Chronic Cerebrospinal Venous Insufficiency In Multiple Sclerosis Research Articles

Chronic Cerebrospinal Venous Insufficiency: A Failed Concept

Chronic Cerebrospinal Venous Insufficiency: A Failed Concept

Evidence against the Involvement of Chronic Cerebrospinal Venous Abnormalities in Multiple Sclerosis. A Case-Control Study

ObjectiveMultiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS. Recently a controversial vascular hypothesis for MS, termed chronic cerebrospinal venous insufficiency (CCSVI), has been advanced. The objective of this study was to evaluate the relative prevalence of the venous abnormalities that define CCSVI.MethodsA case-control study was conducted in which 100 MS patients aged between 18–65 y meeting the revised McDonald criteria were randomly selected and stratified into one of four MS subtypes: relapsing/remitting, secondary progressive, primary progressive and benign. Control subjects (16–70 y) with no known history of MS or other neurological condition were matched with the MS cases. All cases and controls underwent ultrasound imaging of the veins of the neck plus the deep cerebral veins, and magnetic resonance imaging of the neck veins and brain. These procedures were performed on each participant on the same day.ResultsOn ultrasound we found no evidence of reflux, stenosis or blockage in the internal jugular veins (IJV) or vertebral veins (VV) in any study participant. Similarly, there was no evidence of either reflux or cessation of flow in the deep cerebral veins in any subject. Flow was detected in the IJV and VV in all study participants. Amongst 199 participants there was one MS subject who fulfilled the minimum two ultrasound criteria for CCSVI. Using MRI we found no significant differences in either the intra- or extra-cranial venous flow velocity or venous architecture between cases and controls.ConclusionThis case-control study provides compelling evidence against the involvement of CCSVI in multiple sclerosis.

Cognitive impairment and “invisible symptoms” are not associated with CCSVI in MS

BackgroundWe investigated the association between chronic cerebrospinal venous insufficiency (CCSVI) and cognitive impairment (CI) in multiple sclerosis (MS). Moreover, we evaluated the association between CCSVI and other frequent self-reported MS symptoms.MethodsWe looked at the presence of CI in incident MS patients with CCVSI in a population-based cohort of Catania, Italy. All subjects were group-matched by age, sex, disease duration and EDSS score with MS patients without CCSVI, serving as controls. CI was assessed with the Brief Repeatable Battery (BRB) and the Stroop Test (ST) and it was defined by the presence of at least three impaired tests. Fatigue and depressive symptoms were assessed with Fatigue Severity Scale (FSS) and Hamilton Depressive Rating Scale (HDRS), respectively. Bladder and sexual symptoms were assessed with the respective items of the Italian version of Guy's Neurological Disability Scale (GNDS). Quality of life was evaluated with Multiple Sclerosis Quality of Life-54 Instrument (MSQOL-54).ResultsOut of 61 MS patients enrolled in the study, 27 were CCSVI positive and 34 were CCSVI negative. Of them, 43 were women (70.5%); the mean age was 43.9 ± 11.8 years; the mean disease duration was 159.7 ± 113.7 months; mean EDSS was 3.0 ± 2.6. Of them, 36 (59.0%) were classified relapsing-remitting (RR), 12 (19.7%) secondary progressive (SP), seven (11.5%) primary progressive (PP) and six (9.3%) Clinically Isolated Syndrome (CIS). Overall, CI was detected in 29/61 (47.5%) MS patients; particularly 13/27 (48.1%) in the CCSVI positive group and 16/34 (47.0%) in the CCSVI negative group. Presence of CCSVI was not significantly associated with the presence of CI (OR 1.04; 95% CI 0.37-2.87; p-value = 0.9). Not significant differences were found between the two groups regarding the other MS symptoms investigated.ConclusionsOur findings suggest a lack of association between CCSVI and CI in MS patients. Fatigue, depressive, bladder/sexual symptoms and self-reported quality of life are not associated with CCSVI.

Italian multicentre observational study of the prevalence of CCSVI in multiple sclerosis (CoSMo study): rationale, design, and methodology

Chronic cerebro-spinal venous insufficiency (CCSVI) has been proposed as a “congenital malformation” implicated in the pathogenesis of multiple sclerosis (MS). However, numerous studies failed to confirm its presence in MS patients. This paper presents the rationale, design, and methodology adopted in the CoSMo study, conducted with the aim of verifying whether or not CCSVI is linked to MS. The primary endpoint of the CoSMo study is to compare the prevalence of CCSVI in patients with MS versus patients affected by other neurodegenerative diseases (OND) and healthy volunteers. CoSMo is a multicenter, blinded, prevalence study recruiting 2,000 adult subjects, involving 43 MS centers across Italy. Assessment of the presence or absence of CCSVI is performed by color-coded duplex (CCD) sonography and two out of the five criteria according to Zamboni are necessary for the diagnosis of CCSVI. Local CCD examination carried out by a certified sonologist and the central image readings performed by experts in the field are blinded. An advanced protocol is also described in this paper. The application of a rigorous methodological design will definitively confirm whether an association exists between CCSVI and MS. Should an association be observed, this study also further examines the link between CCSVI and the severity of MS. The addition of subgroups without MS and OND also provides information on whether CCSVI is specific to MS only. Results from the CoSMo study will play a crucial role in the possible studies concerning the potential treatment of CCSVI in MS.

