September 8, 2009
Dr. Ellliot Frohman, University of Texas Southwestern Medical Center Neurology, Dallas, Texas and Robert Zivadinov, Jacobs Neurological Institute, Buffalo, NY are chairs for the morning session:
Dr. Frohman makes the introduction. CCSVI is removed from how we think about MS or any other immune mediated diseases. Could other diseases we currently classify as autoimmune be related to venous disease? Autoimmune diseases share in common molecular adhesion molecules. Perhaps Crohn’s could be venous? Validating CCSVI in MS may affect the classification of other autoimmune disorders. This venous model has been overlooked.
Micrographs, histopath proficles, periventricular cuffs, red cells we see in post capillary venules. This is not new. In 1863 -before Charcot.- G.E. Rindfleisch writes of venous congestion in MS.
Could the immune system go anywhere blood goes? Is this why there is an inappropriate immune response? He notes the large crowd in the room (it’s packed) and says he hopes people will speak out. (they will!)
Dr. Paolo Zamboni- Universita degli Studi di Ferrara, Italy director of vascular studies
The drama of CCSVI and MS is that of severe stenosis of the extracranial pathways. Everyone in this room can return home and establish a cooperation between vascular and neurology departments. A simple demonstration - he shows a video demonstration of doppler protocol to aid diagnosis. There is a blocked outflow of blood.
In the normal control groups, there is a monodirectional flow of blood. In MS the periventricular vein has a bidirectional flow. Substitute circles avoid intracranial hypertension. Mean transit time is increased.
Dr. Zamboni proposes a “Menu” for the day-
1. Entree- what is the origin of venous stenosis?
2. Pasta- May we assess consequences of CCSVI in the brain. Perhaps microbleeding is the source of lesions. Just like CVI in other parts of the body- there is microcirculation
Cerebral spinal fluid ultrafiltration and reabsorption depends on transmural pressure.
TMP = IVP-EVP
In venography, there is much higher pressure in MS patients then controls.
Histology- research cited:
-red blood cell extravastion during relapse
-fibrin cuffs in venous hypertension
-iron laden macrophages
are ALL found in MS patients.
3. Main Course- Is CCSVI treatable?
measuring pressure before and after Liberation procedure is significantly changed.
4. Dessert- What are the effects of CCSVI treatment?
and for Today’s Special---Chronic fatigue as a symptom of CCSVI
(you have to love the Italians and their food analogies.)
Byung B. Lee- Georgetown University School of Medicine, Washington-
Dr. Lee began as a transplant surgeon and admitted that his first liver transplant was a disaster. He learned the hard way that the vena cava is not just a single trunk, and venous malformation was a most fearful thing, and a nightmare to a transplant surgeon.
"We doctors have a tendency to specialize in our narrow fields, but I want to appeal to all of us to take a bird’s eyeview. We need to look at the whole picture. We now understand the lower venous system, but it has taken us much too long to bring this knowledge all the way up to the neck and all the way to the junction of the superior vena cava.
Vascular malformations are from embryological defective vessels involved in the later stages of embriogenesis. CVM can develop anywhere in the vascular system as a birth defect. The vascular malformation is one of the CVMS which affects mainly the venous system. There is much we do not know, and we do not know how much we do not know."
Two classifications of venous malformations:
Extratruncular- this is formed by embryonic tissue remnant which carries a risk of growth, because it is mesynchymal. When stimulated by hormones, pregnancy, etc, it can reactivate and grow.
Truncular VM- this is formed as part of the later stage of embryonic development. This form does not have mesencymal cell characteristics. Truncular lesions present as a fetal remnant- such as sciatic veins or superior vena cava malformations
"We cannot stop investigating at the neck in CCSVI! We need to investigate all the way down to the superior vena cava."
Truncular venous malformation lesions are obstructive of dilated lesions: such as we see in IJV aneurisms or iliac vein stenosis. They are more serious to direct involvement of the venous system, and will bring about hemodynamic issues. Why has the jugular been ignored previously? Chronic venous congestions leaves more damage along its related organ or tissue. Venous congestion of the IJV is related to ischemia.
