Increased Incidence of Pseudotumor Cerebri Syndrome Among Users of Tetracycline Antibiotics

Background: To determine whether the use of a tetracycline-class antibiotic is associated with an increased risk of developing pseudotumor cerebri syndrome (PTCS). Methods: We identified patients in the University of Utah Health system who were prescribed a tetracycline-class antibiotic and determined what percentage of those individuals were subsequently diagnosed with PTCS secondary to tetracycline use. We compared this calculation to the number of patients with PTCS unrelated to tetracycline use. Results: Between 2007 and 2014, a total of 960 patients in the University system between the ages of 12 and 50 were prescribed a tetracycline antibiotic. Among those, 45 were diagnosed with tetracycline-induced PTCS. We estimate the incidence of tetracycline-induced PTCS to be 63.9 per 100,000 person-years. By comparison, the incidence of idiopathic intracranial hypertension (IIH) is estimated to be less than one per 100,000 person-years (Calculated Risk Ratio = 178). Conclusions: Although a causative link between tetracycline use and pseudotumor cerebri has yet to be firmly established, our study suggests that the incidence of pseudotumor cerebri among tetracycline users is significantly higher than the incidence of IIH in the general population.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Increased Incidence of Pseudotumor Cerebri Syndrome Among Users of Tetracycline Antibiotics Samuel F. Passi, MD, Ryan Butcher, MS, MBA, Daniel R. Orme, MD, Judith E.A. Warner, MD, Gregory J. Stoddard, MBA, MPH, Alison V. Crum, MD, Ramkiran Gouripeddi, MBBS, MS, Brian H. Kirk, MD, Kathleen B. Digre, MD, Bradley J. Katz, MD, PhD Background: To determine whether the use of a tetracycline-class antibiotic is associated with an increased risk of developing pseudotumor cerebri syndrome (PTCS). Methods: We identified patients in the University of Utah Health system who were prescribed a tetracycline-class Department of Ophthalmology and Visual Sciences (SFP, RB, DRO, JEAW, AVC, BK, KBD, BJK), John A. Moran Eye Center, University of Utah, Salt Lake City, Utah; Department of Family and Preventive Medicine and Department of Orthopaedics (GJS), University of Utah, Salt Lake City, Utah; and Department of Biomedical Informatics and Center for Clinical and Translational Science (RG), University of Utah School of Medicine, Salt Lake City, Utah. Dr. Passi is now with the Eye Institute of Utah, Salt Lake City, UT. Dr. Butcher is now with the Data Science Services/Data Warehouse, Salt Lake City, Utah. Dr. Orme is now with the Department of Neurological Sciences, Rush University Medical Center, Chicago, IL. Dr. Kirk is now with the Department of Ophthalmology, University of Missouri School of Medicine, University Hospital, Columbia, MO. This study was supported in part by an Unrestricted Grant from Research to Prevent Blindness, Inc., New York, NY to the Department of Ophthalmology & Visual Sciences, University of Utah. Presented in part at the 41st Annual Meeting of the North American Neuro-Ophthalmology Society, February 21‐26, 2015, San Diego, CA. S. F. Passi and D. R. Orme were supported by T35 EY026511 (NEI/ NIH) “Medical Student Research Program in Eye Health and Disease”; Principal Investigator Mary Elizabeth Hartnett. FURTHeR is supported by NCRR/ NCATS Grants UL1RR025764 and 3UL1RR025764-02S2, National Center for Clinical and Translational Science 1UL1TR001067, University of Utah Research Foundation, grant 1D1BRH20425 (DHHS), and R01 HS019862 from AHRQ, (DHHS). K. B. Digre, J. E. A. Warner and B. J. Katz are named on a patent or patents related to the treatment of photophobia. B. J. Katz is CEO of Axon Optics, LLC, an internet company that sells eyewear for the treatment of photophobia. B. J. Katz provides expert medical testimony in legal proceedings and some of these proceedings involve the treatment of PTCS. The remaining authors report no conflicts of interest. Address correspondence to Bradley J. Katz, MD, PhD, Department of Ophthalmology and Visual Sciences and Department of Neurology, John A. Moran Eye Center at the University of Utah, 65 N Mario Capecchi Drive, Salt Lake City, UT 84132; E-mail: Bradley.Katz@hsc. utah.edu Passi et al: J Neuro-Ophthalmol 2022; 42: 323-327 antibiotic and determined what percentage of those individuals were subsequently diagnosed with PTCS secondary to tetracycline use. We compared this calculation to the number of patients with PTCS unrelated to tetracycline use. Results: Between 2007 and 2014, a total of 960 patients in the University system between the ages of 12 and 50 