In Vivo Corneal Confocal Microscopy Research Articles

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.

Use of In Vivo Corneal Confocal Microscopy to Guide Excimer Laser With Adjunctive Mitomycin C for Treatment of Recalcitrant Acanthamoeba Keratitis.

The aim of this study was to describe 3 cases of recalcitrant Acanthamoeba keratitis (AK) that were successfully treated using in vivo corneal confocal microscopy (IVCM) to guide excimer laser ablation depth with adjunctive mitomycin C 0.02%. Three patients diagnosed with AK did not respond to several weeks of intensive topical therapy with antiamoebic agents. The patient underwent phototherapeutic keratectomy with topical mitomycin C 0.02% application. The maximum stromal depth of cysts measured by IVCM was 80 μm, 100 μm, and 240 μm, and the stromal ablation depths were 80 μm, 100 μm, and 100 μm, respectively. In all 3 eyes, AK resolved after a single excimer laser application, and topical treatment was gradually discontinued within 6 weeks afterward. In 1 eye, penetrating corneal transplantation was performed 6 weeks after phototherapeutic keratectomy because of ongoing severe corneal pain. IVCM and histology of the corneal transplant did not reveal any Acanthamoeba cysts within the excised corneal button. No recurrence was observed during the follow-up period of 19 to 34 months. IVCM-guided phototherapeutic keratectomy with mitomycin C 0.02% seems to be a safe and successful approach for the treatment of AK, especially in cases of resistance to topical treatment. Corneal IVCM should be performed before laser application to measure cyst depth, determine ablation depth, and assess postoperative treatment success.

Clinical applications of confocal microscopy to corneal innervation

In vivo corneal confocal microscopy (IVCM) is a non‐invasive ophthalmic imaging technique that provides images of the cornea at the cellular level. Despite the uses in ocular surface pathologies, in the last decades IVCM has been used to provide more knowledge in refractive surgery wound healing (LASIK and PRK), dry eye disease, and in some corneal infections (amoebas and filamentous fungi). The observation of the corneal cells, both normal and inflammatory, and the possibility of quantification of the corneal nerve density and quality with manual or automated tools, makes IVCM have a significant potential to improve the diagnosis and prognosis in several systemic and corneal conditions. Neuropathic pain has multiple aetiologies, but a major feature is small fibre dysfunction or damage. IVCM has been utilized to show small nerve fibre loss in patients with diabetic and other neuropathies. IVCM has comparable diagnostic utility to intraepidermal nerve fibre density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fibre loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease, and dementia. Patients with small fibre neuropathy have IVCM nerve changes. In conclusion, IVCM has good diagnostic and prognostic capability and fulfils the criteria as an end point for clinical trials in corneal, and peripheral and central neurodegenerative diseases.

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.

Clinical and Morphological in Vivo Confocal Microscopy Findings following a Modified Biphasic Higher Fluence Transepithelial Corneal Crosslinking

Purpose: To compare the refractive efficacy and morphological changes in the cornea following a novel biphasic higher fluence transepithelial corneal crosslinking (BI-TE-CXL) and transepithelial corneal crosslinking (TE-CXL) in adults keratoconus. Methods: Patients with progressive keratoconus who required corneal crosslinking were assigned to the BI-TE-CXL group (32 eyes, phase 1: 7.2 J/cm2 for 5 min and 20 s of pulsed-light exposure, KXL, Glaukos-Avedro; phase 2: 3.6 J/cm2 for 6 min and 40 s of continuous light exposure at the front curvature apex with a 6 mm diameter light spot, UVX-2000, IROC) or the TE-CXL group (32 eyes, uniform 7.2 J/cm2 for 5 min and 20 s of pulsed-light exposure, KXL, Glaukos-Avedro). Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal fluorescein staining (CFS), corneal topography, anterior segment optical coherence tomography (AS-OCT), and in vivo corneal confocal microscopy (IVCM) were performed 3, 6, 12 and 24 months after surgery. Results: The CFS scores in the BI-TE-CXL group were significantly higher than those in the TE-CXL group on the first two days after surgery (p < 0.001). The Kmax (at 12 and 24 months) and CDVA (logMAR) were significantly lower in the BI-TE-CXL group than those in the TE-CXL group (p < 0.05). The corneal demarcation line under AS-OCT was visible in 81.3% of patients in the BI-TE-CXL group and 15.6% in the TE-CXL group. The depth of the demarcation line under IVCM was significantly deeper in the BI-TE-CXL group (248.3 ± 25.0 μm) than that of the TE-CXL group (136.5 ± 15.6 μm) in the central cornea (p < 0.001). The cross-linked collagen structures in the central cornea were still present after 12 months in the BI-TE-CXL group. No significant difference in sub-basal nerve density between the two groups (p > 0.05). Conclusions: Following BI-TE-CXL, CDVA was significantly improved, accompanied by deeper demarcation line depth and persistent crosslinked structures in the central corneal stroma.

