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A granulocytosis associated with rufinamide: A case report
Brain & Development 37 (2015) 825–828 www.elsevier.com/locate/braindev
Case Report
A granulocytosis associated with rufinamide: A case report Minako Ide, Takeo Kato ⇑, Masatoshi Nakata, Keiko Saito, Takeshi Yoshida, Tomonari Awaya, Toshio Heike Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan Received 27 August 2014; received in revised form 29 December 2014; accepted 30 December 2014
Abstract Background: Rufinamide, a triazole derivative, is a novel antiepileptic drug (AED) chemically unrelated to other current AEDs. Previous studies on pediatric epilepsy treatment with rufinamide have demonstrated a frequency of leukopenia as an adverse event of 0.5%, and there has been no report of the development of agranulocytosis. Here, we report a patient with Lennox–Gastaut syndrome (LGS) who developed agranulocytosis associated with fever and skin rash with rufinamide. To the best of our knowledge, this is the first reported case of agranulocytosis induced by rufinamide. Patient: A 10-year-old boy with a history of herpes encephalitis at the age of 1 year developed LGS, and was administered rufinamide as add-on therapy to valproate, lamotrigine, and clonazepam because of difficulties in controlling tonic seizures. Eighteen days after initiation of rufinamide, agranulocytosis developed associated with high fever and skin rash, all of which resolved after withdrawal of rufinamide. Bone marrow aspiration demonstrated normocellular marrow with selective decrease of mature myeloid series, and suggested that agranulocytosis was not related to malignancy or serious infection. Conclusion: This case suggests that rufinamide may induce the potentially serious adverse effect of agranulocytosis. Patients should be monitored for clinical signs of agranulocytosis and consideration should be given to routine blood count determination for early detection of this. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Drug-induced agranulocytosis; Rufinamide; Hypersensitivity reactions; Lennox–Gastaut syndrome
1. Introduction Drug-induced agranulocytosis (DIAG) is a rare but serious adverse event evoked by drug administration [1]. Agranulocytosis is a severe form of neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mm3. Patients with agranulocytosis may develop severe infection or sepsis. The annual incidence of DIAG and acute neutropenia has been reported to ⇑ Corresponding author at: Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3301; fax: +81 75 752 2361. E-mail address: [email protected] (T. Kato).
range from 2.4 to 15.4 cases per million [1]. Many kinds of drugs, especially antipsychotics and antiepileptic drugs (AEDs), are associated with DIAG [2,3]. Rufinamide, a triazole derivative, is a novel AED chemically unrelated to other current AEDs. It has been postulated that the main mechanism of action is suppression of neuronal hyperexcitability by prolonging the inactivation phase of voltage-gated sodium channels [4,5]. It was recently approved in Japan as an adjuvant drug in patients with Lennox–Gastaut syndrome (LGS) older than four years of age. Previous studies have reported that common adverse effects are somnolence, vomiting, and headache, and that the majority of these adverse events are mild in severity and well
http://dx.doi.org/10.1016/j.braindev.2014.12.010 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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tolerated [5]. The incidence of neutropenia during antiepileptic treatment with rufinamide has been reported to be infrequent (1/100–1/1000) according to the prescribing information approved by the U.S. Food and Drug Administration, and DIAG associated with rufinamide has not been reported so far. Agranulocytosis was not mentioned in Thome-Souza’s study in 2014 [6]. Here, we report a patient with LGS who developed agranulocytosis associated with rufinamide administration. 2. Case The patient was a 10-year-old boy with a history of herpes encephalitis at the age of 1 year who developed LGS. Due to difficulties in controlling tonic seizures, rufinamide (200 mg/day) was administered as add-on therapy to valproate, lamotrigine, and clonazepam. Laboratory studies immediately before starting rufinamide revealed a white blood cell (WBC) count of 6900 cells/mm3 and a neutrophil count of 3200 cells/ mm3 with normal differential. The dose was increased to 400 mg at day 17 of rufinamide administration. Soon afterwards, he developed cheek rash and high fever. The rash gradually spread to the trunk and limbs, with the lesions fusing together. The high fever of 40 °C lasted for three days. Rufinamide was stopped on the third day of the rash. Because he lost appetite and he was very unwell, he was admitted to our hospital the next day. The high fever of 40 °C was already replaced with a low-grade fever in the region of 37 °C. At that stage the rash covered his face, trunk and limbs. It consisted of regular, round-shaped, characteristic target lesions less than 1 cm in diameter, consistent with erythema multiforme. There were no other abnormalities; in particular, there were no mucosal membrane lesions and there was no lymphadenoma or hepatosplenomegaly. Laboratory results revealed agranulocytosis, with WBC count of 5300 cells/mm3. (see Figs. 1 and 2). Blood examination revealed increased C-reactive protein (1.3 mg/dl; normal level is less than 0.2 mg/dl) and lactate dehydrogenase (606 IU/L; normal level is 124–226 IU/L) without any evidence of multiple organ involvement. Liver enzymes and coagulation parameters were within the normal range. Tests for Epstein–Barr virus, parvovirus B19, measles virus, rubella virus, herpes simplex virus, and mycoplasma were all negative. Autoantibodies were not detected. Bone marrow aspiration revealed normocellular marrow with complete absence of mature myeloid series (i.e., almost complete absence of segmented and band neutrophils with normal metamyelocytes or more immature myeloid cells), without any signs of malignancy or hemophagocytic syndrome. Erythropoiesis and thrombopoiesis were not affected. A drug patch test (DPT) for rufinamide was performed, but the result was negative.
