Brain Injury
ISSN: 0269-9052 (Print) 1362-301X (Online) Journal homepage: http://www.tandfonline.com/loi/ibij20
Hypereosinophilic syndrome with central nervous system involvement: Two case reports and literature review Hao Chen, Hafiz Khuram Raza, Jia Jing, Dayong Shen, Peng Xu, Su Zhou, Jie zu, Xinxin Yang, Wei Zhang, Shenyang Zhang, Fang Hua & Guiyun Cui To cite this article: Hao Chen, Hafiz Khuram Raza, Jia Jing, Dayong Shen, Peng Xu, Su Zhou, Jie zu, Xinxin Yang, Wei Zhang, Shenyang Zhang, Fang Hua & Guiyun Cui (2017): Hypereosinophilic syndrome with central nervous system involvement: Two case reports and literature review, Brain Injury, DOI: 10.1080/02699052.2017.1357835 To link to this article: http://dx.doi.org/10.1080/02699052.2017.1357835
Published online: 25 Sep 2017.
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Date: 26 September 2017, At: 06:06
BRAIN INJURY https://doi.org/10.1080/02699052.2017.1357835
Hypereosinophilic syndrome with central nervous system involvement: Two case reports and literature review Hao Chen a, Hafiz Khuram Raza a, Jia Jingb, Dayong Shena, Peng Xua, Su Zhoua, Jie zua, Xinxin Yanga, Wei Zhanga, Shenyang Zhanga, Fang Huaa, and Guiyun Cuia Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; bDepartment of Biology, Georgia State University, Atlanta, USA
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a
ABSTRACT
ARTICLE HISTORY
Objective: To report two cases of hypereosinophilic syndrome (HES) with central nervous system involvement and explore its possible pathogenesis. Methods: We have analysed the clinical data and relevant features of two patients who presented themselves to The Affiliated Hospital of Xuzhou Medical University between 2012 and 2015. We have reviewed the relevant literature, elaborated the possible pathogenesis, and discussed the treatment options. Results: Both patients had consistently high levels of absolute eosinophil count which led to multiple cerebral infarcts in the arterial border zone and smallvessel disease. Blood tests were taken several times during their course of disease showing elevated eosinophils. Both patients underwent head computed tomography (CT), magnetic resonance imaging, and magnetic resonance angiography, which indicated small-vessel disease and watershed infarction. Glucocorticoids, improvement cycle, and neuro-nutrition treatments resulted in a significant improvement of their clinical state. Conclusion: HES can involve central nervous system by causing small-vessel disease and watershed infarction, which can be its presenting features. Repeated blood tests should be done to rule out HES in central nervous system lesion.
Received 6 September 2016 Revised 15 April 2017 Accepted 17 July 2017
Introduction Hypereosinophilic syndrome (HES) is a rare group of disorders, characterized by the presence of marked and unexplained blood and tissue eosinophilia, which is often associated with end-organ damage. Clinical manifestations are accredited to the eosinophilia and not otherwise explained in the clinical setting (1). The eosinophilias cause an extensive range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders (2).
Case 1 (Refer to timeline-1) A 25-year-old man presented to our hospital on 7 November 2013 and had a persistent headache and blurred vision for 5 days. He denied any past history of such symptoms. The patient reported that the pain was pulsatile pain of varying degree, and in his right temporal region. He further reported that vision became unclear and blurred at the same time and got worse as the headache aggravated. He had no fever, nausea or vomiting, aching, and numbness in his limbs. On physical examination, he was revealed to be conscious and had clear speech. Other signs were poor distant vision; pupils large, round, and sensitive to light; bilateral nasolabial fold symmetry; soft palate bilateral symmetry; uvula in the centre; normal pharyngeal reflex; soft neck (no resistance); normal upper limb and lower limb muscle strength;
KEYWORDS
Central nervous system; hypereosinophilic syndrome; magnetic resonance imaging (MRI); small-vessel disease
normal muscle tension; no muscle atrophy; bilateral upper limb radial reflex, biceps femoris reflex and triceps reflex (++); bilateral lower limb knee reflex, Achilles tendon reflex (++), bilateral Hoffman’s sign (–), bilateral Babinski’s sign (+); and Kerning’s sign (–). Laboratory examination showed that his white blood cell (WBC) count was 12.2 × 109/L with 15.9% eosinophils and the absolute eosinophil count (AEC) was 1.94 × 109/L. Other laboratory tests included ANA positive; Hs-CRP: 6.18 (0–5) mg/L, prothrombin time (PT) 14.5 (11–14) sec, PT ratio 1.26 (0.9–1.2). The tests for virus detection, antineutrophil cytoplasmic antibodies (ANCA), thyroid function, PR3-Ab, and MPO-Ab were all normal. A cranial computer tomography (CT) scan revealed multiple spots and patches located in his right frontal lobe, occipital lobe, parietal lobe, and right basal ganglia region (Figure 1). No abnormality was found in his cranial computed tomography angiogram (CTA) and cerebral digital subtraction angiography (DSA). Cerebral infarction was diagnosed with the support of clinical history. However, Neuro Behcet’s disease and nodular vasculitis could not be excluded. No attention was paid to the increase in the number of eosinophils at that time. His clinical state improved significantly after treatment with anti-platelet agents and neurotrophic drugs. The patient discharged himself from the hospital on 20 November 2013, but he continued to take the antiplatelet drugs. The patient was readmitted to the hospital on 25 December, 2013, due to repeated attacks of dizziness for 1
CONTACT Guiyun Cui [email protected] Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Huaihai West Road, Xuzhou, Jiangsu, China, 221006 Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/IBIJ. © 2017 Taylor & Francis Group, LLC
