„Chronische zerebrospinale venöse Insuffizienz” bei Multipler Sklerose – Ist die Multiple Sklerose eine Erkrankung des zerebrospinalen venösen Abflusssystems?

Zusammenfassung

Das pathogenetische Konzept der Multiplen Sklerose (MS) beruht auf einer multifaktorellen autoimmunen Entzündungsreaktion. Seit Kurzem wird vor allem durch die Arbeitsgruppe um Paolo Zamboni postuliert, dass eine chronische Behinderung des venösen Blutflusses aus dem zentralen Nervensystem (ZNS) die wesentliche Ursache der MS sei. Dies hat den Begriff der „chronischen zerebrospinalen venösen Insuffizienz” (chronic cerebrospinal venous insufficiency, CCSVI) bei MS geprägt. Das Konzept der „CCSVI” basiert auf duplexsonografischen Untersuchungen, die zeigten, dass eine Behinderung des venösen Blutflusses mit pathologischem Reflux nahezu ausschließlich bei MS-Patienten und nicht bei gesunden Personen vorhanden ist. Das diesen Befunden zugrunde liegende pathophysiologische Konzept beinhaltet, dass eine chronische Behinderung des Abflusses mit konsekutiver Druckerhöhung im venösen System sekundär zu einer pathologischen Eisenablagerung im ZNS führt, welches in der Folge eine chronische Entzündungsreaktion sowie neurodegenerative Prozesse induziert bzw. unterhält. Diese Theorie des „CCSVI” bei MS hat sehr schnell eine große Aufmerksamkeit der Medien sowie Patienten aber auch in neurowissenschaftlichen Kreisen auf sich gezogen. Insbesondere mögliche therapeutische Konsequenzen mit einem transvenösen interventionellen Behandlungsansatz werden gegenwärtig diskutiert. Ergebnisse neuerer Studien, welche auch andere bildgebende Methoden berücksichtigen, stellen jedoch das „CCSVI-Konzept” substanziell infrage. In dieser Übersichtsarbeit wird das Konzept der „CCSVI” bei der MS methodenkritisch analysiert und im Kontext der MS-Pathophysiologie sowie der aktuellen Literatur diskutiert. Zusammenfassend ergibt sich derzeit auf der Grundlage der aktuell verfügbaren Daten keine Indikation zu einer interventionellen Behandlung vermeintlicher venöser Anomalien.

Abstract

Chronic impaired venous outflow from the central nervous system has recently been claimed to be associated with multiple sclerosis (MS) pathology. This resulted in the term chronic cerebrospinal venous insufficiency (CCSVI) in MS. The concept of CCSVI is based on sonography studies showing that impaired venous outflow leading to pathological reflux is almost exclusively present in MS patients but not in healthy controls. Based on these findings, a new pathophysiological concept has been introduced suggesting that chronic venous outflow obstruction and venous reflux in the CNS result in pathological iron depositions leading to inflammation and neurodegeneration. The theory of CCSVI in MS has rapidly generated tremendous interest in the media and among patients and the scientific community. In particular, the potential shift in treatment concepts possibly leading to an interventional treatment approach including balloon angioplasty and venous stent placement is currently being debated. However, results from recent studies involving several imaging modalities have raised substantial concerns regarding the CCSVI concept in MS. In this review article, we explain the concept of CCSVI in MS and discuss this hypothesis in the context of MS pathophysiology and imaging studies which have tried to reproduce or refute this theory. In addition, we draw some major conclusions focusing in particular on the crucial question as to whether interventional treatment options are expedient. In conclusion, the present conclusive data confuting the theory of CCSVI in MS should lead to reluctance with respect to the interventional treatment of possible venous anomalies in MS patients.

