Topiramate is licensed for the treatment of epilepsy and for migraine prophylaxis, but is also used off-licence for a wide range of indications. With the increasing use of topiramate, reports have emerged that topiramate can cause metabolic acidosis in some patients. It does this by impairing both the normal reabsorption of filtered HCO3 − by the proximal renal tubule and the excretion of H + by the distal renal tubule. This combination of defects is termed mixed renal tubular acidosis (RTA). The mechanism involves the inhibition of the enzyme carbonic anhydrase, which is consistent with the fact that genetic deficiency of carbonic anhydrase is associated with mixed RTA. Topiramate-induced RTA can make patients acutely ill, and chronically, can lead to nephrolithiasis, osteoporosis and, in children, growth retardation. There is no proven method for predicting or preventing the effect of topiramate on acid–base balance, but patients with a history of renal calculi or known RTA should not receive topiramate. The utility of regular monitoring of HCO3 − levels has not been proven and is not routine practice currently. For patients with persistent RTA, topiramate should usually be discontinued as alternative agents are available.
Keywords: Acid–base balance, carbonic anhydrase, epilepsy, nephrolithiasis, osteoporosis, renal tubular acidosis, topiramate
Topiramate is a sulphamate-substituted monosaccharide licensed for the monotherapy and adjunctive treatment of generalized tonic-clonic seizures or partial onset seizures with or without secondary generalization, for the adjunctive treatment of seizures in Lennox–Gastaut syndrome [1 ], and for migraine prophylaxis [2 ]. Topiramate is also being used off-label for an ever increasing number of other indications. Several studies have demonstrated the efficacy of topiramate in the treatment of bipolar disorder [3 ] and in the treatment of post-traumatic stress disorder [4 ]. Topiramate has also shown promise as an antiobesity agent [5 ] and in treating alcohol dependence [6 ]. Investigational uses of topiramate include treatment of bulimia nervosa [7 ], obsessive-compulsive disorder [8 ], idiopathic intracranial hypertension [9 ], neuropathic pain [10 ], infantile spasm [11 ] and as an aid in smoking cessation [12 ].
With the increasing use of topiramate, reports have emerged of serum and urine biochemical derangements induced by this medication (see below). In the present review, we will examine the extent of these derangements and discuss the possible underlying mechanisms and clinical effects.
Topiramate induces metabolic acidosis in some patients
Case reports indicate that topiramate can cause metabolic acidosis in some patients. Burmeister et al. [13 ], for example, reported the case of a 46-year-old prescribed topiramate for vertigo who developed metabolic acidosis with a pH of 7.31 and serum HCO3 − of 8.9 mM (normal range not provided). Similarly, Ozer and Altunkaya [14 ] reported the case of a 58-year-old patient on topiramate for refractory temporal lobe epilepsy who developed metabolic acidosis with a pH of 7.29 and serum HCO3 − of 20 mM. Philippi et al. [15 ] found that metabolic acidosis developed in eight out of nine children after 8–26 days of topiramate treatment with a minimum pH of 7.22 and serum HCO3 − of 15 mM. At present, there are no published prospective systematic studies of the effect of topiramate on serum pH and there is an important clinical need for studies of this nature.
A number of studies have assessed the effects of topiramate on serum HCO3 − levels. A low plasma HCO3 − concentration represents, by definition, a metabolic acidosis. In controlled clinical trials, 32% of adults receiving 400 mg of topiramate daily had a persistent treatment-emergent reduction in serum HCO3 − concentrations to <20 mM compared with 1% in placebo-treated patients (see topiramate prescribing information, http://www.topamax.com. accessed 25 June 2009). More marked lowering of serum
HCO3 − concentrations (<17 mM and >5 mM decrease from pretreatment) was seen in 7% of patients receiving 400 mg of topiramate vs. none in the placebo group. Rarely, patients experienced severe decrements to values below 10 mM. In a retrospective cohort study conducted in an outpatient neurology clinic [16 ], 26 patients out of 54 (48%) had low serum HCO3 − concentrations (<22 mEq l −1 ) while on topiramate. Mean serum HCO3 − concentrations before and during topiramate therapy were 26.8 ± 2.9 mEq l −1 and 21.7 ± 3.6 mEq l −1. respectively, with a mean difference of 5.1 (P < 0.001). Welch et al. [17 ] compared 32 topiramate-treated subjects and 50 healthy volunteers in a cross-sectional study and found that topiramate-treated subjects had significantly lower serum total carbon dioxide content (23.8 ± 2.0 vs. 26.1 ± 2.1 mEq l −1 ; P < 0.001). The relationship between HCO3 − concentration and dose of topiramate was not adequately defined in any of the above studies.
What is the mechanism of topiramate-induced metabolic acidosis?
The anion gap (AG), which corresponds to the presence of unmeasured anions, allows for the differentiation of two groups of metabolic acidosis. Metabolic acidosis with a high AG is associated with acid accumulation from increased acid production or acid ingestion. Metabolic acidosis with a normal AG is associated with the loss of HCO3 − from the kidney or gastrointestinal tract, or the failure of the kidney to excrete H +. When metabolic acidosis occurs without an increase in the anion gap, the chloride concentration is typically increased [18 ].
A number of case reports have documented that topiramate induces hyperchloraemic normal anion gap [14. 19 –21 ] metabolic acidosis. There are two major causes of this form of metabolic acidosis. The first is HCO3 − loss from the gastrointestinal tract (most commonly due to diarrhoea), and the second is a selective defect in renal H + excretion or HCO3 − absorption, termed renal tubular acidosis (RTA). Many case reports have also shown that topiramate-induced metabolic acidosis is associated with an alkaline urine [19. 20 ], and positive urinary anion gap [20 ]. These findings suggest that the normal-AG metabolic acidosis seen with topiramate use is a result of a defect in the renal regulation of acid–base balance. Taken together with the fact that gastrointestinal disorders that might lead to HCO3 − loss have been excluded, it seems that topiramate-induced metabolic acidosis is the result of RTA.
More detailed biochemical studies make it possible to differentiate between different types of RTA. Understanding the specific type of RTA induced by topiramate is important as it will allow delineation of the molecular mechanisms underlying this adverse effect and, through this, the development of predictive and preventive strategies.
Elucidating the type of RTA induced by topiramate
Types of RTA
RTA is characterized by acidosis and electrolyte disturbances due to impaired renal H + excretion or impaired HCO3 − resorption. Type 2 (proximal) RTA is due to the inability to reabsorb filtered HCO3 − in the proximal tubule. Since 85–90% of filtered HCO3 − is normally reabsorbed in the proximal tubule, this impairment leads to increased delivery of HCO3 − to the distal portion of the nephron. As the distal tubule is overwhelmed, HCO3 − spills into the final urine, leading to metabolic acidosis. Type 1 (distal) RTA is characterized by impaired acid secretory capacity in the collecting tubules. This defect leads to inability to excrete the daily acid load, resulting in progressive H + retention and a drop in plasma HCO3 − concentration [18 ]. Table 1 lists the biochemical features that can be used to differentiate between the types of RTA.