Recovery Of Corneal Sensation Research Articles

Corneal Reinnervation in Patients With Severe Neurotrophic Keratopathy Secondary to Herpes Zoster Ophthalmicus After Treatment With Autologous Serum Tear Drops

Purpose: The purpose of this study was to assess potential corneal reinnervation and recovery of corneal sensation in patients with severe neurotrophic keratopathy (NK) secondary to herpes zoster ophthalmicus (HZO) after treatment with topical autologous serum tears (AST). Method: Four cases of HZO with severe NK were followed clinically and by serial laser in vivo confocal microscopy (IVCM, HRT3/RCM, Heidelberg Engineering GmbH) before and during treatment with 20% AST drops 8 times a day. Two masked observers reviewed the IVCM images and assessed corneal nerve alterations. Results: At baseline, all patients had complete loss of corneal sensation. In addition, IVCM showed complete lack of the subbasal corneal nerve plexus in all patients. All 4 patients were refractory to conventional therapies and were treated with AST drops. All patients demonstrated significant nerve regeneration by IVCM within 3 to 7 months of treatment. The total nerve density increased to a mean ± SEM of 10,085.88 ± 2,542.74 μm/mm2 at the last follow-up. Corneal sensation measured by Cochet–Bonnet esthesiometry improved to a mean ± SEM of 3.50 ± 1.30 cm. Interestingly, 3 of 4 patients developed stromal keratitis with stromal thinning within weeks of corneal reinnervation, which was reversed by adding topical steroids. Conclusions: Autologous serum tears are effective in restoring corneal subbasal nerves and sensation in patients with severe NK secondary to HZO. However, this group of patients may require concurrent topical immunomodulation and antiviral therapy while on AST to prevent stromal keratitis.

Collagen analogs with phosphorylcholine are inflammation-suppressing scaffolds for corneal regeneration from alkali burns in mini-pigs

The long-term survival of biomaterial implants is often hampered by surgery-induced inflammation that can lead to graft failure. Considering that most corneas receiving grafts are either pathological or inflamed before implantation, the risk of rejection is heightened. Here, we show that bioengineered, fully synthetic, and robust corneal implants can be manufactured from a collagen analog (collagen-like peptide-polyethylene glycol hybrid, CLP-PEG) and inflammation-suppressing polymeric 2-methacryloyloxyethyl phosphorylcholine (MPC) when stabilized with the triazine-based crosslinker 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The resulting CLP-PEG-MPC implants led to reduced corneal swelling, haze, and neovascularization in comparison to CLP-PEG only implants when grafted into a mini-pig cornea alkali burn model of inflammation over 12 months. Implants incorporating MPC allowed for faster nerve regeneration and recovery of corneal sensation. CLP-PEG-MPC implants appear to be at a more advanced stage of regeneration than the CLP-PEG only implants, as evidenced by the presence of higher amounts of cornea-specific type V collagen, and a corresponding decrease in the presence of extracellular vesicles and exosomes in the corneal stroma, in keeping with the amounts present in healthy, unoperated corneas.

Ciclosporin A in ophthalmology: A systematic review

Aim: To systematically analyse data from randomized controlled trials of topical Ciclosporin with the aim of assessing the uses and effectiveness of Ciclosporin in different conditions, optimal dosage and adverse effect profile. Methods: 24 RCTs that had evaluated the uses and efficacy of Ciclosporin in different ocular conditions were selected and were used in this review. Articles published upto December 2018 were identified from the following sources- Medline, Scopus, Web of science and references from relevant articles. Results: The average JADAD score was 3.16. Symptomatic relief and objective improvement of ocular signs were noted in most cases of allergic eye disease, moderate to severe dry eye disease and lid margin inflammatory disease. It was also found to accelerate post surgical corneal nerve healing and recovery of corneal sensation. It was not effective in post keratoplasty graft rejection. Adverse effects reported were minimal and included symptoms like ocular stinging. Conclusions: Even though topical Ciclosporin A is an attractive treatment option in many ocular conditions, more structured RCTs are needed to standardize the dose and provide a detailed adverse effect profile.

Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice.

