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Etiologies of simultaneous cerebral infarcts in multiple arterial territories: A simple literature-based pooled analysis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263244
Keywords: Acute multiple infarcts in multiple cerebral circulation, atrial fibrillation, cardio-embolism, diffusion weighted imaging
Acute multiple infarcts in multiple cerebral circulations (AMIMCC) are traditionally defined on neuroimaging as noncontiguous infarcts located in more than one cerebral circulation. They may occur as a single event secondary to the shower of emboli or may be separated in time.[1],[2] Increasing use of advanced imaging modalities such as diffusion-weighted MRI scan (DWI), which can identify hyperacute infarcts and differentiate old from recent infarcts with greater sensitivity than computed tomography (CT) scan has enhanced the detection of AMIMCC in clinical practice.[3] AMIMCCs pose a diagnostic challenge as their optimal workup has remained elusive and there is no clear guideline on the best secondary prevention strategy. AMIMCC have generally been thought to be embolic in etiology with emboli arising either from the heart or great vessels.[3] Therefore, a number of care providers choose anticoagulation as the default secondary prevention strategy for these patients. However, several studies [4],[5] have shown the possible role of underlying nonembolic causes. In this article, we attempt to explore the frequency of various AMIMCC etiologies through a systematic review and pooled analysis of the available literature.
We conducted a systematic review of the literature through six different resources – PubMed, Scopus, Embase, Clinicaltrial. gov, WHO International Clinical Trials Registry Platform (ICTRP), and Cochrane library. Forward and backward citation tracking was also conducted (search protocol is available in Supplement 1). Studies reporting multiple acute strokes in more than one territories based on DWI imaging were reviewed and included in the analysis. Vascular territories were defined as per the model proposed by Tatu et al.[6] Anterior circulation was classified into an anterior cerebral artery (ACA), a superior division of the middle cerebral artery (MCA), an inferior division of the MCA, perforating branches of the MCA, medullary branches of the MCA, and anterior choroidal artery. The arterial territories for posterior circulation were superficial posterior cerebral artery (PCA), perforating branches of PCA, basilar artery (BA), superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA). AMIMCCs in our analysis were defined as multiple acute DWI lesions in more than one cerebral arterial territories, as per the above-mentioned model. Superior and inferior division of MCA were considered as two separate territories. Studies with limited inclusion criteria (such as stroke among patients with malignancy), limited subgroup analysis, lack of DWI for stroke diagnosis, and those in non-English languages were excluded from this study. Stroke etiologies were categorized into cardioembolic (atrial fibrillation, patent foramen ovale, atrial septal aneurysm, akinetic left ventricular aneurysm, etc.), large artery disease (>50% stenosis of appropriate large artery, anatomical variation, aortic arch atheroma, arterial dissection, etc.), intracranial atherosclerosis and small artery disease, hematological disorders, and malignancies.
A total of 17,773 search results were retrieved. By removing duplicates, screening the title and abstracts, and excluding non-English abstracts, 25 full texts were fully studied. Due to incomplete workup and diagnosis and inadequate use of DWI in AMIMCC diagnosis, four studies [7],[8],[9],[10] (280 AMIMCC patients) were excluded. Among 15,056 patients from 21 included studies, 1,914 (13%) patients had AMIMCC. One hundred and ninety-nine patients were excluded as their workup and diagnosis were not reported. Therefore, 1,715 patients were included in our analysis. The mean age of the included patients was 69.6 ± 4.8 years. The patients' distribution according to gender was not reported in one study,[2] and in the remaining studies, 57% of the patients were males [Figure 1].
Cardioembolism was the most common cause of AMIMCC and was reported in 638 (37.2%) patients. Among patients with a cardioembolic source, 41.5% had bilateral anterior circulation strokes whereas 66.7% had multiple infarctions in anterior and posterior circulations. Large artery disease, including an aortic atheroma, was the second most common etiology in 440 (25.7%) patients. Among patients with large artery diseases, 30.5% had bilateral anterior circulation strokes and 9.6% had strokes in the anterior and posterior circulations. The remaining had cerebral infarctions in different large arterial territories (e.g., ipsilateral ACA and MCA territories), malignancies and hematological disorders (2.1%), small vessel pathologies, and intracranial small vessel atherosclerosis (1.8%). Other minor causes of AMIMCC were inflammatory disorders such as vasculitis and infection (0.2%), and iatrogenic including infarctions following coronary artery bypass grafting and angiography (0.1%). Forty-four (2.6%) patients had more than one underlying etiology, and 472 (27.6%) patients had an undetermined etiology [Table 1].
