2.26.2011

Reviewing the CCSVI research..

In my role as education person for the local MS Society, I've been called upon to try and figure out a presentation re: CCSVI.  The only problem is that little research has been completed to date.  There are status updates to the research funded by the MS Societies on their pages, but I went wandering through the other research looking for something else that might have been done.
Here are my conclusions:
Anyone associated with Dr.s Zamboni, Haacke, Simka, or their research institute have found that CCSVI has positive results.  Sample sizes are small, and my impression is that the several published papers resulted mainly from the same study set.
Anyone who is a neurologist finds no benefits from the CCSVI procedure. Their study sizes are also small, except for one study that looked for brain ferritin levels (following the iron damage hypothesis) which looked at 1408 patients with brain disorders and normals and found an increased amount of ferritin in people with various forms of MS and brain damage of other sorts.
Interestingly, studies by interventional radiologists also don't find a positive association between CCSVI treatment and MS improvement.
"Improvement" is, as has been said before, stated in terms of fatigue level improvement, some sensory improvement.  As someone who is dead tired all the time and numb from stem to stern, this sounds vaguely appealing, except for the costs. And the transience of the improvement. The study summaries are below.
The small sample sizes are a problem, as so much difference can be explained by random changes, especially in a variable disease like MS.  It's also a problem that most of the studies were unblinded - in other words, the experimenters knew who they were looking at.  This allows for bias and in fact, if you happen to have a vested interest in the results, like the neurologists who have invested years in the autoimmune theory, or the Zamboni group who are currently marketing the only machine capable of detecting the hard to find CCSVI (some conflict of interest there, methinks), bias comes in inevitably.
On the good side, the whole debate has increased interest in MS research.  On the bad side, several people have, for some unknown reason, decided the current researchers are not capable of doing a proper study, and so have stopped sending money to the MS Society.  Instead we should be sending more, and demanding unbiased studies, multisectorial, blinded, and large. We won't know for sure until we get those studies done. Until then, taking a stand is perhaps premature.


Study/date
Blinded?
Number of participants
results
The perfect crime? CCSVI not leaving a trace in MS.
J Neurol Neurosurg Psychiatry. 2011 Feb 4. [Epub ahead of print]
Yes ++
20 MS, 20 controls
No retrograde blood flow
Conclusions This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.

Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control studyInt Angiol. 2010 Apr;29(2):158-75.
No
16 RRMS
8 controls
All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC
Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume.

CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study.
Int Angiol. 2010 Apr;29(2):140-8.
No
16 MS
8 controls
Vascular Hemodynamic changes occur more frequently in MS patients than controls. Altered VH is associated with abnormal CSF flow dynamics and decreased brain volume.

No Evidence of Chronic Cerebrospinal Venous Insufficiency at Multiple Sclerosis Onset
Claudio Baracchini, MD,1 Paola Perini, MD,1,2 Massimiliano Calabrese, MD,1,2 Francesco Causin, MD,3 Francesca Rinaldi, MD,1,2 and Paolo Gallo, MD, PhD1
No
50 MS
60 global amnesia
60 healthy.
Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS.

Intracranial venous pressure is normal in patients with multiple sclerosis.
No
29 MS
28 Controls
19 patients with increased intracranial pressure
There is no evidence of an increased intracranial venous pressure in MS patients.
Cardiovasc Intervent Radiol. 2011 Feb;34(1):1-2. Epub 2010 Dec 7.
Cardiovascular and Interventional Radiological Society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency.
No
Comment only
Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in proress Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population.
PMID: 21136256 [PubMed - in process]

Nervenarzt. 2010 Jun;81(6):740-6.
["Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients].
[Article in German]
No
?
The "venous hypothesis" is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the "chronic cerebrospinal venous insufficiency (CCSVI)" cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive "therapeutic" approaches, especially if they are performed outside of clinical trials.
Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency.
Neurology. 2010 Nov 2;75(18):1617-22. Epub 2010 Sep 29.

No
cross-sectional (n = 1,408) longitudinal (n = 29) patients with MS and a range of neurologic disorders.

Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period.
CONCLUSION: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition
No cerebrocervical venous congestion in patients with multiple sclerosis.
Ann Neurol. 2010 Aug;68(2):173-83.
No
56 MS
20 Controls

Sonography study, flow analysis, CCSVI criteria
Our results challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Future studies should elucidate the difference between patients and healthy subjects in BVF regulation.
No MS patient had >1 CCSVI criterion
Int Angiol. 2010 Apr;29(2):189-92.
Chronic cerebro-spinal venous insufficiency: report of transcranial magnetic stimulation follow-up study in a patient with multiple sclerosis.
No
I patient
The demonstration of a modification of the cerebrovenous function with both clinical manifestation and via TMS suggests that the hampered cerebral venous return may contribute to the clinical course of MS.

Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study.
Int Angiol. 2010 Apr;29(2):176-82.
No.
31
fatigue testing 1, 6 and 12 mos post-procedure
The reestablishment of cerebral venous return dramatically reduced CF perception in a group of MS patients with associated CCSVI, suggesting that CF is likely the symptom of CCSVI.


Note: Patients were identified as having CCSVI and Chronic Fatigue
Chronic cerebrospinal venous insufficiency and multiple sclerosis Omar Khan MD1,*, Massimo Filippi MD2, Mark S. Freedman MD3, et al
ANN NEUROL 2010;67:286–290


In this Point of View, we discuss the recent investigations that led to the description of CCSVI as well as the conceptual and technical shortcomings that challenge the potential relationship of this phenomenon to MS. The need for conducting carefully designed and rigorously controlled studies to investigate CCVSI has been recognized by the scientific bodies engaged in MS research. At present, invasive and potentially dangerous endovascular procedures as therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.
Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study
.    Peter Sundström MD, PhD1,*, Anders Wåhlin MSc2, Khalid et al
No
21 MS 20 control
We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis. ANN NEUROL 2010;68:255–259
Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe?
T Ludyga *, M Kazibudzki *, M Simka * , M Hartel , M wierad *, J Piegza *, P Latacz *, L Sedlak * and M Tochowicz *
No
564 procedures in 331 MS patients with CCSVI
The procedures appeared to be safe and well tolerated by the patients, regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants long-term follow-up.
No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study
Yes
20 MS, 20 control
MRV studies (magnetic resonance venography)
A completely normal venous anatomy was observed in 10 MS patients and 12 controls. Anomalies of the venous system (venous stenosis/occlusions) were found in 10 MS patients and eight healthy controls. An anomalous venous system in combination with associated alternative venous drainage was observed in six MS patients and five healthy controls. Flow quantification showed no venous backflow in any MS patient or control.
Conclusions Findings suggestive of anomalies of the cranial venous outflow anatomy were frequently observed in both MS patients and healthy controls. Given the normal intracranial venous flow quantification results, it is likely that these findings reflect anatomical variants of venous drainage rather than clinically relevant venous outflow obstructions.
Iron and Neurodegeneration in Multiple Sclerosis Michael Khalil,1, 2 Charlotte Teunissen,2 and Christian Langkammer1
Multiple Sclerosis International Volume 2011, Article ID 606807,


In summary, increased iron deposition has been consistently reported to occur in MS, but its role in pathogenetic processes of this disease has not yet been completely clarified. Quantitative MRI and histopathologic analyses of postmortem MS brains should complement these     [9] studies.






2.25.2011

Well, it's one of those days...

Got up, poured my cereal in my coffee mug.
It's gone downhill from there.
I'm trying to get organized for my move to heaven  Nova Scotia (specifically, Dartmouth) and my brain is NOT cooperating. I am mixed up between trying to organize paperwork, throw out items, book movers, change addresses, etc., etc. and my desk is a disaster, my hair is a spectacle, and my dog is becoming surly. It's just about time to take him for a walk and mail a variety of things, but first I have to figure out the byzantine rules for getting money back from the drug support program here in Ontario for my horrendously expensive Copaxone. And other drugs.
Expensive disease, this. And it's only beginning. The pharmacist figures out I spent $16,000 on meds last year - most of it covered by insurance, thank gods, but this year my coverage stops at $2400 (the max available under my insurance). Even the support program only pays for 80%. As my income is about twice my drug total, life is looking a bit grim. Perhaps I will have to just give them up. Or maybe the makers of Copaxone, Teva pharmaceuticals, who were in fact fined for overcharging, could lower their prices a wee bit. I know, overall, it is less costly than the alternative - crippling disease progression - and it seems to have stopped that for me. I know it's expensive to make, and involves years of research - I know they have to charge a hefty fee.  But perhaps a wee bit less hefty would be a big help.