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Intracranial hemorrhage detection over time using susceptibility-weighted magnetic resonance imaging Juliane Schelhorn, Carolin Gramsch, Cornelius Deuschl, Harald H Quick, Felix Nensa, Christoph Moenninghoff and Marc Schlamann Acta Radiol published online 25 November 2014 DOI: 10.1177/0284185114559958 The online version of this article can be found at: http://acr.sagepub.com/content/early/2014/11/25/0284185114559958

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Acta Radiol OnlineFirst, published on November 25, 2014 as doi:10.1177/0284185114559958

Original Article

Intracranial hemorrhage detection over time using susceptibility-weighted magnetic resonance imaging

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Juliane Schelhorn1, Carolin Gramsch1, Cornelius Deuschl1, Harald H Quick2,3, Felix Nensa1, Christoph Moenninghoff1 and Marc Schlamann1

Abstract Background: The reliable detection of intracranial hemorrhages is important, but just 1 year after the hemorrhage onset it might be missed using T2-weighted spin-echo and gradient-echo sequences. Susceptibility-weighted imaging (SWI) is a new magnetic resonance imaging sequence that is extremely sensitive in hemorrhage detection and that might improve the detection of hemorrhages over time. Purpose: To investigate whether the detectability of intracranial blood and its degradation products is independent of the time span after intracranial hemorrhage using SWI. Material and Methods: Sixty-six consecutive patients (28 men, 38 women) with definitely known time point of intracranial hemorrhage and available SWI sequence (1.5 or 3 T) were analyzed retrospectively. Twenty-one patients had a SWI follow-up. All SWI images were assessed by two radiologists in consensus regarding hemorrhage visibility using a 5-point scale. Statistical analysis was performed using Spearman’s correlation test. Results: Median time interval between hemorrhage and first available SWI measurement was 819 days (range, 0 days to 13.2 years). Nine of 66 patients had an isolated subarachnoid hemorrhage (iSAH) and were therefore analyzed separately. In eight of these nine patients the hemorrhage could clearly be detected, the remaining one had minor iSAH. Spearman analysis showed no significant correlation between time span and visibility (P ¼ 0.660). In the remaining 57 patients (no iSAH) the hemorrhage was always visible achieving at least 3/5 points on the 5-point scale, and Spearman’s analysis revealed only a weak correlation between time span and visibility (r ¼ 0.493, P < 0.001). Conclusion: The detectability of blood and its degradation products using SWI is reliably possible over a long period after intracranial hemorrhage.

Keywords Intracranial hemorrhage, hemosiderin, susceptibility-weighted imaging (SWI), magnetic resonance imaging (MRI) Date received: 9 September 2014; accepted: 26 October 2014

Introduction The reliable detection of intracranial hemorrhage is crucial not only for correct therapeutic management of patients but also for neuroradiological/neurological medical assessment. In brain-injured patients in particular the detection of even small post-traumatic hemorrhages like microbleeds is important, as it is known that in patients with diffuse axonal injury presenting with microbleeds the white matter damage is more extensive and results in a poorer functional outcome (1). Furthermore, in the chronic condition diffuse axonal

1 Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany 2 Erwin L Hahn Institute for Magnetic Resonance Imaging, Essen, Germany 3 Highfield and Hybrid MR Imaging, University Hospital Essen, Essen, Germany

Corresponding author: Juliane Schelhorn, University Hospital Essen, Department of Diagnostic and Interventional Radiology and Neuroradiology, Hufelandstrasse 55, 45147 Essen, Germany. Email: [email protected]

