Original Article
Venous Hemodynamic Insufficiency Severity Score variation after endovascular treatment of chronic cerebrospinal venous insufficiency
Phlebology 2015, Vol. 30(4) 250–256 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355514524193 phl.sagepub.com
Filippo Scalise1,2, Eugenio Novelli2,3, Massimiliano Farina2,4, Luciano Barbato2,5 and Salvatore Spagnolo2,5
Abstract Introduction: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of the internal jugular veins (IJVs) and/or azygos veins with disturbed flow and formation of collateral venous channels. The presence of CCSVI has been associated with multiple sclerosis (MS). Percutaneous venous angioplasty (PVA) has been proposed to improve extracranial outflow; however, a non-invasive, post-procedural follow-up outcome measure has not been established. Aim of the study: To evaluate the short-term hemodynamic follow-up of CCSVI after PVA using color Doppler ultrasound (CDU) and to investigate whether hemodynamic variation correlated with clinical variation. Materials and methods: Forty-five patients affected by MS with confirmed CCSVI underwent IJVs PVA. Venous hemodynamic (VH) parameters indicative of CCSVI and the Venous Hemodynamic Insufficiency Severity Score (VHISS) were evaluated by CDU at baseline and 3 months post-PVA. Concurrently, the MS-related disability status (EDSS) was evaluated. Results: The VH parameters and VHISS 3 months after IJVs PVA significantly decreased: the VH parameters 32.1% and the VHISS 33.8% (p < 0.001). The EDSS score 3 months after IJVs PVA was significantly lower than the baseline (5.5%, p < 0.001). Using the median value of the VHISS variation as the cut-off, we were able to identify two groups of patients: responders, group A; and non-responders, group B. The EDSS score variation at 3 months was 0.310 in group A and 0.275 in group B (p ¼ 0.746). Conclusions: CCSVI endovascular treatment can induce an improvement in VH parameters and the VHISS. The neurological disability score (EDSS) also improved after PVA; however, there was no correlation to the VHISS variation after PVA, MS type and duration.
Keywords CCSVI, color Doppler ultrasound, percutaneous venous angioplasty, jugular veins
severity of the blocked outflow can be scored using the Venous Hemodynamic Insufficiency Severity
Introduction Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition, mainly that is characterized by venous valvular abnormalities (e.g. vein web, annulus, inverted flaps or septum) and stenoses which involves extracranial venous efferent cerebral paths (azygos and/ or internal jugular veins (IJVs)).1,2 The obstructed normal venous outflow results in the activation of additional circles (condylar veins, pterygoid plexus, thyroid veins, and anterior and external jugular veins) as the result of increased flow resistance along the principal drainage pathways.2 It has been proposed that the
1 Cardiac and Vascular Catheterization Laboratory, Policlinico di Monza, Monza, Italy 2 CCSVI Research Center, Policlinico di Monza, Monza, Italy 3 Biostatistics Unit, Policlinico di Monza, Monza, Italy 4 Vascular Surgery, Policlinico di Monza, Monza, Italy 5 Cardiovascular Surgery Department, Policlinico di Monza, Monza, Italy
Corresponding author: Filippo Scalise, Cardiac and Vascular Catheterization Laboratory, Policlinico di Monza, Via Amati 111, 20900 Monza, Italy. Email: [email protected]
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Table 1. VHISS contribution score. Parameter
Definition
Score range
Venous segments with reflux in two posture Reflux in DCVs in two posture VH2 VH3 Mono o bilateral B-mode anomalies Venous segments with blocks VH4 VH5 Negative CSA VHISS Score VH1 þ VH2 þ VH3 þ VH4 þ VH5 VH1
0–8 0–4 0–2 0–8 0–4 0–16a
DCVs: deep cerebral veins; negative CSA: negative difference in the cross-sectional area (CSA) of the internal jugular veins; VHISS: Venous Hemodynamic Insufficiency Severity Score; VH: venous hemodinamic. a The maximum is limited by the mutually exclusive nature of VH1, VH3, and VH4.
