Pharmacologic Mydriasis Secondary to Topical Glycopyrronium Tosylate Cloths: Clinical Characterization From a Multicenter Analysis

Topical glycopyrronium tosylate (GT) is an anticholinergic medication for treatment of axillary hyperhidrosis. Pharmacologic mydriasis and anisocoria from topical GT has been reported and may be underrecognized. This study aims to clinically characterize patients presenting with pharmacologic mydriasis from exposure to this medication.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Pharmacologic Mydriasis Secondary to Topical Glycopyrronium Tosylate Cloths: Clinical Characterization From a Multicenter Analysis Aaron R. Kaufman, MD, Shawn Gulati, MD, MPH, John H. Pula, MD, Timothy M. Janetos, MD, MBA, Neena R. Cherayil, MD, Eric Chiu, MD, Emily Anne Shepherd, MD, Karl C. Golnik, MD, MEd, Enrique Garcia-Valenzuela, MD, PhD, Peter W. MacIntosh, MD, Brooke T. Johnson, DO, Kimberlee M. Curnyn, MD Background: Topical glycopyrronium tosylate (GT) is an anticholinergic medication for treatment of axillary hyperhidrosis. Pharmacologic mydriasis and anisocoria from topical GT has been reported and may be underrecognized. This study aims to clinically characterize patients presenting with pharmacologic mydriasis from exposure to this medication. Methods: This study is a retrospective observational case series. A multicenter chart review of 16 patients diagnosed with pharmacologic mydriasis secondary to topical GT was performed. Results: Eight patients (50.0%) were age 18 years and younger, and 14 patients (87.5%) were female. Unilateral mydriasis (anisocoria) occurred in 14 patients (87.5%). Fourteen patients (87.5%) did not initially volunteer topical GT as a “medication,” and the history of topical GT exposure needed to be elicited with further questioning. Hand hygiene details were known for 12 patients, and all reported that they did not wash their hands after GT application. Six patients (37.5%) were soft contact lens users. One patient Department of Ophthalmology and Visual Sciences (ARK, SG, PWM, BTJ, KMC), Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois; NorthShore University Health System (JHP), Evanston, Illinois; Department of Ophthalmology (TMJ, NRC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Neurology (NRC), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Des Peres Eye Center (EC), Des Peres, Missouri; Department of Ophthalmology (EAS), Rush University Medical Center, Chicago, Illinois; Department of Ophthalmology (KCG), University of Cincinnati College of Medicine (KCG), Cincinnati, Ohio; Cincinnati Eye Institute (KCG), Cincinnati, Ohio; and Midwest Retina Consultants (EG-V), Arlington Heights, Illinois. This work at the University of Illinois at Chicago was supported by Core Grant for Vision Research P30 EY001792 from NEI/NIH and an unrestricted departmental grant from the Research to Prevent Blindness. The authors report no conflicts of interest. Address correspondence to Aaron R. Kaufman, MD, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 1855 W. Taylor Street M/C 648, Chicago IL 60612; E-mail: [e-mail] 530 had possible exposure through a family member’s use of the medication. Ocular symptoms were common (blurry vision [11 patients, 68.8%] and eye dryness [7 patients, 43.8%]), but systemic anticholinergic symptoms were uncommon (such as constipation [1 patient, 6.3%] and urinary symptoms [3 patients, 18.8%]). Conclusions: Mydriasis associated with topical GT seems to be a consequence of local exposure rather than systemic toxicity. Because patients may not volunteer topical GT as a medication, eliciting a history of exposure often requires further specific questioning. Soft contact lens wear and poor postapplication hand hygiene seem to be associated with mydriasis in GT use. Journal of Neuro-Ophthalmology 2022;42:530–534 doi: 10.1097/WNO.0000000000001567 © 2022 by North American Neuro-Ophthalmology Society T he glycopyrronium tosylate (GT) 2.4% cloth (Qbrexza, Dermira, Inc, Menlo Park, CA) has been approved by the US Food and Drug Administration (FDA) for the treatment of axillary hyperhidrosis in adults and pediatric patients older than age 9 years (1). GT is a competitive antagonist for cholinergic receptors (2). The medication is recommended to be applied to the axillae once daily (1). Hyperhidrosis has high prevalence in the United States (4.8%, corresponding to 15.3 million people) (3). This condition negatively interferes with daily life and can have substantial negative social and emotional consequences (3). GT not only effectively reduces sweating in hyperhidrosis (4–7) but also improves patients’ quality of life (8). Mydriasis may occur in patients using GT: in the ATMOS-1 and ATMOS-2 trials (replicate phase