University of Pisa
Department of Translational Research and New Technologies
in Medicine and Surgery
Residency Program in Diagnostic Radiology
(2012-2017)
Chairman: Prof. Davide CaramellaPercutaneous angioplasty of internal jugular and azygous veins in patients with
chronic cerebrospinal venous insufficiency and multiple sclerosis: preliminary
results for a randomized controlled trial.
Supervisor:
Candidate
Prof. Davide Caramella, MD Dr. Fabio Signorini, MD Academic Year 2015-2016Abstract
Purpose: The aim of this study is to assess the hemodynamic efficacy and safety of Percutaneous
Transvenous Angioplasty (PTA) in patients with CCSVI and MS, comparing the pressure values measurements obtained by venous catheterization (CV) in the three IJV segments (J1-J2-J3) and azygos vein before and after PTA, to the neurophysiopathological clinical parameters of multiple sclerosis.
Study design and methods: This is a Phase II monocentric clinical, prospective, open randomized trial assessing the efficacy and safety of PTA. From December 2011 to November 2017, 55 patients with relapsing remitting MS, secondary progressive MS or primary progressive MS, positive at color-doppler sonography (CDS) for at least two Zamboni criteria for CCSVI and a neurologist-confirmed diagnosis of MS, have been enrolled. After providing their informed consent, patients were admitted to our department and underwent diagnostic phlebography and endovascular treatment for CCSVI. Primary endpoints are (1) a quantitative evaluation of postoperative gradient pressure in the three IJV segments (J1-J2-J3) and azygos vein, (2) comparing them to the neurophysiopathological clinical parameters between two groups (group A Sperimental, n=31; group B Control, n=35) and different stages of MS (RR0; n=30) (SP1; n=15) (PP2; n=10). Procedural success and complications within 30 days have been included as secondary endpoints.
Results: Post-PTA angiographic control showed stenosis resolutions in all patients. Postoperative
gradient pressure measurements decreased in the three IJV segments (J1-J2-J3), azygos vein and different stages of MS with no statistical significance (p value: >0,05). No stents were ever implanted in the IJV. The feasibility rate was as high as 53/55 (96.3%): 2 patients (3.6%) were not catheterizable and in 5 patients (9.1%) orthodromic access for performing PTA was chosen only on left jugular vein. Overall major and minor complication rates at 30 days were 0,05% and 0,02%, respectively. Clinical analysis did not show significant improvement (or worsening) associated with the intervention between groups ( A, sperimental / B, control, p value >0,05), and different stages of MS (RR 0=30 p value >0,05) (SP1= 15, p value >0,05) (PP2= 10, p value >0,05).
Conclusion: Endovascular treatment of the IJV proved to be a safe procedure (major complication
<0,05%) with no significant improvement of flow haemodynamic parameters and no significant variations of clinical conditions in patients with CCSVI and MS. The study provided standardization of diagnostic (ECDs) and angiographic (PTA) protocols, useful in possible future multicentric, blinded, randomized clinical trials.
Keywords: percutaneous angioplasty, chronic cerebrospinal venous insufficiency, multiple sclerosis,
Introduction:
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. Since 2009, chronic cerebrospinal venous insufficiency (CCSVI) has been suggested by the international scientific community as a nosological entity, characterized by restricted venous outflow from the brain, mainly due to blockages of the internal jugular and azygos veins [1,2]. Dilatation procedure of the stenotic veins, performed by percutaneous trans-catheter angioplasty (PTcA), suggested possible improvement in MS clinical course and quality of life.
The available clinical trials, about the association between CCSVI and SM, and the effects of corrective angioplasty treatment, have showed contradictory results and do not provide evidence of actual efficacy of the treatment. Results since 2009 have been extremely discordant, showing association percentages between CCSVI and SM ranging from 0 to 100% [3-5]. The results of the "CoSMo"[3] study proved a prevalence of CCSVI in SM patients of 3.26% and 2.13% in healthy controls, while the meta-analysis conducted by Zwischenberger and Beasley [4] had opposite conclusions with a significant association between CCSVI and SM (odds ratio 1.885, p value <0.0001). However both studies are not flaweless and cannot considered for an absolute reference.
The diagnosis of CCSVI is performed by ultrasonography based on the presence of at least 2 of 5 Zamboni’s specific morpho-functional diagnostic criteria related to internal jugular and vertebral veins (Table I).
Using extracranial and transcranial sonography it’s possible to distinguish MS patients from controls with 100% sensitivity and specificity [6].
It has been shown that the presence of at least two or more (2/5) Zamboni’s criteria (parameters 1–5) in the same patient were suggestive for diagnosis of CCSVI and that PTA was indicated to solve cerebral venous drainage impairment [1]. Zamboni et al. [8] showed that endovascular treatment (PTA) of CCSVI significantly improved MS clinical outcome, especially in the relapsing remitting group (p value < 0.0001), with reduction of the relapse rate by more than four times in the year subsequent to the procedure as compared with the preceding year.
Mandato KD, Zamboni P and Petrov L et all. observed no significant post-operative complications in patients with CCSVI and MS with different stage disease [9-11]. However restenosis or back to the past for defective venous drainage can occure frequentely. In a follow-up of 18 months, a 43% of restenosis was observed for treatments performed at internal jugular veins [8,13].
The lack of a standard reference therapy for MS patients, the impossibility to obtain a completely unbiased study design for endovascular procedures and the disagreement between different specialists seem to impair a substantial solution of the problem: is the endovascular treatment in patients with SM and CCSVI effective or not? The aims of this study are to assess the hemodynamic efficacy and safety of PTA in patients with CCSVI and MS and compare the pressure value measurements obtained by venous catheterization (CV) and clinical outcomes before and after endovascular procedure in patients with SM and CCSVI.
