Hira et al. BMC Neurology
(2019) 19:288
https://doi.org/10.1186/s12883-019-1515-z

CASE REPORT

Open Access

Multiple cerebral infarction diagnosed as
Eosinophilic Granulomatosis with
Polyangiitis by autopsy
Kenichiro Hira1, Hideki Shimura1* , Riyu Kamata1, Masashi Takanashi2, Akane Hashizume3, Keiji Takahashi1,
Mizuho Sugiyama1, Hiroshi Izumi3, Nobutaka Hattori4 and Takao Urabe1

Abstract
Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of unknown cause
involving the brain and accompanied by prominent eosinophilia. Intracardiac thrombosis is a major cardiac
complication of EGPA that may cause thromboembolism.
Case presentation: A 53-year-old man presenting with abulia (consciousness disturbance) and left upper limb
paralysis was admitted to our hospital. His case was complicated by penetrating branches, small vessel infarcts, and
endocardial thrombosis in the right and left ventricle. Cardiomyopathy was also observed. Sixteen days after
admission, the patient died from intracranial hemorrhage. Brain autopsy revealed two major findings: 1) large
hemorrhagic infarction caused by cardiac embolism; and 2) granuloma and eosinophil infiltration. Vasculitis was
accompanied by eosinophil infiltration in the cortical blood vessels and granuloma.
Conclusions: In this case study, we report autopsy findings of brain infarction in a patient with EGPA and endocardial
thrombosis. The brain infarction was caused by the cardiac embolisms and vasculitis.
Keywords: Eosinophilic granulomatosis with polyangiitis (EGPA), Multiple cerebral infarction, Hypereosinophilia,
Intracardiac thrombus

Background
Eosinophilic granulomatosis with polyangiitis (EGPA)
causes bronchial asthma and allergic rhinitis as a preceding symptom and results in vasculitis accompanied
with eosinophilia [1, 2]. In rare cases, EGPA is thought
to exhibit multiple cerebral infarction in cortical, subcortical, and watershed areas, and mechanisms of vasculitis and special granules secreted by eosinophils have
been considered [3]. Furthermore, because of the presence of left ventricular thrombus due to eosinophilic
myocarditis, embolism is considered a cause, but the
details are unknown [3].
Here, we describe pathological findings showing brain
infarction caused by both cardiac embolism and eosinophilic vasculitis in a patient with EPGA.
* Correspondence: miurashimura@yahoo.co.jp
1
Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1
Tomioka, Urayasu, Chiba 279-0021, Japan
Full list of author information is available at the end of the article

Case presentation
A 53-year-old man, with no medical history, was diagnosed with influenzae virus infection and was administered oseltamivir phosphate 2 weeks before developing
ischemic stroke. There was no prior bronchial asthma or
allergic rhinitis. There were no symptoms such as weight
loss, polyneuropathy, myalgia, arthralgia, or gastrointestinal bleeding. There were no abnormalities in blood collection as a result of the physical examination. He was
found by a neighbor at home in a left lateral decubitus
position and was taken to our hospital. He presented
with abulia and left upper limb paralysis. He was in a
state of collapse for several days, and there were decubituses in the left upper and lower limbs. In addition, he
showed disseminated intravascular coagulation and was
in a septic state. Vital signs showed mild fever (body
temperature: 37.7 °C), but blood pressure, pulse rate, respiratory rate, and arterial oxygen saturation by pulse
oxymetry were within normal ranges. Chest X-ray and

