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
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
PHE. 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 r
PHE as observed by others.10
Further, we found an association between longer admission PTT and greater r
PHE 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 r
PHE measured on CT.21
In our study we could not find a strong association between elevated platelet counts and r
PHE, 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 r
PHE 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
PHE 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
In another study12
higher 24 hour r
PHE 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 r
PHE 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.