Purpose:
Referring to the data obtained from the multicentric study on the diagnosis and treatment of CCSVI in patients with MS, currently in progress at our hospital after permission of local ethical committee, the aims of this study are to assess the successful and safety of PTA in patients with CCSVI and MS in term of hemodynamic change before and after PTA, comparing the pressure value measurements obtained by venous catheterization (CV) in the three IJV segments (J1-J2-J3) and azygos vein to the neurophysiopathological clinical outcomes of multiple sclerosis. Procedural success and complications within 30 days have been included as secondary endpoints.Matherials and methods:
From December 2011 to November 2017, 418 patients were registered, but only 165 (39.5%) had a neurologist-confirmed diagnosis of MS (relapsing remitting MS (RR 0=30), secondary progressive MS (SP1= 15) or primary progressive MS (PP2= 10)(TableII).
Table II. Flow chart population
The informed consent was obtained in 161/165 patients, that were evaluated with diagnostic Doppler ultrasonography in the sitting and supine positions. We analysed the morphology of the IJV, azygous, vertebral (VV) and intracranial veins using high-resolution B-mode ultrasonography. The ECD examination protocol for the diagnosis of CCSVI reported below is obtained by means of the methodology originally proposed by Zamboni. Further it is curated and edited on behalf of the SIRM Vascular and Interventional Radiology Section.
Out of 161 patients, 47 (29.2%) had normal ultrasonographic findings, while 114 patients (70.8%) had CCSVI, which included IJV or vertebral veins morphological abnormalities, was verified. Following
Zamboni’s echographic study protocol it is considered suggestive for diagnosis of CCSVI, thus selecting patients for endovascular procedure, the presence of at least two or more (2/5) echographic criteria in the same patient [8,10,11] (Table III). Participants at randomization phase included 66/114 patients (57%) with MS and CCSVI.
Table III. Inclusion and exclusion Criteria
To create a control group the patients were randomized into two groups (experimental group A, n=31; control group B, n=35). Simple type (1: 1) central randomization, through the consultation of the random number tables (Table IV), was considered as appropriate.
The randomization procedure was chosen to prevent generating imbalance between the two groups of confounding factors related to patient characteristics. The group A was considered the experimental group whose patients underwent PTA immediately after enrolment, while the group B constituted the control group whose patients remained waiting for a subsequent PTA. Thus 24 patients of the control group (B) underwent a dilative angioplasty procedure within 6 months period after enrolment, while 11 patients of the group B drop out between baseline (T0) and PTA. To consider the efficacy of the
experimental treatment as the only distinguishing characteristic between the two groups we performed the assessment of clinical outcome change based on two consecutive measurements of clinical parameters as before/after PTA in experimental group A, while as two simple
consecutive measurements without PTA in the control group B. We supposed that this unusual and customized study design is necessary to evaluate the efficacy of experimental treatment based on PTA against non-treatment at the initial stage of the study without applying other form of control (including not well accepted sham procedure or placebo endovascular procedure). Once the endovascular procedure was performed the patients of control group B meet the same conditions of the experimental group A, definitively resulting in a unique longitudinal cohort of patients in which the endovascular procedure was the treatment choice.
Repeteated measurements of clinical outcomes rely on cinematics test, potential-based tests, and neuroresistive tests were performed and analyzed in the experimental group (A), first time at baseline T0 and second time after the angioplasty procedure (past one months). PTA was performed on average 47 days after basaline T0 tests. In control group (B), were performed and analyzed test first time at baseline T0 and second time past six months, before the angioplasty procedure. (Table IV). The neuro-functional parameters considered are: 1) pattern PEV; 2) PEM upper limbs, by transcranial magnetic stimulation (TMS); 3) PEM lower limbs, by transcranial magnetic stimulation (TMS); 4) motor disability; 5) Pathological Fatigue; 6) Urinary Urgency; 7) Algic syndrome; 8) Autonomy; 9) Quality of life. (Attachment 1 Table II.) ECD Protocol for CCSVI Diagnosis: CCSVI assessment was performed by a single skilled and trained operator with an experience of vascular ultrasound of more than twenty years and who gained his attended cerficate at Zamboni’s center training before starting the experimental study. All the echographic examinations were performed by using a CCSVI dedicated color duplex system ultrasonic device, Esaote MyLab VINCO, equipped with a
linear transducer of 3.5–10MHz for extracranial veins evaluation and aphased array transducer of 2.0-3.3 MHz for intracranic veins assessment.
The evaluation of these veins is obtained by associating, in addition to the usual colorimetric and Doppler analysis, a particular technology defined as Quality Doppler Profile (QDP technology). QDP allows multiple signals to be captured at the same time using a larger number of sample volumes positioned on different vessels so that not only are the 3 directions visible at the same time, but we can also detected whether changes in the inspiration and exhalation occur Flow direction.
Each probe has a specific preset and software programmed to detect the 5 parameters proposed by Zamboni. The Ecocolordoppler has to be set with a PRF (Pulse Repetition Frequency) working at levels <= 1.00 KHz to allow the detection of venous haemodynamic parameters. Before starting the exam, the patient receives instructions about respiratory maneuvers, which can be used in the following exam: • Quiet breathing: it is required to inhale and exhale with the nose without moving the shoulders in order to activate the respiratory pump and check if there is induction of cerebral spinal drainage.
• Deep breathing: it involves inhalation and forced exhalation through the mouth with the aim of obtaining the maximum flow in the vessels to be examined (especially for the study of intracranial vessels) and to evaluate the proper functionality of the valve apparatus, in particular the opening during inhalation and expiration.
• Valsalva's Maneuver: the purpose is to correctly locate the internal jugular veins (which are not detected by ultrasonography) as well as to evaluate the continence of the valvular apparatus. The patient has to push with the abdomen keeping mouth and nose closed.
