglia. Current techniques include visual rating, relaxation time mapping, and imaging of local field 

shifts, where some of these techniques have already been validated with mass spectrometry or synchrotron 

technology. Recent studies suggest that iron accumulation in the basal ganglia is an epiphenomenon of MS as 

it is directly linked to disease progression and accumulated neurodegeneration as measured by brain atrophy. 

The fact that iron levels are normal at a very early stage of the disease is in line with this assumption. In 

contrast, iron in and around MS lesions seems to be more directly related to local disease activity where it 

might also act as a trigger or promoter of the neurodegenerative cascade. Current efforts therefore focus on 

iron assessment in and around lesions but are limited by the diamagnetic effect of myelin and its orientational 

dependency. New insights are expected from newer approaches such as quantitative susceptibility mapping 

and from their application at ultra-high field strengths. 


TUESDAY – FEBRUARY 21, 2012 1:00pm-1:30pm 

The future of 4D imaging of flow (Michael Markl, USA) 

The intrinsic motion sensitivity of magnetic resonance imaging (MRI), which is exploited in phase contrast (PC) 

MRI, can be used directly acquire and quantify blood flow. PC-MRI can be employed to encode blood flow 

velocities along all dimensions and offers the possibility to acquire spatially registered information on threedirectional 

blood flow simultaneously with the morphological data within a single examination. 4D flow MRI 

permits the assessment of three-directional blood flow within entire 3D vascular structures in-vivo. In addition 

to the 3D visualization of complex cardiac and vascular flow patterns, quantitative flow analysis and derived 

vessel wall parameters such as wall shear stress (WSS), pulse wave velocity, or 3D pressure difference maps can 

provide quantitative information on the impact of altered hemodynamics associated with vascular pathologies. 

Since flow-sensitive 4D MRI provides full temporal and spatial 3D coverage, the distribution of vessel wall and 

flow parameters along an entire vessel of interest can be derived from a single measurement without being 

dependent on predefined multiple 2D acquisitions. The presentation will provide an introduction into 

methodological aspects related to dynamic 3D flow MR imaging, 3D visualization, and quantification of 

vascular hemodynamic based on 4D flow MRI. Applications and recent advances for the evaluation of normal 

and pathological 3D blood flow in different vascular territories will be discussed, with a focus on intracranial 

and cervical vascular hemodynamic. 



Flow characteristics in a study of 300 MS patients (E. Mark Haacke, USA) 

Studies of venous flow of MS patients have been performed mostly with ultrasound imaging. Our recent work 

using contrast enhanced MRA (CE-MRA), 2D time-of-flight MRV (TOF-MRV) and phase contrast MRI (PC-MRI) 

has shown that the internal jugular vein (IJV) flow at the cervical 6 (C6) level is reduced for patients with 

anatomically stenotic IJVs. In this work, we study the venous flow characteristics in MS patients. The study was 

approved by local institutional review board. Three hundred (300) clinically definite MS patients signed 

informed consent forms and participated in the study. Three-dimensional CE-MRA data were collected to 

locate IJV stenoses by examination of the vasculature and multiple 2D TOF-MRV data with high in-plane 

resolution was used to measure vessel cross-sectional area (CSA) to determine stenoses. Thresholds of 25mm 2 

around the cervical 6 (C6) level and 12.5mm 2 around the C2 level were used to determine IJV stenosis. Based 

on this stenosis assessment, all MS subjects were divided into 2 groups, non-stenotic (NST) and stenotic (ST). 

Blood flow was measured with 2D PC-MRI imaging around C6 level perpendicular to the IJVs on a 3T Siemens 

Magnetom Tim Trio with the following parameters: TR = 14.4ms, TE = 4.41ms, flip angle = 25 o , FOV = 

256mm×256mm, in-plane resolution = 0.57mm×0.57mm, slice thickness = 4mm and maximum encoding 

velocity (VENC) = 50cm/sec. Retrospective pulse gating was used and a total of 25 images were reconstructed 

during one cardiac cycle. Vessel segmentation was achieved manually using our in-house MATLAB software. 

Occasional aliasing in major vessels was mostly corrected by a simple phase unwrapping algorithm [2]. 

Statistical analysis was performed to compare the quantitative findings among the groups. Paired and unpaired 

t-tests were performed as appropriate to evaluate the statistical significance of the differences. The flow images 

from all subjects were inspected to insure good quality. Of the 300 subjects, the flow data from 22 cases were 

deemed of bad quality and were not included in the study. 

Of the remaining 278 subjects, 135 (48.6%) were determined to be in the NST group and 143 (51.4%) in the ST 

group. There was no significant difference between the total arterial flow rates for the NST and ST groups 

(16.4±2.6, 16.7±2.9, respectively; p=0.40). This finding indicate that the method was not biased toward any 

group for flow measurement. On the venous side, the blood flow through the LIJV was found to be significantly 

less than that of the RIJV (4.6 ± 2.1 vs. 7.0 ± 2.4mL/sec, respectively; p2/3), (34.1, 56.6) % were type II (1/3


A Physics Link Between Cerebral Venous Reflux and Venous Hypertension, Hypoxia and Scleroses 

(Trevor Tucker, CANADA) 

This presentation postulates that an obstruction at a lower extremity of an internal jugular vein (IJV), in 

accordance with the physics of fluid dynamics, causes a standing pressure wave within the vein. This pressure 

wave would possess regions of large pressure fluctuations and other regions of relatively little fluctuation which 

also have substantially lower peak pressure values. If the wavelength of the pressure wave is comparable to the 

distance from the obstruction to the venule end of the capillary bed, then a region of high pressure fluctuation 

would exist at the venules. Depending on the degree of obstruction, the pressure fluctuations at the venules of 

the capillary bed could be substantially greater than those that would exist in a healthy, unobstructed vein. 

This increase in blood pressure fluctuation at the venule end of the capillary bed, which would be equivalent to 

local hypertension, is predicted to reduce the pressure drop across the bed which, in turn, would reduce blood 

flow through the bed in accordance with Darcy’s Law. Such a reduction in blood flow through the bed would 

be accompanied by a reduction in the transfer of oxygen, glucose and other nutrients into the brain tissue in 

accordance with Fick’s Principle. The reduction in oxygen levels in the brain tissue (i.e. hypoxia), would, in turn, 

be associated with increased fatigue and decreased mental acuity in the subject patient. In addition, cerebral 

hypoxia may be associated with vasoconstriction of the endothelium and promotion of both leukocyteendothelial 

adherence and angiogenesis (ie. growth of collateral veins). The deprivation of oxygen adjacent to 

the venules may also result in cell death, including endothelial, and oligodendrocyte cells. The death of 

oligodendrocyte cells would result in the deterioration of the myelin surrounding the brain’s neural axons. The 

presentation also postulates that, in cases of sufficient obstruction, particularly with a hypoxia-weakened 

endothelium, localized hypertension at the venule end of the capillary bed may be sufficiently high to cause a 

disruption in the blood-brain barrier. Such a disruption of the blood-brain barrier could then allow the 

migration of leukocytes from the blood into the brain tissue, enabling autoimmune cell attack on myelin, which 

has deteriorated from the reduction in repair function normally provided by oligodendrocyte cells. In addition, 

the presentation also briefly addresses other factors, such as gender, aging, vitamin D deficiency, cigarette 

smoking and viral infection on the potential amount of local hypertension, on endothelium compliance and on 

a potentially enhanced predisposition toward blood-brain barrier disruption and leukocyte cell attack on 

weakened myelin. Such leukocyte attack on myelin has long been associated with multiple sclerosis. 



Investigating the vasculature of the eye (Timothy Q. Duong, USA) 

The ocular circulation plays a crucial role in maintaining proper function of the eye and the retina. Starting from 

the ophthalmic artery, the posterior ciliary artery divides into (i) the temporal and nasal long posterior ciliary 

arteries (LPCA) supporting the choroid, ciliary body, and iris, and (ii) the central retinal artery which branches 

radially on the retinal surface supporting the inner retina (1). The retina is nourished by the retinal and 

choroidal circulations (2). The retinal vessels penetrate inner portion of the retina, whereas the choroidal vessels 

are located outside the retina, behind the retinal pigment epithelium. The outer retina, located between these 

two vascular layers, is avascular. In addition to the needs for very high spatial resolution, the eye is located in a 

region of high magnetic susceptibility and eye motion. This presentation will describe some challenges and 

solutions to performing high-resolution MRA, blood flow and other hemodynamic-based MRI to investigate 

the retinas under basal conditions and evoked responses. These studies may prove useful in studying 

microvascular pathologies and neurovascular dysfunction in the eye and retina. 



Retinal abnormalities in multiple sclerosis patients with associated chronic cerebrospinal venous insufficiency 

(Marian Simka, POLAND) 

This study was aimed at the assessment of retinal abnormalities in multiple sclerosis patients in the context of 

chronic cerebrospinal venous insufficiency using optical coherence tomography (OCT) of the retina and the 

optic nerve. We examined 239 multiple sclerosis patients, including 220 patients with associated chronic 

cerebrospinal venous insufficiency and 19 MS patients without venous pathology. The following OCT 

parameters were assessed: average ganglion cell complex thickness, global loss volume, focal loss volume and 

average retinal nerve fibre layer thickness. Abnormalities in azygous and internal jugular veins were evaluated 

using catheter venography. We found a much higher prevalence of abnormal OCT parameters in the patients 

with previous history of optic neuritis, not only on the side of inflammatory event, but also in the contralateral 

eye. This finding is in line with already existing body of evidence. The new and intriguing discovery is that we 

found statistically significant higher prevalence of abnormal OCT values in multiple sclerosis patients with 

unique type of vascular abnormality, namely: with unilateral stenosis of internal jugular vein. Patients who were 

not found venous abnormalities, as well as those presenting with pathologic azygous or bilateral internal 

jugular venous outflows, did not demonstrate a changed frequency of abnormal OCT parameters. Potential 

association between venous malformations and eye manifestations of multiple sclerosis, as has been 

demonstrated in this report, justifies further studies on this topic. 

Financial disclosure: American Access Care, Euromedic Specialist Clinics


CCSVI – The Eyes Have It (Diana Driscoll, USA) 

The eye is the only place in the body that allows us to view blood vessels directly, without dye or the need to 

look through tissue. The optic nerves are considered to be an extension of the brain and are also easily visible. 

The eyes give us unparalleled access to information involving neurovascular disease. Dr. Diana, both a doctor 

and a patient (Ehlers-Danlos Syndrome with Postural Orthostatic Tachycardia Syndrome and early MS), has a 

unique vantage point to offer clinical research and will discuss the implications of the results of one of her 

clinical trials examining the fundus of patients with a high probability of CCSVI. She will also discuss clinical 

applications of her “cavernous sinus theory” and how it affects those with MS, EDS/POTS and Chronic Lyme 

disease, adding credence to the effects of CCSVI on these patients. Finally, by considering the causes of the 

ocular findings in these patients and tying them into systemic manifestations of neurovascular disease, she has 

been able to focus on new therapeutic targets for both systemic treatment and prevention of restenosis postangioplasty. 

She discusses her theory on how the onset and progression of many of these neurovascular 

disorders occur, what they have in common, and how unique, early therapeutic trials are resulting in significant 

improvements in symptoms -- including reversal of diplopia, clearing of brain fog, return of executive function, 

greatly improved autonomic function, halting of the formation of brain lesions, and an overall improvement in 

functionality and sense of well being. 

Financial disclosure: National CCSVI Society

WEDNESDAY – FEBRUARY 22, 2012 8:50am-9:10am 

MRI outcomes in MS (Robert Zivadinov, USA) 

Multiple sclerosis (MS) is considered an inflammatory neurologic disease with suspected autoimmune origin 

that is characterized by pathologic changes, including the presence of multifocal, demyelinated plaques 

associated with inflammatory reaction and glial scar formation. It is characterized by myelin destruction and 

repair as well as axonal loss, which cause intermittent and accumulating neurological dysfunction along 

immunopathogenic mechanisms which are still unknown. MR imaging has become a routine clinical 

examination in MS and is used to help the diagnosis and monitoring of the natural course of the disease. 

Characteristic MS abnormalities, commonly seen as areas of high signal throughout the central nervous system 

(CNS), are best demonstrated by proton-density or T2-weighted images (T2-WI); T1-weighted images (T1-WI) 

reveal hypointense abnormalities that, if permanent, are proven to correlate with axonal loss and severe matrix 

destruction. Gadolinium (Gd)-enhanced MRI is 5-10 times more sensitive than clinical data in the assessment of 

disease activity, and reveals leakage through the blood-brain barrier (BBB), which is thought to be the earliest 

detectable change in the development of new lesions. Not only is MRI of great value in supporting a diagnosis 

of MS, but also several of its metrics are valid surrogate marker for monitoring disease evolution both in 

natural history and in experimental trials. Currently the number of new and enlarged lesions on serial T2- 

weighted imaging (WI) and the number and the volume of total or new enhancing lesions on serial postcontrast 

T1-WI are the main MRI endpoint measures used in MS clinical trials. However, neither of the 

conventional MRI metrics provide sufficient information about the extent and severity of the inflammatory and 

neurodegenerative phases of the disease. Non-conventional MRI techniques appear to be better surrogate 

markers for monitoring the destructive pathological processes related to disease activity and clinical 

progression. They are able to reveal the underlying substrate of intrinsic pathology within lesions and normal 

appearing brain tissue (NABT) that include edema, inflammation, demyelination, axonal loss, and 

neurodegeneration. They contribute to the increasing evidence for gray matter (GM) pathology in patients with 

MS, revealing plaques in the periventricular and deep white matter (WM) of the hemispheres, extensive 

demyelination in the cerebral cortex, and severe atrophy of both WM and GM. Hypointense lesions on T1-WI 

(black holes), the use of new cell-specific contrast agents, magnetization transfer imaging (MTI), myelin water 

fraction (MWF), diffusion-weighted and tensor imaging (DWI and DTI), proton MRI spectroscopy (MRS), 

susceptibility-weighted imaging (SWI), functional MRI (fMRI) and high field MRI are emerging as promising 

tools for improving our understanding of the pathophysiology of MS. Due to their ability to detect the 

neurodegenerative aspects of MS, including recent evidence for cortical demyelination, these techniques are 

receiving increased attention as clinically relevant markers of disease progression. 



Cognitive outcomes in MS (Ralph Benedict, USA) 

Multiple sclerosis (MS) is associated with cognitive deficits that include problems in auditory/verbal memory, 

visual/spatial memory, cognitive processing speed/working memory, and executive control/function. Given that 

an extensive battery to assess these varied domains is not feasible in most clinical trials, brief cognitive 

assessments have been proposed that are psychometrically sound regarding sensitivity, reliability, and validity. 

In this presentation, the speaker will summarize the results from two task forces on this topic: [a] the NINDS 

Common Data Elements Work Group, and [b] the Brief International Cognitive Assessment for MS (BICAMS). 

Both programs have recommended the Symbol Digit Modalities Test, a measure of cognitive processing speed, 

for MS clinical trials. In addition, memory and executive function outcomes have been suggested for 

circumstances that permit a more comprehensive assessment. Future work is planned to further validate these 

outcomes with respect to clinically meaningful change. 

Financial Disclosure: Biogen Idec, Bayer, EMD Serono, Genzyme, Accorda Shire


CCSVI interdisciplinary approach (Bianca Weinstock-Guttman, USA) 

Recently, a new vascular condition called chronic cerebrospinal venous insufficiency (CCSVI) was proposed to 

be linked to multiple sclerosis (MS). CCSVI is characterized by impaired blood outflow from the central nervous 

system to the periphery, secondary to anatomical abnormalities of the major neck and azygos veins. As of now, 

the available data cannot determine whether CCSVI is a cause, consequence or mere association with MS 

although the higher prevalence of CCSVI found in progressive MS patients may suggest that CCSVI may play a 

contributory role on disease progression. Similarly the role of intra- and extra-cranial venous system 

impairment in the pathogenesis of other various vascular inflammatory and neurodegenerative disorders 

requires further evaluation. Physiological inter-individual variation of the cerebral venous anatomy and the lack 

of standardized diagnostic guidelines for evaluation of the intra- and extra-cranial cerebrospinal venous system 

provided contradictory findings and consequently more questions are raised than plausible answers were 

given. Taking in consideration these multiple challenges only a corroborative team work that include vascular 

specialists, neurologists with special interest in MS and neuroimaging will be necessary to provide the 

appropriate network to understand, assess and eventual treat CCSVI. Further studies are necessary to define 

the role of CCSVI in health vs. disease in general and in MS and other inflammatory conditions in special before 

any open label therapeutic interventions are implemented. 

Financial Disclosure: Teva Neurosciences, Biogen Idec, EMD Serono, Pfizer, Novartis, Acorda, ITN


Lessons from endovascular management of lower extremity venous obstruction (Seshadri Raju, USA) 

Management of symptomatic chronic venous disease has largely focused on reflux. With modern imaging 

techniques, it is now recognized that iliac vein obstruction is present in over half the general population in 

silent form. In CVI patients with severe symptoms, such lesions are present in >90% when examined with IVUS. 

The obstructive lesions are present at arterial crossover points in primary disease; postthrombotic lesions are 

more diffuse. In either case diagnostic sensitivity of venograhy or other venous testing is only about 50%; that 

of IVUS is ≈90%. In about 30% of CVI patients, Iliac vein obstruction is the only discernible pathology and 

should be suspected when distal reflux is trivial or absent. In postthrombotic limbs, the obstructive iliac lesion 

which may be occult on venography, is the symptomatic pathology even when venographic femoro-popliteal 

disease is readily apparent. In a series of 982 limbs cumulative patency of iliac vein stents were an astonishing 

100% for primary limbs and 86% for postthrombotic limbs at 6 years. There was no mortality and morbidity 

was minimal (1.5%). There was significant improvement of pain and swelling in 74% and 62% (cumulative) with 

complete relief of these symptoms in 65% and 32% respectively at 6 years. Quality of life (CIVIQ) improved 

significantly. Clinical outcome was substantial and durable even when associated severe reflux including axial 

reflux was left uncorrected. 58% (cumulative) of active ulcers most with underlying uncorrected reflux healed 

and remained healed at 6 years after stent placement. Iliac vein stenting is easily combined with percutaneous 

saphenous ablation when significant saphenous reflux is present. Iliac vein stenting is the corrective procedure 

of choice in symptomatic CVI patients. 

Financial Disclosure: Veniti, Inc.


Consequences of venous obstruction involving other vascular beds (Salvatore Sclafani, USA) 

This presentation will focus upon venous obstructions caused by compressive forces outside the cerebrospinal 

venous circuit that may result in OUTFLOW obstruction or increased INFLOW into the cerebrospinal venous 

circuit. Venous thoracic outlet syndrome relates to obstruction of the axillary or subclavian vein as it exits the 

chest over the first rib. Also known as Paget Schroetter disease, it is a thrombosis caused by subclavian 

stenosis, often after vigour exercise. Patients present with a painful swollen and cyanotic upper extremity with 

weakness and paresthesia. Collateral veins are visible in the chest and shoulder. On occasion, it may cause 

OUTFLOW obstruction of the valvular area of the inferior jugular vein and may increase INFLOW into the 

cerebrospinal circuit by collaterals extending into the neck from the upper extremity. Renal vein stenosis 

caused by compression, most commonly by the aorta and superior mesenteric artery, is referred to as the 

Nutcracker phenomenon when asymptomatic and the Nutcracker syndrome when symptoms are present. 

Symptoms and signs include proteinuria, hypertension, unilateral hematuria, chronic back or pelvic pain, 

varicoeles and pelvic congestion syndrome, and, interestingly, chronic fatigue. MRI, CT and ultrasound are 

noninvasive screening tests; venography with hemodynamic measurements and intravascular ultrasound are 

confirmatory. In renal vein obstruction, hemiazygous and ascending lumbar collaterals may become 

cerebrospinal INFLOW veins of significance because renal venous blood flow is so great (500 ml/min). 

Endovascular stenting and reimplantation or transposition procedures are the treatment of choice. May- 

Thurner syndrome describes a clinical scenario associated with compression of the left iliac vein between the 

right common iliac vein and the lower lumbar spine. Originally thought to occur in young overweight teenaged 

and young adult women, it is found in about 37% of patients with history of DVT or reflux. Symptoms include 

progressive leg edema with no history of thrombotic problems, venous claudication, and mild complaints 

consistent with chronic venous insufficiency. Physical examination can demonstrate mild to severe edema, 

chronic leg skin changes, development of varicosities, significant venous collateral vessels, and ulceration. CT 

and MR may show compression, but venography with hemodynamic measurements and intravascular 

ultrasound are definitive. Venous collateral vessels include cross pelvic venous drainage and the left ascending 

lumbar vein that can act as a cerebrospinal INFLOW vein. Failure to treat the stenosis after iliac DVT is 

associated with persistent occlusive disease. Treatments include thrombectomy or thrombolysis and stenting. 

Financial Disclosure: American Access Care Physicians


Open procedures are now reserved for stent failures only Occlusion, recanalization and thrombolysis 

(Bulent Arslan, USA) 

Disorders of the venous circulation is a common medical problem, well know by all health personnel as 

opposed to CCSVI which is not even known by many physicians. Venous disorders include thrombosis of the 

deep veins, which may result in pulmonary emboli, a deadly condition. Etiologies of stenoses or occlusions of 

veins can be congenital, external compression or mass lesions (tumors, lymph nodes, muscles, etc). If condition 

is simple such as isolated thrombosis of femoro-popliteal veins then treatment is systemic anticoagulation. 

However if the condition is more complex resulting in significant symptoms, pain, patient discomfort, ischemia 

of the leg, ambulation problems then endovascular interventions usually provide relief, utilizing catheter 

directed thrombolysis, thrombectomy, angioplasty and stenting. Venous problems most commonly involve the 

lower extremities, but upper extremity involvement is not uncommon and management is similar except in 

cases of anatomic compression of the subclavian veins (Thoracic Inlet Syndrome), which requires surgery as a 

definitive treatment. A relatively less know condition,” Pelvic Congestion Syndrome” is also being recognized 

more and more commonly. PCS is development of varicosities of the pelvic veins and sometimes associated 

with outflow obstruction, namely compression of the left renal vein by superior mesenteric artery (Nutcracker 

Syndrome). In addition to embolization of the pelvic veins, stenting of the renal vein by improving venous 

outflow provides relief in these patients who present with chronic pelvic pain. Similarity of the anatomic 

problems to CCSVI is interesting. 


WEDNESDAY – FEBRUARY 22, 2012 1:20pm-1:40pm 

Collagen Expression in Neck Brain Draining Veins (Matteo Coen, SWITZERLAND) 

Venous anomalies have been associated with different neurological conditions and the presence of a vascular 

involvement in multiple sclerosis (MS) has long been ascertained. In view of the recent debate regarding the 

existence of cerebral venous outflow impairment in MS due to anomalies of the azygos or internal jugular veins 

(IJVs), we have studied the morphological and biological features of brain draining veins in MS patients. We 

examined: 1) IJVs specimens (N=5) from MS patients with diagnosis of chronic cerebrovascular venous 

insufficiency who underwent surgical reconstruction of the IJV, as well as specimens of the great saphenous 

vein (N=2) used for surgical reconstruction; 2) different vein specimens (N=9) from a MS patient dead of an 

unrelated cause; and 3) autoptical and surgical IJV specimens (N=10) from patients without MS. Collagen 

deposition was assessed by means of Sirius red staining followed by polarized light examination. The 

expression of collagen type I and III, cytoskeletal proteins (α-smooth muscle actin and smooth muscle myosin 

heavy chains), inflammatory markers (CD3 and CD68) were investigated. The extracranial veins of MS patients 

showed focal thickenings of the wall characterized by a prevailing yellow-green birefringence (corresponding 

to thin, loosely packed collagen fibers) correlated to a higher expression of type III collagen. No differences in 

cytoskeletal protein and inflammatory marker expression were observed. The IJVs of MS patients presenting a 

focal thickening of the vein wall are characterized by the prevalence of loosely packed type III collagen fibers in 

the adventitia. The role of this finding in MS pathogenesis needs further testing. 



