Concentric Reversible Visual Field Loss, Nyctalopia, and Dyschromatopsia with Ezetimibe Therapy

Abstract

This is a case of ezetimibe-induced concentric field loss, dyschromatopsia, and nyctalopia in a patient with no prior history of retinal dystrophy or drug hypersensitivity. A 55-year-old Caucasian woman presents with a 1-year history of increasing concentric visual field loss, nyctalopia, photophobia, and colour vision impairment. These symptoms correlated with the commencement of ezetimibe therapy 10 mg daily for hypercholesterolaemia. She demonstrated repeatable bilateral visual field constriction on 30-2 Humphrey visual filed testing and colour vision impairment on Ishihara plates (OD: 1/17, OS: 1/17). Biochemical and radiological screening for carcinoma-associated retinopathy was unremarkable. A working diagnosis of drug-induced rod-cone dysfunction was made. Her visual symptoms and field changes completely resolved 3 months after cessation of ezetimibe therapy. This case suggests that ezetimibe is a potential cause of rod-cone dysfunction and should be considered as a differential in patients with new unexplained visual symptoms.

Introduction

Ezetimibe is a second-line lipid-lowering agent that selectively inhibits cholesterol absorption at the intestinal wall, thereby lowering low-density lipoprotein cholesterol [1]. It is clinically indicated in combination with statin (HMG-CoA reductase inhibitors) therapy in patients with hypercholesterolaemia who do not achieve satisfactory cholesterol levels on maximal dose of statin alone, or as a monotherapy in patients who are intolerant of statins [1, 2].

Adverse drug reactions (ADRs) have been reported with statins and ezetimibe. They are however generally well tolerated as monotherapy or in combination [1, 2]. Musculoskeletal symptoms (myalgia, arthralgia), followed by gastrointestinal (nausea, diarrhoea, abdominal pain) symptoms, are the commonly reported ADRs for ezetimibe monotherapy [3, 4]. By comparison, musculoskeletal and connective tissue disorders were most common adverse events (76%) for the combination ezetimibe and simvastatin [4]. A PubMed, Cochrane, MEDLINE, and EMBASE search did not yield any publications to date describing ezetimibe monotherapy-induced visual changes. However, several medications (including ezetimibe) have been reported to be associated with a secondary cone-rod dystrophy (CRD) in the Rare Disease Hub, but its mechanism of action is not well understood [5].

We describe a patient with no prior history of retinal dystrophy who presents with progressively worsening concentric visual field loss, photophobia, nyctalopia, and dyschromatopsia after commencing ezetimibe monotherapy for hypercholesterolaemia, which completely resolved 3 months after discontinuation with no further complications. The clinical case report guideline (CARE Checklist) has been reviewed and completed by the authors for this case report and attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000530221).

Case Presentation

A 55-year-old Caucasian female was referred by her optometrist for investigation of visual deterioration. She presented with a 1-year history of progressive peripheral visual field loss, nyctalopia, and dyschromatopsia. These symptoms correlated with commencement of ezetimibe 10 mg daily for hypercholesterolaemia. She has a history of statin intolerance, asthma, and rosacea. There is no family history of a retinal dystrophy, and prior ocular examinations were normal.

On examination visual acuity was normal (OD: 6/6, OS: 6/7.5), corrected with multifocal glasses (OD: +1.50/+1.00 × 145, OS: +1.20/+0.50 × 11). Pupils were equal and reactive to light bilaterally, with no relative afferent pupillary defect. Repeatable concentric visual field constriction was confirmed in both eyes on 30-2 Humphrey visual field testing at presentation (shown in Fig. 1a, b) and at 3 months’ follow-up (shown in Fig. 2a, b). Significant impaired bilateral colour vision was noted on Ishihara colour plate testing (OD: 1/17, OS: 1/17). Retinal electrophysiology testing (mfERG, ffERG, PERG, mfVEP) was conducted in both eyes within 4 weeks after ezetimibe therapy was ceased. The results were reported as unremarkable. Electrophysiology testing was not repeated due to limitations in access during the COVID-19 period.

Fig. 1.

Concentric visual field restrictions on a 30-2 Humphrey field analyser in (a) right eye and (b) left eye at presentation, with mean deviation of −10.08 dB (OD) and −16.46 dB (OS). The visual threshold greyscale map, numerical sensitivity plot, total deviation, and pattern deviation for each eye are shown from left to right.

