http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(6): 955–956 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.900423
CASE REPORT
Valproate-induced hyperammonemic encephalopathy in a renal transplanted patient Christina Melexopoulou1, Smaragdi Marinaki1, Maria Darema1, Chrysanthi Skalioti1, Athina Efthimiou2, George Zavos3, and John N. Boletis1 1
Department of Nephrology and Transplantation, Laiko General Hospital, Athens, Greece, 2Department of Neurology, Laiko General Hospital, Athens, Greece, and 3Department of Transplantation, Laiko General Hospital, Athens, Greece
Abstract
Keywords
Neurological complications after renal transplantation constitute an important cause of morbidity and mortality. Their differential diagnosis is difficult and essential for subsequent patient’s management. Valproate-induced hyperammonemic encephalopathy is an uncommon but serious effect of valproate treatment. Here, we describe the case of a 15-year-old girl who was on a long-term therapy with valproate due to epilepsy and revealed impaired consciousness with hyperammonemia 12 days after renal transplantation. After withdraw of valproate, patients’ symptoms resolved within 24 h. Clinicians should increase their awareness for potential complication of valproate, especially in transplanted patients.
Hyperammonemia, neurological complications, renal transplantation, valproate, valproate-induced hyperammonemic encephalopathy
Introduction Central nervous system complications in transplant recipients are an important cause of morbidity and mortality. The incidence of such complications in this patient population reaches 30%.1 There are several causes of neurological problems following renal transplantation posing a diagnostic and therapeutic challenge to clinicians. Valproate-induced hyperammonemic encephalopathy (VHE) is a serious disease, with potentially life-threatening complications.2 High clinical suspicion and early diagnosis is mandatory for the reversion of this serious condition. We present a patient who revealed VHE within a few days after renal transplantation.
Case report A 15-year-old girl underwent renal transplantation due to chronic renal failure secondary to vesicoureteral reflux after being on hemodialysis for 3 years. From her medical history she had only epilepsy treated with valproate (VPA) 500 mg twice daily the last 13 months. She received a renal transplant from a deceased donor and was started on an immunosuppression consisting of mycophenolate sodium, tacrolimus and
Address correspondence to Christina Melexopoulou, Department of Nephrology and Transplantation, Laiko Hospital, 17 Agiou Thoma street, 11527, Athens, Greece. Tel: +306973463591; Fax: +302132061243; E-mail: [email protected]
History Received 18 December 2013 Accepted 21 February 2014 Published online 25 March 2014
prednisone. She had a normal post-operative course, without abnormal neurological symptoms or signs and progressive improvement in creatinine clearance. Twelve days posttransplantation, the patient complained of dizziness and vomiting. Within a day she became gradually lethargic. Initial laboratory findings including electrolytes, aminotransferases, white blood cell count, hemoglobulin, urea and urinalysis were normal. Serum creatinine was 1.6 mg/dL (glomerular filtration rate 42 mL/min/1.73 m2, estimated by the abbreviated Modification of Diet in Renal Disease Study formula). Serum levels of tacrolimus were about 6 ng/mL. Neurological examination did not reveal any focal neurological deficit. Valproate levels were 91.76 mg/mL (normal levels: 50–100 mg/mL). Serum ammonia was high 147 mg/dL (normal levels575 mg/dL) and it was the only abnormal laboratory finding. The most frequent cause of hyperammonemia is liver and/ or kidney dysfunction. Our patient did not demonstrate any clinical sign or laboratory evidence of liver or kidney failure. After having excluded other rare causes as urease-producing bacterial infections and hyperalimentation, the diagnosis of VHE was – as often – a diagnosis of exclusion. The patient was treated with valproic acid, a drug that could have produced hyperammonemia. VPA was withheld and replaced with levetiracetam 500 mg twice daily. Following this therapeutic amendment, patients’ symptoms resolved over 24 h. Three days later the serum ammonia was 24 mg/dL. The diagnosis of VHE was also established by the therapeutic criterion and the rapid clinical improvement after VPA withdrawal.
