Corneal Subbasal Nerve Plexus Research Articles

Deep-learning based analysis of in-vivo confocal microscopy images of the subbasal corneal nerve plexus’ inferior whorl in patients with neuropathic corneal pain and dry eye disease

PurposeTo evaluate and compare subbasal corneal nerve parameters of the inferior whorl in patients with dry eye disease (DED), neuropathic corneal pain (NCP), and controls using a novel deep-learning-based algorithm to analyze in-vivo confocal microscopy (IVCM) images. MethodsSubbasal nerve plexus (SNP) images of the inferior whorl of patients with DED (n = 49, 77 eyes), NCP (n = 14, 24 eyes), and controls (n = 41, 59 eyes) were taken with IVCM and further analyzed using an open-source artificial intelligence (AI)-based algorithm previously developed by our group. This algorithm automatically segments nerves, immune cells, and neuromas in the SNP. The following parameters were compared between groups: nerve area density, average nerve thickness, average nerve segment tortuosity, junction point density, neuroma density, and immune cell density. Results160 eyes of 104 patients (63 % females), aged 56.8 ± 15.4 years, were included. The mean nerve area density was significantly lower in the DED (P = 0.012) and NCP (P < 0.001) groups compared to the control group. The junction point density was lower in the NCP group compared with control (P = 0.001) and DED (P = 0.004) groups. The immune cell density was higher in the DED group compared with controls (P < 0.001). ConclusionsDeep-learning-based analysis of IVCM images of the corneal SNP inferior whorl distinguished a decreased mean nerve area density in patients with DED and NCP compared with controls and an increased immune cell density in patients with oGVHD- and SS-associated DED. These findings suggest that the inferior whorl could be used as landmark to distinguish between patients with DED and NCP.

Corneal nerve fiber morphology following COVID-19 infection in vaccinated and non-vaccinated population

To examine corneal subbasal nerve changes in patients who received vaccination against SARS-CoV-2 virus and underwent COVID-19 infection compared to infected non-vaccinated patients and healthy controls. Twenty-nine eyes of 29 vaccinated patients (mean age: 36.66 ± 12.25 years) within six months after PCR or Ag test proven COVID-19 infection and twenty-eight eyes of 28 age-matched infected, non-vaccinated patients (mean age: 42.14 ± 14.17 years) were enrolled. Twenty-five age-matched healthy individuals (mean age: 47.52 ± 18.45 years) served as controls. In vivo confocal microscopy (Heidelberg Retina Tomograph II Rostock Cornea Module, Germany) was performed in each group. Corneal subbasal nerve plexus morphology and corneal dendritic cells (DC) were evaluated. Significantly higher corneal nerve fiber density (P < 0.001), nerve branch density (P < 0.001), nerve fiber length (P < 0.001), total branch density (P = 0.007), nerve fiber area (P = 0.001) and fractal dimension (P < 0.001) values were observed in vaccinated patients after COVID-19 infection compared to the non-vaccinated group. Significantly higher DC density was observed in the non-vaccinated group compared to the control group (P = 0.05). There was a statistically significant difference in the size of mature DCs (P < 0.0001) but the size of immature DCs did not differ significantly among the 3 groups (P = 0.132). Our results suggest that SARS-CoV-2 vaccination may have a protective effect against the complications of COVID-19 disease on the corneal subbasal nerve fibers.

Co-existence of Neurotrophic Keratopathy in Eyes With Limbal Stem Cell Deficiency

