Recently, evidence has emerged – and widely publicised – that a condition called “chronic cerebro-spinal venous insufficiency (CCSVI)” may play a role in the pathogenesis of multiple sclerosis (MS). Paolo Zamboni, professor and director of the Vascular Diseases Centre at the University of Ferrara (Italy), and co-workers detected anomalies of venous drainage from the brain and spinal cord in all 65 (100%) people with MS in their cohort (published earlier this year in the Journal of Neurology, Neurosurgery and Psychiatry). Using venous ultrasound as well as venography (where a dye or contrast agent is injected through a catheter) they reported four patterns of restricted blood flow due to narrowing in the internal jugular, azygos and superior cava vein system. In none (0%) of their 235 strong control population (i.e. people with no known disease of the nervous system and people with neurological conditions other than MS such as Parkinson’s or motor neuron disease) did they find abnormalities similar to that found in the group of 65 people with MS.
Based on these findings, Professor Zamboni and his colleagues have started treating people with MS using a technique called endovascular balloon angioplasty, which widens the blood vessels using a catheter that has a balloon attached to its tip; when the balloon is inflated the vessel is opened. In a few cases they have resorted to inserting a stent, or rigid tube, in places where narrowing had been detected. Preliminary results following treatment of 75 patients with MS were reported earlier this year at the 31st Charing Cross Symposium “Vascular and Endovascular Controversies Update”. At that point patients had been followed up for a maximum of one year. Zamboni’s team reported positive trends using a panel of outcome measures of efficacy; i.e. (i) the MS functional composite (MSFC) scale, which measures walking speed, upper limb function and cognition, (ii) quality of life (MSQoL-54) and (iii) relapse rate.
The recent collaboration of Professor Zamboni’s group with MS experts from Buffalo (NY) and Detroit (MI) has propelled “CCSVI and MS” to a new level of publicity. This group plans to investigate 1,600 adults and 100 children with a diagnosis of possible or definite MS alongside 300 healthy controls and 300 patients with autoimmune and/or neurodegenerative diseases other than MS. Apart from using doppler ultrasound of head and neck blood vessels this group will also use magnetic resonance imaging (MRI) of the brain with particular focus on brain iron levels; the effects of excess iron has been implicated for some time in the tissue destruction that occurs in various brain disorders including MS.
The “big idea” underlying the presumed link between CCSVI and MS is that narrowing in large veins outside the central nervous system (CNS) leads to stagnation of venous blood in small veins within the CNS and, subsequently, to iron deposition and inflammation around these veins with damaging knock-on effects (e.g. demyelination & axonal loss). Zamboni likens the perivascular MS lesion to a venous ulcer of the leg emerging from a varicose vein. The origin of increased iron in varicose legs is the leaking of red blood cells in conditions with stasis of blood in the veins.
Extravasation of red blood cells and thrombosis of small veins have indeed been seen in MS brain tissue, too. However, such findings are rare and far outnumberd by evidence suggesting different early abnormal events in MS lesion development including (i) migration through the blood brain barrier of autoreactive T cells or (ii) oligodendrocyte death.
There are numerous further questions that need to be addressed in order to draw any reasonable conclusion from Zamboni and co-workers’ findings: How does CCSVI explain relapses and remissions? What is the mechanism underlying apparent narrowing in large veins of people with MS? Are these vascular changes primary or secondary to MS? What is the association between these changes and apparent iron deposition in the brain of patients with MS? Is there an animal model that responds with inflammation and demyelinaton following stasis in large skull veins? Is there any evidence from people with MS who have been – for reasons other than MS – on drugs to thin the blood? And so forth…
We will follow the Ferrara/Buffalo/Detroit-collaboration on CCSVI in MS with interest, and we understand a first preliminary analysis is due within the next few months. For the time being, patients and their families should be re-assured that there is currently very little – if any – evidence in favour of endovascular treatment for MS. These procedures are invasive and carry a risk. Without firm evidence from properly conducted clinical trials we would not recommend this therapy.
Klaus Schmierer & Gavin Giovannoni