Aktuelle Neurologie 2013; 40(08): 445-451
DOI: 10.1055/s-0033-1351271
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Übersicht und Analyse internationaler Fall-Kontroll-Studien zu „Chronischen zerebrospinalen venösen Insuffizienz“ (CCSVI) und Multipler Sklerose

Review and Analysis of International Case-Control Studies on CCSVI and Multiple Sclerosis
C. Krogias
1   Neurologische Klinik, St. Josef-Hospital Bochum, ­Ruhr-Universität Bochum
,
G. Tsivgoulis
2   Klinik für Neurologie, „Attikon“ Hospital, Universität Athen, Griechenland
,
M. Grond
3   Klinik für Neurologie, Kreisklinikum Siegen
,
H. P. Hartung
4   Neurologische Klinik, Heinrich-Heine Universität ­Düsseldorf
,
B. Hemmer
5   Neurologische Klinik, Klinikum rechts der Isar, ­Technische Universität ­München
,
W. Oertel
6   Klinik für Neurologie, Philipps-Universität Marburg
,
H. Wiendl
7   Klinik für Neurologie, Universitätsklinikum Münster
,
R. Gold
1   Neurologische Klinik, St. Josef-Hospital Bochum, ­Ruhr-Universität Bochum
› Author Affiliations
Further Information

Publication History

Publication Date:
12 September 2013 (online)

Zusammenfassung

Hintergrund:

Die neurosonologische Befundkonstellation „Chronischen zerebrospinalen venösen Insuffizienz“ (CCSVI) wurde initial als hochspezifischer und hochsensitiver Befund bei Patienten mit Multipler Sklerose (MS) beschrieben. Es wurde postuliert, dass ein Rückstau in zerebralen Venen ursächlich für die pathophysiologischen Prozesse bei der MS sei. Inzwischen sind mehrere Fall-Kontroll-Studien zur Prävalenz einer CCSVI bei MS-Patienten mit sehr widersprüchlichen Ergebnissen publiziert worden.

Methoden:

Neben einer Übersicht über die Datenlage zur „venösen Hypothese“ erfolgt eine Meta-Analyse der Ergebnisse aus den bisher publizierten internationalen Fall-Kontroll-Studien.

Ergebnisse:

In 25 Studien wurden 2 012 MS-Patienten und 1 425 gesunde Kontrollen untersucht. Die Konstellation einer „CCSVI“ nach neurosonologischen Kriterien wurde bei 876 (41,7%) der Patienten und 147 (10,3%) der Gesunden beschrieben (OR=3,2; 95% CI=2,5–4,0). Bei der Bewertung dieser Meta-Analyse ist jedoch die hohe Heterogenität (I2=82%) zu berücksichtigen. Die Analyse dreier deutscher Studien ergab eine sehr geringe CCSVI-Prävalenz von ca. 2% in beiden Gruppen (OR=0,5; 95% CI=0,1–3,1) und ist durch keinerlei Heterogenität (I2=0%) in Ihrer Aussage eingeschränkt.

Schlussfolgerungen:

Im Vergleich zur Erstbeschreibung konnte keine der folgenden interna­tionalen Fall-Kontrollstudien die hohe Spezifität bzw. Sensitivität einer CCSVI bei MS reproduzieren. Bei einer allgemeinen Meta-Analyse der teils widersprüchlichen Daten ist die hohe Heterogenität zu berücksichtigen, sodass genauere Meta-Analysen mit erweiterten Sensitivitätsanalysen notwendig sind. Die in Deutschland durchgeführten Studien haben keine Hinweise für eine „venöse Genese“ der MS ergeben. Die Ergebnisse unterstützen nachhaltig die Empfehlung, dass ­interventionelle Verfahren zur Erweiterung der venösen Halsgefäße nicht mehr außerhalb von klinischen Studien durchgeführt werden sollten.

Abstract

Background:

A constellation of neurosonological findings called “chronic cerebrospinal venous insufficiency” (CCSVI) was introduced as a highly specific and highly sensitive finding in multiple sclerosis (MS) patients. It was postulated that impaired venous cerebral drainage initiates the pathological processes of MS. Several published case-control of studies evaluating the association of CCSVI with MS report inconsistent findings.

Methods:

Besides an overview of the postulated concept of “venous hypothesis”, we performed a meta-analysis of the results from publ­ished case-control studies evaluating the association of CCSVI with MS using ultrasound criteria.

Results:

In 25 eligible studies, 2 012 MS pa­tients and 1 425 healthy controls were investigated. The constellation of CCSVI was described in 876 (41.7%) of the patients and in 147 (10.3%) of the controls (OR=3.2; 95% CI=2.5–4.0). However, considerable heterogeneity (I2=82%) across these studies was documented. The analysis of the 3 German studies revealed a very low prevalence of CCSVI of only about 2% in both groups (OR=0.5; 95% CI=0.1–3.1) without ­heterogeneity (I2=0%).