Is CCSVI a disease? (Robert Zivadinov, USA) 

A condition called chronic cerebrospinal venous insufficiency (CCSVI) has been proposed and reported with 

high frequency in patients with multiple sclerosis (MS), although the condition was also found in patients with 

other CNS diseases and subjects without known CNS pathology. More recent reports suggest that some non- 

CNS diseases (especially of the bowel system) may be associated with CCSVI. CCSVI is described as a vascular 

condition characterized by anomalies of the main extra-cranial cerebrospinal venous routes that possibly 

interferes with normal blood outflow of brain parenchyma. In order for CCSVI to be a disease, a phenotype of 

clinical symptoms associated with this condition needs to be determined. The rate of transfer of nutrients 

(primarily oxygen and glucose) from the capillary bed into the brain fluid is proportional to the rate of blood 

flow through the capillary bed. An obstruction of the extra-cranial venous drainage pathways may significantly 

reduce the supply of brain nutrients and potentially result in hypoxia. In a recent prospective, 12-month, 

Endovascular Venous Treatment for MS (EVTMS) follow-up study that enrolled 15 MS patients, we noticed that, 

post intervention, the majority of treated patients reported immediate temporary improvements in subjective 

complaints of fatigue and cognitive impairment. In another recent study, the reestablishment of cerebral 

venous return reduced chronic fatigue perception in a group of 31 MS patients with CCSVI who underwent the 

endovascular procedure, suggesting that fatigue could likely be associated with CCSVI. Neither study was 

randomized, controlled or blinded; however, both suggest that the impact of removing an obstruction in the 

IJV or azygos veins could increase blood flow through the cerebral capillary bed, with consequent increase in 

the transfer of oxygen, glucose and other nutrients into the brain, which may result in immediate temporary 

reduction of subjective complaints of fatigue and cognitive impairment. Additional improvement of symptoms 

may be related to PTA of extra-cranial veins. These include headache, sleep disturbances, brain fog, and 

heating. It remains to be determined whether the presence of CCSVI is characterized by a particular clinical 

phenotype in patients with CNS and non-CNS diseases. The clinical phenotype will likely depend on the 

regional predilection of CCSVI pathology. 



A national approach to gather prospective data for MS outcomes 

(Donald J. Ponec, USA and David Hubbard, USA) 

The Society for Interventional Radiology Consensus Panel, published in 2011, recommended that all 

interventional radiologists doing the CCSVI procedure participate in studies or registries to promote the 

collection of clinical outcome and adverse event data. At the present time in the United States we are aware of 

only one placebo-controlled trial conducted by Dr. Zivadinov and colleagues at the University of Buffalo, and 

two uncontrolled registries, one by Dr. Siskin at the University of Albany and one by the Hubbard Foundation 

based in San Diego. It is currently unknown how many venoplasty procedures on MS patients are being 

performed by IRs or vascular surgeons outside of any study or registry. We call on the ISNVD, SIR, AAN and 

the various MS societies to strongly encourage patients who choose to pursue treatment to do so only under 

the auspices of a study or registry. Minimal requirements include collection of adverse events, a measure of 

clinical outcome such as a quality of life measure, documentation of pre-treatment testing such as Dopplerultrasound 

and MR venography, and documentation of the procedure including sites treatment, balloon sizes 

and pressures and stents. We recognize that serial MRIs to monitor lesion load and atrophy may be unrealistic 

given the costs and lack of funding sources, and that more data is needed before a comprehensive 

randomized, blinded placebo controlled study can be designed and implemented. However, every effort should 

be made to include this data in order to properly document and understand if possible why this procedure 

works for some sub-category of MS patients while not for others. 

Financial Disclosure: American Access Centers (Ponec) 

Financial Disclosure: Vascular Access Center, CCSVI Alliance (Hubbard)


CCSVI Clinical Trial Design from a Neurologist’s Perspective (Jack Burks, USA) 

In Sunday’s talk I discussed the opportunity for a collaborative approach to designing and implementing 

scientifically rigorous research to put CCSVI into perspective. For most neurologists, they do not know what to 

think of CCSVI except over 100 other “breakthrough treatments” for MS have reached this stage of patient 

interest – and none have been successful over time. Therefore, to get involved, most neurologists are insisting 

on scientifically sound data as well as a halt to the commercialization (charging patients for angioplasty) on 

desperately ill MS patients. Legitimate clinical trials should precede “fee for service”. Further, much CCSVI data 

at neurology meetings are negative, i.e. CCSVI does not exist. “Why should we fund studies to get rid of flying 

saucers?” Most believe CCSVI will naturally go the way of snake venom and bee stings. However, collaborative 

efforts are gaining attention from some neurologists. The next step is developing a trusting collaboration 

between Neurologists, CCSVI Diagnosticians and Endovascular Interventionalists. This also might include 

patient groups, immunologists, iron metabolism experts, other health care professionals, MS advocacy groups, 

and other interested parties. A format: A multidisciplinary steering committee convenes a conference entitles 

“What do we really know about CCSVI and MS - and how can we put CCSVI into a scientific and clinical 

perspective through more scientific research?” Six questions will begin the collaborative process. 1) What data 

do we agree are known facts about CCSVI and MS, based on solid scientific data? 2) What postulates do we 

think might be true, but lack solid scientific data? 3) What postulates do we agree are not known? 4) What 

research is needed to fill the knowledge gaps? Prioritize these issues. 5) What are the roles of each 

collaborative group in implementing the research designs and clinical trials? 6) How can the research be 

funded? With this approach, scientific data will drive the CCSVI success – or not. 

Financial Disclosure: Acorda, Allergan, Avanir, Bayer, Novartis, Serono, Sanofi-Aventis

ORAL ABSTRACTS 

Monday, February 20, 2012 

ID Title First Author Time 

157 Evaluation of cerebrospinal fluid flow in multiple sclerosis patients using phase contrast Marcella Lagana 11:30am-11:35am 

MRI 

133 A lumped-parameter model for the study of cerebrospinal venous flow Stefania Marcotti 11:35am-11:40am 

122 Consensus on ultrasound chronic cerebrospinal venous insufficiency screening criteria Sandra Morovic 4:20pm-4:25pm 

Tuesday, February 21, 2012 


124 Assessing Abnormal Iron Content in Deep Gray Matter of Patients with Multiple Charbel Habib 11:40am–11:45am 

Sclerosis versus Healthy Subjects 

139 Iron deposition in clinically isolated syndrome Jesper Hegemeier 11:45am–11:50am 

143 Iron deposition and disability in MS Robert Zivadinov 11:50am–11:55am 

Wednesday, February 22, 2012 


91 Quality of Life Changes After Endovascular Treatment for CCSVI in Patients with MS Kenneth Mandato 1:40pm–1:45pm 

92 The Role of Doppler Ultrasound in the Diagnosis of Chronic Cerebrospinal Venous Kenneth Mandato 1:45pm–1:50pm 

Insufficiency (CCSVI) in Patients with Multiple Sclerosis 

112 Internal jugular vein valve morphology in the patients with CCSVI; angiographic findings Mamoon Al-Omari 1:50pm–1:55pm 

and schematic demonstrations 

132 Enhanced imaging of simultaneous TOF-MRA and SWI Yongquan Ye 1:55pm–2:00pm 

134 The Cerebral Perfusion Patterns of Patients with Multiple Sclerosis (MS) using MRI Yi Zhong 2:00pm–2:05pm 

167 Flow through Internal jugular vein is reduced for multiple sclerosis patients with 

stenoses compared to those without observed by MRI 

165 Intravascular Ultrasound for detection of Azygous and Internal Jugular vein (IJV) 

abnormalities as part of the PREMiSe (Prospective Randomized Endovascular therapy in 

Multiple Sclerosis) study 

166 Measurement of Azygos venous blood flow in patients with Multiple Sclerosis using 

MRI 

113 Prevalence of Chronic Cerebrospinal Vascular Insufficiency (CCSVI) in patients with 

multiple sclerosis and healthy controls: a systematic review of the literature and 

metaanaalysis 

Wei Feng 

Yuval Karmon 

Aisha Tai 

Andrew Dueck 

2:05pm–2:10pm 

2:10pm–2:15pm 

2:15pm–2:20pm 

2:25pm–2:25pm

POSTER ABSTRACTS 

Monday, February 20, 2012 


129 Does Thoracic pump influence blood flow velocity in cerebral veins? Erica Menegatti 10:05am-10:10am 

119 Azygos compression and effect of respiratory cycle during CCSVI Venography Michael A. Arata 10:10am–10:15am 

141 Multimodal imaging approach sclerosis for screening of chronic cerebrospinal venous Kresimir Dolic 10:15am–10:20am 

insufficiency in patients with multiple 

140 Iron deposition in pediatric multiple sclerosis patients Jesper Hegemeier 2:35pm–2:40pm 

142 Iron deposition in multiple sclerosis lesions Jesper Hegemeier 2:40pm–2:45pm 

125 Mathematical model for the hemodynamics of extracranial veins: effect of posture and 

respiratory maneuver 

114 Interventionalist Documentation of Fluoroscopy Time in Venous Angioplasty for CCSVI 

Reports Correlated With Lower Fluoroscopy Times 

Lucas O. Mueller 

Nina Grewal 

2:45pm–2:50pm 

2:50pm–2:55pm 

Tuesday, February 21, 2012 


158 Cardiac effects in the multiple sclerosis patient – implications for avoidance of Diana Driscoll 10:05am–10:10am 

restenosis after CCSVI angioplasty 

137 Venous Angioplasty In Multiple Sclerosis: Long Term Clinical Outcome Of A Cohort Of Fabrizio Salvi 

10:10am–10:15am 

Relapsing-Remitting Patients 

147 Acetazolamide as a medical treatment option for patients with neurodegenerative Diana Driscoll 10:15am–10:20am 

disease in conjunction with or independent of, angioplasty for Chronic 

121 Evaluation of muscle metabolism in multiple sclerosis: A near infrared spectroscopybased 

Anna Maria Malagoni 10:20am–10:25am 

approach 

130 A model of filtration and transport of solutes across the Blood Brain Barrier Laura Facchini 3:05pm–3:10pm 

97 Endovascular management of CCSVI: Single Center Experience Hector Ferral 3:10pm–3:15pm 

95 Removal of the obstructions in the extracranial venous pathway improves the clinical 

disability in multiple sclerosis 

115 Quality of Life Improvement after Endovascular Treatment of Chronic Cerebrospinal 

Venous Insufficiency 

Miro Denislic 

Nina Grewal 

3:15pm–3:20pm 

3:20pm–3:25pm 

Wednesday, February 22, 2012 


131 Improvement of chronic fatigue after endovascular treatment for chronic cerebrospinal Marian Simka 

10:05am–10:10am 

venous insufficiency in the patients with multiple sclerosis 

126 Treatment Outcomes for CCSVI in the UK Barun Majumber 10:10am–10:15am 

94 Findings on Venography in MS Patients Undergoing an Evaluation for CCSVI: Kenneth Mandato 10:15 am–10:20am 

Correlation with MS Subtype and the Presence of Visual Symptoms at the Time 

117 Adverse Post CCSVI Treatment Outcome - A Case Report - What We Can Learn Raj Attariwala 10:20am–10:25am 

154 Vascular fundus changes observed in patients with high probability of CCSVI (Chronic Diana Driscoll 2:35pm–2:40pm 

Cerebrospinal Venous Insufficiency) 

155 Does metal-induced hypersensitivity, a risk factor for venous stenosis and restenosis, Vera Stejskal 

2:40pm–2:45pm 

contribute to brain and venous abnormalities in multiple sclerosis sufferers? 

168 Bruxism and Temporal Bone Hypermobility in Patients with Multiple Sclerosis David Williams 2:45pm–2:50pm 

167 Flow through Internal jugular vein is reduced for multiple sclerosis patients with 

stenoses compared to those without observed by MRI 

Zhen Wu 

2:50pm–2:55pm

Evaluation of Cerebrospinal Fluid Flow in Multiple 

Sclerosis with Phase Contrast MRI 

Laganà MM 1 , Balagurunathan D 2 , Chaudhary A 2 , Utriainen D 2 , Hubbard D 3 , Haacke EM 2,4 . 

1 

Magnetic Resonance Laboratory, Fondazione Don Gnocchi, IRCCS Santa Maria Nascente, 20148 Milan, Italy; 2 Magnetic Resonance Innovations, Inc., Detroit, 

MI 48202; 3 Applied fMRI Institute, San Diego, CA 92131; 4 Departments of Radiology and Biomedical Engineering, Wayne State University Detroit MI 48201. 

INTRODUCTION AND AIMS 

The relationship between the cerebrospinal fluid (CSF) flow, blood flow 

and pulsatile brain movement have been modeled for 20 years as a 

hemodynamic phenomena consequent to the systolic arterial inflow to the 

brain [1], [2]. Phase Contrast (PC) Magnetic Resonance (MR) allows for 

the investigation and quantification of arterial, venous, CSF flow and, 

therefore, provides the potential for understanding their mechanical 

coupling. It has been used for the study of healthy volunteers [3]-[6] and 

pathological diseases [7]-[9]. An unbalance in the temporal coupling and 

amplitude changes of the flow curves has been evaluated as responsible for 

pathological disease, such as normal-pressure hydrocephalus [8] and 

Alzheimer’s Disease [7] and to be able to predict the treatment outcome of 

Arnold-Chiari I malformation [9]. Recent pilot studies have investigated 

aqueduct CSF amplitude modifications in Multiple Sclerosis (MS) patients 

[10]-[12], showing different results. This work investigates CSF, arterial and 

venous dynamics (in terms of amplitude and mutual timing) at the level of 

the upper cervical cord in a large cohort of MS patients and in a group of 

healthy controls. 

MATERIAL AND METHODS 

Subjects: 92 MS patients [males/females=26/66, mean age(SD)= 49(10) years] 

(47 Relapsing-Remitting (RR), 28 Secondary-Progressive (SP), 17 Primary 

Progressive (PP) and 28 healthy controls (HC) [males/females=13/15, mean 

age(SD)= 42(11) years]. 

MRI protocol: Brain axial FLAIR, TOF of the neck and axial 2D PC positioned at 

C2 level were obtained from all the MS patients with a 3T Siemens scanner and 

from the healthy subjects with a 3T or a 1.5T Siemens scanner. PC sequence 

was acquired twice, with VENC=15cm/s (PC15) for the CSF flow measure and 

with VENC=50cm/s (PC50) for the vessels of the neck flow measures, with pulse 

triggering for cardiac gating. 

MRI processing: In-house software (FlowQ) was used for the flow quantification. 

Regions Of Interest (ROIs) were manually drawn for the CSF area (sequence 

PC15) and the for the vessels as shown in Figure 1 (sequence PC50). Phase 

values of every pixel inside the ROIs were mapped to velocity (offset correction 

with ROIs in the muscle area). Siemens convention: caudal velocities are 

negative, cranial velocities are positive. 

Flow parameters and statistical analysis: Estimation of: flow rates as a function of 

the cardiac cycle (CC); peaks amplitude and timing (%CC) of Internal Carotid 

Arteries (ICAs), Internal Jugular Veins (IJVs) and CSF flow rates; CSF stroke 

volumes (separate integration of the positive and negative CSF flow rate curves); 

Cerebral Blood Flow (CBF) as the sum of all the measured arterial flows. 

Independent t-tests were used for group comparisons. Correlations between 

variables have been assessed with Spearman’s rank correlation coefficient. 

Figure 1 – 1: Magnitude image; 2: Phase image; A: localization of 1-2 images at C2 level for the flow quantification of the main 

arteries and veins. 3: Magnitude image; 4: Phase image; B: localization of 3-4 images at C2 level for the CSF flow quantification. 

Cranial 

Caudal 

Outflow 

onset 

Systolic peak 

CSF negative 

peak 

Systolic IJVs peaks 

End of 

Outflow 

Figure 2 – Parameters computed by the CSF, ICAs and IJVs flow curves. 

RESULTS 

CSF flow curves showed the usual bimodal pattern for both MS and 

controls, but with different CSF caudal peak flow rate (p

POLITECNICO DI MILANO 

mlagana@dongnocchi.it 

stefania.marcotti@mail.polimi.it 

A lumped-parameter model for the study of 

cerebrospinal venous flow 

Marcotti S 1 , Marchetti L 1 , Laganà MM 2 , Fiore GB 1 , Barberio A 2 , Viotti S 3 , Votta E 1 , 

Redaelli A 1 , Cecconi P 2 

1 

Bioengineering Department, Politecnico di Milano, Milan, Italy; 

2 

Magnetic Resonance Laboratory, Fondazione Don Gnocchi ONLUS, IRCCS Santa Maria Nascente, 

Milan, Italy; 

3 

Università degli Studi di Milano, Milan, Italy. 

Introduction 

An impaired cerebrospinal venous drainage, defined as chronic 

cerebrospinal venous insufficiency (CCSVI), has been recently 

hypothesized to be one of the possible causes of Multiple Sclerosis (MS) [1]. It 

is possible to delve into this hypothesis modeling the venous drainage in 

brain and spinal column areas and simulating the intracranial flow changes due 

to extracranial morphological stenoses. This study aims at: 

1. constructing a lumped parameter model of the cerebrospinal venous 

district, based on anatomical data 

2. using the model for the simulation of different venous impairment 

patterns 

3. comparing the output of the model with in vivo controls’ data from 

healthy subjects 

4. comparing the CCSVI simulations with MS patients’ data 

Material and Methods 

1. A lumped parameter model of the neck and brain venous flow was created, 

grounding on anatomical knowledge. Morphology and vessels’ diameters 

and lengths were taken from literature [2]. 

• Each venous vessel was modeled as a hydraulic resistance, calculated 

through Poiseuille law 

• The inputs of the model were inlet arterial flow rates of the intracranial, 

vertebral and lumbar districts 

• The outputs were pressures and flows of each vessel, obtained solving the 

attained linear system with a Matlab® script 

2. Four pathological patterns observed in MS [1] were simulated through 

the model, properly modifying the diameters of those specific vessels 

which are supposed to be impaired by CCSVI and adding collateral 

vessels 

3. 12 healthy controls (HC) (Male/Female = 11/3; median age (range) = 

24.5 (22-52) years) were examined using a 1.5 T Magnetic Resonance (MR) 

Siemens Magnetom Avanto scanner. Neck and intracranial veins’ flow rates 

were estimated with Phase Contrast MR. MeanflowsoftheHCgroup 

were compared with the physiological output flows computed with the 

model. MR Time of Flight (TOF) images were also acquired to visualize and 

compare vessels’ morphologies 

The standard protocol for the CCSVI diagnosis [1] was used and neck 

vessels’ flow rates were estimated with Pulsed Wave Doppler ECD. 

Flow rates resulting from these simulations were compared with the 

clinical observations of the MS group. 

Fig. 3 ECD image of an internal 

jugular vein’s reflux in a MS 

patient 

Results 

Fig. 4 TCCD image of a superior petrosal 

sinus’ reflux in a MS patient 

• MRI images of the HC showed a high inter-subject morphological 

variability 

• Average values obtained in HC matched with good agreement the 

outputs of the model 

Fig. 5 Model of physiological pattern (arrows indicate flow directions). Short forms 

stand for: ophthalmic veins OVl, OVr; basal veins of Rosenthal Rl, Rr; internal 

cerebral veins ICVl, ICVr; inferior and superior sagittal sinus ISS, SSS; great vein of 

Galen GV; straight sinus SS; transverse sinus TSl, TSr; anterior and posterior occipital 

sinus POS, POSl, POSr, AOSl, AOSr; cavernous sinus CSl, CSr; superior and inferior 

petrosal sinus SPSl, SPSr, IPSl, IPSr; sigmoid sinus SSl, SSr; internal jugular veins 

IJVl, IJVr; vertebral veins VVl 1…6, VVr 1…6; cervical plexus CPa, CPp, CP 1…7; 

linkage vessels between cervical plexus and vertebral veins CPVVl 1…6, CPVVr 1…6; 

thoracic plexus TP 1…12; azygos vein AZ 1…12; linkage vessels between thoracic 

plexus and azygos vein TPAZ 1…12; inferior vena cava CV, CV1, CV2; lumbar plexus 

LP 1…2; lumbar vein LV 1…2; linkage vessels between lumbar plexus and lumbar vein 

LPLV 1…2. 

• As regards the pathological simulations, the model showed inverted flow 

direction in the venous vessels which have been usually found to be 

affected by reflux in real clinical MS cases 

Fig. 1 RM-TOF images of 3 healthy controls. Is it possible to notice the differences 

in disposition, morphology and vessels’ number 

SSIGM right 

SSIGM left 

TS left 

TS right 

SSS 

SS 

Fig. 6 Example of model of pathological pattern: by reducing diameter of IJVs and 

AZ, the model predicts inverted flow in SPS and TP, as observed in MS group 

Discussion 

Fig. 2 RM-Phase Contrast images analyzed to estimate flow rates of sigmoid sinus 

(SSIGM), transverse sinus (TS), straight sinus (SS) and superior sagittal sinus (SSS) 

4. 184 MS patients (Male/Female = 103/81; median age (range) = 42 (14- 

75) years) were evaluated by an expert radiologist with ECD and 

Transcranial Color Doppler (TCCD) Esaote MyLabVinco. 

The proposed model can predict physiological and pathological 

behaviors with good fidelity. Nevertheless, it could be improved taking into 

account vessels' compliance and the thoracic pump effect. Moreover, 

due to the high variability of vessel morphology among subjects, the 

collection of a larger number of healthy controls is mandatory, so to assess 

which hemodynamic and morphological patterns characterize this group and 

better discriminate with respect to the MS population. In general, this model 

could represent the first step towards the definition of patient specific 

models , from MRI exams. 

References 

[1] Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall'Ara S, Bartolomei I, Salvi F. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009; 80:392-399. 

[2] Newton TH, Potts DG. Radiology of the skull and brain – Angiography (Volume two/book 3; part XIII: Veins). MediBooks, Great Neck, NY 1974.

ISNVD Consensus On Ultrasound 

Chronic Cerebrospinal Venous 

Insufficiency Screening Criteria 

MOROVIC 1,2 S, MENEGATTI 1 E, VISELNER 3 G, NICOLAIDES 4 AN, ZAMBONI 1 P 

The Intersociety Faculty* 

1 

Vascular Diseases Center, University of Ferrara, Ferrara, Italy; 2 Dept. of Neurology, UHC Sestre milosrdnice Zagreb, Croatia; 3 Neurological Institute Mondino, 

University of Pavia, Pavia, Italy; 4 Vascular Screening and Diagnostic Centre, Cyprus 

Chronic Cerebrospinal Venous Insufficiency (CCSVI) is a syndrome 

characterized by stenoses or obstructions of the internal jugular vein 

(IJV) and/or azygos veins (AZV) with disturbed flow and formation of 

collateral venous channels. Most common venous lesions are truncular 

vascular malformations (intraluminal defects, segmental hypoplasia). 

In order to ensure a high reproducibility of duplex scanning with 

comparable accuracy between centres, recommendations with a detailed 

protocol, standard methodology, and criteria have been proposed. 

Even though considered a gold standard for determining the anatomical site, 

type and extent of lesions producing CCSVI, catheter venography is invasive 

and cannot be used as a screening method. Ultrasound is therefore an ideal 

screening tool; it is non-invasive, can be performed at beside, and allows a 

real-time assessment of venous status. It is a valuable diagnostic test since 

high sensitivity and specificity have been demonstrated, in presence of 

which, catheter venography will only be needed when a decision has already 

been made for intervention. 

During a Consensus Meeting, on March 13 th 2011, at the 1 st ISNVD Meeting in Bologna, Italy, experts agreed on protocol recommendations for CCSVI 

screening criteria using ultrasound. At least two criteria have to be positive for a diagnosis of CCSVI to be considered. 

The new, revised and accepted criteria are: 

1. A) Bidirectional flow in one or both of the IJVs in both postures, or bidirectional flow in one position with absence of flow in the other 

position and/or B) reversal or bidirectional flow in one or both vertebral veins (VVs) in both positions. 

Normal flow with insignificant reflux less than 0.2 

sec. 

Reflux of 0.4 sec duration. 

Reflux of 0.84 sec duration. 

2. Bidirectional flow in the intracranial veins and sinuses. (An additional criterion) 

Bidirectional flow in the IJV seen in longitudinal 

view. Red color indicated reflux. 

*International Society for Neurovascular 

Diseases (ISNVD) in cooperation with 

International Union of Angiology (IUA), European 

Venous Forum (EVF), International Union of 

Phlebology (UIP), American College of Phlebology 

(ACP), Austral- Asian College of Phlebology 

(AAsCP), Società Italiana di Chirurgia Vascolare 

ed Endovascolare (SICVE), Società Italiana di 

Angiologia e Patologia Apparato Vascolare 

(SIAPAV) 

*Faculty: D. Neuhardt (USA)-ACP representative; 

M. B. Griffin (UK)-EVF representative; C. Setacci 

(Italy)-SICVE representative; A. Cavezzi (Italy)- 

UIP representative; B. B: Lee (USA)-IUA 

representative; P. Thibault (Australia)-AAsCP 

representative; G. Andreozzi (Italy)-SIAPAV 

representative; M. Al-Omari (Jordan); S. 