Fig. 1. Clinical course, white blood cell count (black), neutrophil count (white), and medications. In the record of the counts of white blood cells and neutrophils, black circles indicate white blood cells and white circles indicate neutrophils. Day 1 indicates the start of symptoms, including fever and skin rash. Abbreviations: LTG, lamotrigine; VPA, valproate; CZP, clonazepam.
Since his symptoms seemed to have improved after cessation of the drug on the third day, he was not treated with granulocyte colony-stimulating factor (G-CSF) or any other treatment, and was just observed. Fever did not recur after cessation of the drug. The rash did not worsen thereafter and resolved spontaneously. Mature neutrophils appeared in blood on the 5th day, with a count of 990 cells/mm3 on the 7th day, and increased to normal range on the 9th day. All the symptoms resolved very soon after the rufinamide was withdrawn; therefore we concluded that they were all highly likely to have been induced by the rufinamide. 3. Discussion Here, we reported a case of rufinamide-associated agranulocytosis. In this case, agranulocytosis developed two weeks after initiation of rufinamide add-on therapy, and resolved immediately after cessation of the drug. Furthermore, bone marrow aspiration demonstrated normocellular marrow with complete absence of mature myeloid series without any signs of malignancy. DPT, the diagnostic gold standard test in drug allergies, was negative in this case. However, the sensitivity of this test is not high, implying that a negative result does not exclude the possibility of DIAG. Since all the abnormalities resolved after cessation of the drug, we concluded that a causal relationship between rufinamide administration and agranulocytosis was highly likely in this case. A pooled analysis of 7 clinical studies on pediatric epilepsy treatment of rufinamide has demonstrated that the frequency of leukopenia defined as an ANC of <1500 cells/mm3 as an adverse event is 0.5% (2 out of 391 cases), and there have been no reports of the
M. Ide et al. / Brain & Development 37 (2015) 825–828
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Fig. 2. (A) Cheek rash. (B) Rash on his left arm spread and fused together, with regular round shape and characteristic target lesion. (C) Bone marrow. Scale bar = 50 lm.
development of agranulocytosis [5]. This is the first reported case of agranulocytosis associated with rufinamide. Some reports have suggested bone marrow suppression as one potential mechanism [7]. However, bone marrow aspiration demonstrated normocellular marrow with selective decrease of mature myeloid series in this case, suggesting the mechanism was not bone marrow suppression. Previous reports have demonstrated that several AEDs, including carbamazepine, phenytoin, zonisamide, and phenobarbital, are associated with agranulocytosis [8,9]. These drugs are oxidized by cytochrome P450 enzyme. It has been speculated that this process generates reactive oxygen species (ROS) leading to neutrophil apoptosis or antibody formation [9]. However, metabolism of rufinamide occurs via hepatic hydrolysis and is not affected by cytochrome P450. Although the mechanism of DIAG in this case was unclear, we concluded that it was highly likely that the rufinamide caused the agranulocytosis.
