Percutaneous transluminal angioplasty for the treatment of limb threatening ischemia: Do the results...

Percutaneous transluminal angioplasty for treatment of

chronic cerebrospinal venous insufficiency (CCSVI) in

multiple sclerosis patients (Review)

van Zuuren EJ Fedorowicz Z Pucci E Jagannath VA Robak EW

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012 Issue 12

httpwwwthecochranelibrarycom

Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients

(Review)

Copyright copy 2012 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

4OBJECTIVES

5METHODS

8RESULTS

Figure 1 9

10DISCUSSION

11AUTHORSrsquo CONCLUSIONS

11ACKNOWLEDGEMENTS

12REFERENCES

16CHARACTERISTICS OF STUDIES

25DATA AND ANALYSES

25ADDITIONAL TABLES

30HISTORY

30CONTRIBUTIONS OF AUTHORS

31DECLARATIONS OF INTEREST

31SOURCES OF SUPPORT

31DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iPercutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients

(Review)


[Intervention Review]

Percutaneous transluminal angioplasty for treatment ofchronic cerebrospinal venous insufficiency (CCSVI) inmultiple sclerosis patients

Esther J van Zuuren1 Zbys Fedorowicz2 Eugenio Pucci3 Vanitha A Jagannath4 Edward W Robak5

1MS Consumer Oegstgeest Netherlands 2UKCC (Bahrain Branch) The Cochrane Collaboration Awali Bahrain 3UO Neurologia

- Ospedale di Macerata ASUR Marche - Zona Territoriale 9 Macerata Italy 4Department of Paediatrics American Mission Hospital

Manama Bahrain 5MS Consumer Fredericton Canada

Contact address Esther J van Zuuren MS Consumer Oegstgeest Netherlands EJvan_Zuurenlumcnl

Editorial group Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Publication status and date New published in Issue 12 2012

Review content assessed as up-to-date 3 April 2012

Citation van Zuuren EJ Fedorowicz Z Pucci E Jagannath VA Robak EW Percutaneous transluminal angioplasty for treatment of

chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients Cochrane Database of Systematic Reviews 2012 Issue

12 Art No CD009903 DOI 10100214651858CD009903pub2


A B S T R A C T

Background

Multiple sclerosis (MS) is a leading cause of neurological disability in young adults The most widely accepted hypothesis regarding its

pathogenesis is that it is an immune-mediated disease It has been hypothesised more recently that chronic venous congestion may be

an important factor in the pathogenesis of MS This concept has been named rsquochronic cerebrospinal venous insufficiencyrsquo (CCSVI) and

is characterised by stenoses of either the internal jugular or azygos veins or both It is suggested that these stenoses restrict the normal

blood flow from the brain causing the deposition of iron in the brain and the eventual triggering of an auto-immune response The

proposed treatment for CCSVI is percutaneous transluminal angioplasty also known as the rsquoliberation procedurersquo which is claimed to

improve the blood flow in the brain thereby alleviating some of the symptoms of MS

Objectives

To assess the effects of percutaneous transluminal angioplasty for the treatment of CCSVI in people with MS

Search methods

We searched the following databases up to June 2012 The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous

System Group Specialised Register CENTRAL in The Cochrane Library 2012 Issue 5 MEDLINE (from 1946) EMBASE (from

1974) and reference lists of articles We also searched several online trials registries for ongoing trials

Selection criteria

Randomised controlled trials assessing the effects of percutaneous transluminal angioplasty in adults with multiple sclerosis that have

been diagnosed to have CCSVI

Data collection and analysis

Our searches retrieved 159 references six of which were to ongoing trials Based on assessment of the title or abstract or both we

excluded all of the studies with the exception of one which was evaluated following examination of the full text report However this

study also did not meet our inclusion criteria and was subsequently excluded

1Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients

(Review)


Main results

No randomised controlled trials met our inclusion criteria

Authorsrsquo conclusions

There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment

of CCSVI in people with MS Clinical practice should be guided by evidence supported by well-designed randomised controlled trials

closure of some of the gaps in the evidence may be feasible at the time of completion of the six ongoing clinical trials

P L A I N L A N G U A G E S U M M A R Y

The more popularly known rsquoLiberation procedurersquo for treatment of venous stenoses (CCSVI) in the brain of MS sufferers

Multiple sclerosis (MS) is an inflammatory disease of the nervous system and the most frequent cause of neurological disability in

young adults Myelin the material that wraps around and protects the nerves becomes damaged and this results in scarring and the

formation of scar-like plaques

MS is considered to be an immune-mediated disease in which the personrsquos own immune system attacks the nervous system and most

of the current drug therapies are based on this hypothesis

However a new theory has been recently proposed with a suggestion that impaired blood flow in the veins draining the central nervous

system so called chronic cerebrospinal venous insufficiency (CCSVI) may play a role in the cause of MS CCSVI is thought to be

congenital and it may result in iron deposits which in turn trigger the immune system to attack the central nervous system thus

damaging the myelin The proposed treatment for CCSVI is balloon angioplasty which entails the widening of narrowed (stenosed)

veins the commonly named rsquoliberation procedurersquo This theory has gained a lot of attention via the Internet mainly among the patientsrsquo

community and the increased interest by the media has further enhanced the expectations of people suffering with MS We searched

the relevant literature but found no studies that matched the criteria of methodological quality necessary for their inclusion in this

review

There is currently no evidence to support or refute the efficacy and the safety of angioplasty for CCSVI in people with MS Well-

designed and robust studies are warranted

B A C K G R O U N D

Unfamiliar terms are listed in the rsquoGlossary of termsrsquo in Table 1

Description of the condition

Definition signs and symptoms

Multiple sclerosis (MS) is a leading cause of neurological disability

in young adults The disease is characterised by demyelination ax-

onal loss and inflammation (Compston 2008) Four clinical forms

of MS can be distinguished relapsing-remitting (RRMS) sec-

ondary progressive (SPMS) primary progressive (PPMS) and pro-

gressive relapsing (PRMS) MS (Lublin 1996) RRMS and SPMS

are the clinical forms of MS that account for approximately 80

to 85 of sufferers and SPMS evolves from the RRMS form

(Lublin 1996)

MS is heterogeneous both histopathologically and clinically

(Lucchinetti 1996) and the natural history can be difficult to

predict In most cases it begins as RRMS with episodic largely

reversible neurological dysfunction (Nessler 2010) Natural his-

tory studies have shown that after a period of approximately

10 years almost 50 of people with MS gradually develop per-

manent disability (ie SPMS) which may also include acute re-

lapses (Weinshenker 1989) After a median of 15 to 28 years

(Tremlett 2006 Weinshenker 1989) from disease onset a disabil-

ity milestone equivalent to the use of an assistive walking device is

reached Whether current disease-modifying drugs (DMDs) alter

these prognostics is unknown Clinical features include all of the

symptoms caused by the impairment of the central nervous system


(Review)


(CNS) (eg loss of vision double vision muscle weakness sen-

sory disturbances bladder dysfunction impotence constipation

ataxia vertigo tremor spasticity pain cognitive impairment and

dysarthria) fatigue anxiety and depression are also frequent oc-

currences (Compston 2008) Magnetic resonance imaging (MRI)

can support the clinical diagnosis and it is integrated with clinical

and other para-clinical diagnostic methods (eg examining cere-

brospinal fluid and evoked potentials) to facilitate the diagnosis

of MS (Polman 2011) MRI parameters are also used as surrogate

markers of disease activity and progression

The disease has an adverse impact on the health-related quality of

life (HRQoL) of people with MS and their families and may also

pose a financial burden even when the disease is not physically

disabling

Epidemiology and causes

The most widely accepted hypothesis on the pathogenesis of

MS is that it is an immune-mediated disease characterised by

lymphocytic infiltration leading to damage of myelin and axons

(Compston 2008)

Although the aetiology is largely indeterminate a large propor-

tion of the scientific community considers that MS develops in

genetically predisposed subjects and that environmental factors

play a central role in its pathogenesis based on immune-mediated

mechanisms It is thought that aberrant immune responses to self

or foreign antigens cause and perpetuate inflammation (Frohman

2006) The inflammation leads to demyelination and subsequent

axonal damage However the role of inflammation is considered

to be complex and may include both beneficial and detrimen-

tal effects (Martino 2002) Some researchers also consider that

a cryptic aetiological agent may be the primary cause of axonal

damage and demyelination as well as inducing an inflammatory

response that could play a secondary role (Barnett 2006 Maggs

2004 Trapp 1998)

The age of onset of MS is usually between 20 and 40 years

(Ascherio 2007) Incidence is low in childhood and is rarer at the

age of 50 years or older Female to male ratios vary between 151

and 251 in most populations but this ratio has increased over the

last decade (up to 2011) (Sellner 2011) The incidence and preva-

lence of MS varies geographically (Ebers 2008 Simpson 2011)

High-frequency areas (prevalence in excess of 60 per 100000 peo-

ple) include all of Europe in addition to southern Canada north-

ern US New Zealand and south-east Australia In many of these

areas the prevalence is more than 100 per 100000 people This

geographic variance may be explained in part by racial differences

white populations especially those from northern Europe appear

to be most susceptible People of Asian African or American In-

dian origin have the lowest risk with other groups intermediate

MS is most likely to be caused by a complex interaction between

polygenetic and environmental factors (Hohlfeld 2011) The ma-

jor histocompatibility complex confers the greatest genetic risk

on susceptibility to MS Recent work has highlighted the impor-

tance of both HLA-DR and HLA-DQ in determining risk (Burrell

2011) There is also a widely held belief of an association between

geographical latitude and MS with the risk of MS increasing from

south to north Exceptions to the gradient are likely to be as a

result of genetic and behavioural-cultural variations (Ebers 2008

Simpson 2011) Geographical latitude and sunshine exposure and

the resulting increase in vitamin D levels which are closely related

are major environmental factors associated with the risk of devel-

oping MS (Burrell 2011 Comabella 2012 Simpson 2011) The

involvement of UV light in the production of vitamin D has gen-

erated a perception that vitamin D is itself the latitudinal factor

that influences the risk of developing MS Direct support for this

comes from a prospective study showing that low serum 25-hy-

droxyvitamin D (25-OH-D) (the circulating form of vitamin D)

levels are associated with an increased risk of MS (Munger 2006)

Other factors that have been suggested include exposure to Ep-

stein Barr virus with an almost 100 prevalence in MS patients

and tobacco smoking (Burrell 2011 Ebers 2008)