The cardio system is the first system to develop in an embryo. At 15-16 days from gestation, there is a primitive vascular system. "Veins are so important, that God made them in pairs- to overcome any defects. They are more important than arteries."
The IJVs are the dominant deep vein to drain the brain. Below the diaphragm, the veins converge, and problems can also arise there. Dr. Lee couldn't repair the IVC after taking the liver out of his patient, because of stenosied veins. Often, the liver is the victim - such as Budd Chiari syndrome.
Dr. Frohman asks Dr. Lee-
Why the latency for onset of MS compared to other VM disease?
Dr. Lee states that some cases of Budd Chiari are diagnosed at age 30, not all are pediatric. It depends on the level of vena cava obstruction. It is too late to repair by the time they do a liver biopsy. The venous system is not like the atrial system- extra pressure makes it very vulnerable. Acute venous hypertension is easy to find and obvious, but this is not the issue---it is the slower progress such as CCSVI. What we do not know is what we do not know.
Another doctor asks-
Is there any evidence in the literature if there are potential environmental influences on the mother which might affect VMs?
Dr Lee states that the current embryology knowledge we use today was established in 1890-1920s. There is no known connection to venous system and environmental influences....yet. There needs to be more research.
VMs show up and most of them come back. Because certain malformations have those mesynchymal cells, they reactivate in tuncular venous malformations.
Neonatal surgery is finally catching up to the pace, and in 5-10 years, a neonatal surgeon may understand the implication of VMs.
Dr. Frohman asks: Looking at Budd Chiari in the hepatic system, is there anything analogous to MS?
Dr. Lee: "Yes, Budd Chiari shows up primarily in Caucasians." This is part of the reason Dr. Lee believes the evidence points towards a congenital cause of venous congestion.
Dr. Guilio Gabbiani from the Centre Medical Universitaire in Geneve, Switzerland
speaking on jugular wall changes in MS. His laboratory was interested in the fibrotic changes. He was interested in learning the importance of venous morphology, and is surprised so little is known.
Comparing arteries to veins:
Arteries are thicker and there is more resistance.
Dr. Gabbiani took 5 specimens from IJV tissue removed by Dr. Zamboni from some of the patients he treated endovascularly. The tissue was from the area NOT damaged by angioplasty.
He compared it to healthy tissue from autopsy controls.
He looked at eosin, hematoxylin, Miller’s elastic stain and masons truchrome.
He found smooth muscle cells were numerous and increased in MS compared to controls. He then used isoelectric focusing to measure contractions in the smooth muscle cells via actin heterogeneity to ID the smooth muscle cells in the veins.
There is an increased expression of smooth muscle actin in MS, much more than controls.
By red staining for collagen and using unpolarized and polarized light, he saw that there is less collagen 1 type fibers in the MS jugular vein tissue, and more collagen III fibers in MS. This is the exact opposite of the controls.
Connective tissue in MS switches from collagen I to collagen III and this takes place in the IJVs. This switch also happens in fibromatosis, colloids and hypertrophied scars, and this remodeling may play a role in CCSVI disturbances.
Dr. Lee makes a comment:
This collagen conversion from I to III happens in the arteries had no idea it could happen in the veins as well!
Dr. Gabbiani answers: Collagen III is stiffer, and fibrosis takes place for some reason. There was no inflammation on the tissue samples, but inflammation might have occurred before the the intervention and the fibrotic changes happened. All is still speculation, we do not know.
Dr. Zivadinov asks, so the testing was in the normal, non-stenosed part of the IJV?
Answer: Yes, we are trying to examine the normal part of the vein not affected by stenosis.
Another doctor from Rochester, MN asks,
This switch from collagen I to III is related to myofibril process. So myofibril process may be derived from smooth muscle cells. Maybe there is a connection between the two processes?
Answer: Varicose veins actually have lower type III collagen, which is the reverse of what they see in the IJVs.
There needs to be a plan to confirm that this is type B collagen, and an active fibrosis, which is not found in varicose veins.
