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IntroductionCerebrovascular diseases are a major global healthproblem, result in high morbidity and mortality, and are the leading cause of disability.1 Over the past fewyears, developments in endovascular treatments forcerebrovascular diseases have expanded the horizon oftreatment by use of minimally invasive techniques. Inendovascular treatment, drugs and devices areintroduced through catheters or microcatheters placedinto blood vessels through the skin. The initial work ofHaschek, Lindenthal, and Moniz2 led to development ofcerebral angiography as a diagnostic method. In the early1960s, Luessenhop and Velasquez3 showed thatintracranial vessels could be catheterised with flow-directed balloon tipped catheters, and in 1974,Serbinenko4 reported use of balloon tipped micro-catheters and detachable balloons for treatment ofintracranial aneurysms—starting the use of endovascularprocedures as a method of treatment.

The basic principle of all endovascular proceduresinvolves percutaneous entry into the femoral, radial, orbrachial artery5,6 by use of a modification of Seldinger’stechnique.7 Guide catheters or sheaths are introducedthrough the aorta into the supra-aortic vessel of interest.Microcatheters, balloon catheters, and stent deliverydevices are introduced through the guide catheter andguided to the target lesion with flexible microwires.Advanced designs of microcatheters including flowdirected and magnetically guided microcatheters8 haveallowed highly selective delivery of coils, embolicmaterials, and drugs into regions of interest.

Acute ischaemic strokeIn 1958, Sussmann and Fitch9 reported successfulrecanalisation of an acutely occluded internal carotidartery after intra-arterial injection of plasmin. Subsequentattempts at intra-arterial administration of thrombolyticswere unsuccessful because the time window for

Lancet 2004; 363: 804–13

Cerebrovascular Diseases Program, Department of Neurology andNeurosciences, University of Medicine and Dentistry of New Jersey,Newark, NJ, USA (Prof A I Qureshi MD)

Correspondence to: Prof Adnan I Qureshi, Neurological Institute ofNew Jersey, 90 Bergen Street, DOC-8100, University of Medicineand Dentistry of New Jersey, Newark, NJ 07103-2425, USA(e-mail: aiqureshi@hotmail.com)

intervention was not clearly understood and doctors hadlittle experience in guiding catheters into the intracranialvessels. With better understanding of the time window,randomised trials10,11 showed the benefit of usingintravenous alteplase for patients with ischaemic strokepresenting within 3 h of symptom onset. However,57–58% of the patients given intravenous alteplase died orbecame dependent as a result of the stroke, highlightingthe need for new strategies.10–12 The intra-arterial approachhas been promoted because a high concentration ofthrombolytic agents can be delivered into the thrombus,complemented by mechanical disruption to facilitatethrombolysis.13–15 Despite the observation in uncontrolledstudies13–15 that recanalisation rates were higher with intra-arterial thrombolysis than with intravenous thrombolysis,clinical benefit might be compromised with the delaybefore starting treatment with the intra-arterial approach.Use of the intra-arterial approach for patients withischaemic stroke who are expected to have a limitedresponse to intravenous treatment has gained morepopularity than for the intra-arterial approach being usedas a first-line approach. Criteria that have been proposedor used for selection of patients include severeneurological deficits (National Institute of Health StrokeScale [NIHSS] score �10;15,16 table 1), presentationbetween 3 h and 6 h after symptom onset,17 recent historyof major surgical procedures (within 14 days),18 andocclusion of major cervical or intracranial vessels.16,19,20

The procedure is done as follows: an initial angiogramis done to determine the site of occlusion and to identify

Endovascular treatment of cerebrovascular diseases andintracranial neoplasms

Adnan I Qureshi

Cerebrovascular diseases are an important cause of morbidity and mortality worldwide. Endovascular treatment hasemerged as a minimally invasive approach to treat cerebrovascular diseases and possibly intracranial neoplasms.Practice patterns for selection of patients for endovascular treatment are continuously being modified on the basis ofnew information derived from clinical studies. In this review, I discuss the various endovascular treatments fordiseases such as ischaemic stroke, carotid and intracranial stenosis, intracranial aneurysms, arteriovenousmalformations, malignant gliomas, and meningiomas.

Search strategy and selection criteria

I based my review on personal knowledge of the subjectsupplemented by data derived from multi-centre randomisedtrials, non-randomised controlled studies with independentoutcome ascertainment, and selected observational studies.The information was identified with multiple searches onMEDLINE from 1985 to the present by cross referencing keywords of cerebrovascular disease, stroke, intracranialneoplasms, or clinical trials, with intra-arterial thrombolysis,angioplasty, stent, embolisation, detachable coils, intra-arterialchemotherapy and intra-arterial infusion. I also reviewedabstracts from pertinent scientific meetings. Information abouttechnological developments was also acquired throughindustrial resources available for clinical investigators (http://image.thelancet.com/extras/03art6147webappendix.pdf).