Conclusions:

Compared to the first description, no subsequent international case-control study could reproduce the high specificity and sensitivity of CCSVI in MS. There is high heterogeneity across the different studies, so that further comprehensive meta-analyses with additional sensitivity analyses are required. The studies conducted in Germany have clearly and consistently shown no evidence for the “venous multiple sclerosis hypothesis”. Interventional procedures should therefore not be performed outside the setting of randomised clinical trials.

 
  • Literatur

  • 1 Gold R, Rieckmann P. Pathogenese und Therapie der Multiplen Sklerose. 4. Auflage . Bremen: UNI-MED Verlag; 2012
  • 2 Zamboni P, Galeotti R, Menegatti E et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009; 80: 392-399
  • 3 Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab 2009; 29: 1867-1878
  • 4 Zamboni P. The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 2006; 99: 589-593
  • 5 Ackermann Z, Seidenbaum M, Loewenthal E et al. Overload of iron in the skin of patients with varicose ulcers. Possible contributing role of iron accumulation in progression of the disease. Arch Dermatol 1988; 124: 1376-1378
  • 6 Colleridge-Smith PD, Thomas P, Scurr JH et al. Causes of venous ulceration: a new hypothesis. BMJ 1988; 296: 1726-1727
  • 7 Wilkinson LS, Bunker C, Edwards JC et al. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg 1993; 17: 669-675
  • 8 Takase S, Pascarella L, lerond L et al. Venous hypertension, inflamma­tion and valve remodelling. Eur J Vasc Endovasc Surg 2004; 28: 484-493
  • 9 Adams CW, Poston RN, Buk SJ. Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J Neurol Sci 1989; 92: 291-306
  • 10 Weilbach FX, Chan A, Toyka KV et al. The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis. Clin Exp Immunol 2004; 135: 49-55
  • 11 Martino G, Adorini L, Rieckmann P et al. Inflammation in multiple sclerosis: the good, the bad, and the complex. Lancet Neurol 2002; 1: 499-509
  • 12 Kuenz B, Lutterotti A, Khalil M et al. Plasma levels of soluble adhesion molecules sPECAM-1, sP-selectin and sE-selectin are associated with relapsing-remitting disease course of multiple sclerosis. J Neuroimmunol 2005; 167: 143-149
  • 13 Fog T. The topography of plaques in multiple sclerosis with special reference to cerebral plaques. Acta Neurol Scand 1965; 15 (Suppl): 1-161
  • 14 Kidd D, Barkhof F, McConnell R et al. Cortical lesions in multiple sclerosis. Brain 1999; 122: 17-26
  • 15 Zamboni P, Menegatti E, Galeotti R et al. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci 2009; 282: 21-27
  • 16 Nicolaides AN, Morovic S, Menegatti E et al. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound: recommendations for a protocol. Funct Neurol 2011; 26: 229-248
  • 17 Krogias C, Schröder A, Wiendl H et al. “Chronic cerebrospinal venous insufficiency” and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt 2010; 81: 740-746
  • 18 Doepp F, Paul F, Valdueza JM et al. No cerebrocervical venous conges­tion in patients with multiple sclerosis. Ann Neurol 2010; 68: 173-183
  • 19 Zivadinov R, Marr K, Cutter G et al. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology 2011; 77: 138-144
  • 20 Baracchini C, Perini P, Calabrese M et al. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol 2011; 69: 90-99
  • 21 Al-Omari MH, Rousan LA. Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int Angiol 2010; 29: 115-120
  • 22 Zaniewski M, Kostecki J, Kuczmik W et al. Neck duplex Doppler ultrasound evaluation for assessing chronic cerebrospinal venous insufficiency in multiple sclerosis patients. Phlebology 2012; [Epub ahead of print] PubMed PMID: 22357458
  • 23 Mayer CA, Pfeilschifter W, Lorenz MW et al. The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry 2011; 82: 436-440
  • 24 Laupacis A, Lillie E, Dueck A et al. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ 2011; 183: E1203-E1212
  • 25 http://handbook.cochrane.org/chapter_9/9_analysing_data_and_­undertaking_meta_analyses.htm
  • 26 Zamboni P, Menegatti E, Weinstock-Guttman B et al. The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. Funct Neurol 2009; 24: 133-138
  • 27 Centonze D, Floris R, Stefanini M et al. Proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity. Ann Neurol 2011; 70: 51-58
  • 28 Tsivgoulis G, Mantatzis M, Bogiatzi C et al. Extracranial venous hemodynamics in multiple sclerosis: a case-control study. Neurology 2011; 77: 1241-1245
  • 29 Auriel E, Karni A, Bornstein NM et al. Extra-cranial venous flow in patients with multiple sclerosis. J Neurol Sci 2011; 309: 102-104