During the examination in the supine position and quiet breath, many IJVs were not visible. During the Valsalva maneuver the same IJVs were visible and evaluable. However the Valsalva maneuver is not recommend to diagnose CCSVI related hemodynamic alterations because of his anti-phisiological nature and his utility is just intended simply to localized the anatomical position of the internal jugular vein and to distinguish between ”true” hypoplasia with the lack of venous lumen dilation and “pseudo” hypoplasia in which a progressive lumen venous dilatation turns it up.
the left one; second part of the exam involves a transcranial part; in third part the patient is placed upright (90 ° head) following the same protocol, in order to confirm eventually positive findings found out at the first part of the exam. Extracranial part of the US exam: 1) Transverse area's measurement of Internal jugular veins
With a transverse scan located in J2 is possible to evaluate the perviety of the IJV, besides is also possible to measure the IJV's transverse area, making a minimal compression on the skin with the transducer (because we do not want a change the IJV diameter) oriented perpedicularly in comparison to the vessel's path (ellipse on the freezed image obtained with a software).
The comparison between the difference of the area misured with the inclination of 0° and 90° allows the evaluation of the compliance of the IJV in relation with the patient's posture [10]. Physiologically subtracting the area measured in orthostatism and clinostatism we obtaine a positive result (∆area) and this is due to a good compliance and a correct cerebral venous outflow. Instead if the compliance is not efficient we obraine a negative ∆area, and this can be explained by the loss of the postural regolation wich is necessary to ensure the correct cerebral venous outflow. 2) Evaluation of the venous reflux Analysis of IJV and Vertebral veins: We studied the IJV, both with transvers and longitudinal scan in each segments (J1-J2-J3), and the flow direction was evaluated with the color parameter compared to the one viewed in the carotid artery. The diagnosis of venous reflux can be made only if during normal breathing, we register at the end of the inspiratory phase an inversion of the flow's direction for at least 2 seconds. The venous reflux diagnosis can only be formulated if during normal breathing we register an invertion of the flow direction at the end of the inspiration phase for at least two seconds. Is necessary to obtaine a spectrographic and colorimetric report, because from this is possible to calculate with precision the time paramether. Further by using QDP technology the operator can be helped to evaluate more than one type of venous reflux suggesting a partial venous reflux (or bidirectional venous flow) instead of a total venous reflux.
In case of difficult jugular exploration because of the collarbone, is possible to use a microconvex probe, which thanks to his shape allows a better observation of the IJV's distal segment.
Vertebral veins are studied with longitudinal scan after viewing the path of the vertebral artery, evaluating the opposite direction of the flow in the veins compared to the arterys. Usually the hemodynamic evaluation of the venous cerebral outflow is done in the intracanalicular portion of the vertebral veins, and also for this venous distric is necessary to obtain a spectrographic and colorimetric report.
Further evalualtion is needed to identify the possible presence of intraspinal circles's opacization, which is possible in case of azygos vein's obstruction or ileolombar/ ascending lombar vein's agenesis; in theese situations the blood is forced to flow trough the internal vertebral plexeses because of the agenesis of the external ones. This causes an overload of the internal plexeses, which is visible with ECD, therefore the view of the internal vertebral plexeses means an obstruction of the extravertebral plexeses. 3) Evaluation of venous flow absence (arrest of the cerebral venous outflow) Flow is not evident with ECD in IJV/VV the scan is made as for the evaluation of the flow's direction. To demonstrate the absence of the flow, a decrease of the PRF to 0.7 Mhz is needed. 4) B-mode evaluation of the morphologic abnormalities We perform a B-mode scan of the whole IJV to highlight the potential presence of venous abnormalities. The microconvex probe can be used to study better the point of comunication between IJV and the subclavan vein, because at this point is located the valvular apparatus and is essential to evaluate his functionality both during normal breathing and deep breathing. This way we are able to see the opening and closing of the valve according to the breathing phases, and to provoke an arrest of the cerebral venous blood outflow. Transcranial part of the US exam: 5) transcranial part of the US exam The transcranial part is performed with a phased array probe (2.0-3.3 mHz). We used two methods for the intracranial venous reflux: 1. traditional, transparietal for the study of the Rosenthal vein
2. untraditional, supracondylar for the study of the skull base veins and the grey substance veins. We performe this method positioning the probe at the level of the mandibular condyle with an inclination of 45°-60°, then we use the color module (CFM) and we ask the patient to perform a relaxed breathing.
The intracranial veins have both during inspiration and exhalation the same flow direction, for example the blood in the grey substance veins goes from the grey substance to the white substance. Only in pathological conditions is possible to view a change of this direction, and this is the sign of an intracranial reflux.
At the end of the extracranial and transcranial evaluation performed in orthostatism we change the patient's position to clinostatism, and after about 5 minutes we repeat the exaxt same procedure for all the districts.
Completed the aquisition of all the morphologic and hemodynamic data, we fill out a report, which process all the data automatically thanks to a software. In the report are specified the pathological data, which allow us to diagnose CCSVI and to define an emodynamic gravity score (VHISS). The exam is complitely performed in protected rooms for duration of approximately 90 minutes. The partial videorecording, including the view of the main venous abnormalities and the photographic records has been performed in all the patients. Endovascular procedure:
Based on the clinical characteristics of the patient, he underwent to PTA by local anesthesia and transfemoral approach.
The SIRM (Sezione di Radiologia Vascolare ed Interventistica) has described the guidelines for the correct execution of the angioplastic treatment of CCSVI in patients affected by MS.
The procedure is executed with two angiographic device (GE INNOVA 4100 Cath/Angio Suite and GE Healthcare InnovaTM IGS 540 Image Guided System) in a room prepared for angiography and interventional radiology. This device allows the aquisition of multiple two-dimensional images along a circular trajectory greater than 180°.
The 2D projections obtained are converted in axial images similar to those of the TC with a reconstruction algorithm 3D cone-beam.
Patient preparation: 1 informed consent; 2 local anesthesias in groin area; 3 heparinization of the
patient
Diagnostic procedure:
• Placement of a 15 cm long valvular introducer 7-9 Fr (Cordis®, AVANT+ introducer, Cordis Cashel, chair Road Cashel. Co Tipperary. Ireland) in the femoral vein with Seldinguer technique, possibly in the left one because helps the ascending catheterization of the left Ileo lumbar vein (IL).