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injury might be identified solely by the detection of residual microbleeds. Therefore the reliable visualization of microbleeds or hemosiderin is mandatory, even after a long period following trauma. Today magnetic resonance imaging (MRI) is regarded as the most sensitive method for evaluation of the brain, especially in braininjured patients. For the visualization of blood degradation remnants in MRI, the usage of T2-weighted (T2W) spin-echo and gradient-echo sequences has been suggested. However, a loss of detectability of hemosiderin in both sequences has been demonstrated in 10–20% of cases 1 year after trauma (2,3). Between 1997 and 2004 Reichenbach et al. developed susceptibility-weighted imaging (SWI) which is a threedimensional high resolution gradient echo sequence with complete flow compensation (4–6). In contrast to conventional MRI sequences SWI combines both magnitude and phase information. It visualizes phase contrasts caused by local susceptibility differences between adjacent tissues. Hence, due to different susceptibilities of deoxyhemoglobin, hemosiderin, ferritin, and calcium in contrast to the surrounding tissue, SWI is extremely sensitive in detection of hemorrhage and calcification (7–9) leading to a four times more sensitive detection of hemorrhage compared to T2* imaging (10). Numerous publications have dealt with the technical background and diagnostic value of SWI in various neurological diseases and post-traumatic pathologies including neoplasm, multiple sclerosis, dementia, venous anomalies, arteriovenous malformations, and intracranial hemorrhage (7,11–14). However, so far no investigation has focused on the detectability of intracranial blood or its degradation products over time using SWI, which is a major question in medical assessment of brain damage. Hence, the aim of this study was to investigate SWI with regard to its usability in long-term detection of hemorrhage/blood degradation products.

Material and Methods Patients Retrospective analysis and use of patient data were approved by the local ethics committee. By database analysis the radiology reports of all patients who received cranial cross-sectional imaging between January 2008 and February 2013 were analyzed. Keywords used were ‘‘intracerebral hemorrhage’’, ‘‘intracerebral bleeding’’, ‘‘intracerebral hematoma’’, ‘‘subarachnoid hemorrhage’’, ‘‘subarachnoid bleeding’’, and ‘‘subarachnoid hematoma’’. A total of 5745 patients were primarily detected and screened with respect to the inclusion criteria: (i) exactly defined time point of intracranial bleeding (by clinical history

and/or initial cross-sectional imaging [either computed tomography or MRI]); and (ii) available follow-up MRI including SWI. Exclusion criteria were: (i) subdural or epidural hematoma; (ii) previous intracranial bleeding/hemorrhage; and (iii) repetitive intracranial bleeding (between occurrence of the index bleeding and the follow-up MRI including SWI). Finally 66 patients (28 boys/men, 38 girls/women) were enrolled in the study. The mean age at time of hemorrhage was 39.9  20.2 years (range, 2 days to 73.8 years). The intracranial hemorrhage was spontaneous in 48 patients and traumatic/iatrogenic in 18 patients. In three patients with spontaneous hemorrhage an arteriovenous malformation was detected. No hemorrhagic neoplasm was included. In total 38 patients had undergone neurosurgical procedures including an isolated ventricular drainage in 26 patients. The median interval between time point of intracranial bleeding and the first available SWI measurement was 819 days (range, 0 days to 13.2 years, Supplemental material, online only). In 21 patients (2 patients with isolated subarachnoid hemorrhage (iSAH), 19 patients without iSAH) repetitive MR examinations including SWI were available. In these 21 patients the mean time interval between both MR examinations including SWI was 10.2  10.0 months (range, 52 days to 35 months). Pooling all available SWI measurements (including both examinations in patients with repetitive SWI measurements) the median time interval between hemorrhage and available SWI measurement was 607 days (range, 0 days to 13.2 years). MRI including SWI. All MRI scans were performed on several 1.5 T MR systems (Magnetom Aera, Avanto, Espree, Siemens AG, Healthcare Sector, Erlangen, Germany) or on a 3 T MR system (Magnetom Skyra, Siemens AG, Healthcare Sector) using a dedicated head/neck radiofrequency coil. Exemplarily the SWI parameters of the Aera 1.5 T system were: TR, 49 ms; TE, 40 ms; flip angle (FA), 15 ; and slice thickness, 2 mm. The parameters of the SWI sequence of the Skyra 3 T system were: TR, 28 ms; TE, 20 ms; FA, 15 ; and slice thickness, 2 mm. All SWI measurements were retrospectively re-evaluated by two experienced neuroradiologists (>7 years and >13 years of experience). The conspicuity of hemorrhage was graded in consensus using a 5-point scale: 1, not visible hemorrhage; 2, poorly visible hemorrhage; 3, moderately visible hemorrhage; 4, well visible hemorrhage; and 5, excellently visible hemorrhage.

Statistical analysis For statistical analysis SPSS software package was utilized (version 19.0, IBM, Armonk, NY, USA).

