Abstract

Posterior circulation ischaemic stroke (PCIS) is a disease of high mortality and morbidity. However, current research predominantly focuses on the anterior circulation, specifically the internal carotid artery. Recommendations of change are required for the improvement of clinical outcomes. This article discusses the neuroimaging techniques used for diagnosis and three new research perspectives in neuroradiology concerning PCIS, which are namely (1) clinically significant anatomical variants, (2) artery-artery embolisation and, (3) collateralisation. The anatomical variants discussed include: (a) vertebral artery hypoplasia/agenesis, (b) Artery of Percheron, and (c) vertebrobasilar dolichoectasia. Such research perspectives are expected to increase clinical awareness and diagnostic accuracy, ensuring prompt treatment, improved patient care and ameliorated treatment outcomes. This article also suggests that, in the field of collateralisation in PCIS, prognostication can be improved by the construction of risk stratification models and synthesis of new therapeutic strategies.

 

Introduction

Posterior circulation ischaemic stroke (PCIS) is defined as any cerebrovascular accident lasting for more than 24 hours arising from large arteries belonging to the posterior circulation [1], accounting for 20% of all ischaemic strokes [2]. Most pathologies concern the vertebral, basilar, and posterior cerebral arteries. The superior cerebellar, anterior inferior cerebellar, posterior inferior cerebellar, and subclavian arteries, although part of the posterior circulation, are rarely implicated in stroke [3]. As compared to its anterior counterpart, PCIS is an under-researched discipline. A PubMed search showed that the carotid artery appeared in more than 10,000 titles of articles published in the past 50 years, as compared to approximately 2,000 for vertebral arteries, and under 2,000 for both basilar and posterior cerebral arteries each [4].

The amount of research performed in this area is discordant with its public health significance. PCIS is a disease of high mortality and morbidity. An Australian observational study found that the annual adjusted incidence rate of PCIS was 17 / 100,000 person-years [5]. With reference to data derived from the New England Medical Center Posterior Circulation registry, the 30-day mortality rate was found to be 3.6% [6]. According to a Turkish study, the one-year mortality rate for PCIS was 11.7%. Within the first three months, recurrent stroke within the posterior circulation (after index PCIS event) occurred in 5.8% of all patients. This was increased to 9.8% at one-year follow-up.

This article aims to elevate general clinical awareness towards PCIS, which is fundamental towards the reduction of diagnostic delays, increase in earlier detection, and improvement of clinical outcomes. Owing to the paramount significance of neuroimaging in diagnosing cerebrovascular diseases, the article first discusses significant imaging modalities and relevant diagnostic algorithms.  It then proceeds in the direction of suggesting three key directions in which future neuroradiological research can adopt: (1) anatomical variants of clinical significance, (2) artery-artery embolisation, and (3) collateralisation. A more secure PCIS research base is likely to improve the average clinician’s understanding towards this enigmatic clinical entity, thus improving patient care.

 

Figure 1: Illustration of the Circle of Willis, and other major arteries of the cerebrovascular system. Case courtesy of OpenStax College, Radiopaedia.org. From the case rID: 42608

Methods

A literature search was performed on PubMed, MEDLINE and ScienceDirect (Elsevier) for publications written exclusively in English or featuring abstracts written in English. Search terms used to search for publications include the following: ‘posterior circulation’, ‘ischaemic stroke’, ‘diagnosis’, ‘vertebral arteries’, ‘basilar arteries’, ‘clinical features’, ‘vertebrobasilar dolichoectasia’, ‘artery of Percheron’,  ‘vertebral artery hypoplasia’, ‘vertebral artery agenesis’, ‘ischaemic stroke prognosis’, ‘neuroimaging for posterior circulation’, ‘perfusion imaging for posterior circulation’, ‘collateralisation in stroke’. Publications were selected for this review if they were relevant to posterior circulation ischaemic stroke.

 

Neuroimaging Techniques

 

Neuroimaging is an indispensable part of the diagnostic algorithm for PCIS. Neuroimaging could aid the clinician with better localisation of the lesion, since clinical discernment between PCIS and anterior circulation events is much less favourable in terms of sensitivity and specificity [7]. Neuroimaging helps visualise two types of structures in the brain: the parenchyma, and the large arteries of the cerebrovascular system. Unfortunately, due to limitations in our current understanding of the physical sciences and bioengineering, small perforators such as the lenticulostriate arteries, still cannot be individually visualised.

Multiple national guidelines [2, 8, 9], recommend the use of both computed tomography (CT) and magnetic resonance (MR) imaging when approaching a patient with a suspected cerebrovascular accident. According to British guidelines [2], posterior circulation cerebrovascular accidents are best diagnosed through MRI. Massachusetts General Hospital advises the use of MRI after detecting the presence of proximal occlusion [9]. For PCIS, MRI is more sensitive than CT structural imaging in the first 24 hours of onset [10, 11]. This is associated with CT-related ‘beam-hardening’ artefacts ascribed to the interface of the skull.

A standard CT Suite consists of non-contrast-enhanced CT (NCCT) and CT Angiography (CTA), done without delay within the first 12 hours of onset [2, 12]. NCCT is used for the visualisation of changes in brain tissue during ischaemia and infarction. CTA is used for the assessment of vascular patency. A standard MRI suite consists of structural imaging sequences (T1-weighted, T2-weighted, T2-weighted-fluid-attenuated-inversion-recovery [FLAIR], and diffusion-weighted [DWI]), and vascular imaging (magnetic resonance angiography, or MRA) [12]. According to the neuroimaging algorithm of Massachusetts General Hospital, perfusion MR imaging is also performed if the patient is clinically deemed unsuitable for endovascular treatment, or presents with infarcts exceeding 70 cc in volume [12].