Bastianello (Italy); C. B. Beggs (UK); P. Cecconi 

(Italy); V. Demarin (Croatia); C. Franceschi 

(France); A. Galassi (Italy); E. M. Haacke (USA); 

A. Lagace (Canada); N. Liasis (Greece); T. Ludyga 

(Poland); M. Lugli (Italy); O. Maleti (Italy); M. 

Mancini (Italy); M. Marioni (Italy); K. Marr (USA); 

S. McDonald (Canada); N. Morrison (USA); S. 

Sclafani (USA); A. Scuderi (Brasil); S. Shepherd 

(UK); M. Simka (Poland); A. Stella (Italy); R. 

Zivadinov (USA). 

Visualization of the Power 

Doppler signal (instead of 

Color Doppler for an 

increased spatial resolution) 

of the Superior Petrosal 

Sinus (1), Inferior Petrosal 

Sinus (2), contralateral 

Inferior Petrosal Sinus (3) 

and (partially) contralateral 

Superior Petrosal Sinus (4), 

from the Transcaranial 

window at the level of the 

condyloid process of the 

mandible. 

Example of Reflux: the blood flow at the 

level of the Superior Petrosal Sinus 

(SPS) shows opposite directions 

between inspiration and expiration; this 

finding shows the presence of reversed 

blood flow within the examined vessel 

between the two phases of respiration. 

The blood flow direction of the Inferior 

Petrosal Sinus (IPS) is not detectable 

during Expiration. The blood flow 

direction of the Contralateral Inferior 

Petrosal Sinus (CIPS) is not detectable 

during Inspiration and Expiration 

Example of No Reflux: the blood 

flow at the level of the Superior 

Petrosal Sinus (SPS) shows the 

same direction between 

inspiration and expiration; the 

blood flow direction of the Inferior 

Petrosal Sinus (IPS) is not 

detectable during Expiration; the 

blood flow direction of the 

Contralateral Inferior Petrosal 

Sinus (CIPS) is not detectable 

during Inspiration and Expiration 

3. A) Reduction of IJV cross sectional area (CSA) in supine position to ≤0.3 cm 2 which does not increase with Valsalva manoeuvre 

(performed at the end of the examination) and/or B) Intraluminal defects such as flaps, septa or malformed valves combined with 

hemodynamic changes (block, reflux, increased blood flow velocity). Valve leaflet/s immobility confirmed by M-mode. 

membrane 

CSA reduction to ≤0.3 cm2 

Intraluminal defect-B mode 

M-mode evaluation of jugular valve showing 

mobility of the leaflets (arrow). 

Valve leaflets immobility demonstrated in M- 

mode (arrow). 

4. A) Absence of detectable flow in 

the IJV and/or VV, despite numerous 

deep inspirations, in both sitting and 

upright positions, or B) In one 

posture absence of detectable flow in 

IJV and/or VV, despite numerous 

deep inspirations and bidirectional 

flow detected in the other position, 

same side. 

Absence of detectable flow in longitudinal scan 

of an IJV in supine posture. 

5. A) CSA of the IJV is greater in the sitting position than in the lying 

position or B) Appears almost unchanged despite change in posture. 

All measurements should be performed on both sides, and in 

the sitting and lying position. Criteria 1 and 4 are positive 

only if present in both positions. 

Example of Cross Sectional Area (CSA) 

measurement of the IJV in supine position. 

Example of Cross Sectional Area (CSA) 

measurement of the IJV in sitting position 

Performance of CCSVI screening, by following these recommendations ensures a high 

comparable accuracy between centres. 

reproducibility of duplex scanning with

Background 

Iron deposition in clinically isolated syndrome 

Jesper Hagemeier 1 , Bianca Weinstock-Guttman 2 , Niels Bergsland 1 , Mari Heininen-Brown 1 , Ellen Carl 1 , Cheryl Kennedy 1 , 

Christopher Magnano 1 , David Hojnacki 2 , Michael G. Dwyer 1 , Robert Zivadinov 1,2 

1 

Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, NY, USA; 

2 

The Jacobs Neurological Institute, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA 

 

 

1 

- 

 

 

- 

 

 

 

 

 

 

 

 

 

 

 

Methods 

 

- 

 

 

 

- 

 

- 

 

 

 

 

 

Table 1. Demographic, clinical and MRI characteristics 

of the study groups. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: HC = healthy controls; CIS = clinically isolated syndrome; 

SD = standard deviation; EDSS = Expanded Disability Status Scale; 

NGMV = normalized gray matter volume; NWMV = normalized 

white matter volume; NBV = normalized brain volume; NLVV = 

normalized lateral ventricular volume; NA = not available 

All lesion and brain volumes are expressed in milliliters. Of the 42 

CIS patients, 33 presented with brain T2 lesions and 9 with spinal 

cord T2 lesions. 

Differences between the groups were tested using the chi-square 

(gender) test and Student’s t-test. 

 

 

 

 

 

 

 

 

 

 

- 

 

 

 

 

- 

- 

 

 

Results 

 

 

 

 

 

- 

 

 

 

 

 

Table 2. Differences in the subcortical deep 

gray-matter mean phase of abnormal phase tissue 

(MP-ATP) between clinically isolated syndrome 

patients and healthy controls. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: CIS = clinically isolated syndrome; HC = healthy controls; 

SDGM = subcortical deep gray matter; SD = standard deviation; 

d = effect size 

MP-APT is expressed in radians. 

Differences between groups were tested using the Mann-Whitney U test. 

 

 

 

 

 

Table 3. Differences in the volume of mean phase of 

abnormal phase tissue volume (MP-ATP) between 

clinically isolated syndrome patients and 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


SDGM = subcortical deep gray matter; SD = standard deviation; 

d = effect size 

All volumes are reported in milliliters. 

Differences between groups were tested using the 

Mann-Whitney U test. 

Table 4. Differences in the subcortical deep gray-matter 

normalized volumes between clinically isolated syndrome 

patients and healthy controls. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


SDGM = subcortical deep gray matter; SD = standard deviation; d = 

effect size 

All volumes are reported in milliliters. 

Differences between groups were tested using the student t-test. 

Conclusions 

- 

- 

- 

 

- 

- 

 

 

 

 

References 

 

- 

 

 

 

-

Iron desposition and disability in MS 

Robert Zivadinov 1,2 , MD, PhD, Jesper Hagemeier 1 , MS, Mari-Heininen Brown 1 , BA, Guy U. Poloni 1 , PhD, Niels Bergsland 1 , MS, 

Christopher R. Magnano 1 , MS, Cheryl Kennedy 1 , LMSW, MPH, Ellen Carl 1 , BA, MS, Michael G. Dwyer 1 , MS, Bianca Weinstock-Guttman 2 , MD 

1 


2 


Background 

 

- 

 

 

 

 

- 

 

 

- 

 

- 

 

 

 

 

 

 

 

- 

 

- 

 

 

 

 

 

 

 

 

Results 

- 

 

 

 

 

 

- 

- 

- 

 

 

 

 

 

 

 

 

Table 4. Backward stepwise regression between 

total SDGM variables and clinical outcomes, 

when conventional MRI measures are 

added to the model 

 

 

 

 

--- --- --- --- 

--- --- 

--- --- --- --- 

 

 

 

 

Abbreviations: EDSS: expanded disability status scale; SDGM: 

subcortical deep gray matter; MP-APT: mean phase of the abnormal 

phase tissue; LV: lesion volume; NCV: normalized cortical volume; 

NWMV: normalized white matter volume 

Effect sizes representing the variance explained by the outcome 

variables: 1 adjusted R 2 = .328, 2 adjusted R 2 = .326, 

Increase in effect size compared to models including only 

conventional MRI measures: 1 adjusted R 2 increase = ---, 

2 

adjusted R 2 increase = .049 

The models were adjusted for age and gender 

Table 1. Demographic, clinical and conventional MRI characteristics 

in MS patients 

 

 

RR 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Abbreviations: MS: multiple sclerosis; RR: relapsing-remitting; 

SP: secondary progressive; SD: standard deviation 

All lesion and brain volumes are expressed in milliliters. Differences between RR and SPMS 

groups were tested using the chi-square test, Student’s t-test and the Mann-Whitney U test, 

as appropriate 

Table 2. Comparison of SDGM MP-APT and volume structures between RR and SPMS patients 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Abbreviations: MP-APT: mean phase of the abnormal phase tissue; SDGM: subcortical deep gray matter; 

RR: relapsing-remitting; SP: secondary progressive 

MP-APT is expressed in radians. All normalized deep GM volumes are expressed in milliliters. 

Differences between groups were assessed using the Mann-Whitney U test 

Methods 

 

 

 

 

 

 

 

 

- 

 

 

 

 

 

- 

 

 

 

 

 

 

 

- 

 

 

 

 

 

- 

 

 


MRI variables and clinical outcomes 

Conclusions 

 

 

 

 

--- --- --- --- 

--- --- 

--- --- 

--- --- --- --- 

--- --- --- --- 

--- --- --- --- 

--- --- --- --- 

Abbreviations: EDSS: Expanded Disability Status Scale; 

SDGM: subcortical deep gray matter; MP-APT: mean phase of the 

abnormal phase tissue; LV: lesion volume; NCV: normalized cortical 

volume; NWMV: normalized white matter volume 


variables: 1 adjusted R 2 = .329, 2 adjusted R 2 = .304 


 

 

 

 

 

 

 


 

 

 

 

 

--- --- 

--- --- 

--- --- 

--- --- 

--- --- 

Abbreviations: EDSS: Expanded Disability Status Scale; 

MP-APT: mean phase of abnormal phase tissue 


variables: 1 adjusted R 2 = .371, 1 adjusted R 2 = .354 


 

 

 

 

 

References 

 

-

Short-Term Outcomes After Endovascular Treatment 

for Chronic Cerebrospinal Venous Insufficiency (CCSVI) 

in Patients with Multiple Sclerosis 

Kenneth Mandato, MD; Kiran P. Sekhar, MD; Wilder Rucker, MD; 

Monica Chappidi, MD; Meridith Englander, MD; Gary P. Siskin, MD 

DEPARTMENT OF RADIOLOGY, ALBANY MEDICAL CENTER, ALBANY, NY 

PURPOSE: O evaluate short-terms outcomes after endovascular 

treatment for CCSVI in patients with MS. 

MATERIALS AND METHODS: M : A retrospective study of all MS patients 

treated for CCSVI during a 4- month period was performed. 

The study population consisted of patients who completed preand 

post- procedure MSQOL-54 (Multiple Sclerosis Quality of Life) 

questionnaires. (see Table 1) The MSQOL-54 has 14 scored components 

resulting in physical health (PHS) and mental health (MHS) 

composite scores. The questionnaire scores were compared to determine 

the effect of treatment on quality of life and to determine 

if MS subtype and years since MS diagnosis were associated with 

an improvement in QOL. 

TABLE 1: KEY COMPONENTS OF THE MSQOL-54 

 

 

 

 

 

 

 

 

 

RESULTS: S: 213 patients with MS were treated during the study period. 

The study population consisted of 192 patients (mean age 48.5 

years; 34% male and 66% female) for a 90% response rate (mean 

response time 109.4 +/- 39.6 days). MS subtypes included relapsing 

remitting (RRMS)(n=96), secondary progressive (SPMS)(n=66), 

and primary progressive (PPMS)(n=30). 189 patients (98.4%) underwent 

angioplasty (PTA) alone; the indications for angioplasty 

included a 50% stenosis or a 50% stenosis associated with a 

flow abnormality in either the right or left internal jugular vein or the 

azygos vein. (see Figures 1A-1C) 3 patients underwent PTA with 

stent placement (1.6%) due to diminished flow after angioplasty. 

(see Figures 2A-2D) A mean of 2.2 vessels were treated per procedure. 

In the 192 patients, the mean PHS and MHS changed from 

43.2 to 52.4 (p0.05) and from 5.1 to 65.2 (p0.05) respectively. 

PHS improvement was seen in % with RRMS, 59% with SPMS, 

and % with PPMS; these changes were all statistically significant 

(p0.05). MHS improvement was seen in 4% with RRMS, 50% 

with SPMS, and 0% with PPMS; these changes were all statistically 

significant (p0.05). However, SPMS patients were less liely than 

RRMS and PPMS patients to improve their PHS (p0.05) or MHS 

(p0.05). PHS improvement was seen in 4% with 5 yrs since the 

diagnosis of MS, 8% with 5-10 yrs since the diagnosis of MS, and 

66% with >10 yrs since the diagnosis of MS; these changes were 

significant in all groups (p0.05). MHS improvement was seen in 

1% with 5 yrs since the diagnosis of MS, 8% with 5-10 yrs since 

the diagnosis of MS, and 60% with >10 yrs since the diagnosis of 

MS; these changes were significant in all groups (p0.05). However, 

the years since MS diagnosis were not associated with changes in 

PHS (p=0.239) or MHS (p=0.01). 

CONCLUSIONS: NS: Endovascular treatment of CCSVI can produce 

significant, short-term improvement in physical and mental healthrelated 

QOL. However, improvement occurred less often in patients 

with SPMS than in patients with RRMS and PPMS. In addition, while 

the years since MS diagnosis did not appear to be related to QOL 

improvement after angioplasty, the frequency of improvement was 

less in patients with >10 yrs since MS diagnosis when compared 

with patients diagnosed within 10 years of the procedure. While this 

retrospective data is encouraging, a prospective randomized trial 

is needed to rigorously evaluate the role of endovascular CCSVI 

treatment in MS and to understand the implications of the present 

study in terms of patient selection. 

1A 1B 1C 

FIGURE 1A: Severe stenosis of left internal jugular vein FIGURE 1B: 

and reduced high pressure angioplasty FIGURE 1C: Significant improvement in antegrade 

flow and luminal diameter following angioplasty 

FIGURE 2A: Significant long segment stenosis of 

left internal jugular vein FIGURE 2B: 10 mm angioplasty 

of long segment stenosis FIGURE 2C: 

Angioplasty of mid left internal jugular vein complicated 

by flow limiting dissection with thrombus 

formation FIGURE 2D: Significant improvement 

in luminal caliber and antegrade flow following 

placement of overlapping 10 mm and 12 mm selfexpanding 

stents. 

2A 2B 2C 2D

Purpose 

Kenneth Mandato, MD; Jedidiah G Almond, MD; Meridith Englander, MD 

Shirish Parikh, MD; Gary P Siskin, MD 

Radiology at Albany Medical College Albany, NY 

To evaluate the ability of ultrasound (US) to diagnose chronic 

cerebrospinal venous insufficiency (CCSVI) in patients with 

multiple sclerosis. 

Materials and Methods 

A retrospective study of all MS patients treated for CCSVI 

during an 8-month period was performed. The study 

population consisted of all patients undergoing US of the 

internal jugular veins (IJV) within 24 hours of venography. 

Patients who received a diagnostic ultrasound at another 

institution before undergoing treatment were not included 

in this analysis. US was performed utilizing the protocol 

described by Zamboni, et al. A positive US met 2/5 criteria 

for CCSVI. The US results were also evaluated based on the 

findings on each side (right or left). A positive unilateral US 

met 2/4 criteria (without the transcranial evaluation of the 

deep cerebral veins). A positive venogram was defined as 

one identifying a ≥50% stenosis in at least one vein, 

including the azygos vein. The US and venography findings 

were then compared to determine if US is an effective tool 

for diagnosing CCSVI. 

Figure 1A: Realtime doppler sonography reveals normal 

 

 

 

 

 

 

 

 

 

venography 

Results 

416 patients were treated during the study period; the study 

population consisted of 310 patients (mean age 49 years; 

30% male and 70% female). 224/310 patients (72%) had a 

positive US, and 155 (69%) of these patients had a positive 

CV; 86/310 patients (28%) had a negative US, and 66 (77%) 

of these patients had a positive venogram (p=0.240) [Figures 

1A, 1B]. An ROC curve was generated to further evaluate 

ultrasound as a diagnostic test and the AUC=0.463. 300/310 

(97%) patients underwent PTA of at least one vessel (215/224 

with a positive US and 85/86 with a negative US) because 

venography showed either a ≥50% stenosis or a flow 

abnormality in association with a

Internal jugular vein valve morphology in the patients with CCSVI; angiographic 

nings an schematic emonstrations 

MH Al-Omari, A Al-bashir: Jordan University of Science & Technology, Jordan 

Purpose: to give venographic and schematic descriptions of the most common valvular 

and perivalvular anomalies found in the lower part of internal jugular vein in patient with 

CCSVI. 

Introuction: CCSVI is a syndrome characterized by abnormal venous hemodynamics 

resulting from numerous obstacles in the main veins draining the central nervous system. 

IJV is the commonest vein affected. Most of the abnormalities in this vein are located at 

the level of jugular valve. 

Materials an methos: retrospective analysis of 556 jugular venograms in 278 

MS/CCSVI patients. 

Results: 

Normal IJV valve (Fig. 1): The most frequently observed morphology was two-leaet 

valve. These valve leaets were movable during entire cardiac cycle. 

Jugular valve morphology in CCSVI patients: In these patients the valves are 

malformed and compromise venous drainage. Jugular valve is considered pathologic only 

if such a valve is associated with poor venous outow, reux, or outow through 

collaterals. Also a small distance between valve leaets is thought to be abnormal 

1-Jugular valve stenosis without severe structural abnormality:-Annulus -Fused 

leaets -Transverse Leaets. (Fig. 2) 

2-Abnormal valve leaets:-Accessory leaet -Ectopic leaet -Long leaets . (Fig. 3) 

3-Septum or membranous obstruction: -Septum. (Fig. 4).-Membrane 

4-Severely malorme valves: -Inverted Valve -Sigmoid Valve (Fig. 5)-Double Valve 

Fig.1 Fig.2 Fig.3 Fig.4 Fig.5 

Conclusions 

Jugular valves play pivotal roles in the pathophysiology of CCSVI. Valve morphology is 

highly variable. All pathologic valves in CCSVI patients are associated with altered 

venous hemodynamics. 

References: [1] Zamboni P et al. J. Neurol. Neurosurg. Psychiatry 80(4),392–399 (2009). 

[2] Zamboni P et al. Curr Neurovasc Res 2009, 6:204-12.

A non-linear subtraction method for MRA 

Yongquan Ye1, Jiani Hu1, Dongmei Wu2, and E.Mark Haacke1 

1Radiology, Wayne State University, Detroit, MI, United States, 

2Department of Physics, East China Normal University, Shanghai, China, People's Republic of 

Introduction 

Results 

Discussion 

Researchers have been pushing the limit to better 

reveal angiography with very high resolution MRI 

techniques. With reduced partial volume effects, it 

is possible to show smaller vessels with diameter 

on the scale as the voxel size [1]. However, one of 

the major issues of high resolution MRA is the 

greatly reduced SNR, which in turn leads to lower 

CNR between vessels and surrounding tissues. One 

theoretically promising way to enhance such CNR 

is to acquire both flow-rephased and -dephased 

images and subtract the latter from the former to 

drastically reduce the tissue signal [2]. However, 

since both arteries and veins will have hypointensity 

signal in the dephased images, the direct 

subtraction results will contain both vessels [2,3]. 

In this study, we proposed an interleaved-TR GRE 

TOF sequence with variable TE to simultaneously 

acquire both re- and dephased images, and a nonlinear, 

self-squaring process to reduce 

contamination in the subtracted MRA. 

Method and Materials 

Our interleaved-TR sequence is shown in Fig.1. For 

the first TR, fully flow compensated echo was 

acquired with a shorter TE1 for good TOF MRA; 

and for the second TR, a pair of bipolar gradients 

with 24mT/m amplitude and 10ms total duration 

(i.e. VENC ≈ 1cm/s) replaced the FC gradients to 

dephase the moving blood signal. With the bipolar 

gradient inserted, TE2 is longer than TE1. Noncontrast 

enhanced images were acquired with 

following protocol: voxel size = 0.5x0.5x1mm3, 48 

slices, BW = 150Hz/px, TR/TE1/TE2 = 25/8/15ms, 

FA = 15º, 2x GRAPPA. The scan was performed on 

a Siemens Verio 3T system using 32-ch head coil. 

For non-linear subtraction, all images were selfsquared 

voxel-by-voxel, then the self-squared 

dephased images were subtracted from the selfsquared 

rephased images and the finally the 

subtraction results were MIPped over 12 slices. The 

original images also underwent the same 

subtraction and MIP process and the results were 

compared. 

References 

[1] Dagirmanjian et al, JCAT, 1995;19(5):700 

[2] Kimura et al, MRM, 2009;62:450 

[3] Gedat et al, MRI, 2011;29:835 

Fig.2 displays the original images and their MIP/mIP results, 

as well as the 

subtraction and the MIP of the subtraction of both original and 

self-squared 

data. The subtraction of the original images showed heavy 

contamination of veins (Fig.2e and 2g), while the subtraction 

of the self-squared images mostly showing only the arteries 

(Fig.2f and 2h). The veins are removed Fig.3 shows the cross 

section profiles of a vein and an artery from the linear 

subtraction (solid lines) and the self-squared subtraction (dash 

lines). 

Fig.1 Illustration of interleaved-TR TOF sequence. 

Fig.2 Original rephased (a) and dephased (b) images. (c) is the MIP result of 

(a), and (d) is the mIP result of (b). Self-squared results corresponding to (a)- 

(d) are similar in contrast and thus not shown here. (e) is the subtraction result 

of the original images, (f) is the subtraction result of the self-squared images, 

and (g) and (f) are the MIP result of (e) and (f) respectively. The solid arrow 

indicates an artery and the dotted arrow indicates a vein, and the red lines 

indicate the cross section profile location. 

(a) (b) 

Fig.3 Cross section profiles of a vein (a) and an artery (b) for linear 

subtraction (solid lines) and non-linear self-squared subtraction (dash lines), 

obtained from positions indicated in Fig.2e and 2f. 

The incapability of separating arteries and 

veins has always been the major issue for the 

linear subtraction between rephase/dephase 

data. Due to the non-selective nature of the 

dephasing process in reducing all blood 

signals, a direct linear subtraction will show 

both veins and arteries with hyper-intensity 

signal (Fig.2g) relative to tissues. For a specific 

tissue, the signal acquired in our interleaved- 

TR sequence can be expressed as S TR1 = 

S ss exp(-TE 1 /T 2 *) and S TR2 = S ss F(VENC) exp(- 

TE 2 /T 2 *), where S ss is the steady state signal 

and F(VENC) is the flow dependent dephase 

function. Therefore, the final subtraction result 

is affected by the steady state, flow velocity 

and T 2 *. In the linear subtraction, let S TR1 - 

S TR2 =D 1 , then for the self-squared subtraction 

one will have: 

 

 

Comparing veins and tissues, it’s obvious that 

D 1v > D 1t , and as a result veins has higher 

signal 

in the linearly subtracted images 

(Figs.2e and 3a). However, because S TR1v < 

S TR1t due to the faster T2* decay of venous 

blood and S TR2v < S TR2t due to the dephasing, 

one have S TR1v + S TR2v < S TR1t + S TR2t . With 

proper VENC value and TEs, is it possible to 

realize D 2v < D 2t , thus making veins invisible in 

the self-squared subtraction results and the 

subsequent MIP, as demonstrated in Figs.2f, 

2h and 3a. Arteries, on the other hand, will still 

have the highest signal after the self-squared 

subtraction due to the very large signal change 

between rephased/dephased images. 

In summary, we have proposed a simple nonlinear 

subtraction method by self-squaring the 

images prior to the subtraction, which not only 

can enhance the artery/tissue contrast as the 

linear subtraction, but also can greatly reduce 

the contamination from the venous side. Our 

rephased/dephased interleaved sequence and 

the non-linear subtraction method is promising 

in finding extensive applications such as 

traumatic brain injury (TBI) diagnosis and 

evaluations. Further studies will include 

quantitative modeling for CNR analysis, as well 

as optimizing the scanning protocol and post 

processing methodology.

The Cerebral Perfusion of Patients with 

Multiple Sclerosis (MS) using MRI 

Zhong Y 1 , Utriainen D 2 , Feng W 1 , Hubbard D 3 , Haacke EM 1,2 

1 

Depts of Radiology and Biomedical Engineering, Wayne State University, Detroit MI 48201 USA; 

2 

Magnetic Resonance Innovations, Inc, Detroit, MI 48202 USA; 

3 

Applied fMRI Institute, San Diego, CA 92131 USA; 

Introduction: 

Contacts: Yi Zhong (neuzhong@gmail.com), 

E. Mark Haacke (nmrimaging@aol.com) 

Multiple sclerosis (MS) is an inflammatory disease with no clear causes. Currently, there has been a resurgence of interest in the venous 

component of MS (1,2). Along the lines of poor flow (not with a specific focus on venous abnormalities), a number of papers in the last decade 

have shown that there is reduced perfusion in the brain (3,4). Using 2D phase contrast (PC) flow measurements, our own work (5) has shown that 

there is abnormally low internal jugular venous (IJV) flow in MS patients. The goal of this present work was to take the arterial information from 

the upper neck level (C2) and use it to find the average perfusion by normalizing it to brain volume. The internal carotid arteries and the vertebral 

arteries were included. The thought was that reduced perfusion would correlate with abnormally low IJV flow. 