were prescribed a tetracycline antibiotic. Among those, 45 were diagnosed with tetracycline-induced PTCS. We estimate the incidence of tetracycline-induced PTCS to be 63.9 per 100,000 person-years. By comparison, the incidence of idiopathic intracranial hypertension (IIH) is estimated to be less than one per 100,000 person-years (Calculated Risk Ratio = 178). Conclusions: Although a causative link between tetracycline use and pseudotumor cerebri has yet to be firmly established, our study suggests that the incidence of pseudotumor cerebri among tetracycline users is significantly higher than the incidence of IIH in the general population. Journal of Neuro-Ophthalmology 2022;42:323–327 doi: 10.1097/WNO.0000000000001536 © 2022 by North American Neuro-Ophthalmology Society P seudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with normal brain parenchyma, absence of hydrocephalus, mass lesion, or underlying infection or malignancy (1). PTCS can be classified as primary, that is, idiopathic intracranial hypertension (IIH), or secondary (2,3). Tetracyclines are a class of antibiotics that have long been considered to be a precipitating factor for PTCS (4–8). The tetracycline class of antibiotics includes tetracycline, doxycycline, minocycline, tigecycline, and others. Patients with PTCS typically present with headache, transient visual obscurations, diplopia, and pulsatile tinnitus (1). Although a causative link between tetracycline use and PTCS has not been firmly established, studies have recognized the onset of 323 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution PTCS in patients who use tetracycline antibiotics, and improvement of symptoms after discontinuation of the medication (7–11). The course of tetracycline-induced PTCS (PTC-T), however, is variable in duration of antibiotic use before the onset of symptoms and duration of symptoms after discontinuation of the antibiotic (9,12). We recently compared the clinical features of PTC-T and IIH and found that although there were many similarities, there were also important differences (13). Specifically, we found that PTC-T patients were younger and were less likely to be obese than those diagnosed with IIH. We also found that the duration of illness tended to be shorter and recurrence rates tended to be lower in the PTC-T group compared with the IIH group. The incidence of PTC-T is not known. A comparison of the incidence of PTCS among tetracycline-users and the incidence of IIH among the general population could potentially strengthen the suggestion of causation (14,15). This information could also aid providers in the decision to prescribe tetracycline antibiotics and help guide patient education regarding adverse drug reactions. METHODS We searched the University of Utah Health system’s records to estimate the incidence of PTC-T. We created a REDCap (Research Electronic Data Capture) database and populated it by searching records for a diagnosis of pseudotumor cerebri or IIH (ICD code 348.2 for dates of service before 2015). This query provided us with a list of all patients who were diagnosed with all-cause PTCS and IIH between 2007 and 2014. We confirmed that each patient had been evaluated by and diagnosed with PTCS by a University of Utah neuro-ophthalmologist. We then searched this group for patients who developed signs and symptoms of PTCS within 30 days of starting a tetracycline antibiotic and who had resolution of their condition with cessation of the antibiotic, with or without ancillary treatment. Because tetracyclines are infrequently prescribed before age 12 and because IIH is rarely diagnosed after age 50, we limited our search to those patients between 12 and 50 years old. We used the Federated Utah Research and Translational Health e-Repository (FURTHeR) query tool (16) to query the University of Utah Enterprise Data Warehouse for patients between the ages of 12 and 50 who were prescribed tetracycline-class antibiotics between 2007 and 2014. This database aggregates all clinical data from electronic medical records within the University of Utah health care system. U of U Health is a state-wide provider of primary, secondary, and tertiary health care that includes 5 hospitals, 12 community health care centers, and a health plan that covers more than 190,000 patients (https://healthcare.utah.edu/ about/; last accessed April 10, 2021). We then estimated the incidence of PTC-T per 100,000 person-years by dividing the number of patients with PTC-T by the number of 324 patients who had been prescribed a tetracycline antibiotic, dividing by the 8 years covered by the study, and then multiplying by 