Different vascular imaging techniques contribute to varying degrees of diagnostic accuracy. MRA often over-estimates stenotic events which serves as a limitation in quantifying stenotic degrees [13 14]. CTA, on the other hand, is preferred [15], where the advent of multi-phase CTA is expected to further improve diagnostic accuracy [16]. The sensitivity of CTA reaches 100% as compared to 93.9% by contrast-enhanced MRA [13].

Digital subtraction angiography (DSA) is the gold-standard for diagnosing vascular pathologies, including severe carotid stenoses (70-99%) and peripheral artery disease, but is rarely used due to its invasiveness [17, 18, 19].

 

Correlates and Perspectives

 

This article then proceeds to discuss three future research directions: (1) clinically significant anatomical variants, (2) artery-artery embolisation and (3) collateralisation.

 

(1)    Clinically Significant Anatomical Variants

Analysing and differentiating between anatomical variants is important for radiologists. However, recognising clinically significant anatomical variants has broad-sweeping implications for the internist. Vertebral artery hypoplasia/agenesis, artery of Percheron infarction, and vertebrobasilar dolichoectasia, are the three variants to be elucidated below. They are associated with significantly worse functional and survival outcomes. This is exacerbated by generally low clinical awareness and their omission in current research, which is apt to delay diagnosis so that patients cannot receive appropriate treatment, such as endovascular therapy, in clinically beneficial timeframes.

With renewed focus in this direction, not only can we tailor current treatment modalities to the needs of subgroups of patients with these anatomical variants, but the internist can also identify such neuroimaging findings more readily and improve patient care.

 

(a)    Vertebral Artery Hypoplasia/Agenesis

Important observations can be made from our current understanding on both vertebral artery hypoplasia and agenesis.

The prevalence of dominant vertebral arteries is 50% in the general population [20]. Whether the hypoplastic vertebral artery anchors greater risk of ischaemic events is still uncertain. According to Thierfelder and colleagues [21], given that arterial dominance is assigned if the diameter is ?2 mm and that an asymmetry ratio of ≤1:1.7 of both vertebral arteries is established, there is ipsilateral hypoperfusion of the cerebellar vascular territory. According to Mitsumura and colleagues [22], vertebral artery hypoplasia is an independent factor for vertebral artery occlusion (OR: 4.2; 95% CI: 1.2-15.0). It is a small-cohort observational study, which may explain the wide confidence intervals of the results. Collateral supply and the compensatory function of the contralateral counterpart also influence clinical outcomes [23]. For instance, patients with chronic disease are given more time for collaterals to be developed in response to reduced territorial perfusion. Such collaterals gradually replace the function of the occluded/severely stenosed artery.

As for vertebral artery agenesis, unilateral disease is associated with vascular aplasia elsewhere [24]. Moreover, due to the congenital abnormality, there might be efforts of compensation shown by the development of more complex vascular networks. Recently, Lu and colleagues reported the case of an 18-year old female found to have segmental vertebral artery agenesis, where the intracranial portions of the afflicted vertebral artery and the basilar artery were supplied by a network of arteries and veins connected to the anterior and posterior spinal arteries, dubbed ‘vertebral rete mirabile’ [25]. It was also associated with a similar phenomenon in the anterior circulation (carotid rete mirabile). Another case report from India showed the co-existence of both carotid and vertebrobasilar rete mirabile, and a vein of Galen aneurysmal malformation [26]. It was also shown that 50% of all patients with rete mirabile in the posterior circulation presented with acute stroke (ischaemic and/or haemorrhagic). At the same time, this association can be incidental because it is not yet confirmed by large-scale observational studies [27]. Currently, there is no identifiable clinical data regarding the association between vertebral artery agenesis, rete mirabile formation, and survival outcomes.

Needless to say, although modern medicine has unearthed significant clinical associations regarding both congenital variations of vertebral arteries, it is crucial to reflect on what we do not yet know and what can be done about it.

As explained above, vertebral artery hypoplasia is associated with higher risk of arterial occlusion. Although it is highly prevalent in the general population, research in this area is scarce. It is still unknown whether such patients report higher mortality rates and stroke recurrence, let alone the presence of any concurrent major cardiovascular events, such as ischaemic heart disease and peripheral artery disease. On one hand, since it is associated with vertebral occlusion, one might assert that it is more likely that the patient will experience cerebellar infarction. On the other hand, hypoplasia may be linked with more robust arterial development elsewhere (like the spinal arteries), and collateral formation. Risk factors, as well as triggers underlying acute cerebrovascular accidents, are also not elucidated by modern trials. This is particularly important since vertebral artery hypoplasia is likely to be congenital, where there is a gap between the emergence of the clinical entity, and the onset of any acute manifestation.

Even less data is currently available for vertebral artery agenesis. Individual case reports form the backbone of what we know about the subject. Most of them focus on the elaboration of the anatomical correlates of vertebral artery agenesis. They lack clinically significant discussions in both survival and mortality outcomes.

Expanding the factual base in this area enables clinicians to more quickly pick up the abnormality. Elucidating on clinical associations and risk factors also enable more seamless identification of patients bearing higher risk of having such congenital abnormalities. The chance of diagnostic delay is reduced. Since congenital malformations, even when asymptomatic, are likely to impact on the ease of vascular access when treating strokes in other vascular territories, early identification facilitates more significant rates of recanalisation and improves treatment outcomes.

