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Table of Contents
CLINICOPATHOLOGICAL PEARLS
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 216-218

Topiramate: Is it friend or hostile to the patients?


Department of Medicine, Division of Nephrology, King Khalid University Hospital, Riyadh, Saudi Arabia

Date of Submission18-Sep-2019
Date of Decision12-Nov-2019
Date of Acceptance21-Dec-2019
Date of Web Publication02-Jul-2020

Correspondence Address:
Akram Askar
Department of Medicine, Division of Nephrology, King Khalid University Hospital, Post Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_42_19

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How to cite this article:
Askar A. Topiramate: Is it friend or hostile to the patients?. J Nat Sci Med 2020;3:216-8

How to cite this URL:
Askar A. Topiramate: Is it friend or hostile to the patients?. J Nat Sci Med [serial online] 2020 [cited 2020 Aug 12];3:216-8. Available from: http://www.jnsmonline.org/text.asp?2020/3/3/216/288826




  Introduction Top


Topiramate is a neuronal stabilizing agent approved by the Food and Drug Administration for the treatment of generalized and partial seizures, as well as for the prevention of headache and migraine.[1] This drug affects the body metabolism by lowering serum bicarbonate levels while increasing urinary bicarbonate levels, resulting in elevated urine pH levels.[2] It decreases the urine citrate level, resulting in increased blood acidity levels. Overall acid–base balance is shifted favoring conditions to form calcium phosphate stones.[3]

It was originally synthesized as a structural analog of fructose-1,6-diphosphate – hoping it would inhibit fructose-1,6-bisphosphatase and thereby blocking gluconeogenesis. It has, however, no significant effect on this enzyme. It is also structurally similar to acetazolamide and is found to inhibit carbonic anhydrase II and IV and to reduce seizure frequency in experimental animal models.[4] It is this structural resemblance that makes topiramate prone to causing renal tubular acidosis (RTA)[5] and normal anion gap (AG) metabolic acidosis (MA) (50%–70%).

It is indicated as initial monotherapy for epileptic patients ≥10 years with partial-onset or primary generalized tonic–clonic seizures. It is also indicated as adjunctive therapy for epileptic adults and children ≥2 years with partial-onset or primary generalized tonic–clonic seizures.

Other than that, topiramate is used off-label for conditions such as adjunctive treatment for bipolar disorder, cluster headaches, eating disorders, vanity dieting, fibromyalgia, depression, posttraumatic stress disorder, alcoholism, sleep disorders, and in healing scars.

Nephrolithiasis (calcium phosphate) is relatively frequent (5% in children and 1.5% in adults), but metabolic acidosis is a more common complication of topiramate use to occur in 50% within children and 70% within adults.


  Case Report Top


A 14-year-old female known to have cerebral palsy and hydrocephalus, for which she was treated with ventriculoperitoneal shunt, along with congenital brain atrophy and epilepsy, presented now with vomiting, anorexia, and right loin pain.

She had a medication history of several antiepileptic drugs, including phenobarbitone, phenytoin, carbamazepine, and levetiracetam. She was, however, started on topiramate for the past 8 years. On presentation, she was on levetiracetam and topiramate.

She looked unwell and hypovolemic with dry mucous membranes, but on examination, she was afebrile with stable pulse of 88 bpm, respiratory rate of 18 bpm, and blood pressure of 110/72 mmHg. There was, however, tenderness at the right loin and suprapubic area.

The analysis showed urinary tract infection (UTI) with many pus cells. Laboratories showed leukocytosis (22 × 109/L), while serum chemistry was as follows:

Cr = 43 mcm/L, Na = 141, Cl = 110, HCO3= 17 mEq/L, K + = 3.4/3.7, and urea = 1.2.

Arterial blood gases showed pH = 7.35, PaCO2= 30, and HCO3= 17.

AG turned out to be higher: Na − (Cl + HCO3) =14.

Utilizing the delta/delta equation, a higher AG MA, in this case, was associated with normal AG.

△/△ ratio was calculated as follows:

△AG = Measured AG − normal AG (14 – 10 = 4)

△HCO3= Normal HCO3− measured HCO3(24 − 17 = 7)

△/△ =4/7 = 0.57 (where <1 suggests a combined normal and high AG MA).

An abdominal ultrasound was carried out showing right-sided nephrolithiasis with stone impacting ureterovesical junction, along with resulting right hydronephrosis.

The final diagnosis was made for MA and nephrolithiasis precipitating UTI. The patient stones were managed conservatively, and topiramate was substituted with carbamazepine. The high AG MA in our patient was owing to the UTI and ensuing sepsis, while the normal AG was due to use.