Chronic Kidney Disease Has No Impact on Tear Film Substance P Concentration in Type 2 Diabetes.

The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM-CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM-no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann-Whitney U tests were used in the analysis of data for two-group comparisons. There was no substantial difference between the T2DM-CKD and T2DM-no CKD groups for tear film substance P concentration (4.4 (0.2-50.4) and 5.9 (0.2-47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2-50.4) and 3.3 (0.3-40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p < 0.01) were reduced significantly in the T2DM-CKD group compared to the T2DM-no CKD group. There were significant differences in corneal nerve fiber density (21.0 ± 8.1 and 15.8 ± 7.7 no/mm2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes.

Comparison of Novel Wide-Field InVivo Corneal Confocal Microscopy With Skin Biopsy for Assessing Peripheral Neuropathy in Type 2 Diabetes.

Comparison of intraepidermal nerve fiber density with automated wide-field corneal nerve fiber density in participants with type 2 diabetes revealed no correlation between these parameters. Intraepidermal and corneal nerve fibers both detected neurodegeneration in type 2 diabetes, but only intraepidermal nerve fibers were associated with clinical measures of diabetic peripheral neuropathy. A lack of association of corneal nerves with peripheral neuropathy measures suggests that corneal nerve fibers may be a poor biomarker for diabetic peripheral neuropathy.

Corneal nerve fiber involvement in chronic inflammatory demyelinating polyneuropathy.

Despite the primary myelin-related pathophysiology, small fiber neuropathy (SFN) and axonal degeneration are also considered to be involved and associated with disabling symptoms and impaired quality of life in chronic inflammatory demyelinating polyneuropathy (CIDP). Demonstration of SFN usually requires complex or invasive investigations. In vivo corneal confocal microscopy (IVCCM) has evolved as a non-invasive, easily applied method for quantification of small fiber involvement in peripheral nerve disorders. We aimed to investigate the potential role of IVCCM in CIDP. In this cross-sectional study, 15 patients with CIDP underwent assessment with clinical disability scales, neuropathic pain (NP) and autonomic symptom questionnaires, nerve conduction studies, and IVCCM. IVCCM parameters were analyzed and compared to those from 32 healthy controls. Corneal nerve fiber density (CNFD) and corneal nerve fiber length (CNFL) were significantly decreased in the CIDP group, compared to those in controls (p = 0.03 and p = 0.024, respectively). Langerhans cells and fiber tortuosity were increased in CIDP patients (p = 0.005 and p = 0.001, respectively). IVCCM parameters were significantly lower in patients with NP compared to those in patients without NP. IVCCM shows promise as a non-invasive complementary biomarker in the assessment of demyelinating polyneuropathies, providing insights into the potential pathophysiology of these non-length-dependent neuropathies.