Score (VHISS).3 Subjects with CCSVI have a higher frequency of venous reflux, blocked flow, B-mode abnormalities, and reduced IJVs compliance, which led to an increased VHISS.3 CCSVI implies a pathological condition for which a non-invasive diagnosis is based mainly on the detection of 2 positive venous hemodynamic (VH) criteria on Color Doppler Ultrasound (CDU) in the extracranial (neck) and intracranial veins and is made by assessing five proposed VH criteria.1,4–6 The overall VHISS was defined as a weighted sum of the scores contributed by each individual VH criterion. For each of the five VH parameters, a ‘‘VHISS contribution score’’ was assigned using the scheme described by Zamboni.3–6 The formula for VHISS calculations was as follows: VHISS ¼ VHISS1 þ VHISS2 þ VHISS3 þ VHISS4 þ VHISS5. The subscripts in this formula indicate the subscores for the five VH criteria (Table 1). The VHISS is an ordinal measure of the overall extent and number of VH flow pattern anomalies. A higher VHISS value indicates a more severe anomaly. The minimum possible VHISS value was 0 and the maximum was 16. The maximum is limited by the mutually exclusive nature of VH1, VH3 and VH4. The hemodynamic alterations in CCSVI observed in different studies consisted of a higher frequency of venous segments exhibiting reflux, flow block, B-mode imaging evidence of extracranial venous stenoses, and reduced compliance in the IJVs; these factors led to an increased VHISS.3,6 Based on this evidence, percutaneous venous angioplasty (PVA) of the IJVs and the azygos vein has been proposed as a mechanism for improving obstructed venous outflow.7–10 Early reports by Zamboni et al. describe high rates of clinical improvement in patients with multiple sclerosis (MS) after angioplasty of stenotic IJV and azygos veins.7 Said study underscored a significant reduction of the relapse rate in the first year after venous balloon angioplasty
and the endovascular treatment improve significantly the validate outcome measure in MS; treatment of azygos and IJVs showed a 1-year patency of 95% and 70%, respectively.7 Other recent studies have confirmed the safety and low procedural risk of said intervention with a 1.2% incidence of venous thrombosis.8 Endovascular treatment also improved the quality of life in middle-term follow-up patients.8 Salvi et al. reported a significant reduction of annual relapse rates and cumulative disability in patients with relapsing-remitting (RR) MS treated with IJV angioplasty.9 The venous angioplasty procedure was always performed in patients with a diagnosis of CCSVI ascertained by CDU of efferent cerebral vessels and deep cerebral veins and the interventions were based on anatomical information regarding internal jugular districts, related substitute circles and azygos vein obtained by catheter venography. CCSVI endovascular treatment is followed by significant improvement of IJV flow hemodynamic parameters and decrease in the EDSS score.10 In particular CDU showed a significant improvement in cross-sectional area parameters and significant decrease in confluence velocity values associated with a significant decrease in postoperative IJV pressure gradient.10 However, a post-procedural non-invasive outcome measure to follow-up CCSVI has not been established.
Aim of the study In our study, we prospectively evaluated the post-PVA variations in the short-term CDU hemodynamic parameters in patients with CCSVI. We also assessed the post-PVA EDSS variations at 1 and 3 months to investigate whether variation in the hemodynamic parameters correlated with clinical variation.
Methods Forty-five patients with CCSVI and clinically proven MS according to the revised McDonald criteria11 were prospectively evaluated. Twenty-six women and 19 men were enrolled in the study (time since MS diagnosis ranged from 1 to 40 years, with a mean of 12.5 years). The mean age of the participants was 46 years. The clinical features of the subjects are shown in Table 2. The exclusion criteria were as follows: recent MS relapse, presence of central nervous system vascular malformations, brain or spinal tumors; inflammatory vascular diseases; congenital vascular abnormalities; stenosis/occlusions of the supra-aortic trunks or previous TIA or stroke; or chronic venous insufficiency within the lower or upper extremities. Three patients were excluded: two patients with recent MS relapse, one patient with a previous stroke. Patients were
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Table 2. Patient characteristics (n ¼ 45). Female gender Age (years) Affected venous zones MS subtype RRMS SPMS PPMS Disease duration (years) EDSS VHISS VH parameters
26 (57.8%) 46.6 11.1 2.2 0.5 19 (42.2%) 20 (44.4%) 6 (13.3%) 12.5 7.6 5.4 2.1 6.2 2.5 3.1 1.0
EDSS: Expanded Disability Status Scale; VHISS: Venous Hemodynamic Insufficiency Severity Score; VH: venous hemodynamic.
assessed by an independent neurologist pre- and postoperatively. The clinical evaluation, including neurological deficit and severity of disability, was based on the EDSS.