 

(b)    Artery of Percheron Abnormalities

Artery of Percheron accounts for 0.1-2% of all ischaemic stroke [28]. It is an anatomical variant supplying both the paramedian thalamus and rostral midbrain which branches from the proximal segment of one of the posterior cerebral arteries, serving as an integral part of the posterior cerebral circulation [29]. Therefore, occlusion of this artery is very likely to present with paramedian thalamic strokes. Thalamic strokes are associated with worsened clinical outcomes. According to a Turkish study performed on 16 patients followed up for 7 years [30], thalamic dementia occurred in 25% of patients with bilateral thalamic infarction. Two patients suffered from loss of psychic self-activation and motor abilities. A broad range of alternative clinical manifestations were also reported, including visual field defects (n=2; due to the involvement of the lateral geniculate body of the thalamus), aggressiveness and behavioural inappropriateness (n=6; due to frontal lobe dysfunction), and palilalia (n=1).1 There is currently no discernible survival outcome data associated with thalamic ischaemic stroke. However, since the same anatomical region is affected, studies done on thalamic haematoma (haemorrhagic stroke) can give us an insight. In an observational study reported by Mori and colleagues [31], 12% of patients with thalamic haemorrhage died from the index event after a mean of 6 days (±6 days). 6% of patients died of systemic complications after a mean of 23 days (±18 days).

Due to its rareness, it is often neglected in clinical practice. A case study showed a patient with Artery of Percheron occlusion presenting with obtusion. However, the initial CT was misinterpreted which constituted to a significant diagnostic delay [32]. There are two clinical challenges associated with the identification of this clinically significant anatomical variant: (1) extensive aetiological investigation required [33], and (2) sudden onset of coma and other severe effects [34]. This is understandable since the old maxim ‘common things come first’ pervades in clinical medicine. Clinicians are advised and actively encouraged to think about more common diagnoses before examining rarer ones. However, this does not mean rare diagnoses do not ever arise. In fact, once they arise, they are possibly associated with worse clinical outcomes if there is a delay in accurate diagnosis, as seen in the occlusion of the Artery of Percheron. Moreover, early thrombolytic therapy results in good clinical recovery [35]. This makes clinical awareness and early, accurate diagnosis, even more important in order to improve patient care.

Current research in this area remains scarce. However, there are four common patterns of occlusion which can shed some light to the internist: 1) bilateral paramedian thalamic with midbrain (43%), 2) bilateral paramedian thalamic without midbrain (38%), 3) bilateral paramedian thalamic with anterior thalamus and midbrain (14%), and 4) bilateral paramedian thalamic with anterior thalamus without midbrain (5%) [36]. The ‘Midbrain V-Sign’ on MRI is also expected to increase diagnostic ease.

 

 

Figure 2: Variations of medial thalamomesencephalic blood supply, showing the normal variant (left), Artery of Percheron (middle), and the arcade (right). Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org. From the case rID: 35924

(c)    Vertebrobasilar Dolichoectasia

Vertebrobasilar Dolichoectasia is the distention, elongation and tortuosity of the vertebral and/or basilar artery(ies) [37]. It is a clinically significant issue, with a study showing that 30% of patients with vertebrobasilar dolichoectasia experienced pontine infarction [38]. It is associated with high all-cause mortality (36%) and rate of fixed/transient posterior circulation dysfunction [39]. There is also increasing evidence that it is associated with higher risk of stroke recurrence. Chen and colleagues reported that 19.1% of patients presenting with vertebrobasilar dolichoectasia suffered from recurrent ischaemic stroke in a maximum follow-up period of 30 months [40]. Two patients (1.8%) died of the recurrent cerebrovascular event. Diffuse intracranial dolichoectasia was also significantly correlated with recurrence of ischaemic stroke (HR: 7.020; 95% CI: 2.199–22.418; p=?0.001).

There is also mounting evidence that vertebrobasilar dolichoectasia leads to multiple, recurrent ischaemic strokes within a short period of time, resulting in significant impairment in cognitive, sensory and motor functions. Moreover, if the condition is not identified promptly, treatment decisions might affect later prognosis and functional outcomes. Moriyoshi and colleagues reported the case of a 78-year old male patient who presented with sudden right hemiparesis [41]. Although intracranial arterial dolichoectasia was identified alongside an acute infarct, the normal protocol was adopted and the patient was given thrombolysis. Anti-thrombotic therapy was given during long-term follow-up. However, the patient experienced four more strokes in the ensuing half-year. It was postulated that anti-thrombotic therapy increased the diameter, thus worsening the degree of ectasia, of the basilar artery. A case report from France also showed that untreated basilar artery dolichoectasia could lead to bilateral deafness pursuant to thrombo-embolism [42]. It concerned a 54-year old patient who had imaging-confirmed dolichoectasia and experienced three cerebrovascular accidents, culminating in multiple infarctions of the pons.  

Hypertension is also deduced, from case series, to be a significant factor affecting the progression of vertebrobasilar dolichoectasia [43]. Early identification leads to more prudent attention to fluctuations in blood pressure. Patients are also more likely to receive a different anti-hypertensive regimen (principally in terms of dosage) for more effective control.