Corneal nerves are mainly derived from the ophthalmic branch of the trigeminal ganglion (TG). Corneal neuropathy contributes to epithelial degenerative changes in diabetic keratopathy. Efficient drug delivery to TG may be beneficial for the treatment of diabetic keratopathy. This article described intranasal delivery of nanomicelle curcumin to correct pathophysiological conditions in TG to promote corneal epithelial/nerve wound healing in streptozotocin-induced diabetic mice. A diabetic mice model with corneal epithelium abrasion was established. Ocular topical and/or intranasal nanomicelle curcumin treatments were performed, and treatment efficacy and mechanisms of action were explored. Results showed that intranasal nanomicelle curcumin treatment promoted corneal epithelial wound healing and recovery of corneal sensation. Enhanced accumulation of reactive oxygen species, reduced free radical scavengers, increased mRNA expressions of inflammatory cytokines, and decreased mRNA expressions of neurotrophic factors in the cornea and TG neuron were observed in diabetic mice with corneal epithelium abrasions. Intranasal nanomicelle curcumin treatment effectively recovered these pathophysiological conditions, especially that of the TG neuron, and a strengthened recovery was observed with ocular topical combined with intranasal treatment. These findings indicated that intranasal curcumin treatment effectively helped promote diabetic corneal epithelial/nerve wound healing. This novel treatment might be a promising strengthened therapy for diabetic keratopathy.

Degeneration and regeneration of corneal nerves in response to HSV-1 infection.

Herpes simplex virus type 1 (HSV-1) infection is one cause of neurotrophic keratitis, characterized by decreases in corneal sensation, blink reflex, and tear secretion as consequence of damage to the sensory fibers innervating the cornea. Our aim was to characterize changes in the corneal nerve network and its function in response to HSV-1 infection. C57BL/6J mice were infected with HSV-1 or left uninfected. Corneas were harvested at predetermined times post infection (pi) and assessed for β III tubulin, substance P, calcitonin gene-related peptide, and neurofilament H staining by immunohistochemistry (IHC). Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. Expression of genes associated with nerve repair was determined in corneas by real time RT-PCR, Western blotting, and IHC. Semaphorin 7A (SEMA 7A) neutralizing antibody or isotype control was subconjunctivally administered to infected mice. The area of cornea occupied by β III tubulin immunoreactivity and sensitivity significantly decreased by day 8 pi. Modified reinnervation was observed by day 30 pi without recovery of corneal sensation. Sensory fibers were lost by day 8 pi and were still absent or abnormal at day 30 pi. Expression of SEMA 7A increased at day 8 pi, localizing to corneal epithelial cells. Neutralization of SEMA 7A resulted in defective reinnervation and lower corneal sensitivity. Corneal sensory nerves were lost, consistent with loss of corneal sensation at day 8 pi. At day 30 pi, the cornea reinnervated but without recovering the normal arrangement of its fibers or function. SEMA 7A expression was increased at day 8pi, likely as part of a nerve regeneration mechanism.

Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor.

Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose-treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied by attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt, epidermal growth factor receptor (EGFR), and Sirt1 activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted epithelial wound healing, recovery of corneal sensation, improvement of mitochondrial function, and reactivation of Akt, EGFR, and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose-treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a neurokinin-1 (NK-1) receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 receptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.

Effect of Macrophage Migration Inhibitory Factor on Corneal Sensitivity after Laser In Situ Keratomileusis in Rabbit

