Abstract
Secondary eosinophilia has recently gained attention as a potential contributor to vascular pathologies, including aneurysms. This case report delves into the intricate relationship between secondary eosinophilia and cerebral aneurysms, a connection yet to be fully explored in medical literature. The case centers on a 31-year-old female who presented with leg pain, a purpuric rash, and gastrointestinal symptoms following an uncomplicated pregnancy. The skin biopsy revealed perivascular and interstitial dermatitis with a significant eosinophilic infiltration of unclear etiology. Laboratory investigations showed a markedly elevated immunoglobulin E (IgE) level at 8400 kU/L. Her condition escalated to a diffuse subarachnoid hemorrhage and the discovery of a left superior cerebellar artery aneurysm. This unusual presentation, combined with the challenge of differentiating secondary eosinophilia from primary eosinophilic disorders, raises questions about the pathophysiological mechanisms and clinical implications of eosinophils in aneurysm formation. We discuss the potential link between eosinophils and vascular damage and emphasize the need for further research in understanding this association. Clinically, this case underscores the importance of considering vascular complications in patients with unexplained eosinophilia. Sharing such cases contributes to a more informed and nuanced approach to similar future presentations, guiding diagnostic and therapeutic strategies.
Introduction
The link between aneurysms and secondary eosinophilia is a subject of growing interest in the field of vascular medicine. Eosinophils, primarily known for their roles in allergic and parasitic responses, have been increasingly recognized as potential contributors to vascular pathologies, including aneurysms. To date, no relationship between hypereosinophilia and cerebral aneurysms has been reported.
Clinical outcomes of eosinophilia vary based on the affected tissue, with eosinophil accumulation and activation leading to complications such as tissue fibrosis, thrombosis, and allergic inflammation. 1 Further exploration of this relationship has the potential to enhance our understanding of aneurysm pathophysiology and guide the development of more effective diagnostic and therapeutic strategies for patients with eosinophilia-associated aneurysms.
This case report explores the diverse array of potential vascular complications in patients presenting with unexplained eosinophilia. In addition, the role of eosinophils in tissue inflammation and damage, especially in the context of aneurysm formation, will be discussed. The clinical implications of eosinophilia are examined, with an emphasis on diagnostic challenges and potential therapeutic strategies.
Case Presentation
A 31-year-old female from Siberia, with an unremarkable past medical history and a recent uncomplicated pregnancy culminating in a cesarean section 3 months prior, presented with a chief complaint of progressive bilateral lower extremity pain that began 3 weeks ago. This pain had intensified over the past 2 days and was accompanied by a purpuric rash on the legs for the past week. In addition, she reported a week-long history of persistent vomiting, rendering her unable to retain any food, and several episodes of non-bloody diarrhea. This was coupled with epigastric abdominal pain. The patient had previously consulted her primary care physician regarding the leg pain, who attributed it to potential complications from epidural anesthesia. She denied any fever, chills, recent travel, consumption of raw food, or exposure to sick contacts.
Upon admission, her vitals were stable, and she was afebrile. Initial laboratory results are summarized in Table 1.
Laboratory results on admission.
The most significant laboratory finding was marked eosinophilia, both percent (74%) and absolute count (19.3 × 10³/µL). Urinalysis was unremarkable, hepatitis panel unremarkable, Influenza/RSV/COVID combo negative, blood cultures negative, and HIV screening test negative. An echocardiogram was promptly obtained that showed no structural or functional abnormalities, effectively ruling out myocarditis. Rheumatology was consulted, and recommended a skin biopsy. The pathology results from the skin biopsy revealed perivascular and interstitial dermatitis with a significant eosinophilic infiltration of unclear etiology, and negative for vasculitis (Figure 1). The patient’s breastfeeding status posed a challenge in medication selection, and methylprednisolone 40 mg IV daily was initiated with a recommendation to discard pumped milk for about 4 hours after administration. The patient subsequently noted some improvement in symptoms. Further laboratory investigations revealed a markedly elevated IgE level of 8400 kU/L, a slightly elevated IgG level of 1708 kU/L, and a mildly elevated IgD level of 15 kU/L, while IgA and IgM levels were within normal limits. Tryptase value was within normal limits. Antinuclear Antibody (ANA), Cytoplasmic Antineutrophil Cytoplasmic Antibodies (c-ANCA), and Perinuclear Antineutrophil Cytoplasmic Antibodies (p-ANCA) were all within normal limits, as were complement levels and angiotensin-converting enzyme levels. Urine protein electrophoresis was unremarkable. Serological testing for Lyme disease, Epstein-Barr virus, and Cytomegalovirus antibodies, as well as a comprehensive parasitic workup, including stool studies and tests for Strongyloides, yielded negative results.
