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Knowledge on natural history and clinical impact of perihematomal edema (PHE) associated with intracerebral hemorrhage (ICH) is limited. We aimed to define the time course, predictors and clinical significance of PHE measured by serial MR imaging.
Patients with primary supratentorial ICH of ≥ 5cc underwent serial MRIs at pre-specified intervals during the first month. Hematoma (Hv) and PHE (Ev) volumes were measured on FLAIR. Relative PHE (rPHE) was defined as Ev/Hv. Neurological assessments were performed at admission and with each MRI. Barthel Index, modified Rankin and extended Glasgow outcome scales were done at 3 months.
Twenty-seven patients with 88 MRIs were prospectively included. Median Hv and Ev on the first MRI were 39 and 46cc. Median peak absolute Ev was 88cc. Larger hematomas produced larger absolute Ev (r2=0.6) and smaller rPHE (r2 =0.7). Edema volume growth was fastest in the first two days, but continued until 12±3 days. In multivariate analysis, a higher admission hematocrit was associated with a greater delay in peak PHE (p=0.06). Higher admission PTT was associated with higher peak rPHE (p=0.02). Edema volume growth correlated with a decline in neurologic status at 48 hours (81 Vs 43cc, p=0.03), but not with 3-month functional outcome.
Perihematomal edema volume measured by MRI increases most rapidly in the first two days after symptom onset and peaks towards the end of the 2nd week. The timing and magnitude of PHE volume is associated with hematological factors. Its clinical significance deserves further study.
Intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality.1 In addition to hematoma-induced direct tissue injury, thrombin and iron from hemoglobin breakdown leads to inflammation and neurotoxicity in the perihematomal tissue with blood brain barrier (BBB) injury and perihematomal edema (PHE) formation. 2, 3 Perihematomal edema worsens mass effect and tissue shifts and may contribute to further tissue injury and poor outcome.4
In contrast to edema after ischemic stroke5, peak PHE volume has been reported to occur at 1-5 days by some and in the 1st or 3rd week by others. 4, 6-10 Hematoma volume, coagulation factors, statins and hyperglycemia have been proposed to influence PHE volume.10, 11 However, the impact of PHE volume on functional outcome remains uncertain.4, 6, 9, 12, 13 Preliminary clinical studies are exploring neuroprotective strategies to attenuate perihematomal injury and edema formation based on the assumption that PHE influences ICH outcome.3, 14 In order to interpret the effects of such interventions, full understanding of the natural history and clinical significance of PHE is needed.15
In this prospective study, we aimed to define the natural history, associated factors and the clinical impact of PHE using serial magnetic resonance imaging (MRI) during the first month following spontaneous ICH. We hypothesized that the natural history of PHE formation in ICH differs from that after ischemic stroke and that PHE adversely affects neurological status and functional outcome.
The study was approved by our hospital's institutional review board. Consecutive men and non-pregnant women >18 years with a primary supratentorial ICH of ≥5cc and <100cc with symptom onset < 24 hours prior to admission and a Glasgow Coma Scale score (GCS) of ≥ 6 were included after obtaining informed consent from the patient or their surrogate. Exclusion criteria were: inability to undergo MRI due to metallic objects or unstable medical condition, ICH due to underlying structural lesion or coagulopathy, systemic disease with limited life expectancy, surgical or stereotactic hematoma evacuation/thrombolysis, recombinant Factor VIIa therapy, and intraventricular hemorrhage (IVH) with a Graeb score of ≥ 8.
Demographic and clinical data was prospectively collected (Table 1). Laboratory data included complete blood count (CBC), comprehensive metabolic panel, coagulation studies and urine toxicology. At admission, blood pressure (BP), temperature, GCS and pre-admission mRS were recorded. NIHSS was obtained at admission, 24, 48 and 72 hours, 1, 2 and 3 weeks (or on the last hospital day) and with each MRI. ICH management adhered to contemporaneous AHA guidelines with antihypertensives to keep mean arterial pressure (MAP) ≤130 mm Hg. Two patients had ventriculostomy for IVH for less than a week. Twenty-one (78%) patients received osmotic therapy. No patient received corticosteroids. Functional outcome was determined at 3 months using Barthel Index (BI), extended Glasgow Outcome Scale (eGOS) and mRS either by telephone interview or at clinic follow-up. If patients died earlier than 3 months, their last known scores were used.