956
C. Melexopoulou et al.
Discussion The neurological complications after renal transplantation are a diagnostic and therapeutic challenge to clinicians. They may be categorized as due to immunosuppressive drugs (posterior reversible encephalopathy syndrome associated with calcineurin inhibitors3) or other medications, metabolic disorders, stroke, infections, neuropathies and malignancies.4 Timeline of symptom onset can aid diagnosis. In our case, symptoms of encephalopathy occurred abruptly 12 days post-transplantation and the only abnormal laboratory finding was hyperammonemia. There are multiple causes of hyperammonemia. Hepatic dysfunction constitutes the most common etiology. A patient with hyperammonemia and normal hepatic function requires further diagnostic evaluation. This should include medications that specifically inhibit the urea cycle, urease producing bacterial infections, certain surgical treatments, hyperalimentation and urea cycle disorders.5 Our patient was treated with valproate, a drug that can cause hyperammonemia. Valproate is an effective drug that is widely used in neurology and in psychiatry. It is usually well tolerated and most of its side effects are mild and transient. Valproateinduced hyperammonemic encephalopathy is an uncommon but serious adverse event of VPA treatment. The incidence of VHE is not known, but asymptomatic hyperammonemia has been reported in 16–52% of patients receiving VPA therapy.6 VHE may present as acute or sub-acute onset of impaired consciousness ranging from drowsiness to coma, increased seizure frequency and gastrointestinal symptoms.7 Although VPA is extensively metabolized in the liver, VHE typically occurs with normal liver function. Serum VPA levels are within the therapeutic range in most individuals and raised serum ammonia levels may be the only abnormal finding.8 Our patient had all these negative diagnostic findings. Valproate can lead to hyperammonemia and encephalopathy by several ways. The main mechanism is the inhibition of hepatic mitochondrial carbamoylphosphate synthetase-1, the enzyme that begins the urea cycle, which leads to an increase in ammonia level in the blood.9 Another possible mechanism, is the inhibition of carnitine transportation into the mitochondria, which is responsible for the shift in the balance of metabolism toward protein catabolism with subsequent hyperammonemia. Possible risk factors for VHE occurrence10 are the combination of VPA with other antiepileptic medication, urea cycle disorders, polypharmacy and hypercatabolic state.5,11 Renal transplantation has not been associated so far with VHE. However, the interaction of VPA with the immunosuppressive drugs could potentially trigger the manifestation of VHE. The mainstay of VHE treatment is discontinuation of VPA, which leads to complete recovery in these patients. L-carnitine supplementation has been shown to improve the symptoms of
Ren Fail, 2014; 36(6): 955–956
VHE.12 Treatments with furosemide and mannitol may also be used for severe VPA toxicity, as they may play a significant role in reducing cerebrocellular edema and hyperammonemia. In cases of severe hyperammonemia hemodialysis may also be a therapeutic option.13 VHE requires early diagnosis and management since delay in recognition can have deleterious results. In conclusion, it is critical that clinicians increase their awareness of the possibility of VHE in patients receiving VPA, especially in transplanted patients who receive multiple drugs, most of which are metabolized in the liver. Neurological complications in transplanted patients are frequent and complex and differential diagnosis is often difficult. In any case, early recognition, diagnosis and immediate intervention are essential.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Agildere AM, Basaran C, Cakir B, Ozgul E, Kural F, Haberal M. Evaluation of neurologic complications by brain MRI in kidney and liver transplant recipients. Transplant Proc. 2006;38:611–618. 2. Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand. 2006;114:1–7. 3. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494–500. 4. Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol. 2012;14:332–347. 5. Bezinover D, Douthitt L, McQuillan PM, et al. Fatal hyperammonemia after renal transplant due to late-onset urea cycle deficiency: a case report. Transplant Proc. 2010;42:1982–1985. 6. Alqahtani S, Federico P, Myers RP. A case of valproate-induced hyperammonemic encephalopathy: look beyond the liver. CMAJ. 2007;177:568–569. 7. Sunkavalli KK, Iqbal FM, Singh B, Koneru J. Valproate-induced hyperammonemic encephalopathy: a case report and brief review of the literature. Am J Ther. 2013;20:569–571. 8. Cheng M, Tang X, Wen S, Yue J, Wang H. Valproate (VPA)associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012. Compr Psychiatry. 2012;54:562–567. 9. Lewis C, Deshpande A, Tesar GE, Dale R. Valproate-induced hyperammonemic encephalopathy: a brief review. Curr Med Res Opin. 2012;28:1039–1042. 10. Yamamoto Y, Takahashi Y, Suzuki E, et al. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res. 2012;101:202–209. 11. Chopra A, Kolla BP, Mansukhani MP, Netzel P, Frye MA. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. Gen Hosp Psychiatry. 2012;34:290–298. 12. Mock CM, Schwetschenau KH. Levocarnitine for valproic-acidinduced hyperammonemic encephalopathy. Am J Health Syst Pharm. 2012;69:35–39. 13. Tsai MF, Chen CY. Valproate-induced hyperammonemic encephalopathy treated by hemodialysis. Ren Fail. 2008;30:822–824.