The first step in the management of DIAG is the discontinuation of the suspected drug. In addition, it has been recommended that G-CSF be used in severe cases [8] but it was not necessary to administer this in our case. If recognized early and the responsible drug is discontinued, DIAG does not usually develop into a serious condition. However, misdiagnosis or delayed diagnosis could result in severe infection and death. The estimated mortality rate associated with DIAG is reported to be 5–10% in Western countries [2]. We concluded that rufinamide might induce agranulocytosis. It is not possible, on the basis of this single report, to make recommendations with regard to routine testing for white cell count and differential count in patients who are treated with rufinamide but this is an issue which should receive further consideration, especially if additional case reports come to light. Clinicians should be made aware of agranulocytosis as a possible serious adverse effect of rufinamide; if any signs associated with agranulocytosis such as unusual infection,
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rash or fever develop, the patient should be assessed promptly by a physician who should arrange for the white cell count and differential to be checked. The authors have no financial or personal relations that could pose a conflict of interest. References [1] Andre`s E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr Opin Hematol 2008;15:15–21. [2] Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008;23(suppl1):27–41. [3] Stu¨bner S, Grohmann R, Engel R, Bandelow B, Ludwig WD, Wagner G, et al. Blood dyscrasias induced by psychotropic drugs. Pharmacopsychiatry 2004;37:S70–8. [4] Hsieh DT, Thiele EA. Efficacy and safety of rufinamide in pediatric epilepsy. Ther Adv Neurol Disord 2013;6:189–98.
[5] Wheless JW, Conry J, Krauss G, Mann A, LoPresti A, Narurkar M. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol 2009;24:1520–5. [6] Thome-Souza Sigride, Kadish Navah E, Ramgopal Sriram, Sanchez Fernandez Ivan, Bergin Ann M, Bolton Jeffrey, et al. Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience. Epilepsia 2014;55:1235–44. [7] Ural AU, Avcu F, Gokcil Z, Nevruz O, Cetin T. Leukopenia and thrombocytopenia possibly associated with lamotrigine use in a patient. Epileptic Disord 2005;7:33–5. [8] Tesfa D, Keisu M, Palmblad J. Idiosyncratic drug-induced agranulocytosis: possible mechanisms and management. Am J Hematol 2009;84:428–34. [9] Lu W, Uetrecht JP. Peroxidase-mediated bioactivation of hydroxylated metabolites of carbamazepine and phenytoin. Drug Metab Dispos 2008;36:1624–36.
Case Report
A granulocytosis associated with rufinamide: A case report Minako Ide, Takeo Kato ⇑, Masatoshi Nakata, Keiko Saito, Takeshi Yoshida, Tomonari Awaya, Toshio Heike Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan Received 27 August 2014; received in revised form 29 December 2014; accepted 30 December 2014
Abstract Background: Rufinamide, a triazole derivative, is a novel antiepileptic drug (AED) chemically unrelated to other current AEDs. Previous studies on pediatric epilepsy treatment with rufinamide have demonstrated a frequency of leukopenia as an adverse event of 0.5%, and there has been no report of the development of agranulocytosis. Here, we report a patient with Lennox–Gastaut syndrome (LGS) who developed agranulocytosis associated with fever and skin rash with rufinamide. To the best of our knowledge, this is the first reported case of agranulocytosis induced by rufinamide. Patient: A 10-year-old boy with a history of herpes encephalitis at the age of 1 year developed LGS, and was administered rufinamide as add-on therapy to valproate, lamotrigine, and clonazepam because of difficulties in controlling tonic seizures. Eighteen days after initiation of rufinamide, agranulocytosis developed associated with high fever and skin rash, all of which resolved after withdrawal of rufinamide. Bone marrow aspiration demonstrated normocellular marrow with selective decrease of mature myeloid series, and suggested that agranulocytosis was not related to malignancy or serious infection. Conclusion: This case suggests that rufinamide may induce the potentially serious adverse effect of agranulocytosis. Patients should be monitored for clinical signs of agranulocytosis and consideration should be given to routine blood count determination for early detection of this. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Drug-induced agranulocytosis; Rufinamide; Hypersensitivity reactions; Lennox–Gastaut syndrome
1. Introduction Drug-induced agranulocytosis (DIAG) is a rare but serious adverse event evoked by drug administration [1]. Agranulocytosis is a severe form of neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mm3. Patients with agranulocytosis may develop severe infection or sepsis. The annual incidence of DIAG and acute neutropenia has been reported to ⇑ Corresponding author at: Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3301; fax: +81 75 752 2361. E-mail address: [email protected] (T. Kato).
