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Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus
Brain & Development 28 (2006) 534–536 www.elsevier.com/locate/braindev
Case report
Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus Yosuke Kakisaka a,*, Kazuhiro Haginoya a, Hiroyuki Yokoyama a, Mamiko Ishitobi a, Keisuke Wakusawa a, Ikuko Sato a, Noriko Togashi a, Taro Kitamura a, Naomi Fukuyo a, Yasushi Yoshihara b, Kazuie Iinuma a a
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-Machi, Aobaku, Sendai, Miyagi 980-8574, Japan b Department of Pediatrics, Iwaki-Kyoritsu Hospital, Uchigo, Iwaki, Fukushima 973-8402, Japan Received 5 September 2005; received in revised form 25 January 2006; accepted 2 February 2006
Abstract We used tacrolimus to successfully treat a patient with childhood-onset oropharyngeal myasthenia gravis (MG). A girl (2 years, 5 months old) with oropharyngeal MG responded partially to treatment including pyridostigmine bromide, intravenous immunoglobulin, and prednisolone (2 mg/kg/day) for 7 weeks, but this resulted in worsening of her eye symptoms. By contrast, tacrolimus at 2 mg/day resulted in complete remission of the MG, which made it possible to reduce the dose of prednisolone. This is a rare report of the use of tacrolimus as an effective treatment for patients with intractable childhood-onset MG. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Childhood; Immunosuppressant; Myasthenia gravis; Tacrolimus
1. Introduction Myasthenia gravis (MG), a chronic T-cell-dependent autoimmune disorder of neuromuscular transmission, is induced by the production of an antibody to the nicotinic acetylcholine receptor (AchR). MG is characterized by weakness and easy fatigability of the skeletal, bulbar, and extraocular muscles [1]. Conventional therapies for MG in children include anticholinesterases, immunosuppressive agents such as prednisolone (PSL), intravenous administration of immunoglobulin, and thymectomy. Although the aforementioned treatments improve the prognosis for MG and reduce MG-induced mortality, some cases of MG are intractable. It has been reported that intractable adult-onset MG that cannot be *
Corresponding author. Tel.: +81 22 717 7287; fax: +81 22 717 7290. E-mail address: [email protected] (Y. Kakisaka). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.02.001
controlled with steroids can be improved by administering tacrolimus (FK506) [2–4], a macrolide compound that is derived from Streptomyces tsukubanesis [5]. Reports describing the efficacy of tacrolimus in patients with childhood-onset MG are very limited [8]. We report here the successful use of tacrolimus to treat a patient with childhood-onset MG.
2. Case report A young girl (2 years, 5 months old) with no history of disease and no family history of MG developed eyelid ptosis and strabismus of the right eye in December 2004, with no systemic symptoms such as respiratory failure or limb weakness. A diagnosis of ocular MG was made based on neurological examination and the results of the edrophonium test. However, the patient was negative for serum AchR antibodies (AchRAb). Treatment with
Y. Kakisaka et al. / Brain & Development 28 (2006) 534–536
pyridostigmine bromide was initiated, but this was ineffective. Because there had been no improvement in her ocular symptoms, she was referred to our hospital on 6 January 2005. She was admitted to our hospital on 27 January 2005, after developing dysphonia and difficulty with swallowing a few days previously; these symptoms were worsening at the time of admission (see Fig. 1). On admission, the patient weighed 15 kg. At the time, she was conscious and did not exhibit weakness of the upper limbs or gait disturbance. However, clinical examination revealed severe bilateral eyelid ptosis that did not change markedly during the course of the day, total paralysis of the bilateral extraocular muscles, and facial asymmetry owing to weakness of the lower facial muscles. Bulbar symptoms such as dysphonia and dysphagia were also present. Soon after admission, treatment with 15 mg PSL (1 mg/kg/day) was initiated. However, her symptoms worsened rapidly, and on the second day after admission she developed respiratory failure and was sent to an intensive care unit to receive mechanical ventilation. A chest X-ray appeared normal, and chest computed tomography revealed no thymoma. The results of blood tests were within the normal range, except for elevated levels of serum AchRAb (1.7 nmol/ L; normal range, <0.3). There was no waning of the response to repetitive stimulation of the median nerve at a frequency of 5 Hz. The patient was diagnosed with MG crisis and received ventilation support for 1 week, during which immunoglobulin (400 mg/kg) was administered intrave-
535
nously for 5 days. This therapy relieved the respiratory failure, and the patient was allowed to leave the intensive care unit, although the immunoglobulin had no effect on the palsy of the bilateral extraocular muscles. After additional immunoglobulin therapy (400 mg/kg for 5 days), the dose of PSL was increased to 30 mg/ day (2 mg/kg). The augmented dose of PSL resulted in incomplete improvement of limited ocular movement for 6 weeks. However, by the seventh week, ptosis of the right eyelid began to redevelop. After receiving fully informed consent from the patient’s parents, tacrolimus (1 mg/day) was administered once daily at night. At the start of tacrolimus treatment, the patient was receiving 30 mg/day PSL. The dose of tacrolimus was increased gradually to 2 mg based on a published report [8]. Her right-side eyelid ptosis began to improve on the eighth day after starting tacrolimus. The ocular movements also improved gradually. Finally, two weeks after starting tacrolimus treatment, she showed complete improvement of the bilateral eyelid ptosis and suppressed eye movements and a decrease in the serum concentration of AchRAb (0.5 nmol/L). Subsequently, the dose of PSL was decreased gradually from 30 mg/day to 5 mg every other day without any problems. The patient was followed up as an outpatient through December 2005 and did not exhibit any symptoms in response to continued treatment with 2 mg/day tacrolimus. The trough blood concentration of tacrolimus ranged from 1.9 to 3.8 ng/ml during the most recent 6 months. A decrease in the lymphocyte count, a known side effect of tacrolimus, was
Fig. 1. Summary of clinical course and treatment.
