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Effect of antiepileptic drug polytherapy on crystalluria
Effect of Antiepileptic Drug Polytherapy on Crystalluria Tohshin Go, MD, PhD Urolithiasis is a rare side effect of antiepileptic drugs. To clarify the risk factors for urolithiasis induced by antiepileptic drugs, the effect of antiepileptic drug monotherapy on crystalluria was studied, and zonisamide or sulthiame therapy and alkaline urine were demonstrated to be risk factors. In the next investigation, the effect of antiepileptic drug polytherapy on crystalluria was retrospectively studied in epilepsy patients treated for more than 1 month during the last 7 years. A total of 278 urine specimens from epilepsy patients aged between 7 months and 36 years were enrolled in this study. The mean age was 12.3 years. There were 109 samples from females and 169 from males. Antiepileptic drugs administered in this study were valproate (174 urinary samples), zonisamide (139), carbamazepine (138), phenobarbital (65), phenytoin (52), acetazolamide (17), clonazepam (15), sulthiame (6), ethosuximide (6), nitrazepam (4), and clobazam (4). Epilepsy patients treated with antiepileptic drug polytherapy were frequently found to have crystalluria in patients demonstrating alkaline urine and taking acetazolamide, zonisamide (particularly with high serum levels), or many antiepileptic drugs in combination. Regular urinalysis seems to be necessary in these patients, and the evaluation for urolithiasis should be performed if persistent crystalluria is demonstrated. © 2005 by Elsevier Inc. All rights reserved. Go T. Effect of antiepileptic drug polytherapy on crystalluria. Pediatr Neurol 2005;32:113-115.
kidney stones in ⱕ1.5% of patients [3]. A patient with urolithiasis resulting from felbamate was also described [4]. Although crystalluria does not always indicate urolithiasis, it is frequently associated and may be useful in the diagnosis of urolithiasis if crystalluria is persistent and of a specific type [5]. Therefore in the previous study, the effect of antiepileptic drug monotherapy on crystalluria was studied in children and young adults to clarify the risk factors for urolithiasis associated with antiepileptic drugs. As a result, zonisamide or sulthiame therapy and alkaline urine were found to be risk factors [6]. In the present investigation, the relationship between antiepileptic drug polytherapy and crystalluria was retrospectively studied. Patients and Methods The medical records were reviewed in all epilepsy patients who were treated with antiepileptic drug polytherapy for more than 1 month at the Department of Pediatrics, Red Cross Hospital, during the last 7 years. Urine samples were collected more than 1 month after changing the combination of antiepileptic drugs during routine clinical examinations at the hospital. Urine samples were examined using test paper and microscope. Multiple urine samples from the same patient were considered independent and included in the study when patients were treated with different combinations of antiepileptic drugs. Patients with pyuria, bacteriuria, hematuria, or proteinuria were excluded from the study. Serum electrolytes, creatinine, urea nitrogen, the concentration of antiepileptic drugs, and blood ammonia were usually measured at the same time. Urine from patients with abnormal serum electrolytes, creatinine, urea nitrogen, or blood ammonia was not included in this study. The antiepileptic drugs had been prescribed at the normal recommended dosage and the serum concentrations of these antiepileptic drugs were within the therapeutic range. Statistical analysis was performed using Mann-Whitney nonparametric tests and chi-square tests.
Introduction
Results
Urolithiasis is a rare side effect of antiepileptic drugs in children and young adults. Among the various antiepileptic drugs, acetazolamide [1] and zonisamide [2] are wellknown causes. Topiramate was also reported to result in
A total of 278 urine specimens from 202 epilepsy patients (one urine sample from 126 patients and two from 152 patients) aged between 7 months and 36 years were enrolled in this study. The mean age was 12.3 years. There
From the Department of Infants’ Brain and Cognitive Development, Tokyo Women’s Medical University, Tokyo, Japan.
Communications should be addressed to: Dr. Go; 8-1 Kawada-cho, Shinjuku-ku; Tokyo 162-8666; Japan. Received February 16, 2004; accepted September 8, 2004.
