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Idiopathic hypereosinophilic syndrome complicated by central sinovenous thrombosis
Brain & Development 29 (2007) 182–184 www.elsevier.com/locate/braindev
Case report
Idiopathic hypereosinophilic syndrome complicated by central sinovenous thrombosis Ryoichi Sakuta, Yuzo Tomita, Makiko Ohashi, Toshiro Nagai, Nobuyuki Murakami
*
Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan Received 2 June 2006; received in revised form 5 August 2006; accepted 8 August 2006
Abstract Idiopathic hypereosinophilic syndrome (IHES) is a rare disorder affecting cardiac, pulmonary and nervous systems with peripheral neuropathy, encephalopathy and cerebral thromboembolism. We report a 7-year-old boy with IHES who developed central sinovenous thrombosis and cerebral hemorrhage. Although he had hypereosinophilia for more than 6 months, he was asymptomatic until the sudden onset of vomiting and headache due to superior sagittal sinus thrombosis. Molecular analysis in peripheral blood did not reveal any mutation in the Fip1-like-platelet-derived growth factor receptor a chain (FIP1L1-PDGFRA) gene which was recently reported to be mutated in IHES. Since there must be symptoms or signs of organ involvement to fulfill the IHES criteria, we could not make a diagnosis of IHES until the onset of central nervous system involvement. We suggest that anti-coagulant therapy should be considered for asymptomatic patients with hypereosinophilia because hypereosinophilia may induce thrombosis in various organs. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Idiopathic hypereosinophilic syndrome; Cerebral sinovenous thrombosis; Fusion protein
1. Introduction The diagnostic criteria of idiopathic hypereosinophilic syndrome (IHES) proposed by Chusid et al. [1] is as follows: (1) persistent eosinophilia of at least 1500/ll for a minimum of 6 months; (2) lack of evidence for parasitic, allergic, or other recognized causes of eosinophilia; and (3) symptoms and signs of organ system involvement. The syndrome has been reported to involve a variety of organ systems: cardiovascular, cutaneous, nervous and pulmonary systems. From recent studies, IHES is classified into two major forms: myeloproliferative and lymphocytic variants [2]. In the myeloproliferative variant, the patients have clinical and biological features reminiscent of chronic myelogenous leukemia and various myeloprolif*
Corresponding author. Tel.: +81 48 965 1111; fax: +81 48 965 9367. E-mail address: [email protected] (N. Murakami). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.08.004
erative disorders. Recently, Fip1-like-platelet-derived growth factor receptor a chain (FIP1L1-PDGFRA) mutation was reported to cause IHES [3]. Patients with FIP1L1-PDGFRA mutation appear to have the myeloproliferative variant of IHES and in whom imatinib is said to be effective [4]. On the other hand, interleukin5 overproduced by T-cell clone appears to induce eosinophilia in the lymphocytic variant of IHES. The mutation has not been identified in patients with the lymphocytic variant and in children with IHES [5]. Here, we present a 7-year-old Japanese boy with IHES who suddenly developed central sinovenous thrombosis and cerebral hemorrhage.
2. Clinical observation A 7-year 10-month-old Japanese boy had a history of Haemophils Influenzae-meningitis at the age of 3 years. He was diagnosed as having symptomatic epilepsy and
R. Sakuta et al. / Brain & Development 29 (2007) 182–184
placed on sodium valproate at 6 years 3 months of age. At the age of 7 years, he was found to have white blood cell (WBC) count of 31,300/ll (normal: 4500–13,500/ll) and eosinophil count of 20,000/ll (normal: 90–250/ll). He had never been known to have allergic diseases such as asthma or atopic dermatitis. Although he had no fever, arthralgia or rash, he continued to have eosinophilia of 8700–24,500/ll. Ten months after the onset of eosinophilia the sudden onset of headache and vomiting brought him to our hospital. On admission, he was alert without fever but could not walk alone. His heart sounds were clear without arrhythmia. His blood pressure was 122/70 mmHg. He did not have cough, dyspnea or rash. His neurologic examination was unremarkable with normal deep tendon reflexes without ataxia. His WBC count was 26,900/ll and eosinophils count 15,200/ll. Blood sodium valproate concentration was 119 lg/ml. Blood ammonia level was normal. Serum IgE was 288 IU/ml (normal < 250 IU/ml). EEG showed focal spikes in the left temporal region. On day 2, numbers of WBC and eosinophils were normal but platelet count fell from 173,000 to 50,000/ll. On day 4, his headache suddenly worsened. He became less responsive with Glasgow Coma Scale of II-30. At the same time he developed a left hemiplegia. Head CT scan revealed a right cerebral hemorrhage and enhanced CT scan demonstrated the empty delta sign indicating superior sagittal sinus thrombosis (Fig. 1A) and cerebral angiography confirmed occlusion of the sagittal sinus (Fig. 1B). Diagnosis of sagittal sinus thrombosis and left cerebral hemorrhage was made. Blood counts revealed WBC and eosinophils counts were normal, 9500 and 95/ll, respectively, and
