Corneal recovery after lasik for high myopia: a 2-yearprospective confocal microscopic study

J A O Moilanen,1,2 J M Holopainen,1 M H Vesaluoma,1 T M T Tervo1

1 Helsinki University CentralHospital, Department ofOphthalmology, Helsinki, Finland;2 Centre for Military Medicine,Aero Medical Centre, Helsinki,Finland

Correspondence to:Dr J Moilanen, Centre forMilitary Medicine, Aero MedicalCentre, Helsinki, Finland;jukka.moilanen@hus.fi

Accepted 20 June 2008Published Online First23 July 2008

ABSTRACTAim: To quantify human corneal recovery after moderateto high myopic laser in situ keratomileusis (LASIK) in a 2-year prospective follow-up study.Methods: Fifteen eyes of 15 patients (mean refraction210.1 (SD 2.4) D) were examined preoperatively andpostoperatively at day 1, 5 days, 2 weeks, 1, 3 and6 months and 2 years. Biomicroscopy, visual acuity andrefraction were examined prior to imaging studies. An invivo tandem scanning confocal microscope was used toobtain images from the central cornea. Subbasal nervedensity was measured as the total length of nerve trunksin confocal image per mm2. Keratocyte density wascalculated manually from stromal sublayers. The thicknessof the altered keratocyte zone was measured on bothsides of the LASIK interface.Results: At the end of the follow-up, all patients had a20/20 BCVA, and nine of 15 patients were within ¡0.5 Dof the intended correction. The total corneal thicknessremained unaltered, but epithelial hyperplasia was seen at2 years. Keratocyte density in the anterior stroma andposterior to the flap interface showed a slight decreaseduring the follow-up. Subbasal nerve density decreased82% in 5 days after LASIK. A gradual increase wasobserved from 2 weeks postoperatively, but even 2 yearsafter the operation the nerve density was only 64% fromthe preoperative values.Conclusions: Subbasal nerve fibre density shows agradual recovery throughout the follow-up. However, onlythree subjects showed totally regenerated subbasal nervefibres at 2 years. This may correlate with the observeddecrease in the density of the most anterior keratocytes.Corneal remodelling seemed to continue for at least2 years.

Laser in situ keratomileusis (LASIK) is the mostpopular technique to correct ametropia. Since thesurgical procedure is performed on an otherwisehealthy tissue, it must be safe and predictable asalready shown.1–4 Postoperative regression of therefractive effect, the development of dry eyesymptoms, risk of iatrogenic keratectasia, flapcomplications or infections still remain occasionalclinical problems.5–16

The corneal stroma makes ,90% of the cornealthickness and is composed of a heterodimericcomplex of type I and V collagen bundles arrangedin lamellae.17 The quiescent, mesenchymal derivedfibroblasts, keratocytes, are the major cell popula-tion located between the collagen lamellae.18 Wheninjured, keratocytes either undergo rapid apoptosisor transform into repair phenotypes of migratingkeratocytes/myofibroblasts,17 19 which eventuallymay lead to decreased transparency of the cornea.19

There is also evidence that after LASIK, stromalkeratocyte density decreases.20–22

The sensory innervation of the cornea is derivedfrom the ophthalmic and maxillary branches of thetrigeminal nerve. At the limbus, these nerves losetheir myelin sheath and emerge into the cornealstroma as thick bundles. These bundles runtowards corneal apex, divide and bend anteriorly,and eventually penetrate the Bowman membraneto form the subbasal nerve plexus between theBowman layer and the basal epithelial cell layer.13

In LASIK the microkeratome cuts the subbasalnerve fibre bundles and the superficial stromalnerves in the flap margin. Subsequently, theexcimer laser photoablation obliterates the nervesof the stromal bed. These changes initially inducecorneal hypoesthesia lasting .6 months.23–26

In vivo confocal microscopy (ivCM) has becomean important technique to follow corneal changesafter corneal refractive procedures27–30 enablingvisualisation and quantification of histologicalalterations in vivo. In this prospective 2-year study,we have evaluated changes at different corneallayers as well as the recovery of corneal subbasalnerves following LASIK utilising ivCM.

