Risk factors for CCSVI are similar to risk factors for developing MS, UB study shows
The first study to investigate risk factors for the vascular condition called CCSVI (chronic cerebrospinal venous insufficiency) in volunteers without neurological disease has identified what the researchers call a remarkable similarity between this condition and possible or confirmed risk factors for multiple sclerosis (MS).
The University at Buffalo study investigated associations between CCSVI and demographic, clinical and environmental risk factors in a large control group of volunteers who did not have known central nervous system disease.
“Our results suggest that risk factors for CCSVI in this group of volunteers are remarkably similar to those of possible or confirmed importance to MS, but we do not yet understand the whole story,” says Robert Zivadinov, MD, PhD, FAAN, professor of neurology at the UB School of Medicine and Biomedical Sciences, and senior author on the study.
Published today (Nov. 30) in PLoS One, the current study of 252 volunteers “was designed to help provide scientists and the MS patient community with new information that, combined with the results of studies that are still ongoing at UB, will ultimately help explain CCSVI and its relationship to MS,” according to Kresimir Dolic, a lead author on the study. Dolic, a radiologist from the Department of Radiology, University Hospital, Split, Croatia, was a visiting fellow at the Buffalo Neuroimaging Analysis Center, part of UB’s Department of Neurology, where the study was conducted.
CCSVI refers to impaired blood flow from the central nervous system to the periphery. It has been hypothesized that this narrowing of veins restricts blood flow from the brain, altering brain drainage, and may contribute to brain tissue injury that is associated with MS.
Yet, while CCSVI has generated intense interest among MS patients worldwide, and while independent scientific studies, including one of the largest to date being conducted by Zivadinov and UB colleagues, have suggested an association with MS, none have found conclusively that the condition is associated with MS.
What is Chronic cerebrospinal venous insufficiency (CCSVI)?
Chronic cerebrospinal venous insufficiency is described as a chronic problem (ongoing) where blood from the brain and spine has trouble getting back to the heart.
It is caused by a narrowing in the veins (stenosis) that drain the brain and the spine. Blood takes longer to return to the heart, and it can reflux back into the brain and spine or cause oedema and leakage of red blood cells and fluids into the tissues of the brain and spine.
Blood that remains in the brain too long creates a delay in deoxyginated blood leaving the head (“slowed perfusion”). This can cause hypoxia, a lack of oxygen in the brain. Plasma and iron from blood deposited in the brain tissue can also be very damaging leading to iron along with other unwelcome cells crossing the crucial brain-blood barrier.
For this reason, the UB team decided that it was critical to proceed with this prospective study to determine the risk factors for CCSVI in individuals without neurological disease.
Chronic Cerebrospinal Venous Insufficiency - A new paradigm and therapy for multiple sclerosis
Chronic cerebrospinal venous insufficiency (CCSVI) is a hemodynamic condition in which cerebrospinal venous drainage is altered and inhibited. Outflow obstructions of the internal jugular veins (IJVs), vertebral veins, and/or azygos vein (AZV) and their tributaries result in stasis or reflux of these outflow veins and redirection of flow through vicarious circuits. Cerebral blood flow and brain perfusion are retarded and may result in cerebral atrophy, venous microhemorrhage, and cerebral hypertension. Moreover, stasis may evolve into occlusions of these veins or the dural sinuses.
The previously reported acute outflow obstructions of the dural sinuses and jugular veins have been due to hypercoagulable states, inflammation, iatrogenic trauma during prolonged catheterization, and compression by neck neoplasms and adenopathy. These occlusions and stenoses cause acute manifestations of cerebral venous outflow obstruction. Mental confusion, severe headaches, weakness and lethargy, acute visual disturbances, and facial and glottic edema are clinically obvious and quite severe. Treatment of the obstructions, by angioplasty, angioplasty and stenting, or thrombolysis and stenting, results in prompt and satisfactory amelioration of these symptoms. It has also been shown that acute jugular incompetence can result in transient global amnesia. The fact that venous insufficiency can cause acute neurological disturbances was convincingly demonstrated in a case report about a patient with a patent arm dialysis arteriovenous shunt who developed increasing headaches, gait disturbance, and cognitive dysfunction that significantly improved after ligation of that shunt.
