American Heart Association


Article Commentary: “Association of Enlarged Perivascular Spaces and Anticoagulant-Related Intracranial Hemorrhage”

Song J. Kim, MD

Best JG, Barbato C, Ambler G, Du H, Banerjee G, Wilson D, Shakeshaft C, Cohen H, Yousry TA, Al-Shahi Salman R, et al. Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage. Neurology. 2020;95:e2192-e2199.

The clinical significance of cortical superficial siderosis, cortical microbleeds, and cortical subarachnoid hemorrhages — imaging markers of cerebral amyloid angiopathy (CAA) — has become clearer over the years as representing future and recurrent risk of symptomatic intracranial hemorrhages (sICH), especially lobar bleeds. Recently, enlarged perivascular spaces (EPVS) in the basal ganglia (BG-EPVS) and the centrum semiovale (CS-EPVS) have also come to the attention of researchers as possibly linked to hypertensive arteriopathy and CAA, respectively. Given this, could EPVS carry a risk of symptomatic intracranial hemorrhage (sICH) in patients starting anticoagulation? 

To answer this question, Best et al. conducted a post-hoc analysis of the CROMIS-2 (AF) study, a multicenter prospective cohort study examining the relationship between cerebral microbleeds and anticoagulant-related sICH over a 2-year follow-up period. Using baseline MRI imaging pre-anticoagulation, the number of BG-EPVS and CS-EPVS were enumerated and dichotomized (greater than 10 or less than 10). The association of EPVS with symptomatic intracranial hemorrhage was then investigated using Cox Regression analysis, which also incorporated other variables such as cortical microbleeds and lacunes.

Age Excludes Women from Intracerebral Hemorrhage Trials

Saurav Das, MD  

Greige T, Norton C, Foster LD, Yeatts SD, Thornhill A, Griffin J, Wang J, Hrdlicka CM, Selim M, on behalf of the iDEF Investigators. Why Are Women Less Represented in Intracerebral Hemorrhage Trials? Stroke. 2021;52:442–446.

Despite a higher burden of intracerebral hemorrhage (ICH) in women, their enrollment in clinical trials is low. Given sex differences in pathophysiology and outcomes following ICH, disparities in enrollment limit the generalizability of trial results. In this study, Dr. Greige et al. examine the reasons for exclusion of women compared to men from the Intracerebral Hemorrhage Deferoxamine (iDEF) trial. The iDEF trial was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase 2 trial that evaluated the use of deferoxamine mesylate versus placebo (saline) infusions in patients with ICH at 40 hospitals in Canada and the United States. The trial results were published in Lancet Neurology in May 2019.1 The screening log for all ICH patients found ineligible to participate in this study was reviewed to identify the reason for exclusion (of the 29 pre-defined reasons). Chi-square test was used to evaluate whether women and men differed with regard to reason for exclusion; adjustments for multiple testing were made during analyses. 

Determining Prognosis of Intracerebral Hemorrhage by Imaging: Wait (24 Hours) and See

Raffaele Ornello, MD

Lun R, Yogendrakumar V, Demchuk AM, Aviv RI, Rodriguez-Luna D, Molina CA, et al. Calculation of Prognostic Scores, Using Delayed Imaging, Outperforms Baseline Assessments in Acute Intracerebral Hemorrhage. Stroke. 2020;51:1107–1110.

The prognosis of intracerebral hemorrhage (ICH) is poor, and it is hard to identify factors which can predict a good or bad outcome. Besides, ICH is usually a fast-progressing clinical picture, in which early and delayed imaging may show completely different pictures.

The multicenter, prospective, observational cohort of the PREDICT study (Prediction of Hematoma Growth and Outcome in Patients With Intracerebral Hemorrhage Using the CT-Angiography Spot Sign) included 280 patients with a 90-day case-fatality of 25%. The study assessed the predictive accuracy for 90-day mortality of the ICH Score, FUNC Score, and modified ICH Score using imaging data at initial presentation and at 24 hours. Analyses were performed using receiver operating characteristic curves. Compared with early imaging, brain imaging performed 24 hours after ICH onset significantly improved the accuracy of prognostic scores; in detail, the area under the curve increased from 0.78 to 0.82 for ICH score, from 0.76 to 0.84 for FUNC Score, and from 0.74 to 0.82 for modified ICH score. The study findings are limited by the absence of complete 24-hour clinical data. Nevertheless, the study points out that waiting 24 hours from symptom onset might improve the prediction of ICH prognosis.

A possible consequence of this study is that early withdrawal of ICH care might be unjustified, as physicians can provide reliable estimates of patients’ prognosis only after several hours from ICH onset. More interventions in the hyperacute phase of ICH might be needed, and several studies suggest the efficacy of such early interventions. Waiting 24 hours before withdrawing care might be a viable option in ICH.