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Figure 1. Head CT (1A) showing low density lesion in right frontal and occipital lobe. Head CTA (1B) showing no significant abnormalities. Cerebral angiography DSA (1C–1D) showing no significant abnormality. Brain MRI (1E–1H) showing right frontal and occipital lobe infarction. Follow up brain MRI + MRA (1I–1L) showing multiple lesions in right frontal and temporal lobe while no significant abnormality in vasculatures. Relevant Past History Bronchiectasis for 20 years Hypertension for 10 years Diagnostic Evaluations WBC count: 14.52X10^9/L Eosinophil count: 7.16 X 10^9/L CT: Multiple infarcts MRA: Intracranial artery atherosclerosis Brain MRI: Multiple infarcts Spinal MRI: Cervical degenerative changes EMG: Nerve root compression
Laboratory Results WBC count: 16.95X10^9/L Eosinophil count: 9.04X 10^9/L ESR: 44(0-20) mm/h Serum AAG: 155.0 (51-117) mg/dl Hs-CRP: 68.50 (0-5) mg/L RF: 104 (0-25) IU/mL Tumor antigen: 40.72 (0-35) u/ml
Chief Complaint Right upper limb numbness and weakness for 18 hours
May 3rd 2012
Patient admitted to hospital
Physical Examination Corner of mouth deviated to left side Nasolabial groove was shallow Decreased perception of pinprick in right upper limb
Diagnosis Hpereosinophilic syndrome Cerebral infarction
May 5th 2012
Blood tests were re-performed Initial Treatment • Antiplatelet therapy • Neurotropic drugs • Prednisone
May 30th Patient discharged from hospital and continued to take antiplatelet drugs 2012 prednisone Physical Examination Coma with no reaction to painful stimuli Unequal pupil size Pupillary reaction to light was absent Babinski’s sign positive
Laboratory Results WBC count: 16.59X10^9/L Eosinophil count: 3.94 X 10^9/L
Chief Complaint Headache with left limb weakness for 12 hours Unconsciousness for 2 hours Diagnostic Evaluations Head CT: Basal ganglia haemorrhage, compression of right lateral ventricle, midline deviated to left and multiple cerebral infarcts.
Physical Examination Mild coma with response to painful stimuli Vital signs were stable
Neuroimaging Head CT: Obvious absorption of haematoma
Timeline-1
June 17th Patient readmitted to hospital 2012
Laboratory Results WBC count: 10.01X10^9/L Eosinophil count: 1.69X 10^9/L
Jun 18th 2012
Oct 17th 2012
Management • Depressive craniectomy • Evacuation of hematoma
Final Follow-up Patient was referred to local rehabilitation center for further treatment
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week. On neurological examination, his left side nasolabial groove was shallow. The rest of the signs were not significantly changed. Laboratory examination showed that his WBC count was 22.4 × 109/L with 14.4% eosinophils, the AEC was 3.23 × 109/L, and platelet count was 40 × 109/L. Other laboratory tests included the following: homocysteine (HCY) was 19.1 (5.0–18.8) umol/L, PT was 15.1 sec, PT-activated clotting time (ACT) PT ratio was 1.31, and fibrinogen (FIB) was 4.427 (2.000–4.000) g/l. The patient was referred to the haematology department on 31 December 2013, taking account of the high level of eosinophil count and thrombocytopenia. The result of bone marrow cytomorphologic examination was consistent with the eosinophilia syndrome and thrombocytopenia. His symptoms improved after glucocorticoids and supportive therapies. Rechecking his blood count on 6 January 2014 showed that eosinophils were 1.29 × 109/L, red blood cell (RBCs) count was 4.66 × 1012/L, platelet count was126 × 109/ L, the percentage of eosinophils was 7.7%, and WBC count was 16.7 × 109/L. He discharged himself from the hospital on 7 January 2014. Oral prednisone was prescribed to him. He was later followed up with blood tests which showed that his WBC count was 12.8 × 109/L with 13.9% eosinophils and the AEC was 1.78 × 109/L. Brain magnetic resonance (MR) scan and magnetic resonance angiography (MRA) revealed that the size of the infarction was reduced. His vasculatures were good. No obvious abnormal stenosis and expansion signs were evident in the lumen.
Case 2 (Refer to timeline-2) A 57-year-old woman was admitted to our hospital on 3 May 2012 and had complaints of numbness and weakness in her right upper extremity for 18 hours. Her past history was significant for bronchiectasis for 20 years and hypertension for 10 years. She had no fever, neck stiffness or limb pain, and seizures. On physical examination, she was revealed to be conscious and had clear speech. On neurological examination, her right side nasolabial groove was shallow and her corner of mouth was deviated towards the left side. Muscle strength was graded 4 in her right upper extremity. Sensory examination demonstrated decreased pinprick perception in her right upper extremity. Rest of the neurological examination was insignificant. The results of laboratory investigations were notable for a WBC count of 14.52 × 109/L (reference range, 3.3–9.5 × 109/L) with 49.3% eosinophils. The AEC was 7.16 × 109/L. The patient’s blood lipids, blood sugar levels, liver function tests, renal function tests, and myocardial enzymes were all normal. Her cranial CT scan showed multiple cerebral infarctions with part of encephalomalacia foci (Figure 2). Cranial and cervical MRA showed intracranial artery atherosclerosis. A cervical spine MR scan revealed degenerative changes and a slight herniation of the cervical disc. Her brain MR scan showed multiple cerebral infarcts with part of encephalomalacia foci and a new infarction in the parietal lobe. The result of electromyogram indicated nerve root compression in her right upper extremity. The patient’s condition continued to aggravate even after symptomatic treatment. She developed weakness in her both upper extremities with repeated hiccups. Her muscle strength was
