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Gangliocytoma Presenting With Tacrolimus Neurotoxicity in a Renal Transplant Recipient: Case Report
Gangliocytoma Presenting With Tacrolimus Neurotoxicity in a Renal Transplant Recipient: Case Report S. Alagoz, S. Gulcicek, M. Oruc, S. Trabulus, and N. Seyahi* Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
ABSTRACT Tacrolimus is a widely used macrolide immunosuppressant in transplant surgery, with mild and major neurologic side effects. A 21-year-old woman had undergone preemptive transplantation of a kidney from her mother. On the 1st postoperative day, the patient had headache, nausea, vomiting, and agitation. Magnetic resonance imaging (MRI) of the brain showed hyperintensity and a lesion in the right mesial temporal lobe. After we switched from tacrolimus to cyclosporine, the symptoms regressed. Persistence of the lesion, confirmed by repeated MRI, required that the patient be operated on. Pathologic examination showed the gangliocytoma, a rare brain tumor. Our case shows that preexisting brain lesions may cause tacrolimus-induced neurotoxicity in the early postoperative period.
T
ACROLIMUS is a macrolide immunosuppressant frequently used after solid organ transplantation. The neurologic complications of tacrolimus are usually mild (tremor, paresthesia, and myalgia), but severe symptoms, such as encephalopathy, seizures, and coma, have also been documented [1]. Gangliocytomas are rare brain tumors and typically occur in children and young adults. Seizures are the most common symptom [2]. We report a case of asymptomatic incidental gangliocytoma presenting with tacrolimus-induced neurotoxicity.
CASE REPORT A 21-year-old woman had undergone preemptive transplantation of a kidney from her mother in January 2014. Her medical history was unremarkable except for chronic renal disease due to nephrolithiasis, which she had since 2005. Pre-transplantation evaluation and neurologic examination of the patient was normal. The postoperative initial immunosuppressive regimen consisted of a triple drug combination of tacrolimus (0.15 mg/kg/d orally; target level, 8e10 ng/mL), mycophenolate sodium (720 mg twice a day orally), and prednisolone (25 mg/d orally) following methylprednisolone (1 g pulse intraoperative) and basiliximab (20 mg/d during surgery and on 4th postoperative day) induction. On the 1st postoperative day, the patient experienced sudden headache, nausea, vomiting, and agitation. On physical examination, her pulse was 114 beats per minute, blood pressure 140/95 mm Hg, body temperature was 37.1 C, and respiratory rate 19 breaths per minute. Her neurologic examination was normal. Magnetic resonance imaging (MRI) 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.09.004
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showed right mesial temporal hyperintensity on the fluid-attenuated inversion recovery (FLAIR) image and a lesion with indefinite contours, without contrast enhancement, and of expansive character in the right mesial temporal lobe on the T2-weighted sequences (Fig 1). The diffusion-weighted MRI showed no abnormality. The lumbar puncture did not show an increase in the intracranial pressure. The cerebrospinal fluid had normal characteristics, such as clear color, no cells, no bacteria, negative Ziehl-Neelsen stain, 34 mg/dL protein, 120 mg/dL glucose with 177 mg/dL peripheral glucose, and normal cytology. Laboratory investigations showed a white blood cell count of 11,850/mL, hemoglobin of 9.7 g/dL, hematocrit of 28.8%, platelet of 115,700/mL, C-reactive protein of 23.8 mg/L, blood urea of 53 mg/dL, serum creatinine of 2.06 mg/dL, serum sodium of 139 mmol/L, serum potassium of 3.7 mmol/L, serum calcium of 8.4 mg/dL, magnesium of 1.6 mg/dL, and total cholesterol of 155 mg/dL. The provisional diagnosis of encephalitis due to herpes could not be excluded. For this reason, acyclovir (600 mg/d orally) therapy was started. Because the symptoms of the patient did not subside, we thought that it could be associated with tacrolimus and therefore decided to switch from tacrolimus to cyclosporine (6 mg/kg/d orally) on the 2nd postoperative day. Consequently, the patient’s symptoms were dramatically resolved. On the 4th postoperative day, the 2-hour post-dose cyclosporine level was 1,107.9 ng/mL and the tacrolimus level was 2.4 ng/mL. Because the cerebrospinal fluid examination
*Address correspondence to Nurhan Seyahi, Istanbul University, Halaskargazi c. No: 209-211, Huzur ap. D.2, Sisli, 34360, Istanbul, Turkey. E-mail: [email protected] ª 2016 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 3142e3144 (2016)
GANGLIOCYTOMA PRESENTING WITH TACROLIMUS NEUROTOXICITY
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Fig 1. (A) Axial and (B) coronal T2-weighted images of the patient, showing the lesion with indefinite contours, without contrast enhancement, and of expansive character in the right mesial temporal lobe.
