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Abstract

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.

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Letters to the Editor
19 January 2011
Reply from the authors
Axel Petzold, UCL Institute of Neurology
Viki Worthington ([email protected])

We thank Dr. Brenner for a testable hypothesis on how CCSVI- related breakdown of the blood brain barrier may result in development of autoimmunity against proteins of the central nervous system (CNS) and thus cause multiple sclerosis (MS).

Does CCSVI cause the development of autoantibodies against CNS proteins in humans? Khan et al. made the observation that development of MS was not reported as a complication after removal of jugular veins in head and neck cancer. [6] Considering the articles cited by Dr. Brenner [2,3], it is possible that there was no CNS damage in these patients and perhaps long-term survival is required to allow for the development of MS.

In our study, oligoclonal bands were present in 98% of the MS patients. [7] We did not search for CNS antigens because oligoclonal bands in MS are of low affinity [8] and difficult to analyze. There is evidence that development of autoimmunity to CNS proteins can be neuroprotective. [9] The sceptical reader may still have a valid point in asking if MS is an autoimmune disease.

Sena et al. address monitoring treatment response in MS. Our data are similar to that of Dr. Sena's group and shows the potential for estimating biological activity of interferons indirectly by measuring biomarkers for activated glia. [4,7,10]

In the accompanying editorial to our study, Drs. van Rensburg and van Toorn [11] outlined a more holistic approach to longitudinally investigating the iron metabolism in patients with MS. In this context, knowledge of the patient's treatment as pointed out by Dr Sena is essential.

In our cohort, only nine patients were on interferon (Avonex n=3, Betaferon n=4, Rebif 22 n=2). The post-hoc analysis showed no significant differences in CSF ferritin levels between those treated with interferon and naive patients either at baseline (p=0.18) or 3-year follow-up (p=0.41), but the study was underpowered for a meaningful analysis.

A future study investigating the effect of interferon therapy in MS may also need to consider the development of drug-related autoantibodies.

References

6. Khan O, Filippi M, Freedman MS et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol 2010;67: 286-290.

7. Petzold, A, Eikelenboom M, Gveric D et al. Markers for different glial cell responses in multiple sclerosis: Clinical and pathological correlations. Brain, 2002;125: 1462-1473.

8. Luxton RW, Zeman A, Holzel H et al. Affinity of antigen-specific IgG distinguishes multiple sclerosis from encephalitis. J Neurol Sci 1995;132:11-19.

9. Yoles E, Hauben E, Palgi O et al. Protective autoimmunity is a physiological response to CNS trauma. J Neurosci , 2001;21:3740-3708.

10. Petzold A, Brassat D, Mas P et al. Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis. Mult Scler 2004;10:281-283.

11. van Rensburg SJ. Van Toorn R. The controversy of CCSVI and iron in multiple sclerosis: Is ferritin the key? Neurology 2010;75:1581-1582.

Disclosures: See original article for full disclosure list.

19 January 2011
Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency
Armando Sena
Rui Pedrosa, Veronique Ferret-Sena

In their recent report, Worthington et al. [1] found increased CSF ferritin levels in some patients with MS. However, no information was provided by the authors regarding eventual medications prescribed at the time of ferritin analysis.

We recently reported that serum ferritin levels were significantly increased in relapsing-remitting MS patients at 12 months after initiating interferon beta therapy. [4] In this context, it is interesting that Worthington et al. found that an increase of CSF ferritin from baseline to 3-year follow-up was related to the degree of improvement on the ambulation index and the T1 lesion volume in secondary progressive patients.

These data could suggest a potential value of ferritin levels in monitoring individual responses to interferon beta therapy. Future studies are required to test this hypothesis and explore the role of iron metabolism in the disease. A recent study has shown that intra-macrophage free iron levels regulate inflammatory responses and the production of interferon beta and other cytokines. [5]

References

4. Sena A, Pedrosa R, Ferret-Sena V et al. Interferon beta therapy increases serum ferritin levels in patients with relapsing-remitting multiple sclerosis. Mult. Scler. 2008;14:857-859.