III double-blinded randomized controlled trials of topical GT for axillary hyperhidrosis) (4–7), mydriasis occurred in 6.8% of all patients (5) and 16% of pediatric patients (6). Kaufman et al: J Neuro-Ophthalmol 2022; 42: 530-534 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution In addition, since this medication’s FDA approval in 2018, there have been increasing clinical reports of patients presenting with pharmacologic mydriasis and anisocoria secondary to topical GT. This unusual cause of pharmacologic mydriasis and anisocoria may be underrecognized owing to its recent FDA approval; however, cases may be occurring with increasing frequency as dermatologic prescribing patterns progress (9). Any patient with new anisocoria requires careful diagnostic evaluation because processes such as Horner syndrome and third nerve palsy may occur secondary to life-threatening processes; by contrast, pharmacologic mydriasis/anisocoria from topical GT is a benign process. Accurate diagnosis of pharmacologic mydriasis/anisocoria from topical GT requires cognizance of this emerging clinical presentation. Accordingly, there is a need for increased awareness and improved understanding of the clinical features of patients presenting with pharmacologic mydriasis or anisocoria from topical GT. Detailed descriptions of patients presenting with pharmacologic mydriasis associated with topical GT have been limited to small case series and case reports (10–15). This study herein describes the largest reported analysis of patients with pharmacologic mydriasis secondary to inadvertent ocular exposure to topical GT to better characterize clinical characteristics of these patients and identify possible risk factors for exposure. Three patients in this series have been previously preliminarily reported in a cautionary letter to the editor in which only limited clinical details about the patients were provided (9). Additional data from these 3 patients and all data regarding the other patients in this series are newly reported in a multicenter analysis. METHODS This study received Institutional Review Board (IRB) approval at the University of Illinois at Chicago College of Medicine to serve as the primary site for investigation and to receive deidentified data from the other participating sites. All other sites separately obtained IRB approval or IRB exemption status per their institutional protocols. This study was also conducted in accordance with both the Health Insurance Portability and Accountability Act and the Declaration of Helsinki. A multicenter retrospective chart review was performed at the participating sites: Illinois Eye and Ear Infirmary/ University of Illinois at Chicago, Northwestern University, Des Peres Eye Center, NorthShore University HealthSystem, Rush University Medical Center, University of Cincinnati College of Medicine/Cincinnati Eye Institute, and Midwest Retina Consultants. The study inclusion criteria were all consecutive patients diagnosed with pharmacologic mydriasis secondary to topical GT. Diagnosis was made based on the history of exposure to topical GT with compatible examination findings of pharmacologic mydriasis and clinical exclusion of alternative diagnoses by clinical history, examination, pharmacologic testing, and/or imaging. A chart review was Kaufman et al: J Neuro-Ophthalmol 2022; 42: 530-534 performed for patient demographic information, details of topical GT use, mechanism for ocular exposure to GT, visual acuity, pupil size, imaging, ancillary pharmacologic testing, anticholinergic symptoms, and follow-up length. Owing to the multicenter and retrospective nature of the study, incomplete data were available for several patients. RESULTS Demographic Information Demographic information for the patients in this series is summarized in Table 1. A total of 16 patients (18 eyes with mydriasis) met the inclusion criteria for this study. Fourteen (87.5%) of the patients were female. Two patients (12.5%) had bilateral mydriasis; of the remaining patients with unilateral mydriasis, the right eye was mydriatic in 7 patients (43.8%). Eight patients (50.0%) were age 18 years and younger, and 1 of the 8 patients (12.5%) had bilateral mydriasis. Eight patients were older than age 18, and 1 of the 8 patients (12.5%) had bilateral mydriasis. Elicitation of History of Glycopyrronium Tosylate Use Three patients (18.8%) listed topical GT either spontaneously or when asked about medications in general. In the remaining 13 patients (81.3%), eliciting a history of GT exposure required additional questioning including asking specifically about exposure to Qbrexza/GT, topical products in general, or deodorants. Mechanism for Ocular Exposure to Glycopyrronium Tosylate Soft contact