Ischemic Stroke in Hypereosinophilic Syndrome: A Clinicopathologic Study of Two Cases

ABSTRACT

Ischemic stroke is a rare complication of hypereosinophilic syndrome (HES). Manifestations of stroke in HES have been described in the radiologic literature; however the pathologic characterization of central nervous system (CNS) involvement in HES is limited. In this small case series, we present two post‐mortem neuropathologic examinations of patients exhibiting CNS infarcts associated with HES and review the relevant literature.

1. Introduction

Hypereosinophilic syndrome (HES) is a multisystem disorder characterized by the presence of hypereosinophilia (HE) with associated organ injury and dysfunction. HE is defined by a blood eosinophil count of over 1.5 × 10⁹/L and/or pathological confirmation of HE [1]. The proposed histologic criteria of HE include: (1) bone marrow demonstrating eosinophils constituting over 20% of cells, (2) infiltration of eosinophils in affected tissues, or (3) significant eosinophil granule protein deposition [2].

HES has highly variable clinical presentations and underlying etiologies. It is classified as either a primary/neoplastic disorder of myeloid lineage cells, a secondary/reactive disorder, or is idiopathic if no provoking cause is ascertained after investigation [2]. Various etiologies can lead to secondary HES, the most common including the major atopies (eosinophilic asthma and atopic dermatitis), infections, or paraneoplastic mechanisms related to hematolymphoid or solid malignancies. Some of the less common secondary etiologies of HES include eosinophilic granulomatosis with polyangiitis, polyarteritis nodosa, IgG4 inflammatory disease, hyper IgE syndrome, and inflammatory bowel disease [2].

The precise mechanisms leading to organ damage in HES are under investigation. Persistent HE can result in eosinophil infiltration of various tissues, release of cytotoxic mediators, and resultant organ damage [1]. The neuropathologic characterization of central nervous system (CNS) involvement in HES is scarce. We describe the post‐mortem neuropathologic findings in 2 patients with HES and review the literature on this rare entity.

1.1. Patient 1: Clinical Course

The first patient was a 49‐year‐old female presenting with polyarthralgia and a diffuse rash following a course of clindamycin for a dental infection. Her initial bloodwork demonstrated HE (5.3 × 10⁹/L). Her presentation was attributed to drug reaction with eosinophilia and systemic symptoms. She was given IV methylprednisolone followed by a prednisone taper; however, the HE progressed, necessitating hospital admission and escalated treatment including methylprednisolone, prednisone, and hydroxyurea. Her HE escalated further despite therapy (peak 208.3 × 10⁹/L), and she developed leukocytosis (peak 142.2 × 10⁹/L) and neutrophilia (peak 72.5 × 10⁹/L). A bone marrow (BM) biopsy showed hypercellularity and eosinophilic hyperplasia without dysplasia. Cytogenetic analysis, flow cytometry, and fluorescence in situ hybridization (FISH) to assess for FIP1L1/CHIC2/PDGFRA, PDGFRB, FGFR1, JAK2, and BCR‐ABL rearrangements, were negative for myeloproliferative disorders. A workup for autoimmune and infectious etiologies was negative (RF, anti‐nuclear antibody, anti‐neutrophilic cytoplasmic antibody, DNA double strand antibody, cyclic citrullinated peptide antibody, cardiolipin antibody, blood cultures, EBV, CMV, HAV, HBV, HCV, HIV, HTLV, Strongyloides, stool culture, Shiga toxin, Schistosoma). Echocardiogram demonstrated a small left ventricular (LV) cavity and no valvular abnormalities. Ten days after admission, she acutely deteriorated with confusion and global weakness requiring intensive care unit admission. CT head imaging showed multifocal hypoattenuating areas within the right frontal and parietal lobes, bilateral occipital lobes, and left cerebellar hemisphere (Figure 1A). Cyclophosphamide was added to her therapy regimen. The patient continued to deteriorate with multiorgan failure refractory to medical management and died approximately 12 days after admission.

FIGURE 1.