Recovery of Corneal Innervation after Treatment in Dry Eye Disease: A Confocal Microscopy Study

To analyze the changes in corneal innervation by means of in vivo corneal confocal microscopy (IVCM) in patients diagnosed with Evaporative (EDE) and Aqueous Deficient Dry Eye (ADDE) and treated with a standard treatment for Dry Eye Disease (DED) in combination with Plasma Rich in Growth Factors (PRGF). Eighty-three patients diagnosed with DED were enrolled in this study and included in the EDE or ADDE subtype. The primary variables analyzed were the length, density and number of nerve branches, and the secondary variables were those related to the quantity and stability of the tear film and the subjective response of the patients measured with psychometric questionnaires. The combined treatment therapy with PRGF outperforms the standard treatment therapy in terms of subbasal nerve plexus regeneration, significantly increasing length, number of branches and nerve density, as well as significantly improving the stability of the tear film (p < 0.05 for all of them), and the most significant changes were located in the ADDE subtype. the corneal reinnervation process responds in a different way depending on the treatment prescribed and the subtype of dry eye disease. In vivo confocal microscopy is presented as a powerful technique in the diagnosis and management of neurosensory abnormalities in DED.

In Vivo Corneal Confocal Microscopy in Multiple Sclerosis: Can it Differentiate Disease Relapse in Multiple Sclerosis?

This study aims to investigate the role of in vivo corneal confocal microscopy (IVCCM) in the detection of corneal inflammatory activity and subbasal nerve alterations in patients with multiple sclerosis (MS) and to further determine whether IVCCM can be used to detect (acute) disease relapse. Prospective cross-sectional study, with a subgroup follow-up. This single-center study included 58 patients with MS (MS-Relapse group [n=27] and MS-Remission group [n=31]), and 30 age- and sex-matched healthy control subjects. Patients with a history of optic neuritis or trigeminal symptoms were excluded. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and dendritic cell (DC) density were evaluated in all patients with MS and control subjects by IVCCM. Patients in the MS-Relapse group who were in remission for ≥6 months after the MS incident underwent a repeat IVCCM. No statistical difference was observed between the MS-Relapse and MS-Remission groups regarding age, sex, MS duration, and the number of relapses (P > .05). Compared with healthy control subjects, all subbasal nerve parameters were significantly lower (CNFD: P < .001, CNFL: P < .001, CNBD: P < .001), and the DC density was significantly higher (P=.023) in patients with MS. However, no significant difference was observed between MS-Relapse and MS-Remission groups in terms of CNFD (mean [SE] difference -2.05 [1.69] fibers/mm2 [95% confidence interval {CI} -1.32 to 5.43]; P < .227), CNFL (mean [SE] difference -1.10 [0.83] mm/mm2 [95% CI -0.56 to 2.75]; P < .190), CNBD (mean [SE] difference -3.91 [2.48] branches/mm2 [95% CI -1.05 to 8.87]; P < .120), and DC density (median [IQR], 59.38 [43.75-85.0] vs 75.0 [31.25-128.75]; P=.596). The repeat IVCCM in relapse patients (n=16 [59.3%]) showed a significant increase in CNFD (P=.036) and CNBD (P=.018), but no change was observed in CNFL (P=.075) and DC density (P=.469). Although increased inflammation and neurodegeneration can be demonstrated in patients with MS compared with healthy control subjects, a single time point evaluation of IVCCM does not seem to be sufficient to confirm the occurrence of relapse in patients with MS. However, IVCCM holds promise for demonstrating early neuroregeneration in patients with MS.

Ocular Morpho-Functional Evaluation in ATTRv Pre-Symptomatic Carriers: A Case Series.

The present study aimed to investigate ocular findings in hereditary transthyretin amyloidosis (ATTRv) pre-symptomatic carriers. Fourteen ATTRv pre-symptomatic carriers, who are patients with positive genetic testing but without signs or symptoms of the disease, were retrospectively evaluated. Retinal morphology was assessed using optical coherence tomography (OCT) and OCT-angiography. Retinal function was evaluated using cone b-wave and photopic negative response (PhNR). Pupillometry and in vivo corneal confocal microscopy (IVCM) were performed. ATTRv pre-symptomatic carriers presented a significantly reduced central macular thickness (CMT) (p = 0.01) and outer nuclear layer (ONL) thickness (p = 0.01) in comparison to normal controls. No differences were found when analyzing sub-foveal choroidal thickness, retinal nerve fiber layer and ganglion cell complex. In comparison to healthy controls, pre-symptomatic carriers presented an attenuated superficial retinal vascular network and a significantly augmented PhNR amplitude (p = 0.01). However, PhNR implicit times, B-wave amplitude and B-wave peak time did not show significant differences in comparison to controls. No differences were found for pupillometric values. All the examined eyes presented alterations in the IVCM. Preclinical ocular structural and functional abnormalities can be found in ATTRv pre-symptomatic carriers. Thus, an extensive ophthalmological evaluation should be included at the baseline visit and during follow-up. Considering the availability of new drugs potentially able to prevent or delay disease progression, the identification of new disease biomarkers appears to be particularly promising.

