Optic neuropathy secondary to perhexiline and amiodarone

Background

Perhexiline maleate is an antianginal agent used for the management of refractory angina pectoris. The use of perhexiline maleate is now less common due to its high rate of toxicity, including neuropathic, hepatic and ocular side effects.1 Amiodarone was also originally developed as an antianginal drug but is now more commonly prescribed for its antiarrhythmic properties. It has been associated with the development of vortex keratopathy, anterior subcapsular cataract, maculopathy and visual loss secondary to optic neuropathy (ON).2

We report a case of bilateral optic disc swelling secondary to perhexiline and amiodarone, which improved following cessation of the causative agent. Comprehensive work-up was essential to validate the diagnosis of perhexiline-induced ON after excluding other potentially life-threatening and sight-threatening causes.

Case presentation

A 71-year-old man presented to the ophthalmologist with an incidental finding of bilateral optic disc swelling that was noticed by his optometrist. He was asymptomatic on presentation and has a previous medical history significant for hypertrophic cardiomyopathy and ischaemic heart disease, for which he was treated with perhexiline maleate at 150 mg per day for the past 2 years.

On assessment, best-corrected visual acuities were 6/9 in the right and 6/7.5 in the left. There was no relative afferent pupillary defect and Ishihara colour plate testing was normal. Visual fields testing (HVF30-2) was normal in the right eye and showed non-specific mild defects in the left eye. Cranial nerves examination was unremarkable. Fundus examination showed bilateral hyperemic optic disc swelling that is worse in the left eye (figure 1A,B). Optical coherence tomography (OCT) of the optic discs showed marked swelling of the retinal nerve fibre layer (RNFL; figure 2). A subsequent fundus fluorescein angiography revealed hyperfluorescence at the optic discs (figure 1C,D).

Investigations

CT and MRI of the brain and orbits were unremarkable. Cerebrospinal fluid (CSF) examination showed mildly elevated protein with opening pressure of 24.5 cm CSF, normal biochemistry and negative infective screen. Blood work showed a mildly elevated C reactive protein (35 mg/L) and raised erythrocyte sedimentation rate (60 mm/hour). Inflammatory screenings, including angiotensin-converting enzyme, antinuclear antibodies, antineutrophil cytoplasmic antibody, rheumatoid factor and double-stranded DNA antibodies, were all normal. In view of raised inflammatory markers, a biopsy of the patient’s right temporal artery was performed and showed normal histology. Infective screen, including tests for syphilis and tuberculosis, was also negative. Positron emission tomography (PET) scan was done that showed an incidental intestinal mass that was resected and noted to be a low-grade adenomatous polyp. Perhexiline levels were not elevated (0.37 mg/L) and the patient had no hepatic or renal dysfunction. Investigations were guided by specialist teams from neurology, rheumatology and internal medicine.

Differential diagnosis

Potential life-threatening and sight-threatening causes of bilateral optic disc swelling were considered, including raised intracranial pressure (ICP), pseudopapillitis, autoimmune or connective tissue disease, vasculitis and malignancy. All differential diagnoses were appropriately excluded following an extensive work-up consisting of biochemical screening, relevant imaging (CT, MRI, PET scans), temporal artery biopsy and lumbar puncture. The elevated erythrocyte sedimentation rate (ESR) was attributed to a concurrent upper respiratory tract infection with pericarditis, which was later discovered and required inpatient treatment. Non-arteritic anterior ischaemic ON (NAION) was also considered but deemed less likely due to duration of clinical signs greater than 3 months and eventual complete resolution. In the absence of an identifiable aetiology, perhexiline-induced ON was suspected.

Treatment

Perhexiline was ceased 1 month following initial presentation. A short 3-week tapering course of oral prednisolone was trialled with no significant response.

Outcome and follow-up

The patient’s visual acuity, optic nerve function and optic disc swelling remained clinically unchanged in the initial 8 weeks following presentation. One month following cessation of perhexiline, disc swelling was persistent on fundus examination, but subclinical improvement was first noted on OCT RNFL (figure 2). At 9 months’ follow-up and 8 months following cessation of perhexiline, the disc swelling had completely resolved (figure 2).

At 23 months’ follow-up, the patient had newfound bilateral vortex keratopathy and recurrence of bilateral optic disc swelling. He had remained clinically asymptomatic and reported to having started amiodarone (200 mg per day) for atrial fibrillation 6 months prior. Best-corrected visual acuities were 6/7.5 bilaterally. Optic nerve function tests and OCT showed significant RFNL thickening bilaterally (figure 2A). HVF30-2 showed constricting field defects in both eyes, with left worse than right (figure 2B).

In view of a similar clinical picture to the patient’s first presentation, amiodarone-induced ON was inferred. Amiodarone was discontinued in discussion with the patient’s cardiologist. At follow-up 6 months after cessation of amiodarone, there was partial improvement in his disc swelling (figure 1E,F; and figure 2A) and both his vision and optic nerve function remained stable.