Delayed perihematomal edema in three patients with spontaneous intracerebral hemorrhage

INTRODUCTION

Spontaneous intracerebral hemorrhage (sICH) accounts for 10–15% of strokes, with high disability and mortality rates.^[1] Complications such as hematoma expansion and perihematomal edema (PHE) worsen outcomes in these patients.^[2] PHE usually follows three stages: Early (1–4 h), intermediate (4–72 h), and delayed (beyond 72 h), lasting up to 2–4 weeks.^[3] Definitions of delayed perihematomal edema (DHE) vary. One study defines it as a 3 mL increase in PHE volume from 12–20 days compared to 5–9 days, suggesting a 14-day threshold where PHE can worsen after hematoma absorption.^[4] Another study identified the best cutoff for poor outcomes as a 3.34 mL increase from 4–7 to 8–14 days, and 3.78 mL from 8–14 to 15–21 days.^[5] Hemoglobin breakdown products, like free iron, trigger reactive oxygen species and inflammation, leading to delayed brain edema and injury.^[3] In our study, DHE was defined as worsening PHE despite significant hematoma absorption by day 14. Using this definition, we describe three interesting cases of DHE.

CASE 1

A 38-year-old man, an occasional smoker with no comorbidities, presented with sudden left-sided weakness. He was conscious, with a pulse of 84 bpm and blood pressure (BP) of 164/84 mmHg. Neurological examination revealed left upper motor neuron (UMN) facial palsy, 1/5 power in the left upper limb, 2/5 in the lower, and a National Institutes of Health Stroke Scale (NIHSS) score of 10. Non-contrast computed tomography (NCCT) showed an 18-cc right putamen haemorrhage with intraventricular extension and a 5 mm midline shift (Intracerebral hemorrhage [ICH] score = 0). Comprehensive workup, including coagulation profile, vasculitis screen, abdominal ultrasound, and digital subtraction angiography (DSA), was inconclusive. Sodium levels were normal, and BP remained <140/90 mmHg. He was discharged on day 7 (modified Rankin Scale [mRS]-4). Forty-three days later, he returned with a headache and an NIHSS score of 4. NCCT showed increased PHE and midline shift [Figure 1]. Relatives declined surgery, and conservative treatment resolved symptoms. At 90 days, mRS was 2.

Close

Figure 1:

(a) Right putamen hemorrhage of size 18 cc with intraventricular extension and a midline shift of 5 mm to the left. (b) Digital subtraction angiography showing normal right internal carotid artery and right vertebral artery run. (c) Non-contrast computed tomography at 43 days after the patient had complained of a headache for 3 days. (d) Follow-up imaging at 90 days.

Export to PPT

CASE 2

A 38-year-old man with alcohol use (100 mL/day for 1 year) presented with sudden right-sided weakness, facial deviation, and slurred speech. Pulse was 80 bpm and BP 130/70 mmHg. Neurological exam showed right UMN facial palsy and 0/5 power in the right limbs (NIHSS 18). NCCT revealed a 20-cc left putamen hemorrhage with no midline shift (ICH score 0). The comprehensive workup was inconclusive. He was discharged on day 7. 25 days later, he returned with apathy, disorientation, and a headache. NCCT showed resolving hematoma, PHE, and an 11 mm midline shift [Figure 2]. Sodium levels were normal. He was discharged after conservative treatment on day 30.

Close

Figure 2:

Axial non-contrast computed tomography on (a) day 1 of the index event showed a left putamen bleed and (b) a delayed perihematomal edema at day 25.

Export to PPT

CASE 3

A 45-year-old man with renal calculi, obstructive uropathy, and hypertension presented to a local practitioner with sudden left-sided weakness. He remained drowsy and was taking unknown medications. 20 days later, he was admitted to our hospital with sudden right-sided weakness and loss of consciousness. His Glasgow Coma Scale was E1V1M4, pulse 80 bpm, and BP 170/80 mmHg. NCCT revealed an old right putamen haemorrhage with PHE and a fresh 15 cc left putamen and globus pallidus haemorrhage (ICH score 2). A comprehensive workup, like Case 1, was performed, but all findings were normal, except DSA, which could not be done due to his unstable condition. Worsening PHE and poor sensorium necessitated bilateral frontotemporal decompression [Figure 3]. At 90 days, his mRS was 5.

