Finally, it's time for CCSVI to rest in peace!
JAMA Neurol. 2017 Nov 18. doi: 10.1001/jamaneurol.2017.3825. [Epub ahead of print]
Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial.
Zamboni P1, Tesio L2,3, Galimberti S4, Massacesi L5, Salvi F6, D'Alessandro R6, Cenni P7, Galeotti R8, Papini D9, D'Amico R10, Simi S11, Valsecchi MG4, Filippini G12; Brave Dreams Research Group.
Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial.
To determine the efficacy and safety of venous PTA in patients with MS and CCSVI.
Design, Setting, and Participants:
We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat.
Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham).
Main Outcomes and Measures:
Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions.
Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68; P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91; P = .03: adjusted P = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63; P = .45; adjusted P = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28; P = .03; adjusted P = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01; P = .15; adjusted P = .30).
Conclusion and Relevance:
Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.
In the disolute world of academia, careers are made on reputation alone, and nothing comes as close to questioning this as scientific integrity. Dr Paolo Zamboni first shot to fame following claims that 90% of MS subjects in an unblinded study demonstrated narrowing of their veins (internal jugular or azygous veins - see diagram above) leading to insufficient venous drainage of the brain. He was able to quickly link this with at the time known evidence of MS lesions having excess iron deposition and hypothesised that anomalous venous outflow may be a mechanism for this. And, so the phrase chronic cerebrospinal venous insufficiency (CCSVI) was invented and entered into the MS vocabulary (Singh and Zamboni J Cerebral Blood Flow & Metabolism, 2009).
A decade on, after innumerable procedures to dilate supposed narrowed veins, the theory is disproved by MS researchers across the globe, leading to overarching statements from the EFNS, ENS Multiple Sclerosis Scientist Panel, and ECTRIMS Executive Committee: we "...emphasize the high risk and absence of a scientific basis for "liberation procedures" in MS patients". So can Dr Zamboni find his way back from the footprints of obscurity? According to quaint and whimsical humorists in JAMA Neurology anything is possible.
This publication is openly available to all and is work from the 'Brave Dreams' (Brain Venous Drainage Exploited Against Multiple Sclerosis) team, which is a multi-centre, placebo-controlled (i.e. sham procedures were undertaken ?ethical) trial to investigate the safety and efficacy of CCSVI procedures in Italy. The trial comprised of both RRMS and SPMS, with disability scores (EDSS) 2-5.5 and a disease duration of 15y or less, also not receiving MS treatments (immunosuppressive or immunomodulatory) for at least 6 months. MS participants were assigned to either real dilatation or sham procedure at a 2:1 ratio. To maintain the blinding, during the sham procedures the surgeon had to pass the catheter into the venous system. In those assigned to the real dilatation, but there was no evidence of a narrowing, they still received the catheter venography but without the dilatation procedure. The endpoints were assessed at one year and included functional (not MSFC or EDSS but a composite of walking control, balance, manual dexterity, postvoid residual urine volume and visual acuity) as well as an MRI endpoints (T2 lesion loads, gadolinium enhancement, proportion of subjects free of new lesions).
The findings were that 41% in the real dilatation group and 49% in the sham group improved on the functional end point, and functional stability was maintained in 23% in the real dilation group and 22% in the sham group. A mixed outcome (improvement and worsening in some aspects) was found in 22% in the real dilatation group and 11% in the sham group. As for MRI, the number of new lesions on MRI at 12 months were not significantly different between the two groups, and the proportion of those free of new lesions did not differ between the two groups. Whilst, at 12 months 68% in real dilatation and 57% in the sham group (not statistically significant) were free of new or enlarging T2 lesions, and 73% in real dilatation and 49% in the sham group (P=0.08) were free of gadolinium enhancing lesions. Safety wise, there were no serious adverse events related to either the dilation procedure or the sham procedure.
The bottom line is that venous dilatation procedures did not result in clinical improvement or a statistically significant improvement in MRI activity. The findings of this larger randomised, properly blinded study, therefore did not confirm the earlier positive findings from open-label pilot studies.
Hopefully, this lays to rest CCSVI theorists and activists once and for all. Especially, since it comes from the man himself.