Venöse Multiple Sklerose Hypothese | CCSVI

Multiple sclerosis (MS) is believed to be an immune-mediated neurodegenerative disorder of the human central nervous system which usually affects younger adults with certain genetic backgrounds. The causes and cure for MS remain elusive. Based on the recent advances in our understanding of the pathogenic mechanisms of MS, it appears to represents a heterogeneous group of disorders with dissimilar pathophysiology and neuropathology. Currently, there is no unifying hypothesis to explain the pathogenesis of this complex disease. The three prevailing concepts on the pathogenesis of MS include viral, immunological, and vascular hypotheses. This review presents MS as a neuroinflammatory disease with a significant vascular component and examines the existing evidence for the role of cerebral endothelial cell dysfunction in the pathogenesis of this progressive central nervous system (CNS) inflammatory disorder.

Aim: To visualize and validate iron deposition in two cases of multiple sclerosis using rapid scanning X-Ray Fluorescence (RS-XRF) and Susceptibility Weighted Imaging (SWI). Material and Methods: Two (2) coronal cadaver brain slices from patients clinically diagnosed with multiple sclerosis underwent magnetic resonance imaging (MRI), specifically SWI to image iron content. To confirm the presence of iron deposits and the absence of zinc-rich myelin in lesions, iron and zinc were mapped using RS-XRF. Results: MS lesions were visualized using FLAIR and correlated with the absence of zinc by XRF. XRF and SWI showed that in the first MS case, there were large iron deposits proximal to the draining vein of the caudate nucleus as well as iron deposits associated with blood vessels throughout the globus pallidus. Less iron was seen in association with lesions than in the basal ganglia. The presence of larger amounts of iron correlated reasonably well between RS-XRF and SWI. In the second case, the basal ganglia appeared normal and acute perivascular iron deposition was absent. Conclusion: Perivascular iron deposition is seen in some but not all MS cases, giving credence to the use of SWI to assess iron involvement in MS pathology in vivo.

MS-Patienten haben offenbar einen abnormen venösen Blutfluss im Gehirn. Darauf deuten moderne bildgebende Verfahren. Ob die Störungen Auswirkungen der MS sind oder den MS-Verlauf beeinflussen, ist noch unklar.

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OBJECTIVES: Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of multiple sclerosis (MS). If the presumed mechanism of venous stasis-related parenchymal iron deposition and neurodegeneration were true, then upregulation of intrathecal iron transport proteins may be expected. METHODS: This was a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurologic disorders. RESULTS: Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. CONCLUSION: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.

The prevailing view on multiple sclerosis etiopathogenesis has been challenged by the suggested new entity chronic cerebrospinal venous insufficiency. To test this hypothesis, we studied 21 relapsing-remitting multiple sclerosis cases and 20 healthy controls with phase-contrast magnetic resonance imaging. In addition, in multiple sclerosis cases we performed contrast-enhanced magnetic resonance angiography. We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis.

It is regretful that Drs. Doepp and co-authors’ attempt to reproduce Professor Zamboni’s discovery of a link between multiple sclerosis and disturbance of the outflow veins of the brain and spine has been unsuccessful. It is particularly unfortunate that the authors’ misunderstanding of Dr. Zamboni’s publications about this subject have led to their conclusions that “No cerebrocervical venous congestion in patients with multiple sclerosis" exists

The authors mis-state several of the criteria for a positive ultrasound examination. They state that reflux must be present in both internal jugular veins or both vertebral veins. This is not accurate. Reflux in any one of these veins was considered a positive criteria by Zamboni.

It appears to me that Dr Doepp and colleagues have tried to elicit reflux by testing for incompetent valves in the lower jugular vein. Incompetent valves result in reversal of blood flow from the heart back up into the jugular veins. They used the Valsalva maneurer, a technique to increase pressure in the chest that reverses blood flow. However, Zamboni explicitly states that one should assess flow “never in (by) a forced condition such as the Valsalva manoeuvre.”

That the authors’ attempts were unsuccessful is not surprising. The ultrasound examination used by Zamboni is a simple one but the description of the technique has not been fully elaborated in his papers. Thus performance of the ultrasound by some investigators is often at variance and this may lead to differences of results. At my own institution, we were surprised that non-invasive testing by ultrasound did not correlate with the very obvious obstructive phenomena seen on catheter venography, which remains the Gold Standard of assessing veins. We also had difficulty identifying CCSVI on ultrasound, initially using the Valsalva maneuver during out testing. In fact we were able to find an obstruction in only one patient of twenty. It was only after being shown how to correctly perform this simple screening test by the Zamboni team during a visit to Ferrara, that we have become facile in detecting these abnormalities. It is clear that there is a learning curve to the use of this technique.

Nor does this paper refute the concept of CCSVI. Doppler ultrasound is only a screening test for CCSVI. When Doppler shows signs of CCSVI, the gold standard test of catheter venography is indicated to detect the sites of potential obstruction. Doppler is not the definitive test of CCSVI because it cannot assess the azygous vein, an important contributor to cerebrspinal venous outflow resistance. Catheter venographies routinely show evidence of outflow obstructions. Sluggish flow, reversal of flow, extensive collateral veins, strictures, duplications, reversed valves, thickened incompletely opening valves and misplaced valves are among the many abnormalities seen in MS patients that we never see in patients without MS.

The paper by Sundstrom and coauthors similarly rejected the CCSVI hypothesis by performing MR venograms and flow quantification in the neck. MR venography is suboptimal as a screening test because it underestimates and overestimates stenoses quite regularly. One can see from their illustrations two MRV images. It is noteworthy that neither image shows the portion of the jugular vein where lesions causing flow resistance are usually found: behind the clavicle as the vessel enters the chest. Both images show considerable collateral vasculature suggestive of CCSVI. Moreover the image on the right on page 258 purports to show a stenosis with an arrow. It is well known that most of the narrowings referred to by the white arrow are a common transient, non-stenotic narrowing caused by a true narrowing below the clavicle. Catheter venography shows abnormalities that cannot be detected by MRV.

I was struck by the rapidity of publication of both articles. Surprising! Both papers were accepted within six weeks. I have never had such rapid decision, editing and publication of any of my more than 120 publications.

This debate is going to be a challenging one. One side wants randomized prospective trials to prove efficacy. However while many proceduralists have noted sometimes impressive gains for patients, these proceduralists need to evaluate nuances of techniques before consensus can be built regarding the best approach to therapy. Only then can intelligent, carefully designed randomized prospective trials begin. Some who commonly perform randomized trials will try to reduce the work of those who will try to develop the best practices because they are not randomized. However, in my view this is a necessary initial step toward the final trials.

Source: This Is MS, 11 Aug 2010

MS-Patienten haben einen abnormen venösen Blutfluss im Gehirn - darauf weisen Studien mit modernen bildgebenden Verfahren bei MS-Patienten. Deutsche Forscher zweifeln jedoch an den Ergebnissen. Unklar ist auch, ob die vermuteten venösen Störungen Folge oder Ursache einer MS sind.