Corneal Nerve Branch Density Research Articles

Clinical Outcomes of Minimally Invasive Corneal Neurotization After Cerebellopontine Angle Neurosurgical Procedures

PurposeTo report 12 patients with neurotrophic keratopathy due to the trigeminal nerve injury after intracranial tumor surgeries underwent minimally invasive corneal neurotization and evaluate the outcomes of corneal reinnervation.MethodsTwelve patients (12 eyes) with neurotrophic keratopathy caused by the trigeminal nerve injury after intracranial surgeries received minimally invasive corneal neurotization. All the preoperative central corneal sensation was under 5 mm, and minimally invasive corneal neurotization was performed over 6 months after the intracranial surgery. Follow-up was conducted 1 week and 1 month after the surgery and then every 3 months. Twelve healthy age-matched participants were enrolled as controls. The indicators included corneal sensation, best-corrected visual acuity, corneal nerve fiber length and branch density, diameter of nerve trunk, corneal ulcer lesion ratio, and sensation of the contralateral forehead.ResultsMean follow-up was 24.7 ± 7.1 months. Mean central corneal sensation rose from 0.4 ± 1.4 to 31.7 ± 21.8 mm. Corneal nerve fiber length improved from 9.56 ± 5.00 to 14.96 ± 4.65 mm/mm2 and corneal nerve branch density and diameter of nerve trunk both increased (p < .01 and p < .05, respectively). Corneal lesion ratio decreased from 0.17 ± 0.12 to 0.10 ± 0.10 (p < .01).ConclusionsMinimally invasive corneal neurotization promotes corneal reinnervation for patients with neurotrophic keratopathy induced by the trigeminal nerve injury after intracranial surgeries. The process of corneal reinnervation after minimally invasive corneal neurotization often lasts over 12 months, and it takes about 18 months to return to a higher level. Corneal sensation and corneal nerve fiber length are related to clinical outcomes such as corneal ulcer lesion and best-corrected visual acuity. The effect on the sensation of the contralateral side forehead is temporary, and most patients can restore normal forehead sensation of the contralateral side.

Changes in corneal nerve morphology and function in patients with dry eyes having type 2 diabetes.

BACKGROUNDDry eye syndrome (DES) is a common disease with various clinical manifestations. DES had a significant association with diabetes. Blink reflex (BR) is also known as trigeminal nerve facial reflex. The stimulation of corneal nerves is one of the origins of BR stimulation. The parasympathetic fibers sent out through the facial nerve are the outlet of tear reflexes. BR can be used to assess the function of the corneal nerve closed-loop; however, whether the BR changes in these patients is unclear.AIMTo understand the morphology and function of the corneal nerve in patients with dry eyes having diabetes or not. METHODSThis study enrolled 131 patients who visited the inpatient and outpatient services of ophthalmology and endocrinology departments between January 2019 to August 2020 with subjective symptoms of dry eyes and non-dry eye reasons, as well as volunteers such as colleagues. The patients were divided into four groups: DEwDM, with dry eyes having type 2 diabetes mellitus (T2DM); DMnDE, with T2DM not having dry eyes; DEnDM, with dry eyes not having diabetes; and nDMnDE, with neither dry eyes nor diabetes. The tear film break-up time, Schirmer I test, in vivo confocal microscopy, and BR were performed.RESULTSThe DEwDM, DMnDE, DEnDM, and nDMnDE groups included 56, 22, 33, and 20 patients, respectively. Sex and age were not statistically different among the four groups. The nerve fiber length (NFL) of patients in the DEwDM, DEnDM, and DMnDE groups reduced (P < 0.001, P = 0.014, and P = 0.001, respectively). No significant difference in corneal nerve fiber density (NFD) (P = 0.083) and corneal nerve branch density (NBD) (P = 0.195) was found among the four groups. The R1 Latency of blink reflexes increased only in the DEwDM group (P = 0.008, P = 0.001, P < 0.001, compared with the DMnDE, DEnDM, and nDMnDE groups, respectively). The NBD and R1 Latency were different between DEwDM and DEnDM groups in patients with moderate and severe dry eyes. CONCLUSIONThe corneal nerve morphology changed in patients with dry eyes or diabetes, or with both, while the function of corneal nerve closed-loop reduced only in those with dry eyes and diabetes.