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.

Update on Corneal Confocal Microscopy Imaging

In vivo corneal confocal microscopy (IVCM) is a non-invasive ophthalmic imaging technique that provides images of the cornea at the cellular level. Despite the uses in ocular surface pathologies, in the last decades IVCM has been used to provide more knowledge in refractive surgery wound healing, in neuropathies diagnosis, etc. The observation of the corneal cells, both normal and inflammatory, and the possibility of quantification of the corneal nerve density with manual or automated tools, makes IVCM have a significant potential to improve the diagnosis and prognosis in several systemic and corneal conditions.

Tear film substance P in patients treated with neurotoxic chemotherapy

Neurotoxic chemotherapy has been shown to be associated with reduced corneal nerves and ocular surface discomfort. Substance P is a neuropeptide expressed by sensory nerves including those in the densely innervated cornea. It is involved in both pain signaling and the regulation of epithelial and neural health. While its levels in tear fluids have been used as a neuropathic biomarker in diabetes, investigations of tear concentrations of substance P in chemotherapy-induced peripheral neuropathy have not been explored. The current cross-sectional study assessed substance P expression in tears of patients following neurotoxic chemotherapy treatment. Patients treated with paclitaxel (n = 35) or oxaliplatin (n = 30) 3–24 months prior to assessment were recruited along with healthy controls (n = 25). Flush tear collection, in-vivo corneal confocal microscopy and neurotoxicity assessments were also conducted. Enzyme-linked immunosorbent assays were used to measure substance P concentrations in collected tears, while total protein content (TPC) was measured with the bicinchoninic acid method (BCA). General linear models were used for statistical analysis. Substance P concentration was reduced in paclitaxel-treated patients [Median (Interquartile range, IQR): 1.11 (0.20–2.24) ng/ml)] compared to the oxaliplatin group [4.28 (1.01–10.73) ng/ml, p = 0.02]. Substance P expressed as a proportion of TPC was also lower in the paclitaxel group [0.00006 (0.00001–0.00010) %] compared to the oxaliplatin group [0.00018 (0.00008–0.00040) %, p = 0.005]. Substance P concentration and its percentage in TPC were also reduced in the paclitaxel group when compared to healthy controls [4.61 (1.35–18.51) ng/ml, p = 0.02; 0.00020 (0.00006–0.00060) %, p = 0.04, respectively]. Higher cumulative dose of paclitaxel was correlated with a reduction in substance P concentrations (r = −0.40, p = 0.037), however no associations were found with corneal nerve parameters or neuropathy severity (p > 0.05). While these findings show evidence for the dysregulation of tear film substance P following paclitaxel treatment, longitudinal studies should be conducted to investigate how substance P levels in tears change during treatment.

Corneal Dendritic Cell Dynamics Are Associated with Clinical Factors in Type 1 Diabetes.