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graded 3 and 4 in the right and left upper extremity. Both lower limb muscle strength was graded 5. The rest of neurological examination was the same as before. Rechecking of blood cells count showed that the WBC count was 16.95 × 109/L (reference range, 3.3–9.5 × 109/L) with 53.3% eosinophils. The AEC was 9.04 × 109/L. The following tests were also performed: rheumatic immune series – serum α1 acid glycoprotein (AAG): 155.0 (51–117) mg/dl; Hs-CRP: 68.50 (0–5) mg/L, RF 104 (0– 25) IU/mL, tumour antigen 40.72 (0–35) u/ml, erythrocyte sedimentation rate: 44(0–20) mm/h. The examination of her blood smear showed that the total number of WBCs was increased. Blood biochemistry, coagulation function, selfimmunity series, virus test, thyroid function, and HCY were all normal. The results were negative for the detection of parasites (EB-DNA, CMV-DNA, and purified protein derivative (PPD) test). Bone marrow cytology accorded with the expression of eosinophilia. Based on the result above, HES combined with cerebral infarction was diagnosed. The patient’s condition gradually stabilized after treatments with anti-platelet agents and prednisone. However, the eosinophil count was still high (5.06.95 × 109/L). Immunosuppressive agents were suggested, but her family members refused. The patient discharged herself from hospital on 30 May 2012, but continued to take anti-platelet drugs and prednisone. The patient was readmitted to the hospital on 17 June 2012 due to the onset of unconsciousness for 2 hours. Her family members reported that she had complained of a headache and weakness in her left limbs for 12 hours. She undertook a cranial CT scan, which showed right basal ganglia haemorrhage. The size of haemorrhage was about ‘6.6×3.5×5.5 cm’. The right lateral ventricle was compressed, the midline deviated to left, and multiple cerebral infarctions were noted. On hospital day (HD) 1, the patient’s condition was aggravated. She was re-examined by a head CT scan which revealed that the haemorrhage of the right basal ganglia had now moved into the ventricle. Her neurological examination revealed moderate coma without reaction to painful stimuli in her left limbs. The size of both pupils was not equal (the diameter: left 2.0 mm, right 4.0 mm), the pupillary reaction to light was absent, and Babinski’s sign was positive. Laboratory examination showed that her WBC count was 16.59 × 109/L (reference range, 3.3–9.5 × 109/L) with 23.7% eosinophils and the AEC was 3.94 × 109/L. Decompressive craniectomy and evacuation of hematoma were performed successfully on 18 June 2012. The patient, at that time, had a mild coma with reaction to the painful stimuli. Vital signs of this patient were steady. Laboratory examination of her blood showed that the WBC count was 10.01 × 109/L (reference range, 3.3–9.5 × 109/L) with 16.9% eosinophils and the AEC was 1.69 × 109/L. She underwent a cranial CT scan that revealed obvious absorption of hematoma. On 19 October 2012, the patient was referred to the local rehabilitation hospital for further treatment.
Discussion Chusid et al. (3) established the criteria to define HES in 1975 which included (1) blood eosinophilia ≥1500/mm3 for more than 6 months, (2) lack of evidence for known causes of eosinophilia, and (3) presumptive signs of end-organ damage. The above-
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Figure 2. Head CT(2A) showing multiple low-density patchy lesions with unclear edges around ventricles. Head and neck MRA (2B-2D) showing roughness of siphon segment of both internal carotid arteries. Brain MRI (2E–2H) showing low signal lesion (T1WI), high signal lesion (T2WI, FLAIR), and a part of high signal lesion (DWI). Head CT (after discharge) (2I) showing multiple patchy lesions around ventricles. Head CT (2J–2L) showing right basal ganglia haemorrhage with significantly increased pressure on the right side and multiple cerebral infarcts. Head CT and CTA (follow-up after 80–90 days) (2M–2P) showing haematoma absorption and arterial calcification.
mentioned criterion had marked limitations because significant end-organ damage prompts the patient to seek treatment so the requirement of eosinophilia for 6 months cannot always be fulfilled. Simon et al. explained and refined the criteria (1). The upper limit of normal for the range of percentage eosinophils in the peripheral blood is 3–5%, with a corresponding AEC of 350–500/ mm3. The severity of eosinophilia has been arbitrarily divided into mild (AEC from the upper limit of normal to 1500/mm3), moderate (AEC 1500–5000/mm3), and severe (AEC > 5000/mm3) (2). The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. The expert group agreed on coalescing terminologies and criteria and a classification that depicts various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the HES (4). HES is most commonly diagnosed in patients aged between 10 and 50 years. In our report, one patient was a young boy aged 25 years (Case 1), while the other was a 57-year-old female (Case 2). There is a male predominance with a male-tofemale ratio of 9:1.
Since HES is a heterogeneous group of disorders, it may involve multiple organ system. The presentation can be sudden and dramatic but, more often, the onset is insidious. Clinically, HES can present with the potentially lethal variable spectrum of target organ damage, predominantly the skin, heart, lungs, gastrointestinal tract, and central and peripheral nervous systems. As in our study, both patients presented with neurological symptoms indicating cerebral infarction. Involvement of other organs, hepatomegaly, splenomegaly, and microvascular thrombosis related to endothelial damage occur with variable frequencies. The nature and severity of organ damage is unpredictable and varies individually. For a given level of blood eosinophilia, some patients develop relatively mild symptoms, which may not warrant therapy, whereas at the other end of the spectrum, some patients with rapid complications may require immediate medical care (5,6). HES can involve both central nervous system and peripheral nervous system, but the direct eosinophil infiltration is often not seen on pathologic examination, making the exact mechanism of end-organ dysfunction somewhat unclear (6,7). Neurological complications are usually of three types: brain infarction, encephalopathy, and sensory polyneuropathy.
