Time window for recanalization in basilar artery occlusion · blood flow around the clot, but not its direction. Time-of-flight (TOF) magnetic resonance angiogra-phy (MRA) is ineffective

MEDICALHYPOTHESIS

Perttu J Lindsberg MDJohanna Pekkola MDDaniel Strbian MD MSc

(Stroke Med)Tiina Sairanen MD MSc

(Stroke Med)Heinrich P Mattle MDGerhard Schroth MD

Correspondence toDr Lindsbergperttulindsberghusfi

Time window for recanalization in basilarartery occlusionSpeculative synthesis

ABSTRACT

Basilar artery occlusion (BAO) is one of the most devastating forms of stroke and few patientshave good outcomes without recanalization Most centers apply recanalization therapies forBAO up to 12ndash24 hours after symptom onset which is a substantially longer time window thanthe 45 hours used in anterior circulation stroke In this speculative synthesis we discuss recentadvances in BAO treatment in order to understand why and under which circumstances longersymptom duration might not necrotize the brainstem and turn therapeutic attempts futile Weraise the possibility that distinct features of the posterior circulation eg highly developedpersistent collateral arterial network reverse filling of the distal basilar artery and delicateplasma flow siding the clot might sustain brittle patency of brainstem perforators in the faceof stepwise growth of the thrombus Meanwhile the tissue clock characterizing the rapid necrosisof a typical anterior circulation penumbra will not start During this perilous time period recan-alization at any point would salvage the brainstem from eventual necrosis caused by imminentreinforcement and further building up of the clot Neurologyreg 2015851806ndash1815

GLOSSARYAICA 5 anterior inferior cerebellar artery BA 5 basilar artery BAO 5 basilar artery occlusion BASICS 5 Basilar ArteryInternational Cooperation Study CTA 5 CT angiography DWI 5 diffusion-weighted imaging IAT 5 intra-arterial thrombol-ysis ICA 5 internal carotid artery IVT 5 IV thrombolysis MCA 5 middle cerebral artery MRA 5 magnetic resonanceangiography mRS 5 modified Rankin Scale OTT 5 onset-to-treatment time pc-ASPECTS 5 posterior circulation AlbertaStroke Program Early CT Score PCA 5 posterior cerebral artery PCom 5 posterior communicating artery PCS 5 posteriorcirculation stroke PICA 5 posterior inferior cerebellar artery PWI 5 perfusion-weighted imaging RCT 5 randomized con-trolled trial SCA 5 superior cerebellar artery sICH 5 symptomatic intracerebral hemorrhage TOF 5 time-of-flight VA 5vertebral artery

Basilar artery occlusion (BAO) is associated with high mortality (85ndash95) if recanalizationdoes not occur Evidence of the relative efficacies of different therapy protocols of IV throm-bolysis (IVT) or intra-arterial thrombolysis (IAT) or mechanical endovascular treatment is basedon retrospective or prospective patient cohorts since there is only one randomized controlledtrial (RCT) with 16 patients1 In a systematic analysis comparing the outcomes after variableprotocols to achieve recanalization in BAO there was only negligible likelihood of good out-come (2) in the absence of recanalization but reaching at least partial recanalization increasedthe odds of favorable outcome to 382 Based on largely empirical evidence many strokecenters have adopted recanalization therapy protocols with time windows much wider than45 hours from symptom onset which is used for stroke thrombolysis in general This articlesummarizes evidence and presents a hypothesis that assists in conceiving why we can helppatients with BAO even after a long period after onset

THE TIME WINDOW IN BAO RECANALIZATION PROTOCOLS The spontaneous recanalization rate of BAOwithin the natural course is not known but is thought to be relatively low and not to exceed 20 within aclinically meaningful time window of 12ndash24 hours3 Indeed many centers apply thrombolysis for BAO upto 12ndash24 hours after symptom onset245 In the systematic analysis of BAO case series the treatment delayfluctuated between 7 and 48 hours after symptom onset2 In the IVT series the fraction treated within

From Neurology Clinical Neurosciences (PJL DS TS) and Research Programs Unit Molecular Neurology (PJL) Biomedicum HelsinkiUniversity of Helsinki and Helsinki University Hospital the Department of Radiology (JP) HUS Medical Imaging Center Helsinki UniversityCentral Hospital and University of Helsinki Finland and the Departments of Neurology (HPM) and Diagnostic and InterventionalNeuroradiology (GS) Inselspital University of Bern Switzerland

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

1806 copy 2015 American Academy of Neurology

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

source httpsdoiorg107892boris74572 | downloaded 2452020

12 hours was 77 and within 6 hours 29 In theIAT series the corresponding fractions were 76 and42 respectively In the Helsinki IVT cohort (n 5

184)6 favorable outcome (modified Rankin Scale[mRS] 0ndash3) was achieved in 39 of those treatedwithin 6 hours in 36 within 6ndash12 hours and in36 above 12 hours If patients with extensive infarc-tion already at baseline are excluded at least 50reached mRS 0ndash3 even when treated beyond 12hours The rates of the 2 worst outcomes (mRS 5or 6) were comparable in these 3 time windows51 57 and 50 respectively Recanalizationtook place in 82 70 and 75 respectively6

Timing of treatment has been a significant prognosticpredictor in univariate analyses but not in multivariableanalyses adjusted for extent of baseline ischemicchanges67 Halving the onset-to-treatment time (OTT)after 2005 in Helsinki did not translate into therapeuticimprovement (Lindsberg et al unpublished data2015) These data do not back a firm time windowfor therapies attempting to reverse BAO

In a recent analysis of the Basilar Artery Interna-tional Cooperation Study (BASICS) registry (n 5

