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*Read only for medical professionals as a common clinical phenomenon, but do you really understand it? Intracerebral hemorrhage is a common clinical disease, prone to perihematomal edema (perihematomaledema, PHE)
.
Severe PHE can cause significant mass effect and lead to severe intracranial hypertension, increasing the risk of death in patients
.
Hematoma evacuation has been proven to be an effective measure for the treatment of PHE
.
The MISTIEII trial showed that minimally invasive surgery combined with tissue plasminogen activator can effectively reduce the volume of PHE
.
Furthermore, continuous infusion of hypertonic saline has been identified as a safe approach to control PHE progression in the early stages of ICH and it does not appear to affect the blood-brain barrier (BBB)
.
It is particularly important for neurologists to understand the time course and mechanism of PHE growth in intracerebral hemorrhage
.
Case data A 49-year-old female patient was admitted to the hospital because of "sudden headache, left limb weakness, and slurred speech for 3 hours"
.
▌ The patient with the history of the present illness had a sudden headache after getting up 3 hours ago (6:00 in the morning) to do farm work
.
Immediately, left limb weakness and slurred speech appeared, which gradually worsened to the point that the lower limbs could not stand and walk, and the left upper limbs were difficult to hold and lift
.
Associated with decreased mental state, decreased responsiveness, and increased sleep
.
With a history of hypertension for 5 years, the highest blood pressure measured was 180/? mmHg, taking amlodipine besylate regularly (Anezhen 5mg qd), the blood pressure control is unknown
.
Denied other medical history
.
Denies smoking and drinking
.
Denied family history of hereditary disease
.
▌ Physical examination on admission: T: 36.
6℃; P: 65 times/min; R: 19 times/min; BP: 169/90mmHg; cardiopulmonary and abdominal examinations were negative
.
▌ Neurological examination: lethargy, slurred speech, uncooperative cognitive examination
.
Left isotropic hemianopia, bilateral pupils of equal size and circle, and sensitive to light
.
The bilateral forehead lines are symmetrical, and the left nasolabial fold becomes shallower, showing that the angle of the mouth is skewed to the right
.
The articulation was unclear, and the rest of the cranial nerves were uncooperative
.
Left limb pain and touch decreased
.
The muscle strength of the right limb was grade 5, the muscle strength of the left limb was grade 3, and the muscle tension was moderate
.
Bilateral tendon reflexes are present symmetrically
.
Left Babinski sign (+)
.
Slight neck resistance, bilateral Kernig sign (-)
.
GCS (E3+V3+M6) 12 points
.
Figure 1.
Emergency craniocerebral CT showed right putamen hemorrhage 3 hours after the onset of the disease, the amount of bleeding (V)=1.
787×4.
635×2.
5/2≈10ml▌ The admission blood routine white blood cells were 19.
30*109/L, and the percentage of neutrophils was 76.
4%; Blood biochemistry: alanine aminotransferase 66IU/L, serum potassium 2.
7mmol/L, triglyceride 1.
95mmol/L; blood coagulation full set: D-dimer 0.
31mg/L; thyroid function, tumor markers, four items of rheumatism, anti-inflammatory The nuclear antibody spectrum was unremarkable
.
Chest CT showed hypostatic pneumonia
.
Diagnostic Considerations? How to treat? A middle-aged woman with a history of hypertension, CT scan of the brain showed that the high-density shadow was located in the basal ganglia (putamen), which is a common site of hypertensive intracerebral hemorrhage
.
No history of trauma or surgery
.
Denied the use of antithrombotic drugs
.
Admission blood routine, coagulation test, and vasculitis antibody test showed no abnormality, and head and neck CTA ruled out vascular malformations and aneurysms
.
The etiology of cerebral hemorrhage is considered to be hypertensive
.
Treatment plan: urapidil to control blood pressure, piperacillin tazobactam for anti-infection, omeprazole for stomach protection, oxiracetam to improve brain metabolism, electrolyte supplementation and nutritional support treatment
.