Review

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randomly allocated to receive either saruplase (n=121) orplacebo (n=59) through a microcatheter placed in thethrombus over a 2 h period. The recanalisation rate wassignificantly higher in the saruplase group (66%) than inthe control group (18%, p<0·001). Despite a higher rateof symptomatic intracranial haemorrhages, the rate offavourable outcome (modified Rankin scale of 0–2 at90 days) was significantly higher in patients givensaruplase (40%) than in those given placebo (25%p=0·04).

Another approach under investigation is the starting ofintravenous thrombolysis in the period between initialassessment and intra-arterial treatment.27,28 In theInterventional Management of Stroke (IMS) study,28

80 patients with an initial NIHSS of 10 of greater weregiven intravenous thrombolysis followed by intra-arterialthrombolysis. Treatment was started within 3 h, with0·6 mg/kg intravenous alteplase followed by cerebralangiography in 78 patients. Intra-arterial alteplase (up to22 mg) was started in 64 of 78 patients in whom athrombus was seen. Part or complete recanalisation wasachieved in 41 of the 64 patients after intra-arterialtreatment. The rate of symptomatic intracerebralhaemorrhage within 36 h of treatment was 6·2%; overallmortality was 16%, and 30% of the patients had little orno disability at 90 days. An indirect comparison with thepatients given intravenous alteplase (0·9 mg/kg) in theprevious study10 did not show any significant differences inmortality or symptomatic intracerebral haemorrhagerates, although a higher rate of asymptomaticintracerebral haemorrhages was noted. The comparisonbetween different studies is limited by differences in

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collateral supply to the affected region. The angiogramcan also be incorporated into a scheme to stratify patientsinto expected rate of recanalisation and short-termoutcome after intra-arterial thrombolysis (panel).21 Amicrocatheter is advanced to the occluded vessel into thethrombus, and thrombolytics are administered (figure 1).Some of the thrombolytics used include urokinase,22,23

saruplase,17,24 alteplase,25,26 and reteplase14,15 (table 1). Thedose of thrombolytics is titrated on the basis ofangiographic recanalisation. Although recanalisationstrongly correlates with clinical outcome, other factorssuch as age and initial severity of neurological deficits alsoaffect the outcome.22,23 The phase III randomised,multicentre trial Prolyse in Acute CerebralThromboembolism II17 determined the clinical efficacy ofintra-arterial saruplase in 180 patients with middlecerebral artery occlusion within 6 h of symptom onset.Patients with an NIHSS score of 4 or greater were

PROACT I24 PROACT II17 EMS Bridging Trial27 IMS28

IA saruplase Controls IA saruplase Controls IV/IA alteplase IA alteplase IV/IA alteplase(n=26) (n=14) (n=121) (n=59) (n=17) (n=18) (n=80)

Time to start of treatment (h) 0–6 0–6 0–6 0–6 0–3 0–3 0–3Initial NIHSS* 17 19 17 17 16 11 17·5†Part or complete recanalisation 60% 14% 66% 18% 82% 71% 71%Symptomatic intracranial haemorrhages 15% 7% 10% 2% 0% 6% 6%‡(at 24 h)Modified Rankin Scale 0–1§ 31% 21% 26% 7% 35% 50% 30%Death 27% 43% 25% 27% 29% 6% 16%

PROACT=Prolyse in Acute Cerebral Thromboembolism. EMS=Emergency Management of Stroke. IMS=Interventional Management of Stroke. NIHSS=National Instituteof Health Stroke Scale. IA=intraarterial. IV=intravenous. *National Institute of Health Stroke Scale (NIHSS)=42 point scale that assesses performance in 15 neurological functions including language, neglect, and motor strength to measure stroke severity. Higher score corresponds to more severe neurological deficits.†Excludes motor score for unaffected side. ‡Within 36 h. §Modified Rankin Scale=simplified overall assessment of functional outcome in which a score of 0 indicatesthe absence of symptoms and a score of 5, severe disability.

Table 1: Results of multicentre prospective trials assessing intra-arterial thrombolysis for acute ischaemic stroke

Figure 1: Treatment of middle cerebral artery occlusion withintra-arterial thrombolysisAcute occlusion (arrow) of proximal right middle cerebral artery (grade 3B)in patient with ischaemic stroke (left). Recanalisation after intra-arterialthrombolysis with flow visualised in superior and inferior division(arrowheads) of middle cerebral artery (right).

