Ischemic stroke complicated by intracerebral hemorrhage in patients with hypereosinophilic syndrome: a case series

Abstract

Patients with hypereosinophilic syndrome (HES) suffer from thrombotic events including ischemic stroke. Simultaneous occurrence of stroke and intracerebral hemorrhage (ICH) in such patients have rarely been reported. Here, we describe two patients with HES who suffered from ischemic stroke complicated by ICH. In case 1, we used a recombinant tissue plasminogen activator for acute ischemic stroke without treating hypereosinophilia; consequently, ICH occurred. In case 2, the patient had an ischemic stroke and ICH upon admission. In both cases, we used glucocorticoids to control hypereosinophilia, and no additional ischemic stroke or ICH occurrence was observed. These cases suggest that patients with HES can experience both ischemic and hemorrhagic strokes simultaneously and emphasize the importance of early control of eosinophilia to reduce the risk of cerebrovascular complications.

Plain language summary

Brain strokes with bleeding in people with hypereosinophilic syndrome (HES): a case series

Hypereosinophilia means high levels of a type of white blood cell called eosinophils. It is caused by various conditions. Patients with hypereosinophilia without a known secondary cause is called hypereosinophilic syndrome (HES). Stroke, which happens when blood flow to the brain is blocked, has been seen in people with HES. However, it is very unusual for stroke and bleeding in the brain to happen at the same time. We describe two patients with HES who had both stroke and bleeding in the brain. In one patient, a clot-busting drug was given for stroke before treating the high eosinophil levels, and bleeding in the brain followed. In the other patient, both stroke and brain bleeding were present at the time of hospital admission. In both cases, treatment with steroids reduced the eosinophil levels, and no further strokes or brain bleeding occurred. These cases suggest that HES can cause both types of brain injury at the same time and highlight the importance of early treatment to control eosinophils to lower the risk of brain complications.

Background

Hypereosinophilia can be induced by various conditions such as atopic and allergic disease, parasite infections, and adverse drug reactions. ¹ When no underlying etiology for hypereosinophilia is identified, the condition is classified as hypereosinophilic syndrome (HES), which is characterized by sustained eosinophil counts exceeding 1500/µL and eosinophil-related organ damage in the absence of a known secondary cause. Eosinophil granule proteins such as eosinophil cationic proteins and eosinophil peroxidase cooperatively mediate cytotoxicity. ² Patients with HES suffer from thrombotic events including ischemic stroke, ³ which has been previously reported; however, the simultaneous occurrence of ischemic stroke and intracerebral hemorrhage (ICH) has rarely been reported. ⁴ Herein, we describe the cases of two patients with HES who developed both ischemic stroke and ICH.

Case presentation

Case 1

An 82-year-old woman was admitted with sudden-onset dysarthria and numbness of the right upper limb. She was transferred to our hospital 1 h and 20 min after the onset. Her medical history included asthma and chronic heart failure. The physical examination revealed no remarkable findings. The neurological examination revealed dysarthria and right facial hemiparesis. The National Institutes of Health Stroke Scale (NIHSS) score was 3. Laboratory examinations revealed elevated eosinophil counts (8120/µL, accounting for 59.8% of the total white blood cells). D-dimer and fibrin degradation product levels were also elevated (5.1 and 12.5 µg/mL, respectively), whereas other laboratory findings were unremarkable.

Head computed tomography (CT) revealed no evidence of ICH, and an acute ischemic stroke was suspected (Figure 1(a)). Magnetic resonance imaging (MRI) of the brain revealed several punctate lesions with restricted diffusion in the right frontal and temporal lobes and left centrum semiovale (Figure 1(b)). Extracranial and intracranial magnetic resonance angiography revealed no abnormalities. The patient was diagnosed with acute ischemic stroke and started on intravenous administration of recombinant tissue plasminogen activator (rt-PA; 0.6 mg/kg) 2 h 42 min after symptom onset. Immediately after initiating the rt-PA injection, she developed transcortical motor aphasia and deterioration of the paresis of her right upper limb. Head CT revealed multiple ICHs in the bilateral frontal lobes and cerebellar hemispheres (Figure 1(c)).

Figure 1.

Imaging findings of the patient in case 1. (a) Initial head CT shows no ICH or ischemic lesions. (b) Initial brain DWI reveals several dot-like ischemic lesions in the right frontal and temporal lobes and left centrum semiovale. (c) Head CT performed on the 2nd day of hospitalization reveals multiple ICHs in the bilateral frontal lobes and cerebellar hemispheres. (d) Follow-up DWI performed at 6 months after discharge reveals no additional lesions.