619) Vergouwen et al8 found that the prognosiswas related to the time from symptom onset andpatients with severe strokes at presentation treatedbeyond 9 hours after onset had poor clinical outcomeUnlike pivotal recanalization studies in anterior cir-culation stroke patients with extensive infarct signsalready at baseline were not excluded in the BASICSregistry In the Helsinki series of BAO (n 5 184) asimilar decay of therapeutic efficacy is seen beyond 9hours but this time dependency disappeared whenthe results were adjusted for the extent of baselineischemia (posterior circulation Alberta Stroke Pro-gram Early CT Score [pc-ASPECTS])69 Patientstreated later than 9 hours were simply more likelyto have extensive infarctions before treatment

RCTs of stroke have usually excluded patients pre-senting with characteristic posterior circulation symp-toms Therefore the time window for recanalizationin posterior circulation stroke has not been ascertainedin RCTs Many published case series have recruited pa-tients with substantially longer symptom times thanconsidered suitable for the anterior circulation up to45ndash6 hours for IVT or IAT and 8 hours for mechan-ical thrombectomies4 This has created an array ofspeculations where eg different collateral circulationpatterns or fewer hemorrhages due to lesser infarctvolumes have been conceived to increase the ischemiatolerance of brain tissue in the BA territory10

COLLATERAL BLOOD FLOW DYNAMICS DURINGBAO Once the trunk of the basilar artery (BA) hasbeen occluded by a sudden (thrombo)embolus bloodpressure at the junction of posterior cerebral arteries

(PCAs) drops immediately Depending on the indi-vidual vascular anatomy blood flow within the circleof Willis is partially diverted from the anterior circu-lation through posterior communicating arteries(PComs) to fill this relative void and supply bloodflow to the PCAs Depending on the level at whichthe BA trunk is occluded there will probably bereverse filling (reflux) to the distal BA maintainingthe patency of the superior cerebellar artery (SCA)branching from it as well as any number of perforatortrunks and lateral circumferential arteries that remainunblocked by the clot (see figures 1 2 4 and 9 fromreference 11) This phenomenon is observed fre-quently when individuals with varying degrees of ver-tebral artery (VA) or even BA stenosisocclusion areexamined electively with digital subtraction angiogra-phy of the anterior circulation and reversed filling ofthe distal BA can be observed to augment distal bas-ilar patency also during the acute phase of BAO(figures 1C 2C and 3 A and B)

The significance of reverse flow gradient into BAalso underlies the rationale of therapeutic stepwiseVA occlusion in the treatment of true giant fusiformBA aneurysms Before the advent of flow-divertingstents this procedure was the only way to try to pre-vent rupture by lessening the pressure and flow insidethe sac Naturally the sufficiency of the BA reverseflow had to be tested during acute temporary occlu-sion which proves its existence also in the acute set-ting of complete vertebrobasilar occlusion1213

Detecting the reverse flow in the upper BA in theacute BAO setting would require selective catheteri-zation of the cerebral arteries This is not routinelydone if the BAO has been diagnosed with CT angi-ography (CTA) CTA may demonstrate minuteblood flow around the clot but not its directionTime-of-flight (TOF) magnetic resonance angiogra-phy (MRA) is ineffective in showing very slow orreverse flow in the BA because physical propertiesof TOF MRA require fast blood flow to producevisible flow enhancement

Reverse flow from the PCom may augment residualcirculation in the branches distal to the BA clot and de-pending on the pressure gradient may helpmaintain minute flow within the oligemic region Asmall BAO series (n5 20) raised the idea that effectivecollateral flow to the BAmay prolong ischemia toleranceand lead to more favorable outcomes14 Of patients withcollateral filling of the distal BA 5 (83) had a goodneurologic outcome and 1 did not Of those withoutcollateral flow 1 (17) had a good neurologic outcomeand 5 did not Additional recent studies have corrobo-rated the significance of collaterals as a prognosticpredictor71516

A second distinctive feature of collateral flow inBAO is the redundant blood supply from the VAs

Neurology 85 November 17 2015 1807


When the BA is blocked usually one VA remainsopen ie the origin of at least one and often bothposterior inferior cerebellar arteries (PICAs) are openIn addition PICAs can be supplied by reverse flow inthe anterior spinal artery which originates unilaterallyor bilaterally from the distal VA or PICA In the cer-vical segment the anterior spinal artery is well sup-plied by branches of the ascending and profoundcervical arteries which can compensate unilaterallyor bilaterally occluded VAs17 PICA is a strong collat-eral to the anterior inferior cerebellar artery (AICA)and SCA and thus to the brainstem perforating arte-rioles (figures 2 EndashG 3E and 4 AndashD) In BAO thissystem may as well maintain brainstem vitality forsignificant periods if the clot does not graduallyextend to block the perforating arteries

THE RADICULAR AND ANASTOMOTIC BRAINSTEMVASCULAR SUPPLY One way to comprehend thedelicate layout of the vasculature arising from the BAis to inspect the conceptual homology of the anatomicallayout of vertebrobasilar and spinal arteries The BA canbe viewed to be formed by fusion of the longitudinal

neural system which in its most primitive form consistsof loosely connected channels running along the ventralsurface of the brainstem Later during fetal develop-ment the channels will form longitudinal arterial circu-lations that will fuse on the ventral pontine surface toform the BA Lasjaunias et al viewed the arterial circu-lation of the brainstem and cerebellum as natural exten-sions of the segmental radicular vascular layout foundin the spinal cord (figure 5 see wwwneuroangioorg)Lescher et al18 have recently utilized high-resolutionangiographic techniques to further visualize thisconcept

If one considers the BA to be an extension of theanterior spinal artery and its branches and perforatorsas homologs of the coronary and sulco-commissuralarteries of the segmental spinal circulation the rela-tionship between the sequential buildup of an ascend-ing clot and stepwise intensified clinical coursereflecting successive brainstem infarctions makes per-fect sense (figure 6A) This concept of stepwisegrowth of the BA thrombus is compatible with theclinical course characterized by repeated periods ofsudden worsening of clinical symptoms before