lens use was common and was reported in 6 patients (37.5%). Both cases of bilateral mydriasis TABLE 1. Patient demographic information No. patients (n) Male:female patients Patient age (mean ± SD), yr Age #18 Age .18 Ethnicity White Hispanic Black Unknown Laterality of mydriasis Right eye only Left eye only Both eyes Context for ophthalmic consultation Outpatient Inpatient Emergency room 16 2:14 25.5 ± 12.2 8 (50.0%) 8 (50.0%) No. patients (%) 9 (56.3%) 3 (18.8%) 2 (12.5%) 2 (12.5%) No. patients (%) 7 (43.8%) 7 (43.8%) 2 (12.5%) No. patients (%) 14 (87.5%) 0 (0%) 2 (12.5%) 531 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution occurred in contact lens users. Eight patients (50.0%) reported knowingly rubbing the eye and/or touching the face after GT application. One patient had applied GT to his scalp (patient was bald) including close to the eyes. Details of hand hygiene were known for 12 patients, and none of these patients would routinely wash their hands after GT application. No patients reported using gloves when applying GT. One patient did not use GT herself but reported that her daughter used this medication, and the patient was ultimately felt to have had possible exposure to GT through her daughter’s use. Pupillary mydriasis began a mean of 2.3 ± 2.3 days (range 0 [same day]—7 days) before presentation for ophthalmic consultation. Time from the start of topical GT use until presentation with pharmacologic mydriasis was known for 8 patients, with a mean of 9.5 ± 9.3 weeks (range 1 day—6 months). Anticholinergic Symptoms Anticholinergic symptoms reported by patients are summarized in Table 2. The most commonly reported symptoms were blurry vision (11 patients, 68.8%), eye dryness (7 patients, 43.8%), and headache (7 patients, 43.8%). Symptoms of systemic toxicity were uncommon: Constipation was reported in 1 patient (6.3%), and urinary symptoms were reported in 3 patients (18.8%). Examination and Testing The Snellen distance visual acuity in mydriatic eyes ranged from 20/20 to 20/30. In unilateral mydriasis, the Snellen visual acuity was one or more lines worse in the affected than in the unaffected eye for 2 of 14 patients (14.3%). Pharmacologic testing with topical pilocarpine was performed in 4 patients, and none of them had pupil constriction after pilocarpine administration. Radiologic imaging had been obtained before ophthalmic consultation in 3 patients: 1) One patient had CT angiography and noncontrast CT of the head, 2) one patient had MRI of the brain and orbits and MR angiography, and 3) one patient had CT angiography and an MRI of the brain. All imaging TABLE 2. Symptoms reported by patients with mydriasis from topical glycopyrronium tosylate Symptom Blurry vision Eye dryness Headache Dry mouth Nasal dryness Urinary symptoms (including retention, hesitation, etc.) Constipation 532 No. Patients (%) 11 7 7 3 3 3 (68.8%) (43.8%) (43.8%) (18.8%) (18.8%) (18.8%) 1 (6.3%) obtained was unrevealing of an alternate diagnosis. No additional imaging was obtained after ophthalmic consultation. Follow-Up and Resolution All patients were counseled regarding either cessation of topical GT or continuing usage of GT with appropriate postapplication hand hygiene. Four patients were initially reassessed at 1 week of follow-up, and complete resolution of the mydriasis had occurred in 3 of 4 patients (75.0%). In the patient with incomplete resolution at 1 week, resolution was noted at the next follow-up appointment 3 weeks after initial presentation. Three patients were reassessed at 2 weeks after initial presentation, and resolution of mydriasis occurred in all cases. One patient who was initially reassessed at 4 weeks of follow-up (with resolution at that time) reported several episodes of waxing and waning pupillary dilation before clinical reassessment. Two patients were reassessed by telephone: One of these patients reported resolution by 2 days after presentation, and the other reported resolution by 1 week after presentation. Six patients did not have follow-up because of either nonadherence with follow-up or the anticipated self-limited course of pharmacologic mydriasis. CONCLUSIONS This retrospective study illustrates the importance of a carefully taken history in the evaluation of a patient presenting with pupillary mydriasis or anisocoria. Diagnosis of pharmacologic mydriasis and anisocoria from topical GT requires elicitation of the explanatory history of GT exposure. In this study, most of the patients did not initially volunteer GT on the list of medications that they were using, and further questioning was accordingly needed. Perhaps many patients do not view topical GT as a medication per se (15). Alternatively, patients might not be initially forthcoming