Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

Abstract

Acute intracerebral hemorrhage (ICH) is a devastating type of stroke worldwide. Neuronal destruction involved in the brain damage process caused by ICH includes a primary injury formed by the mass effect of the hematoma and a secondary injury induced by the degradation products of a blood clot. Additionally, factors in the coagulation cascade and complement activation process also contribute to secondary brain injury by promoting the disruption of the blood-brain barrier and neuronal cell degeneration by enhancing the inflammatory response, oxidative stress, etc. Although treatment options for direct damage are limited, various strategies have been proposed to treat secondary injury post-ICH. Perihematomal edema (PHE) is a potential surrogate marker for secondary injury and may contribute to poor outcomes after ICH. Therefore, it is essential to investigate the underlying pathological mechanism, evolution, and potential therapeutic strategies to treat PHE. Here, we review the pathophysiology and imaging characteristics of PHE at different stages after acute ICH. As illustrated in preclinical and clinical studies, we discussed the merits and limitations of varying PHE quantification protocols, including absolute PHE volume, relative PHE volume, and extension distance calculated with images and other techniques. Importantly, this review summarizes the factors that affect PHE by focusing on traditional variables, the cerebral venous drainage system, and the brain lymphatic drainage system. Finally, to facilitate translational research, we analyze why the relationship between PHE and the functional outcome of ICH is currently controversial. We also emphasize promising therapeutic approaches that modulate multiple targets to alleviate PHE and promote neurologic recovery after acute ICH.

Figure 1

The imaging characteristics of PHE at different stages after ICH. (a) Cranial CT images on days 1, 2, 4, and 7 after acute ICH in a patient. PHE (a rim around the hematoma indicated by yellow arrows) was not prominent on day 1 after ICH and gradually increased from days 1 to 7 after ICH. (b) MRI characteristics of PHE at 8 hours, 27 hours, day 4, and day 10, respectively, after the onset of symptoms in 4 patients with ICH. The red arrows in the T1WI images indicate the location of the hematoma. The signal characteristics of the hematomas changed over time in the T1WI and T2WI images after ICH, with PHE presented as a thin or wide rim with a strong signal in the T2WI and FLAIR images in the areas surrounding the hematoma. A strong signal on the DWI image but a weak signal on the ADC map appeared in the perihematomal area 8 hours after ICH. It may represent the appearance of ionic edema or cytotoxic edema in the perihematomal area. However, typical imaging characteristics of vasogenic edema in the perihematomal region were observed at 27 hours, day 4, and day 10 after the onset of the symptom. Vasogenic edema presented as a normal signal on the DWI images, and a strong signal surrounds the hematoma on the ADC map at 27 hours, day 4, and day 10 after ICH in 3 patients. Abbreviations: CT: computed tomography; PHE: perihematomal edema; ICH: intracerebral hemorrhage; T1WI: T1-weighted MRI; T2WI: T2-weighted MRI; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ADC: apparent diffusion coefficient.

Figure 2

Impairment in brain lymphatic drainage and the formation of cerebral edema. The meningeal lymphatic system constitutes the brain lymphatic drainage system in the dorsal part of the skull and the glymphatic system (a glia-dependent system of the perivascular space) present in the brain parenchyma. The meningeal lymphatics are involved in maintaining homeostasis and immune surveillance in the brain. The glymphatic system provides a pathway to remove interstitial solutes and wastes in the brain parenchyma. It is also a bidirectional exchange pathway between ISF and CSF. However, the meningeal lymphatic system may only function as a drainage pathway. The brain lymphatic drainage system is a crucial drainage route for ISF/CSF into the cervical lymph nodes (CLNs) or peripheral blood. Brain injury may alter the drainage function of the meningeal lymphatic system and glymphatic system and subsequently aggravate brain edema after ischemic stroke, subarachnoid hemorrhage, TBI, etc. High ICP may reduce the flow of the lymphatic system from the ISF/CSF to the CLN or the venous sinus. Impairment in the glia-dependent system of the perivascular space, especially dislocation of AQP4 in the endfeet of the astrocyte of the glymphatic system, can lead to an increase in ISF/CSF influx to the brain parenchyma with a decrease in efflux from the brain parenchyma to ISF/CSF or CLN/blood. Reduction in the function of the lymphatic and glymphatic systems can also lead to a decrease in waste clearance and an increase in immunocyte accumulation in the injured brain. Although animal studies have indicated that brain lymphatic drainage dysfunction may facilitate the formation of brain edema after ICH, no studies have explored its relationship in patients with ICH. Abbreviations: CSF: cerebrospinal fluid; ISF: interstitial fluid; CLNs: cervical lymph nodes; TBI: traumatic brain injury; ICP: intracranial pressure; AQP4: aquaporin 4; ICH: intracerebral hemorrhage.

Figure 3

The evolution of PHE and its potential therapeutic targets. Clot retraction, activation of thrombin in the coagulation cascade, and toxicity of RBC degradation products can contribute to PHE formation after acute ICH. Furthermore, abnormal electrolyte and water transport and thrombin and RBC lysis-induced inflammatory and oxidative stress responses are critical in the formation of PHE. PHE can be classified as ionic (cytotoxic) and vasogenic edema according to the mechanisms and imaging characteristics. Although various variables, including cerebral venous drainage and the glymphatic system, can affect the severity of PHE, more accurate methods for quantifying PHE should be developed. PHE can aggravate the severity of brain injury, but the relationship between PHE and functional outcomes after ICH was conflicting. Strategies to alleviate PHE warrant further exploration by targeting ICP, thrombin, lysis of the RBC, inflammation, controlling blood pressure, reducing hematoma volume, etc. Abbreviations: PHE: perihematomal edema; RBC: red blood cell; MMPs: matrix metallopeptidases; AQP4: aquaporin 4; BBB: blood-brain barrier; ICP: intracranial pressure.