 

Figure 3: Coronal view of a non-contrast computed tomography (NCCT) scan of the brain showing an elongated and ectatic basilar artery which measures up to 9 mm in diameter at its proximal segment. Case courtesy of Dr. Eduardo Torres, Radiopaedia.org. From the case rID: 65518

 

(2)    Artery-Artery Embolisation

 

After discussing about individual arteries, it is sensible to proceed in the direction of inter-artery interactions. Alongside cardio-embolism, it is an alternative mechanism for detachments of the parent thrombotic lesion to travel up the vascular system. This is likely to result in embolic occlusion of arteries of the smaller calibre. This can be illustrated by the varying diameters of arteries in the cerebrovascular circulation. The mean diameters of the normal right vertebral artery are found to be  2.43 mm x 3.61 mm, relative to 2.83 mm x 3.94 mm on the left [44]. According to definition, arterioles in the brain have a diameter of 10-100 ?m [45]. A thrombotic lesion over the vertebral artery of a certain degree may appear to be asymptomatic due to the lack of disturbance towards haemodynamic parameters. However, once embolism occurs, the smaller lesion can be dislodged in one of the perforating arterioles, resulting in occlusive disease and impairment in vascular supply of that particular cerebral territory.

Although artery-artery embolisation accounts for 32% of all PCIS [46, 47], literature in this area is scarce. Many studies are case series featuring small sample sizes from the 20th century. It is unfortunate since clinical outcomes are poor when multiple arteries can be affected. According to Koroshetz and colleagues [48], 12 patients experienced artery-artery embolism between vertebral and posterior cerebral arteries, where half presented with occipital infarction. 1 patient experienced concurrent basilar artery occlusion.

Few studies focus on subclavian arteries, despite that they give rise to the vertebral arteries and when affected, are likely to give rise to serious haemodynamic effects.  According to the study reported by Ricotta and colleagues [49], 13 patients presented with transient vertebrobasilar ischaemia and subclavian disease in a 5-year period. 10 patients experienced transient diplopia while 8 patients suffered from transient gait disturbances. 1 patient reported of cortical blindness, suggesting posterior cerebral artery involvement. Most patients (n=12/13) had no recurrence of neurological manifestations after surgical treatment. Jithoo and colleagues reported a patient suffering from visual disturbances after experiencing penetrative subclavian injury [50].  The occipital lobe was affected by a lesion caused by occlusion of the posterior cerebral artery. The carotid and vertebral arteries were found to be patent, thus suggestive of distant embolisation from the subclavian artery.

These case reports reinforce the idea that if a lesion is promptly detected and treated appropriately, it is likely that patient outcomes are improved dramatically. Conversely, if the parent lesion is missed, the patient is expected to experience more frequent neurological manifestations of a wider variety. They also emphasise the importance of unearthing any traumatic aetiology.

More research is encouraged in elucidating the trends of artery-artery embolisation in PCIS, and the risk factors behind the phenomenon. Larger observational studies can be performed to assess the prevalence of the phenomenon in all patients with PCIS, as well as particular predilections of arterial involvement. This leads to two possible areas of improvement in clinical care. Firstly, it potentially offers us advice as to whether the dosage of anti-thrombotic therapy and thrombolysis should be varied in cases of PCIS in virtue of the difference in prevalence in artery-artery embolisation between PCIS and anterior circulation events. Secondly, thrombotic lesions in the vertebral artery, if detected, can be risk-assessed. The premise is that high-risk plaques in the vertebral artery display specific morphological features and are more likely to embolise. If a neuroimaging technique can be used conveniently in the clinical setting to see if a patient accommodates a high-risk plaque, more aggressive treatment can be advised at an earlier stage. This is expected to improve both survival and functional outcomes.  

Progress in this area is already made by investigating plaque characteristics in the anterior circulation. Kamtchum-Tatuene and colleagues reported common imaging characteristics of high-risk plaques in the internal carotid artery [51]. Common neuroimaging findings included echolucency (42.3%; 95% CI: 32.2%-52.8%), ulceration (13.1%; 95% CI: 3.5%-27.1%), and microembolic signals (14.3%; 95% CI: 10.0%-19.2%). A similar meta-analysis should be done for PCIS. With regard to a convenient imaging modality used in cerebrovascular screening, a natural candidate would be duplex ultrasonography (DUS). It is meritorious for its high availability and low cost relative to other modalities, such as CT and MRI. Initial data showed that although DUS was fair in estimating the presence of significant (exceeding 50%) stenoses in the vertebral artery (area under receiver operating characteristic curve, or AUROC: 0.73; 95% CI: 0.63-0.83), anatomical trajectories of the vertebral arteries (especially V1 segments) make it difficult for clinical interpretation [52].

 

(3)    Collateralisation and Brain Perfusion

After examining the possible research impact of both clinically significant anatomical variants, and artery-artery embolisation, it is suggested that more research in the perfusion of the entire posterior circulation should also be performed. The presence of collateral blood supply is known to contribute to better functional outcomes and lower stroke recurrence, since collaterals replace the diseased artery in supplying its vascular territory [53].  This can be illustrated by the finding that the presence of bilateral posterior communicating arteries leads to more favourable outcomes in patients having suffered from basilar artery occlusion after being treated with endovascular therapy [54].

 

(a)    Types of Collaterals

There are three classes of collaterals [55, 56, 57]: (1) primary collaterals, which are connections in the Circle of Willis; (2) secondary collaterals, which are leptomeningeal vessels (including anastomoses between smaller, distal vessels); and (3) tertiary collaterals, which originate from the de novo angiogenesis of microvessels around the area of ischaemia. Primary collaterals between anterior and posterior circulations are similar since they both concern the large arteries of the Circle of Willis. However, there is limited scientific data on the efficacies and comprehensiveness of secondary collaterals between the two circulations. It is still unknown whether PCIS leads to higher dependence on ipsilateral leptomeningeal connections.