Dr. Frohman asks: Is there a therapeutic procedure for fibrosis or will this need to be repeated?
answer: Fibromytosis is intrinsic, fibroses can be cured. We do not know yet.
Dr. Frohman: Has the procedure (Liberation) been repeated by Dr. Zamboni?
answer: Yes. There is a 50% recurrence of stenosis in the IJVs after balloon angioplasty. Dr. Zamboni believes there is a different morphology at work after surgery- patients improve when veins remain open, and restonosis indicates progression.
Dr. Mark Haacke, the MRI Institute for Biomedical Research. Detroit, MI
MRI-SWI (susceptibility weighted imagery) cerebral veins and iron deposition-
Dr. Haacke developed SWI to see specific patterns in the venous structure. His findings in MS brains is consistent with everything presented today regarding venous structure, oxygen and iron deposition.
He offers thanks to the foundation and Bologna for the openness of discussion and the freedom of ideas. He asserts that CCSVI does not go against what we know about MS--however it will further define it.
In normal brain tissue, iron appears as ferritin 80% of the time and hemeiron 20%.
Iron can be visualized on SWI- it shows up at 3 tesla as dark gray. Capillary density absorbs most iron, and the basal ganglia is where it appears most.
In imaging MS brains, there is an increase in basal ganglia and thalamus iron, and this can serve as a bio marker fro MS. Iron deposition progresses over time. The more iron, the worse the patient outcome will be.
Iron in the thalamus is a good bio marker for MS progression, without measuring brain lesions. Iron content and area of iron deposition increase with time.
There is a dramatic increase in iron in the brain in young people with MS as compared to controls, and this can be related to venous reflux. MS lesions show up on SWI as high in iron content.
Dawson’s Fingers enhance on SWI with LOTS of iron. There is a uniform relationship between the veins and lesions.
Is this iron a form of demyelination? Microbleeding? Perhaps it is hemosiderin?
BOLD technology- a means to measure blood oxygen levels. SWI is sensitive to local iron content- but neuros weren’t interested in this, no one has cared about output function.
In 7 Tesla MRIs, you can see venules. we can see the microvascular response to iron deposition. Perfusion weighted imagery gives us the complete picture.
Progressive MS shows a loss of oxygen in the brain. A complete change in cerebral hemodynamics, it is much worse the RRMS.
SWIM technology- is an attempt to quantify the de-oxyginated saturation of the veins. Iron builds up counter current to the flow, it gets much worse with time.
Dr. Haacke wonders if in Sturge Weber syndrome there is a venous obstruction? No one has ever looked. Neuros focus on the brain to the exclusion of the rest of the body. SWI technology will provide new and accurate markers for studying abnormal iron content in the MS brain.
Iron acts as an inflammatory agent in he brain. There is a microvascular breakdown and ischemic areas lose cerebral bloodflow.
The pieces of the puzzle fit when considering how CCSVI can do this to the MS brain.
Can SWI be used as a bio marker in early MS? Should we be treating MS with cheating agents and antiinflammatories?
MS patients have an increased amount of iron in the basal ganglia- and this may very well be from venous obstruction. There are 1000 systems in the world that can do SWI technology. There is now spin software available on line- so that anyone can use SWI capabilities http://www.mrimaging.com
The technology exists- we need to create a complete MS protocol; one that considers oxygen saturation, iron deposition, and perfusion time.
Dr. Bianca Weinstock-Guttman, Jacobs Neurological Institute, Buffalo, NY
Speaking on MRI and doppler correlations in the Buffalo study-there are many questions due to the missing pieces in the autoimmune theory-
Why is it inflammatory elements and neurodegeneration occur concurrently?
MS as a venous disease was hard to prove with old technology. Dopplers and new technology show us specific venous abnormalities-
7 Tesla shows us that the majority of lesions are venocentric.
Cerebrospinal fluid dynamics are dependent on venous drainage. It is a balance between CSF ultrafiltration from the veins of the lateral ventricles and the CSF reabsorption.
The Buffalo study used 16 patients- 8 from Italy, 8 from Buffalo with 8 controls- 4 from Italy and 4 from Buffalo.