range from 2.4 to 15.4 cases per million [1]. Many kinds of drugs, especially antipsychotics and antiepileptic drugs (AEDs), are associated with DIAG [2,3]. Rufinamide, a triazole derivative, is a novel AED chemically unrelated to other current AEDs. It has been postulated that the main mechanism of action is suppression of neuronal hyperexcitability by prolonging the inactivation phase of voltage-gated sodium channels [4,5]. It was recently approved in Japan as an adjuvant drug in patients with Lennox–Gastaut syndrome (LGS) older than four years of age. Previous studies have reported that common adverse effects are somnolence, vomiting, and headache, and that the majority of these adverse events are mild in severity and well
http://dx.doi.org/10.1016/j.braindev.2014.12.010 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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M. Ide et al. / Brain & Development 37 (2015) 825–828
tolerated [5]. The incidence of neutropenia during antiepileptic treatment with rufinamide has been reported to be infrequent (1/100–1/1000) according to the prescribing information approved by the U.S. Food and Drug Administration, and DIAG associated with rufinamide has not been reported so far. Agranulocytosis was not mentioned in Thome-Souza’s study in 2014 [6]. Here, we report a patient with LGS who developed agranulocytosis associated with rufinamide administration. 2. Case The patient was a 10-year-old boy with a history of herpes encephalitis at the age of 1 year who developed LGS. Due to difficulties in controlling tonic seizures, rufinamide (200 mg/day) was administered as add-on therapy to valproate, lamotrigine, and clonazepam. Laboratory studies immediately before starting rufinamide revealed a white blood cell (WBC) count of 6900 cells/mm3 and a neutrophil count of 3200 cells/ mm3 with normal differential. The dose was increased to 400 mg at day 17 of rufinamide administration. Soon afterwards, he developed cheek rash and high fever. The rash gradually spread to the trunk and limbs, with the lesions fusing together. The high fever of 40 °C lasted for three days. Rufinamide was stopped on the third day of the rash. Because he lost appetite and he was very unwell, he was admitted to our hospital the next day. The high fever of 40 °C was already replaced with a low-grade fever in the region of 37 °C. At that stage the rash covered his face, trunk and limbs. It consisted of regular, round-shaped, characteristic target lesions less than 1 cm in diameter, consistent with erythema multiforme. There were no other abnormalities; in particular, there were no mucosal membrane lesions and there was no lymphadenoma or hepatosplenomegaly. Laboratory results revealed agranulocytosis, with WBC count of 5300 cells/mm3. (see Figs. 1 and 2). Blood examination revealed increased C-reactive protein (1.3 mg/dl; normal level is less than 0.2 mg/dl) and lactate dehydrogenase (606 IU/L; normal level is 124–226 IU/L) without any evidence of multiple organ involvement. Liver enzymes and coagulation parameters were within the normal range. Tests for Epstein–Barr virus, parvovirus B19, measles virus, rubella virus, herpes simplex virus, and mycoplasma were all negative. Autoantibodies were not detected. Bone marrow aspiration revealed normocellular marrow with complete absence of mature myeloid series (i.e., almost complete absence of segmented and band neutrophils with normal metamyelocytes or more immature myeloid cells), without any signs of malignancy or hemophagocytic syndrome. Erythropoiesis and thrombopoiesis were not affected. A drug patch test (DPT) for rufinamide was performed, but the result was negative.
Fig. 1. Clinical course, white blood cell count (black), neutrophil count (white), and medications. In the record of the counts of white blood cells and neutrophils, black circles indicate white blood cells and white circles indicate neutrophils. Day 1 indicates the start of symptoms, including fever and skin rash. Abbreviations: LTG, lamotrigine; VPA, valproate; CZP, clonazepam.