183
platelets count had also decreased to 66,000/ll. The prothrombin time (PT) was prolonged to 14.3 s (normal: 12.3 s) and activated partial thromboplastin time (APTT) to 47.6 s (normal: 37.3 s). Fibrinogen was 155 mg/dl (normal: 155–415 mg/dl), but FDP was increased to 24.9 lg/ml (normal: <10 lg/ml). D-dimmer was increased to 16.67 lg/ml (normal: <0.72 lg/ ml) and thrombin anti-thrombin III complex (TAT) to 28.3 ng/ml (normal: l < 3.2 ng/ml). These findings reflect increased coagulabilitiy which may lead to thrombosis. Antigens of protein S and protein C, anti-thrombin III activity, anti-cardiolipin IgG antibody and anti-cardiolipin antibody, cardiolipin antibody beta 2-glycoprotein-1 complex were within normal limits. ECG and echocardiography were normal. Chromosomal analysis was normal. Molecular analysis on DNA extracted from peripheral blood showed no mutation of FIP1L1-PDGFRA. He was treated with anti-coagulation with heparin and warfarin, and his consciousness recovered to normal by day 14. His left hemiplegia gradually improved and he had no residual deficit by 3 months after the onset. Since sodium valproate was thought to be a contributing factor to the eosinophilia, it was withdrawn after day 30. On day 46, WBC and eosinophil counts suddenly increased to 19,900 and 11,700/ll, respectively, but they gradually normalized within 2 weeks. He was discharged with no neurological deficit 4 months after the onset and his serum IgE was 33 IU/ml. One year and 3 months after the episode, he was started back on sodium valproate to control his seizures, but WBC and eosinophil counts remained unchanged.
Fig. 1. Superior sagittal sinus (arrow) is not enhanced, showing so-called ‘‘empty delta sign’’. Note hematomas in right hemisphere (A). On cerebral angiography the superior sagittal sinus is not visualized (arrow) (B). A, enhanced brain CT; B, cerebral angiography. a, anterior; p, posterior.
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R. Sakuta et al. / Brain & Development 29 (2007) 182–184
3. Discussion Idiopathic hypereosinophilic syndrome fulfilling the criteria proposed by Chusid et al. [1] is a rare condition, particularly in children. Lack of evidence for parasitic, allergic, or other recognized causes of eosinophilia is one of the diagnostic criteria for IHES. Our patient had been placed on sodium valproate which has been reported to induce increased interleukin-5 level which can cause eosinophilia [6]. However, the drug may not be responsible for the eosinophilia in our patient because eosinophil count increased to 11,700/ll 11 days after its withdrawal and eosinophilia did not recur after re-administration of sodium valproate for his seizure disorder. He did not have any allergic diseases and his serum IgE was normalized two months after the onset of the disease. Therefore, our patient fulfilled the diagnostic criteria for IHES. Idiopathic hypereosinophilic syndrome is divided into the myeloproliferative and lymphocytic variants [2]. Patients with IHES, who have anemia and/or thrombocytopenia, hepatomegaly, splenomegaly, chromosomal abnormalities and circulating leukocyte precursors, qualify for the myeloproliferative variant of IHES. These clinical and biological features are thought to be associated with chronic myelogenous leukemia and other myeloproliferative disorders. Recently, mutation in Fip1-like-platelet-derived growth factor receptor a chain (FIP1L1-PDGFRA) gene was reported to cause IHES [3]. In patients with the myeloproliferative variant of IHES, the FIP1L1-PDGFRA mutation has been found and imatinib appears to be effective in patients with the mutation [4]. On the other hand, the lymphocytic variant of IHES is defined as a primitive lymphoid disorder characterized by nonmalignant expansion of a T-cell population to produce eosinophilpoietic cytokines including interleukin-5 [2]. Our patient did not have the FIP1L1-PDGFRA gene-mutation, and clinical and biological features were not reminiscent of chronic leukemia and various myeloproliferative disorders. Therefore, our patient may have the lymphocytic variant of IHES although serum interleukin-5 level was not investigated. Idiopathic hypereosinophilic syndrome has been reported to involve a variety of organs including heart, lung, skin and nervous system in adults. Peripheral neuropathy, encephalopathy and cerebral infarction have been reported as complications of IHES [7]. Schulman et al. first described an 11-year-old boy with IHES who developed central sinovenous thrombosis 6 days after predonine therapy [8]. Ours is a second report of IHES with central sinovenous thrombosis.
