Corneal Denervation Research Articles

Sublimbal orbital fat transposition in neurotrophic keratopathy: a case series

Neurotrophic keratopathy is a progressive condition resulting from corneal denervation, leading to the development and persistence of corneal ulcers. Among the pathogenetic treatment methods there are corneal neurotization, a technically challenging approach associated with a prolonged rehabilitation period, and the usage of recombinant human nerve growth factor (cenegermin), which is practically inaccessible due to its high cost and lack of registration in Russian Federation. We propose a technique of orbital fat transposition to the sclerocorneal pocket for the treatment of persistent ulcers associated with neurotrophic keratopathy. This method is based on neuronal embryology of orbital adipose tissue, as well as the abundance of neurotrophic factors and stem cells. This method was applied to three patients with different etiologies of neurotrophic keratopathy, reaching the observation endpoint in two months after the operation. Visual acuity was ranging from 0.005 to 0.01. All patients received standard therapy for 1–2 months without significant improvement. Surgery was then performed using the proposed technique, which involves repositioning the medial and central orbital fat pads into the sclerocorneal pocket. In the postoperative period, partial epithelialization was observed in all patients during the first week, followed by complete healing and scar formation. The maximum visual acuity in 2 months ranged from 0.06 to 0.3.

CGRP Released by Corneal Sensory Nerve Maintains Tear Secretion of the Lacrimal Gland.

This study aims to elucidate the calcitonin gene-related peptide (CGRP) mediation and primary mechanism of corneal sensory nerves on tear production of the lacrimal gland. Mouse corneal denervation models were constructed through surgical axotomy, pharmacologic treatment with capsaicin or resiniferatoxin, and Trpv1-Cre/DTR mice with diphtheria toxin injection. The capsaicin-treated mice received subconjunctival injection of CGRP or substance P, while the normal C57BL/6J mice were administered with CGRP receptor antagonist BIBN-4096. Furthermore, double immunostaining of c-FOS+ and choline acetyltransferase was used to evaluate the activation of the superior salivatory nucleus (SSN). Mouse lacrimal glands were collected for transcriptomic sequencing and subsequent RNA and protein expression analysis. The corneal denervated mice exhibited a significant reduction in corneal sensitivity and tear secretion. In capsaicin-treated mice, tear secretion decreased to 2.5 ± 0.5mm compared to 6.3 ± 0.9mm in control mice (P < 0.0001). However, exogenous administration of CGRP in capsaicin-treated mice increased tear secretion from 2.6 ± 0.5mm to 4.5 ± 0.5mm (P = 0.0009), while BIBN-4096 treatment reduced tear secretion to 3.4 ± 0.5mm when compared to 7.3 ± 0.7mm in control mice (P = 0.0022). Furthermore, c-FOS+ cell number in the SSN increased by twofold (P = 0.0168) after CGRP administration compared with capsaicin-treated mice. In addition, the expressions of CCNA2, Ki67, PCNA, and CDK1 in acinar cells of the lacrimal gland were impaired by corneal denervation and alleviated by CGRP administration. CGRP released by corneal sensory nerves mediates tear secretion of the lacrimal gland, providing a new strategy for improving tear secretion in patients with neurotrophic keratitis.

Insights on the Choice and Preparation of the Donor Nerve in Corneal Neurotization for Neurotrophic Keratopathy: A Narrative Review.

The article introduces neurotrophic keratopathy (NK), a condition resulting from corneal denervation due to various causes of trigeminal nerve dysfunctions. Surgical techniques for corneal neurotization (CN) have evolved, aiming to restore corneal sensitivity. Initially proposed in 1972, modern approaches offer less invasive options. CN can be performed through a direct approach (DCN) directly suturing a sensitive nerve to the affected cornea or indirectly (ICN) through a nerve auto/allograft. Surgical success relies on meticulous donor nerve selection and preparation, often involving multidisciplinary teams. A PubMed research and review of the relevant literature was conducted regarding the surgical approach, emphasizing surgical techniques and the choice of the donor nerve. The latter considers factors like sensory integrity and proximity to the cornea. The most used are the contralateral or ipsilateral supratrochlear (STN), and the supraorbital (SON) and great auricular (GAN) nerves. Regarding the choice of grafts, the most used in the literature are the sural (SN), the lateral antebrachial cutaneous nerve (LABCN), and the GAN nerves. Another promising option is represented by allografts (acellularized nerves from cadavers). The significance of sensory recovery and factors influencing surgical outcomes, including nerve caliber matching and axonal regeneration, are discussed. Future directions emphasize less invasive techniques and the potential of acellular nerve allografts. In conclusion, CN represents a promising avenue in the treatment of NK, offering tailored approaches based on patient history and surgical expertise, with new emerging techniques warranting further exploration through basic science refinements and clinical trials.