CT head of Patient 1 (A) demonstrates multifocal areas of hypoattenuation involving the right frontal and parietal lobes and left occipital lobe (arrowheads) consistent with multifocal infarcts. CT head of Patient 2 (B) highlights hypoattenuation of the occipital lobes, consistent with bilateral occipital infarcts.

1.2. Patient 1: Pathologic Findings

General autopsy findings included acute eosinophilic pneumonia and microthrombi in several organs: the spleen, adrenal gland, kidneys, gastrointestinal tract, and vaginal mucosa. The microthrombi were frequently associated with ulceration and/or infarcts. The heart demonstrated Loeffler endocarditis with biventricular thrombi. There were multifocal acute myocardial infarcts associated with thrombi of intramyocardial coronary artery branches. Eosinophilic infiltrates were seen in the subendocardial tissue and adjacent to the intraventricular thrombi.

Coronal brain sections demonstrated regions of gray discolouration with petechial hemorrhages in multifocal neocortical regions, and in bilateral cerebellar hemispheres (Figure 2A,B). Microscopy showed multifocal cerebral and cerebellar subacute infarcts across multiple arterial territories associated with occlusive thromboemboli in small parenchymal and leptomeningeal arteries (Figure 2C,D). Multiple microabcesses contained a mixed infiltrate consisting of neutrophils, monocytes, and a disproportionately large number of eosinophils (Figure 2F). There were no micro‐organisms apparent on appropriate stains.

FIGURE 2.

Pathology of Patient 1: Coronal brain sections demonstrate multifocal areas of ill‐defined gray discolouration involving the inferior temporal lobe (A, arrows) and left cerebellar cortex (B, arrows) and dentate nucleus (arrowhead). Multiple leptomeningeal (C) and cerebral (D) blood vessels demonstrate occlusion by thromboembolic material, with the latter showing necrotic neurons in the surrounding parenchyma (arrowheads). An infarct involves the left cerebellar dentate nucleus (E). A microabscess demonstrating a mixed inflammatory cell infiltrate with a disproportionately large number of eosinophils (F).

1.3. Patient 2: Clinical Course

The second patient was a 63‐year‐old female presenting with a 5‐day history of fever, cough, dyspnea, and new‐onset right arm/hand numbness and weakness. Her bloodwork showed HE of 9.1 × 10⁹/L. CT head demonstrated multiple infarcts involving the right frontal lobe, left postcentral gyrus, bilateral occipital lobes, and bilateral cerebellar hemispheres (Figure 1B). A cardiac source of emboli was considered. A Holter monitor was negative for atrial fibrillation. CT chest demonstrated subendocardial hypoattenuation in the left ventricle and peripheral opacification of the left lower lobe, raising the suspicion of eosinophilic cardiomyopathy and eosinophilic pneumonia, respectively. Echocardiogram showed no evidence of a LV thrombus or valvular disease. Cardiac MRI revealed no cardiac wall motion abnormalities or abnormal enhancement. Workup for infectious and autoimmune etiologies was negative (RF, anti‐nuclear antibody, DNA double strand antibody, neutrophil cytoplasmic antibodies, blood culture, HIV, stool culture and parasite PCR panel, Trichinella, Filaria, Toxocara canis, and Strongyloides). A bone marrow aspirate and biopsy demonstrated eosinophilia without evidence of hematolymphoid malignancy with negative flow cytometry and cytogenetic analysis. The patient was diagnosed with idiopathic HES and started on prednisone with taper and prophylactic apixaban. She was discharged to a rehabilitation center where she progressed well from a rehabilitative perspective and was ultimately discharged home with reported residual deficits of gait unsteadiness and blurry vision. Her HE resolved following prednisone therapy.

Approximately 2 years after her initial presentation, she presented with a 1‐day history of acute “brain fog” and dizziness. Neurological examination was notable for a mild left facial droop. Her bloodwork showed HE (8.9 × 10⁹/L), with a notable interval increase from bloodwork performed 2 months earlier (0.3 × 10⁹/L). CT head showed evidence of the previous infarcts, but there was no acute intracranial abnormality. The working diagnosis was poststroke recrudescence precipitated by a urinary tract infection. She was treated with antibiotics. Two days after her admission, she reported deterioration in her vision. Ophthalmology was consulted; however several hours later she was found unresponsive and without a pulse. Cardiorespiratory resuscitation was unsuccessful.