A more recent hypothesis suggests that chronic venous congestion

may be an important factor in the pathogenesis of MS (Zamboni

2006 Zamboni 2009a Zamboni 2010 Zamboni 2011a) The

predominantly venotopic location of MS lesions in the CNS is

postulated to be a consequence of local erythrocyte extravasation

owing to elevated transmural venous pressure (rsquovenous conges-

tionrsquo ie analogous to lower-limb chronic venous insufficiency)

followed by erythrocyte degradation and iron-driven phagocytosis

and subsequent lymphocytic infiltration (Singh 2009) This con-

cept has been named rsquochronic cerebrospinal venous insufficiencyrsquo

(CCSVI) and is characterised by stenoses of the internal jugular

veins azygos veins or both which restrict the normal blood flow

from the brain along with the appearance of small collateral veins

that may have developed to reduce the impact of the stenoses

(Zamboni 2009a) In his initial study Zamboni found CCSVI

in all subjects in the study group that were diagnosed with MS

and none in the healthy controls (Zamboni 2009a) Zambonirsquos

research group maintained that CCSVI can be non-invasively and

reliably diagnosed through the use of combined transcranial and

extracranial echo colour Doppler (ECD) by individuals trained to

recognise the indicators of CCSVI (Menegatti 2008 Menegatti

2011 Zivadinov 2011b)

ECD is used to measure five variables

1 reflux in the internal jugular veins (IJVs) or in the vertebral

veins (VVs) or both with the head in any position

2 reflux in the deep cerebral veins

3 high-resolution B-mode evidence of IJV stenoses

4 flow not detected by Doppler in the IJVs or VVs or both

5 reverted postural control of the main cerebral venous outflow

pathways

The diagnosis of CCSVI needs to fulfil at least two of these five

ECD indicators (Zamboni 2009a)

There has been some criticism of several of the limitations in the


(Review)


ultrasound-based investigation used to measure the rather com-

plex and dynamic (ie postural dependent) cerebrospinal venous

outflow These include the wide individual variability operator

dependence and intra- and inter-rater bias the difficulty of stan-

dardising values for diagnostic criteria and the necessity of venog-

raphy as a gold standard (Doepp 2010 Hojnacki 2010 Wattjes

2011 Zivadinov 2011b) A high degree of correlation between

CCSVI and MS was found in a number of studies (Al-Omari 2010

Bavera 2011 Hojnacki 2010 Simka 2010) but this has been con-

tested by other studies (Baracchini 2011 Centonze 2011 Doepp

2010 Krogias 2010 Marder 2011 Mayer 2011 Sundstroumlm 2010

Tsivgoulis 2011 Yamout 2010) More recently it has also been

suggested that CCSVI could be related to MS disability since the

higher frequency of CCSVI found in people with MS was associ-

ated with higher disability longer disease duration and progressive

forms (Patti 2012)

Several reviews have reported that the incidence of CCSVI varies in

people with MS ranging from 0 to 100 and from 0 to 23

in healthy controls (Ghezzi 2011 Zivadinov 2011b) One study of

499 people with MS found an increased prevalence of CCSVI but

with a modest sensitivity and specificity and suggestive of a less

likely primary causative role for CCSVI in the development of MS

(Zivadinov 2011a) A further study found no relationship between

CCSVI and HLA DRB11501 a genetic variation that has been

consistently linked to MS (Weinstock-Guttman 2011) Attempts

have been made to correlate CCSVI with specific symptoms of

MS in particular an association with fatigue (which often severely

affects people with MS) (Malagoni 2010)

The hypothesised association between CCSVI and MS implicates

CCSVI as a treatable cause of MS and hence it has formed the

basis for the so called rsquoliberation procedurersquo (Zamboni 2009c)

which is based on the technique of balloon angioplasty (Zamboni

2009b Zamboni 2011b) Venous stent placement has also been

used to treat CCSVI in people with MS but this treatment has

been associated with a small number of serious adverse events

(AEs) (Anon 2010 Burton 2011 Ludyga 2010 Petrov 2011)

These concerns were addressed by Zamboni and his group who

indicated that stents were not used in the rsquoliberation procedurersquo

that they perform (Giacobbi 2012 Multiple Sclerosis Society of

Canada 2012)

Much of the research on this topic has over recent years generated

a major interest and continuing debate in the scientific community

on the definition of CCSVI as a pathological entity the correlation

between CCSVI and MS the proposed etiopathogenetic mecha-

nisms and as a consequence on the utility of its treatment (Bagert

2011 Drsquohaeseleer 2011 Diaconu 2012 Dorne 2010 Fragoso

2011 Ghezzi 2011 Khan 2010 Lazzaro 2011 Reekers 2011 van

Rensburg 2010 Waschbisch 2011 Zivadinov 2011b)

Description of the intervention

Percutaneous transluminal angioplasty (PTA) involves the inser-

tion of a small catheter with a balloon attachment via the femoral

vein in the groin Initially a venogram is performed so that images

can be obtained to identify the narrowed sections of the veins The

catheter is then inserted and advanced into the right and left IJVs

as well as the azygos veins The balloon is inflated at the narrowed

section of the vein thereby increasing its diameter and improving

the flow of blood The procedure is performed with venographic

control

How the intervention might work

According to Zamboni by reducing the venous pressure the clin-

ical course of MS fatigue and quality of life (QoL) parame-

ters might improve (Malagoni 2010 Zamboni 2009b Zamboni

2009c)

Why it is important to do this review

The MS-CCSVI hypothesis has generated both enthusiasm and

skepticism among people with MS and the specialists who treat

them The rsquoliberation procedurersquo has attracted considerable atten-

tion among people with MS as well as the media and on the Inter-

net (Fragoso 2011 Mayer 2011 Vera 2012) Consumers have been

frequently exposed to media hyperbole with exaggerated claims

that have led to unrealistic expectations (Qiu 2010) As a con-

sequence CCSVI treatment has been offered to MS patients in

many countries mostly not at conventional MS centres or within

research trials in spite of the lack of confirmation of early evi-

dence from Zambonirsquos pivotal trials (Diaconu 2012 Senato della

Repubblica 2010)

Recognising the significant interest of this topic to people with MS

and notwithstanding the lack of consensus in the scientific com-

munity about the relationship between MS and CCSVI a system-

atic review is now needed to examine the potential benefits and

risks of this intervention This review also attempted to highlight

possible methodological issues in existing and proposed clinical

trials in order to provide an evidence-based review of the effect of

treating CCSVI in people with MS Our aim in this review was

to contribute in such a way that the expectations of people with

MS and the claims of efficacy made by clinicians are realistic and

stay within the boundaries of the evidence-based medicine (EBM)

paradigm

O B J E C T I V E S

To assess the effects of percutaneous transluminal angioplasty for

the treatment of CCSVI in people with MS


(Review)


M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) Trials were not excluded on

the basis of duration of follow-up

Types of participants

Participants of both genders gt 17 years with a diagnosis of

MS according to the original or the revised McDonald criteria

(McDonald 2001 Polman 2005 Polman 2011) and with diag-

nosis of CCSVI according to Zambonirsquos criteria (Zamboni 2009a)

or other relevant internationally recognised and validated criteria

Types of interventions

PTA alone or in combination with other MS treatments versus

no treatment sham treatment or other MS treatments PTA asso-

ciated with stenting was not considered in this review

Types of outcome measures

Primary outcomes

Assessments at 12 months 24 months and at the end of the sched-

uled follow-up period in the primary studies

1 The number of participants with at least one AE

bull serious AE according to (ICH Expert Working Group

1994)

bull any other AE reported during or after the PTA procedure

2 The number of participants who experienced progression on the

Expanded Disability Status Scale (EDSS) (Kurtzke 1983) Def-

initions of progression reported in the original studies were ac-

cepted However we tried to evaluate this outcome using the def-

inition of progression as a persistent worsening of at least 1 point

in EDSS recorded outside a relapse and confirmed by a follow-up

assessment at six months a persistent half-point increase was to

be adopted if baseline EDSS was 55 or worse

3 Patient reported outcomes (PROs) could include any of the

following if reported

bull change in quality of life (QoL) assessed using any validated

disease specific (eg MSQOL-54 (Vickrey 1995) MSQLI

(Fischer 1999) MusiQoL (Simeoni 2008)) or generic

instrument (eg short form 36 (SF-36) (Rudick 2007))

bull mean change in well-being as measured with a visual

analogue scale (VAS)

bull mean change in Modified Fatigue Impact Scale (MFIS)

(Kos 2005) or other recognised and validated MS-fatigue scale

bull or any other PRO

Secondary outcomes



1 Restenosis of target vessel primary and secondary patency

Primary patency is the interval following the initial angioplasty

procedure until a re-intervention is performed to preserve patency

Secondary patency is defined as the interval following the initial

angioplasty procedure until treatment of the vein is abandoned

due to an inability to treat the original lesion (Diehm 2007)

2 Mean change in cognitive functions assessment through vali-

dated battery in MS (ie Brief Repeatable Battery of Neuropsy-

chological Tests (BRBNT) (Rao 1991))

3 In the RRMS subgroup only the number of participants expe-

riencing at least one relapse We accepted definitions of relapse as

reported in the original studies

Search methods for identification of studies

Although there were no language restrictions on included studies

we did not retrieve any relevant non-English papers We will not

apply any language restrictions on any studies identified for future

updates of the review and will arrange to translate any studies not

in the English language

Electronic searches

We searched the following databases

bull the Cochrane Multiple Sclerosis and Rare Diseases of the

Central Nervous System Group Specialised Register (to June

2012) (Appendix 1)

bull the Cochrane Central Register of Controlled Trials

(CENTRAL) (The Cochrane Library 2012 Issue 5) (Appendix 2)

bull MEDLINE (PubMed) (1946 to June 2012) (Appendix 3)

bull EMBASE (embasecom) (1974 to June 2012) (Appendix 4)

Searching other resources

References from published studies

We examined the bibliography of one study (Zamboni 2012)

which although it was subsequently excluded did not provide any

further references to potentially eligible RCTs If any of the on-

going studies are included in future updates their bibliographical

references will be examined accordingly


(Review)


Ongoing trials registers

We searched the following ongoing trials registers

1 the metaRegister of Controlled Trials wwwcontrolled-

trialscom

2 the US National Institutes of Health Ongoing Trials

Register wwwclinicaltrialsgov

3 the Australian and New Zealand Clinical Trials Registry

wwwanzctrorgau

4 the World Health Organization International Clinical Trials

Registry platform wwwwhointtrialsearch

Correspondence

We contacted trial investigators to request missing data or to clarify

study details (see Table 2)


Selection of studies

Three review authors (EvZ VJ and EP) independently assessed

the abstracts of studies resulting from the searches Based on as-

sessments of the titles and abstracts of the other references it was

clear that none of the studies were eligible for inclusion and they

were therefore excluded We obtained a full-text copy of the sin-

gle potentially eligible study (Zamboni 2012) The three review

authors then independently assessed this study resolved any dis-

agreements through discussion and consensus and subsequently

excluded it

Table of methods archived for use in future updates

Issue Method

Data extraction and management Details of eligible trials will be extracted and summarised using structured

data extraction forms by two review authors (EvZ and ZF) Disagreements

will be resolved by discussion The data will be checked for consistency

by the same two review authors Study details will be entered into the

rsquoCharacteristics of included studiesrsquo table in RevMan (RevMan 2011)

The review authors will only include data if there will be an independently

reached consensus and any disagreements will be resolved by discussion

between the review authors

The following details will be extracted

1 trial methods - method of allocation masking of participants and

outcomes assessors and date and setting of study

2 participants - sample size age sex inclusion and exclusion criteria

exclusion of participants after randomisation and proportion of losses at

follow-up

3 intervention and comparison - length of study type and treatment

details

4 outcomes - primary and secondary outcomes reported in the study

5 notes - if our primary outcomes were addressed and other

comments

Assessment of risk of bias in included studies The review authors (EvZ and ZF) will independently assess the risk of

bias using The Cochrane Collaboration tool for assessing risk of bias

as described in Chapter 8 Section 85 in the Cochrane Handbook forSystematic Reviews of Interventions (Higgins 2011) The following domains

will be rated separately for any included study as rsquolow risk of biasrsquo rsquohigh

risk of biasrsquo and rsquounclearrsquo if the risk of bias was uncertain or unknown