Grading scheme for stratification of patients withacute ischaemic stroke based on initial site ofocclusion and collateral supply21

Grade 0: No occlusion

Grade 1: Middle cerebral artery occlusion (M3 region); oranterior cerebral artery occlusion (A2 or distal segments); orocclusion of one branch of basilar/vertebral artery

Grade 2: Middle cerebral artery occlusion (M2 region); oranterior cerebral artery occlusion (A1 and A2 segments); orocclusion of two or more branches in the basilar/ vertebral artery

Grade 3: Middle cerebral artery occlusion (M1 region)Grade 3A Lenticulostriate arteries spared or leptomeningeal

collaterals visualised, or bothGrade 3B No sparing of lenticulostriate arteries nor

leptomeningeal collaterals visualised

Grade 4: Internal carotid artery occlusion (collaterals present)Grade 4A Collaterals fill middle cerebral arteryGrade 4B Collaterals fill anterior cerebral artery only

Basilar artery occlusion (partial filling direct or via collaterals)

Grade 4A Anterograde filling (predominant)Grade 4B Retrograde filling (predominant)

Grade 5: Internal carotid artery occlusion (no collaterals)Basilar artery occlusion (complete)

Interobserver variability and correlation with recanalisation, and short-termfavourable outcome and mortality have been described in patients withacute ischaemic stroke undergoing intra-arterial thrombolysis previously.21

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methods of administration, thrombolytic agents, anddoses.

Mechanical devices can facilitate binding ofthrombolytics to clot bound fibrin and promote the lyticprocess,29 and can be divided into devices that eitherdisrupt or retrieve the thrombus. Thrombus disruptiondevices include angioplasty balloon catheters; snaredevices; and specialised intravascular catheters that emitultrasound, pressurised saline solution with resorption, orphotoacoustic energy. Adequate safety and feasibility has

been shown in the phase I studies involving 14 patientstreated with ultrasound emitting catheter30 and 26 patientstreated with a photoacoustic energy emitting system31 forocclusions in the anterior and posterior circulation.A phase I study32 reported adequate safety and feasibilityof a helical retrieval wire that engages and subsequentlyremoves thrombi, in 30 patients treated within 8 h ofstroke onset.

Use of platelet glycoprotein IIb/IIIa inhibitors has beensuggested to prevent platelet activation and reocclusion,33

and is being investigated in several phase I studies asadjuvant treatment to intra-arterial thrombolysis.

Carotid stenosisRandomised trials have shown the benefit of carotidendarterectomy in reducing the risk of stroke in patientswith moderate to severe symptomatic (�50%)34–36 orasymptomatic (�60%)37 carotid artery stenosis. However,in general practice, perioperative complications aresometimes high enough that potential benefits areobscured when carotid endarterectomy is done onpatients with unfavourable clinical and anatomicalcharacteristics.38–42 Carotid angioplasty with stentplacement (CAS) was initially introduced as an alternativetreatment for revascularisation of carotid artery stenosis inhigh-risk surgical candidates43 on the basis of successfulclinical trials of endovascular revascularisation forcoronary and peripheral circulation.44,45 CAS can be donein high-risk surgical groups, including patients with severecoronary artery disease,46,47 anticipated coronary arterybypass surgery,48,49 congestive heart failure,50 high lyingcervical lesions,51 contralateral carotid occlusion,52

restenosis after the procedure,53 radiation inducedstenosis,54 or dissection-related stenosis,55 with high

Figure 2: Treatment of cervical internal carotid artery stenosiswith stent placementHigh-grade stenosis of cervical internal carotid artery on angiography (left;arrows). Schematic representation of stent placement (red) with distalprotective device in place (blue) (middle). Near complete resolution ofstenosis on angiography done after stent placement (right).

Design Inclusion criteria Number of Technical 1-month all 1 month stroke patients success stroke rate and death rate

Carotid angioplasty and stent placement without distal protection deviceNaylor and colleagues72 Single centre randomised >70% symptomatic ICA stenosis 7 100% 71% 43%WALL STENT trial73 Multicentre �60% symptomatic 107 97% NA 12%

randomised ICA stenosis CAVATAS79 Multicentre randomised Mean ICA stenosis 86 (SD 9) 251 (88% 89% 8% 10%

(ECST criteria) symptomatic)Brooks and colleagues78 Single centre randomised >70% symptomatic ICA stenosis 53 100% 0% 0%Memotherm Carotid Multicentre prospective registry �50% symptomatic ICA stenosis 71 (73 93% 3% 3%Stent Study74 or �70% asymptomatic ICA lesions)

stenosisEndoTex Coiled Sheet Multicentre prospective �70% symptomatic or 44 100% 7% 9%Stent Trial75 registry asymptomatic ICA stenosisLink and colleagues76 Single centre randomised >70% symptomatic ICA stenosis 8 100% 0% 0%

Carotid angioplasty and stent placement with distal protection devicesReimers and colleagues68 Multicentre prospective registry �70% symptomatic or asymptomatic 84 97% 1% 1%