Non-Contrast CT Signs for Acute Intracerebral Hematoma Expansion Prediction: Alternatives to Spot Sign

Piyush Ojha, MBBS, MD, DM

Law ZK, Ali A, Krishnan K, Bischoff A, Appleton JP, Scutt P, et al. Noncontrast Computed Tomography Signs as Predictors of Hematoma Expansion, Clinical Outcome, and Response to Tranexamic Acid in Acute Intracerebral Hemorrhage. Stroke. 2020;51:121–128.

Spontaneous intracerebral hemorrhage (ICH) remains a major cause of morbidity and mortality worldwide. Hematoma expansion affects 30-40% of patients with acute ICH within the first few hours of onset; hence, its prevention is an important treatment target in acute ICH care to prevent neurological worsening and poor long-term outcome, thus necessitating more close neurological monitoring. Although the presence of spot sign in Computed Tomography (CT) angiography predicts hematoma expansion, only a minority of ICH patients receives contrast injection during the initial imaging. Since non-contrast CT (NCCT) is widely available and used, NCCT markers represent an important alternative for prediction of hematoma expansion. 

NCCT signs can be divided into density markers (swirl sign, blend sign, black hole sign, hypodensity and fluid level) and shape markers (irregular shape, island sign and satellite sign).

Various observational studies, RCT populations and meta-analyses have suggested that NCCT signs markers might be reliable predictors of hematoma expansion and poor outcome in ICH, but with different effect size and strength of association.

Antiplatelet Therapy and Functional Outcomes After ICH

Lina Palaiodimou, MD

Murthy SB, Biffi A, Falcone GJ, Sansing LH, Torres Lopez V, Navi BB, et al. Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage and Functional Outcomes. Stroke. 2019

Initiation of antithrombotic therapy (antiplatelet or anticoagulant) after intracerebral hemorrhage (ICH) has long been a matter of conflict among clinicians dealing with stroke patients. Given that the treatment of ICH in the acute phase is mostly supportive, one can understand the anxiety of the clinicians who want to prevent an ICH recurrence. However, according to American Heart Association/American Stroke Association (AHA/ASA) guidelines, the recommendation that “anticoagulation after nonlobar ICH and antiplatelet monotherapy after any ICH might be considered, particularly when there are strong indications for these agents” is not well established (Class IIb) and is based on evidence derived from nonrandomized studies (Level of Evidence B). That is why studies aiming to shed light on this matter are more than welcome from the scientific community of stroke.

The study by Murthy et al. is an attempt to enrich the scarce data regarding the impact of antiplatelet therapy (APT) initiation after ICH on functional outcomes. For that reason, the authors separately analyzed data from 3 large cohort studies [ICH study at Massachusetts General Hospital (MGH), Virtual International Stroke Trials Archive-ICH (VISTA-ICH), ICH database of Yale University School of Medicine], consisting of 1801 ICH patients in total. Inclusion criteria were: diagnosis of primary ICH in CT-scan, age >18 years, and complete follow up at 90 days. Exclusion criteria were: previous history of ICH, secondary cause of ICH, and prior use of anticoagulants.

Cerebral Amyloid Angiopathy and Disruption of the Blood-Brain Barrier

Kara Jo Swafford, MD

Freeze WM, Bacskai BJ, Frosch MP, Jacobs HIL, Backes WH, Greenberg SM, et al. Blood-Brain Barrier Leakage and Microvascular Lesions in Cerebral Amyloid Angiopathy. Stroke. 2019;50:328–335.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid-b (Ab) deposition within walls of small to medium sized arteries, arterioles and capillaries in the cerebral cortex and leptomeninges. It is observed in approximately 33% of the general aged population and 90% of those with Alzheimer’s disease. CAA can lead to cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs), as well as cerebral atrophy, structural network disruption and cognitive decline. In the elderly, CAA is the most common cause of lobar intracerebral hemorrhage.

Freeze et al performed a postmortem study to investigate the role of blood-brain barrier (BBB) disruption in CAA-related brain injury, hypothesizing that BBB leakage is associated with CAA severity and is present predominantly in parietooccipital regions because of CAA’s predilection for affecting blood vessels in these regions. Eleven CAA confirmed cases were compared to 7 controls without neurological disease. BBB disruption was measured by plasma protein (fibrin, IgG) extravasation in the cortex. CAA severity was graded based on presence of Aβ. Microvascular lesions (CMBs, CMIs) were assessed using histopathology and MRI.