• Ascending chateterization (recomended with catheter 4Fr Radifocus® Glidecath® - Hydrophilic Angiographic Catheter, Vertebral/ Simmons/Sidewinder1; Cordis®, SIM 1, Super Torque®; Cordis®, H1, Super Torque®) of the left IL followed by the flebography (mdc injection: 20-30 ml, 4 ml/s) of the lumbar district in postero-anterior projection wich aims to study the paravertebral vein circulation. If the catheteterization of the left IL is complicated, could be catheterizated a lateral sacral vein or directly a lumbar vein. • VCS catheterization and manometry • Azygos vein catheterization, manometry and flebography in postero-oblique projection (mdc injection: 10-30 ml, 3-8 ml/s)
• IJV manometry, and flebography in postero-anterior and oblique projection after the placement of the cathter at the height of the mandibular angle (mdc injection: 8 ml, 3 m/s). It's advisable to let the patient breathe deeply and make the valsalva maneuvere, because theese procedures help the venous outflow and the valves opening. Vertebral veins retrograd catheterization and flebography with manual injection. Significant stenosis is generally defined as any artery lumen reduction greater than 50% on angiographic exam, which is somewhat arbitrary [5]. Although CV is considered the gold standard for detection of venous anomalies indicative of CCSVI [41], no established criteria or guidelines currently exist. New categorical criteria, categorized into four grades based on IJV venographic flow patterns, were recently proposed [12].
Grade 1: venous outflow slowed down, no reflux detected (Figure 1);
Grade 2: venous outflow slowed down, mild reflux and/or prestenotic dilation of the vein (Figure 2);
Figure 1: Grade 1 (1- IJV; 2- Stenotic Valve)
Figure 2: Grade 2 (1- IJV; 2- Stenotic Valve; 3- Prestenotic dilatations of the vein)
Figure 3: Grade 3 (1- IJV; 2- stenosis; 3- outflow through collaterals) Figure 4: Grade 4 (1- internal jugular vein; 2- no outflow through IJV; 3- outflow through collaterals)
Grade 3: venous outflow slowed down, with reflux and outflow through collaterals (Figure 3);
Grade 4: no outflow through the vein, huge outflow through collaterals (Figure 4).
In our study, all these grades are considered abnormal and if these coinciding with ECD's diagnosis, require endovascular correction (Table V) [12].
VENOUS DISOBSTRUCTION WITH ANGIOPLASTIC PROCEDURE: Cervical venous angioplasty for CCSVI can be performed by the National Health Service for free (ICD-9-CM: 3950) in interventional radiology centers accredited for the treatment of vascular patologies. After dimonstration of CCSVI with flebographic (Table VI) and ECD criteria, the endovascular procedure (PTA) was performed in the stenotic segments. The PTA was executed with adequate size compliant baloon catheters, at level of stenosis in extracranial and azygos veins. In case of significative stenosis was performed an invasive evaluation of the pressure and the trans-stenotic pressure gradient. Interventional procedure of Azygos vein: − angioplasty with compliant baloon catheters (Wanda™ PTA Balloon / Atlas® GOLD PTA Dilatation Catheters): 8-12 mm (caliber), 2-4 cm (lenght) inflated with a maximum of 14-18 atm, the insufflation lasts for 30-60 sec and is repeated several times − after the angiopasty is performed flebography and control manometry of the Azygos. Interventional procedure of jugular veins: − angioplasty with compliant baloon catheters (Wanda™ PTA Balloon / Atlas® GOLD PTA Dilatation Catheters): 10-22 mm (caliber), 2-6 cm (lenght) inflated with a maximum of 18 atm − when the post-procedure result is not sufficient, the dilatation is performed with non compliant baloons (Atlas® GOLD PTA Dilatation Catheters) inflated with high pressure (18-20 atm) the insufflation lasts for 30-60 sec and is repeated several times − after the angiopasty is performed flebography and control manometry of the jugular veins. Interventional procedure of vertebral veins: − angioplasty with compliant baloon catheters (Wanda™ PTA Balloon/ Atlas® GOLD PTA Dilatation Catheters): 8-10 mm (caliber), 2-4 cm (lenght) inflated with a maximum of 8 atm. We used baloons with length between 2-60 mm (mean 45 mm; median 40 mm) and caliber between 8-22 mm (mean 12 mm; median 10mm), in all patients after the procedure a pressure evaluation was performed in basal conditions and during Valsalva maeuvre.
Related to the venous lesions morphology (presence/assence on upstream venous dilatation, presence/assence of intracranial veins apperance and type of the minus impression on the compliant balloon) we were able to distinguish the following abnormalities: Venous abnormalities: • Hypoplasia: the vein is underdeveloped and with reduced caliber for long segments, also during Valsalva maneuvre, is not visible any minus on the compliant baloon during PTA. (Fig. 5)
• Vascular septum: the vein has an abnormal flap in different plane of valvular’s level, wich causes a sub-total occlusion with presence of extracranial plessus veins opacization (vertebral vein/paravertebral vein).(Fig. 6 a)
• Unclassifiable: the vein has a wall abnormality wich causes a sinificant oblstacle to the flow at the level of the juncion between IJV and brachiocephalic vein, with presence on upstream venous dilatation and minus impression on the compliant balloon, without any further classifiable abnormailty.(Fig. 6b; 6c)
Figure 5: Hypoplasia. Orthodromic access for performing PTA on left jugular vein.