1.4. Patient 2: Pathologic Findings

General autopsy findings demonstrated eosinophilia within the bone marrow and spleen, and small artery thromboses in multiple organs (heart, lungs, thyroid, and kidney). Cardiac examination revealed Loeffler myocarditis, with profuse eosinophilic infiltrates within the ventricular myocardium, an associated LV thrombus, and widespread fibrosis and myocyte necrosis.

Coronal brain sections demonstrated blurring of the gray‐white junction in the bilateral anterior and posterior watershed regions. Microscopy showed bihemispheric cerebral infarcts, which were especially prominent in the bilateral MCA/ACA and MCA/PCA watershed territories. These ranged from microinfarcts, some of which showed eosinophilic neurons and neovascularization, to cavitated cystic infarcts with numerous macrophages (Figure 3A–C). There were organizing microthrombi in cerebral and leptomeningeal arteries, with the latter demonstrating a thrombus with abundant surrounding eosinophils (Figure 3D,E). There was an infarct in the left hippocampal CA2/CA1 junction, and acute anoxic‐ischemic change of the right hippocampus (Figure 3F). Rare microinfarcts were identified in the cerebellum.

FIGURE 3.

Pathology of Patient 2: The occipital cortex demonstrates multifocal infarcts of various ages ranging from acute/subacute infarcts characterized by paleness and vacuolation (arrowheads) to chronic infarcts showing cystic degeneration (A, arrows). The areas of chronic infarct show numerous foamy macrophages (arrow) with surrounding astrogliosis (B, arrowhead). The acute/subacute infarcts show vacuolization of neuropil, hypereosinophilic neurons, and neovascularization (C). Multiple leptomeningeal blood vessels show occlusive thrombi with surrounding eosinophils (D, E). The left hippocampus demonstrates an infarct within the pyramidal cell layer of the cornu ammonis with numerous necrotic neurons and prominent neuropil vacuolization (F).

2. Discussion

We present the clinicopathologic findings of ischemic stroke in idiopathic HES in two patients. A recent multicenter prospective study demonstrated that CNS complications of HES are rare and were apparent in only 3% of cases [1]. CNS disease in HES can manifest as stroke, vasculitis, spinal cord damage, meningitis/meningoencephalitis, or isolated cranial nerve damage. Ischemic stroke in HES can manifest in two patterns: watershed distribution and multi‐territorial distribution representing an embolic pattern [2]. In this case series, neuropathologic examination revealed a multi‐territorial embolic infarct pattern in Patient 1 and a watershed infarct pattern in Patient 2. Clinical progression of the cases differed substantially. Patient 1 had rapid onset and progression resulting in death despite aggressive immunosuppressive therapy. In contrast, Patient 2 demonstrated HE resolution and neurologic stabilization with treatment. Notably, the HE recurred 2 years later with relapsed cardiac and neurologic involvement. Case 2 raises an important HES therapeutic consideration, specifically whether maintenance immunosuppressive therapy is warranted in remission to prevent HE relapse. Lefèvre et al. demonstrated that up to 16% of patients with idiopathic HES have a single flare that recovers spontaneously or after corticosteroid tapering without future relapses [1]. This finding suggests that long‐term treatment is not required in all patients with idiopathic HES. However, 28% of patients in their cohort demonstrated relapsing–remitting disease, and this indicates that the optimal therapy regimen and duration require further study.

The neuropathologic findings of HES have been previously well‐documented in 8 cases (Table 1). Among these, the mean age of presentation was 46 and affected both sexes equally. All cases were consistent with idiopathic HES. Five cases resulted in patient death, while 3 cases demonstrated improvement of symptoms and HE with treatment. The neuropathologic findings revealed vasculitis (n = 2) [3, 4], limbic encephalitis (n = 1) [5], mass lesion (n = 2) [6, 8], venous sinus thrombosis with hemorrhagic infarct (n = 1) [9], and ischemic infarct (n = 2) [7, 10]. Of the two cases with reported pathological findings of infarcts, both were in a watershed distribution and also had cardiac thrombi. The case presented by Grigoryan et al. [7] additionally showed infarcts outside watershed zones on imaging and demonstrated fibrin/platelet occlusion of arterioles on microscopy.