Large Analysis Confirms Poor Outcome of Intracerebral Hemorrhage in Patients on Treatment with Antiplatelets and Vitamin K Antagonists

Raffaele Ornello, MD

Sprügel MI, Kuramatsu JB, Gerner ST, Sembill JA, Beuscher VD, Hagen M, et al. Antiplatelet therapy in primary spontaneous and oral anticoagulation–associated intracerebral hemorrhage. Stroke. 2018

The exact effect of antiplatelet therapy (APT) on the characteristics and outcome of intracerebral hemorrhage (ICH) is interesting especially among patients treated with oral anticoagulation (OAC).

The present pooled analysis of two retrospective cohort studies and a prospective single-center study assessed the influence of APT on the characteristics and functional outcome of ICH in patients with primary spontaneous ICH, vitamin K antagonist (VKA)-associated ICH, and non-VKA-OAC (NOAC)-associated ICH. Compared with patients with VKA-associated ICH not under APT, those with VKA-associated ICH under APT had a lower proportion of 3-month favorable outcome, defined as modified Rankin Scale scores 0-3, higher 3-month mortality, and larger hematoma volume; on the other hand, APT did not influence the characteristics and outcome of ICH among patients with primary spontaneous or NOAC-associated ICH.

Combining CT Biomarkers for Prediction of Hematoma Expansion

Lina Palaiodimou, MD

Morotti A, Boulouis G, Charidimou A, Schwab K, Kourkoulis C, Anderson C, et al. Integration of Computed Tomographic Angiography Spot Sign and Noncontrast Computed Tomographic Hypodensities to Predict Hematoma Expansion. Stroke. 2018

Recently, there is increasing interest regarding available therapeutic options that can restrict hematoma expansion after spontaneous intracerebral hemorrhage (ICH) and may contribute to improved functional outcomes. Despite the initial enthusiasm in different therapeutic strategies (tranexamic acid, blood pressure lowering medication, etc.), the efficacy of such an approach has not been validated in the context of a randomized controlled clinical trial.

The question arises, whether these disappointing results would be different, if inclusion criteria were stricter (narrower time window) or based on patient selection using specific biomarkers. One proposed radiological biomarker is the presence of intrahematoma hypodensities (HD), which are defined as any hypodense region inside the hematoma, as seen in a non-contrast computed tomography (NCCT), having any morphology and size, disconnected from surrounding brain parenchyma. Another biomarker is the spot-sign (SS), which can be seen in a CT angiography (CTA) and is defined as presence of at least one focus of contrast, pooling within the hemorrhage and lack of connection with normal or abnormal vessels surrounding the hemorrhage. Both of these biomarkers have been shown to independently predict hematoma expansion in ICH and can be obtained by readily available imaging techniques.

Beware of Nonconvulsive Status Epileptics in Intracerebral Hemorrhage Patients

Mohammad Anadani, MD

Matsubara S, Sato S, Kodama T, Egawa S, Nakamoto H, Toyoda K, et al. Nonconvulsive Status Epilepticus in Acute Intracerebral Hemorrhage. Stroke. 2018

Nonconvulsive status epileptics (NCSE) is one of the known complications of intracerebral hemorrhage (ICH). However, the incidence and predictors of NCSE after ICH are not well reported.

In this article, the authors aimed to report the frequency and predictors of NCSE in the nontraumatic ICH and to investigate the effect of NCSE on the functional outcome.

This study was a retrospective, single-center study of patients with nontraumatic ICH who were admitted within three days of symptoms onset. NCSE was defined based on the modified Salzburg Consensus Criteria. Lobar hemorrhage was defined as ICH in the frontal, parietal, temporal, occipital or insular lobe.

Size of Ruptured Intracranial Aneurysm — Is Epidemiology Really Changing?

Tapan Mehta, MBBS, MPH

Korja M, Kivisaari R, Jahromi BR, Lehto H. Size of Ruptured Intracranial Aneurysms Is Decreasing: Twenty-Year Long Consecutive Series of Hospitalized Patients. Stroke. 2018

Since the 1980s, the epidemiology of cerebrovascular diseases has changed significantly. Primary, secondary and tertiary prevention interventions have advanced with technology, and they are sufficient enough to change the epidemiologic outlook of cerebrovascular diseases. In addition to the advances in medical and surgical interventions, awareness for controlling the vascular risk factors has also increased, including a significant decrease in prevalence of smoking. Understanding epidemiology of intracranial aneurysm has become even more important in today’s era given more and more treatment options are becoming available, which are effective and safe.

Korja et. al present an interesting and novel epidemiologic trend in Finnish population suggesting a decrease in size of ruptured intracranial aneurysms over the past two decades.