1 sequence generation

2 allocation concealment

3 blinding of participants personnel

4 blinding of outcomes assessment

5 incomplete outcome data


(Review)


(Continued)

6 selective outcome reporting

7 other bias

These assessments will be reported in the rsquoRisk of biasrsquo table for each

included study

To summarise risk of bias of the included studies for future included

studies we will consider the domains of sequence generation allocation

concealment blinding of outcome assessors and incomplete outcome data

in order to classify the studies into three classes As rsquolow risk of biasrsquo when

all of these criteria will be met rsquohigh risk of biasrsquo when at least one of them

will be unmet and rsquounclear risk of biasrsquo in the remainder

Measures of treatment effect We will present continuous outcomes where possible on the original scale

as reported in each individual study If similar outcomes are reported

using different scales these will be standardised by dividing the estimated

coefficient by its standard deviation (SD) thereby allowing comparisons

to be made between scales

Dichotomous outcomes data will be presented as risk ratios (RR) All

outcomes data will be reported with their associated 95 confidence

intervals and will be analysed in RevMan using the Mantel Haenzel test

unless stated otherwise

Unit of analysis issues The outcomes sought in this review will require studies of long dura-

tion with repeated observations on participants for several time periods

of follow-up and are therefore likely to present unit of analysis issues

Outcomes data will be grouped according to the clinically important time

points specified in the rsquoTypes of outcome measuresrsquo section of the review

and we will follow the recommendations on their analysis and reporting

provided in Section 934 of the Cochrane Handbook for Systematic Reviewsof Interventions (Higgins 2011)

Dealing with missing data We will try to contact the investigators of any included studies to obtain

missing or inadequately reported data If data are unavailable we will

follow the advice provided in Section 1612 of the Cochrane Handbookfor Systematic Reviews of Interventions (Higgins 2011) This may include

sensitivity analyses in which we will impute missing data and compare the

results for the best-worst case scenario with the worst-best case scenario

for the key primary outcomes

Assessment of heterogeneity We will assess clinical heterogeneity by examining the characteristics of the

studies the similarity between the types of participants the interventions

and the outcomes as specified in the criteria for included studies Statistical

heterogeneity will be assessed using a Chi2 test and the I2 statistic We will

report heterogeneity as important if it was at least moderate to substantial

with an I2 statistic gt 50 (Higgins 2011)

Assessment of reporting bias If a sufficient number of trials assessing similar effects are identified for

inclusion in this review publication bias will be assessed according to the

recommendations on testing for funnel plot asymmetry (Egger 1997) as

described in Section 10431 of the Cochrane Handbook for Systematic


(Review)


(Continued)

Reviews of Interventions (Higgins 2011) If asymmetry is identified we

will try to assess other possible causes and these will be explored in the

discussion if appropriate

Data synthesis Two review authors (EvZ and ZF) will analyse the data in RevMan (

RevMan 2011) and will report them as specified in Chapter 9 of the

Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)

Data synthesis will only carried out if we are able to identify a sufficient

number of studies (N ge three) investigating similar treatments and which

have reported data that could be pooled (Treadwell 2006) We will use

a fixed-effect model to combine the results of individual studies and if

heterogeneity is identified random-effects models will be fitted

Subgroup analysis and investigation of heterogeneity We will only conduct subgroup analyses if a sufficient number of studies

(gt 10) with moderate-to-substantial heterogeneity (as defined above) are

included Although we did not identify a sufficient number of studies

at this time in future updates it will be of clinical relevance to consider

carrying out a subgroup analysis based on the different subtypes of MS

the duration and the baseline EDSS level

Sensitivity analysis If a sufficient number of studies are included in future updates we plan to

conduct sensitivity analyses to assess the robustness of our review results

by repeating the analysis with the following adjustments exclusion of

studies with unclear sequence generation unclear or inadequate allocation

concealment unclear or inadequate blinding of outcomes assessment and

completeness of follow-up

R E S U L T S

Description of studies

See Characteristics of excluded studies Characteristics of ongoing

studies

Results of the search

The electronic searches retrieved 159 references to studies which

included six ongoing clinical trials (see the rsquoCharacteristics of

ongoing studiesrsquo section) After examination of the titles and ab-

stracts four duplicate references were removed and a further 148

references were also subsequently excluded from the review A

full-text copy of the one remaining study (Zamboni 2012) was

obtained assessed independently for eligibility by three authors

(EvZ EP and VJ) and only excluded after consensus was reached

For further details see the rsquoStudy Flow Diagramrsquo (Figure 1)


(Review)


Figure 1 Flow diagram


(Review)


Included studies

No studies were included

Excluded studies

One study was excluded after evaluation of a full text copy of the

report (Zamboni 2012) (see Characteristics of excluded studies)

Risk of bias in included studies


Effects of interventions

No randomised controlled trials were found that fulfilled the in-

clusion criteria

D I S C U S S I O N

Summary of main results

Unfortunately at present no randomised controlled trials could

be included in this review (see Table 3) We identified one poten-

tially eligible study but after extensive discussion and consultation

with the other review authors and methodology experts this study

was excluded (Zamboni 2012) The investigators indicated that

in conducting this study they had attempted to address some of

the methodological concerns which had been raised (Khan 2010)

about their earlier study (Zamboni 2009b) ie the lack of a con-

trol group and blinded and objective measurement of MRI How-

ever our own assessments of the risk of bias in their recent study

called into question the methods used to generate the allocation

sequence which were not truly random and largely due to a lack

of clarity in the report we raised concerns as to whether any of

the outcomes assessments were blinded Our attempts to clarify

some of these trial conduct details with the principal investigator

proved unsuccessful

Overall completeness and applicability ofevidence

Several ongoing studies were identified that may eventually help

to fill in some of the gaps in the evidence for the efficacy and safety

of PTA for CCSVI (see the rsquoCharacteristics of ongoing studiesrsquo

section) In view of the lack of evidence there is a pressing need for

well designed randomised controlled trials which can help inform

and guide clinical practice

Quality of the evidence

There is currently no high level evidence to support or refute

the efficacy and safety of PTA for the treatment of CCSVI in

participants with multiple sclerosis

Potential biases in the review process

We made every attempt to limit bias in the review process by

ensuring a comprehensive search for potentially eligible studies

The authorsrsquo independent assessments of eligibility of studies for

inclusion in this review minimised the potential for additional

bias

Agreements and disagreements with otherstudies or reviews

In view of the lack of studies included in this review we are in broad

agreement with the relevant NICE guidance (NICE 2012) that

ldquocurrent evidence on the efficacy of percutaneous venoplasty for

chronic cerebrospinal venous insufficiency (CCSVI) for multiple

sclerosis (MS) is inadequate in quality and quantityrdquo Concurrent

with our implications for research the guidance also recommends

further randomised controlled trials but that these studies should

ldquoclearly define selection criteria and patient characteristicsrdquo as well

as ldquotechnical success which may include measurement of pressure

gradients across treated vein segments before and after venoplasty

Outcomes should include clinical and quality of life measuresrdquo

The findings of a recent systematic review and meta-analysis re-

ported a positive association between CCSVI and MS but also

concluded that poor reporting of the success of blinding and

marked heterogeneity among the included studies precluded any

definitive conclusions (Laupacis 2011) Although this meta-anal-

ysis did not specifically address the effect of percutaneous trans-

luminal angioplasty on CCSVI it does nevertheless help improve

our understanding of a possible association if not causal relation-

ship between CCSVI and MS

The objectives of a further review were to ldquocritically analyse the

scientific basis of CCSVI and the current literature on the rela-

tionship between CCSVI and MS as well as the methodology

of the ultrasound that has been claimed to provide evidence of

impaired cerebral venous drainagerdquo (Baracchini 2012) This was

a classical literature review which although it did not provide


(Review)


any evidence that a systematic and complete search of the rele-

vant research had been conducted did nevertheless provide a valu-

able and comprehensive background to the theory surrounding

CCSVI the related diagnostic criteria and the proposed therapy

However in concluding that ldquono piece of the CCSVI puzzle has a

solid supportive scientific evidencerdquo the authors failed to provide

any indication of how studies on which their conclusions appear

to have been based were selected critically evaluated and could

be designated as reliable sources of evidence either for or in their

opinion against the efficacy of the rsquoliberationrsquo procedure or in-

deed were capable of rejecting the CCSVI hypothesis The con-

clusions of their literature review on the CCSVI hypothesis would

also appear to be at some divergence with the systematic review

(Laupacis 2011) which reported evidence of a ldquostrong associationrdquo

between CCSVI and MS Futhermore their caution against any

further ldquocontrolled liberation trials until solid scientific evidence

of a causal relationship between CCSVI and MS has been clearly

demonstratedrdquo would appear to countermand the recommenda-

tions of the systematic review as indeed the recommendations of

our review See rsquoImplications for researchrsquo

A U T H O R S rsquo C O N C L U S I O N S

Implications for practice


the use of percutaneous transluminal angioplasty for treatment of

chronic cerebrospinal venous insufficiency in people with MS As

MS is a chronic and distressing disease accompanied by increasing

disability and with a huge impact on quality of life the importance

of assessing the efficacy and safety of this intervention should not

be underestimated

The FDA has recently alerted health care professionals and patients

about injuries and death associated with the use of an experimental

procedure called rsquoliberation therapyrsquo in addition to the ldquopotential

dangers of unproven treatment for multiple sclerosisrdquo (FDA news

release 2012) There is a degree of urgency in trying to resolve these

uncertainties which is compounded by the high expectations of

people suffering with MS who are looking for some improvement

in their condition and who might choose to undergo PTA based

on the results of testing for CCSVI (Qiu 2010)

Implications for research

A review of percutaneous transluminal angioplasty for treatment of

CCSVI in people with MS provides an example of the implications

for research when no eligible studies had been found This review

highlights the need for randomised controlled trials to evaluate

the effects of this intervention and which can ultimately provide

reliable evidence to help inform clinical decision making

Any future randomised controlled trials must be well-designed

well-conducted and adequately delivered with subsequent report-

ing including high-quality descriptions of all aspects of methodol-

ogy Reporting should conform to the Consolidated Standards of

Reporting Trials (CONSORT) statement (httpwwwconsort-

statementorg) which will enable appraisal and interpretation of

results and accurate judgements to be made about the risk of bias

and the overall quality of the evidence

Although it is uncertain whether reported quality mirrors actual

study conduct it is noteworthy that studies with unclear method-

ology have been shown to produce biased estimates of treatment

effects (Schulz 1995)

Further small and methodologically unsound studies should be

discouraged as they can be considered unethical and only add

further to the existing confusion about the pros and cons of CCSVI

and the effects of ldquoliberation therapyrdquo in MS

For further research recommendations based on the EPICOT

(evidence population intervention comparison outcomes and

time) format (Brown 2006) see Table 4

A C K N O W L E D G E M E N T S

The review authors would like to thank the Cochrane Multiple

Sclerosis and Rare Diseases of the Central Nervous

System Group and the peer reviewers and referees for their help

in developing this review


(Review)