RRMS disease EDSS between 0-5.5
disease duration 5-10 years
on FDA approved medication
have normal renal function
Acute attack within 20 days
pre-existing medical condition
Abnormal renal function
no problem with MRI
Italian patients came to Buffalo for 4 days and were examined with MRIs, rated for EDSS and MSFC followed by dopplers. All was blinded, and due to the high functionality of the MS patients it was difficult to discern who was control. The TCDs and ECDs followed Zamboni’s protocol and were overseen by his team. Out of the criteria of 5, at least 2 had to present in order to be considered CCSVI. all 16 MS patients had CCSVI.
The MS patients had a decrease in brian volume, and less gray matter volume than the controls. The third ventricle was dilated compared to controls.
The velocity of the CSF- the average net CSF flow in MS patients was strongly associated with a retrograde flow- velocity is lower in both directions in MS.
The more abnormal the criteria, the more the gray matter loss, the more brain atrophy, the worse the disease progression- the more venous stenosis was found.
Dr. Miller asks-
Were there any other additional parameters? Were patients on aspirin therapy, did you measure blood pressure? Any correlations?
Dr. Weinstock- Guttman
This is a work in progress. All the MS patients vitals were normal, half of the patients smoked, but all had abnormalities. Our large ongoing study at Jacobs will look at environmental factors.
Dr. Frohman comments:
I have seen this happen in “normal pressure hydrocephalus- (NPH) Where there is a loss of gait, cognitive and bladder issues and the lesions disappear because the expanded ventricle swallows the lesion. I have shunted the brains of NPH patients, and they showed remarkable improvements. Again, the enlargement of the third ventricle precedes the changes.
Data on CSF flow and the accumulation of lesions: Lower CSF pressure shows a correlation to lesion volume.
The large study at Jacobs will include other neurological diseases so that the technicians will not know who has MS. There will be variable levels of progression, and the study is again blinded.
Dr. Alessandra Ferlini - geneticist at Universite deglie Studi di Ferrara
SNPs are single nucleotide polymorphisms- and they reveal a multi-loci susceptibility to MS. The 4 specific loci are MS1, MS3, MS4, MS2. These are the chromosomes most linked to MS.
Genetics is still questioned in this research, since there are undefined environmental factors.
Genome inflation- a characteristic of SNPs may hamper the true definition of identified genetic loci by SNP association. More studies are needed.
Interactome- the interaction of phonemics, genomics, preteomic, metabolic studies- all together-
This is done in genomic studies using CGH array rather than SNPs
The Ferrara study looked at CNVs (copy number variations) of chromosome 6p21.32 (HLA locus) in CCSVI patients.
CGH verified the occurrence of CNVs in the major locus of MS patients.
15 unrelated CCSVI patients were tested. No relation between the topography of CNVs and phenotype were shown, but there was a significant relation between the number of extragenic CNVs and the phenotype correlated with venous malformations.
HSPAIL, HSPIA, HSPIB (heat shock proteins) were related to angiogeniesis and immunity. HLADLAZ and CD4 are involved in proinflammatory disease and tumor angiogensis. There are multiple gene disorders, and environment has a large influence.
The genome imbalance may be sensitive to environmental factors.
There was a significant correlation between the number of CNVs and the number of venous malformations. The number of polymorphic CNVs in the HLa region linked to MS does correlate with the number of venous malformations in MS patients.
This is a new way to study genetic disorders- to look for mutations on more than one genome. It is a very complex system, and cannot be narrowed to one genome.
Dr. Frohman asks if this has been tested in families? Are there genes affected in relatives with other autoimmune diseases?
Dr. Ferlini answers that this is a pilot study, and it is the first time looking at this paradigm. Future testing will look at families.
Dr. Lee comments that we have much genetic data on lymphatic malformation, yet no studies on the genetics of venous malformation. The veno-lymphatic systems need to be brought together. They have been separated and we need more venous information.
Dr. Ferlini comments that a similar phenotype can involve many genes, it depends on how they interact in the pathway. We need to locate many genes and understand how they interrelate, when they switch on and off, and how they interact in polygenetic disorders.
