Journal club

1.Vascular Diseases Center,University of Ferrara, Ferrara,Italy; 2. Department of Neurology,Bellaria Hospital, Bologna, Italy

.• F. A Schelling observed “striking widening of the main

venous passageways in the skulls of victims of multiple sclerosis”

• venous involvement in the development of cerebral lesions of multiple sclerosis- “venous back jets”.

• MS plaques, which usually are perivenous in location, especially in the brain.

• Haemodynamics of cerebral venous return depends on posture and the mechanic movement of respiration

• high-resolution echocolour Doppler (ECD) • transcranial colourcoded Doppler sonography (TCCS) • MR and selective injection venography are limited in

evaluating cerebral venous haemodynamics but provide excellent morphological but static details.

• Evaluated the abnormalities of the cerebral venous outflow in patients with MS using ECD-TCCS and selective venography

METHODS

Patients • 65 patients affected by clinically defined MS

(CDMS) (the revised McDonald criteria). 35 patients with a relapsing-remitting (RR)

clinical course 20 with secondary progressive (SP) 10 with primary progressive (PP)• Expanded disability disease score (EDSS) • Detailed data • PP patients and 18 out of 55 RR-SP were not

under treatment at the time of the evaluation.

Methods

Controls• 235 subjects

• 60 healthy subjects matched for age and gender with MS patients (HM-C).

• 82 healthy subjects older than the median age of onset of CDMS

• 45 patients affected by other neurological diseases (OND)

• 48 other controls not affected by neurological diseases but scheduled for venography (HAV-C) for other

pathologies.

Methods

• Exclusion criteria• Behcet disease, vasculitis, cerebral vascular

malformations and congenital vascular malformations (Klippel–Trenaunay, Parkes–Weber, Servelle–Martorell

and Budd–Chiari syndromes).

• Patients and controls underwent a non-invasive study of cerebrospinal venous return at the Vascular Lab

• ultrasound technicians and physicians interpreting the data were blinded to the patient diagnostic category.

Methods• Study of cerebrospinal venous drainage• subject positioned on a tilt bed by combining the extracranial ECD methodology for investigating the IJVs and VVs with that of the

TCCS for studying the deep cerebral veins (DCVs)

• focused in particular on the detection of five parameters, which are absent in normal subjects:

• 1. reflux in the IJVs and/or VVs in sitting and supine posture;• 2. reflux in the DCVs;• 3. high-resolution B-mode evidence of IJV stenoses;• 4. flow not Doppler-detectable in the IJVs and/or VVs;• 5. reverted postural control of the main cerebral venous outflow

pathways.

• ECD-TCCS criteria for venography• two of the five • Indication to continue the study using selective

venography in all suspected subjects.• ultrasonography as a screening to venography. • Ethics Committee approved an additional

venographic investigation in HAV-C group preoperative screening for venous return anomalies was negative

• SELECTIVE VENOGRAPHY• 65 with MS fulfilling the ECD-TCCS screening criteria

and 48 controls of the HAV-C group• Stenosis and pressures.• Statistical analysis one-way ANOVA analysis of variance two-sided Fisher exact test Mann– Whitney test x2 test for independence. p Values up to 0.05 were considered statistically

significant

Results USG

Results -venography

• detection of 2/5 TCCS-ECD criteria of was always related to multiple significant extracranial venous stenosis

• None of the HAV-C subjects who underwent venographic investigation with negative ultrasound had any stenotic patterns.

• Azygous vein in the MS group was affected in 86% of cases, membranous obstruction of the junction with the superior vena cava, twisting, septum and atresia,

• jugular veins- stenosed unilaterally or bilaterally in 59/65 patients (91%). frequently annulus and septum, followed by atresia

• Extracranial venous wall stenoses did not differ significantly in patients treated with immunosuppressant/immunomodulator agents or in never-treated patients (p=ns,Fischer exact test).

• Venous pressure- Pressures measured in patients and controls respectively were not significantly different

• In contrast, the pressure gradient measured in CDMS across the stenosies was significantly different.

• Four patterns of chronic cerebrospinal venous insufficiency places of venous steno-obstruction, pathways of venous reflux and substitute collateral circles

• location of venous obstruction seems to be a key element influencing the clinical course of the disease.

• Types A and B correlated with a RR course (83%) with a conversion in the SP course in 70% of cases.

• In contrast, the PP forms occurred more frequently in the type D pattern (75%)

discussion

• Association between MS and the altered modality of venous return

• complex haemodynamic picture defined as CCSVI, characterised by multiple substitute circles, with a very high incidence of reflux

• Substitute circles are alternative pathways or vicarious venous shunts that allow for the piping of blood toward available venous segments outside the CNS.

• permit redirection of the deviated flow, preventing intracranial hypertension which over time become overloaded because of their own draining flow and the shunted flow

Diagnosis of CCSVI

• “Vascular picture characterized by combined stenosies of the principal pathways of extracranial and extravertebral venous drainage”

• Our results need to address two main questions: 1. Does CCSVI influence the clinical course of MS? • four main patterns of CCSVI the location, number and association of venous

stenosis, and the modality of collateral circulation.• location of venous obstruction plays a key role in

determining the clinical course.• longitudinal studies are needed, with clinical and

advanced MRI analyses of MS diffusion over time and space in relation to the CCSVI patterns discovered

Are venous stenoses the cause or products of MS?