ICA stenosis (88 lesions)CAFE-Germany trial77 Multicentre prospective registry �60% symptomatic ICA stenosis or 54 100% 3% 3%

�70% asymptomatic ICA stenosis (58 lesions)Italian study66 Multicentre prospective registry �75% symptomatic ICA stenosis or 30 93% 0% 0%

�80% asymptomatic ICA stenosisCAFE study67 Multicentre prospective registry �60% symptomatic ICA stenosis or 75 95% 0% 0%

�70% asymptomatic ICA stenosisFilterWire EX Multicentre prospective registry �50% symptomatic ICA stenosis or 35 97% 0% 0%International study62 �70% asymptomatic ICA stenosis (36 lesions)Neuroshield study68 Multicentre prospective registry �50% symptomatic ICA stenosis or 162 patients 94% 1% 2%

�70% asymptomatic ICA stenosis (164 arteries)SAPPHIRE50* Multicentre randomised �50% symptomatic ICA stenosis or 156 89% 4% 5%

�80% asymptomatic ICA stenosisCREST80 Multicentre prospective registry �50% symptomatic ICA stenosis or 169 NA 4% 4%

�70% asymptomatic ICA stenosisARCHeR70* Multicentre prospective registry �50% symptomatic ICA stenosis or 437 93% 5% 7%

�80% asymptomatic ICA stenosis

ICA=internal carotid artery. ECST=European Carotid Surgery Trial. CAVATAS=Carotid and Vertebral Artery Transluminal Angioplasty Study. CAFE=Carotid Angioplast-Stenting Free of Emboli. SAPPHIRE=Study of Angioplasty with Protection in Patients at High Risk for Endarterectomy. ARCHeR=Acculink for Revascularization ofCarotids in High-Risk Patients. CREST=Carotid Revascularization Endarterectomy vs Stent Trial. NA=not available. *Includes only high surgical risk patients.

Table 2: Summary of clinical studies investigating technical success and acute procedural results for carotid angioplasty and stentplacement

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specified size of the pores of the filter. Another antiembolisystem consists of a guiding catheter with an occlusionballoon that induces reversal of intracranial flow toprevent intracranial flow of emboli. The results of phase Iand II studies50,66–70 have shown high technical success andlow rates of stroke or death associated with CAS whendone with distal protection devices (table 1). A systematicreview71 reported that occurrence of minor and majorstroke is lower in reports from CAS done with distalprotection compared with this procedure done withoutprotection.

Over the past few years, several non-randomised studiesand randomised comparisons with carotid endarterectomyhave investigated the safety and effectiveness of CAS(table 2) Two studies50,70 have strongly advocated thesafety and possible benefit of CAS with distal protectionin high-risk surgical patients. In the Study of Angioplastywith Protection in Patients at High Risk forEndarterectomy (SAPPHIRE) trial50 307 high-riskpatients were randomly allocated to either CAS or carotidendarterectomy, and 402 patients deemed not suitable forcarotid endarterectomy were enrolled into a stent registry.At 30-day follow-up, the combined rate of death, stroke,or myocardial infarction was significantly lower for the156 patients who had CAS and distal protection (6%)compared with the 151 patients who received carotidendarterectomy (13%). The combined rate of death,stroke, or myocardial infarction was 8% in the patientsenrolled in the stent registry. At 1 year, ipsilateral strokerate was 3·8% and 5·3% for patients who received CASand endarterectomy, respectively. Overall, 6·9% of thepatients who received CAS and 12·6% of those who hadan endarterectomy had died by 1 year. The non-randomised Acculink for Revascularisation of Carotids inHigh-Risk Patients (ARCHeR) study70 reported a rate of8% for the combined endpoint of death, stroke, ormyocardial infarction at 30 days in 437 high-risk patientsrecruited in the study. Subset analysis showed thatpatients with restenosis can be treated, with a less than1% rate of stroke or death. Secondary endpoints are beingassessed 6-monthly for up to 30 months.

Improvement in technology and operator experience,and results of clinical trials have led to broader acceptanceof the use of CAS in patients who are not at a high risk. Inthe multicentre randomised Carotid and Vertebral ArteryTransluminal Angioplasty Study (CAVATAS),79 the rateof perioperative major stroke or death with carotidstenosis in 251 patients randomly assigned to endovas-cular treatment was much the same as that for253 patients allocated to carotid endarterectomy (6% vs6%, respectively). Stents were used in 26% of thepatients treated with an endovascular procedure. Ahigher rate of cranial neuropathy and major neck andgroin haematomas was seen in patients assigned tocarotid endarterectomy than in those receivingendovascular treatment. No substantial difference in therate of ipsilateral stroke between the groups was noted,with survival analysis up to 3 years after randomisation.However, the rate of severe stenosis or occlusion in thetreated carotid artery at 1 year was higher afterendovascular treatment (18%) than after carotidendarterectomy (5%, p<0·001). The US NationalInstitute for Neurological Disorders and Stroke fundedCREST study (Carotid Revascularisation Endarterect-omy vs Stent Trial)80 is comparing the efficacy of CASwith carotid endarterectomy in 2500 patients withsymptomatic stenosis. A lead-in phase was set up fordoctors to do 20 CAS procedures before doing proce-dures on randomised patients. The early results from the

