Clinical characteristics of drug-induced optic neuropathy cases associated with voriconazole administration for chronic pulmonary aspergillosis

doi:10.21203/rs.3.rs-4900903/v1

Background

Visual abnormalities are relatively common side effects of voriconazole use, but optic neuropathy is rare and not well recognized. The aim of this study was to investigate the characteristics of patients diagnosed with optic neuropathy during voriconazole treatment.

Methods

We reviewed six patients who developed optic neuropathy during voriconazole treatment at our hospital. Visual acuity and critical flicker fusion frequency (CFF) tests were used to diagnose optic neuropathy.

Results

Voriconazole was used to treat chronic pulmonary aspergillosis in all patients. The median time to onset of optic neuropathy was 181 (72–292) days, the dose was 5.87 (5.55–10.36) mg/kg/day, and the trough value was 1.85 (0.59–2.37) µg/ml. One patient was not using any other drugs during voriconazole treatment, but the other five patients used ethambutol concomitantly. The median dose of ethambutol was 13.89 (12.93–15.63) mg/kg/day, which was within the optimal range, and the duration of use was 70 (22–104) months. The participants using ethambutol had been using the drug for a longer period than typically associated with ethambutol-induced optic neuropathy. Peripheral neuropathy of the lower extremities was observed in four of six cases, coinciding with the appearance of optic neuropathy.

Conclusions

Voriconazole-associated optic neuropathy may be more likely to occur in cases of concomitant ethambutol treatment or peripheral neuropathy. It is important to be aware of possible optic neuropathy during voriconazole treatment and to perform visual acuity examinations for early detection.

Voriconazole

Optic neuropathy

Vision loss

Chronic pulmonary aspergillosis

Voriconazole, an azole antifungal drug approved in Japan in 2005, has emerged as a key treatment for invasive pulmonary aspergillosis. Voriconazole is active against Aspergillus, in addition to various other fungi, especially Fusarium, Skedosporium, and Candida.

Pulmonary aspergillosis can be categorized as invasive and chronic. Invasive pulmonary aspergillosis often occurs in severely immunocompromised patients such as bone marrow transplant recipients. Chronic pulmonary aspergillosis often occurs in patients with chronic respiratory diseases with structural destruction, such as old pulmonary tuberculosis, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, interstitial pneumonia, and non-tuberculous mycobacterial infection.^1,2 Therefore, patients using voriconazole should be aware of its potential side effects and drug interactions, since many such patients are being treated for chronic respiratory diseases.

Voriconazole is known to cause visual abnormalities, liver damage, and phototoxicity. Visual abnormalities are reported to occur in approximately 30% of voriconazole users, with symptoms such as foggy vision, photophobia, and color blindness.³ These visual abnormalities often improve spontaneously without dose reduction or discontinuation of voriconazole.⁴ However, in rare cases, optic neuropathy during voriconazole treatment may occur, requiring discontinuation of treatment.^5–7 Few case reports of voriconazole-associated optic neuropathy exist, and the associated patient characteristics are currently unknown.^5–7 The purpose of this study was to address this gap in understanding by examining the background and clinical features of patients who developed optic neuropathy during voriconazole use.

We reviewed the medical records of 25 patients with a confirmed diagnosis of optic neuropathy out of 370 patients prescribed voriconazole at our hospital between January 2015 and September 2021. Among these, we selected six patients who developed optic neuropathy while taking voriconazole (Fig. 1). The starting date of observation was first treatment, and follow-up of patients continued until death or the last visit to our hospital in March 2023. The critical flicker fusion frequency (CFF) test measures the blink frequency, accompanying a patient’s recognition of a transition from blinking light to continuous light or from continuous light to blinking light, and utilizes light with changing flicker frequency. A CFF value of 35 or higher was considered normal.⁸ This study was approved by the Ethics Committee of the National Hospital Organization Tokyo National Hospital (no. 230031).