Establishing a Mouse Model of Chlorpromazine-Induced Corneal Trigeminal Denervation.

This study aimed to establish a mouse model of chlorpromazine-induced corneal trigeminal denervation (CCTD). Retrobulbar chlorpromazine injections were administered to 6- to 8-week-old C57BL/6j mice to induce corneal denervation. Additionally, apoptosis was assessed in isolated primary trigeminal ganglion cells after culturing in a conditioned medium containing chlorpromazine. Finally, the success rate of model generation, mortality and complication rates, and model-preparation learning curves were compared between the CCTD model and the electrocoagulation and axotomy models. Chlorpromazine retrobulbar injections resulted in trigeminal denervation, leading to a reduced blink reflex, corneal nerve density, and corneal epithelium thickness. Furthermore, 90% (9/10) of the mice developed epithelial defects, accompanied by increased apoptosis and inhibited proliferation of corneal epithelial cells. In vitro, trigeminal ganglion cell apoptosis increased after culturing in a conditioned medium containing chlorpromazine. Moreover, the CCTD model exhibited a higher success rate, longer survival rate, and lower complication rate compared to the electrocoagulation and axotomy models. Crucially, the learning curve demonstrated that the method used to generate the CCTD model was easy to learn. The CCTD model is a user-friendly mouse model for studying corneal trigeminal denervation that offers a less invasive alternative to existing models. The CCTD model serves as a valuable tool for investigating the functional mechanisms of corneal trigeminal nerves and their interactions with corneal cells.

Effective optical zone following small incision lenticule extraction: a review.

Small incision lenticule extraction (SMILE) is a "flapless" keratorefractive surgery with excellent safety, efficacy, stability, and predictability for myopia correction. A recent global multicenter study also reported good refractive outcomes for hyperopic SMILE. SMILE has shown advantages including improved biomechanical strength, fewer dry eye symptoms, less corneal denervation, and fewer surgery-induced higher-order aberrations over laser in situ keratomileusis (LASIK). However, night vision complaints, including glare, halos, and starbursts, could still occur after SMILE. These symptoms have been proven to be closely related to the effective optical zone (EOZ), which is defined as the achieved area of corneal ablation. A larger postoperative EOZ may indicate better visual quality, making EOZ an important safety parameter for keratorefractive surgeries. As SMILE has gained wider application globally, the EOZ following SMILE has also been increasingly studied in the field of refractive surgery. This review provides an update on topics related to the EOZ after SMILE, including its measurement and influencing factors, aiming to benefit the personalization of the surgical algorithm and ultimately improve the visual quality after the SMILE procedure.

Impact of corrected refractive power on the corneal denervation and ocular surface in small-incision lenticule extraction and LASIK.