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.

Altered Circulating microRNAs in Patients with Diabetic Neuropathy and Corneal Nerve Loss: A Pilot Study.

An alteration in circulating miRNAs may have important diagnostic and therapeutic relevance in diabetic neuropathy. Patients with type 2 diabetes mellitus (T2DM) underwent an assessment of neuropathic symptoms using Douleur Neuropathique 4 (DN4), the vibration perception threshold (VPT) using a Neurothesiometer, sudomotor function using the Sudoscan, corneal nerve morphology using corneal confocal microscopy (CCM) and circulating miRNAs using high-throughput miRNA expression profiling. Patients with T2DM, with (n = 9) and without (n = 7) significant corneal nerve loss were comparable in age, gender, diabetes duration, BMI, HbA1c, eGFR, blood pressure, and lipid profile. The VPT was significantly higher (p < 0.05), and electrochemical skin conductance (p < 0.05), corneal nerve fiber density (p = 0.001), corneal nerve branch density (p = 0.013), and corneal nerve fiber length (p < 0.001) were significantly lower in T2DM patients with corneal nerve loss compared to those without corneal nerve loss. Following a q-PCR-based analysis of total plasma microRNAs, we found that miR-92b-3p (p = 0.008) was significantly downregulated, while miR-22-3p (p = 0.0001) was significantly upregulated in T2DM patients with corneal nerve loss. A network analysis revealed that these miRNAs regulate axonal guidance and neuroinflammation genes. These data support the need for more extensive studies to better understand the role of dysregulated miRNAs’ in diabetic neuropathy.

Corneal nerve loss in patients with TIA and acute ischemic stroke in relation to circulating markers of inflammation and vascular integrity

Vascular and inflammatory mechanisms are implicated in the development of cerebrovascular disease and corneal nerve loss occurs in patients with transient ischemic attack (TIA) and acute ischemic stroke (AIS). We have assessed whether serum markers of inflammation and vascular integrity are associated with the severity of corneal nerve loss in patients with TIA and AIS. Corneal confocal microscopy (CCM) was performed to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) in 105 patients with TIA (n = 24) or AIS (n = 81) and age matched control subjects (n = 56). Circulating levels of IL-6, MMP-2, MMP-9, E-Selectin, P-Selectin and VEGF were quantified in patients within 48 h of presentation with a TIA or AIS. CNFL (P = 0.000, P = 0.000), CNFD (P = 0.122, P = 0.000) and CNBD (P = 0.002, P = 0.000) were reduced in patients with TIA and AIS compared to controls, respectively with no difference between patients with AIS and TIA. The NIHSS Score (P = 0.000), IL-6 (P = 0.011) and E-Selectin (P = 0.032) were higher in patients with AIS compared to TIA with no difference in MMP-2 (P = 0.636), MMP-9 (P = 0.098), P-Selectin (P = 0.395) and VEGF (P = 0.831). CNFL (r = 0.218, P = 0.026) and CNFD (r = 0.230, P = 0.019) correlated with IL-6 and multiple regression analysis showed a positive association of CNFL and CNFD with IL-6 (P = 0.041, P = 0.043). Patients with TIA and AIS have evidence of corneal nerve loss and elevated IL6 and E-selectin levels. Larger longitudinal studies are required to determine the association between inflammatory and vascular markers and corneal nerve fiber loss in patients with cerebrovascular disease.

Corneal Nerve Parameter Reference Values for Chinese Adults Assessed by Corneal Confocal Microscopy.