Perivascular and interstitial dermatitis with a significant eosinophilic infiltration of unclear etiology (green arrow), and intact vascular wall lacking fibrinoid necrosis, supporting a non-vasculitic process (black arrow).
Given her persistent abdominal complaints and family history of rectal cancer in her mother at age 38, a computed tomography (CT) scan of the abdomen and pelvis was performed, revealing only omental thickening with no other significant findings. Gastroenterology was consulted, leading to an esophagogastroduodenoscopy and colonoscopy with biopsies taken. A distal esophageal biopsy revealed intraepithelial eosinophils (Figure 2). While this finding could be nonspecific, biopsies from the proximal or middle esophagus, which are typically needed for a definitive diagnosis of eosinophilic esophagitis, were not included in the sampling. Helicobacter pylori stool antigen came back positive, and the patient was started on amoxicillin 1 g BID, clarithromycin 500 mg BID, metronidazole 500 mg BID, pantoprazole 40 mg BID, and bismuth subsalicylate tablets for 14 days. The patient was advised regarding the side effects of the therapy, and she decided to stop breastfeeding. IV Steroid therapy was transitioned to oral prednisolone 60 mg daily. With a non-contributory rheumatological workup, hematology was consulted to rule out primary eosinophilia. A bone marrow biopsy with flow cytometry was performed, which demonstrated a normocellular marrow for her age with eosinophilia (29% of cells) without morphologic or immunophenotypic evidence of advanced myelodysplasia, acute leukemia, metastatic neoplasm, plasma cell neoplasm, or lymphoma. Fluorescence in situ hybridization test for myeloproliferative neoplasms with eosinophilia panel was negative for a deletion at 4q12 (including CHIC2) and fusion of the FIP1L1 and PDGFRA genes, negative for a rearrangement involving PDGFRB, and negative for a rearrangement involving FGFR1. Based on these results, the patient did not have classic hypereosinophilic syndrome and was diagnosed with secondary or reactive eosinophilia.
Biopsy of distal esophagus showing squamous mucosa with basal cell hyperplasia consistent with chronic mucosal irritation (green arrow) and intraepithelial eosinophils (black arrow).
On the tenth day of her hospital stay, the patient developed severe headaches, confusion, altered mental status, and hand cramps. A stroke code was activated, and an immediate CT scan of the head revealed a diffuse subarachnoid hemorrhage with communicating hydrocephalus and mild intraventricular hemorrhage, accompanied by diffuse sulcal effacement. A subsequent CT angiography (CTA) identified a fusiform aneurysm (6 mm × 4 mm) in the midportion of the left superior cerebellar artery, with no large vessel occlusion. A cerebral angiogram confirmed a ruptured fusiform aneurysm in the left superior cerebellar artery, along with unruptured right and left paraophthalmic segment aneurysms and aneurysmal dilatation of the distal right vertebral artery. No vasospasm was observed (Figure 3). The findings were consistent with Hunt and Hess grade III. The patient was promptly transferred to the neurosurgery unit, where a right frontal external ventricular drain (EVD) was placed, and Onyx embolization of the left superior cerebellar artery was performed (Figure 4). A repeat cerebral angiogram in the following days led to the successful endovascular occlusion of the right paraophthalmic aneurysm using a flow diverter. Interval CT head imaging showed a left cerebellar infarct and tract hemorrhage with intraventricular hemorrhage along the EVD, likely secondary to recirculation and an overall decrease in the amount of subarachnoid hemorrhage.
Cerebral angiogram showing an aneurysm arising from the mid-portion of the left superior cerebellar artery.
