Brave dreams, or not

A blast from the past. Just when we thought CCSVI had died a quiet death the Brave Dreams trial is reported. It is clear that venoplasty in pwMS with “CCSVI”, a non-disease, are not cured of having MS. 

However, it appears that venoplasty may have some weak antiinflammatory effects.  A secondary assessment in subjects with favourable venograms had a significantly higher probability of being free of new cerebral lesions than patients with unfavourable venograms. The interesting question is how does stretching your veins have an anti-inflammatory effect in MS.

One hypothesis would be via the stimulation of the parasympathetic afferent or sensory nerve fibres that innervate cerebral veins and venous sinuses. There is an extensive literature on the potential mechanisms of how parasympathetic stimulation, using the vagal nerve, could be anti-inflammatory. 

I suspect exploring the mechanisms of how venoplasty is anti-inflammatory is academic because the treatment effect is so small and is nowhere close to the effectiveness of licensed DMTs. Why would you have venoplasty if you could be on a more effective DMT?

I hope this will finally be the last we hear about CCSVI. I want to stress when you apply medical philosophical principles, CCSVI is not a disease; it does not fulfil the contemporary definition of being a disease entity. In short, there is not clinicopathological correlate that defines CCSVI as being a disease. A better descriptor for CCSVI would be that it is a meme.

Definition: A meme an image, video, piece of text, etc., that is copied and spread rapidly by Internet users, often with slight variations.

Zamboni, et al. for the Brave Dreams Research Group. Effects of Venous Angioplasty on Cerebral Lesions in Multiple Sclerosis: Expanded Analysis of the Brave Dreams Double-Blind, Sham-Controlled Randomized Trial. J Endovasc Ther 1526602819890110 2019 Nov 17.

Purpose: To evaluate if jugular vein flow restoration in various venographic defects indicative of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) patients can have positive effects on cerebral lesions identified using magnetic resonance imaging (MRI).

Materials and methods: The Brave Dreams trial ( identifier NCT01371760) was a multicenter, randomized, parallel-group, double-blind, sham-controlled trial to assess the efficacy of jugular venoplasty in MS patients with CCSVI. Between August 2012 and March 2016, 130 patients (mean age 39.9±10.6 years; 81 women) with relapsing/remitting (n=115) or secondary/progressive (n=15) MS were randomized 2:1 to venography plus angioplasty (n=86) or venography (sham; n=44). Patients and study personnel (except the interventionist) were masked to treatment assignment. MRI data acquired at 6 and 12 months after randomization were compared to the preoperative scan for new and/or >30% enlargement of T2 lesions plus new gadolinium enhancement of pre-existing lesions. The relative risks (RR) with 95% confidence interval (CI) were estimated and compared. In a secondary assessment, venograms of patients who underwent venous angioplasty were graded as “favorable” (n=38) or “unfavorable” (n=30) for dilation according to the Giaquinta grading system by 4 investigators blinded to outcomes. These subgroups were also compared.

Results: Of the 130 patients enrolled, 125 (96%) completed the 12-month MRI follow-up. Analysis showed that the likelihood of being free of new cerebral lesions at 1 year was significantly higher after venoplasty compared to the sham group (RR 1.42, 95% CI 1.00 to 2.01, p=0.032). Patients with favorable venograms had a significantly higher probability of being free of new cerebral lesions than patients with unfavorable venograms (RR 1.82, 95% CI 1.17 to 2.83, p=0.005) or patients in the sham arm (RR 1.66, 95% CI 1.16 to 2.37, p=0.005).

Conclusion: Expanded analysis of the Brave Dreams data that included secondary/progressive MS patients in addition to the relapsing/remitting patients analyzed previously showed that venoplasty decreases new cerebral lesions at 1 year. The secondary analysis confirmed the efficacy of the Giaquinta grading system in selecting patients appropriate for venoplasty who were more likely to be free from the accumulation of new cerebral lesions at MRI.

Bonaz et al.  Anti-inflammatory Properties of the Vagus Nerve: Potential Therapeutic Implications of Vagus Nerve Stimulation. J Physiol, 594 (20), 5781-5790 2016 Oct 15.

Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα-related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation.

CoI: nil

6 thoughts on “Brave dreams, or not”

  1. “Why would you have venoplasty if you could be on a more effective DMT?”
    Which effective DMT are you referring to that inhibits the real MS or “non active” progressive MS? The current treatments work just as well as CCSVI, which is ZERO.
    There is not one single meaningful treatment to stop the real MS or progressive MS. There are plenty of immunosuppressive treatments that work to reduce Gd MRI changes and relapse rates by working on a downstream reaction via stopping peripheral B cells or T cells or both but there are zero effective treatments to work on destructive innate immunity changes that are causing the real MS or progressive MS.
    Hopes for MS patients are quickly vanishing as they wait for breakthroughs that will never ever come while Pharma and it’s associated researchers continue to push their recycled non-innovative immunosuppressant model for continued massive profits.
    History will not be kind to those involved in this stagnant era for outrageous profits for ineffective drugs. Researchers have not at all heeded the warnings that in fact created CCSVI in the first place. Instead, they continue to mock it instead of learning that it was born out of ineffective treatments in a frustrated suffering MS population.

  2. I had CCSVI in 2012 and it has changed my life. I will never be normal again as my muscles were starved of oxygen for so long. My Internal Jugular and Azygous veins were ballooned. I got the feeling back in my body once the bruising had worn off. I am hoping it will be you I am seeing in January Prof G. I have videos of me before & after treatment. I know my veins are still badly damaged and this is why I am coming to see you to see if you can help me finish off my treatment of repair. I am a mystery. Anyone else following the same path as me. I do feel very isolated with this. Tracy. x

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