5. Wang L, Harrington L, Trebicka E, et al. Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J. Clin. Invest. 2009;119:3322-3328.

Disclosures: Dr. Sena serves as an advisory board member at Merck Serono and has received research grants from Merck Serono, Bayer Shering, Biogen idec and Sanofi-Aventis. Dr. Pedrosa has received compensation as an advisor board member of Novartis and research grants from Merck Serono, Bayer-Schering, Biogen idec and Sanofi-Aventis. Dr. Ferret-Sena reports no disclosures.

17 February 2011
Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency
Michael R. Haupts, Director, Augustahospital Anholt
Meyer-Schwickerath R, Hacker A, Haug C, Fink F, Seidel D, Hartung HP

We read the article by Worthington et al. with interest. [1] It has been postulated that stenoses in extracerebral veins may result in intracerebral congestion and thus cause multiple sclerosis (MS). Neither a recent approach to verify upregulation of intrathecal iron transport proteins nor studies with similar imaging techniques could verify this hypothesis. [1-3]

We assessed intracranial venous pressure in MS via intraocular venous occlusion pressure (VOP). Ophthalmodynamometry methodology has been previously described. [4] In 30 MS and acute disseminated encephalomyelitis (ADEM) patients (1 ADEM, 5 remitting-relapsing MS, 24 progressive forms, mean age 47.3 +/- 11.4 yrs, mean EDSS 6.0 +/- 1.2; duration of MS 15.1 +/-8.8 yrs.), VOP (15.1 +/- 2.1 cm Hg) was not different than 33 healthy controls (15.3 +/- 2.4 cm Hg, mean age 55.7 +/- 16.7 yrs).

VOP was pathologically raised (27.2 +/- 5.0 cm Hg) in only 13 patients with proven intracranial pressure (ICP) pathology (age 41.8+-24.4 yrs). VOP is based on intra- and extra-cerebral venous pressure through an anastomotic net with outflow through jugular and spinal veins, thus depending on the same anatomical substrate postulated for chronic cerebro-spinal venous insufficiency (CCSVI) mechanisms in MS.

Our data provide no evidence of an increase in intracranial venous pressure in MS patients so venous congestion is implausible. This may further substantiate the findings from Worthington et al. [1]

References

1. Worthington V, Killestein J, Eikelenboom MJ, et al. Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology 2010;75:1617-1622.

2. Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol 2010;68:173-183.

3. Antel J, Thompson A, Carroll W. Chronic cerebrospinal venous insufficiency. Mult Scler 2010;16:770.

4. Meyer-Schwickerath R, Kleinwaechter T, Firsching R, Papenfuss HP. Central retinal venous outflow pressure. Graefes Arch Clin Exp Ophthalmol 1995;233:783-788.

Disclosure: Dr. Haupts received travel funding and speaker honoraria from Bayer HealthCare, Biogen-Idec, Merck Serono GmbH, Teva Sanofi Aventis; received royalties for publications of book chapters by Elsevier and Thieme publishers. Prof. Hartung has served in scientific advisory boards for Merck Serono, and Biogen Idec; received travel funding and speaker honoraria from Biogen Idec (travel and speaker honoraria), Merck Serono GmbH (travel and speaker honoraria), Novartis Pharma GmbH (travel and speaker honoraria), Teva Sanofi Aventis (travel and speaker honoraria), Bayer HealthCare (travel and speaker honoraria), Octapharma (travel and speaker honoraria); compensated for consultancies from Merck Serono, Biogen Idec, Novartis Pharma GmbH; and served on the speakers' bureau for Giodepoint Global. Drs. Meyer-Schwickerath, Hacker, Haug, Fink and Seidel report no disclosures.

17 February 2011
Reply from the Authors
Axel Petzold, Free University Medical Center
F. Barkhof, C. Polman

We agree with Haupts et al. that a venous outflow problem should be consistently detectable in MS patients if CCSVI were a major etiological feature. Because the vasculature of the brain is hidden, there are methodological difficulties in indirectly assessing the intracerebral venous outflow. [2,5]

It is logical to examine the retina, as it is the only place where blood vessels of the brain can be seen. It has been shown that a venous outflow problem causes increase in the VOP of the central vein of the retina. [4] The new data by Haupts et al. show that the venous occlusion pressure (VOP) was essentially normal in patients with MS (15.1 +/- 2.1 cm Hg) and identical to a healthy control population (15.3 +/- 2.4 cm Hg).

