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An Evidenced Based Consensus Approach
Brave Dreams is a multicentre blinded randomised controlled trial to determine safety and effectiveness of venous angioplasty for MS. Much of the evidence supporting the need for trials of this nature originated in 2009 and in the outcomes of numerous subsequent angioplasty interventions. A related trial is ongoing at the Alfred Hospital, Melbourne, Australia.
On 18 November 2016 Dr Zamboni provided an update at the 2016 Veith Symposium (and subsequently} about what is being learnt from the Brave Dreams trial. "Brave Dreams is a randomised controlled sham clinical trial of CCSVI primarily in Relapsing Remitting MS. It is understood that the trial outcomes will be released at the 2017 Veith Symposium in November 2017 and also highlighted in February 2018 at the Australian College of Phlebology's annual Conference in Melbourne.
Dr. Zamboni stressed that this type of trial is unique and should become the gold standard for MS treatments. He said "NO drug trial has ever been weighted and measured in such a precise, objective way".
He said "The recently concluded Brave Dreams trial is a scientifically robust, double-blinded, placebo controlled trial. The trial outcomes are currently embargoed--meaning we will not know specific results until it is published in a peer-reviewed journal. The study has 130 participants - over 90% of whom completed follow up. It uses objective measurements including MRI and other quality of life endpoints.
Because it is an interdisciplinary study involving neurologists, interventionalists, vascular and imaging specialists, it is going to take a lot of work to get the results vetted by all, and written up in a manuscript everyone agrees to". Dr. Zamboni stressed that this is essential, in order to have the science taken seriously and published. He went on to say:
What we do know
This was a six center study throughout Italy. 200 subjects started the year long study, 125 people completed it. They were mostly RRMS and some SPMS (under 5.5 EDSS) who were investigated, treated (or not if they were in the sham control) and followed a year through completion of this study.
There were primary endpoints, which Dr. Zamboni explained were OBJECTIVE. This means that these changes were not subjective, or based on patient's feelings, but were measurable by approved medical instrumentation. These objective measurements included volume of bladder, visual acuity, timed walking and manual dexterity, as well as MRI lesion consideration. All of these measurements were looked and compared during 3, 6, 9, and year intervals.
The first paper will report on these primary endpoints after treatment, and will hopefully be available by November 2017.
Cross Disciplinary Collaboration is Needed
Dr. Zamboni asked us all to "be patient". There will be more coming on how CCSVI treatment improves perfusion and cerebrospinal flow, as well as how it helps with depression, memory, fatigue, and cognition. This research is more "like an opera"--it is going to take cross-disciplinary collaboration and cooperation. Across disciplines and countries.
Ending the Diagnostic Controversy - An Important Step
In an interview (reported in January 2017) Professor Zamboni discusses how his method of measuring venous flow looks at flow velocity and how the jugular venous pulse (JVP) is synchronized with the carotid artery and heartbeat. By also looking at normal subjects, all three of these measurements are synchronized in a determinate interval of time. The venous pulse begins with the heart contraction, giving a positive wave up to the brain. Each movement of the heart is reflected in the jugular vein. nb:
The beauty of this method is that it's just numbers...like an EKG readout. You can't give a neurological "opinion" on numbers. It is, or it isn't, normal. Dr. Zamboni is seeing that the distance of waves is much wider and more regular in normals, than in patients with CCSVI. This new non-invasive method provides a precise picture of the heart-brain axis, and will help end the diagnostic controversy of CCSVI. It will also help to clarify who should be looked at further with venogram, and can also be used as a follow-up method for patients after venoplasty treatment.
More about the Doppler Ultrasound CCSVI diagnostic controversy
Angioplasty Procedure is Effective - but for some more is needed
Clearance rates (the speed at which blood moves through the internal jugular veins) is much slower for people with CCSVI compared with normals. Example shows normal clearance rate of less than 2 seconds compared with more than 6 seconds for jugular vein with CCSVI. After angioplasty treatment the same vein showed improvement in clearance rate showing the procedure was effective.