© 2005 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2004.09.001 ● 0887-8994/05/$—see front matter
Go: AED Polytherapy on Crystalluria 113
Table 1. Age, sex, and duration of treatment in epilepsy patients treated with antiepileptic drug polytherapy in total (Total) and that including zonisamide
Total with crystalluria Total without crystalluria ZNS with crystalluria ZNS without crystalluria
Age (yr)*
Male/ Female
Duration of Treatment* (yr)
11.4 ⫾ 0.7 12.8 ⫾ 0.5 10.4 ⫾ 0.8 12.3 ⫾ 0.7
60/39 108/79 43/25 42/29
6.5 ⫾ 1.7 7.9 ⫾ 1.5 5.5 ⫾ 0.9 5.6 ⫾ 1.2
* Values are mean ⫾ standard error. Abbreviation: ZNS ⫽ Zonisamide
were 109 samples from females and 169 from males. The antiepileptic drugs administered in this study were valproate (174 urinary samples), zonisamide (139), carbamazepine (138), phenobarbital (65), phenytoin (52), acetazolamide (17), clonazepam (15), sulthiame (6), ethosuximide (6), nitrazepam (4), and clobazam (4). There were 222 samples from patients treated with two antiepi-
leptic drugs, 45 from three antiepileptic drugs, 10 from four antiepileptic drugs, and one from five antiepileptic drugs. Age, sex, and duration of treatment did not significantly differ between patients with and without crystalluria (Table 1). The frequency of crystalluria was significantly higher (P ⬍ 0.02) in patients treated with more than two antiepileptic drugs than in patients treated with only two antiepileptic drugs (Fig 1a). The pH distribution in patients with crystalluria was apparently (P ⬍ 0.0001) shifted to the alkaline side compared with that in patients without crystalluria (Fig 1b). The frequency of crystalluria was much higher in patients treated with antiepileptic drug polytherapy that included acetazolamide (P ⬍ 0.0001) or zonisamide (P ⬍ 0.0001) than in those not taking acetazolamide or zonisamide (Fig 1c). With respect to other antiepileptic drugs, there was no significant difference in the frequency of crystalluria. In patients treated with antiepileptic drug polytherapy that included zonisamide, there was no significant difference in age, sex, or duration of treatment between patients with and without crystalluria (Table 1). However, zoni-
Figure 1. (a) The frequency of crystalluria was significantly different in epilepsy patients taking polytherapy with two, three, and more than three antiepileptic drugs. (b) The pH distribution also significantly differed among patients with and without crystalluria. (c) Patients with antiepileptic drug polytherapy that included acetazolamide (AZM) or zonisamide (ZNS) were more likely to have crystalluria than those not taking AZM or ZNS.
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Figure 2. Zonisamide (ZNS) concentration (a) and pH distribution (b) significantly differed between patients with and without crystalluria who were taking ZNS.
samide concentration was higher in patients with crystalluria (P ⬍ 0.03) than in those without crystalluria (Fig 2a). The pH distribution in zonisamide-taking patients with crystalluria was significantly (P ⬍ 0.05) shifted to the alkaline side compared with that in patients without crystalluria (Fig 2b). Discussion In the previous study, the frequency of crystalluria in the control subjects, epilepsy patients before antiepileptic drug treatment, and patients with antiepileptic drug monotherapy were 14.0%, 13.1%, and 14.5%, respectively [6]. Compared with these values, the frequency of crystalluria associated with antiepileptic drug polytherapy was demonstrated to be higher, and even much higher, in patients treated with many antiepileptic drugs in combination in the present study. Urolithiasis was occasionally reported in children [4,7] and adults [1,2] with antiepileptic drug therapy. In most cases, it was not associated with antiepileptic drug monotherapy but polytherapy [1,2,4,7]. The present study is consistent with this finding. This study indicates that epilepsy patients treated with antiepileptic drug polytherapy are likely to have crystalluria, especially in those patients demonstrating alkaline urine and taking acetazolamide or zonisamide (particularly with high serum levels). These results were not the influence of abnormal renal function or hyperammonemia,
because the serum creatinine, urea nitrogen, and blood ammonia levels of all the patients were within normal ranges. Both acetazolamide and zonisamide are carbonic anhydrase inhibitors and known to induce urolithiasis [1,2,7]. The present study is consistent with this finding. Regular urinalysis seems to be necessary in epilepsy patients with zonisamide concentration higher than 18 g/mL, antiepileptic drug polytherapy including acetazolamide, and combination treatment of more than two antiepileptic drugs. The evaluation for urolithiasis should also be performed if persistent crystalluria is demonstrated. References [1] Paisley KE, Tomson CRV. Calcium phosphate stones during long-term acetazolamide treatment for epilepsy. Postgrad Med J 1999; 75:427-8. [2] Leppik IE, Willmore LJ, Homan RW, et al. Efficacy and safety of ZNS: Results of a multicenter study. Epilepsy Res 1993;14:165-73. [3] Glauser TA. Topiramate. Semin Pediatr Neurol 1997;4:34-42. [4] Sparagana SP, Strand WR, Adams RC. Felbamate urolithiasis. Epilepsia 2001;42:682-5. [5] Begun FP, Foley WD, Peterson A, White B. Urolithiasis: Patient evaluation. Laboratory and imaging studies. Urol Clin North Am 1997;24:97-116. [6] Go T. Effect of antiepileptic drug monotherapy on crystalluria in children and young adults. J Neurol 2003;250:1251-2. [7] Kubota M, Nishi-Nagae M, Sakakihara Y, et al. ZNS-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev 2000; 22:230-3.
