Importance of Ancillary Testing for Voriconazole-Induced Short Term Transient Visual Disturbances
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ABSTRACT
BACKGROUND
Voriconazole is in the class of triazole antifungal medications which can cause various ocular side effects including subjective visual disturbances. This emphasizes the importance of ancillary testing to evaluate for ocular toxicity. This case report aims to highlight the effects of voriconazole-induced ocular effects, transient visual changes, and the multidisciplinary approach necessary to manage patients using the medication for a moderate duration.
CASE REPORT
A 59-year-old white male presented to the clinic complaining of visual disturbances and altered color vision. The patient had been battling a systemic fungal infection for six months and was started on voriconazole, a broad-spectrum antifungal medication. After taking the medication, he reported experiencing visual disturbances. After running a series of tests at certain time intervals pertinent to the dosing schedule, it was confirmed that voriconazole was the contributing factor to the patient’s chief complaint.
CONCLUSION
Voriconazole is a relatively safe and well-tolerated drug, but it can cause acute symptoms shortly after treatment. It is important to run a series of baseline ancillary tests and monitor patients on this medication with frequent follow up examinations to avoid ocular toxicity. This case report highlights the needs for ancillary testing and studies to assess patients undergoing long term treatment with voriconazole for fungal infections.
Keywords: visual disturbance, altered color and visual perception, induced ocular toxicity, transient visual disturbances, voriconazole
INTRODUCTION
 Voriconazole is an effective triazole antifungal medication that is used to treat a wide variety of fungal infections. Common ocular side effects of this drug include transient visual disturbances, hallucinations, enhanced visual perception, photopsia, and color vision defects.1 Due to drug metabolism and how it is processed in the body, the reported visual side effects of voriconazole are short-term.2 When taken orally, voriconazole can reach a maximum bioavailability of 95% within the body.2 The drug is most effective at treating infections from fungi including Aspergillus, Candida spp., and Fusarium spp.2
Ancillary testing that can be done to evaluate ocular or visual side effects include electroretinogram (ERG), visual evoked potentials, optical coherence tomography (OCT), visual field testing, color vision, and contrast sensitivity testing. These modes of testing allow the clinician to evaluate for structural or functional changes occurring in the retinal pathway. It has been understood that the retinal effects are reversible yet affect the ON-bipolar cells of both rods and cones.1 ERG and OCT are important devices to utilize when evaluating the specific locations of the retina post-treatment. Visual field testing, color vision and contrast sensitivity testing are most useful when determining a patient’s functional vision deficits after treatment with the drug.
CASE REPORT
A 59-year-old white male presented with a chief complaint of altered visual perception shortly after taking a dose of voriconazole. He reported starting voriconazole 250 mg bid orally six months prior to the visit, following leg surgery and a subsequent fungal infection of the wound. After taking each dose, he reported experiencing enhanced visual perception, where lights were brighter and colors were altered. This experience typically started 30 minutes after ingestion and lasted for about an hour. The patient denied any other ocular or visual complications at the initial visit.
Testing on the first clinical examination was completed while the patient was not experiencing visual disturbances. The patient’s best corrected Snellen visual acuity was 20/20 OD and 20/20 OS. All neurological testing was unremarkable with pupils equal, round, reactive to light, and no afferent pupillary defect. Red cap desaturation and brightness sensitivity testing results were unremarkable for both eyes. Ishihara color plate testing was 7/7 in each eye. Anterior segment examination was normal with tonometry measurements as normotensive in both eyes. Posterior segment evaluation revealed no retinopathy or signs of optic neuropathy, specifically examining for disruption of the retinal layers or optic atrophy, respectively. At the next follow up appointment set in two weeks time, a plan was established to investigate short term visual disturbances at the time when the drug was ingested.
Due to the transient nature of his visual complaints, some testing was performed prior to taking voriconazole, during the period in which the visual disturbances were experienced and one hour after. The time-sensitive ancillary tests performed were Farnsworth D-15 and contrast sensitivity. Prior to ingesting the medication, the patient performed the Farnsworth D-15 with ease. The patient would then subjectively report increased concentration required to take the same test after 30 minutes from dosing. After his visual side effects had subsided, the patient noted that all color vision testing became substantially easier for him. The patient completed the D-15 testing with 100% accuracy at all time periods. The Mars Letter Contrast Sensitivity Test was performed prior to taking voriconazole, 30 minutes after taking the medication, and an hour and a half after taking the medication. A significant decrease in log contrast sensitivity was noted after 30 minutes of taking the medication. Directly after the visual disturbances had worn off, findings had returned to baseline (Table 1).