Copyright of Renal Failure is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CASE REPORT
Valproate-induced hyperammonemic encephalopathy in a renal transplanted patient Christina Melexopoulou1, Smaragdi Marinaki1, Maria Darema1, Chrysanthi Skalioti1, Athina Efthimiou2, George Zavos3, and John N. Boletis1 1
Department of Nephrology and Transplantation, Laiko General Hospital, Athens, Greece, 2Department of Neurology, Laiko General Hospital, Athens, Greece, and 3Department of Transplantation, Laiko General Hospital, Athens, Greece
Abstract
Keywords
Neurological complications after renal transplantation constitute an important cause of morbidity and mortality. Their differential diagnosis is difficult and essential for subsequent patient’s management. Valproate-induced hyperammonemic encephalopathy is an uncommon but serious effect of valproate treatment. Here, we describe the case of a 15-year-old girl who was on a long-term therapy with valproate due to epilepsy and revealed impaired consciousness with hyperammonemia 12 days after renal transplantation. After withdraw of valproate, patients’ symptoms resolved within 24 h. Clinicians should increase their awareness for potential complication of valproate, especially in transplanted patients.
Hyperammonemia, neurological complications, renal transplantation, valproate, valproate-induced hyperammonemic encephalopathy
Introduction Central nervous system complications in transplant recipients are an important cause of morbidity and mortality. The incidence of such complications in this patient population reaches 30%.1 There are several causes of neurological problems following renal transplantation posing a diagnostic and therapeutic challenge to clinicians. Valproate-induced hyperammonemic encephalopathy (VHE) is a serious disease, with potentially life-threatening complications.2 High clinical suspicion and early diagnosis is mandatory for the reversion of this serious condition. We present a patient who revealed VHE within a few days after renal transplantation.
Case report A 15-year-old girl underwent renal transplantation due to chronic renal failure secondary to vesicoureteral reflux after being on hemodialysis for 3 years. From her medical history she had only epilepsy treated with valproate (VPA) 500 mg twice daily the last 13 months. She received a renal transplant from a deceased donor and was started on an immunosuppression consisting of mycophenolate sodium, tacrolimus and
Address correspondence to Christina Melexopoulou, Department of Nephrology and Transplantation, Laiko Hospital, 17 Agiou Thoma street, 11527, Athens, Greece. Tel: +306973463591; Fax: +302132061243; E-mail: [email protected]
History Received 18 December 2013 Accepted 21 February 2014 Published online 25 March 2014
prednisone. She had a normal post-operative course, without abnormal neurological symptoms or signs and progressive improvement in creatinine clearance. Twelve days posttransplantation, the patient complained of dizziness and vomiting. Within a day she became gradually lethargic. Initial laboratory findings including electrolytes, aminotransferases, white blood cell count, hemoglobulin, urea and urinalysis were normal. Serum creatinine was 1.6 mg/dL (glomerular filtration rate 42 mL/min/1.73 m2, estimated by the abbreviated Modification of Diet in Renal Disease Study formula). Serum levels of tacrolimus were about 6 ng/mL. Neurological examination did not reveal any focal neurological deficit. Valproate levels were 91.76 mg/mL (normal levels: 50–100 mg/mL). Serum ammonia was high 147 mg/dL (normal levels575 mg/dL) and it was the only abnormal laboratory finding. The most frequent cause of hyperammonemia is liver and/ or kidney dysfunction. Our patient did not demonstrate any clinical sign or laboratory evidence of liver or kidney failure. After having excluded other rare causes as urease-producing bacterial infections and hyperalimentation, the diagnosis of VHE was – as often – a diagnosis of exclusion. The patient was treated with valproic acid, a drug that could have produced hyperammonemia. VPA was withheld and replaced with levetiracetam 500 mg twice daily. Following this therapeutic amendment, patients’ symptoms resolved over 24 h. Three days later the serum ammonia was 24 mg/dL. The diagnosis of VHE was also established by the therapeutic criterion and the rapid clinical improvement after VPA withdrawal.