100,000. Statistical and Sensitivity Analysis To compute the incidence of tetracycline-induced PTCS, we required an accurate numerator (the number of cases of PTCT) and an accurate denominator (the number of patients at risk, or the number of patients taking any of the tetracycline antibiotics) for the State of UT. The John Moran Eye Center, part of U of U Health, is the only tertiary ophthalmology center in UT, so we assumed our numerator, the number of cases in the U of U Health system, would be equal to the total number of cases in the State of UT. We could estimate the number of patients at risk in the U of U Health system as the total number of patients with a U of U Health system tetracycline prescription. We obtained the Utah population from the US Census. By assuming that the patients seen in the U of U Health system are representative of the patients in the entire state of UT, and knowing the portion of the Utah population who receives their primary, secondary, and tertiary health care in the U of U Health system, we could estimate the number of patients in the entire state who had a tetracycline prescription. This number would then provide a statewide denominator of patients at risk. Because of the small number of cases, we multiplied the number of cases by 100,000 to obtain the 1-year incidence per 100,000 patients, which is the same as cases per 100,000 person-years. Because our calculation required a statewide denominator that was not directly derived from individual patient prescription data, we termed this portion of the study a sensitivity analysis, where the accuracy of the calculation depends on the accuracy of the assumptions. RESULTS For the period 2007–2014, our database contained a total of 274 patients diagnosed with PTCS or IIH. Of these 274 patients, 45 patients had a new diagnosis of PTC-T (16.4%). This cohort included 41 women, 3 men, and one female who was transitioning to male. The average age was 20.8 years (range 12–41 years). Forty of these 45 patients listed a Utah zip code in their home address. Six patients had been prescribed doxycycline, 37 had been prescribed minocycline, and 2 had been prescribed tetracycline. At the end of 2014, the FURTHeR query contained records for 2,547,636 patients. For the time period 2007– 2014, 876,358 of these patients were between the ages of 12 and 50 years. Of these, 960 (0.11%) received a new prescription for a tetracycline antibiotic. Table 1 documents which antibiotics were prescribed to these 960 patients. Using these 960 tetracycline patients as our “at-risk” population, we estimated the incidence of PTC-T to be Passi et al: J Neuro-Ophthalmol 2022; 42: 323-327 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Tetracycline-class antibiotics prescribed to our 960 at-risk patients Demeclocycline 5 Doxycycline Minocycline Tetracycline Tigecycline 792 120 32 11 We queried the Federated Utah Research and Translational Health e-Repository (FURTHeR) to determine which antibiotics were prescribed to University of Utah Health system patients ages 12–50 during the years 2007–2014. 45 PTC-T patients/960 tetracycline patients/8 years of study · 100,000 = 586 per 100,000 person-years. Sensitivity Analysis Because the John A Moran Eye Center at the University of Utah is the only tertiary eye clinic in the state, we are confident that most Utah patients with PTCS and PTC-T during the study period were seen at our institution. However, we only captured the tetracycline prescriptions that were written within the U of U Health system. Therefore, our calculation of incidence is an overestimate. We were only able to obtain electronic health record data for the last 2 years of the study, 2013 and 2014. During these 2 years, U of U Health provided care to approximately 11.05% of the Utah population (University of Utah Health Electronic Health Record; last accessed July 10, 2020). During these 2 years, U.S. Census Bureau documented that the average population of Utah was 2,922,072. Assuming the population of Utah resembled the University system’s patient population in the proportion of those who were prescribed a tetracycline-class antibiotic, and in proportion of the population in the 12–50 years age range, we estimated the total number of patients at risk in Utah to be 8,809 (Table 2). Using the estimate of the at-risk population for the state, we then recalculated the incidence of PTC-T, the incidence of PTCS, the risk difference, and the risk ratio (Table 3). This analysis estimated the incidence of PTC-T to be 63.9 per 100,000 patient-years and the incidence of PTCS to be 0.4 per 100,000 patient-years (Risk Difference = 0.0050539; 95% CI (0.0035728, 0.0065351); P , 0.001; Risk Ratio = 178; 95% CI = 130, 245). DISCUSSION The incidence of IIH among the general population is estimated to be between 0.65 and 0.9 per 100,000 personyears (14,15), although with increasing obesity rates, this incidence may be as high as 2 per 100,00 person-years (17). We estimated the incidence of PTCS in Utah to be 0.4 per 100,000 person-years. In 2019, the age-adjusted prevalence of obesity in Utah adults (29.9%) was slightly lower than in the U.S.