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technical success rates and acceptable periproceduralcomplication rates. However, some patients who are athigh risk for carotid endarterectomy, such as those whoare older (�80 years),56 with fluctuating neurologicaldeficits,57 and intraluminal thrombus also seem to be athigh risk for CAS.

All patients receive aspirin and ticlopidine orclopidogrel before and up to 1 month after the procedureon the basis of data derived from coronary intervention.58

Balloon angioplasty and stent delivery are undertakenthrough guide sheaths placed in the common carotidartery proximal to the stenosis (figure 2). Two classes ofstents are currently used59—ie, balloon-expandable andself-expanding, which are made of either stainless steel orthermal expansion alloy (nitinol). Balloon angioplasty canbe done before stent placement to facilitate stent deliveryor after placement to treat residual stenosis. Theeffectiveness of adjuvant use of platelet glycoproteinIIb/IIIa inhibitors such as abciximab and eptifibatide inthe immediate perioperative period is controversial.60,61 Asmall randomised comparison62 between abciximab bolusbefore the CAS and standard antithrombotic treatmentdid not show any reduction in perioperative ischaemicevents (19% vs 8%, respectively).

Release of microemboli composed of thrombotic andplaque substances63 into the cerebral circulation isfrequent during CAS, as detected by transcranial dopplerultrasound.64 MRI suggests that 15% of patients developnew lesions in the brain after this procedure, although halfof them are asymptomatic.64 An indirect comparison65

suggests that the rate of new brain lesions is higher thanthe 5% rate reported for carotid endarterectomy. Distalprotective devices consisting of occlusive balloons, filterdevices, or flow-reversal devices have been introduced toreduce the incidence of embolic particles to the brain.50,66–70

A low-pressure occlusion balloon is placed distal to thesite of CAS to trap blood flow and embolic materialbefore entry in the intracranial circulation. Filtrationdevices placed intravascularly distal to the site of theintervention filter blood to retain particles exceeding the

Figure 3: Left middle cerebral artery stenosis before (A) andafter (B) primary stent placementSymptomatic stenosis of the left middle cerebral artery on angiography(arrow; A). Resolution of stenosis after primary stent placement (B). Insetshows stent geometry within the artery in an unsubtracted angiographicimage. Histological analysis after 7 months shows intimal tissue growthover the struts of the stents (arrows) within the cross sectional view ofthe artery (C and D).

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169 patients treated in the lead-in phase set up reported acombined rate of death, stroke, or myocardial infarctionwithin 30 days after the procedure of 4%, suggesting apotential equivalence to carotid endarterectomy forpatients who are not high risk.

Intracranial stenosisIntracranial stenosis is responsible for 8–10% of allischaemic strokes.81,82 The yearly rate of recurrent strokein patients with intracranial stenosis is about 8–12%83,84

and for those who do not respond to antithrombotictreatment, the rate of recurrent ischaemic events can beas high as 52%.85 Patients with symptomatic vertebrobas-ilar stenosis have a low stroke-free survival rate of 76% at12 months and 48% at 5 years.82 Percutaneous translumi-nal angioplasty with possible stent placement has beenrecommended for treatment of intracranial stenosis,especially for patients who did not respond to anti-thrombotic treatment or who have vertebrobasilarstenosis. Small patient series86–88 have shown thefeasibility of percutaneous transluminal angioplasty orstent placement for symptomatic intracranial stenosis,with major complication rates of lower than 5%(figure 3). Long-term follow-up suggests encouragingipsilateral stroke prevention rates as high as 96% for thefirst year87 and about 87% for 3 years after endovasculartreatment.86 It should be stressed that no directcomparisons are available between best medicaltreatment and endovascular treatment for intracranialstenosis. The prospective multicentre Stenting inSymptomatic Atherosclerotic Lesions of Vertebral andIntracranial Arteries (SSYLVIA) study89 assessed43 patients with intracranial stenosis and 18 withextracranial vertebral artery stenosis. Successful stentplacement was achieved in 95% of the patients with a 1-month postprocedural stroke rate of 7%. At 6 months,recurrent stenosis of greater than 50% was recorded in30% of the intracranial arteries. Of the 42 patients with12-month follow-up, four patients had a stroke after 30 days that was related to the target lesion. Furtherdevelopments in stent design are expected to improvelong-term benefits of the procedure.

