Case Report

€ffler Endocarditis with Multiple Cerebral Embolism Lo Shuzhen Wang, MD, Aiqin Wang, BD, Bin Guo, MD, Shaowei Zhu, MD, Zhaofu Chi, MD, and Xiuhe Zhao, PhD

Idiopathic hypereosinophilic syndrome is an uncommon leukoproliferative systemic disorder characterized by the sustained eosinophilia and target organ damage. We report the case of a 56-year-old man presenting with multiple cerebral embolism, L€ offler endocarditis, and hypereosinophilia. This patient also had pleural, bone marrow, and skin involvement. The unique feature was multifocal embolisms in the brain. Key Words: L€ offler’s endocarditis—cerebral embolism—hypereosinophilic. Ó 2013 by National Stroke Association

Introduction Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by persistent eosinophilia with manifestations in various organ systems.1 It is a rare condition with an unknown prevalence and poor prognosis. Cardiac involvement is common in HES, and eosinophilic myocarditis is a major cause of morbidity and mortality among patients with HES.2 In 1936, L€ offler reported 2 patients who had marked peripheral eosinophilia and a peculiar type of fibrosing endomyocarditis, which is known as L€ offler endocarditis.3 Brain infarcts are because of either thromboembolism from endomyocardial fibrosis or vascular endothelial toxicity of eosinophilic cells. Cerebral infarction as a complication of HES is rarely documented. Here we report a rare case of a 56-year-old man presenting with multiple cerebral embolism, L€ offler endocarditis, and hypereosinophilia.

From the Department of Neurology, Qilu Hospital, Shandong University, Jinan, Shandong Province, China. Received September 21, 2013; revision received October 22, 2013; accepted October 24, 2013. Conflicts of interest: Nothing to report. Address correspondence to Xiuhe Zhao, PhD, Department of Neurology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong Province, China. E-mail: zhaoxiuhe@sdu. edu.cn. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.023

Case Report A 56-year-old man was admitted to the hospital in July 2013 with continuous left hand numbness and headache for a duration of 1 week. He had no fever, cough, dyspnea, and chest pain. He had paroxysmal left hand numbness 2 months before this attack. He had history of bad-controlled diabetes for 8 years and a surgery history of varicose veins in both lower limbs 5 years ago. He was a farmer, lived in his birthplace, and never moved out of his county. There was no family history of such disease. The man did not complain of palpitations, peripheral edema, fever, chills, sweats, weight loss, use of tobacco or alcohol, intravenous drug abuse, or other risk factors for human immunodeficiency virus infection. He had a temperature of 35.9 C, respiration rate of 18, a blood pressure of 124/78 mm Hg, and a pulse rate of 96 beats/minute. On physical examination, there were sporadic erythematous papules through the prothorax and arm pits. A grade 4/6 harsh systolic murmur was heard at the precordium, and the oxygen saturation was 100% in room air. Neurologic examination showed that the left upper limb muscle power was 4/5 grade. No other abnormalities were found. Laboratory evaluation revealed a white blood cell count of 18.91 3 109/L (normal values, 4-10 3 109/L), of which 13.48 3 109/L were eosinophils (71.30%, normal values: 0-.5 3 109/L, or 0%-5%), neutrophil count of 4.02 3 109/L, 21.30% (normal values: 2-7 3 109/L, or 50%-70%), lymphocyte count of .95 3 109/L, 5.00%

