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

Paolo Zamboni, Antonio Bertolotto, Paolo Boldrini, Patrizia Cenni, Roberto D'Alessandro, Roberto D'Amico, Massimo Del Sette, Roberto Galeotti, Stefania Galimberti, Alessandro Liberati, Luca Massacesi, Donato Papini, Fabrizio Salvi, Silvana Simi, Andrea Stella, Luigi Tesio, Maria Grazia Valsecchi, Graziella Filippini, Chair of the Steering Committee, Paolo Zamboni, Antonio Bertolotto, Paolo Boldrini, Patrizia Cenni, Roberto D'Alessandro, Roberto D'Amico, Massimo Del Sette, Roberto Galeotti, Stefania Galimberti, Alessandro Liberati, Luca Massacesi, Donato Papini, Fabrizio Salvi, Silvana Simi, Andrea Stella, Luigi Tesio, Maria Grazia Valsecchi, Graziella Filippini, Chair of the Steering Committee

Abstract

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. Chronic cerebrospinal venous insufficiency (CCSVI) has recently been described as a vascular condition characterized by restricted venous outflow from the brain, mainly due to blockages of the internal jugular and azygos veins. Despite a wide variability among studies, it has been found to be associated with MS. Data from a few small case series suggest possible improvement of the clinical course and quality of life by performing percutaneous balloon angioplasty (PTA) of the stenotic veins.

Study design and methods: This is a multicenter, randomized, parallel group, blinded, sham-controlled trial to assess the efficacy and safety of PTA. Participants with relapsing remitting MS or secondary progressive MS and a sonographic diagnosis of CCSVI will be enrolled after providing their informed consent. Each participant will be centrally randomized to receive catheter venography and PTA or catheter venography and sham PTA. Two primary end points with respect to efficacy at 12 months are (1) a combined end point obtained through the integration of five functional indicators, walking, balance, manual dexterity, bladder control, and visual acuity, objectively measured by instruments; and (2) number of new brain lesions measured by T2-weighted MRI sequences. Secondary end points include annual relapse rate, change in Expanded Disability Status Scale score, proportion of patients with zero, one or two, or more than two relapses; fatigue; anxiety and depression; general cognitive state; memory/attention/calculus; impact of bladder incontinence; and adverse events. Six hundred seventy-nine patients will be recruited. The follow-up is scheduled at 12 months. Patients, treating neurologists, trained outcome assessors, and the statistician in charge of data analysis will be masked to the assigned treatment.

Discussion: The study will provide an answer regarding the efficacy of PTA on patients' functional disability in balance, motor, sensory, visual and bladder function, cognitive status, and emotional status, which are meaningful clinical outcomes, beyond investigating the effects on inflammation. In fact, an important part of patients' expectations, sustained and amplified by anecdotal data, has to do precisely with these functional aspects.

Trial registration: Clinicaltrials.gov NCT01371760.

Figures

Figure 1
Figure 1
Meta-analysis of diagnosis of chronic cerebrospinal venous insufficiency (presence of at least two parameters according to Zamboni criteria in patients with multiple sclerosis (MS)) versus healthy controls.
Figure 2
Figure 2
Study flow chart.