TABLE 1.

Review of literature describing pathological findings with CNS manifestations of HES.

Author/Year	Age/sex	Past medical history	Presenting symptoms	Investigations	Neuroimaging	Treatment	Outcome	Pathologic findings	CNS manifestation
Noro et al. [3]	74 F	Allergic rhinitis, colon cancer, HTN	Progressive L hemiparesis	HE; elevated IgE, β2‐microglobulin, and sIL‐2R, ESR. Normal CRP, ANCA, proteinase 3‐ANCA, RF, CSF	Heterogeneously enhancing mass in the internal capsule and corona radiata	CS	Resolution of symptoms and lesions on imaging	Brain biopsy: Eosinophil‐rich non‐granulomatous small vessel vasculitis	Vasculitis
Rice et al. [4]	39 M	Nephrotic syndrome, LP, alopecia, fluctuating HE	HA, aLOC, myoclonus, ataxia, papilledema	HE; CSF HSV and VZV PCR, and serum ANCA negative; BM biopsy: HE, no malignancy; Echo: Normal	High signal of WM and enhancement of perivascular spaces; PCA narrowing	IV MP, oral CP followed by mycophenol‐ate	Encephalopathy and HE normalized; stable at 24 months	Brain biopsy: CNS vasculitis without presence of eosinophils or granulomatous inflammation.	Vasculitis
Kobayashi et al. [5]	34 M	N/A	Fatigue, anorexia with progression to fever, HA, tremor, vertigo	HE; normal CRP, IgE, ANA, anti‐DNA antibodies, MPO, ANCA, and RF; negative infectious workup BM aspirate: HE without atypia	Extensive b/l lesions in the MTLs, frontal and insular regions, internal capsule, and medulla	Acyclovir and MP pulse therapy	Day 11: resolution; Day 21: HA, aLOC, seizures. Day 69: death	Autopsy: Loss of myelin with inflammation and necrosis. Loss of neurons in R hippocampus. HSV‐1, HHV‐6 IHC Negative	Limbic encephalitis
Kanamori et al. [6]	43 F	N/A	Relapsing R eosinophilic OM. 4 months later severe HA, fever, anorexia	HE; ↑ IgE; ANA, RF, anti‐Jo1, SS‐A, SS‐B, Gal antibodies negative. CSF pleocytosis and ↑protein with eosinophilia but no atypical cells; CSF infectious studies negative	Enhanced mass lesion in R lateral ventricle with brainstem leptomeningeal enhancement	CS, whole brain RT	aLOC, CN palsy and ataxic respiration. Died 3 days after initiation of RT.	Autopsy: R lateral ventricle mass with fibrosis and inflammatory infiltrates. Medullary infiltrates. Cardiac fibrosis with myocardial eosinophils; BM: Normal	Intraventricular mass lesion and leptomeningeal disease
Grigoryan et al. [7]	48 M	HTN, obesity	5‐day h/o distal LE paresthesia + fatigue, focal deficits	HE; ANCA, IgG, TSH, T3, T4, RF normal; Infectious studies negative; ↑IgE, IL‐4, & IL‐5; BM aspirate: HE, no malignancy; Echo: no thrombus or vegetation.	Multifocal bilateral infarcts within and extending beyond watershed zones	IV MP	Resolved HE death 22 days after presentation	Autopsy: Multifocal infarcts with fibrin/platelet occlusion of small arterioles. Myocardial infarction; endocardial organizing thrombi	Multifocal ischemic infarctions
Battineni et al. [8]	46 F	Chronic sinusitis and HES (on therapy)	Diplopia, ptosis, and $\downarrow$ vision in L eye.	HE; SPEP normal; ↑serum IgE, parasite serology negative, PFTs negative for asthma; BM aspirate: hyperplastic BM with eosinophils	Mass in the left cavernous sinus with infiltration to adjacent structures	CS and imatinib	Improvement in L eye vision and motility, facial numbness. $\downarrow$ Mass size.	Biopsy: Nerves and BV surrounded by fibrosis, fat necrosis and infiltration by plasma cells, eosinophils, lymphocytes, and histiocytes.	Inflammatory pseudotumor
Kanno et al. [9]	34 F	N/A	Subcutaneous induration of left thigh	HE	CT head on day 30: hemorrhagic infarction of the L cerebral hemisphere	Day 19: steroids; Day 30: Craniotomy	Post‐operative deterioration, death on day 33.	Autopsy: L TST and hemorrhagic infarction. LV thrombi. Thrombophlebitis in L thigh, lungs, liver; BM: HE	L TST and hemorrhagic infarct
Sarazin et al. [10] (Patient 1)	51 M	2‐year history of HES (on hydroxyurea)	10‐day h/o progressive aLOC and left hemiplegia	HE; Echo and cardiac MRI: large scale endomyocardial fibrosis	CT and MRI head: multiple bilateral cerebellar and cerebral infarcts in distal vascular fields	AC, aspirin, high‐dose IV MP and short courses of Vepesid	Stabilized. 2 years later relapse of HE with infarcts leading to death.	Autopsy: Recent and old b/l infarcts watershed regions. Large scale endomyocardial fibrosis and LV thrombus.	Watershed acute and chronic infarcts

