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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