References

    1. Pugliatti M, Rosati G, Cartone H, Riise T, Drulovic J, Vécsei L, Milanov I. The epidemiology of multiple sclerosis in Europe. Eur J Neurol. 2006;13:700–722. doi: 10.1111/j.1468-1331.2006.01342.x.
    1. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA). Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46:907–911. doi: 10.1212/WNL.46.4.907.
    1. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, Ebers GC. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112:133–146. doi: 10.1093/brain/112.1.133.
    1. Unger EF. Interferon β-1b (Betaseron) treatment of secondary progressive forms of multiple sclerosis. Medical Officer Clinical Review of the June 28, 2000 Amendment to Supplemental BLA 98–0737 (STN103471 file) Emeryville, CA: Chiron Corp; 2001. Available at .
    1. Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D’Amico R, Rice GPA. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet. 2003;361:545–552. doi: 10.1016/S0140-6736(03)12512-3.
    1. La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, Rovaris M, Fredrikson S, Filippini G. Interferon β for secondary progressive multiple sclerosis. Cochrane Database Syst Rev. 2012;1:CD005181. doi: 10.1002/14651858.CD005181.pub3.
    1. Rojas JI, Romano M, Ciapponi A, Patrucco L, Cristiano E. Interferon β for primary progressive multiple sclerosis. Cochrane Database Syst Rev. 2010;1:CD006643. doi: 10.1002/14651858.CD006643.pub3.
    1. Martinelli Boneschi F, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2005;4:CD002127. doi: 10.1002/14651858.CD002127.pub2.
    1. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–1880. doi: 10.1056/NEJMoa1107829.
    1. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L. TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415. doi: 10.1056/NEJMoa0907839.
    1. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012;78:1069–1078. doi: 10.1212/WNL.0b013e31824e8ee7.
    1. Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:392–399.
    1. Zamboni P, Menegatti E, Galeotti R, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci. 2009;282:21–27. doi: 10.1016/j.jns.2008.11.027.
    1. Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab. 2009;29:1867–1878. doi: 10.1038/jcbfm.2009.180.
    1. Laupacis A, Lillie E, Dueck A, Straus S, Perrier L, Burton JM, Aviv R, Thorpe K, Feasby T, Spears J. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ. 2011;183:E1203–E1212.
    1. Al-Omari MH, Rousan LA. Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int Angiol. 2010;29:115–120.
    1. Auriel E, Karni A, Bornstein NM, Nissel T, Gadoth A, Hallevi H. Extra-cranial venous flow in patients with multiple sclerosis. J Neurol Sci. 2011;309:102–104. doi: 10.1016/j.jns.2011.07.005.
    1. 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. doi: 10.1002/ana.22228.
    1. Blinkenberg M, Akeson P, Sillesen H, Lövgaard S, Sellebjerg F, Paulson OB, Siebner HR, Sørensen PS. Chronic cerebrospinal venous insufficiency and venous stenoses in multiple sclerosis. Acta Neurol Scand. in press.
    1. Centonze D, Floris R, Stefanini M, Rossi S, Fabiano S, Castelli M, Marziali S, Spinelli A, Motta C, Garaci FG, Bernardi G, Simonetti G. Proposed chronic cerebrospinal venus insufficiency criteria do not predict MS risk nor MS severity. Ann Neurol. 2011;70:51–58.
    1. 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.
    1. Floris R, Centonze D, Fabiano S, Stefanini M, Marziali S, Del Giudice C, Reale CA, Castelli M, Garaci F, Melis M, Gandini R, Simonetti G. Prevalence study of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: preliminary data. Radiol Med. in press.
    1. 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] [in German] Nervenarzt. 2010;81:740–746. doi: 10.1007/s00115-010-2972-1.
    1. Marder E, Gupta P, Greenberg BM, Frohman EM, Awad AM, Bagert B, Stüve O. No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis. Arch Neurol. 2011;68:1521–1525. doi: 10.1001/archneurol.2011.185.
    1. Mayer CA, Pfeilschifter W, Lorenz MW, Nedelmann M, Bechmann I, Steinmetz H, Ziemann U. The perfect crime? Chronic cerebrospinal venous insufficiency not leaving a trace in MS. J Neurol Neurosurg Psychiatry. 2011;82:436–440. doi: 10.1136/jnnp.2010.231613.
    1. Mehrpour M, Najimi N, Fereshtehnejad SM, Safa FN, Mirzaeizadeh S, Motamed MR, Nabavi M, Sahraeian MA. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a case–control study from Iran. Perspect Med. 2012;1:375–380. doi: 10.1016/j.permed.2012.02.037.
    1. Tsivgoulis G, Mantatzis M, Bogiatzi C, Vadikolias K, Voumvourakis K, Prassopoulos P, Piperidou C, Heliopoulos I. Extracranial venous hemodynamics in multiple sclerosis: a case–control study. Neurology. 2011;77:1241–1245. doi: 10.1212/WNL.0b013e318230a149.
    1. Zaniewski M, Kostecki J, Kuczmik W, Ziaja D, Opala G, Swiat M, Korzeniowski T, Majewski E, Urbanek T, Pawlicki K. Neck duplex Doppler ultrasound evaluation for assessing chronic cerebrospinal venous insufficiency in multiple sclerosis patients. Phlebology. in press.
    1. Zivadinov R, Marr K, Cutter G, Ramanathan M, Benedict RH, Kennedy C, Elfadil M, Yeh AE, Reuther J, Brooks C, Hunt K, Andrews M, Carl E, Dwyer MG, Hojnacki D, Weinstock-Guttman B. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. 2011;77:138–144. doi: 10.1212/WNL.0b013e318212a901.
    1. Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, Mascoli F, Salvi F. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009;50:1348–1358. doi: 10.1016/j.jvs.2009.07.096.