Institutional review board approval This study was approved by the Ethics Committee of our Institution, and all patients gave their consent for diagnostic and endovascular procedures. CDU examination. Cerebro-venous hemodynamics were performed by an expert vascular sonographer using CDU Scanning (MyLab Vinco US SystemÕ , Esaote S.p.A., Florence, Italy) equipped with a linear array transducer probe operating bandwidth 3–11 MHz (B-modes frequencies: 3.5 – 5.0 – 6.6 – 10.0 MHz; Doppler frequencies: 3.3 – 5.0 MHz) for extracranial scans. The transcranial approach was performed with a phased array transducer probe operating bandwidth 1–4 MHz (B-modes frequencies: 2.0 – 2.5 – 3.3 MHz; Doppler frequencies: 1.6 – 2.0 – 2.5 MHz). Morphological and functional characteristics of intraand axtra-cranial were investigated while the subjects were in supine (0 ) and upright sitting (90 ) positions according to the revised protocol by an expert panel of the International Society for Neurovascular Disease (ISNVD).12 The same status was used for the examination of the deep cerebral veins. A diagnosis of CCSVI was made if two of the five Zamboni’s criteria were met.4 We also used the VHISS to define the degree of hemodynamic CCSVI severity.3,4 Furthermore, we performed a reconstruction of the longitudinal ultrasound scans of the IJVs to provide a better definition and understanding of these veins. As reported in a recent study,13 we detected normal veins with a telescopic appearance; veins with valvular defects mainly located in the proximal segment; miopragic veins with a typical aspect of an
‘‘hourglass’’, isolated or associated with valvular defects, and hypoplastic veins with the diameter broadly across the entire length. In agreement with recent studies13,14 we defined as hypoplastic those IJVs with proximal longitudinal anteroposterior diameters two standard deviations less than the mean (5.45 mm). An electro-mechanical tilting chair was used to ensure that the subject moved as little as possible (no voluntary muscle movements and contractions) during position changes. Patients were asked to maintain a sufficient level of hydration during the 12 h before the examination. A head support was used to prevent the neck from hypo- or hyper-extending and to prevent rotation to the left or right side. A pillow was placed on the subject’s thorax as a support for the sonographer’s arm; this feature was particularly useful when the subject was in a sitting position. Catheter venography. The procedure was performed under local anesthesia in an angiographic suite (Innova 2100Õ , General Electric, Fairfield, CT, USA). After the IJVs were selectively catheterized, venography was performed in a minimum of three projections. A first injection (4–10 mL/s) was performed to assess the anatomy and possible activation of collateral pathways. Then, the catheter was pulled back into the jugular bulb, below the confluence of the common facial vein, and a second injection was performed (4–10 mL/s) to assess the junction anatomy, valve morphology and presence of anomalies. Selective catheterization of the azygos vein was performed using a 5-F Super TorqueÕ Cobra catheter (Cordis Corporation, Hialeah, FL, USA). A hydrophilic 0.035 wire RadifocusÕ (Terumo Corporation, Somerset, NJ, USA) was progressed up to L3, where the azygos vein is usually in continuity with the ascending right lumbar vein. Two or more injections (4–10 mL/s) were usually required to assess the azygos system anatomy. A 30 left oblique projection was required to assess arch and valve morphology as well as adequate drainage. IJV angioplasty. Before proceeding with IJV angioplasty, systemic unfractionated heparin was administered (depending on patient weight, routinely 5000 IU). A 6 F guide catheter was placed into the IJV, and an IVUS examination was performed in only 25 patients (55.5%). Based on the evidence acquired by the CDU examination, angiography and IVUS, IJVs angioplasty was performed. The choice of the angioplasty balloon was based on 20% IJV diameter oversizing or, when the IVUS examination was performed, on the IJV cross-sectional area measurement. After PVA, the angiographic catheter was inserted into the IJV, and a control injection was performed to document the efficacy of the procedure and the absence of complications
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(dissection, rupture and thrombosis). The use of stents in the IJV was excluded. Four hours after the conclusion of the procedure, a first low-molecular-weight heparin (LMWH) subcutaneous injection was administered at a prophylactic dosage; this treatment was continued daily for one month.