Dr. Patricia Coyle , Stony Brook University Hospital, NY dept. of Neurology officiates- She is very excited about this new field of MS research, and wants to limit her comments to allow the speakers more time.
Dr. Roberto Galeotti , Azienda Ospedaliero- Universitaria di Ferrara, vascular surgeon
speaks as to the results of the endovascular Liberation treatment in an open label CCSVI study.
The endovascular approach uses the left femoral access, into the left renal vein, into the azygos, bilateral IJVs and bilateral VVs.
standard CDMS qualifications-
In each patient there were found valve malformations, stenosis, hypoplasia, with collateral pathways, In the azygos there were seen membranous obstructions, like what is found in Budd-Chiari syndrome. There was also a twisting of the arch, agennesis , compression and reflux.
The procedure used a compliant balloon to open the veins. If the compliant balloon didn’t work, a high pressure balloon was used.
Venous pressure post procedure was improved, there was an improvement in vascular hemodynamics and rate of compliance.
There were no reports of thrombosis, some headache as a result
The azygos vein had a 4% rate of restenosis at 18 months- the only case was a retwisting
The jugular veins had a rate of 47% of restenosis at 18 months
The team is considering a redilation of the IJVs using open neck surgery or stents.
Dr. Lee has questions-
He thinks stenting the venous system is not well-enough understood. Thinks perhaps open neck surgery might be better.
This is not known at this point. (Again, discussing it with Dr. D at dinner- he believes the jugs wouldn’t stay open for long on their own, due to compression or crimping...not from his experience.)
Dr. Lee asserts that an multi-plane study of the venous system in necessary, not just in the supine position. He is also concerned with the radiation doses is venography (Which is why MRV is preferred at Stanford.)
Dr. Fabrizio Salvi , UOC Neuroliogica Oepedale Bellaria, Bologna Italy-presents the clinical outcomes-
MS is a terrible, all too common disease. It presents in the young and its course is unpredictable and variable.
50% of MS patients are non-ambulatory after 25 years.
Three years ago, the universities of Bologna and Ferrara formed a collaboration. Doppler is the exam of choice for CCSVI according to Zamboni’s 5 step protocol.
Is CCSVI a hallmark of MS? Will treatment modify MS progression?
The Journal of Vascular Surgery will have the results of the Liberation procedure in October-
At 12 months, 27% of the MS patients were relapse free, At 18 months, 50% of the patients were relapse free. All the relapses were associated with jugular restonosis. Those with patency of veins remained relapse free.
The progressive form of MS seems less sensitive to treatment. HOWEVER, there is a stabilization of progression at 18 months, and an inversion of the progressive course. It just takes more time.
In RRMS, headache, sleep problems, memory issues, heat intolerance all abated with treatment.
50% of all MS patients have sleep disorders-
After treatment, patients had better sleep, many had a return of dreams
(Dr. D and I talked about this. Jeff is dreaming again, vividly and remembering it. He had stopped dreaming the past couple of years. His sleep is much improved, no more apnea and less myclonic jerks. Dr. D was excited. This is the kind of thing we had no idea would be affected, and it needs to be understood.)
There were increases in working memory and increases in body temps.
(Again, this is being seen in the Stanford patients.)
18 patients in the throes of acute relapse were given the Liberation procedure. There was no need for steroids, and there was an immediate decrease in venous pressure and abating of symptoms.
After Liberation treatment, the TCD reflects a disappearance of reflux and ventricular diameter decreases as well.
A question from the audience- Are there any animal models?
Answer- EAE is unsatisfactory as a model of CCSVI-
one study showed that iron deficient mice could not develop EAE, and that may be applicable.
There is a need for a controlled study before we can show efficacy and a randomized study...
Dr. Michael Dake Stanford University, Stanford California- chairman of interventional radiology dept.
Dr. Dake began his career as a pulmonologist. He is now chairman of interventional radiology at Stanford. He was brought into this discussion because of the persistence of someone in the audience. Someone who thought this model of CCSVI in MS made sense. He admits that he is not as knowledgeable about MS as others, but he is learning. He announces that next week there will be an “ecumenical meeting” of professors of multi-disciplines at Stanford to discuss CCSVI in MS.
