My own speculation: I suspect that Zamboni may have it backwards, that subtle immune problems often precede both neuroinflammation and endothelial dysfunction which leads to CCSVI in some cases. When circulatory problems lead to weakened immune response in the CNS, pathogens are more likely to penetrate both endothelial tissues and nerve sheaths. When the immune system goes after these, it causes further damage. There is positive feedback between endothelial dysfunction, dysautonomia, circulatory problems and further nerve damage, so it is not always clear which defect starts the process.
The connection between circulatory function, tissue perfusion and immune function is already basic physiology. No doctor should be surprised when patients with reduced cardiac output have poor immune function. This also applies to special cases where there is reduced perfusion in particular tissues, e.g. strangulation of an inguinal hernia and gangrene. In simple cases the connection is immediate and obvious. When the reduced perfusion is episodic, and not seen in the clinic, it is much harder to pin down. The CNS consumes a large fraction of the body's energy/oxygen budget, and requires better supply of oxygenated blood than most of the body to function normally. It also has a very complicated blood-brain barrier which functions to isolate the CNS from many immune activities. This is especially subject to damage by interruptions in the supply of oxygen/glucose, and to slow or weak immune response caused by reduced circulation. To function effectively, immune cells must reach potential sites of infection quickly, and in sufficient numbers. Information about the pathogens they find there must be carried back to other immune cells, such as dendritic cells, which then pass this to B-cells which make antibodies and T-cells which carry out cell-mediated immune response. If circulation is weak, all rates at which immune response functions are reduced. Pathogens which are already present, but normally held in check by immune activity, can then penetrate further into tissues where they do not belong. Later response by T-cells going after these pathogens then causes further damage to the invaded tissues.
See the
topics discussing Pender's recent results in treatment of secondary progressive MS. At this point I don't know that EBV (HHV-4) is the only culprit. There are family resemblances between the human herpes viruses, and some like VZV (HHV-3) are well known to hide out in ganglia during the long period between active chicken pox and active shingles. There are also cases in which common viruses like HSV (HHV-1 or HHV-2) invade the brain, causing a fatal encephalitis. There is even research finding HCMV (HHV-5) at high incidence in particular kinds of brain tumors. These viruses are prime candidates for pathogens hiding in plain sight which will take advantage of problems like those described here. The jury is still out concerning HHV-6/7.