Go: AED Polytherapy on Crystalluria 115
kidney stones in ⱕ1.5% of patients [3]. A patient with urolithiasis resulting from felbamate was also described [4]. Although crystalluria does not always indicate urolithiasis, it is frequently associated and may be useful in the diagnosis of urolithiasis if crystalluria is persistent and of a specific type [5]. Therefore in the previous study, the effect of antiepileptic drug monotherapy on crystalluria was studied in children and young adults to clarify the risk factors for urolithiasis associated with antiepileptic drugs. As a result, zonisamide or sulthiame therapy and alkaline urine were found to be risk factors [6]. In the present investigation, the relationship between antiepileptic drug polytherapy and crystalluria was retrospectively studied. Patients and Methods The medical records were reviewed in all epilepsy patients who were treated with antiepileptic drug polytherapy for more than 1 month at the Department of Pediatrics, Red Cross Hospital, during the last 7 years. Urine samples were collected more than 1 month after changing the combination of antiepileptic drugs during routine clinical examinations at the hospital. Urine samples were examined using test paper and microscope. Multiple urine samples from the same patient were considered independent and included in the study when patients were treated with different combinations of antiepileptic drugs. Patients with pyuria, bacteriuria, hematuria, or proteinuria were excluded from the study. Serum electrolytes, creatinine, urea nitrogen, the concentration of antiepileptic drugs, and blood ammonia were usually measured at the same time. Urine from patients with abnormal serum electrolytes, creatinine, urea nitrogen, or blood ammonia was not included in this study. The antiepileptic drugs had been prescribed at the normal recommended dosage and the serum concentrations of these antiepileptic drugs were within the therapeutic range. Statistical analysis was performed using Mann-Whitney nonparametric tests and chi-square tests.
Introduction
Results
Urolithiasis is a rare side effect of antiepileptic drugs in children and young adults. Among the various antiepileptic drugs, acetazolamide [1] and zonisamide [2] are wellknown causes. Topiramate was also reported to result in
A total of 278 urine specimens from 202 epilepsy patients (one urine sample from 126 patients and two from 152 patients) aged between 7 months and 36 years were enrolled in this study. The mean age was 12.3 years. There
From the Department of Infants’ Brain and Cognitive Development, Tokyo Women’s Medical University, Tokyo, Japan.
Communications should be addressed to: Dr. Go; 8-1 Kawada-cho, Shinjuku-ku; Tokyo 162-8666; Japan. Received February 16, 2004; accepted September 8, 2004.