On the second day of admission, dehydration drugs were added: 20% mannitol 125ml q 8h
.
Figure 2.
The patient's hematoma did not expand from 3 hours to 4 days after onset, but the surrounding edema gradually increased
.
Three days after the onset of symptoms, the patient's headache was relieved, and his consciousness returned to a conscious state
.
Antihypertensive drugs were changed to oral administration and neurorehabilitation was initiated
.
On the 9th day of the onset, he complained of pain in the forehead and occiput, which was persistent and severe
.
With nocturnal sleep disturbance and visual hallucinations, occasional unanswered questions, disorientation
.
Figure 3.
Compared with the 4th day of the onset, the hematoma volume of the patient was slightly reduced on the 9th day of the onset, and the surrounding edema was further expanded
.
On the 9th day of onset, albumin 100ml qd + furosemide, 10ml q 12h + 3% hypertonic salt 195ml q 8h were given, and mannitol dehydration was continued before continuing
.
After 4 days, the patient's headache symptoms gradually decreased, the nighttime sleep improved, and the hallucinations were ignored.
.
At the time of discharge (1 month after onset), the patient's speech function recovered, and his memory decreased, and his family members could assist in walking
.
During the 2-month follow-up, the patient could walk independently and take care of himself in daily life
.
Questions The patient was hospitalized for 1 month, the hematoma volume did not expand, and the surrounding edema volume grew significantly
.
In this case, edema around the hematoma was seen within 3 hours of onset, and the peak edema was on the 9th day of onset
.
Although the edema expanded, the patient's neurological deficit symptoms did not worsen, and the prognosis was relatively good at follow-up
.
So, how long is the peak period of edema around the hematoma and how long does it last? What is the mechanism of edema formation around hematoma? PHE is an increase in water content in the brain tissue adjacent to a parenchymal hemorrhage
.
Its development is considered a hallmark of secondary brain injury and is associated with thrombin activation, inflammatory immune responses, BBB disruption, and hemoglobin cytotoxicity after intracerebral hemorrhage
.
PHE can cause significant mass effect and lead to severe intracranial hypertension
.
In experimental models of intracerebral hemorrhage, PHE usually occurs within 2 hours, peaks on day 3, and lasts for 7 days
.
However, the peak period of edema for intraparenchymal infusion of thrombin and infusion of red blood cells was 24-48 h and 3-5 days, respectively
.
Therefore, different pathophysiological mechanisms may influence the temporal pattern of PHE formation
.
Figure 4.
Temporal pattern of PHE formation For human studies, the development of PHE is divided into 2 phases (rapid growth phase and slow growth phase)
.
Rapid PHE growth phase within 24 h after intracerebral hemorrhage
.
Subsequently, the PHE growth rate (cm/d) slowed down and was negatively correlated with the time to onset
.
The volume of PHE peaked around 1-2 weeks after the onset of intracerebral hemorrhage, and could last up to 3 weeks in a few patients
.
Figure 5.
Different pathophysiological mechanisms dominate the development of PHE in different stages of intracerebral hemorrhage ▌ The first stage (dominated by cytotoxic edema) is activated in the first few hours (1-4h) after intracerebral hemorrhage, and the blood coagulation cascade is activated.
Clot shrinkage, apoptosis, and hematoma destruction cause brain atrophy to create a relatively large perihematoma space, resulting in decreased perihematoma hydrostatic pressure
.
Interstitial colloid osmotic pressure increases as serum proteins are squeezed out after clot retraction
.
Together, these changes lead to the initial transport of water to brain tissue, resulting in edema
.
After cerebral hemorrhage, due to the stimulation of blood components, the Na+ and Cl- channels of the cell membrane are activated, so that the water molecules in the interstitial brain tissue enter the brain parenchyma
.
Interstitial ion content in the brain tissue decreases, thereby increasing the crystal osmotic pressure difference within the capillaries and between the brain tissue interstitium, driving ionic edema through a transendothelial osmotic gradient
.