Our results indicated that more than 10% of the ischemic stroke patients might have AMIMCC. Although cardioembolism is the most common cause of AMIMCC, a significant number of patients had nonembolic etiologies. Clinical manifestations and a head CT scan can be nonspecific among some of the patients with AMIMCC.[3],[11] Moulin et al., in their large hospital-based stroke registry observed that AMIMCC is associated with an increased in-hospital mortality and morbidity.[12] The increased mortality may be driven by underlying etiologies, and therefore, requires time-sensitive and comprehensive evaluation and management. Moreover, AMIMCC has been shown to have an increased likelihood of recurrence. Braemswig et al., have demonstrated that the presence of scattered and multiple territory DWI lesions is independently associated with the appearance of new DWI lesions.[13] Therefore, the role of properly selected secondary prevention measures among patients with multiple infarctions should be overemphasized. Overall, cardioembolism is the most common cause of AMIMCC. Among the cardioembolic causes, atrial fibrillation appears to be the leading cause. In a study by Depuydt et al., atrial fibrillation was responsible for 39% of the AMIMCC.[3] Similarly, Saito et al., showed that atrial fibrillation is the most common etiology among the cardioembolic group.[14] Other underlying causes include myocardial infarction, patent foramen ovale, atrial septal aneurysm, endocarditis, and heart failure with a low ejection fraction (<35%). Novotny et al., in their study, using the negative correlation between the time to DWI imaging and the frequency of AMIMCC, reported that in cardioembolism, release of concurrent emboli leads to AMIMCC.[2] Nevertheless, the majority of reports underestimated the frequency of paroxysmal atrial fibrillation due to a lack of long-term heart monitoring after discharge. Large artery disease was the second most common cause of AMIMCC accounting for 25.7% of the cases. Chung et al., reported large artery atherosclerosis as the most common cause of AMIMCC involving the middle cerebral artery territory infarction.[4] Large artery atherosclerosis can lead to multiple infarcts in different cerebral circulations by various mechanisms. There may be embolization of a plaque from the large artery into multiple smaller arteries or the presence of an anatomical aberration in which a unilateral internal carotid artery supplies bilateral cerebral circulation through cross-flow from the stenotic internal carotid artery to the contralateral anterior cerebral artery. Similarly, a single artery that supplies both medial zones of the hemisphere, or a “fetal type of posterior cerebral artery” that arises from the internal carotid artery, can cause simultaneous infarctions in anterior and posterior circulations.[11] Novotny et al., by studying the positive correlation between the time to DWI imaging and the frequency of AMIMCC, reported that the release of successive emboli from a large artery plaque leads to multiple acute cerebral infarctions.[2] Saito et al., reported that bilateral infarcts among 16% of the patients were caused by unilateral carotid artery disease.[14] Similarly, Roh et al., also reported multiple infarcts caused by the presence of an anatomical vascular aberration.[11] Hematological causes of AMIMCC also require attention and a focused workup. We found that hematological conditions are responsible for approximately 2% of cases of AMIMCC. Various mechanisms, including hypercoagulable states (either primary or secondary due to malignancies), disseminated intravascular coagulation (DIC), and nonbacterial thrombotic endocarditis (NBTE) are implicated in the causation of multiple infarcts due to hematological pathologies. Fagniez et al., reported that 2.2% of multiple infarcts were secondary to hematological conditions, with myeloproliferative disorders being the most common cause.