Figure 1 Images from a 47-year-old manwith CT angiographyndashconfirmed tandem occlusion of the proximal BAand left SCA

Digital subtraction angiography (DSA) of the left dominant vertebral artery (VA) (A) confirms proximal basilar artery (BA)occlusion (arrow) about 5 mm distally from the junction of both VAs and at the origin of the dominating left anterior inferiorcerebellar artery (LAICA) Reflux to the right vertebral artery (RV) is evident Lateral projection of the early venous phase ofleft vertebral artery injection (B) shows a faint retrograde filling of the left superior cerebellar artery (SCA) but no opacifi-cation of the distal basilar artery Right internal carotid artery (ICA) injection (C) demonstrates retrograde filling of the distalbasilar artery and shows a thrombus also in the mesencephalic segment of the left SCA (asterisk in C) After stentrieverthrombectomy of the basilar artery left vertebral injection (D) shows anterograde flow in the BA with reflux into the rightICA Control DSA of the right ICA after recanalization of the BA (E) shows faint opacification of the distal BA due a balancedflow backward and forward Diffusion-weighted MRI (F G) shows small scattered ischemic lesions in the left SCA territoryThe brainstem however was spared despite 7 hours of thromboembolic occlusion of the proximal BA

1808 Neurology 85 November 17 2015


full-blown BAO with locked-in syndrome tetraple-gia and coma

Detailed anatomical studies have demonstratedthat a considerable amount of artery-to-artery anasto-moses exist between the superficial brainstem arteriesbut there is a lack of anastomoses between the inter-nal brainstem arteries19 In fact these internal arteriescan be considered as ldquothe other cerebral end arter-iesrdquo19 So a considerable network of anatomical anas-tomoses and recruitment of potential anastomosesand above described collaterals arising from anteriorand vertebral circulation can assist in maintaining thelarger supplying superficial arteries patent in acuteBAO (figure 2 EndashG and 3E) However once thepenetrating internal brainstem arteries lose patencythe irreversible necrosis will ensue rapidly

CHARACTERISTICS OF BASILAR CLOT Empiricalknowledge from long-lasting endovascular facilitiessupports a few distinctive features of BA clotsThese clots are not so tightly compacted or tetheredto the vascular wall compared with clots lodgedelsewhere in the cerebral vessels In fact onrepeated imaging the clots seem to be roving a bitThis may relate to systolic-diastolic pressureamplitudes lower than eg the anterior circulationand to the fact that the distal pressure is not zeroand is fluctuating through the cardiac cycle 4Dphase-contrast MRI pulsatile flow velocities haverevealed that the systolic pressure peak is mounted afew milliseconds sooner to the internal carotidartery (ICA) bed than in the BA20 On lateralprojections often a thin layer of open lumen exists

Figure 2 Digital subtraction angiography images of a 42-year-old woman with right VA dissection and basilarthrombosis show the potential collateral routes that can maintain blood flow to the posteriorcirculation during BAO

The clinical information and technical angiographic details of this case have been published previously32 Left vertebralartery (VA) injection (A) demonstrates the thrombosed basilar artery (BA) segment (dotted line) beginning distal to anteriorinferior cerebellar artery origins Injections to right (B) and left (C) common carotid arteries during BA occlusion (BAO) showfilling of both posterior cerebral arteries (PCAs) and basilar tip from the anterior circulation Immediately after BAO recan-alization right VA injection (D) shows patent basilar artery opacification of both PCAs and oscillating flow in both posteriorcommunicating arteries (PComs) connected to the anterior circulation There is diminished contrast attenuation in the PCAsand distal BA confirming pressure transmission from the anterior circulation via the PComs into the basilar tip and distal BAThis type of pressure condition (functional arterial pressure immediately distal and proximal to the basilar thrombus) mayprevent the thrombus from adhering tightly to the basilar artery wall and facilitate minute capillary flow around the throm-bus Slightly time-shifted systolic pressure gradients pounding the clot from opposite directions can generate piston-likemovement or stepwise migration of the nonadherent clot During BAO left VA injection (EndashG) shows that the distal BA alsoreceives collateral flow through leptomeningeal anastomoses from left posterior inferior cerebellar artery (PICA) to distalbranches of the left superior cerebellar artery (SCA) The flow direction in the right SCA is reversed (arrows) Slow small-volume flow can also be seen between the thrombus and the BA wall in the late phases of the DSA run (F and G asterisk) Asthe brainstem perforators directly originate from the periphery of the BA trunk such minute flow might be able to sustainbrainstem viability for a period of time during BAO



between clot and the dorsal origins of the brainstemperforators Milliseconds apart the systolic pressurewaves are pounding the clot from the oppositedirections This may permit an element of plasmaflow facilitated by the minute piston-like migrationsof the still nontethered blood clot This oil around thepiston may keep the perforators patent longer than iftheir origins were occluded by a tightly attached clotExamples of the described plasma flow are seen infigures 2 F and G and 4 D and E and illustratedschematically in figure 6B This is exclusively seen inthe BA but not at all in occlusions in the anteriorcirculation such as middle cerebral artery (MCA)occlusions

This scenario would explain the common empiri-cal observation that BAO is seemingly much more

prone to reocclusion after thrombolysis comparedwith anterior circulation The short-acting fibrino-lytics may initially only detach the clot from thevascular wall but without anticoagulation thrombec-tomy or longer lasting fibrinolytics the clot willbuild up again allowing the clinical syndrome toreappear