▌ The second stage (mainly vasogenic edema) BBB disorder caused by a series of neuroinflammatory reactions in 4-72h of cerebral hemorrhage
.
① Mechanical disruption of thrombin and hematoma activates the Toll-like receptor 4 and nuclear factor kB (NF-kB) pathways
.
NF-kB activates and regulates the transcription of cytokines, chemokines and MMPs; Toll-like receptor 4 activates microglia
.
②Activated thrombin induces the expression of chemokines and adhesion molecules, and promotes the recruitment and infiltration of inflammatory cells around the hematoma
.
③Thrombin can further activate astrocytes and microglia through protease-activated receptor 4
.
Hyperactivation of microglia may amplify neuroinflammatory responses by releasing reactive oxygen species, tumor necrosis factor-α, and cytokines
.
④ BBB opening activates the complement cascade, increasing the production of anaphylatoxins and chemokines
.
▌ The third stage (delayed stage of vasogenic edema caused by lysis of red blood cells) 72 hours after intracerebral hemorrhage, although red blood cells begin to dissolve within 24 hours after intracerebral hemorrhage
.
Three days after the onset of intracerebral hemorrhage, hemoglobin and iron-related toxicity resulting from lysis of red blood cells dominate the PHE process
.
Red blood cells are dissolved into hemoglobin by the membrane attack complex produced by complement, and then hemoglobin is oxidized to methemoglobin, thereby rapidly releasing heme
.
Then, heme is degraded to free iron by heme oxygenase
.
Free iron also stimulates the production of reactive oxygen species and MMP-9, promoting inflammatory responses and BBB damage
.
Deposition of hemosiderin upregulates AQP-4, which exacerbates cerebral edema and peaks on days 3-7
.
Hemoglobin and heme can also directly activate Toll-like receptor 4, microglia, and NF-kB pathways, further promoting the inflammatory response
.
References: [1] Chen Y, Chen S, Chang J, Wei J, Feng M, Wang R (2021) PerihematomalEdemaAfterIntracerebralHemorrhage:AnUpdateonPathogenesis,RiskFactors,andTherapeuticAdvances.
FrontImmunol 2021;12.
.
Severe PHE can cause significant mass effect and lead to severe intracranial hypertension, increasing the risk of death in patients
.
Hematoma evacuation has been proven to be an effective measure for the treatment of PHE
.
The MISTIEII trial showed that minimally invasive surgery combined with tissue plasminogen activator can effectively reduce the volume of PHE
.
Furthermore, continuous infusion of hypertonic saline has been identified as a safe approach to control PHE progression in the early stages of ICH and it does not appear to affect the blood-brain barrier (BBB)
.
It is particularly important for neurologists to understand the time course and mechanism of PHE growth in intracerebral hemorrhage
.
Case data A 49-year-old female patient was admitted to the hospital because of "sudden headache, left limb weakness, and slurred speech for 3 hours"
.
▌ The patient with the history of the present illness had a sudden headache after getting up 3 hours ago (6:00 in the morning) to do farm work
.
Immediately, left limb weakness and slurred speech appeared, which gradually worsened to the point that the lower limbs could not stand and walk, and the left upper limbs were difficult to hold and lift
.
Associated with decreased mental state, decreased responsiveness, and increased sleep
.
With a history of hypertension for 5 years, the highest blood pressure measured was 180/? mmHg, taking amlodipine besylate regularly (Anezhen 5mg qd), the blood pressure control is unknown
.
Denied other medical history
.
Denies smoking and drinking
.
Denied family history of hereditary disease
.
▌ Physical examination on admission: T: 36.
6℃; P: 65 times/min; R: 19 times/min; BP: 169/90mmHg; cardiopulmonary and abdominal examinations were negative
.
▌ Neurological examination: lethargy, slurred speech, uncooperative cognitive examination
.
Left isotropic hemianopia, bilateral pupils of equal size and circle, and sensitive to light
.
The bilateral forehead lines are symmetrical, and the left nasolabial fold becomes shallower, showing that the angle of the mouth is skewed to the right
.