Time-lapsed in vivo corneal confocal microscopy (IVCCM) has shown that corneal dendritic cells (DCs) migrate at approximately 1 µm/min in healthy humans. We have undertaken IVCCM of the whorl region to compare the density of rounded DCs, and DCs with (wDCs) and without (woDCs) dendrites and dynamics; trajectory (length travelled/time), displacement (distance from origin to endpoint/time) speeds and persistence ratio (displacement/trajectory) of woDCs in subjects with type 1 diabetes (T1D) (n = 20) and healthy controls (n = 10). Only the wDC density was higher (p = 0.02) in subjects with T1D compared to controls. There was no significant difference in cell dynamics between subjects with T1D and controls. woDC density correlated directly with HDL cholesterol (r = 0.59, p = 0.007) and inversely with triglycerides (r = −0.61, p = 0.005), whilst round-shaped cell density correlated inversely with HDL cholesterol (r = −0.54, p = 0.007). Displacement, trajectory, and persistency correlated significantly with eGFR (mL/min) (r = 0.74, p < 0.001; r = 0.48, p = 0.031; r = 0.58, p = 0.008, respectively). We show an increase in wDC density but no change in any other DC sub-type or alteration in cell dynamics in T1D. However, there were associations between DC density and lipid parameters and between DC dynamics and renal function. IVCCM provides evidence of a link between immune cell dynamics with lipid levels and renal function.

Corneal Confocal Microscopy Features and Tear Molecular Profile in Study Participants with Discordance between Ocular Surface Disease Clinical Signs and Discomfort.

Various ocular surface conditions such as dry eye disease can present with severe discomfort and pain. However, it is clinically challenging to establish etiology and prescribe correct treatment in patients who have a lot of discordance between symptoms and signs. To understand the basis of such discordance, we stratified subjects with ocular surface pain based on concordance between the severity of signs and symptoms and evaluated corneal structural features and tear molecular factors. All subjects underwent slit lamp examination, dry eye evaluation, and ocular surface disease index (OSDI) scoring. Subjects were stratified into group 1—without symptoms or clinical signs; group 2—without symptoms but with signs; group 3—with similar severity of symptoms and signs; and group 4—with symptom severity greater than that of the signs. Laser scanning in vivo confocal microscopy (IVCM) and tear fluid analysis for soluble factors by multiplex ELISA was performed for all subjects. Patients with a higher grade of symptoms and signs showed increased corneal dendritic cell (cDC) density (p < 0.05) which was more pronounced in subjects with discordance between the symptoms and signs (group 4). A significantly higher proportion of microneuroma-like structures and cDC were observed in group 4. IL-17A levels were significantly elevated in the tears of subjects with more discomfort. Our results demonstrate that corneal IVCM and the measurement of tear film factors can help clinicians improve diagnosis and treatment choice. Stratifying patients with ocular surface discomfort on the basis of discordance between symptoms and clinical signs may help identify patients who need additional adjunctive targeted therapy to resolve their condition.

Small Fibre Peripheral Alterations Following COVID-19 Detected by Corneal Confocal Microscopy.

A large spectrum of neurological manifestations has been associated with coronavirus disease 2019 (COVID-19), and recently, the involvement of small fibers has been suggested. This study aims to investigate the involvement of small peripheral nervous fibers in recovered COVID-19 patients using in-vivo corneal confocal microscopy (CCM). Patients recovered from COVID-19 and a control group of healthy subjects underwent in-vivo CCM. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), corneal nerve fiber total branch density (CTBD), corneal nerve fiber area (CNFA), corneal nerve fiber width (CNFW), fiber tortuosity (FT), number of beadings (NBe), and dendritic cells (DC) density were quantified. We enrolled 302 eyes of 151 patients. CNBD and FT were significantly higher (p = 0.0131, p < 0.0001), whereas CNFW and NBe were significantly lower (p = 0.0056, p = 0.0045) in the COVID-19 group compared to controls. Only CNBD and FT resulted significantly correlated to antiviral drugs (increased) and corticosteroids (decreased). No significant relationship with disease severity parameters was found. COVID-19 may induce peripheral neuropathy in small fibers even months after recovery, regardless of systemic conditions and therapy, and CCM may be a useful tool to identify and monitor these morphological changes.

