Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure of unknown cause. Patients commonly present with headache, pulse-synchronous tinnitus, and papilledema; loss of vision is a potential consequence of treatment failure for IIH patients (1). IIH patients often develop an array of symptoms, which can limit functional independence and lead to decline in quality of life (2).
Currently, there is no cure for IIH and available treatments include: 1) weight reduction, 2) pharmacologic therapies, and 3) surgical procedures if medical management fails. The most widely used pharmacologic therapy is acetazolamide, a carbonic anhydrase inhibitor. Acetazolamide, synthesized in 1950, has been used to control intracranial hypertension for nearly 6 decades and remains the initial treatment of choice for IIH patients (3,4).
Acetazolamide acts by reducing cerebrospinal fluid (CSF) production, thereby lowering intracranial pressure (5,6). Specifically, acetazolamide is believed to affect the transport of certain ions across the choroid plexus epithelium, causing a reduction in CSF production (5,7). An early study has demonstrated a 6.0%–50.0% reduction in CSF production in humans (8). Later studies have also demonstrated acetazolamide's clinical significance via beneficial treatment effects. Celebisoy et al (9) reported improvements in visual field grades among IIH patients treated with acetazolamide. In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), patients with mild visual loss showed modest improvement in visual field function and reduction in papilledema grade and intracranial pressure while using the maximally tolerated dosage of the drug (up to 4 g/d) (7).
Concern has been raised regarding the risk of nephrolithias in patients taking acetazolamide (10,11). This medication is believed to increase the risk for nephrolithiasis due to impaired renal function (12,13). Its action on carbonic anhydrase in the proximal renal tubules prevents both hydrogen ion excretion and bicarbonate reabsorption resulting in distal renal tubular acidosis and alkaline urine (14,15). These physiologic alterations promote the crystallization of calcium phosphate.
Acetazolamide-induced nephrolithiasis can be characterized by a stone's chemical composition. Acetazolamide-induced stones are at least 50% calcium phosphate and represent only 5% of all renal stones (16). In contrast, calcium oxalate stones make up approximately 75% of all stones found in the general population, which develop independent of urine pH. The prevalence of calcium oxalate stones is 8.8%–10.6% in men and 7.1% in women (17).
Although acetazolamide-associated renal stone formation has been documented among various disorders using acetazolamide as a treatment (glaucoma, seizures, neuromuscular disease), it has not been described in a large IIH patient population with extended duration of use and follow-up (7,10,11,18). In a study of 515 glaucoma patients, Kass et al (10) reported the occurrence of at least one stone to be 11–15 times greater when comparing acetazolamide-treated patients with those without the drug. Despite the demonstrated increased risk, findings of the IIHTT noted an occurrence of only 2 stone cases in 86 (2.3%) acetazolamide users over a 6-month period (7).
To further examine this possible side effect of acetazolamide, we analyzed an extensive collection of patient information gathered on a large IIH patient population by the Intracranial Hypertension Registry (IHR).
Study Design and Data Source
Our study was retrospective following the case–control design. The IHR provided study data from previously collected questionnaires and medical records of patients with IIH. Data contained information on patients enrolled from January 2003 to October 2013. Enrollment procedures required completion of an initial questionnaire on demographic and clinical information and consent to medical record collection. Annual questionnaires were administered to each enrolled patient along with the collection of any updated medical records. For purposes of this study, several additional data points required abstraction from medical records. Medical record abstraction was performed by medical staff and reviewed by Registry coordinators. Our study received Institutional Review Board approval in 2013 by Oregon Health & Science University.
A total of 1,154 Registry patients were confirmed as meeting the Modified Dandy Criteria for IIH (19). Patients were excluded for having an incomplete questionnaire (n = 89), incomplete information regarding the diagnosis of IIH (n = 27), or if they were less than 18 years or greater than or equal to 89 years at the time of the study (n = 146). We further limited our study population to only patients with a history of acetazolamide use for IIH treatment, as indicated in patient questionnaires (n = 789). After a review of the 789 patients' medical records for confirmation of acetazolamide use and abstraction of all diagnoses, including nephrolithiasis, and ancillary medication use, exclusionary criteria were applied to remove patients likely to develop a stone from other known factors (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A182): overlap of acetazolamide use with other commonly prescribed drugs for IIH treatment (n = 78), history of systemic diseases associated with renal stone development (n = 12), history of renal stones (n = 28), and insufficient acetazolamide treatment duration (n = 1). After careful review of the remaining 789 patients for any exclusionary criteria, the final study sample included 670 patients.