Intracranial aneurysmsIntracranial aneurysms are an important health problemworldwide, affecting about 2% of the population.90 In1941, Werner and colleagues91 inserted silver wires into anintracranial aneurysm by use of a transorbital approach toprevent rupture by protecting the susceptible wall of theaneurysm from the stress of pulsatile blood. Subsequently,placement of iron particles, detachable balloons, andpushable platinum coils was attempted.2 In the late 1980s,soft platinum coil soldered to astainless steel delivery wire wasintroduced that could be deliveredthrough a microcatheter into theaneurysm sac.92 Current applied to thedelivery wire resulted in a positivecharge on platinum coils that attractedred blood cells and platelets, inducinglocal thrombosis followed by detach-ment when the current dissolved thejunction between stainless steeldelivery wire and platinum coil. Theimmediate protection against ruptureoccurs by reduction of blood pulsa-tions within the fundus and might notinvolve a prominent thromboticresponse. Eventually, an organised

thrombus forms within the aneurysm, covered by anendothelialised layer of connective tissue that covers theneck’s ostium.93,94

Endovascular treatment is done under generalanaesthesia or awake state in selected patients.95

Endovascular coils are placed into the aneurysm sac untilno further filling is seen. Modifications in coil designshave improved the ability to obliterate the aneurysm sac.Several types of coil that use other detachmentmechanisms or have bioactive coating of coil surface arenow available. Strategies such as temporary inflation ofballoon (balloon remodelling technique),96 intravascularstent placement,97 and neck-bridge devices98 in front of theostium of the aneurysm have improved the results ofembolisation for broad neck aneurysms (figure 4). Aliquid embolic agent, an ethyl vinyl alcohol polymer, hasalso been used in conjunction with intravascular stents toobliterate complex aneurysms.99

In August, 2002, 100 000 patients with intracranialaneurysms were estimated to have been treated withdetachable coils at sites throughout the world.100 Initially,endovascular treatment was considered for patients whowere regarded as poor candidates for surgical clipping,which includes older patients (�65 years),101 those withpoor clinical grade,102 those whose aneurysms are locatedin the posterior circulation103 or cavernous segment ofinternal carotid artery,100 and those who present between3 and 10 days after symptom onset104 or have activecerebral vasospasm.105 In a meta-analysis106 of 37 studiesand 1256 patients, aneurysms were nearly obliterated in88% of patients and completely obliterated in 54% oftreated patients, with a permanent complication rate of4% and procedure-related mortality of 1·1%. Long-termfollow-up has reported a yearly haemorrhage rate of 1·4%over 141 patient-years.107 The magnitude of initialobliteration107 and the size of the intracranial aneurysm108

seem to affect the long-term risk of bleeding from treatedaneurysms. Occasional aneurysm regrowth andrecanalisation have been reported.109

With improvement in clinical experience and coildesigns, embolisation is being used for patients who couldbe treated by conventional surgical clipping.100 The firstrandomised phase II trial110,111 compared the outcomes ofsurgical clipping (n=57) and embolisation (n=52) inpatients with acute (within 72 h) aneurysmal sub-arachnoid haemorrhage. Significantly better angiographicresults were achieved after surgery in patients withanterior cerebral artery aneurysms and after endovasculartreatment in those with posterior circulation aneurysms.The technique-related mortality rate was 4% and 2% inthe surgical and endovascular groups, respectively. 1 yearafter the procedure, good or moderate recovery was seen

Figure 4: Treatment of distal vertebral artery aneurysm with placement of stent andcoilsRegrowth of distal vertebral artery aneurysm after initial coil placement (arrow; left). The anatomy wasunfavourable for primary coil placement because of a wide neck. Schematic representation (middle) ofstent placement in front of the ostium of the aneurysm to provide a base to retain the coils in theaneurysm. Near complete obliteration of the aneurysm after stent and coil placement (right).

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in 75% and 79% of surgically and endovascular treatedpatients, respectively. No late rebleedings have beenreported. The second randomised, multicentre phase IIIInternational Subarachnoid Aneurysm Trial (ISAT)112

compared the safety and efficacy of embolisation withneurosurgical clipping in 2143 patients with rupturedaneurysms suitable for either treatment. 1070 patientswere randomly assigned to surgery and 1073 toendovascular treatment. Recruitment was stopped prema-turely, after a planned interim analysis showed reduceddeath and disability in the embolisation group. A higherproportion of patients allocated to surgery (31% of 793)were dependent or dead at 1 year compared with thoseallocated to embolisation (24% of 801). However, asecond procedure was needed more frequently in patientsgiven endovascular treatment than those who underwentsurgery (121 patients vs 33 patients), with no significantdifference in time to second treatment. The risk ofrebleeding from the ruptured aneurysm after 1 year wastwo per 1276 and zero per 1081 patient-years for patientsallocated to endovascular and surgical treatment,respectively. The study will continue to ascertain therebleeding rate over 5 years to compare the durability ofthe two treatments.