956
C. Melexopoulou et al.
Discussion The neurological complications after renal transplantation are a diagnostic and therapeutic challenge to clinicians. They may be categorized as due to immunosuppressive drugs (posterior reversible encephalopathy syndrome associated with calcineurin inhibitors3) or other medications, metabolic disorders, stroke, infections, neuropathies and malignancies.4 Timeline of symptom onset can aid diagnosis. In our case, symptoms of encephalopathy occurred abruptly 12 days post-transplantation and the only abnormal laboratory finding was hyperammonemia. There are multiple causes of hyperammonemia. Hepatic dysfunction constitutes the most common etiology. A patient with hyperammonemia and normal hepatic function requires further diagnostic evaluation. This should include medications that specifically inhibit the urea cycle, urease producing bacterial infections, certain surgical treatments, hyperalimentation and urea cycle disorders.5 Our patient was treated with valproate, a drug that can cause hyperammonemia. Valproate is an effective drug that is widely used in neurology and in psychiatry. It is usually well tolerated and most of its side effects are mild and transient. Valproateinduced hyperammonemic encephalopathy is an uncommon but serious adverse event of VPA treatment. The incidence of VHE is not known, but asymptomatic hyperammonemia has been reported in 16–52% of patients receiving VPA therapy.6 VHE may present as acute or sub-acute onset of impaired consciousness ranging from drowsiness to coma, increased seizure frequency and gastrointestinal symptoms.7 Although VPA is extensively metabolized in the liver, VHE typically occurs with normal liver function. Serum VPA levels are within the therapeutic range in most individuals and raised serum ammonia levels may be the only abnormal finding.8 Our patient had all these negative diagnostic findings. Valproate can lead to hyperammonemia and encephalopathy by several ways. The main mechanism is the inhibition of hepatic mitochondrial carbamoylphosphate synthetase-1, the enzyme that begins the urea cycle, which leads to an increase in ammonia level in the blood.9 Another possible mechanism, is the inhibition of carnitine transportation into the mitochondria, which is responsible for the shift in the balance of metabolism toward protein catabolism with subsequent hyperammonemia. Possible risk factors for VHE occurrence10 are the combination of VPA with other antiepileptic medication, urea cycle disorders, polypharmacy and hypercatabolic state.5,11 Renal transplantation has not been associated so far with VHE. However, the interaction of VPA with the immunosuppressive drugs could potentially trigger the manifestation of VHE. The mainstay of VHE treatment is discontinuation of VPA, which leads to complete recovery in these patients. L-carnitine supplementation has been shown to improve the symptoms of
Ren Fail, 2014; 36(6): 955–956
VHE.12 Treatments with furosemide and mannitol may also be used for severe VPA toxicity, as they may play a significant role in reducing cerebrocellular edema and hyperammonemia. In cases of severe hyperammonemia hemodialysis may also be a therapeutic option.13 VHE requires early diagnosis and management since delay in recognition can have deleterious results. In conclusion, it is critical that clinicians increase their awareness of the possibility of VHE in patients receiving VPA, especially in transplanted patients who receive multiple drugs, most of which are metabolized in the liver. Neurological complications in transplanted patients are frequent and complex and differential diagnosis is often difficult. In any case, early recognition, diagnosis and immediate intervention are essential.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Agildere AM, Basaran C, Cakir B, Ozgul E, Kural F, Haberal M. Evaluation of neurologic complications by brain MRI in kidney and liver transplant recipients. Transplant Proc. 2006;38:611–618. 2. Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand. 2006;114:1–7. 3. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494–500. 4. Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol. 2012;14:332–347. 5. Bezinover D, Douthitt L, McQuillan PM, et al. Fatal hyperammonemia after renal transplant due to late-onset urea cycle deficiency: a case report. Transplant Proc. 2010;42:1982–1985. 6. Alqahtani S, Federico P, Myers RP. A case of valproate-induced hyperammonemic encephalopathy: look beyond the liver. CMAJ. 2007;177:568–569. 7. Sunkavalli KK, Iqbal FM, Singh B, Koneru J. Valproate-induced hyperammonemic encephalopathy: a case report and brief review of the literature. Am J Ther. 2013;20:569–571. 8. Cheng M, Tang X, Wen S, Yue J, Wang H. Valproate (VPA)associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012. Compr Psychiatry. 2012;54:562–567. 9. Lewis C, Deshpande A, Tesar GE, Dale R. Valproate-induced hyperammonemic encephalopathy: a brief review. Curr Med Res Opin. 2012;28:1039–1042. 10. Yamamoto Y, Takahashi Y, Suzuki E, et al. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res. 2012;101:202–209. 11. Chopra A, Kolla BP, Mansukhani MP, Netzel P, Frye MA. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. Gen Hosp Psychiatry. 2012;34:290–298. 12. Mock CM, Schwetschenau KH. Levocarnitine for valproic-acidinduced hyperammonemic encephalopathy. Am J Health Syst Pharm. 2012;69:35–39. 13. Tsai MF, Chen CY. Valproate-induced hyperammonemic encephalopathy treated by hemodialysis. Ren Fail. 2008;30:822–824.
Copyright of Renal Failure is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
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