BRAIN INJURY
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No significant relevant past history Chief Complaint Persistent headache for 5 days Blurred vision Physical Examination Positive Babinski’s sign bilaterally
Nov 7th 2013
Diagnostic Evaluations WBC count: 12.2×10^9/L Eosinophil count: 1.94 X 10^9/L MRI: Multiple infarcts
Patient admitted to hospital
Initial Treatment • Antiplatelet therapy • Neurotropic drugs
Diagnosis Cerebral infarction (watershed infarction)
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Nov 20th Patient discharged from hospital and continued to take antiplatelet drugs 2013 Physical Examination Nasolabial groove on the left side was shallow
Chief Complaint Episodes of dizziness for one week
Dec 25th 2013
Patient readmitted to hospital
Dec 31st 2014
Patient referred to hematology department
Laboratory Results WBC count: 22.4 10^9/L Eosinophil count: 3.23 X 10^9/L Platelet count: 40 10^9/L
Laboratory Results Light-chain immunoglobulin: 6.660 Hs-CRP: 14.8 mg/L erythropoietin (EPO) 0.60
Diagnosis Hpereosinophilia Thrombocytopenia
Laboratory Results Eosinophil count: 1.29×10^9/L platelet count: 126×10^9/L
Management • Glucocorticoids (symptoms improved) • Supportive therapies Jan 6th 2014
Jan 7th 2014 Neuroimaging Cranial MRI and MRA revealed the lesion of infarction was reduced.
Laboratory Results WBC count: 12.8×10^9/L Eosinophil count: 1.78 X 10^9/L
May 5th 2014
Blood tests were reperformed
Patient discharged from hospital and continued to take prednisoe
Final Follow-up
timeline-2
Brain infarcts caused by vascular endothelial toxicity of eosinophilic cells lead to embolic strokes or transient ischemic episodes. This thromboembolic event can be the primary presentation of HES in most patients. In the early stage of HES, strokes are small and may occur in the arterial border zones, but later larger cortical and subcortical areas also become involved. Both of our patients had multiple cerebral infarcts. Small-vessel involvement was suspected in both cases. Watershed infarction in the arterial border zone was diagnosed in the first patient. Encephalopathy is another neurologic complication of HES in which patients may present with changes in behaviour, confusion, ataxia, and memory loss. The exact pathogenesis of encephalopathy is unknown, but encephalopathic changes are more likely due to markedly elevated absolute eosinophilic count. Pathological studies in cases of eosinophilia-related encephalopathy have revealed cerebral infarctions in the arterial watershed zones. Therefore, it seems more likely that those small infarctions in arterial border zones are responsible for encephalopathy in cases of HES. These small infarcts, which were often missed earlier, are now easily identified due to recent development in neuroimaging. The third type of neurologic dysfunction associated with HES is peripheral neuropathies which can happen
in about half of HES patients with neurologic manifestations (8,9). With the help of neuroimaging and specific clinical features, we were able to identify small-vessel lesion for both patients. Non-specific features of HES may include muscle pain, cough, low-grade fever, rash, and dyspnea (8). Treatment of HES is complicated and depends on the type of HES. The goal of therapy is to reduce the signs and symptoms and maintain the eosinophil count below 1500/ μL. Eosinophil-derived substances (major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin) (10) are responsible for thromboembolic complications associated with HES. Therefore, the main goal of therapy for symptomatic HES is to decrease the eosinophilic burden on the blood and tissues (11). Corticosteroids are the cornerstone of therapy, and treatment is generally started with oral prednisone for 1–2 weeks before the dose is slowly tapered (11). Corticosteroids, i.e. prednisone, had generally a good response in our patient. In the case of recurrence, interferon alfa or hydroxyurea can be considered as corticosteroid-sparing agents (12). Side effects of corticosteroids should not be ignored. Immunosuppressive agents were suggested to our second patient but were refused by her family members. Administration of
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monoclonal antibodies is another option in the management of HES. A number of agents that target eosinophils are currently in clinical development for the treatment of eosinophilic disorders (13). Among these, the humanized monoclonal anti-IL-5 antibody, mepolizumab, has been the best studied in HES. Mepolizumab, an agent designed to target eosinophils, can result in corticosteroid sparing. Rothenberg et al. (14) conducted a placebo-controlled trial evaluating the safety and efficacy of mepolizumab in patients with the HES. The addition of the mepolizumab may allow a reduction in the dose of glucocorticoids. Although most patients have a good response to corticosteroids, side effects are common and can lead to considerable morbidity. Verstovesk et al. (15) treated 11 patients with advanced HES with alemtuzumab that resulted in a brisk decline in AEC and the percentage of eosinophils in the peripheral blood in all patients. Ten patients (91%) achieved the complete haematological response in a median of 2 weeks.
Acknowledgments Hao Chen and Hafiz Khuram Raza contributed equally to this work.
Disclosure statement Paper supported by the National Natural Science Foundation of China (Grant No. 81271268).
ORCID http://orcid.org/0000-0003-0393-723X Hao Chen http://orcid.org/0000-0002-1748-7359 Hafiz Khuram Raza
References 1. Simon HU, Rothenberg ME, Bochner BS, Weller PF, Wardlaw AJ, Wechsler ME, Rosenwasser LJ, Roufosse F, Gleich GJ. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126(1):45–49. doi:10.1016/j.jaci.2010.03.042. 2. Gotlib J. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol. 2014;89:325–37. doi:10.1002/ajh.v89.3.
