BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been introduced as a chronic state of impaired cerebral or cervical venous drainage that may be causally implicated in multiple sclerosis (MS) pathogenesis. Moreover, percutaneous transluminal angioplasty of extracranial veins termed "Liberation treatment" has been proposed (based on nonrandomized data) as an alternative therapy for MS. METHODS: A comprehensive literature search was conducted to identify available published, peer-reviewed, clinical studies evaluating (1) the association of CCSVI with MS, (2) the reproducibility of proposed ultrasound criteria for CCSVI detection (3) the safety and efficacy of "Liberation treatment" in open-label and randomized-controlled trial (RCT) settings. RESULTS: There is substantial heterogeneity between ultrasound case-control studies investigating the association of CCSVI and MS. The majority of independent investigators failed to reproduce the initially reported high prevalence rates of CCSVI in MS. The prevalence of extracranial venous stenoses evaluated by other neuroimaging modalities (contrast or MR venography) is similarly low in MS patients and healthy individuals. One small RCT failed to document any benefit in MS patients with CCSVI receiving "Liberation treatment", while an exacerbation of disease activity was observed. "Liberation treatment" has been complicated by serious adverse events (SAEs) in open-label studies (e.g., stroke, internal jugular vein thrombosis, stent migration, hydrocephalus). CONCLUSION: CCSVI appears to be a poorly reproducible and clinically irrelevant sonographic construct. "Liberation treatment" has no proven efficacy, may exacerbate underlying disease activity and has been complicated with SAEs. "Liberation treatment" should stop being offered to MS patients even in the settings of RCTs.

1st Department of Neurology Eginition Hospital School of Medicine University of Athens Athens Greece

2nd Department of Neurology Attikon Hospital School of Medicine University of Athens Athens Greece

2nd Department of Neurology Attikon Hospital School of Medicine University of Athens Athens Greece ; International Clinical Research Center Department of Neurology St Anne's University Hospital Brno Czech Republic ; Department of Neurology University of Tennessee Health Science Center Memphis TN

Department of Neurology Laboratory of Experimental Neurology and Neuroimmunology AHEPA Hospital Aristotle University of Thessaloniki Thessaloniki Greece

Department of Neurology School of Medicine University of Ioannina Ioannina Greece

Department of Neurology St Josef Hospital Ruhr University Bochum Germany

Komentář v

Brain Behav. 2015 Jan;5(1):1-2. doi: 10.1002/brb3.308. PubMed

Zobrazit více v PubMed

Ackermann Z, Seidenbaum M, Loewenthal E. Rubinow A. 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. PubMed

Adams CW, Poston RN. Buk S. Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J. Neurol. Sci. 1989;92:291–306. PubMed

Al-Omari MH. Rousan LA. Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int. Angiol. 2010;29:115–120. PubMed

Alroughani R, Lamdhade S. Thussu A. Endovascular treatment of chronic cerebrospinal venous insufficiency in multiple sclerosis: a retrospective study. Int. J. Neurosci. 2013;123:324–328. PubMed

Baracchini C, Perini P, Calabrese M, Causin F, Rinaldi F, Gallo P. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann. Neurol. 2011;69:90–99. PubMed

Barbato L, Scalise F, Grasso MA. Spagnolo S. Iron man: extreme endovascular treatment for chronic cerebrospinal venous insufficiency. Eur. J. Cardiothorac. Surg. 2014;pii:ez294. , and. [Epub ahead of print] PubMed

Barkhof F. Wattjes MP. Multiple sclerosis: CCSVI deconstructed and discarded. Nat. Rev. Neurol. 2013;9:661–662. PubMed

Blinkenberg M, Akeson P, Sillesen H, Lövgaard S, Sellebjerg F, Paulson OB, Siebner HR, et al. Chronic cerebrospinal venous insufficiency and venous stenoses in multiple sclerosis. Acta Neurol. Scand. 2012;126:421–427. PubMed

