Vascular aspects of multiple sclerosis
June 21, 2011 at 1:35pm
I have the complete review paper from Lancet Neurology. It is a review of recent research in MS and is a compilation of the many studies we've linked on this page. The endothelium, hypoperfusion, ischemia , CCSVI and the many terms we've learned over the past two years are all mentioned. I do not want to violate copyright laws, and can't copy and paste the full paper, but I'll give a brief breakdown. You'll see text from the paper in italics, and then my comments.
Note the word "might" is used extensively. They review the research connecting the vascular system to MS. While this is not earth-shattering to those of us who know CCSVI, up close and personal--it is encouraging to see this review in a neurological journal.
Vascular aspects of multiple sclerosis
Miguel D’haeseleer, Melissa Cambron, Ludo Vanopdenbosch, Jacques De Keyser
Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals.
#1 People with MS have ischemic stroke more often than healthy people.
Inflammation is widely accepted to play an integral part in the pathogenesis of atherosclerosis.18,19 Endothelial dysfunction is an early step towards overt atherosclerosis and the immune system seems to be highly involved in both processes.20 Endothelial dysfunction has been described in the very early stage of rheumatoid arthritis, probably as a result of inflammatory disease activity.21 Rheumatoid arthritis is an autoimmune disease22 in which increased cardiovascular morbidity and mortality has been noted.23 Alterations in endothelial function, as well as platelet activation and thrombophilia, have been reported in MS.24–26 Moreover, oxidative stress contributes to the development of endothelial dysfunction.27 Higher amounts of systemic and CNS oxidative stress have been reported in patients with MS than in healthy controls.28–30
The concentration of plasma homocysteine, which is believed to be an independent cardiovascular risk factor,31 is also raised in patients with MS.32,33 The cause of the increase in homocysteine concentration is unknown, but it occurs independently of serum concentrations of vitamin B12, vitamin B6, or folate.34 There is evidence that hyperhomocysteinaemia can cause endothelial dysfunction, even at moderately increased concentrations of homocysteine.35,36
The above evidence suggests that the increased frequency of ischaemic stroke in MS might be mediated through converging inflammatory pathways, oxidative stress, and raised homocysteine concentrations leading to endothelial dysfunction.
What this section is saying is that oxidative stress, endothelial dysfunction, endothelin-1 levels and homocysteine levels are higher in pwMS, and may contribute to higher stroke levels. (We've talked about this on here for awhile, it's why I created the endothelial health program for Jeff--I noted this connection in his serum numbers, and tried to help him thru diet, supplements, exercise and lifestyle.)
The researchers are positing that this is all due to inflammation and the immune system in MS. They believe it all begins there. But they have no proof of this. It's just their theory--their way of looking at the evidence thru their prism of MS as immune. But what we've discussed on here is that all of these factors are also found in diffuse cerebral hypoxia, or low levels of O2 in the brain. We don't need to involve the immune system in this theory if we look at it thru the prism of reduced oxygenation in the brain due to slowed blood flow.
Here's another paper that links high homocysteine levels to cerebral ischemia--
Over the last decade, following in vitro and in vivo observations of a homocysteine-associated vascular pathology, convincing epidemiological evidence has been gathered on the relation between moderate elevation of plasma homocysteine and vascular disease, including cerebral ischemia.
#2 People with MS have slower blood flow (hypoperfusion) through their brains
These results suggest that decreased cerebral blood flow in normal appearing white matter is already present in the very early stages of the disease. Compared with patients with clinically isolated syndrome and healthy control individuals, patients with relapsing-remitting MS also had significantly decreased CBF in the putamen, which might suggest a continuum of decreases in tissue perfusion, beginning in the white matter and spreading to grey matter as the disease progresses. However, this hypothesis needs to be confirmed.