The articulation was unclear, and the rest of the cranial nerves were uncooperative
.
Left limb pain and touch decreased
.
The muscle strength of the right limb was grade 5, the muscle strength of the left limb was grade 3, and the muscle tension was moderate
.
Bilateral tendon reflexes are present symmetrically
.
Left Babinski sign (+)
.
Slight neck resistance, bilateral Kernig sign (-)
.
GCS (E3+V3+M6) 12 points
.
Figure 1.
Emergency craniocerebral CT showed right putamen hemorrhage 3 hours after the onset of the disease, the amount of bleeding (V)=1.
787×4.
635×2.
5/2≈10ml▌ The admission blood routine white blood cells were 19.
30*109/L, and the percentage of neutrophils was 76.
4%; Blood biochemistry: alanine aminotransferase 66IU/L, serum potassium 2.
7mmol/L, triglyceride 1.
95mmol/L; blood coagulation full set: D-dimer 0.
31mg/L; thyroid function, tumor markers, four items of rheumatism, anti-inflammatory The nuclear antibody spectrum was unremarkable
.
Chest CT showed hypostatic pneumonia
.
Diagnostic Considerations? How to treat? A middle-aged woman with a history of hypertension, CT scan of the brain showed that the high-density shadow was located in the basal ganglia (putamen), which is a common site of hypertensive intracerebral hemorrhage
.
No history of trauma or surgery
.
Denied the use of antithrombotic drugs
.
Admission blood routine, coagulation test, and vasculitis antibody test showed no abnormality, and head and neck CTA ruled out vascular malformations and aneurysms
.
The etiology of cerebral hemorrhage is considered to be hypertensive
.
Treatment plan: urapidil to control blood pressure, piperacillin tazobactam for anti-infection, omeprazole for stomach protection, oxiracetam to improve brain metabolism, electrolyte supplementation and nutritional support treatment
.
On the second day of admission, dehydration drugs were added: 20% mannitol 125ml q 8h
.
Figure 2.
The patient's hematoma did not expand from 3 hours to 4 days after onset, but the surrounding edema gradually increased
.
Three days after the onset of symptoms, the patient's headache was relieved, and his consciousness returned to a conscious state
.
Antihypertensive drugs were changed to oral administration and neurorehabilitation was initiated
.
On the 9th day of the onset, he complained of pain in the forehead and occiput, which was persistent and severe
.
With nocturnal sleep disturbance and visual hallucinations, occasional unanswered questions, disorientation
.
Figure 3.
Compared with the 4th day of the onset, the hematoma volume of the patient was slightly reduced on the 9th day of the onset, and the surrounding edema was further expanded
.
On the 9th day of onset, albumin 100ml qd + furosemide, 10ml q 12h + 3% hypertonic salt 195ml q 8h were given, and mannitol dehydration was continued before continuing
.
After 4 days, the patient's headache symptoms gradually decreased, the nighttime sleep improved, and the hallucinations were ignored.
.
At the time of discharge (1 month after onset), the patient's speech function recovered, and his memory decreased, and his family members could assist in walking
.
During the 2-month follow-up, the patient could walk independently and take care of himself in daily life
.
Questions The patient was hospitalized for 1 month, the hematoma volume did not expand, and the surrounding edema volume grew significantly
.
In this case, edema around the hematoma was seen within 3 hours of onset, and the peak edema was on the 9th day of onset
.
Although the edema expanded, the patient's neurological deficit symptoms did not worsen, and the prognosis was relatively good at follow-up
.
So, how long is the peak period of edema around the hematoma and how long does it last? What is the mechanism of edema formation around hematoma? PHE is an increase in water content in the brain tissue adjacent to a parenchymal hemorrhage
.
Its development is considered a hallmark of secondary brain injury and is associated with thrombin activation, inflammatory immune responses, BBB disruption, and hemoglobin cytotoxicity after intracerebral hemorrhage
.
PHE can cause significant mass effect and lead to severe intracranial hypertension
.