Patients with IHES may develop thrombosis of the aorta and portal veins [9,10]. Activated eosinophils and their granular proteins including eosinophil cationin protein, major basic protein, are thought to modify coagulation and fibrinolysis in eosinophilia, resulting in thrombosis. Therefore anti-coagulant therapy should be considered. Our patient had eosinophilia for 11 months but with no symptom until the sudden onset of central sinovenous thrombosis. We could not establish a diagnosis of IHES before the central sinovenous thrombosis because there was no organ involvement. When we see a patient with hypereosinophilia even without any symptoms, we should consider anti-coagulant therapy to prevent the sudden onset of thrombotic complications.
Acknowledgment The authors thank Dr. Yasuhide Hayashi, Gunma Children’s Medical Center for the analysis of FIP1L1PDGFRA gene.
References [1] Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with reviews of the literature. Med (Baltimore) 1975;54:1–27. [2] Roufosse F, Cogan E, Goldman M. Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy 2004;59:673–89. [3] Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–14. [4] Leiferman KM, Gleich GJ. Hypereosinophilic syndrome: case presentation and update. J Allergy Clin Immunol 2004;113:50–8. [5] Katz HT, Haque SJ, Hsieh H. Pediatric hypereosinophilic syndrome (HES) differs from adult HES. J Pediatr 2005;146:134–6. [6] Makis AC, Tzoufi M, Kateri MD, Bourantas KL, Papadopoulou ZL. Valproate-induced eosinophilia in children with epilepsy: role of interleukin-5. J Child Neurol 2005;20:150–2. [7] Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 1985;102:109–14. [8] Schulman H, Hertzog L, Zirkin H, Hertzanu Y. Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in childhood. Pediat Radiol 1999;29:595–7. [9] Johnston MB, Woodcock MA. Acute aortic thrombosis despite anticoagulant therapy in idiopathic hyper eosinophilic syndrome. J R Soc Med 1998;91:492–3. [10] Kikuchi K, Minami K, Miyakawa H, Ishibashi M. Portal vein thrombosis in hypereosinophilic syndrome. Am J Gastroenterol 2002;97:1274–5.
Case report
Idiopathic hypereosinophilic syndrome complicated by central sinovenous thrombosis Ryoichi Sakuta, Yuzo Tomita, Makiko Ohashi, Toshiro Nagai, Nobuyuki Murakami
*
Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan Received 2 June 2006; received in revised form 5 August 2006; accepted 8 August 2006
Abstract Idiopathic hypereosinophilic syndrome (IHES) is a rare disorder affecting cardiac, pulmonary and nervous systems with peripheral neuropathy, encephalopathy and cerebral thromboembolism. We report a 7-year-old boy with IHES who developed central sinovenous thrombosis and cerebral hemorrhage. Although he had hypereosinophilia for more than 6 months, he was asymptomatic until the sudden onset of vomiting and headache due to superior sagittal sinus thrombosis. Molecular analysis in peripheral blood did not reveal any mutation in the Fip1-like-platelet-derived growth factor receptor a chain (FIP1L1-PDGFRA) gene which was recently reported to be mutated in IHES. Since there must be symptoms or signs of organ involvement to fulfill the IHES criteria, we could not make a diagnosis of IHES until the onset of central nervous system involvement. We suggest that anti-coagulant therapy should be considered for asymptomatic patients with hypereosinophilia because hypereosinophilia may induce thrombosis in various organs. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Idiopathic hypereosinophilic syndrome; Cerebral sinovenous thrombosis; Fusion protein
1. Introduction The diagnostic criteria of idiopathic hypereosinophilic syndrome (IHES) proposed by Chusid et al. [1] is as follows: (1) persistent eosinophilia of at least 1500/ll for a minimum of 6 months; (2) lack of evidence for parasitic, allergic, or other recognized causes of eosinophilia; and (3) symptoms and signs of organ system involvement. The syndrome has been reported to involve a variety of organ systems: cardiovascular, cutaneous, nervous and pulmonary systems. From recent studies, IHES is classified into two major forms: myeloproliferative and lymphocytic variants [2]. In the myeloproliferative variant, the patients have clinical and biological features reminiscent of chronic myelogenous leukemia and various myeloprolif*
Corresponding author. Tel.: +81 48 965 1111; fax: +81 48 965 9367. E-mail address: [email protected] (N. Murakami). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.08.004
erative disorders. Recently, Fip1-like-platelet-derived growth factor receptor a chain (FIP1L1-PDGFRA) mutation was reported to cause IHES [3]. Patients with FIP1L1-PDGFRA mutation appear to have the myeloproliferative variant of IHES and in whom imatinib is said to be effective [4]. On the other hand, interleukin5 overproduced by T-cell clone appears to induce eosinophilia in the lymphocytic variant of IHES. The mutation has not been identified in patients with the lymphocytic variant and in children with IHES [5]. Here, we present a 7-year-old Japanese boy with IHES who suddenly developed central sinovenous thrombosis and cerebral hemorrhage.