R E F E R E N C E S

References to studies excluded from this review

Zamboni 2012 published data only

Zamboni P Galeotti R Weinstock-Guttman B Kennedy

C Salvi F Zivadinov R Venous angioplasty in patients

with multiple sclerosis results of a pilot study Journal of

Vascular Surgery 201243(1)116ndash22 [PUBMED PMID

21839654]

References to ongoing studies

ACTRN12612000302853 published and unpublished data

ACTRN12612000302853 A randomised blinded

controlled study of percutaneous transluminal angioplasty

(PTA) for extracranial vein stenoses in patients with multiple

sclerosis (MS) wwwanzctrorgau

NCT01089686 unpublished data only

NCT01089686 Study to evaluate treating chronic

cerebrospinal venous insufficiency (CCSVI) in multiple

sclerosis patients wwwclinicaltrialsgov


NCT01201707 Evaluation of angioplasty in the treatment

of chronic cerebrospinal venous insufficiency (CCSVI) in

multiple sclerosis wwwclinicaltrialsgov


NCT01371760 BRAVE-DREAMS (BRAin VEnous

DRainage Exploited Against Multiple Sclerosis)

wwwclinicaltrialsgov


NCT01450072 Prospective randomized endovascular

therapy in multiple sclerosis - PREMiSE



NCT01555684 Functional changes following

percutaneous venoplasty in multiple sclerosis patients


Additional references

Al-Omari 2010

Al-Omari MH Rousan LA Internal jugular vein

morphology and hemodynamics in patients with multiple

sclerosis International Angiology 201029(2)115ndash20

[PUBMED PMID 20351667]

Anon 2010

Anon Experimental multiple sclerosis vascular shunting

procedure halted at Stanford Annals of Neurology 201067

(1)A13ndash5 [PUBMED PMID 20186848]

Ascherio 2007

Ascherio A Munger KL Environmental risk factors for

multiple sclerosis Part I the role of infection Annalsof Neurology 200761(4)288ndash99 [PUBMED PMID

17444504]

Bagert 2011

Bagert BA Marder E Stuumlve O Chronic cerebrospinal

venous insufficiency and multiple sclerosis Archives ofNeurology 201168(11)1379ndash84 [PUBMED PMID

21747006]

Baracchini 2011

Baracchini C Perini P Calabrese M Causin F Rinaldi

F Gallo P No evidence of chronic cerebrospinal venous

insufficiency at multiple sclerosis onset Annals of Neurology201169(1)90ndash9 [PUBMED PMID 21280079]

Baracchini 2012

Baracchini C Atzori M Gallo P CCSVI and MS no

meaning no fact Neurological Sciences 2012May 9Epub

ahead of print [PUBMED PMID 22569567]

Barnett 2006

Barnett MH Sutton I The pathology of multiple sclerosis

a paradigm shift Current Opinion in Neurology 200619(3)

242ndash7 [PUBMED PMID 16702829]

Bavera 2011

Bavera PM Mendozzi L Cavarretta R Agus GB Venous

extracranial Duplex ultrasound and possible correlations

between multiple sclerosis and CCSVI an observational

study after 560 exams Acta Phlebologica 201112(2)

109ndash13

Brown 2006

Brown P Brunnhuber K Chalkidou K Chalmers I Clarke

M Fenton M et alHow to formulate research questions

BMJ 2006333(7572)804ndash6

Burrell 2011

Burrell AM Handel AE Ramagopalan SV Ebers GC

Morahan JM 1 Epigenetic mechanisms in multiple

sclerosis and the major histocompatibility complex (MHC)

Discovery Medicine 201111(58)187ndash96 [PUBMED

PMID 21447278]

Burton 2011

Burton JM Alikhani K Goyal M Costello F White C

Patry D et alComplications in MS patients after CCSVI

procedures abroad (Calgary AB) Canadian Journal ofNeurological Sciences 201138(5)741ndash6 [PUBMED

PMID 21856578]

Centonze 2011

Centonze D Floris R Stefanini M Rossi S Fabiano S

Castelli M et alProposed chronic cerebrospinal venous

insufficiency criteria do not predict multiple sclerosis risk or

severity Annals of Neurology 201170(1)51ndash8 [PUBMED

PMID 21786298]

Comabella 2012

Comabella M Khoury SJ Immunopathogenesis of multiple

sclerosis Clinical Immunology 2012 Vol 142 issue 1


Compston 2008

Compston A Coles A Multiple sclerosis Lancet 2008372

(9648)1502ndash17 [PUBMED PMID 18970977]


(Review)


Drsquohaeseleer 2011

Drsquohaeseleer M Cambron M Vanopdenbosch L De Keyser

J Vascular aspects of multiple sclerosis Lancet Neurology

201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012

Diaconu CI Conway D Fox RJ Rae-Grant A Chronic

cerebrospinal venous insufficiency as a cause of multiple

sclerosis controversy and reality Current TreatmentOptions in Cardiovascular Medicine 201214(2)203ndash14


Diehm 2007

Diehm N Baumgartner I Jaff M Do DD Minar E

Schmidli J et alA call for uniform reporting standards

in studies assessing endovascular treatment for chronic

ischaemia of lower limb arteries European Heart Journal200728(7)798ndash805 [PUBMED PMID 17317699]

Doepp 2010

Doepp F Paul F Valdueza JM Schmierer K Schreiber

SJ No cerebrocervical venous congestion in patients with

multiple sclerosis Annals of Neurology 201068(2)173ndash83


Dorne 2010

Dorne H Zaidat OO Fiorella D Hirsh J Prestigiacomo

C Albuquerque F et alChronic cerebrospinal venous

insufficiency and the doubtful promise of an endovascular

treatment for multiple sclerosis AACN Clinical Issues in

Critical Care Nursing 20102(4)309ndash11

Ebers 2008

Ebers GC Environmental factors and multiple sclerosis

Lancet Neurology 20087(3)268ndash77 [PUBMED PMID

18275928]

Egger 1997

Egger M Davey Smith G Schneider M Minder C Bias

in meta-analysis detected by a simple graphical test BMJ

1997315(7109)629ndash34 [PUBMED PMID 9310563]

FDA news release 2012

FDA FDA issues alert on potential dangers of unproven

treatment for multiple sclerosis httpwwwfdagov

NewsEventsNewsroomPressAnnouncements

ucm303538htm (released 10 May 2012)

Fischer 1999

Fischer JS LaRocca NG Miller DM Ritvo PG Andrews

H Paty D Recent developments in the assessment of

quality of life in multiple sclerosis (MS) Multiple Sclerosis19995(4)251ndash9 [PUBMED PMID10467384]

Fragoso 2011

Fragoso YD The internet racing ahead of the scientific

evidence The case of ldquoliberation treatmentrdquo for multiple

sclerosis Arquivos de Neuro-Psiquiatria 201169(3)525ndash7


Frohman 2006

Frohman EM Racke MK Raine CS Multiple sclerosis

- the plaque and its pathogenesis New England Journalof Medicine 2006354(9)942ndash55 [PUBMED PMID

16510748]

Ghezzi 2011

Ghezzi A Comi G Federico A Chronic cerebro-spinal

venous insufficiency (CCSVI) and multiple sclerosis

Neurological Sciences 201132(1)17ndash21 [PUBMED

PMID 21161309]

Giacobbi 2012

Giacobbi S Zamboni attacks Ottawa - Canadian studies

doomed to failure [Zamboni attacca Ottawa ndash Gli studi

canadesi destinati al fallimento] CCSVI nella Sclerosi

Multipla - Onlus (available at httpwwwccsvi-smorgq=

node425) (accessed 4 May 2012)

Higgins 2011

Higgins JPT Green S (editors) Cochrane Handbook for

Systematic Reviews of Interventions 510 [updated March

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Hohlfeld 2011

Hohlfeld R Barkhof F Polman C Future clinical challenges

in multiple sclerosis relevance to sphingosine 1-phosphate

receptor modulator therapy Neurology 201176(8 Suppl 3)

S28ndash37 [PUBMED PMID 21339488]

Hojnacki 2010

Hojnacki D Zamboni P Lopez-Soriano A Galleotti R

Menegatti E Weinstock-Guttman B et alUse of neck

magnetic resonance venography Doppler sonography and

selective venography for diagnosis of chronic cerebrospinal

venous insufficiency a pilot study in multiple sclerosis

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ICH Expert Working Group 1994

ICH Expert Working Group Clinical Safety

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wwwichorgproductsguidelinesefficacyarticleefficacy-

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Khan 2010

Khan O Filippi M Freedman MS Barkhof F Dore-

Duffy P Lassmann H et alChronic cerebrospinal venous

insufficiency and multiple sclerosis Annals of Neurology


Kos 2005

Kos D Kerckhofs E Carrea I Verza R Ramos M Jansa J

Evaluation of the Modified Fatigue Impact Scale in four

different European countries Multiple Sclerosis 200511(1)

76ndash80

Krogias 2010

Krogias C Schroumlder A Wiendl H Hohlfeld R Gold R

ldquoChronic cerebrospinal venous insufficiencyrdquo and multiple

sclerosis critical analysis and first observation in an

unselected cohort of MS patients [in German] Nervenarzt201081(6)740ndash6 [PUBMED PMID 20386873]

Kurtzke 1983

Kurtzke JF Rating neurologic impairment in multiple

sclerosis an expanded disability status scale (EDSS)


(Review)


Neurology 198333(11)1444ndash52 [PUBMED PMID

6685237]

Laupacis 2011

Laupacis A Lillie E Dueck A Straus S Perrier L Burton

JM et alAssociation between chronic cerebrospinal venous

insufficiency and multiple sclerosis a meta-analysis

Canadian Medical Association Journal 2011183(16)

E1203ndash12 [PUBMED PMID 21969411]

Lazzaro 2011

Lazzaro MA Zaidat OO Mueller-Kronast N Taqi MA

Woo D Endovascular therapy for chronic cerebrospinal

venous insufficiency in multiple sclerosis Frontiers in

Neurology 2011244 [PUBMED PMID 21808631]

Lublin 1996

Lublin FD Reingold SC Defining the clinical course

of multiple sclerosis results of an international survey

National Multiple Sclerosis Society (USA) Advisory

Committee on Clinical Trials of New Agents in Multiple

Sclerosis Neurology 199646(4)907ndash11 [PUBMED

PMID 8780061]

Lucchinetti 1996

Lucchinetti CF Bruumlck W Rodriguez M Lassmann H

Distinct patterns of multiple sclerosis pathology indicates

heterogeneity on pathogenesis Brain Pathology 19966(3)


Ludyga 2010

Ludyga T Kazibudzki M Simka M Hartel M Swierad

M Piegza J et alEndovascular treatment for chronic

cerebrospinal venous insufficiency is the procedure safe

Phlebology 201025(6)286ndash95 [PUBMED PMID

21107001]

Maggs 2004

Maggs FG Palace J The pathogenesis of multiple sclerosis

is it really a primary inflammatory process Multiple Sclerosis200410(3)326ndash9 [PUBMED PMID 15222700]