Case Definition and Control Selection
The case definition required the development of at least one symptomatic stone during acetazolamide treatment for IIH. Initiation of acetazolamide treatment was required to precede stone development, supporting the hypothesized causal relationship between exposure and outcome. We found stone development during treatment for all identified cases. Potential asymptomatic (silent) renal stones were not included in the case definition. A total of 19 patients of 670 met the case definition. After case identification, 40 controls were randomly selected from the remaining pool of 651 patients.
Abstraction of acetazolamide dose and duration was performed on all identified patients and controls (n = 59). For patient cohort, the time examined for acetazolamide use was from IIH diagnosis to stone development (stone development contraindicates further acetazolamide use). For all identified cases in our study, treatment was immediately terminated after stone development.
For controls, the time examined was from IIH diagnosis to last documented use of acetazolamide in medical records. To ensure a sufficient treatment length had elapsed for stone development among controls, the median duration of acetazolamide use was compared between cases and controls. Our study patients took acetazolamide for approximately 123 days before renal stone diagnosis (minimum = 30 days, maximum = 943 days), controls for 380.5 days (minimum = 31, maximum = 1,310 days). As expected, due to contraindications, our results illustrated greater treatment duration for controls than cases and suggested sufficient follow-up time for stone development.
To accommodate change in dosages, a weighted average was calculated to determine overall mean daily dosage. The weighted average was accomplished by calculating the total amount (grams) of acetazolamide taken for a period, defined by the start and stop dates of a specific acetazolamide dose. The total acetazolamide amount per treatment period was then summed for all periods and divided by the total treatment duration (days).
Clinical Signs and Symptoms
Several classic clinical signs and symptoms of IIH were examined in relation to stone development during acetazolamide treatment: headache, pulse-synchronous tinnitus, transient visual obscurations, diplopia, and papilledema. The presence of these signs and symptoms was self-reported in patient questionnaires, except for papilledema, which was abstracted from medical records.
A 2-sample t test and Fisher exact testing were performed to assess the significance between group means and proportions, respectively (cases vs controls). Odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated using exact logistic regression to investigate the relationship of daily acetazolamide use and the clinical presentation of IIH (signs and symptoms) with stone development. Statistical significance was set at α = 0.05; CIs reflect a 95% confidence level. Analysis was conducted using STATA statistical software (version 11.2; Stata Corp, College Station, TX).
Among the pool of eligible patients (n = 670), 19 (2.8%) patients were identified as having developed a stone during acetazolamide treatment for IIH. Among cases, 15 (73.7%) patients had their first stone within 1 year from the start of acetazolamide treatment and 17 (89.5%) within 1.5 years.
Patient demographics for cases (stone development) and controls are presented in Table 1. For all study subjects, one man was identified in the case group. The mean age at the time of IIH diagnosis was 30.1 and 33.8 years for cases and controls, respectively. With the exception of one control patient, all patients were either overweight or obese; the majority of subjects were classified as obese, 84.2% in cases and 90.0% in controls. The mean body mass index was 38.7 kg/m2 for cases and 40.3 kg/m2 for controls. The majority of patients were Caucasian and non-Hispanic in both groups. Across all demographic variables, statistical significance was not observed (P > 0.05).
Weighted averages were calculated to determine the average daily acetazolamide amount taken for IIH treatment. The daily minimum and maximum doses among cases are 0.5 and 2.1 g/d, respectively. Correspondingly, we found 0.3 and 3.2 g/d among controls. The mean daily acetazolamide use was estimated at 1.0 g/d (standard deviation [SD] = 0.43) for cases and 1.2 g/d (SD = 0.71) for controls, which did not differ significantly (P = 0.34). The estimated effect measure for the relationship between daily acetazolamide use and stone development was OR = 0.95 (95% CI: 0.86–1.05) for a 100-mg increase in acetazolamide dose. Results did not reach statistical significance.