Figure 6: Vascular septum (a); Unclassifiable Venous abnormalities (b; c)
Valvular abnormalities:
• Thickened valve: this valve's abnormality causes a significant obstacle to the outflow with MdC stasis and venous dilatation in the upper segments, and possible presence of intracranial veins opacization, without minus impression on the compliant balloon. (Fig. 7 a, b)
• Valve Anulus: this valve's abnormality causes a significant circular stenosi showed by a circular minus impression on the compliant balloon. (Fig. 7 c, d)
Figure 7: Thickened valve (a; b); Valve Anulus (c; d)
Occasionally after the procedure were observed complications as small bleedings with hematomas in the vascular access, as temporay headache (with spontaneous resolution). The post-procedure observation lasted in mean 4 hours and the patients were dimitted with a compressive groin medication, placed over the insertion point. Low molecular weight heparin was given pre-emptively for the following three weeks in all the patients who were subjected to the angioplastic procedure. Evaluation of neurofunctional outcomes: Neurophysiopathology tests: We can divide the Tests in three categories: (Attachment 1: Table II a-b-c-d-e for clinical evaluation ; Table III f, g, h for standardised results) − Cynematic tests (n=12); because of strumental reasons the reaction times were excluded − Evoked potential tests (n=16)
− Neurofuntional tests (n=27) Almost all the tests provided quantitative results, except for three wich provided qualitative results. For each test we tried to figure out if was possible to show an improvement (or a deterioration) of the clinical results of a group compared to the other, considering two measurements at time T0 (baseline) and T1 (after PTA). Therefore we selected those tests with at least five patients with pathological values at T0 (to evaluate a
possible improvement) or normal values at T0 (to evaluate a possible deterioration) both in the
sperimental and the control group.
For clinical improvement analysis the following tests were excluded: Attentive matrices test, Trail making test-a, Trail making test-b, Trail making test-c, WEIGL, DSST, MMSE, clinical evaluation of disarthria and dysphagia; so we analyzed tests. For clinical deterioration analysis the following tests were excluded: Mental MSQL and physical MSQL. Evoked potentials were evaluated only for the clinical deterioration, because improvement is never possible due to the irreversible neurologic damage in MS.
Statistical analysis:
Pressure Analysis: Continuous data were described by mean and standard deviation. To evaluate the
normality of the quantitative data distributions, the Kolmogorov-Smirnov test was performed. In order to compare the pressure variables between the two groups (experimental and control) of each single stretch of the jugular district, the Student t test for independent samples (two-tailed) was used and to search differences between pressure variables related to the three stages of illness ( RR0, SP1 and PP2), one-way ANOVA was applied. Differences were considered significant at p < 0.05. All analyses, descriptive and inferential, were performed using the SPSS v.23 technology.
Neurophysiopathologic analysis: we conducted the Analysis with two methods, the first one with
unrefined standardized data (z-score) and the other with a clinical approach (using anyway the unrefined data gained by the tests). A number of patients greater than 5 was allowed to notice an improvement/deterioration statistically significant.
In particular, established alfa and the power (0,05 and 0,8 respectively) with n=5 is possible to evaluate as statistically significant, a variation between the two measurements of at least the 80 %, wich is particularly high.
For theese statistical analysis we used the Chi-quadrat test or the Fisher's exact test, when possible (n<40). Hence we built a 2x2 contingency table, describing in the columns the groups (control/sperimental) and in the rows the clinical variation (improvement yes/no, deterioration yes/no). The variability of the unrefined data, before and after the procedure is substantial, so was chosen to standardize the data due to make them more comparable (using z-score). Therefore we calculated the time variation (T1 – T0) of the z-score for each quantitative test, and then we compared the two groups using a student's T-test (two tailed). The established significance level was 5% (p-value< 0,05).
Institutional review board approval
The aim of this study is to offer for free, in highly specialized centers a treatment that is provided by a lot of private structures for a fee, both here in italy and in other countries. The patients affected by MS and the associations believe that would be very important, to provide this procedure in landmarks as public hospitals. The study was conducted following the rules of the Good Clinical Practice (GCP), and we asked to each patient to sign an informed consent, after informing them about the right to exit from the study whenever they wanted. We will realize standard procedure to ensure the full respect of the privacy's right for all the patients of the study.Results:
Demographic, clinical and vascular characteristics of the patients are summarized in Table VI.
Endovascular procedure:
Endovascular therapy showed a stenosis resolution in all the patients, by evaluation of the vascular remodeling in the post-PTA angiografic control.
The feasibility rate was as high as 96,3% (2, 3.6% no catheterizable; 5, 9,1% Orthodromic access for performing PTA only on left jugular vein). No stents were ever implanted in the IJV.
Left ascending ileolumbar vein catheterisation was performed in all patients and no lateral sacral catheterisation or direct lumbar spine. Local anesthesia was performed in all patients in the venous access site by administration of 5000 UI of heparin in 48/55 patients (87%) and 7500 UI in 7/55 (12%). Three types of non-ionic iodine contrast media were used: Visipaque 320 in 49/55 patients (89%), Ultravist 370 in 4/55 patients, (7.2%) Xenetix 350 in 2/55 (3.6%).
The most common location of IJV’s abnormalities was J1 segment (83.6% J1dx and 92.7% J1sx); CV flebography showed, in 65.5% (DX) and 70.9% (SX) of the patients unclassifiable venous abnormalities (Table VI). Valvular abnormalities in IJV were detected in 32/55 patients (58.1%).
The most common imaging of Venous abnormalities was hypoplasia (12.7%, 1.8% dx only J3 and 10.9% sx in J1-2-3) and presence of Vascular septum (9.09%, 7.3%dx and 1.8%sx), while most abnormalities detected were Unclassifiable anormalies (65.5% dx and 70.9% sx).
The most common imaging of Valvular abnormalities was Valve Anulus (7.3%sx), but most of the analyzed segments did not detect valvular anomalies (85.5%dx and 76.4%sx).
IJV PTA was performed bilaterally in 81.8% of patients, unilaterally in 14.5% and in 7.2% of patients azygous vein and bilateral IJV PTA was done (Table VI). PTA of the left IJV only was done in 5 patients, and of the right IJV only in 3 patients while in 8 patients, we did bilateral IJV PTA. Left IJV PTA was done in 49 patients and right IJV PTA in a total of 47 patients. In 4 patients (7.2%), we did azygous vein PTA. Gradient pressure values were measured prior and after PTA in the IJV segment (J1-2-3). We were able to measure IJV and SVC gradient pressure in a total of 52/55 patients. The reasons why we were not able to measure the pressure gradients in some of the patients were: very small inner IJV
diameter (n=2, J3sx for hypoplasia), expressed IJV stenosis (n=1, J3sx for tight stenosis and hypoplasia) during the ortodromic access procedure.