(31.5) (18). The lower incidence of PTCS we calculated may be explained, in part, by UT’s lower obesity rate. We estimated the incidence of PTCS among patients taking tetracycline antibiotics to be at least 63.9 per 100,000 person-years, markedly greater than the estimated incidence of IIH and PTCS in the general population. Although it is possible that some of our patients developed PTCS coincidental to their exposure to a tetracycline antibiotic, we were careful to only include patients who developed signs and symptoms of PTCS within 30 days of starting the drug and whose signs and symptoms improved with cessation of the antibiotic. Eldweik et al (19) (2019) recently reviewed claims data from a nationwide insurer and found that in an unadjusted, multivariable Cox regression model, there TABLE 2. Determination of at-risk patients Population Served by University of Utah Health System Utah Population Total population (all ages) 2,547,636 (8-year total) in the FURTHeR database 2,922,072 from the U.S. Census Bureau 2,922,072 · 8 study yrs = 23,376,576 (8-yr total) Population age 12–50 876,358 (8-yr total) in the FURTHeR database 23,376,576 · 34.4% = 8,041,278 (estimated (34.4% of patients in the database) 8-yr total) Ages 12–50 yrs and 960 (8-yr total) in the FURTHeR database 8,041,278 · 0.11% = 8,809 (8-yr total) prescribed a tetracycline (0.11% of the patients in the database ages 12–50 yrs) Ages 12–50 with PTCS 274 (8-yr total) 274 (8-yr total) Ages 12–50 with PTC-T 45 (8-yr total) 45 (8-yr total) Percentages have been rounded for simplicity. Because we acknowledged that our estimate of the incidence of tetracycline-induced pseudotumor cerebri syndrome (PTC-T) was an overestimate, we estimated the number of at-risk patients in the State of Utah. FURTHeR, Federated Utah Research and Translational Health e-Repository; PTCS, pseudotumor cerebri syndrome; PTC-T, tetracyclineinduced pseudotumor cerebri syndrome. Passi et al: J Neuro-Ophthalmol 2022; 42: 323-327 325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Sensitivity analysis Prescribed Tetracycline Yes No PTCS (8 yrs) 45 At-risk population (8 yrs) 8,809 8-yr incidence 45/8,809 = 0.00510841 Incidence rate (per 100,000 person- (45/8,809) · 100,000 = 510.8 per yrs over 8 yrs) 100,000 person yrs 1-yr incidence 510.8/8 = 63.9 per 100,000 persons Risk ratio = 178; 95% CI = 130–245 274–45 = 229 8,041,278–8,809 = 8,032,469 229/8,032,469 =0.00002851 (229/8,032,469) · 100,000 = 2.8 per 100,000 person yrs 2.8/8 = 0.4 per 100,000 persons The incidence rate per 100,000 person-years is also an estimate of the 1-year incidence. Using our estimate of at-risk patients for the state of Utah, we performed a sensitivity analysis to correct our overestimate of the incidence of tetracycline-induced pseudotumor cerebri syndrome (PTC-T). FURTHeR, Federated Utah Research and Translational Health e-Repository; PTCS, pseudotumor cerebri syndrome. was a 70%–91% increased risk of papilledema or PTCS in tetracycline antibiotic users. After adjusting for confounders, the increased risk was no longer statistically significant. The differences in methodology and the lack of clinical data in the Eldweik study may explain, in part, the different conclusions reached by Eldweik et al and the conclusions presented here. Almost all of our PTC-T patients were women. This observation indicates that tetracycline antibiotics are more likely to cause PTC-T in patients with a gender-associated susceptibility. This and other observations have led us to hypothesize that PTC-T represents a spectrum of disease in susceptible individuals (13). There are some patients who develop PTC-T, discontinue the antibiotic, and never develop PTCS again. There are other PTC-T patients who discontinue the antibiotic and improve, but later develop PTCS. Although a preponderance of our PTC-T patients had been prescribed minocycline, it is not possible for us to determine whether this antibiotic is more likely to induce PTC-T compared with other antibiotics in this class. It is interesting, however, that the tetracycline use pattern among PTC-T (37/ 45 = 82.2%) differs quite markedly from