for cytomegalovirus, herpes simplex virus types 1 and 2, enterovirus, and bacteria proved to be negative, antiviral therapy (except valganciclovir) was withdrawn on postoperative day 11. Repeated MRI studies performed 1, 3, 6, and 10 months after the transplantation showed persistence of the lesion. The patient had to be operated on for cranial mass 10 months after the transplantation. The pathologic examination showed a low-grade glial tumor (World Health Organization grade 1 gangliocytoma). Fifteen months after the transplantation, urea was 37 mg/dL and creatinine 1.09 mg/dL. Overall condition of the patient was good and the symptoms were resolved. The patient remains on maintenance immunosuppression of 125 mg/d cyclosporine, 1,440 mg/d mycophenolate sodium, and 5 mg/d prednisolone.
DISCUSSION
Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are the main components of the immunosuppressive regimen in renal transplantation. The cellular effects of these 2 agents are similar. They inhibit calcineurin activation, lowering interleukin-2 production in the T cells [3]. The incidence of neurotoxicity, one of the major adverse effects of calcineurin inhibitors, is higher in patients receiving tacrolimus rather than cyclosporine. Because both sensory and motor functions may be adversely affected, patients may present with a wide range of neurologic and psychiatric disorders. Severe symptoms could manifest as psychoses, hallucinations, cortical blindness, seizures, cerebellar ataxia, posterior reversible leukoencephalopathy syndrome, and coma. Mild symptoms include headache, tremor, insomnia, mood changes, and neuralgia. The latter are more
frequent than major symptoms, occurring in almost 40% of transplant patients [4]. The exact mechanism of CNI-associated neurotoxicity is unknown. Risk factors for the development of CNI-related neurotoxicity are the use of methylprednisolone, arterial hypertension, fluid overload, hypocholesterolemia, hyponatremia, hypernatremia, hypomagnesemia, hypoglycemia, hepatic encephalopathy, concomitant treatments (metoclopramide), surgical time >7 hours, preexisting blood-brain barrier alterations, and preexisting brain disease [4]. High levels of tacrolimus may contribute to drug-associated neurotoxicity. However, an association between the tacrolimus level and severity of the symptoms was not readily apparent [5]. Symptoms of neurotoxicity can be treated by reducing the doses of immunosuppressants or switching between tacrolimus and cyclosporine [4]. Another alternative is switching the immunosuppressive protocol to CNI-free immunosuppression (eg, sirolimus/mycophenolic acid) [4,6]. Early CNI-induced neurotoxicity is considered when neurologic symptoms occur within 4 weeks after transplantation [4]. However, when we reviewed the literature, we could not find any tacrolimus-induced neurotoxicity that emerged before the 12th day [7]. To our knowledge, the present case is unique in demonstrating neurotoxicity in the 1st day of tacrolimus treatment. Early onset of tacrolimus-induced neurotoxicity may be due to a preexisting brain tumor. In our case, the use of methylprednisolone and hypomagnesemia may have triggered the neurotoxicity in our patient. Routine cranial imaging is not a part of the pre-transplantation evaluation. Our patient was young, her medical history did not include any neurologic
3144
symptoms, and her neurologic examination was normal. Therefore, we did not perform cranial imaging before transplantation. Gangliocytomas are rare brain tumors and typically occur in children and young adults. The average age in most series is w20 years. Seizures are the most common symptom, and long-standing epilepsy is frequent [2]. Gangliocytomas comprise a spectrum of low-grade tumors with large well differentiated neurons as the sole neoplastic component. These tumors may emerge anywhere in the neuraxis; most are located in the supratentorial region and in the temporal lobes. On MRI, these tumors show hyperintensity on T2weighted images. Surgical resection of the entire tumor whenever possible remains the preferred approach [8]. To the best of our knowledge, our case is unique as we have shown that gangliocytoma, which is a rare brain tumor, may cause early onset of tacrolimus-induced neurotoxicity. Therefore, a triggering brain lesion should be kept in mind in patients with CNI-induced neurotoxicity in the early postoperative period, and cranial imaging should be performed.