Fig. 2.

Concentric visual field restrictions on a 30-2 Humphrey field analyser in (a) right eye and (b) left eye at 3 months’ follow-up, with a mean deviation of −28.43 dB (OD) and −16.42 dB (OS). The visual threshold greyscale map, numerical sensitivity plot, total deviation, and pattern deviation for each eye are shown from left to right.

The optic nerves were clinically normal and there was no evidence of a retinal lesion nor active intraocular inflammation. There were no phenotypic signs of a retinal dystrophy nor carcinoma-associated retinopathy. Optical coherence tomography (OCT) of the maculae was unremarkable and the retinal nerve fibre layer on OCT was also normal. Magnetic resonance imaging of brain, optic apparatus, and orbits was unremarkable.

The following laboratory investigations were unremarkable: baseline haematology, pituitary profiling, inflammatory markers, autoimmune screening (including anti-retinal antibodies, anti-extractable nuclear antigen, anti-nuclear antibody, anti-dsDNA, complement, lupus anticoagulant), serum electrophoresis, and thrombophilia studies. Abdominal ultrasound and chest X-ray were normal. This workup for carcinoma-associated retinopathy was negative.

The patient ceased ezetimibe. Three months after discontinuation of ezetimibe, there was near complete resolution of the bilateral concentric field loss and significant symptom improvements (shown in Fig. 3a, b). Twelve months after therapy discontinuation, visual fields returned to baseline in both eyes, and there were no new symptoms (shown in Fig. 4a, b). Given the satisfactory clinical recovery and potential risks, ezetimibe rechallenge was not instituted. Due to intolerance to both statin and ezetimibe therapy in the presence of dyslipidaemia, the patient was referred to cardiology for further treatment options.

Fig. 3.

Significant improvement of visual fields on a 30-2 Humphrey field analyser in (a) right eye and (b) left eye 3 months after discontinuation of therapy, with a mean deviation of −1.98 dB (OD) and −1.60 dB (OS). The visual threshold greyscale map, numerical sensitivity plot, total deviation, and pattern deviation for each eye are shown from left to right.

Fig. 4.

Complete resolution of visual field deficits on a 30-2 Humphrey field analyser in (a) right eye and (b) left eye 12 months after discontinuation of therapy, with a mean deviation of +1.25 dB (OD) and +0.25 dB (OS). The visual threshold greyscale map, numerical sensitivity plot, total deviation, and pattern deviation for each eye are shown from left to right.

Discussion

Ezetimibe is a safe alternative for patients with dyslipidaemia who are resistant or intolerant of statin monotherapy [6]. Adverse effects with ezetimibe monotherapy are infrequently reported, with comparable incidence of adverse effects to statin [7, 8]. By far musculoskeletal-connective tissue disorders (49.8%) and gastrointestinal symptoms (40.8%) are the most reported adverse effects for ezetimibe monotherapy [7, 9].

Whilst visual impairment is a well-reported, albeit rare, side effect of statin therapy, there is limited information on ezetimibe-associated cone-rod dysfunction [5]. The exact mechanism of statin-induced vision impairment is also poorly understood [10, 11]. Presentations vary between case series and can include blurred vision, diplopia, and visual field defects [10–12]. A retrospective study by Mizranita et al. [11] demonstrated that out of 131,755 statin-related adverse events reported to the Food and Drug Administration (FDA) between 1988 and 2013, 2325 (1.8%) were ocular events, out of which blurred vision (48.4%) and visual impairment (25.7%) were most common. In addition, majority of ocular events (60%) occurred in the absence of other systemic systems, only 5.6% cases reported multi-system involvement (e.g., muscle, liver) [13]. Similarly, a retrospective analysis by Fraunfelder et al. [10] demonstrated that on adverse drug events involving 256 statin-related cases, only 49 (19.1%) cases were ocular in origin. The most common visual complaint was ophthalmoplegia (46.9%), followed by diplopia (36.7%), and ptosis (16.3%).