In a patient with a suspected diagnosis of MS with an increased VOP, the VOP may be a quantitative alternative to the bedside examination in assessing spontaneous venous pulsation (SVP). [6-8] Typically, SVP is seen as a narrowing of the diameter of the central retinal vein during the systole. Presence of SVP suggests a normal venous outflow and can be observed in about 90% normal subjects. The central retinal vein leaves the optic nerve about 1 cm behind the globe, just after passing through the subarachnoid space. An increase in the intracranial pressure will cause cessation of the SVP.

Any other compression of the central retinal vein may cause a relevant venous outflow problem abolishing SVP [6-8] and increasing VOP. [4] We have not observed loss of SVP in MS patients except in those with acute optic neuritis. Patients with suspected MS and increased VOP --or absent SVP--should be examined for possible alternative diagnoses.

The data presented by Haupts et al. provide indirect evidence against a venous outflow problem in MS and are consistent with our observations using MRI venography [9] and clinical experience.

References

5. Khan O, Filippi M., Freedman MS et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol 2010:67;286-290.

6. Lascaratos G, Ahmed S, Madill SA. Pearls & Oy-sters: spontaneous venous pulsation and its role in differentiating papilledema from pseudopapilledema. Neurology 2010:75;e53-e54.

7. Levin BE. The clinical significance of spontaneous pulsations of the retinal vein. Arch Neurol 1978;35:37-40.

8. Jacks AS and Miller, NR. Spontaneous retinal venous pulsation: aetiology and significance. J Neurol Neurosurg Psychiatry 2003:74;7-9.

9. Wattjes MP, van Oosten BW, de Graaf WL et al. Association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study. J Neurol Neurosurg Psychiatry. 2010 Oct 27. [Epub ahead of print]

For disclosures, please see original article.

19 January 2011
Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency
Steven R Brenner, Neurolgist
None

I read the article by Worthington et al. with interest. The authors assessed the etiologic role of chronic venous insufficiency and multiple sclerosis (MS). [1]

Chronic cerebral venous insufficiency may result in an altered blood brain barrier and subsequent exposure of brain constituents ordinarily isolated from the vascular immune system, resulting in autoimmunization to the brain. This autoimmunization to the brain could then result in development of secondary autoimmunity to the brain and development of MS.

While the blood brain barrier will ordinarily prevent blood and vascular components from penetrating into the brain, a less recognized role of the blood brain barrier may be to isolate the brain from the immune system. If the blood brain barrier fails, then autoimmunization to the brain and development of MS may occur.

Experimental spinal cord injury from spinal cord contusion triggers systemic immunity and development of oligoclonal IgG activity against multiple CNS proteins [2] similar to the oligoclonal bands seen in MS. Sera from MS patients has polyclonal IgGs which interact with myelin basic protein. [3]

The oliglclonal IgG's in serum may result from CNS exposure to the vascular system, due to blood brain barrier breakdown from chronic venous insufficiency, causing auto-vaccination with CNS components and subsequent development of MS due to autoimmunity to the central nervous system.

References

1. Worthington V, Killerstein J, Eickelenboom MJ, et al. Normal CSF ferritin levels in MS suggest against etiologic role of chroic venous insufficiency. Neurology 2010;75:1617-1622.

2. Ankeny DP, Lucin KM, Sanders VM, CmGaughy VM, Popovich PG. Spinal cord Injury triggers sytesmic autoimmunity: evidence for chronic B lymphocyte activation and luupu-like autoantibody synthesis. J Neurochem 2006;99:1073-1087.

3. Polosukhina DI, Kanyshkova TB, Doronin BM, et al. Hydrolysis of myelin basic protein by polyclonal catalytic IgGs from the sera of patients with multiple sclerosis. J Cell Mol Med 2004;8:359-368.