Postoperative gradient pressure decreased in the three IJV segments (J1-J2-J3) and azygos vein but it’s not statistically significant (P>0.05) (Table VI- VIa).
Pressure Variables Group N Average DS p-value
J3 DX DIFF. BASELINE A 25 -0,80 2,000 ns B 20 -1,40 2,644 J3 DX DIFF. VALSALVA A 25 -0,20 5,723 ns B 20 -0,30 4,014 J2 DX DIFF. BASELINE A 25 -1,12 2,068 ns B 20 -1,35 2,007 J2 DX DIFF. VALSALVA A 25 -0,56 7,142 ns B 20 -0,25 3,985 J1DX DIFF. BASELINE A 25 -2,00 2,273 ns B 20 -2,05 2,460 J1DX DIFF. VALSALVA A 25 -0,88 5,747 ns B 20 0,50 6,637 J3SX DIFF. BASELINE A 24 -1,04 1,042 ns B 18 -1,11 2,139 J3 SX DIFF. VALSALVA A 24 2,50 9,051 ns B 18 1,11 6,685 J2 SXDIFF. BASELINE A 25 -1,16 1,434 ns B 18 -1,56 2,431 J2 SX DIFF. VALSALVA A 25 1,48 7,682 ns B 19 0,26 9,723 J1 SXDIFF. BASELINE A 25 -1,12 0,881 ns B 19 -1,74 2,077 J1 SXDIFF. VALSALVA A 25 -0,04 7,294 ns B 19 -0,47 9,817 DIFF. VAZY BASELINE POST-PRE A 2 0,50 ,707 ns B 2 -0,50 2,121 DIFF. VAZY VALSALVA POST-PRE A 2 -1,50 2,121 ns B 2 0,00 7,071
Table VI. Pressure variables of each single section of the jugular/VCS region (post-pre) in patients
underwent to bilateral PTA, between two study groups. ns : not significant.
Pressure Variable Group N Average DS p-value
J3 DIFF BASELINE SX A 5 0,200 0,8367 ns B 3 -2,333 2,5166 J3 DIFF VALSALVA SX A 5 1,200 3,7683 ns B 3 4,333 10,1160 J2 DIFF BASELINE SX A 5 0,600 1,1402 ns B 3 -2,000 2,0000 J2 DIFF VALSALVA SX A 5 3,800 8,7006 ns B 3 -2,000 2,0000 J1 DIFF BASELINE SX A 5 0,000 1,2247 ns B 3 -2,000 1,7321 J1 DIFF VALSALVA SX A 5 -4,000 5,1478 ns B 3 -8,667 6,1101
Table VIa. Pressure variables of each single section of the jugular region (post-pre) in patients
underwent to monolateral PTA (SX) between the two study groups. ns: not significant.
No statically significant difference was noted when gradient pressures were observed after percutaneous angioplasty in different stages of MS (RR 0=30 p value> 0.05)(SP1= 15, p value> 0.05)(PP2= 10, p value> 0.05) Table VIb.
Pressure Variable Sperimental Control
N Average DS N Average DS p-value
J3DXDIFF. BASELINE RR0 14 -1,143 2,1070 11 -1,273 1,7373 ns SP1 8 0,125 1,8077 5 -,800 4,0866 PP2 6 -0,667 1,5055 4 -2,500 3,1091 Totale 28 -0,679 1,9255 20 -1,400 2,6438 J3DXDIFF.VALSALV A RR0 14 -0,143 4,7045 11 1,091 3,9104 ns SP1 8 -0,750 7,8876 5 -3,200 4,3818 PP2 6 1,833 4,4907 4 -0,500 2,0817 Totale 28 0,107 5,6065 20 -,0300 4,0144 J2DXDIFF. BASELINE RR0 14 -1,500 2,1750 11 -1,636 2,5796 ns SP1 8 0,000 1,3093 5 -1,400 1,1402 PP2 6 -0,667 2,5033 4 -0,500 ,5774 Totale 28 -0,893 2,0788 20 -1,350 2,0072 J2DXDIFF.VALSALV A RR0 14 1,286 7,1729 11 -0,455 4,6982 ns SP1 8 -1,250 9,7651 5 0,800 3,4928 PP2 6 -0,333 6,6533 4 -1,000 2,8284 Totale 28 0,214 7,6805 20 -0,250 3,9852 J1DXDIFF. BASELINE RR0 14 -2,571 2,4088 11 -1,909 2,8091 ns SP1 8 -0,750 1,9821 5 -3,400 2,0736 PP2 6 -1,333 2,0656 4 -0,750 ,9574 Totale 28 -1,786 2,2991 20 -2,050 2,4597 J1DXDIFFVALSALVA RR0 14 -0,071 6,9223 11 0,818 8,6350 ns SP1 8 -3,125 4,1897 5 0,200 2,8636 PP2 6 -2,833 4,7504 4 0,000 4,3205 Totale 28 -1,536 5,8340 20 0,500 6,6372 J3SXDIFF. BASELINE RR0 13 -0,846 1,4051 12 -1,250 2,1794 ns SP1 8 -1,000 0,5345 6 -1,167 2,5626 PP2 5 -1,200 0,8367 3 -1,667 2,0817 Totale 26 -0,962 1,0763 21 -1,286 2,1712 J3SXDIFFVALSALVA RR0 13 2,923 10,4918 12 2,667 7,7733 ns SP1 8 -0,625 5,2082 6 2,667 5,5015 PP2 5 5,000 8,4558 3 -5,000 3,4641 Totale 26 2,231 8,7330 21 1,571 7,0397 J2SXDIFF. BASELINE RR0 14 -1,214 1,6257 12 -1,833 2,8551 ns SP1 8 -1,500 1,0690 6 -1,500 1,5166 PP2 5 0,000 1,0000 3 -1,000 1,7321 Totale 27 -1,074 1,4392 21 -1,619 2,3340 J2SXDIFFVALSALVA RR0 14 2,429 6,6299 13 0,846 7,0575 ns SP1 8 -1,875 9,1720 6 -0,333 14,4037 PP2 5 3,400 6,2290 3 -3,333 4,7258 Totale 27 1,333 7,4317 22 -0,045 9,0579 J1SXDIFF. BASELINE RR0 14 -0,786 0,5789 13 -2,154 2,1926 ns SP1 8 -1,500 1,0690 6 -1,500 1,8708 PP2 5 -1,200 1,0954 3 -0,667 1,1547 Totale 27 -1,074 0,8738 22 -1,773 1,9984 J1SXDIFFVALSALVA RR0 14 -1,857 7,5840 13 -2,000 11,7118 ns SP1 8 1,375 6,1164 6 -0,833 7,3598 PP2 5 3,000 6,5574 3 -1,333 5,5076 Totale 27 0,000 7,0438 22 -1,591 9,7182
Table VIb. Pressure variables of each single section of the jugular region (post-pre) in patients underwent to PTA between the two study groups and in different stages of MS. ns: not significant. Postoperative complications (with in 30 days from the procedure): (Table VII)
Major postoperative complications included: acute in-segment thrombosis (3, 0.05 %); no deaths, stroke, anafilattic shock, myocardial infarction, major bleeding events requiring open surgery , IJV/azygos vein rupture/dissection, Surgical opening of common femoral vein to remove balloon fragments or clinical deterioration of MS.