Brod SA, Kramer LA, Cohen AM, Barreto AD, Bui TT, Jemelka JR, et al. Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment. Mult. Scler. 2013;19:1499–1507. PubMed PMC

Burton JM, Alikhani K, Goyal M, Costello F, White C, Patry D, et al. Complications in MS patients after CCSVI procedures abroad (Calgary, AB) Can. J. Neurol. Sci. 2011;38:741–746. PubMed

Chafe R, Born KB, Slutsky AS. Laupacis A. The rise of people power. Nature. 2011;472:410–411. PubMed

Colleridge-Smith PD, Thomas P, Scurr JH. Dormandy JA. Causes of venous ulceration: a new hypothesis. BMJ. 1988;296:1726–1727. PubMed PMC

Comi G, Battaglia MA, Bertolotto A, Del Sette M, Ghezzi A, Malferrari G, et al. Observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in mulitple sclerosis: results from the CoSMo study. Mult Scler. 2013;19:1508–1517. PubMed

Costello F, Modi J, Lautner D, Bhayana D, Scott JN, Davenport WJ, et al. Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with multiple sclerosis. CMAJ. 2014;186:E418–E426. PubMed PMC

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. PubMed

Doležal O, Horáková D, Gdovinová Z. Szilasiová J. Serious complication of percutaneous angioplasty with stent implantation in so called “chronic cerebrospinal venous insufficiency” in multiple sclerosis patient. Prague. Med. Rep. 2012;113:289–293. PubMed

Dolic K, Marr K, Valnarov V, Dwyer MG, Carl E, Hagemeier J, et al. Sensitivity and specificity for screening of chronic cerebrospinal venous insufficiency using a multimodal non-invasive imaging approach in patients with multiple sclerosis. Funct. Neurol. 2011;26:205–214. PubMed PMC

Dolic K, Marr K, Valnarov V, Dwyer MG, Carl E, Karmon Y, et al. Intra- and extraluminal structural and functional venous anomalies in multiple sclerosis, as evidenced by 2 noninvasive imaging techniques. AJNR Am. J. Neuroradiol. 2012;33:16–23. PubMed PMC

Filippi M, Rocca MA, Barkhof F, Bakshi R, Fazekas F, Khan O, et al. Multiple sclerosis and chronic cerebrospinal venous insufficiency: the neuroimaging perspective. AJNR Am. J. Neuroradiol. 2011;32:424–427. PubMed PMC

Ghezzi A, Annovazzi P, Amato MP, Capello E, Cavalla P, Cocco E, et al. Adverse events after endovascular treatment of chronic cerebro-spinal venous insufficiency (CCSVI) in patients with multiple sclerosis. Mult. Scler. 2013a;19:961–963. PubMed

Ghezzi A, Annovazzi P, Cocco E, Coarelli G, Lugaresi A, Rovaris M, et al. Endovascular treatment of CCSVI in patients with multiple sclerosis: clinical outcome of 462 cases. Neurol. Sci. 2013b;34:1633–1637. PubMed

Gold R, Linington C. Lassmann H. Understanding pahtogenesis and theray of multiple sclerosis via animal models: 70 years of merits and culprits in experimantal autoimmune encephalomyelitis research. Brain. 2006;129:1953–1971. PubMed

Hojnacki D, Zamboni P, Lopez-Soriano A, Galleotti R, Menegatti E, Weinstock-Guttman B, et al. Use of neck magnetic resonance venography, Doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls. Int. Angiol. 2010;29:127–139. PubMed

Hubbard D, Ponec D, Gooding J, Saxon R, Sauder H. Haacke M. Clinical improvement after extracranial venoplasty in multiple sclerosis. J. Vasc. Interv. Radiol. 2012;23:1302–1308. PubMed

