Gentamicin (Gentak; Akorn, Lake Forest, IL) toxicity manifests as a vaso-occlusive event with nonperfusion areas demarcating the macular infarction. The postulated etiology is a vascular or receptor-mediated process.1 The availability of optical coherence tomography (OCT) has improved understanding of this macular insult, but few published cases report use this diagnostic tool.2,3 The current case adds to literature by using swept-source OCT (SS-OCT) to image early gentamicin toxicity within 12 hours of subconjunctival injection. By reporting outer retinal damage to be the initial event, in contravention to prior reports,2,3 it seeks to enhance our understanding of the pathology of this dreaded complication of gentamicin injection.
Pioneering work by the Aminoglycoside Toxicity Study Group has clearly identified intraocular administration of gentamicin to cause retinal toxicity resulting in macular infarction and visual loss. The same been extensively reported and studied by both in vitro and in vivo studies.1,4,5 However, subconjunctival use of gentamicin has not been subjected to same scrutiny with isolated case reports of macular toxicity in cases with scleral thinning, inadvertent perforation, or in sutureless sclerotomies during 25-gauge vitrectomy.2,6–8 This aspect needs further study, especially in the current scenario where prophylactic subconjunctival gentamicin is routinely employed post-cataract surgery.
A 31-year-old male was operated for a post-traumatic subluxated cataract in left eye. Preoperative best-corrected visual acuity (BCVA) was counting fingers 1 meter in the left eye (OS) and 20/20 in the right eye (OD). Intraocular pressure was normal, and angle structures and fundus findings were unremarkable. He underwent an intracapsular cataract extraction with anterior vitrectomy in OS and received intracameral cefuroxime (1 mg/0.1 mL) and subconjunctival gentamicin injection (20 mg/0.5 mL) for infection prophylaxis in the inferior quadrant under direct visualization after ballooning the conjunctiva, with no inadvertent perforation. No scleral thinning was noted intraoperatively or thereafter.
As the surgery was performed in the later part of the day, the eye patch was removed the next day morning (12 hours post-surgery). His vision had reduced to hand motions. Examination revealed mild corneal edema, significant anterior chamber reaction (3+ cells), and dilated fixed pupil in the aphakic eye. Fundus exam revealed mild vitritis, significant macular edema, retinal whitening, superficial hemorrhages and a normal optic disc (Figure 1a). SS-OCT (DRI OCT Triton Plus; Topcon, Tokyo, Japan) scan through macula showed large neurosensory detachment measuring 588 μm in height with central subfield thickness (CST) of 929 μm. The inner retinal layers were intact; however, the outer nuclear and photoreceptor layers depicted large cystoid spaces (Figure 2a). Fluorescein angiography (FA) showed perivascular staining and an enlarged foveal avascular zone (Figure 1b).
Color fundus photograph of the left eye macula shows retinal whitening, intraretinal hemorrhages (a), retinal ischemia, and perivascular hyperfluorescence (b) in the early phase of gentamicin toxicity (12 hours). The unremitting infarction on day 4 shows profound retinal necrosis (c) and marked ischemia (d).
Transverse optical coherence tomography scans through the macula on day 1 (a) show great elevation of neurosensory retina, large cystoid spaces in the outer nuclear layer, and preserved integrity of inner retinal layers. Progressive decrease in detachment height and increased disorganization of the inner retinal layers are evident across day 2 (b), day 4 (c), and at 2 weeks (d).
At 36 hours' follow-up, the neurosensory detachment had reduced to 381 μm in height with CST of 744 μm. At this point, the inner retinal layers also began to show fuzzy borders (Figure 2b). Retinal whitening and intraretinal hemorrhages were more pronounced.
As both gentamicin and cefuroxime were in recommended dosages, drug toxicity due to inadvertent egress of gentamicin into the vitreous was suspected, keeping in mind the risk factors of aphakia.2,9 A pars plana vitrectomy was immediately performed to wash out residual drug to decrease the toxicity in pursuance to recommendations by Jalali et al. and Chu et al.10,11 However, the retinal infarction progressed relentlessly during next 3 days (Figure 1c), and FA on day 4 revealed increased vascular staining, pruning and extensive retinal ischemia (Figure 1d).