Key words

brain - CNS - head/neck - ultrasound color Doppler - MR imaging - inflammation

Literatur

• 1 Frohman E M, Racke M K, Raine C S. Multiple sclerosis – the plaque and its pathogenesis.  NEJM. 2006;  354 942-955
• 2 McFarland H F, Martin R. Multiple sclerosis: a complicated picture of autoimmunity.  Nat Immunol. 2007;  9 913-919
• 3 Holst B, Schippling S, Fiehler J. Diagnosis and heterogeneity of MS in MRI.  Fortschr Röntgenstr. 2008;  180 112-119
• 4 Wattjes M P, Barkhof F. High field MRI in the diagnosis of multiple sclerosis: high field – high yield?.  Neuroradiology. 2009;  51 279-292
• 5 Montalban X, Tintoré M, Swanton J et al. MRI criteria for MS in patients with clinically isolated syndromes.  Neurology. 2010;  74 427-434
• 6 Weir B S. Multiple sclerosis – a vascular etiology.  Can J Neurol Sci. 2010;  37 745-757
• 7 Putnam T J. Lesion of of „encephalomyelitis” and multiple sclerosis.  JAMA. 1937;  108 1477-1480
• 8 Zamboni P, Menegatti E, Bartolomei I et al. Intracranial venous hemodynamics in multiple sclerosis.  Curr Neurovasc Res. 2007;  4 252-258
• 9 Zamboni P, Galeotti R, Menegatti E et al. Chronic cerebrospinal venous insuffiency in patients with multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2009;  80 392-399
• 10 Rudick R A. Multiple sclerosis: Is multiple sclerosis caused by venous insufficiency?.  Nat Rev Neurol. 2010;  6 472-474
• 11 Khan O, Filippi M, Freedman M S et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis.  Ann Neurol. 2010;  67 286-290
• 12 Zamboni P, Menegatti E, Galeotti R et al. The value of cerebral Doppler venous hemodynamics in the assessment of multiple sclerosis.  J Neurol Sci. 2009;  282 21-27
• 13 Andeweg J. The anatomy of collateral venous flow from the brain and its value in etiological interpretation of intracranial pathology.  Neuroradiology. 1996;  38 621-628
• 14 Clemens H J. Die Venensysteme der menschlichen Wirbelsäule. Morphologie und funktionelle Bedeutung. Berlin: Walter de Gruyter & Co; 1961
• 15 Valdueza J M, Münster von T, Hoffmann O et al. Postural dependency of the cerebral venous outflow.  Lancet. 2000;  355 200-201
• 16 Schreiber S, Lürtzing F, Götze R et al. Extrajugular pathways of human cerebral venous blood drainage – assessed by duplex ultrasound.  J Appl Physiol. 2003;  94 1802-1805
• 17 Nedelmann M, Eicke B M, Dieterich M. Functional and morphological criteria of internal jugular valve insufficiency as assessed by ultrasound.  J Neuroimaging. 2005;  15 70-75
• 18 Stolz E, Kaps M, Kern A et al. Transcranial color-coded duplex sonography of intracranial veins and sinuses in adults. Reference data from 130 volunteers.  Stroke. 1999;  30 1070-1075
• 19 Lichtenstein D, Saifi R, Augarde R et al. The internal jugular veins are asymmetric. Usefulness of ultrasound before catheterization.  Intensive care Med. 2001;  27 301-305
• 20 Doepp F, Schreiber S J, Münster von T et al. How does the blood leave the brain? A systematic ultrasound analysis of the cerebral venous drainage patterns.  Neuroradiology. 2004;  46 565-570
• 21 Hoffmann O, Weih M, Münster von T et al. Blood flow velocities in the vertebral veins of healthy subjects: A duplex sonography study.  J Neuroimaging. 1999;  9 198-200
• 22 Zamboni P, Lanzara S, Mascoli F et al. Inflammation in venous disease.  Int Angiol. 2008;  27 361-369
• 23 Singh A V, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis.  J Cereb Blood Flow Metab. 2009;  29 1867-1878
• 24 Zivadinov R, Schirda C, Dwyer M G et al. Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study.  Int Angiol. 2010;  29 158-175
• 25 Zivadinov R, Heininen-Brown M, Schirda C et al. Multiple Sclerosis patients with chronic cerebrospinal venous insufficiency present with increased iron concentration on susceptibility-weighted imaging in deep grey matter.  Mult Scler. 2010;  16 S268 (P774)
• 26 Querfurth H W, Arms S W, Lichy C M et al. Prediction of intracranial pressure from noninvasive transocular venous and arterial hemodynamic measurements a pilot study.  Neurocrit Care. 2004;  1 183-194
• 27 Meyer-Schwickerrath R, Haug C, Hacker A et al. Intracranial venous pressure is normal in patients with multiple sclerosis.  Mult Scler. 2011;  [Epub ahead of print]