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Hira et al. BMC Neurology

(2019) 19:288

computed tomographic imaging of the chest showed no
abnormality. An electrocardiogram showed ST depression in chest leads indicating either ischemic change
along the entire circumference of the heart or cardiomyopathy. Laboratory findings showed no leukocytosis
(8900 /μl; normal range, 4000–8000 /μl), but hypereosinophilia (1020 /μl; normal range, 0–400 /μl) and an elevated IgE (9372 IU/ml; normal range, 18–501 IU/ml).
Elevated CRP (6.4 mg/dl; normal range, 0–0.3 mg/dl)
was observed. Prothrombin time international normalized ratio was 1.37, activated partial thromboplastin time
was 30.5 s, D-dimer was 37.8 μg/dl (normal range, 0–
1 μg/dl), fibrinogen degradation products was 79.9 μg/dl
(normal range, 0–5 μg/dl), fibrinogen was 261 mg/dl
(normal range, 150–400 mg/dl), and soluble fibrin was
114.4 μg/dl (normal range, 0–7 μg/dl). Protein S total
level was 57% (normal range, 60–150%) and activity was
28% (normal range, 73.7–146.3%). Protein C was within
normal range. Myeloperoxidase-antineutrophil cytoplasmic antibodies and cytoplasmic ANCA were negative. Viruses and fungi that cause myocarditis, such as
human immunodeficiency virus, adenoviruses, group
A and B coxsackieviruses, Cytomegalovirus, echovirus,
Epstein-Barr virus, influenza A and B viruses, Candida
antigens, and Aspergillus antigens were all negative
by blood tests. A bone marrow biopsy was also performed at autopsy. There was no clonality on flow
cytometry. The FIP1L1–PDGFRA fusion gene (4q12)
was not detected by fluorescence in situ hybridization.
Bone marrow findings showed no hematologic malignancies causing hypereosinophilia.
Magnetic resonance imaging of the brain revealed ischemic infarcts in the left caudate nuclei, bilateral cortex, subcortical region, bilateral watershed area, brain

Page 2 of 4

stem, and cerebellum (Fig. 1a). No obvious blood vessel
obstruction or stenosis was observed by magnetic resonance angiography. Transthoracic echocardiography
showed intramural thrombus with left ventricle and
right ventricle involvement. Ejection fraction and wall
motion were within normal ranges, and there were no
valvular disease. In carotid ultrasonography, hypertrophy of the intima-media thickness and blood flow
abnormality were not observed.
The patient was diagnosed as reactive hypereosinophilic syndrome (HESR). He was administered 200 mg/day
aspirin for acute cerebral infarction. Consciousness disturbance began to improve. Since we confirmed intracardiac thrombus by cardiac ultrasound on hospital day
5 (Fig. 2a, b), he was administered 14,800 units of
unfractionated heparin for 24 h. On hospital day 6, his
consciousness level worsened to coma caused by cerebral hemorrhage. We performed a burr-hole evacuation,
but, on hospital day 16, he died.
Autopsy was conducted with the family’s consent.
Autopsy findings revealed the following: 1) granulomas
with epithelial cells and eosinophil infiltration; and 2)
vasculitis accompanied by fibrinoid necrosis in the kidney, lung, colon, gallbladder, stomach, liver, spleen,
heart, and pancreas. In the left ventricle of the heart,
thickening of the wall, narrowing of the lumen, and
thrombosis was observed around the circumference
(Fig. 2c). Thrombus was also observed in the right ventricle (Fig. 2c). Granuloma formation was present in the
blood vessels of the right coronary artery and, in the left
ventricular myocardium, myocardial cell shedding, inflammatory cell infiltration such as macrophages and lymphocytes, and partial fibrosis were observed. The brain was
severely damaged by infarction with hemorrhage (Fig. 1b).

Fig. 1 Diffusion Weighted Magnetic Resonance Imaging of cerebrum (a) / brain autopsy findings (b) / Eosinophilic granulomatosis in brain (c).
On admission, there were multiple infarctions which had a mixture of small infarction and large hemorrhagic infarction. Multiple small cerebral
infarct lesions in the cortex and subcortex were caused by vasculitis and eosinophil infiltration

Hira et al. BMC Neurology

(2019) 19:288

Page 3 of 4

Fig. 2 Intramural thrombus in left (a) and right ventricle (b) detected by transthoracic echocardiography. / Formalin-fixation of left ventricle (c).
Both ventricular chambers were narrowed by the thrombus. Scale bar: 100µm

In addition to thromboembolic infarction, we observed
vasculitis accompanied by eosinophil infiltration in the
parenchymal small arteries. The autopsy findings indicated that the patient had systemic eosinophilic polyangiitis that included the brain (Fig. 1c). Pathological study
revealed that the cause of the cerebral infarction was the
coexistence of cardiogenic cerebral embolism and cerebral
vasculitis with eosinophilic infiltration by EGPA.