Background Confocal corneal microscopy is an excellent new noninvasive tool for assessing diabetic peripheral neuropathy. We aimed to investigate the clinical variables associated with corneal nerve parameters and establish reference values for clinical use in healthy Chinese adults. Methods The study enlisted 257 healthy volunteers (137 females and 120 males) from two clinical academic centers in China. Two experts captured and selected images of the central corneal subbasal nerve plexus at each center using the same corneal confocal microscopy instrument according to a commonly adopted protocol. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were measured using fully automated software (ACCMetrics). The correlation between clinical indicators and confocal corneal microscopy measures was determined using partial correlation. Quantile regression was used to calculate reference values and estimate the effects of clinical factors on the normative values of confocal corneal microscopy measures. Results Females had significantly higher CNFD, CNBD, and CNFL than males. There was no correlation between age, glycated hemoglobin (HbA1c), height, weight, body mass index (BMI), and any corneal nerve fiber parameter in both sexes. In either sex, age, weight, height, BMI, and HbA1c did not affect the 0.05th quantile values of any corneal nerve parameter. Conclusions This study establishes sex-adjusted reference values for corneal confocal microscopy measures in Chinese adults and provides a reference for clinical practice and research with this technique.

Semiautomated and Automated Quantitative Analysis of Corneal Sub-Basal Nerves in Patients With DED With Ocular Pain Using IVCM.

PurposeInvestigate the correlation and agreement between the results of semiautomated and fully automated quantitative analysis of the corneal sub-basal nerve plexus (SNP) in patients with dry eye disease (DED) with ocular pain using in vivo confocal microscopy (IVCM).MethodA total of 50 voluntary participants were enrolled in this study, i.e., 25 DED patients with ocular pain and 25 healthy controls. Each patient underwent an evaluation of ocular symptoms that utilized: the Ocular Surface Disease Index (OSDI), the Ocular Pain Assessment Survey (OPAS), the tear film breakup time (TBUT) test, the Schirmer test, corneal staining, and IVCM. Five SNP images of the cornea of each eye were selected and analyzed using a semiautomated analysis software (NeuronJ) and a fully automated method (ACCMetrics) to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL).ResultsThe intraclass correlation coefficient (ICC) of the CNFD (0.460 [0.382–0.532], p < 0.001), CNBD (0.608 [0.545–0.665], p < 0.001), and CNFL (0.851 [0.822–0.875], p < 0.001) represents the repeatability and consistency of measurements by the NeuronJ and ACCMetrics software. The CNFL values (r = 0.881, p < 0.001) obtained using the two methods have extremely high correlation, and similarly, the CNFD values (r = 0.669, p < 0.001) and CNBD values (r = 0.703, p < 0.001) are highly correlated. The CNFL had the biggest area under the curve (AUC; 0.747 [0.700–0.793], p < 0.001) when using ACCMetrics. In DED patients with ocular pain, the mean CNFD values for semiautomated and fully automated quantization were 23.5 ± 8.1 and 23.8 ± 8.6 n/mm2; the mean CNBD values were 46.0 ± 21.3, 35.7 ± 23.3 n/mm2; and the mean CNFL values were 19.3 ± 4.3 and 15.2 ± 3.8 mm/mm2, which were significantly lower than healthy subjects (p < 0.001).ConclusionThere is a significant correlation between the measurements obtained via ACCMetrics and NeuronJ, especially for CNFL, which can be considered as the primary indicator in the diagnosis of DED with ocular pain. The SNP of the disease was significantly lower than that of healthy subjects.

Abstract WMP120: Vascular Risk Factor Reduction Is Associated With Corneal Nerve Regeneration In Patients With Tia And Ischemic Stroke