3. Chusid MJ, Dale CD, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54:1–27. doi:10.1097/00005792197501000-00001. 4. Valent P, Klion D, Horny HP, Roufosse F, Gotlib J, Weller PF, Hellmann A, Metzgeroth G, Leiferman KM, Arock M, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012;130:607–12. doi:10.1016/j.jaci.2012.02.019. 5. Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol. 2010;126(1):39–44. doi:10.1016/j.jaci.2010.04.011. 6. Akuthota P, Weller PF. Spectrum of eosinophilic end-organ manifestations. Immunol Allergy Clin North Am. 2015;35(3):403–11. doi:10.1016/j.iac.2015.04.002. 7. Sheikh J, Weller PF. Clinical overview of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007;27(3):333–55. doi:10.1016/j.iac.2007.07.007. 8. Khwaja GA, Duggal A, Kulkarni A, et al. Hypereosinophilia–an unusual cause of multiple embolic strokes and multi-organ dysfunction. J Clin Diagn Res: JCDR. 2013;7(10):2316–18. 9. Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med. 1985;102:109. doi:10.7326/0003-4819-102-1-109. 10. Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: current concepts and treatments. Br J Haematol. 2009;145 (3):271–85. doi:10.1111/j.1365-2141.2009.07599.x. 11. Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clinic Proc. 2010;85(2):158–64. doi:10.4065/ mcp.2009.0503. 12. Butterfield JH. Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis. Acta Haematol. 2005;114 (1):26–40. doi:10.1159/000085560. 13. Wechsler ME, Fulkerson PC, Bochner BS, Gauvreau GM, Gleich GJ, Henkel T, Kolbeck R, Mathur SK, Ortega H, Patel J. Novel targeted therapies for eosinophilic disorders. J Allergy Clin Immunol. 2012;130(3):563–71. doi:10.1016/j. jaci.2012.07.027. 14. Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, Schwartz LB, Rosenwasser LJ, Ring J, Griffin EF. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358(12):1215–28. doi:10.1056/ NEJMoa070812. 15. Verstovsek S, Tefferi A, Kantarjian H, Manshouri T, Luthra R, Pardanani A, Quintás-Cardama A, Ravandi F, Ault P. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15(1):368–73. doi:10.1158/1078-0432.CCR-08-1302.
ISSN: 0269-9052 (Print) 1362-301X (Online) Journal homepage: http://www.tandfonline.com/loi/ibij20
Hypereosinophilic syndrome with central nervous system involvement: Two case reports and literature review Hao Chen, Hafiz Khuram Raza, Jia Jing, Dayong Shen, Peng Xu, Su Zhou, Jie zu, Xinxin Yang, Wei Zhang, Shenyang Zhang, Fang Hua & Guiyun Cui To cite this article: Hao Chen, Hafiz Khuram Raza, Jia Jing, Dayong Shen, Peng Xu, Su Zhou, Jie zu, Xinxin Yang, Wei Zhang, Shenyang Zhang, Fang Hua & Guiyun Cui (2017): Hypereosinophilic syndrome with central nervous system involvement: Two case reports and literature review, Brain Injury, DOI: 10.1080/02699052.2017.1357835 To link to this article: http://dx.doi.org/10.1080/02699052.2017.1357835
Published online: 25 Sep 2017.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ibij20 Download by: [Nanyang Technological University]
Date: 26 September 2017, At: 06:06
BRAIN INJURY https://doi.org/10.1080/02699052.2017.1357835
Hypereosinophilic syndrome with central nervous system involvement: Two case reports and literature review Hao Chen a, Hafiz Khuram Raza a, Jia Jingb, Dayong Shena, Peng Xua, Su Zhoua, Jie zua, Xinxin Yanga, Wei Zhanga, Shenyang Zhanga, Fang Huaa, and Guiyun Cuia Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; bDepartment of Biology, Georgia State University, Atlanta, USA
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a
ABSTRACT
ARTICLE HISTORY
Objective: To report two cases of hypereosinophilic syndrome (HES) with central nervous system involvement and explore its possible pathogenesis. Methods: We have analysed the clinical data and relevant features of two patients who presented themselves to The Affiliated Hospital of Xuzhou Medical University between 2012 and 2015. We have reviewed the relevant literature, elaborated the possible pathogenesis, and discussed the treatment options. Results: Both patients had consistently high levels of absolute eosinophil count which led to multiple cerebral infarcts in the arterial border zone and smallvessel disease. Blood tests were taken several times during their course of disease showing elevated eosinophils. Both patients underwent head computed tomography (CT), magnetic resonance imaging, and magnetic resonance angiography, which indicated small-vessel disease and watershed infarction. Glucocorticoids, improvement cycle, and neuro-nutrition treatments resulted in a significant improvement of their clinical state. Conclusion: HES can involve central nervous system by causing small-vessel disease and watershed infarction, which can be its presenting features. Repeated blood tests should be done to rule out HES in central nervous system lesion.
Received 6 September 2016 Revised 15 April 2017 Accepted 17 July 2017
Introduction Hypereosinophilic syndrome (HES) is a rare group of disorders, characterized by the presence of marked and unexplained blood and tissue eosinophilia, which is often associated with end-organ damage. Clinical manifestations are accredited to the eosinophilia and not otherwise explained in the clinical setting (1). The eosinophilias cause an extensive range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders (2).
