As promised yesterday---here are the two new negative studies presented at ECTRIMS. These are the studies which got the fanfare, and which you will be reading about in the medical press. This is part of the new approach to disprove CCSVI--by claiming that MS creates venous stenosis--(see the chicken and egg essay from yesterday.) Now that neurologists realize they can no longer say CCSVI doesn't exist---since too many pwMS around the world know they have it--they are changing the script to say, well, you may have CCSVI, but it's caused by MS.
The first study is nominated for a best research prize at ECTRIMS.
The lead investigator is a neurologist at American University in Beirut, and is currently conducting research into stem cell therapies. Dr. Bassem Yarmout is a neuroscientist, not a vascular doctor or interventional radiologist. However he worked with his vascular colleagues at the University.
This is from a press release from the American University of Beirut--
"In conclusion, this study showed that extracranial venous stenosis is a late manifestation in multiple sclerosis and unlikely to induce a state of chronic cerebrospinal venous insufficiency since only a minority of patients has a single venous stenosis early in the disease. It is more likely to be a secondary phenomenon, possibly present in other neurological diseases, reflecting chronic brain disease and atrophy."....
"The extensive network of anastomoses in the cerebrospinal venous system precludes the possibility of cerebrospinal congestion secondary to a single vein stenosis."
http://www.aub.edu.lb/news/archive/preview.php?id=111181
--In other words, there are plenty of other veins to drain the brain. What's one stenotic vein? It won't be a problem. The trouble is, CCSVI is not JUST about stenotic veins. It's about what they create, which is venous REFLUX. It appears that Dr. Bassem's team did not test for reflux. He looked for stenotic veins, but that's only part of the story. There's webs, valves, and, most importantly, flow. Remember, Dr. Zamboni's words..."it's not about the architecture (stenosis), it's about the flow." Here's the abstract---
Pathology 2
Friday, October 15, 2010, 15:30 - 17:00
Chronic cerebrospinal venous insufficiency is an unlikely cause of multiple sclerosis
B. Yamout, A. Herlopian, Z. Issa, R.H. Habib, A. Fawaz, J. Salameh, H. Wadih, H. Awdeh, N. Muallem, R. Raad, A. Al-Kutoubi (Beirut, LB)
Introduction: A state of chronic cerebrospinal venous insufficiency (CCSVI) secondary to extracranial venous stenosis (EVS) was suggested as a possible cause of multiple sclerosis (MS). Methods: In this study we performed selective extracranial venous angiography (SV) on 42 patents with early MS (EMS): clinically isolated syndrome (CIS) or relapsing remitting MS (RRMS) of less than 5 years duration, and late MS (LMS): RRMS of more than 10 years duration. We also reviewed available MRI and clinical relapse data in patients with documented EVS.
Results: EVS was present in 7/29 (24%) patients with EMS and 12/13(92%) patients with LMS, a highly significant statistical difference (p<0.0001). Only 3/42 (7%) patients (all in the LMS group) had 2 vessel stenosis, while the rest had only 1 vessel involved. The incidence of EVS in CIS was 9% compared to 33% in RRMS of less than 5 years duration.
The most important factor in determining presence of EVS was disease duration: mean=9.4±6.8 years in 19 patients with EVS compared to 3.2±4.1 years in patients without (p<0.005), which stayed significant after controlling for age at disease onset and gender (p<0.002). Within the EMS group, patients with (n=7) and without (n=22) EVS had similar EDSS (1.43±2.13 and 0.8±0.008, p=0.85) and disease duration (mean =2.1 and 2.4 years, p=0.521), suggesting similar disease severity. The 7 EMS patients with stenosis had a total of 14 relapses since disease onset. No clear correlation could be found between site of EVS and relapse anatomical localization. A total of 97 spine and brain MRIs available since disease onset on all 19 patients with stenosis were reviewed. Again no clear correlation could be seen between the location of gadolinium enhancing (Gd+) lesions and site of EVS. Conclusion: CCSVI is an unlikely cause of MS since it is not present in most cases early in the disease, and in only a minority of MS patients affects more than 1 extracranial vein. It is likely to be a late secondary phenomenon, possibly related to chronic central nervous system (CNS) disease and atrophy.