Statistical analysis Continuous data are shown as the mean standard deviation (SD) and categorical data as counts and percentages. Comparisons between the preoperative and 3-month follow-up data (VHISS, CCSVI, and EDSS) were evaluated using the t-test for paired samples with parametric distributions and the Wilcoxon’s signedrank test for non-parametric distributions. The evolution of the patients’ disability (EDSS score) over time (pre-PTA, at 30 days and at the 3-month follow-up) was analyzed using the repeated-measures analysis of variance (ANOVA) model. Data were collected and reviewed in Microsoft Excel, and statistical analyses were performed with SPSSÕ 13.0 (SPSS Inc., Chicago, IL, USA). All two-tailed p values 30% experienced a corresponding but non-significant variation in EDSS; this variation occurred regardless of the MS type or duration. This apparent discrepancy between the significant improvement in the hemodynamic parameters (VH and VHISS) and non-significant improvement in the clinical parameters (EDSS) could be explained by two main considerations. First, the EDSS has a low sensitivity for identifying clinical improvements in MS patients. While this scale is widely used in most MS studies, it is not often used in day-to-day medicine and is not sensitive to changes in a patient’s condition, particularly once they have difficulty walking. These shortcomings of the EDSS have been described as follows: the EDSS over-emphasizes the ability to walk, is insensitive to cognitive dysfunction in MS, is difficult to calculate with complex rules for rating findings on neurological exam and translating these into scores on functional system status, and is not sensitive to many clinical changes that a person with MS experiences. Second, the lack of correlation
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between a significant improvement in the hemodynamic and clinical parameters may have occurred because our patient population was suffering from MS with a high baseline level of disability (EDSS average 5.4) and progressive disease. Even the rehabilitation of motor dysfunction in patients with MS is affected by the degree of disability at baseline and duration of the disease, which likely occurs because of the prevalence of stabilized neurological damage.17 The statistical analysis of our population allowed us to identify ‘‘responder’’ patients with a VHISS reduction >30%. A significant change in the VHISS could be considered an index of the efficacy of PVA in terms of ‘‘hemodynamic’’ success but not in terms of ‘‘clinical’’ success. With regard to the group of nonresponders, one of the possible causes of failure of the angioplasty procedure could be related to the observed high percentage of miopragic jugular veins, due to the increased distensibility of the vein wall.13 The small sample analyzed does not permit us to derive definitive conclusions; however, it does allow us to formulate a working hypothesis to be transferred to a study with a larger population. Currently, we are not able to determine which group of CCSVI patients will achieve the greatest clinical and quality-of-life improvements when treated by endovascular methods. In addition, we do not know whether the method described here can be used as a diagnostic parameter to assess the success of endovascular treatment in immediate- and mid-term follow-up. With the growing number of patients treated with endovascular procedures and the methodology and quality of available studies, there is an urgent need for a well-designed randomized controlled trial. In addition, there is an urgent need for unified multimodal CCSVI diagnostic criteria.
Conclusion In patients treated with IJV PVA, we have observed a significant reduction in the VHISS, an index that is able to determine venous flow alterations in CCSVI patients. In patients with a VHISS variation of >30% after PVA, there is a corresponding but non-significant improvement in the EDSS. For this reason, we believe that the VHISS can be very helpful in assessing the hemodynamic response to angioplasty procedure for these patients; however, additional randomized studies with more subjects will be needed to determine whether there is a correlation between VHISS variation and clinical improvement. Close cooperation among neurologists, radiologists/interventional cardiologists, and vascular surgeons is required to reach definitive conclusions.
Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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. Zamboni P, Consorti G, Galeotti R, et al. Venous collateral circulation of the extra-cranial cerebrospinal outflow routes. Curr Neurovasc Res 2009; 6: 204–212. 3. 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. 4. Zamboni P, Morovic S, Menegatti E, et al. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound – recommendations for a protocol. Int Angiol 2011; 30: 571–597. 5. 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(1–2): 21–27. 6. Menegatti E, Genova V, Tessari M, et al. The reproducibility of colour Doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. Int Angiol 2010; 2: 121–127. 7. Zamboni P, Galeotti R, Menegatti E, et al. Venous angioplasty in patients with multiple sclerosis: results of a pilot study. Eur J Vasc Endovasc Surg 2009; 50: 1348–1358. 8. Mandato KD, Hegener PF, Siskin GP, 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. 9. Salvi F, Bartolomei I, Buccelato E, et al. Venous angioplasty in multiple sclerosis: neurological outcome at two years in a cohort of relapsing-remitting patients. Funct Neurol 2012; 27: 55–59. 10. Radak D, Kolar J, Sagic D, et al. Percutaneous angioplasty of internal jugular and azygous veins in patients with chronic cerebrospinal venous insufficiency and multiple sclerosis: early and mid-term results. Phlebology 2014; 29: 367–375. 11. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria’. Ann Neurol 2005; 58: 840–846. 12. 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. 13. Farina M, Novelli E and Pagani R. Cross-sectional area variations of internal jugular veins during supine head
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rotation in multiple sclerosis patients with chronic cerebrospinal venous insufficiency: a prospective diagnostic controlled study with duplex ultrasound investigation. BMC Neurol 2013; 13: 162. 14. Lim CL, Keshava SN and Lea M. Anatomical variations of the internal jugular veins and their relationship to the carotid arteries: A CT evaluation. Australas Radiol 2006; 50: 314–318. 15. 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: a cross-sectional preliminary report. BMC Med 2011; 9: 22. 16. Zamboni P, Menegatti E, Weinstock-Guttman B, et al. CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study. Int Angiol 2010; 29: 140–148. 17. Liberatore G, Clarelli F, Nuara A, et al. Predictors of effectiveness of multidisciplinary rehabilitation treatment on motor dysfunction in multiple sclerosis. Mult Scler 2013; Epub ahead of print DOI: 10.1177/ 1352458513508834.
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Venous Hemodynamic Insufficiency Severity Score variation after endovascular treatment of chronic cerebrospinal venous insufficiency
Phlebology 2015, Vol. 30(4) 250–256 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355514524193 phl.sagepub.com
Filippo Scalise1,2, Eugenio Novelli2,3, Massimiliano Farina2,4, Luciano Barbato2,5 and Salvatore Spagnolo2,5
Abstract Introduction: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of the internal jugular veins (IJVs) and/or azygos veins with disturbed flow and formation of collateral venous channels. The presence of CCSVI has been associated with multiple sclerosis (MS). Percutaneous venous angioplasty (PVA) has been proposed to improve extracranial outflow; however, a non-invasive, post-procedural follow-up outcome measure has not been established. Aim of the study: To evaluate the short-term hemodynamic follow-up of CCSVI after PVA using color Doppler ultrasound (CDU) and to investigate whether hemodynamic variation correlated with clinical variation. Materials and methods: Forty-five patients affected by MS with confirmed CCSVI underwent IJVs PVA. Venous hemodynamic (VH) parameters indicative of CCSVI and the Venous Hemodynamic Insufficiency Severity Score (VHISS) were evaluated by CDU at baseline and 3 months post-PVA. Concurrently, the MS-related disability status (EDSS) was evaluated. Results: The VH parameters and VHISS 3 months after IJVs PVA significantly decreased: the VH parameters 32.1% and the VHISS 33.8% (p < 0.001). The EDSS score 3 months after IJVs PVA was significantly lower than the baseline (5.5%, p < 0.001). Using the median value of the VHISS variation as the cut-off, we were able to identify two groups of patients: responders, group A; and non-responders, group B. The EDSS score variation at 3 months was 0.310 in group A and 0.275 in group B (p ¼ 0.746). Conclusions: CCSVI endovascular treatment can induce an improvement in VH parameters and the VHISS. The neurological disability score (EDSS) also improved after PVA; however, there was no correlation to the VHISS variation after PVA, MS type and duration.
Keywords CCSVI, color Doppler ultrasound, percutaneous venous angioplasty, jugular veins
severity of the blocked outflow can be scored using the Venous Hemodynamic Insufficiency Severity
Introduction Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition, mainly that is characterized by venous valvular abnormalities (e.g. vein web, annulus, inverted flaps or septum) and stenoses which involves extracranial venous efferent cerebral paths (azygos and/ or internal jugular veins (IJVs)).1,2 The obstructed normal venous outflow results in the activation of additional circles (condylar veins, pterygoid plexus, thyroid veins, and anterior and external jugular veins) as the result of increased flow resistance along the principal drainage pathways.2 It has been proposed that the
1 Cardiac and Vascular Catheterization Laboratory, Policlinico di Monza, Monza, Italy 2 CCSVI Research Center, Policlinico di Monza, Monza, Italy 3 Biostatistics Unit, Policlinico di Monza, Monza, Italy 4 Vascular Surgery, Policlinico di Monza, Monza, Italy 5 Cardiovascular Surgery Department, Policlinico di Monza, Monza, Italy
Corresponding author: Filippo Scalise, Cardiac and Vascular Catheterization Laboratory, Policlinico di Monza, Via Amati 111, 20900 Monza, Italy. Email: [email protected]
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Table 1. VHISS contribution score. Parameter
Definition
Score range
Venous segments with reflux in two posture Reflux in DCVs in two posture VH2 VH3 Mono o bilateral B-mode anomalies Venous segments with blocks VH4 VH5 Negative CSA VHISS Score VH1 þ VH2 þ VH3 þ VH4 þ VH5 VH1
0–8 0–4 0–2 0–8 0–4 0–16a
DCVs: deep cerebral veins; negative CSA: negative difference in the cross-sectional area (CSA) of the internal jugular veins; VHISS: Venous Hemodynamic Insufficiency Severity Score; VH: venous hemodinamic. a The maximum is limited by the mutually exclusive nature of VH1, VH3, and VH4.