Minor post-operative complications included: puncture site bleeding or groin hematoma (1, 0.01%), common femoral artery pseudoaneurysm (1, 0.01%); no mild contrast reaction, transient cardiac arrhythmia , lung migration of a balloon fragment.
Major postoperative complications
N. Event/%
Acute in-segment thrombosis IJV
3, 0,05 %
Deaths
0
Stroke
0
Anafilattic shock
0
Myocardial infarction
0
Major bleeding events requiring open surgery
0
IJV/azygos vein rupture/dissection,
0
Surgical opening of common femoral vein to remove
balloon fragments
0
Clinical deterioration of MS
0
Minor postoperative complications
N. Event/%
Puncture site bleeding or groin hematoma
1, 0,01%
Common femoral artery pseudoaneurysm
1, 0,01%
Mild contrast reaction
0
Transient cardiac arrhythmia
0
Lung migration of a balloon fragment
0
Neurophysiopathologic tests: According to individual opinion of disease status, at the end of six mounth after PTA significant or mild improvement was not present. During follow-up, none of patients reported worsening of symptoms. The results are summirized in Attachment 1 Table II and III: 1. Tables II a/b describe the evaluation of the improvement in neurorehabilitative and cynematic tests. 2. Tables II c/d/e describe the evaluation of the deterioration in cynematic tests, neurofunctional tests, and evoked potential
3. Tables III f/g/h describe the evaluation of the improvement in cynematic (f) and neurorehabilitative tests (g) and the deterioration in evoked potential (h) (using z-score).
The clinical results did not showed any statistical significance after the procedure about both improvement and deterioration, of a group compared to the other. Cinematics test (balance, motor, sensory), Potential-based tests, and Neuroresistive tests not showed a significant clinical improvement. The variability of the unrefined data, before and after the procedure is substantial, so was chosen to standardize the data due to make them more comparable (using z-score). Therefore we calculated the time variation (T1 – T0) of the z-score for each quantitative test.
Discussion:
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. According to the recently published Consensus Document of the International Union of Phlebology on the diagnosis and treatment of venous malformations [13], Chronic cerebrospinal venous insufficiency (CCSVI) has been recognized as venous truncular lesions of obstructing characteristics that are localized in the territory of IJVs and/or AV.Association between CCSVI and SM has showed contradictory results, with association percentages ranging from 0 to 100% [3-5].
of at least 2 of 5 Zamboni’s specific morpho-functional diagnostic criteria related to internal jugular veins, vertebral veins (Table I) [11]. The presence of at least two or more (2/5) Zamboni’s criteria (parameters 1–5) in the same patient were suggestive for diagnosis of CCSVI and that PTA was indicated [9-11]. Zamboni et all. showed that endovascular treatment (PTA) of CCSVI significantly improved MS clinical outcome, especially in the relapsing remitting group (P < 0.0001) with reduction of the relapse rate by more than four times in the year subsequent to the procedure as compared with the preceding year. Dilatation procedure of the stenotic veins, performed by percutaneous-catheter angioplasty (PTcA), suggests possible improvement in MS clinical course and quality of life.
Mandato KD, Zamboni P. and Petrov L. et all., observed no significant post-operative complications in patients with CCSVI and MS with different stage disease [9-11]. In a follow-up of 18 months, a 43% of restenosis was observed for treatments performed at internal jugular veins [8].
Following the resolution issued by the Superior Health Council (CSS) in February 2011, this study was proposed to evaluate hemodynamic efficacy and safety of PTA in patients with CCSVI and MS and compare the pressure values obtained by venous catheterization (CV) to the neurophysiopathological clinical parameters of multiple sclerosis [19, 15-23].
To date, the use of PTA in patients with SM and venous pathology due to CCSVI is limited "exclusively" to controlled clinical trials, randomized and approved by the Ethics Committees.
In accordance with these limitations, AOUP has activated a care pathway aimed at clarifying the therapeutic utility of percutaneous angioplasty treatment in patients with chronic cerebrospinal venous insufficiency and multiple sclerosis.
In our study PTA was performed in 55 patients with CCSVI and clinically proven MS. CCSVI diagnosis was established according to Zamboni’s criteria (our study parameters 1–5) [9-11].
The Valsalva maneuver is a new parameter to distinguish between True Hypoplasia and “Pseudo-Hypoplasia”; during the examination in the supine position and quiet breath, many IJVs were not visible. During the Valsalva maneuver the same IJVs were visible and evaluable.
As well as in Zamboni’s study the majority of our patients had relapsing remitting form of the disease (30 pts), than secondary progressive MS form (15 pts) while ten patients had primary progressive MS form.