PurposeTo investigate whether neurotrophic keratopathy is present in limbal stem cell deficiency (LSCD) by measuring corneal sensation and characterizing corneal subbasal nerve plexus. DesignProspective, cross-sectional “case-control” comparative study. MethodsForty-six eyes with LSCD and 14 normal eyes were recruited from 2019 to 2022. Corneal sensation was measured using a Cochet-Bonnet esthesiometer and subbasal nerve plexus was imaged using in vivo confocal microscopy (IVCM) at the central cornea and 4 limbal regions. Subbasal nerve density (SND, number of nerve/mm2), subbasal nerve length (SNL, total length of nerve/mm2) and subbasal nerve branch density (SNBD, number of branch/mm2) were quantified. LSCD was graded to stage 1, 2 and 3 using a previously established staging method` consisting of clinical scores, basal cell density, central corneal epithelial thickness and SNL. ResultsThe mean (±SD) cornea sensation in the central cornea and limbus were 29.2 ± 21.5 and 33.6 ± 15.1 mm in the LSCD group and 57.6 ± 5.8 and 54.3 ± 4.7 mm in the control group, respectively (all P < 0.001). In sectoral LSCD, the sensation in the affected regions (29.1 ± 17.6 mm) decreased significantly compared to the unaffected regions (41.4 ± 18.2 mm, P < 0.001). Central corneal SND, SNL and SNBD were reduced by 84.6%, 82.6%, and 89.2%, respectively in LSCD compared to the control (all P < 0.05). The central corneal sensation negatively correlated with the severity of LSCD (rho = -0.64, P < 0.0001) and positively correlated with SND, SNL, and SNBD (rho=0.63, 0.66, and 0.56, respectively; all P < 0.001). ConclusionsCorneal sensation was reduced in eyes with LSCD. The degree of corneal sensation reduction positively correlated with the severity of LSCD. This finding demonstrated the co-existence of neurotropic keratopathy in LSCD.

Corneal innervation changes ın Alzheimer's: implications for sensory dysfunction.

To compare, between Alzheimer's disease (AD) patients and healthy individuals, corneal subbasal nerve plexus (CSNP) parameters and corneal sensitivities. Twenty-two patients who were followed up with Alzheimer's disease (Alzheimer's group) and 18 age- and gender-matched healthy individuals (control group) were included in this cross-sectional study. CSNP parameters, including nerve fiber length (NFL), nerve fiber density (NFD), and nerve branch density (NBD), were evaluated using in vivo confocal microscopy. Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. The results were compared between the two groups. In the Alzheimer's group, NFL was 12.2 (2.4) mm/mm2, NFD was 12.5 [3.1] fibers/mm2, and NBD was 29.7 [9.37] branches/mm2. In the control group, NFL was 16.5 (2.0) mm/mm2, NFD was 25.0 [3.13] fibers/mm2, and NBD was 37.5 [10.9] branches/mm2. All three parameters were significantly lower in the Alzheimer's group compared to the control group (p < 0.001, p < 0.001, and p = 0.001, respectively). Similarly, corneal sensitivity was significantly lower in the Alzheimer's group (55.0 [5.0] mm) compared to the control group (60.0 [5.0] mm) (p < 0.001). We determined that, in AD, corneal sensitivity decreases significantly, in parallel with the decrease in corneal nerves. Changes in the corneal nerve plexus and a decrease in corneal sensitivity may be used in the early diagnosis and follow-up of AD. In addition, ocular surface problems secondary to these changes should also be kept in mind.

Corneal subbasal nerve plexus reinnervation and stromal cell morphology with different cap thicknesses in small incision lenticule extraction

PurposeThe corneal cap thickness is a vital parameter designed in small incision lenticule extraction (SMILE). The purpose was to investigate the changes in corneal subbasal nerve plexus (SNP) and stromal cells with different cap thicknesses and evaluate the optimized design for the surgery.MethodsIn this prospective, comparative, non-randomized study, a total of 108 eyes of 54 patients who underwent SMILE were allocated into three groups with different corneal cap thicknesses (110 μm, 120 μm or 130 μm group). The SNP and stromal cell morphological changes obtained from in vivo corneal confocal microscopy (IVCCM) along with their refractive outcomes were collected at 1 week, 1 month, 3 months and 6 months postoperatively. One-way analysis of variance (ANOVA) was used to compare the parameters among the three groups.ResultsThe SNPs in the three groups all decreased after surgery and revealed a gradual increasing trend during the 6-month follow-up. The values of the quantitative nerve metrics were significantly lower in the 110 μm group than in the 120 μm and 130 μm groups, especially at 1 week postoperatively. No difference was detected between the 120 μm and 130 μm groups at any time point. Both Langerhans cells and keratocytes were activated after surgery, and the activation was alleviated during the follow-up.ConclusionsThe SMILE surgeries with 110 μm, 120 μm or 130 μm cap thickness design achieved good efficacy, safety, accuracy and stability for moderate to high myopic correction while the thicker corneal cap was more beneficial for corneal nerve regeneration.