  Discussion Top


Topiramate is used mainly to treat epilepsy and migraine prophylaxis, but it is also used for a wide range of other indications.[6] Topiramate-induced MA has been reported as its use increased over the past years. The drug impairs the function of both: (1) proximal renal tube – in normal reabsorption of filtered HCO3− and (2) distal renal tubule – in excretion of H +. This renal defect is termed as mixed RTA. Topiramate-induced RTA can cause acute illness and in the long term lead to nephrolithiasis, osteoporosis, and growth retardation in children.[2]

Two large-scale cohort studies, one done in 1996 in the UK while others in 2015 in Taiwan,[7],[8] reported the occurrence of kidney stone formation to be insignificant with topiramate. The first study was done on 1809 individuals; most of them were under treatment for ≥1 year. This study reported nephrolithiasis in 1.5% of the patients.[8] The second cohort study includes 1377 individuals with gender-matched control group with the same number of patients.[7] Urolithiasis was found in 2.9% of the total of 2754 patients.[7] This study similar to the one done by Shorvon [8] ruled out the risk of urolithiasis related to topiramate. It is important to note, however, that we did not find any cohort study of similar size done on pediatric patients.

Reviewing the literature reveals almost all large population-based cohort studies being done on adults.[7],[8] Case report and retrospective studies, however, include both pediatric and adult patients.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19]

The first study reporting calcium phosphate-based lithiasis due to topiramate was published in 2002.[11] Two cases were then presented reporting on topiramate-induced nephrolithiasis. After that initial report, many case reports followed by publishing topiramate-induced nephrolithiasis. In 2004, Lamb et al.[12] profiled patients being treated with topiramate for stone formation risk based on their biochemical analysis. Their findings concluded that metabolic imbalance induced by topiramate increased urolithiasis risk. The study reported three cases in which calcium phosphate stones were treated. Similarly, a stone risk-profiling was done on 32 patients being treated with topiramate. A cross-sectional study was done which also includes 50 normal individuals. Statistical analysis of biochemical analysis of the patients indicated a significant increase in stone-forming risk factors in patients being treated compared to normal individuals.[3]

Following several case reports on the risk of topiramate-induced stone formation, Vega et al.[13] called for further case–controlled and long-term prospective, randomized studies in the US. A study of four women treated for chronic pain and mood stabilization using topiramate reported the development of calcium phosphate and oxalate-based lithiasis.[9] The treatment plan was devised by discontinuing drug in two patients, reducing in the third, while maintaining in the fourth. Increased fluid intake and the use of potassium citrate were advised for patients on the drug. A case report of a 53-year-old female with chronic kidney disease was prescribed topiramate for depression. During treatment, she developed kidney injury and proximal renal tube dysfunction. The report states the Naranjo Adverse Drug Reaction Probability Scale of 6, indicating that the complications were developed due to the prescribed drug. Discontinuity of the treatment resulted in the disappearance of the complications, which confirmed the causality.[10]

Goyal et al.[14] reported the risk of kidney stone formation due to antiepileptic drugs in children. The clinical evidence of urolithiasis in 24 children under investigation was much higher (54%) than for the adult population (1.5%). In a study done on 96 children, Mahmoud et al. reported kidney stone formation in 5 (5.2%) children taking topiramate for at least 1 year.[16] In another study, among 41 children taking topiramate, 4.8% developed kidney stones, whereas acid–base imbalance was reported in ≥50% of patients.[17]

A systematic review done on studies between 1996 and 2013 reports increased the risk toward drug-induced stone due to metabolic disturbances owing to topiramate treatment.

The patient in this case report had normal vital signs on presentation. She, however, looked unwell and dehydrated. Urine analysis revealed UTI and elevated pus cells. The test results revealed MA when the delta/delta ratio was computed. An abdominal computed tomography showed right-sided nephrolithiasis, along with resulting right hydronephrosis [Figure 1]. The final diagnosis was MA and nephrolithiasis precipitating UTI. UTI caused high AG MA in our patient, while the normal AG was due to Topamax use. Topiramate was discontinued to manage the patient as she was placed back on carbamazepine with conservative management of her nephrolithiasis.
Figure 1: Axial section at the level of mid-portion of the right kidney showing multiple small renal stones with mild hydronephrotic changes

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Final diagnosis

The final diagnosis was made for MA and nephrolithiasis precipitating UTI.

