ISNVD Scientific Meeting 2017

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Over 20 countries were represented at this year’s International Society of Neurovascular Diseases Annual Scientific Meeting in Taormina, Sicily, 4-6th May. CCSVI Australia supported Kerri Cassidy’s attendance in order for us to keep abreast of the latest research relating to CCSVI and Multiple Sclerosis and board member Maree Thomson also attended. Attached is a summary of the scientific presentations considered most relevant to people with MS and CCSVI as well as coverage of the first International Patient Associations gathering.

Official Opening

Paolo Zamboni, Stephen Alexander and Pierfrancesco Veroux conducted the opening ceremony.  The ISNVD is at an all-time high for membership with over twenty countries represented.  Zamboni reflected that the soul of the society is the interdisciplinary team that are working together to solve various unknowns in neurovascular conditions.

There were close to 100 presentations over the three days and it would have been impossible to provide information on them all.  Given the fast pace of each presentation the main points have been collated below.  Presentations focused on arterial research, such as stroke, have not been included in this report. Following are the brief summaries of presentations most relevant to people with MS/CCSVI in plain language so that a layperson can understand.

Alfred Study Update
Brave Dreams
International Patient Associations Meeting
Scientific Presentations

 

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Alfred Study Update – Dr Helen Kavnoudias

Helen Kavnoudias – our continued gratitude for her work.

Comparative findings of multimodal imaging of the internal jugular veins in MS patients, Dr Helen Kavnoudias:

We were able to quantify limitations of the different imaging modalities to measure abnormalities of the Internal Jugular Vein and confirm that multimodal imaging is required. Agreement between all modalities was only 50%. Agreement between Angiography and Ultrasound was 60%, Angioplasty and MRV was 64% and Ultrasound and MRV was 70%. This confirms that incorporating IVUS would be beneficial.

Ultrasound imaging for the control arm was obtained before, and in approximately half of patients there were significant differences in the result over the twelve months – high variability within individual patients. Patients were reported as normal at one time point and significantly abnormal (stenosis/flow) at a different time point.

Some comparative analysis has been completed between the treatment and sham to 24 months. There was no significant difference in two parameters: cerebral arterial flow and between the groups the EDSS was reported and found not to be significant at 12 months. However, there was a significant difference in EDSS (disability scale) at 24 months (p=0.016). This EDSS significance gives momentum to continue with further enrolments which will recommence this year.

Patients were provided a second treatment for restenosis. There were two relapses recorded over the 24 month period. Studies that don’t follow patients for at least 24 months may fail to appreciate improvement over a longer period.

Dr Kavnoudias gave special thanks to Prof Ken Thomson for taking on the initial research.

 

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Brave Dreams Update
Regrettably the Brave Dream results are still under embargo awaiting completion of peer review.  The release of this information will be important considering the large variability in prevalence of CCSVI in Multiple Sclerosis across several studies.  Brave Dreams is a multi-centre trial across Italy that includes a sham arm.  Inclusion criteria is patients with either RRMS or SPMS experiencing an EDSS between 2-5.5 and a disease duration less than 15y years (in contrast to Canadian Study).  A total of 204 patients were initial identified for the trial, RRMS (177).  74 were ineligible due to clinical criteria.  130 were enrolled and randomised and 127 completed the protocol.  Neurologist assessors are blinded and quality of life measured.  One key point is that quality training was given to effectively diagnose and treat CCSVI and certification was required.  There were several functional endpoint measures; new MRI lesions, Cog State, memory, attention, fatigue, bladder, anxiety and depression.  Prof Zamboni’s closing statement was that he believes something important will be reported.

Paolo Zamboni will be presenting Brave Dreams at the Australasian College of Phlebology in Melbourne, February 2018.  We are hopeful that the peer review process will be complete so that Prof Zamboni can give the full results of this essential study.

 

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International Patient Associations Meeting

Kerri Cassidy, Prof Zamboni, Maree Thomson after International Patient Associations Meeting.