Holter electrocardiography revealed no abnormalities. Transthoracic and transesophageal echocardiography revealed no mural thrombi. We also searched for the underlying causes of hypereosinophilia. The patient had no history of exposure to medications commonly associated with drug-induced eosinophilia. Laboratory investigation revealed increased C reactive protein (2.4 mg/dL) and erythrocyte sedimentation rate (70 mm/h). It also revealed increased IgE levels (212 IU/mL). Test results for HIV1 and 2 were negative. Serum vitamin B12 level was within the normal range. Test results for antinuclear antibodies, perinuclear ANCA, and cytoplasmic ANCA were negative and FIP1L1-PDGFRA fusion was not detected. Whole-body CT revealed no apparent neoplastic lesions. Skin and gastric mucosal biopsies showed unremarkable findings.

We diagnosed the patient with HES. Oral methylprednisolone (mPSL) was administered on the 3rd day of hospitalization (20 mg/day, 0.5 mg/kg/day). The eosinophil count returned to within the normal range on the 4th day (308/µL; 3.2% of the total white blood cells). The patient’s symptoms gradually improved with rehabilitation. We tapered the total dose of mPSL by 10% every 2 weeks, and she was discharged 3 months after onset with 9 mg/day of mPSL. We did not initiate antiplatelet therapy because the patient developed symptomatic ICH. Her total eosinophil count remained within the normal range, and no recurrence was observed on MRI performed 6 months after discharge (Figure 1(d)).

Case 2

An 82-year-old woman with bronchial asthma for 30 years presented with sudden-onset dysarthria and right-sided hemiparesis, including her face; her NIHSS score was 8. The patient was afebrile and did not exhibit any signs of respiratory failure. Physical examination results were unremarkable. Head CT revealed a small high-density lesion, suggesting ICH in the left frontal lobe (Figure 2(a)). Brain MRI revealed multiple small ischemic lesions in the bilateral cerebral and cerebellar hemispheres and brainstem (Figure 2(b)). Magnetic resonance angiography revealed no abnormalities. Laboratory examination revealed elevated eosinophil counts (10,156/µL; 26.7% of total white blood cells). Concurrent ischemic and hemorrhagic strokes, possibly related to hypereosinophilia, were suspected. A diagnostic workup, similar to that performed in Case 1, was conducted to investigate the underlying cause of hypereosinophilia. No secondary etiologies were identified.

Figure 2.

Imaging findings of the patient in Case 2. (a) Initial head computed tomography shows a small intracerebral hemorrhage in the left frontal lobe. (b) Initial brain DWI reveals multiple small ischemic lesions in the bilateral cerebral and cerebellar hemispheres and brainstem. (c) DWI performed on the 2nd day of hospitalization reveals new ischemic lesions, especially in the bilateral frontal lobes. (d) Follow-up DWI performed on the 17th day of hospitalization reveals no additional lesions. (e) Magnetic resonance imaging performed at 6 months after discharge shows no additional lesions.

Therefore, we diagnosed the patient with HES and initiated oral mPSL therapy (30 mg/day, 0.5 mg/kg/day) on the day of admission to normalize the eosinophil count. The next day, her right-sided hemiplegia deteriorated, and the NIHSS score worsened to 12. The eosinophil count increased to 15,585/µL (54.4% of the total white blood cells), and new ischemic lesions were observed in the brainstem and bilateral cerebellar and cerebral hemispheres on MRI (Figure 2(c)). We intensified the treatment to intravenous mPSL pulse therapy for 3 days (500 mg/day), followed by oral mPSL (70 mg). Loeffler myocarditis, which is characterized by thrombus formation along the damaged endocardium, is associated with hypereosinophilia ⁴ and could not be ruled out. The patient was considered to be at high risk for recurrent ischemic stroke and was started on continuous intravenous infusion of unfractionated heparin (7500 units daily). Neurological deterioration stabilized on the 3rd day, and the eosinophil count gradually decreased and returned to within the normal range on the 6th day of hospitalization (322/µL; 4.3% of the total white blood cells). Atrial fibrillation or arrhythmia that could account for ischemic stroke was not detected on Holter electrocardiography. Transthoracic and transesophageal echocardiography did not reveal an intracardiac thrombus. We terminated heparin infusion and initiated oral clopidogrel (75 mg/day). The oral mPSL dose was tapered by 10% every 2 weeks, starting on the 13th day of hospitalization.