All patients had non-contrast head CT at admission and selected patients had a CT angiogram or catheter angiogram. MR imaging was done on a 1.5 Tesla GE Signa Horizon NV/i scanner (EXCITE III) equipped with cardiac-enhanced gradients (40 mT/m) at 48±12 hours, 7±1 day, 14±2 days and when feasible, at 21±3 days. MRI's had the following sequences: T1 localizer, axial T2, Gradient Recall Echo (GRE) (TR/TE=550/30 msec, 24 contiguous sections, 256×256 matrix, field of view (FOV) 24 cm, 5/1.5mm slice thickness/gap), Spin Echo Echo-Planar Imaging Diffusion Weighted Imaging (DWI) (256×256 acquisition matrix, 24 cm FOV, 5/1.5mm slice thickness/gap, 20-23 contiguous sections, X, Y, Z axes averaged, b=0 and 1000 sec/mm2, TR/TE=6000/72 msec), Fast Spin Echo Fluid Attenuated Inversion Recovery imaging (FSE-FLAIR) (TR/TE =8802/120 msec, 24 contiguous sections, 512×512 matrix, FOV 24 cm, slice thickness/gap=5/1.5mm) and 3D time of flight MRA.
Hematoma volume (Hv) was measured on the admission CT using ABC/2 method and also on FLAIR sequence of the first MRI. Perihematomal edema volume (Ev) was measured on FLAIR sequence of consecutive MRIs (Figure 1).11, 15 Measurements were independently done by two investigators using in-house developed software (UCLA/Stanford Stroke Centers Image Processing Program). The hematoma was manually outlined on the FLAIR slices of the first MRI. Hematoma volume was then automatically calculated for each slice from the measured area and corresponding slice thickness. The Hv from all such slices was added to give baseline total Hv. Similarly, the total lesion area (PHE + hematoma) was manually outlined on the FLAIR slices and the total lesion volume (Ev + Hv) was calculated. The difference between the total lesion volume and baseline Hv was considered the Ev at that time point. For all subsequent time points, baseline Hv was used when deriving the Ev (e.g. Ev at 7 days = total lesion volume at 7days – Hv on the first MRI). Relative PHE (rPHE) was defined as Ev/Hv.12
Edema volume at ICH onset was assumed to be zero cc. Inter- and intra-rater reliability for volume measurements were determined using the intraclass correlation coefficient (ICC). The association of the following factors (age, gender, HTN, diabetes mellitus, antiplatelet use, admission BP, temperature, CBC, PTT, INR and glucose, osmotic therapy, ICH location, presence or absence of IVH, Hv and time to initial MRI) with the timing of peak Ev, the magnitude of early (< 48 hour) rPHE and peak rPHE was determined. Categorical variables were compared using χ2 and Fisher exact tests and continuous variables with Mann-Whitney U test. Multivariate analysis was done using backward stepwise method with p < 0.2 on univariate analysis as a predictor inclusion criterion. Patients were also divided into groups based on 48 hour and peak rPHE values using receiver operating analysis (ROC) curves: rPHE of < 1.2 Vs ≥ 1.2 at 48 hours and < 2 Vs ≥ 2 at peak. These groups were used to determine if rPHE influenced neurological and functional outcome, using Mann-Whitney U test (NIHSS), Kruskal-Wallis (eGOS, mRs) and correlation co-efficient using linear regression analysis (BI). Neurological deterioration was defined as an increase in NIHSS of ≥ 2 points. Data analyses were performed using the SPSS 17.0 software package (SPSS, Chicago, IL.)
Twenty-seven patients were prospectively enrolled and their data are shown in Table 1. 88 MRIs were obtained; five patients had two MRIs, ten patients had three MRIs and twelve patients had four MRIs at a mean time of 35±26 hours, 7.7±2.2 days, 14.9±3.5 days and 22.3±2.7 days. ICC for Hv and Ev measurements was 0.98 (95% CI 0.95-0.99) and 0.96 (95% CI 0.88-0.99), respectively. There was a strong correlation between ICH volume measured on the admission CT and the first MRI in patients that had these scans done ≤ 24 hours apart (n=15, r2 = 0.93). Hematoma expansion was ruled out in the nine patients who had initial MRI < 20 hours from symptom onset by checking Hv on a follow-up CT done at or beyond the time of anticipated hematoma expansion. Median Hv and Ev measured on the FLAIR sequence of the initial MRI was 39cc (IQR 17, 61) and 46cc (IQR 29, 72), with a median rPHE of 1.28 (IQR 0.93, 1.77).
Patients who had three or more MRI's are included in this analysis (n=22). In 17 patients, a true peak Ev was determined and in the others, the time of the last MRI was assumed as time of peak Ev, as the PHE growth curve had flattened by this point. Edema growth was fastest in the first 48 hours, and continued up to a mean of 12±3 days (range 6-18 days) (Figure 2). Median peak Ev was 88cc (IQR 57,107; range 17 – 130cc) and median rPHE was 1.99 (IQR 1.38, 3.05; range 115% - 654%)
In univariate analysis, later occurrence of peak PHE was associated with male sex (p=0.02) and higher hematocrit (p=0.04) whereas higher admission MAP (p=0.17), lower platelet count (p=0.17), and higher INR (p=0.12) showed a trend. The presence of IVH was associated with an earlier peak (p=0.01). Hematoma volume was not associated with timing of peak PHE (p=0.29). In multivariate analysis, a higher admission hematocrit showed a trend towards a delayed time to peak PHE (p=0.06) and so did the interaction between baseline hematocrit and male sex (p=0.01).