Alterations in the Ocular Surface and Corneal Subbasal Nerve Plexus Following Various Retinal Surgical Procedures: A One-Year Confocal Microscopy Prospective Study.

To evaluate the effects of retinal surgery on the ocular surface and corneal subbasal nerve plexus (SNP). Ninety-eight patients undergoing 23-gauge pars plana vitrectomy for various vitreoretinal disorders were prospectively studied. We collected detailed operative and perioperative data, measuring dry eye syndrome (DED) severity and Ocular Surface Disease Index (OSDI) scores before surgery and at postoperative intervals. In vivo confocal microscopy (IVCM) quantified SNP and dendritic cell (DC) densities. Fifty-three patients were analyzed. Post-surgery, OSDI scores rose from a baseline of 5.5 ± 3.5 to 12.24 ± 6.5 at one month, later reducing to 7.8 ± 4.0 after a year. DED severity increased from 0.6 ± 0.6 initially to 1.6 ± 0.6 at three months, returning to near baseline (0.9 ± 0.6) one year after surgery. DC densities increased notably by the third (58.85 ± 75.6 cells/mm²) and ninth (59.95 ± 86 cells/mm²) postoperative months, especially in patients undergoing combined phacoemulsification, vitrectomy, and C3F8 gas tamponade. SNP parameters, particularly nerve fiber density and length, showed significant declines one month post-surgery, not recovering to baseline levels within a year. Fiber density dropped from 19.06 ± 8.3 fibers/mm² preoperatively to 4.68 ± 4.8 fibers/mm² at one month, partially recovering to 10.64 ± 8.2 fibers/mm² at twelve months. Fiber length decreased from 13.31 ± 3.2 mm/mm² to 6.86 ± 3.4 mm/mm² at one month, later improving to 9.81 ± 4.5 mm/mm² at twelve months, notably in patients with silicone oil (SiO2) tamponade. Retinal surgery, especially when combined with phacoemulsification and C3F8 or SiO2 tamponade, significantly affects ocular surface integrity and SNP density, with these changes lasting up to a year. Expanded studies with more patients and longer follow-up, using finer 25- and 27-gauge vitrectomy tools, are recommended to confirm and extend these findings.

Structural and functional changes of binocular corneal innervation and ocular surface function after unilateral SMILE and tPRK

AimsTo evaluate the bilateral changes in the sub-basal nerve plexus of the cornea and ocular surface function after unilateral small incision lenticule extraction (SMILE) and transepithelial photorefractive keratectomy (tPRK) procedures.Methods34...

Corneal nerves and amyotrophic lateral sclerosis: an in vivo corneal confocal imaging study.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disorder. Diagnosis is challenging due to its clinical heterogeneity and the absence of definitive diagnostic tools, leading to delays averaging between 9.1 and 27months. In vivo corneal confocal microscopy, assessing the sub-basal nerve plexus of the cornea, has been proposed as a potential biomarker for ALS. We aimed to determine whether the assessment of corneal nerves using in vivo confocal microscopy can serve as an imaging biomarker for ALS. A single-centre prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. The corneal sub-basal nerve plexus was analysed using in vivo confocal microscopy. An automated algorithm (ACCMetrics) was used to evaluate corneal parameters: nerve fibre density, nerve branch density, nerve fibre length, nerve fibre area, nerve total branch density, nerve fibre width, and nerve fractal dimension. Twenty-two patients with ALS and 30 controls were included. No significant differences were found between ALS and control groups for all corneal parameters (p > 0.05). Corneal sensitivity did not differ between groups, and no correlation was identified between corneal nerve parameters and ALS disease duration, severity and rate of progression (p > 0.05). The present study does not support the use of in vivo corneal confocal microscopy as an early diagnostic or prognostic tool for ALS. Further research, especially longitudinal investigations, is needed to understand any potential corneal innervation changes as ALS progresses.

Corneal Sub-Basal Nerve Plexus Regeneration Pattern following Implantable Collamer Lens Implantation for Myopia: A Prospective Longitudinal In Vivo Confocal Microscopy Study.