The above considerations may also explain whythrombus aspiration is generally much easier in theBA than in the anterior circulation The BA clotsmay also be less compacted perhaps reflecting a higherwater content Due to the bidirectional arterial accessfibrinolytics may penetrate the clot more efficientlythan in the MCA or ICA which could explain whythe recanalization rates of systemic thrombolysis aresignificantly higher in the BA The degree of collateralcirculation was recently shown to significantly promoterecanalization16 Furthermore we have shown thatcontrary to the MCA clot where 8 mm has been dem-onstrated to be a cutoff length for efficacy of IVT thereis no such cutoff for BAO thrombus2122

IS THERE A PENUMBRA IN BAO In their report of10 individuals with acute BAO Ostrem et al10 ob-tained brain scans on average 4 hours 10 minutes afteronset and found evidence of diffusion-weightedimaging (DWI)ndashperfusion-weighted imaging (PWI)mismatch in 5 patients which included brainstemcerebellum and posterior cerebral hemispheres Thismismatch comprised 49ndash99 of the total perfusionabnormality on early scans and did not entirelyproceed to infarction following post-thrombolyticclinical improvement Furthermore in no case wasthere a reversal of diffusion abnormality in thebrainstem or cerebellum It could not be determinedwhether the pretreatment perfusion deficit representedoligemia rather than penumbra We have not foundadditional reports of reversal of prethrombolytic DWIor PWI lesions within the posterior fossa but there aretechnical difficulties in imaging penumbra-like flowconditions in the posterior fossa as noted byothers2324 However the absence of BA territorycirculation in the vast literature of ischemicpenumbra is striking In fact considering perforantinternal brainstem arteries as the other cerebral endarteries18 would actually suggest that in line with thevulnerable region of hemispheric deep penetratingarteries no penumbra can exist in the pons after theinternal arteries have been occluded

OTHER POTENTIAL EXPLANATIONS FOR LONGTIME WINDOW In BAO the exact onset of symp-toms has often been an issue In a series of 85 patientswith postmortem verified basilar or bilateral distal VAocclusions onset was sudden in 20 patients suddenbut preceded by prodromal symptoms in 11 patients

Figure 3 Digital subtraction angiography images of a 68-year-old manwith BAO

Right (A) and left (B) internal carotid artery injections show filling of the basilar tip (circle) andboth posterior cerebral arteries (PCAs) from the anterior circulation despite small-caliberposterior communicating arteries (PComs) (narrow vessel segments between the arrows)Selective contrast injection through a 5F aspiration catheter with its tip immediately proxi-mal to the basilar artery occlusion (BAO) (C) outlines the thrombus with its convex bordercontrasted to the open vessel (arrow) Pontine perforators above the thrombus are faintlyvisible Lateral projections of the superselective basilar artery (BA) injection (D E) visualizethe collateral network between the perforating arteries at the ventral brainstem surface thiscan be recognized as a fine contrast line immediately dorsal to but still clearly separate fromthe BA lumen (arrows in E) The origin of perforators from this collateral network can be seenat the level of the BAO and short distance distal to it In addition to recruitment of collateralflow from the anterior circulation and the pontine collateral network there was leptomenin-geal flow to the distal BA from the posterior inferior cerebellar artery similarly to case 1 (notshown) Reverse flow from the SCA is evident (asterisk in E) The patient presented with sud-den loss of consciousness but recovered to modified Rankin Scale score 1 after basilarthrombus aspiration with only a small right thalamoperforator infarct at his follow-up MRI



and progressive in 54 patients25 Fifty-three patientshad prodromes that cleared completely (TIA) beforethe start of a progressive or sudden onset Half ofthese patients had their first symptoms during the 2weeks before admission but the rest had their TIAlonger ago In our understanding the onset of BAOshould be limited to the monophasic course of acuteBAO symptoms which can be gradual progressiveand full-blown at the outset

It has been suggested that the presumably longertime window for BAO recanalization therapies couldbe attributed to the relative scarcity of post-thrombolytic symptomatic intracerebral hemorrhage(sICH) the most feared complication ruining the ben-efits of stroke thrombolysis10 To this end Sarikayaet al26 compared the post-thrombolytic outcomes of95 patients with posterior circulation stroke (PCS) withthose of 788 patients with anterior circulation strokeand found that PCS was an independent predictor oflower sICH frequency (p 5 0001) In our large con-secutive series of BAO thrombolysis where good out-comes were strikingly not limited to short OTTsincreased OTT did not influence rates of sICH6

Does the caudal brain have physiologically longertolerance against tissue ischemia Indeed paramount

ultrastructural differences exist between phylogeneti-cally diverse CNS structures For example the humancerebellum contains more neurons than the rest of thebrain combined and the blood supply is characterizedby a lack of anastomoses between the cortical penetra-tor branches2728 Not much is known of the patencyof CBF autoregulatory capacity in the cerebellum andbrainstem Using transcranial Doppler and inhalationof CO2 Reinhard et al28 demonstrated that cerebel-lar autoregulation was at least as efficient as that in theMCA territory The vertebrobasilar circulation hasless developed autonomic innervations which hasbeen linked to a lower autoregulatory ability in thePCA29 while the autoregulatory response and CO2

reactivity of the BA have been found equal to theMCA30 However these observations cannot beextended beyond hemodynamic and physiologic fluc-tuations to provide an answer

HYPOTHESIS Why should the benefit of recanaliza-tion be less time-dependent in BAO than in anteriorcirculation occlusions This counterintuitive pointcould arise from the anatomical vascular layout ofthe brainstem being different from that in usualanterior circulation strokes To explain this we

Figure 4 Digital subtraction angiography (DSA) and MRI of a 9-year-old boy with BAO

