Multiple sclerosis-- animal model, and a comment on ccsvi

Multiple Sclerosis- venous changes seen in an animal model, but probably not CCSVI





Nathoo N, Agrawal SM, Wu Y, Haylock-Jacobs S, Yong VW, Foniak T, Barnes S, Obenaus A, and Dunn JF. Susceptibility weighted imaging in the experimental autoimmune encephalomyelitis model of multiple sclerosis indicates elevated deoxyhemoglobin as well as iron deposition and demyelination. Multiple Sclerosis Journal 22: epub Oct 1, 2012.

http://msj.sagepub.com/content/early/2012/11/19/1352458512460602




Multiple sclerosis is mysterious. One can get MS and not progress, one can have periodic relapses or progress to a continuous disease. The plaques in the brain are linked to MS for sure, but the extent of plaque development isn’t strongly related to symptoms. There is one thing all agree about—there is a strong inflammatory component. The trigger that starts off the process is not known.

It’s not often in any research area that a theory is proposed which is so controversial, it polarizes the research and patient community. This happened with CCSVI, the theory proposed by Dr. Zamboni that blocked draining veins initiate the cascade of degeneration called MS.

The main hypothesis requires that the main veins draining the brain be mostly, or totally blocked. This can be checked. There are enough papers out like Baracchini's below to be able to say that many, if not most MS patients do not have blocked draining veins. The research in this area is active and a steady stream of results are forthcoming. Within a year, we should know if this is a cause or an association.

What such a controversy does do is focus attention on the problem. Regardless of the outcome, this will be good for the field of MS research in the long run.

Our recent paper is an example of this. We would not have done the study without there being a strong interest in what is happening to the vasculature of MS patients.

A new MRI method, termed susceptibility weighted imaging (SWI), is being used to study iron deposition. It has been used in studies associated with CCSVI. One aspect of the progression would be iron deposited in the brain. Iron is bad. We suggested that if animal models had an association with MS, then we should see similar SWI based lesions. If we saw them in animal models, we would be able to do careful histology on the lesions to find the cause.

Nabeela Nathoo, a PhD student in my lab, undertook this study. She did find SWI lesions in the cerebellum and spinal cord of the EAE mouse model of MS. What was surprising was that although some were caused by iron, most were caused by deoxyhemoglobin in the blood. It is possible that there is a chronic low oxygen condition (hypoxia) in the cord and cerebellum. These results have little or no impact on the CCSVI theory, as they are in small veins within the cord, not draining veins in the brain, and the model isn’t initiated by blocking veins. However they represent a new finding supporting some type of vascular association. Science is as much fact as interpretation, and my interpretation is that this vascular association is a symptom that we could use to track disease progression and treatment. It gives us a clue, suggesting metabolic changes in the tissue that change oxygen extraction. Perhaps there is reduced metabolic rate--this causes decreases in flow and increases in deoxyhemoglobin.

This study shows that we can use the EAE model to study the cause of the SWI based lesions. Understanding the cause of these lesions will provide new evidence supporting one of the theories of MS progression, and provide new data on how changes in the vasculature might relate to such progression. Nabeela’s thesis is ongoing. Tune in next year for the next installment.


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Paper cited above.
1.         Baracchini C, Perini P, Causin F, Calabrese M, Rinaldi F, and Gallo P. Progressive multiple sclerosis is not associated with chronic cerebrospinal venous insufficiency. Neurology 77: 844-850, 2011. OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) had been suggested to play a major pathogenetic role in multiple sclerosis (MS), but recent data on early stages of MS have not confirmed this theory. Nonetheless, CCSVI could represent a late phenomenon of MS or be associated with progression of disability. Thus, we studied CCSVI prevalence in primary progressive (PP) and secondary progressive (SP) MS, to clarify whether CCSVI characterizes the progressive forms of this disease. METHODS: A total of 35 patients with SPMS, 25 patients with PPMS, and 60 age- and gender-matched normal controls (NC) were enrolled into a cross-sectional study. Extracranial and transcranial high-resolution venous echo color Doppler sonography (ECDS-TCDS) was performed in all patients and NC. Those patients having any abnormal ultrasound finding were asked to undergo selective venography (VGF). RESULTS: Patients with PPMS (11 women, 14 men; mean age 47 +/- 11 years) had a disease duration of 11 +/- 7 years and Expanded Disability Status Scale (EDSS) score of 6.0 +/- 0.5. Patients with SPMS (22 women, 13 men; mean age 45 +/- 14.5 years) had a disease duration of 18 +/- 14 years and EDSS score of 6.0 +/- 0.8. TCDS was normal in all patients. ECDS showed one or more abnormal findings in 9/60 (15.0%) patients (7/35 [20.0%] SPMS, 2/25 [8.0%] PPMS) and in 14/60 (23.3%) NC (p not significant for all comparisons). CCSVI criteria were fulfilled in 0 NC and 4 (6.7%) patients with MS: 3 SPMS and 1 PPMS. VGF, performed in 6/9 patients, was abnormal only in one case who had bilateral internal jugular vein stenosis. CONCLUSION: Our findings indicate that CCSVI is not a late secondary phenomenon of MS and is not associated with disability.

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