Saturday, 6 October 2012

CCSVI at ECTRIMS

Next week Prof G is at ECTRIMS and the news starts here

Multiple stenosis or multiple sclerosis?

G. Panczel, C. Rozsa, K. Kovacs, I. Szikora, Z. Berentei, I. Gubucz, M. Marosfoi, A. Rozsa (Budapest, HU)

Introduction. An alternative etiology of MS named chronic cerebrospinal venous insufficiency (CCSVI) has recently been proposed by Zamboni et al. By venous ultrasound (US) and venography they found venous stenosis present in all MS patients and none of control subjects, most of these stenoses were multiple, affecting mainly the internal jugular veins both sides but also the azygos and vertebral veins. The aim of our study was to determine if cerebral venous outflow –evaluated by Doppler US and venous DSA- differs significantly in MS patients and controls.
Patients and methods. We enrolled 20 patients (47,1 ± 10,8 y, 6 males, 14 females) who were scheduled for a control angiography after interventional therapy of intracerebral aneurysm and had no venous pathology or MS. 14 MS patients were also enrolled who underwent a CCSVI interventional work-up abroad (45,4 ± 12,8 y; 5 males, 9 females). Stenosis of proximal IJV was measured by DSA, flow volume (FV) was measured by duplex US and IJV patency was evaluated by power-US method.
Results. DSA examination: 80% of controls had >50% stenosis in the right and 94.7% on the left side; mean degree of stenosis was 69 ±17% and 73 ± 13% (right and left IJV). All MS patients also had IJV stenosis, mean value of stenosis was 62 ±14% and 66 ± 13% (right and left IJV). There was no significant difference in the degree of stenosis between groups.
US measurements: FV of IJV was normal in both groups, both sides (controls: right: 692 ± 430 ml/min; left: 502 ± 303 ml/min; MS patients: right: 603 ± 469 ml/min; left: 584 ± 319 ml/min;). None of the patients and controls had IJV stenosis on power duplex US.
Discussion. Normal FV and power duplex US findings proved that the IJV stenosis shown by DSA was not real. The virtual stenosis is explained by the fact that the contrast agent descending the IJV is diluted at the venous confluence by the non-contrast blood stream of subclavian vein raising a false impression of a local high-grade stenosis. We concluded that haemodynamically significant venous stenosis –a key feature of CCSVI, cannot be found in MS patients. 
Fact or artifact this study argues for the latter 

Endovascular treatment of CCSVI in patients with multiple sclerosis: clinical outcome of an Italian cohort of 462 cases

A. Ghezzi, P.O. Annovazzi, M.P. Amato, R. Balgera, P. Banfi, M. L. Bartolozzi, R. Bergamaschi, A. Bertolotto, A. Bianchi, A Bosco, E. Capello, M. Capobianco, R. Capra, P. Cavalla, R. Clerici, G. Coarelli, E. Cocco, N. De Rossi, C. Di Tillio, M.T. Ferrò, A. Gallo, P. Gallo, L. Lamantia, A. Lugaresi, G. Lus, S. Malucchi, L. Moiola, L. Provinciali, F. Patti, P. Perini, P. Perrone, A. Protti, M.E. Rodegher, P. Rossi, M. Rottoli, M. Rovaris, G. Salemi, M. Salvetti, I. Simone, M.R. Tola, M. Trojano, F. Vitetta, M.G. Marrosu, G. Comi and MS Study Group, Italian Society of Neurology

Backgound and objectives Although the relationship between MS and CCSVI is not defined and there is no proven demonstration that endovascular treatment of CCSVI is effective to improve MS evolution, many patients decide to undergo such a treatment. The Italian Multiple Sclerosis Study Group-Italian Society of Neurology has promoted a multicentric study to collect clinical information on MS subjects who have spontaneously decided to be submitted to endovascular treatment.
 