Over 50 patients representing various CCSVI patient groups around the globe attended the meeting chaired by Professor Zamboni and Carol Schumacher from the Annette Funicello Research Fund for Neurological Diseases.

The heart-warming keynote testimonial was given by Nicoletta Mantovani, International Patient Spokesperson for CCSVI and wife of the late Luciano Pavarotti.  Nicoletta echoed the experiences of many people with Multiple Sclerosis as she shared her story of learning she had MS at aged 23 when she was told to expect that she would require a wheelchair.  She felt that doctors treated her like a number, giving her lots of medication which changed nothing.  She decided to cease taking medication and seek elsewhere for answers.  Nicoletta stated, “My husband taught me to see MS as an opportunity. I went to listen to Zamboni and I heard answers I’d never had before.”  After she had the vein procedure she says she, “saw another world. Like I had been behind glass and now I sensed that everything was real.”  Since then she has had no more MS attacks.

Nicoletta concluded her speech by saying:

“We need to work so that everyone has the possibility to see if this can help, research to make this available from a moral point of view.  We need to make known to government that whilst it is not for everyone, it can help people.”

Zamboni acknowledged the important work on CCSVI at Melbourne’s Alfred Hospital where significant improvements are being seen in Multiple Sclerosis.  He hopes to see the paper soon!  He thanks Kerri Cassidy and the ongoing work of Australians for CCSVI in MS.

The microphone was given for individual groups to provide updates including Kerri Cassidy from CCSVI Australia, Sharon Richardson from the CCSVI Alliance and Linda from the Canadian CCSVI Coalition.  Linda called on the international community to help complete funding for the Australian CCSVI research.

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Scientific Presentations:

Doppler Ultrasound diagnosis of CCSVI
Intracranial pressure changes following decompression of Internal Jugular Vein
Venous stent for treatment of venous outflow from the brain
Multiple Sclerosis environmental and genetic study – BNAC
Parkinsons and Multiple Sclerosis
The Facial Vein’s association with global and regional atrophy in MS
Multiple Sclerosis and the Nutcracker Syndrome
Coagulation pathways in Multiple Sclerosis
The Central Vein Sign
Higher frequency of neck vessels in MS
Gray matter damage and cognitive impairment
Aqueductal Cerebrospinal Fluid Pulse and mathematical modelling
Brain Drain – NASA study
CCSVI Genetic study
Embryonic interpretation of hemodynamic consequences in defective venous development
CCSVI Tracking Project ongoing analysis
Significant improvement after endovascular treatment for CCSVI
Meniere’s Syndrome
Comments on Canadian Study

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Doppler Ultrasound diagnosis of CCSVI.

Erica Menegatti from Zamboni’s team in Ferrara presented on how accuracy can be improved for quantifying venous return (venous drainage) using Doppler Ultrasound.  She emphasised that veins are elliptical and calculations assuming that veins are circular will distort venous flow measurements.  Additionally, Menegatti highlighted the importance of measuring the jugular vein pulse and how the cross-sectional area changes throughout the cardiac cycle.  Measuring this change has implications for blood, cerebrospinal fluid and lymph.  Future research will be focusing on the brain/heart connection in cognitive impairment and Alzheimer’s.

Karen Marr has also been studying jugular flow quantification and compared automated calculations and manual based calculations using Doppler Ultrasound.  Marr reiterated that different calculation methods produced varied results and that the computer calculations are based on the assumption that the cross section of a jugular vein is circular.  The main message being that manual measurement using the elliptical assumption is more accurate and consistent for veins.

Carlo Virgilio elaborated on further reasons for inconsistent ultrasound findings.  Virgilio’s expertise is assessing internal jugular veins by Doppler prior to angioplasty and suggests postural change, respiration, cardiac function, hydration and rotation of the head should be considered.

