by CCSVI Alliance

Reported by:  CCSVI Alliance Director Christine Righeimer

On Saturday June 18, 2011, on behalf of the CCSVI Alliance, I had the honor of attending the Society of Vascular Surgeons Annual Meeting held in Chicago, Illinois. Dr. Manish Mehta personally extended an invitation to the Alliance to hear him present his IRB study results at a plenary meeting of vascular surgeons from around the world. 

The plenary meeting included a wide range of topics in addition to CCSVI. Each doctor assigned to speak was allotted a very short amount of time to present the findings of his/her study. Dr. Mehta spent exactly 23 minutes to present his findings and take questions from the audience of vascular surgeons.  You can imagine how thankful I was to have brought a small tape recorder to help me accurately recall his comments so the Alliance could share the results of his study! The following summary is based on my notes and my attempt to transcribe his comments as closely as possible. Dr. Mehta’s published results can be found at:

http://www.vascularweb.org/educationandmeetings/2011VascularAnnualMeeting/programindetail/Pages/Ss35.aspx].

Introduction:

Dr. Mehta’s study is called “A Prospective Analysis of Endovascular Management of Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis.” According to the written synopsis, the objective of the study was to evaluate “the safety, feasibility and efficacy of percutaneous transluminal angioplasty (PTA) of extracranial venous stenosis and its influence on the clinical outcomes MS”.

Dr. Mehta began by reviewing the history of MS for his audience. He shared that MS was first described in the 14th century. In 1868, a doctor first connected the symptoms to a diagnosis of MS. In the 1930s, a neurosurgeon in Boston studied the effects of ligating (tying off) the internal jugular veins in a canine model; his findings were consistent with the canines developing MS type plaques, and he concluded that inadequate drainage of the internal jugular veins were an antecedent to developing MS. Dr. Mehta stated that today “there is no cure for MS and most treatments focus on immunosuppression that have significant side effects.”  He went on to describe how our understanding of the possible etiology of MS has evolved over time in that in the 1960s the cause of MS was considered to be related to possible allergic reactions, in the 1980s the autoimmune theory came into play, and in the past couple of years our thinking is evolving yet again as we consider the role of CCSVI in MS.

Next Dr. Mehta asked, “So what is CCSVI?” 

Dr. Mehta discussed the specifics of Dr. Zamboni’s 2009 study and its discoveries. He explained how Dr. Zamboni connected the dots in abnormalities in principal pathways that drain the central nervous system in identifying jugular and azygous venous stenosis or valvular abnormalities in patients with MS. Dr. Zamboni proposed that chronic reduced blood flow (statis) or reflux can be associated with cerebrospinal venous reflux and inflammation and termed this CCSVI. This in turn can weaken the blood brain barrier and cause the hemoglobin filled red blood cells (RBC) to escape into the brain matter where the hemosiderin (breakdown product of hemoglobin) from the RBC could potentially act as the inflammatory mediator responsible for the autoimmune responses. 

There has since been a randomized control trial that looked at neurodegenerative disorders and MS. Through the use of transcranial and extracranial venous doppler ultrasound, this trial identified that when compared to healthy controls, MS patients have a “significantly higher incidence of having central internal jugular vein stenosis and/ or reflux."

The Albany Vascular Group Liberation Study

At this point, Dr. Mehta stated, “That’s what led us to the LIBERATION Study: the utiLIty of chronic cereBrospinal vEnous insufficiency peRcutaneous Angioplasty for mulTIple sclerOsis: The AlbaNy Vascular Group study.” He explained that this important study is a “prospective, multispecialty (vascular surgeons and neurologists), double blinded and randomized clinical trial” with a standardized technical approach that seeks to enroll 600 trial patients followed by detailed data analysis/publication. He further explained that because there is a learning curve associated with any new procedures, the Albany Vascular Group also included a prospective longitudinal arm as part of the study with 125 patients that will be presented here.

The mean age of 125 participants was 47; 62% were women; 54% relapse remitting; 34% secondary progressive; and 12% primary progressive.  All patients underwent evaluation via selective venography of their bilateral internal jugular veins (IJV), as well as the azygous veins (AZ). Only those with evidence of greater than 50% stenosis underwent percutaneous angioplasty (PTA). 