Results. 31 Italian MS centres have participated to this study. A form has been standardized to collect complete demographic, clinical, MRI and safety data. All consecutive MS patients who have declared (spontaneously or asked by physicians) to have been submitted to endovascular treatment of CCSVI have been included in the database. Complete data are available of 462 patients (279 females) (mean age 44+/-10 y), 45% with RR-MS , 55% with SP/PP-SM. The mean EDSS score before the intervention was 5.0+/-2.0. After a mean follow up of 30.7+/-36.1 weeks, the mean EDSS was 5.1+/-2.0 and 98 patients developed one or more relapses (tot. 144). MRI data of 171 patients were available, after a follow up of 28 weeks, showing the appearance of new T2 or gadolinium enhancing lesions in 61 patients. A subjective clinical improvement was reported by 53% of patients; clinical status was unchanged in 33% and worsened by 15% of cases. In subjectively improved patients the mean pre-intervention EDSS was 4.9+/-2.0; it was 5.0+/-2.1 after the surgical procedure. Serious adverse events have been observed in 15 cases: jugular venous thrombosis in 7, inguinal haematoma in 3, ischaemic stroke in 2, post-ischemic encephalopathy in 1, hydrocephalus in 1; one subject died because of myocardial infarction 3 months after the intervention.
 
Conclusions. The results of our study, with the limitations due to the observational design, do not show any clear beneficial effect of endovascular treatment for CCSVI in MS. The subjective positive effects reported by about 50% of patients can be largely due to the high expectation of patients for an intervention called “liberation”. The intervention is not totally free from serious adverse events, which occurred in 15/462 cases.

So about 50% of Msers felt better but on at least disability scales there was no improvement, so not quite as impressive as many of the Youtube videos. The group appear to suggest that this is due to a placebo effect.  There were some (about 3-4%) serious side-effects from having the treatment

A prospective follow-up of the venous haemodynamics in patients with MS: the fluctuating natural course of CCSVI

L.H. Visser, L. van den Berg, A. van der Zande, G. van den Berg, B. Westerhuis (Tilburg, Maassluis, NL)

Introduction: A new treatable venous disorder, chronic cerebrospinal venous insufficiency (CCSVI), has been proposed in patients with multiple sclerosis (MS). The natural course of CCSVI has not been examined yet. Moreover, its relation with iron metabolism is suggested but has not been examined prospectively.
Methods: We performed extra- and transcranial echo colour Doppler (ECD) in 90 MS patients and 41 healthy controls (HC), applying the same methods used by Zamboni et al. To document the natural course of venous haemodynamics a random subgroup of 52 patients and 28 HC were re-examined by ECD. Indices of iron metabolism and presence of peripheral signs of impaired venous flow were also examined.
Results: First ECD showed CCSVI in 8 (8.9%) of the 90 MS patients and 0 HC (p=0.11). The 8 CCSVI-positive MS patients were older (P=0.02), had less often RR-MS (P=0.02) and had more neurological disability (P=0.001) and longer duration of disease (P=0.02) in comparison to the 82 CCSVI-negative MS patients. Multivariate analysis revealed that EDSS remained an independent factor associated with CCSVI (Odds ratio 1.89 (95 %CI 1.17-3.05, p-value 0.009). CCSVI-positive patients had more often bilateral telangiectasia at the legs (P=0.008), reticular veins (P=0.006) and venous stasis dermatitis (P=0.004). The diagnosis CCSVI could not be reconfirmed in 3 out of 5 patients at follow-up, while 2 new CCSVI-MS patients were detected. No relation was found between CCVSI and impaired iron metabolism in MS patients.
Conclusions: CCSVI is uncommon and is a secondary epiphenomenon in MS and is related with more neurological disability and presence of varicose veins at the legs. Determining CCSVI by ECD is unreliable because of the fluctuating natural course of the extracranial venous haemodynamics.

A systematic review of the association between chronic cerebrospinal venous insufficiency and multiple sclerosis

J.M. Burton on behalf of the Canadian CCSVI Systematic Review Group

Background: It has been proposed that multiple sclerosis (MS) is caused by ultrasound detectable abnormalities in the anatomy and flow of intra and extra-cerebral veins, a condition termed chronic cerebrospinal venous insufficiency (CCSVI).
 
Objectives: This updated systematic review, supported by the Canadian Institutes of Health Research, was undertaken to examine the evidence of an association between CCSVI and MS using rigorous methods.
 
Methods: Literature searches of the electronic databases Ovid MEDLINE (2005-March 2012), the Cochrane Central Register of Controlled Trials (2005-March 2012) and EMBASE (2005-March 2012) were undertaken. Studies had to report original data in a peer-reviewed publication, use either Doppler ultrasonography or magnetic resonance venography (MRV), and assess MS patients vs healthy controls (HC) and/or those with other neurological disorders (OND). Cochrane Review manager was used to generate odds ratios and plots.
 