The patient presented with ataxia somnolence seizures and impaired consciousness DSA demonstrated absent left pos-terior communicating artery (PCom) and hypoplastic right PCom The lateral DSA projection of the right vertebral artery (VA)injection (AndashD frames shown at 1-second intervals) show that extensive collaterals provide flow to the basilar tip (circle)from posterior inferior cerebellar artery (PICA) via superior cerebellar artery (SCA) During the early and late venous phase at6ndash7 seconds after injection (D E) small perforating arteries can be recognized at the site of the basilar artery occlusion(BAO) (dotted line in C) and distal to it After intra-arterial local thrombolysis with 750000 IU urokinase 12 hours aftersymptom onset lateral (E) and anterioposterior (F) views of the right VA injection show partial recanalization Thrombus isstill visible inside the BA lumen in its middle and distal segment (arrows E) The brainstem perforators however are bettervisualized On admission diffusion-weighted MRI (G) already shows ischemic lesions in the right cerebellum right poster-olateral pons and left paramedian anterior pons Follow-up imaging (H) shows no additional ischemic lesions in the ponseven though the basilar artery flow could not be completely restored In this case minute flow around the margins of thethrombus may have been sufficient to maintain brainstem vitality Several sources of the collateral flow can be visualizedwith DSA but it is also possible that other collateral flow networks remain below its spatial resolution (approximately200 mm in this case)



propose several vascular mechanisms that most oftenact simultaneously but this depends on the individualclot location location of local atherosclerotic plaquesand individual developmentally determined vascularanatomy

1 A blood clot lodged in the BA will create a reversecirculation arterial backflow from the circle ofWillis through the PComs to the distal BA whicheither directly from BA perforators or throughrecruiting and fueling the anastomotic and collat-eral vascular networks will maintain the vitalbrainstem structures viable for a considerable timeif the clot does not enlarge and the brainstem doesnot have lethal ischemia The prerequisite for thisin terms of individual anatomy would of coursebe sufficient patency of PComs and a relativeimportance of the fetal anterior circulation in themesencephalic blood supply In our understand-ing in the anterior circulation there is no similarchance of emergency reserve of arterial blood tosupply a relatively small volume but critical brainarea that would be prognostically as decisive as the

brainstem Who knows if this peculiar arrange-ment represents a phylogenetic construct to securethe vitality of brainstem in various vascular orhemodynamic catastrophes

2 While arterial backflow (reflux) maintains thebrainstem viable at least with the progressivelysymptomatic proximal or midbasilar presenta-tions the blood clot may be building up stepwiseby new layers of clot each blocking the small cir-cumferential and perforating brainstem arteries(figure 6A) In fact the reflux may furnish a con-tinuous supply of coagulable blood to the site ofthrombus formation As the clot grows stepwisedistally ischemia at each sequential level of perfo-rators triggers a crescendo of multiple new infarctsThis would be clearly at variance with the situa-tion in anterior circulation large artery strokeswhere a thromboembolus will initially becomelodged and create a substantial penumbral tissueat risk which the persistent ischemia will time-dependently necrotize into the eventual infarctcore In such infarctions there is no successive clotformation and the extent of eventual infarction is

Figure 5 Lasjauniasrsquo view of analogy of pontine circulation with spinal radicular segmental circulation

The image on the left shows the brainstem alone with schematic illustration of vertebrobasilar system with frequent trans-verse perforators (transverse pontine arteries) The image on the right with cerebellum shown portrays superior cerebellarartery (SCA) posterior inferior cerebellar artery (PICA) and anterior inferior cerebellar artery (AICA) as perforators whichenlarged to take over the territory of cerebellar hemispheres This perspective makes it straightforward to comprehendmultiple SCA PICA and AICA variations found often within the vertebrobasilar arterial system This segmental metamericorganization applies to the posterior circulation at the levels of the medulla oblongata and pons The upper part of the pos-terior circulation supplying the mesencephalon (distal to the site of fetal trigeminal artery including the basilar tip) is embry-ologically part of the anterior circulation and lacks metameric organization At birth the relative importance of the anteriorand posterior circulations in the mesencephalic blood supply depends on the time and individual pattern of fetal trigeminalartery involution Figure courtesy Maksim Shapiro MD (wwwneuroangioorg) Reproduced with permission



determined by the patency of collateral blood flowrecruited at the outset in the infarct peripheryIndeed it was shown recently that there is aninteraction of time and collaterals in tissue lossIn the anterior circulation stroke time alone isnot a significant predictor of outcome but collat-erals are When collaterals are removed from themultivariable models time becomes significant15

The time window in which the tissue at risk cansurvive is determined by a physiologic tissue clockthat starts to tick immediately24 This clock limitsthe tolerable period to a few hours as we knowfrom the pooled pivotal trials of thrombolysis

3 In the proposed fundamentally different stepwiseBAO clot growing either in anterior or caudaldirection in any patient with BAO who has sur-vived the first hours without extensive brainsteminfarction the brainstem may be kept alive bymultiple sources of residual and compensatoryblood circulation Besides backflow (reflux) fromthe anterior circulation through the PComs con-siderable blood supply can be provided caudallyfrom anastomotic vascular networks as well as thePICA-derived collaterals to both AICA and SCAsystems Anastomoses between the superficialbrainstem arteries may become recruited by

abnormal hemodynamic and blood pressure gra-dient circumstances

4 Finally in some occasions a layer of plasma flowbetween the nonadherent and sometimes migrat-ing blood clot and the vessel wall can maintainbrittle patency of the BA side branches and brain-stem perforators (figures 2 F and G and 6B)Fibrinolytic mechanisms and therapeutic agentscan prolong this plasma flow (figure 4 E and F)and make it possible to eventually terminate thishazardous situation by performing a thrombec-tomy The recent work by Lescher et al18 high-lights the numerous intricate small BA sidebranches and perforators and if enough attentionis not paid to the existence of these vital vesselseven modern stentriever thrombectomy proce-dures will carry the risk of periprocedural brain-stem necrosis despite perfect recanalization results