Malagoni 2010

Malagoni AM Galeotti R Menegatti E Manfredini F

Basaglia N Salvi F et alIs chronic fatigue the symptom of

venous insufficiency associated with multiple sclerosis A

longitudinal pilot study International Angiology 201029


Marder 2011

Marder E Gupta P Greenberg BM Frohman EM

Awad AM Bagert B et alNo cerebral or cervical venous

insufficiency in US veterans with multiple sclerosis

Archives of Neurology 2011 Vol 68 issue 121521ndash5


Martino 2002

Martino G Adorini L Rieckmann P Hillert J Kallmann B

Comi G et alInflammation in multiple sclerosis the good

the bad and the complex Lancet Neurology 20021(8)

499ndash509 [PUBMED 12849335]

Mayer 2011

Mayer CA Pfeilschifter W Lorenz MW Nedelmann M

Bechmann I Steinmetz H et alThe perfect crime CCSVI

not leaving a trace in MS Journal of Neurology Neurosurgery

and Psychiatry 201182(4)436ndash40 [PUBMED PMID

21296899]

McDonald 2001

McDonald WI Compston A Edan G Goodkin D Hartung

HP Lublin FD et alRecommended diagnostic criteria for

multiple sclerosis guidelines from the International Panel

on the diagnosis of multiple sclerosis Annals of Neurology


Menegatti 2008

Menegatti E Zamboni P Doppler haemodynamics of

cerebral venous return Current Neurovascular Research


Menegatti 2011

Menegatti E Genova V Tessari M Malagoni AM

Bartolomei I Zuolo M et alThe reproducibility of colour

Doppler in chronic cerebrospinal venous insufficiency

associated with multiple sclerosis International Angiology201029(2)121ndash6 [PUBMED PMID 20351668]

Multiple Sclerosis Society of Canada 2012

Multiple Sclerosis Society of Canada CCSVI and MS

httpccsvicaprocedurehtml (assessed 4 May 2012)

Munger 2006

Munger KL Levin LI Hollis BW Howard NS Ascherio

A Serum 25-hydroxyvitamin D levels and risk of multiple

sclerosis JAMA 2006296(23)2832ndash8 [PUBMED

PMID 17179460]

Nessler 2010

Nessler S Bruumlck W Advances in multiple sclerosis research

in 2009 Journal of Neurology 2010257(9)1590ndash3


NICE 2012

National Institute for Health and Clinical Excellence

Percutaneous venoplasty for chronic cerebrospinal

venous insufficiency for multiple sclerosis guidance

guidanceniceorgukipg420 (accessed on 28 March 2012)

Patti 2012

Patti F Nicoletti A Leone C Messina S DrsquoAmico E Lo

Fermo S et alMultiple Sclerosis and CCSVI A population-

based case control study PLoS One 20127(8)e41227

[PUBMED 22870210]

Petrov 2011

Petrov I Grozdinski L Kaninski G Iliev N Iloska M

Radev A Safety profile of endovascular treatment for

chronic cerebrospinal venous insufficiency in patients with

multiple sclerosis Journal of Endovascular Therapy 201118


Polman 2005

Polman CH Reingold SC Edan G Filippi M Hartung HP

Kappos L et alDiagnostic criteria for multiple sclerosis

2005 revisions to the ldquoMcDonald Criteriardquo Annalsof Neurology 200558(6)840ndash6 [PUBMED PMID

16283615]

Polman 2011

Polman CH Reingold SC Banwell B Clanet M Cohen

JA Filippi M et alDiagnostic criteria for multiple


(Review)


sclerosis 2010 revisions to the McDonald criteria Annals

of Neurology 201169(2)292ndash302 [PUBMED PMID

21387374]

Qiu 2010

Qiu J Venous abnormalities and multiple sclerosis another

breakthrough claim Lancet Neurology 20109(5)464ndash5


Rao 1991

Rao SM Leo GJ Ellington L Nauertz T Bernardin L

Unverzagt F Cognitive dysfunction in multiple sclerosis II

Impact on employment and social functioning Neurology199141(5)692ndash6 [PUBMED PMID 1823781]

Reekers 2011

Reekers JA Lee MJ Belli AM Barkhof F Cardiovascular

and Interventional Radiological Society of Europe

commentary on the treatment of chronic cerebrospinal

venous insufficiency Cardiovascular and Interventional

Radiology 201134(1)1ndash2 [PUBMED PMID 21136256]

RevMan 2011

The Nordic Cochrane Centre The Cochrane Collaboration

Review Manager (RevMan) 51 Copenhagen The Nordic

Cochrane Centre The Cochrane Collaboration 2011

Rudick 2007

Rudick RA Miller D Hass S Hutchinson M Calabresi PA

Confavreux C et alHealth-related quality of life in multiple

sclerosis effects of natalizumab Annals of Neurology 2007


Schulz 1995

Schulz KF Chalmers I Hayes RJ Altman DG Empirical

evidence of bias Dimensions of methodological quality

associated with estimates of treatment effects in controlled

trials JAMA 1995273(5)408ndash12

Sellner 2011

Sellner J Kraus J Awad A Milo R Hemmer B Stuumlve O

The increasing incidence and prevalence of female multiple

sclerosis - a critical analysis of potential environmental

factors Autoimmunity Reviews 201110(8)495ndash502


Senato della Repubblica 2010

Commissione Parlamentare di inchiesta sullrsquoefficacia e

efficienza del Servizio Sanitario Nazionale Senate of the

Republic XVI Legislature Transcript no 79 Hearing of

Professor Paolo Zamboni and Dr Fabrizio Salvi 82nd

session 22 September 2010 [Senato della Repubblica XVI

Legislatura Resoconto stenografico 79 Audizione del prof

Paolo Zamboni e del Dr Fabrizio Salvi 82deg seduta 2010]

httpwwwsenatoitdocumentirepositorycommissioni

servizio˙sanitario16Stenografici079˙definitivopdf

(accessed 30 April 2012)

Simeoni 2008

Simeoni M Auquier P Fernandez O Flachenecker P

Stecchi S Constantinescu C Validation of the Multiple

Sclerosis International Quality of Life questionnaire

Multiple Sclerosis 200814(2)219ndash30 [PUBMED PMID

17942521]

Simka 2010

Simka M Kostecki J Zaniewski M Majewski E Hartel

M Extracranial Doppler sonographic criteria of chronic

cerebrospinal venous insufficiency in the patients with

multiple sclerosis International Angiology 201029(2)


Simpson 2011

Simpson S Jr Blizzard L Otahal P Van der Mei I Taylor

B Latitude is significantly associated with the prevalence

of multiple sclerosis a meta-analysis Journal of Neurology

Neurosurgery and Psychiatry 201182(10)1132ndash41


Singh 2009

Singh AV Zamboni P Anomalous venous blood flow

and iron deposition in multiple sclerosis Journal of

Cerebral Blood Flow and Metabolism 200929(12)1867ndash78


Sundstroumlm 2010

Sundstroumlm P Waringhlin A Ambarki K Birgander R Eklund

A Malm J Venous and cerebrospinal fluid flow in multiple

sclerosis a case-control study Annals of Neurology 201068


Trapp 1998

Trapp BD Peterson J Ransohoff RM Rudick R Moumlrk S

Bouml L Axonal transection in the lesions of multiple sclerosis

New England Journal of Medicine 1998338(5)278ndash85


Treadwell 2006

Treadwell JT Tregear SJ Reston JT Turkelson CM A

system for rating the stability and strength of medical

evidence BMC Medical Research Methodology 2006652

[DOI 1011861471-2288-6-52]

Tremlett 2006

Tremlett H Devonshire V Is late-onset multiple sclerosis

associated with a worse outcome Neurology 200667(6)


Tsivgoulis 2011

Tsivgoulis G Mantatzis M Bogiatzi C Vadikolias K

Voumvourakis K Prassopoulos P et alExtracranial venous

hemodynamics in multiple sclerosis a case-control study


21849653]

van Rensburg 2010

van Rensburg SJ van Toorn R The controversy of CCSVI

and iron in multiple sclerosis is ferritin the key Neurology


Vera 2012

Vera C Herr A Mandato K Englander M Ginsburg L

Siskin GP Internet-based social networking and its role in

the evolution of chronic cerebrospinal venous insufficiency

Techniques in Vascular and Interventional Radiology 201215


Vickrey 1995

Vickrey BG Hays RD Harooni R Myers LW Ellison GW

A health-related quality of life measure for multiple sclerosis


(Review)


Quality of life Research 19954(3)187ndash206 [PUBMED

PMID 7613530]

Waschbisch 2011

Waschbisch A Manzel A Linker RA Lee D Vascular

pathology in multiple sclerosis mind boosting or myth

busting Experimental amp Translational Stroke Medicine20113(1)7 [PUBMED PMID 21756314]

Wattjes 2011

Wattjes MP van Oosten BW de Graaf WL Seewann A

Bot JC van den Berg R et alNo association of abnormal

cranial venous drainage with multiple sclerosis a magnetic

resonance venography and flow-quantification study

Journal of Neurology Neurosurgery and Psychiatry 201182


Weinshenker 1989

Weinshenker BG Bass B Rice GP Noseworthy J Carriere

W Baskerville J et alThe natural history of multiple

sclerosis a geographically based study 2 Predictive value of

the early clinical course Brain 1989112 (Pt 6)1419ndash28


Weinstock-Guttman 2011

Weinstock-Guttman B Zivadinov R Cutter G Tamantildeo-

Blanco M Marr K Badgett D et alChronic cerebrospinal

vascular insufficiency is not associated with HLA

DRB11501 status in multiple sclerosis patients PLoS One20116(2)e16802 [PUBMED PMID 21340025]

Yamout 2010

Yamout B Herlopian A Issa Z Habib RH Fawaz A

Salame J et alExtracranial venous stenosis is an unlikely

cause of multiple sclerosis Multiple Sclerosis 201016(11)


Zamboni 2006

Zamboni P The Big Idea iron-dependent inflammation in

venous disease and proposed parallels in multiple sclerosis

Journal of the Royal Society of Medicine 200699589ndash93


Zamboni 2009a

Zamboni P Galeotti R Menegatti E Malagoni AM

Tacconi G DallrsquoAra S et alChronic cerebrospinal venous

insufficiency in patients with multiple sclerosis Journal ofNeurology Neurosurgery and Psychiatry 200980(4)392ndash9


Zamboni 2009b


Gianesini S Bartolomei I et alA prospective open-label

study of endovascular treatment of chronic cerebrospinal

venous insufficiency Journal of Vascular Surgery 200950


Zamboni 2009c

Zamboni P Galeotti R Menegatti E Malagoni AM Mascoli

F DallrsquoAra S et alRationale and preliminary report of

endovascular treatment of multiple sclerosis the liberation

procedure Vascular and Endovascular Controversies

Update 31st International Symposium Charing Cross

Controversies Challenges Consensus London BIBA

Medical 200971ndash9

Zamboni 2010

Zamboni P Galeotti R The chronic cerebrospinal venous

insufficiency syndrome Phlebology 201025(6)269ndash79


Zamboni 2011a

Zamboni P Menegatti E Weinstock-Guttman B Dwyer

MG Schirda CV Malagoni AM et alHypoperfusion of

brain parenchyma is associated with the severity of chronic

cerebrospinal venous insufficiency in patients with multiple

sclerosis a cross-sectional preliminary report BMCMedicine 2011922 [PUBMED PMID 21385345]