about using topical GT because of perceived social stigma of hyperhidrosis. In addition, use of topical GT by family members should be considered. A case of an infant child of an adult treated with topical GT has been previously reported (15), and in this study, an adult patient may have been exposed through her daughter’s use of the medication. When evaluating the patient with acute onset of pupillary mydriasis, the clinician should use adequate questioning about topical GT use: asking about use specifically of Qbrexza/GT, topical products in general, and/or deodorants (12,15). Because some cases may involve exposure to GT through another party, questioning the patient directly regarding possible exposure may be more sensitive to finding a possible link rather than review of the patient’s medication list alone. Accurate diagnosis by clinical history may assuage patient anxiety and avoid nondiagnostic imaging, which is both expensive and unnecessary (9,10,13,14). In the Kaufman et al: J Neuro-Ophthalmol 2022; 42: 530-534 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution absence of clinical suspicion for an alternate etiology for mydriasis, radiologic imaging does not play a role in the evaluation of the patient with mydriasis suspected to be pharmacologic in nature. Thus, imaging should not be obtained unless the mydriasis does not spontaneously resolve after appropriate observation. Rates of imaging obtained before ophthalmic consultation were overall low in this series, which might be related to accessibility of ophthalmic/neuro-ophthalmic consultation, duration of symptom onset, and effective imaging stewardship by referring providers. When the diagnosis of pharmacologic mydriasis/anisocoria from topical GT is missed, rates of nondiagnostic imaging ordered are likely higher. Pediatric patients represent an important subset of topical GT users regarding risk for ocular anticholinergic toxicity. The ATMOS-1 and ATMOS-2 trials reported that in comparison with the overall study population, pediatric patients had higher rates of eye dryness (4% vs 2.4%), blurry vision (12% vs 3.5%), and mydriasis (16% vs 5.3%) (5,6). It was proposed that more frequent ocular side effects in children might be caused by children touching their faces more frequently (6). In this study, 50% of patients were aged 18 years and younger. Other series have also reported multiple pediatric patients (14). Accurate diagnosis of mydriasis and anisocoria as occurring secondary to topical GT is particularly important in pediatric patients, in whom radiographic imaging stewardship to reduce radiation exposure is essential (9). In this series, most of the cases of mydriasis were unilateral, which is consistent with the ATMOS-1 and ATMOS-2 trials, in which 74% of mydriasis cases were unilateral (5). However, the pediatric post hoc analysis of these trials reported bilaterality to be more common in pediatric patients, as 25% of pediatric mydriasis cases were unilateral (6). By contrast, in the current series, unilateral mydriasis was equally common in both patients aged 18 years and younger and in patients older than age 18 years. However, only 2 patients total in this series presented bilaterally. Bilateral pharmacologic mydriasis might be less likely to be noticed by the patient than pharmacologic anisocoria and consequently less likely to present for evaluation. In this series and previous reports (14), most of the patients with pharmacologic mydriasis or anisocoria from topical GT were female. This is likely a reflection of hyperhidrosis demographic trends in general. Although hyperhidrosis affects men and women in equal numbers, women are more likely to seek treatment (16). By extension, GT use may be more common in female patients. Soft contact lens use may be a risk factor for mydriasis from topical GT, as it was common in our patient cohort. Cases associated with contact lens use have also been previously reported (12,14). In the setting of the poor postapplication hand hygiene observed in this study, it is logical that a patient who applies topical GT and then manipulates their soft contact lenses would inadvertently cause ocular exposure to topical GT. Moreover, this pathway to pharKaufman et al: J Neuro-Ophthalmol 2022; 42: 530-534 macologic mydriasis could result in bilateral exposure. Indeed, both cases of bilateral mydriasis in this series occurred in contact lens users. In this study, symptoms of systemic anticholinergic toxicity were less common than ocular anticholinergic symptoms. Eye dryness and blurry vision were reported much more frequently than were constipation and urinary symptoms. The predominance of ocular symptoms suggests that most of the patients may have developed mydriasis from