© 2005 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2004.09.001 ● 0887-8994/05/$—see front matter
Go: AED Polytherapy on Crystalluria 113
Table 1. Age, sex, and duration of treatment in epilepsy patients treated with antiepileptic drug polytherapy in total (Total) and that including zonisamide
Total with crystalluria Total without crystalluria ZNS with crystalluria ZNS without crystalluria
Age (yr)*
Male/ Female
Duration of Treatment* (yr)
11.4 ⫾ 0.7 12.8 ⫾ 0.5 10.4 ⫾ 0.8 12.3 ⫾ 0.7
60/39 108/79 43/25 42/29
6.5 ⫾ 1.7 7.9 ⫾ 1.5 5.5 ⫾ 0.9 5.6 ⫾ 1.2
* Values are mean ⫾ standard error. Abbreviation: ZNS ⫽ Zonisamide
were 109 samples from females and 169 from males. The antiepileptic drugs administered in this study were valproate (174 urinary samples), zonisamide (139), carbamazepine (138), phenobarbital (65), phenytoin (52), acetazolamide (17), clonazepam (15), sulthiame (6), ethosuximide (6), nitrazepam (4), and clobazam (4). There were 222 samples from patients treated with two antiepi-
leptic drugs, 45 from three antiepileptic drugs, 10 from four antiepileptic drugs, and one from five antiepileptic drugs. Age, sex, and duration of treatment did not significantly differ between patients with and without crystalluria (Table 1). The frequency of crystalluria was significantly higher (P ⬍ 0.02) in patients treated with more than two antiepileptic drugs than in patients treated with only two antiepileptic drugs (Fig 1a). The pH distribution in patients with crystalluria was apparently (P ⬍ 0.0001) shifted to the alkaline side compared with that in patients without crystalluria (Fig 1b). The frequency of crystalluria was much higher in patients treated with antiepileptic drug polytherapy that included acetazolamide (P ⬍ 0.0001) or zonisamide (P ⬍ 0.0001) than in those not taking acetazolamide or zonisamide (Fig 1c). With respect to other antiepileptic drugs, there was no significant difference in the frequency of crystalluria. In patients treated with antiepileptic drug polytherapy that included zonisamide, there was no significant difference in age, sex, or duration of treatment between patients with and without crystalluria (Table 1). However, zoni-
Figure 1. (a) The frequency of crystalluria was significantly different in epilepsy patients taking polytherapy with two, three, and more than three antiepileptic drugs. (b) The pH distribution also significantly differed among patients with and without crystalluria. (c) Patients with antiepileptic drug polytherapy that included acetazolamide (AZM) or zonisamide (ZNS) were more likely to have crystalluria than those not taking AZM or ZNS.
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Figure 2. Zonisamide (ZNS) concentration (a) and pH distribution (b) significantly differed between patients with and without crystalluria who were taking ZNS.
samide concentration was higher in patients with crystalluria (P ⬍ 0.03) than in those without crystalluria (Fig 2a). The pH distribution in zonisamide-taking patients with crystalluria was significantly (P ⬍ 0.05) shifted to the alkaline side compared with that in patients without crystalluria (Fig 2b). Discussion In the previous study, the frequency of crystalluria in the control subjects, epilepsy patients before antiepileptic drug treatment, and patients with antiepileptic drug monotherapy were 14.0%, 13.1%, and 14.5%, respectively [6]. Compared with these values, the frequency of crystalluria associated with antiepileptic drug polytherapy was demonstrated to be higher, and even much higher, in patients treated with many antiepileptic drugs in combination in the present study. Urolithiasis was occasionally reported in children [4,7] and adults [1,2] with antiepileptic drug therapy. In most cases, it was not associated with antiepileptic drug monotherapy but polytherapy [1,2,4,7]. The present study is consistent with this finding. This study indicates that epilepsy patients treated with antiepileptic drug polytherapy are likely to have crystalluria, especially in those patients demonstrating alkaline urine and taking acetazolamide or zonisamide (particularly with high serum levels). These results were not the influence of abnormal renal function or hyperammonemia,
because the serum creatinine, urea nitrogen, and blood ammonia levels of all the patients were within normal ranges. Both acetazolamide and zonisamide are carbonic anhydrase inhibitors and known to induce urolithiasis [1,2,7]. The present study is consistent with this finding. Regular urinalysis seems to be necessary in epilepsy patients with zonisamide concentration higher than 18 g/mL, antiepileptic drug polytherapy including acetazolamide, and combination treatment of more than two antiepileptic drugs. The evaluation for urolithiasis should also be performed if persistent crystalluria is demonstrated. References [1] Paisley KE, Tomson CRV. Calcium phosphate stones during long-term acetazolamide treatment for epilepsy. Postgrad Med J 1999; 75:427-8. [2] Leppik IE, Willmore LJ, Homan RW, et al. Efficacy and safety of ZNS: Results of a multicenter study. Epilepsy Res 1993;14:165-73. [3] Glauser TA. Topiramate. Semin Pediatr Neurol 1997;4:34-42. [4] Sparagana SP, Strand WR, Adams RC. Felbamate urolithiasis. Epilepsia 2001;42:682-5. [5] Begun FP, Foley WD, Peterson A, White B. Urolithiasis: Patient evaluation. Laboratory and imaging studies. Urol Clin North Am 1997;24:97-116. [6] Go T. Effect of antiepileptic drug monotherapy on crystalluria in children and young adults. J Neurol 2003;250:1251-2. [7] Kubota M, Nishi-Nagae M, Sakakihara Y, et al. ZNS-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev 2000; 22:230-3.
Go: AED Polytherapy on Crystalluria 115