CASE REPORT

In vivo confocal m

icroscopy findingsin central toxic keratopathy

Scott C.H. Hau, MSc, MCOptom, Bruce D. Allan, MD, FRCOphth

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Central toxic keratopathy is an uncommon complication after laser in situ keratomileusis. Wereport the confocal microscopy findings in a case of central toxic keratopathy that confirm lossof keratocytes from the corneal stromal bed in the acute phase, with gradual repopulation overthe following year.

Financial Disclosure: Neither author has a financial or proprietary interest in any material ormethod mentioned.

J Cataract Refract Surg 2012; 38:710–712 Q 2012 ASCRS and ESCRS

Central toxic keratopathy, an uncommon complica-tion after laser in situ keratomileusis (LASIK) and pho-totherapeutic keratectomy, was described in a caseseries (23 eyes) by Somnez and Maloney in 2007.1 Itis characterized by the sudden onset of central or para-central corneal opacification, stromal tissue thinning,and “mud-crack” striae in the stromal bed appearing3 to 6 days postoperatively. An associated hyperopicrefractive shift partially resolves with the recovery ofcorneal clarity over a 3- to 18-month time course.1,2

Although central toxic keratopathy typically occursin the context of diffuse lamellar keratitis (DLK), opa-cification of the corneal stromal bed is thought to benoninflammatory.1 Imaging studies using Scheimp-flug technology and anterior-segment optical coher-ence tomography (AS-OCT)2,3 suggest that cornealthinning and striae in post-LASIK central toxic kerat-opathy are confined to the stromal tissue bed withno direct involvement of the LASIK flap. Somnezand Maloney1 hypothesize that localized keratocyteapoptosis may explain the corneal stromal compaction

ust 19, 2011.ubmitted: September 15, 2011.ember 19, 2011.

s Eye Hospital, London, United Kingdom.

part by the United Kingdom National Institute forh Biomedical Research Centre in Ophthalmologyye Hospital and University College London Institutegy.

author: Scott C.H. Hau, MSc, MCOptom, Moorfields62 City Road, London EC1V 2PD, United Kingdom.au@moorfields.nhs.uk.

SCRS and ESCRS

by Elsevier Inc.

and thinning observed in central toxic keratopathyand suggest that this might be confirmed by confocalmicroscopic study. To our knowledge, in vivo confocalmicroscopy imaging has not been reported. We pres-ent the confocal microscopy findings in a patientwho developed central toxic keratopathy afteruneventful LASIK.

CASE REPORT

A 50-year-old man had uneventful bilateral wavefront-guided LASIK using an S4-IR excimer laser and an IntralaseFS60 femtosecond laser (Abbot Medical Optics, Inc.). Thepreoperative refractive error was �7.00 �0.50 � 20 in theright eye and�6.50�1.25� 170 in the left eye. The correcteddistance visual acuity (CDVA) was 20/15 in each eye. Onpostoperative day 3, moderate DLK developed in botheyes. The patient was using topical dexamethasone 0.1%preservative-free eyedrops 4 times daily. The frequencyincreased to every hour after the diagnosis of stage II DLK.

On postoperative day 5, the DLK was improving but thevisual acuity in the left eye had deteriorated. The uncor-rected visual acuity was 20/30 in the right eye and 20/120in the left eye. On slitlamp examination, there was traceDLK in both eyes. In the left eye, a paracentral stromal opac-ity extended approximately 40% in depth posterior to the in-terface associated with stromal thinning and mud-crackstriae (Figure 1, A). The RTVue (Optovue, Inc.) AS-OCTrevealed a hyperreflective zone extending posteriorly fromthe flap interface into deep stroma (Figure 1, B). The centralcorneal thickness (CCT) was 368 mm, the residual stromalbed thickness was 244 mm, and the flap thickness was124 mm. In vivo confocal microscopy was performed usingthe HRT II confocal microscope with the Rostock CornealModule (Heidelberg Engineering GmbH). Large areas of hy-perreflectivity were seen in the subepithelial and Bowmanlayers. No keratocytes or inflammatory cells were seen inthe flap stroma (at 80 mm), the flap interface (at 125 mm), orwithin the stromal bed beneath the interface (at 200 mm),but keratocytes started to reappear from 350 mm (Figure 1,C to F). At 1 week, it was not possible to image the

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doi:10.1016/j.jcrs.2012.01.010

Figure 1. Corneal images in a patient with post-LASIK central toxic keratopathy with clinical photographs (column 1), AS-OCT (column 2), andconfocal microscopic sections through the flap stroma (80 mm depth), flap interface (125 mm depth), anterior stromal bed (200 mm depth), andposterior stroma (350 mmdepth) (columns 3 to 6). Images were taken in the acute phase at 1 week (top row), 3 months (middle row), and 12 months(bottom row). Prominent mud-crack striae in the stromal bed (arrows in A, G,M) had not completely resolved at 12 months. Arrowheads indicatethe flap interface level in AS-OCT images (B, H, N).

711CASE REPORT: CONFOCAL MICROSCOPY OF CENTRAL TOXIC KERATOPATHY

endothelium. In vivo confocal imaging of the unaffected(right) eye revealed a normal keratocyte density at eachstromal level sampled.