Discussion and conclusions
EGPA is a vasculitis syndrome also known as allergic
granulomatous angiitis or Churg Strauss syndrome.
EGPA is a part of HESR, in which asthma and allergic
rhinitis appear and symptoms due to vasculitis develop
[1]. Symptoms of EGPA are peripheral neuritis, purpura,
gastrointestinal ulcer, cerebral infarction, cerebral
hemorrhage, and epicarditis [2]. The annual incidence of
EGPA is approximately 2.7–3.4/million [4]. EGPA treatment includes prednisolone, immunosuppressants, and
gamma globulin [5]. The prognosis in approximately
90% of patients is remission within 6 months [6]. Our
patient did not have asthma, neuropathy, or other clinical symptoms before the onset of stroke. The 5-year
survival rate of EGPA may be as high as 70%, but advanced age (≥65 years old), myocardial disorder, impaired renal function (Cr > 1.58 mg/dl), and severe
gastrointestinal ischemia are detrimental prognostic factors [7]. In particular, myocardial injury is correlated
with a high risk of death [8]. Approximately 50% of
EGPA cases are ANCA positive [8]. In positive cases, the
recurrence rate tends to be high and the death rate tends
to be low, while, in negative cases, the recurrence rate is
low (8.7%) and the mortality rate tends to be high [8].
Compared to ANCA-positive patients, ANCA-negative
patients show cardiomyopathy more frequently, and
their mortality rate is higher. On the other hand, the risk
of relapse may be lower. In addition, ANCA positive patients tend to have more clinical vasculitis manifestations, such as peripheral neuropathy or renal disfunction
[8]. While the difference between ANCA-negative EGPA
and HES, the therapeutic effect is reported to be better

and faster with EGPA than with HES [8]. About 50–60%
of people diagnosed with HES are reported to have myocarditis [9], and about 35–65% of patients diagnosed
with HES have neurological complications [10, 11].
Therefore, if eosinophils are increased in patients with
myocarditis and there are no neurological complications,
ANCA-negative EGPA should be considered.
Cerebral infarction occurs in 3–10% of EGPA cases
[12]. A mechanism of cerebral infarction is that proteins,
such as major basic protein and eosinophil peroxides, secreted from eosinophils activated by IL-5 impair nerve
tissue and local thrombosis results from tissue factor in
secretory granules [13, 14]. In addition, eosinophilia may
cause microthrombosis by increasing procoagulant activity or increasing blood viscosity and decreasing the
clearance of microthrombus [13, 14]. Cardiogenic embolism is the most likely cause of cerebral infarction in
the watershed area. A total of 16.4% of patients with
EGPA have myocarditis, but the occurrence of intracardiac thrombosis is rare [8]. Our literature search revealed only 24 cases of EGPA developing cerebral
infarction, of which, 8 cases had myocarditis and 3 cases
had intracardiac thrombosis. All of those cases were diagnosed as EGPA at the time of arrival at hospital. Interestingly, our patient developed cerebral infarction
without allergic symptoms or asthma. For the diagnosis
of EGPA, it is important to clarify the presence of
microvascular granulomatosis or fibrinoid necrotizing
vasculitis with marked eosinophil infiltration by tissue
biopsy. However, in this case, tissue biopsy could not be
performed due to exacerbation of the patient’s general
condition, and granulomas and vasculitis with eosinophil
infiltration of the whole body organs was confirmed by
post mortem examination. In this case, the patients had
ventricular thrombus as well as hypereosinophilia. We
could not use high dose steroids, since high dose steroids might worse thrombus.
In this study, we report the pathological determination
of cerebral infarction in a patient with EGPA. Pathological study revealed that the mechanism of cerebral infarction included multiple factors of vasculitis,

Hira et al. BMC Neurology

(2019) 19:288

Page 4 of 4

eosinophil infiltration, and embolism caused by intracardiac thrombus. Thus, we speculate that 1) the watershed
area and multiple cerebral infarct lesions in the cortex
and subcortex were caused by vasculitis and eosinophil
infiltration, while 2) the relatively large infarction lesions
(Caudate nucleus) and penetration of the infarcts found
in the branch area were caused by cardiac embolism.
We propose that myocarditis and intracardiac
thrombus should be investigated when a large infarct lesion is observed in EPGA patients. Since pathological
findings revealed that large infarction was caused by cardiac embolism and small infarction was caused by vasculitis, EGPA should be considered in cases of multiple
cerebral infarction and increased eosinophils.