Giaqunita considered an integrated method of assessment using Intravenous Ultrasound (IVUS), Doppler Ultrasound and catheter venography.  Whilst Doppler Ultrasound can give cross sectional areas of the vessels, this is not enough to guide treatment decisions.  The challenge is to define flow abnormalities.  IVUS can provide more information such as hypoplasia and presence of muscle compression can be detected prior by the ‘pencil tip’ sign.  The Doppler is limited in practice and research, catheter venography gives valuable information but is less sensitive in assessing the exact abnormality.  Combining IVUS, DUS and CV provide an appropriate method for vessel sizing and stenosis assessment.  Petrov added that agreed protocols are now required.

 

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Intracranial pressure changes following decompression of Internal Jugular Vein

Prof Paolo Zamboni identified that consideration of intracranial pressure changes is often absent from discussions about CCSVI.  Zamboni noted that there is a decrease in cerebrospinal fluid pressure after treating the IJV and that intracranial pressure normalises.  He states that new stent devices that include venous compliance are needed with mechanical properties that can counteract possible external compression.

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Venous stent for treatment of venous outflow from the brain

The current need is a dedicated venous scaffold that is able to maintain long term patency as many MS patients are young.  Current venous stents exert uniform continuous force against the vessel walls which give permanent dilation to the vein.  Jugular veins require compliance – to be able to collapse when in upright position.  An innovative compliant venous scaffold has been developed with novel shape and configuration and have been tested in an animal study.  The first implant confirmed concepts, shape and force of scaffold and that it could adapt to the vein anatomy to avoid migration.  Safety and endothelial response was studied in 12 pigs using devices of 12mm and 14mm widths and 38mm and 48mm lengths.  A total of 32 devices were implanted and positioning was precise and no migration occurred.  No increase in wall thickness was detected with excellent patency.  Next step is human trials.

 

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Multiple Sclerosis environmental and genetic study – BNAC

Robert Zivadinov presented on five year follow up study of 296 subjects (207 with MS).  The aim is to observe lifestyle factors in people with Multiple Sclerosis, other neurological diseases and healthy controls and to understand the change over time. Zivadinov suggested that progression of MS is related to underlying cardiovascular comorbidities.  Functional MRI has now been introduced to the study to determine the probability of how brain lesions affect neural networks and its connection with vascular networks.  Zivadinov concluded that this study will provide a great deal of data and stated, “we will be able to explore more data in collaboration together.”

 

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Parkinsons Disease and Multiple Sclerosis

An extremely interesting presentation by Marcella Lagana focused on a comparison of venous abnormalities, neurodegeneration and cerebrovascular reactivity between Parkinsons Disease and Multiple Sclerosis patients and healthy controls.  It was found that there were a higher number of internal jugular vein abnormalities in MS where a lower venous flow rate was detected on average.  There were a higher number of abnormalities in the right jugular vein in PD.  Correlations were found between brain atrophy and reduced global grey matter cerebral blood flow in people with MS.  Perfusion was found to be correlated with cognitive measure.

Mark E Haacke continues to observe flow abnormalities in Parkinson’s Disease.  In particular, a higher prevalence of Dural Sinus abnormalities occur on the rights side in PD.  In the current study, abnormal venous outflow (<7ml/sec) has been observed in 27% of PD and in MS, 42% with jugular stenosis have abnormal outflow.  Interestingly, Haacke is finding high iron content in local regions of the brain in PD as a function of age and suggests this may explain two types of PD determined by the iron concentration and its location in the brain.

 

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The Facial Vein’s association with global and regional atrophy in MS

Dejan Jakimovski presented the correlation between a low or retrograde facial vein flow with more advanced brain atrophy in Multiple Sclerosis.  It was stated that the peripheral venous system is not fully understood with problems in classification due to the large variations in veins.  Jakimovski suggested that the facial vein, which is measured by calculating the internal jugular vein flow above and below the facial vein, may be significant.  This flow was measured in MS patients compared with healthy controls.  It was found that patients with lower facial vein flow had more advanced MS and Jakimovski suggested that this vein may be an alternative pathway for head/neck drainage.