At 3 months, the stromal opacity had faded (Figure 1, G)and less hyperreflectivity was evident on AS-OCT(Figure 1, H) but some striae were present in the stromalbed (Figure 1, G). In vivo confocal microscopic sections ofthe flap stroma, the interfacial zone, and the anterior residualstromal bed showed activated keratocyte repopulation ateach level (Figure 1, I to K). There was no difference in theappearance of the keratocytes in the posterior corneal stroma(Figure 1,L). The endothelial cell densitywas2400 cells/mm2.

One year postoperatively, the manifest refraction andCDVA were �0.25 �0.75 � 2 (20/15) in the right eye andC0.75 �1.75 � 27 (20/20) in the left eye. Residual striae inthe subinterfacial stroma were still visible (Figure 1, M),and a further reduction in the degree of hyperreflectivity atthe flap interface was seen on AS-OCT (Figure 1, N). TheCCT had increased to 441 mm, the residual stromal bedwas 282 mm, and the flap thickness was 132 mm.Confocal mi-croscopy showed a keratocyte density similar to thatobserved at 3 months in the flap stroma (Figure 1, O), buta higher keratocyte cell density was seen in the flap interfaceand the anterior stromal bed (Figure 1, P to Q). Keratocytedensity and morphology were unchanged in the posteriorstroma at 350 mm (Figure 1, R). The endothelial cell densitywas 2520 cells/mm2.

DISCUSSION

Confocal microscopic findings in this case of centraltoxic keratopathy are consistent with the hypothesisof Somnez and Maloney1 that the stromal compac-tion and consequent hyperopic shift that characterizethe condition may be, at least in part, explained bykeratocyte apoptosis in the affected central cornealzone. Subsequent keratocyte repopulation is

J CATARACT REFRACT SURG

accompanied by a partial recovery of corneal thick-ness and an improvement in the refractive findings.The cell depopulation we observed was not accompa-nied by any inflammatory cell infiltrate. Although, asin our case, central toxic keratopathy may emerge inthe context of mild DLK, the absence of inflammatorycells in confocal imaging is consistent with Somnezand Maloney’s view that the opacification andcorneal shape changes are not driven by inflamma-tion and that topical steroid treatment is not indi-cated once background DLK has resolved. Eventhough the etiology of central toxic keratopathy isnot known, it would appear to be a noninflammatoryapoptotic event, possibly triggered by inflammationin susceptible individuals, but not a continuum ofthe spectrum of increasing inflammatory severity de-scribed as stage IV DLK by Linebarger et al.4 Somnezand Maloney1 describe the condition as central toxickeratopathy, but there is no evidence for a toxicmechanism driving keratocyte apoptosis in centraltoxic keratopathy.

Anterior segment-OCT findings in a case of centraltoxic keratopathy reported 1 month after surgery byLiu and Manche3 suggest that corneal thicknesschanges were confined to the stromal bed with no in-volvement of the overlying flap. In the casewe present,dense hyperreflectivity in the 1-week postoperativeimages made accurate location of the flap interfacedifficult, but no cells were seen in the flap stroma(Figure 1, C). This suggests that keratocyte apoptosisin the acute phase of central toxic keratopathy involvedboth the flap and the anterior stromal bed.

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712 CASE REPORT: CONFOCAL MICROSCOPY OF CENTRAL TOXIC KERATOPATHY

Moshirfar et al.2 report that tissue loss declined orhalted within 2 weeks of surgery in cases of centraltoxic keratopathy and that CCT recovered within 6weeks of diagnosis. Although we found keratocyterepopulation by 3 months, keratocyte density ap-peared to be lower in the anterior stroma than inthe posterior stroma 12 months after the initial diag-nosis of central toxic keratopathy. Normal keratocytedensity is higher in the anterior than the posteriorstroma.5 The lower anterior keratocyte density weobserved suggests that cell population in this regionhas not fully recovered at 12 months. In Somnezand Maloney’s case series,1 opacification had clearedin all cases by 18 months and LASIK retreatment wasperformed at that point without recurrence of centraltoxic keratopathy. The patient we present had revi-sion surgery 15 months after the refraction hadbeen stable for 6 months. Although we are not ableto comment further on the time course of corneal tis-sue recovery in central toxic keratopathy at a cellularlevel, it is interesting to note that the repopulatingkeratocytes had an activated phenotype at the1-year examination.

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REFERENCES1. Sonmez B, Maloney RK. Central toxic keratopathy: description of

a syndrome in laser refractive surgery. Am J Ophthalmol 2007;

143:420–427

2. Moshirfar M, Hazin R, Khalifa YM. Central toxic keratopathy. Curr

Opin Ophthalmol 2010; 21:274–279

3. Liu A, Manche EE. Anterior segment optical coherence tomogra-

phy imaging of central toxic keratopathy. Ophthalmic Surg Lasers

Imaging 2010 Apr 2 [Epub ahead of print]

4. Linebarger EJ, Hardten DR, Lindstrom RL. Diffuse lamellar kera-

titis: diagnosis and management. J Cataract Refract Surg 2000;

26:1072–1077

5. Patel SV, McLaren JW, Hodge DO, Bourne WM. Normal human

keratocyte density and corneal thickness measurement by using

confocal microscopy in vivo. Invest Ophthalmol Vis Sci 2001;

42:333–339. Available at: http://www.iovs.org/content/42/2/333.

full.pdf. Accessed December 16, 2011

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First author:Scott C.H. Hau, MSc, MCOptom

Moorfields Eye Hospital, London,United Kingdom