PATIENTS AND METHODSPatientsThe study group comprised 15 eyes of 15 healthymyopic patients (nine females, six males, mean age32.9 (SD 9.7) years (range 21–52 years). The meanrefractive error in the treated eyes was 210.1(2.4) D (spherical equivalent, range 25.1 to213.9 D, mean astigmatism 21.1 (0.7) D, range20.5 to 23.25 D). All patients were selectedconsecutively and operated by the same surgeon(Tervo, TMT). The refractive correction aimed atemmetropia or as near emmetropy as possible inorder to spare at least 250 mm of stromal bed. Eachpatient gave informed consent. The Ethical com-mittee of the Helsinki University Central Hospitalhad approved the study protocol, and the princi-ples of the Declaration of Helsinki for researchinvolving human subjects were followed.

Study protocolEach patient was examined preoperatively and at 1and 5 days, 2 weeks, 1, 3 and 6 months and 2 years(mean 27.3 months, range 24–37) postoperatively.Examination at each visit included visual acuitymeasurement, refraction, biomicroscopy andivCM.

Confocal microscopyAfter clinical examination, corneas were examinedby a tandem scanning ivCM (TSCM; Model 165A;

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Tandem Scanning Corp., Reston, VA) for morphologicalevaluation and to measure the thickness of the differentsublayers of central cornea as described previously.31–33

Additionally, a confocal microscopy through focusing (CMTF)mode was used to scan the cornea four to six times fromepithelium to endothelium and back for thickness measure-ments, and for keratocyte density calculations at various cornealdepths.

Subbasal nerve fibre bundlesThe density of the subbasal nerve fibres was measured in eachvisit from the best possible image acquired. From these images(coronal section 4506360 mm), one investigator marked allvisible nerve fibres and measured the total length of the nerves(Adobe Photoshop 7.0). The nerve density was then expressedas mm/mm2. The number of long (.200 mm) subbasal nervefibres was manually counted from the same images andexpressed as number/mm2.

Keratocyte densityOne or two best-quality images with no motion artefact fromeach corneal layer were selected: most anterior keratocytes,midstromal keratocytes 120 mm (ie, in the mid flap) and 240 mm(approx. 80 mm posterior to the interface) from the epithelium,10 mm anterior and 10 mm posterior to the interface, andposterior stroma just anterior to the endothelium. Keratocytenuclei were manually counted from selected images. Keratocytedensity was then expressed as cells/mm2.

Thickness measurementsCMTF intensity profile curves exhibit the intensity of thebackscattered light from the corneal layers, where epithelium,subbasal nerves, most anterior keratocytes and endotheliumcomprise the areas of the highest intensity. The location of theflap interface is shown in the CMTF curve as a drop ofintensity. Additionally, the interface exhibits bright, smallparticles. With these landmarks we calculated the thickness ofthe epithelium, stroma, LASIK flap and the whole cornea.

The thickness of the area that expressed altered/migratorykeratocytes and increased backscattering of light both anteriorand posterior to the flap interface was measured as well.

LASIK procedureManifest and cycloplegic refraction, biomicroscopy, cornealpachymetry, topography and fundus inspection were examinedprior to surgery. All patients received a standard LASIKprocedure. A Hansatome microkeratome (Bausch & LombSurgical, San Dimas, CA) was used to create a corneal flapwith a superior hinge (thickness 160 mm, diameter 8.5 or9.5 mm). An excimer laser (VISX Star 2, VISX; Santa Ana, CA)was used to ablate the stroma to a mean depth of 98 (9) mm(SD, range 81–110 mm).

STATISTICSAll measured parameters were compared individually acrosstime using repeated-measures of variance (ANOVA) with post-hoc Bonferroni–Dunn correction. A p value less than 0.02 wasconsidered significant.