Corneal dendritic cells and the subbasal nerve plexus following neurotoxic treatment with oxaliplatin or paclitaxel

Immune cell infiltration has been implicated in neurotoxic chemotherapy for cancer treatment. However, our understanding of immune processes is still incomplete and current methods of observing immune cells are time consuming or invasive. Corneal dendritic cells are potent antigen-presenting cells and can be imaged with in-vivo corneal confocal microscopy. Corneal dendritic cell densities and nerve parameters in patients treated with neurotoxic chemotherapy were investigated. Patients treated for cancer with oxaliplatin (n = 39) or paclitaxel (n = 48), 3 to 24 months prior to assessment were recruited along with 40 healthy controls. Immature (ImDC), mature (MDC) and total dendritic cell densities (TotalDC), and corneal nerve parameters were analyzed from in-vivo corneal confocal microscopy images. ImDC was increased in the oxaliplatin group (Median, Md = 22.7 cells/mm2) compared to healthy controls (Md = 10.1 cells/mm2, p = 0.001), but not in the paclitaxel group (Md = 10.6 cells/mm2). ImDC was also associated with higher oxaliplatin cumulative dose (r = 0.33, p = 0.04) and treatment cycles (r = 0.40, p = 0.01). There was no significant difference in MDC between the three groups (p > 0.05). Corneal nerve parameters were reduced in both oxaliplatin and paclitaxel groups compared to healthy controls (p < 0.05). There is evidence of elevation of corneal ImDC in oxaliplatin-treated patients. Further investigation is required to explore this potential link through longitudinal studies and animal or laboratory-based immunohistochemical research.

Characteristics of ocular findings of patients with neuronal intranuclear inclusion disease.

This study aimed to explore the ocular characteristics of neuronal intranuclear inclusion disease (NIID), caused by GGC repeat expansion in the NOTCH2NLC gene, combined with the systemic clinical manifestations, and propose early diagnostic features of NIID. Six patients (12 eyes) were enrolled in this study. In vivo corneal confocal microscopy (IVCCM), fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), full-field electroretinography (ERG), and electromyography were performed. The average corneal nerve fiber density (CNFD) was 6.83 ± 4.96 number/mm2, and the corneal nerve fiber length (CNFL) was 6.76 ± 1.96mm/mm2. The nerves were looser and more curved in affected individuals. Dendritic cells were observed in patients with NIID. Chorioretinal atrophy, hyper-AF spots, and outer retinal abnormalities were observed during FAF imaging and OCT examinations. In full-field ERGs, the amplitudes of the a-wave and b-wave reduced or extinguished over time. The compound muscle action potential and motor nerve conduction velocity of the left common peroneal nerve decreased substantially. The findings of IVCCM and retinal changes should be included in the diagnostic criteria for NIID. Corneal confocal characteristics may precede the systemic neurological manifestations and provide a clinical basis for the early treatment and staging of the disease. ClincalTrials.gov. Identifier: ChiCTR21000500227.

Corneal Sensation and Nerve Fiber Changes in Patients With Interstitial Cystitis.

Central sensitization syndromes are associated with ocular surface discomfort and certain changes in corneal sensation. The aim of this study was to evaluate corneal changes in patients with interstitial cystitis (IC). Thirty patients with IC and 32 healthy control subjects were included in this study. All patients had a detailed ophthalmological examination including measurement of corneal sensation with Cochet-Bonnet esthesiometer, tear breakup time, Schirmer I test, and Ocular Surface Disease Index questionnaire. After these examinations, corneal subbasal nerve plexus of the patients was evaluated with in vivo corneal confocal microscopy (IVCM) and the images were analyzed using fully automated software (ACC Metrics Corneal Nerve Fiber Analyzer V.2). There was no significant difference between the groups regarding age and gender distribution. Corneal sensation was significantly higher in patients with IC (P = 0.03), whereas tear breakup time, Schirmer I test, and Ocular Surface Disease Index scores were similar between the patients and controls. IVCM demonstrated nerve fiber loss in patients with IC. Corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length were significantly reduced in patients with IC compared with healthy controls (P < 0.001, P = 0.04, and P < 0.001, respectively). Patients with IC had increased corneal sensation and decreased nerve fiber density in IVCM analysis. Corneal nerve fiber loss might decrease the induction threshold of the remaining fibers to induce peripheral sensitization, which may also trigger central sensitization in long term.