2. Clinical observation A 7-year 10-month-old Japanese boy had a history of Haemophils Influenzae-meningitis at the age of 3 years. He was diagnosed as having symptomatic epilepsy and
R. Sakuta et al. / Brain & Development 29 (2007) 182–184
placed on sodium valproate at 6 years 3 months of age. At the age of 7 years, he was found to have white blood cell (WBC) count of 31,300/ll (normal: 4500–13,500/ll) and eosinophil count of 20,000/ll (normal: 90–250/ll). He had never been known to have allergic diseases such as asthma or atopic dermatitis. Although he had no fever, arthralgia or rash, he continued to have eosinophilia of 8700–24,500/ll. Ten months after the onset of eosinophilia the sudden onset of headache and vomiting brought him to our hospital. On admission, he was alert without fever but could not walk alone. His heart sounds were clear without arrhythmia. His blood pressure was 122/70 mmHg. He did not have cough, dyspnea or rash. His neurologic examination was unremarkable with normal deep tendon reflexes without ataxia. His WBC count was 26,900/ll and eosinophils count 15,200/ll. Blood sodium valproate concentration was 119 lg/ml. Blood ammonia level was normal. Serum IgE was 288 IU/ml (normal < 250 IU/ml). EEG showed focal spikes in the left temporal region. On day 2, numbers of WBC and eosinophils were normal but platelet count fell from 173,000 to 50,000/ll. On day 4, his headache suddenly worsened. He became less responsive with Glasgow Coma Scale of II-30. At the same time he developed a left hemiplegia. Head CT scan revealed a right cerebral hemorrhage and enhanced CT scan demonstrated the empty delta sign indicating superior sagittal sinus thrombosis (Fig. 1A) and cerebral angiography confirmed occlusion of the sagittal sinus (Fig. 1B). Diagnosis of sagittal sinus thrombosis and left cerebral hemorrhage was made. Blood counts revealed WBC and eosinophils counts were normal, 9500 and 95/ll, respectively, and
183
platelets count had also decreased to 66,000/ll. The prothrombin time (PT) was prolonged to 14.3 s (normal: 12.3 s) and activated partial thromboplastin time (APTT) to 47.6 s (normal: 37.3 s). Fibrinogen was 155 mg/dl (normal: 155–415 mg/dl), but FDP was increased to 24.9 lg/ml (normal: <10 lg/ml). D-dimmer was increased to 16.67 lg/ml (normal: <0.72 lg/ ml) and thrombin anti-thrombin III complex (TAT) to 28.3 ng/ml (normal: l < 3.2 ng/ml). These findings reflect increased coagulabilitiy which may lead to thrombosis. Antigens of protein S and protein C, anti-thrombin III activity, anti-cardiolipin IgG antibody and anti-cardiolipin antibody, cardiolipin antibody beta 2-glycoprotein-1 complex were within normal limits. ECG and echocardiography were normal. Chromosomal analysis was normal. Molecular analysis on DNA extracted from peripheral blood showed no mutation of FIP1L1-PDGFRA. He was treated with anti-coagulation with heparin and warfarin, and his consciousness recovered to normal by day 14. His left hemiplegia gradually improved and he had no residual deficit by 3 months after the onset. Since sodium valproate was thought to be a contributing factor to the eosinophilia, it was withdrawn after day 30. On day 46, WBC and eosinophil counts suddenly increased to 19,900 and 11,700/ll, respectively, but they gradually normalized within 2 weeks. He was discharged with no neurological deficit 4 months after the onset and his serum IgE was 33 IU/ml. One year and 3 months after the episode, he was started back on sodium valproate to control his seizures, but WBC and eosinophil counts remained unchanged.
Fig. 1. Superior sagittal sinus (arrow) is not enhanced, showing so-called ‘‘empty delta sign’’. Note hematomas in right hemisphere (A). On cerebral angiography the superior sagittal sinus is not visualized (arrow) (B). A, enhanced brain CT; B, cerebral angiography. a, anterior; p, posterior.