Table 1. Contrast sensitivity testing confirmed the subjective decrease experienced by the patient. Log contrast sensitivity is noted as higher in both the ‘before dosing’ and ‘1.5 hours after dosing’ columns
Additionally at the time of the follow up examination, additional ancillary testing was warranted to assess for potential retinopathy or optic neuropathy. To assess for structural damage, OCT imaging of both the optic nerve and macula were completed and found to be unremarkable, despite being on voriconazole for six months (Figure 1). Functional testing with Humphrey Visual Field 10-2 did not render significant defects that could be attributed to ocular toxicity (Figure 2). OCT and visual field testing were not performed within the 30-minute time frame as damage evident on these specific tests were more likely to develop after prolonged usage of the drug.
Figure 1. OCT RNFL scans for each eye show normal retinal nerve fiber layer thickness with no signs of optic atrophy. Structural OCT macular scans show normal macular center thickness and foveal contour with intact inner plexiform layer.
Figure 2. 10-2 Humphrey visual field test showing a few scattered defects in each eye. These defects were regarded as non-specific and not indicative of macular toxicity.
Long term usage of the drug is typically considered to be around six months, aligning with the time the onset of usage for the patient in this report. OCT testing for the patient showed that no structural damage has occurred within six months of taking the drug. Visual distortions were planned to be monitored on a six-month basis due to pending discontinuation of the drug. The patient was to continue following with his infectious disease specialist for the remainder of his treatment with the drug at the current time.
DISCUSSION
 Voriconazole treats ocular and systemic fungal infections by preventing the biosynthesis of ergosterol, the element responsible for cell wall formation.2 Its clinical indications are noted as treating a wide variety of fungal species, such as Aspergillus.3 Due to the pharmacokinetic profile of voriconazole, the drug has an extensive bioavailability. It reaches maximum concentrations within the body 1-2 hours after administration, with side effects occurring within 30 minutes of dosing.2,3 After the drug is metabolized, side effects tend to terminate and become reversible.
Studies have shown that retinal toxicity and optic neuropathy can occur in the setting of treating a patient with voriconazole.3 Visual disturbances can occur after each dosage and toxicity can occur within two months of initiation of the drug.2,4 By way of ancillary testing, the eye care provider can evaluate ocular health both structurally and functionally.
Voriconazole is metabolized through the cytochrome P450 complex within the liver cell, with the CYP2C19 enzyme as the main enzyme responsible for breakdown within the body.2 As the drug is metabolized, it releases an effect on certain transduction pathways within the retina. The main pathway affected in the retina is the block of transduction from the mGluR6-TRPM1 signal pathway of ON-bipolar cells.3 When looking at the testing for functional response of the retina, it is mainly the TRPM1 gene of the retinal pathway that is responsible for driving the response of a light adapted state.3 When voriconazole blocks this pathway, a patient may develop visual perceptive changes.
Electroretinogram testing is noted as being useful when assessing for visual side effects.1 When conducting ERG testing, it has been observed that the b-wave of the ERG is diminished in patients taking voriconazole approximately 30 minutes after dosing; however, all ERG testing is proposed to have returned to normal baseline testing 24 hours after the initial dosing when the drug has been fully eliminated and metabolized by the body.1,3 The area of the retina affected is the ON-bipolar cells of the rod and cone pathway, due to the diminished response of the b-wave of the ERG testing.1 B-wave signaling corresponds to the side effects of altered light and contrast sensitivity while taking voriconazole. Contrast sensitivity testing of the patient confirmed altered contrast and light perception; ERG testing was unavailable. OCT imaging of the patient showed no structural changes to the inner plexiform layer of the retina despite the patient demonstrating transient functional deficits (Figure 1).
An element to consider with voriconazole usage is how dosing can affect transient visual disturbances. Voriconazole affects the mGluR6-TRPM1 signal transduction pathway of the ON-bipolar cells, but the amount of dosing has no significant effect on the frequency or intensity of visual disturbances subjectively reported by patients using this treatment.1,5 Dosing should be altered depending on whether the patient is an adult or a child, as elimination and metabolism of the drug differs with age.5 However, transient visual disturbances have been observed at the same intensity despite the level of dosing.6 Typical dosing is 400 mg bid orally for adults; yet studies have tested various effects with 400 mg, 200 mg, and 100 mg.2,4
It has been proposed that voriconazole can act as a vehicle in increasing the risk of toxic optic neuropathy when interacting with other drugs, such as ethambutol.6 Ethambutol is a drug that can lead to reduced CYP2C19 activity, a main enzyme responsible for voriconazole metabolism.4,7 Due to reduced enzyme activity, increased voriconazole concentration in the blood plasma can lead to transient visual disturbances and optic neuropathy when interacting with ethambutol. Consequently, only patients who are poor metabolizers of the enzyme experience neurotoxicity.4 Not enough research has been done to evaluate how visual function is regained, yet prognosis can be positive for younger patients who discontinue treatment of voriconazole and ethambutol when used simultaneously.4 Some patients may never fully regain full visual function from toxic optic neuropathy as a result of dual treatment with ethambutol and voriconazole.