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Multiple Sclerosis and the Nutcracker Syndrome

Sal Sclafani discussed the effectiveness of stenting the left renal vein to improve spinal cord blood flow.  He defines CCSVI as a clinical syndrome caused by inhibition of cerebrospinal venous hemodynamics.  Sclafani stated that there are several causes of spinal venous congestion and numerous radial veins, which are valveless, until the vertebral veins.  His focus is renal vein compression, or nutcracker syndrome, where the left renal vein transverses over the aorta.  Sclafani believes that many neurological symptoms are associated with Nutcracker Syndrome and there is a strong association with Multiple Sclerosis.  In his experience of treating 100 patients with MS, 60% have a greater than 50% stenosis of the renal vein.

 

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Coagulation pathways in Multiple Sclerosis

Francesco Bernardi discussed the anticoagulant and cytoprotective proteins present in MS compared with healthy controls.  Protein C is a major anticoagulant, anti-inflammatory and cytoprotective factor involved in stabilisation of the endothelial barrier.  Protein C is lower in MS than in HCs and Bernardi suggested that dysregulation of procoagulant/anticoagulant molecules may contribute to MS progression.

 

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The Central Vein Sign

Stefano Viotti has been studying the characterisation of MS lesions using SWI and QSM with 1.5T MRI.  Viotti stated that iron plays a crucial role in normal brain function and that iron deposition may enable differentiation between MS and other lesions.  Lesions in MS are different from others as there is a central vein visible in MRI.

 

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Higher frequency of neck vessels in MS

Dejan Jakimovski has studied arterial, venous and collateral vessels in the neck showing an association that is beyond BMI, age and gender factors.  MS is a multifactorial interplay between body systems and there has historically been discrepancies in attempts to create an all-inclusive approach.  In the age and sex matched study of MS (193) and healthy controls (193) it was found that MS patients had lower cross-sectional areas at all levels in arterial vessels, with no significant difference in the internal jugular veins however there are a higher number of collateral vessels in MS.  Jakimovski suggested that decreased carotid arteries are recruiting collaterals to compensate and the current 5-year study is comparing the change that occurs in these vessels over time.  Zamboni commented at conclusion of this presentation that they have found that collaterals decrease when fixing venous flow.

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Gray matter damage and cognitive impairment

Franco Patti observed that cognitive impairment is associated with fatigue and depression in Multiple Sclerosis and is present in 43-70% of pwMS. It is more common in SPMS and males appear to be less protected and language is affected in progressive MS.  Patti believes that cognitive impairment is underestimate in MS; it may be subtle and there is a large variation between patients, often being focal rather than global.  It is important to understand that many factors affect cognitive impairment, whilst lesion load may predict cognitive impairment there is not convincing evidence. The volume of white matter and atrophy appears to be involved.

 

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Aqueductal Cerebrospinal Fluid Pulse and mathematical modelling

Kerri discusses brain hemodynamics and Multiple Sclerosis with Clive Beggs (right)

Always interesting to listen to is Clive Beggs who presented on a statistical approach to analysing aqueductal CSF pulse.  A phenomenon he found was that a strong correlation exists between the venous blood stored throughout a cardiac cycle and the motion of CSF.  Beggs explained that the brain is a rigid container, fluids can only press against other fluids therefore, the only compliance is in CSF and venous outflow.  It is suggested that creating a system of linear equations to measure venous outflow, CSF and aCSF may have potential as a diagnostic tool.

Eleuterio Toro continued the mathematical theme by looking at modelling of interacting fluid compartments in the central nervous system.  He stated that there are 600 neurological conditions involving CNS fluid and that being able to measure extra cellular fluid compartments may help differentiate them.  He used a mouse to create a model of arterial, venous, CSF and lymphatic flows and highlighted the importance of studying these components together rather than in isolation.  Toro suggested that the lymphatic system has possibly been more neglected than the venous system.

 

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Brain Drain – NASA study

Zamboni’s team have been involved in measuring cerebral venous return (CVR) in astronauts during space flight.  Giacomo Gadda explained that veins are collapsible vessels in different positions and in microgravity there is a fluid shift resulting in increasing pressure for the brain.  The CVR pathways form an intricate network of vessels that effect brain hemodynamics and physiology. Using the plethysmography device there were able to measure changes in CVR under various conditions. Gadda observed a correlation between vision impairments and microgravity symptoms.