RESULTSClinical findingsOne patient suffered from postoperative epithelial erosion(table 1, patient 7), and another (table 1, patient 2) developed

a steroid-induced rise in IOP and interface fluid 3 weekspostoperatively accompanied with marked regression. The pre-and postoperative (at 6 months and 2 years) BCVAs andpostoperative UCVAs, and the corresponding refractions areshown in table 1. All patients had a BCVA 20/20 or better at6 months and 2 years. Six patients gained one line of BCVA,and two patients lost a line of BCVA.

Nine of 15 patients were within ¡0.5 D, and 11/15 patientswere within ¡1.0 D of the intended refraction at their finalfollow-up at 2 years. We observed a mean myopic regression of20.4 (0.6) D from 6 months to 2 years postoperatively.

Biomicroscopical examination showed a clear central corneaat all time-points for each patient. Mild epitheliopathy, that issmall punctate lesions, was seen in 6/15 patients 6 monthspostoperatively, and in two patients at 2 years. Subjectively, 8/15 patients reported symptoms of dry eyes for at least 1 year.

IN VIVO CONFOCAL MICROSCOPY

Corneal thicknessThe corneal thickness was evaluated by tandem scanningthrough focusing scans and found to be 533 (23) mm (range500–573 mm) preoperatively. This was reduced to 481 (26) mm(range 442–527 mm and 470 (34) mm, range 420–521 mm) at6 months and 2 years postoperatively (fig 1). Preoperatively, thethickness of the corneal epithelium was 49 (6) mm, and at day 1this increased to 55 (8) mm, presumably due to epithelialoedema. At day 5, the epithelial thickness decreased to 52(7) mm. and subsequently increased gradually to 62 (6) mm at2 years (p,0.0001 for all time points compared with preopera-tive thickness). This finding is highlighted also in analysing thethickness of the LASIK flap showing a gradual increase in itsthickness (not shown). The stromal bed thickness remainedunchanged during the follow-up.

KeratocytesKeratocyte densities in the whole stroma as well as in itsdifferent sublayers are shown in table 2. The postoperativeanterior keratocyte density was decreased by 3 months to92.5%, and continued to decrease at 6 months (86.9%) and2 years (81.9%). This decrement was statistically significant at2 years postoperatively (p = 0.0017). The keratocyte densities at120 mm and 240 mm postepithelial surface and just anterior tothe Descement’s membrane remained unaltered during thefollow-up (fig 2, table 2).

We then analysed the keratocyte densities just anterior (pre-IF; 10 mm anterior to the interface) and posterior (post-IF;10 mm posterior to the interface) to the LASIK flap interface.The pre-IF keratocyte density remained unchanged through thefollow-up (387 (86) and 347 (119) cells/mm2 at day 1 and2 years, respectively; p = 0.68). The post-IF keratocyte densityremained unaltered up to 3 months after LASIK (p.0.99). Adecrease, however, in the post-IF keratocyte density wasobserved at both 6 months and 2 years.

Altered/migratory keratocytes were observed both anteriorand posterior to the LASIK interface. The thickness of thealtered/migratory keratocyte area was found to be the highestat postoperative day 1, 42 (10) mm, and then showed a gradualdecline down to 6 (17) mm at 2 years after LASIK (fig 3). Inaccordance with the decrement in the thickness of the stromallayer where these altered cells were observed, the intensity ofthe backscattered light decreased from 201 (93) (day 1) to 10(33) intensity units (2 years postoperatively). This decrement

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was found to be significant at all time points compared withday 1 (fig 3).

Nerve density and regenerationThe subbasal nerve fibre bundle (nfb) length/area preoperativelywas 14.84 (5.6) mm/mm2. The postoperative nfb density wasdecreased at all postoperative follow-ups, with the greatestreduction evident at day 5 following LASIK. These data areshown in fig 4. A gradual increase in the nerve length wasobserved up to the last follow-up. However, even in the lastfollow-up, the length/mm2 was significantly lower comparedwith preoperative number (fig 4; p,0.0001).