ocular/periocular inoculation rather than as a consequence of systemic toxicity. Low rates of anticholinergic side effects in supervised topical GT application in Phase I trials (17) and lower systemic GT concentrations from topical vs oral glycopyrrolate administration (17) support the notion that mydriasis from topical GT is more likely related to local toxicity than systemic toxicity in most cases. Michael et al (11) suggest that systemic toxicity may sometimes occur as a dose-related effect, as they reported a patient in which medication inappropriately applied multiple times each day with application to multiple skin sites (axilla, neck, and face) resulted in mydriasis and significant accompanying systemic anticholinergic symptoms. Complaint of blurry vision might be explained by the cycloplegic effect of the anticholinergic drug. However, in this series, visual acuity at near was not assessed, so an association between diminished near acuity from cycloplegia and complaint of blurry vision was not able to be formally evaluated. Glycopyrrolate and its derivatives are not routinely used ophthalmically; accordingly, the ocular pharmacokinetics of glycopyrrolate and its derivatives are not well-characterized (2). This study provides possible clues about duration of ocular effect. However, definitive conclusions are limited by unknown amount of ocular inoculum, potential for repeated ocular exposure, and inability to extricate direct ocular exposure from ocular effects of systemic toxicity. In this study, most patients re-examined at 1 week of followup and all patients re-examined at 2 or more weeks of follow-up had confirmed resolution of their mydriasis. The precise time points before the clinic follow-up at which mydriasis resolved are not known. One patient who was not re-examined clinically reported by telephone assessment that mydriasis had resolved 2 days later, but it is unknown whether a subtle residual anisocoria undetectable to the patient may have remained. Previous reports have reported resolution of mydriasis from topical GT at 2–12 days after initial examination (7,13–15). We consequently recommend patients with working diagnosis of pharmacologic mydriasis from topical GT be reassessed (through either clinical examination or telephone/telehealth) at approximately 2 weeks to evaluate for clinical resolution. Appropriate postapplication hand hygiene is essential to prevent inadvertent ocular exposure to GT. In vitro testing has shown that washing with soap may remove up to 99% of GT from the skin (18). Siscos et al (19) have also proposed a prudent strategy: topical GT application with 533 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution gloves, which circumvents risk for ocular exposure completely. Providers who prescribe topical GT and providers diagnosing mydriasis from topical GT should counsel the patient about appropriate use: 1) washing hands with soap and water immediately after applying GT or wearing gloves when applying and 2) avoiding application to the face or the periocular region (12). 6. 7. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. R. Kaufman, S. Gulati, and K. M. Curnyn; b. Acquisition of data: A. R. Kaufman, S. Gulati, J. H. Pula, T. M. Janetos, N. R. Cherayil, E. Chiu, E. A. Shepherd, K. C. Golnik, E. Garcia-Valenzuela, and K. M. Curnyn; c. Analysis and interpretation of data: A. R. Kaufman, P. W. MacIntosh, B. T. Johnson, and K. M. Curnyn. Category 2: a. Drafting the manuscript: A. R. Kaufman and K. M. Curnyn; b. Revising it for intellectual content: A. R. Kaufman, S. Gulati, J. H. Pula, T. M. Janetos, N. R. Cherayil, E. Chiu, E. A. Shepherd, K. C. Golnik, E. Garcia-Valenzuela, P. W. MacIntosh, B. T. Johnson, and K. M. Curnyn. Category 3: a. Final approval of the completed manuscript: A. R. Kaufman, S. Gulati, J. H. Pula, T. M. Janetos, N. R. Cherayil, E. Chiu, E. A. Shepherd, K. C. Golnik, E. Garcia-Valenzuela, P. W. MacIntosh, B. T. Johnson, and K. M. Curnyn. 8. 9. 10. 11. ACKNOWLEDGMENTS The authors thank Joseph Baker and Bhavana Kolli in the University of Illinois at Chicago Ophthalmic Clinical Trials and Translational Center for their assistance in obtaining IRB approval for this study. 12. 13. 14. REFERENCES 1. Lamb YN. Topical glycopyrronium tosylate in primary axillary hyperhidrosis: a profile of its use. Clin Drug Investig. 2019;39:1141–1147. 2. Chabicovsky M, Winkler S, Soeberdt M, Kilic A, Masur C, Abels C. Pharmacology, toxicology and clinical safety of glycopyrrolate. Toxicol Appl Pharmacol. 2019;370:154–169. 3. Doolittle J, Walker P, Mills T, Thurston J. Hyperhidrosis: an update on prevalence and severity in the United States. Arch Dermatol Res. 2016;308:743–749. 4. 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