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Normal distribution of the investigated parameters was tested by Kolmogorov-Smirnov test. In normally distributed data mean values and standard deviations, otherwise medians were calculated. For statistical analysis all available SWI measurements were pooled considering the available SWI follow-ups in 21 patients as separate measurements. Patients with iSAH were analyzed separately, because of the possible cleaning effect of circulating cerebrospinal fluid. Correlation between hemorrhage conspicuity and time span after hemorrhage was analyzed by Spearman’s correlation analysis.

in the follow-up MRI including SWI (Table 1). Hemorrhage visibility was rated in all 57 patients with at least 3 out of 5 points (Figs 1–3). In the patient with the longest time interval between hemorrhage occurrence and SWI measurement (13.5 years) the visibility was rated with 4 out of 5 points. Spearman’s correlation analysis of all pooled SWI measurements (n ¼ 57 þ 19 ¼ 76) revealed a low correlation between conspicuity (5-point scale) and time span after hemorrhage (r ¼ 0.493, P < 0.001).

Patients with iSAH Results Patients without iSAH Using SWI, in all 57 patients without iSAH the hemorrhage was detected both in the first and if available

Nine patients presented with an iSAH. In all but one visibility of the iSAH/blood degradation products was rated with at least 2 out of 5 points on the 5-point scale of conspicuity. The remaining patient without detectable bleeding in the follow-up MRI had minor iSAH

Table 1. Visibility of intracranial hemorrhages using SWI classified by means of a 5-point scale.

iSAH (n ¼ 11) No iSAH (n ¼ 76)

1: Not visible

2: Poorly visible

3: Moderately visible

4: Well visible

5: Excellently visible

1/11 0/76

2/11 0/76

2/11 7/76

2/11 7/76

4/11 62/76

Date of all 66 patients are presented including both the first and if available the follow-up SWI. iSAH, isolated subarachnoid hemorrhage; No iSAH, intracranial hemorrhage other than iSAH.

Fig. 1. A 35-year-old woman with left temporoparietal intracerebral hemorrhage caused by thrombosis of sinus transversus and sigmoideus, the bleeding was surgically evacuated on the day of onset. (a) First SWI measurement 21 days after onset, respectively operation (1.5 T): the typical hypointensive rim is seen (5 points on the 5-point visibility scale) (arrow); (b) SWI follow-up 3 months after onset (3 T): the core presents shrunken whereas the hypointensive rim has persisted (5 points on the 5-point visibility scale) (arrow).

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Fig. 2. A 41-year-old woman with right postcentral intracerebral hemorrhage of unknown genesis. (a) Primary SWI measurement on the day of onset (1.5 T): typical hypointensive rim and edema (5 points on the 5-point visibility scale) (arrow); (b) SWI follow-up 27.5 months later (3 T): the core is no longer detectable but the typical adjacent hypointensive rim has persisted allowing persistent detectability (4 points on the 5-point visibility scale) (arrow).

Fig. 3. Bar chart of the patients without an iSAH plotting the conspicuity of hemorrhage (5-point scale) versus the time span after hemorrhage.

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Fig. 4. A 61-year-old woman with a tiny iSAH. (a) Primary SWI measurement 1 day after occurrence (1.5 T): little hypointensive material is present in the subarachnoid space adjacent to the right cerebellar hemisphere (5 points on the 5-point visibility scale) (arrow); (b) SWI follow-up 2.5 months later (1.5 T): no visible traces of the previous iSAH were detected (1 point on the 5-point visibility scale).

with extremely circumscribed hemorrhage (Figs 4 and 5, Table 1). Spearman’s correlation analysis of all pooled SWI measurements (n ¼ 9 þ 2 ¼ 11) revealed no significant correlation between hemorrhage conspicuity and time span after hemorrhage (r ¼ –0.150, P ¼ 0.660).