The total number of lesions (places where there is a stenosis or restriction in a vein) was 230 in the 125 study patients, accounting for an average of 1.8 lesions/ patient.  Majority of the lesions were located in the IJV: right IJV - 41%; left IJV - 49%; and AZ - 10%. The majority of the patients with venous stenosis and/ or reflux were also noted to have “well developed collateral pathways.”   Following PTA, patients were seen at 3 months and 6 months, and underwent objective evaluations via duplex ultrasound, EDSS, and timed 25-foot walk, as well as subjective evaluations by MS quality of life-54 (MSQOL), and modified fatigue impact score (MFIS).  At an average follow-up of 4.5 months, recurrent central venous stenosis was noted in 8%, and occlusion occurred in 2%.  There were no major complications or death. 

Dr. Mehta showed the audience a video of blood flow in “normal” jugular and azygous veins. He then showed a video identifying delayed emptying in a jugular and azygous vein, an angioplasty procedure using a 14mm balloon, and the blood flow difference in the drainage subsequent to the angioplasty.

He explained that a clinical neurological evaluation was performed on patients at every one, three and six months. Dr., Mehta stated that to date, 79 patients have followed up with the team. In evaluating those participants, the team used several scores and scales including, the objective EDSS and the 25 foot timed walk. The EDSS evaluation is an evaluation by a neurologist of pyramidal, cerebellar, motor, brain stem, and sensory nerve function; however, Dr. Mehta also pointed out that the EDSS has its limitations in measuring patients that are not ambulatory, especially those with primary progressive MS and advanced secondary progressive MS. 

The EDSS evaluation revealed “statistically significant improvement” in relapsing remitting MS patients and “a trend towards improvement” in those with secondary progressive MS.  There was no difference noted in the EDSS scores of primary progressive MS patients partly due to the inability of those patients to ambulate both before and after the procedure.  Dr Mehta pointed out that the EDSS has its limitations in evaluating patients that are non-ambulatory and many patients in advanced stages of primary and secondary progressive MS fall into this category.

Pre and post procedure evaluation of timed 25-foot walk indicated that all MS patients that were able to ambulate had significant improvements.  In addition to the more objective scoring measures, patients were also asked to complete more subjective (self-reported) MS Quality of Life (MSQOL) and Modified Fatigue Impact Scale (MFIS) questionnaires. The MSQOL identified post procedure “statistically significant improvement in physical ability and mental ability."   Furthermore, Dr. Mehta stated that “there were statistically significant improvements in the MFIS as well, and overall greater than 80% of patients reported these improvements."

Dr. Mehta described MS as a very elusive disease where the “symptomology is all over the charts and very difficult to even identify two identical patients.” That being said, a sub-analysis of the MSQOL-54, indicated several patient symptoms that were noted to have significant improvements, these include; 1) loss of balance, 2) lower extremity weakness, 3) incontinence, 4) decreased co-ordination, 5) vertigo, 6) fatigue, 7) heat intolerance, and 8) memory loss. About 70-80% of all MS patient reported these symptoms pre-procedure and over 2/3rds of these patients reported significant improvements.  Relapsing remitting and secondary progressive MS patients experienced the greatest benefits, although there was a trend toward improvement in the quality of life of primary progressive patients as well; however this finding was not adequately powered to demonstrate statistical significance with the current small sample size.

Based on the Liberation study results to date, Dr Mehta concluded that for MS patients with CCSVI, angioplasty of the internal jugular veins and azygous veins appears to be safe, and associated with MS patients experiencing “significant clinical, as well as quality of life improvements”.  

End of Presentation. Beginning of Q & A:

At this point, Dr Peter Gloviczki (the moderator) from the Mayo Clinic stated “this is a beautifully documented presentation of an extremely controversial treatment of Multiple Sclerosis that currently has no cure”. The panel then opened up the floor to attendees to present their questions.  

Dr. Mark Adelman from NY began by asking Dr. Mehta if certain patients that are prone to cerebral vascular venous hypertension such as patients that have had their jugulars ligated (tied off) and sacrificed and patients that have stenosis secondary to central line placement are more likely to develop MS. 

Dr. Mehta first qualified his response by stating that he is not a neurologist, but that he is aware of some evidence of MS-like lesions developing in people with Behcet’s disease and other degenerative diseases and malformations that can cause cerebral hyperfusion that do not have MS; however the question as to why those patients don’t necessarily have MS “is a question that remains to be answered”.

Dr. Mehta further stated: “MS is a very complex disease and I don’t think that central venous stenosis is THE answer to all MS issues. I think this is one of a many multifactorial facets into a problem and I think we are at the tip of the iceberg where we are just scratching the surface and identifying a lesion or a problem point that might have some impact. There are studies that are being done with MR imaging that are identifying volume of veins within the cerebral cortex of patients with neurodegenerative disorders including MS versus normal non-neurodegenerative disorder patients and there is some suggestion that patients with MS or a neurodegenerative disorder might have a lower volume of venous [flow] in their brain. So I think it’s way too early to tell.”