To evaluate the impact of corrected refractive power on the corneal denervation and ocular surface in small-incision lenticule extraction (SMILE) and laser in situ keratomileusis (LASIK). Singapore National Eye Center, Singapore. Prospective study. 88 eyes undergoing SMILE or LASIK were divided into low-moderate (manifest refractive spherical equivalent [MRSE] <-6.0 diopters [D]) and high myopic (MRSE ≥-6.0 D) groups. In vivo confocal microscopy and clinical assessments were performed preoperatively and at 1 month, 3 months, 6 months, and 12 months postoperatively. In SMILE, high myopic treatment presented with significantly greater reduction in the corneal nerve fiber area (CNFA) and nerve fiber fractal dimension (CFracDim) compared with low-moderate myopic treatment (both P < .05). There was a significant and negative correlation between the corrected MRSE and the reduction in corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length, CNFA, and CFracDim after SMILE (r = -0.38 to -0.66, all P < .05). In LASIK, a significant correlation between the MRSE and the changes in CNBD, corneal nerve fiber total branch density, CNFA (r = -0.37 to -0.41), and corneal nerve fiber width (r = 0.43) was observed (all P < .05). Compared with SMILE, LASIK had greater reduction in CNBD and CNFA for every diopter increase in the corrected MRSE. High myopic SMILE, compared with low-moderate myopic SMILE, resulted in significantly lower tear break-up time at 1 and 6 months (both P < .05). The changes in CNFA and CFracDim were significantly associated with Schirmer test values (both P < .001). Postoperative corneal denervation was related to corrected refractive power in both SMILE and LASIK. With the same refractive correction, LASIK led to more prominent corneal denervation.

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy.

Neurotrophic keratopathy is a persistent defect of the corneal epithelium, with or without stromal ulceration, due to corneal nerve deficiency caused by a variety of etiologies. The treatment options for neurotrophic keratopathy are limited. In this study, an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor (CTH-mNGF). Its effectiveness was evaluated in corneal denervation (CD) mice and patients with neurotrophic keratopathy. In the preclinical setting, CTH-mNGF was assessed in a murine corneal denervation model. CTH-mNGF was transparent, thermosensitive, and ensured sustained release of mNGF for over 20 hours on the ocular surface, maintaining the local mNGF concentration around 1300 pg/mL in vivo. Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice. A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy. Patients received topical CTH-mNGF twice daily for 8 weeks. Fluorescein sodium images, Schirmer's test, intraocular pressure, Cochet-Bonnet corneal perception test, and best corrected visual acuity were evaluated. In total, six patients (total of seven eyes) diagnosed with neurotrophic keratopathy were enrolled. After 8 weeks of CTH-mNGF treatment, all participants showed a decreased area of corneal epithelial defect, as stained by fluorescence. Overall, six out of seven eyes had fluorescence staining scores < 5. Moreover, best corrected visual acuity, intraocular pressure, Schirmer's test and Cochet-Bonnet corneal perception test results showed no significant improvement. An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes. This study demonstrates that CTH-mNGF is transparent, thermosensitive, and has sustained-release properties. Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy, being convenient and cost effective.

Schwann Cells Are Key Regulators of Corneal Epithelial Renewal.

Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration. This study defines the critical role of the corneal axon-ensheathing SCs in homeostatic and regenerative corneal epithelial cell renewal. SC localization in the cornea was determined by in situ hybridization and immunohistochemistry with SC markers. In vivo SC visualization and/or ablation were performed in mice with inducible corneal SC-specific expression of tdTomato and/or Diphtheria toxin, respectively. The relative locations of SCs and LSCs were observed with immunohistochemical analysis of harvested genetically SC-prelabeled mouse corneas with LSC-specific antibodies. The correlation between cornea-innervating axons and the appearance of SCs was ascertained using corneal denervation in rats. To determine the limbal niche cellular composition and gene expression changes associated with innervation-dependent epithelial renewal, single-cell RNA sequencing (scRNA-seq) of dissociated healthy, de-epithelized, and denervated cornea limbi was performed. We observed limbal enrichment of corneal axon-associated myelinating and non-myelinating SCs. Induced local genetic ablation of SCs, although leaving corneal sensory innervation intact, markedly inhibited corneal epithelial renewal. scRNA-seq analysis (1) highlighted the transcriptional heterogenicity of cells populating the limbal niche, and (2) identified transcriptional changes associated with corneal innervation and during wound healing that model potential regulatory paracrine interactions between SCs and LSCs. Limbal SCs are required for innervation-dependent corneal epithelial renewal.

Fibromyalgia syndrome and the eye-Implications in corneal ultrastructure on confocal microscopy.