Tertiary collaterals are more dynamic. According to Iwasawa and colleagues [58], collaterals could be formed from ‘arteriogenesis’ instead of chronic stenosis. This process is a response to acute fluid shear stress which occurs between the territories of stenotic/occluded and surrounding arteries. This is induced by vascular flow from high-flow to low-flow regions via traversing pre-existing arterioles. Ultimately, the proliferation of both smooth muscle and endothelial cells leads to vessel formation. The role of angiogenesis in stroke collateralisation, where hypoxia is the main trigger, remains controversial [58]. Regarding the variations in haemodynamic parameters between the anterior and posterior circulation, it would be informative to compare their capabilities in forming de novo tertiary collaterals for supporting cerebral perfusion in cerebrovascular accidents.

 

(b)    Collateral Investigation Techniques

To investigate the extent of collateralisation in the posterior circulation, varying neuroimaging techniques can be employed. Parameters of collateralisation estimation are generally categorised into structure and function. Digital subtraction angiography analyses the extent and structure of the collateral network whereas perfusion techniques, such as CT and MR perfusion, are used for evaluating the efficacy of the said network. Four parameters are used in CT perfusion: CBF (cerebral blood flow), CBV (cerebral blood volume), MTT (mean transit time) and TTP (time to peak) [59]. MTT is the most sensitive in assessing neurological improvement and tissue salvage in hyperacute ischaemic stroke [60].

Several clinical scales are available for evaluating the prognosis of a given patient. However, most of them are modelled after studies done on patients with anterior circulation stroke(s). The ASITN/SIR collateral scale is based on digital subtraction angiography where collateral status is divided into grades 0-4, with grades 0-1, 2 and 3-4 respectively indicative of poor, moderate and good flow [61]. ASPECTS (Alberta stroke program early CT score) is based on multiphase-CTA and is used in patients with middle cerebral artery stroke (part of the anterior circulation). 10 points are available and 1 point is deducted for every region, both parenchymal and vascular, involved. Patients with 7 points or below are expected to have worse functional outcomes at three months of follow-up [62]. Both scales are shown to exhibit higher correlation between the extent of early infarct core and mismatch volume [63].

In recent years, ASPECTS has been adapted for the posterior circulation (pc-ASPECTS) [64]. A posterior circulation-specific grading scale has emerged (PC-CS). It is verified with patients from the Basilar Artery International Cooperation Study, which focuses on the prediction of functional outcomes after basilar artery occlusion [65].

 

Figure 4: Illustration of the Alberta stroke program early CT score (ASPECTS) of the middle cerebral artery. Case courtesy of Dr Osamah A. A. Alwalid, Radiopaedia.org. From the case rID: 72706

 

Figure 5: Illustration of the acute stroke prognosis early CT score (ASPECTS) of the posterior circulation. Case courtesy of Dr Osamah A. A. Alwalid, Radiopaedia.org. From the case rID: 72707

 

(c)    Proposed Research Directions

A possible research direction is to commence by investigating the differences in structure and function of collateral networks in the anterior and posterior circulation. DSA data can be utilised for collateral structure analysis where the ASITN/SIR criteria are applied to grading the differences in comprehensiveness and extent of collateralisation in both circulations. Collateralisation efficacy can then be evaluated by pc-ASPECTS with the use of multi-phase CTA. These observations form the basis of further investigation of the biochemical drivers contributing to such variations, especially in the area of tertiary collateral formation. Where these drivers, or variations thereof, are identified, this can inform therapeutic strategies, hopefully bridging our current knowledge gap and introducing more favourable outcomes for patients with PCIS. This explanation is also informative as to why PCIS reports worse clinical outcomes than anterior circulation events. For instance, according to Lucitti and colleagues [66], global reduction of VEGF-A (vascular endothelial growth factor) and Flk1 (molecular receptor of VEGF) during embryogenesis contributed to reduction in the extent of collateralisation. Such changes persisted in adulthood. Presuming that there are inherent differences in levels of VEGF-A/Flk-1 between the posterior and anterior circulations, the extent of this difference can be used as a surrogate marker for clinical outcomes. Patients with lower levels of global VEGF-A/Flk-1, and their corresponding percentiles, could be used for estimating the risk of future PCIS and any recurrent cerebrovascular event. An inclusion of this marker in routine clinical assessment can also inform clinical decision-making, such that high-risk patients are given prophylactic treatment for PCIS, or ischaemic stroke in general.

Although this example merely offers a simplistic view of clinical research, it simultaneously illuminates the myriads of possibilities that arise by embarking on this path.

 

Conclusion

 

PCIS remains a disease of high mortality and morbidity. However, it does not receive the attention in clinical research that it deserves. Neuroimaging is a vital mode of investigation and future research directions can focus on dissecting the following: (1) clinically significant anatomical variants, (2) artery-artery embolisation, and (3) collateralisation. This prospectively broadens our understanding towards this debilitating illness and raises clinical awareness. As clinicians become more aware of PCIS in general, it is more likely that patients will receive prompt care and diagnostic delays can be reduced. Moreover, advances in neuroimaging and collateralisation in the posterior circulation can perhaps proffer us the answer as to why functional outcomes in PCIS are significantly worse than anterior circulation events, and ideas of therapeutic strategies and risk stratification. 