Score (VHISS).3 Subjects with CCSVI have a higher frequency of venous reflux, blocked flow, B-mode abnormalities, and reduced IJVs compliance, which led to an increased VHISS.3 CCSVI implies a pathological condition for which a non-invasive diagnosis is based mainly on the detection of 2 positive venous hemodynamic (VH) criteria on Color Doppler Ultrasound (CDU) in the extracranial (neck) and intracranial veins and is made by assessing five proposed VH criteria.1,4–6 The overall VHISS was defined as a weighted sum of the scores contributed by each individual VH criterion. For each of the five VH parameters, a ‘‘VHISS contribution score’’ was assigned using the scheme described by Zamboni.3–6 The formula for VHISS calculations was as follows: VHISS ¼ VHISS1 þ VHISS2 þ VHISS3 þ VHISS4 þ VHISS5. The subscripts in this formula indicate the subscores for the five VH criteria (Table 1). The VHISS is an ordinal measure of the overall extent and number of VH flow pattern anomalies. A higher VHISS value indicates a more severe anomaly. The minimum possible VHISS value was 0 and the maximum was 16. The maximum is limited by the mutually exclusive nature of VH1, VH3 and VH4. The hemodynamic alterations in CCSVI observed in different studies consisted of a higher frequency of venous segments exhibiting reflux, flow block, B-mode imaging evidence of extracranial venous stenoses, and reduced compliance in the IJVs; these factors led to an increased VHISS.3,6 Based on this evidence, percutaneous venous angioplasty (PVA) of the IJVs and the azygos vein has been proposed as a mechanism for improving obstructed venous outflow.7–10 Early reports by Zamboni et al. describe high rates of clinical improvement in patients with multiple sclerosis (MS) after angioplasty of stenotic IJV and azygos veins.7 Said study underscored a significant reduction of the relapse rate in the first year after venous balloon angioplasty
and the endovascular treatment improve significantly the validate outcome measure in MS; treatment of azygos and IJVs showed a 1-year patency of 95% and 70%, respectively.7 Other recent studies have confirmed the safety and low procedural risk of said intervention with a 1.2% incidence of venous thrombosis.8 Endovascular treatment also improved the quality of life in middle-term follow-up patients.8 Salvi et al. reported a significant reduction of annual relapse rates and cumulative disability in patients with relapsing-remitting (RR) MS treated with IJV angioplasty.9 The venous angioplasty procedure was always performed in patients with a diagnosis of CCSVI ascertained by CDU of efferent cerebral vessels and deep cerebral veins and the interventions were based on anatomical information regarding internal jugular districts, related substitute circles and azygos vein obtained by catheter venography. CCSVI endovascular treatment is followed by significant improvement of IJV flow hemodynamic parameters and decrease in the EDSS score.10 In particular CDU showed a significant improvement in cross-sectional area parameters and significant decrease in confluence velocity values associated with a significant decrease in postoperative IJV pressure gradient.10 However, a post-procedural non-invasive outcome measure to follow-up CCSVI has not been established.
Aim of the study In our study, we prospectively evaluated the post-PVA variations in the short-term CDU hemodynamic parameters in patients with CCSVI. We also assessed the post-PVA EDSS variations at 1 and 3 months to investigate whether variation in the hemodynamic parameters correlated with clinical variation.