Methods: 

A total of 140 patients with clinically definite MS were imaged (mean 

age 48 years, range 27-74 years,100 women, 40 men) under the 

standard CCSVI protocol. Two groups were defined based on the 

observation of patients’ venous anatomy. Specifically, if the subject’s 

jugular veins showed a stenosis (less than 12.5mm 2 at C1/C2 or less 

than 25mm 2 from C3 downward, then they were classified as being in 

the stenotic group. Otherwise they were classified as non-stenotic. 

There were 75 with stenosis and 65 with no stenosis. There were 26 

age matched normal controls (mean age 38 years, range 23-59 years) 

used for comparison. Flow quantification was performed at the C2 

level and only the internal carotid arteries and the vertebral arteries 

were included. The average cerebral blood flow (CBF) was defined as , 

where tA represents the total arterial flow to the brain per minute per 

100gm tissue. The brain was extracted by first performing a skull 

stripping and then keeping the cerebrum, cerebellum and brainstem 

(including the pons). 

Figure 1. 3D FLAIR data 

acquired in the sagittal plane 

(A) was used to calculate brain 

volume for subjects. (B-D) 

demonstrate the postextraction 

brain signal which 

was used in calculating total 

brain volume. Note the 

inclusion of the cerebrum, 

cerebellum, the pons, and the 

ventricular cerebrospinal fluid. 

Results: 

The average CBF (in ml/min/100gm tissue) as a function of the total 

IJV flow (in ml/sec) is plotted in Figure 2. Practically, if there is no 

relationship between total CBF and total IJV flow, Figure 1 should 

show a population of similar CBF (ignoring age-dependence) spread 

out across the total IJV flow. This plot can be better understood if it is 

further broken down into age ranges. The MS population was divided 

into 2 subgroups with age ranges of less than50 years and greater 

than 50 years (included 50Y). The linear trend is much more apparent 

now when viewed one group at a time (see for example the cases with 

no apparent stenosis.) Overall there is also a trend for not only 

reduced CBF for the older population but also a reduced outflow in 

the IJVs . The linear fits yielded the following results: for the stenotic 

MS younger than 50 years, y=0.604x+45.3, R 2 = 0.060; for the stenotic 

MS patients older than 50 years, y=0.141x+48.2, R 2 =0.001 ; for the 

non-stenotic MS patients, y=2.167x+24.5,R 2 =0.233 ; and for the 

normal controls, y=0.113x+46.2, R 2 =0.001. The non-stenotic has a 

stronger linear correlation with CBF. Higher average CBF (β=.46, 

p

FLOW THROUGH THE INTERNAL JUGULAR VEIN IS REDUCED 

FOR MULTIPLE SCLEROSIS PATIENTS WITH STENOSES 

COMPARED TO THOSE WITHOUT OBSERVED BY MRI 

W. Feng 1 , D. Utriainen 2 , Z. Wu 3 , D. Hubbard 4 , E. M. Haacke 1,2 

1 

Department of Radiology, Wayne State University, Detroit, Michigan 48201; 2 Magnetic Resonance Innovations, Inc., Detroit, MI 48202; 

3 

Department of Surgery, Morehouse School of Medicine, Atlanta, Georgia, 30310; 4 Applied fMRI Institute, San Diego, CA 92131 

INTRODUCTION 

Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to play an important role in multiple sclerosis (MS) patients [1]. Studies of venous flow of MS patients 

were mostly performed with ultrasound imaging. Our recent work using contrast enhanced MRA (CE-MRA), 2D time-of-flight MRV (TOF-MRV) and phase contrast MRI (PC- 

MRI) has shown that the internal jugular vein (IJV) flow at the cervical 6 (C6) level is reduced for patients with anatomically stenotic IJVs [2]. Stenoses of the IJVs usually occur 

at either upper neck level (around C2) or lower neck level (around C6). Here we further investigate the extracranial venous flow characteristics by studying the differences 

between the MS populations with stenotic IJVs at C2 and C6 levels. 

METHODS 

The study was approved by local institutional review board. Two hundred and seventeen (217) clinically definite MS patients and 15 normals signed informed consent forms 

and participated in the study. Three-dimensional CE-MRA data were collected to locate IJV stenoses by examination of the vasculature and multiple 2D TOF-MRV data with 

high in-plane resolution was used to measure vessel cross-sectional area (CSA) to determine stenoses. Thresholds of 25mm 2 around the cervical 6 (C6) level and 12.5mm 2 

around the C2 level were used to determine IJV stenosis. Based on this stenosis assessment, all subjects were divided into 3 groups, non-stenotic (NST), C2 stenotic (C2ST) 

and C6 stenotic (C6ST). Subjects with both C2ST and C6ST were classified as C6ST. Blood flow was measured with 2D PC-MRI imaging around C6 level perpendicular to the 

IJVs on a 3T Siemens Magnetom Tim Trio with the following parameters: TR = 14.4ms, TE = 4.41ms, flip angle = 25 o , FOV = 256mm×256mm, in-plane resolution = 

0.57mm×0.57mm, slice thickness = 4mm and maximum encoding velocity (VENC) = 50cm/sec. Retrospective pulse gating was used and a total of 25 images were 

reconstructed during one cardiac cycle. Vessel segmentation was achieved manually using our in-house MATLAB software. Occasional aliasing in major vessels was mostly 

corrected by a simple phase unwrapping algorithm [2]. Statistical analysis was performed to compare the quantitative findings among the groups. Paired and unpaired t-tests 

were performed as appropriate to evaluate the statistical significance of the differences. 

RESULTS 

Of the 217 subjects, 99 (45.6%) were determined to be in the NST 

group, 54 (24.9%) in the C2ST group and the remaining 64 (29.5%) in 

the C6ST group. Table 1 shows the quantitative flow measurements. 

There was no significant difference among the total arterial flow rates 

for the NST, C2ST and C6ST groups (16.16±2.73, 16.80±2.96 and 

16.26±2.56 mL/sec, respectively; p=0.18 between NST and C2ST, 

p=0.29 between C2ST and C6ST). For the whole population, the flow 

difference through the left and right common carotid arteries were not 

significant (6.51±1.31 vs. 6.57±1.34 mL/sec, respectively; p = 0.37). 

These findings, while not directly on the venous system, indicate that 

the method was not biased toward any group. On the venous side, the 

blood flow through the LIJV was found to be significantly less than that 

of the RIJV (4.31 ± 2.66 vs. 6.36 ± 3.06mL/sec, respectively; p2/3), (28.7, 54.0, 47.6, 33.3) % were type II (1/3 1/3; type 

III: FIJV/Fta

Intravascular Ultrasound for detection of Azygous and Internal Jugular vein (IJV) abnormalities as part of the 

PREMiSe (Prospective Randomized Endovascular therapy in Multiple Sclerosis) study 

Y Karmon 1,2 , R Zivadinov 3 , B Weinstock-Guttman 2 , C Kennedy 3 , K Dolic 3 , K Marr 3 , V Valnarov 3 , A Siddiqui 1 

1 

Department of Neurosurgery, 2 The Jacobs Neurological Institute, and the 3 Buffalo Neuroimaging Analysis Center, State 

University of New York, Buffalo, NY 

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) is a condition recently reported in patients with multiple 

sclerosis (MS) [1]. A set of 5 extra- and trans-cranial venous Doppler Sonography (DS) criteria was proposed [1, 2] and reported 

to be in accordance with catheter venography (CV) for the depiction of both Azygous and IJV stenosis [1, 3]. Despite being 

the “gold standard” for assessing vascular problems, angiography only provides a luminography with little data on the vessel's 

wall, or intraluminal structures. Our aim was to investigate for presence and type of mechanical impediments to the cranial/ 

spinal cord venous drainage and suspected deranged flow using CV based intravascular ultrasound (IVUS). 

METHODS: PREMiSe is an endovascular angioplasty study enrolling patients with relapsing MS according to the revised 

McDonald criteria[4,5], and who had Expanded Disability Status Scale [6] between 0-5.5 and fulfilled ≥2 CCSVI Doppler 

sonography criteria at screening. The study was planned in two phases. The first phase was an open label and included 10 

patients, whereas the second phase is placebo-controlled, blinded and randomized and will include total of 20 patients. The 

current study is based on 10 patients participating in phase I and 16 in phase II. CV comprised visualization of AZY vein, right 

IJV (RIJV) and left IJV (LIJV) in that order [3]. IVUS was performed using IVUS Eagle Eye Gold catheter (Volcano, CA), across 

suspected stenotic segments (≥50% restriction) of the IJV's and azygous vein (AZY), in the phase I, and in all vessels in the phase 

II. Abnormal predefined IVUS parameters included the presence of stenosis, presence or absence of respiratory pulsatility 

and the presence of various intraluminal defects (septa, multiple channeled vein, intraluminal hyperechoic filling defect, 

double/parallel lumen), and abnormally thickened wall. 

RESULTS: The study included twenty six patients (mean age 45.7, SD=9.7; male=9, females=17; average disease duration 

10.1 years) with clinical and MRI proven MS (20 Relapsing remitting MS, 6 secondary progressive MS) that have fulfilled ≥2 

CCSVI Doppler sonography criteria at screening. Out of 18 Azygous veins that were investigated with IVUS, 16 (88%) demonstrated 

various intraluminal defects. Pulsatility was reduced in 7 (38.8%), and stenosis was demonstrated in 10 (55.5%). IVUS 

of LIJV detected intraluminal defects in 7 out of 22 patients, reduced pulsatility in 14, and stenosis in 8. All patients who had 

a stenosis by IVUS also demonstrated intraluminal defects. IVUS of the RIJV showed intraluminal anomalies in 4 patients 

(20%), reduced pulsatility in 10 (50%), and stenosis in 5 (25%) patients out of 20 patients investigated. 

CONCLUSIONS: Detailed IVUS imaging demonstrated a very high rate of intraluminal anomalies in the azygous vein during 

the PREMiSe study. Similar anomalies were also found in the LIJV and RIJV in lower rates respectively. Stenosis demonstrated 

by IVUS was demonstrated in a decreasing order in the azygous vein, left IJV and RIJV as well. IVUS provides 

diagnostic advantages over "gold standard" CV in detecting intraluminal extra-cranial venous abnormalities indicative of 

CCSVI. 

References: 

1. Zamboni, P., et al., Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg 

Psychiatry, 2009. 80(4): p. 392-9. 

2. Zamboni, P., et al., . 

J Neurol Sci, 2009. 282(1-2): p. 21-7. 

3. Zamboni, P., et al., A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. 

J Vasc Surg, 2009. 50(6): p. 1348-58 e1-3. 

4. Polman, C.H., et al., Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol, 2005. 

58(6): p. 840-6. 

5. Lublin, F.D. and S.C. Reingold, Defining the clinical course of multiple sclerosis: results of an international survey. National 

Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology, 

1996. 46(4): p. 907-11. 

6. Kurtzke, J.F., Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology, 

1983. 33(11): p. 1444-52.

Measurement of Azygos Venous Blood Flow in Patients with 

Multiple Sclerosis Using MRI 

Tai A., Kokeny P., Utriainen D., Sethi S., Feng, W., Hubbard D., Haacke E.M. 

Introduction 

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the brain and spinal 

cord of unknown etiology. Recent studies are being focused on the association between 

chronic cerebrospinal venous insufficiency (CCSVI) and MS [1,2]. CCSVI, defined as 

impaired venous drainage from the brain and spinal cord due to outflow obstruction in 

the extracranial venous system, mostly related to anomalies in the internal jugular and 

azygos veins, has been postulated as a cause of MS. These obstructions may result in the 

opening of collateral vessels for blood drainage from the CNS. The collaterals associated 

with the azygos vein play an important role in providing an alternate drainage pathway 

of the cerebrospinal blood flow due to its connections with the vertebral vein, the 

superior vena cava and inferior vena cava. Previous studies have reported a high 

number of obstructions in the azygos vein in MS patients [1]. Increased blood flow 

through this vessel has been observed in different gastrointestinal diseases with portal 

hypertension, [3-6] because of its role in the porto-caval anastomosis. However, 

quantitative flow measurement in the azygos vein of MS patients has not been reported 

to date. The aim of this study is to provide average azygos flow from a large sample of 

the MS population. 


112 patients (mean age=49.3, SD=9.5 years, male=30, female=82) with clinical and MRI 

proven multiple sclerosis and 23 age matched healthy controls (mean age=39.8, 

SD=10.1 years) were used in this study. Data from 7 patients were excluded from the 

results as outliers, leaving 105 for statistical analysis. Patients were then divided 

according to the type of MS: relapsing-remitting (44/105), primary progressive (15/105) 

and secondary progressive (32/105). 14 patients’ MS types were unknown. Flow 

quantification was accomplished using 2D phase contrast MRI (on a 3T Siemens 

scanner) to assess the azygos venous blood flow, the cross-sectional area, and any 

abnormal flow patterns in the vessel. Blood flow was measured at two levels in the 

azygos: one at the upper level immediately below the arch and the other at a lower 

level. An in-house software (FlowQ) written in MATLAB was used to quantify blood flow 

based on phase signal intensity. Vessel area was found by manually drawing regions-ofinterest 

(ROIs) around the azygos vein. Values inside the ROIs were mapped to velocity 

using the VENC value of 40cm/sec after ROIs for offset correction were drawn in the 

muscle area indicating the no flow areas. 

a b c d e f 

Images of the upper azygos vein. Figure a: magnitude image; b: phase image; c: localizer of a-b. 

1 

Frequency 

3 

5 

18 

16 

14 

12 

10 

8 

6 

4 

2 

0 

Frequency 

Flow (mL/sec) 

20 

18 

16 

14 

12 

10 

8 

6 

4 

2 

0 

6 

5 

4 

3 

2 

1 

0.05). 

Frequency 

8 

7 

6 

5 

4 

3 

2 

1 

0 

Azygos UL Flow of Different MS Types 

Prevalence of Chronic Cerebrospinal Vascular Insufficiency (CCSVI) in patients with 

multiple sclerosis and healthy controls: a systematic review of the literature and metaanalysis 

Andrew Dueck David, MD; Erin Lille , MS; Andreas Laupacis , MD. 

Background: Chronic cerebrospinal venous insufficiency, a term used to describe ultrasounddetectable 

abnormalities in the anatomy and flow of intra- and extracerebral veins, has been 

suggested to be correlated with multiple sclerosis. We conducted a meta-analysis of studies that 

reported the frequency of chronic cerebrospinal venous insufficiency among patients with and 

those without multiple sclerosis. 

Methods: We searched MEDLINE and EMBASE as well as bibliographies of relevant articles 

for eligible studies. We included studies if they used ultrasound to diagnose chronic 

cerebrospinal venous insufficiency and compared the frequency of the venous abnormalities 

among patients with and those without multiple sclerosis. 

Results: We identified ten eligible studies: nine included healthy controls, and five also included 

a control group of patients with neurologic diseases other than multiple sclerosis. Chronic 

cerebrospinal venous insufficiency was more frequent among patients with multiple sclerosis 

than healthy controls (pooled odds ratio [OR] 12.8, 95% confidence interval [CI] 2.8-59.1), but 

there was extensive unexplained heterogeneity among the studies. The association remained 

significant in the most conservative sensitivity analysis (OR 4.0, 95% CI 1.4-11.0), in which we 

removed the initial study by Zamboni and colleagues and added a study that did not find chronic 

cerebrospinal venous insufficiency in any patient. Although chronic cerebrospinal venous 

insufficiency was also more frequent among patients with multiple sclerosis than among controls 

with other neurologic diseases (OR 32.5, 95% CI 0.6–1775.7), the association was not 

statistically significant, the 95% CI was wide, and the OR was less extreme after removal of the 

study by Zamboni and colleagues (OR 3.5, 95% 0.8–15.8). 

Interpretation: Our findings showed a positive association between chronic cerebrospinal 

venous insufficiency and multiple sclerosis. However, poor reporting of the success of blinding 

and marked heterogeneity among the studies included in our review are of concern and should be 

targets of future research.

DOES THORACIC PUMP INFLUENCE 

CEREBRAL VENOUS RETURN? 

Menegatti E 1 , Pomidori L 2 , Morovic S 1 , Cogo AL 2 , Malagoni AM, 1 Conforti P 1 , Tessari M 1 , Sisini F 3 , Taibi A 3 , Gambaccini M 3 , Zamboni P 1 . 

1 

Vascular Diseases Center, University of Ferrara, Italy; 2 Biomedical Sport Studies Center Ferrara, Italy, University of Ferrara, Italy; 3 Department of Physics, University of Ferrara Italy. 

Background and Purpose: Vis a fronte (thoracic pump) 

represents the aspiration of blood created by the negative pressure 

of the pleural cavity respect to the atmospheric pressure (AP). It 

accounts for –3 cmH 2 O at rest till -8 cmH 2 O at deep inspiration. The 

aim of the present study is to assess the haemodynamic effects 

induced by the thoracic pump in the intra and extracranial veins of 

the cerebral venous system on healthy volunteers. 1 

Statistical analysis 

Data are expressed as meanSD. The normal distribution of data 

was verified by the Kolmogorov-Smirnov test. Data were compared 

using unpaired Student T-Test, Mann-Whitney test, and Kruskall- 

Wallis test, as appropriate. A p value of 0.05 or less was considered 

statistically significant. Data were analysed using the software 

program Medcalc 11.6 (Medcalc Software, Mariakerke, Belgium). 

3. Relationship between intra and extracranial venous haemodinamics (Figure 5) 

R = 0.70, 

p

Azygos compression and effect of respiratory cycle during CCSVI venography. 

Michael Arata Andrew, MD 

OBJECTIVE. Chronic Cerebrospinal Venous Insufficiency (CCSVI) is venous 

hypertension of the cerebrospinal veins resulting from a flow obstructing lesion in the 

jugular and azygos veins. It is most often are result of venous valve malfunction. 

Extrinsic venous compression in these veins may also result in flow obstruction. It has 

been suggested that the compression of the azygous vein is a result of respiratory 

motion rather than a fixed lesion. We retrospectively reviewed the azygous venographic 

images obtained during the CCSVI procedure. Azygos venogram technique included 

imaging at full inspiration and after complete exhalation. Evaluation of the relative 

frequency of azygos vein compression during CCSVI venogram and the effect of 

respiratory motion on the degree of compression was undertaken. 

MATERIALS AND METHODS. A database search was performed of all CCSVI 

procedures performed over a two month period starting July 2011. Review of the 

azygos portion of these venograms was undertaken. Determination of the presence of 

significant stenosis, defined as 50% or greater was performed. If a significant stenosis 

was present the lesion was compared to assess for change associated with respiration. 

RESULTS. Over the two month study period, 54 CCSVI procedures were performed 

and had azygous imaging performed with full inspiration and complete expiration. 

Compression resulting in significant stenosis was identified in 26% (n=14). The 

significant stenosis was only present at complete exhalation in 19% (n=10). Stenoses 

of greater than 70% did not change with respiration (n=4). 

CONCLUSION. Venous compression of the azygos vein can produce flow obstructing 

lesions in up to 1/4 of patients. Imaging at full inspiration is helpful to identify fixed flow 

limiting lesions. Fixed lesions that do not change with respiration tend to be of a more 

significant degree of stenosis

in patients with multiple sclerosis 

Kresimir Dolic 1 , Karen Marr 1 , Vesela Valnarov 1 1 , Ellen Carl 1 1 , Colleen Kilanowski 1 , 

David Hojnacki 2 , Bianca Weinstock-Guttman 2 , Robert Zivadinov 1,2 

1 

 

2 

 

Background 

 

 

- 

 

 

 

 

 

 

- 

 

- 

 

Methods 

Table 3. Prevalence, sensitivity and 

 

hemodynamic criteria in MS patients and 


Legend: MS - Multiple Sclerosis; HC - Healthy 

Controls; NPR - Non-progressive; PR - Progressive; 

VH - venous hemodynamic criteria. 

a 

p-value for chi-square test represents comparison 

between HC and MS; b p-value for chi-square test 

represents comparison between non-progressive and 

progressive MS patients. 

Sensitivity of MS vs. HC and NPR-MS vs. PR-MS is 

represented in italics. 

 

 

 

 

 

 

 

 

 

(27.5) (25.9) 

(52) (56.9) 

(69) (79.3) 

(21.6) (27.6) 

(18.1) (27.6) 

(64.3) (75.9) 

(87.1) (94.8) 

(78.2) (84.5) 

(14.1) (13.8) 

 

 

 

 

 

 

- 

 

- 

 

 

 

 

 

 

 

 

 

 

Table 1. Demographic and clinical characteristics in 

multiple sclerosis patients and healthy controls. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

--- --- 

 

 

--- --- 

 

 

 

 

 

 

 

 

 

 

 

--- 

--- --- 

 

 

 

 

 

 

 

 

Legend: MS – Multiple Sclerosis; HC - Healthy Controls; RR - Relapsing- 

Remitting; PP - Primary progressive; SP - Secondary Progressive; 

 

NPR - Non-progressive; PR - Progressive. 

Of the 171 MS patients, 121 (70.7%) were on disease-modifying therapy. These 

included 34 patients on glatiramer acetate, 33 on interferon-beta 1a I.M., 22 on 

natalizumab, 20 on interferon-beta 1a S.C. and 12 on combination therapy. 

The differences between the study groups were tested using the chi-square test, 

Student’s t-test and Mann-Whitney rank sum test. 

Table 2. Intra- and inter-rater reproducibility of CCSVI 

criteria on Doppler sonography between two trained operators in 

20 MS patients and 7 healthy controls. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ICC ICC ICC 

 

 

--- --- --- 

 

 

 

 

 

 

Legend: ICC - inter-class correlation; VH - venous hemodynamic 

criteria; IJV - internal jugular vein; VV - vertebral vein. 

Intra- and inter-rater reproducibility was calculated using Cohen’s Kappa and 

inter-class correlation tests. 

 

healthy controls on 2D-Time-of-Flight venography and 3D-Time Resolved Imaging of Contrast Kinetics. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

- 

 

 

 

 

 

 

 

- 

 

 

 

 

 

 

 

 

Results 

 

 

 

- 

 

 

 

 

 

 

 

 

 

 

 

Discussion 

- 

 

 

 

 

 

- 

 

 

- 

 

 

 

 

 

 

 

- 

 

- 

 

References 

 

 

 

 

 

 

 

 

 

 

 

- 

 

 

 

 

 

 

 

 

(32.2) (44.8) (22.1) (44.6) 

(13.5) (24.1) (3.8) (12.1) 

 

 

 

 

 

 

 

 

 

 

(91.2) 

(23.4) 

(34.5) 

(21.6) 

(12.3) 

 

 

 

 

 

 

 

 

 

 

 

(93.1) 

(22.4) 

(32.8) 

(31) 

(6.9) 

 

 

 

 

 

 

(88.5) 

(21.2) 

(29.2) 

(16.8) 

(14.2) 

(89.3) 

(25.9) 

(25.9) 

(27.6) 

(6.9) 

(1.4) (1.3) 

 

 

 

 

 

 

Legend: MS - Multiple Sclerosis; HC - Healthy Controls; NPR - Non-progressive; PR - Progressive; TOF - Time-of-Flight venography; 

TRICKS - Time Resolved Imaging of Contrast KineticS; n - number. 

The frequency differences between the study groups were tested using the chi-square test, whereas the number of collaterals was tested using the Mann-Whitney rank 

sum test. Sensitivity of MS vs. HC and NPR-MS vs. PR-MS is represented in italics. 

Table 5. Flow morphology of internal jugular veins in multiple 

sclerosis patients and healthy controls on 2D-Time-of-Flight 

venography and 3D-Time Resolved Imaging of Contrast Kinetics. 

 

 

 

 

 

 

multimodal venous hemodynamic criteria in MS patients and 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: MS - Multiple Sclerosis; HC - Healthy Controls; 

NPR - Non-progressive; PR - Progressive; TOF - Time-of-Flight venography; 

TRICKS - Time Resolved Imaging of Contrast KineticS; n - number. 

 

groups were evaluated using the Mann Whitney rank sum test. 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: MS - Multiple Sclerosis; HC - Healthy Controls; 

NPR - Non-progressive; PR - Progressive; VH - venous hemodynamic criteria.