More thoughts on this abstract and how the study was designed--
--First of all, there has never been a suggestion that white matter lesions as shown on MRI are indicative of any specific CCSVI stenotic lesion localization. Looking for a correlation between white matter lesions and stenosis and not finding one, then using that as evidence of lack of importance of CCSVI, is absurd. Dr. Zamboni has correlated patterns of stenosis and reflux in veins to TYPES of MS....RRMS, SPMS, and PPMS--he cites 4 different patterns of reflux in his research, and ties them to disease type, NOT to MRI LESION LOCATION. And as many scientists now agree, white matter lesions are not a good biomarker for disability. Many people with PPMS have few lesions, and more disability. My husband has over 20 cerebral lesions and is RRMS. It's not about lesions. Grey matter atrophy and iron deposition is a much better biomarker for MS progression and disease severity. This is all a moot point.
--Secondly, as Dr. Zamboni has stated time and time again, it is not about stenosis alone, it is about blood FLOW. It is about reflux and slowed flow. The doctors treating CCSVI are measuring flow inside the veins, which can be altered by webs, inverted valves and other anomalies that are not visualized as stenosis. This study is simply looking at stenosis, not flow. Will be interesting to read the full paper and see if they even measured flow levels once inside the patients.
--Thirdly, how can this researcher jump to the conclusion, from this small number of patients, that CCSVI is a result of MS? He calls patients with RRMS for greater than ten years, "late stage MS" and notes that 92% of them have stenotic veins....this is not inconsequential evidence to the reality of CCSVI. Dr. Simka's much larger study (over 500 patients) says that he found no correlation to age or disease length to severity of disease.
And, just in case you wonder who might be paying for all of these venographies (as we know, they ain't cheap), thanks to our reader, David, for providing us the link to the AUB's medical trial funding sources-
http://www.aub.edu.lb/ogc/funding/Pages/agencies.aspx
Private - Clinical Funding
Boston Scientific, Bristol Myers Squibb, Eli Lilly Suisse S.A., Eli Lilly Vienna, Essex Chemie A.G, GlaxoSmithKline, Gulf Pharmaceutical Industries (Julphar), Hoffmann-La Roche Ltd., MERCK, Merck Europe/FDC - Pharmabel, Merck Serono International, Merck Sharp & Dohme Idea Inc (MSD), NOVARTIS, Novartis Pharma Services, Novo Nordisk, Sanofi-Aventis, Sanofi-Synthelabo, Schering AG , Wyeth Pharmaceuticals
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The next negative study is from the Neurological MS Clinic at the University of Padova, Italy and the MS Center/Neurology Clinic of the Veneto region-- these doctors have worked together before, studying mitoxantrone and cyclophosphamide in MS patients
http://www.ncbi.nlm.nih.gov/pubmed/16609811
http://www.springerlink.com/content/x13x142421767347/
No evidence of chronic cerebrospinal venous insufficiency in clinically isolated syndrome suggestive of multiple sclerosis
C. Baracchini, P. Perini, M. Calabrese, F. Causin, F. Farina, F. Rinaldi, P. Gallo (Padua, IT)
Background: A complex scenario of abnormalities of the cerebrospinal venous outflow termed "chronic cerebrospinal venous insufficiency" (CCSVI), has been reported in patients with multiple sclerosis (MS). Sonographic criteria of CCSVI include reflux in the deep cerebral veins and/or the internal jugular (IJVs) and vertebral veins (VVs), stenosis of the IJVs, missing flow in IJVs and VVs, and inverse postural response of the cerebral venous drainage.
CCSVI has been suggested to be the cause of MS, however no data on the prevalence of CCSVI at MS clinical onset has been published up to this date. In order to demonstrate a possible causative relationship between CCSVI and MS, we performed extra- and transcranial color-coded venous sonography (ECCvS, TCCvS) in clinically isolated syndromes (CIS) suggestive of MS.
Materials and Methods: Fifty consecutive patients with CIS suggestive of MS and evidence of dissemination in space of lesions (i.e., possible MS, pMS) were enrolled into the study. All patients underwent a detailed diagnostic workup, including CSF examination, brain and spinal MRI with gadolinium, ECCvS and TCCvS. Patients with abnormal ultrasound findings underwent selective venography (VGF).