Background and Purpose: Vascular risk factors are associated with transient ischemic attack (TIA), acute ischemic stroke (AIS) and corneal nerve damage. We have assessed if an improvement in vascular risk factors in patients with TIA and AIS is associated with corneal nerve regeneration. Methods: Patients with TIA or AIS and control subjects underwent assessment of clinical and vascular risk factors and corneal confocal microscopy (CCM) at baseline and 1-year follow up. Results: Eighty-one patients with TIA (n=28), AIS (n=53) and control subjects (n=56) were studied. Systolic blood pressure (SBP)( P =0.000), diastolic blood pressure (DBP) ( P =0.000) and HbA1 c (P=0.000) were significantly higher and HDL ( P =0.000), corneal nerve fiber length (CNFL) (P=0.000), corneal nerve fiber density (CNFD) (P=0.000) and corneal nerve branch density (CNBD) (P=0.003) were significantly lower in patients with TIA/AIS compared to controls. At follow up, there was a significant decrease in triglycerides (-0.37 mmol/l, P=0.005), total cholesterol (-1.12 mmol/l, P=0.000); LDL-cholesterol (-1.08 mmol/l, P=0.000), SBP (-24.76 mmHg, P=0.000), DBP (-14.24 mmHg, P=0.000) and HbA1 c (-0.50 mmol/l, P=0.027) and an increase in HDL (0.10 mmol/l, P=0.010), CNFL (1.48 mm/mm 2 , P=0.018), CNFD (1.66 no./mm 2 , P=0.024), and CNBD (26.90 no./mm 2 , P=0.000). The improvement in lipids and blood pressure was associated with an increase in corneal nerve parameters ( P &lt;0.05). Conclusions: An improvement in vascular risk factors in patients with TIA or AIS is associated with corneal nerve regeneration. CCM could be used to assess the effectiveness of risk factor reduction in patients with TIA or AIS.

Corneal confocal microscopic characteristics of acute angle-closure crisis

BackgroundTo investigate characteristics of the acute angle-closure crisis (AACC) and fellow eyes using confocal microscopy.MethodsUnilateral AACC patients hospitalized at the Xi’an People’s Hospital from October 2017 to October 2020 were recruited in this cross-sectional study. Age-matched participants scheduled for cataract surgery were enrolled as a healthy control group. Corneal epithelial cells, subepithelial nerve fiber plexus, stromal cells, and endothelial cells were examined by confocal and specular microscopy.ResultsThis study enrolled 41 unilateral AACC patients (82 eyes) and 20 healthy controls (40 eyes). Confocal microscopy revealed that the corneal nerve fiber density, corneal nerve branch density and corneal nerve fiber length were reduced significantly in AACC eyes. The stromal cells were swollen and the size of the endothelial cells was uneven with the deposition of punctate high-reflective keratic precipitate on the surface. In severe cases, the cell volume was enlarged, deformed, and fused. The corneal subepithelial nerve fiber, stromal layer, and endothelial layer were unremarkable in the fellow eyes, and the density of the endothelial cells was 2601 ± 529 cells/mm2, which was higher than 1654 ± 999 cells/mm2 in AACC eyes (P < 0.001). Corneal edema prevented the examination of 17 eyes using specular microscopy and in only four eyes using confocal microscopy. There were no significant differences in endothelial cell density between confocal and specular microscopy in the AACC eyes (P = 0.674) and fellow eyes (P = 0.247). The hexagonal cell ratio reduced significantly (P < 0.001), and average cell size and coefficient of variation of the endothelial cells increased significantly compared with fellow eyes (P < 0.001, P = 0.008).ConclusionsAACC eye showed decreased density and length of corneal subepithelial nerve fiber plexus, activation of stromal cells, increased endothelial cell polymorphism, and decreased density.

Biomarkers of in vivo limbal stem cell function

PurposeTo evaluate in vivo parameters as biomarkers of limbal stem cell function and to establish an objective system that detects and stage limbal stem cell deficiency (LSCD). MethodsA total of 126 patients (172 eyes) with LSCD and 67 normal subjects (99 eyes) were included in this observational cross-sectional comparative study. Slit-lamp biomicroscopy, in vivo laser scanning confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT) were performed to obtain the following: clinical score, cell morphology score, basal cell density (BCD), central corneal epithelial thickness (CET), limbal epithelial thickness (LET), total corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and tortuosity coefficient. Their potential correlations with the severity of LSCD were investigated, and cutoff values were determined. ResultsAn increase clinical score correlated with a decrease in central cornea BCD, limbal BCD, CET, mean LET, maximum LET, CNFL, CNFD, CNBD, and tortuosity coefficient. Regression analyses showed that central cornea BCD, CET and CNFL were the best parameters to differentiate LSCD from normal eyes (Coef = 3.123, 3.379, and 2.223; all p < 0.05). The rank correlation analysis showed a similar outcome between the clinical scores and the central cornea BCD (ρ = 0.79), CET (ρ = 0.82), and CNFL (ρ = 0.71). A comprehensive LSCD grading formula based on a combination of these parameters was established. ConclusionsA comprehensive staging system combining clinical presentation, central cornea BCD, CET, and CNFL is established to accurately and objectively diagnose LSCD and stage its severity.