In comparison to statin, ocular adverse effects of ezetimibe are less well documented. To date, there are no published reports of visual impairment associated with ezetimibe monotherapy in the literature (MEDLINE, PubMed, EMBASE, and Cochrane databases), and its mechanism of action remains unknown. A case report by Kim et al. [13] in the Korean Journal of Pharmacology described a new-onset visual field defect in a 73-year-old woman with no significant medical history after taking combination atorvastatin and ezetimibe 10/10 mg therapy, which resolved after discontinuation. The details of the case could not be elucidated due to language restrictions and the analysis was limited to the abstract. The author suggested that atorvastatin, instead of ezetimibe, was the probable cause of visual field defect [13]. Despite a paucity of published cases in the literature, several medications (including ezetimibe) have been documented in the Rare Disease Hub as potential causes of secondary CRDs [5]. In contrast with inherited and sporadic forms CRDs which have no cure, drug-induced secondary CRDs are potentially reversible with prompt medication discontinuation [14–16]. Therefore, physicians should have low threshold for ophthalmological referral and visual testing in patients who present with unexplained visual symptoms, as the clinical course of CRDs is rapid and can cause irreversible blindness if untreated [15, 16].

Based on the World Health Organisation – Uppsala Monitoring Centre (WHO-UMC) [17] causality assessment criteria for suspected ADRs, there is a “probably/likely” relationship between ezetimibe and visual disorders (shown in Table 1). Similarly, a “probable” relationship was identified using the Naranjo Adverse Drug Reaction Probability Scale (shown in Table 2) [18]. This is supported by demonstratable visual symptoms and visual field abnormalities within a reasonable timeline after commencing ezetimibe therapy. The symptoms resolved after medication withdrawal and were unlikely attributed to other diseases or medications. However, the accuracy of these assessments is limited by the absence of a positive rechallenge and definitive pharmacological explanation.

Table 1.

WHO-UMC causality assessment criteria for suspected ADRs

Causality term	Assessment criteria
Certain	• Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically • Rechallenge satisfactory, if necessary
Probably/likely	• Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible	• Event or laboratory test abnormality with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely	• Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/unclassified	• Event or laboratory test abnormality • More data for proper assessment needed, or • Additional data under examination
Unassessable/unclassified	• Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified

WHO-UMC, World Health Organization – Uppsala Monitoring Centre.

Table 2.

Naranjo Adverse Drug Reaction Probability Scale

Question	Yes	No	N/A	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0	0
2. Did the adverse event appear after the suspected drug was administered?	+2	−1	0	+2
3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?	+1	0	0	+1
4. Did the adverse reaction reappear when the drug was re-administered?	+2	−1	0	0
5. Are there alternative causes other than the drug that could on their own have cause the reaction?	−1	+2	0	+2
6. Did the reaction appear when a placebo was given?	−1	+1	0	0
7. Was the drug detected in the blood or other fluids in concentrations known to be toxic?	+1	0	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
9. Did the patient have a similar reaction to the same or similar drug in any previous exposure?	+1	0	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score	+6
Conclusion	Probable

Score interpretation: definite ≥9, probable 5–8, possible 1–4, doubtful 0; N/A, not applicable.

Conclusion

To our knowledge, this is one of the first case reports of ezetimibe monotherapy causing rod-cone dysfunction. The patient reported nyctalopia and repeatable visual field constriction was confirmed on Humphrey visual field testing (i.e., rod dysfunction). The patient also had impaired colour vision on Ishihara colour plate testing which improved after cessation of ezetimibe therapy (i.e., cone dysfunction). Clinicians should be aware of this ADR-related vision impairment, which may be reversible if detected early. Therefore, we encourage clinicians to consider medication causes as differential diagnosis in patients who present with unexplained new-onset visual symptoms and systematically go through the options after serious red flags like malignancy have been excluded.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research did not receive grants for funding from any individual or agency in the commercial, private, or not-for-profit sectors.

Author Contributions

All authors attest that they meet the current ICMJE criteria for authorship. I would like to express sincere gratitude to my supervisor Associate Professor Veronica Preda (BS[Med], MBBS[Hons], MPH, FRACP, PhD), whose guidance and advice were integral and invaluable throughout the project. In addition, I would like to give special thanks to Dr. James Jabbour (MBBS, Bsc[Med], MPH, FRANZCO), who kindly provided clinical data, revisions, and ongoing support that have made this research possible. Veronica Preda and James Jabbour treated the subject and participated in the design and coordination of the study. Zhengchao Xu collected the data and wrote the manuscript. Veronica Preda and James Jabbour reviewed and revised the manuscript. All authors have read and approved the final version of the manuscript.

Funding Statement

This research did not receive grants for funding from any individual or agency in the commercial, private, or not-for-profit sectors.

Data Availability Statement

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.