 

References

 

[1] Mackay MT, Prabhu SP, Coleman L. Stroke. Childhood Posterior Circulation Arterial Ischaemic Stroke. 2010;41:2201-2209.

 

[2] Gulli G, Marquardt L, Rothwell PM, Markus HS. Stroke risk after posterior circulation stroke/transient ischemic attack and its relationship to site of vertebrobasilar stenosis pooled data analysis from prospective studies. Stroke (2013) 44(3):598–60410.1161/STROKEAHA.112.669929.

 

[3] Crossman AR, Neary D. Neuroanatomy: an Illustrated Colour Text. 6th ed. Elsevier; 2019.

 

[4] Caplan LR, The Intracranial Vertebral Artery: A Neglected Species. Cerebrovasc Dis 2012;34:20-30.

 

[5] Thrift AG, Dewey HM, Sturm JW, et al. Incidence of stroke subtypes in the North East Melbourne Stroke Incidence Study (NEMESIS): differences between men and women. Neuroepidemiology. 2009; 32:11–18. doi:10.1159/000170086.

 

[6] Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation registry. Ann Neurol. 2004; 56:389–398. doi:10.1002/ana.20204.

 

[7] Tao WD, Liu M, Fisher M, et al. Posterior versus anterior circulation infarction: how different are the neurological deficits? Stroke. 2012 Aug;43(8):2060-5.

 

[8] Guidelines for the Early Management of Patients with Acute Ischemic Stroke- A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947.

 

[9] Gonzalez RG, Copen WA, Schaefer PW, et al. The Massachusetts General Hospital acute stroke imaging algorithm: an experience and evidence based approach. J NeuroIntervent Surg 2013;5:i7-i12.

 

[10] Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet. 2007;369:293-8.

 

[11] Hwang DY, Silva GS, Furie KL, Greer DM. Comparative Sensitivity of Computed Tomography vs. Magnetic Resonance Imaging for Detecting Acute Posterior Fossa Infarct. J Emerg Med. 2012 May; 42(5): 559-565.

 

[12] Smajlovic D, Sinanovic O. Sensitivity of the neuroimaging techniques in ischemic stroke. Med Arh. 2004;58(5):282-4.

 

[13] Khan S, Cloud GC, Kerry S, et al. Imaging of vertebral artery stenosis: a systematic review Journal of Neurology, Neurosurgery & Psychiatry 2007;78:1218-1225.

 

[14] Mak HK, Wong CW, Yau KKW, et al. Computed tomography evaluation of intracranial atherosclerosis in Chinese patients with transient ischemic attack or minor ischemic stroke- its distribution and association with vascular risk factors. Journal of Stroke and Cerebrovascular Disease 2009; 18(2): 158-163.

 

[15] Gonzalez RG, Lev MH, Goldmacher GV, et al. Improved Outcome Prediction Using CT Angiography in Addition to Standard Ischemic Stroke Assessment: Results from the STOPStroke Study. PLoS ONE 2012 7(1): e30352.

 

[16] Menon BK, d'Esterre CD, Qazi EM, et al. Multiphase CT Angiography: A New Tool for the Imaging Triage of Patients with Acute Ischemic Stroke. Radiology. 2015;275(2):510-520. doi:10.1148/radiol.15142256.

 

[17] Mair G, Wardlaw JM. Imaging of acute stroke prior to treatment: current practice and evolving techniques. Br J Radiol;87:20140216.

 

[18] Herzig R, Burval S, Krupka B, Vlachová I, Urbánek K, Mares J. Comparison of ultrasonography, CT angiography, and digital subtraction angiography in severe carotid stenoses. Eur J Neurol. 2004;11(11):774-781. doi:10.1111/j.1468-1331.2004.00878.x

 

[19] Dias-Neto M, Marques C, Sampaio S. Digital Subtraction Angiography or Computed Tomography Angiography in the Preoperative Evaluation of Lower Limb Peripheral Artery Disease - A Comparative Analysis. Rev Port Cir Cardiotorac Vasc. 2017;24(3-4):174.

 

[20] Katsanos AH, Kosmidou M, Kyritsis AP, Giannopoulos S. Is Vertebral Artery Hypoplasia a Predisposing Factor for Posterior Circulation Cerebral Ischaemic Events? A Comprehensive Review. Eur Neurol 2013;70:78-83.

 

[21] Thierfelder KM, Baumann AB, Sommer WH. Vertebral Artery Hypoplasia: Frequency and Effect on Cerebellar Blood Flow Characteristics. Stroke 2014;45:1363-8.

 

[22] Mitsumura H, Miyagawa S, Komatsu T, Hirai T, Kono Y, Iguchi Y. Relationship between Vertebral Artery Hypoplasia and Posterior Circulation Ischemia. Journal of Stroke and Cerebrovascular Diseases. 2016;25(2):266-269. doi:10.1016/j.jstrokecerebrovasdis.2015.09.027.

 

[23] Szárazová A, Bartels E, Tur?áni P. Vertebral artery hypoplasia and the posterior circulation stroke. Perspectives in Medicine. 2012;1(1-12):198-202. doi:10.1016/j.permed.2012.02.063

 

[24] Vasovi? L, Trandafilovi? M, Vlajkovi? S, Djordjevi? G, Dakovi?-Bjelakovi? M, Pavlovi? M. Unilateral Aplasia versus Bilateral Aplasia of the Vertebral Artery: A Review of Associated Abnormalities. Biomed Res Int. 2017;2017:1-20. doi:10.1155/2017/7238672

 

[25] Lu J, Liu J, Wang L, Qi P, Wang D. Bilateral segmental agenesis of carotid and vertebral arteries with rete mirabile and the prominent anterior and posterior spinal arteries as compensations. Interv Neuroradiol. 2014;20(1):13-19. doi:10.15274/INR-2014-10003.