5 As long as the brainstem structures have tolerableoligemia a tissue clock will not start to tick Conse-quently the narrow time window for recanalizationtherapy is not in effect On the contrary recanaliza-tion at any point in time when the brainstem is stillvital would rescue the situation by preventing immi-nent infarctions of vital brainstem structures associ-ated with further accumulation of clot material

Figure 6 Distinctive features of the evolution of clot in basilar artery

(A) In this drawing the clot is building up sequentially onto the initial thromboembolus (clot 1) to the rostral direction Anal-ogous stepwise thrombus growth can naturally occur also to the caudal direction The clinical syndrome is changing abruptlycorresponding to stepwise advances in the deeply ischemic brainstem territory whenever a new set of perforating brain-stem arteries is being occluded by new clot layers (2 and 3) (B) This drawing represents the situation where substantialreflux of arterial pressure gradient is being conveyed from the anterior territory through the posterior communicating arter-ies (arrows) In some instances the initial thromboembolus may not lodge to the basilar tip but rather floats on this arterialreflux thus avoiding attachment to the arterial wall Instead a piston-like or migrating clot movement can occur due to thesystolic pressure waves separated by milliseconds pounding the clot from anterior and caudal directions This can generateplasma flow between the clot and arterial wall (figures 2 F and G and 4 D and E) which in turn maintains brittle patency ofthe brainstem perforator vasculature Fibrinolytic therapy may detach a tethered clot and reinstate tissue circulation alongwith neurologic function but this may be transient if the thrombus cannot be extracted or dissolved



However once the brainstem perforating internalarteries have been occluded there is no more timefor rescue therapies This concept is coherent withthe observation that the presence of extensive poste-rior circulation infarctions as determined bypc-ASPECTS score is the single most significantprognostic baseline factor6 To require lack of exten-sive brain infarction in the area supplied by theoccluded artery before approving the patient forrecanalization therapy is conceptually no differentfrom what we require when we attempt to salvagethe penumbra in the anterior circulation strokes

THE WAY FORWARD The clinical management willprobably shift towards rapid deployment of efficientendovascular techniques in reversing BAO Our con-cepts emphasize that delay from symptom onsetshould not be regarded as an argument against aggres-sive therapies if the parenchyma of the criticallyischemic posterior circulation territory is still viableOn the other hand MRI or noncontrast CT imagingof brainstem and additional parenchyma of the BA ter-ritory need to be systematically evaluated to revealextended infarctions prior to costly treatments Novel de-velopments such as artefact-free CT image acquisitionalgorithms may assist evaluation of parenchymalstructures in the posterior fossa

The hypotheses proposed here can potentially betested using novel techniques of determining microvas-cular perfusion and tissue viability in conjunction withever perfecting recanalization techniques It remains tobe seen whether dynamic CT perfusion imaging ormultimodel MRI can be refined to produce reliableestimates of tissue viability as in the anterior circulationCenters that use primary angiography for patient selec-tion will be able to use dynamic 3D rotational angiog-raphy and test in clinical trials tissue viability algorithmsbased on microvascular perfusion such as capillaryindex score31 Clearly evaluation of the patency of col-laterals will be more important than today

AUTHOR CONTRIBUTIONSDrs Lindsberg and Schroth conceptualized and designed the study Drs

Schroth Mattle Pekkola Strbian and Sairanen collected data and partic-

ipated in data analysis Drs Schroth and Pekkola analyzed all radiologic

data Dr Lindsberg made the first draft and all others wrote parts of it

andor reviewed it critically

ACKNOWLEDGMENTAcademic stroke research in Helsinki is supported by financial resources

from governmental and nonprofit foundations the Helsinki University

Central Hospital governmental subsidiary funds for clinical research

(DS PJL) the Finnish Medical Foundation (DS) the Finnish Acad-

emy (PJL) the Sigrid Juseacutelius Foundation (PJL) the Maire Taponen

Foundation (TS PJL) and the Paavo Nurmi Foundation (PJL) The

authors thank Helena Schmidt for drawing the illustrations in figure 6

STUDY FUNDINGNo targeted funding reported

DISCLOSUREP Lindsberg reports no commercial disclosures Financial resources from

governmental and nonprofit foundations have been received from the

Helsinki University Central Hospital governmental subsidiary funds for

clinical research the Finnish Academy the Sigrid Juseacutelius Foundation

the Maire Taponen Foundation and the Paavo Nurmi Foundation

J Pekkola reports no disclosures relevant to the manuscript D Strbian

reports no commercial disclosures Financial resources from governmental

and nonprofit foundations have been received from the Helsinki Univer-

sity Central Hospital governmental subsidiary funds for clinical research

and the Finnish Medical Foundation T Sairanen has received travel

expenses to a scientific conference with the support of Boehringer

Ingelheim Pharmaceuticals Inc Financial resources from nonprofit foun-

dations have been received from the Maire Taponen Foundation

H Mattle has received outside of the submitted work honoraria for

speaking or advisory boards from the following companies speakerrsquos fees

from Bayer Biogen Covidien Daiichi Sankyo Neuravi Novartis Sanofi

Genzyme Serono and Teva and consulting fees from AstraZeneca Bayer

Biogen Boehringer Ingelheim Covidien Daiichi Sankyo Genzyme

Merck-Serono Neuravi Novartis Pfizer SanofiGenzyme Servier and

Teva G Schroth reports no disclosures relevant to the manuscript Go

to Neurologyorg for full disclosures

Received March 25 2015 Accepted in final form July 20 2015

REFERENCES1 Macleod MR Davis SM Mitchell PJ et al Results of a

multicentre randomised controlled trial of intra-arterial

urokinase in the treatment of acute posterior circulation

ischaemic stroke Cerebrovasc Dis 20052012ndash17

2 Lindsberg PJ Mattle HP Therapy of basilar artery occlu-

sion a systematic analysis comparing intra-arterial and

intravenous thrombolysis Stroke 200637922ndash928

3 Smith WS Intra-arterial thrombolytic therapy for

acute basilar occlusion pro Stroke 200738(2 suppl)