Jurkiewicz E, Kotulska K, Nowak K, Chelstowska S, Armata M, Chmielewski D. Bilska M. MR venography in children and adolescents with multiple sclerosis does not show increased prevalence of extracranial veins anomalies. Eur. J. Paediatr. Neurol. 2014;18:218–222. PubMed

Krogias C, Schröder A, Wiendl H, Hohlfeld R. Gold R. “Chronic cerebrospinal venous insufficiency” and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt. 2010;81:740–746. PubMed

Krogias C, Tsivgoulis G, Grond M, Hartung HP, Hemmer B, Oertel W, et al. Review and analysis of international Case-Control Studies on CCSVI and multiple sclerosis. Akt. Neurol. 2013;40:445–451.

Laupacis A, Lillie E, Dueck A, Straus S, Perrier L, Burton JM, et al. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ. 2011;183:E1203–E1212. PubMed PMC

Ludyga T, Kazibudzki M, Simka M, Hartel M, Swierad M, Piegza J, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology. 2010;25:286–295. PubMed

Mandato KD, Hegener PF, Siskin GP, Haskal ZJ, Englander MJ, Garla S, et al. Safety of endovascular treatment of chronic cerebrospinal venous insufficiency: a report of 240 patients with multiple sclerosis. J. Vasc. Interv. Radiol. 2012;23:55–59. PubMed

Mayer CA, Pfeilschifter W, Lorenz MW, Nedelmann M, Bechmann I, Steinmetz H. Ziemann U, et al. The perfect crime? CCSVI not leaving a trace in MS. J. Neurol. Neurosurg. Psychiatry. 2011;82:436–440. PubMed PMC

Menegetti E, Genova V, Tessari M, Malagoni AM, Bartolomei I, Zuolo M, et al. The reproducibility of colour Doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. Int. Angiol. 2010;29:121–126. PubMed

Nicolaides AN, Morovic S, Menegetti E, Viselner G. Zamboni P. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound: recommendations for a protocol. Funct. Neurol. 2011;26:229–248. PubMed PMC

Petrov I, Grozdinski L, Kaninski G, Iliev N, Iloska M. Radev A. Safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J. Endovasc. Ther. 2011;18:314–323. PubMed

Pullman D, Zarzeczny A. Picard A. Media, politics and science policy: MS and evidence from the CCSVI Trenches. BMC Med. Ethics. 2013;14:6. PubMed PMC

Rodger IW, Dilar D, Dwyer J, Bienenstock J, Coret A, Coret-Simon J, et al. Evidence against the involvement of chronic cerebrospinal venous abnormalities in multiple sclerosis. A case-control study. PLoS ONE. 2013;8:e72495. PubMed PMC

Samson K. Experimental multiple sclerosis vascular shunting procedure halted at Stanford. Ann. Neurol. 2010;67:A13–A15. PubMed

Siddiqui AH, Zivadinov R, Benedict R, Karmon Y, Yu J, Hartney ML, et al. Prospective randomized trial for venous angioplasty in MS. Neurology. 2014;83:441–9. PubMed PMC

Simka M, Ludyga T, Kazibudzki M, Latacz P. Swierad M. Multiple sclerosis, an unlikely cause of chronic cerebrospinal venous insufficiency: retrospective analysis of catheter venography. JRSM Short Rep. 2012;3:56. PubMed PMC

Singh AV. Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J. Cereb. Blood Flow Metab. 2009;29:1867–1878. PubMed

Sundström P, Wåhlin A, Ambarki K, Birgander R, Eklund A. Malm J. Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann. Neurol. 2010;68:255–259. PubMed

Takase S, Pascarella L, lerond L, Bergan JJ. Schmid-Schönbein GW. Venous hypertension, inflammation and valve remodelling. Eur. J. Vasc. Endovasc. Surg. 2004;28:484–493. PubMed

Thapar A, Lane TR, Pandey V, Shalhoub J, Malik O, Ellis M, et al. Internal jugular thrombosis post venoplasty for chronic cerebrospinal venous insufficiency. Phlebology. 2011;26:254–256. PubMed