Case 1 (Refer to timeline-1) A 25-year-old man presented to our hospital on 7 November 2013 and had a persistent headache and blurred vision for 5 days. He denied any past history of such symptoms. The patient reported that the pain was pulsatile pain of varying degree, and in his right temporal region. He further reported that vision became unclear and blurred at the same time and got worse as the headache aggravated. He had no fever, nausea or vomiting, aching, and numbness in his limbs. On physical examination, he was revealed to be conscious and had clear speech. Other signs were poor distant vision; pupils large, round, and sensitive to light; bilateral nasolabial fold symmetry; soft palate bilateral symmetry; uvula in the centre; normal pharyngeal reflex; soft neck (no resistance); normal upper limb and lower limb muscle strength;
KEYWORDS
Central nervous system; hypereosinophilic syndrome; magnetic resonance imaging (MRI); small-vessel disease
normal muscle tension; no muscle atrophy; bilateral upper limb radial reflex, biceps femoris reflex and triceps reflex (++); bilateral lower limb knee reflex, Achilles tendon reflex (++), bilateral Hoffman’s sign (–), bilateral Babinski’s sign (+); and Kerning’s sign (–). Laboratory examination showed that his white blood cell (WBC) count was 12.2 × 109/L with 15.9% eosinophils and the absolute eosinophil count (AEC) was 1.94 × 109/L. Other laboratory tests included ANA positive; Hs-CRP: 6.18 (0–5) mg/L, prothrombin time (PT) 14.5 (11–14) sec, PT ratio 1.26 (0.9–1.2). The tests for virus detection, antineutrophil cytoplasmic antibodies (ANCA), thyroid function, PR3-Ab, and MPO-Ab were all normal. A cranial computer tomography (CT) scan revealed multiple spots and patches located in his right frontal lobe, occipital lobe, parietal lobe, and right basal ganglia region (Figure 1). No abnormality was found in his cranial computed tomography angiogram (CTA) and cerebral digital subtraction angiography (DSA). Cerebral infarction was diagnosed with the support of clinical history. However, Neuro Behcet’s disease and nodular vasculitis could not be excluded. No attention was paid to the increase in the number of eosinophils at that time. His clinical state improved significantly after treatment with anti-platelet agents and neurotrophic drugs. The patient discharged himself from the hospital on 20 November 2013, but he continued to take the antiplatelet drugs. The patient was readmitted to the hospital on 25 December, 2013, due to repeated attacks of dizziness for 1
CONTACT Guiyun Cui [email protected] Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Huaihai West Road, Xuzhou, Jiangsu, China, 221006 Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/IBIJ. © 2017 Taylor & Francis Group, LLC
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Figure 1. Head CT (1A) showing low density lesion in right frontal and occipital lobe. Head CTA (1B) showing no significant abnormalities. Cerebral angiography DSA (1C–1D) showing no significant abnormality. Brain MRI (1E–1H) showing right frontal and occipital lobe infarction. Follow up brain MRI + MRA (1I–1L) showing multiple lesions in right frontal and temporal lobe while no significant abnormality in vasculatures. Relevant Past History Bronchiectasis for 20 years Hypertension for 10 years Diagnostic Evaluations WBC count: 14.52X10^9/L Eosinophil count: 7.16 X 10^9/L CT: Multiple infarcts MRA: Intracranial artery atherosclerosis Brain MRI: Multiple infarcts Spinal MRI: Cervical degenerative changes EMG: Nerve root compression
Laboratory Results WBC count: 16.95X10^9/L Eosinophil count: 9.04X 10^9/L ESR: 44(0-20) mm/h Serum AAG: 155.0 (51-117) mg/dl Hs-CRP: 68.50 (0-5) mg/L RF: 104 (0-25) IU/mL Tumor antigen: 40.72 (0-35) u/ml
Chief Complaint Right upper limb numbness and weakness for 18 hours
May 3rd 2012
Patient admitted to hospital
Physical Examination Corner of mouth deviated to left side Nasolabial groove was shallow Decreased perception of pinprick in right upper limb
Diagnosis Hpereosinophilic syndrome Cerebral infarction
May 5th 2012
Blood tests were re-performed Initial Treatment • Antiplatelet therapy • Neurotropic drugs • Prednisone
May 30th Patient discharged from hospital and continued to take antiplatelet drugs 2012 prednisone Physical Examination Coma with no reaction to painful stimuli Unequal pupil size Pupillary reaction to light was absent Babinski’s sign positive
Laboratory Results WBC count: 16.59X10^9/L Eosinophil count: 3.94 X 10^9/L
Chief Complaint Headache with left limb weakness for 12 hours Unconsciousness for 2 hours Diagnostic Evaluations Head CT: Basal ganglia haemorrhage, compression of right lateral ventricle, midline deviated to left and multiple cerebral infarcts.
Physical Examination Mild coma with response to painful stimuli Vital signs were stable
Neuroimaging Head CT: Obvious absorption of haematoma
Timeline-1
June 17th Patient readmitted to hospital 2012
Laboratory Results WBC count: 10.01X10^9/L Eosinophil count: 1.69X 10^9/L
Jun 18th 2012
Oct 17th 2012
Management • Depressive craniectomy • Evacuation of hematoma
Final Follow-up Patient was referred to local rehabilitation center for further treatment
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BRAIN INJURY
week. On neurological examination, his left side nasolabial groove was shallow. The rest of the signs were not significantly changed. Laboratory examination showed that his WBC count was 22.4 × 109/L with 14.4% eosinophils, the AEC was 3.23 × 109/L, and platelet count was 40 × 109/L. Other laboratory tests included the following: homocysteine (HCY) was 19.1 (5.0–18.8) umol/L, PT was 15.1 sec, PT-activated clotting time (ACT) PT ratio was 1.31, and fibrinogen (FIB) was 4.427 (2.000–4.000) g/l. The patient was referred to the haematology department on 31 December 2013, taking account of the high level of eosinophil count and thrombocytopenia. The result of bone marrow cytomorphologic examination was consistent with the eosinophilia syndrome and thrombocytopenia. His symptoms improved after glucocorticoids and supportive therapies. Rechecking his blood count on 6 January 2014 showed that eosinophils were 1.29 × 109/L, red blood cell (RBCs) count was 4.66 × 1012/L, platelet count was126 × 109/ L, the percentage of eosinophils was 7.7%, and WBC count was 16.7 × 109/L. He discharged himself from the hospital on 7 January 2014. Oral prednisone was prescribed to him. He was later followed up with blood tests which showed that his WBC count was 12.8 × 109/L with 13.9% eosinophils and the AEC was 1.78 × 109/L. Brain magnetic resonance (MR) scan and magnetic resonance angiography (MRA) revealed that the size of the infarction was reduced. His vasculatures were good. No obvious abnormal stenosis and expansion signs were evident in the lumen.