DISCUSSIONIn this prospective non-randomised clinical trial, we haveexamined the long-term effects of myopic LASIK on cornealthickness, keratocyte density and nerve recovery. In essence, wefound that the total corneal thickness remained unchanged afterLASIK. Yet, epithelial hyperplasia continued at least up to2 years, in keeping with previous results.10 34 35 The anteriorstromal keratocyte density continued to decrease up to 2 years,whereas no changes were observed in the mid-stromal orposterior keratocytes. Furthermore, altered/migratory kerato-cytes were present in the corneal stroma up to 6 months, after

Table 1 Visual acuity and refraction pre- and postoperatively

Patient

Preoperatively

Postoperatively

6 months 2 years

BCVA Refraction UCVA BCVA Refraction UCVA BCVA Refraction

1 20/20 29.25 20/32 20/20 20.25 20/32 20/20 20.5

2 20/32 213.13 20/200 20/25 23.5 20/200 20/20 25.75

3 20/20 29.5 20/32 20/20 20.88 20/100 20/20 22

4 20/16 25.13 20/20 20/20 0.68 20/25 20/20 0

5 20/20 29.13 20/32 20/20 0 20/25 20/20 0

6 20/20 210.25 20/25 20/20 0 20/32 20/16 20.38

7 20/16 27.38 20/32 20/25 20.88 20/40 20/20 21.13

8 20/20 210.13 20/25 20/20 20.25 20/40 20/20 20.5

9 20/16 27.75 20/16 20/16 20.13 20/16 20/16 0

10 20/20 29.75 20/16 20/16 0 20/20 20/16 20.25

11 20/25 213.88 20/32 20/20 20.5 20/32 20/20 20.75

12 20/25 213 20/200 20/25 22.75 20/100 20/25 23

13 20/20 213 20/32 20/16 20.75 20/25 20/20 20.5

14 20/20 210.25 20/16 20/16 0 20/16 20/16 0

15 20/20 210.25 20/40 20/16 21.25 20/40 20/20 21.75

The target refraction in patients 2, 7, 11, 12, 13, 14 and 15 was 20.5, 20.5, 20.25, 21.25, 20.5, 20.5 and 20.25 D,respectively.BCVA, best corrected visual acuity; UCVA, uncorrected visual acuity.

Figure 1 Thickness of the whole cornea (&), epithelium (#) andstroma (D) estimated by CMTF scans before and after LASIK.

Figure 2 Keratocyte density before and after LASIK. The keratocytedensity at the anterior stroma (&) was decreased at 2 years post-LASIKfrom the density before LASIK. Cell densities in all remaining stromallayers (#), middle flap keratocytes; m, mid-stromal keratocytes; ,,posterior keratocytes) remained unchanged.

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which these cells almost vanished by 2 years. Finally, our resultsshow that the subbasal nerve density was only about two-thirdsof the preoperative value at 2 years.

Epithelial and stromal thicknessAlthough statistically not significant, the total thickness of thecornea seemed to decrease slightly from 6 months to 2 yearspostoperatively. A minute epithelial hyperplasia accompaniedthis finding, and a myopic regression of 20.4 (0.6) D wasobserved. In contrast to previous studies,11 36–38 it seems feasibleto suggest that myopic regression is not caused by changes inthe corneal thickness. Accordingly, there are a few hypotheticalaetiologies for the myopic regression: changes in the axialdimensions of the globe and/or subtle keratectasia may causethe observed regression. Alternatively, corneal viscous andelastic properties may have changed, causing altered biomecha-nics after LASIK.12

Keratocyte densityThe anterior keratocyte density was decreased at .3 months(fig 2, table 2). This finding is in accordance with our previouscase-series20 which showed a similar time-dependent pattern in

keratocyte density decrement following LASIK. In that study,significant changes in keratocyte cell density manifested at.6 months. Yet, Erie et al in their prospective LASIK seriesfound that the decrement in anterior keratocyte density wasmore rapid and was evident already 1 month after LASIK.22 39 Atpresent, the reason for this discrepancy is unknown but may berelated to differences in the method of depth and cellcalculations, analysis of data, and refractive treatment (10 Dcompared with 6.6 D in Erie’s series). We observed that thekeratocyte density in the pre-IF stroma was not changed duringthe follow-up, to 2 years. A significant decrease in keratocytecell density was, however, observed at the post-IF stroma at>3 months.