 

[26] Mondel PK, Saraf R, Limaye US. Bilateral carotid and vertebral rete mirabile with vein of Galen aneurysmal malformation: an unreported association. BMJ Case Rep. 2014;2014:bcr2014011349. Published 2014 Nov 20. doi:10.1136/bcr-2014-011349.

 

[27] Burger IM, Siclari F, Gregg L, Gailloud P. Bilateral segmental agenesis of the vertebrobasilar junction: developmental and angiographic anatomy. AJNR Am J Neuroradiol. 2007;28(10):2017-2022. doi:10.3174/ajnr.A0719.

 

[28] Sandvig A, Lundberg S and Neuwirth J. Artery of Percheron infarction: a case report. J Med Case Rep. 2017; 11: 221.

 

[29] Matheus MG, Castillo M. Imaging of acute bilateral paramedian thalamic and mesencephalic infarcts. AJNR Am J Neuroradiol. 24 (10): 2005-8.

 

[30] Kumral E, Evyapan D, Balkır K, Kutluhan S. Bilateral thalamic infarction. Acta Neurol Scand. 2001;103(1):35-42. doi:10.1034/j.1600-0404.2001.00141.x

 

[31] Mori S, Sadoshima S, Ibayashi S, Fujishima M, Iino K. Impact of Thalamic Hematoma on Six-Month Mortality and Motor and Cognitive Functional Outcome. Stroke. 1995;26(4):620-626. doi:10.1161/01.str.26.4.620.

 

[32] Kichloo A, Jamal SM, Zain EA, Wani F, Vipparala N. Artery of Percheron Infarction: A Short Review. J Investig Med High Impact Case Rep. 2019;7:2324709619867355. doi:10.1177/2324709619867355

 

[33] Shah AR, Ali R. Artery of Percheron Infarct - a diagnostic and prognostic conundrum! J Pak Med Assoc. 2018 Jan;68(1):123-126.

 

[34] Rivera-Lara L, Henninger N. Delayed Sudden Coma Due to Artery of Percheron Infarction. Arch Neurol. 2011;68(3):386–387. doi:10.1001/archneurol.2010.377.

 

[35] Premraj Raut T, Baheti G, Hinduja A, Makhija P, Ansari K, Sharma V. Sudden Onset Altered Sensorium: Artery of Percheron Infarct. J Neurol Neurosci. 2017;08(04). doi:10.21767/2171-6625.1000212.

 

[36] Lazzaro NA, Wright B, Castillo M, et al. Artery of Percheron Infarction: Imaging Patterns and Clinical Spectrum. American Journal of Neuroradiology. 2010;31(7):1283-1289. doi:10.3174/ajnr.A2044

 

[37] Kansal R, Mahore A, Dange N and Kukreja S. Dolichoectasia of vertebrobasilar arteries as a cause of hydrocephalus. J Neurosci Rural Pract. 2011 Jan-Jun; 2(1): 62–64.

 

[38] Nishizaki T, Tamaki N, Takeda N, Shirakuni T, Kondoh T, Matsumoto S. Dolichoectatic basilar artery: a review of 23 cases. Stroke. 1986;17(6):1277-1281. doi:10.1161/01.str.17.6.1277

 

[39] Ubogu EE, Zaidat OO. Vertebrobasilar dolichoectasia diagnosed by magnetic resonance angiography and risk of stroke and death: a cohort study. Journal of Neurology, Neurosurgery & Psychiatry 2004;75:22-26.

 

[40] Chen Z, Zhang S, Dai Z et al. Recurrent risk of ischemic stroke due to Vertebrobasilar Dolichoectasia. BMC Neurol. 2019; 19. doi:10.1186/s12883-019-1400-9.

 

[41] Moriyoshi H, Furukawa S, Iwata M, et al. Rinsho Shinkeigaku. 2017;57(3):124-129. doi:10.5692/clinicalneurol.cn-000989.

 

[42] Davous P, Tillier JN, Torrent J. Surdité totale après infarctus protubérantiels multiples. Dolichoectasie du tronc basilaire [Total deafness after multiple pontine infarctions. Dolichoectasia of the basilar trunk]. Rev Neurol (Paris). 1991;147(3):234-237.

 

[43] Lin YW, Chen CH, Lai ML. The dilemma of treating vertebrobasilar dolichoectasia. Clin Pract. 2012;2(4):e84. Published 2012 Oct 17. doi:10.4081/cp.2012.e84.

 

[44] Mehinovic A, Isakovic E, Delic J. Variations in diameters of vertebro-basilar tree in patients with or with no aneurysm. Med Arch. 2014;68(1):27-29. doi:10.5455/medarh.2014.68.27-29.

 

[45] Lee S. Concept of Large Artery and Small Vessel. Stroke Revisited: Pathophysiology of Stroke. 2020:31-36. doi:10.1007/978-981-10-1430-7_3.

 

[46] Caplan LR, Wityk RJ, Pazdera L, Chang HM, Pessin MS, and DeWitt LD. New England Medical Center Posterior Circulation Stroke Registry II. Vascular Lesions. J Clin Neurol. 2005 Apr; 1(1): 31–49.