Alterations to the CYP2C19 enzyme are responsible for elevated effects of visual changes and potential toxicity as it relates to voriconazole and its drug interactions. Normal results on OCT imaging and color vision testing in this patient eliminate the concern for permanent effects of optic nerve toxicity. When prescribing voriconazole as a treatment, it is essential to be cognizant of drug interactions to avoid side effects to the patient. Any drug that acts as an inducer to the cytochrome P450 complex, such as efavirenz, ritonavir, rifampin, carbamazepine, and barbiturates, can increase metabolism of voriconazole within the liver and should be monitored for unwanted effects of drug therapy.8 Glucocorticoids have also been studied as possible CYP450 inducers, leading to reduced plasma trough concentration per dose levels of voriconazole.9 Overall, it is not well studied how each drug-to-drug interaction affects voriconazole treatment, yet CYP450 inducers can affect the efficacy of the drug and lead to possible unwanted side effects.9
After considering the proposed retinal toxicity or toxic optic neuropathy that can occur while taking voriconazole, ancillary testing is crucial in evaluating patients. It has been noted in clinical studies that 30% of patients taking voriconazole experience visual disturbances.2 Although many patients do not take voriconazole in long term situations, nor is it well studied in the long term, it is our recommendation to use OCT imaging to aid in the evaluation of structural damage from ocular toxicity, as voriconazole can be detrimental to the optic nerve head and macula.6 Overall, ancillary ophthalmic tests, such as color vision, contrast sensitivity, OCT, and visual field testing, are important in the assessment of short-term or long-term visual side effects, even though research is limited when establishing a set guideline to management protocols.
CONCLUSION
Voriconazole has many visual side effects yet is relatively safe to take as a treatment for systemic or ocular fungal infections. Studies suggest that this drug induces short-term visual effects, but long-term structural damage is rare and not well documented. The patient in this case is a good example of how ancillary testing was used to document the induced visual disturbances, which highlights the recommendation that patients be monitored and evaluated closely to assess for structural and functional vision loss. It may be important to consider switching a patient on voriconazole to another anti-fungal in the same class if the benefits do not outweigh the side effects of this treatment.6 All patients should be educated on the visual side effects of voriconazole before starting systemic treatment for fungal infections.
REFERENCES
- Kinoshita J, Noriaki Iwata, Mitsuhiro Ohba, et al. Mechanism of Voriconazole-Induced Transient Visual Disturbance: Reversible Dysfunction of Retinal ON-Bipolar Cells in Monkeys. Invest Ophthalmol Vis Sci. 2011;52:5058-5063.
- Greer ND. Voriconazole: the newest triazole antifungal agent. Proc (Bayl Univ Med Cent). 2003;16:241-248.
- Xiong WH, Brown RL, Reed B, et al. Voriconazole, an antifungal triazole that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Invest Ophthalmol Vis Sci. 2015;3:1367-1373.
- Orssaud C, Guillemain R, Louet A. Toxic Optic Neuropathy Due to Voriconazole: Possible Potentiation by Reduction of CYP2C19 Activity. Eur Rev Med Pharmacol Sci. 2021;25:7823–7828.
- Zheng R, Li Y, Guo C, et al. Voriconazole Induced Hallucinations and Visual Disturbances in a Female Child: A Case Report and Literature Review. Front Pediatr. 2021;9:655327.
- Zrenner E, Tomaszewski K, Hamlin J, et al. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study. Ophthalmic Res. 2014;52:43-52.
- Mounier A, Agard E, Douma I, et al. Macular toxicity and blind spot enlargement during a treatment by voriconazole: A case report. Eur J Ophthalmol. 2018;28:NP11-NP14.
- Li T, Liu W, Chen K, Liang S and Liu F. (2017), The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review. J Clin Pharm Ther, 42: 135-146.
- Jia SJ, Gao KQ, Huang PH, Guo R, Zuo XC, Xia Q, Hu SY, Yu Z, Xie YL. Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole. Front Pharmacol. 2021 May 25;12:666296.
Dr. Caitlyn Raia completed her Bachelor of Science degree in Biology with a Dance minor at Muhlenberg College in 2018. She then received her Doctor of Optometry degree with Advanced Studies in Contact Lenses from the Pennsylvania College of Optometry at Salus University in 2022 and completed her residency in Ocular Disease and Low Vision Rehabilitation from the VA New Jersey Health Care System in 2023.
Dr. Mayur Bhavsar graduated from the SUNY College of Optometry in 2007 and completed his residency in Primary Care/ Ocular Disease at the VA New Jersey Healthcare System, where he is currently practicing full time. He serves as the externship director and holds adjunct faculty positions at multiple optometry schools, He was a former vice president and current board member of the NJ Academy of Optometry Chapter.