701ndash703

4 Mattle HP Arnold M Lindsberg PJ Schonewille WJ

Schroth G Basilar artery occlusion Lancet Neurol 2011

101002ndash1014

5 Lindsberg PJ Sairanen T Mattle HP Critical care of

basilar artery occlusion In Schwab S Mendelow D

Hanley D eds Critical Care of the Stroke Patient

Cambridge Cambridge University Press 2014

194ndash205

6 Strbian D Sairanen T Silvennoinen H Salonen O

Kaste M Lindsberg PJ Thrombolysis of basilar artery

occlusion impact of baseline ischemia and time Ann

Neurol 201373688ndash694

7 Jung S Mono ML Fischer U et al Three-month and

long-term outcomes and their predictors in acute basilar

artery occlusion treated with intra-arterial thrombolysis

Stroke 2011421946ndash1951

8 Vergouwen MD Algra A Pfefferkorn T et al for the

Basilar Artery International Cooperation Study (BASICS)

Study Group Time is brain(stem) in basilar artery occlu-

sion Stroke 2012433003ndash3006

9 Strbian D Sairanen T Kaste M Lindsberg PJ Reply to

letter treatment of basilar artery occlusion Ann Neurol

201475161ndash162

10 Ostrem JL Saver JL Alger JR et al Acute basilar artery

occlusion diffusion-perfusion MRI characterization of tis-

sue salvage in patients receiving intra-arterial stroke thera-

pies Stroke 200435e30ndashe34

11 Marinkovic SV Gibo H The surgical anatomy of the

perforating branches of the basilar artery Neurosurgery

19933380ndash87



12 Drake CG Ligation of the vertebral (unilateral or bilateral)

or basilar artery in the treatment of large intracranial

aneurysms J Neurosurg 197543255ndash274

13 Sorteberg A Bakke SJ Boysen M Sorteberg W Angio-

graphic balloon test occlusion and therapeutic sacrifice

of major arteries to the brain Neurosurgery 200863

651ndash660

14 Cross DT III Moran CJ Akins PT Angtuaco EE

Derdeyn CP Diringer MN Collateral circulation and out-

come after basilar artery thrombolysis Am J Neuroradiol

1998191557ndash1563

15 Jung S Gilgen M Slotboom J et al Factors that deter-

mine penumbral tissue loss in acute ischaemic stroke

Brain 20131363554ndash3560

16 Singer OC Berkefeld J Nolte CH et al Mechanical recan-

alization in basilar artery occlusion the ENDOSTROKE

study Ann Neurol 201577415ndash424

17 Kang HS Han MH Kim SH Kwon OK Roh HG

Koh YC Anterior spinal artery as a collateral channel in

cases of bilateral vertebral arterial steno-occlusive diseases

Am J Neuroradiol 200728222ndash225

18 Lescher S Samaan T Berkefeld J Evaluation of the pon-

tine perforators of the basilar artery using digital subtrac-

tion angiography in high resolution and 3D rotation

technique Am J Neuroradiol 2014351942ndash1947

19 Duvernoy HM Human Brain Stem Vessels Including the

Pineal Gland and Information on Brain Stem Infarction

2nd ed Berlin Springer 1999

20 Waringhlin A Ambarki K Birgander R et al Measuring pul-

satile flow in cerebral arteries using 4D phase-contrast MR

imaging Am J Neuroradiol 2013341740ndash1745

21 Riedel CH Zimmermann P Jensen-Kondering U

Stingele R Deuschl G Jansen O The importance of size

successful recanalization by intravenous thrombolysis in

acute anterior stroke depends on thrombus length Stroke

2011421775ndash1777


Lindsberg PJ Intravenous thrombolysis of basilar artery

occlusion thrombus length versus recanalization success


23 Moustafa RR Baron JC Imaging the penumbra in acute

stroke Curr Atheroscler Rep 20068281ndash289

24 Ebinger M De Silva DA Christensen S et al Imaging the

penumbra strategies to detect tissue at risk after ischemic

stroke J Clin Neurosci 200916178ndash187

25 Ferbert A Bruumlckmann H Drummen R Clinical features

of proven basilar artery occlusion Stroke 199021

1135ndash1142

26 Sarikaya H Arnold M Engelter ST et al Outcomes of

intravenous thrombolysis in posterior versus anterior cir-

culation stroke Stroke 2011422498ndash2502

27 Andersen BB Korbo L Pakkenberg B A quantitative

study of the human cerebellum with unbiased stereological

techniques J Comp Neurol 1992326549ndash560

28 Reinhard M Waldkircher Z Timmer J Weiller C

Hetzel A Cerebellar autoregulation dynamics in humans

J Cereb Blood Flow Metab 2008281605ndash1612

29 Haubrich C Wendt A Diehl RR Kloumltzsch C Dynamic

autoregulation testing in the posterior cerebral artery


30 Park CW Sturzenegger M Douville CM Aaslid R

Newell DW Autoregulatory response and CO2 reactivity

of the basilar artery Stroke 20033434ndash39

31 Al-Ali F Elias JJ Tomsick TA Liebeskind DS

Broderick JP for the IMS Study Groups Relative influ-

ence of capillary index score revascularization and time

on stroke outcomes from the Interventional Management

of Stroke III trial Stroke 2015461590ndash1594

32 Nedeltchev K Remonda L Do DD et al Acute stenting

and thromboaspiration in basilar artery occlusions due to

embolism from the dominating vertebral artery Neurora-

diology 200446686ndash691



DOI 101212WNL00000000000021292015851806-1815 Neurology

Perttu J Lindsberg Johanna Pekkola Daniel Strbian et al Time window for recanalization in basilar artery occlusion Speculative synthesis