 

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CCSVI Genetic study

Nicole Ziliotto has been studying exome sequencing and transcriptomic analysis of jugular walls to detect CCSVI biomarkers in Multiple Sclerosis.  Essentially this means that they are identifying genes present in the comorbidity of MS and CCSVI by testing families affected by both.  They compared common DNA variations between patients and healthy controls and found 13 exomic sequences.  In the microarray analysis of jugular wall specimens, 929 differently expressed genes were found involved in aspects such as muscle and blood circulation.

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Embryonic interpretation of hemodynamic consequences in defective venous development

A fascinating presentation by Byung-Boong Lee considered the complex development of the vena cava and the possible complications that can occur during its formation.  Lee highlighted that congenital vascular malformations have been considered ‘mystical’ and not well understood, he suggests that certain defects may precede complications like CCSVI.  Truncular venous malformation such as intraluminal defects can result in stenosis or obstruction and some valve dysfunction is secondary to intraluminal thrombosis.  An interesting point was made; abnormalities may be present from birth but symptoms take a while to develop.  Lee concluded by saying that understanding the evolutionary process of vascular development is essential.

 

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CCSVI Tracking Project ongoing analysis

Hector Ferral presented a statistical analysis on data generated by the patient-initiative from Amsterdam.  The CCSVI Tracking Project was an anonymous, voluntary self-reporting system which received reports from over one thousand people treated for CCSVI.  Data could be analysed from 466 patients with 122 completing 24 months follow up after 1 procedure.  Of these, 66% had balloon angioplasty and 28% received stents.  58% reported significant improvement whilst 15% indicated mild improvements.  Most common improvements cited were related to brain fog and dizziness and 68% reported an overall improvement in quality of life.  Special thanks was given to Margreet Seinstra for her work.

 

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Significant improvement after endovascular treatment for CCSVI

Petrov’s first statement was that “CCSVI treatment really works.”  He has treated over 1300 patients with 65% reporting good results.  He cautions that ongoing benefit depends on long term patency of treatment.  Petrov observed that in some cases there are immediate benefits and hypothesises that as elevated carbondioxide gives an altitude-type sickenss, restoration of venous flow leads to a normal gas exchange.  Blood gas analysis shows difference between MS and controls.  Ferral commented that oxygen saturation does improve with treatment and that his results fit with the finding that vascular pattern matches with perfusion SWI.  Petrov suggested that CCSVI is probably a trigger for more neurological diseases than just MS.  Final emphasis was that lasting improvement depends on keeping veins open.

Giaquinta presented on the clinical benefits of balloon angioplasty in patients with impaired IJVs. There have been few studies published on quality of life measures.  Following treatment of 498 patients, headache and fatigue improved.  Beggs elaborated saying that 117 of this group experienced headache and 394 fatigue which were not mutually exclusive.  Following treatment, RRMS and SPMS had significant improvement in headache and whilst improvement was seen in the PPMS group it was not enough to claim significance.  Fatigue improved and was sustained in the RRMS group and although there was initial improvement seen in the PPMS group, there was later regression on average.

 

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Meniere’s Syndrome

A 24 months study on CCSVI treatment for people with Meniere’s Syndrome was presented by Bruno.  In 312 patients, 89% were found to have CCSVI and PTA was used for those with stenosis greater than 50%.  Mainly type C and B CCSVI was observed.  50 patients reported at the 24-month time point.  There was a 50% improvement in quality of life and 84% indicated an overall good result.

 

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Comments on Canadian Study

Michael Dake stated that the study was well controlled however it is not fair to present this trial as final after only 48 weeks.  It is interesting to note that the sham group display more adverse events than the treated group.  Whilst there was no difference in improvement detected between the sham and treatment groups it is not clear if PTA effectively treated stenosis.

 

Report compiled by Kerri Cassidy, CCSVI Australia.

22nd June 2017

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