536
Y. Kakisaka et al. / Brain & Development 28 (2006) 534–536
observed transiently 10 days after starting the tacrolimus. However, it was not severe and normalized quickly. Other side effects, such as hyperglycemia, elevation of serum creatinine, and lymphoproliferative disorder, were not detected in follow-up as an outpatient.
Acknowledgments We thank Drs. Takashi Ichiyama and Yukihiro Yuhara for their helpful suggestions.
References 3. Discussion Several mechanisms by which tacrolimus produces improvement in MG have been suggested. The main mechanism is the inhibition of the activation of helper T cells by reducing the production of interleukin-2, which leads to a decrease in antibody production by B cells [6]. Tacrolimus is also known to act on the ryanodine receptor, which is located on the surface of the sarcoplasmic reticulum of skeletal muscle and is related to the release of sarcoplasmic Ca2+ to potentiate excitation–contraction coupling in skeletal muscle [9]. As it has often been reported that symptoms improve without a change in the AchRAb titer in the first month after tacrolimus treatment of MG, this mechanism is likely associated with the early benefits in MG. Moreover, a recent study found that tacrolimus enhances the effect of steroids by affecting the immunophilins in steroid receptors and inhibiting steroid exporters [10]. Although favorable trough levels are between 5 and 14 ng/ml in kidney transplantation [7], those in MG are between 3 and 5 ng/ml, which is generally achieved with 3 mg of tacrolimus per day in an adult. The trough concentration was recently controlled between 1.9 and 3.8 ng/ml in our patient with no MG deterioration. No severe or irreversible side effects were observed, only transient lymphocytopenia. In conclusion, tacrolimus should be considered as therapy for patients with intractable childhood-onset MG. This is a rare report of the successful treatment of childhood-onset MG using tacrolimus.
[1] Wolfe GI, Barohn RJ. Neuromuscular junction disorder of childhood. In: Swaiman KF, Ashwal F, editors. Pediatric neurology. St. Louis: Mosby; 1999. p. 1216–26. [2] Yoshikawa H, Mabuchi K, Yasukawa Y, Takamori M, Yamada M. Low-dose tacrolimus for intractable myasthenia gravis. J Clin Neurosci 2002;9:627–8. [3] Konishi T, Yoshiyama Y, Takamori M, Yagi K, Mukai E, Saida T, et al. Clinical study of FK506 in patients with myasthenia gravis. Muscle Nerve 2003;28:570–4. [4] Evoli A, Schino CD, Marsili F, Punzi C. Successful treatment of myasthenia gravis with tacrolimus. Muscle Nerve 2002;25:111–4. [5] Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. 1. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 1987;40:1249–55. [6] Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989;143:718–26. [7] Laskow DA, Vincenti F, Neylan J, Mendez R, Matas AJ. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996;62:900–5. [8] Shibata M, Suzuki Y, Takenaka M, Yamada T, Hattori T, Kinpara Y, et al. A case of intractable childhood-onset systemic myasthenia gravis that was successfully treated with tacrolimus. Shounika Rinsho (in Japanese) 2003;56:1939–42. [9] Takamori M, Motomura M, Kawaguchi N, Nemoto Y, Hattori T, Yoshikawa H, et al. Anti-ryanodine receptor antibodies and FK506 in myasthenia gravis. Neurology 2004;62:1894–6. [10] Davies TH, Ning YM, Sanchez ER. Differential control of glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. Biochemistry 2005;44:2030–8.
