Basics For Endovascular Treatment Of Multiple Sclerosis
(MS): How Can Duplex Identify Large Vein Stenosis: An
Enthusiast’s View
Paolo Zamboni, MD
Vascular Diseases Center, University of Ferrara, Italy
Update on Doppler Sonography for CCSVI Screening
Chronic CerebroSpinal Venous Insufficiency (CCSVI) is a syndrome characterized by stenoses or obstructions
of the internal jugular and/or azygos veins with disturbed flow and formation of collateral venous
channels.1 Ultrasound in the form of duplex scanning uses a combination of physiological measurements
as well as anatomical imaging and has been used for the detection of CCSVI by different centers with
variable results. A high prevalence ranging from 62% to 100% of obstructive lesions has been found by
some teams in patients with multiple sclerosis (MS) compared with low prevalence of 0-25% in controls.1–5
However, absence of such lesions or a lower prevalence (16-52%) has been reported by others.7–11 This
variability could be the result of differences in technique, training, experience or criteria used.
There are 9 published studies. Overall, ultrasonic and venographic studies of the internal jugular and
azygos venous systems in patients with MS have demonstrated a high prevalence of CCSVI (mean 71%;
range 0-100%; n=1336) associated with activation of collaterals.1–11 In contrast, ultrasonic and venographic
examinations of normal controls and patients without MS have demonstrated a much lower prevalence
(mean 7.1%; range 0-22%; n=505).1–11
In order to ensure a high reproducibility of duplex scanning with comparable accuracy between centers
a detailed protocol with standard methodology and criteria has been proposed and approved in a
Consensus Conference held in Bologna (Italy), March 2011, under the umbrella of the International Society
for Neurovascular Diseases in cooperation with the International Union of Phlebology, International Union of Angiology, European Venous Forum, American College of Phlebology, Australasian College
of Phlebology, Italian Society of Vascular and Endovascular Surgery, and the Italian Society of Vascular
Pathology. The manuscript with the detailed protocol will be published sooner in the major vascular
journals.
The increased prevalence of obstruction to the drainage of cerebrospinal veins in patients with MS suggests
that venous obstruction may be a contributory factor in the development and progression of the disease.
CCSVI venous obstruction was found strongly and significantly associated with microcirculatory overload,
especially with reduced cerebral blood flow at perfusion MRI.12 Moreover, CCSVI hemodynamic severity
was significantly correlated with reduced cerebrospinal fluid dynamics. This effect suggests increased
venous pressure in the saggital sinus with consequent decreased reabsorption.13
It has also been suggested that relief of such obstruction may produce clinical benefit. In 2 observational
studies involving 81 MS patients with CCSVI, angioplasty reduced the rate of relapse, improved the Multiple
Sclerosis Functional Composite in patients with relapsing remitting MS,14–15 and improved physical and
mental QOL in relapsing remitting and primary progressive MS.14 In another study of 31 patients followed
for twelve months, angioplasty reduced chronic fatigue as assessed by the Fatigue Severity Scale and
the Fatigue Impact Scale.16 Finally, safety was confirmed in more than 500 procedures.17 However, the
true clinical benefit will only be known when the results of multicenter studies now in progress, become
available.
Clinical Trials on CCSVI Treatment
Clinical trials on CCSVI treatment currently ongoing are the following:
1. Multicenter registry for CCSVI Testing and Treatment
n ClinicalTrials.gov Identifier: NCT01205633
n Patients suspected of CCSVI should register their participation in MRV testing, and if positive,
for catheter venoplasty (with a catheter interventionist in their local community). The procedure
should but may not be covered by patients’ insurance. Patients must be referred by their treating
physician.
2. Study to Evaluate Treating Chronic CerebroSpinal Venous Insufficiency (CCSVI) in Multiple Sclerosis
Patients
n ClinicalTrials.gov Identifier: NCT01089686
n The purpose is to evaluate the safety, feasibility and efficacy of percutaneous transluminal
angioplasty in treating extracranial venous obstructive lesions, and its influence on the clinical
outcomes of MS patients that have been found to have CCSVI.