  • 30 Baracchini C, Perini P, Causin F et al. Progressive multiple sclerosis is not associated with chronic cerebrospinal venous insufficiency. Neurology 2011; 77: 844-850
  • 31 Marder E, Gupta P, Greenberg BM et al. No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis. Arch Neurol 2011; 68: 1521-1525
  • 32 Blinkenberg M, Akeson P, Sillesen H et al. Chronic cerebrospinal venous insufficiency and venous stenoses in multiple sclerosis. Acta Neurol Scand 2012; 126: 421-427
  • 33 Zamboni P, Menegatti E, Conforti P et al. Assessment of cerebral venous return by a novel plethysmography method. J Vasc Surg 2012; 56: 677-685
  • 34 Kantarci F, Albayram S, Demirci NO et al. Chronic cerebrospinal venous insufficiency: does ultrasound really distinguish multiple sclerosis subjects from healthy controls?. Eur Radiol 2012; 22: 970-979
  • 35 Amato M, Saia V, Hakiki B et al. No association between chronic cerebrospinal venous insufficiency and pediatric-onset multiple sclerosis. Mult Scler 2012; 18: 1791-1796
  • 36 Mancini M, Morra VB, Di Donato O et al. Multiple sclerosis: cerebral circulation time. Radiology 2012; 262: 947-955
  • 37 Garaci FG, Marziali S, Meschini A et al. Brain hemodynamic changes associated with chronic cerebrospinal venous insufficiency are not specific to multiple sclerosis and do not increase its severity. Radiology 2012; 265: 233-239
  • 38 Patti F, Nicoletti A, Leone C et al. Multiple sclerosis and CCSVI: a population-based case control study. PLoS One 2012; 7: e41227 DOI: 10.1371/journal.pone.0041227. Epub 2012 Aug 3
  • 39 Barreto AD, Brod SA, Bui TT et al. Chronic cerebrospinal venous insufficiency: Case-control neurosonography results. Ann Neurol 2012; DOI: 10.1002/ana.23839.
  • 40 Lanzillo R, Mancini M, Liuzzi R et al. Chronic cerebrospinal venous insufficiency in multiple sclerosis: a highly prevalent age-dependent phenomenon. BMC Neurol 2013; 13: 20 DOI: 10.1186/1471-2377-13-20.
  • 41 Chambers B, Chambers J, Cameron H et al. Chronic cerebrospinal venous insufficiency is not more prevalent in patients with mild multiple sclerosis: a sonographer-blinded, case-control ultrasound study. Mult Scler 2013; 19: 749-756
  • 42 Leone MA, Raymkulova O, Naldi P et al. Chronic cerebrospinal venous insufficiency is not associated with multiple sclerosis and its severity: a blind-verified study. PLoS One 2013; 8: e56031 DOI: 10.1371/journal.pone.0056031.. Epub 2013 Feb 13
  • 43 Imperiale D, Melis F, Giaccone C et al. Chronic cerebrospinal venous insufficiency in multiple sclerosis: A sonographer-blinded case-control study. Clin Neurol Neurosurg 2013; DOI: pii:S0303-8467(13)00018-8. 10.1016/j.clineuro.2013.01.003. [Epub ahead of print]
  • 44 Van den Berg PJ, Van den Berg GB, Westerhuis LW et al. Occurrence of CCSVI in patients with MS and its relationship with iron metabolism and varicose veins. Eur J Neurol 2013; 20: 519-526
  • 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 Zivadinov R, Siddiqui A, Karmon Y et al. Percutaneous transluminal venous angioplasty (PTVA) is ineffective in correcting chronic cerebrospinal venous insufficiency (CCSVI) and may increase multiple sclerosis (MS) disease activity in the short term: Safety and efficacy results of the 6-month, double-blinded, sham-controlled, prospective, randomized endovascular therapy in MS (PREMiSe) Trial. AAN (San Diego) 2013; Abstract P 04.273
  • 47 Morovic S, Zamboni P. CCSVI is associated with multiple sclerosis. Neurol Res 2012; 34: 770-779
  • 48 Zamboni P, Bertolotto A, Boldrini P et al. Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. Trials 2012; 13: 183 DOI: 10.1186/1745-6215-13-183.
  • 49 Ludyga T, Kazibudzki M, Simka M et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe?. Phlebology 2010; 25: 286-295
  • 50 Burton JM, Alikhani K, Goyal M et al. Complications in MS patients after CCSVI procedures abroad. Can J Neurol Sci 2011; 38: 741-746
  • 51 Thapar A, Lane TR, Pandey V et al. Internal jugular thrombosis post venoplasty for chronic cerebrospinal venous insufficiency. Phlebology 2011; 26: 254-256
  • 52 http://www.dgn.org/images/stories/dgn/presse/PM_DGN_PM_MS_CCSVI_final.pdf
  • 53 Wattjes MP, van Oosten BW, de Graaf WL et al. No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study. J Neurol Neurosurg Psychiatry 2011 82: 429-435
  • 54 Valdueza JM, Doepp F, Schreiber SJ et al. What went wrong? The flawed concept of cerebrospinal venous insufficiency. J Cereb Blood Flow Metab 2013; 33: 657-668
  • 55 Comi G, Battaglia MA, Bertolotto A et al. Italian multicentre observational study of the prevalence of CCSVI in multiple sclerosis (CoSMo study): rationale, design, and methodology. Neurol Sci 2013; [Epub ahead of print]