PurposeTo investigate the effect of macrophage migration inhibitory factor (MIF) on corneal sensitivity after laser in situ keratomileusis (LASIK) surgery.MethodsNew Zealand white rabbits were used in this study. A hinged corneal flap (160-µm thick) was created with a microkeratome, and -3.0 diopter excimer laser ablation was performed. Expressions of MIF mRNA in the corneal epithelial cells and surrounding inflammatory cells were analyzed using reverse transcription polymerase chain reaction at 48 hours after LASIK. After LASIK surgery, the rabbits were topically given either 1) a balanced salt solution (BSS), 2) MIF (100 ng/mL) alone, or 3) a combination of nerve growth factor (NGF, 100 ug/mL), neurotrophine-3 (NT-3, 100 ng/mL), interleukin-6 (IL-6, 5 ng/mL), and leukemia inhibitory factor (LIF, 5 ng/mL) four times a day for three days. Preoperative and postoperative corneal sensitivity at two weeks and at 10 weeks were assessed using the Cochet-Bonnet esthesiometer.ResultsExpression of MIF mRNA was 2.5-fold upregulated in the corneal epithelium and 1.5-fold upregulated in the surrounding inflammatory cells as compared with the control eyes. Preoperative baseline corneal sensitivity was 40.56 ± 2.36 mm. At two weeks after LASIK, corneal sensitivity was 9.17 ± 5.57 mm in the BSS treated group, 21.92 ± 2.44 mm in the MIF treated group, and 22.42 ± 1.59 mm in the neuronal growth factors-treated group (MIF vs. BSS, p < 0.0001; neuronal growth factors vs. BSS, p < 0.0001; MIF vs. neuronal growth factors, p = 0.815). At 10 weeks after LASIK, corneal sensitivity was 15.00 ± 9.65, 35.00 ± 5.48, and 29.58 ± 4.31 mm respectively (MIF vs. BSS, p = 0.0001; neuronal growth factors vs. BSS, p = 0.002; MIF vs. neuronal growth factors, p = 0.192). Treatment with MIF alone could achieve as much of an effect on recovery of corneal sensation as treatment with combination of NGF, NT-3, IL-6, and LIF.ConclusionsTopically administered MIF plays a significant role in the early recovery of corneal sensitivity after LASIK in the experimental animal model.

The effect of recombinant bovine basic fibroblast growth factor on the LASIK-induced neurotrophic epitheliopathy and the recovery of corneal sensation after LASIK

To observe the effects of recombinant bovine basic fibroblast growth factor (r-bFGF) on the LASIK-induced neurotrophic epitheliopathy (LINE) and the recovery of corneal sensation after LASIK. Prospective clinical study. LINE was found in 60 patients out of 1154 cases of LASIK (5.2%). The 60 cases were randomly divided into three groups, each group including 20 cases. Group A was treated with r-bFGF eye drops (fusion protein), four times a day. Group B was treated with r-bFGF eye-gel, four times a day. Group C was treated with 0.1% sodium hyaluronate eye drops as a control. The treatment started since LINE was diagnosed. The typical clinical finding of LINE was punctate corneal erosion, which could be evaluated by slit-lamp examination and fluorescein staining. Masked Cochet-Bonnet esthesiometer was performed in the central cornea one week preoperatively and 1, 3, 6 and 12 months postoperatively. (1) The average times of corneal erosion occurrence were (28.57 ± 37.48) d, (30.82 ± 35.08) d and (16.84 ± 23.70) d in group A, group B and group C respectively. No significant differences were observed among the three groups (F = 1.456, P = 0.238), and the average times of corneal erosion disappearance were (7.19 ± 8.23) d, (2.86 ± 1.73) d and (7.00 ± 6.40) d in group A, group B and group C, respectively. The punctate corneal erosion cured significantly faster in r-bFGF eye-gel treated group (P(1) = 0.007, P(2) = 0.014). (2)The loss of corneal sensation was greatest at 1 week after LASIK in all the three groups and improved at all subsequent examination time points. The corneal sensation gradually recovered through 12 months observation, but the r-bFGF eye-gel treated group showed faster recovery in comparison with the other two groups, had no statistic different at 6 month compared with pre-operation values (F = 0.55, P = 0.064). The r-bFGF eye-gel is effective for both punctate corneal erosion (especially for severe LINE) and recovery of corneal sensation following LASIK surgery.

Recovery of corneal sensitivity in extremely high myopia after laser sub-epithelium keratomileusis