Case 2 (Refer to timeline-2) A 57-year-old woman was admitted to our hospital on 3 May 2012 and had complaints of numbness and weakness in her right upper extremity for 18 hours. Her past history was significant for bronchiectasis for 20 years and hypertension for 10 years. She had no fever, neck stiffness or limb pain, and seizures. On physical examination, she was revealed to be conscious and had clear speech. On neurological examination, her right side nasolabial groove was shallow and her corner of mouth was deviated towards the left side. Muscle strength was graded 4 in her right upper extremity. Sensory examination demonstrated decreased pinprick perception in her right upper extremity. Rest of the neurological examination was insignificant. The results of laboratory investigations were notable for a WBC count of 14.52 × 109/L (reference range, 3.3–9.5 × 109/L) with 49.3% eosinophils. The AEC was 7.16 × 109/L. The patient’s blood lipids, blood sugar levels, liver function tests, renal function tests, and myocardial enzymes were all normal. Her cranial CT scan showed multiple cerebral infarctions with part of encephalomalacia foci (Figure 2). Cranial and cervical MRA showed intracranial artery atherosclerosis. A cervical spine MR scan revealed degenerative changes and a slight herniation of the cervical disc. Her brain MR scan showed multiple cerebral infarcts with part of encephalomalacia foci and a new infarction in the parietal lobe. The result of electromyogram indicated nerve root compression in her right upper extremity. The patient’s condition continued to aggravate even after symptomatic treatment. She developed weakness in her both upper extremities with repeated hiccups. Her muscle strength was
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graded 3 and 4 in the right and left upper extremity. Both lower limb muscle strength was graded 5. The rest of neurological examination was the same as before. Rechecking of blood cells count showed that the WBC count was 16.95 × 109/L (reference range, 3.3–9.5 × 109/L) with 53.3% eosinophils. The AEC was 9.04 × 109/L. The following tests were also performed: rheumatic immune series – serum α1 acid glycoprotein (AAG): 155.0 (51–117) mg/dl; Hs-CRP: 68.50 (0–5) mg/L, RF 104 (0– 25) IU/mL, tumour antigen 40.72 (0–35) u/ml, erythrocyte sedimentation rate: 44(0–20) mm/h. The examination of her blood smear showed that the total number of WBCs was increased. Blood biochemistry, coagulation function, selfimmunity series, virus test, thyroid function, and HCY were all normal. The results were negative for the detection of parasites (EB-DNA, CMV-DNA, and purified protein derivative (PPD) test). Bone marrow cytology accorded with the expression of eosinophilia. Based on the result above, HES combined with cerebral infarction was diagnosed. The patient’s condition gradually stabilized after treatments with anti-platelet agents and prednisone. However, the eosinophil count was still high (5.06.95 × 109/L). Immunosuppressive agents were suggested, but her family members refused. The patient discharged herself from hospital on 30 May 2012, but continued to take anti-platelet drugs and prednisone. The patient was readmitted to the hospital on 17 June 2012 due to the onset of unconsciousness for 2 hours. Her family members reported that she had complained of a headache and weakness in her left limbs for 12 hours. She undertook a cranial CT scan, which showed right basal ganglia haemorrhage. The size of haemorrhage was about ‘6.6×3.5×5.5 cm’. The right lateral ventricle was compressed, the midline deviated to left, and multiple cerebral infarctions were noted. On hospital day (HD) 1, the patient’s condition was aggravated. She was re-examined by a head CT scan which revealed that the haemorrhage of the right basal ganglia had now moved into the ventricle. Her neurological examination revealed moderate coma without reaction to painful stimuli in her left limbs. The size of both pupils was not equal (the diameter: left 2.0 mm, right 4.0 mm), the pupillary reaction to light was absent, and Babinski’s sign was positive. Laboratory examination showed that her WBC count was 16.59 × 109/L (reference range, 3.3–9.5 × 109/L) with 23.7% eosinophils and the AEC was 3.94 × 109/L. Decompressive craniectomy and evacuation of hematoma were performed successfully on 18 June 2012. The patient, at that time, had a mild coma with reaction to the painful stimuli. Vital signs of this patient were steady. Laboratory examination of her blood showed that the WBC count was 10.01 × 109/L (reference range, 3.3–9.5 × 109/L) with 16.9% eosinophils and the AEC was 1.69 × 109/L. She underwent a cranial CT scan that revealed obvious absorption of hematoma. On 19 October 2012, the patient was referred to the local rehabilitation hospital for further treatment.
Discussion Chusid et al. (3) established the criteria to define HES in 1975 which included (1) blood eosinophilia ≥1500/mm3 for more than 6 months, (2) lack of evidence for known causes of eosinophilia, and (3) presumptive signs of end-organ damage. The above-
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Figure 2. Head CT(2A) showing multiple low-density patchy lesions with unclear edges around ventricles. Head and neck MRA (2B-2D) showing roughness of siphon segment of both internal carotid arteries. Brain MRI (2E–2H) showing low signal lesion (T1WI), high signal lesion (T2WI, FLAIR), and a part of high signal lesion (DWI). Head CT (after discharge) (2I) showing multiple patchy lesions around ventricles. Head CT (2J–2L) showing right basal ganglia haemorrhage with significantly increased pressure on the right side and multiple cerebral infarcts. Head CT and CTA (follow-up after 80–90 days) (2M–2P) showing haematoma absorption and arterial calcification.
mentioned criterion had marked limitations because significant end-organ damage prompts the patient to seek treatment so the requirement of eosinophilia for 6 months cannot always be fulfilled. Simon et al. explained and refined the criteria (1). The upper limit of normal for the range of percentage eosinophils in the peripheral blood is 3–5%, with a corresponding AEC of 350–500/ mm3. The severity of eosinophilia has been arbitrarily divided into mild (AEC from the upper limit of normal to 1500/mm3), moderate (AEC 1500–5000/mm3), and severe (AEC > 5000/mm3) (2). The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. The expert group agreed on coalescing terminologies and criteria and a classification that depicts various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the HES (4). HES is most commonly diagnosed in patients aged between 10 and 50 years. In our report, one patient was a young boy aged 25 years (Case 1), while the other was a 57-year-old female (Case 2). There is a male predominance with a male-tofemale ratio of 9:1.