Implantable Collamer Lens (ICL) surgery has increasingly been adopted for myopia correction in recent decades. This study, employing in vivo confocal microscopy (IVCM), aimed to assess the impact of corneal incision during ICL surgery on the corneal sub-basal nerve plexus (SNP) and adjacent immune dendritiform cells (DCs). In this longitudinal study, eyes from 53 patients undergoing ICL surgery were assessed preoperatively and postoperatively over a twelve-month period. Quantification of seven SNP parameters was performed using ACCMetrics V.2 software. Ultimately, the final analysis was restricted to one eye from each of the 37 patients who completed a minimum of three months' postoperative follow-up. Preoperative investigations revealed a positive correlation of DC density with patient age and a negative association with corneal nerve fiber density (CNFD). Additionally, both DCs and CNFD were positively linked to spherical equivalent refraction (SER) and inversely related to axial length (AL). Intriguingly, preoperative DC density demonstrated an indirect relationship with both baseline and postoperative CNFD changes. Post-surgery, an initial surge in DC density was observed, which normalized subsequently. Meanwhile, parameters like CNFD, corneal nerve fiber length (CNFL), and corneal nerve fractal dimension (CNFrD) initially showed a decline following surgery. However, at one-year follow-up, CNFL and CNFrD displayed significant recovery, while CNFD did not return to its baseline level. This study thus delineates the regeneration pattern of SNP and alterations in DC density post-ICL surgery, highlighting that CNFD in the central cornea does not completely revert to preoperative levels within a year. Given these findings, practitioners are advised to exercise caution in older patients, those with high myopia, or elevated preoperative DCs who may undergo delayed SNP regeneration.

Corneal reinnervation in patients with severe neurotrophic keratopathy secondary to herpes zoster ophthalmicus after treatment with autologous serum tear drops.

To study 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). Four cases of HZO with severe NK were followed clinically and by serial laser in vivo confocal microscopy (IVCM, HRT3/RCM, Heidelberg Engineering) before and during treatment with 20% AST drops eight times a day. Two masked observers reviewed the IVCM images and assessed corneal nerve alterations. 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 four patients were refractory to conventional therapies and were treated with AST drops. All patients demonstrated significant nerve regeneration by IVCM within 3-7 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 ulceration within weeks of corneal reinnervation, which was reversed by adding topical steroids. 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.

Corneal confocal microscopy detects damage to the subbasal corneal nerve plexus in patients with chronic inflammatory demyelinating polyneuropathy

Corneal confocal microscopy detects damage to the subbasal corneal nerve plexus in patients with chronic inflammatory demyelinating polyneuropathy

In Vivo Corneal Confocal Microscopy for Detecting Corneal Nerve Fiber Changes in Patients with Different Types of Optic Neuritis: A Cross-Sectional Study

Purpose Optic neuritis (ON), a demyelinating disease of the central nervous system, is often a precursor manifestation of neuromyelitis optica spectrum disorders (NMOSD) or multiple sclerosis (MS). Reduced corneal nerve fiber counts have been found in patients with NMOSD or MS. This study aimed to observe and compare the corneal subbasal nerve plexus in patients with three types of ON and controls without ON using in vivo corneal confocal microscopy (IVCM). Methods Data were analyzed for 77 eyes of 48 patients with ON, grouped according to seropositivity for anti-aquaporin-4 IgG, myelin oligodendrocyte glycoprotein antibody, or no seropositivity, and 35 healthy eyes in the control group. Corneal parameters were quantified based on IVCM images. Visual function indicators were recorded, following which their correlations with IVCM parameters were analyzed. Results Significant differences in IVCM parameters were detected among the different groups. Reductions in corneal nerve fiber counts were negatively correlated with visual acuity. Corneal nerve fibers were significantly more damaged in the affected eye than in the unaffected eye in patients with ON. Conclusion IVCM revealed corneal nerve fiber loss of varying degrees, depending on the type of ON. This indicates that, although ON primarily affects the central nervous system, peripheral nerves, such as the trigeminal nerve, which innervates the corneal subbasal nerve plexus may also be damaged in affected patients.

Effect of repeated intravitreal anti-vascular endothelial growth factor drugs on corneal nerves.