4.

Abbreviation
EGPA: Eosinophilic granulomatosis with polyangiitis

9.

Acknowledgements
None

10.

Authors’ contributions
Acquisition of data: KH, HS, RK, MT, AH, KT, MS. Drafting of the manuscript:
KH, HS, MT. Critical revision of the manuscript for important intellectual
content: HI, NH, TU. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All the data supporting our findings are provided within the manuscript.
Ethics approval and consent to participate
Authors’ institution does not require ethical approval for publication of a
single case report. Written informed consent was obtained from the patient’s
parents.
Consent for publication
Written informed consent was obtained from the patient’s parents for
publication of this Case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1
Tomioka, Urayasu, Chiba 279-0021, Japan. 2Department of Neurology,
Juntendo University Koshigaya Hospital, 560 Fukuroyama, Koshigaya, Saitama
343-0032, Japan. 3Department of Pathology, Juntendo University Urayasu
Hospital, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan. 4Department of
Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan.
Received: 2 August 2019 Accepted: 28 October 2019

References
1. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012
revised international Chapel Hill consensus conference nomenclature of
Vasculitides. Arthritis Rheum. 2013;65(1):1–11. https://doi.org/10.1002/art.
37715.
2. Greco A, Rizzo MI, De Virgilio A, Gallo A, Fusconi M, Ruoppolo G, et al.
Churg-Strauss syndrome. Autoimmun Rev. 2015;14(4):341–8. https://doi.org/
10.1016/j.autrev.2014.12.004.
3. Ghaeni L, Siebert E, Ostendorf F, Endres M, Reuter U. Multiple cerebral
infarctions in a patient with Churg-Strauss syndrome. J Neurol. 2010;257(4):
678–80. https://doi.org/10.1007/s00415-009-5439-1.

5.

6.

7.

8.

11.
12.

13.

14.

Watts RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic
vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum. 2000;
43(2):414–9. https://doi.org/10.1002/1529-0131(200002)43:2<414::AIDANR23>3.0.CO;2-0.
Iwaki K, Ito T, Kitaoka H, Nakajima H. Multiple cerebral infarctions in a
patient with Churg-Strauss syndrome: A case report. Rinsho Shinkeigaku.
2013;53(7):559–62.
Tsurikisawa N, Oshikata C, Kinoshita A, Tsuburai T, Saito H. Longterm
prognosis of 121 patients with Eosinophilic Granulomatosis with Polyangiitis
in Japan. J Rheumatol. 2017;44(8):1206–15. https://doi.org/10.3899/jrheum.
161436.
Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al.
Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A
prospective study in 342 patients. Medicine (Baltimore). 1996;75(1):17–28.
Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF,
et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical
characteristics and long-term followup of the 383 patients enrolled in the
French Vasculitis study group cohort. Arthritis Rheum. 2013;65(1):270–81.
https://doi.org/10.1002/art.37721.
Ogbogu PU, Rosing DR, Horne MK 3rd. Cardiovascular manifestations of
hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007;27(3):
457–75. https://doi.org/10.1016/j.iac.2007.07.001.
Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic
hypereosinophilic syndrome. Ann Intern Med. 1985;102(1):109–14. https://
doi.org/10.7326/0003-4819-102-1-109.
Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood.
1994;83(10):2759–79.
Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. ChurgStrauss syndrome. Clinical study and long-term follow-up of 96 patients.
Medicine (Baltimore). 1999;78(1):26–37.
Nakaoku Y, Mizumoto C, Hagiwara M, Okuno T, Matsui M. Autopsy findings
in case of peripheral T-cell lymphoma with multiple infarctions in setting of
eosinophilia. Jpn J Stroke. 2014;36:361–5.
Ishii J, Yamamoto S, Yoshimura H, Todo K, Kawamoto M, Kohara N. Multiple
cerebral infarctions in a patient with hypereosinophilic syndrome with
Loffler endocarditis: a case report. Rinsho Shinkeigaku. 2015;55(3):165–70.
https://doi.org/10.5692/clinicalneurol.55.165.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.