The background and clinical features of the six patients selected for our study are presented in Tables 1 and 2. The median age was 76 (61–82) years, and all patients were using voriconazole for chronic pulmonary aspergillosis. Five patients were being treated with ethambutol for non-tuberculous mycobacteriosis, and both voriconazole and ethambutol were discontinued after the onset of optic neuropathy. Color blindness and numbness in the lower limbs were observed in four of the six patients (66.7%). Five of the six patients (83.3%) showed improvement in visual acuity after drug discontinuation. One patient (case 6) did not show any improvement in visual acuity, partly due to the short observation period after treatment was discontinued. However, in all the other cases visual acuity improved, with time to improvement varying from 1 to 20 months. All patients had reduced visual acuity and CFF values at onset of the optic neuropathy. However, no date were available from visual acuity test for one patient, and in two cases CFF values were not measured before onset. Six patients used voriconazole for a median of 181 days (range: 72–292), at a dose of 5.89 mg/kg/day (range: 5.55–10.36), with a trough value of 1.85 µg/ml (range: 0.59–2.37) at the onset of vision loss. Five patients were treated with ethambutol, with a median dose of 13.89 mg/kg/day (range: 12.93–15.63) and a median duration of use of 70 months (range: 22–104).

Table 1. Cases of optic neuropathy in patients treated with voriconazole

Case	Age	Sex	Underlying lung disease	Underlying general disease	Symptom	Drug	Outcome	Time to recovery	Reference
Case	Age	Sex	Underlying lung disease	Underlying general disease	Symptom	Drug	Outcome	Time to recovery	Reference
1	82	F	CPA, NTM	-	optic neuropathy, dyschromatopsia, lower extremity numbness	VRCZ, EB, CAM, STFX	recovered	20 months	our case
2	75	F	CPA, BE	breast cancer	optic neuropathy	VRCZ, EM	recovered	3 months	our case
3	77	F	CPA, NTM	Hashimoto's disease	optic neuropathy, dyschromatopsia, lower extremity numbness	VRCZ, EB, LVFX, KM	recovered	3 months	our case
4	80	F	CPA, NTM	ITP	optic neuropathy, night blindness	VRCZ, EB, CAM STFX	recovered	10 months	our case
5	68	F	CPA, NTM	-	optic neuropathy, dyschromatopsia, photophobia, lower extremity numbness	VRCZ, EB, CAM	recovered	15 months	our case
6	61	M	CPA, NTM	cataract, iritis, macular edema,	optic neuropathy, dyschromatopsia, lower extremity numbness	VRCZ, EB, STFX	not recovered		our case
7	74	M	CPA, Tb,	HCV	optic neuropathy, blurred vision	VRCZ	recovered	2 months	5
8	77	M	CPA	-	optic neuropathy, blurred vision, hallucination, dyschromatopsia	VRCZ	recovered	1 month	6
9	15	M	CPA, Tb, CF, pulmonary transplantation	-	optic neuropathy, photophobia, lower extremity numbness	VRCZ, EB	recovered	12 months	7

F: female, M: male, CPA: chronic pulmonary aspergillosis, NTM: non-tuberculous mycobacteriosis, BE: bronchiectasis, Tb: tuberculosis, CF: cystic fibrosis, ITP: idiopathic thrombocytopenia, HCV: hepatitis C virus, VRCZ: voriconazole, EB: ethambutol, STFX: sitafloxacin, CAM: clarithromycin, LVFX: levofloxacin, KM: kanamycin.

Table 2

Visual test and duration or dosage of voriconazole and ethambutol
Case	Visual acuity*			Critical flicker fusion frequency (Hz)^†			VRCZ			EB
Case	pre	onset	post	pre	onset	post	Duration (days)	Trough (µg/mL)	Dose (mg/kg/day)	Duration ^‡ (months)	Dose (mg/kg/day)
1	0.9/0.8	0.4/0.6	0.9/0.9	37/38	15/21	24/27	148	2.37	6.00	36	15.02
2	1.2/1.0	0.7/0.4	1.2/0.9	-	28/28	38/36	72	0.59	5.87	-	-
3	1.0/1.2	0.5/0.3	0.8/0.9	36/38	15/19	28/28	265	1.94	5.55	104	13.89
4	0.7/0.7	0.1/0.2	0.6/0.4	38/35	13/13	35/30	292	1.76	10.36	70	12.93
5	-	0.7/0.8	1.2/1.2	-	33/33	33/31	175	1.73	7.81	87	15.63
6	0.7/1.2	0.1/0.5	0.1/0.6	35/35	23/16	25/21	187	2.08	5.57	22	13.74
7	0.06/0.1	0.04/0.01	0.08/0.09	-	below 20	-	9	-	400 mg/day	-	-
8	-	1.0/0.8	1.0/1.0	-	-	-	about 30	-	100 mg/day	-	-
9	1.0/1.0	0.14/0.1	1.0/1.0	-	-	-	about 120	-	-	about 1	22.2
VRCZ: voriconazole, EB: ethambutol
*Visual acuity is measured in both eyes and described as right/left
†Critical flicker fusion frequency is measured in both eyes and described as right/left (Hz)
‡Cumulative duration of use until ethambutol is discontinued due to optic neuropathy

Two typical cases are presented below.