A direct comparison between endovascular and surgicaltreatment for unruptured aneurysms is not available.

Hospital outcomes have improved for unrupturedintracranial aneurysms in the USA since detachable coilswere introduced.113 Johnston and colleagues114,115 did twoindirect comparisons of surgical clipping and embolisationfor unruptured intracranial aneurysms using a database of60 university hospitals (2357 patients) and a statewidedatabase (2069 patients), respectively. Lower in-hospitalmortality, stay, and costs were noted with endovasculartreatment compared with surgery in both analyses. Aretrospective comparison116 of outcomes between surgicaland endovascular treatment for unruptured aneurysmsthat are suitable for both methods showed a reduced rateof new disability, shorter stays and periods to completerecovery, and lower hospital costs with endovasculartreatment than with surgery.

Arteriovenous malformationsIn 1930, Brooks117 reported closure of carotid-cavernousfistula with surgical introduction of muscle embolus in thecarotid artery. Lussenhop and colleagues118 subsequentlyreported embolisation with silastic spheres and silksutures introduced into the internal carotid artery to treatcerebral arteriovenous malformation. Technical advancessuch as flow directed and other specialised microcathetersand new embolic agents have increased the therapeuticpotential of embolisation for cerebral arteriovenousmalformations. However, embolisation of cerebralarteriovenous malformations on its own is curative in lessthan a quarter of the lesions,119,120 and is one aspect of amultimodality approach to these lesions. Embolisation isindicated mainly before surgery or radiosurgicalintervention in large or giant arteriovenousmalformations120 Other indications include palliativeembolisation to halt progression of symptoms for largenon-surgical or non-radiosurgical arteriovenousmalformations in patients presenting with progressiveneurological deficit secondary to high flow or venoushypertension.120 It should be noted that the role ofembolisation in treatment of arteriovenous malformationsis based mainly on results from observational studies.

Embolisation is done by placing a microcatheter in thedistal portion of an arterial feeder that exclusively suppliesthe arteriovenous malformation. Any normal branches areexcluded on the basis of assessment of vessel architectureand at times physiological testing by injection of short-acting amobarbital sodium and lidocaine through themicrocatheter.121 Embolic materials are divided into solidor liquid agents.122 Solid agents consist of polyvinylalcohol particles, fibres, microcoils, and microballoons.Liquid agents consist of cyanoacrylate monomers such as I-butyl cyanoacrylate and N-butyl cyanoacrylate(figure 5), and polymer solutions such as ethylene vinylalcohol and absolute ethanol. Embolisation is usuallydone through several arterial feeders.

The goals of presurgical embolisation are to decrease thenidus size and to occlude deep, surgically inaccessible ordeep arterial feeding vessels in large arteriovenousmalformations to facilitate surgical excision.119,120 Withsurgical embolisation before surgery, the malformation canbe removed completely through surgery in up to 96% ofpatients.119 Two indirect comparisons have suggested thatembolisation before surgery can shorten the operativetimes, reduce intraoperative blood loss, and improveneurological outcomes in patients with complex arterio-venous malformations such that they are comparable tothose with less complex arteriovenous malformations (ie,not requiring embolisation).123,124 In a randomised trialcomparing N-butyl cyanoacrylate and polyvinyl alcohol forpresurgical embolisation of arteriovenous malformation,125

Figure 5: Treatment of cerebral arteriovenous malformationwith liquid embolic materialLateral view of small arteriovenous malformation (arrow) obtained duringcerebral angiography (A). Nidus and draining vein of the arteriovenousmalformation visualised through selective injection from a microcatheterplaced in the arterial feeder (B). Cast formed within the arterial feeder,nidus, and draining vein by N-butyl cyanoacrylate in an unsubtractedangiographic image (C). The arteriovenous malformation is obliteratedafter embolisation with N-butyl cyanoacrylate (D). Histological analysis ofthe cross-sectional (E) and longitudinal (F) view of the surgicallyevacuated portion of the arteriovenous malformation within 24 h ofembolisation reveals N-butyl cyanoacrylate (white cast) within the bloodvessels of the malformation with intravascular thrombosis.

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embolisation was not possible for technical reasons inthree of the 52 patients randomised to N-butyl cyano-acrylate, and there were two cross-overs from the groupallocated to polyvinyl alcohol. The final lesion reductionangiographically per patient after embolisation wasestimated as 79% for patients administered N-butyl cyano-acrylate and 87% for those given polyvinyl alcohol. Therates of good neurological recovery after embolisation were96% and 93%, respectively. No significant differenceswere recorded in intraoperated time and blood loss, andpostsurgical neurological recovery.