ALAGOZ, GULCICEK, ORUC ET AL
REFERENCES [1] Zivkovic S. Neuroimaging and neurologic complications after organ transplantation. J Neuroimaging 2007;17:110e23. [2] Morris HH, Matkovic Z, Estes ML, et al. Ganglioglioma and intractable epilepsy: clinical and neurophysiologic features and predictors of outcome after surgery. Epilepsia 1998;39:307. [3] Baumgartel K, Mansuy IM. Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 2012;19:375e84. [4] Anghel D, Tanasescu R, Campeanu A, Lupescu L, Podda G, Bajenaru O. Neurotoxicity of immunosuppressive therapies in organ transplantation. J Clin Med 2013;8:170e5. [5] Balderramo D, Prieto J, Cardenás A, Navesa M. Hepatic encephalopathy and post-transplant hyponatremia predict early calcineurin inhibitor-induced neurotoxicity after liver transplantation. Transpl Int 2011;24:812e9. [6] Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000;13:313e26. [7] Hyung Kwun W. Tacrolimus related neurologic complication after pediatric kidney transplantation. J Korean Surg Soc 2011;81: 225e8. [8] Yust-Katz S, Anderson MD, Liu D, et al. Clinical and prognostic features of adult patients with gangliogliomas. Neuro Oncol 2014;16:409e13.
ABSTRACT Tacrolimus is a widely used macrolide immunosuppressant in transplant surgery, with mild and major neurologic side effects. A 21-year-old woman had undergone preemptive transplantation of a kidney from her mother. On the 1st postoperative day, the patient had headache, nausea, vomiting, and agitation. Magnetic resonance imaging (MRI) of the brain showed hyperintensity and a lesion in the right mesial temporal lobe. After we switched from tacrolimus to cyclosporine, the symptoms regressed. Persistence of the lesion, confirmed by repeated MRI, required that the patient be operated on. Pathologic examination showed the gangliocytoma, a rare brain tumor. Our case shows that preexisting brain lesions may cause tacrolimus-induced neurotoxicity in the early postoperative period.
T
ACROLIMUS is a macrolide immunosuppressant frequently used after solid organ transplantation. The neurologic complications of tacrolimus are usually mild (tremor, paresthesia, and myalgia), but severe symptoms, such as encephalopathy, seizures, and coma, have also been documented [1]. Gangliocytomas are rare brain tumors and typically occur in children and young adults. Seizures are the most common symptom [2]. We report a case of asymptomatic incidental gangliocytoma presenting with tacrolimus-induced neurotoxicity.