Methods Forty-five patients with CCSVI and clinically proven MS according to the revised McDonald criteria11 were prospectively evaluated. Twenty-six women and 19 men were enrolled in the study (time since MS diagnosis ranged from 1 to 40 years, with a mean of 12.5 years). The mean age of the participants was 46 years. The clinical features of the subjects are shown in Table 2. The exclusion criteria were as follows: recent MS relapse, presence of central nervous system vascular malformations, brain or spinal tumors; inflammatory vascular diseases; congenital vascular abnormalities; stenosis/occlusions of the supra-aortic trunks or previous TIA or stroke; or chronic venous insufficiency within the lower or upper extremities. Three patients were excluded: two patients with recent MS relapse, one patient with a previous stroke. Patients were
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Table 2. Patient characteristics (n ¼ 45). Female gender Age (years) Affected venous zones MS subtype RRMS SPMS PPMS Disease duration (years) EDSS VHISS VH parameters
26 (57.8%) 46.6 11.1 2.2 0.5 19 (42.2%) 20 (44.4%) 6 (13.3%) 12.5 7.6 5.4 2.1 6.2 2.5 3.1 1.0
EDSS: Expanded Disability Status Scale; VHISS: Venous Hemodynamic Insufficiency Severity Score; VH: venous hemodynamic.
assessed by an independent neurologist pre- and postoperatively. The clinical evaluation, including neurological deficit and severity of disability, was based on the EDSS.
Institutional review board approval This study was approved by the Ethics Committee of our Institution, and all patients gave their consent for diagnostic and endovascular procedures. CDU examination. Cerebro-venous hemodynamics were performed by an expert vascular sonographer using CDU Scanning (MyLab Vinco US SystemÕ , Esaote S.p.A., Florence, Italy) equipped with a linear array transducer probe operating bandwidth 3–11 MHz (B-modes frequencies: 3.5 – 5.0 – 6.6 – 10.0 MHz; Doppler frequencies: 3.3 – 5.0 MHz) for extracranial scans. The transcranial approach was performed with a phased array transducer probe operating bandwidth 1–4 MHz (B-modes frequencies: 2.0 – 2.5 – 3.3 MHz; Doppler frequencies: 1.6 – 2.0 – 2.5 MHz). Morphological and functional characteristics of intraand axtra-cranial were investigated while the subjects were in supine (0 ) and upright sitting (90 ) positions according to the revised protocol by an expert panel of the International Society for Neurovascular Disease (ISNVD).12 The same status was used for the examination of the deep cerebral veins. A diagnosis of CCSVI was made if two of the five Zamboni’s criteria were met.4 We also used the VHISS to define the degree of hemodynamic CCSVI severity.3,4 Furthermore, we performed a reconstruction of the longitudinal ultrasound scans of the IJVs to provide a better definition and understanding of these veins. As reported in a recent study,13 we detected normal veins with a telescopic appearance; veins with valvular defects mainly located in the proximal segment; miopragic veins with a typical aspect of an
‘‘hourglass’’, isolated or associated with valvular defects, and hypoplastic veins with the diameter broadly across the entire length. In agreement with recent studies13,14 we defined as hypoplastic those IJVs with proximal longitudinal anteroposterior diameters two standard deviations less than the mean (5.45 mm). An electro-mechanical tilting chair was used to ensure that the subject moved as little as possible (no voluntary muscle movements and contractions) during position changes. Patients were asked to maintain a sufficient level of hydration during the 12 h before the examination. A head support was used to prevent the neck from hypo- or hyper-extending and to prevent rotation to the left or right side. A pillow was placed on the subject’s thorax as a support for the sonographer’s arm; this feature was particularly useful when the subject was in a sitting position. Catheter venography. The procedure was performed under local anesthesia in an angiographic suite (Innova 2100Õ , General Electric, Fairfield, CT, USA). After the IJVs were selectively catheterized, venography was performed in a minimum of three projections. A first injection (4–10 mL/s) was performed to assess the anatomy and possible activation of collateral pathways. Then, the catheter was pulled back into the jugular bulb, below the confluence of the common facial vein, and a second injection was performed (4–10 mL/s) to assess the junction anatomy, valve morphology and presence of anomalies. Selective catheterization of the azygos vein was performed using a 5-F Super TorqueÕ Cobra catheter (Cordis Corporation, Hialeah, FL, USA). A hydrophilic 0.035 wire RadifocusÕ (Terumo Corporation, Somerset, NJ, USA) was progressed up to L3, where the azygos vein is usually in continuity with the ascending right lumbar vein. Two or more injections (4–10 mL/s) were usually required to assess the azygos system anatomy. A 30 left oblique projection was required to assess arch and valve morphology as well as adequate drainage. IJV angioplasty. Before proceeding with IJV angioplasty, systemic unfractionated heparin was administered (depending on patient weight, routinely 5000 IU). A 6 F guide catheter was placed into the IJV, and an IVUS examination was performed in only 25 patients (55.5%). Based on the evidence acquired by the CDU examination, angiography and IVUS, IJVs angioplasty was performed. The choice of the angioplasty balloon was based on 20% IJV diameter oversizing or, when the IVUS examination was performed, on the IJV cross-sectional area measurement. After PVA, the angiographic catheter was inserted into the IJV, and a control injection was performed to document the efficacy of the procedure and the absence of complications
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(dissection, rupture and thrombosis). The use of stents in the IJV was excluded. Four hours after the conclusion of the procedure, a first low-molecular-weight heparin (LMWH) subcutaneous injection was administered at a prophylactic dosage; this treatment was continued daily for one month.