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(normal values: .8-4 3 10 /L, or 20%-40%), urea nitrogen 8.90 mmol/L (normal values: 2.30-7.80 mmol/L), and lactate dehydrogenase 552 U/L (normal values: 120-230 U/L). Antinuclear antibodies, C-reactive protein, antineutrophil cytoplasma antibodies, blood coagulation, and erythrocyte sedimentation rate were all within normal limits. Stool samples for parasites and urine analysis were negative. Twenty days later after treatment, his peripheral eosinophil count was .29 3 109/L (4.2%), which was normal. A bone marrow biopsy revealed marked eosinophilia with 51% eosinophils but no evidence of abnormal myeloid maturation. His chest computerized tomography scan revealed mild bilateral pleural effusions, inflammation, pulmonary hypertension, and supraclavicular lymphadenectasis. Transthoracic echocardiography showed mild to moderate mitral regurgitation, severe tricuspid regurgitation, and moderate pulmonary hypertension with a peak systolic pulmonary artery pressure of 63 mm Hg. The left ventricular filling was reduced because of endocardial thickening together with a large mass in the left ventricular apex, which was suggestive of a thrombus. The echocardiography also revealed congenital cardiopathy with bicuspid aortic valve and aortic regurgitation. The left ventricular size and ejection fraction were normal. Doppler studies detected restrictive-type diastolic filling with an E/A ratio greater than 2 and decreased deceleration time (102 ms). The first magnetic resonance imaging scan of the brain in his local hospital disclosed multifocal infarctions. Ischemic lesions were seen in bilateral frontal, parietal, temporal, occipital lobe, cerebellum, and corpus callosum (Fig 1). After he came to our hospital, we gave him another examination of cranial magnetic resonance imaging, which showed multiple infarctions in cortical, subcortical, and white matter of both hemispheres, better than the first (Fig 2). And the cervical magnetic resonance angiography was normal. The diagnosis was confirmed as multiple cerebral embolism, L€ offler endocarditis, and idiopathic hypereosinophilic syndrome. Oral anticoagulation with warfarin sodium (3 mg/d) and immunosuppression with 1 mg/ 9

kg/d prednisone were initiated promptly. The treatment also included hydroxycarbamide, furosemide, betablocker metoprolol, and neuroprotective, including edaravone and citicoline. Ten days later, with the improvement of neurologic function, he was transferred to the Hematology Department for further treatment.

Discussion Diagnosis of HES is based on 3 criteria1: (1) an eosinophil count of more than 1500 cells per microliter for at least 6 months, (2) no other evident cause for eosinophilia, including allergic diseases and parasitic infection, and (3) sign or symptoms of organ involvement by eosinophilic infiltration. The exact mechanism of eosinophil-induced tissue damage is not known, but eosinophils are directly cytotoxic and can affect a local release of toxic substances like enzymes, reactive oxygen species, proinflammatory cytokines, and arachidonic acid–derived factors. Hypereosinophilic syndrome occurs at any age, though most cases occur between 20 and 50 years of age, with a peak in the fourth decade of life. More than 90% of patients with HES are men, and the reason is unknown.2 Clinical manifestations of HES are markedly heterogeneous as the disease can either be completely asymptomatic or involve multiple organs.4 In essence, any organ is vulnerable to eosinophilia-associated tissue damage. Major tissue targets include the skin, heart, and nervous system. Other target regions including the lung, gastrointestinal system, articulations, liver, kidneys, and retinal vein may show a variety of additional symptoms. Cutaneous manifestations generally consist of pruritus, erythematous papules, nodules, uricaria, angioedema, mucosal ulcers, and eosinophilic cellulitis. This patient had sporadic erythematous papules through the prothorax and arm pits. Cardiovascular complications are a major source of morbidity and mortality, which are found in 40%-50% of the cases. Cardiac involvement includes progressive subendocardial fibrosis with overlying mural thrombus formation leading to peripheral emboli and restrictive cardiomyopathy, which manifest clinically as heart failure, thromboembolic events, and atrial fibrillation. The classic

Figure 1. Magnetic resonance imaging (MRI) changes coinciding with a favorable turn of the clinical presentation. A diffusion-weighted imaging (DWI) of MRI scan taken 2 days after his onset in the local hospital showed multiple hyperintense lesions in frontal, parietal, temporal, occipital region of both hemispheres, cerebellum, and corpus callosum.

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Figure 2. In parallel to the clinical improvement, DWI findings also ameliorate as seen on a subsequent scan performed 5 days later. The known lesions had decreased.

echocardiographic findings in HES include endomyocardial thickening, 1eft and right ventricular apical thrombus formation, and posterior mitral leaflet involvement. Except the common features mentioned earlier, our patient also had a congenital cardiopathy with bicuspid aortic valve. Neurologic complications involve both the central and peripheral nervous systems. Although patients with either reactive or idiopathic IHS have a high incidence of central nervous system involvement, and particularly brain infarction, most reports omit to detail neurologic examination or cerebral or cardiac imaging, giving no idea of the potential mechanisms of the brain artery occlu-

sions.5 Microembolism in our case was the result of large-scale endomyocardial fibrosis, which is a common finding in hypereosinophilic syndrome, although it is an extremely rare cause of brain infarction. Vasculitis is an inflammation of the vessel wall. Vessels of any type in any organ can be affected, resulting in a wide variety of signs and symptoms.6 Central nervous system angiitis should be differentiated from diseases with multifocal cerebral thromboembolism. Churg–Strauss syndrome is a less common form of vasculitis characterized by an eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis

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affecting small-to-medium vessels. Based on the patient’s history and our clinical observations, the patient could be diagnosed as Churg–Strauss syndrome. Even though cerebral infarctions as a secondary complication of L€ offler endocarditis seem probable, and his cranial magnetic resonance angiography is normal, small-vessel vasculitis cannot be completely ruled out. There is still no definite therapy for idiopathic HES. Corticosteroids were initially the mainstay of HES treatment and are currently recommended as first-line therapy.7 Symptomatic patient should be treated with steroid therapy, prednisolone in a dose of 1 mg/kg/d until clinical improvement occurs, after which the dose should be tapered gradually. Symptomatic patients nonresponsive to steroids should be offered chemotherapeutic agents. The common chemotherapeutic drugs used include hydroxyurea, vincristine, 6-mercaptopurine, busulphan, and chlorambucil.8 Interferon-alpha is recommended for use in HES patients with organ damage and corticosteroid/cytotoxic treatment failure.9 The secondary treatment should be directed at cardiac complications, for example, heart failure and the presence of intracardial thrombus. Occasionally, surgical therapies are needed for cardiovascular complications. Surgical experience of patients with valvular dysfunction secondary to HES is limited, but in more severe cases, acute surgical intervention may be necessary.10 Our patient had idiopathic hypereosinophilic syndrome and cerebral, cardiac, pleural, bone marrow, and skin involvement. The unique feature is the multiple embolism almost throughout the cerebrum, which is presumed because of the endomyocardial fibrosis. By reviewing the literature, there is a rare report like such dispersed infarction in HSE patients. He had no clinical presentation of heart failure and other cardiopathy. Maybe this is because of the early detection. And the

congenital malformation of the heart is thought to be possibly a casual occurrence. We suggest that in the case of bilateral multiple, small, border-zone infarction without proximal large-vessel occlusion, cardiac source of microembolism should be ruled out, and HES should be considered in patients with ischemic stroke and hypereosinophilia.

References 1. Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Intern Med 1968;68:1220-1229. 2. Coelho-Filho OR, Mongeon FP, Mitchell RN, et al. L€ offler endocarditis presenting with recurrent polymorphic ventricular tachycardia diagnosed by cardiac magnetic resonance imaging. Circulation 2010;122:96-99. 3. Parrillo JE. Heart disease and the eosinophil. N Engl J Med 1990;323:1560-1561. 4. Weingarten JS, O’Sheal SF, Margolis WS. Eosinophilic meningitis and the hypereosinophilic syndrome. Case report and review of the literature. Am J Med 1985; 78:674-676. 5. Sarazin M, Caumes E, Cohen A, et al. Multiple microembolic borderzone brain infarctions and endomyocardial fibrosis in idiopathic hypereosinophilic syndrome and in Schistosoma mansoni infestation. J Neurol Neurosurg Psychiatry 2004;75:305-307. 6. Carolei A, Sacco S. Central nervous system vasculitis. Neurol Sci 2003;4(Suppl 1):S8-S10. 7. Tefferi A. Modern diagnosis and treatment of primary eosinophilia. Acta Haematol 2005;114:52-60. 8. Sen T, Ponde CK, Udwadia ZF. Hypereosinophilic syndrome with isolated Loeffler’s endocarditis: complete resolution with corticosteroids. J Postgrad Med 2008; 54:135-137. 9. Wilkins HJ, Crane MM, Copeland K, et al. Hypereosinophilic syndrome: an update. Am J Hematol 2005; 80:148-157. 10. Niemeijer ND, van Daele PL, Caliskan K, et al. L€ offler endocarditis: a rare cause of acute cardiac failure. J Cardiothorac Surg 2012;7:109.

Löffler endocarditis with multiple cerebral embolism.

Idiopathic hypereosinophilic syndrome is an uncommon leukoproliferative systemic disorder characterized by the sustained eosinophilia and target organ...
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