Zamboni 2011b


C Salvi F Zivadinov R Venous angioplasty in patients with

multiple sclerosis results of a pilot study European Journal

of Vascular and Endovascular Surgery 2012 Vol 43 issue


Zivadinov 2011a

Zivadinov R Marr K Cutter G Ramanathan M Benedict

RH Kennedy C et alPrevalence sensitivity and specificity

of chronic cerebrospinal venous insufficiency in MS


21490322]

Zivadinov 2011b

Zivadinov R Ramanathan M Dolic K Marr K Karmon

Y Siddiqui AH et alChronic cerebrospinal venous

insufficiency in multiple sclerosis diagnostic pathogenetic

clinical and treatment perspectives Expert Review of

Neurotherapeutics 201111(9)1277ndash94 [PUBMED

21864074]lowast Indicates the major publication for the study


(Review)


C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Zamboni 2012 Non RCT the sequence generation was not random but based on availability of a passport by participants recruited

in Buffalo and in Italy on alphabetical order Not designed to compare PTA versus no treatment sham treatment

or other MS treatment

RCT = randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

ACTRN12612000302853

Trial name or title A randomised blinded controlled study of percutaneous transluminal angioplasty (PTA) for extracranial vein

stenoses in patients with multiple sclerosis (MS)

Methods Randomised controlled trial

Participants Inclusion criteria

bull signed Participant Information and Consent Form

bull age 18 to 65 years

bull Expanded Disability Disease Scale Score (EDSS) ranging from 0 to 75

bull diagnosis of MS according to the revised McDonald criteria

bull therapy with currently approved disease-modifying treatments

bull normal renal function or pre-hydration

bull no allergy to contrast media or pre-treatment

bull abnormal extracranial vein venogram

stenosis at any level

abnormal filling of vertebral veins following a jugular bulb injection

delayed emptying of the internal jugular vein in the supine position

persistent filling of the internal jugular vein in the erect position

abnormal appearance of the internal jugular valve

stenosis of the thoracic azygos vein

delayed emptying of the thoracic azygos vein

Exclusion criteria

bull pregnancy or planning a pregnancy within the next two years

bull relapse disease progression and steroid treatment in the 30 days preceding study entry (all conditions

significantly modify clinical parameters rendering unreliable any postoperative assessment)

bull pre-existing medical conditions known to be associated with brain pathology including

neurodegenerative disorder cerebrovascular disease and history of alcohol abuse Abnormal renal function

with a calculated e-GFR (estimated glomerular filtration rate) lt 60 and pre-hydration not possible

bull allergy to contrast and pre-treatment not possible

bull refusal to undergo the endovascular treatment or randomisation


(Review)


ACTRN12612000302853 (Continued)

bull previous PTA on extracranial veins

bull unable to adequately perform the CogState cognitive assessment tool because of visual or manual

dexterity impairment

Interventions PTA procedure compared to the control group The control group will get a sham PTA procedure (the

angiogram without the ballooning) at the beginning of the study

Outcomes Primary outcomes of the trial

bull Change in clinical parameters and disease progression as measured by Kurtzke Extended Disability

Status Scale (EDSS) at 1 week 1 3 6 and 12 months compared to baseline

bull Change in clinical parameters and disease progression as measured by the Multiple Sclerosis Functional

Composite Score (MSFC) at 1 week 1 3 6 and 12 months compared to baseline

bull Change in clinical parameters and disease progression as measured by Cognitive Assessment Tool

(CogState) at 1 week 1 3 6 and 12 months compared to baseline

Secondary outcomes of the trial

bull Composite number of procedural and post-procedural adverse events (to 12 months) measured

Common Terminology Criteria for Adverse Events v 4 (CTCAE) at 1 week 1 3 6 and 12 months

compared to baseline

bull Restoration of venous outflow (to 75 from normal outflow) as measured by venogram US

(ultrasound) and MRV (Magnetic Resonance Venography) at 6 and 12 months

bull Change in patient reported quality of life measured by the Multiple Sclerosis Quality of Life-54

Instrument (MSQoL-54) at 1 week 1 3 6 and 12 months compared to baseline

bull Change in patient reported fatigue as measured by the Fatigue Severity Scale (FSS) at 1 week 1 3 6

and 12 months compared to baseline

Starting date April 2012

Contact information Helen Kavnoudias

Radiology Research Unit

Radiology Department

The Alfred

Level 1 Phillip Block

55 Commercial Road

Melbourne Vic 3004 Australia

Tel +61 3 9076 3606

hkavnoudiasalfredorgau

Notes Website assessed 9 July 2012

NCT01089686

Trial name or title Study to evaluate treating chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients



bull must be 18 years old or greater and less than or equal to 65 years of age

bull core of 0 to 7 on the EDSS (Expanded Disability Disease Scale Score) scale


(Review)


NCT01089686 (Continued)

bull diagnosis of relapsing remitting or secondary progressive MSby a neurologist and confirmed by one of

the independent study neurologists

bull presence of greater than or equal to 50 percent stenosis of the extracranial veins as determined by

venogram

bull informed consent signed by patient

Exclusion criteria

bull patient is unwilling to comply with the follow-up

bull patient is pregnant

bull diagnosis of primary progressive MS by a certified neurologist confirmed by one of the study

neurologists

bull presence of less than 50 stenosis of the extracranial veins as determined by venogram

bull presence of other medical illnesses or a psychiatric condition that in the opinion of the investigator

may cause the subject to be non-compliant with the protocol requirements

bull life expectancy is less than 1 year

bull lack of mental capacity to consent

bull creatinine level of greater than 25 or is dialysis dependent

bull enrollment in another clinical study

Interventions Venoplasty versus sham procedure (non-treatment)


bull Incidence of major adverse events

The evaluation of safety will be defined as the incidence of major adverse events at 30 days following the

index procedure The evaluation of feasibility and efficacy will be determined by those patients that do not

have more than 50 restenosis within the 30 day time frame

bull Neurological assessment of MS

An independent neurologist will assess the number of MS attacks that have occurred during 1 year follow-up

period

bull MRIMRA (Magnetic Resonance ImagingMagnetic Resonance Angiography)(evaluation of MS

lesions)

Evaluation of imaging to reveal local iron content change in MS lesions and oxygen saturation changes using

conventional MRAMRI methods by an independent radiologist


bull Mortality

All cause mortality will be evaluated through 1 year

bull Major adverse events

Incidence of all major adverse events will be collected for 1 year

bull Identification of central venous stenosis

Evaluation of the correlation between MRV (Magnetic Resonance Venography) Duplex Ultrasound and

Venogram in identifying central venous stenosis

Starting date August 2010

Contact information Manish Mehta MD

The Center for Vascular Awareness Albany New York US

5 Pine West Plaza Suite 501

Washington Avenue Extension Albany NY 12205

Tel (518) 452-1048


(Review)




NCT01201707

Trial name or title Evaluation of angioplasty in the treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple

sclerosis



bull patients who are willing to comply with the protocol requirements and can be contacted by telephone

bull 18 to 60 years of age

bull clinically defined MS by Polman criteria

bull history of MS as defined above with an EDSS (Expanded Disability Disease Scale Score) between 3

and 6

bull significant stenosis of the internal jugular or azygos vein on the basis of magnetic resonance

venography or Doppler ultrasound

Exclusion criteria

bull renal insufficiency based on an estimated GFR lt 45

bull known severe allergy to iodine or gadolinium-based contrast agents which cannot be adequately pre-

medicated

bull known allergy to nickel

bull pregnancy

bull contraindication to anticoagulation or anti-platelet medication

bull contraindication to drugs used for conscious sedation during interventional procedures including

Versed and Fentanyl

bull history of deep venous thrombosis of the lower extremities

bull occlusion of the right and left common femoral veins

bull any changes in their disease modifying drug regimen for MS during the 6 months prior to enrolment

in this trial This would include the addition of any new medications a change in the dosage of any

medications or the removal of any medications from a patientrsquos drug regimen

bull life expectancy lt 18 months

bull currently enrolled or who plan to enroll in other investigations that conflict with follow-up testing or

confounds data in this trial

Interventions Angioplasty versus no treatment (observation)


bull Impact of CCSVI treatment on quality of life in patients with MS at 1 3 6 12 18 and 24 months

This will be assessed using the Multiple Sclerosis Quality of Life-54 (MSQOL-54) which is a health-related

quality of life measure that combines generic and MS-specific items into a single self-report questionnaire


bull Clinical significance of CCSVI in MS patients at 1 6 12 18 and 24 months

This will be assessed clinically using annualised relapse rates Expanded Disability Status Scale (EDSS) change

and change in the timed 25-foot walk

bull Superiority of angioplasty to observation for treatment of CCSVI at 1 6 12 18 and 24 months

This will be assessed clinically using annualised relapse rates EDSS change and change in the timed 25-foot


(Review)



walk

bull Incidence of CCSVI in patients with MS at baseline

This will be assessed on the basis of the findings on diagnostic venography of the internal jugular and azygos

veins which is the initial procedure performed in these patients

bull Safety of endovascular treatment of CCSVI at 1 3 6 12 18 and 24 months

This is defined as the number and nature of any procedure-related adverse effects

bull Target vessel primary and secondary patency at 1 3 6 12 18 and 24 months

Primary patency is the interval following the initial angioplasty procedure until a re-intervention is performed

to preserve patency Secondary patency is defined as the interval following the initial angioplasty procedure

until treatment of the vein is abandoned due to an inability to treat the original lesion


Contact information Barbara MacDowell

Albany Medical Center

Albany New York United States 12208

Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760

Trial name or title BRAVE-DREAMS (BRAin VEnous DRainage Exploited Against Multiple Sclerosis)



bull patients affected by CCSVI associated with MS

bull relapsing-remitting or secondary progressive or both

bull 18to 65 years old

bull EDSS (Expanded Disability Disease Scale Score) 2 to 5

bull disease duration lt 10 yrs

bull no relapse in the 30 days preceding the procedure

bull clinical stability in the last 6 months with disease modifying treatments

bull patients under the best available therapy

Exclusion criteria

bull patients previously treated for CCSVI or inserted in other clinical trials in the last 3 months

bull under treatment with natalizumab

bull pregnant or refusing to adopt contraception

bull presence of significant comorbidities

bull alcohol-drug abuse

bull thrombophilia

bull contraindication to MR


(Review)



Interventions Venous percutaneous transluminal angioplasty versus sham treatment (catheter venography)


bull Clinical parameters in an integrated functional score from baseline to 12 months

Five neurological parameters will be measured by the means of proper validated tools along 1 year follow-up

The evaluation leads to a score respectively expressed as improved stable fluctuant worsened

bull MRI outcome measures T1Gad active lesion T2 lesion volume MRI evaluation at baseline 6 and 12

months

Standard MRI parameters will be assessed by the means of a blinded centre of lecture

Secondary outcomes

bull EDSS from baseline to 12 months

EDSS will be assessed along 1 year follow-up

bull Chronic fatigue from baseline to 12 months

This highly disabling symptom completely orphan of effective therapy will be measured by M-FIS (Modified-