Disruption of the blood–brain barrier occurs before or during the development of focal MS lesions and can be visualised as local gadolinium-enhancing areas on T1-weighted MRI.37 Compared with NAWM, DSC-MRI has revealed two patterns of perfusion changes in gadolinium-enhancing lesions. Diffuse enhancing areas were characterised by increases in CBF and CBV.46–48 By contrast, in lesions that developed ring enhancement, CBF and CBV changes similar to non-ring-enhancing lesions were seen only in the ring tissue, whereas inside the ring there was a decrease in CBF, suggestive of a central ischaemic zone.48 Some patients have developed new focal MS lesions with diffusion-weighted MRI characteristics similar to those found with acute ischaemia.49 These preliminary data suggest that focal ischaemia might play a part in the development of a subcategory of focal MS lesions.
In this section, the researchers review all of the evidence of hypoperfusion. This exists. PwMS have slower cerebral bloodflow thru their brains. The debate here is again, whether this is due to axonal death and the immune system, or is primarily vascular in nature. Ockham's Razor continues to come to mind. These exact changes can also be found in diffuse cerebral hypoxia.
Here is a paper on cerebral hypoperfusion which reviews how much MS and an ischemic disease which causes white matter lesions, leukoaraiosis, have in common.
From a historical perspective it is worth mentioning that a number of scientists since the middle of the nineteenth century have already put forward the hypothesis that demyelinating lesions in MS may have an ischemic origin (Gottlieb et al, 1990;Murray, 2005; Putnam, 1933), but these ideas have not gained wide acceptance by the scientific community.
Subcortical ischemic brain damage leading to leukoaraiosis is associated with reduced CBF in white matter (Markus et al, 2000) and represents a common cause of cognitive impairment. The cognitive manifestations in leukoaraioisis are very similar to those observed in MS (Schmidt et al, 2006). In a preliminary study, Inglese et al (2008) found a relationship between perfusion changes in deep gray matter and NAWM and neuropsychological dysfunction in patients with both relapsing–remitting and primary progressive MS. Further studies are required to confirm this interesting finding and to investigate whether interventions that increase white matter perfusion in MS might have a beneficial effect on cognitive functions.
#3 The Concept of CCSVI--
Here, the researchers do an adequate job of presenting Zamboni's theory and cite the positive studies which have corroborated Dr. Zamboni and have been published in vascular journals, as well as the more numerous negative studies from the neurology journals. They explain CCSVI well, but also explain how this slowed blood flow could possibly be secondary to MS, via slowed perfusion. However, no mention is made of the congenital, truncular venous malformations that Dr. Zamboni and others have noted in the veins of pwMS. The chicken and the egg debate will continue.
In this Review, we have outlined three forms of vascular abnormalities that have been described in MS. Patients with MS seem to have an increased risk for ischaemic stroke. Endothelial dysfunction secondary to inflammatory responses or raised homocysteine concentrations might play a part, but reduced CBF might predispose patients to the development of these ischaemic brain lesions. The widespread cerebral hypoperfusion in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of ET-1. Impaired cerebral perfusion seems to be especially related to cognitive manifestations of the disease, which is a common symptom associated with substantial decline in activities of daily living. Investigation of whether interventions that improve cerebral perfusion improve cognitive function in patients with MS would be of interest. Statements that suggest that insufficient cerebral venous drainage might play a causative part in MS have shaken both the medical and patient community. Although there is no compelling evidence to suggest that CCSVI is a cause of MS, there are some suggestions of a slower cerebral venous flow in patients with MS, which might be secondary to the reduced CBF. There is at present no evidence for a cerebral venous outflow obstruction or stasis in MS, and endovascular procedures for jugular vein stenoses should be undertaken only in well controlled clinical trials.
To which we all reply, THEN LET US HAVE THE CLINICAL TRIALS! Why is neurology standing in the way of clinical trial approval if this is the only means to test CCSVI? We are sorry to have shaken your preconceived notion of immune and inflammatory-mediated disease, but we really don't care if this is upsetting to you. We want the clinical trials, we want pwMS tested and treated. Nothing less is acceptable.
And, as we've well learned, no neurological paper would be complete without the disclosures:
Ludo Vanopdenbosch has received travel support and lecture fees from Merck Serono, Bayer Schering, Biogen Idec, Novartis, and Teva; institutional grant support from Merck Serono; and fees for board membership from UCB, Merck Serono, Biogen Idec, Novartis, and Teva.
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