Baseline Hv was tightly correlated with Ev at all time points, with the strongest correlation (r2=0.5, 0.6) at 48 hours and 3-7 days respectively (Figure 3). Larger hematomas produced larger edema volumes; however, smaller hematomas produced relatively more edema than larger hematomas (Figure 3). Larger hematomas also had greater variability in Ev in the first 48 hours whereas smaller hematomas had greater variability in Ev between 8-14 days.
In univariate analysis, female sex (p=0.01), smaller Hv (p=0.01), and higher admission PTT (p= 0.04) were associated with higher rPHE at 48 hours, whereas lower hematocrit (p=0.13) and higher platelet count (p=0.12) showed a trend. Only higher admission PTT remained an independent predictor (p=0.03) (Table 2).
In univariate analysis, patients who had rPHE ≥ 2 at peak had smaller Hv (p=0.01), higher rPHE at baseline (p=0.005) and a higher admission PTT (p=0.003) than those with peak rPHE < 2 (Table 3). Higher admission platelet count (p=0.14) and INR (p=0.10) exhibited a trend towards higher peak rPHE. Again, higher PTT (p=0.02) remained an independent predictor for peak rPHE.
Patients with an increase in NIHSS by ≥ 2 at 48 hours had higher absolute Ev compared to those with unchanged or improved NIHSS (mean Ev= 81 Vs 43cc, p=0.03). No such difference was noted when rPHE at 48 hours was used (1.73 Vs 1.56, p=0.2). Patients who had a larger absolute edema volume growth between admission and peak did not have a worse outcome as measured by NIHSS (p=0.68), nor did those with a larger relative edema increase (p=0.49). A larger increase in rPHE (p=0.17) or absolute Ev between the first MRI and peak was also not associated with worsening on NIHSS (p=0.14), eGOS (p=0.52), mRS (p=0.89) or BI (p=0.79 r=0.06). Lastly, a higher peak rPHE was not associated with a worse three month functional outcome on mRS (p=0.8), BI (p=0.7) or eGOS (p=0.49) (Table 3).
Perihematomal edema after ICH as measured by serial MRI is progressive and reaches its maximum volume on average at 12 days after onset with the fastest growth in the first 48 hours. Edema volumes in our study were quite robust with a median of 88cc and exceeded the hematoma volume by 100-600%.9, 11
Our results indicate that the time course of edema formation after ICH is different from that of ischemic stroke.5 It also differs from that of ICH in rodent models14 probably due to the paucity of white matter, the major repository for PHE in humans.16, 17 Human studies of PHE using CT have reported peak PHE volume to occur anywhere between five days and 3-4 weeks after ICH onset.6-9, 18 Volumetric measurement of PHE volume by CT is suboptimal due to the progressive loss in definition and demarcation of the PHE over time.18 The T2 and FLAIR sequences on MRI overcome this difficulty.11, 15 Zazulia et al 6 used midline shift on CT as a surrogate marker for PHE induced mass effect after ICH. In their study, at least in a few patients, PHE progressed into the 2nd week but they were unable to determine the actual growth trajectory of PHE since their patients had only two CT scans. We are aware of one study9 of seven patients with deep ICH using sequential proton density MRI that showed PHE volume was increased at two weeks and was back to baseline at week four.
We found that higher admission hematocrit was associated with a later time-point of peak PHE volume and that the presence of IVH shortened this time. Iron from erythrocyte breakdown is thought to incite perihematomal tissue injury and edema formation.2, 3, 14 Hematocrit is the proportion of blood volume occupied by erythrocytes and is generally higher in males. A higher hematocrit may lead to exposure of the brain to a higher “dose” of erythrocyte degradation products over time, which may account for the greater delay in peak PHE. Conversely, with IVH, there may be a lower “dose” of erythrocyte degradation products due admixture of CSF and blood potentially explaining the shorter time to peak PHE. In animal models, the duration of PHE formation is proportional to the clot size. We did not find this effect in our study population. Baseline Hv had the strongest influence on both absolute Ev11 and rPHE. Larger hematomas produce larger edema volumes but have relatively less edema than smaller hematomas. Again this may be explained by the larger “dose” of erythrocyte degradation products from larger hematomas leading to higher absolute Ev. However, as most of the parenchyma/hematoma interaction takes place at the hematoma surface, smaller hematomas which have a larger surface area/volume ratio may form more rPHE as observed by others.10
Further, we found an association between longer admission PTT and greater rPHE at 48 hours and at the time of peak edema. Similar to traumatic brain injury (TBI), it has been postulated that in ICH the presence of a low grade consumptive coagulopathy from massive release of procoagulant tissue factor leads to higher platelet counts but dysfunctional platelets and a prolonged PTT.10, 19, 20 In addition, it has been speculated that tissue factor induced platelet activation leads to vascular endothelial growth factor release with increased vascular permeability and cerebral edema. 10, 20 Gebel et al., indeed found that elevated platelet counts were associated (albeit weakly) with a higher 24 hour rPHE measured on CT.21 In our study we could not find a strong association between elevated platelet counts and rPHE, although there was a trend towards increased PHE on the univariate analysis.
