Acute retinal pigment epitheliitis associated with intravenous bisphosphonate

Zoledronate is a newer bisphosphonate, primarily used for the treatment of tumour induced hypercalcaemia and skeletal related events in advanced bone malignancy. Bisphosphonates have been associated with a number of ocular side effects including conjunctivitis, episcleritis, scleritis, uveitis, and visual blurring.¹ We report a case of acute retinal pigment epitheliitis following the use of intravenous zoledronate. To our knowledge bisphosphonates have not previously been associated with acute retinal pigment epitheliitis and could find no reference to it in computerised search utilising Medline and Pubmed.

Case report

A 47 year old glazier noted visual blurring and metamorphopsia within a day following intravenous infusion of zoledronate. One month after the infusion and onset of symptoms, his best corrected visual acuity was 6/5 in each eye. There was no vitritis or anterior uveitis. Fundus examination showed subtle clumps of hyperpigmentation surrounded by a paler halo of hypopigmentation in discrete clusters around both maculas at the level of the retinal pigment epithelium (RPE), more visible in the left eye (fig 1). The Amsler grid showed metamorphopsia corresponding to the area of RPE disturbance. The optic discs, retinal vessels, and surrounding retina were normal. Optical coherence tomography was normal. Fundus fluorescein angiography revealed an area of hypofluorescence corresponding to the area of hyperpigmentation, surrounded by an area of hyperfluorescence in the early phase and in the arteriovenous phase (fig 2), while fading in the late phase, with no leakage (fig 3). A detailed history, systems review, and comprehensive investigations were negative.

Figure 1 Colour fundus photograph (A) right eye, (B) left eye. These show subtle clumps of hyperpigmentation surrounded by a paler halo of hypopigmentation in discrete clusters around both maculas at the level of the retinal pigment epithelium, more visible in the left eye.

Figure 2 Fundus fluorescein angiogram, arteriovenous phase (A) right eye, (B) left eye, showing areas of hypofluorescence corresponding to the area of hyperpigmentation, surrounded by an area of hyperfluorescence.

Figure 3 Fundus fluorescein angiogram, late phase (A) right eye, (B) left eye, illustrating fading hyperfluorescence with no leaking.

Comment

Acute retinal pigment epitheliitis (ARPE) or Krill's disease was first described by Krill and Deutman as a benign, acute self limiting inflammatory disorder of the RPE without systemic association, with reduced visual acuity, metamorphopsia, and subtle changes at the level of the RPE.² Clusters of lesions with hyperpigmented centres, surrounded by paler halos, at the posterior pole have been reported as early as 1 month after the onset of symptoms.³ These lesions become less distinct with time leaving an area of subtle pigment mottling. Although most recover over several months Chittum and Kalina describe one case with a persistent small scotoma.³

Acute retinal pigment epitheliitis is thought to represent areas of RPE inflammation with breakdown of the pigment epithelial barrier and subsequent leakage of serous fluid.² Viral causes including hepatitis C have been postulated.²,⁴

Bisphosphonates have been associated with many ocular adverse effects, the majority being inflammatory; anterior and posterior uveitis, episcleritis, scleritis, and optic neuritis.⁵ Blurred vision is well documented and listed by the World Health Organization as a “certain” ocular adverse effect of bisphosphonates⁵ although, the cause of this has not been identified.

Drug induced immunological or toxic reaction have been hypothesised to be responsible for an acute inflammatory reaction in the case of pamidronate.⁶

Unfortunately, most ophthalmic toxicology data rely on voluntary post‐marketing surveillance systems and case reports.⁵ Applying the World Health Organization Causality Assessment Guide⁷ this case of acute retinal pigment epitheliitis is a possible adverse reaction of zoledronate as there was a plausible time relation to drug administration and absence of other drugs or chemicals or of concurrent disease that could explain the adverse effect.

The main limitations of our report are that this is a single case, the eyes were not examined until 1 month after the drug infusion and subsequent onset of symptoms including no examination before the bisphosphonate infusion, and the patient did not undergo a re‐challenge test.

Further reports from similar cases are required to confirm these findings. It is important that ocular symptomatology occurring in association with the use of novel medicines is diagnosed and data drawn to the attention of physicians.