Statistical analysis Continuous data are shown as the mean standard deviation (SD) and categorical data as counts and percentages. Comparisons between the preoperative and 3-month follow-up data (VHISS, CCSVI, and EDSS) were evaluated using the t-test for paired samples with parametric distributions and the Wilcoxon’s signedrank test for non-parametric distributions. The evolution of the patients’ disability (EDSS score) over time (pre-PTA, at 30 days and at the 3-month follow-up) was analyzed using the repeated-measures analysis of variance (ANOVA) model. Data were collected and reviewed in Microsoft Excel, and statistical analyses were performed with SPSSÕ 13.0 (SPSS Inc., Chicago, IL, USA). All two-tailed p values 30% experienced a corresponding but non-significant variation in EDSS; this variation occurred regardless of the MS type or duration. This apparent discrepancy between the significant improvement in the hemodynamic parameters (VH and VHISS) and non-significant improvement in the clinical parameters (EDSS) could be explained by two main considerations. First, the EDSS has a low sensitivity for identifying clinical improvements in MS patients. While this scale is widely used in most MS studies, it is not often used in day-to-day medicine and is not sensitive to changes in a patient’s condition, particularly once they have difficulty walking. These shortcomings of the EDSS have been described as follows: the EDSS over-emphasizes the ability to walk, is insensitive to cognitive dysfunction in MS, is difficult to calculate with complex rules for rating findings on neurological exam and translating these into scores on functional system status, and is not sensitive to many clinical changes that a person with MS experiences. Second, the lack of correlation
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between a significant improvement in the hemodynamic and clinical parameters may have occurred because our patient population was suffering from MS with a high baseline level of disability (EDSS average 5.4) and progressive disease. Even the rehabilitation of motor dysfunction in patients with MS is affected by the degree of disability at baseline and duration of the disease, which likely occurs because of the prevalence of stabilized neurological damage.17 The statistical analysis of our population allowed us to identify ‘‘responder’’ patients with a VHISS reduction >30%. A significant change in the VHISS could be considered an index of the efficacy of PVA in terms of ‘‘hemodynamic’’ success but not in terms of ‘‘clinical’’ success. With regard to the group of nonresponders, one of the possible causes of failure of the angioplasty procedure could be related to the observed high percentage of miopragic jugular veins, due to the increased distensibility of the vein wall.13 The small sample analyzed does not permit us to derive definitive conclusions; however, it does allow us to formulate a working hypothesis to be transferred to a study with a larger population. Currently, we are not able to determine which group of CCSVI patients will achieve the greatest clinical and quality-of-life improvements when treated by endovascular methods. In addition, we do not know whether the method described here can be used as a diagnostic parameter to assess the success of endovascular treatment in immediate- and mid-term follow-up. With the growing number of patients treated with endovascular procedures and the methodology and quality of available studies, there is an urgent need for a well-designed randomized controlled trial. In addition, there is an urgent need for unified multimodal CCSVI diagnostic criteria.
Conclusion In patients treated with IJV PVA, we have observed a significant reduction in the VHISS, an index that is able to determine venous flow alterations in CCSVI patients. In patients with a VHISS variation of >30% after PVA, there is a corresponding but non-significant improvement in the EDSS. For this reason, we believe that the VHISS can be very helpful in assessing the hemodynamic response to angioplasty procedure for these patients; however, additional randomized studies with more subjects will be needed to determine whether there is a correlation between VHISS variation and clinical improvement. Close cooperation among neurologists, radiologists/interventional cardiologists, and vascular surgeons is required to reach definitive conclusions.
Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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