The majority of patients with CCSVI appear to have multiple sclerosis (MS), and the majority of patients with MS have CCSVI. MS is an inflammatory demyelinating disorder of the brain and spine with protean neurological manifestations. It is the most common neurological disorder of young adults. It is quite possible that some of the protean manifestations of MS, including fatigue and lethargy, headaches, and cognitive dysfunction, may actually represent symptoms of CCSVI itself.
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By Salvatore J.A. Sclafani, MD
Commentary by Michael D. Dake, MD,
and Barry T. Katzen, MD
The study found that CCSVI risk factors occurred more frequently in 1) those with a history of mononucleosis, i.e. infected with Epstein-Barr virus; 2) those with irritable bowel syndrome; 3) those who smoke or have a history of smoking.
“All three are confirmed risk factors for MS,” said Bianca Weinstock-Guttman, MD, second author on the study and professor of neurology at UB. According to the results, individuals with CCSVI were 2.7 times more likely than individuals without CCSVI to have infectious mononucleosis, 3.9 times more likely to have irritable bowel syndrome and 1.98 times more likely to have a history of smoking.
“Our finding that a risk factor that is highly significant for MS – Epstein-Barr virus, indicated by a history of infectious mononucleosis – is strongly associated with CCSVI, is important,” says Zivadinov.
“This is the first time a connection has been found between Epstein-Barr virus and CCSVI.
“We know that Epstein-Barr virus is associated with an increased risk for MS,” he explains. “We also know that having mononucleosis when you are young increases the MS risk several-fold. So our finding that Epstein-Barr virus is also correlated with CCSVI is a novel finding that must be explored in future studies.”
In addition, individuals with heart disease - which is not a known MS risk factor - were 2.7 times more likely to have CCSVI, and those with heart murmurs, in particular, were 4.9 times more likely to have CCSVI. Zivadinov added that the study’s finding of a weak, protective effect from the use of dietary supplements was also noted and has to be further explored.
The UB team cautions that the study was preliminary and that these findings must be expanded upon and confirmed in further studies. The volunteer subjects were all part of the prospective Combined Transcranial and Extracranial Venous Doppler Evaluation study at UB. They were either independent individuals, or spouses or relatives of MS patients.
The controls were purposely selected from different sources of recruitment, Zivadinov explains.
“Spouses had no genetic similarity but may have shared environmental risk factors with MS patients, while relatives of MS patients had shared both genetic and environmental background,” he says. “However, no differences in risk factors or frequency of CCSVI were found according to the various sources of recruitment.”
All volunteers were screened for medical histories and underwent physical exams and Doppler sonography examinations of the neck; they also responded to an extensive environmental questionnaire. Individuals were considered to have CCSVI if they had at least two positive venous hemodynamic criteria on Doppler sonography.
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Additional co-authors on the paper are Karen Marr, Vesela Valnarov, Ellen Carl, Jesper Hagemeier, Christina Brooks and Colleen Kilanowski all of UB’s Buffalo Neuroimaging Analysis Center; Bianca Weinstock-Guttman, MD, UB professor of neurology; David Hojnacki of the Jacobs Neurological Institute of UB and Kaleida Health and Murali Ramanathan, PhD, professor of pharmaceutical science at the UB School of Pharmacy and Pharmaceutical Sciences.
The research was funded by the Buffalo Neuroimaging Analysis Center, Baird MS Center and the Jacobs Neurological Institute, all of UB, as well as the Direct MS Foundation and the Jacquemin Family Foundation.
The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. UB’s more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.
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Summary:
A vascular condition called chronic cerebrospinal venous insufficiency (CCSVI), which has attracted global attention as possibly being correlated with MS has, for the first time, been studied for the presence of risk factors in subjects who do not have a neurological disease.
A preliminary University at Buffalo study of 252 volunteers has found an association between CCSVI and as many as three characteristics widely viewed as possible or confirmed MS risk factors. They are: infectious mononucleosis, irritable bowel syndrome and smoking.
The UB researchers conclude that the association of CCSVI risk factors with MS risk factors in subjects without known central nervous system disease is significant and warrants further study.
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Ellen Goldbaum
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University at Buffalo