http://www.ncbi.nlm.nih.gov/entrez/quer ... query_hl=9

Invest Ophthalmol Vis Sci. 2004 Nov;45(11):3991-6.

Corneal reinnervation after LASIK: prospective 3-year longitudinal study.

Calvillo MP, McLaren JW, Hodge DO, Bourne WM.

Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

PURPOSE: To measure the return of innervation to the cornea during 3 years after LASIK.

METHODS: Seventeen corneas of 11 patients who had undergone LASIK to correct myopia from -2.0 D to -11.0 D were examined by confocal microscopy before surgery, and at 1, 3, 6, 12, 24, and 36 months after surgery. In all available scans, the number of nerve fiber bundles and their density (visible length of nerve per frame area), orientation (mean angle), and depth in the cornea were measured.

RESULTS: The number and density of subbasal nerves decreased >90% in the first month after LASIK. By 6 months these nerves began to recover, and by 2 years they reached densities not significantly different from those before LASIK. Between 2 and 3 years they decreased again, so that at 3 years the numbers remained <60% of the pre-LASIK numbers (P <0.001). In the stromal flap most nerve fiber bundles were also lost after LASIK, and these began recovering by the third month, but by the third year they did not reach their original numbers (P <0.001). In the stromal bed (posterior to the LASIK flap interface), there were no significant changes in nerve number or density. As the subbasal nerves returned, their mean orientation did not change from the predominantly vertical orientation before LASIK. Nerve orientation in the stromal flap and the stromal bed also did not change.

CONCLUSIONS: Both subbasal and stromal corneal nerves in LASIK flaps recover slowly and do not return to preoperative densities by 3 years after LASIK. The numbers of subbasal nerves appear to decrease between 2 and 3 years after LASIK. The orientation of the regenerated subbasal nerves remains predominantly vertical.

LASIK nerve damage symptoms persist at 16 months


http://www.ncbi.nlm.nih.gov/entrez/quer ... &DB=pubmed

Ophthalmology. 2001 Jul;108(7):1230-5

Effects of laser in situ keratomileusis on tear production, clearance, and the ocular surface.

Battat L, Macri A, Dursun D, Pflugfelder SC.
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida, USA.

Excerpts from the full text:

• Corneal sensation remained reduced 16 months after LASIK

• Conjunctival sensation remained reduced 16 months after LASIK

• Tear clearance remained reduced 16 months after LASIK.

ABSTRACT

PURPOSE: To evaluate components of the integrated ocular surface/lacrimal gland unit in a series of patients before and after undergoing bilateral laser in situ keratomileusis (LASIK).

DESIGN: Prospective, noncomparative case series. PARTICIPANTS: Forty-eight eyes of 14 men and 34 women (age range, 26-54; mean, 39.2 years) who underwent bilateral LASIK for myopia or myopic astigmatism.

METHODS: LASIK was performed using a VISX Star Excimer Laser (Santa Clara, CA). Patients completed a questionnaire containing 11 questions that evaluated the character and severity of ocular irritation symptoms. Snellen visual acuity, tear fluorescein clearance, corneal fluorescein staining, aqueous tear production by the Schirmer 1 test, and corneal and conjunctival sensitivity were measured in each eye. Corneal surface regularity (SRI) was evaluated with the Tomey TMS-1 (Tomey, Cambridge, MA) topography instrument. Each randomly chosen eye was evaluated 1 to 2 days (T0) before LASIK and 7 days (T1), 1 (T2), 2 (T3), 6 (T4), 12 (T5), and 16 (T6) months postoperatively. A Wilcoxon test, two-tailed paired t test, Friedman test, or analysis of variance were used for statistical comparisons.

MAIN OUTCOME MEASURES: Components of the integrated ocular surface/lacrimal gland unit. RESULTS: Both corneal and conjunctival sensitivity were noted to be significantly decreased from preoperative levels at 1week, 1 month, 12 months, and 16 months postoperatively (P < 0.0002 at each time point). Symptom severity scores were significantly increased at 1 week, 12 months, and 16 months postoperatively (P < 0.007 at all time points). The mean Schirmer 1 test scores were 24 +/- 14 mm preoperatively, and they decreased to 18 +/- 14 mm by 1 month postoperatively (P < 0.001). Tear fluorescein clearance showed a linear increase postoperatively and was significantly greater than baseline (P < 0.001) at each time point. There was a significant increase in punctate corneal fluorescein staining at 1 week postoperatively (P < 0.0001), but staining returned to baseline by 12 months. There was a statistically significant increase in SRI 1 week postoperatively (P < 0.007) with return to baseline levels by 6 months.