3. Evaluation of Angioplasty in the Treatment of Chronic CerebroSpinal Venous Insufficiency (CCSVI) in
Multiple Sclerosis
n ClinicalTrials.gov Identifier: NCT01201707
n The study is being done to determine if venous angioplasty is an effective treatment for CCSVI . The
effectiveness of angioplasty in the treatment of CCSVI is being evaluated by comparison of two
groups of patients: one group with CCSVI diagnosed on a venogram and treated with angioplasty,
and one group with CCSVI diagnosed on a venogram but not treated.
4. PREMiSe-Prospective Randomized Endovascular therapy in Multiple Sclerosis
n The aim of this study is to determine if endovascular intervention via balloon angioplasty to correct
the blockages improves MS symptoms or progression.
5. BRAVE DREAMS-Brain Venous Drainage Exploited Against Multiple Sclerosis
n Approved
n This multi-centric, randomized, double-blind, controlled trial will evaluate clinical efficacy and
safety of the intervention of unblocking the extracranial veins in patients with MS and diagnosis of
CCSVI. The study will compare surgery and venography with venous angioplasty.
References
1. 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.
2. Zivadinov R, Marr K, Cutter G, et al. Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study.
Description of the Design and Interim Results of an Epidemiological Study of the Prevalence of Chronic Cerebrospinal Venous
Insufficiency in MS and Related Diseases. Neurology 2011, Apr 13, epub ahead of print.
3. Al-Omari MH, Rousan LA. Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int Angiol.
2010; 29:115-20.
4. Simka M, Kostecki J, Zaniewski M, et al. Extracranial Doppler sonographic criteria of chronic cerebrospinal venous insuffitiency
in the patients with multiple sclerosis. Int Angiol. 2010;29:109-14.
5. Bastianello S, Bergamaschi F, Viselner G, et al. An international multicenter observatory on prevalence of CCSVI in MS. Abstract
presented at the ISNVD Annual Meeting, Bologna, Italy, March 2011.
6. Zivadinov R, Galeotti R, Hojnacki D et al Value of MR Venography for Detection of Internal Jugular Vein Anomalies in Multiple
Sclerosis: A Pilot Longitudinal Study. Am J Neurorad, 2011 Apr 14, epub ahead of print.
7. Doepp F, Paul F, Valdueza JM, et al. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010;
68:173-83.
8. Mayer CA, Waltraud P, Matthias WL, et al. The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry.
2011;82:436-440.
Basics For Endovascular Treatment Of Multiple Sclerosis
(MS): How Can Duplex Identify Large Vein Stenosis: An
Enthusiast’s View
Paolo Zamboni, MD
Vascular Diseases Center, University of Ferrara, Italy
Notes
2
Presented at the 38th Annual Vascular and
Endovascular Issues, Techniques and Horizons
(VEITHsymposium), November 16–20, 2011,
New York City
9. Yamout B, Herlopian A, Issa Z,et al. Extracranial venous stenosis is an unlikely cause of multiple sclerosis. Mult Scler. 2010;16(11):1341-8.
10. Baracchini C, Perini P, Calabrese M, et al. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset.
Ann Neurol. 2011;69:90-9.
11. Wattjes MP, van Oosten BW, de Graaf WL, et al.J No association of abnormal cranial venous drainage with multiple sclerosis: a
magnetic resonance venography and flow-quantification study. Neurol Neurosurg Psychiatry. 2011:82(4):429-35.
12. Zamboni P, Menegatti E, Weinstock-Guttman B, et al. Hypoperfusion of Brain Parenchyma is Associated with the Severity of
Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis. BMC Medicine, 2011;7:9-22.
13. 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;24:133-8.
14. 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(6):1348-57.
15. Malagoni AM, Galeotti R, Menegatti E, Manfredini et al. Is chronic fatigue the symptom of venous insufficiency associated with
multiple sclerosis? A longitudinal pilot study. Int Angiol. 2010;29(2):176-82.
16. Zamboni P, Galeotti R, Weinstock-Guttman B, et al. Venous angioplasty in patients with multiple sclerosis. Results of a case
control pilot study. EJVES 2011, in press.
17. Ludyga T, Kazibudzki M, Simka M, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure
safe? Phlebology. 2010 Dec;25(6):286-95.
Presented at the 38th Annual Vascular and
Endovascular Issues, Techniques and Horizons
(VEITHsymposium), November 16–20, 2011,
New York City
http://www.veithsymposium.org/pdf/vei/4605.pdf