the prescription pattern in the FURTHeR query (120/960 = 12.5%). The authors suspect that this association with minocycline reflects its preferred use in the treatment of acne vulgaris (20), and not an increased propensity for this antibiotic to cause PTC-T compared with other tetracyclines. The reason for the association between this class of antibiotics and PTCS remains poorly understood, as does the pathophysiology of IIH. Some studies suggest a genetic predisposition to tetracycline-induced PTCS, with possible effects at the arachnoid villi, choroid plexus, or venous capillary bed (21). Retinol and retinol-binding protein have been implicated in the pathogenesis of IIH (22), and retinoic acid catabolism is inhibited by minocycline (23). Regardless of the underlying pathogenesis of the disease and the contribution by tetracycline antibiotics, our data suggest that the use of these medications puts patients at increased risk for the development of PTCS. 326 Limitations In our sensitivity analysis, we considered limiting the number of PTC-T patients to 40, which is the number of those with Utah addresses. However, to do so would have required that we also limit the number of PTCS patients who did not receive tetracycline to those with a Utah zip code. By considering all PTC-T and PTCS patients, not just those with a Utah zip code, we have pushed the result closer to the null hypothesis of no difference. The sensitivity analysis also assumed that any patients in the FURTHeR query who developed PTC-T or PTCS were seen at the John A Moran Eye Center. The analysis also assumed that the proportion of Utah patients who were between ages 12 and 50 is the same as the proportion of patients of the same age who were in the FURTHeR query, and that the proportion of patients in Utah who received a tetracycline antibiotic is the same as the proportion of patients in the FURTHeR query who received a tetracycline antibiotic. Because U of U Health provides primary, secondary, and tertiary care to more than 11% of the Utah population, we believe this assumption is valid. Throughout our statistical analyses, we endeavored to make assumptions that would make it more difficult to show a significant difference (taking the result closer to the null hypothesis of no difference). The fact that we still showed a statically significant difference suggests that the effect is real and perhaps even larger than that shown here. Our data are consistent with the hypothesis that tetracyclines may predispose patients to the development of PTCS. The data presented here demonstrate an association, but not being a clinical trial, do not confirm a cause and effect. Based on our observations, we recommend that physicians who prescribe these antibiotics consider educating their patients about this adverse reaction. Patients who are taking these antibiotics and who experience symptoms of increased intracranial pressure (new headache, pulse-synchronous noises, transient visual obscurations, double vision) should be counseled to contact the prescribing physician for further advice. Patients who report these symptoms while taking these Passi et al: J Neuro-Ophthalmol 2022; 42: 323-327 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution medications should promptly be evaluated by an ophthalmologist, who can determine whether patients have ophthalmic manifestations of increased intracranial pressure. 8. 9. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. E.A. Warner, G. J. Stoddard, R. Gouripeddi, K. B. Digre, and B. J. Katz; b. Acquisition of data: S. F. Passi, R. Butcher, D. R. Orme, J. E.A. Warner, G. J. Stoddard, A. V. Crum, R. Gouripeddi, B. Kirk, K. B. Digre, and B. J. Katz; c. Analysis and interpretation of data: S. F. Passi, R. Butcher, D. R. Orme, J. E.A. Warner, G. J. Stoddard, A. V. Crum, R. Gouripeddi, B. Kirk, K. B. Digre, and B. J. Katz. Category 2: a. Drafting the manuscript: S. F. Passi, R. Butcher, D. R. Orme, J. E.A. Warner, G. J. Stoddard, A. V. Crum, R. Gouripeddi, B. Kirk, K. B. Digre, and B. J. Katz; b. Revising it for intellectual content: S. F. Passi, R. Butcher, D. R. Orme, J. E.A. Warner, G. J. Stoddard, A. V. Crum, R. Gouripeddi, B. Kirk, K. B. Digre, and B. J. Katz. Category 3: a. Final approval of the completed manuscript: S. F. Passi, R. Butcher, D. R. Orme, J. E.A. Warner, G. J. Stoddard, A. V. Crum, R. Gouripeddi, B. Kirk, K. B. Digre, and B. J. Katz. 10. 11. 12. 13. 14. 15. ACKNOWLEDGMENTS The Authors thank Ms. Susan Schulman, Links to Clinical Research, Salt Lake City, UT, USA, for professional editing of the final manuscript. 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