CASE REPORT A 21-year-old woman had undergone preemptive transplantation of a kidney from her mother in January 2014. Her medical history was unremarkable except for chronic renal disease due to nephrolithiasis, which she had since 2005. Pre-transplantation evaluation and neurologic examination of the patient was normal. The postoperative initial immunosuppressive regimen consisted of a triple drug combination of tacrolimus (0.15 mg/kg/d orally; target level, 8e10 ng/mL), mycophenolate sodium (720 mg twice a day orally), and prednisolone (25 mg/d orally) following methylprednisolone (1 g pulse intraoperative) and basiliximab (20 mg/d during surgery and on 4th postoperative day) induction. On the 1st postoperative day, the patient experienced sudden headache, nausea, vomiting, and agitation. On physical examination, her pulse was 114 beats per minute, blood pressure 140/95 mm Hg, body temperature was 37.1 C, and respiratory rate 19 breaths per minute. Her neurologic examination was normal. Magnetic resonance imaging (MRI) 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.09.004
3142
showed right mesial temporal hyperintensity on the fluid-attenuated inversion recovery (FLAIR) image and a lesion with indefinite contours, without contrast enhancement, and of expansive character in the right mesial temporal lobe on the T2-weighted sequences (Fig 1). The diffusion-weighted MRI showed no abnormality. The lumbar puncture did not show an increase in the intracranial pressure. The cerebrospinal fluid had normal characteristics, such as clear color, no cells, no bacteria, negative Ziehl-Neelsen stain, 34 mg/dL protein, 120 mg/dL glucose with 177 mg/dL peripheral glucose, and normal cytology. Laboratory investigations showed a white blood cell count of 11,850/mL, hemoglobin of 9.7 g/dL, hematocrit of 28.8%, platelet of 115,700/mL, C-reactive protein of 23.8 mg/L, blood urea of 53 mg/dL, serum creatinine of 2.06 mg/dL, serum sodium of 139 mmol/L, serum potassium of 3.7 mmol/L, serum calcium of 8.4 mg/dL, magnesium of 1.6 mg/dL, and total cholesterol of 155 mg/dL. The provisional diagnosis of encephalitis due to herpes could not be excluded. For this reason, acyclovir (600 mg/d orally) therapy was started. Because the symptoms of the patient did not subside, we thought that it could be associated with tacrolimus and therefore decided to switch from tacrolimus to cyclosporine (6 mg/kg/d orally) on the 2nd postoperative day. Consequently, the patient’s symptoms were dramatically resolved. On the 4th postoperative day, the 2-hour post-dose cyclosporine level was 1,107.9 ng/mL and the tacrolimus level was 2.4 ng/mL. Because the cerebrospinal fluid examination
*Address correspondence to Nurhan Seyahi, Istanbul University, Halaskargazi c. No: 209-211, Huzur ap. D.2, Sisli, 34360, Istanbul, Turkey. E-mail: [email protected] ª 2016 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 3142e3144 (2016)
GANGLIOCYTOMA PRESENTING WITH TACROLIMUS NEUROTOXICITY
3143
Fig 1. (A) Axial and (B) coronal T2-weighted images of the patient, showing the lesion with indefinite contours, without contrast enhancement, and of expansive character in the right mesial temporal lobe.
for cytomegalovirus, herpes simplex virus types 1 and 2, enterovirus, and bacteria proved to be negative, antiviral therapy (except valganciclovir) was withdrawn on postoperative day 11. Repeated MRI studies performed 1, 3, 6, and 10 months after the transplantation showed persistence of the lesion. The patient had to be operated on for cranial mass 10 months after the transplantation. The pathologic examination showed a low-grade glial tumor (World Health Organization grade 1 gangliocytoma). Fifteen months after the transplantation, urea was 37 mg/dL and creatinine 1.09 mg/dL. Overall condition of the patient was good and the symptoms were resolved. The patient remains on maintenance immunosuppression of 125 mg/d cyclosporine, 1,440 mg/d mycophenolate sodium, and 5 mg/d prednisolone.