CONCLUSIONS: Sensory denervation of the ocular surface after bilateral LASIK disrupts ocular surface tear dynamics and causes irritation symptoms. Patients undergoing LASIK should be informed of these risks.

Eye Contact Lens. 2006 Mar;32(2):88-93.


Evaluation of Corneal Sensitivity to Mechanical and Chemical Stimuli After LASIK: A Pilot Study.

Stapleton F, Hayward KB, Bachand N, Trong PH, Teh DW, Deng KM, Yang EI, Kelly SL, Lette M, Robinson D.

From the Cornea and Contact Lens Research Unit (F.S., K.B.H., N.B., P.H.T., D.W.H.T., K.M.Y.D., E.I.H.Y.), School of Optometry and Vision Science and Vision Cooperative Research Centre, University of New South Wales, Sydney, Australia; and Sydney Laser and Vision Centre (S.L.K., M.L., D.R.), Bondi Junction, Australia.

PURPOSE.: To evaluate the effect of laser in situ keratomileusis (LASIK) on corneal sensitivity, nerve morphology, and tear film characteristics.

METHODS.: A cross-sectional study design was used. Eighteen patients (eight men and 10 women with a mean age of 36.9 +/- 11.2 years) who had undergone bilateral LASIK for low myopia within 18 months of the study and 28 control subjects (16 men and 12 women with a mean age of 27.2 +/- 7.7 years) were enrolled. Central and inferior corneal thresholds to mechanical (air) and chemical (air plus carbon dioxide) stimuli were determined by using a staircase technique. Stimuli of a 1-second duration at 34 degrees C were delivered with a CRCERT-Belmonte aesthesiometer. Images of subbasal nerves in the central cornea were captured with confocal microscopy. Nerve morphology was classified as no nerves, short nerves (<175 mum), or long nerves (>175 mum), with or without interconnections. Noninvasive tear break up time was measured. The phenol red thread test was used to indicate basal tear secretion. Differences between groups were evaluated with analysis of variance, and associations between variables were evaluated with parametric or nonparametric correlation, when appropriate.

RESULTS.: Central corneal mechanical sensitivity was significantly reduced in the post-LASIK group compared with the control subjects (P<0.001). Nerve morphology was associated with mechanical threshold. Nerve morphology, mechanical sensitivity, and tear breakup time improved during the first 1 to 3 months after surgery, with little change thereafter. Chemical sensitivity was associated with tear secretion (P<0.05).

CONCLUSIONS.: Central corneal mechanical sensitivity is reduced in patients after LASIK, with partial recovery seen 3 months after surgery. A similar recovery trend is seen for nerve morphology.

Am J Ophthalmol. 2006 Jun;141(6):1009-1015.e1.


Comparison of Corneal Nerve Regeneration and Sensitivity Between LASIK and Laser Epithelial Keratomileusis (LASEK).

Lee SJ, Kim JK, Seo KY, Kim EK, Lee HK.

Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.

PURPOSE: To compare changes in corneal nerve fibers and keratocyte density by confocal microscopy after laser-assisted in situ keratomileusis (LASIK) and laser epithelial keratomileusis (LASEK).

DESIGN: Prospective, nonrandomized comparative clinical trial.

METHODS: Fifty-six eyes of 28 patients who underwent LASIK and 52 eyes of 26 patients who underwent LASEK were included. Confocal microscopic data of the central cornea, corneal sensitivity, tear film breakup time, and Schirmer values were determined at three and six months after LASIK or LASEK treatment.

RESULTS: In the LASIK group, corneal sensitivity was reduced from preoperative levels at six months after surgery. In the LASEK group, however, there was no difference between baseline and six-month postoperative values. The number of subbasal nerve fibers and the keratocyte density were also different in the LASIK and LASEK groups. The regeneration of corneal nerves correlated strongly with the recovery of corneal sensation and keratocyte density in both groups, whereas the tear film breakup time, Schirmer values, and epithelial thickness did not correlate with corneal nerve regeneration in either group.