Iron deposition in pediatric multiple sclerosis patients 

Jesper Hagemeier 1 , E. Ann Yeh 2 , Mari Heininen-Brown 1 , Niels Bergsland 1 , Michael G. Dwyer 1 , Ellen Carl 1 , 

Bianca Weinstock-Guttman 2 , Robert Zivadinov 1,2 

1 


2 


Background 

 

 

- 

1 

 

 

- 

- 

 

 

 

- 

 

 

Methods 

- 

 

 

 

- 

 

 

 

 

 

 

 

 

 

- 

 

 

 

- 

 

Table 1. Clinical and demographic characteristics of 

healthy control subjects and pediatric MS patients. 

 

 

 

 

 

 

 

 

--- --- 

 

 

--- 

 

 

--- 

 

 

--- --- 

 

 

--- 

 

 

--- 

 

 

--- 

 

 

--- 

 

 

--- --- 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: HC = healthy controls, MS = multiple sclerosis 

Volume measurements are expressed in cubic millimeters. 

Differences between groups in demographic characteristics and 

atrophy measures were tested using the independent samples 

Student’s t-test and chi-squared test. 

Figure. Individual susceptibility-weighted 

 

with the MNI atlas and then averaged together 

to create mean phase images for 21 healthy 

controls (left) and 20 MS patients (right). 

The pulvinar nucleus of thalamus (arrow) appears 

bilaterally brighter in the MS group image, 

and corresponds to our mean phase of the 

 

 

 

 

 

- 

 

 

Results 

- 

 

 

 

 

- 

 

 

- 

 

 

 

 

 

 

 

 

 

 

 

Table 2. Mean phase of the abnormal phase tissue 

(MP-APT) measurements of subcortical deep gray 

matter structures of healthy control subjects and 

pediatric MS patients. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: MP-APT = mean phase of the abnormal phase tissue, 

MS = multiple sclerosis, HC = healthy controls; SDGM = subcortical 

deep gray matter 

MP-APT is expressed in radians. Differences between groups were 

tested using the Mann-Whitney U test. 

Table 3. Volume measurements of subcortical deep 

gray matter structures of healthy control subjects 

and pediatric MS patients. 

Conclusions 

- 

 

 

 

- 

 

 

 

 

 

- 

 

 

 

References 

 

 

 

 

 

 

 

 

- 

- 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Legend: MS = multiple sclerosis, HC = healthy controls 

All normalized deep gray matter volumes are expressed in 

 

using the Student’s t-test.

Iron deposition in pediatric multiple sclerosis patients 

Jesper Hagemeier 1 , E. Ann Yeh, Mari Heininen Brown 1 , Niels Bergsland 1 , Michael G. Dwyer, 1 , 

Ellen Carl 1 , Bianca Weinstock-Guttman 2 , Robert Zivadinov 1,2 

1 Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA; 2 The Jacobs 

Neurological Institute, University at Buffalo, Buffalo, NY, USA 

Abstract 

Background: The extent of iron deposition in the subcortical deep gray matter (SDGM) has 

been extensively investigated in adult but not in pediatric multiple sclerosis (MS) patients. 

Objective: To assess abnormal phase values, indicative of increased iron content, using 

susceptibility-weighted imaging (SWI)-filtered phase of the SDGM in pediatric MS patients and 

healthy controls (HC). 

Methods: Twenty (20) pediatric MS patients (11 female, 9 male) and 21 age- and sex-matched 

HC (10 female, 11 male) were scanned on a 3T GE scanner. Mean age was 15.6 (SD=2.9) years 

in patients, and 14.8 (SD=3) years in HC. Mean phase of the abnormal phase tissue (MP-APT), 

normal phase tissue volume (NPTV) and normalized volume measurements were derived for 

total SDGM, as well as specific structures separately. The study was approved by local 

Institutional Review Board and all participants provided written informed consent. 

Results: Significantly increased MP-APT (28.2%, p

Q 

Q 

Q 

Q 

Simple mathematical model for the 

hemodynamics of extracranial veins and 

effect of posture 

Lucas O. Müller 1 *, Gino I. Montecinos 1 , Laura Facchini 1 , Eleuterio F. Toro 1 

1 Laboratory of Applied Mathematics, University of Trento, Italy 

Purpose 

Results 

We present a simple mathematical model for the main extracranial cerebral venous 

return pathways. The model reproduces physiological patterns of flow distribution 

in supine and upright positions. Moreover, we identify which alterations of these 

pathways might be associated to abnormal flow distributions recently linked to multiple 

sclerosis (MS). 

Physiologic behaviour 

The model reproduces physiological inversion of cerebral venous return flow distribution 

among IJVs and the Vple. 

1.5 

1.5 

Introduction 

α = A A 0 

1.0 

0.5 

0.0 

0.00 0.05 0.10 0.15 

α = A A 0 

1.0 

0.5 

0.0 

0.00 0.05 0.10 0.15 

1.0 

1.0 

In supine position cerebral venous return occurs mainly via the internal jugular 

veins (IJVs), whereas in upright position the flow is redirected to the venous vertebral 

plexus (Vple) due to the collapse of IJVs 1 . A recent work by Monti et al. 5 

relates a dysfunction in cerebral venous return to MS patients. The described 

anomaly regards an increased flow via IJVs and vertebral veins (VVs) in upright 

position with respect to flow through these veins in supine position. Moreover, such 

a dysfunction indicates altered venous hemodynamic behaviour, linking these findings 

to Chronic Cerebro-Spinal Venous Insufficiency 6 (CSSVI). 


We consider a simple network of one-dimensional vessels for the main pathways of 

cerebral venous return. IJVs are modelled as two collapsible vessels, whereas the 

Vple is considered as a rigid vessel. Our model is an improvement of the lumped 

parameter model presented by Gisolf et al. 4 . 

CBF 

CBF 

0.5 

0.0 

0.00 0.05 0.10 0.15 

x [m] 

CBF 

0.5 

0.0 

0.00 0.05 0.10 0.15 

x [m] 

Figure 2: Subject in supine (left) and in upright position (right). Low values of α indicate collapse, 

while values close to unity or higher indicate vessel distention. In supine position IJVs are distended 

an the majority of the CBF passes through them. In upright position IJVs collapse and the flow is 

redirected to the Vple, which does not collapse due to its greater wall stiffness. 

Increased IJV wall stiffness 

Flachenecker et al. 3 found a correlation between MS and cardiovascular autonomic 

dysfunction. Such a dysfunction may alter vasoconstriction control. Our model 

confirms that changes in the IJVs wall stiffness may invert flow distribution. An 

increase from 50 to 2000 Pa was sufficient for inverse flow distribution. 

Increased CVP 

An increased CVP (from -2 to 10 mmHg) in upright position leads to an inversion in 

flow distribution. Moreover, Charkoudian et al. 2 reported that increased CVP may 

alter baroreflex control of sympathetic activity in humans. This would result in a 

combination of smaller increases of CVP and wall stiffness for determining inverse 

flow distribution. 

2 

1.5 

α = A A 0 

1.0 

α = A A 0 

1 

0.5 

0.0 

0.00 0.05 0.10 0.15 

0 

0.00 0.05 0.10 0.15 

1.0 

1.0 

CBF 

0.5 

CBF 

0.5 

LIJV 

Vple 

RIJV 

0.0 

0.00 0.05 0.10 0.15 

x [m] 

0.0 

0.00 0.05 0.10 0.15 

x [m] 

CVP 

Figure 1: Simplified extracranial venous network. CBF: cerebral blood flow; CVP: central venous 

pressure; Vple: vertebral venous plexus, IJV: internal jugular veins (left and right). 

We impose mass conservation and momentum balance for each vessel solving the 

following equations ⎧⎨ 

∂ t A + ∂ x (uA) =0, 

2 

⎩ ∂ t (uA)+∂ x 

(ˆαAu ) + A ρ ∂ (1) 

xp = Agsin θ − f . 

A(x, t) is the cross-sectional area of the vessel, u(x, t) is the cross-sectional averaged 

axial velocity, p(x, t) is the average internal pressure over the cross-section, 

g is the acceleration due to gravity, θ is the angle of the vessel with respect to 

supine position and f (x, t) is the friction force due to viscous stresses. 

A closure is necessary in order to link p(x, t) to A(x, t). This is done via a so called 

tube law 

[ (A(x, ) m ( ) ] n t) A(x, t) 

p(x, t) =p e + K (x) 

− 

. (2) 

A 0 (x) A 0 (x) 

p e is the external pressure, m and n are numbers to be specified. A 0 (x) is the 

equilibrium cross-sectional area and K (x) is the bending stiffness of the vessel 

wall 

[ ] 3 

E(x) h0 (x) 

K (x) = 

12(1 − ν 2 . (3) 

) R 0 (x) 

E(x) is the Young modulus whereas h 0 (x) and R 0 (x) are the equilibrium values for 

wall thickness and vessel radius, respectively. Upstream boundary conditions are 

obtained by solving a non-linear system arising at the junction of the three vessels, 

with a mass source term given by cerebral blood flow (CBF), set to 750 ml min −1 in 

supine position and reduced by 10 % in upright position. The downstream boundary 

condition is given by fixing the central venous pressure (CVP) value. 

We simulate: 

- postural changes: variation of θ in (1) 

- changes of vessels wall stiffness: by variation of E in (3) 

- stenosis: variation of A 0 in (2) along the vessel 

- increased CVP: variation of downstream boundary conditions 

- blocked Vple 

Figure 3: Upright position for increased IJVs wall stiffness (left) and for increased CVP (right). In 

both cases, even if there is a reduction of the cross-section area of IJVs, no collapse occurs and 

the main portion of the flow still passes via these veins. 

IJV Stenosis 

No inversion was observed for stenosis in one or both IJVs. In any case, some 

considerations should be made: 

- IJV stenosis is expected to have a more significant role in supine position, condition 

that can not be assessed by our model because of the simplicity of the network 

- IJV stenosis might be generally associated to alteration of overall vessel mechanical 

properties and might therefore be in any case linked to flow distribution 

inversion in upright position. 

Blocked Vple 

Due to the simplicity of the network the consequences of such a pathology are 

obvious. IJVs collapse but the cerebral venous return still occurs entirely via the 

IJVs. 

Conclusions 

Our simplified model reproduces physiological flow distribution of cerebral venous 

return in supine and upright positions. 

Pathologies that could lead to an inversion of flow distribution are: 

- increased IJVs wall stiffness 

- increased CVP 

- blocked Vple 

IJV stenosis does not imply pathological flow inversion but this might be a consequence 

of the simplicity of the model. 

Current/future work concerns the creation of a closed loop multi-scale model of 

the complete cardiovascular network. Such a model will allow a detailed study of 

CCSVI 6 implications in venous hemodynamics. 

References 

[1] Alperin N. et al., JMRI-J MAGN RESON IM 22, 591-596 (2005). 

[2] Charkoudian N. et al., AM J PHYSIOL-HEART C 287, H1658-H1662 (2004). 

[3] Flachenecker P. et al., J Neurol 246, 578-586 (1999). 

[4] Gisolf J. et al., J PHYSIOL 560, 317-327 (2004). 

[5] Monti L. et al., PLoS ONE 6 (2011). 

[6] Zamboni P. et al., J Neurol Neurosurg Psychiatry 80, 392-399 (2009). 

University of Trento *lucas.mueller@ing.unitn.it Via Mesiano 77, 38123 Trento, Italy

Physician Documentation of Fluoroscopy Time during Venous Angioplasty for 

Chronic Cerebrospinal Venous Insufficiency Correlates with Lower Fluoroscopy Time 

Prabhjot (Nina) Grewal MD, Michael Arata MD, Todd Harris MD 

Synergy Health Concepts, Newport Beach, CA 

PURPOSE: To show that physician documentation of fluoroscopy time during 

venous angioplasty for CCSVI correlates with lower fluoroscopy time. 

INTRODUCTION: Chronic Cerebrospinal Venous Insufficiency (CCSVI) is a 

pathophysiologic state whereby there is venous hypertension created in the 

cerebral veins due to obstructive jugular and azygos vein valves 1 . It is treated 

with balloon angioplasty of these valves to alleviate the hypertension thereby 

normalizing venous pressure. This procedure is done with fluoroscopy, exposing 

patients to radiation. Previous reports of average flouroscopy time during CCSVI 

procedure is 22.9 minutes 2 . We retrospectively reviewed fluoroscopy times and 

doses during the CCSVI procedure, comparing the average time and dose of 

examinations with the time and dose documented in the report to the average 

time and dose of those without documentation. 


procedures performed between January 2011 and August 2011. Fluoroscopy 

time and dose were recorded in the interventionalist’s report starting on June 

15, 2011. Average fluoroscopy time and dose were calculated for three groups: 

all CCSVI procedures, procedures without documentation in the dictated report, 

and procedures including the time and dose in the dictated report. 

Figure 1. Flouroscopy time is 

reduced when inteventionalist’s are 

required to dictated flouroscopy 

time and dose in report. 

Figure 2. Flouroscopy dose does 

not reduce when inteventionalist’s 

are required to dictated flouroscopy 


RESULTS. Over the eight month study period, 682 CCSVI procedures were 

performed and had fluoroscopy time documented. The average fluoroscopy 

time was 8.88 minutes for all procedures, 9.47 minutes for procedures without 

fluoroscopy time reported in the interventionalist’s dictated report (n=485), and 

7.43 minutes for procedures with fluoroscopy time reported in the dictation 

(n=197)(Figure 1). During the same time period 203 procedures were performed 

with fluoroscopy dose documented. The average fluoroscopy dose was 

61.13mGy for all procedures, 60.14mGy for procedures without fluoroscopy 

dose reported in the interventionalist’s dictated report (n=14), and 63.01mGy for 

procedures with dose reported in the dictated report (n=189) (Figure 2). 

CONCLUSION. Fluoroscopy time decreases when an awareness is made 

by the interventionalist to actively report fluoroscopy time in the 

dictated report. Our results did not show that radiation doseage was 

reduced by actively reporting fluoroscopy dose in the dictated report. 

The reason for this may be that during the time period after reporting 

was instituted the cases were of more complex nature requiring more 

flouroscopy to properly image the anatomy. The reporting of radiation 

time and dose is essential in reducing radiation exposure during the 

CCSVI procedure and all procedures done with fluoroscopy. 

1. Zamboni P, et al. Chronic cerebrospinal venous insufficiency inpatients with multiple sclerosis. J Neurol Neurosurg Psyciatry. 2009;80:392-99. 

2. Petrov, I, et al. Safety Profile of Endovascular Treatment for Chronic Cerebrospinal Venous Insufficiency in Patients With Multiple Sclerosis. J Endovasc Therapy. 2011; 18:314-23.

Introduction 

Cardiac Effects In The Multiple Sclerosis Patient – Implications For 

Avoidance Of Restenosis After CCSVI Angioplasty 

Driscoll DL, Francomano CA 

The Harvey Institute For Human Genetics 

Multiple sclerosis patients suffer from numerous neurological and inflammatory symptoms and signs. For this reason, focus on this disease process and appropriate treatments has been centered on the neurological insults to the brain 

and central nervous system, and more recently, has included evidence of abnormal venous drainage from the brain (CCSVI – “Chronic Cerebrospinal Venous Insufficiency”) and related abnormal fluid dynamics. Little attention has 

been paid to the cardiac effects of multiple sclerosis, but a review of literature indicates that such evaluation may provide critical information as to the pathogenesis and treatment of multiple sclerosis, including reducing the frequency 

of restenosis in the patient treated with angioplasty for CCSVI. 

A review of the literature indicates that multiple sclerosis patients (as studied by Akgul F, et al) demonstrate subclinical left ventricular diastolic dysfunction (P < 0.05). The cause of left 

ventricular diastolic dysfunction (when not secondary to medications such as mitoxantrone) is the overproduction of inflammatory cytokines such as TNF-alpha (Tumor Necrosis-alpha), 

Interleukin-6 (IL-6) and Interleukin-1 (IL-1) – all are mast cell mediators. 

For approximately a decade, these inflammatory cytokines have been implicated in the development and progression of heart failure. Additionally, TNF-alpha is known to promote and activate thromboembolism. The actions of such 

inflammatory cytokines in combination with the activation of Matrix Metalloproteinase (MMP) is assumed to cause collagen breakdown in the heart, and cardiac mast cells play an important role in the initiation of this process. 

Similar changes of collagen are occurring in the veins of patients with CCSVI. The study of mast cells and their granulations is critical when reviewing the potential causes of CCSVI and the avoidance of restenosis in the CCSVI 

patient. 

Purpose 

M.S. patients develop left ventricular diastolic dysfunction (LVDD). 1 

Ehlers-Danlos Syndrome (EDS) patients also develop LVDD. 2 Many, if not all, 

EDS patients who develop autonomic dysfunction also have CCSVI. 

Inflammatory cytokines are higher in 

the MS patient 

Red whiskers indicate the standard error of the 

mean cytokine response in MS patients vs. 

normals. Reference: 

* Diagram: Martins T, Rose J, et al. Analysis of 

Proinflammatory and Anti-Inflammatory Cytokine 

Serum Concentrations in Patients with Multiple 

Sclerosis by Using a Multiplexed Immuno assay. Amer 

J of Clin Path. 2011;136(5):696-704 

What occurs on a molecular and chemical level in LVDD and congestive heart failure? 

Can the cause of the changes seen in myocardial tissue reflect the disease process in 

M.S. and/or the cause of restenosis? 

Can this information give us new targets for 

treatment of M.S. and 

PREVENTION OF RESTENOSIS? 

Methods/Result: Literature Review 

Increase in myocardial stress 

Release of TNF-alpha, 

Methods/Result: Literature Review 

(such as increased ventricular 

volume or pressure), 

independent of the underlying 

cause, results in 13 

Increased release of 

ET-1 (a powerful 

vasoconstrictor) 16 

Mast cell degradation 16 

MMP (Matrix 

metalloproteinases) 

activation 7 

Ventricular 

Remodeling LVDD 5 

IL-1, IL-6 3,4,5,14 

Increase in cytokine 

elaboration follows in 

direct relation to the 

severity of the disease 

Proteases released include 

Chymase and Tryptase, 

which, in combination 

with other inflammatory 

cytokines 6,7 cause 

“mediator release 

syndrome” 

Collagen degradation: 

(in vessels, change of collagen 

from collagen 1 to collagen 

3 12,15 ) 

Inflammatory cytokines 

cause numerous 

harmful effects (when 

out of balance with 

anti-inflammatory 

cytokines): fibrosis, 

inflammation, 

endothelial cell 

apoptosis, 

thromboembolism, up 

regulation of cell 

adhesion molecules, 

etc. 8,9,10,11 

Inflammatory Cytokines + MMP = collagen change 

Collagen 1 becomes Collagen 3 

Potential Effects of TNF-alpha in Heart 

Failure: Could these effects also contribute 

to restenosis? 

•Produces left ventricular dysfunction 

•Produces pulmonary edema in humans 

•Produces cardiomyopathy in humans 

•Activates thromboembolism experimentally 

•Promotes thromboembolism experimentally 

•Promotes abnormalities in myocardial metabolism 

experimentally 

•Produces B-receptor uncoupling from adenylate 

cyclase experimentally 

•Abnormalities in mitochondrial energetics 

•Activation of the fetal gene program experimentally 

•Produces cardiac myocyte apoptosis experimentally 

Conclusion: 

Understanding the mechanisms 

involved in LVDD in the M.S. or EDS 

patient, and accepting that vascular 

changes are part of the disease process 

in both conditions, new and unique 

opportunities for treatment and 

prevention of restenosis come to light. 

New medications may include those that block histamine 

(H1 and H2 antagonists), mast cell stabilizers (cromolyn 

sodium and ketotifen), leukotriene blockers 

(montelukast), prostaglandin blockers (aspirin), flavinoids 

(including quercetin and luteolin), juanbi. 

TNF-alpha blockers: many medications for rheumatoid 

arthritis target TNF-alpha, but new medications with 

fewer side effects are also available. 

IL-1 blockers (anakinra, and many IL-6 blockers), 

Chymase inhibitors 

ET-1 blockers: bosentan, sitaxentan, ambisentan 

IL-6 blockers (statins, aspirin, indomethacin) 

Mast cell trigger avoidance should be considered as 

part of the post-angioplasty protocol. 

References 

1. Akgul F, McLek I, Duman T, Seyfeli E, Seydaliyeva T, Yalcin F. Subclinical left ventricular dysfunction in multiple sclerosis. Acta Neurol Scand. 2006 Aug; 114(2):114-8. 

2. McDonnell N, Gorman B, Mandel K, Schurman S, Assanah-Carroll A, Mayer S, Najjar S, Francomano C. Echocardiographic Findings in Classical and Hypermobile Ehlers-Danlos Syndromes. American Journal of Medical Genetics 2006; 

140A:129-136 

3. Kapadia S, Dibbs Z, Kurrelmeyer K, Kaira D, Seta Y, Wang F, Bozkurt B, Oral H, Sivasubramanian N, Mann DL. The role of cytokines in the failing human heart. Cardiol Clin. 1998 Nov;16(4):645-56 PMID 9891594 

4. Birks E, Burton P, Owen V, Mullen A, Hunt D, Banner N, Barton P, Yacoub M. Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts. Circulation. 2000 102:III-352-III-358. 

5. Baumgarten G, Knuefermann P, Mann D. Cytokines as Emerging Targets in the Treatment of Heart Failure. Trends Cardiovasc Med 2000;10:216-223 

6. Molderings G, Brettner S, Homann J, Afrin L. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011;4:10 

7. Janicki J, Brower G, Gardner J, Forman M, Stewart J, Murray D, Chancey A. Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. Cardiovascres Oxford J. 2005 

Oct;69(3):657-665 PMID: 16376329 

8. Heikkila HM, Latti S, Leskinen MJ, Hakala JK, Kovanen PT, Lindstedt KA. Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha. Arterioscler Thromb Vasc Biol. 2008 

Feb;28(2):309-14. PMID: 18079408 

9. Gu Yang, Liu Chang, Alexander SJ, Groome LJ, Wang Y. Chymotrypsin-Like Protease (Chymase) Mediates Endothelial Activation by Factors Derived From Preeclamptic Placentas. Reprod Sci. 2009 September;16(9):905-913. PMCID: 

PMC 3062263 

10. Oyamada S, Bianchi C, Takai S, Chu LM, Sellke FW. Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion. J Pharmacol Exp 

Ther. 2011 Oct;339(1):143-51. PMID:21795433 

11. Howard PS, Renfrow D, Schechter NM, Kucich U. Mast cell chymase is a possible mediator of neurogenic bladder fibrosis. Neurourol Urodyn. 2004;23(4): 374-82. PMID: 15227657 

12. Coen M, Mengatti E, Salvi F, Galeotti R, Mascoli F, Zamboni P, Gabbiani G, Bochaton-Piallat M. Characterization of CCSVI lesions in multiple sclerosis patients. Abstract for ISNVD, 2010. 

13. Munger MA, Johnson B, Amber IJ, Callahan KS, Gilbert EM. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1996 Apr;77(9): 

723-7. 

14. Turnbull A, Rivier C. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiol Rev. 1999. 79;1-71 PMID: 9922367 

15. Palaniyandi S, Nagai Y, Watanabe K, Ma M, Veeraveedu P, et al. Chymase Inhibition Reduces the Progression to Heart Failure After Autoimmune Myocarditis in Rats. Experimental Biology and Medicine. 2007, 232:1213-1221. 

16. Murray DB, Gardner JD, Brower GL, Janicki JS. Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats. Am J Physiol Heart Circ Physioll. 2004 Nov;287(5):H2295-9. 

PMID: 15231495

Venous Angioplasty In Multiple Sclerosis: Long Term Clinical Outcome Of A Cohort Of Relapsing-Remitting 

Patients 

Fabrizio Salvi , MD, PhD; Ilaria Bartolomei , MD, PhD; Elena Buccellato , BS; Erica Menegatti , PhD; Roberto 

Galeotti , MD; Paolo Zamboni , MD. 

Purpose: To report long term clinical outcome of endovascular treatment for chronic cerebrospinal venous 

insufficiency (CCSVI) in patients with multiple sclerosis (MS). 

Methods: Twenty-nine patients with clinically-definite relapsing remitting MS received percutaneous 

transluminal angioplasty for CCSVI at a distance from a clinical relapse and had a regular follow-up extending 

at least 2 years both before and after the first endovascular treatment (mean postoperative follow-up 31 months). 

Results: Overall 44 endovascular therapy sessions were performed without major complications. 

Thirteen of 29 patients (45%) received more than one treatment session because of venous restenosis. 

The annual relapse rate of MS was significantly lower postoperatively (0.45+/-0.62 vs 0.76+/-0.99; p=0.021), 

but it increased in 4 patients. The Expanded Disability Status Scale (EDSS) 2 years after treatment was 

significantly lower compared to the EDSS at the visit obtained 2 years before treatment (1.98+/-0.92 vs 2.27+/- 

0.93; p=0.037), but it was increased in 4 patients. 