(Dr. Dake brought along a colleague, Dr. Joshua Makower, a bio medical designer of diagnostic equipment and another outside the box problem solver. Joshua saw some of the interventions, was fascinated and came to Bologna. )
Dr. Dake explained the Stanford protocol
The Stanford Protocol-
1. An MRI of the brain, MRV of the head and neck and doppler ultrasound
2 A diagnostic venography and endovascular intervention as indicated A night at Stanford hospital
3 Patient is sent home on an anticoagulant program
4. At day 60, a repeat MRI/MRV
Dr. Dake explained why he uses MRV. Firstly, the US lacks the expertise and technical education in doppler technology.
More importantly, MRV provides 4D flow, pulsivity and a velocity profile.
He is finding stenosis of the high jugulars at location at C1-C3 the most common form of occlusion.
MRV is showing that collateral flow is non-pulsatile throughout the cardiac cycle.
Mean transit time is much greater in MS patients.
Collateral flow decreases after stenting.
Dr. Dake believes that one view is NO view, thus the need for MRV.
We need compound angle views and multiple views of the veins and flow
After stenting, collateral flow is no longer preferred, it is like watching a faucet turn off.
(Dr. Dake shows many of the MRV images of the Stanford crew, and they are astounding, as many of you know. I notice how much clearer the area of stenosis appears in the multidimensional view.)
He wants to explain why he is stenting. He believes it takes care of residual stenosis and residual collaterals and remains patent.
He has found 100% venous obstruction in every MS patient tested, now 35. There are a variety of patterns:
IJVs 87.3%, (very high jugulars 52.7%)
dural sinus 3.6%
He is finding that EDSS score correlates with the number of veins treated. The more stenosis, the more progressed the MS is.
He is not sure why his numbers are different from Dr. Zamboni’s in the azygos area, and says that he has not seen this membranous issue in the azygos at all.
Dr. Robert Zivadinov , Jacobs Neurological Institute, neurologist and director of MR imaging dept. was the final presenter-
MS lesions are found in white and gray matter. 60% of all lesions are not visible on MRI, they are in the cortex.
In the last 6-12 months, we have learned so much from the new development of SWI technology. We see gray matter atrophy.
Is inflammation the major pathology underlying disability?
The EVTMS study was an endovascular treatment in cooperation between Ferrara and Jacobs. It will be presented as a poster at ECTRIMS.
MRIS were done at 0, 90, 180, 270 and 360 days. It was a 3 Tesla study to find brain and lesion changes.
Typical RRMS inclusion criteria
All the endovascular treatments were done by Professor Galeotti at Ferrera.
Jacobs actually used the MRV in the neck like Dr. Dake--they did not realize he was doing this, as well. (A competitive comment from Dr. Zivadinov, we’ll have to get our paper out before you!)
Why are some lesions scattered and some are rings? What makes the difference ?
SWI measures the concentration of iron in deep gray matter.
Preliminary results are exciting to see a reduction of brain atrophy and iron accumulation after the Liberation procedure-
MS patients have 40% less veins in the brain than the controls
Atrophy as a result of hemodynamics. Cerebrospinal fluid levels also improve after the procedure.
The results will be finished next month and an independent source will do the final analysis.
Jacobs is also doing a study with 1700 subjects:
900 CDMS adults (500 RRMS, 300SPMS, 50PPMS, and 50 NMOs)
including pediatric MS
There will be central blinding, a physical exam, dopplers, blood specimens, and environmental questionnaire, and neurophysical testing
500 subjects will be finished for 2010 submission to AAN
1000 for the spring of 2010
1700 will be finished for submission to AAN in 2011
Jacobs is looking forward to training other centers in the doppler technology and MRV technology (the best of both worlds)
In closing- Dr. Zamboni reiterates that we need an open exchange of ideas between the variety of medical practices. This is only our initial step in the investigation of CCSVI in MS.