Case 1

An 82-year-old woman, diagnosed with a pulmonary Mycobacterium intracellulare infection, was treated with rifampicin, ethambutol, and clarithromycin for 2.5 years, after which her treatment was switched to erythromycin. Prior to erythromycin use, no visual abnormality was observed. Three years after switching to erythromycin, M. intracellulare was repeatedly detected in her sputum. The patient was diagnosed with chronic pulmonary aspergillosis based on the thickening of the cavity wall on a chest CT scan and a positive finding for anti-Aspergillus antibodies in a blood test. Ethambutol (15.02 mg/kg/day), clarithromycin, and sitafloxacin were used as treatment for the pulmonary M. intracellulare infection and voriconazole was introduced at 9.01 mg/kg/day and maintained at 6.00 mg/kg/day for the chronic pulmonary aspergillosis, with a trough value of 2.37 µg/ml. Four months later, color blindness was observed, followed by optic neuropathy one month later, and ethambutol treatment was discontinued. Five days after discontinuation of ethambutol, the patient presented to the hospital with diplopia, numbness in the lower limbs, and pain in the right fingers. Originally, the patient’s corrected visual acuity was 0.9 on the right and 0.8 on the left, and the CFF values were 37 on the right and 38 on the left, but the patient’s corrected visual acuity decreased to 0.4 on the right and 0.6 on the left, while the CFF value decreased to 15 on the right and 21 on the left. Voriconazole was then discontinued. The patient’s symptoms slowly improved, and after a year and eight months, visual acuity improved to 0.9 on the right and 0.9 on the left, with CFF values improving to 30 on the right and 30 on the left.

Case 2

A 75-year-old woman, taking erythromycin for bronchiectasis, was diagnosed with chronic pulmonary aspergillosis based on cyst wall thickening and shadow infiltration on a chest CT scan, and Aspergillus fumigatus in her sputum. She was started on itraconazole. This was used for six months with poor efficacy, following which voriconazole was administered (7.04 mg/kg/day induction) and maintained at 4.69 mg/kg/day. After two months, the patient's symptoms did not improve, and the dose of voriconazole was increased to 5.87 mg/kg/day, with a trough value of 0.59 µg/ml. Approximately two months after the dosage increase, the patient's corrected visual acuity was 0.7 on the right and 0.4 on the left, with CFF values of 28 on the right and 28 on the left, indicating decreased visual acuity. Voriconazole was discontinued, and two and a half months later her visual acuity had improved to 1.2 on the right and 0.9 on the left, with CFF values of 38 on the right and 36 on the left.

In this study, we evaluated the background of patients who developed optic neuropathy during voriconazole treatment. Well-known symptoms of visual disturbances caused by voriconazole include foggy vision, photophobia, and color blindness, which are reported to occur within about two weeks after starting treatment with voriconazole and often disappear spontaneously in about a week.⁹ However, optic neuropathy, which, necessitates the discontinuation of voriconazole, is rarely observed. In the present study, optic neuropathy appeared after 72–292 days of voriconazole use, and not only in the early stages of treatment.

It has been reported that voriconazole side effects are related to trough value and increase at trough concentrations greater than 5.5–6.0 µg/ml.^10,11 While there are reports that visual symptoms tend to appear at trough levels of voriconazole of 4.2 µg/ml or higher,¹² there are also contradictory reports that suggest they are not related to blood concentration.¹³ In our cases, the trough value at the onset of vision loss was 0.59–2.37 µg/ml, which is lower than 4.2 µg/ml, and no relationship between trough value and side effects was demonstrated.