Next, Professor Piergiorgio Cao, a vascular surgeon from Rome, Italy asked Dr. Mehta three questions:

1. First, he asked Dr. Mehta about how he selected his patients. 

Dr. Mehta responded that in selecting his patients, they accepted the premise from the Buffalo CTEVD randomized trial; which indicated that MS patients as a whole have a significantly higher incidence of central vein stenosis. Therefore the inclusion criteria for this initial longitudinal analysis was all patients with relapsing remitting, secondary progressive, as well as primary progressive MS

1. Second, the doctor asked” How do you show the stenosis because doing a venogram in the neck sometimes it is very difficult to identify exactly what is a false stenosis from true stenosis?” 

Dr. Mehta answered that there is a learning curve to this and with experience the differences between the normal and abnormal internal jugular and azygous venograms was obvious.  Dr. Mehta admitted, however, that sometimes it might be difficult to identify the significance of   an abnormality, and differentiate for example between 50% and 70% stenosis. 

Dr. Mehta further stated that stenosis and reflux are two independent issues. He defined reflux as delaying emptying and said that as part of his study, they required the patient have both stenosis AND reflux to be treated. He then mentioned that as a third arm to this study at the Vascular Group, he and his partners have received IRB approval for normal non-MS subjects to be included in a study for venographic comparative analysis between MS and non-MS patients.  The surgeons in the Albany Vascular Group are planning on enrolling into the study and undergo venograms, and Dr. Mehta extended an invitation to the attendees stating that he welcomes anybody that wants to visit Albany to volunteer for this very important study!!

3). Third, the doctor asked how they could “discriminate regarding the results between the placebo effect which is very common in MS patients from real benefits?”

Dr. Mehta responded that they were measuring using the best tools available to date. He further stated that he believes randomization is a must and that a study needs to be done to identify placebo versus non-placebo. Dr. Mehta also expressed his desire to be able to measure MS lesion regression/progression on MR, but the trouble there is that an angioplasty is not necessarily going to provide long term vein patency which is needed as MS lesion regressions are likely to occur over long-term.

Dr. Sam Ahn from Los Angeles and Dallas, shared that he has seen a similar pattern of venous obstruction in patients with Migraine Syndrome who had a presentation of headaches and after treatment experience significant improvement. He then asked: 

1) Whether any of the patients in the study reported headaches. 

Dr. Mehta advised that the study did not measure headaches. 

1. Whether all of the patients had documentation on MR of plaque in their brain.

Dr. Mehta responded that 100% of the patients had documentation of a diagnosis of MS from an independent neurologist and 92% had MR plaque documentation.

Dr. Puggioni asked Dr. Mehta if they correlated the venogram with intravascular ultrasound. Dr. Mehta responded that they did not and later stated that the role of intravascular ultrasound in CCSVI needs further investigation.

Dr. Juan Parodi asked a question about what manifestations there were of restenosis or occlusion and if patients had a reoccurrence of symptoms. 

Dr. Mehta responded that patients with internal jugular vein restenosis following PTA usually go onto manifest symptoms similar to those prior to the intervention.  He went on to state that interestingly enough patients that had clinical improvement following PTA, often correlated their return of symptoms with restenosis and generally tell them “my veins are blocked again.”  Dr Mehta admitted that in the 8% of patients with recurrence, frequently patients have correctly diagnosed themselves with recurrence long before a  duplex ultrasound is performed.

Dr. Mehta concluded his answers and commented that today we have more questions than answers, and the pendulum appears to be moving in a direction suggesting that patients with MS have a higher incidence of CCSVI, and PTA of the underlying stenosis and/or reflux might result in short term clinical and quality of life improvements.  He also stated that future studies should to focus on improving the longevity of the treatments and for that “venous surgical revascularization options clearly will need to be on the table.”

End of Q & A: Meeting with Dr. Mehta:

Despite the fact that there were still more doctors waiting to ask questions, the panel of moderators ended the session as it had already gone over the time allotted. Dr. Mehta then retired to the hall where many of the doctors followed him to further discuss his results. 

The CCSVI Alliance would like to extend its sincere thanks to Dr. Mehta for inviting it to attend his presentation at the Vascular Surgeon Annual Meeting.