    1. Pisco JM, Rio Tinto H, Bilhim T, Duarte M. Percutaneous transluminal angioplasty and stenting in patients with multiple sclerosis and venous insufficiency: preliminary results [Abstract 33] J Vasc Interv Radiol. 2011;22(Suppl):S17–S18.
    1. Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, Zamboni P. Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study. Int Angiol. 2010;29:176–182.
    1. Lugli M, Morelli M, Guerzoni S, Maleti O. The hypothesis of pathophysiological correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis: rationale of treatment. Phlebology. 2012;27:178–186. doi: 10.1258/phleb.2012.012S24.
    1. 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. doi: 10.1016/j.ejvs.2011.03.035.
    1. 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. doi: 10.1583/11-3440.1.
    1. Ludyga T, Kazibudzki M, Simka M, Hartel M, Swierad M, Piegza J, Latacz P, Sedlak L, Tochowicz M. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology. 2010;25:286–295. doi: 10.1258/phleb.2010.010053.
    1. Mandato K, Hegener P, Siskin G, Haskal ZJ, Englander MJ, Garla S, Mitchell N, Reutzel L, Doti C. 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. doi: 10.1016/j.jvir.2011.09.019.
    1. NHS National Institute for Health and Clinical Excellence. IPG420: Percutaneous Venoplasty for Chronic Cerebrospinal Venous Insufficiency for Multiple Sclerosis. Manchester, UK: Author; 2012. Available at .
    1. Ministero della Salute Consiglio Superiore di Sanità. Trasmissione parere “Insufficienza venosa cerebro-spinale cronica (CCSVI) e sclerosi multipta (SM).” Sessione XLVIII. Italia: Roma; 2011.
    1. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria. Ann Neurol. 2005;58:840–846. doi: 10.1002/ana.20703.
    1. Sekiya N, Nagasaki H. Reproducibility of the walking patterns of normal young adults: test-retest reliability of the walk ratio (step-length/step-rate) Gait Posture. 1998;7:225–222. doi: 10.1016/S0966-6362(98)00009-5.
    1. Rota V, Perucca L, Simone A, Tesio L. Walk ratio (step length/cadence) as a summary index of neuromotor control of gait: application to multiple sclerosis. Int J Rehabil Res. 2011;34:265–269. doi: 10.1097/MRR.0b013e328347be02.
    1. Williams NP, Roland PS, Yellin W. Vestibular evaluation in patients with early multiple sclerosis. Am J Otol. 1997;18:93–100.
    1. Goodkin DE, Goodkin DE, Priore RL, Wende KE, Campion M, Bourdette DN, Herndon RM, Fischer JS, Jacobs LD, Cookfair DL, Rudick RA, Richert JR, Salazar AM, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Whitham RH. et al.Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials. The Multiple Sclerosis Collaborative Research Group (MSCRG) Mult Scler. 1998;4:480–486.
    1. Kalsi V, Fowler CJ. Therapy insight: bladder dysfunction associated with multiple sclerosis. Nat Clin Pract Urol. 2005;2:492–501.
    1. Mowry EM, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, Balcer LJ. Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry. 2009;80:767–772. doi: 10.1136/jnnp.2008.165449.
    1. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS) Neurology. 1983;33:1444–1452. doi: 10.1212/WNL.33.11.1444.
    1. Kos D, Nagels G, D’Hooghe MB, Duportail M, Kerckhofs E. A rapid screening tool for fatigue impact in multiple sclerosis. BMC Neurol. 2006;6:27. doi: 10.1186/1471-2377-6-27.
    1. Honarmand K, Feinstein A. Validation of the Hospital Anxiety and Depression Scale for use with multiple sclerosis patients. Mult Scler. 2009;15:1518–1524. doi: 10.1177/1352458509347150.
    1. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–699. doi: 10.1111/j.1532-5415.2005.53221.x.
    1. Rudick RA, Polman CH, Cohen JA, Walton MK, Miller AE, Confavreux C, Lublin FD, Hutchinson M, O’Connor PW, Schwid SR, Balcer LJ, Lynn F, Panzara MA, Sandrock AW. Assessing disability progression with the Multiple Sclerosis Functional Combined. Mult Scler. 2009;15:984–997. doi: 10.1177/1352458509106212.
    1. Coyne KS, Matza LS, Thompson CL, Kopp ZS, Khullar V. Determining the importance of change in the overactive bladder questionnaire. J Urol. 2006;176:627–632. doi: 10.1016/j.juro.2006.03.088.
    1. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW. AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910. doi: 10.1056/NEJMoa044397.
    1. Westfall PH, Tobias RD, Rom D, Wolfinger RD, Hochberg Y. Multiple Comparisons and Multiple Tests Using the SAS System. Cary, NC: SAS Institute; 1999.
    1. Mariani L, Marubini E. Design and analysis of phase II cancer trials: a review of statistical methods and guidelines for medical researchers. Int Stat Rev. 1996;64:61–88. doi: 10.2307/1403424.
    1. Metha CR, Caine KC. Charts for the early stopping of pilot studies. J Clin Oncol. 1984;2:676–682.
    1. Chafe R, Born KB, Slutsky AS, Laupacis A. The rise of people power. Nature. 2011;472:410–411. doi: 10.1038/472410a.
    1. Ebers GC, Heigenhauser L, Daumer M, Lederer C, Noseworthy JH. Disability as an outcome in MS clinical trials. Neurology. 2008;71:624–631. doi: 10.1212/01.wnl.0000313034.46883.16.
    1. Cadavid D, Tang Y, O’Neill G. Responsiveness of the Expanded Disability Status Scale (EDSS) to disease progression and therapeutic intervention in progressive forms of multiple sclerosis. Rev Neurol. 2010;51:321–329.

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