The most common venous abnormalities observed in Zamboni’s study were annulus stenoses and reflux followed by IJV valve malformation [11], however, the most frequent IJV abnormalities verified in our study were IJV Unclassifiable Venous Abnormalities (65.5% right and 70% left) in the J1 (83.6% right and 92.7% left). In addition, only 34% of patients showed valvular abnormalities after angiographic exam. These results might be due to the fact that, even if CV is considered the ‘gold standard’ for assessing and grading endovascular stenoses, it is merely a lumenography, providing little or no data on the vessel walls or valvular structures.
For example, in precedent studies [25-33], the evaluation of valvular Reflux/Incontinence is not reliable. In case of reflux (presence of venous dilatation in the upper segments and intracranial veins opacization) and incontinence (presence of brachiocephalic, succlavian and Superior Cava veins opacization) it’s not reliable because of the presence of the catheter in the valvular’s apparatus and the use of not standardized diagnostic angiographic paramethers (M.d.C Pressure/volume and catheter’s position). In our study, the diagnostic angiographic procedure was performed with standard parameters in each venous segment, but because of the catheter’s presence, the reflux/incontinence’s paramether as valvular abnormality was not evaluable. In addition, malformed and/or reversed valve cusps can be crossed by the catheter and kept open artificially, thereby preventing documentation of stenosis.
Therefore, in cases where only valvular defects are present, it is extremely difficult to measure the degree of stenosis by CV.
Therefore, operator’s experience and proper training are needed for the recognition of abnormal valves or other pathologic intraluminal structures indicative of CCSVI.
Unlike Zamboni studies [35], pressure measurement is obtained in vivo by angiographic-intraluminal catheter at jugular level in a patient with CCSVI and SM. Data obtained in the three anatomical segments of the jugular vein and VCS, before and after treatment, can be compatible with the data calculated with indirect methods [36].
Normal values showed in literature can not be correctly considered cause of not related to the population being studied. We can affirm that our pressures are accurate (direct and dynamic) and linkable with a population affected by CCSVI and MS.
The SVC gradient was measured within the SVC, in the initial SVC part, just after innominate veins merge and form SVC and just before its confluence with the right atrium.
The gradient was measured just after the malformation, in the J1-J2-J3 IJV part, immediately after the treatement.
No statistically significant difference (p value> 0.05) was noted when gradient pressures were observed after percutaneous angioplasty, both within the IJV, azygos vein and different stages of MS (RR 0=30)(SP1= 15)(PP2= 10) Table VII, VIIa, VIIb.
High values of valsalva pressure measured in the IJV (+11.39mmHg) and SVC (+12.39mmHg) respect to basal pressure before and after PTA could be explained by significant influence of different polmonary volume brithing. The significance of pressure differences is in accordance with no statistically significant gradient pressure after PTA.
We believe that improvement in the IJV flow following PTA had a pressure effect within the IJV in particular on J1 level where more lesion have been treated, according to the absence of stenosis following angioplasty. To date, this paremeters represent the most significant angiographic variable for evalueted a significative stenosis. Unlike Zamboni’s study [15,16,23], we verified significantly decreased number of patients with azygous vein pathological lesions. The best results were obtained in patients with vein or valvular stenosis without ipoplasia (94.5%) with rate of postprocedural major complications.
Following angioplasty, Doppler ultrasonography showed only three cases of acute IJV segment trombosis, but in all of this patiens were showed a complete stenosis with no valid hemodinamic flow and hypoplasia on pre PTA diagnosis by ECD of JVC (J1-J2-J3).
However, since we prolonged the time of heparin administration from 15 to 40 days, such a complication has been solved without permanent clinical complication and whitout worseling variation of extra-intracranic circulations.
We believe hypoplasia in IJV segments is a relative contraindication to PTA, for low angiographic response and high thrombotic risk, even if in a hemodynamically dysfunctional vessel. Stents or open surgery could be an alternative procedure [37,38].
Another complications were puncture site bleeding or groin hematoma (1.8%), common femoral artery pseudoaneurysm (1.8%). It was mostly seen in those patients who had a rapid walking capability postoperative recovery. However, it is not possible to exclude that an inadvertent puncture of the veins
bed might have occurred during the attempts at femoral vein puncture, particularly in those cases where puncturing proved whithout CDS guided. According to the results of the present study (1, 1.8%), a proper pre- evaluation of the target vessel with CDS has been re- ported to reduce the rate of complications at the entry site [39,40]. Like Zamboni [23] and Petrov [33] concluded, percutaneous angioplasty as CCSVI treatment in patients suffering from MS showed satisfactory results as safe and effective procedure in our study as well. The main drawback of the present study is the difficult to enroll a great number of patients over a long period of 6 years, due to very stringent selection criteria and the high cost for SSN. It should be noted that, for some neurophysiopathological tests, the number of pathological (or non-pathological) patients to be tested has been very low and therefore it was difficult to evidence a statistically significant improvement (or worsening). Observing data trends at T0 and T1, statistically
significant variations were not appreciable (only one test showed a single worsening) and the stability of disease on individual patients predominate. In particular, in some tests (n = 5) it was possible to detect a statistically significant improvement in the experimental group after the angioplasty procedure since there was a reduction over 80% of the pathological events, in association with absence of improvement in the group control. In most controlled and randomized clinical trials, improvements are estimated at 20-25% [15-17]. We can therefore conclude that only the evaluation of a greater number of pathologic patients will be able to detect any significant trends.
Conclusion:
The study tried to provide an answer regarding the efficacy of PTA on patients’ functional disability with CCSVI and MS.
Endovascular treatment of the IJV in patients with CCSVI and MS is a safe procedure, well tolerated; with no major post-procedural complications, but not significant improvement of IJV flow haemodynamic parameters.
Cinematics test (balance, motor, sensory), Potential-based tests, and Neuroresistive tests not showed a significant clinical improvement.
The study provided standardization of diagnostic protocols (ECDs) and angiographic (PTA), useful in possible future multicenter, blinded, randomized clinical trials.
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