Conclusions: Endovascular treatment of concurrent CCSVI is safe and repeatable and can reduce the annual 

relapse rates and the cumulative disability in patients with RR-MS. Randomized controlled studies are needed to 

further assess the clinical effects of endovascular treatment of CCSVI in MS.

Acetazolamide as a medical treatment option for patients with 

neurodegenerative disease in conjunction with or independent of, angioplasty 

for Chronic Cerebrospinal Venous Insufficiency (CCSVI) 

Driscoll DL 1 , Code W 2 

Harvey Institute of Human Genetics 1 University of British Columbia, Vancouver, Canada 2 

Introduction 

With the advent of research involving chronic 

cerebrospinal venous insufficiency (CCSVI) in 

patients with neurodegenerative disease, new 

explanations for decreased oxygen perfusion of 

the brain and the potential for Idiopathic 

Intracranial Hypertension need to be considered. 

Recent studies using perfusion magnetic 

resonance imaging in both relapsing and 

progressive forms of MS have shown decreased 

perfusion of the Normal Appearing White Matter 

(NAWM), which does not appear to be secondary 

to axonal loss. 

Recently, a pilot study indicated that 

hypoperfusion of brain parenchyma is associated 

with the severity of chronic cerebrospinal venous 

insufficiency in patients with multiple sclerosis. 

Purpose 

The authors hypothesize that the use of 

acetazolamide, a carbonic anhydrase inhibitor, to 

decrease intracranial pressure may offer these 

patients the benefits of increased cerebral 

perfusion pressure -- immediate reduction of 

symptoms of poor oxygen perfusion of the brain. 

The first action of acetazolamide is to decrease 

the production of cerebral spinal fluid. 

A second action of acetazolamide is its ability to 

increase blood flow in the brain. Pickkers et al 

discuss this in the British Journal of 

Pharmacology where they conclude that 

acetazolamide exerts a direct vasodilator effect in 

vivo in humans mediated by vascular calcium 

activated potassium channels. 

Zaitsu Y and Haacke EM (see references) 

measured a +39.7% increase in cerebral blood 

flow with acetazolamide. 

References 

Methods 

This article describes the results of a pilot study of 

25 patients with either multiple sclerosis (n=23) 

or chronic Lyme (n=2) who were prescribed 

acetazolamide and then evaluated subjectively 

for a change in symptoms related to poor 

cerebral perfusion. 

Symptoms evaluated included 

• poor sleep and sleep patterns, 

• cognitive difficulties (short-term memory issues, 

loss of executive function, loss of focus), 

• change in head discomfort (the “feeling of 

pressure”) or frank headache, and 

• fatigue. 

Dosages of acetazolamide varied, depending on 

patient age and weight, orthostatic tolerance, 

reported sensitivity levels to medication and 

patient response to initial doses. 

Conclusion 

With its multiple mechanisms to 

increase oxygen perfusion in the 

brain and other organs of the body, 

acetazolamide needs to be 

considered as an adjunctive therapy 

for diseases resulting in poor 

oxygen perfusion of the brain. 

The authors encourage double-blind, 

controlled studies for multiple sclerosis 

patients, and affected patients of related 

conditions resulting in poor oxygen 

perfusion. These conditions may include, but 

are not limited to: postural orthostatic 

tachycardia syndrome, chronic fatigue, 

Parkinson’s, Alzheimer’s Disease, Devic’s 

Disease, Idiopathic Intracranial 

Hypertension and small vessel dementia. 4 

This list is by no means conclusive and the 

authors look forward to the possibility that a 

well known, inexpensive drug 

(acetazolamide) could provide great relief for 

these patients, in conjunction with, or 

independent of angioplasty for CCSVI. 

Juurlink BH. The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system 

where mechanisms allowing leukocyte infiltration are readily upregulated? Med Hypotheses. 1998. 

Oct;51(4):299-303. PMID: 9824835 

Pickkers P, Hughes A, Russel F, Thien T, Smits P. In vivo evidence for K(Ca) channel opening properties of 

acetazolamide in the human vasculature. Br J Pharmacol. 2001 January;132(2):443-450. 

Kapadia S, Dibbs Z, Zaitsu Y, Kudo K, Terae S, Haacke EM, et al. Mapping of Cerebral Oxygen Extraction 

Fraction Changes with Susceptibility-weighted Phase Imaging. Radiology. 2011 Oct. PMID: 22031711 

Newman, NJ; Selzer, KA, Bell RA. Association of multiple sclerosis and intracranial hypertension. Journal of 

Neuro-Ophthalmology. 14(4): 189 – 192, 1994. 

O’Brien T, Paine M, Matotek K, Byrne E. Apparent hydrocephalus and chronic multiple sclerosis: a report of two 

cases. Clin Exp Neurol. 1993;30:137-43. PMID: 7712624 

Williams BJ, Skinner HJ, Maria BL. Increased intracranial pressure in a case of pediatric multiple sclerosis. J 

Child Neurol. 2008 Jun;23(6):699-702. PMID: 18539995 

Walters F. Intracranial pressure and cerebral blood flow. Update in Anesthesia. 1998;Issue 8: Article 4:1-4. 

Results 

21 out of 25 patients with chronic Lyme (n=1) or 

multiple sclerosis (n=20) reported significantly 

positive changes in: 

• sleep (quality and quantity), 

• head discomfort (the “feeling of pressure” in their 

heads) or frank headache 

• cognition (short-term memory functions, executive 

functions and the ability to focus), 

• fatigue 

Note: improvement of sleep and head discomfort 

occurred overnight. Improvement in cognition and 

fatigue occurred over weeks to months. 

Side effects included: 

• drowsiness 

• paresthesias 

• worsening of orthostatic tolerance 

• dehydration (causing one patient to drop out of the 

study) 

These effects are recognized side effects of 

acetazolamide and resolved spontaneously or with 

alterations of dosage or dosing frequency. 

Discussion 

Recent studies using perfusion magnetic resonance 

imaging in both relapsing and progressive forms of 

MS have shown decreased perfusion of the Normal 

Appearing White Matter (NAWM), which does not 

appear to be secondary to axonal loss. 

Recently, a pilot study indicated that hypoperfusion of 

brain parenchyma is associated with the severity of 

chronic cerebrospinal venous insufficiency in patients 

with multiple sclerosis. 

The authors hypothesize that the use of acetazolamide 

in these patients assists in brain perfusion through a 

minimum of two modes of actions: 

1) CPP = MAP – ICP 

Cerebral perfusion pressure equals the mean arterial 

pressure minus the intracranial pressure. The 

authors hypothesize that use of acetazolamide, a 

carbonic anhydrase inhibitor, to decrease intracranial 

pressure may offer these patients the benefits of 

increased cerebral perfusion pressure, and the 

immediate reduction of symptoms of poor oxygen 

perfusion of the brain. 

2) A second action of acetazolamide is its 

ability to increase blood flow in the brain. 

Pickkers et al discuss this in the British Journal of 

Pharmacology where they conclude that 

acetazolamide exerts a direct vasodilator effect in 

vivo in humans mediated by vascular calcium 

activated potassium channels. 

In the Pickkers study, acetazolamide infusions 

increased forearm blood flow, with no significant 

changes in the non-infused forearm, blood pressure 

or heart rate.. 

They conclude that acetazolamide exerts a direct 

vasodilator effect in vivo in humans mediated by 

vascular K(Ca) channel activation. They went on to 

conclude that this makes acetazolamide the first drug 

known that specifically modulates this channel. 

In a study using susceptibility-weighted phase imaging, 

researchers noted an increase in cerebral blood flow 

of +39.7% with the use of acetazolamide.

EVALUATION OF MUSCLE METABOLISM IN MULTIPLE SCLEROSIS: 

A NEAR INFRARED SPECTROSCOPY-BASED APPROACH 

Anna Maria Malagoni, MD, PhD, Michele Felisatti, PhD, Nicola Lamberti, BS, 

Paolo Zamboni, MD, Fabio Manfredini, MD 

Vascular Diseases Center, University of Ferrara, Italy 

2nd Annual ISNVD Scientific Meeting 

18-22 February 2012 (Orlando, Florida USA) 

PURPOSE 

•To determine muscle metabolism of gastrocnemius in a static phase 

(oxygen consumption) and in a dynamic phase (oxygen changes during an 

incremental treadmill test) in multiple sclerosis (MS) patients compared to 

healthy subjects, and 

RESULTS 

rmVO 2 

was significantly higher in all MS legs compared to healthy legs (P=0.01) 

(Fig.1), 

•To compare in MS patients the results of the dynamic test with the validated 

6-minute walking test (6MWT). 

INTRODUCTION 

Near Infrared Spectroscopy (NIRS) allows a non invasive study of muscle metabolism 

under static and dynamic conditions. NIRS based methods have been applied for 

healthy and diseased people [1-4], but poorly in studies with MS patients. 

Fig.1.Comparison of resting muscle oxygen 

consumption between Healthy and MS 

subjects 

also analyzing separately PP and RR clinical types (P=0.004) (Fig.2). 

MATERIALS AND METHODS 

SUBJECTS 

MULTIPLE SCLEROSIS (n=28) 

HEALTHY (n=11) 

Legs (n) 56 22 

Sex (n) M=16; F=12 M=6; F=5 

Age (years) 42.7±14.0 33.2±8.9 

Clinical Types Relapsing Remitting (RR): N=19 - 

Primary Progressive (PP): N=9 

Disease duration (years) 9.9±6.3 - 

EDSS 3.8±2.2 - 

Fig.2.Comparison of resting muscle oxygen 

consumption among Healthy and MS 

clinical types 

O 2 

Hb AUC 

, HHb AUC 

, dHb AUC 

, and tHb AUC 

did not 

differ between all MS and healthy legs but 

different patterns of O 2 

Hb AUC 

related to PP 

legs were highlighted with lower values 

than healthy and RR legs (P=0.02) (Fig.3). 

Fig.3.Comparison of oxygenated hemoglobin 

(area under curve values) among Healthy 

and MS clinical types 

1) NIRS evaluation 

a) Static measurement 

Oxygen consumption (rmVO 2 

) at gastrocnemius muscle 

was measured at rest by venous occlusion [5]. 

b) Dynamic measurement 

All healthy subjects and all 

ambulatory MS patients (n=27) 

performed an incremental level 

treadmill test with NIRS probes on 

the gastrocnemius muscle. 

Protocol: starting speed set at 1.0 

Km/h, increases of 0.1 Km/h every 

10 m to exhaustion (maximal speed) 

[4]. 

c) Data processing 

Variations in oxygenated (HbO 2 

), 

deoxygenated (HHb), total (tHb= 

HbO 2 

plus HHb), and differential 

(dHb=HbO 2 

minus HHb) hemoglobin 

were recorded and quantified as 

area-under-curve (AUC) within the 

speed range 1.0-2.0 Km/h [4]. 

Cardiovascular load 

Heart rate was recorded during the 

treadmill test, and the variation of 

beats within the speed range 1.0- 

2.0 Km/h was calculated (dHR). 

2) Six Minutes Walking Test 

a) Incremental treadmill test; b) NIRS 

semiquantitative data; c) Transformation into 

quantitative data by area-under-curve calculation 

In MS ambulatory patients, indoor 6MWT was also 

performed and the distance covered was assessed 

(6MWD). 

A significantly higher dHR 

was observed in all MS 

patients (P=0.0003) (Fig.5) 

compared to healthy 

subjects, also according to 

both MS clinical types 

(P

A model of filtration and solute 

transport across the 

Blood-Brain Barrier 

Laura Facchini Alberto Bellin Eleuterio F. Toro 

Mathematics 

Civil and Environmental Engineering Civil and Environmental Engineering 

University of Trento (Italy) 



laura.facchini@unitn.it alberto.bellin@unitn.it toro@ing.unitn.it 

PURPOSE 

Altered venous hemodynamics affects the transport 

properties of vessel walls [1], creating microbleed, 

perivenular iron stores and hypoxia. 

In the present study, we propose a simple 

mathematical model for water and solute transport 

across vessel wall. 

With the help of suitable analytical and numerical 

solutions of this model, we investigate 

the effect of a blood pressure increase on both 

water flow and molecule transport across the 

Blood-Brain Barrier (BBB). 

1 INTRODUCTION 

In a typical (peripheral) microvessel, the lumen 

side of the endothelial cells composing the vessel 

wall is covered by the glycocalyx, a thin 

membrane which is believed to exert a sieving 

effect on macromolecules. 

Figure 1. Structure of a peripheral blood vessel [modified from 

http://www.hubrecht.eu/research/dekoning/research.html]. 

Since the BBB has the role of protecting the 

Central Nervous System (CNS) from the neurotoxic 

substances contained in the blood, while 

nourishing the surrounding brain tissue, it must 

be highly selective. Indeed, the clefts separating 

adjacent endothelial cells of the BBB are 

partially closed by the tight junctions. Furthermore, 

the microvessels of the CNS are protected 

externally by the basement membrane 

and by the astrocyte feet and the pericytes. 

Figure 2. BBB anatomical structure. 

Under normal conditions, while macromolecules 

cross the BBB through transcellular 

pathways [2], water and small hydrophilic solutes 

follow paracellular pathways through the 

clefts separating adjacent endothelial cells [3]. 

Figure 3. Paracellular and transcellular transport. 

The breakdown of the BBB with the associated 

increase of vessel permeability has been observed 

in traumatic head injury [4], Alzheimer’s 

disease [5] and it has recently been hypothesised 

in Multiple Sclerosis ([6], [7]). 

2 MATERIALS and METHODS 

From the conservation of water and solute mass 

in the steady-state case (following [8]) and after 

simplifications, we derive the following nonlinear 

system of ordinary differential equations 

{ (p ′ + rp ′′ ) − σ(π ′ + rπ ′′ )=0, 

Aπ(π ′ + rπ ′′ )+rπ ′ (Bπ ′ + Cp ′ (1) 

)=0. 

Here 

• r is the distance from the vessel axis, 

• p = p(r) is the hydrostatic pressure, 

• π = π(r) is the osmotic pressure, 

• σ is the reflection coefficient of the wall, 

• A = l p σ 2 −l d , B = l p σ−l d and C = l p (σ−1) 

are physiological parameters, 

• l p is a permeability coefficient, 

• l d is a diffusion coefficient. 

Then we calculate 

P (r) =p(r) − σπ(r), (2) 

q v (r) =−l p [p ′ (r) − σπ ′ (r)], (3) 

q s (r) = π(r) 

ϕRT [Bπ′ (r)+Cp ′ (r)] , (4) 

where 

• P (r) is the net pressure, 

• q v (r) and q s (r) are the volume and solute 

fluxes per unit length of the vessel, 

• ϕ is the Stokes radius, 

• R is the gas constant, 

• T is the absolute temperature. 

Now, using the model, we investigate the effect 

of an increase of blood pressure p c on both water 

flow and molecule transport across the BBB. 

Anatomical parameters are obtained from published 

studies on electron microscopy observations 

of animal brain or mesenteric vessels. 

3 RESULT 

Figures 4 to 6 show our results in graphical 

form. 

Figure 4. Volume flux per unit length of the vessel with respect 

to the blood pressure p c, with typical venular values of σ and l p 

(solid curve), and altered values of σ and l p (dashed curve) simulating 

the glycocalyx/BBB breakdown. 

Figure 5. Solute flux per unit length of the vessel with respect 

to the blood pressure p c, with typical venular values of σ and l p 

(solid curve), and altered values of σ and l p (dashed curve) simulating 

the glycocalyx/BBB breakdown. 

Figure 6. Osmotic (π), hydrostatic (p) and net (P ) pressures 

across the vessel wall, with typical values of venular blood pressure 

p c (solid curves) and altered values (discontinuous curves), 

in both cases of lower and higher than normal blood pressure. 

4 CONCLUSIONS 

• Blood pressure increase (hypertension) 

causes an increase in the volume and solute 

fluxes per unit length across the vessel wall. 

• The glycocalyx (and thus BBB) breakdown 

gives rise to an increase in both fluxes. 

• We have depicted the osmotic, hydrostatic and 

net pressures across the vessel wall. 

• These are very preliminary results and there 

is some work on more sophisticated model. 

References 

[1] Singh A. V. & Zamboni P., J. Cereb. Blood Flow Metab. 29(12), 1867-1878 (2009). 

[2] Pardridge W. M., Molecular Biotechnology 30(1), 57-69 (2005). 

[3] Hawkins B. T. & Davis T. P., Pharmacological Reviews 57(2), 173-185 (2005). 

[4] Fukuda K. et al., Journal of Neurotrauma 12(3), 315-324 (1995). 

[5] Farkas E. & Luiten P. G. M., Progress in Neurobiology 64(6), 575-611 (2001). 

[6] Zamboni P. et al., J. Vas. Med. 50(5), 1348-1358 (2009). 

[7] Tucker T. W., Med. Hypotheses 77(6), 1074-1078 (2011). 

[8] Katchalsky A. & Curran P.F., Harvard Univ. Press Cambridge MA (1965).

2. Mandato K, Hegener PF, Siskin GP et al. Safety of Endovascular 

Treatment of CCSVI: A Report of 240 patients with Mutiple 

Sclerosis. JVIR 2011.E.pub 

Affiliations: Section of Interventional Radiology, RUSH University Medical Center, Chicago, ILCurrent address for Dr. Ferral: Northshore University Healthsystem, Evanston, IL

Physician Documentation of Fluoroscopy Time during Venous Angioplasty for 

Chronic Cerebrospinal Venous Insufficiency Correlates with Lower Fluoroscopy Time 

Prabhjot (Nina) Grewal MD, Michael Arata MD, Todd Harris MD 

Synergy Health Concepts, Newport Beach, CA 

PURPOSE: To show that physician documentation of fluoroscopy time during 

venous angioplasty for CCSVI correlates with lower fluoroscopy time. 

INTRODUCTION: Chronic Cerebrospinal Venous Insufficiency (CCSVI) is a 

pathophysiologic state whereby there is venous hypertension created in the 

cerebral veins due to obstructive jugular and azygos vein valves 1 . It is treated 

with balloon angioplasty of these valves to alleviate the hypertension thereby 

normalizing venous pressure. This procedure is done with fluoroscopy, exposing 

patients to radiation. Previous reports of average flouroscopy time during CCSVI 

procedure is 22.9 minutes 2 . We retrospectively reviewed fluoroscopy times and 

doses during the CCSVI procedure, comparing the average time and dose of 

examinations with the time and dose documented in the report to the average 

time and dose of those without documentation. 


procedures performed between January 2011 and August 2011. Fluoroscopy 

time and dose were recorded in the interventionalist’s report starting on June 

15, 2011. Average fluoroscopy time and dose were calculated for three groups: 

all CCSVI procedures, procedures without documentation in the dictated report, 

and procedures including the time and dose in the dictated report. 

Figure 1. Flouroscopy time is 

reduced when inteventionalist’s are 

required to dictated flouroscopy 


Figure 2. Flouroscopy dose does 

not reduce when inteventionalist’s 

are required to dictated flouroscopy 


RESULTS. Over the eight month study period, 682 CCSVI procedures were 

performed and had fluoroscopy time documented. The average fluoroscopy 

time was 8.88 minutes for all procedures, 9.47 minutes for procedures without 

fluoroscopy time reported in the interventionalist’s dictated report (n=485), and 

7.43 minutes for procedures with fluoroscopy time reported in the dictation 

(n=197)(Figure 1). During the same time period 203 procedures were performed 

with fluoroscopy dose documented. The average fluoroscopy dose was 

61.13mGy for all procedures, 60.14mGy for procedures without fluoroscopy 

dose reported in the interventionalist’s dictated report (n=14), and 63.01mGy for 

procedures with dose reported in the dictated report (n=189) (Figure 2). 

CONCLUSION. Fluoroscopy time decreases when an awareness is made 

by the interventionalist to actively report fluoroscopy time in the 

dictated report. Our results did not show that radiation doseage was 

reduced by actively reporting fluoroscopy dose in the dictated report. 

The reason for this may be that during the time period after reporting 

was instituted the cases were of more complex nature requiring more 

flouroscopy to properly image the anatomy. The reporting of radiation 

time and dose is essential in reducing radiation exposure during the 

CCSVI procedure and all procedures done with fluoroscopy. 

1. Zamboni P, et al. Chronic cerebrospinal venous insufficiency inpatients with multiple sclerosis. J Neurol Neurosurg Psyciatry. 2009;80:392-99. 

2. Petrov, I, et al. Safety Profile of Endovascular Treatment for Chronic Cerebrospinal Venous Insufficiency in Patients With Multiple Sclerosis. J Endovasc Therapy. 2011; 18:314-23.

IMPROVEMENT OF CHRONIC FATIGUE AFTER ENDOVASCULAR 

TREATMENT FOR CHRONIC CEREBROSPINAL VENOUS 

INSUFFICIENCY IN THE PATIENTS WITH MULTIPLE SCLEROSIS 

Marian Simka, Piotr Janas, Tomasz Ludyga, Paweł Latacz, Marek 

Kazibudzki 

Affiliation: Euromedic Specialist Clinics, Department of Vascular & 

Endovascular Surgery, Katowice, Poland 

Purpose. The aim of this study was to evaluate impact of endovascular treatment for chronic cerebrospinal venous 

insufficiency on chronic fatigue in multiple sclerosis patients. 

Methods. Severity of fatigue was assessed in 340 multiple sclerosis patients after the follow-up of 6 months. For this 

evaluation the Fatigue Severity Scale (FSS) was used. 

Results. We found statistically significant improvement of fatigue. Six months after the treatment mean FSS score dropped 

from 4.7 to 3.8. However, these post-procedural changes were not evenly distributed. While the patients with no fatigue 

(FSS

Characteristics of patients who maintained 

improvement at Six Months 

• Number of patients - 50 

• Duration of MS - 5.1 

• M:F- 28:22 

• Type of MS - RR:SP:PP=19:18:13 

• Mean age - 45 (33 -60) 

– Some comments 

• increased Physical activity and mobility, feeling 

energetic and no longer taking afternoon nap 

• Now cycling/swimming 

• Feel strange, increased co -ordination skills 

Characteristics of Patients Who Relapsed After 

Initial Improvement 

• Number of patients -14 

• Duration of MS -11 years 

• M:F=7:7 

• Mean age -49yrs 

• Type of MS-RR:SP:PP -3:5:6 

Characteristics of Patients With No Change After 

Treatment 

• Number of patients - 6 

• Duration of MS -10 years 

• M:F-1:5 

• Mean age -47.5 

• Type of MS-RR:SP-3:3 

MSFC SCORE 

• MSFC SCORE= {Z arm average + Z leg average + Z 

cognitive}/3.0 

• Pre-treatment score 0.040397263 ± 0.56 

• Post treatment score 0.058432175 ± 0.74 

• p=0.11 

• A decrease or an increase in the MSFC score 

represents, respectively, deterioration or 

improvement in neurological functions. 

MSQoL 

QoL(Physical ), p

FINDINGS ON VENOGRAPHY IN MS PATIENTS UNDERGOING AN EVALUATION 

FOR CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY (CCSVI): 

Correlation with MS Subtype and the Presence of Visual Symptoms at the Time of MS Diagnosis 

Kenneth Mandato, MD; Arvin Bagherpour, MD; Lisa Kurian, MD; 

Meridith Englander, MD; Gary P. Siskin, MD 

Department of Radiology, Albany Medical Center, Albany, NY 

PURPOSE: To compare the findings on venography of the internal 

jugular and azygos veins with clinical symptoms and subtype 

of Multiple Sclerosis (MS) in patients undergoing an evaluation 

for chronic cerebrospinal venous insufficiency (CCSVI). 

MATERIALS AND METHODS: A retrospective study of all MS 

patients being evaluated for CCSVI during a 6-month period 

was performed. Findings on venography were classified based 

on the distribution of stenoses within the internal jugular and 

azygos veins, a system described by Bartolomei, et al. (see Table 

1) These findings were compared with MS subtype and with the 

presence or absence of visual symptoms at the time MS was initially 

diagnosed. Positive findings on venography included the 

criteria used for treatment with angioplasty a 50% stenosis or 

a flow abnormality in association with a 50% stenosis in each 

studied vein. 

CONCLUSIONS: The presence of visual symptoms at the time 

of diagnosis, and the subtype of MS, are not predictive of the 

findings seen on catheter venography performed as part of an 

evaluation for CCSVI. This contradicts previously published findings, 

which neatly correlated symptoms at presentation and the 

patients’ MS subtype with the location of venous disease on 

venography. This study leads to questions regarding the role 

that CCSVI plays in directly causing the clinical manifestations 

of MS. A prospective trial assessing the ability of clinical findings 

to predict venography findings and treatment outcome is 

recommended. 