Fibromyalgia is a chronic systemic disorder associated with varied manifestations ranging from fatigue, sleep disturbances, headaches, muscular pain, cognitive issues, or even without symptoms. It is also known to be associated with chronic neuropathic pain.[1,2] Ocular features described include severe pain, necrotizing scleritis, and changes in optic disc perfusion.[3] Small fiber neuropathy and dysautonomia symptoms correlate with corneal denervation more commonly in women with fibromyalgia. These nerve plexus features were found to be associated with neuropathic pain and fibromyalgia in previous studies.[4] These patients have a higher incidence of dry eye disease as compared to the normal population.[5,6] Approximately 50% of patients with fibromyalgia have damage to small unmyelinated nerve fibers around the body.[7] Small fiber polyneuropathy may cause symptoms sometimes identified as fibromyalgia.[8] A skin punch biopsy is a sensitive and specific test that demonstrates the reduction in nerve fiber density associated with small fiber neuropathy. In vivo confocal microscopy (IVCM) is a noninvasive tool that can demonstrate nerve-related changes in the cornea and hence serve as an adjunct to skin biopsy for diagnosis and evaluation of the disease.[9] This photoessay highlights the nerve-related changes and the presence of microneuromas in the cornea and the use of IVCM in aiding in the diagnosis and management of these patients. Case Reports Three patients previously diagnosed with fibromyalgia presented with ocular pain and mild mixed dry eye. IVCM showed decreased corneal nerve fiber branching density with microneuromas in the cornea [Fig. 1]. They were on systemic therapy for chronic pain and their ocular condition was managed with topical anti-inflammatory and lubricating eye drops. These patients can be at a risk for postoperative dry eye and wound-healing complications and should be evaluated in detail preoperatively to avoid this.Figure 1: (a, b, and c) show microneuromas in the subbasal nerve plexus on IVCM of all three patients with fibromyalgia and dry eye. Figure d shows reduced nerve density, e shows altered nerve morphology and f shows the image used for the calculation of nerve density using the CCMetrics softwareFinancial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Corneal nerve changes in herpes zoster ophthalmicus: a prospective longitudinal in vivo confocal microscopy study.

To study the changes in corneal nerves and corneal sensitivity over a 6-month period in patients with herpes zoster ophthalmicus (HZO) compared with healthy subjects. This was a prospective longitudinal study on patients with newly diagnosed HZO. In vivo confocal microscopy (IVCM) corneal nerve parameters and corneal sensitivity were measured and compared between eyes with HZO, contralateral eyes and controls at baseline, 2 and 6 months. Fifteen subjects with HZO and 15 healthy age and sex matched controls were recruited. HZO eyes revealed a reduction in corneal nerve branch density (CNBD) from baseline to 2 months (9.65 ± 5.75 vs. 5.90 ± 6.87/mm2, p = 0.018), and decreased corneal nerve fibre density (CNFD) at 2 months when compared with control (p = 0.025). However, these differences resolved by 6 months. HZO fellow eyes demonstrated increased corneal nerve fibre area (CNFA), corneal nerve fibre width (CNFW) and corneal nerve fractal dimension (CNFrD) at 2 months compared with baseline (p = 0.025, 0.031, 0.009). There was no change in corneal sensitivity for both HZO affected and HZO fellow eyes from baseline or over time, nor was it different from sensitivity in controls. Corneal denervation was present at 2 months in HZO eyes, with an observed recovery by 6 months. HZO fellow eyes demonstrated increased corneal nerve parameters at 2 months, which could represent a proliferative response to nerve degeneration. IVCM is useful in monitoring corneal nerve changes, andis more sensitive in detecting nerve alterations than esthesiometry.

Sustained Release of Tacrolimus From a Topical Drug Delivery System Promotes Corneal Reinnervation.