To investigate the potential effect of repeated intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs on corneal nerves. A total of 64 patients were treated with intravitreal injection of anti-VEGF drugs. There were 19 cases of neovascular age-related macular degeneration (AMD), 20 cases of diabetic macular edema (DME) and 25 cases of retinal vein occlusion (RVO). Twenty-nine cases were treated with aflibercept (2 mg/0.05 mL) whereas 35 cases were managed with ranibizumab (0.5 mg/0.05 mL). A corneal confocal microscope was used to collect images of corneal subbasal nerve plexus, and Image J was used for image analysis. The changes in corneal nerve were compared between 1 month after each injection and before injection. There were no significant differences in the density and length of corneal nerve at specific time after the surgery in comparison with baseline in patients who were given 3 intravitreal injections. There was no significant correlation between the numbers of injections and the changes of the corneal nerves. After 3rd injection, the nerve length of the DME group was markedly lower than that of AMD and RVO groups, the difference was statistically significant (P < .05). The nerve density of the DME group was not significantly different from that of AMD and RVO groups, whereas the nerve length and nerve density of the AMD and RVO groups were not statistically significant between each other also. The corneal nerve length after the 2nd and 3rd injections of Aflibercept were lower than that before surgery, the difference was statistically significant. There were no significant differences in nerve density and nerve length at each time point after Ranibizumab injection. The length and density of the corneal nerve after multiple injections in contralateral eye displayed no significant changes compared with the baseline. Repeated intravitreal anti-VEGF drug can reduce the length of corneal nerves. For patients who need repeated intravitreal injections of anti-VEGF drugs, especially in DM, attention should be paid on the changes affecting the corneal nerves. It is also needed to strengthen the local anti-inflammatory therapy to avoid infection and to use artificial tears to protect the microenvironment of the ocular surface after the surgery.

Collagen mimetic peptide repair of the corneal nerve bed in a mouse model of dry eye disease.

The intraepithelial sub-basal nerve plexus of the cornea is characterized by a central swirl of nerve processes that terminate between the apical cells of the epithelium. This plexus is a critical component of maintaining homeostatic function of the ocular surface. The cornea contains a high concentration of collagen, which is susceptible to damage in conditions such as neuropathic pain, neurotrophic keratitis, and dry eye disease. Here we tested whether topical application of a collagen mimetic peptide (CMP) is efficacious in repairing the corneal sub-basal nerve plexus in a mouse model of ocular surface desiccation. We induced corneal tear film reduction, epithelial damage, and nerve bed degradation through a combination of environmental and pharmaceutical (atropine) desiccation. Mice were subjected to desiccating air flow and bilateral topical application of 1% atropine solution (4× daily) for 2 weeks. During the latter half of this exposure, mice received topical vehicle [phosphate buffered saline (PBS)] or CMP [200 μm (Pro-Pro-Gly)7, 10 μl] once daily, 2 h prior to the first atropine treatment for that day. After euthanasia, cornea were labeled with antibodies against βIII tubulin to visualize and quantify changes to the nerve bed. For mice receiving vehicle only, the two-week desiccation regimen reduced neuronal coverage of the central sub-basal plexus and epithelial terminals compared to naïve, with some corneas demonstrating complete degeneration of nerve beds. Accordingly, both sub-basal and epithelial βIII tubulin-labeled processes demonstrated increased fragmentation, indicative of nerve disassembly. Treatment with CMP significantly reduced nerve fragmentation, expanded both sub-basal and epithelial neuronal coverage compared to vehicle controls, and improved corneal epithelium integrity, tear film production, and corneal sensitivity. Together, these results indicate that topical CMP significantly counters neurodegeneration characteristic of corneal surface desiccation. Repairing underlying collagen in conditions that damage the ocular surface could represent a novel therapeutic avenue in treating a broad spectrum of diseases or injury.

Pre-Ophthalmoscopic Quantitative Biomarkers in Diabetes Mellitus.