Cerebral angiogram after successful embolization of the left superior supra-cerebellar aneurysm.
She remained intubated for 6 days. The patient spiked a few fevers, for which respiratory culture, blood, and cerebrospinal fluid cultures did not show any growth. Infectious disease was consulted for possible eosinophilic meningitis; however, further imaging was deferred, and a tapered prednisone regimen was begun. On day 10 post-EVD placement, the EVD was discontinued after a 24-hour clamp trial, which was conducted after a CT head showed improved ventriculomegaly. The patient had persistent left hemiparesis and bilateral leg paresthesias, for which occupational therapy services were provided 5 times a week for 2 weeks to address balance, neuromuscular re-education, and activities of daily living. On post-subarachnoid hemorrhage day 24, the patient had laboratory results showing normalization of the white blood cell count and eosinophil count and was discharged to a rehabilitation facility on aspirin 81 mg daily, clopidogrel 75 mg daily, and a tapering dose of prednisone. She was given a referral on discharge to hematology and rheumatology. She followed up with the neurosurgery outpatient clinic 1 month later, presenting with residual left-sided dysmetria. A repeat diagnostic cerebral angiogram was recommended in 6 months. The procedure, performed by interventional radiology, showed an interval persistent occlusion of the previously ruptured left superior cerebellar artery aneurysm, interval occlusion of a right paraophthalmic segment aneurysm, no evidence of in-stent stenosis, and an interval stable angiographic appearance of a left paraophthalmic segment aneurysm. A 1-year angiographic follow-up was scheduled.
Discussion
The intricate interplay of secondary eosinophilia and the emergence of cerebral aneurysms, as observed in this case, is a relatively uncharted territory in medical literature. Eosinophilia, typically a marker of allergic reactions, parasitic infections, or certain systemic diseases, has seldom been linked directly to the formation or exacerbation of cerebral aneurysms.
Aneurysms are characterized by the localized weakening and dilatation of blood vessel walls, which can lead to life-threatening complications if left untreated. While primary aneurysms often result from genetic or degenerative factors, secondary aneurysms have been reported in the context of various diseases, including autoimmune disorders, vasculitis, and infections. Notably, secondary eosinophilia has been identified in a subset of aneurysm patients, suggesting a possible association between eosinophilic inflammation and aneurysm development.
Fukata et al reported multiple arterial aneurysms in a 45-year-old man diagnosed with hypereosinophilic syndrome at age 24. Despite his smoking history, long exposure to hypereosinophilia was suspected to contribute to the advancement of arterial aneurysms via eosinophil cytotoxicity. 2 Okinaka et al noted a case of multiple coronary artery aneurysms associated with idiopathic hypereosinophilic syndrome. 3 Demir et al observed a significant relationship between eosinophil count in patients with coronary artery ectasia compared to controls with normal coronary angiograms. 4 Gao et al took this association further and suggested the use of eosinophil count for risk stratification in coronary artery disease. 5 Similar vascular accidents were highlighted in a review of the vascular features of hyperimmunoglobulin E syndrome. One cerebral and 2 cases of aortic aneurysms were reported, although the autopsy of the patient with the ruptured cerebral aneurysm revealed a lymphocytic infiltrate instead of an eosinophilic infiltrate.6,7 Jakob et al noted eosinophilic infiltration of arterial walls and idiopathic blood eosinophilia in a 36-year-old man with 14 years of painless scalp swellings due to multiple aneurysms of the temporal artery. 8
Eosinophils are known to release a variety of pro-inflammatory mediators, such as eosinophil cationic protein and major basic protein, which can induce tissue damage.9,10 Moreover, eosinophils can interact with other immune cells and contribute to a pro-inflammatory microenvironment, potentially leading to endothelial dysfunction and tissue remodeling. 11 In addition, a growing body of evidence suggests that chronic inflammation and autoimmune responses also play a crucial role in aneurysm pathogenesis.8 -10,12
Elevated levels of eosinophils resulting from different factors could be linked to hypereosinophilic syndrome, which includes conditions such as endomyocardial fibrosis, valvular lesions, and dysfunction in the respiratory, gastrointestinal, and nervous systems. In our patient, the absence of common triggers for eosinophilia, such as parasitic infections or known allergic reactions, further complicates the clinical picture. The concomitant presentation of esophagitis with eosinophil infiltration, and skin biopsy also showing eosinophil infiltration, suggests a systemic hyper-eosinophilic response, the etiology of which remains elusive. However, she does not meet the established criteria for eosinophilic granulomatosis with polyangiitis, periarteritis nodosa, or temporal arteritis, conditions occasionally associated with aneurysms and eosinophilia.13 -16
The negative results from the bone marrow biopsy and molecular studies rule out primary eosinophilic disorders, further emphasizing the rarity and complexity of this case. Despite lacking organ involvement and testing negative for autoantibodies, including anti-neutrophil cytoplasmic antibodies, the histological evidence of eosinophil infiltration suggests eosinophil-mediated vascular injury leading to aneurysm formation. Although vasculitis is not a prominent feature of idiopathic secondary eosinophilia, our case suggests that the cerebral arteries may be one of the target tissues of this syndrome.