CONCLUSIONS: The greater decrease in the number of subbasal nerve fibers in the LASIK group compared with the LASEK group may relate to the greater decrease in corneal sensitivity. The pattern of corneal nerve regeneration and the recovery of corneal sensation after LASEK did not differ greatly from that after photorefractive keratectomy in previous studies.

Invest Ophthalmol Vis Sci. 2002 Dec;43(12):3660-4.

Reinnervation in the cornea after LASIK.Lee BH, McLaren JW, Erie JC, Hodge DO, Bourne WM.

Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.

PURPOSE: Nerve fibers in the cornea are disrupted by photorefractive procedures. In this study, the denervation and reinnervation of human central corneas were evaluated by sequential, quantitative measurements of nerves viewed by confocal microscopy in vivo during the first year after LASIK.

METHODS: Seventeen eyes were studied of 11 patients who had undergone LASIK to correct myopia from -2.0 D to -11.0 D. Eyes were treated with an excimer laser with a planned 180- micro m flap. Central corneas were scanned throughout their full thicknesses by confocal microscopy before and at 1 week and 1, 3, 6, and 12 months after LASIK. Nerve fiber bundles appeared as bright, well-defined, linear structures that were sometimes branched and usually appeared in several consecutive frames. The number of nerve fiber bundles per scan in two to eight scans per eye per visit was determined in the subbasal region, the full-thickness stroma, the stromal flap (layer between the most anterior keratocyte and the flap interface), and the stromal bed (layer between the flap interface and the endothelium).

RESULTS: In the subbasal region, the number of nerve fiber bundles decreased by more than 90% 1 week after LASIK and was significantly lower at all times after surgery than it was before surgery (P < 0.001). It increased 6 and 12 months after LASIK, but remained less than half of the preoperative value. In the stromal flap, the number of nerves at all times after surgery was also significantly less than before surgery (P < 0.001) and did not increase significantly by 1 year. In the stromal bed, there were no significant differences among any of the nerve measurements before and after LASIK (P = 0.24).

CONCLUSIONS: In the corneal flap, the number of subbasal and stromal nerve fiber bundles decreases by 90% immediately after LASIK. During the first year after LASIK, subbasal nerve fiber bundles gradually return, although by 1 year their number remains less than half of that before LASIK.

Trans Am Ophthalmol Soc. 2005;103:56-66; discussion 67-8.

Long-term corneal keratoctye deficits after photorefractive keratectomy and laser in situ keratomileusis.

Erie JC, McLaren JW, Hodge DO, Bourne WM.
Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

PURPOSE: To measure changes in keratocyte density up to 5 years after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK).

METHODS: This was a prospective, nonrandomized clinical trial. Eighteen eyes of 12 patients received PRK to correct a mean refractive error of -3.73 +/- 1.30 D, and 17 eyes of 11 patients received LASIK to correct a mean refractive error of -6.56 +/- 2.44 D. Corneas were examined by using confocal microscopy before and 6 months, 1 year, 2 years, 3 years, and 5 years after the procedures. Keratocyte densities were determined in five stromal layers in PRK patients and in six stromal layers in LASIK patients. Differences between preoperative and postoperative cell densities were compared by using Bonferroni-adjusted paired t tests.

RESULTS: After PRK, keratocyte density in the anterior stroma was decreased by 39%, 42%, 45%, and 47% at 6 months, 2 years, 3 years, and 5 years, respectively (P < .001). At 5 years, keratocyte density was decreased by 20% to 24% in the posterior stroma (P < .05). After LASIK, keratocyte density in the stromal flap was decreased by 22% at 6 months (P < .02) and 37% at 5 years (P < .005). Keratocyte density in the anterior retroablation zone was decreased 18% (P < .005) at 1 year and 43% (P < .005) at 5 years. At 5 years, keratocyte density was decreased by 19% to 22% (P < .05) in the posterior stroma.

CONCLUSIONS: Keratocyte density is decreased in the anterior stroma after PRK and in the stromal flap and the retroablation zone after LASIK for up to 5 years. Posterior stromal keratocyte deficits are first noted at 5 years.