Fatigue Impact Scale)

bull Cognitive function from baseline to 12 months

Cognitive functions will be measured by the means of MoCA mental state questionnaire

bull Annualized relapse rate from baseline to 12 months

In the sub population affected by the RR clinical form the number of relapses will be assessed

bull Patency rate from baseline to 12 months

The rate of successful PTA will be assessed by the means of postoperative Doppler sonography

bull Emotional status from baseline to 12 months

Anxiety and Depression Scale for use with multiple sclerosis patients will be administered

bull Memory and cognition from baseline to 12 months

The assessment will be performed by the means of PASAT - Paced Auditory Serial Addition Test

bull Overactive Bladder from baseline to 12 months

Overactive Bladder symptom will be measured by the means of validated Overactive Bladder Questionnaire-

b

Starting date July 2011

Contact information Graziella Filippini MD

S Anna Hospital University of Ferrara Ferrara Italy 44100

Tel 0039 0223941

gfilippiniinstituto-bestait

Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072

Trial name or title Prospective randomized endovascular therapy in multiple sclerosis - PREMiSE



(Review)





bull EDSS (Expanded Disability Disease Scale Score) 0 to 65 (0 to 55 in the phase II of the study)

bull diagnosis of relapsing MS according to the McDonald criteria (Polman 2005)

bull 1 relapse within the past 12 months or GAD positive lesion on an MRI within the past 3 months (only

for phase II of the study)

bull be on treatment with currently FDA approved disease-modifying treatments (excluding Tysabri or

steroids (within the last 30 days prior to enrolment)

bull evidence of ge 2 sonographic parameters of suspicious abnormal extracranial cerebral venous outflow

(see Table 1 background and 15 section)

bull normal renal function creatinine clearance level of gt 60

Exclusion criteria

bull relapse disease progression and Tysabri and steroid treatment in the 30 days preceding study entry

bull pre-existing medical conditions known to be associated with brain pathology (eg neurodegenerative

disorder cerebrovascular disease positive history of alcohol abuse)

bull severe peripheral chronic venous insufficiency

bull abnormal renal function

bull contrast allergy (anaphylaxis)

bull not willing to undergo the endovascular treatment

bull peripheral vascular disease

Interventions Selective venography followed by therapeutic balloon angioplasty versus venography and sham angioplasty


bull Safety at 24 hours and at 1 month

Percent () of patients with Severe Adverse Events (SAE) post-surgical safety outcome in MS patients diag-

nosed with CCSVI that underwent therapeutic angioplasty


bull Preliminary efficacy at 1 3 6 and 12 months

Restoration of venous outflow (more than 75 of normal outflow) as measured by the combined ECDTCD

(Extracranial Venous DopplerTranscranial Doppler) and and MRV following the angioplasty as compared

to baseline as well as compared to a parallel control group of MS patients that will undergo only selective

venography without balloon angioplasty (sham-angioplasty)

Starting date June 2010

Contact information Cheryl Kennedy LMSW MPH

University at Buffalo Neurosurgery

Buffalo New York United States 14209

Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684

Trial name or title Functional changes following percutaneous venoplasty in multiple sclerosis patients



bull Diagnosis of CCSVI using transcranial and extracranial colour Doppler sonography in both supine

and sitting positions The diagnosis requires that 2 or more of the following 5 criteria are met reflux in the

internal jugular or vertebral veins or both with the head in any position reflux in the deep cerebral veins

high-resolution B-mode evidence of internal jugular vein stenosis absence of Doppler-detectable flow in the

internal jugular veins andor vertebral veins loss of postural control of the main cerebral venous outflow

pathways

Exclusion criteria

bull Non ambulatory

Interventions Percutaneous venoplasty versus no treatment


bull Neuromuscular function at 52 days

The venoplasty procedure will be performed at 8 days


bull Free living activity from 0 to 7 days and from 9 to 52 days

Measured by accelerometry


Contact information Angus Hunter PhD

amhunter1stiracuk

University of Stirling Stirling UK FK9 4LA



(Review)


D A T A A N D A N A L Y S E S

This review has no analyses

A D D I T I O N A L T A B L E S

Table 1 Glossary of terms

Antigen Substance or molecule that when introduced into the body triggers the production of

an antibody by the immune system which will then kill or neutralise the antigen that

is recognised as a foreign and potentially harmful invader

Autoreactive Immune response acting against own tissue

Ataxia Neurological sign and symptom that consists of gross lack of coordination of muscle

movements

Axon Part of the neuron that conducts electrical impulses away from the neuronrsquos cell body

Central nervous system Part of the nervous system that integrates the information that it receives from and

coordinates the activity of all parts of the body It includes the brain and the spinal

cord

Cognitive impairment Condition associated with confusion forgetfulness difficulty concentrating and plan-

ning and so on

Congestion Accumulation or overfilling of the blood vessels

Demyelination Loss of the myelin sheath insulating the nerves

Dysarthria Having a problem with articulating

Erythrocyte extravasation Leakage of red blood cells into the surrounding tissue

Gliosis Proliferation of astrocytes (glial cells) in damaged areas of the central nervous system

HLA-DR Major histocompatability complex (MHC) class II cell surface receptor encoded by

the human leukocyte antigen complex on chromosome 6 region 6p2131 HLA-DR

is also involved in several autoimmune conditions disease susceptibility and disease

resistance It is also closely linked to HLA-DQ and this linkage often makes it difficult

to resolve the more causative factor in disease

HLA-DQ A cell surface receptor type protein (MHC class II type) found on antigen presenting

cells The DQ loci are in close genetic linkage to HLA-DR When tolerance to self

proteins is lost DQ may become involved in autoimmune disease

Immuno-mediated disease Conditions that result from abnormal activity of the bodyrsquos immune system


(Review)


Table 1 Glossary of terms (Continued)

Inflammation Response of vascular tissues to harmful stimuli and a protective attempt to remove the

injurious stimuli and to initiate the healing process A cascade of biochemical events

propagates and matures the inflammatory response involving the local vascular system

the immune system and various cells within the injured tissue

Major histocompatability complex (MHC) A large genomic region or gene family found in most vertebrates that encodes MHC

molecules MHC molecules play an important role in the immune system and autoim-

munity

Neuron An electrically excitable cell that processes and transmits information by electrical and

chemical signalling Chemical signalling occurs via synapses specialised connections

with other cells Neurons connect to each other to form networks Neurons are the

core components of the nervous system

Pathological Altered or caused by disease

Pathogenesis The mechanism by which the disease is caused

Phagocytosis Mechanism used to remove pathogens and cell debris

Polygenic disease Disease controlled by several genes at once

Relapse An objective newre-emerging neurological abnormality present for at least 24 hours

in the absence of feverinfection

Reversible Capable of returning to an original conditionsituation

Stenosis Abnormal narrowing in a blood vessel

Tremor Involuntary somewhat rhythmic muscle contraction and relaxation involving to-and-

fro movements of one or more body parts

Venogram An X-ray test that takes pictures of blood flow through the veins in a certain area of

the body

Venotopic Located in the veins

Venous angioplasty A procedure that can be performed during a venogram to open or bypass veins It can

also be used for placement of a stent which keeps a vessel or tissue in an open position

to allow for improved blood flow

Venous congestion Dilation of veins and capillaries due to impaired venous drainage

Vertigo Type of dizziness where there is a feeling of motion when one is stationary


(Review)


Table 2 Contact with investigators

Study ID Response Additional Comment

Zamboni 2012 Nil e-mail zmpunifeit on 24 July 2012 4 August 2012

Dear Professor Zamboni

My colleagues and I are conducting a Cochrane review on

rdquoPercutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous

insufficiency (CCSVI) in multiple sclerosis patientsrdquo and your study ldquoZamboni P Ga-

leotti R Weinstock-Guttman B Kennedy C Salvi F Zivadinov R Venous angioplasty

in patients with multiple sclerosis results of a pilot study Journal of Vascular Surgery

201243(1)116-22rdquo has been identified as potentially eligible for inclusion

To enable us to further assess this trial for inclusion I would be obliged if you could

kindly provide us with the following missing trial details

bull Can we receive the protocol of this study

bull Did restenosis occur in the first 6 months after PTA in the immediate group or

later

bull When exactly did the relapses occur in both groups (time after start of the study)

bull In which group occurred the vasovagal collapse (immediate PTA or delayed

PTA)

Table 3 Percutaneous transluminal angioplasty compared to no treatment sham treatment or other MS treatment for


Percutaneous transluminal angioplasty compared to no treatment sham treatment or other MS treatment for participants

with multiple sclerosis

Patient or population participants with multiple sclerosis

Intervention percutaneous transluminal angioplasty

Comparison no treatment sham treatment or other MS treatment

Outcomes Illustrative comparative risks

(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments

Assumed risk Corresponding

risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)



participants with multiple sclerosis (Continued)

Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes The corresponding risk

(and its 95 confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention

(and its 95 CI)

CI Confidence interval RR Risk ratio

GRADE Working Group grades of evidence

High quality Further research is very unlikely to change our confidence in the estimate of effect

Moderate quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change

the estimate

Low quality Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to

change the estimate

Very low quality We are very uncertain about the estimate

1 We did not address study designs other than RCT the current evidence is mainly based on observational studies and the quality of

this evidence should be considered low to very low


(Review)


Table 4 Research recommendations based on a gap in the evidence of the effects of percutaneous transluminal angioplasty

for treatment of chronic cerebrospinal venous insufficiency in multiple sclerosis patients

Core elements Issues to consider Status of research for this review

Evidence (E) What is the current state of the evidence This systematic review identified no RCTs No evi-

dence of effectiveness of percutaneous transluminal an-

gioplasty (PTA) for treatment of chronic cerebrospinal

insufficiency (CCSVI) in MS patients

Population (P) Diagnosis disease stage comorbidity risk factors gen-

der age ethnic group specific inclusion or exclusion

criteria clinical setting

Inclusion criteria

bull participants of both genders gt 17 years with a

diagnosis of MS according to the original or the

revised McDonald criteria (McDonald 2001Polman

2005Polman 2011)

bull diagnosis of CCSVI according to Zambonirsquos

criteria (Zamboni 2009a) or other relevant

internationally recognised and validated criteria

Exclusion criteria

bull pregnancy

bull relapse

bull corticosteroid treatment 30 days before study

entry

bull pre-existing medical conditions known to be

associated with brain pathology

bull allergy to contrast media

bull disease progression

bull previous PTA treatment

bull patients with renal insufficiency

bull patients with a contraindication to

anticoagulation or anti-platelet medication

bull patients with a history of deep venous thrombosis

of the lower extremities

bull patients with occlusion of the right and left

common femoral veins

bull patients with a life expectancy lt 18 months

Intervention (I) Type frequency dose duration prognostic factor The study duration should be at least 12 months as-

sessing percutaneous transluminal angioplasty alone or

in combination with other MS treatments

Comparison (C) Type frequency dose duration prognostic factor No treatment sham treatment or other MS treatments

Outcome (O) Which clinical or patient-related outcomes will the re-

searcher need to measure improve influence or accom-

plish Which methods of

measurement should be used

1 The number of patients with at least one AE

bull serious AE according to ICH Expert Working

Group 1994

bull any other AE reported during or after the PTA

procedure

2 The number of participants who experienced progres-

sion on the Expanded Disability Status Scale (EDSS)

(Kurtzke 1983)


(Review)



for treatment of chronic cerebrospinal venous insufficiency in multiple sclerosis patients (Continued)