Finally, we found a significant association between worsening of NIHSS in patients with larger absolute Ev at 48 hours, which is most likely explained by the increased mass effect and tissue shifts from the steep trajectory of PHE growth during this time period.
We did not find any adverse impact of either a larger increase in admission- peak edema, first MRI- peak edema or peak rPHE on three month functional outcome. Our dataset may be underpowered to detect such association which deserves further study. In addition, functional outcome is driven to a major extent by the hematoma volume itself. Indeed, in the INTERACT study, larger Ev and rPHE growth in the first 72 hours after ICH were associated with poor functional outcome but this association ceased to be significant when adjusted for baseline Hv.22 In another study12 higher 24 hour rPHE values predicted good 12 week functional outcome. Preliminary studies that have explored the clinical significance of delayed PHE (i.e. beyond one week) have also failed to show an association with clinical deterioration.6, 9 The conflicting findings between the clinical impact of early and late PHE may be explained by the underlying tissue reaction in the perihematomal area at different time points. Hyperacute PHE (< 24 hours) is thought to be due to clot retraction and therefore more effective hemostasis, leading to higher rPHE and better outcome.12 At 24-72 hours, erythrocyte degradation products begin to play a role in neurotoxicity leading to higher Ev and neurological worsening. Conversely, delayed PHE may be a reflection of an immature BBB during tissue healing and may not be detrimental clinically.
It should be kept in mind that the T2 signal that we measure on MRI and interpret as vasogenic edema, may in fact not all represent increased water content in the perihematomal tissue. Some of the signal changes may be caused by cell injury that may not necessarily correlate with blood-brain barrier injury and edema itself. Determination of the diffusivity characteristics in the perihematomal region at various time points rather than just measuring edema volumes may provide further insight.
The strengths of this study include its prospective character, inclusion of a fairly typical population of patients with primary ICH (including deep and superficial hematomas), edema measurements by MRI, and the large number of observations per patient. An important weakness is that the number of patients provides only limited power for multivariate analyses.
Furthermore, the hematoma's FLAIR signal characteristics change from hypo or iso-intense to hyper-intense beyond one week, preventing accurate determination of Hv at later time points due to blurring of the boundary between the hyper-intense hematoma periphery and the hyper-intense PHE. Therefore, we used the Hv from the first MRI for all Ev calculations recognizing that we may have underestimated edema volume at later time points to some extent.
Perihematomal edema as measured by MRI rapidly increases in the first 48 hours after ICH onset and peaks towards the end of the 2nd week. Hematoma volume is the major determinant of PHE volume; however, smaller hematomas have relatively more edema. Variability among patients in timing and volume of PHE is associated with hematological factors including hematocrit and PTT. Absolute edema volume growth in the first 48 hours after ICH onset is associated with neurological worsening. However, the clinical significance of early versus delayed PHE appears to be different and deserves further exploration in larger datasets.
The authors would like to thank Beth Hoyte and Didem Aksoy for their assistance in preparation of the figures included in this manuscript.
2. Dr. Wijman received funding for this research from the NIH, grant 2R01: NS034866-08 and from PDL Biopharma.
Disclosures: 1. Dr. Venkatasubramanian received support for this research from the Neurocritical Care Society fellowship award in Cerebrovascular Diseases and Neurotrauma 2006-2008.
Chitra Venkatasubramanian, Clinical Assistant Professor, Neurology and Neurological Sciences, Stanford University, CA.
Michael Mlynash, Stanford Stroke Center, Stanford University.
Anna Finley-Caulfield, Clinical Assistant Professor, Neurology and Neurological Sciences, Stanford University.
Irina Eyngorn, Stanford Stroke Center, Stanford University.
Rajalakshmi Kalimuthu, Stanford Stroke Center.
Ryan W. Snider, Stanford Stroke Center, Stanford University.
Christine Anne Wijman, Associate Professor of Neurology and Neurological Sciences, Stanford University.