The purpose of this study was to assess whether retinal microvascular or corneal nerve abnormalities occur earlier in diabetes mellitus (DM) and to identify imaging biomarkers in order to help prevent the subsequent irreversible retinal and corneal complications. The study comprised 35 eyes of 35 healthy volunteers and 52 eyes of 52 patients with type 1 and type 2 DM. Swept-source optical coherence tomography (OCT), OCT angiography, and in vivo corneal confocal microscopy were performed in both groups. Corneal sub-basal nerve plexus and vessel density (VD) of superficial capillary plexus (SCP) and deep capillary plexus (DCP) were evaluated. All corneal sub-basal nerve fiber parameters were decreased in patients with DM compared with healthy subjects and the difference was significant for each result except for nerve fiber width (P = 0.586). No significant correlation was obtained between any nerve fiber morphology parameters and disease duration or HbA1C. VD in SCP was significantly decreased in the superior (P < 0.0001), temporal (P = 0.001), and nasal quadrant (P = 0.003) in the diabetes group. In DCP, only superior VD (P = 0.036), decreased significantly in the diabetes group. Ganglion cell layer thickness in the inner ring showed a significantly lower value in patients with DM (P < 0.0001). Our results implicate a more pronounced and earlier damage to the corneal nerve fibers compared to the retinal microvasculature in patients with DM. In DM, an earlier and more pronounced damage to the corneal nerve fibers was observed compared to the retinal microvasculature.

Decreased corneal subbasal nerve fiber length and density in diabetic dogs with cataracts using in vivo confocal microscopy.

To determine whether there is a difference in corneal sensitivity and corneal subbasal nerve plexus (CSNP) morphology in cataractous dogs with diabetes mellitus (DM) versus without DM. Twenty six domestic dogs with cataracts of various breeds presented for phacoemulsification, 13 with DM and 13 without DM. The inclusion criteria for the study were dogs with bilateral cataracts and no clinical evidence of corneal disease. The diabetic group had documented hyperglycemia and was currently treated with insulin. The non-diabetic group had no evidence of DM on examination and bloodwork. Complete ophthalmic examination, corneal esthesiometry, and in vivo confocal microscopy of the CSNP was performed for both eyes of each dog. The CSNP was evaluated using a semi-automated program and statistically analyzed. The mean (±SD) CSNP fiber length was significantly decreased in diabetic (3.8 ± 3.0 mm/mm2 ) versus non-diabetic (6.7 ± 1.9 mm/mm2 ) dogs. Likewise, the mean (±SD) fiber density was significantly decreased in diabetic (8.3 ± 3.1 fibers/mm2 ) versus non-diabetic (15.5 ± 4.9 fibers/mm2 ) dogs. The corneal touch threshold was significantly reduced in diabetic (2.1 ± 0.8cm) versus non-diabetic (2.8 ± 0.4cm) dogs. There was a non-significant trend towards subclinical keratitis in diabetic (9/13) versus non-diabetic (4/13) dogs. Morphological and functional abnormalities of the CSNP were present in dogs with DM, including decreased fiber length, fiber density, and corneal sensitivity. These findings are consistent with diabetic neuropathy and could contribute to clinically significant corneal complications after cataract surgery.

Corneal deposits and nerve alterations in Bietti Corneoretinal Crystalline Dystrophy imaged using in vivo confocal microscopy.

To evaluate the imaging features of corneal deposits and nerve alterations in Chinese patients with Bietti Corneoretinal Crystalline Dystrophy (BCD) using in vivo confocal microscopy (IVCM). Twenty patients with BCD and 20 age- and sex-matched healthy controls were enrolled in this retrospective, observational study. Corneal deposits and sub-basal nerve plexus (SNP) were observed by IVCM. Parameters of SNP including total nerve density/number, main nerve trunk density/number, and branch nerve density/number were analyzed by Neuron J. Corneal deposits were observed in both eyes of all patients by IVCM. These crystals appeared as dot-shaped, needle-shaped, and rod-shaped hyperreflective bodies and were located not only in the sub-epithelium and stroma of cornea, but in endothelium which were not reported before. There was a decrease of total nerve density (P < 0.001), main nerve trunk density (P = 0.007), and branch nerve density (P = 0.001), in BCD compared to controls. The number of total nerves/frame (P = 0.001), main nerve trunks/frame (P = 0.005), and branch nerves/frame (P = 0.006) in BCD were lower than controls. New findings in locations of corneal crystals by IVCM expand the phenotype spectrum of BCD. Corneal deposits may be useful for diagnosis of BCD, especially ones without retinal deposits. Corneal nerve parameters were reduced in BCD, which may provide new insights to be further explored to contribute to our understanding of BCD. IVCM is a promising tool to evaluate corneal deposits and nerve alterations in BCD.