• literature revealed descriptions of associations between the extracranial venous obstructive malformations and myelopathies

• Venous hypertension has been hypothesised as a cause of MS-not found to be significantly different

• Pressure gradient across a stenosis

• Absence of Doppler and venographic features of CCSVI in controls suggests that venous obstructions may be causative of CDMS

• RR-SP group did not demonstrate an increased number of extracranial venous stenosing lesions in untreated as compared with treated.

• On the basis of this study, they propose the introduction of the ECD-TCCS protocol when a patient presents the first acute episode of demyelinating origin, mostly involving the optic nerve, the so-called clinically isolated syndrome (CIS).

• Currently, only longitudinal clinical and MRI observation in time and space is capable of establishing the possible conversion of a CIS into a CDMS.

• Assessment of the intraobserver and interobserver variability coefficient- is a limitation of this study

• Longitudinal studies regarding pathogenesis

A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency

• evaluated the safety of CCSVI endovascular treatment and its influence on the clinical outcome of the associated MS

• Sixty-five consecutive patients underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months.

• Vascular outcome measures were postoperative complications, venous pressure, and patency rate.

• Neurologic outcome measures were cognitive and motor function assessment, rate of MS relapse, rate of MR active positive-enhanced gadolinium MS lesions (Gad+), and quality of life (QOL) MS questionnaire

• Results-CCSVI endovascular treatment significantly improved MS clinical outcome measures, especially in the RR group: the rate of relapse-free patients changed from 27% to 50% postoperatively (P < .001) and of MR Gad+ lesions from 50% to 12% (P < .0001).

• Zamboni- AAN,Nat MS society april 14 • Attention in all media, scientific literature

and internet• Search for "liberation procedure" in

Google yielded as of August 2010 more than 2.5 million hits.

• Internet has also been used to make commercial advertisement of places where stenting for CCSVI is performed.

• Disease progression in multiple sclerosis (MS) may be related to toxic effects of parenchymal iron deposition following chronic cerebrospinal venous insufficiency (CCSVI).

• Biochemically, presence of iron in the CNS stimulates intrathecal expression of ferritin.

• Thus quantification of ferritin provides an indirect test for deposition of iron in the CNS.

• Hypotheses

1.If CCSVI-related parenchymal iron deposition were to be a major pathologic feature of MS, this should be reflected in CSF ferritin levels

2.Ongoing parenchymal iron deposition due to CCSVI should lead to an increase in CSF ferritin over time and related to progression either clinically or as detected on brain MRI.

methods

• Patients -All patients with MS were from a previously published Dutch cohort

• Controls- patients presenting with headaches and normal CT brain imaging who underwent a lumbar puncture.

• Two control groups with a intracranial bleed were included.

• An inflammatory control group consisted of patients with meningoencephalitis (ME, n 147).

• Aliquots of CSF samples were coded and stored in polypropylene tubes .

Clinical assessment

• Disability was recorded on 4 clinical scales: the Expanded Disability Status Scale score (EDSS), an ambulation index and a 9-hole PEG test (9HPT)

• Progression of disability was calculated over the 3-year interval on the EDSS scale by at least 1 point for an EDSS 5.5 or at least 0.5 point for an EDSS 5.5.

• Cognitive function was tested only at follow-up using the PASAT

• CSF analysis. CSF ferritin levels were measured using a sensitive in-house ELISA (upper reference limit of 12 ng/mL.)

• Spectrophotometry was used for analysis of CSF pigments.

• MRI. MRI examinations were performed at 1.0 T or 1.5 T at baseline and follow-up. The T2 lesion volume (T2LV) and T1 lesion volume (T1LV) were calculated.

• Data analysis. All statistical analyses were performed in SAS (version 9.1).

Cross-sectional study

• High CSF ferritin levels were more common in patients with SPMS, siderosis, ME, and SAH if compared to the control patients ( p 0.0001 for each).

• There was no correlation of baseline CSF ferritin levels with the baseline EDSS, 9HPT, or AI either in the pooled cohort of patients with MS or clinical subtypes .

• There was no correlation of baseline CSF ferritin levels with either the T1LV or T2LV in the pooled cohort, patients with PPMS or RRMS.

• In patients with SPMS, an inverse correlation of CSF ferritin levels with the T2LV was found (R 0.65, p 0.0063).

Longitudinal study

• Twenty-nine of the patients with MS agreed to a 3-year follow-up lumbar puncture.

• In patients with MS, there was no change of CSF ferritin levels over time (F 0.29, p 0.29).

• There was no correlation of the follow-up CSF ferritin levels with follow-up EDSS, 9HPT, AI, or PASAT

• there was an inverse correlation of AI with CSF ferritin. (p 0.004).

• There was no correlation between follow-up CSF ferritin levels and the follow-up T2LV in either the pooled cohort or any of the clinical subtypes

discussion

• cross-sectional - CSF ferritin levels in patients with RRMS or PPMS remaining essentially within the previously published normal range of less than 12 ng/mL provide indirect lack of evidence for iron deposition

• longitudinal study- almost all patients with MS CSF ferritin levels either remained within the normal range or if initially elevated decreased below the cutoff of 12 ng/mL.

Thank you