The reason why the anterior keratocyte density in the flapdecreases after LASIK is unknown. Our group and others haveproposed that this finding may be related to the denervation ofthe corneal flap leading to a loss of neurotrophic influence onkeratocytes.20 40 If this was the reason, then we would expectthat the decrease in cell density would manifest relativelyrapidly in weeks rather than after several months when thenerves are already regenerating (fig 4). Alternatively, thekeratocytes could undergo apoptosis due to activation of the

Table 2 Keratocyte density in the corneal sublayers preoperatively and postoperatively at 3 months,6 months and 2 years (cells/mm2)

Preop 3 months 6 months 2 years

Anterior keratocytes 983 (178) 909 (162) 854 (168) 795 (130)*

Mid-flap keratocytes 532 (100) 494 (103) 501 (137) 491 (101)

Pre-if keratocytes 356 (106) 360 (108) 347 (119)

Post-if keratocytes 400 (108) 277 (103) 294 (88)

Mid-stromal keratocytes 501 (76) 450 (76) 412 (128) 441 (89)

Posterior keratocytes 390 (44) 380 (62) 375 (52) 431 (17)

*Statistically significant decrease.Anterior keratocytes, most anterior identifiable keratocyte layer; Mid-flap keratocytes, layer in the flap 120 mm posterior to thesurface; Mid-stromal keratocytes, layer in the stroma 240 mm posterior to the surface; Post if keratocytes, layer in the stromal bed10 mm posterior to the flap interface; Posterior keratocytes, most posterior keratocytes anterior to endothelium; Pre if keratocytes,layer in the flap 10 mm anterior to the flap interface.

Figure 3 Change in the total thickness of the altered keratocyte zone(m) in the flap and stromal bed, that is anteriorly (&) and posteriorly (N)to the flap interface before and after LASIK. The cell and backgroundbackscattered light intensity (%) decreased over time, along with thedecrement of altered keratocytes.

Figure 4 Mean density of central corneal subbasal nerves per mm2

(&) and mean number of long (.200 mm) subbasal nerves (%) perconfocal microscopy frame. The density and mean number of longsubbasal nerves were the lowest 5 days postoperatively andregenerated gradually thereafter.

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apoptotic pathways.41 However, this latter hypothesis is notsupported by at least two independent observations. First, afteran epithelial scrape or PRK/LASIK wound, almost immediatekeratocyte apoptosis is observed, and this apoptotic death ofkeratocytes is rapidly downregulated.42 Second, the keratocyteswould need a specific signal for apoptosis to be manifested inthe long-term because this process is an ‘‘all or nothing’’ type ofreaction. It is arguable that such a signal would be elicitedmonths after the injury when most of the cornea has alreadyhealed.43 Yet, anterior keratocytes have been subjected to excessstress arising from the excimer procedure and become prema-turely senescent. Accordingly, in this ‘‘one hit too much’’scenario, the ability of keratocytes to protect against and correctharmful events (such as UV radiation) diminishes after excimerlaser procedure, and so these cells are more prone to permanentdamage and therefore die. The clinical significance of thegradual loss of keratocytes is unknown, and it may be that acritical density of keratocytes is needed to maintain cornealclarity and strength. At least in this study and in previousstudies,22 this limit was not exceeded, as the corneas in both ofthese studies were clear.