• 28 Es A CGM, der Grond von J, Crain A JM et al. Caudate nucleus hypointensity in the elderly is associated with markers of neurodegeneration on MRI.  Neurobiol Ageing. 2008;  29 1839-1846
• 29 Hammond K E, Metcalf de M, Okuda D T et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 T with sensitivity to iron.  Ann Neurol. 2008;  64 707-713
• 30 Worthington V, Killestein J, Eikelenboom J et al. Normal CSF ferritin levels in MS patients suggest against etiologic role of chronic venous insufficiency.  Neurology. 2010;  75 1617-1622
• 31 Ghezzi A, Comi G, Frederico A. Chronic cerebro-spinal venous insufficiency (CCSVI) and multiple sclerosis.  Neurol Sci. 2011;  32 17-21
• 32 Hojnacki D, Zamboni P, Lopez-Sorinano et al. Use of magnetic resonance venography, Doppler sonography, and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis and healthy controls.  Int Angiol. 2010;  29 127-139
• 33 Krogias C, Schröder A, Wiendl H et al. „Chronische cerebrospinale venöse Insuffizienz” und Multiple Sclerose. Kritische Analyse und erste Untersuchungen an einem unselektierten MS-Kollektiv.  Nervenarzt. 2010;  81 740-746
• 34 Doepp F, Paul F, Valdueza J M et al. No cerebro-cervical venous congestion in patients with multiple sclerosis.  Ann Neurol. 2010;  68 173-183
• 35 Mayer C A, Pfeilschifter W, Lorenz M W et al. The perfect crime? CCSVI not leaving a trace in MS.  J Neurol Neurosurg Psychiatry. 2011;  82 436-440
• 36 Baracchini C, Perini P, Calabrese M et al. No evidence of chronic cerebrospinal venous insufficiency in multiple sclerosis onset.  Ann Neurol. 2011;  69 90-99
• 37 Pelc N J. Flow quantification and analysis methods.  Magn Reson Clin N Am. 1995;  3 413-424
• 38 Grinstead J W, Sinha S, Tateshima S et al. Visualization and quantification of flow and velocity fields in intracranial arteriovenous malformations using phase-contrast MR angiography.  AJR. 2006;  186 553-555
• 39 Oktar S O, Yücel C, Karaosmanoglu D et al. Blood-flow volume quantification in internal carotid and vertebral arteries: comparison of 3 different ultrasound techniques with phase contrast MR imaging.  AJNR Am J Neuroradiol. 2006;  27 363-369
• 40 Sundström P, Wåhlin A, Ambarki K et al. Venous and cerebrospinal fluid flow in multiple sclerosis: a case control study.  Ann Neurol. 2010;  68 255-259
• 41 Wattjes M P, Oosten B W, Graaf de W L et al. No association of abnormal cranial venous system drainage with multiple sclerosis: A MR venography and flow-quantification study.  J Neurol Neurosurg Psychiatry. 2011;  82 429-435
• 42 Zivadinov van R, Lopez-Soriano A, Weinstock-Guttmann B et al. Use of magnetic resonance venography for characterization of the extra-cranial venous system in patients with multiple sclerosis and healthy controls subjects.  Radiology. 2011;  258 562-570
• 43 Alikhani K, Kremenschutzky M C. Magnetic resonance findings of the cervical veins in patients followed at the MS clinic in London, Ontario.  Mult Scler. 2010;  16 S270 (P778)
• 44 Yamout B, Herlopian A, Issa Z et al. Extracranial venous stenosis is an unlikely cause of multiple sclerosis.  Mult Scler. 2010;  16 1341-1348
• 45 Zamboni P, Galeotti R, Menegatti E et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency.  J Vasc Surg. 2009;  50 1348-1358
• 46 Zamboni P, Galeotti R, Weinstock-Guttmann B et al. Endovascular treatment for chronic cerebrospinal venous insufficiency in multiple sclerosis. A pilot study.  Mult Scler. 2010;  16 S171 (P508)
• 47 Ludyga T, Kazibudzki M, Simka M et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe?.  Phlebology. 2010;  25 286-95
• 48 Samson K. Experimental multiple sclerosis vascular shunting procedure halted at Stanford.  Ann Neurol. 2010;  1 A13-A15
• 49 The Liberation Treatment: A whole new approach to MS, CTV W 5 [online]. http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091120/W5_liberation_091121/0091121
• 50 Reekers J A, Lee M J, Belli A M et al. Cardiovascular and interventional radiological society of Europe commentary on the treatment of chronic cerebrospinal insufficiency.  Cardiovasc Intervent Radiol. 2011;  34 1-2
• 51 Chiu J J, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives.  Physiol Rev. 2011;  91 327-387
• 52 Chronic cerebrospinal venous insufficiency (CCSVI). The National Multiple Sclerosis Society [online]. http://www.nationalmssociety.org/research/intriguing-leads-on-the-horizon/ccsvi. index.aspx