TABLE 1: PATTERNS OF CCSVI OBSERVED IN MS CASES 

Type A: Stenosis of proximal azygous vein associated with unilateral internal 

jugular vein (IJV) stenosis 

Type B: Significant stenoses of both IJVs and the proximal azygous vein 

Type C: Bilateral IJV stenoses with normal azygous vein 

Type D: Multifocal azygous vein stenoses with or without IJV abnormalities 

1A 

1B 

RESULTS: 318 patients were treated during the study period; the 

study population consisted of 251 patients (mean 49.4 years; 

3% male and 63% female) with complete historical data available 

for analysis. The distribution of MS subtypes was as follows 

122/251 (49%) had relapsing remitting MS, 6/251 (30%) 

had secondary progressive MS, and 53/251 (21%) had primary 

progressive MS. 0 patients had visual symptoms at the time of 

initial diagnosis of MS (39 patients had visual symptoms alone; 

31 patients had visual and other symptoms). Based on the previously 

described classification system for venography findings, 

38/251 (15.1%) patients had a Type A pattern (see Figures 1A- 

1D), 100/251 (39.8%) patients had a Type B pattern, 108/251 

(43.0%) patients had a Type C pattern, and 5/251 (2.0%) patients 

had a Type D pattern. An analysis of this data determined 

that the findings on venography were not associated with MS 

subtype (p=0.590) or with the presence or absence of visual 

symptoms (p= 0.0912). 

1C 

FIGURE 1A: Conventional azygous venography in the left anterior oblique projection shows 

a “kinking” form of stenosis with retrograde flow into intercostal vessels. FIGURE 1B: 

Hemodynamically significant severe stenosis in the left internal jugular vein in the same patient 

with proximal azygous vein stenosis (type A) FIGURE 1C: 10mm balloon angioplasty of 

the proximal azygous vein was performed. FIGURE 1D: Significant improvement in azgyous 

diameter and antegrade flow with regression of intercostal collaterals following angioplasty. 

The patient also underwent left IJV angioplasty (not shown) with marked clinical improvement 

within 24 hours. 

REFERENCES: EREN 

RENC 

: Bartolomei I, et al. Int Angiol 2010; 29183-188 

amboni, et al. ournal eurol eurosurg Psychiatry 2009; 80 392-399 

1D

FINDINGS ON VENOGRAPHY IN MS PATIENTS UNDERGOING AN EVALUATION 

FOR CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY (CCSVI): 

Correlation with MS Subtype and the Presence of Visual Symptoms at the Time of MS Diagnosis 

Kenneth Mandato, MD; Arvin Bagherpour, MD; Lisa Kurian, MD; 

Meridith Englander, MD; Gary P. Siskin, MD 

Department of Radiology, Albany Medical Center, Albany, NY 

PURPOSE: To compare the findings on venography of the internal 

jugular and azygos veins with clinical symptoms and subtype 

of Multiple Sclerosis (MS) in patients undergoing an evaluation 

for chronic cerebrospinal venous insufficiency (CCSVI). 

MATERIALS AND METHODS: A retrospective study of all MS 

patients being evaluated for CCSVI during a 6-month period 

was performed. Findings on venography were classified based 

on the distribution of stenoses within the internal jugular and 

azygos veins, a system described by Bartolomei, et al. (see Table 

1) These findings were compared with MS subtype and with the 

presence or absence of visual symptoms at the time MS was initially 

diagnosed. Positive findings on venography included the 

criteria used for treatment with angioplasty a 50% stenosis or 

a flow abnormality in association with a 50% stenosis in each 

studied vein. 

CONCLUSIONS: The presence of visual symptoms at the time 

of diagnosis, and the subtype of MS, are not predictive of the 

findings seen on catheter venography performed as part of an 

evaluation for CCSVI. This contradicts previously published findings, 

which neatly correlated symptoms at presentation and the 

patients’ MS subtype with the location of venous disease on 

venography. This study leads to questions regarding the role 

that CCSVI plays in directly causing the clinical manifestations 

of MS. A prospective trial assessing the ability of clinical findings 

to predict venography findings and treatment outcome is 

recommended. 

TABLE 1: PATTERNS OF CCSVI OBSERVED IN MS CASES 

Type A: Stenosis of proximal azygous vein associated with unilateral internal 

jugular vein (IJV) stenosis 

Type B: Significant stenoses of both IJVs and the proximal azygous vein 

Type C: Bilateral IJV stenoses with normal azygous vein 

Type D: Multifocal azygous vein stenoses with or without IJV abnormalities 

1A 

1B 

RESULTS: 318 patients were treated during the study period; the 

study population consisted of 251 patients (mean 49.4 years; 

3% male and 63% female) with complete historical data available 

for analysis. The distribution of MS subtypes was as follows 

122/251 (49%) had relapsing remitting MS, 6/251 (30%) 

had secondary progressive MS, and 53/251 (21%) had primary 

progressive MS. 0 patients had visual symptoms at the time of 

initial diagnosis of MS (39 patients had visual symptoms alone; 

31 patients had visual and other symptoms). Based on the previously 

described classification system for venography findings, 

38/251 (15.1%) patients had a Type A pattern (see Figures 1A- 

1D), 100/251 (39.8%) patients had a Type B pattern, 108/251 

(43.0%) patients had a Type C pattern, and 5/251 (2.0%) patients 

had a Type D pattern. An analysis of this data determined 

that the findings on venography were not associated with MS 

subtype (p=0.590) or with the presence or absence of visual 

symptoms (p= 0.0912). 

1C 

FIGURE 1A: Conventional azygous venography in the left anterior oblique projection shows 

a “kinking” form of stenosis with retrograde flow into intercostal vessels. FIGURE 1B: 

Hemodynamically significant severe stenosis in the left internal jugular vein in the same patient 

with proximal azygous vein stenosis (type A) FIGURE 1C: 10mm balloon angioplasty of 

the proximal azygous vein was performed. FIGURE 1D: Significant improvement in azgyous 

diameter and antegrade flow with regression of intercostal collaterals following angioplasty. 

The patient also underwent left IJV angioplasty (not shown) with marked clinical improvement 

within 24 hours. 

REFERENCES: EREN 

RENC 

: Bartolomei I, et al. Int Angiol 2010; 29183-188 

amboni, et al. ournal eurol eurosurg Psychiatry 2009; 80 392-399 

1D

Vascular Fundus Changes Observed In Patients 

With A High Probability of CCSVI 

Driscoll DL 1 , Francomano CA 1 , Driscoll RA 2 

Harvey Institute For Human Genetics 1 , Total Eye Care 2 

1a 

1b 

2a 

2b 

3a 

3b 

3c 

Figure Key 

1a: MS, left eye 

1b: MS, right eye 

2a: MS, likely EDS, left eye 

2b: MS, likely EDS, right eye 

3a: EDS, left eye (has CCSVI) 

3b: EDS, right eye (has CCSVI –IJV valve 

more affected in this eye) 

3c: same patient; notice how right fundus 

corresponds to worse stenosis on right 

side.

Does metal-induced hypersensitivity, a risk factor for 

venous stenosis and restenosis, contribute to brain and 

venous abnormalities in multiple sclerosis sufferers? 

Stejskal V PhD 1 , Tsamopoulos N MD 2 , Manginas N MD 3 

1 

Dept of Immunology, University of Stockholm. 2 Dept of Interventional Neuroradiology, Mediterraneo Hospital, Athens, Greece. 3 Dept of Interventional Cardiology, Mediterraneo Hospital, Athens, Greece 

PURPOSE 

RESULTS 

We asked why restenosis occurred in the majority of multiple sclerosis patients treated by percutaneous transluminal angioplasty (PTA) for 

 

subsequent 

restenosis after PTA. 

 

34 patients with central nervous (CNS) and systemic symptoms suspected to have been caused by dental amalgam. Similar changes were not 

 

® 

patients with CNS symptoms and MRI changes were found against inorganic mercury, phenyl mercury, gold and lead. 

INTRODUCTION 

 

observed reduced signal density on T2 weighted magnetic resonance images (MRI) of the basal ganglia in the brain of MS patients and 

 

areas of low density in T2 weighted imaging and the location of iron deposits as well as the correlation between the extent of gray matter T-2 

 

An important factor for restenosis, sometimes observed after cardiovascular stenting, is immune reactivity to metals in the stents. Thus, cellular 

hypersensitivity (Type 4, delayed type allergy) to stent materials increases the risk for restenosis in patients who are patch test positive to nickel 

 

Thus, patients suffering from gold allergy developed restenosis more frequently than similarly treated non-allergic patients, or patients with gold 

allergy but implanted with nickel or titanium-coated stents (Fig 1). The frequency of gold sensitization increases with the number of dental gold 

restorations. Further, in addition to cadmium and lead, which induce arrhythmias and high blood pressure, many studies indicate the role of 

 

In addition to patch testing, metal allergy may be diagnosed by determining the presence of memory T lymphocytes in peripheral blood. 

This so-called Lymphocyte Transformation Test (LTT) has been used for many years and has been standardized and validated in the form of 

MELISA ® ® detects abnormal cellular reactivity in patients suffering from 

 

is shown in Fig 2 and described in more detail below. The clinical relevance of MELISA ® 

reactivity following the replacement of sensitizing metals with non-metallic dental materials. In mercury-allergic patients suffering from multiple 

 

 

 

 

 

MATERIALS AND METHODS 

FIG 1 

FIG 2 

MELISA ® - MEmory Lymphocyte Immuno Stimulation A 

 

present in the environment and in dental restorations, as well as from other sources (Figs 3 and 4). 

 

FIG 3 

 

FIG 4 

 

 

Interestingly, titanium dioxide (TiO 2 ), previously thought to be “bio-inert”, stimulated the MS patients’ lymphocytes. Exposure to TiO 2 is very 

common, since it is added to pharmaceutical drugs as well as to foods, cosmetics and supplements. Titanium activates vein endothelial cells in 

vitro 

Further, TiO 2 

 

 

and abnormal deposition of iron in the brain and veins of MS patients. 

Accumulation of iron around the vein endings in the gray matter and the presence of lymphocytes and macrophages around demyelinating 

plaques could be due to dissemination of metal ions released from dying blood macrophages entering the brain through a damaged blood brain 

barrier. 

Local brain macrophages (oligodendrocytes) might further ingest the metal debris and become damaged in the process. Since 

 

CONCLUSION 

 

 

deposits in the basal ganglia. 

 

 

 

 

 

FIG 11 

FIG 12 

 

TABLE 1 

 

 

(SI). A value over 3 indicated a positive reaction to the given allergen. 

Baksi R et al. Gray matter T2 hypointensity is related to plaques and atrophy in the brain of multiple sclerosis patients. J Neurol Sci 2001; 185: 19-26 

Dreyer BP et al. Magnetic resonance imaging in multiple sclerosis; decreased signal in thalamus and putamen. Ann Neurol 1987; 22: 546-550 

Ekqvist S et al. High frequency of contact allergy to gold in patients with endovascular coronary stents. Br J Dermatol 2007; 157: 730–738 

Guo M et al. Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV) – transferrin by cancer cells: understanding the mechanisms of action of the anti-cancer drug Titanocene dichloride. Biochemistry 2000 Vol 39(33): 10023-33 

Houston MS. Role of Mercury Toxicity in Hypertension, Cardiovascular Disease, and Stroke. J Clin Hypertens (Greenwich)2011; 13: 621–627 

Köster R et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 2000; 356: 1895-1897 

Nemmar A, Melghit K, Badreldin H.Exp Biol Med 233: 610–619, 2008 

Prochazkova J et al.Neuroendocrinol Lett 2004; 25(3): 211–218 

Svedman C et al. A correlation found between contact allergy to stent material and restenosis of the coronary arteries. Contact Dermatitis 2009; 60: 158–164 

Stejskal V et al. MELISA - an in vitro tool for the study of metal allergy. Toxic. in Vitro 1994(8), No. 5: 99-1000 

Stejskal V et al. Diagnosis and treatment of metal-induced side-effects: Neuroendocrinol Lett 2006, 27 (Suppl. 1): 7-16 

Tibbling L et al. Immunological and brain MRI changes in patients with suspected metal intoxication. Int J of Occupational Medicine and Toxicol 1995; 4: 285-294 

Virtanen JK et al. Mercury, Fish Oils, and Risk of Acute Coronary Events and Cardiovascular Disease, Coronary Heart Disease, and All-Cause Mortality in Men in Eastern Finland. Arterioscler Thromb Vasc Biol. 2005; 25: 228-233 

Wagner M et al. Heavy metals ion induction of adhesion molecules and cytokines in human endothelial cells. Pathobiology 1997; 65: 241-252 

Zamboni P et al.Journal of Vascular Surgery 2009(50); 6: 1348-1358 

Zamboni P et al. J R Soc Med. 2006 Nov; 99(11): 589-93 

Zamboni P et al. CCSVI in patients with multiple sclerosis. J Neurol Neurosurg Psych 2009, 80: 392-399

Bruxism and Temporal Bone Hypermobility in Patients with Multiple Sclerosis 

David E. Williams 

Introduction: 

Many of the disease elements of MS are similar to those of long term cranial trauma. Anatomical observations by the principle author have suggested 

that one possible source of trauma could be instigated by bruxism via cranial suture insufficiency. In this study, the authors investigated the link between 

jaw clenching/bruxism and temporal bone movement associated with multiple sclerosis (MS). 

Materials and Methods: 

Twenty-one subjects participated in this study (10 patients with MS and 11 controls). To quantify the change in intracranial 

dimension between the endocranial surfaces of the temporal bones during jaw clenching, an ultrasonic pulsed phase locked loop (PPLL) device was 

used. A sustained jaw clenching force of 100 lbs was used to measure the mean change in acoustic pathlength (_L) as the measure of intracranial 

distance. 

Results: 

In the control subjects the mean _L was 0.27 mm±0.24. In ubjects with MS the mean _L was 1.71 mm±1.18 (p

GeneralMagneticResonanceImaging(MRI)ProtocolfortheStudyofChronicCerebrospinalVenous 

Insufficiency(CCSVI)inMultipleSclerosisPatients 

 

TheMRICCSVIProtocolusesaconventionalneuroimagingprotocolforMSwithadditionalspecialized 

sequencestostudythevasculatureinthebrain,neckandspineaswellastheironcontentinthebrain. 

Onthevascularside,bothanatomicandflowinformationiscollected.AmajorbenefitofusingMRIis 

thatitprovidestheneurologistwithwhatheneedsforassessingMS,itprovidestheinterventionalist3D 

planninganditprovidesallpartieswithcriticalflowinformationwhichmaywellbecomeakeymarker 

fordecidingwhenorwhennottotreatapatient.MRIisalsooperatorindependentforthemostpart 

andthesameprotocolscanberunonmostmanufacturers’systems.Thedataarealsoeasilyreproduced 

when run on the same equipment from site to site.Potential biomarkers for CCSVI and MS can be 

identifiedfromthedata.MRIcanalsolongitudinallytracktheprogressofthe diseaseovertimevia 

lesioncountsandtype,physiologicchangeslikebloodflowandcerebrospinalfluid(CSF)dynamics,and 

provideabaselineforfuturescans. 

 

Thefollowingimagingprotocolispresentedfora3TeslaSiemensScannerbutcanbeextendedtoother 

field strengths and manufacturers.The scans proposed are: 2D time of flight MR venography (TOF 

MRV), timeresolved contrast enhanced 3D MR angiography and venography (MRAV), 3D volumetric 

interpolatedbreathholdexamination(VIBE),phasecontrastflowdataatdifferentlevelsintheneckand 

thoracic cavity, as well as the conventional T2 weighted imaging (WI), T2 fluid attenuated inversion 

recovery(FLAIR),susceptibilityweightedimaging(SWI),andpreandpostcontrastT1weightedimaging 

(WI)ormagnetizationpreparedrapidgradientecho(MPRAGE)imaging.Perfusionscanningcanalsobe 

addedintothisprotocolforasmallincrementintime(roughly3minutesextra). 

 

2DTOFMRVscansareusedtodetectbloodflowinarteriesandveins.Usingasaturationband,anyflow 

towardthehead(arterialflow)willbesaturated,andtheflowtowardstheheart(venousflow)willbe 

highlightedinavelocitydependentmanner.Fromthissequence,veinsarewellvisualizedanditcanbe 

determinediftheyarepatent,occluded,orstenosed.Sincethedataarecollectedwithhighresolution, 

vesselcrosssectioncanalsobecalculatedtoevaluatethedegreeofstenosis. 

 

3DCEMRAVcanalsobeusedtoevaluatevascularabnormalities.ThescanusesaT1reducingcontrast 

agentwhichpassesthroughallvesselsandleadstoincreasedsignalforvesselsinT1weightedscans. 

Fromthedata,3Danatomicalassessmentscanbedonetoevaluatevesselpatency.Atresias,aplasias, 

truncularmalformations,valveissues,andstenosescanbedetected. 

 

3D VIBE pre and postcontrast can be used to evaluate structural patency of vessels as well as 

inhomogeneousenhancementofthetissue.Itisanalternateapproachtothe3DdynamicCEapproach 

justdiscussedandtakesmuchlonger(althoughstillrelativelyfast). 

 

2DPCMRIimagesareusedtoassessflowdynamicsintheheadandneckveinsandarteries,theazygous 

vein,andCSFattheC2cervicallevel.Thisinformationisvaluablebecauseitcanbothcorroborateand 

complimenttheinformationseeninthe2DTOFMRVand3DCEMRAV.Itisnotuncommontovisualize 

themajorveinsonlylatertofindthatmanyoftheveinshavecompromisedbloodflow. 

 

Susceptibility Weighted Imaging (SWI) is useful because the image contrast is based on the intrinsic 

susceptibilitiesoftissues.Forexample,veinsarerichindeoxyhemoglobinwhichisparamagneticand 

providesclearvisibilityofvenousstructures.Quantificationofironinthegraymatteraswellaslesions 

canbeaccomplishedusingT2*,phaseorsusceptibilitymappingfromthephaseimages.SWIisalso

useful in assessing blood products such as microbleeds and hemorrhagespossibly due to traumatic 

braininjury,vasculardementia,orMS.SWIMRAcanrevealarteriesandveinsontheorderofafew 

hundredmicronsbymeansofadualechosequence.MRAandMRVdatacanbeobtainedatthesame 

time. 

 

Formoreconventionalimaging,T2WIisusedtoshowtissuewithlongT2componentssuchasedema, 

CSF,tumors,andMSlesions.3DT2FLAIRisusedbecausetheimageshavesuppressedCSFsignal.FLAIR 

showsperiventricularlesionswellwithouttheinterferencefromCSF.Lesionquantityandvolumecan 

lsobeassessedwithFLAIR.Eventuallyitmaybepossibletocomparelesionvolumewithbloodflowor 

patient’sphysiologicalchangesovertime.T1WIisusedattwopartsofthescanningprotocoltoimage 

the head: initially before contrast agent injection, and after contrast agent injection.Lesions that 

enhancepostcontrastareconsideredasacute. 

 

PWIisusedtoevaluatethehemodynamicsofthebrain.Fromthisdataitispossibletoassessmean 

transittime(MTT)whichisthetimeittakesforcontrastagenttopassthroughthemicrovasculature;the 

cerebralbloodvolume(CBV)andthecerebralbloodflow(CBF). 

 

Notallthesescansneedtoberunoneverypatient.Thefullprotocolbelowisusedinaresearchmode. 

Whilethefullprotocolscantakesroughly1hour,22minutestorun,thereareshorterprotocolswith 

andwithoutcontrastthatcanreducethescantime.Removingthecontrastdependentsequencescan 

reducethetotalscantimetoapproximately52minutes.Foraposttreatmentscanwithoutcontrastand 

azygousdata,thescantimewouldbereducedtoapproximately34minutes:lesions,ironcontent, 

anatomyfrom2DTOFMRV,andbloodflowwouldstillbeabletobeassessed. 

 

ScanningProcedure 

 

Initially,registerthepatientalongwithhis/herheightandweight.Thisplaysanimportantrolein 

flowquantification(FQ). 

Activateappropriate(head,neckandspine)coilsforimagingtheregionofinterest. 

Makesuretoputthepulsetriggeronthesubject's(left/right)indexfingerorforabetterflow 

quantificationcardiacgatingcanbeused. 

Initially,westartimagingtheheadusingSWI,T2,MPRAGE,FLAIR,VIBE,andPWIsequences. 

Make sure to use the head and neck coils. Inject 5cc of contrast agent on the 10 th 

measurementofPWIsequence. 

Later, move the table to center at the neck and acquire T2, 3D CE MRAV, and flow 

quantification (FQ) sequences. Make sure to use the head neck coils. Inject the remaining 

contrastagentonthe3 rd measurementof3DCEMRAV. 

The FQ plane will be set perpendicular to the CSF flow at C2/C3 necklevel with a VENC of 

10cm/sec,andsetperpendiculartotheinternaljugularveins(IJV’s)attheC2/C3,C5/C6and 

C7/T1necklevelswithavencof50cm/sec. 

Next,movethetablecenterbacktotheheadandacquirethedatausingthepostgadolinium 

sequencesVIBE,andMPRAGE. 

Toimagetheazygous,movethetabletocenteratthemidsternum.Usetheneckandspine 

coils.Acquire2DTOFMRVandFQsequences.UseaVENCof50cm/secfortheFQsequence.

ThemotivationforthisprotocolofcoursecomesfromthemajorthrusttodayfromDr.Zamboni’s 

workthatthereisanassociationofabnormalvenousflowinpatientswithMS.However,theCCSVI 

protocolnowprovidesanewmeansbywhichtocompareflowabnormalitieswithpatient’sstatus, 

thenumberoflesionsandflowdeficitstothebrain,forexample.Othercomparisonscanbedone 

withironcontentintheformoftransferring,ferritinandhemosiderin.Stillothertestscouldbedone 

comparingtheflowabnormalitieswithgeneticdefectsorgeneassociation.Theusualcomparisons 

withlesionloadandEDSSorMSIS29couldalsobeperformed. 

 

Theotherissuecomesintrainingneuroradiologistsandneurologistshowtoreadimagesshowingeither 

abnormalvascularanatomyorinterpretingwhatisnormalflowandwhatisabnormalflow.Trainingmay 

needtoinvolveunderstandingthetechnicallimitationsofthesemethodsaswell. 

 

MRIPROTOCOL1:THEFULLPROTOCOLWITHCONTRAST 

BODYOF 

EXAMINATION 

HEAD 

VENDORMRIACRONYMS 

TIMEOF 

MRISEQUENCE 

Siemens GE Philips 

AQUISITION 

SWI GRE SWI SWI1X0.5X2 07:28 

T2 T2 T2 T2 02:30 

3D 

04:03 

MPRAGE 

FGRE,3 

DFast 

3DTFE MPRAGE 

SPGR 

FLAIR FLAIR FLAIR FLAIRSAG 05:20 

VIBE LAVAXV THRIVE VIBESAGPRE 01:45 

PWI PWI PWI PWIINJECT5CCCONTRAST 01:58 

TOTAL 

TIME 

22:04 

MovethetablecenterattheNECK 

T2 T2 T2 T2SAG 02:22 

TOF TOF TOF 2DTOFMRV* 06:57* 

NECK 

3D 

3DMRAVDYNAMIC–CORONALINJECT 

11:59 

TRICKS TRAK 

02:52 

FLASH 

REMAININGCONTRAST 

18:56* 

FQ FQ FQ 

FLOWQUANTIFICATIONATCSFAND 01:42(x4) 

THREENECKLEVELS 

MovethetablecenterattheORBITALRIDGE 

VIBE LAVAXV THRIVE VIBEPOST 01:45 

3D 

04:03 

HEAD(POST 

FGRE,3 

GAD) MPRAGE 

3DTFE MPRAGEPOST 

DFast 

05:48 

SPGR 

MovethetablecenterattheMIDSTERNUM 

TOF TOF TOF 2DTOFMRV(azygous) 10:39 

AZYGOUS TOF TOF TOF 2DTOFMRV(azygousarch) 05:12 17:33 

FQ FQ FQ FLOWQUANTIFICATION 01:42 

TotalScanTime: 

Forheadandneckonlywithout2DTOFjustunder40minutes 

Forheadandneckonlywith2DTOFjustunder45minutes 

Forhead,neckandazygousunderonehour

MRIPROTOCOLFLOWCHARTWITHOUTCONTRAST 

 

BODYOF 

VENDORMRIACRONYMS 

TIMEOF TOTAL 

MRISEQUENCE 

EXAMINATION Siemens GE Philips 

AQUISITION TIME 

SWI GRE SWI SWI1X0.5X2 06:39 

T2 T2 T2 T2 02:30 

HEAD 

3DFGRE, 

MPRAGE 3DFast 3DTFE MPRAGE 04:03 

18:32 

SPGR 

FLAIR FLAIR FLAIR FLAIRSAG 05:20 

MovethetablecenterattheNECK 

TOF TOF TOF 2DTOFMRV 06:57 

T2 T2 T2 T2SAG 02:22 

NECK 

FLOWQUANTIFICATION 01:42(x4) 16:07 

VIBE LAVAXV THRIVE ATCSFANDTHREENECK 

LEVELS 

MovethetablecenterattheMIDSTERNUM 

TOF TOF TOF 2DTOFMRV(azygous) 10:39 

AZYGOUS TOF TOF TOF 

2DTOFMRV(azygous 05:12 

arch) 

17:33 

FQ FQ FQ FLOWQUANTIFICATION 01:42 

 

Totalscantimeforhead,neckandazygous:justunder53minutes 

Totalscantimeforheadandneck:justunder35minutes

Magnetic Resonance Imaging (MRI) Traumatic Brain Injury Protocol 

The MRI TBI Protocol uses a conventional neuroimaging protocol for MS with additional specialized 

sequences to study the vasculature in the brain, neck and spine as well as the iron content in the brain. 

