Chronic cerebro-spinal venous insufficiency (CCSVI) is a syndrome in which the flow of blood in the cervical and thoracic veins, from the central nervous system (CNS) to the heart, is compromised and less efficient. It is proposed that insufficient venous blood flow, in turn, promotes development of brain dysfunction, especially multiple sclerosis.
The reported blood flow compromises involve both reduced and intermittently reversed (reflux) flow velocities in the cerebral veins, changed brain capillary dynamics (altering the blood-brain barrier), and are reportedly associated with stenosis of the jugular and azygos veins. Such a vascular picture was described by Paolo Zamboni in 2008, who also reported an association of CCSVI with multiple sclerosis (MS). The hypothesis has generated optimism, especially from patients, for more effective treatment options for multiple sclerosis. It has also been received with skepticism by some in the medical community, as well as efforts by some institutions to support research into it.
This syndrome was described on 2008 by Paolo Zamboni, one of the main defenders of its relationship with multiple sclerosis. CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis. It was soon followed by small open-label study which reported a positive effect of angioplasty in MS patients with CCSVI by the same research group. The first international symposium took place in 2009, at Bologna, Italy. Venous stenosis due to developmental abnormalities was established as the primary cause of CCSVI by the International Union of Phlebology. In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.
Symptoms and consequences
Potential consequences of the syndrome could be hypoxia, delayed perfusion, reduced drainage of the catabolites and increased transmural pressure, and iron deposits around the cerebral veins.
When MS patients diagnosed with CCSVI in the Zamboni’s studies underwent catheterization of the azygous and IJV veins, the authors claimed that such veins were stenosed in around 90% of the cases. Nevertheless this part of the study was not blinded, reducing its reliability. A vascular component in MS had been cited previously.
It has been theorized by Zamboni and colleagues that the malformed blood vessels caused increased deposition of iron in the brain, which in turn triggers autoimmunity and degeneration of the nerve’s myelin sheath. Nevertheless iron deposition occurs in different neurological diseases such as Alzheimer’s disease or Parkinson’s disease but CCSVI was not seen in their control group with neurological problems.
CCSVI was first found combining extracranial and transcranial doppler sonography. Five parameters of venous drainage have been proposed to be characteristic of the syndrome, although having two of them is enough for diagnosis of CCSVI:
- reflux in the internal jugular and vertebral veins,
- reflux in the deep cerebral veins,
- high-resolution B-mode evidence of stenosis of the internal jugular,
- flow in the internal jugular or vertebral veins that could not be detected with Doppler, and
- reverted postural control of the main cerebral venous outflow pathways.
Use of Magnetic resonance venography for the diagnosis of CCSVI in MS patients has limited value, and has been proposed to be used only in combination with other techniques.
While the initial article on CCSVI claimed that abnormal venous function parameters were not seen on healthy people others have noted that this is not the case. In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did. Such outstanding results have raised suspicions on a possible spectrum bias, which originates on a diagnostic test not being used under clinically significant conditions.
While the original results have been replicated in a second study, others have found CCSVI to only occur in 20% of MS patients.
There has been a small pilot study which used balloon angioplasty to treat MS patients who had been diagnosed of CCSVI and had their cerebral veins stenosed. This study reported a clinical benefit, specially in those patients with the relapsing-remitting subtype. In the follow-up of these patients (up to 18 months) there was a very high rate of re-stenosis (around 50%). Improvements in this study are hard to interpret due to the lack of a control group and blindness among the evaluators, small treated sample, and use of approved therapies for the disease among patients.
The high re-stenosing rates led the authors of the pilot study to propose that the use of stents might be a more feasible treatment. Rare but serious adverse events have been reported when using stents. Some US hospitals have banned the surgical procedure outside of clinical trials until more evidence to support its use is available.
A larger study is ongoing at Buffalo Neuroimaging Analysis Center to study the relationship between CCSVI and MS with a press release claiming preliminary results supporting the link.
The Multiple Sclerosis Society of Canada has committed to funding further experimental trials on the hypothesis, though the head of the organization noted that the results “merit serious and robust studies” but also “pleaded with patients to not do anything drastic until the theory is tested and proven”.
The hypothesis has generated optimism, especially from patients, for more effective treatment options for multiple sclerosis. It has been received with caution or skepticism by some experts, who found it to rely on too limited data to support at least some of the following claims: (a) that the syndrome actually exists; (b) that it could be causative of (or a co-factor in) multiple sclerosis; (c) that vascular treatments for the syndrome would prevent or reduce the incidence of multiple sclerosis.
Both the neurology community and some MS organizations such as the National Multiple Sclerosis Society of the USA recommend not to use the proposed treatment until its effectiveness is confirmed by controlled studies