This information is current as of November 16 2015

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reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

12 hours was 77 and within 6 hours 29 In theIAT series the corresponding fractions were 76 and42 respectively In the Helsinki IVT cohort (n 5

184)6 favorable outcome (modified Rankin Scale[mRS] 0ndash3) was achieved in 39 of those treatedwithin 6 hours in 36 within 6ndash12 hours and in36 above 12 hours If patients with extensive infarc-tion already at baseline are excluded at least 50reached mRS 0ndash3 even when treated beyond 12hours The rates of the 2 worst outcomes (mRS 5or 6) were comparable in these 3 time windows51 57 and 50 respectively Recanalizationtook place in 82 70 and 75 respectively6

Timing of treatment has been a significant prognosticpredictor in univariate analyses but not in multivariableanalyses adjusted for extent of baseline ischemicchanges67 Halving the onset-to-treatment time (OTT)after 2005 in Helsinki did not translate into therapeuticimprovement (Lindsberg et al unpublished data2015) These data do not back a firm time windowfor therapies attempting to reverse BAO

In a recent analysis of the Basilar Artery Interna-tional Cooperation Study (BASICS) registry (n 5

619) Vergouwen et al8 found that the prognosiswas related to the time from symptom onset andpatients with severe strokes at presentation treatedbeyond 9 hours after onset had poor clinical outcomeUnlike pivotal recanalization studies in anterior cir-culation stroke patients with extensive infarct signsalready at baseline were not excluded in the BASICSregistry In the Helsinki series of BAO (n 5 184) asimilar decay of therapeutic efficacy is seen beyond 9hours but this time dependency disappeared whenthe results were adjusted for the extent of baselineischemia (posterior circulation Alberta Stroke Pro-gram Early CT Score [pc-ASPECTS])69 Patientstreated later than 9 hours were simply more likelyto have extensive infarctions before treatment

RCTs of stroke have usually excluded patients pre-senting with characteristic posterior circulation symp-toms Therefore the time window for recanalizationin posterior circulation stroke has not been ascertainedin RCTs Many published case series have recruited pa-tients with substantially longer symptom times thanconsidered suitable for the anterior circulation up to45ndash6 hours for IVT or IAT and 8 hours for mechan-ical thrombectomies4 This has created an array ofspeculations where eg different collateral circulationpatterns or fewer hemorrhages due to lesser infarctvolumes have been conceived to increase the ischemiatolerance of brain tissue in the BA territory10

COLLATERAL BLOOD FLOW DYNAMICS DURINGBAO Once the trunk of the basilar artery (BA) hasbeen occluded by a sudden (thrombo)embolus bloodpressure at the junction of posterior cerebral arteries

(PCAs) drops immediately Depending on the indi-vidual vascular anatomy blood flow within the circleof Willis is partially diverted from the anterior circu-lation through posterior communicating arteries(PComs) to fill this relative void and supply bloodflow to the PCAs Depending on the level at whichthe BA trunk is occluded there will probably bereverse filling (reflux) to the distal BA maintainingthe patency of the superior cerebellar artery (SCA)branching from it as well as any number of perforatortrunks and lateral circumferential arteries that remainunblocked by the clot (see figures 1 2 4 and 9 fromreference 11) This phenomenon is observed fre-quently when individuals with varying degrees of ver-tebral artery (VA) or even BA stenosisocclusion areexamined electively with digital subtraction angiogra-phy of the anterior circulation and reversed filling ofthe distal BA can be observed to augment distal bas-ilar patency also during the acute phase of BAO(figures 1C 2C and 3 A and B)

The significance of reverse flow gradient into BAalso underlies the rationale of therapeutic stepwiseVA occlusion in the treatment of true giant fusiformBA aneurysms Before the advent of flow-divertingstents this procedure was the only way to try to pre-vent rupture by lessening the pressure and flow insidethe sac Naturally the sufficiency of the BA reverseflow had to be tested during acute temporary occlu-sion which proves its existence also in the acute set-ting of complete vertebrobasilar occlusion1213

Detecting the reverse flow in the upper BA in theacute BAO setting would require selective catheteri-zation of the cerebral arteries This is not routinelydone if the BAO has been diagnosed with CT angi-ography (CTA) CTA may demonstrate minuteblood flow around the clot but not its directionTime-of-flight (TOF) magnetic resonance angiogra-phy (MRA) is ineffective in showing very slow orreverse flow in the BA because physical propertiesof TOF MRA require fast blood flow to producevisible flow enhancement

Reverse flow from the PCom may augment residualcirculation in the branches distal to the BA clot and de-pending on the pressure gradient may helpmaintain minute flow within the oligemic region Asmall BAO series (n5 20) raised the idea that effectivecollateral flow to the BAmay prolong ischemia toleranceand lead to more favorable outcomes14 Of patients withcollateral filling of the distal BA 5 (83) had a goodneurologic outcome and 1 did not Of those withoutcollateral flow 1 (17) had a good neurologic outcomeand 5 did not Additional recent studies have corrobo-rated the significance of collaterals as a prognosticpredictor71516

A second distinctive feature of collateral flow inBAO is the redundant blood supply from the VAs







































































































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints








































































































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints
































































































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints

























































































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints















































































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints





































































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints





























































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints



















































701ndash703



101002ndash1014





194ndash205















201475161ndash162







19933380ndash87









651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints










651ndash660




1998191557ndash1563



Brain 20131363554ndash3560






















2011421775ndash1777












1135ndash1142






































Reprints















Reprints




Documents

Time window for recanalization in basilar artery occlusion · blood flow around the clot, but not its direction. Time-of-flight (TOF) magnetic resonance angiogra-phy (MRA) is ineffective