In experimental models of intracerebral hemorrhage, PHE usually occurs within 2 hours, peaks on day 3, and lasts for 7 days
.
However, the peak period of edema for intraparenchymal infusion of thrombin and infusion of red blood cells was 24-48 h and 3-5 days, respectively
.
Therefore, different pathophysiological mechanisms may influence the temporal pattern of PHE formation
.
Figure 4.
Temporal pattern of PHE formation For human studies, the development of PHE is divided into 2 phases (rapid growth phase and slow growth phase)
.
Rapid PHE growth phase within 24 h after intracerebral hemorrhage
.
Subsequently, the PHE growth rate (cm/d) slowed down and was negatively correlated with the time to onset
.
The volume of PHE peaked around 1-2 weeks after the onset of intracerebral hemorrhage, and could last up to 3 weeks in a few patients
.
Figure 5.
Different pathophysiological mechanisms dominate the development of PHE in different stages of intracerebral hemorrhage ▌ The first stage (dominated by cytotoxic edema) is activated in the first few hours (1-4h) after intracerebral hemorrhage, and the blood coagulation cascade is activated.
Clot shrinkage, apoptosis, and hematoma destruction cause brain atrophy to create a relatively large perihematoma space, resulting in decreased perihematoma hydrostatic pressure
.
Interstitial colloid osmotic pressure increases as serum proteins are squeezed out after clot retraction
.
Together, these changes lead to the initial transport of water to brain tissue, resulting in edema
.
After cerebral hemorrhage, due to the stimulation of blood components, the Na+ and Cl- channels of the cell membrane are activated, so that the water molecules in the interstitial brain tissue enter the brain parenchyma
.
Interstitial ion content in the brain tissue decreases, thereby increasing the crystal osmotic pressure difference within the capillaries and between the brain tissue interstitium, driving ionic edema through a transendothelial osmotic gradient
.
▌ The second stage (mainly vasogenic edema) BBB disorder caused by a series of neuroinflammatory reactions in 4-72h of cerebral hemorrhage
.
① Mechanical disruption of thrombin and hematoma activates the Toll-like receptor 4 and nuclear factor kB (NF-kB) pathways
.
NF-kB activates and regulates the transcription of cytokines, chemokines and MMPs; Toll-like receptor 4 activates microglia
.
②Activated thrombin induces the expression of chemokines and adhesion molecules, and promotes the recruitment and infiltration of inflammatory cells around the hematoma
.
③Thrombin can further activate astrocytes and microglia through protease-activated receptor 4
.
Hyperactivation of microglia may amplify neuroinflammatory responses by releasing reactive oxygen species, tumor necrosis factor-α, and cytokines
.
④ BBB opening activates the complement cascade, increasing the production of anaphylatoxins and chemokines
.
▌ The third stage (delayed stage of vasogenic edema caused by lysis of red blood cells) 72 hours after intracerebral hemorrhage, although red blood cells begin to dissolve within 24 hours after intracerebral hemorrhage
.
Three days after the onset of intracerebral hemorrhage, hemoglobin and iron-related toxicity resulting from lysis of red blood cells dominate the PHE process
.
Red blood cells are dissolved into hemoglobin by the membrane attack complex produced by complement, and then hemoglobin is oxidized to methemoglobin, thereby rapidly releasing heme
.
Then, heme is degraded to free iron by heme oxygenase
.
Free iron also stimulates the production of reactive oxygen species and MMP-9, promoting inflammatory responses and BBB damage
.
Deposition of hemosiderin upregulates AQP-4, which exacerbates cerebral edema and peaks on days 3-7
.
Hemoglobin and heme can also directly activate Toll-like receptor 4, microglia, and NF-kB pathways, further promoting the inflammatory response
.
References: [1] Chen Y, Chen S, Chang J, Wei J, Feng M, Wang R (2021) PerihematomalEdemaAfterIntracerebralHemorrhage:AnUpdateonPathogenesis,RiskFactors,andTherapeuticAdvances.
FrontImmunol 2021;12.