Full-field electroretinography showed diminished amplitudes and delayed implicit times of both a- and b-waves, with absent oscillatory potentials. Imaging by OCT showed thickened, disorganized inner retinal layers with reflectance of hemorrhages in outer nuclear layer (Figure 2c). Two weeks postoperatively, the BCVA was hand movements, macula was pale, and retinal vessels were occluded and were lined with large intraretinal hemorrhages. Repeat OCT showed attached sensory retina, disorganized and hyperreflective inner retina, thick and hypoechoic outer retina, and a CST of 400 μm (Figure 2d).
We had a rare opportunity of capturing the sequential retinal changes of gentamicin toxicity on OCT from 12 hours to 14 hours of exposure until 2 weeks later. We report new early, in vivo findings, which show that the injury starts from outer layers of retina and then involves the inner layers, contrary to the prior reports that showed gentamicin toxicity to affect inner retinal layers primarily.3,12 Experimental studies in rabbit,1 porcine,13 and monkey eyes14 have reported inner retinal involvement to be the predominant event. The earliest inner retinal change was noted in pigs with vacuolation of nerve fiber layer occurring within 6 hours to 12 hours of toxicity.13 Electrophysiological corroboration by selective elimination of b-wave (bipolar / Müller cells) with relative sparing of a-wave (photoreceptors) again points to inner retinal layer involvement.1,15
In counterpoint, a few histopathological studies in rabbit document retinal pigment epithelium (RPE) necrosis and photoreceptor disruption as the initial event followed by involvement of inner retina.16,17 A study in monkey eyes revealed cytoplasmic vacuolization of photoreceptors and Muller cell necrosis to be the initial injury markers5 similar to our case findings.
FA findings of perivascular hyperfluorescence with minimal perfusion defects in early phase of toxicity progressing to widespread nonperfusion in late stages seen in this case was a novel observation in a human subject. A similar phenomenon was noted in primates where the vascular occlusion progressed in a graded manner as the necrosis worsened.5,14 The findings corroborate the previous evidence that the primary toxic effect of gentamicin is to neural retina, with vascular changes being secondary.1,14 But why the toxicity predominantly involves the macula remains unexplained. The SS-OCT findings of early outer retinal involvement in our case may throw light on these unanswered queries. As the central macula is populated by cone photoreceptors,18 there could be an unknown affinity of gentamicin for central macula in early phase of the toxicity. This may explain why the initial stages of toxicity spares the inner retina although the drug reaches retina through vitreous cavity. Clarification as to the exact level of retinal injury may be further understood by experiments on human cell line cultures using fluorescein tagged gentamicin to demonstrate its selective uptake by photoreceptors in outer retina in early stage of toxicity.
Subconjunctival use of gentamicin has been infrequently, yet not rarely reported to cause retinal toxicity.2,6,8,19 For most of these reports, scleral breach in form of scleral thinning, inadvertent intraocular perforation and/or adjacent unsutured sclerotomies has been implicated. An experimental study has confirmed increased penetration of gentamicin through thinned sclera causing localized photoreceptor damage.17 This case differs by lack of any such factor and raises aspects of safety of subconjunctival use of this drug in an aphakic eye.
In conclusion, our findings may differ from previously documented sequence of events due to observation of the toxicity features in the very initial phase (within 12 hours), as well as the use of the newer-generation SS-OCT with improved delineation.2,3 This case queries the accepted cascade of gentamicin toxicity and proposes that the neurological insult to the outer retinal layer is the initiating event in this blinding condition. It also seeks to be a wake-up call to discourage prophylactic use of subconjunctival gentamicin when studies have questioned its efficacy,20 especially since its ingress into vitreous cavity with subsequent devastating effects cannot be ruled out.
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- Heath Jeffery RC, Bowden FJ, Essex RW. Subconjunctival gentamicin-induced macular toxicity following sutureless 25-gauge vitrectomy. Clin Exp Ophthalmol. 2017;45(3):301–304. doi:10.1111/ceo.12842 [CrossRef]
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- Campochiaro PA, Lim JI. Aminoglycoside toxicity in the treatment of endophthalmitis. The Aminoglycoside Toxicity Study Group. Arch Ophthalmol. 1994;112(1):48–53. doi:10.1001/archopht.1994.01090130058017 [CrossRef]
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- Cardascia N, Boscia F, Furino C, Sborgia L. Gentamicin-induced macular infarction in transconjunctival sutureless 25-gauge vitrectomy. Int Ophthalmol. 2008;28(5):383–385. doi:10.1007/s10792-007-9148-4 [CrossRef]
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