Discussion A parenchymal hemorrhage is defined as blood extravasation into the surrounding tissue, which immediately starts to degrade. First, oxyhemoglobin (diamagnetic) converts into deoxyhemoglobin (paramagnetic) by oxygen release. After about 3 days the blood clot (paramagnetic) shrinks and deoxyhemoglobin transforms into initially still intracellular methemoglobin (15). Consecutively, due to lysis of erythrocytes the methemoglobin is released into the extracellular space and after months the hematoma finally is cleared away by macrophages that break down methemoglobin intracellularly into hemosiderin (paramagnetic) and store it (16–18). Initially owing to a breakdown of the blood–brain barrier these macrophages can migrate. But in the course of time the blood-brain barrier restores and impedes further macrophage migration resulting in stationary hemosiderin storing macrophages. According to Oehmichen et al. the hemosiderin increasingly mineralizes, persists over years, and is detectable up to 44 years after traumatic cortical hemorrhages in autopsies (18).

Using spin-echo T1-weighted, spin-echo T2W, and gradient-echo T2W sequences an acute or subacute parenchymal hemorrhage is reliably detectable. Additionally the age of the hemorrhage can mostly be estimated due to the successive blood degradation resulting in different degradation products with specific signals in MRI sequences (15). In contrast to intraparenchymatous bleedings in SAHs the blood leaks into the subarachnoid space with circulating cerebrospinal fluid. Hence, blood spreads in the adjacent subarachnoid space compounding the detection of subarachnoid hemorrhages by T2w and EPI sequences (19). Due to the protein content of blood, acute subarachnoid bleedings can be detected by fluid attenuated inversion recovery (FLAIR) and proton density (PD) sequences (19). A chronic SAH can present as superficial siderosis and normally T2W and T2*W imaging is recommended for its detection (20–22). Our data suggest a low correlation between hemorrhage visibility and time span after hemorrhage in patients with parenchymatous intracerebral hemorrhages. However, in most cases with long time span after hemorrhage the hemorrhage visibility was excellent or at least good using SWI. Though, the time spans after hemorrhage were not normally distributed and had a predominance of short time spans. Moreover, in cases with iSAH no correlation between hemorrhage visibility and timespan was

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Fig. 5. Bar chart of the patients with iSAH plotting the conspicuity of hemorrhage (5-point scale) versus the time span after hemorrhage.

found. In summary, we interpret the current results as a strong indicator for the persistent good detectability of hemorrhage remnants over time using SWI. These results are concordant with the known pathophysiological changes in parenchymal hemorrhages in which after sequential degradation hemosiderin results and persists stationary for a long time (18). And due to the susceptibility differences of this stationary paramagnetic hemosiderin to the surrounding tissue, the remnants of hemorrhage are detectable for a long time interval by SWI. Inoue et al. demonstrated that subarachnoid hemorrhages can confidently be detected up to 16 years after onset by use of gradient recalled echo and echo planar T2*W imaging as well (20). However, in contrast to conventional MR sequences such as T2W or T2*W imaging SWI additionally gathers phase information to enhance the contrast between tissues with different susceptibilities (6). Because an existing phase difference does not necessarily lead to a T2* effect, SWI is even more sensitive than T2*W imaging (7) and it is conclusive that hemorrhage detection using SWI is even more reliable in the course of time as our results suggest. The study is not without limitations. First, this was a retrospective study and the recruitment based solely on database analysis of radiology reports and clinical history. To compensate this fact, all SWI images were reanalyzed for this study. Second, the number of

included patients was small, caused by the very strict inclusion criteria. Third, patients with a short period after hemorrhage were over-represented. In addition, different MR scanners with different field strengths have been utilized. As increasing field strength leads to higher sensitivity for susceptibility artifacts the detectability of hemosiderin using 3T or even 7 T scanners is increased (23). In the current study the 1.5 T and 3 T scanners were used both for the initial and subsequent MR examination, hence, we believe the use of both field strengths did not distinctly confound our findings. In conclusion, the results of this study show that hemosiderin is detectable over a long period of time following intracranial hemorrhage using SWI. This is of high importance in neuroradiological medical assessment. Therefore, the use of SWI as inherent part of the MRI protocol of the brain, especially in brain injured patients or patients with previous or suspected intracranial hemorrhage, is highly recommended. Conflict of interest None declared.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Intracranial hemorrhage detection over time using susceptibility-weighted magnetic resonance imaging.

The reliable detection of intracranial hemorrhages is important, but just 1 year after the hemorrhage onset it might be missed using T2-weighted spin-...
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