From the full text:

Alternatively, a causal relationship between decreased keratocyte density and decreased innervation after LASIK has been hypothesized.11-13,22 Müller and coworkers23 documented direct innervation of keratocytes by stromal nerves. A normal stromal keratocyte population may depend on a normal density of corneal nerves. Transplanted corneas, for example, have both keratocyte24 and nerve deficits.22 We recently showed that subbasal nerves were still reduced 21% by 5 years after LASIK, although nerve densities were not significantly different from preoperative densities (Erie JC, et al, ARVO Meeting, 2005, E-abstract 4355). What effect, if any, a reconstituted nerve density has on future keratocyte densities is unknown. It is likely that the epithelium, stroma, and nerves all participate, to varying degrees, in the homeostasis of stromal keratocytes. Their eventual effect on keratocyte density after PRK and LASIK will require longer follow-up.
The clinical significance of a reduced keratocyte population after PRK and LASIK and its effect on the long-term health of the cornea is unknown.

Br J Ophthalmol. 2008 Jul 23. [Epub ahead of print]
Corneal recovery after LASIK for high myopia A 2-year prospective confocal microscopic study.
Moilanen JA, Holopainen JM, Vesaluoma MH, Tervo TM.
Department of Ophthalmology, Helsinki, Finland.

AIM: To quantify human corneal recovery after moderate to high myopic laser in situ keratomileusis (LASIK) in a two year prospective follow-up study.

METHODS: Fifteen eyes of 15 patients (mean refraction -10.1 +/- 2.4 D) were examined preoperatively and postoperatively at day 1, 5 days, 2 weeks, 1, 3 and 6 months and 2 years. Biomicroscopy, visual acuity and refraction were examined prior to imaging studies. An in vivo tandem scanning confocal microscope was used to obtain images from the central cornea. Subbasal nerve density was measured as the total length of nerve trunks in confocal image per mm2. Keratocyte density was calculated manually from stromal sublayers. The thickness of the altered keratocyte zone was measured on both sides of the LASIK interface.

RESULTS: At the end of the follow-up all patients had a 20/20 BCVA and nine of 15 patients were within +/-0.5 D of the intended correction. Total corneal thickness remained unaltered, but epithelial hyperplasia was seen at 2 years. Keratocyte density in the anterior stroma and posterior to the flap interface showed a slight decrease during the follow-up. Subbasal nerve density decreased 82 % in five days after LASIK. A gradual increase was observed from two weeks postoperatively, but even 2 years after the operation the nerve density was only 64 % from the preoperative values.

CONCLUSIONS: Subbasal nerve fiber density shows a gradual recovery throughout the follow-up. However, only three subjects showed totally regenerated subbasal nerve fibers at 2 years. This may correlate with the observed decrease in the density of the most anterior keratocytes. Corneal remodelling seemed to continue for at least 2 years.

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OSN SuperSite Breaking News 10/2/2008

Surgeons link nerve recovery to decrease in anterior keratocyte density after LASIK

Sub-basal nerve fiber density shows a gradual yet incomplete recovery that may be associated with a reduction in the density of the most anteriorly located keratocytes more than 2 years after LASIK, a prospective study found.

J. A. O. Moilanen, MD, and colleagues evaluated the 2-year effects of myopic LASIK on corneal thickness, keratocyte density and nerve recovery among 15 eyes of 15 patients with an average refractive error of –10.1 D at baseline. The investigators obtained visual acuity, refraction, biomicroscopy and in vivo confocal microscopy measurements for each patient at 1 and 5 days, 2 weeks, 1, 3 and 6 months and 2 years postoperatively.

At 2 years, all patients had achieved a best corrected visual acuity of 20/20, and nine patients had progressed to within ±0.5 D of intended correction.

Although the total corneal thickness had not changed, epithelial hyperplasia persisted for the duration of follow-up, investigators found.

The density of keratocytes in the anterior stroma and posterior to the flap decreased slightly over follow-up; however, the investigators observed no such reductions in mid-stromal or posterior keratocytes.

Although sub-basal nerve density had decreased 82% at 5-day postop, nerve density was only 64% of the preoperative value at 2 years, according to the study, published in the October issue of British Journal of Ophthalmology.

Eye Contact Lens. 2008 Nov;34(6):322-5.
Corneal subbasal nerve density: a comparison of two confocal microscopes.
Erie EA, McLaren JW, Kittleson KM, Patel SV, Erie JC, Bourne WM.
From the Department of Ophthalmology, Mayo Clinic, Rochester, MN.

PURPOSE.: To compare subbasal nerve densities estimated from images recorded by the tandem scanning and the ConfoScan 4 confocal microscopes.