The patient exhibited gradual neurological improvement during rehabilitation. Additional lesions were not observed on MRI performed on the 17th day (Figure 2(d)). The patient was discharged to another hospital for rehabilitation 3 months after symptom onset. The patient maintained a normal eosinophil count without relapse on MRI with 9 mg/day of mPSL (Figure 2(e)).

Discussion

Here, we describe the cases of two patients with HES who developed ischemic stroke and ICH. In Case 1, rt-PA administration before the normalization of eosinophil counts induced ICH. In Case 2, both ischemic and hemorrhagic lesions were simultaneously identified upon admission. Although hypereosinophilia is a well-recognized risk factor for thrombotic complications, the coexistence of ischemic stroke and ICH is rare and poses diagnostic and therapeutic challenges.^4,5

Although the patient had preceding medical history of asthma, eosinophilic granulomatosis with polyangiitis (EGPA) could not be diagnosed owing to a lack of objective evidence of vasculitis. HES is an important differential diagnosis to consider when diagnosing for EGPA. A border-zone pattern of cerebral ischemia along with the involvement of other cortical regions, is a feature of HES-related stroke. ⁶

We hypothesized that the simultaneous occurrence of ischemia and ICH was caused by eosinophilic vasculitis involving cerebral vessels, together with age-related vascular fragility. Eosinophilic vasculitis is a pathological feature in patients with ANCA-negative hypereosinophilia. ⁷ An autopsy of a patient with hypereosinophilia who developed both ICH and ischemic stroke revealed eosinophilic infiltration of small arteries, suggesting the role of eosinophilic vasculitis in cerebrovascular injury. ⁵ Additionally, we speculate that age-related vascular fragility may have contributed to the pathogenesis. Aging can cause a reduction in brain microcirculation and blood-brain barrier dysfunction. ⁸ Therefore, we speculate that the combination of eosinophilic vasculitis and age-related vascular fragility contributed to the simultaneous development of ischemic and hemorrhagic strokes. Clinicians should be aware that elderly patients with active eosinophilic disease may be at risk of not only ischemic stroke but also ICH.

Remission-induction treatment with high-dose glucocorticoids is important for patients with HES. ⁶ Eosinophils are rapidly cleared from the peripheral circulation within 60–120 min after glucocorticoid administration and a recent study suggested that the rapid decline reflects bone marrow homing of eosinophils rather than apoptosis. ⁹ Anti-IL-5 biologics such as mepolizumab have recently emerged as effective steroid-sparing options for HES. ⁶ Although not used in our cases, they are an important therapeutic alternative to consider for patients with HES. In Case 2, the administration of glucocorticoids normalized eosinophil counts and prevented additional stroke occurrence. In contrast, case 1 illustrates the potential risk of anticoagulant therapy. Intravenous thrombolysis with rt-PA led to ICH. A similar result was previously reported in which anticoagulant therapy triggered ICH, resulting in death. ⁴ Although anticoagulant therapy, including rt-PA, is not contraindicated in patients with hypereosinophilia, extreme caution should be exercised in its use because of the underlying risk of ICH.

This case series has several limitations. First, the proposed mechanism remains speculative because pathological confirmation was not obtained. Second, anticoagulant therapy with unfractionated heparin was initiated in case 2 because Loffler syndrome could not be entirely excluded; however, this decision was not based on the established guidelines.

Conclusion

Patients with EGPA associated with hypereosinophilia can experience both ischemic and hemorrhagic strokes, possibly due to eosinophilic vasculitis. Initiating glucocorticoid therapy is essential for mitigating vasculitis and preventing recurrent events. Anticoagulant therapy, including rt-PA, may pose a bleeding risk in patients with active eosinophilic vasculitis and should be delayed until eosinophil counts normalize.

Supplemental Material

sj-docx-1-tan-10.1177_17562864261416619 – Supplemental material for Ischemic stroke complicated by intracerebral hemorrhage in patients with hypereosinophilic syndrome: a case series

Supplemental material, sj-docx-1-tan-10.1177_17562864261416619 for Ischemic stroke complicated by intracerebral hemorrhage in patients with hypereosinophilic syndrome: a case series by Masaoki Hidaka, Satomi Mezuki, Mio Yokoi, Masato Osaki, Tomoaki Akiyama, Shinya Yamaguchi, Tetsuro Sayama, Tetsuro Ago and Shuji Arakawa in Therapeutic Advances in Neurological Disorders