Embolisation is used to reduce the nidus of arteriovenousmalformations to less than 3 cm and obliterate intranidal orvenous aneurysms before radiosurgical intervention.126 In astudy126 of 125 patients who were poor surgical candidatesor who had refused surgery, embolisation produced totalocclusion in 11% of arteriovenous malformations andreduced the volume in 76% of arteriovenous malforma-tions, to make radiosurgery possible. Radiosurgeryproduced total occlusion in 65% of the partly embolisedarteriovenous malformations. Angiographic follow-up ofarteriovenous malformations embolised with cyanoacrylatedemonstrated a 12% recanalisation rate within 1 year.

Dural arteriovenous fistulas are derived from meningealarteries and drain into dural sinuses or meningeal veinsand can have retrograde drainage into subarachnoidveins.127 Treatment includes transarterial, transvenous, orcombined endovascular obliteration of the fistula byselective catheterisation and potentially the drainingsegment of the dural venous sinus. In patients where thefistulas are related to venous hypertension secondary tototal or part sinus occlusion, recanalisation withangioplasty and stent is sometimes effective.128

Intracranial tumours Intra-arterial delivery of chemotherapeutic agents into thevascular bed of intracranial tumours has been suggested toachieve a high concentration in selected regions of thebrain.129 A phase III trial130 showed no difference insurvival between the 153 patients with newly resectedmalignant glioma who were randomly allocated tointracarotid injection of carmustine and the 126 whoreceived this compound intravenously. Serious toxiceffects in the intra-arterial group, consisting of irreversibleencephalopathy, visual loss, and white matter necrosis,restricted the benefit. Improved tolerance of intra-arterialchemotherapy, particularly carboplatin, has been reportedwith a combination of selective intra-arterial delivery intointracranial vessels, pulsatile infusion, and dose based onestimation of local cerebral blood flow.131 A new approachhas used intra-arterial lobradimil, a bradykinin analogue,to increase the permeability of the brain tumour capillariesconcomitantly with carboplatin.132 A dose escalationstudy133 and a phase II study134 of intra-arterial lobradimiland carboplatin in patients with malignant recurrentgliomas have reported acceptable safety and tolerance. Inthe phase II study, the disease stabilised in 13 patients andprogressed in 28 patients after treatment.

The extensive vascularity of neoplasms is vulnerable tosuperselective intra-arterial injection of embolic particles.This notion has gained popularity for meningiomas as apreoperative adjuvant therapy.135 The highly vascular bedof meningiomas is easily identified on angiography, and isamenable to selective microcatheterisation if fed mainlyfrom the branches of external carotid artery. The goal is toinject embolic material such as polyvinyl alcohol particles,gelfoam powder, fibrin glue, microfibrillar collagen, orgelatin microspheres until the vascular blush is completelyobliterated. Indirect comparisons between results of

surgical removal of meningiomas with and withoutpreoperative embolisation suggest that embolisationreduces blood loss and the number of transfusions neededduring surgery.136 This benefit is more likely to be seen inlarge tumours than small,135 and when a high degree ofobliteration of tumour vascularity could be achieved.137

Preoperative embolisation has been recommended forgiant meningiomas, meningiomas with malignant orangioblastic characteristics, and those involving criticalvascular structures. The ideal time interval betweenembolisation and subsequent surgical evacuation iscontroversial, but an observational study138 suggested thatgreatest tumour softening is seen 7–9 days afterembolisation facilitating surgical removal.

Future applicationsThe safety and efficacy of endovascular procedures forcerebrovascular diseases is expected to improve with newtechnology. New applications such as intra-arterialdelivery of stem cells derived from bone marrow todamaged regions of the brain have shown promise inexperimental models.139 These cells can be deposited inthe regions of injured brain, survive, and express proteinssimilar to neurons. The intra-arterial route has also beenproposed as a method for delivering plasmid DNAincorporated into liposomes into regions of ischaemicinjury in the brain.140 Cationic liposomes protect the DNAfrom the extracellular environment and provide amechanism for DNA transfer to target cells by lipidfusion. Endovascular procedures are rapidly expandingthe range of treatment options for cerebrovasculardiseases and neoplasms. However, rigorous assessmentand understanding of these procedures is necessary toensure safe, effective, and appropriate use.

Conflict of interest statementA Qureshi has received grant support from Boston Scientific, CordisTherapeutics, Cor Therapeutics, Centocor therapeutics, C R Bard, andSan Francisco Science/PICS. He has also received consultant fees fromEndoTex Interventional Systems and Boston Scientific and anhonorarium from Boehringer Ingelheim.

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