Case report
Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus Yosuke Kakisaka a,*, Kazuhiro Haginoya a, Hiroyuki Yokoyama a, Mamiko Ishitobi a, Keisuke Wakusawa a, Ikuko Sato a, Noriko Togashi a, Taro Kitamura a, Naomi Fukuyo a, Yasushi Yoshihara b, Kazuie Iinuma a a
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-Machi, Aobaku, Sendai, Miyagi 980-8574, Japan b Department of Pediatrics, Iwaki-Kyoritsu Hospital, Uchigo, Iwaki, Fukushima 973-8402, Japan Received 5 September 2005; received in revised form 25 January 2006; accepted 2 February 2006
Abstract We used tacrolimus to successfully treat a patient with childhood-onset oropharyngeal myasthenia gravis (MG). A girl (2 years, 5 months old) with oropharyngeal MG responded partially to treatment including pyridostigmine bromide, intravenous immunoglobulin, and prednisolone (2 mg/kg/day) for 7 weeks, but this resulted in worsening of her eye symptoms. By contrast, tacrolimus at 2 mg/day resulted in complete remission of the MG, which made it possible to reduce the dose of prednisolone. This is a rare report of the use of tacrolimus as an effective treatment for patients with intractable childhood-onset MG. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Childhood; Immunosuppressant; Myasthenia gravis; Tacrolimus
1. Introduction Myasthenia gravis (MG), a chronic T-cell-dependent autoimmune disorder of neuromuscular transmission, is induced by the production of an antibody to the nicotinic acetylcholine receptor (AchR). MG is characterized by weakness and easy fatigability of the skeletal, bulbar, and extraocular muscles [1]. Conventional therapies for MG in children include anticholinesterases, immunosuppressive agents such as prednisolone (PSL), intravenous administration of immunoglobulin, and thymectomy. Although the aforementioned treatments improve the prognosis for MG and reduce MG-induced mortality, some cases of MG are intractable. It has been reported that intractable adult-onset MG that cannot be *
Corresponding author. Tel.: +81 22 717 7287; fax: +81 22 717 7290. E-mail address: [email protected] (Y. Kakisaka). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.02.001
controlled with steroids can be improved by administering tacrolimus (FK506) [2–4], a macrolide compound that is derived from Streptomyces tsukubanesis [5]. Reports describing the efficacy of tacrolimus in patients with childhood-onset MG are very limited [8]. We report here the successful use of tacrolimus to treat a patient with childhood-onset MG.
2. Case report A young girl (2 years, 5 months old) with no history of disease and no family history of MG developed eyelid ptosis and strabismus of the right eye in December 2004, with no systemic symptoms such as respiratory failure or limb weakness. A diagnosis of ocular MG was made based on neurological examination and the results of the edrophonium test. However, the patient was negative for serum AchR antibodies (AchRAb). Treatment with
Y. Kakisaka et al. / Brain & Development 28 (2006) 534–536
pyridostigmine bromide was initiated, but this was ineffective. Because there had been no improvement in her ocular symptoms, she was referred to our hospital on 6 January 2005. She was admitted to our hospital on 27 January 2005, after developing dysphonia and difficulty with swallowing a few days previously; these symptoms were worsening at the time of admission (see Fig. 1). On admission, the patient weighed 15 kg. At the time, she was conscious and did not exhibit weakness of the upper limbs or gait disturbance. However, clinical examination revealed severe bilateral eyelid ptosis that did not change markedly during the course of the day, total paralysis of the bilateral extraocular muscles, and facial asymmetry owing to weakness of the lower facial muscles. Bulbar symptoms such as dysphonia and dysphagia were also present. Soon after admission, treatment with 15 mg PSL (1 mg/kg/day) was initiated. However, her symptoms worsened rapidly, and on the second day after admission she developed respiratory failure and was sent to an intensive care unit to receive mechanical ventilation. A chest X-ray appeared normal, and chest computed tomography revealed no thymoma. The results of blood tests were within the normal range, except for elevated levels of serum AchRAb (1.7 nmol/ L; normal range, <0.3). There was no waning of the response to repetitive stimulation of the median nerve at a frequency of 5 Hz. The patient was diagnosed with MG crisis and received ventilation support for 1 week, during which immunoglobulin (400 mg/kg) was administered intrave-
535
nously for 5 days. This therapy relieved the respiratory failure, and the patient was allowed to leave the intensive care unit, although the immunoglobulin had no effect on the palsy of the bilateral extraocular muscles. After additional immunoglobulin therapy (400 mg/kg for 5 days), the dose of PSL was increased to 30 mg/ day (2 mg/kg). The augmented dose of PSL resulted in incomplete improvement of limited ocular movement for 6 weeks. However, by the seventh week, ptosis of the right eyelid began to redevelop. After receiving fully informed consent from the patient’s parents, tacrolimus (1 mg/day) was administered once daily at night. At the start of tacrolimus treatment, the patient was receiving 30 mg/day PSL. The dose of tacrolimus was increased gradually to 2 mg based on a published report [8]. Her right-side eyelid ptosis began to improve on the eighth day after starting tacrolimus. The ocular movements also improved gradually. Finally, two weeks after starting tacrolimus treatment, she showed complete improvement of the bilateral eyelid ptosis and suppressed eye movements and a decrease in the serum concentration of AchRAb (0.5 nmol/L). Subsequently, the dose of PSL was decreased gradually from 30 mg/day to 5 mg every other day without any problems. The patient was followed up as an outpatient through December 2005 and did not exhibit any symptoms in response to continued treatment with 2 mg/day tacrolimus. The trough blood concentration of tacrolimus ranged from 1.9 to 3.8 ng/ml during the most recent 6 months. A decrease in the lymphocyte count, a known side effect of tacrolimus, was
Fig. 1. Summary of clinical course and treatment.