PurposeCorneal nerve fibers provide sensation and maintain the epithelial renewal process. Insufficient corneal innervation can cause neurotrophic keratopathy. Here, topically delivered tacrolimus is evaluated for its therapeutic potential to promote corneal reinnervation in rats.MethodsA compartmentalized neuronal cell culture was used to determine the effect of locally delivered tacrolimus on sensory axon regeneration in vitro. The regenerating axons but not the cell bodies were exposed to tacrolimus (50 ng/mL), nerve growth factor (50 ng/mL), or a vehicle control. Axon area and length were measured after 48 hours. Then, a biodegradable nanofiber drug delivery system was fabricated via electrospinning of a tacrolimus-loaded polycarbonate–urethane polymer. Biocompatibility, degradation, drug biodistribution, and therapeutic effectiveness were tested in a rat model of neurotrophic keratopathy induced by stereotactic trigeminal nerve ablation.ResultsSensory neurons whose axons were exposed to tacrolimus regenerated significantly more and longer axons compared to vehicle-treated cultures. Trigeminal nerve ablation in rats reliably induced corneal denervation. Four weeks after denervation, rats that had received tacrolimus topically showed similar limbal innervation but a significantly higher nerve fiber density in the center of the cornea compared to the non-treated control. Topically applied tacrolimus was detectable in the ipsilateral vitreal body, the plasma, and the ipsilateral trigeminal ganglion but not in their contralateral counterparts and vital organs after 4 weeks of topical release.ConclusionsLocally delivered tacrolimus promotes axonal regeneration in vitro and corneal reinnervation in vivo with minimal systemic drug exposure.Translational RelevanceTopically applied tacrolimus may provide a readily translatable approach to promote corneal reinnervation.

OCULAR SURFACE AND TEAR FILM CHANGES AFTER MANUAL SMALL INCISION CATARACT SURGERY

BACKGROUND: Manual small incision cataract surgery (MSICS) continues to be the mainstay of cataract surgeries in developing countries like India. Dry eye related symptoms like constant foreign body sensation, ocular surface discomfort, redness, watering are frequent phenomenon after cataract surgery. SICS may worsen lid margin anatomy, cause corneal denervation, cause reduction in number of Goblet cells and perpetuate tear lm instabilities of a patient's eye after surgery. To analyzeOBJECTIVE: changes in tear lm indices after SICS This is a prospective observational study of 12 months duration from April 2020 toSTUDY DESIGN: March 2021 done on 110 different patients undergoing cataract surgery 45-70 years age group by MSICS method . 110 (48 male,METHODS: 62 female) patients who underwent MSICS during the aforementioned period were selected for the study. Tear Meniscus Height (TMH), Schirmer's Test 1(ST1), Tear Film Break Up Time (TBUT) evaluation was done 1 day preoperatively, 1 week, 1 month and 3 month post operatively and the values were noted. Collected data was analyzed by paired t test using MS EXCEL and SPSS V23. The mean ageRESULTS: of the 110 patients was 60.21years. The mean preoperative values of the tear lm indices ST1, TBUT, TMH were found to be respectively 19.15 ± 8.59 mm, 16.70 ± 5.27 seconds, 0.39 ± .13 mm. 1 month and 3 month post operatively mean ST1 values were found to be 14.89 ± 6.15 and 14.40 ± 5.48 mm; mean TBUT values were 13.37 ± 4.76 and 12.93 ± 4.74 seconds; mean TMH was found to be 0.30 ± 0.10 and 0.29 ± 0.09. The progressive deterioration of tear lm indices over our study period was found to be statistically signicant. SICS causesCONCLUSION: signicant deterioration of tear lm indices and perpetuates ocular surface discomfort and dry eye disease post operatively. Operating surgeons must pay attention to dry eye signs, symptoms post operatively even in a well operated healthy eye to ensure optimal post-operative comfort to the patient.

Commentary: Corneal neurotization

Commentary: Corneal neurotization

Corneal Sensitivity and Patient-Reported Dry Eye Symptoms in a Prospective Randomized Contralateral-Eye Trial Comparing Laser In Situ Keratomileusis and Small Incision Lenticule Extraction