Traboulsee AL, Knox KB, Machan L, Zhao Y, Yee I, Rauscher A, et al. Prevalence of extracranial venous narrowing on catheter venography in people with multile sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study. Lancet. 2014;383:138–145. PubMed

Tsivgoulis G, Mantatzis M, Bogiatzi C, Vadikolias K, Voumvourakis K, Prassopoulos P, et al. Extracranial venous hemodynamics in multiple sclerosis: a case-control study. Neurology. 2011;77:1241–1245. PubMed

Tsivgoulis G, Sergentanis TN, Chan A, Voumvourakis K, Triantafyllou N N, Psaltopoulou T, et al. Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies. Ther. Adv. Neurol. Disord. 2014;7:114–136. PubMed PMC

Valdueza JM, Doepp F, Schreiber SJ, van Oosten BW, Schmierer K, Paul F. Wattjes MP. What went wrong? The flawed concept of cerebrospinal venous insufficiency. J. Cereb. Blood Flow Metab. 2013;33:657–668. PubMed PMC

Wattjes MP, van Oosten BW, de Graaf WL, Seewann A, Bot JC, van den Berg R, 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. PubMed

Weilbach FX, Chan A, Toyka KV. Gold R. The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis. Clin. Exp. Immunol. 2004;135:49–55. PubMed PMC

Wilkinson LS, Bunker C, Edwards JC, Scurr JH. Smith PD. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J. Vasc. Surg. 1993;17:669–675. PubMed

Yamout B, Herlopian A, Issa Z, Habib RH, Fawaz A, Salame J, et al. Extracranial venous stenosis is an unlikely cause of multiple sclerosis. Mult. Scler. 2010;16:1341–1348. PubMed

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. PubMed PMC

Zamboni P, Galeotti R, Menegetti E, Malagoni AM, Tacconi G, Dall'Ara S, Bartolomei I, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiatry. 2009a;80:392–399. PubMed PMC

Zamboni P, Menegetti E, Galeotti R, Malagoni AM, Tacconi G, Dall'Ara S, et al. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J. Neurol. Sci. 2009b;282:21–27. PubMed

Zamboni P, Galeotti R, Menegetti E, Malagoni AM, Gianesini S, Bartolomei I, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J. Vasc. Surg. 2009c;50:1348–1358. PubMed

Zamboni P, Galeotti R, Weinstock-Guttman B, Kennedy C, Salvi F. Zivadinov R. Venous angioplasty in patients with multiple sclerosis: results of a pilot study. Eur. J. Vasc. Endovasc. Surg. 2012;43:116–122. PubMed

Zaniewski M, Kostecki J, Kuczmik W, Ziaja D, Opala G, Swiat M, et al. Neck duplex Doppler ultrasound evaluation for assessing chronic cerebrospinal venous insufficiency in multiple sclerosis patients. Phlebology. 2013;28:24–31. PubMed

Zivadinov R, Marr K, Cutter G, Ramanathan M, Benedict RH, Kennedy C, et al. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. 2011;77:138–144. PubMed

Zivadinov R, Cutter G, Marr K, Ramanathan M, Benedict RH, Bergsland N, et al. No association between conventional brain MR imaging and chronic cerebrospinal venous insufficiency in multiple sclerosis. AJNR Am. J. Neuroradiol. 2012;33:1913–1917. PubMed PMC

Zivadinov R, Karmon Y, Dolic K, Hagemeier J, Marr K, Valnarov V, et al. Multimodal noninvasive and invasive imaging of extracranial venous abnormalities indicative of CCSVI: results of the PREMiSe pilot study. BMC Neurol. 2013;13:151. PubMed PMC

Zwischenberger BA, Beasley MM, Davenport DL. Xenos ES. Meta-analysis of the correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis. Vasc. Endovasc. Surg. 2013;47:620–624. PubMed