Five of the six cases were treated with voriconazole and ethambutol, and it was necessary to consider both drugs as potential causes of optic neuropathy. Most of these patients using voriconazole also used ethambutol. About 33% of patients with chronic pulmonary aspergillosis treated with antifungal agents in our hospital were patients with chronic pulmonary aspergillosis complicated non-tuberculous mycobacteriosis, which in recent years has been reported to have a worse prognosis than non-tuberculous mycobacteriosis alone.^14,15 In fact, all five patients were using ethambutol for treating pulmonary non-tuberculous mycobacteriosis. It has been reported that ethambutol-induced optic neuropathy occurs 1–12 months after the start of ethambutol treatment.^16,17 In all five cases of ethambutol use in our study, ethambutol was used for more than 22 months, a median duration of 70 months, which is much longer than the time linked to ethambutol-induced optic neuropathy, suggesting that voriconazole is associated with the optic neuropathy in these patients. In patients with non-tuberculous mycobacteriosis-associated aspergillosis, voriconazole-associated optic neuropathy may be masked by ethambutol. In reality, discontinuation of ethambutol is inevitable upon the appearance of vision loss, but ethambutol is an important drug in the treatment of non-tuberculous mycobacterial infections to prevent macrolide resistance.^18,19 Therefore, failure to reinstate treatment with ethambutol may have a seriously negative impact on treatment. If voriconazole is strongly suspected as the cause of optic neuropathy in a patient with non-tuberculous mycobacteriosis, re-administration of ethambutol may be considered after visual recovery.

Although there were many cases of concomitant use of ethambutol and voriconazole, case 2 in the present study and two of the three cases (Table 1, Table 2) reported in the literature featured optic neuropathy when voriconazole was used alone. The Pharmaceuticals and Medical Devices Agency, which provides information on adverse drug reactions in Japan, reported 33 cases of vision loss as an adverse reaction to voriconazole and included only three cases related to ethambutol use.²⁰ French pharmacovigilance centers reported six cases of voriconazole-associated toxic optic neuropathy, three of which were related to voriconazole alone.⁷ Although voriconazole is not listed in reviews as the causative agent of toxic optic neuropathy, several cases of optic neuropathy due to voriconazole alone have been observed, and physicians prescribing voriconazole should be aware of this fact.²¹

In addition to our six cases, three other cases (Table 1, Table 2) of voriconazole-associated optic neuropathy have been reported in other studies. Since neither the amount of voriconazole used per body weight nor the blood concentrations have been included in previous reports, it is significant that those indicators were found to be less relevant to optic neuropathy in the present study. This study used the CFF test in addition to visual acuity tests in the diagnosis of optic neuropathy and evaluated optic nerve function more accurately.

One report indicates that the blood concentration of voriconazole increased with concomitant use of ethambutol, inducing vision loss.⁷ Voriconazole is primarily metabolized by Cytochrome P450 (CYP) 2C19 and partly by CYP 3A4 and CYP 2C9. Ethambutol moderately inhibits CYP 2C19,²² while clarithromycin and erythromycin inhibit CYP 3A4. Therefore, these drugs may cause an increase in the blood concentration of voriconazole.²³ In the present study, macrolide antibiotics were used in combination in cases 1, 2, 4, and 5. CYP 2C19, the main metabolizing enzyme of voriconazole, is a polymorphic gene, and blood levels of voriconazole are known to vary among individuals, but it has been reported that blood levels of voriconazole also fluctuate within individuals, for example, increasing during severe inflammatory episode.^24,25 In our cases, the blood concentration of voriconazole was normal at the time of onset of optic neuropathy, but there was an increase in blood concentration during treatment, which may have triggered the optic neuropathy.

Numbness of the lower extremities was observed in four of our six cases and in one of three cases from previous reports. Peripheral neuropathy can be caused by drugs, diabetes mellitus, vitamin deficiency, folic acid deficiency, paraproteinemia, autoimmune diseases, renal failure, and hypothyroidism. Triazole antifungal agents are reported to cause axonal neuropathy with sensory predominance, and peripheral neuropathy is reported to occur in 9% of patients treated with voriconazole.²⁶ The blood levels of voriconazole were reported as normal at the time when voriconazole-associated peripheral neuropathy appeared,²⁶ matching this study’s findings. Among our four cases of peripheral neuropathy, case 3 had a history of Hashimoto's disease, but thyroid function was in the normal range. Although ethambutol is considered an unlikely causative agent of peripheral neuropathy,^27–29 its involvement could not be ruled out. However, in three of our four cases, peripheral neuropathy appeared at the same time as optic neuropathy, which might be associated with voriconazole.