On the vascular side, both anatomic and flow information is collected. A major benefit of using MRI is 

that it provides the neurologist with what he needs for assessing MS, it provides the interventionalist 3D 

planning and it provides all parties with critical flow information which may well become a key marker 

for deciding when or when not to treat a patient. MRI is also operator independent for the most part 

and the same protocols can be run on most manufacturers’ systems. The data are also easily reproduced 

when run on the same equipment from site to site. Potential biomarkers for CCSVI and MS can be 

identified from the data. MRI can also longitudinally track the progress of the disease over time via 

lesion counts and type, physiologic changes like blood flow and cerebrospinal fluid (CSF) dynamics, and 

provide a baseline for future scans. 

The following imaging protocol is presented for a 3-Tesla Siemens Scanner but can be extended to other 

field strengths and manufacturers. The scans proposed are: 2D time of flight MR venography (TOF 

MRV), time-resolved contrast enhanced 3D MR angiography and venography (MRAV), 3D volumetric 

interpolated breath-hold examination (VIBE), phase-contrast flow data at different levels in the neck and 

thoracic cavity, as well as the conventional T2 weighted imaging (T2WI), T2 fluid attenuated inversion 

recovery (FLAIR), susceptibility weighted imaging (SWI), and pre and post contrast T1 weighted imaging 

(T1WI) or magnetization prepared rapid gradient echo (MPRAGE) imaging. Perfusion scanning can also 

be added into this protocol for a small increment in time (roughly 3 minutes extra). Finally, we add 

diffusion tensor imaging (DTI) as a measure of microscopic changes in water diffusion. Both fractional 

anisotropy (FA) and apparent diffusion coefficient (ADC) measures are used from this data. 

2D TOF MRV scans are used to detect blood flow in arteries and veins. Using a saturation band, any flow 

toward the head (arterial flow) will be saturated, and the flow towards the heart (venous flow) will be 

highlighted in a velocity-dependent manner. From this sequence, veins are well visualized and it can be 

determined if they are patent, occluded, or stenosed. Since the data are collected with high resolution, 

vessel cross-section can also be calculated to evaluate the degree of stenosis. 

3D CE MRAV can also be used to evaluate vascular abnormalities. The scan uses a T1 reducing contrast 

agent which passes through all vessels and leads to increased signal for vessels in T1 weighted scans. 

From the data, 3D anatomical assessments can be done to evaluate vessel patency. Atresias, aplasias, 

truncular malformations, valve issues, and stenoses can be detected. 

3D VIBE pre- and post-contrast can be used to evaluate structural patency of vessels as well as 

inhomogeneous enhancement of the tissue. It is an alternate approach to the 3D dynamic CE approach 

just discussed and takes much longer (although still relatively fast). 

2D PC-MRI images are used to assess flow dynamics in the head and neck veins and arteries, the azygous 

vein, and CSF at the C2 cervical level. This information is valuable because it can both corroborate and 

compliment the information seen in the 2D TOF MRV and 3D CE MRAV. It is not uncommon to visualize 

the major veins only later to find that many of the veins have compromised blood flow. 

Susceptibility Weighted Imaging (SWI) is useful because the image contrast is based on the intrinsic 

susceptibilities of tissues. For example, veins are rich in deoxyhemoglobin which is paramagnetic and 

provides clear visibility of venous structures. Quantification of iron in the gray matter as well as lesions

can be accomplished using T2*, phase or susceptibility mapping from the phase images. SWI is also 

useful in assessing blood products such as microbleeds and hemorrhages -possibly due to traumatic 

brain injury, vascular dementia, or MS. SWI-MRA can reveal arteries and veins on the order of a few 

hundred microns by means of a dual-echo sequence. MRA and MRV data can be obtained at the same 

time. 

For more conventional imaging, T2WI is used to show tissue with long T2 components such as edema, 

CSF, tumors, and MS lesions. 3D T2 FLAIR is used because the images have suppressed CSF signal. FLAIR 

shows periventricular lesions well without the interference from CSF. Lesion quantity and volume can 

lso be assessed with FLAIR. Eventually it may be possible to compare lesion volume with blood flow or 

patient’s physiological changes over time. T1WI is used at two parts of the scanning protocol to image 

the head: initially before contrast agent injection, and after contrast agent injection. Lesions that 

enhance post-contrast are considered as acute. 

PWI is used to evaluate the hemodynamics of the brain. From this data it is possible to assess mean 

transit time (MTT) which is the time it takes for contrast agent to pass through the microvasculature; the 

cerebral blood volume (CBV) and the cerebral blood flow (CBF). 

Not all these scans need to be run on every patient. The full protocol below is used in a research mode. 

While the full protocol scan takes roughly 1 hour, 22 minutes to run, there are shorter protocols with 

and without contrast that can reduce the scan time. Removing the contrast-dependent sequences can 

reduce the total scan time to approximately 52 minutes. For a post-treatment scan without contrast and 

azygous data, the scan time would be reduced to approximately 34 minutes: lesions, iron content, 

anatomy from 2D TOF MRV, and blood flow would still be able to be assessed. 

Scanning Procedure 

Initially, register the patient along with his/her height and weight. This plays an important role in 

flow quantification (FQ). 

Activate appropriate (head, neck and spine) coils for imaging the region of interest. 

Make sure to put the pulse trigger on the subject's (left/right) index finger or for a better flow 

quantification cardiac gating can be used. 

Initially, we start imaging the head using SWI, T2, MPRAGE, FLAIR, VIBE, and PWI sequences. 

Make sure to use the head and neck coils. Inject 5cc of contrast agent on the 10 th 

measurement of PWI sequence. 

Later, move the table to center at the neck and acquire T2, 3D CE MRAV, and flow 

quantification (FQ) sequences. Make sure to use the head neck coils. Inject the remaining 

contrast agent on the 3 rd measurement of 3D CE MRAV. 

The FQ plane will be set perpendicular to the CSF flow at C2/C3 neck level with a VENC of 

10cm/sec, and set perpendicular to the internal jugular veins (IJV’s) at the C2/C3, C5/C6 and 

C7/T1 neck levels with a venc of 50cm/sec. 

Next, move the table center back to the head and acquire the data using the post gadolinium 

sequences - VIBE, and MPRAGE. 

To image the azygous, move the table to center at the mid sternum. Use the neck and spine 

coils. Acquire 2D TOF MRV and FQ sequences. Use a VENC of 50 cm/sec for the FQ sequence.

The motivation for this protocol of course comes from the major thrust today from Dr. Zamboni’s 

work that there is an association of abnormal venous flow in patients with MS. However, the CCSVI 

protocol now provides a new means by which to compare flow abnormalities with patient’s status, 

the number of lesions and flow deficits to the brain, for example. Other comparisons can be done 

with iron content in the form of transferring, ferritin and hemosiderin. Still other tests could be done 

comparing the flow abnormalities with genetic defects or gene association. The usual comparisons 

with lesion load and EDSS or MSIS-29 could also be performed. 

The other issue comes in training neuroradiologists and neurologists how to read images showing either 

abnormal vascular anatomy or interpreting what is normal flow and what is abnormal flow. Training may 

need to involve understanding the technical limitations of these methods as well. 

MRI PROTOCOL 1: THE FULL PROTOCOL WITHOUT CONTRAST 

BODY OF VENDOR MRI ACRONYMS 

TIME OF 

MRI SEQUENCE 


AQUISITION 

SWI/MRA GRE GRE SWI - 1 x 0.5 x 2 mm 3 07:28 

T2 T2 T2 T2 02:30 

HEAD 

SWI/MRA GRE GRE SWI - 0.5 x 0.5 x 1.0 mm 3 07:28 

FLAIR FLAIR FLAIR FLAIR-SAG 05:20 

DTI DTI DTI 2 x 2 x 2 mm 3 - 30 Directions 06:50 

ASL ASL ASL 3 x 3 x 3 mm 3 04:44 

3-D 

MPRAGE Fast 3D TFE MPRAGE 04:03 

SPGR 

Move the table center at the NECK 

T2 T2 T2 T2-SAG 02:22 

TOF TOF TOF 2D TOF MRV 06:57 

NECK 

FLOW QUANTIFICATION AT CSF AND 

FQ FQ FQ 

01:42 (x5) 

THREE NECK LEVELS 

Total Scan Time: roughly 57 minutes 

MRI PROTOCOL 1: PARTIAL HEAD ONLY PROTOCOL WITHOUT CONTRAST 


TIME OF 

MRI SEQUENCE 


AQUISITION 


T2 T2 T2 T2 02:30 

HEAD 




3-D 

MPRAGE Fast 3D TFE MPRAGE 04:03 

SPGR 

Total Scan Time: roughly 30 minutes 

TOTAL 

TIME 

38:23m 

17:49m 

TOTAL 

TIME 

29:55m

MRI PROTOCOL 1: THE FULL PROTOCOL WITH CONTRAST 


TIME OF 

MRI SEQUENCE 


AQUISITION 


T2 T2 T2 T2 02:30 

MPRAGE 

3-D Fast 

04:03 

3D TFE MPRAGE 

SPGR 

HEAD 



ASL ASL ASL 3 x 3 x 3 mm 3 04:44 

VIBE 

LAVA- 

XV 

THRIVE VIBE-SAG-PRE 01:45 

PWI PWI PWI PWI - INJECT 5CC CONTRAST 01:58 

Move the table center at the NECK 

T2 T2 T2 T2-SAG 02:22 

TOF TOF TOF 2D TOF MRV* 06:57* 

NECK 

3D FLASH TRICKS TRAK 

3D MRAV DYNAMIC –CORONAL- INJECT 

REMAINING CONTRAST 

02:52 

FQ FQ FQ 

FLOW QUANTIFICATION AT CSF AND 

THREE NECK LEVELS 

01:42 (x5) 

Move the table center at the ORBITAL RIDGE 

LAVA- 

VIBE 

THRIVE VIBE-POST 01:45 

XV 

HEAD (POST 

3-D 

GAD) 

FGRE, 

MPRAGE 

3D TFE MPRAGE-POST 04:03 

3-D Fast 

SPGR 


Total Scan Time: less than 80 minutes 

TOTAL 

TIME 

32:33 

13:44 

20:41* 

15:48

The 2 nd Annual ISNVD Scientific Meeting 

February 18–22 th 2012 Orlando, Florida, USA 

Catheter venography for the assessment of internal jugular veins and 

azygous vein – consensus document 

Contrary to some well-recognized venous territories, relatively little is known about anatomy, 

physiological flow and hemodynamics in the internal jugular veins. Even less is known about the 

azygous vein. Consequently, catheter angiography and interpretation is currently performed according 

to the rules governing examination of other veins. Still, differences exist between techniques and 

interpretation amongst centers. Since our knowledge about anatomy and physiology of veins that may 

play a role in pathophysiology of neurological disorders (especially: multiple sclerosis) in the setting 

of the so-called chronic cerebrospinal venous insufficiency (CCSVI) is at its infancy, there are many 

problems that should be addressed. 

1. Vascular access. 

Most venographies are currently performed through femoral access. Access through an upper 

extremity vein is a theoretical option in the case of agenesis of inferior vena cava. A direct puncture of 

the internal jugular vein can also be used, but can be technically challenging if such a vein is 

hypoplastic or collapsed. Thus, femoral access is the preferred route. However, there are some issues, 

which need to be considered when using femoral access. 

Firstly, the pressure measurement in the internal jugular vein may not be reliable (jugular valve is 

potentially kept open by the diagnostic catheter – hypothetically reducing or eliminating any crossvalve 

pressure differential). Options may include using a smaller caliber device such as a pressuresensing 

wire, which is less disruptive to valves or for accurate pressure measurement direct jugular 

access could be considered. 

Secondly, there is discussion about which femoral vein (right or left), should be punctured. Insertion 

of the catheter through the left femoral vein allows a much easier assessment of left iliac vein (May- 

Thurner syndrome), the ascending lumbar veins and the left renal vein (Nutcracker syndrome). On the 

other hand, access through right femoral vein makes access and angioplasty of the left internal jugular 

and azygous veins much easier particularly in the case of tortuous iliac and left brachiocephalic veins. 

In addition, there is currently no evidence to support angioplasty of asymptomatic stenosis of the left 

iliac or left renal vein, thus a potential benefit from left femoral access is not clear. We therefore 

recommend right femoral vein access for routine assessment of the internal jugular and azygous veins 

and possible consideration of angioplasty. Left femoral vein access may be an option if the screening 

of additional veins, such as left iliac vein is planned. 

2. Angiographic contrast. 

Angiographic contrast may be used diluted (1:1) or non-diluted. Diluted contrast allows better 

visualization of endoluminal structures (valve leaflets, webs, etc.). However, non-diluted contrast 

allows better opacification of epidural and other collaterals as well as better estimation of overall 

features of veins particularly stenosis. 

There is no clear consensus on whether contrast should be hand or pressure injected. Hand injections 

are performed using smaller volumes of contrast under lower pressure. Pressure injectors are higher

volume and higher pressure. There are proponents for both approaches. While hand injection mimics 

physiological venous flow, pressure injectors are more accurate, reproducible, make some flow related 

analyses quantifiable. Either or both approaches may be utilized in any case depending on the 

objectives desired. There are some modern injectors that allow low-pressure administration of contrast 

and perhaps such an equipment should be preferentially used. 

3. Interpretation of venographic pictures. Left versus right IJV 

It may seem obvious that venography of both internal jugular veins should be interpreted in the same 

way. But there are some arguments favoring a different approach to the right vs. left (or: dominant vs. 

non-dominant) jugular vein. Right internal jugular vein is usually bigger, its valve has longer leaflets; 

left internal jugular vein is smaller and has more transversally oriented valve leaflets. Perhaps these 

parameters should be taken into account while deciding if the vein assessed should be interpreted as 

normal, or pathological and requiring endovascular treatment. These dilemmas will be of special 

importance if the definition of pathology were based on quantitative assessment of the flow (which in 

most normal individuals is asymmetric). It is important to emphasize that asymmetry between the 

jugular veins itself is not pathological, however other attributes such as stenoses, need to be 

considered in the context of each individual jugular vein. In terms of what is a stenosis, there is little 

consensus, the authors of already published research have utilized an arbitrary definition of 50% 

luminal restriction when compared to nominal diameter of the proximal vein. However, the jugular 

vein stenosis in particular is more difficult to assess because of the routine dilatation of the vein 

cranially to the valve. Therefore, perhaps a nominal diameter of the vein proximal to the bulb or most 

dilated part of the distal jugular should be utilized. 

A few other considerations that are relevant in regards the jugular veins are, that unless the 

diagnostic catheter is placed at the level of the skull base/jugular foramen, one is likely to miss a 

multitude of anatomical and flow related anomalies in the upper jugular vein. Additionally, if an 

angled catheter is used and it is pointed medially, the injected contrast will specifically opacify 

through the mastoid and condylar emissary veins the vertebral and cervical epidural plexuses 

suggesting an underlying hemodynamic anomaly when none exists. Therefore, it is important that the 

angled catheters are directly laterally at the level of the jugular foramen. Frequently, the transverse 

process of the C1 vertebra will visibly indent the jugular vein (since the vein lies on this bony 

structure) however, a balloon will inflate under minimal pressure and Valsalva maneuver will enlarge 

the compressed vein during angiography or IVUS confirming this normal relationship. 

4. Interpretation of venographic pictures. Jugular valve. 

What should be regarded as a pathologic valve? Currently there are two ways of thinking. Firstly, 

some interpret jugular valve as abnormal if a narrowing at its level is detected: using venography, 

through inflating a compliant angioplastic balloon, or through intravascular ultrasound (IVUS). 

Secondly, some suggest that the valve should be interpreted as abnormal only if flow disturbances are 

found (no outflow through the vein, venous outflow slowed down, reversed flow direction, outflow 

through collaterals, etc). Probably more research in healthy individuals is needed to solve this 

problem. Such a research, however, will not be easy to perform taking into account an invasive nature 

of venography. 

5. Interpretation of venographic pictures. Azygous vein 

There is widespread discrepancy between performance and interpretation of azygous venograms. 

Firstly, there are no standards as to where exactly along the course of the azygous vein should a 

contrast injection be made, any injection made in the arch is likely to miss pathology in more proximal 

portions, while abdominal injections in a much smaller caliber vessel may artificially induce reverse

flow and evidence of increased collaterals including epidural channels. A standard position may be at 

the level of the diaphragm (T-12), since this allows estimation of essentially the entire spinal cord 

venous flow, since the spinal cord conus (terminal segment of the spinal cord) is typically located at 

L1. 

Secondly, interpretation varies as well, with some suggesting that any narrowing over 50% is 

pathology. Others interpret narrowing as pathological only if accompanied by reversed flow or huge 

outflow through collateral network. Consequently, azygous vein pathology is diagnosed in some 

centers in 80-90% of the cases, while others find pathology in only 5-10% of the patients. 

The valve of the azygous vein is typically seen at its junction with superior vena cava. Sometimes it 

is very difficult to go with diagnostic wires and catheters across this valve. For the time being, it 

remains unclear if such a difficult passing through represents a pathology oron the contraryis the 

sign of a perfectly competent valve. It should also be remembered that azygous vein is typically 

narrowed where it is arching over the right main bronchus and “stenosis” in this area is not necessarily 

pathological. In addition, some azygous lesions are simply reflective of intra-thoracic pressures and 

therefore much more likely to be a product of respiratory cycles (phasic) than true anatomical lesions. 

Therefore, anytime a lesion is identified, it may be worthwhile investigating it during an inspiratory 

arrest to induce maximal thoracic venous return during angiography or simply through IVUS, which 

will show variations in luminal dimensions during the various respiratory phases. 

6. Which “lesions” should be addressed. 

For the purpose of this discussion, we will assume that severe stenoses, associated with significant 

and apparent flow abnormalities (as noted above, such as: reversal, collaterals, etc.) will be treated. 

However, how do we assess the not-obviously stenosed jugular valves, narrowings of the azygous vein 

and internal jugular veins that are not accompanied by significant hemodynamic disturbances, or 

hemodynamically significant lesions in the veins, which are not clearly involved in neurological 

pathology (iliac, renal, etc.)? Although both venography and balloon angioplasty are safe, they are not 

risk-free. Thus, venography should not be performed in every assessable vein, but only in the veins 

that are likely to be both affected and manageable. The more extensive the examination, the higher the 

contrast load, nephrotoxicity risk, vascular iatrogenic complications and cumulative radiation dose. 

Similarly, angioplasty should be performed only to address the lesions, which have been implicated 

as causal for CCSVI. Which of the above-mention measures should be applied, remains an open 

question. This dilemma is likely to be solved only by well-designed prospective studies, but some 

preliminary conclusions can potentially be drawn from currently available literature. It should be 

assumed that a vein responsible for neurological pathology is draining the part of the central nervous 

system containing anatomic structures that are responsible for neurological deficits (for example: 

ataxia that is usually caused by cerebellar plaques is more likely to be caused by abnormal outflow in 

the jugular veins, which drain the cerebellum than by abnormal azygous outflow; on the contrary: 

plaques in the thoracic segment of the spinal cord are more likely to be linked to pathological azygous 

outflow). 

7. Phasic stenosis 

Should a narrowing of the vein, which is not visible permanently, but only during a fraction of 

cardiac or respiratory cycle, be regarded as pathology? And does such a lesion require treatment? 

Balloon angioplasty is very likely to not be successful. Stenting of the “phasic” stenosis may be 

associated with a high risk of stent migration. Moreover, intimal hyperplasia inside the stent in these 

cases seems to be a big problem. Perhaps such lesions should be left untouched, until other therapeutic 

strategies are developed.

8. Classification of outflow abnormalities. 

According to the published classification, abnormal venographic flow patterns were categorized into 

four grades: 

grade 1: venous outflow slowed down, no reflux detected; 

grade 2: venous outflow slowed down, mild reflux and/or pre-stenotic dilation of the vein; 

grade 3: venous outflow slowed down, with reflux and outflow through collaterals; 

grade 4: no outflow through the vein, huge outflow through collaterals. 

9. Should we assess stenoses of intracranial sinuses 

Catheterization, mechanical and chemical thrombolysis, angioplasty and stenting of intracranial 

venous sinuses are performed by neurointerventionalists for venous thrombosis, pseudotumor cerebri 

associated with venous stenosis and a few other uncommon disorders. However, the magnitude of 

possible complications is significantly higher than the same interventions in extracranial veins. The 

most dreaded complication is perforation of the jugular bulb or sinus or wire perforation of a cortical 

or cerebellar vein with devastating and usually fatal intracerebral hemorrhage. In addition, the 

anatomical features of extracranial veins, such as plasticity, compliance and deformability are simply 

not there for these venous channels encased partly in bone and partly in rigid leafs of dura permeated 

by delicate and unpredictable draining veins. Therefore, the questions regarding management of 

intracranial sinuses are: 

- Should we perform venography of these veins routinely, or only in very selected cases, since 

most of the doctors will not manage a lesion in this location even if detected, while the risk of 

diagnostic venography in this particular area cannot be neglected. 

- Should we perform therapeutic procedures in this territory, or rather should we wait until an 

evidence of clinical benefit from the treatments for CCSVI performed in other venous 

territories will be more obvious. 

- Pre-procedural evaluation of intracranial vein routinely consists of MR venography. It is wellknown 

that there is a lot of artifacts associated with this imaging test, for example very often 

left transverse sinus does not show at MRV, while actually it is perfectly patent; what is the 

best way to evaluate these veins before and after endovascular treatment? 

10. How to evaluate and manage stenoses in the upper part of the internal jugular vein, 

especially at the level of jugular foramen. 

In some patients the upper (cranial to the facial vein) internal jugular vein is narrow, hypoplastic, 

sometimes with associated flow impairment. The questions regarding this particular problem are: 

- Should we interpret such a vein as pathologic according to diameter measurements (if yes, 

which cutoff should be applied) 

- Alternatively, should we rather look at flow disturbances, especially at backflow of injected 

contrast 

- What is the best mode of management of such stenosed venous segment: standard balloon 

angioplasty (pro – a relatively safe procedure; contra – high rate of restenosis), stenting (pro – 

more efficient than PTA; contra – risk of migration, risk of thrombotic or hyperplastic 

occlusion), cutting balloon (pro more efficient than PTA, more safe than stenting; contra – 

thrombotic or bleeding complications possible; still, not very likely). 

11. The role for IVUS in the assessment of CCSVI 

Should IVUS be an integral part of venography? What are advantages and disadvantages of such an 

approach?

Doctors who are using IVUS routinely have found this diagnostic tool to be incredibly helpful as an 

adjunctive to catheter venography. No matter how one manipulates contrast dilution or injection 

speed, venography does not come close to the sensitivity of IVUS in detection of endoluminal 

anomalies (septae, thrombus, chronic organized/recanalized thrombus, valvular anomalies, valve 

leaflet morphology, phasic venous anatomical variability, etc.). IVUS can be performed extremely 

safely with minimal change in guide catheters being utilized, fluoroscopy time and contrast volume. 

While many patients demonstrate venographic anomalies, IVUS yields many more anomalies, since 

CCSVI appears to be principally an endoluminal disease. Thus, a combination of venography and 

IVUS provides a comprehensive assessment of venous anatomy, endoluminal structures and flow, 

which would be inadequate with either technique by itself. 

At the moment the use of IVUS is recommended for the diagnosing CCSVI. However, actual 

diagnostic value of this test should be evaluated by ongoing research. Of special importance will be 

the problem – whether the management of lesions that can be diagnosed only with IVUS and not with 

venography alone, will give an additional clinical benefit to the patients. 

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