More may be needed for more complex Obstructions
Is vein repair always needed? The challenge is that simple angioplasty is not enough for about 50% of people. Membranes or immobile leaflets in the vein are suitable for treatment. Long, immobile and asymmetric leaflets, muscle entrapments compressing the vein and hypoplasia are not successfully treated with angioplasty. Muscle compression can block flow and may require open surgery to relieve intracranial pressure. Perfusion changes in the brain can be seen on PET following this procedure of several case studies. We will see additional techniques for treating veins not suitable for angioplasty including new stents designed for intracranial system. nb:
Associated Research - The Sooner the Better
In August 2017 the Journal of Vascular Surgery reported on a study involving 797 consecutive patients with venous outflow anomalies who underwent standardized, operator-independent catheter venography and angioplasty (PTA) of the internal jugular veins. The aim of the study was to investigate the anatomic factors and patient characteristics that might influence the efficacy of such interventions. PTA resulted in an increased outflow through the IJVs in most patients. However, younger individuals with transverse endoluminal defects and higher pre-PTA flows are more likely to respond well to PTA compared with those who exhibit hypoplasia, stenosis, or longitudinal endoluminal defects. Researchers observed ''the earlier patients receive CCSVI angioplasty the better''. The study also teased out which types of blood flow problems will respond best.
On 2 October 2015 the Journal Veins and Lymphatics published details of a four year independent follow up of 366 persons treated with venoplasty (PTA) for CCSVI conditions - comprising 264 relapsing remitting, 62 secondary progressive and 40 primary progressive. Outcomes were evaluated against 11 commonly reported MS symptoms. Results for the relapsing remitting group were described as ''significantly good''. Greatest improvements related to blurred vision 99.2%, concentration 98.6%, fatigue 98.5%, headache 98.6%, sleep 93.2%, vertigo 90.9%, balance 88.5%, numbness and mobility 83.3%, temperature intolerance 75%, bladder control 66.6%. While the progressive experiences are different they are statistically significant. Researchers observed ''the overwhelming PTA results in the RR group lead us to say the sooner the better''.
The reason for reduced neuronal density
There is now also significant evidence (July 2017) that it is the blood clotting protein Fibrinogen that triggers an Immune attack on the Brain. Severe Fibrinogen deposits in the motor cortex are accompanied by significantly reduced neuronal density. The role of the primary motor cortex is to generate neural impulses that control the execution of movement. Disturbingly, the significance of this vascular contribution to MS is yet to be widely appreciated by some MS researchers.
Some Earlier Observations by Paolo Zamboni (2013)
Cerebral Venous Return is a novel, exciting field of research. As a pioneer, I would say that when I began investigating the intra and extra cranial cerebral veins, very few data were available something about 10-12 years ago. Cerebral venous return is very complex from embryological, anatomical and physiological point of view. As usual in science, this contributed to open even more questions.
Impaired cerebral venous return and the description of chronic cerebrospinal venous insufficiency (CCSVI) could open new perspectives in the understanding of neurodegenerative process, where a powerful regulator of chronic inflammation as the drainage is, was always absent among the pathogenetic mechanisms of this group of disease. Professor Zamboni subsequently went on to say In short, there are 3 meta-analyses available:
1. Lau1pacis A, Lillie E, Dueck A, et al. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ 2011;183:E1203-12.[Pubmed]
2. Tsivgoulis G, Sergentanis TN, Chan A, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies. Therapeutic Advances in Neur Dis 2013.[Full-text]
3. Zwischenberger BA, Beasley MM, Davenport DL, Xenos ES. Meta-analysis of the correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis. Vasc Endovasc Surg 2013.[Pubmed]
All the 3 above-mentioned meta-analyses confirm a significant prevalence of CCSVI in MS. Only six out of 19 comparable studies deny the association between CCSVI and multiple sclerosis. But while the first two meta-analysis showed heterogeneity among the studies, the third demonstrated clearly a significant double risk in having MS when CCSVI is detected, without any heterogeneity.
Source - Veins and Lymphatics June 2013 - a new Open Access, online-only, peer-reviewed journal by PAGEPress, Pavia, Italy
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