To prospectively compare corneal sensation and patient-reported symptoms of dry eye in individuals undergoing laser in situ keratomileusis (LASIK) and small incision lenticule extraction (SMILE). Prospective randomized contralateral-eye clinical trial. 80 eyes of 40 patients with myopia at Byers Eye Institute at Stanford University were randomized to receive wavefront-guided femtosecond LASIK in one eye and SMILE in the fellow eye. Cochet-Bonnet esthesiometry was performed to assess corneal sensitivity preoperatively and at the 1-, 3-, 6-, and 12-month postoperative visits. Participants also completed questionnaires at each visit to determine the Ocular Surface Disease Index (OSDI). Eyes that underwent LASIK compared to SMILE demonstrated more corneal denervation at the postoperative 1-month (mean 2.1 vs 3.6 cm, P < .001), 3-month (3.5 vs 5.4 cm, P < .001), and 6-month (4.7 vs 5.7 cm, P < .001) visits. At the 12-month visit, both groups had returned to baseline corneal sensitivity (5.9 vs 5.9 cm, P=.908). There was no difference in OSDI between the 2 groups at any visit. Mean OSDI improved from the preoperative to the postoperative 12-month visit in both LASIK (15.3 to 8.6, P=.020) and SMILE (15.1 to 9.5, P=.029) groups. LASIK resulted in greater corneal denervation compared to SMILE in the early postoperative period, though this difference was no longer apparent after 12 months. Despite this, there was no difference in self-reported dry eye symptoms between the 2 groups. Patient-reported dry eye symptoms improved after both LASIK and SMILE procedures.

Comparison of the effects of corneal and lacrimal gland denervation on the lacrimal functional unit of rats.

This study aimed to compare the changes in the lacrimal functional unit in the following two models of neurogenic dry eye syndrome: sensory denervation of the cornea versus autonomic denervation of the lacrimal gland. The neural network supports the lacrimal functional unit. It can be divided into afferent (sensory) and efferent (autonomic) pathways and is affected by severe diseases that compromise the lacrimal functional unit. Male Wistar, 8-week-old rats were divided into the following three groups: 1) control naïve (n=16 animals); 2) autonomic denervation: where rats were subjected to right lacrimal gland nerve ablation and evaluated after 1 and 2 months (1M and 2M) after the procedure (n=7 animals per subgroup, autonomic denervation 1M and autonomic denervation 2M, respectively); 3) sensory denervation induced by 0.2% benzalkonium chloride eye drops, twice a day for 7 days in the right eye (n=10 animals). The corneal sensitivity was measured using the eye wipe test with capsaicin (10 µM). The quantitative real-time PCR was performed to compare the mRNA expressions of proinflammatory cytokines, such as Il-1β, Il-6, Tnf, Mmp9, in the cornea, trigeminal ganglion, and lacrimal gland. In addition, the mRNA of the promitotic factors in the lacrimal gland, such as Bmp7, Runx1, Runx3, Fgf10, and Smad1, was compared. Sensory denervation induced corneal hyperalgesia (p=0.001). Sensory denervation and autonomic denervation increased the mRNA of proinflammatory cytokines in the cornea and lacrimal gland (p<0.05), but only sensory denervation increased the mRNA levels of Il-1β and Tnf in the trigeminal ganglion (p<0.05) compared with the control naïve. Autonomic denervation and sensory denervation models can have common features, such as inflammation of different parts of the lacrimal functional unit. However, hyperesthesia and inflammatory markers in the trigeminal ganglion because of sensory denervation and the expression of regenerative mediators in the lacrimal gland owing to autonomic denervation are the distinguishing features of these diseases that can be explored in future studies assessing dry eye syndrome secondary to neural damage of the lacrimal functional unit.

Tear Neuromediator and Corneal Denervation Following SMILE.

To investigate the changes in tear neuromediators and corneal subbasal nerve plexus following small incision lenticule extraction (SMILE) and to study its association with different refractive power of corrections. Thirty patients were included for tear neuromediator analysis (40 eyes) and corneal nerve analysis using in vivo confocal microscopy scans (20 eyes). Tear samples were collected preoperatively and 1 week and 1, 3, 6, and 12 months postoperatively and analyzed for the substance P, calcitonin gene-related peptide (CGRP), and nerve growth factor (NGF) concentrations using the enzyme-linked immunosor-bent assay (ELISA). Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), and corneal nerve branch density (CNBD) decreased significantly postoperatively, then gradually increased from 3 months onward, but did not recover to the baseline levels at 12 months. Tear substance P and CGRP levels remained stable over 12 months. Tear NGF levels demonstrated a small peak at 1 week before decreasing significantly compared to preoperative levels at 6 months (P = .03) and 12 months (P = .007). The 1-month reduction in CNFL, tear substance P, and CGRP concentrations were significantly correlated with the corrected spherical equivalent (SE) (r = 0.71 for CNFL; r = -0.33 to -0.52 at different time points for substance P and CGRP, respectively, all P < .05). Compared to the low to moderate myopia group, the high myopia group (corrected SE greater than -6.00 diopters) had a significantly greater decrease in CNFD, significantly higher tear substance P concentrations at 1 week, 1 month, and 6 months, and significantly higher tear CGRP concentrations at 1 and 6 months. These results provide new insight into the neurobiological responses and their potential implications in corneal nerve damage and recovery after SMILE. High myopia treatment was associated with greater corneal denervation and neuroinflammation. [J Refract Surg. 2021;37(8):516-523.].