CCSVI and MS: a statement from the European Society of neurosonology and cerebral hemodynamics

To systematically review the ultrasonographic criteria proposed for the diagnosis of chronic cerebrospinal venous insufficiency (CCSVI). The authors analyzed the five ultrasonographic criteria, four extracranial and one intracranial, suggested for the diagnosis of CCSVI in multiple sclerosis (MS), together with the references from which these criteria were derived and the main studies that explored the physiology of cerebrospinal drainage. The proposed CCSVI criteria are questionable due to both methodological and technical errors: criteria 1 and 3 are based on a scientifically incorrect application of data obtained in a different setting; criteria 2 and 4 have never been validated before; criterion 2 is technically incorrect; criteria 3 and 5 are susceptible to so many external factors that it is difficult to state whether the data collected are pathological or a variation from the normal. It is also unclear how it was decided that two or more of these five ultrasound criteria may be used to diagnose CCSVI, since no validation of these criteria was performed by different and independent observers nor were they blindly compared with a validated gold-standard investigation. The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) has considerable concerns regarding the accuracy of the proposed criteria for CCSVI in MS. Therefore, any potentially harmful interventional treatment such as transluminal angioplasty and/or stenting should be strongly discouraged.

Extra- and Transcranial Echo Colour Doppler in the Diagnosis of Chronic Cerebrospinal Venous Insufficiency

A new venous disorder, chronic cerebrospinal venous insufficiency (CCSVI), has been proposed in patients with multiple sclerosis (MS). It is a vascular condition characterized by an impaired cerebrospinal venous drainage due to obstructions in the main extracranial cerebrovenous outflow routes (i.e. internal jugular veins [IJV] and/or azygos veins). In this review, the studies which assessed the prevalence of CCSVI in MS by echo colour Doppler (ECD) will be discussed. The technical aspects of determination of the five CCSVI criteria: (1) reflux in the IJV and/or vertebral veins in supine and upright position, (2) reflux in the deep cerebral veins, (3) high-resolution B-mode proximal IJV stenosis, (4) flow not Doppler detectable in IJVs and/or vertebral veins (VVs) and (5) reverted postural control of the main cerebrovenous outflow pathway are described in detail. We conclude that so far there are many studies with contradictory results, and as yet a strong scientific base to support the evidence for a causative relationship of CCSVI and MS is lacking. Recent studies call into question the validity of using ECD as a proper and reliable test for the diagnosis of CCSVI. One explanation for the variety in interpretation of the individual CCSVI criteria, with the wide-ranging percentages CCSVI, could be the different methods by using ECD to determine various criteria.

Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS

Background: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS). A subject is considered CCSVI positive if ≥2 venous hemodynamic (VH) criteria are fulfilled. Objective: To determine prevalence of CCSVI in a large cohort of patients with MS, clinically isolated syndrome (CIS), other neurologic diseases (OND), and healthy controls (HC), using specific proposed echo-color Doppler (ECD) criteria. Methods: Transcranial and extracranial ECD were carried out in 499 enrolled subjects (289 MS, 163 HC, 26 OND, 21 CIS). Prevalence rates for CCSVI were calculated in 3 ways: first, using only the subjects for whom diagnosis was certain (i.e., borderline subjects were excluded); secondly, including the borderline subjects in the “no CCSVI” group; and finally, taking into account subjects who presented any of the VH criteria. Results: CCSVI prevalence with borderline cases included in the “no CCSVI” group was 56.1% in MS, 42.3% in OND, 38.1% in CIS, and 22.7% in HC ( p p p p = 0.004). Conclusions: Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS.

Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS

Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS). A subject is considered CCSVI positive if ≥ 2 venous hemodynamic (VH) criteria are fulfilled. To determine prevalence of CCSVI in a large cohort of patients with MS, clinically isolated syndrome (CIS), other neurologic diseases (OND), and healthy controls (HC), using specific proposed echo-color Doppler (ECD) criteria. Transcranial and extracranial ECD were carried out in 499 enrolled subjects (289 MS, 163 HC, 26 OND, 21 CIS). Prevalence rates for CCSVI were calculated in 3 ways: first, using only the subjects for whom diagnosis was certain (i.e., borderline subjects were excluded); secondly, including the borderline subjects in the "no CCSVI" group; and finally, taking into account subjects who presented any of the VH criteria. CCSVI prevalence with borderline cases included in the "no CCSVI" group was 56.1% in MS, 42.3% in OND, 38.1% in CIS, and 22.7% in HC (p < 0.001). The CCSVI prevalence figures were 62.5% for MS, 45.8% for OND, 42.1% for CIS, and 25.5% for HC when borderline cases were excluded (p < 0.001). The prevalence of one or more positive VH criteria was the highest in MS (81.3%), followed by CIS (76.2%), OND (65.4%), and HC (55.2%) (p < 0.001). CCSVI prevalence was higher in patients with progressive than in nonprogressive MS (p = 0.004). Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS.

„Chronische zerebrospinale venöse Insuffizienz” bei Multipler Sklerose - Ist die Multiple Sklerose eine Erkrankung des zerebrospinalen venösen Abflusssystems?

Chronic impaired venous outflow from the central nervous system has recently been claimed to be associated with multiple sclerosis (MS) pathology. This resulted in the term chronic cerebrospinal venous insufficiency (CCSVI) in MS. The concept of CCSVI is based on sonography studies showing that impaired venous outflow leading to pathological reflux is almost exclusively present in MS patients but not in healthy controls. Based on these findings, a new pathophysiological concept has been introduced suggesting that chronic venous outflow obstruction and venous reflux in the CNS result in pathological iron depositions leading to inflammation and neurodegeneration. The theory of CCSVI in MS has rapidly generated tremendous interest in the media and among patients and the scientific community. In particular, the potential shift in treatment concepts possibly leading to an interventional treatment approach including balloon angioplasty and venous stent placement is currently being debated. However, results from recent studies involving several imaging modalities have raised substantial concerns regarding the CCSVI concept in MS. In this review article, we explain the concept of CCSVI in MS and discuss this hypothesis in the context of MS pathophysiology and imaging studies which have tried to reproduce or refute this theory. In addition, we draw some major conclusions focusing in particular on the crucial question as to whether interventional treatment options are expedient. In conclusion, the present conclusive data confuting the theory of CCSVI in MS should lead to reluctance with respect to the interventional treatment of possible venous anomalies in MS patients.

Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB1*1501 status in multiple sclerosis patients.

BackgroundChronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.Methodology/Principal FindingsThis study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients.Conclusions/SignificanceThe lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.

The chronic cerebrospinal venous insufficiency syndrome

Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome characterized by stenosies of the internal jugular and/or azygous veins (IJVs-AZ) with opening of collaterals and insufficient drainage proved by reduced cerebral blood flow and increased mean transit time in cerebral MRI perfusional study. The present review is aimed to give a comprehensive overview of the actual status of the art of the diagnosis and treatment of this condition. As far as the origin of venous narrowing is concerned, phlebographic studies of the IJVs and AZ systems demonstrated that venous stenoses were likely to be truncular venous malformations; mostly, they are intraluminal defects such as malformed valve, septa webs. CCSVI condition has been found to be strongly associated with multiple sclerosis (MS), a disabling neurodegenerative and demyelinating disease considered autoimmune in nature. In several epidemiological observations performed at different latitudes on patients with different genetic backgrounds, the prevalence of CCSVI in MS ranges from 56% to 100%. To the contrary, by using venous MR and/or different Doppler protocols, CCSVI was not detected with the same prevalence. Two pilot studies demonstrated the safety and feasibility in Day Surgery of the endovascular treatment of CCSVI by means of balloon angioplasty (PTA). It determines a significant reduction of postoperative venous pressure. Restenosis rate was found out elevated in the IJVs, but negligible in the AZ. However, PTA seems to positively influence clinical and QoL parameters of the associated MS and warrants further randomized control trials.

Chronic cerebrospinal venous insufficiency and multiple sclerosis

A chronic state of impaired venous drainage from the central nervous system, termed chronic cerebrospinal venous insufficiency (CCSVI), is claimed to be a pathologic phenomenon exclusively seen in multiple sclerosis (MS). This has invigorated the causal debate of MS and generated immense interest in the patient and scientific communities. A potential shift in the treatment paradigm of MS involving endovascular balloon angioplasty or venous stent placement has been proposed as well as conducted in small patient series. In some cases, it may have resulted in serious injury. In this Point of View, we discuss the recent investigations that led to the description of CCSVI as well as the conceptual and technical shortcomings that challenge the potential relationship of this phenomenon to MS. The need for conducting carefully designed and rigorously controlled studies to investigate CCVSI has been recognized by the scientific bodies engaged in MS research. Several scientific endeavors examining the presence of CCSVI in MS are being undertaken. At present, invasive and potentially dangerous endovascular procedures as therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.