3 Patient reported outcomes (PROs) to include any of

the following if reported

bull change in QoL assessed using any validated

disease specific (eg MSQOL-54 (Vickrey 1995)

MSQLI (Fischer 1999) MusiQoL (Simeoni 2008)) or

generic instrument (eg short form 36 (SF-36)

(Rudick 2007))

bull mean change in well-being as measured with a

visual analogue scale (VAS)

bull mean change in Modified Fatigue Impact Scale

(MFIS) (Kos 2005) or other recognised and validated

MS-fatigue scale


4 Restenosis of target vessel primary and secondary pa-

tency

5 Mean change in cognitive functions assessment

through validated battery of tests in MS (ie Brief Re-

peatable Battery of Neuropsychological Tests (BRBNT)

(Rao 1991))

3 In the RRMS subgroup only the number of partici-

pants experiencing at least one relapse

Time stamp (T) Date of literature search or recommendation July 2012

Study type What is the most appropriate study design to address

the proposed question

bull Randomised controlled trial (adequately

poweredmulti-centred)

bull Methods concealment of allocation sequence

bull Blinding because blinding of participants and

trialists may not be feasible outcomes assessors and

data analysts should be blinded to the intervention

received by the participants

bull Setting hospitaluniversity with adequate follow-

up (at least 12 months)

H I S T O R Y

Protocol first published Issue 6 2012

Review first published Issue 12 2012


(Review)


C O N T R I B U T I O N S O F A U T H O R S

The trial search coordinator of the Cochrane MSRDCNS Group was responsible for running the search

Esther van Zuuren (EvZ) was responsible for organising the retrieval of papers writing to authors of papers for additional information

screening search results screening retrieved papers against inclusion criteria appraising the quality of papers obtaining and screening

data on unpublished studies

Zbys Fedorowicz (ZF) and EvZ will be responsible in future updates for reviewing the studies and extracting outcome data assessing

risk of bias from the papers and entering it into RevMan

ZF EvZ and Eugenio Pucci (EP) will be responsible in future updates for writing the effects of intervention analysis and interpretation

of the data

All review authors contributed to writing the review

EvZ ZF VJ and Edward Robak (ER) conceived the idea for the review and are the guarantors for the review

ZF and EvZ will update the review

D E C L A R A T I O N S O F I N T E R E S T

EP has received funds from a non-profit association the ldquoAssociazione Marchigiana sclerosi multipla e altre malattie neurologicherdquo

this association has received donations from Biogen Dompeacute Merck-Serono and Bayer-Schering In the last five years (2007 to 2012)

EP has also received honoraria reimbursement for attending congresses and grant support for organising scientific activities from the

above-mentioned drug industries and from Aventis UCB Lundbeck and Novartis The other review authors have no financial conflicts

of interest and they do not have any associations with any parties who may have vested interests in the results of this review One of the

authors (ER) has undergone the procedure under consideration in this review

S O U R C E S O F S U P P O R T

Internal sources

bull No sources of support Netherlands

External sources


D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

There are no differences between the protocol and the review


(Review)


T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

4OBJECTIVES

5METHODS

8RESULTS

Figure 1 9

10DISCUSSION

11AUTHORSrsquo CONCLUSIONS

11ACKNOWLEDGEMENTS

12REFERENCES

16CHARACTERISTICS OF STUDIES

25DATA AND ANALYSES

25ADDITIONAL TABLES

30HISTORY

30CONTRIBUTIONS OF AUTHORS

31DECLARATIONS OF INTEREST

31SOURCES OF SUPPORT

31DIFFERENCES BETWEEN PROTOCOL AND REVIEW

iPercutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients

(Review)
















A B S T R A C T

Background








Objectives


Search methods




Selection criteria








(Review)


Main results




















review



B A C K G R O U N D












(Lublin 1996)















(Review)















disabling





(Compston 2008)














2004 Trapp 1998)


































































pathways





(Review)

















forms (Patti 2012)
























Canada 2012)


















control





2009c)













Repubblica 2010)












paradigm

O B J E C T I V E S




(Review)


M E T H O D S


Types of studies














Primary outcomes





1994)





















Secondary outcomes





















Electronic searches




2012) (Appendix 1)













(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)
















A B S T R A C T

Background








Objectives


Search methods




Selection criteria








(Review)


Main results




















review



B A C K G R O U N D












(Lublin 1996)















(Review)















disabling





(Compston 2008)














2004 Trapp 1998)


































































pathways





(Review)

















forms (Patti 2012)
























Canada 2012)


















control





2009c)













Repubblica 2010)












paradigm

O B J E C T I V E S




(Review)


M E T H O D S


Types of studies














Primary outcomes





1994)





















Secondary outcomes





















Electronic searches




2012) (Appendix 1)













(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


Main results




















review



B A C K G R O U N D












(Lublin 1996)















(Review)















disabling





(Compston 2008)














2004 Trapp 1998)


































































pathways





(Review)

















forms (Patti 2012)
























Canada 2012)


















control





2009c)













Repubblica 2010)












paradigm

O B J E C T I V E S




(Review)


M E T H O D S


Types of studies














Primary outcomes





1994)





















Secondary outcomes





















Electronic searches




2012) (Appendix 1)













(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)















disabling





(Compston 2008)














2004 Trapp 1998)


































































pathways





(Review)

















forms (Patti 2012)
























Canada 2012)


















control





2009c)













Repubblica 2010)












paradigm

O B J E C T I V E S




(Review)


M E T H O D S


Types of studies














Primary outcomes





1994)





















Secondary outcomes





















Electronic searches




2012) (Appendix 1)













(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)

















forms (Patti 2012)
























Canada 2012)


















control





2009c)













Repubblica 2010)












paradigm

O B J E C T I V E S




(Review)


M E T H O D S


Types of studies














Primary outcomes





1994)





















Secondary outcomes





















Electronic searches




2012) (Appendix 1)













(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


M E T H O D S


Types of studies














Primary outcomes





1994)





















Secondary outcomes





















Electronic searches




2012) (Appendix 1)













(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)





trialscom




wwwanzctrorgau



Correspondence













excluded it


Issue Method














follow-up


details



comments












(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


(Continued)


7 other bias


included study








































(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


(Continued)
























R E S U L T S



studies












(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)




(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


Included studies


Excluded studies







clusion criteria

D I S C U S S I O N

















proved unsuccessful

















bias





























(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)






























be underestimated










































(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


R E F E R E N C E S







21839654]




























Al-Omari 2010





Anon 2010




Ascherio 2007



17444504]

Bagert 2011



21747006]

Baracchini 2011




Baracchini 2012




Barnett 2006




Bavera 2011





109ndash13

Brown 2006



BMJ 2006333(7572)804ndash6

Burrell 2011





PMID 21447278]

Burton 2011




PMID 21856578]

Centonze 2011





PMID 21786298]

Comabella 2012




Compston 2008




(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)





201110(7)657-66 [PUBMED PMID 21683931]

Diaconu 2012





Diehm 2007





Doepp 2010





Dorne 2010






Ebers 2008



18275928]

Egger 1997









Fischer 1999




Fragoso 2011





Frohman 2006



16510748]

Ghezzi 2011




PMID 21161309]

Giacobbi 2012






Higgins 2011




Hohlfeld 2011





Hojnacki 2010
















Khan 2010





Kos 2005




76ndash80

Krogias 2010





Kurtzke 1983




(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)



6685237]

Laupacis 2011






Lazzaro 2011





Lublin 1996






PMID 8780061]

Lucchinetti 1996





Ludyga 2010





21107001]

Maggs 2004



Malagoni 2010






Marder 2011






Martino 2002




499ndash509 [PUBMED 12849335]

Mayer 2011





21296899]

McDonald 2001






Menegatti 2008




Menegatti 2011








Munger 2006




PMID 17179460]

Nessler 2010




NICE 2012





Patti 2012




[PUBMED 22870210]

Petrov 2011






Polman 2005




16283615]

Polman 2011




(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)




21387374]

Qiu 2010




Rao 1991




Reekers 2011






RevMan 2011




Rudick 2007





Schulz 1995





Sellner 2011

















Simeoni 2008





17942521]

Simka 2010






Simpson 2011






Singh 2009





Sundstroumlm 2010





Trapp 1998





Treadwell 2006




[DOI 1011861471-2288-6-52]

Tremlett 2006




Tsivgoulis 2011





21849653]

van Rensburg 2010




Vera 2012






Vickrey 1995




(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)



PMID 7613530]

Waschbisch 2011




Wattjes 2011







Weinshenker 1989











Yamout 2010





Zamboni 2006





Zamboni 2009a





Zamboni 2009b






Zamboni 2009c








Zamboni 2010




Zamboni 2011a






Zamboni 2011b






Zivadinov 2011a





21490322]

Zivadinov 2011b








(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)










ACTRN12612000302853




















Exclusion criteria










(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)





























The Alfred


55 Commercial Road


Tel +61 3 9076 3606



NCT01089686







(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)






venogram


Exclusion criteria




neurologists
















period


lesions)




bull Mortality












Tel (518) 452-1048


(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)




NCT01201707


sclerosis







and 6



Exclusion criteria



medicated


bull pregnancy



Versed and Fentanyl





















(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)



walk














Tel (518) -262-5356

macdowbmailamcedu

Katy Regan

Tel (518) -262-5938

regankmailamcedu


NCT01371760












Exclusion criteria






bull thrombophilia



(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)









months


Secondary outcomes


















b




Tel 0039 0223941


Paolo Zamboni MD

Tel 0039 0532237694


NCT01450072




(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)














Exclusion criteria
























Tel 716-859-7068

Jennifer Gay

Tel 716-887-5200

jgayubnscom



(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)


NCT01555684









pathways

Exclusion criteria

bull Non ambulatory










amhunter1stiracuk




(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)











movements




cord


ning and so on
















(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)









munity
















the body








(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)
















later



PTA)









(95 CI)

Relative effect

(95 CI)

No of Partici-

pants

(studies)

Quality of the

evidence

(GRADE)

Comments


risk

No treatment

sham treatment

or other MS

treatment

Percu-

taneous trans-

luminal angio-

plasty

Serious ad-

verse events ac-

cording to ICH

Expert Working

Group 1994

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included


(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)




Any other ad-

verse events

reported during

or after the PTA

procedure

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Change in QoL

assessed using

any validated

disease specific

or generic in-

strument

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

well-being as

measured with a

visual analogue

scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Mean change in

Modified

Fatigue Impact

Scale (MFIS) (

Kos 2005)

or other recog-

nised and vali-

dated MS-

fatigue scale

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included

Any

other patient re-

ported outcome

- - Not estimable 0

(0)

No evidence

from RCTs1

No RCT

included



(and its 95 CI)





the estimate


change the estimate





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)












Inclusion criteria




2005Polman 2011)




Exclusion criteria

bull pregnancy

bull relapse


entry
























Group 1994


procedure



(Kurtzke 1983)


(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)










(Rudick 2007))





MS-fatigue scale



tency




(Rao 1991))















H I S T O R Y




(Review)










of the data












Internal sources


External sources





(Review)










of the data












Internal sources


External sources





(Review)


Percutaneous transluminal angioplasty for the treatment of limb threatening ischemia: Do the results...

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Transcript of Percutaneous transluminal angioplasty for the treatment of limb threatening ischemia: Do the results...