 

[47] Yamamoto Y, Georgiadis AL, Chang HM, Caplan LR. Posterior cerebral artery territory infarcts in the New England Medical Center Posterior Circulation Registry. Arch Neurol. 1999;56(7):824-832. doi:10.1001/archneur.56.7.824

 

[48] Koroshetz WJ, Ropper AH. Artery-to-artery embolism causing stroke in the posterior circulation. Neurology. 1987 Feb;37(2):292-5.

 

[49] Ricotta J, Ouriel K, Green R, DeWeese J. Embolic lesions from the subclavian artery causing transient vertebrobasilar insufficiency. J Vasc Surg. 1986;4(4):372-375. doi:10.1016/0741-5214(86)90233-8

 

[50] Jithoo R, Nadvi SS and Robbs JV. Vertebral Artery Embolism Post Subclavian Artery Injury with Occipital Lobe Infarction. Eur J Vasc Endovasc Surg 2000 19, 85–86.

 

[51] Kamtchum-Tatuene J, Noubiap J, Wilman A, Saqqur M, Shuaib A, Jickling G. Prevalence of High-risk Plaques and Risk of Stroke in Patients With Asymptomatic Carotid Stenosis. JAMA Neurol. 2020;77(12):1524. doi:10.1001/jamaneurol.2020.2658.

 

[52] Rozeman AD, Hund H, Westein M, et al. Duplex ultrasonography for the detection of vertebral artery stenosis: A comparison with CT angiography. Brain Behav. 2017;7(8):e00750. Published 2017 Jun 29. doi:10.1002/brb3.750

 

[53] Liu L, Ding J, Leng X on behalf of the Chinese Society of Cerebral Blood Flow and Metabolism, the Chinese Stroke Association, et al Guidelines for evaluation and management of cerebral collateral circulation in ischaemic stroke 2017 Stroke and Vascular Neurology 2018;3.

 

[54] Goyal N, Tsivgoulis G, Nickele C, et al. Posterior circulation CT angiography collaterals predict outcome of endovascular acute ischemic stroke therapy for basilar artery occlusion. Journal of NeuroInterventional Surgery 2016;8:783-786.

 

[55] Nishijima Y, Akamatsu Y, Weinstein PR, Liu J. Collaterals: implications in cerebral ischemic diseases and therapeutic interventions. Brain Res. 2015 Oct 14; 1623: 18–29.

 

[56] Jung S, Wiest R, Gralla J, McKinley R, Mattle H, Liebeskind D. Relevance of the cerebral collateral circulation in ischaemic stroke: time is brain, but collaterals set the pace. Swiss Med Wkly. 2017 Dec 11;147:w14538.

 

[57] Liebeskind DS. Collateral circulation. Stroke 2003;34:2279–84.

 

[58] Iwasawa E, Ichijo M, Ishibashi S, Yokota T. Acute development of collateral circulation and therapeutic prospects in ischaemic stroke. Neural Regen Res. 2016 Mar; 11(3): 368–371.

 

[59] Lui YW, Tang ER, Allmendinger AM, Spektor V. Evaluation of CT perfusion in the setting of cerebral ischemia: patterns and pitfalls. AJNR Am J Neuroradiol. 2010;31(9):1552-1563. doi:10.3174/ajnr.A2026.

 

[60] Ford AL, An H, Kong L, et al. Clinically-relevant reperfusion in acute ischemic stroke MTT performs better than Tmax and TTP. Transl Stroke Res. 2014 Jun; 5(3): 415–421.

 

[61] Higashida RT, Furlan AJ, Roberts H, et al; Technology Assessment Committee of the American Society of Interventional and Therapeutic Neuroradiology; Technology Assessment

Committee of the Society of Interventional Radiology. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003;34:e109–e137.

 

[62] Pexman JW, Barber PA, Hill MD, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. American Journal of Neuroradiology. 2001 Sep 1;22(8):1534-42.

 

[63] Seker F, Potreck A, Möhlenbruch M, Bendszus M, Pham M. Comparison of four different collateral scores in acute ischemic stroke by CT angiography. J Neurointerv Surg. 2016;8(11):1116-1118.

 

[64] Puetz V, Sylaja PN, Coutts SB, et al. Extent of hypoattenuation on CT angiography source images predicts functional outcome in patients with basilar artery occlusion. Stroke. 2008;39(9):2485-2490. doi:10.1161/STROKEAHA.107.511162.

 

[65] van der Hoeven EJ, McVerry F, Vos JA, et al. Collateral flow predicts outcome after basilar artery occlusion: The posterior circulation collateral score. BASICS registry investigators. Int J Stroke. 2016 Oct;11(7):768-75.

 

[66] Lucitti JL, Mackey JK, Morrison JC, Haigh JJ, Adams RH, Faber JE. Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17. Circ Res. 2012;111(12):1539-1550. doi:10.1161/CIRCRESAHA.112.279109

 

Declaration from author regarding figures in the manuscript: All figures are extracted from Radiopaedia, where they are covered by the Creative Commons Attribution-Non-commercial-Share Alike 3.0 Unported Licence. This means that the author of this article can copy and alter the images downloaded without seeking prior permission from the website, provided that the images are used for non-commercial purposes. The captions contain the correct statements of attribution to original copyright owners. For more details, refer to the URL: https://radiopaedia.org/licence?lang=gb

 

Cover image: Image by David Mark from Pixabay