no evidence of ccsvi in multiple sclerosis

NO EVIDENCE OF CCSVI

IN MULTIPLE SCLEROSIS

Jean-Baptiste Ricco

Vascular Surgery Department

University of Poitiers, France

CCSVI HYPOTHESIS

Raised venouspressures

Damage tointracranial

vascularendothelium

Incite inflammatoryresponse and breach of

blood‐brain barrierDevelop intoMS lesions

ZAMBONI CRITERIA

DOPPLER CRITERIA FOR CCSVI

ZAMBONI CRITERIAZAMBONI CRITERIA

FOR CCSVIZAMBONI CRITERIA

FOR CCSVI


ZAMBONI CRITERIA

2 POSITIVE ZAMBONI CRITERIA FOR CCSVI


• CCSVI criteria fulfilled in all MS patients (n=109)

• and none of the controls (n=177)

CONCLUSIVE

ANALYSIS

MS CONTROL SENSITIVITY

SPECIFICITY

(95% CI)

≥ 2 POSITIVE

CRITERIA

109/109 0/177 100% (97-100)

100% (98-100)

• 65 MS patients compared to 235 controls

• “MS was strongly associated with CCSVI”

CRITERIA MS CONTROL Odds ratio

1 46/65 0/235 1123 (p<0.0001)

2 40/65 0/235 748 (p<0.0001)

3 24/65 1/235 137 (p<0.0001)

4 34/65 7/235 36 (p<0.0001)

5 36/65 25/235 10 (p<0.0001)

J Neurol Neurosurg Psychiatry 2009

METHODOLOGICAL ISSUES

• Potential observer bias in the US measurements,

• No description of blinding was provided

• The principal interpreting physician was identified

as PZ in the article.

• No description of any methods to limit

intraobserver or interobserver bias

• The rate of relapse-free patients improved from

27% to 50% (p<0.001)

• The rate of gadolinium-enhancing lesions on MRI

decreased from 50% to 12% (p<0.01)

• The Multiple Sclerosis Functional Composite score

improved significantly in this MS cohort. (p<0.01)

AFTER PTA

J VASC SURG 2009

MAJOR FLAWS

• Open-label study, no blinding of neurologists

• No control group

• A 66% of subjects with MS who had not previously

received DMT (disease-modifying-therapy) at the time

of baseline data collection were asked to start

standard DMT in order to enroll in the PTA study. A

major confounding factor

- Zamboni P. Curr Neurovasc Res 2007

- Zamboni P. J Neurol Neurosurg 2009

- Zamboni P. Funct Neurol 2009

-Zamboni P. J Vasc Surg 2009

-Zamboni P. Eur J Vasc Endovasc Surg 2011

- Baracchini C et al. Ann Neurol 2011

- Centonze D et al. Ann Neurol 2011

- Doepp F et al. Ann Neurol 2010

- Mayer CA et al. J Neurol Neurosurg 2011

- Zivadinov R et al. Neurology 2011

- Marder E et al. Arch Neurol 2011

- Tsivgoulis et al. Neurology 2011

- Auriel et aL. J Neurol Sciences 2011

- Blinkenberg et al. Acta Neurologica

Scandinavia 2012

- Comi et al (CosMo study) ECRIMS 2012

- Laukentaus SJ EJVES 2013

- Imperiale D Clinical Neurology and

Neurosurgery 2013

- Traboulsee AL Lancet 2013

CCSVI BY OTHER AUTHORS

FOREST PLOT

Estimate Lower bound Upper bound p-Value

1.56 0.95 2.56 0.08

Heterogeneity

tau^2 Q(df=12) Het. p-Value I^2

0.45 34.56 < 0.01 65%

• Case-control study

• 35 centers

• 1202 patients with MS

• 382 healthy controls

• 232 with other neurological diseases

G. Comi, G Mancardi for the CoSMo study

Sponsor: Italian Multiple Sclerosis Foundation

Illustration of the vascular abnormalities comprising the proposed entity chronic

cerebrospinal venous insufficiency. Figure adapted from R. Fox, Neurology 2011.

DIAGNOSIS of CCSVI

1

2

3

4

5

≥ 2 out the 5 CCSVI criteria have to be met

CENTRALIZED BLINDED EXAMINATION

• Duplex images were sent to an independent central

expert who performed a second blinded reading

• In case of disagreement, the exam was sent to the

two other central Duplex experts and the final

diagnosis was made by a majority

• Data collection and monitoring were carried out by an

independent organization and centralized

Independent central DU evaluation

Prof. Erwin Stolz, Neurologische Klinik-Giessen (Germany)

Prof. Massimo Del Sette, Ospedale S. Andrea - Italy

Dott. Giovanni Malferrari, Arcispedale S. Maria Nuova -Reggio Emilia - Italy

CCSVI PREVALENCE

3.26 2.13 3.10

0

2

4

6

8

10

12

14

16

18

20

MS HC OND

CC

SV

I p

rev

ale

nc

e (

%)

ns

MS: Multiple Sclerosis, HC: Healthy Controls, OND: Other Neurological Diseases

NS (p=0.30)

NS (p=0.99)

CoSMo STUDY

These results do not support the hypothesis of

the role of CCSVI as a potential causal factor in

the development of MS

CCSVI - THE FINAL CURTAIN

Traboulsee AL et al. Lancet, 2013 published on line October 9

This study aimed to establish the prevalence of

extracranial venous narrowing in people with

MS, unaffected full siblings, and unrelated

healthy volunteers.


Blinded, case-control, multicentre study

177 adults: 79 with MS, 55 siblings, and 43

controls,

The authors assessed narrowing of the IJV and

azygous veins with catheter venography and

ultrasound criteria for CCSVI by Zamboni


79 with MS

98 controls

177

enrolled

• Ultrasound

• Venography

All assessing study

team were masked to

participant status

MS

(N=79)

UNAFFECTED

SIBLINGS

(N=54)

HEALTHY

CONTRO

LS

(N=38)

P

VALUE

ULTRASOUND

≥2/5 POSITIVE

44% 31% 45% 0.27

ZAMBONI

VENOGRAPHY

CRITERIA

2% 2% 3% 1.0

> 50% NARROWING

ON VENOGRAPHY

74% 66% 70% 0.81

> 50% NARROWING

WITH ABNORMAL

FLOW

51% 45% 70% 0.51

0% 10% 20% 30% 40% 50% 60%

0

1

2

3

4

5

Controls Siblings MS

① High-resolution B-mode

anomalies

② Reflux in the deep cerebral

veins / Flow not doppler-

detectable in the IJV/ vertebral

vein

③ Reflux in the IJV / vertebral

veins

④ Reversed postural control of

the main cerebral venous

outflow

CCSVI ULTRASOUND

CRITERIA

The sensitivity of ultrasound CCSVI criteria for detection of >50% narrowing seen on catheter venography was 0.40 [0.31-0.50]

The agreement was equally poor in MS patients and healthy controls.

This review provides no evidence

that extracranial venous anatomy

differs between patients with MS

and healthy controls

These results also challenge both

the validity of ultrasound for the

purpose of detecting CCSVI and its

existence as a disorder

The angioplasty for CCSVI which was

tendentiously termed liberation

treatment earned Internet coverage and

kindled the hopes of desesperate

patients.

It is clear that no reason exists to

allocate further resources to CCSVI

research, be they financial or

intellectual

Liberation Treatment India

A no Obligation, No Cost, Patient Helpline for Liberation

Treatment in India

www.liberationtreatmentindia.co

m

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no evidence of ccsvi in multiple sclerosis

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