Corneal nerve fiber measures independently predict progression from MCI to dementia: Follow‐up of the Qatar Longitudinal Study Cohort

AbstractBackgroundThere is an urgent need for biomarkers of neurodegeneration to identify individuals with MCI at higher risk for developing dementia. Corneal confocal microscopy (CCM) is a non‐invasive imaging biomarker which has identified corneal nerve loss in individuals with mild cognitive impairment (MCI) and dementia. This study assessed the predictive capability of CCM and MRI brain volumetry for progression from participants with MCI to dementia.MethodIn this prospective study, participants aged 50‐85 with MCI underwent assessment of clinical dementia rating (CDR), Montreal cognitive assessment (MoCA), MRI brain volumetry and CCM at baseline and CDR and MoCA at 1‐4 year follow‐up.ResultThe study cohort comprised 107 participants with MCI aged 68.4±7.7 years. Over a median follow‐up of 2.4 years, 33 of 107 participants (30.8%) with MCI progressed to dementia. Corneal nerve fibre density (P&lt;0.0001), branch density (P&lt;0.0001) and length (P&lt;0.0001) were significantly lower in MCI participants who progressed to dementia. Reduced baseline corneal nerve fiber density (≤25 fiber/mm2), length (≤15 mm/mm2) and branch density (≤44 branches/mm2) accurately predicted future dementia (area under the curve (AUC) = 71‐74%, P≤0.0001). Reduced baseline intra‐cranial volume percentage (ICV %), hippocampus (≤0.44%), whole brain (≤69.4%), frontal lobe (≤10.8%), amygdala (≤0.17%), cortical gray matter (≤29%), thalamus (≤0.90%) and increased ventricle (≥3.0%) volume predicted future dementia (AUC = 65‐78%, P&lt;0.05), whilst temporal, parietal, occipital lobe, entorhinal cortex, cingulate gyrus and brainstem did not. The adjusted odds ratios (AOR) for progression to dementia were 5.1‐11.1 times higher with abnormal corneal nerve fiber measures (P&lt;0.05), 5.9 higher with abnormal hippocampal volume (P&lt;0.05) and 10.8 times higher with whole‐brain volume (P&lt;0.05).ConclusionThe predictive capability of CCM is comparable to hippocampal and whole brain volume for progression to dementia in individuals with MCI.

Reduced Corneal Sensitivity With Neuronal Degeneration is a Novel Clinical Feature in Wolfram Syndrome

To evaluate corneal sensitivity and corneal nerve morphology among patients with Wolfram syndrome (WFS). An observational clinical case series with confirmatory experiments. We included a group of 12 patients with biallelic mutations in the WFS1 gene and a control group composed of 30 individuals with type 1 diabetes (T1D). All participants (n=42) underwent a complete ophthalmic examination, esthesiometry, and retinal nerve fiber layer assessment using optical coherence tomography. Morphologic assessment of corneal neuropathy by in vivo corneal confocal microscopy was conducted in 11 patients with WFS (both eyes) and 1 WFS patient (1 eye) as well as in 24 patients with T1D (both eyes in 6 patients and 1 eye in 18 patients). Additionally, corneas from Wfs1KO mice and their wild-type littermates were subjected to laser scanning confocal microscopy. Corneal sensitivity was significantly reduced in patients with WFS compared with patients with T1D (4.50 cm [interquartile range, 3.50-5.50 cm] vs 6.00 cm [interquartile range, 6.00-6.00 cm]; P < 10-5). Additionally, corneal nerve fiber and branch density as well as nerve fiber length were low among patients with WFS. Corneal sensitivity correlated with macular average thickness (R=0.6928; P=.039) and best-corrected visual acuity (R=-0.61; P=.002) in the WFS group. Similarly, Wfs1 knockout mice also presented corneal neurodegeneration changes when corneal nerve fiber density and length were measured using laser scanning confocal microscopy. Decreased corneal sensitivity and corneal nerve degeneration are observed in WFS. Corneal sensitivity is linked with the degree of disease progression as measured by visual acuity and retinal thinning.