Since HES is a heterogeneous group of disorders, it may involve multiple organ system. The presentation can be sudden and dramatic but, more often, the onset is insidious. Clinically, HES can present with the potentially lethal variable spectrum of target organ damage, predominantly the skin, heart, lungs, gastrointestinal tract, and central and peripheral nervous systems. As in our study, both patients presented with neurological symptoms indicating cerebral infarction. Involvement of other organs, hepatomegaly, splenomegaly, and microvascular thrombosis related to endothelial damage occur with variable frequencies. The nature and severity of organ damage is unpredictable and varies individually. For a given level of blood eosinophilia, some patients develop relatively mild symptoms, which may not warrant therapy, whereas at the other end of the spectrum, some patients with rapid complications may require immediate medical care (5,6). HES can involve both central nervous system and peripheral nervous system, but the direct eosinophil infiltration is often not seen on pathologic examination, making the exact mechanism of end-organ dysfunction somewhat unclear (6,7). Neurological complications are usually of three types: brain infarction, encephalopathy, and sensory polyneuropathy.
BRAIN INJURY
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No significant relevant past history Chief Complaint Persistent headache for 5 days Blurred vision Physical Examination Positive Babinski’s sign bilaterally
Nov 7th 2013
Diagnostic Evaluations WBC count: 12.2×10^9/L Eosinophil count: 1.94 X 10^9/L MRI: Multiple infarcts
Patient admitted to hospital
Initial Treatment • Antiplatelet therapy • Neurotropic drugs
Diagnosis Cerebral infarction (watershed infarction)
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Nov 20th Patient discharged from hospital and continued to take antiplatelet drugs 2013 Physical Examination Nasolabial groove on the left side was shallow
Chief Complaint Episodes of dizziness for one week
Dec 25th 2013
Patient readmitted to hospital
Dec 31st 2014
Patient referred to hematology department
Laboratory Results WBC count: 22.4 10^9/L Eosinophil count: 3.23 X 10^9/L Platelet count: 40 10^9/L
Laboratory Results Light-chain immunoglobulin: 6.660 Hs-CRP: 14.8 mg/L erythropoietin (EPO) 0.60
Diagnosis Hpereosinophilia Thrombocytopenia
Laboratory Results Eosinophil count: 1.29×10^9/L platelet count: 126×10^9/L
Management • Glucocorticoids (symptoms improved) • Supportive therapies Jan 6th 2014
Jan 7th 2014 Neuroimaging Cranial MRI and MRA revealed the lesion of infarction was reduced.
Laboratory Results WBC count: 12.8×10^9/L Eosinophil count: 1.78 X 10^9/L
May 5th 2014
Blood tests were reperformed
Patient discharged from hospital and continued to take prednisoe
Final Follow-up
timeline-2
Brain infarcts caused by vascular endothelial toxicity of eosinophilic cells lead to embolic strokes or transient ischemic episodes. This thromboembolic event can be the primary presentation of HES in most patients. In the early stage of HES, strokes are small and may occur in the arterial border zones, but later larger cortical and subcortical areas also become involved. Both of our patients had multiple cerebral infarcts. Small-vessel involvement was suspected in both cases. Watershed infarction in the arterial border zone was diagnosed in the first patient. Encephalopathy is another neurologic complication of HES in which patients may present with changes in behaviour, confusion, ataxia, and memory loss. The exact pathogenesis of encephalopathy is unknown, but encephalopathic changes are more likely due to markedly elevated absolute eosinophilic count. Pathological studies in cases of eosinophilia-related encephalopathy have revealed cerebral infarctions in the arterial watershed zones. Therefore, it seems more likely that those small infarctions in arterial border zones are responsible for encephalopathy in cases of HES. These small infarcts, which were often missed earlier, are now easily identified due to recent development in neuroimaging. The third type of neurologic dysfunction associated with HES is peripheral neuropathies which can happen
in about half of HES patients with neurologic manifestations (8,9). With the help of neuroimaging and specific clinical features, we were able to identify small-vessel lesion for both patients. Non-specific features of HES may include muscle pain, cough, low-grade fever, rash, and dyspnea (8). Treatment of HES is complicated and depends on the type of HES. The goal of therapy is to reduce the signs and symptoms and maintain the eosinophil count below 1500/ μL. Eosinophil-derived substances (major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin) (10) are responsible for thromboembolic complications associated with HES. Therefore, the main goal of therapy for symptomatic HES is to decrease the eosinophilic burden on the blood and tissues (11). Corticosteroids are the cornerstone of therapy, and treatment is generally started with oral prednisone for 1–2 weeks before the dose is slowly tapered (11). Corticosteroids, i.e. prednisone, had generally a good response in our patient. In the case of recurrence, interferon alfa or hydroxyurea can be considered as corticosteroid-sparing agents (12). Side effects of corticosteroids should not be ignored. Immunosuppressive agents were suggested to our second patient but were refused by her family members. Administration of
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monoclonal antibodies is another option in the management of HES. A number of agents that target eosinophils are currently in clinical development for the treatment of eosinophilic disorders (13). Among these, the humanized monoclonal anti-IL-5 antibody, mepolizumab, has been the best studied in HES. Mepolizumab, an agent designed to target eosinophils, can result in corticosteroid sparing. Rothenberg et al. (14) conducted a placebo-controlled trial evaluating the safety and efficacy of mepolizumab in patients with the HES. The addition of the mepolizumab may allow a reduction in the dose of glucocorticoids. Although most patients have a good response to corticosteroids, side effects are common and can lead to considerable morbidity. Verstovesk et al. (15) treated 11 patients with advanced HES with alemtuzumab that resulted in a brisk decline in AEC and the percentage of eosinophils in the peripheral blood in all patients. Ten patients (91%) achieved the complete haematological response in a median of 2 weeks.
Acknowledgments Hao Chen and Hafiz Khuram Raza contributed equally to this work.
Disclosure statement Paper supported by the National Natural Science Foundation of China (Grant No. 81271268).
ORCID http://orcid.org/0000-0003-0393-723X Hao Chen http://orcid.org/0000-0002-1748-7359 Hafiz Khuram Raza
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