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R. Sakuta et al. / Brain & Development 29 (2007) 182–184
3. Discussion Idiopathic hypereosinophilic syndrome fulfilling the criteria proposed by Chusid et al. [1] is a rare condition, particularly in children. Lack of evidence for parasitic, allergic, or other recognized causes of eosinophilia is one of the diagnostic criteria for IHES. Our patient had been placed on sodium valproate which has been reported to induce increased interleukin-5 level which can cause eosinophilia [6]. However, the drug may not be responsible for the eosinophilia in our patient because eosinophil count increased to 11,700/ll 11 days after its withdrawal and eosinophilia did not recur after re-administration of sodium valproate for his seizure disorder. He did not have any allergic diseases and his serum IgE was normalized two months after the onset of the disease. Therefore, our patient fulfilled the diagnostic criteria for IHES. Idiopathic hypereosinophilic syndrome is divided into the myeloproliferative and lymphocytic variants [2]. Patients with IHES, who have anemia and/or thrombocytopenia, hepatomegaly, splenomegaly, chromosomal abnormalities and circulating leukocyte precursors, qualify for the myeloproliferative variant of IHES. These clinical and biological features are thought to be associated with chronic myelogenous leukemia and other myeloproliferative disorders. Recently, mutation in Fip1-like-platelet-derived growth factor receptor a chain (FIP1L1-PDGFRA) gene was reported to cause IHES [3]. In patients with the myeloproliferative variant of IHES, the FIP1L1-PDGFRA mutation has been found and imatinib appears to be effective in patients with the mutation [4]. On the other hand, the lymphocytic variant of IHES is defined as a primitive lymphoid disorder characterized by nonmalignant expansion of a T-cell population to produce eosinophilpoietic cytokines including interleukin-5 [2]. Our patient did not have the FIP1L1-PDGFRA gene-mutation, and clinical and biological features were not reminiscent of chronic leukemia and various myeloproliferative disorders. Therefore, our patient may have the lymphocytic variant of IHES although serum interleukin-5 level was not investigated. Idiopathic hypereosinophilic syndrome has been reported to involve a variety of organs including heart, lung, skin and nervous system in adults. Peripheral neuropathy, encephalopathy and cerebral infarction have been reported as complications of IHES [7]. Schulman et al. first described an 11-year-old boy with IHES who developed central sinovenous thrombosis 6 days after predonine therapy [8]. Ours is a second report of IHES with central sinovenous thrombosis.
Patients with IHES may develop thrombosis of the aorta and portal veins [9,10]. Activated eosinophils and their granular proteins including eosinophil cationin protein, major basic protein, are thought to modify coagulation and fibrinolysis in eosinophilia, resulting in thrombosis. Therefore anti-coagulant therapy should be considered. Our patient had eosinophilia for 11 months but with no symptom until the sudden onset of central sinovenous thrombosis. We could not establish a diagnosis of IHES before the central sinovenous thrombosis because there was no organ involvement. When we see a patient with hypereosinophilia even without any symptoms, we should consider anti-coagulant therapy to prevent the sudden onset of thrombotic complications.
Acknowledgment The authors thank Dr. Yasuhide Hayashi, Gunma Children’s Medical Center for the analysis of FIP1L1PDGFRA gene.
References [1] Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with reviews of the literature. Med (Baltimore) 1975;54:1–27. [2] Roufosse F, Cogan E, Goldman M. Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy 2004;59:673–89. [3] Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–14. [4] Leiferman KM, Gleich GJ. Hypereosinophilic syndrome: case presentation and update. J Allergy Clin Immunol 2004;113:50–8. [5] Katz HT, Haque SJ, Hsieh H. Pediatric hypereosinophilic syndrome (HES) differs from adult HES. J Pediatr 2005;146:134–6. [6] Makis AC, Tzoufi M, Kateri MD, Bourantas KL, Papadopoulou ZL. Valproate-induced eosinophilia in children with epilepsy: role of interleukin-5. J Child Neurol 2005;20:150–2. [7] Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 1985;102:109–14. [8] Schulman H, Hertzog L, Zirkin H, Hertzanu Y. Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in childhood. Pediat Radiol 1999;29:595–7. [9] Johnston MB, Woodcock MA. Acute aortic thrombosis despite anticoagulant therapy in idiopathic hyper eosinophilic syndrome. J R Soc Med 1998;91:492–3. [10] Kikuchi K, Minami K, Miyakawa H, Ishibashi M. Portal vein thrombosis in hypereosinophilic syndrome. Am J Gastroenterol 2002;97:1274–5.