Evaluation of Hinge Position on Corneal Sensation and dry Eye after Laser in Situ Keratomileusis (LASIK) in Thi-Qar Governorate

Purpose: This investigation planned to assess the impacts of Laser In Situ Keratomileusis (LASIK)with prevalent and nasal pivot areas on corneal sensation and dry eye condition. Planned randomizedsimilar investigation was completed from February 2018 to December 2019. The subsequent term werepreoperatively evaluated just as 1week and 1,3,6 months postoperatively. This examination included 600eyes of 420 patients (180 guys and 240 females), all patients went through LASIK medical procedure forrectification of nearsightedness as well as nearsighted astigmatism utilizing MEL 90 Excimer laser for stromalremoval , Moria M2, SBK microkeratomes were utilized to make a prevalent and nasal pivoted folds. At thepoint when patients chose to have medical procedure, they were randomized to get nasal or predominantpivot medical procedure based on the randomization succession. Focal Cochet-Hat esthesiometry, Schirmerfundamental tear discharge test, tear film separation time (TBUT) were assessed preoperatively and at multiweek , 1, 3, and a half year postoperatively. After medical procedure, the corneal sensation diminishedessentially in both nasal-pivot and prevalent pivot folds at multi week however got back to gauge by halfyear. The Schirmer essential emission test esteems were not altogether changed postoperatively in the nasalpivoted and predominant pivoted eyes. TBUT diminished inconsequential at multi week and multi monthpostoperatively and recouped by 3 months after medical procedure in the two gatherings. There were nohuge contrasts in all the abstract and target boundaries tried between nasal-pivoted and unrivaled pivotedfolds whenever point. There is no intraoperative and postoperative inconveniences in everyone’s eyes.There was a huge decrease in corneal sensation following LASIK in nasal and predominant gatherings.Sensation improved at untouched stretches and re-visitations of nearly, preoperative levels around a halfyear postoperatively. Related with the corneal denervation is a prompt postoperative increment in dry-eye asestimated by TBUT and schirmer test that improved utilizing oils and with ensuing visits.

Dorsal root ganglia: fibromyalgia pain factory?

This perspective article focuses on dorsal root ganglia (DRG) as potential fibromyalgia main pain source. Humans possess 31 pairs of DRG lying along the spine. These ganglia have unique anatomical and physiological features. During development, DRG are extruded from the central nervous system and from the blood-brain barrier but remain surrounded by meningeal layers and by cerebrospinal fluid. DRG house the pain-transmitting small nerve fiber nuclei; each individual nucleus is tightly enveloped by metabolically active glial cells. DRG possess multiple inflammatory/pro-nociceptive molecules including ion channels, neuropeptides, lymphocytes, and macrophages. DRG neurons have pseudo-unipolar structure making them able to generate pain signals; additionally, they can sequester antigen-specific antibodies thus inducing immune-mediated hyperalgesia. In rodents, diverse physical and/or environmental stressors induce DRG phenotypic changes and hyperalgesia. Unfolding clinical evidence links DRG pathology to fibromyalgia and similar syndromes. Severe fibromyalgia is associated to particular DRG ion channel genotype. Myalgic encephalomyelitis patients with comorbid fibromyalgia have exercise-induced DRG pro-nociceptive molecules gene overexpression. Skin biopsy demonstrates small nerve fiber pathology in approximately half of fibromyalgia patients. A confocal microscopy study of fibromyalgia patients disclosed strong correlation between corneal denervation and small fiber neuropathy symptom burden. DRG may be fibromyalgia neural hub where different stressors can be transformed in neuropathic pain. Novel neuroimaging technology and postmortem inquest may better define DRG involvement in fibromyalgia and similar maladies. DRG pro-nociceptive molecules are attractive fibromyalgia therapeutic targets.