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.

Corneal nerve loss is related to the severity of painful diabetic neuropathy

Background and purposePreviously it has been shown that patients with painful diabetic neuropathy (PDN) have greater corneal nerve loss compared to patients with painless diabetic neuropathy. This study investigated if the severity of corneal nerve loss was related to the severity of PDN.MethodsParticipants with diabetic neuropathy (n = 118) and healthy controls (n = 38) underwent clinical and neurological evaluation, quantitative sensory testing, nerve conduction testing and corneal confocal microscopy and were categorized into those with no (n = 43), mild (n = 34) and moderate‐to‐severe (n = 41) neuropathic pain.ResultsCorneal nerve fibre density (p = 0.003), corneal nerve fibre length (p < 0.0001) and cold perception threshold (p < 0.0001) were lower and warm perception threshold was higher (p = 0.002) in patients with more severe pain, but there was no significant difference in the neuropathy disability score (p = 0.5), vibration perception threshold (p = 0.5), sural nerve conduction velocity (p = 0.3) and amplitude (p = 0.7), corneal nerve branch density (p = 0.06) and deep breathing heart rate variability (p = 0.08) between patients with differing severity of PDN. The visual analogue scale correlated significantly with corneal nerve fibre density (r = −0.3, p = 0.0002), corneal nerve branch density (r = −0.3, p = 0.001) and corneal nerve fibre length (r = −0.4, p < 0.0001). Receiver operating curve analysis showed that corneal nerve fibre density had an area under the curve of 0.78 with a sensitivity of 0.73 and specificity of 0.72 for the diagnosis of PDN.ConclusionsCorneal confocal microscopy reveals increasing corneal nerve fibre loss with increasing severity of neuropathic pain and a good diagnostic outcome for identifying patients with PDN.

Corneal nerve loss as a surrogate marker for poor pial collaterals in patients with acute ischemic stroke

In patients with acute ischemic stroke, pial collaterals play a key role in limiting neurological disability by maintaining blood flow to ischemic penumbra. We hypothesized that patient with poor pial collaterals will have greater corneal nerve and endothelial cell abnormalities. In a cross-sectional study, 35 patients with acute ischemic stroke secondary to middle cerebral artery (MCA) occlusion with poor (n = 12) and moderate-good (n = 23) pial collaterals and 35 healthy controls underwent corneal confocal microscopy and quantification of corneal nerve and endothelial cell morphology. In patients with MCA stroke, corneal nerve fibre length (CNFL) (P < 0.001), corneal nerve fibre density (CNFD) (P = 0.025) and corneal nerve branch density (CNBD) (P = 0.002) were lower compared to controls. Age, BMI, cholesterol, triglycerides, HDL, LDL, systolic blood pressure, NIHSS and endothelial cell parameters did not differ but mRS was higher (p = 0.023) and CNFL (p = 0.026) and CNBD (p = 0.044) were lower in patients with poor compared to moderate-good collaterals. CNFL and CNBD distinguished subjects with poor from moderate-good pial collaterals with an AUC of 72% (95% CI 53–92%) and 71% (95% CI 53–90%), respectively. Corneal nerve loss is greater in patients with poor compared to moderate-good pial collaterals and may act as a surrogate marker for pial collateral status in patients with ischemic stroke.

Comparing the results of manual and automated quantitative corneal neuroanalysing modules for beginners

