Man with complicated history presents for retina consultation
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A 65-year-old man presented to the retina service for a preoperative cataract surgery evaluation after being followed for years for presumed retinitis pigmentosa.
His medical history included developmental disability, schizophrenia, Parkinson’s disease, asthma, heart failure with reduced ejection fraction, atrial fibrillation, neurogenic bladder, prediabetes and hyperlipidemia. His medications included albuterol, atorvastatin, budesonide, carbidopa-levodopa, apixaban, metoprolol, omeprazole, thioridazine and trimethoprim-sulfamethoxazole. He was a long-term group home resident.
Source: James Kwan, MD, and Kendra Klein-Mascia, MD
His ocular history included exposure keratopathy resulting in a visually significant corneal scar in the left eye, cataracts in both eyes, presumed retinitis pigmentosa and amblyopia in the left eye. He had been followed for regular eye examinations by the comprehensive ophthalmology service for 6 years with report of slowly progressive vision decrease in the right eye. Vision in the left eye was subjectively stable given he was light perception only by history. Cataract surgery was being considered; however, he was referred for a formal retina consultation to evaluate to what degree his presumed progressing retinitis pigmentosa may be contributing to his vision loss.
Examination
The patient’s central visual acuity was 20/80 in the right eye and light perception in the left eye. IOP was 6 mm Hg in both eyes. The right pupil was round and reactive to light with no afferent pupillary defect. The left pupil was unable to be examined due to significant baseline corneal scar. Confrontation visual fields revealed central restriction in the right eye, with testing unable to be done in the left eye. Extraocular movements were full.
Anterior examination in the right eye demonstrated mild anterior stromal haze of the cornea and 2+ nuclear sclerotic cataracts. The left eye had significant stromal haze of the cornea with associated neovascularization and irregular epithelial surface, in addition to a 3+ milky nuclear sclerotic cataract.
The dilated fundus exam was limited by patient cooperation; however, diffuse retinal pigment epithelium (RPE) atrophy, thinning, attenuated vessels and pigment clumping were noted in both eyes. Color fundus photos (Figure 1) were obtained but were limited in quality due to patient cooperation.
Testing
Adjunctive testing was performed, including OCT of the macula and electroretinogram (ERG). OCT of the macula (Figure 2; only the right eye shown) demonstrated diffuse thinning and outer retinal loss, including that of the RPE. Hypertransmission was noted through the areas of RPE loss. ERG of both eyes (Figure 3) showed global depression in both scotopic and photopic conditions.
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Retina consultation
Given the patient’s history of progressive visual decline and nyctalopia, outer retinal disruption on OCT and long-standing psychiatric history requiring thioridazine, thioridazine retinopathy was diagnosed. Upon further review, the patient had been on thioridazine for 40 years and was currently maintained on a daily dose of 100 mg. Per the patient’s caregivers, previous attempts to discontinue this medication had led to unacceptable levels of aggression, so he was kept on it in the interest of patient safety.
Management
The decision was made to recommend cessation of thioridazine in lieu of another appropriate psychiatric medication, in coordination with the patient’s primary care physician and psychiatrist. Extensive discussion took place, given that the vision loss secondary to chronic thioridazine exposure was likely permanent, as evidenced by the near total loss of the outer retina. Additionally, given the patient’s significant retinal pathology, it was determined that cataract surgery would not ultimately aid in improving the patient’s quality of vision and was not pursued. At the most recent follow-up, 2 months after the initial consultation, the patient and family had proceeded with discontinuing thioridazine. Vision was subjectively improved although objectively stable, and the patient was subsequently declared legally blind.
Discussion
Thioridazine, a phenothiazine derivative, is a first-generation antipsychotic that is indicated in the treatment of acute and chronic psychosis, depressive disorders, behavioral disorders and psychoneurotic manifestations. When used for schizophrenia specifically, thioridazine is typically reserved for treatment-refractory cases after other antipsychotics have failed. Judicious allotment of this medication is particularly important because after its initial introduction to the market in 1978, thioridazine was found to cause an increased rate of QTc prolongation. Coordinated monitoring with the patient’s primary care physician is of paramount importance to mitigate the development of life-threatening arrhythmias.
Thioridazine retinopathy is a known complication of the long-standing use of this medication at high doses. Typically, sustained doses greater than 800 mg of thioridazine are considered to be hazardous to retinal health. The mechanism for retinal damage is not fully understood, but it is known that dopamine has a neuroprotective effect and that phototoxicity (by way of oxidative disruption of rhodopsin) may occur as a consequence of thioridazine’s mechanism of action as a dopamine receptor antagonist. Additionally, histologic studies have been performed that demonstrate a high degree of thioridazine directly binding melanin granules within the uvea and RPE, which may directly cause toxicity to these structures as well as secondary loss of the choriocapillaris.
In the retina, outer retinal structures, especially the RPE and photoreceptors, are particularly susceptible to damage. The periphery is often first involved with centripetal progression as increasingly severe disease sets in. As such, peripheral vision loss and nyctalopia are classic presenting signs; later in the course, central vision loss and even blindness may manifest. Adjunctive testing can help further evaluate the degree of a patient’s retinal dysfunction. ERG classically demonstrates a diminished b-wave amplitude, delayed a-wave implicit time and delayed b-wave implicit time in scotopic conditions. This diffuse rod and cone dysfunction may be reversible if drug cessation occurs soon enough in the disease course; however, the pigmentary manifestations are usually permanent. OCT is also routinely employed and expectedly will show a variable degree of RPE and photoreceptor loss in addition to choriocapillaris attenuation. Additionally, high-dose thioridazine use may affect other parts of the eye, especially the lens. In the lens, there is a dose-dependent increased risk for cataract formation, in particular that of anterior polar cataracts.
- References:
- Beach SR, et al. Psychosomatics. 2013;doi:10.1016/j.psym.2012.11.001.
- Chiang TK, et al. Biomolecules. 2022;doi:10.3390/biom12101390.
- Corradetti G, et al. Int J Retina Vitreous. 2019;doi:10.1186/s40942-019-0172-0.
- Feinberg SM, et al. Thioridazine. https://www.ncbi.nlm.nih.gov/books/NBK459140/. Updated Feb 6, 2023.
- LiverTox: Clinical and research information on drug-induced liver injury. https://www.ncbi.nlm.nih.gov/books/NBK547852/. Updated June 6, 2024.
- Pardue MT, et al. Prog Retin Eye Res. 2018;doi:10.1016/j.preteyeres.2018.02.002.
- Richa S, et al. CNS Drugs. 2010;doi:10.2165/11533180-000000000-00000.
- For more information:
- Edited by Jonathan T. Caranfa, MD, PharmD, and Angell Shi, MD, of New England Eye Center, Tufts University School of Medicine. They can be reached at jcaranfa@tuftsmedicalcenter.org and ashi@tuftsmedicalcenter.org.
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