Correlation Between Corneal Nerve Density and Symptoms of Small Fiber Neuropathy in Patients With Fibromyalgia: The Confounding Role of Severe Anxiety or Depression.

A consistent line of investigation proposes fibromyalgia as a dysautonomia-associated neuropathic pain syndrome. Comorbid anxiety or depression amplifies fibromyalgia symptoms. The recent recognition of small fiber neuropathy in fibromyalgia patients supports the neuropathic nature of the illness. Corneal confocal microscopy accurately identifies small nerve fiber pathology. The newly developed Small-Fiber Symptom Survey captures the spectrum of small fiber neuropathy symptoms. We aimed to correlate corneal nerve density with different fibromyalgia disease severity questionnaires including the Small-Fiber Symptom Survey. We defined the possible confounding role of comorbid anxiety or depression severity in the clinical-pathological association. This is a case series of 28 women with fibromyalgia. A single ophthalmologist quantified corneal subbasal plexus nerve density. Corneal innervation was correlated (Spearman ρ) with the following clinical questionnaires scores: Small-Fiber Symptom Survey, Revised Fibromyalgia Impact Questionnaire, and COMPASS-31 (Composite Autonomic Symptom Survey 31-Item Score). Validated inquiry forms assessed the comorbid anxiety and/or depression severity. There were no clinical-pathological correlations in the group as a whole. In the subgroup of fibromyalgia women without severe anxiety or depression (n = 13), there was a strong negative correlation between corneal nerve density with the Small-Fiber Symptom Survey score (ρ = -0.771, p = 0.002) and COMPASS-31 score (ρ = -0.648, p = 0.017). Patients with profound anxiety or depression (n = 15) had more intense symptoms but had not clinical-pathological correlations. Small fiber neuropathy and dysautonomia symptoms correlate with corneal denervation in women with fibromyalgia without severe anxiety or depression. This clinical-pathological association reinforces fibromyalgia as a dysautonomia-related neuropathic pain syndrome. Severe anxiety or depression distorts fibromyalgia symptoms. Corneal confocal microscopy may become a useful procedure to study fibromyalgia patients.

Shp2-mediated MAPK pathway regulates ΔNp63 in epithelium to promote corneal innervation and homeostasis

Corneal nerve fibers serving sensory, reflex, and neurotrophic functions sustain corneal homeostasis and transparency to promote normal visual function. It is not known whether corneal epithelium is also important for the corneal innervation. Herein, we generated a compound transgenic mouse strain, K14rtTA;tetO-Cre (TC);Shp2flox/flox, in which Shp2 was conditionally knocked out from K14-positive cells including corneal epithelium (Shp2K14ce-cko) upon doxycycline (dox) administration. Our data reveal that Shp2K14ce-cko caused corneal denervation. More specifically, corneal epithelium thickness and corneal sensitivity reduced dramatically in Shp2K14ce-cko mice. In addition, corneal epithelial wound healing after debridement was delayed substantially in the mutant mice. These defects manifested in Shp2K14ce-cko mice resemble the symptoms of human neurotrophic keratopathy. Our in vitro study shows that neurite outgrowth of the mouse primary trigeminal ganglion cells (TGCs) was inhibited when as cocultured with mouse corneal epithelial cells (TKE2) transfected by Shp2-, Mek1/2-, or ∆Np63-targeted siRNA but not by Akt1/2-targeted siRNA. Furthermore, ∆Np63 RNA interference downregulated Ngf expression in TKE2 cells. Cotransfection experiments reveal that Shp2 tightly monitored ΔNp63 protein levels in HEK293 and TKE2 cells. Taken together, our data suggest that the Shp2-mediated MAPK pathway regulated ΔNp63, which in turn positively regulated Ngf in epithelium to promote corneal innervation and epithelial homeostasis