This study aimed to evaluate the reliability of in vivo confocal microscopic neuroanalysis by beginners using manual and automated modules. Images of sub-basal corneal nerve plexus (SCNP) from 108 images of 18 healthy participants were analyzed by 7 beginner observers using manual (CCMetrics, [CCM]) and automated (ACCMetrics, [ACCM]) module. SCNP parameters analyzed included corneal nerve fiber density (NFD), corneal nerve branch density (NBD), corneal nerve fiber length (NFL), and tortuosity coefficient (TC). The intra-observer repeatability, inter-observer reliability, inter-module agreement, and left–right eye symmetry level of SCNP parameters were examined. All observers showed good intra-observer repeatability using CCM (intraclass correlation coefficient [ICC] > 0.60 for all), except when measuring TC. Two observers demonstrated especially excellent repeatability in analyzing NFD, NBD, and NFL using manual mode, indicating the quality of interpretation may still be observer-dependent. Among all SCNP parameters, NFL had the best inter-observer reliability (Spearman’s rank-sum correlation coefficient [SpCC] and ICC > 0.85 for the 3 original observers) and left–right symmetry level (SpCC and ICC > 0.60). In the additional analysis of inter-observer reliability using results by all 7 observers, only NFL showed good inter-observer reliability (ICC = 0.79). Compared with CCM measurements, values of ACCM measurements were significantly lower, implying a poor inter-module agreement. Our result suggested that performance of quantitative corneal neuroanalysis by beginners maybe acceptable, with NFL being the most reliable parameter, and automated method cannot fully replace manual work.

Corneal nerve fiber loss relates to cognitive impairment in patients with Parkinson\u2019s disease

Cognitive impairment in Parkinson’s disease (PD) adversely influences quality of life. There is currently no available biomarker to predict cognitive decline in PD. Corneal confocal microscopy (CCM) has been used as a non-invasive tool for quantifying small nerve damage in PD. The present study investigated whether corneal nerve measures were associated with cognitive function in PD. Patients with PD were classified into those with normal cognitive function (PD-CN), mild cognitive impairment (PD-MCI), and dementia (PDD). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were quantified with CCM and compared with a control group. Sixty-five PD patients and thirty controls were studied. CNFD was decreased and CNBD was increased in PD patients compared to controls (P < 0.05). CNBD and CNBD/CNFD ratio was higher in PD-CN compared to controls. CNFD was positively correlated with the Montreal cognitive assessment (MoCA) score (r = 0.683, P < 0.001), but negatively associated with unified Parkinson disease rating scale (UPDRS)-part III (r = −0.481, P < 0.001) and total UPDRS scores (r = −0.401, P = 0.001) in PD patients. There was no correlation between CNFD and Levodopa equivalent daily dose (LEDD) (r = 0.176, P = 0.161). CNFD, CNBD, CNFL, and CNBD/CNFD ratio was lower with increasing Hoehn and Yahr stage. PD patients show evidence of corneal nerve loss compared with controls and corneal nerve parameters are associated with the severity of cognitive and motor dysfunction in PD. CCM could serve as an objective in vivo ophthalmic imaging technique to assess neurodegeneration in PD.

Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta-analysis.

ABSTRACTIntroductionCorneal confocal microscopy (CCM) is a rapid non‐invasive ophthalmic imaging technique that identifies corneal nerve fiber damage. Small studies suggest that CCM could be used to assess patients with diabetic peripheral neuropathy (DPN).AimTo undertake a systematic review and meta‐analysis assessing the diagnostic utility of CCM for sub‐clinical DPN (DPN−) and established DPN (DPN+).Data sourcesDatabases (PubMed, Embase, Central, ProQuest) were searched for studies using CCM in patients with diabetes up to April 2020.Study selectionStudies were included if they reported on at least one CCM parameter in patients with diabetes.Data extractionCorneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length (IWL) were compared between patients with diabetes with and without DPN and controls. Meta‐analysis was undertaken using RevMan V.5.3.Data synthesisThirty‐eight studies including ~4,000 participants were included in this meta‐analysis. There were significant reductions in CNFD, CNBD, CNFL, and IWL in DPN− vs controls (P < 0.00001), DPN+ vs controls (P < 0.00001), and DPN+ vs DPN− (P < 0.00001).ConclusionThis systematic review and meta‐analysis shows that CCM detects small nerve fiber loss in subclinical and clinical DPN and concludes that CCM has good diagnostic utility in DPN.

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.].

Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID

Background/AimsLong COVID is characterised by a range of potentially debilitating symptoms which develop in at least 10% of people who have recovered from acute SARS-CoV-2 infection. This study has quantified...