Healthy individuals (HC) and patients with transient global amnesia (TGA) constituted our control groups.
--Now, you might be thinking, WHY did they include patients with transient global amnesia (TGA) in the control group?? Transient global amnesia??? They included them, because they have read (as we all have on this page) Dr. C.P. Chung's research over the past ten years which correlates internal jugular vein valve insufficiency (IJVV) to transient global amnesia. Dr. Chung has noted that those people who have episodes of amnesia have valves in their jugular veins that do not work right when put under pressure. Dr. Chung's research included venous reflux shown on doppler ultrasound only with VALSALVA MANUEVER. OK. What is valsalva manuever and why does this matter? More to come....
Results: Mean age of pMS was 33.0+/-8.5 years, 35 (70%) were female, EDSS was 1.6+/-0.5. The onset was monosymptomatic in 27 (54%). Forty-two (81%) had IgGOB in the CSF. TCCvS was normal in all pMS patients. ECCvS abnormal findings were found in 26/50 (52.0%) pMS, in 32% of HC and in 68% of TGA patients.
----The highest number of people with abnormal doppler results were the TGA group. 68% of the TGA patients showed abnormal doppler results. Why is this important? Because in order to find abnormal findings in TGA patients, they must have employed valsalva manuever. THAT's what causes reflux in Dr. Chung's studies. Valsalva manuever is when you force air against a closed airway...like when you want to unclog your ears on the airplane, so you pinch your nose and blow...This forcing of air is what made the flow reflux in TGA patients in all of Dr. C.P. Chung's studies.
Here is Chung on his findings in TGA---he got abnormals using valsalva maneuver-
"Venous reflux in the internal jugular vein branches (JB) was found frequently in patients of certain neurologic disorders. We hypothesized that the retrograde-flow in JB is associated with retrograde hypertension transmitted from the internal jugular vein (IJV), which presumably underlies those neurologic disorders. In this study, we used color-Doppler imaging to evaluate the dynamic venous flow patterns in the IJV and its branches in 50 normal individuals (21 men, 29 women; mean age: 40.9 ± 14.9 y, range: 22 to 70 y). The flow-direction of all detected JB (n = 100) was flowing into the IJV at baseline. During the Valsalva maneuver (VM), 38 JB (38%) had a retrograde-flow. Retrograde-flow in JB was significantly associated with IJV valve incompetence (OR = 7.6; 95% CI = 2.6 to 21.8; p = 0.0002) and greater IJV blood flow volume (blood flow volume >670 mL/min) (OR = 6.6; 95% CI = 1.8 to 24.5; p = 0.0052), both of which may reflect higher IJV pressure transmission during VM. The sonographic findings can be used in the future studies of diseases that are suspected to be related with retrograde cerebral venous hypertension due to an elevated IJV venous pressure."
----BUT Dr. Zamboni has stated, you cannot use valsalva manuever to do the doppler tests for CCSVI. He even references Dr. Chung's papers in his CCSVI research, and says this is different because he does not use valsalva to find CCSVI. The CCSVI doppler test employs normal inspiration and exhalation. PwMS show reflux during normal breathing, NOT valsalva. The fact they found so many abnormal findings in TGA patients in this study raised a red flag to me. I'll bet you they did the doppler testing using valsalva manuever. And that makes the rest of the study a moot point. Because only 8 out of the 50 pwMS showed THEIR version of CCSVI, which was not really CCSVI. It was reflux due to valsalva manuever. Ironically, when doing valsalva, many pwCCSVI open up their veins temporarily and reflux stops for them.
---And now, they do the venography--
Eight out of 50 pMS patients (16.0%) met the CCSVI criteria: 6 were classified as Type C, one as Type B, one as type A, while none as Type D. VGF was completed in all these patients, except for one who developed a paroxysmal supraventricular tachycardia and the exam was stopped. Venography was normal in 6, while 1 patient had a hypoplasia of the right IJV. Conclusions: Our findings do not support the hypothesis that cerebral venous congestion plays a causative role in the pathogenesis of MS.
So, here are 2 more negative studies to add to the pile. Hope the full papers give some more clarification to the testing means, which seem to me, from the abstracts, to have veered from Dr. Zamboni's research once again.
more to come,
Joan