Five out of six cases in our study, and all three cases in a previous report, showed recovery of visual acuity after discontinuation of voriconazole. The time from drug discontinuation to visual acuity improvement varied from 1 to 20 months in this study. In six cases of voriconazole-associated optic neuropathy reported in French pharmacovigilance centers, one patient recovered visual acuity, three did not improve, and two had an unknown follow-up.⁷ Because the mechanism of voriconazole-associated optic neuropathy is unknown, voriconazole is often discontinued when optic neuropathy is observed, as is the case with ethambutol, in order to avoid irreversible vision loss.

Although the mechanism of voriconazole-associated optic neuropathy is currently unknown, it has been reported that in patients with voriconazole-associated visual impairment the b-wave is attenuated in electroretinograms. This is similar to complete congenital stationary night blindness (cCSNB).³⁰ Since the b-wave is composed of ON-bipolar cell neurotransmission, the impairment of ON-bipolar cells may constitute a factor in voriconazole-associated optic neuropathy. However, symptoms of visual impairment caused by cCSNB differed from those related to voriconazole treatment. CCSNB can cause night blindness, but rarely causes photophobia or optic neuropathy. Furthermore, night blindness was present in only one of the six cases in this study. The differences in symptoms suggest that these diseases are not the same, but it may be possible to determine whether voriconazole is the cause of optic neuropathy by using electroretinograms. Further research in this field is needed.

This study was subject to several limitations. The research was conducted only at a single center, and the number of patients was small. The total number of cases, including those reported previously, was only nine, and a greater sample size would be desirable. To select cases, we checked the medical records for voriconazole use and optic neuropathy, but a selection bias may have been present since optic neuropathy may not have been on the list of diseases if the patients were diagnosed at other hospitals. Further, since some of our cases were concomitantly treated with ethambutol, we were not able to make a strict diagnosis of optic neuropathy associated with voriconazole, and there is a need to investigate the possibility of optic neuropathy associated with drug interaction. Finally, although CYP 2C19 is polymorphic, we did not examine this aspect in our study nor consider the evaluation of blood concentration by the metabolizing enzyme.

We report several cases of voriconazole-associated optic neuropathy. Special attention should be paid to those cases featuring concomitant use of ethambutol and the appearance of peripheral neuropathy. It is important to actively promote ophthalmological examinations for early detection of optic neuropathy when voriconazole is used. The origin and development of ophthalmologic adverse events associated with voriconazole are unknown, and further studies in this area are warranted.

CFF: critical flicker fusion frequency

cCNSNB: complete congenital stationary night blindness

CYP: cytochrome P450

Acknowledgments

We would like to thank Uni-edit (https://uni-edit.net/) for editing and proofreading this manuscript.

Funding

This work was supported by the Research Grant on Allergic Diseases and Immunology from the Japan Agency for Medical Research and Development [Grant Number 23ek0410097].

Author information

Author affiliations

Ryo Sato, Junko Suzuki, Keita Takeda, Ibuki Kosai, Masato Watanabe, Kyuto Odashima, Osamu Narumoto, Masahiro Shimada, Yuka Sasaki, Yoshiteru Morio, Atsuhisa Tamura, and Hirotoshi Matsui. Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan.

Kei Nakayama. Center for Ophthalmology, National Hospital Organization Tokyo National Hospital, Tokyo, Japan.

Contributions

JS conceived the study. RS and JS designed the study. RS, JS, and HM wrote the manuscript. RS, JS, KN, KT, IK, MW, KO, ON, MS, YS, YM, and AT contributed to data collection. HM supervised the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ryo Sato.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the National Hospital Organization Tokyo National Hospital (no. 230031). The study was performed in accordance with the relevant guidelines and regulations. All the participants provided their informed consent to participate in this study.

Consent for publication

Written informed consent was obtained from the patients for the publication of this case report.

Availability of data and materials

All data generated and analyzed in this study are included in this paper. Raw data are available upon request from the corresponding author.

Competing interests

The authors declare no competing interests.

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No competing interests reported.

Clinical characteristics of drug-induced optic neuropathy cases associated with voriconazole administration for chronic pulmonary aspergillosis

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Results

Case 1

Case 2

Discussion

Conclusion

Abbreviations

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References

Additional Declarations

Status:

Version 1