No relevant conflict of interest.

Information & Authors

Information

Published In

Neurology®
Volume 75Number 18November 2, 2010
Pages: 1617-1622
PubMed: 20881272

Publication History

Received: April 9, 2010
Accepted: June 21, 2010
Published online: September 29, 2010
Published in print: November 2, 2010

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Disclosure

Dr. Worthington reports no disclosures. Dr. Killestein serves on scientific advisory boards for Novartis and Merck Serono; serves on the editorial board of Multiple Sclerosis International; serves as a consultant for Merck Serono; and has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme Corporation, and Novartis. Dr. Eikelenboom reports no disclosures. Dr. Teunissen serves on a scientific advisory board for and has received funding for travel from Innogenetics; has a patent pending re: Array for antibody biomarker detection in multiple sclerosis; and receives research support from the Institute of Clinical and Experimental Neurosciences, The Netherlands Organisation for Scientific Research (NWO), the European Union, the Dutch Foundation for MS Research, and Koninklijk Wilhelmina Fonds/Dutch Cancer Society. Dr. Barkhof serves on scientific advisory boards for Lundbeck Inc., Bayer Schering Pharma, Sanofi-Aventis, UCB, Novartis, Biogen Idec, BioMS Medical, and Merck Serono; serves on the editorial boards of Brain, the Journal of Neurology, Neurosurgery, and Psychiatry, European Radiology, the Journal of Neurology, and Neuroradiology; has received speaker honoraria from Novartis and Merck Serono; serves as a consultant for Sanofi-Aventis, UCB, Novartis, Biogen Idec, BioMS Medical, and Medicinova, Inc.; and receives research support from the Dutch MS Research Foundation. Dr. Polman serves on scientific advisory boards for Actelion Pharmaceuticals Ltd., Biogen Idec, Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., Merck Serono, GlaxoSmithKline, UCB, Roche, and Antisense Therapeutics Limited; serves on the editorial boards of Lancet Neurology and Multiple Sclerosis; has received speaker honoraria from Biogen Idec, Bayer Schering Pharma, Novartis, and Teva Pharmaceutical Industries Ltd.; and receives research support from Biogen Idec, Bayer Schering Pharma, GlaxoSmithKline, Novartis, UCB, Merck Serono, Teva Pharmaceutical Industries Ltd., the European Community (EEC), and the Dutch Multiple Sclerosis Society. Dr. Uitdehaag serves on a scientific advisory board for Merck Serono; served on the editorial board of Tijdschrift voor Neurologie en Neurochirurgie (Dutch journal); receives royalties from the publication of Evidence Based Neurology (Blackwell Publishers, 2007); has served as a consultant for Novartis; and has received research support from the Dutch MS Research Foundation. Dr. Petzold has served (2009) on one single scientific advisory board meeting for and has received funding for one single travel from Novartis; serves on the editorial board of Multiple Sclerosis International; receives royalties from the publication of “Die Anaemien” (Engl anaemias) (Shaker Verlag, 1999); served on the advisory board for the (EA)YNT-Schering fellowship for clinical training in multiple sclerosis (2000–2005); and has received research support from the Dutch MS Research Foundation.

Authors

Affiliations & Disclosures

V. Worthington, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
J. Killestein, MD, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
M.J. Eikelenboom, MD, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
C.E. Teunissen, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
F. Barkhof, MD, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
C.H. Polman, MD, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
B.M.J. Uitdehaag, MD, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.
A. Petzold, MD, PhD
From the Department of Neuroimmunology (V.W., A.P.), UCL Institute of Neurology, Queen Square, London, UK; and MS Center Amsterdam (J.K., M.J.E., C.E.T., F.B., C.H.P., B.M.J.U., A.P.), Free University Medical Center, Amsterdam, the Netherlands.

Notes

Address correspondence and reprint requests to Dr. Axel Petzold, Free University Medical Center, Department of Neurology, MS Center Amsterdam, Amsterdam, the Netherlands [email protected] or [email protected]
Study funding: Supported by the Dutch Foundation of Multiple Sclerosis Research (J.E.).

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