To evaluate the changes in corneal sensitivity following laser epithelial keratomileusis (LASEK) and epiploic laser in situ keratomileusis (Epi-LASIK) in treatment of extremely high myopia. Thirty-seven eyes of 37 patients underwent LASEK and Epi-LASIK to correct myopia, their equivalent sphere ranged from -9.50 DS to -12.50 DS, astigmatism < +/- 1.50 DC. Cornea sensitivity was measured with a Cochet-Bonnet esthesiometer at central part of the cornea. Treated eyes were divided into two groups by different operation methods: Epi-LASIK group and LASEK group. After the operation, each group was divided into two sub-groups according to the eyes with or without obvious epithelium edema. Obvious epithelium sheet edema happened in 6 eyes after LASEK and 3 eyes among them were due to broken epithelium sheets during the operation. By 2 weeks, 1, 2, 3 and 6 months after Epi-LASIK, corneal sensitivity recovered to 79.31%, 84.49%, 87.92%, 92.24% and 93.98% of preoperative level, respectively. Compare to the Epi-LASIK, cornea sensitivity after LASEK recovered to 69.64%, 78.57%, 83.21%, 85.70% and 87.86% of preoperative level, respectively. The recovery of corneal sensation in LASEK group was slower than that of Epi-LASIK group. The difference between these two groups was statistically significant at 2 weeks after the operation (P < 0.05). In LASEK group, there was a trend towards a great reduction in corneal sensitivity in epithelium edema eyes and the recovery was slower in these eyes. The difference of corneal sensitivity recovery between these two sub-groups was statistically significant (P < 0.05). The recovery of corneal sensitivity in extremely high myopia after Epi-LASIK is faster than that after LASEK, and reached to the platform stage by 3 months. The epithelium sheet edema after LASEK affects corneal sensitivity recovery.

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

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). Prospective, nonrandomized comparative clinical trial. 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. 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. 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.

Femtosecond laser versus mechanical keratome flaps in wavefront-guided laser in situ keratomileusis

To compare the outcomes of wavefront-guided laser in situ keratomileusis (LASIK) performed using the IntraLase femtosecond laser with the outcomes using the Hansatome mechanical microkeratome. Private clinic, Overland Park, Kansas, USA. In a prospective contralateral-eye study performed under institutional review board supervision, 51 consecutive patients (102 eyes) had bilateral wavefront-guided LASIK for myopia using the Alcon LADARVision laser. One eye of each patient was randomized to have the flap created with the IntraLase femtosecond laser and the other flap using a standard compression head Hansatome microkeratome. All other treatment parameters were the same. The IntraLase group had significantly better mean uncorrected visual acuity (UCVA) at all intervals from 1 day to 3 months postoperatively. The mean spheroequivalent at 3 months was more myopic with the Hansatome (-0.34 diopter [D] +/- 0.28 [SD]) than with the IntraLase (-0.19 +/- 0.24 D) (P<.01). The mean residual astigmatism at 3 months was also significantly higher in the Hansatome group than in the IntraLase group (0.32 +/- 0.25 D and 0.17 +/- 0.20 D, respectively) (P<.01). The differences in UCVA persisted after spheroequivalent outcomes were controlled for but equilibrated when the analysis was modified to control for manifest postoperative astigmatism. Aberrometry showed significantly higher astigmatism and trefoil in the Hansatome group. Recovery of corneal sensation and epithelial integrity was similar between groups. The statistically better UCVA and manifest refractive outcomes after LASIK with the IntraLase femtosecond laser may be the result of differences in postoperative astigmatism and trefoil. These findings are consistent with previous findings of better astigmatic outcomes with the IntraLase laser and may have clinical significance for wavefront-guided treatments.

Recovery of corneal sensation after myopic correction by laser in situ keratomileusis with a nasal or superior hinge

The authors measured corneal sensation with a Cochet-Bonnet esthesiometer in 75 patients before and 1, 3, 6, and 12 months after photorefractive keratectomy (21 patients) and laser in-situ keratomileusis (LASIK) with nasal (21 patients) and superior (33 patients) hinges. There was no statistically significant change in corneal sensation following photo refractive keratectomy. Following LASIK, corneal sensation was significantly decreased at 1 and 3 months (P < .05) but not at 6 and 12 months when compared with preoperative values. Corneal sensitivity was in the normal range in 31.5% of LASIK patients at 3 months, in 57.4% at 6 months, and in 82.1% at 12 months. A significantly greater decrease in corneal sensation occurred with a nasal hinge than a superior hinge (P < .01). The authors conclude that recovery of corneal sensation had begun 3 months after LASIK and was complete by 12 months. The reason for greater reduction of corneal sensation with a superior hinge than a nasal hinge is unclear and requires further investigation.—Michael D. Wagoner