Our study also investigated the clinical presentation of IIH and its association with stone development during acetazolamide treatment (Table 2). The majority of patients in both groups complained of headaches, tinnitus, and transient visual obscurations. Diplopia was subjectively reported by nearly half the patients in both groups. Papilledema was present in most patients for both case and control groups. Our study did not find evidence to support the relationship between a specific sign or symptom of IIH and later stone development (P > 0.05).
Of 670 patients who were taking acetazolamide in our study, a total of 19 (2.8%) patients developed a stone during acetazolamide treatment for IIH. Among these 19 patients, the majority developed a stone within the first year of treatment and nearly all within 1.5 years. Both daily use of acetazolamide and the clinical presentation of IIH (signs and symptoms) in relation to stone development during acetazolamide treatment were not statistically significant.
The proportion of identified patients with stone development during acetazolamide treatment is consistent with a publication by the NORDIC study group reporting, at 6 months, 2.3% of acetazolamide subjects with renal stones (7). Previous studies documented percentages as low as 0.0% to a high of 15% (18,20). This range is due, in part, to variable case definitions and applied exclusion criteria across all studies. Our estimate used the largest reported sample of patients and represented stone formation attributed only to the duration and dose of acetazolamide by applying our exclusionary criteria. Our findings suggest that among those patients with IIH and taking acetazolamide, stone development is a relatively infrequent occurrence. Acetazolamide duration and dose were similar between those who did and did not develop stones.
Our results also suggest that among those who are most likely to develop a stone from acetazolamide treatment, formation will likely occur within the first year and a half of treatment. This is consistent with the study by Kass et al (10), which reported that among patients with acetazolamide-induced stones 75% developed a stone within the first year. We did not find an association between acetazolamide daily dosage and subsequent stone development. Results must be interpreted with caution and limited to the ranges observed in our study sample; the maximum daily dosage observed in our patient cohort was just over 2 g/d. We recommend treating physicians to closely monitor for stone development particularly within the first year and a half of acetazolamide treatment, regardless of the prescribed dosage.
Although our study used a large patient sample with consistent data collection and entry criteria, certain limitations exist that merit further consideration. Outcome status was dependent on completed medical record collection. It is possible that cases were missed, lowering the percentage found in our sample. However, a thorough database search and medical record review were performed to mitigate the bias of missed cases. Additionally, given our case definition, it is likely that a small subpopulation of asymptomatic stones was missed, which would further lower the number of identified cases. This limitation is likely inherent in all similar studies as a stone diagnosis would likely be detected and documented by chance via an unrelated surgical procedure or imaging study. Furthermore, detection of silent stones in asymptomatic IIH patients would require unjustifiable repeated imaging or invasive procedures both during and after acetazolamide treatment. Furthermore, the focus of our study was the investigation of stones attributed to acetazolamide usage. Although exclusionary criteria were employed, it is impossible to be certain if all causes of stone were due to acetazolamide. Future studies should investigate stone composition for more accurate case identification. Correct exposure status is also a concern. Both treatment duration and dosages were abstracted from collected medical records. Medical records may not necessarily reflect actual dosages taken by the patient, which could lead to exposure misclassification and an underestimation of any differences between groups. Finally, due to the small number of identified cases, we were not able to adjust for potential confounding with adequate statistical power. Demographic and clinical histories between groups, however, were comparable suggesting no major differences. Future studies should include behavioral and economic factors, including dietary modifications for optimal IIH treatment, detailed health-care access information, and use more sophisticated analyses to investigate the effect of dosage change over time.
Our results demonstrate 4 critical findings: 1) stone formation from acetazolamide is a relatively infrequent occurrence within the IIH population; 2) among patients who develop a stone, formation is likely to occur within the first year and half; 3) there is no evidence to support the association between acetazolamide daily dosage and stone development; and 4) no unique IIH disease features at the time of diagnosis are associated with stone development. In light of our findings, acetazolamide should be administered with caution and justification. If deemed necessary to continue acetazolamide after initial stone occurrence, one might consider periodic ultrasound examinations, diet management, prophylactic urinary pH adjustments if indicated, and nephrological consultation (21,22).
The authors acknowledge the expert help and support from the volunteer staffs of the Intracranial Hypertension Registry (IHR) and Oregon Health & Science University. The authors are particularly indebted to the IHR Program Manager, Ralpha Newton, for encouragement and her tireless effort.
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