以急性缺血性中風和心機酵素升高為表現的嗜酸性細胞增多綜合症 Hypereosinophilic syndrome presented as acute ischaemic stroke and raised cardiac enzymes

Hong Kong Journal of Emergency Medicine
Hypereosinophilic syndrome presented as acute ischaemic stroke and
raised cardiac enzymes
CY Cheung 張志遠, CL Fu 符朝麗, CS Li 李俊生
The hypereosinophilic syndromes (HES) are a group of disorders marked by the sustained overproduction
of eosinophils, resulting in multiple organ damage. We report a 55-year-old lady presented with sudden
onset of left-sided limb weakness and hypereosinophilia. Cerebral computerised tomography scan showed
multiple small infarctions in bilateral corona radiata and right thalamus. A transesophageal echocardiogram
revealed endomyocardial damage with mural thrombus suggesting Loeffler endocarditis. The multiple cerebral
infarctions were probably due to cardiac thromboembolism. Treatment with prednisolone led to significant
clinical improvement. This case illustrates hypereosinophilia should be considered in patients with multiple
cerebral infarctions. (Hong Kong j.emerg.med. 2012;19:349-352)
Keywords: Cerebral infaction, coronary thrombosis, endocarditis, hematopoietic system; steroids
The hypereosinophilic syndromes (HES) are a group of
disorders marked by the sustained overproduction of
eosinophils, resulting in multiple organ damage.
Cardiac involvement mostly presents as endomyocardial
damage, which may lead to thrombus formation and
Correspondence to:
Cheung Chi Yuen, PhD, MRCP
Queen Elizabeth Hospital, Department of Medicine,
30 Gascoigne Road, Kowloon, Hong Kong
Email: [email protected]
Fu Chiu Lai, MRCP
Li Chun Sang, FRCP
congestive heart failure. Thromboembolic strokes are not
uncommon. Here we report a patient, presented with
multiple cerebral infarctions and endomyocardial damage
was subsequently diagnosed to have HES.
A 55-year-old Chinese lady presented with 1-day
history of left-sided limb weakness. She had neither
chest pain nor shortness of breath. She had no
significant past medical history except bleeding gastric
ulcer. She never smoked or drank. Neurological
examination revealed left hemiparesis with muscle
power graded 2/5. Cardiac examination revealed a
pansystolic murmur over the apex with radiation to
axilla. Both lymphadenopathy and hepatosplenomegaly
were absent. The white cell count was 42.3x10 9/L
(eosinophil count 30.4x109/L, neutrophil count 9.5x109/L,
lymphocyte count 2.2x10 9/L and monocyte count
1.4x109/L). There were no blast cells in the peripheral
blood. The haemoglobin was 13.1 g/dL and the platelet
count was 158x10 9/L. The clinical history and basic
investigations did not reveal a clue to any identifiable
cause of hypereosinophilia which includes parasitic
infection, neoplasm, vasculitis or allergy. Moreover,
there were also no prior clinical signs and symptoms
suggestive of Churg-Strauss syndrome. The creatinine
kinase was 485 IU/L (normal <192 IU/L) and troponin I
12.2 ng/mL (normal <0.3 ng/mL). The blood glucose
was 4.4 mmol/L, total cholesterol was 3.9 mmol/L
(LDL-cholesterol=2.4 mmol/L, HDL-cholesterol=
0.6 mmol/L) and triglyceride was 1.9 mmol/L.
Autoimmune markers including antinuclear factor and
antineutrophil cytoplasmic antibodies were all negative.
The electrocardiogram showed sinus rhythm with
diffuse anterolateral ST segment depression. A
transesophageal echocardiogram showed ruptured
chordae tendineae of the anterior mitral valve leaflet
Hong Kong j. emerg. med.  Vol. 19(5)  Sep 2012
with severe mitral regurgitation. There was a small
thrombus at anterior mitral valve leaflet (Figure 1) with
heterogeneous infiltration around aor tomitral
junction. The blood culture revealed no bacterial
growth. The C-reactive protein was <3.4 mg/L.
Cerebral computed tomography (CAT) scan showed
multiple small non-enhancing hypodense areas in
bilateral corona radiata and right thalamus, which were
suggestive of recent cerebral infarction (Figure 2).
Doppler ultrasound of both carotid arteries did not
reveal any haemodynamically significant stenosis. Bone
marrow aspirate revealed marked eosinophilia (54%
of marrow myeloid cells) without evidence of abnormal
and/or clonal mast cells and T lymphocytes. Trephine
biopsy also revealed no abnormal cellular infiltrate.
There were no karyotypic abnormalities. Polymerase
chain reaction (PCR) for FIP1L1-PDGFRalpha gene
fusion was negative. PCR for BCR-ABL was also
She refused anticoagulation therapy and was given
clopidogrel. Moreover, prednisolone 60 mg daily was
started after the diagnosis of HES was confirmed. The
RA=right atrium; RV=right ventricle; LA=left atrium; LV=left ventricle
Figure 1. Transesophageal echocardiogram showing a small vegetation at anterior mitral valve leaflet (arrow).
Cheung et al./Hypereosinophilic syndrome
Figure 2. Cerebral computed tomography scan showed
multiple small hypodense areas in bilateral corona radiata and
right thalamus.
eosinophil count normalised within 3 days. The dosage
of corticosteroid gradually tailed down without
recurrence of hypereosinophilia. The limb muscle
power also gradually improved. The troponin I level
dropped to 0.12 ng/mL two weeks after hospitalisation
(3 days after corticosteroid). Coronary angiogram was
normal. She refused mitral valve replacement and also
defaulted follow up after discharge from hospital.