Since his symptoms seemed to have improved after cessation of the drug on the third day, he was not treated with granulocyte colony-stimulating factor (G-CSF) or any other treatment, and was just observed. Fever did not recur after cessation of the drug. The rash did not worsen thereafter and resolved spontaneously. Mature neutrophils appeared in blood on the 5th day, with a count of 990 cells/mm3 on the 7th day, and increased to normal range on the 9th day. All the symptoms resolved very soon after the rufinamide was withdrawn; therefore we concluded that they were all highly likely to have been induced by the rufinamide. 3. Discussion Here, we reported a case of rufinamide-associated agranulocytosis. In this case, agranulocytosis developed two weeks after initiation of rufinamide add-on therapy, and resolved immediately after cessation of the drug. Furthermore, bone marrow aspiration demonstrated normocellular marrow with complete absence of mature myeloid series without any signs of malignancy. DPT, the diagnostic gold standard test in drug allergies, was negative in this case. However, the sensitivity of this test is not high, implying that a negative result does not exclude the possibility of DIAG. Since all the abnormalities resolved after cessation of the drug, we concluded that a causal relationship between rufinamide administration and agranulocytosis was highly likely in this case. A pooled analysis of 7 clinical studies on pediatric epilepsy treatment of rufinamide has demonstrated that the frequency of leukopenia defined as an ANC of <1500 cells/mm3 as an adverse event is 0.5% (2 out of 391 cases), and there have been no reports of the
M. Ide et al. / Brain & Development 37 (2015) 825–828
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Fig. 2. (A) Cheek rash. (B) Rash on his left arm spread and fused together, with regular round shape and characteristic target lesion. (C) Bone marrow. Scale bar = 50 lm.
development of agranulocytosis [5]. This is the first reported case of agranulocytosis associated with rufinamide. Some reports have suggested bone marrow suppression as one potential mechanism [7]. However, bone marrow aspiration demonstrated normocellular marrow with selective decrease of mature myeloid series in this case, suggesting the mechanism was not bone marrow suppression. Previous reports have demonstrated that several AEDs, including carbamazepine, phenytoin, zonisamide, and phenobarbital, are associated with agranulocytosis [8,9]. These drugs are oxidized by cytochrome P450 enzyme. It has been speculated that this process generates reactive oxygen species (ROS) leading to neutrophil apoptosis or antibody formation [9]. However, metabolism of rufinamide occurs via hepatic hydrolysis and is not affected by cytochrome P450. Although the mechanism of DIAG in this case was unclear, we concluded that it was highly likely that the rufinamide caused the agranulocytosis.
The first step in the management of DIAG is the discontinuation of the suspected drug. In addition, it has been recommended that G-CSF be used in severe cases [8] but it was not necessary to administer this in our case. If recognized early and the responsible drug is discontinued, DIAG does not usually develop into a serious condition. However, misdiagnosis or delayed diagnosis could result in severe infection and death. The estimated mortality rate associated with DIAG is reported to be 5–10% in Western countries [2]. We concluded that rufinamide might induce agranulocytosis. It is not possible, on the basis of this single report, to make recommendations with regard to routine testing for white cell count and differential count in patients who are treated with rufinamide but this is an issue which should receive further consideration, especially if additional case reports come to light. Clinicians should be made aware of agranulocytosis as a possible serious adverse effect of rufinamide; if any signs associated with agranulocytosis such as unusual infection,
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rash or fever develop, the patient should be assessed promptly by a physician who should arrange for the white cell count and differential to be checked. The authors have no financial or personal relations that could pose a conflict of interest. References [1] Andre`s E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr Opin Hematol 2008;15:15–21. [2] Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008;23(suppl1):27–41. [3] Stu¨bner S, Grohmann R, Engel R, Bandelow B, Ludwig WD, Wagner G, et al. Blood dyscrasias induced by psychotropic drugs. Pharmacopsychiatry 2004;37:S70–8. [4] Hsieh DT, Thiele EA. Efficacy and safety of rufinamide in pediatric epilepsy. Ther Adv Neurol Disord 2013;6:189–98.
[5] Wheless JW, Conry J, Krauss G, Mann A, LoPresti A, Narurkar M. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol 2009;24:1520–5. [6] Thome-Souza Sigride, Kadish Navah E, Ramgopal Sriram, Sanchez Fernandez Ivan, Bergin Ann M, Bolton Jeffrey, et al. Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience. Epilepsia 2014;55:1235–44. [7] Ural AU, Avcu F, Gokcil Z, Nevruz O, Cetin T. Leukopenia and thrombocytopenia possibly associated with lamotrigine use in a patient. Epileptic Disord 2005;7:33–5. [8] Tesfa D, Keisu M, Palmblad J. Idiosyncratic drug-induced agranulocytosis: possible mechanisms and management. Am J Hematol 2009;84:428–34. [9] Lu W, Uetrecht JP. Peroxidase-mediated bioactivation of hydroxylated metabolites of carbamazepine and phenytoin. Drug Metab Dispos 2008;36:1624–36.