This study evaluated cerebrospinal venous drainage in patients with multiple sclerosis (MS) using ultrasound and venography techniques. 65 MS patients and 235 controls underwent ultrasound screening of internal jugular and vertebral veins, which found abnormalities in MS patients like reflux and stenosis not seen in controls. Venography of patients and 48 controls confirmed extensive extracranial venous abnormalities in MS patients, including stenosis of the internal jugular, azygous, and other veins, but not in controls. Abnormal venous drainage patterns correlated with MS subtypes and progression. The results provide evidence that chronic cerebrospinal venous insufficiency (CCSVI) is strongly associated with MS and may influence its clinical course.

1. Journal club

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

4. .
• 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

7. 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.

9. 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.

11. 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.

12. 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.

14. • 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

15. • 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

16. Results USG

17. 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).

18. • 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%)

22. 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

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

25. • 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

26. 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.

27. • 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

28. 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).

29. • 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.

32. • 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.

33. 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 .

35. 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

36. • 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).

37. 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).

42. 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

43. 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.

44. Thank you