The HES are characterised by sustained overproduction
of eosinophils, in which eosinophilic infiltration and
mediator release can cause damage to multiple organs.1,2
The original definition of HES included three defining
features:3 (1) Blood eosinophilia of 1500/microliter,
present for more than six months. (2) No other apparent
aetiologies for eosinophilia, such as parasitic infection or
allergic disease. (3) Signs and/or symptoms of eosinophilmediated end-organ dysfunction. Some HES patients, as
in our patient, may require therapeutic interventions
before the six month period specified in the first criterion,
in order to treat or prevent potentially disabling or lifethreatening complications of sustained hypereosinophilia.
As a result, the six month duration criterion is no longer
applied in the modern definition because there is no
reason to withhold treatment in a patient with sustained
and potentially deleterious hypereosinophilia once
underlying diseases have been excluded. With the
recent advances in molecular and genetic diagnostic
techniques and recognition of different clinical
presentations, it was found that HES should encompass
a heterogeneous group of conditions: namely
'myeloproliferative variants (M-HES)', 'lymphocytic
variants (L-HES)', 'familial eosinophilia', 'undefined
HES', 'overlap eosinophilic diseases', and 'eosinophilassociated diseases'.2 The relative frequencies of these
variants are also not yet clear and may differ among
referral centres. M-HES results from clonal expansion
of eosinophilic precursors due to various mutations
while L-HES results from increased secretion of
eosinophilic cytokines like interleukin 5 by T
lymphocytes. However, most HES patients lack
aetiologic understanding for their hypereosinophilia
and belong to the 'undefined HES' subcategory. 2
Diagnosis of undefined HES requires the exclusion of
clonal eosinophilia and absence of phenotypically
abnormal and/or clonal T lymphocytes. This requires
careful assessment of the peripheral blood smear, bone
marrow morphologic features, cytogenetic analysis,
molecular studies including screening for FIP1L1PDGFRalpha gene fusion, and peripheral blood
lymphocyte phenotyping and T-cell receptor gene
rearrangement studies.
The most common presenting clinical manifestations
of HES are cardiac (54-73%), cutaneous (50-73%),
pulmonary (40-64%) and neurologic (35-73%).
Cardiac involvement is a major cause of mortality and
morbidity among patients with HES. 1,3,4 However,
recent data suggest that organ involvement may vary
considerably, based on the HES subtype. In fact, the
cardiac manifestations of HES are more likely to occur
with M-HES. Eosinophil-mediated cardiac damage
invo lves in creased numbers of eos inophils in
conjunction with other ill-defined stimuli that recruit
and/or activate eosinophils within the heart tissues.
Extracellular deposition of eosinophil granule proteins
and evidence of eosinophil activation are present at
sites of myocardial injury.4 Eosinophil-mediated heart
damage evolves through three stages: 1 (1) An acute
necrotic stage; (2) An intermediate phase characterised
Hong Kong j. emerg. med.  Vol. 19(5)  Sep 2012
by thrombus formation along the damaged
endocardium; (3) A fibrotic stage. Common findings
include shortness of breath, chest pain, signs of heart
failure, cardiomegaly, mitral or tricuspid regurgitation
and T wave abnormalities on the electrocardiogram.
Several reports have shown that contrast-enhanced
cardiac magnetic resonance imaging (MRI) reliably
detects all stages and aspects of eosinophil-mediated
heart damage, including the early stage of myocardial
eosinophilic inflammation. Endomyocardial biopsy
may be required to provide the definitive diagnosis
of eosinophil-associated cardiac involvement.
Echocardiography or cardiac MRI can demonstrate
intracardiac thrombi and may also show evidence of
fibrosis in the fibrotic stage. Elevated cardiac enzymes
in our patient can be sensitive indicators of early and
ongoing eosinophil-associated myocardial damage.
features of M-HES is the tyrosine kinase inhibitor,
imatinib mesylate. 7 Patients with co-existing cardiac
disease should receive concomitant glucocorticoids
when therapy with imatinib is initiated to prevent acute
necrotising myocarditis. However, cardiac symptoms
due to structural abnormalities resulting from
endomyocardial fibrosis, and fixed neurological deficits
may not improve with imatinib therapy.8,9
In conclusion, this case illustrates that HES might
cause endomyocardial injury and ischemic strokes. For
young patients with cerebral infarctions but without
traditional risk factors, early appropriate analysis of
the differential count of white blood cells would be
indicated to rule out this rare but treatable disease.
Neurologic presentations of HES are largely caused by
cerebral infraction, although other manifestations such
as encephalopathy, peripheral neuropathy, or longitudinal
and/or transverse sinus thrombosis may also occur.5 The
infarction in our patient is probably related to the tiny
emboli subsequent to intracardiac thrombus or
vegetations formation. Moreover, the symptoms can also
be attributed to the cerebrovascular endothelial damage
and neurotoxicity from eosinophilic degranulation related
to hypereosinophilia.5
Anticoagulation with warfarin and/or antiplatelet
agents is often instituted once an embolic event has
occurred. Warfarin is usually initiated for a mural
thrombus in the heart, or venous thrombus in an
intracranial sinus. Rapid lowering of the eosinophil
count is important. Patients with HES should be
evaluated for the presence of FIP1L1-PDGFRalpha
fusion. In patients who do not have the FIP1L1PDGFRalpha fusion, the mainstay of treatment is
corticosteroid. Prednisone challenge is best performed
at the time of diagnosis to ascertain whether blood
eosinophilia is suppressible by corticosteroids. A
prolonged eosinopenic response 4 to 12 hours after
administration is associated with better prognosis.
Hydroxyurea and interferon alfa have also been
effective in a number of small case series.6 On the other
hand, the first-line therapy for patients with FIP1L1PDGFRalpha-positive disease or patients with other
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