METHODS.: Confocal microscopy was used to estimate subbasal nerve density in 62 corneas of 40 subjects (18 corneas of 18 normal subjects and 44 corneas of 22 patients between 1 and 12 months after LASIK). At each examination, corneas were scanned first by using tandem scanning and then by using a ConfoScan 4 confocal microscope. Subbasal nerves from 2 to 4 scans per cornea were traced by using a semi-automated nerve analysis program. Nerve density was expressed as total nerve length divided by the sample area (mum/mm). Differences in nerve density between instruments were examined by using paired tests.

RESULTS.: In normal corneas, subbasal nerve density was 10,658 +/- 5,581 mum/mm (mean +/- SD) with the ConfoScan 4 and 5,534 +/- 1,850 mum/mm with the tandem scanning microscope (P<0.0001). One to 12 months after LASIK, mean subbasal nerve density was 2,477 +/- 3,514 mum/mm estimated with the ConfoScan 4 and 844 +/- 983 mum/mm estimated with the tandem scanning (P =0.0003). Estimates of nerve density were correlated between instruments (r = 0.71, P<0.0001), although the mean difference between instruments was 2,308 +/- 3,885 mum/mm (P<0.0001).

CONCLUSIONS.: Mean subbasal nerve density estimated with the ConfoScan 4 was 2 to 3 times higher than density estimated with the tandem scanning confocal microscope. These differences must be considered when comparing subbasal nerve densities between studies that use different confocal microscopes.

Oliver Stachs, PhD; Andrey Zhivov, MD; Robert Kraak, MD; Marine Hovakimyan, PhD; Andreas Wree, MD and Rudolf Guthoff, MD. Structural-functional Correlations of Corneal Innervation After LASIK and Penetrating Keratoplasty. Journal of Refractive Surgery Vol. 26 No. 3 March 2010

Excerpts:

Although two-dimensional mapping after LASIK was achieved only with reduced quality, none of the patients showed a whorl-shaped [normal] pattern of the subbasal nerve plexus. Nevertheless, morphological changes in nerves were found. One week after LASIK, no nerve fibers were found at all, and only very thin nerve fibers were present 1 month after surgery. In 9 of 10 eyes, the subbasal nerve plexus was present in the central flap zone and corneal sensitivity was positive in these corneas. During follow-up, the number of nerves returned to near-normal. However, nerve fibers were mostly non-branching and intensively curved.

Degeneration of nerve structures, characterized by thinning or even complete absence of subbasal nerve fibers, is visible in the flap area just a few hours after LASIK. The subbasal nerve plexus was not detectable 1 week after LASIK, although the first very thin nerve fibers were visualized 1 month after the procedure. Although the subbasal nerve plexus incorporating parallel and branched fibers began to be visualized 1 year postoperatively, complete physiological reinnervation was not seen up to 2 years after LASIK. The whorl-shaped [normal] configuration of the subbasal nerve plexus was not detected in any patient. In most cases, the subbasal nerve fibers recovered to a near-normal state but abnormal curved or thin and non-branching subbasal nerves were found in all corneas. Subbasal nerve density after LASIK has been reported to be reduced by 51%, 35%, and 34% at 1, 2, and 3 years, respectively. The same investigators showed that after 5 years of follow-up, subbasal nerve density was not significantly different from that before LASIK. Examination of subbasal nerves after LASIK has also shown the presence of elongated nerve fibers by 3 months postoperatively, but interconnections were not observed before 6 months. A significant decrease in mean corneal sensation has been demonstrated 1 week postoperatively. In the present study, corneal sensation was shown to recover after a few months, and this finding is consistent with other published results indicating that sensation in the central cornea is again comparable to preoperative values 3 or 6 months after LASIK. Corneal sensation also recovers to normal levels in patients with low and high myopia after 3 and 6 months, respectively. However, shorter (3 weeks) and longer (9.3 months) time periods to sensation recovery after LASIK have also been reported. Normal levels of sensation in the central cornea are considered to be >50 mm, and our findings further demonstrate that corneal sensation plateaus at 12 months postoperatively when it reaches 90% to 100% of esthesiometry values measured in normal corneas, although at earlier time points corneal sensation is markedly lower. A positive correlation has been reported between subbasal nerve morphology and corneal sensation. Nevertheless, normal sensation does not always depend on normal corneal nerve anatomy. This may be due to folding of Bowman’s layer, to smaller nerve thickness compared to healthy individuals, and to the fact that the regenerated nerves do not run exactly parallel to Bowman’s layer.