Clinicopathological pearls

  1. Topiramate has been reported to cause nephrolithiasis and metabolic acidosis.
  2. These untoward effects of topiramate are more pronounced in pediatric than adult patients. Evidence based on case reports indicates a higher risk factor in children (70% MA, 5% lithiasis) than in adults (50% MA, 1.5% lithiasis)
  3. Since topiramate is used as long-term therapy, to avoid its hostility, a proper management scheme against its side effects must be devised.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian of the patient has given the consent for her images and other clinical information to be reported in the journal. The legal guardian understands that the patient's name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This study was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Kingdom of Saudi Arabia.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Langtry HD, Gillis JC, Davis R. Topiramate. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy. Drugs 1997;54:752-73.  Back to cited text no. 1
    
2.
Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: Extent, mechanism and effects. Br J Clin Pharmacol 2009;68:655-61.  Back to cited text no. 2
    
3.
Welch BJ, Graybeal D, Moe OW, Maalouf NM, Sakhaee K. Biochemical and stone-risk profiles with topiramate treatment. Am J Kidney Dis 2006;48:555-63.  Back to cited text no. 3
    
4.
Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000;41 Suppl 1:S35-9.  Back to cited text no. 4
    
5.
Haque SK, Ariceta G, Batlle D. Proximal renal tubular acidosis: A not so rare disorder of multiple etiologies. Nephrol Dial Transplant 2012;27:4273-87.  Back to cited text no. 5
    
6.
Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. Topiramate for migraine prevention: A randomized controlled trial. JAMA 2004;291:965-73.  Back to cited text no. 6
    
7.
Shen AL, Lin HL, Tseng YF, Lin HC, Hsu CY, Chou CY. Topiramate may not increase risk of urolithiasis: A nationwide population-based cohort study. Seizure 2015;29:86-9.  Back to cited text no. 7
    
8.
Shorvon SD. Safety of topiramate: Adverse events and relationships to dosing. Epilepsia 1996;37 Suppl 2:S18-S22.  Back to cited text no. 8
    
9.
Merino-Salas S, Arrabal-Polo MA, Cano-Garcia Mdel C, Arrabal-Martin M. Calcium nephrolithiasis induced by topiramate. Arch Esp Urol 2014;67:284-7.  Back to cited text no. 9
    
10.
Meseeha MG, Attia MN, Kolade VO. Topiramate as a rare cause of reversible Fanconi syndrome and acute kidney injury: A case report and literature review. J Community Hosp Intern Med Perspect 2016;6:30510.  Back to cited text no. 10
    
11.
Kuo RL, Moran ME, Kim DH, Abrahams HM, White MD, Lingeman JE. Topiramate-induced nephrolithiasis. J Endourol 2002;16:229-31.  Back to cited text no. 11
    
12.
Lamb EJ, Stevens PE, Nashef L. Topiramate increases biochemical risk of nephrolithiasis. Ann Clin Biochem 2004;41:166-9.  Back to cited text no. 12
    
13.
Vega D, Maalouf NM, Sakhaee K. Increased propensity for calcium phosphate kidney stones with topiramate use. Expert Opin Drug Saf 2007;6:547-57.  Back to cited text no. 13
    
14.
Goyal M, Grossberg RI, O'Riordan MA, Davis ID. Urolithiasis with topiramate in nonambulatory children and young adults. Pediatr Neurol 2009;40:289-94.  Back to cited text no. 14
    
15.
Fukumoto R, Katayama K, Hayashi T, Matsuoka A, Fujimoto N, Koide T, et al. Two cases of urolithiasis induced by topiramate. Hinyokika Kiyo 2011;57:125-8.  Back to cited text no. 15
    
16.
Mahmoud AA, Rizk T, El-Bakri NK, Riaz M, Dannawi S, Al Tannir M. Incidence of kidney stones with topiramate treatment in pediatric patients. Epilepsia 2011;52:1890-3.  Back to cited text no. 16
    
17.
Corbin Bush N, Twombley K, Ahn J, Oliveira C, Arnold S, Maalouf NM, et al. Prevalence and spot urine risk factors for renal stones in children taking topiramate. J Pediatr Urol 2013;9:884-9.  Back to cited text no. 17
    
18.
Dell'Orto VG, Belotti EA, Goeggel-Simonetti B, Simonetti GD, Ramelli GP, Bianchetti MG, et al. Metabolic disturbances and renal stone promotion on treatment with topiramate: A systematic review. Br J Clin Pharmacol 2014;77:958-64.  Back to cited text no. 18
    
19.
Giannopoulou EZ, Gortner L, Peterlini S, Gottschling S, Yilmaz U, Meyer S. Topiramate-induced nephrolithiasis. Clin Case Rep 2015;3:508-9.  Back to cited text no. 19
    


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