Abbreviations: ↑, increased; ↓, decreased; AC, anticoagulation; aLOC, altered level of consciousness; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; b/l, bilateral; BM, bone marrow; BV, blood vessels; CN, cranial nerve; CNS, central nervous system; CP, cyclophosphamide; CRP, C‐reactive protein; CS, corticosteroids; CSF, cerebrospinal fluid; Echo, echocardiogram; CT, computed tomography; ESR, erythrocyte sedimentation rate; h/o, history of; HA, headache; HE, hypereosinophilia; HES, hypereosinophilic syndrome; HHV‐6, human herpes virus 6; HSV, herpes simplex virus; HTN, hypertension; IgE, immunoglobulin E; IgG, immunoglobulin G; IHC, immunohistochemistry; IL, interleukin; IV, intravenous; L, left; LE, lower extremity; LP, lichen planus; LV, left ventricular; mo, months; MP, methylprednisolone; MPO, myeloperoxidase; MRI, magnetic resonance imaging; MTL, mesial temporal lobe; N/A, not available; OM, otitis media; PCA, posterior cerebral artery; PCR, polymerase chain reaction; PFTs, pulmonary function tests; PV, perivascular; R, right; RF, rheumatoid factor; RT, radiation therapy; sIL‐2R, soluble interleukin‐2 receptor; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; TST, transverse sinus thrombosis; VZV, Varicella Zoster virus; WM, white matter.

Similarly, the two patients presented herein demonstrated cerebral infarcts (watershed and embolic distributions), cerebral small vessel occlusion, and cardiac thrombi. These cases are unique in that they demonstrated abundant eosinophils in association with the cerebral infarcts, which speaks to potential pathomechanisms at play. It is possible that HE within the cerebral vasculature led to localized microthrombi formation because of eosinophil‐derived cytotoxic mediators, or this may represent cardioembolic infarcts derived from the known ventricular thrombus showing adjacent eosinophilic infiltrates (Patient 1). The precise mechanism leading to the various patterns of stroke in HES requires further research to be fully elucidated.

In summary, we present the pathology of two patients with CNS involvement of HES characterized by ischemic stroke. The cases illustrate the aggressiveness of CNS disease and the challenges of its medical management. We highlight the microscopic presence of eosinophils in association with the ischemic infarcts and discuss potential pathomechanisms.

Funding

This work was supported by the Mary Easton Center for Alzheimer disease at UCLA.

Ethics Statement

The authors have nothing to report.

Consent

Each patient's respective family provided informed consent for autopsy for diagnostic examination, education, and quality improvement.

Conflicts of Interest

The authors declare no conflicts of interest.

Martin K. C., Straathof D., Lai C., and Vinters H. V., “Ischemic Stroke in Hypereosinophilic Syndrome: A Clinicopathologic Study of Two Cases,” Neuropathology 46, no. 1 (2026): e70038, 10.1111/neup.70038.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.