In this patient’s case, corticosteroid therapy was used to manage complications related to eosinophilia and subsequent brain hemorrhage with aneurysms. Rheumatology recommended starting with methylprednisolone 40 mg daily, advising the patient to discard breast milk for the first 4 hours after administration. The treatment was later transitioned to oral prednisolone 60 mg daily. Following the brain hemorrhage, hematology adjusted the dose of prednisolone to 50 mg daily to address cerebral inflammation, reduce cerebral edema, and stabilize the blood-brain barrier. Corticosteroids are effective in reducing vascular permeability and controlling intracranial pressure, which is particularly critical in the context of eosinophilia, a condition known for heightened inflammatory responses that can exacerbate hemorrhagic events.
After initial stabilization, hematology recommended a gradual tapering of the steroid dose: reducing prednisolone to 40 mg daily, then to 30 mg after 10 days, and subsequently to 20 mg. This cautious tapering approach was advised to prevent potential withdrawal effects and allow for the gradual resolution of inflammation. The patient was discharged with specific instructions on how to taper the steroids slowly, highlighting the importance of adherence to this regimen to avoid a rebound of inflammatory symptoms. In addition, follow-up appointments with neurosurgery and hematology were arranged to monitor the patient’s progress and to reassess the need for ongoing therapy as needed. Corticosteroid use in managing cerebral edema is supported by the literature, demonstrating its role in reducing intracranial pressure, stabilizing cerebral perfusion, and preventing secondary brain injury.17,18
As highlighted by this case, identifying secondary eosinophilia in patients with aneurysms may have clinical implications. It could aid in risk stratification, as aneurysms associated with eosinophilic inflammation may exhibit different natural histories or responses to therapy. In addition, therapeutic strategies aimed at modulating eosinophilic inflammation, such as corticosteroids or immunomodulatory agents, may be considered in select cases to manage aneurysms more effectively. 19 The relationship between eosinophilia and aneurysms is an emerging area of research. Further investigations are needed to elucidate the specific mechanisms by which eosinophils contribute to aneurysm pathogenesis and whether targeting eosinophilic inflammation can provide therapeutic benefits. This warrants large-scale clinical studies to establish the prevalence of eosinophilia in aneurysm populations and to assess its impact on outcomes and treatment strategies.
Conclusion
While the direct causative link between eosinophilia and cerebral aneurysms remains to be established, this case prompts clinicians to be vigilant about potential vascular complications in patients presenting with unexplained eosinophilia. Further exploration of this relationship has the potential to enhance our understanding of aneurysm pathophysiology and guide the development of more effective diagnostic and therapeutic strategies for patients with eosinophilia-associated aneurysms. Sharing such unique cases enriches the collective knowledge of the medical community, fostering a more informed and nuanced approach to similar future presentations.
Footnotes
Acknowledgements
We are grateful to our colleagues and the medical staff at Maimonides Medical Center for their support and assistance throughout this process. Special thanks to Dr. Somal for her invaluable insight, clinical judgment, and effective patient management that greatly enhanced the quality and depth of this case.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent
Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
Guarantor
Rita Dennise Moncayo Wilches.