536
Y. Kakisaka et al. / Brain & Development 28 (2006) 534–536
observed transiently 10 days after starting the tacrolimus. However, it was not severe and normalized quickly. Other side effects, such as hyperglycemia, elevation of serum creatinine, and lymphoproliferative disorder, were not detected in follow-up as an outpatient.
Acknowledgments We thank Drs. Takashi Ichiyama and Yukihiro Yuhara for their helpful suggestions.
References 3. Discussion Several mechanisms by which tacrolimus produces improvement in MG have been suggested. The main mechanism is the inhibition of the activation of helper T cells by reducing the production of interleukin-2, which leads to a decrease in antibody production by B cells [6]. Tacrolimus is also known to act on the ryanodine receptor, which is located on the surface of the sarcoplasmic reticulum of skeletal muscle and is related to the release of sarcoplasmic Ca2+ to potentiate excitation–contraction coupling in skeletal muscle [9]. As it has often been reported that symptoms improve without a change in the AchRAb titer in the first month after tacrolimus treatment of MG, this mechanism is likely associated with the early benefits in MG. Moreover, a recent study found that tacrolimus enhances the effect of steroids by affecting the immunophilins in steroid receptors and inhibiting steroid exporters [10]. Although favorable trough levels are between 5 and 14 ng/ml in kidney transplantation [7], those in MG are between 3 and 5 ng/ml, which is generally achieved with 3 mg of tacrolimus per day in an adult. The trough concentration was recently controlled between 1.9 and 3.8 ng/ml in our patient with no MG deterioration. No severe or irreversible side effects were observed, only transient lymphocytopenia. In conclusion, tacrolimus should be considered as therapy for patients with intractable childhood-onset MG. This is a rare report of the successful treatment of childhood-onset MG using tacrolimus.
[1] Wolfe GI, Barohn RJ. Neuromuscular junction disorder of childhood. In: Swaiman KF, Ashwal F, editors. Pediatric neurology. St. Louis: Mosby; 1999. p. 1216–26. [2] Yoshikawa H, Mabuchi K, Yasukawa Y, Takamori M, Yamada M. Low-dose tacrolimus for intractable myasthenia gravis. J Clin Neurosci 2002;9:627–8. [3] Konishi T, Yoshiyama Y, Takamori M, Yagi K, Mukai E, Saida T, et al. Clinical study of FK506 in patients with myasthenia gravis. Muscle Nerve 2003;28:570–4. [4] Evoli A, Schino CD, Marsili F, Punzi C. Successful treatment of myasthenia gravis with tacrolimus. Muscle Nerve 2002;25:111–4. [5] Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. 1. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 1987;40:1249–55. [6] Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989;143:718–26. [7] Laskow DA, Vincenti F, Neylan J, Mendez R, Matas AJ. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996;62:900–5. [8] Shibata M, Suzuki Y, Takenaka M, Yamada T, Hattori T, Kinpara Y, et al. A case of intractable childhood-onset systemic myasthenia gravis that was successfully treated with tacrolimus. Shounika Rinsho (in Japanese) 2003;56:1939–42. [9] Takamori M, Motomura M, Kawaguchi N, Nemoto Y, Hattori T, Yoshikawa H, et al. Anti-ryanodine receptor antibodies and FK506 in myasthenia gravis. Neurology 2004;62:1894–6. [10] Davies TH, Ning YM, Sanchez ER. Differential control of glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. Biochemistry 2005;44:2030–8.