Central Corneal Subbasal Nerve Plexus Abnormalities in Sjögren Disease: A Pilot Study.

Small-fiber neuropathy (SFN) is known to be associated with Sjögren disease (SjD), and in vivo corneal confocal microscopy can identify features compatible with SFN. Here, we performed a descriptive study to identify features of SFN of the corneal subbasal nerve plexus using in vivo confocal microscopy. We recruited 10 participants from the Sjögren's International Collaborative Clinical Alliance (SICCA), 1 new participant (in an effort to expand the SICCA cohort), and 22 healthy controls. All participants underwent slit-lamp examination and in vivo confocal microscopy of the central corneal subbasal nerve plexus centered about the central whorl to create a 30-image montage. Each image was analyzed with automated software (ACCmetrics, Manchester, United Kingdom) to produce 7 nerve metrics. We performed t-tests and age-adjusted regressions to make comparisons of nerve metrics between participants with SjD and healthy controls. Most nerve metrics were significantly lower in participants with SjD compared with healthy controls. The mean corneal nerve fiber density was found to be 3.5 mm/mm 2 in participants with SjD compared with 10.6 mm/mm 2 in healthy controls (95% confidence interval, -8.4 to -0.93; P = 0.02). Within the 11 participants with SjD, 22 eyes were analyzed on confocal microscopy, and 16 of those eyes (from 9 individuals) did not have an identifiable central whorl. Within the 22 healthy controls, 22 eyes (right eye alone) were analyzed on confocal microscopy, and 21 of those eyes had an identifiable central whorl. SjD exhibits lower corneal nerve metrics compared with healthy controls. These findings suggest that features compatible with SFN can distinguish SjD from healthy controls and may serve as a potential novel biomarker in identifying SjD.

Corneal Sub-Basal Nerve Plexus in Non-Diabetic Small Fiber Polyneuropathies and the Diagnostic Role of In Vivo Corneal Confocal Microscopy.

In vivo corneal confocal microscopy (IVCM) allows the immediate analysis of the corneal nerve quantity and morphology. This method became, an indispensable tool for the tropism examination, as it evaluates the small fiber plexus in the cornea. The IVCM provides us with direct information on the health of the sub-basal nerve plexus and indirectly on the peripheral nerve status. It is an important tool used to investigate peripheral polyneuropathies. Small-fiber neuropathy (SFN) is a group of neurological disorders characterized by neuropathic pain symptoms and autonomic complaints due to the selective involvement of thinly myelinated Aδ-fibers and unmyelinated C-fibers. Accurate diagnosis of SFN is important as it provides a basis for etiological work-up and treatment decisions. The diagnosis of SFN is sometimes challenging as the clinical picture can be difficult to interpret and standard electromyography is normal. In cases of suspected SFN, measurement of intraepidermal nerve fiber density through a skin biopsy and/or analysis of quantitative sensory testing can enable diagnosis. The purpose of the present review is to summarize the current knowledge about corneal nerves in different SFN. Specifically, we explore the correlation between nerve density and morphology and type of SFN, disease duration, and follow-up. We will discuss the relationship between cataracts and refractive surgery and iatrogenic dry eye disease. Furthermore, these new paradigms in SFN present an opportunity for neurologists and clinical specialists in the diagnosis and monitoring the peripheral small fiber polyneuropathies.

Imaging of corneal nerves with in vivo confocal microscopy (IVCM)

AbstractThe subbasal corneal nerve plexus may serve as an important biomarker in ocular surface disease and ocular as well as systemic neuropathies. Changes in number and density of nerves, “beadings” and or tortuosity correlate to clinical signs of Dry Eye Disease. The same is true for atopic keratoconjunctivitis where – in addition – the number of perineural inflammatory cells was significantly increased. In patients with type 1 diabetes mellitus, the corneal subbasal nerve plexus was abnormal in 50% although classified as “normal” by the clinical and electrophysiological based tests for peripheral neuropathies. Although in vivo confocal microscopy is a wonderful tool to assess corneal nerves as reliable biomarkers, it is not generally available, the quality of different equipment may vary, and the analysis of nerves is still time‐consuming.