[5] Other rare causes of AMIMCC, such as vasculitis, need special workup, including a complementary biological test with cerebrospinal fluid (CSF) analysis, cerebral angiography, and cerebral biopsy. Iatrogenic causes such as cerebral infarction post-cerebral angiography or cardiac catheterization are among the other rare causes of AMIMCC. We found that about 27.6% of cases of AMIMCC are of undetermined etiology. This is probably because of the lack of an approved comprehensive workup protocol following the initial investigations. For example, the diagnosis of vasculitis requires a cerebrospinal fluid (CSF) analysis, cerebral angiography, and cerebral biopsy, that are not routinely performed in clinical practice. Many patients with AMIMCC require a comprehensive workup including long-term cardiac monitoring, blood, and even CSF tests for the diagnosis of hypercoagulable states and vasculitis, and appropriate imaging based on individual cases involving transesophageal echocardiography and cerebral angiography. Moreover, special attention should be paid to the cerebral vessel anatomy and different variations as well as the age of each lesion on magnetic resonance imaging. Our study had some limitations. Out of the 21 studies, 15 had a retrospective observational design. The definition of AMIMCC varies among studies; however, the included studies satisfied our inclusion criteria. There were variations among studies in terms of in-hospital clinical investigations and post-discharge follow-ups. Moreover, out of 1715 patients, 472 (27.6%) patients had undetermined etiologies. We were also not able to obtain a detailed demographic information and risk profile of our cohort. In summary, AMIMCC occurs in more 10% of stroke patients. Although cardioembolism is the most common cause of AMIMCC, a significant number of patients have nonembolic etiologies. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Supplement 1 I: Review Title Mechanism of simultaneous cerebral infarcts in multiple arterial territories: a literature-based pooled analysis II: Limitations of Search Date/Time: No Language: No Document Type: No Publication Status: No III: Resources and Number of Results
A.PubMed 1. ”Cerebrovascular Disorders”[MH] 2. ”Cerebral Infarction”[MH] OR “Brain Infarction”[MH] OR “Brain Ischemia”[MH] OR “Hypoxia-Ischemia, Brain”[MH] 3. ”Stroke”[MH] OR “Stroke, Lacunar”[MH] OR “Infarction, Posterior Cerebral Artery”[MH] OR “Brain Stem Infarctions”[MH] OR “Infarction, Middle Cerebral Artery”[MH] OR “Infarction, Anterior Cerebral Artery”[MH] 4. Stroke[TW] OR cerebr* vascul* infarct*[TW] OR cerebrovasc* infarct*[TW] OR cerebr* vasc* event*[TW] OR cerebrovasc* event*[TW] OR cva[TW] 5. #1 OR #2 OR #3 OR #4 6. ”Causality”[MH] OR “Etiology”[MH] OR (incidence[MH:noexp] OR “epidemiology”[MH] 7. multifocal[TW] OR multiple[TW] OR bihemispher*[TW] OR multiple territories[TW] OR multiple cerebral circulations[TW] 8. #5 AND #6 AND #7 B.EMBASE 9. 'brain infarction'/exp OR 'brain ischemia'/exp OR 'cerebrovascular accident'/exp OR 'cerebral artery disease'/exp OR 'occlusive cerebrovascular disease'/exp 10. 'lacunar stroke'/exp OR 'middle cerebral artery occlusion'/exp OR ('brain artery'/exp AND 'artery occlusion'/exp) 11. ((brain ischemia) OR (ischemic brain) OR (cerebral ischemia) OR (ischemic attack) OR (transient ischemic attack) OR (ischemic stroke) OR (acute ischemic stroke) OR (cerebral infarction) OR (brain infarction) OR (ischemic brain infarction) OR (ischemic cerebral infarction) OR stroke):ti,ab 12. #1 OR #2 OR #3 13. 'Causality'/exp OR 'epidemiological data'/exp OR 'epidemiology'/exp OR 'prevalence'/exp OR 'incidence'/exp 14. ((Multifocal) OR (multiple) OR (bihemispheric) OR (multiple territories) OR (multiple cerebral circulations)):ti,ab 15. #4 AND #5 AND #6 C.Scopus 1. TITLE-ABS-KEY ((brain ischemia) OR (brain hypoxia-ischemia) OR (transient ischemic attack)) 2. TITLE-ABS-KEY (stroke OR (lacunar stroke) OR (posterior cerebral artery infarction) OR (brain stem infarctions) OR (middle cerebral artery infarction) OR (anterior cerebral artery infarction)) 3. #1 OR #2 4. TITLE-ABS-KEY ((multifocal) OR (multiple) OR (bihemispheric) OR (multiple territories) OR (multiple cerebral circulations)) 5. TITLE-ABS-KEY ((causality) OR (epidemiology) OR (prevalence) OR (incidence)) 6. #3 AND #4 AND #5 D.International Clinical Trials Registry Platform ((cerebral infarction) OR (brain infarction)) AND (multiple OR multifocal) E. ClinicalTrials.Gov ((cerebral infarction) OR (brain infarction)) AND (multiple OR multifocal) F.Cochrane Library ((cerebral infarction) OR (brain infarction)) AND (multiple OR multifocal)
[Figure 1]
[Table 1]
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