Results: There are now 14 studies in this review comparing the frequency of CCSVI by ultrasonography in MS patients, 11 of which compared MS vs HC, and 5 of which compared MS vs OND. CCSVI was diagnosed more frequently in MS patients vs HC (OR 8.11, 95% CI 2.85, 23.09), but with extremely high heterogeneity of frequency and magnitude of association (I2=84%). Sensitivity analysis on this data awaits the addition of more studies. Five studies comparing MS to OND found a higher frequency of CCSVI in MS, but heterogeneity was considerable and results not statistically significant. Three small studies of MRV in MS vs HC found no significant differences between groups. MS clinical outcomes could not be interpreted as trials were neither randomized nor properly controlled. Most trials did not follow patients beyond the peri-procedure period but reported a small number of early complications including arrhythmias, hemorrhage and vein wall dissection/ rupture. Case reports of post-procedure complications have documented stent and cerebral vein thrombosis, PE, accessory nerve injury, hemorrhage and death.
 
Conclusion: This systematic review found a statistically significant association between CCSVI and MS vs HC, but not clearly between MS and OND. However, heterogeneity and methodological limitations pertaining to randomization methods, control groups and failure to blind prevent a definitive conclusion. At present, results demonstrate only an association between CCSVI and MS, not a causal relationship
 

Chronic cerebrospinal venous insufficiency in MS/CIS is not consistently observed with a blinded ultrasound protocol

K. Knox, J. Gitlin, S. Harvey, C. Hayward, S. Wiebe, C. Voll, P. Szkup, R. Otani (Saskatoon, CA)

Criteria proposed by Zamboni et al. for Chronic Cerebrospinal Venous Insufficiency (CCSVI) were initially reported to be 100% associated with Multiple Sclerosis and never seen in controls. Subsequent research has not replicated these findings. Multiple factors are suggested to have a role in the reproducibility of findings, including duration of disease and blinding of the ultrasonographer.
Objective: To evaluate the prevalence of CCSVI in MS, clinically isolated syndrome (CIS), and age-matched healthy controls using a blinded approach.
Methods: Five subjects with MS, ten with CIS, and fifteen healthy controls were recruited to participate. Two experienced ultrasonographers were trained in the Zamboni protocol for the assessment of CCSVI criteria: 1) Reflux in internal jugular veins (IJV) and/or vertebral veins (VV) >0.88 seconds; 2) Reflux in deep cerebral veins >0.5 seconds; 3) Cross sectional IJV area <= 0.3cm2; 4) No Doppler-detectable flow in the IJVs or VVs; and 5) Reverted postural flow of the main cerebral venous outflow pathways. Subjects were scanned on either a Philips or ESAOTE device. Nine subjects (1 MS, 1 CIS, 7 controls) were assessed for the five proposed CCSVI criteria. In 21 subjects, the 2nd CCSVI criterion was not assessed due to technicalities and delays in obtaining Health Canada approval for use of the ESAOTE. In order to maintain blinding, a research assistant positioned and covered the subjects, exposing the neck prior to the arrival of the ultrasonographer. Subjects were instructed not to speak during the procedure and to facilitate this, background music was played. A research assistant remained in the room during all procedures. Assessment of blinding through an exit survey was completed by the ultrasonographer.
Results: Median ages were 47.00 (MS), 44.14 (CIS), and 44.61 years (controls). Median duration of disease since symptom onset were 27.67 (MS) and 2.86 years (CIS). Four of five subjects with longstanding MS, 0/10 subjects with CIS and 2/15 control subjects fulfilled >=2 criteria for CCSVI. Blinding of the ultrasonographer was maintained for 29/30 subjects.
Conclusion: This pilot study could not confirm that CCSVI is present only in disease (MS or CIS) and never in controls when evaluated by blinded ultrasonographers trained in the Zamboni CCSVI protocol. We provide a detailed description of blinding methods not routinely reported previously and this may be important in the interpretation of the CCSVI literature.

So this study did not confirm the original incidence of CCSVI with MS and health controls, but this study did report that more MSers had CCSVI criteria than controls in a blinded study.

However you can have the alternative Take from the Hubbard Foundation...no CoI there then click Here



Dr Hubbard Foundation reported "Thirteen of the 21 abstracts were ultrasound studies and predictably were negative, inconclusive, and/or repetitive. I think we have all learned that ultrasound is not able to provide diagnostic criteria for the hypothesis of chronic cerebro-spinal venous insufficiency, and internal jugular ultrasound will not help us understand what is happening in the small veins of the CNS white matter where MS lesions occur.