Close

Figure 3:

(a) Axial non-contrast computed tomography revealed an old right putaminal bleed with gliosis and a fresh putaminal and globus pallidus bleed of volume 15 cc, (b) axial SWI substantiating the findings. (c) The patient underwent bilateral frontotemporoparietal decompression after 24 h of presentation. (d) Follow-up imaging at 30 days.

Export to PPT

DISCUSSION

We present three cases of DHE following sICH, a rare yet significant complication. DHE was observed as late as 43 days post-sICH (range: 20–43 days). Two patients demonstrated considerable improvement with medical management, achieving an mRS score of 2, while the third patient required surgical intervention, resulting in an mRS of 5 at 90 days.

While early PHE often requires urgent intervention, data on DHE remain scarce. Hematoma volume is the strongest factor influencing PHE, alongside hematoma expansion, intraventricular haemorrhage, platelet count, partial thromboplastin time (PTT), and serum ferritin.^[6,7] Patient demographics, comorbidities, fever, infection, and plasma sodium levels may also affect PHE progression.^[7-9] In addition, younger age and alcohol use have been associated with an increased risk of DHE.^[4]

While clear predictors of DHE remain elusive, our cases suggest that younger age, even with small hematoma volumes, and alcohol use may contribute to its development.

These findings suggest that DHE should be considered in younger patients with sICH and worsening symptoms, as older patients often experience asymptomatic brain expansion due to atrophy.^[4] Routine parameters such as platelet count, PTT, and sodium were normal, indicating the need to look beyond conventional markers. These cases highlight the unpredictable nature of DHE and suggest the role of individual susceptibility and non-traditional risk factors, which merit further investigation.

The mechanisms underlying DHE are complex and extend well beyond the acute cytotoxic and vasogenic edema typically observed in the early stages of PHE. Initially, cytotoxic edema predominates, driven by energy failure, astrocytic swelling, and dysfunction of ion pumps, which is often exacerbated by excitotoxic glutamate release. This sets the stage for ionic edema, facilitated by increased expression of aquaporin-4 channels in astrocytic foot processes, leading to intracellular water accumulation.

Over the subsequent days, vasogenic edema becomes the primary contributor, resulting from disruption of the blood-brain barrier. This breakdown is mediated by thrombin activation, pro-inflammatory cytokines, matrix metalloproteinases-9 (particularly), and reactive oxygen species. The inflammatory cascade typically peaks around 48–72 h post-ICH but can persist or re-emerge, particularly in patients with ongoing microglial activation or secondary insults.

In the delayed phase, which was evident in our cases, erythrocyte lysis plays a central role. Haemoglobin degradation products, particularly free iron, accumulate in the perihematomal region over 1–2 weeks and contribute significantly to secondary brain injury. Experimental studies have shown that iron exacerbates oxidative stress, promotes nitric oxide generation, and activates microglia and macrophages. Ferroptosis, a form of regulated iron-dependent cell death, has been implicated in these processes and may be attenuated by iron chelators such as deferoxamine, which have demonstrated efficacy in reducing phospholipid peroxidation and neuronal injury in animal models.^[10]

In our series, Cases 1 and 2 exhibited progressive edema several weeks after hematoma resolution, consistent with the delayed phase described above. While the role of iron chelation in such scenarios remains speculative, these cases highlight the need for further investigation into its therapeutic potential. Our management approach was entirely conservative, comprising tight BP control (maintaining systolic BP < 140 mmHg), intravenous mannitol administration to mitigate cerebral edema, and close neurological monitoring. The utility of corticosteroids or other anti-inflammatory therapies remains uncertain, as these were not employed in our cases. However, the evolving understanding of neuroinflammation and ferroptosis suggests that future trials of targeted therapies, including iron chelation and anti-inflammatory agents, may be warranted in selected patients with DHE.^[10]

Notably, Cases 1 and 2 displayed significant edema and midline shift while maintaining good sensorium, challenging the usual poor prognosis linked to DHE. Specifically, Case 1 improved from an mRS score of 5–2 at 90 days, which is uncommon for patients with delayed edema. This indicates that prompt management of significant PHE can lead to favourable outcomes.

These cases underline the complexity of predicting DHE, particularly in younger sICH patients. This underscores the need for further research into the underlying causes of DHE and an exploration of the immune mechanisms underlying this phenomenon.

CONCLUSION

DHE should be considered in young sICH patients presenting with new or worsening symptoms. Larger studies are necessary to explore the mechanisms and enhance management strategies for DHE.