DISCUSSION
Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are the main components of the immunosuppressive regimen in renal transplantation. The cellular effects of these 2 agents are similar. They inhibit calcineurin activation, lowering interleukin-2 production in the T cells [3]. The incidence of neurotoxicity, one of the major adverse effects of calcineurin inhibitors, is higher in patients receiving tacrolimus rather than cyclosporine. Because both sensory and motor functions may be adversely affected, patients may present with a wide range of neurologic and psychiatric disorders. Severe symptoms could manifest as psychoses, hallucinations, cortical blindness, seizures, cerebellar ataxia, posterior reversible leukoencephalopathy syndrome, and coma. Mild symptoms include headache, tremor, insomnia, mood changes, and neuralgia. The latter are more
frequent than major symptoms, occurring in almost 40% of transplant patients [4]. The exact mechanism of CNI-associated neurotoxicity is unknown. Risk factors for the development of CNI-related neurotoxicity are the use of methylprednisolone, arterial hypertension, fluid overload, hypocholesterolemia, hyponatremia, hypernatremia, hypomagnesemia, hypoglycemia, hepatic encephalopathy, concomitant treatments (metoclopramide), surgical time >7 hours, preexisting blood-brain barrier alterations, and preexisting brain disease [4]. High levels of tacrolimus may contribute to drug-associated neurotoxicity. However, an association between the tacrolimus level and severity of the symptoms was not readily apparent [5]. Symptoms of neurotoxicity can be treated by reducing the doses of immunosuppressants or switching between tacrolimus and cyclosporine [4]. Another alternative is switching the immunosuppressive protocol to CNI-free immunosuppression (eg, sirolimus/mycophenolic acid) [4,6]. Early CNI-induced neurotoxicity is considered when neurologic symptoms occur within 4 weeks after transplantation [4]. However, when we reviewed the literature, we could not find any tacrolimus-induced neurotoxicity that emerged before the 12th day [7]. To our knowledge, the present case is unique in demonstrating neurotoxicity in the 1st day of tacrolimus treatment. Early onset of tacrolimus-induced neurotoxicity may be due to a preexisting brain tumor. In our case, the use of methylprednisolone and hypomagnesemia may have triggered the neurotoxicity in our patient. Routine cranial imaging is not a part of the pre-transplantation evaluation. Our patient was young, her medical history did not include any neurologic
3144
symptoms, and her neurologic examination was normal. Therefore, we did not perform cranial imaging before transplantation. Gangliocytomas are rare brain tumors and typically occur in children and young adults. The average age in most series is w20 years. Seizures are the most common symptom, and long-standing epilepsy is frequent [2]. Gangliocytomas comprise a spectrum of low-grade tumors with large well differentiated neurons as the sole neoplastic component. These tumors may emerge anywhere in the neuraxis; most are located in the supratentorial region and in the temporal lobes. On MRI, these tumors show hyperintensity on T2weighted images. Surgical resection of the entire tumor whenever possible remains the preferred approach [8]. To the best of our knowledge, our case is unique as we have shown that gangliocytoma, which is a rare brain tumor, may cause early onset of tacrolimus-induced neurotoxicity. Therefore, a triggering brain lesion should be kept in mind in patients with CNI-induced neurotoxicity in the early postoperative period, and cranial imaging should be performed.
ALAGOZ, GULCICEK, ORUC ET AL
REFERENCES [1] Zivkovic S. Neuroimaging and neurologic complications after organ transplantation. J Neuroimaging 2007;17:110e23. [2] Morris HH, Matkovic Z, Estes ML, et al. Ganglioglioma and intractable epilepsy: clinical and neurophysiologic features and predictors of outcome after surgery. Epilepsia 1998;39:307. [3] Baumgartel K, Mansuy IM. Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 2012;19:375e84. [4] Anghel D, Tanasescu R, Campeanu A, Lupescu L, Podda G, Bajenaru O. Neurotoxicity of immunosuppressive therapies in organ transplantation. J Clin Med 2013;8:170e5. [5] Balderramo D, Prieto J, Cardenás A, Navesa M. Hepatic encephalopathy and post-transplant hyponatremia predict early calcineurin inhibitor-induced neurotoxicity after liver transplantation. Transpl Int 2011;24:812e9. [6] Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000;13:313e26. [7] Hyung Kwun W. Tacrolimus related neurologic complication after pediatric kidney transplantation. J Korean Surg Soc 2011;81: 225e8. [8] Yust-Katz S, Anderson MD, Liu D, et al. Clinical and prognostic features of adult patients with gangliogliomas. Neuro Oncol 2014;16:409e13.