Dawson et al43 showed that several months (>6 months)after LASIK, the altered/migratory keratocytes became quies-cent, and a hypocellular scar is formed. This finding is alsohighlighted in this study (fig 3) showing that the activated/migratory keratocytes are gradually lost and the backscatteredlight is even more rapidly lost after LASIK. It seems that at anearly phase, altered/migratory keratocytes are metabolicallyvery active and participate in the normal wound-healingresponse. They then slowly return to their normal quiescentphenotype, although they contain a higher number of intracel-lular vacuoles.43

InnervationWe found that there is a gradual but incomplete regeneration ofsubbasal nerve fibre bundles at 2 years after LASIK. This is inaccordance with earlier studies by Calvillo et al44 and Erie et al.28

However, Patel and McGhee45 showed that there is a vortexpattern of subbasal nerve fibres at the corneal apex. As thelength and density of the nerve fibre bundles are measured froma 0.16 mm2 image area, the orientation of the nerve bundlesmay appear to fluctuate during the follow-up, thus affecting thedensity measurements. To minimise this, for analysis we usedthose images that presented with most nerves in the images inseveral subsequent CM scans.

Reinnervation studies on corneal grafts indicated that even ifepithelial innervation is restored, only minimal neural regenera-tion takes place in the stroma.46 Accordingly, we and othershave shown that corneal sensation to mechanical stimulus isrestored by approximately 6 months after LASIK.15 24–26 Yet,permanent or at least very long-term stromal nerve damage mayfollow (fig 4) and this might affect future healing of cornealwounds.

Funding: Supported in part by Grants from The Finnish Eye Foundation, Helsinki,Finland; The Eye and Tissue Bank Foundation, Helsinki, Finland; Evald and Hilda NissiFoundation, Espoo, Finland; Friends of the Blind, Helsinki, Finland; and The HelsinkiUniversity Central Hospital Research Fund, Helsinki, Finland.

Competing interests: None.

Ethics approval: The Ethical committee of the Helsinki University Central Hospitalapproved the study protocol.

Patient consent: Obtained.

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Emergence of diplopia and oscillopsia due to Heimann-Bielschowsky phenomenon after cataract surgery

ABSTRACTThe Heimann-Bielschowsky phenomenon (HBP) refers to coarse vertical oscillation of the eyewith impaired vision. The ocular movements are strictly monocular, occurring only in the eyewith amblyopia. The vertical oscillation is of equal velocity in both vertical directions, or maysometimes be greater in the downward than upward direction. HBP develops several years afterloss of vision. It can be differentiated from dissociated nystagmus in spasmus nutans, congenitalnystagmus and internuclear ophthalmoplegia based on the strict unilaterality, vertical directionand low frequency. Previously, only a few reports described the development of oscillopsia due toHBP after cataract surgery, which resolved spontaneously or responded to gabapentin. However,visual impairments due to diplopia or oscillopsia from HBP after cataract surgery have receivedlittle attention. We report a man who developed persistent vertical diplopia and oscillopsia due toHBP after a cataract operation, which markedly impaired his vision.

c To view the full report and accompanying video please go to: http://bjo.bmj.com/cgi/content/full/92/10/1402/DC1c All videos from the BJO video report collection are available from: http://bjo.bmj.com/video/collection.dtl

S-H Jeong1, Y-M Oh1, J-M Hwang2, J S Kim1

1 Department of Neurology, College of Medicine, Seoul National University, Seoul National University Bundang Hospital,Gyeonggi-do, Korea; 2 Department of Ophthalmology, College of Medicine, Seoul National University, Seoul National UniversityBundang Hospital, Gyeonggi-do, Korea

Correspondence to: J S Kim, Department of Neurology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Korea; jisookim@snu.ac.kr

Funding: JSK was supported by the second stage Brain Korea 21 Project in 2006.

Competing interests: None.

Br J Ophthalmol 2008;92:1402. doi:10.1136/bjo.2007.135624

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2008 92: 1397-1402 originally published online July 23,Br J Ophthalmol J A O Moilanen, J M Holopainen, M H Vesaluoma, et al. studya 2-year prospective confocal microscopic Corneal recovery after lasik for high myopia:

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