Corneal neuropathy involves corneal nerve damage that disrupts ocular surface integrity, negatively impacting quality-of-life from pain and impaired vision. Any ocular or systemic condition that damages the trigeminal nerve can lead to corneal neuropathy. However, the condition currently does not have standardized diagnostic criteria or treatment protocols. The primary aim of this systematic review was to evaluate the efficacy and safety of interventions for treating corneal neuropathy. Randomized controlled trials (RCTs) that investigated corneal neuropathy treatments were eligible if the intervention(s) was compared to a placebo or active comparator. Comprehensive searches were conducted in Ovid MEDLINE, Ovid Embase and clinical trial registries from inception to July 2022. The Cochrane Risk-of-Bias 2 tool was used to assess study methodological quality. Certainty of the body of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Overall, 20 RCTs were included. Evaluated interventions comprised regenerative therapies (n = 6 studies), dietary supplements (n = 4), anti-glycemic agents (n = 3), combination therapy (n = 3), supportive therapies (n = 2) and systemic pain pharmacotherapies (n = 2). Nine RCTs were judged at high risk of bias for most outcomes. Definitions for corneal neuropathy in the populations varied substantially across studies, consistent with lack of consensus on diagnostic criteria. A diverse range of outcomes were quantified, likely reflecting absence of an agreed core outcome set. There was insufficient evidence to draw definitive conclusions on the efficacy or safety of any intervention. There was low or very low certainty evidence for several neuroregenerative agents and dietary supplements for improving corneal nerve fiber length in corneal neuropathy due to dry eye disease and diabetes. Low or very low certainty evidence was found for neuroregenerative therapies and dietary supplements not altering corneal immune cell density. This review identifies a need to standardize the clinical definition of corneal neuropathy and define a minimum set of core outcome measures. Together, this will provide a foundation for improved phenotyping of clinical populations in studies, and improve the capacity to synthesize data to inform evidence-based care. Protocol registration: PROSPERO ID: CRD42022348475.

Corneal neuromas, also termed microneuromas, refer to microscopic, irregularly-shaped enlargements of terminal subbasal nerve endings at sites of nerve damage or injury. The formation of corneal neuromas results from damage to corneal nerves, such as following corneal pathology or corneal or intraocular surgeries. Initially, denervated areas of sensory nerve fibers become invaded by sprouts of intact sensory nerve fibers, and later injured axons regenerate and new sprouts called neuromas develop. In recent years, analysis of corneal nerve abnormalities including corneal neuromas which can be identified using in vivo confocal microscopy, a non-invasive imaging technique with microscopic resolution, has been used to evaluate corneal neuropathy and ocular surface dysfunction. Corneal neuromas have been shown to be associated with clinical symptoms of discomfort and dryness of eyes, and are a promising surrogate biomarker for ocular surface diseases, such as neuropathic corneal pain, dry eye disease, diabetic corneal neuropathy, neurotrophic keratopathy, Sjögren\'s syndrome, bullous keratopathy, post-refractive surgery, and others. In this review, we have summarized the current literature on the association between these ocular surface diseases and the presentation of corneal microneuromas, as well as elaborated on their pathogenesis, visualization via in vivo confocal microscopy, and utility in monitoring treatment efficacy. As current quantitative analysis on neuromas mainly relies on manual annotation and quantification, which is user-dependent and labor-intensive, future direction includes the development of artificial intelligence software to identify and quantify these potential imaging biomarkers in a more automated and sensitive manner, allowing it to be applied in clinical settings more efficiently. Combining imaging and molecular biomarkers may also help elucidate the associations between corneal neuromas and ocular surface diseases.

To describe the association between Sars-CoV-2 infection and small fiber neuropathy in the cornea identified by in vivo corneal confocal microscopy.
Twenty-three patients who had overcome COVID-19 were recruited to this observational retrospective study. Forty-six uninfected volunteers were also recruited and studied as a control group. All subjects were examined under in vivo confocal microscopy to obtain images of corneal subbasal nerve fibers in order to study the presence of neuroma-like structures, axonal beadings and dendritic cells. The Ocular Surface Disease Index (OSDI) questionnaire and Schirmer tear test were used as indicators of Dry Eye Disease (DED) and ocular surface pathology.
Twenty-one patients (91.31%) presented alterations of the corneal subbasal plexus and corneal tissue consistent with small fiber neuropathy. Images from healthy subjects did not indicate significant nerve fiber or corneal tissue damage. Eight patients reported increased sensations of ocular dryness after COVID-19 infection and had positive DED indicators. Beaded axons were found in 82.60% of cases, mainly in patients reporting ocular irritation symptoms. Neuroma-like images were found in 65.22% patients, more frequently in those with OSDI scores >13. Dendritic cells were found in 69.56% of patients and were more frequent in younger asymptomatic patients. The presence of morphological alterations in patients up to 10 months after recovering from Sars-CoV-2 infection points to the chronic nature of the neuropathy.
Sars-CoV-2 infection may be inducing small fiber neuropathy in the ocular surface, sharing symptomatology and morphological landmarks with DED and diabetic neuropathy.

OBJECTIVE: Explore potential of 31 tear biomarkers involved in screening for diabetic peripheral neuropathy (DPN). Assess the utility of aesthesiometry for measuring corneal damage in DPN and determine optimal cutoff point for detecting DPN.
METHODS: Screening test pilot study recruited 90 participants from a tertiary hospital in Lima, Peru. Participants were grouped by diabetes and neuropathy status. Tears collected on Schirmer strips, and proteins measured by both ELISA and multiplex-bead assay. Corneal sensitivity was measured by aesthesiometry, and DPN by vibration perception threshold testing.
RESULTS: There were 89 participants included in the analysis. The mean age was 55.7 ± 1.46, and 58.4% were female. MMP-9 and TGF-alpha concentrations were higher in participants with DPN versus diabetes alone, though not significant. Aesthesiometry was decreased in individuals with DPN when compared to participants with diabetes alone (p < 0.01) and normal controls (p < 0.01). Optimal cutoff point for aesthesiometry was found to be 5.8 cm, with 79% sensitivity and 75% specificity.
CONCLUSIONS: Tears are an insufficient standalone tool for detecting DPN based on the biomarkers analyzed. Aesthesiometry is a simple, inexpensive, and accurate method to assess corneal damage associated with moderate-severe DPN, and its integration into screening practices has potential to improve detection of DPN in poor-resource settings.

The article presents a clinical case of Fabry\'s disease accompanied by changes in the eye and gives detailed description of standard ophthalmological examination and results of some modern methods of assessing macro- and micro-structure of certain ocular tissues. Fabry\'s disease (also known as Anderson-Fabry disease, diffuse angiokeratoma of the body, hereditary dystonic lipidosis) is a progressive hereditary multi-systemic disease; more specifically, it is a progressive congenital defect in the metabolism of tissues of the human body. It is included in the list of orphan diseases. One of its local manifestations is development of dystrophic changes in the structure of the cornea with tendency to progress. Early diagnosis of Fabry\'s disease is crucial, but its extensive and \'mixed\' symptoms often mask the true causes of pathological changes, which leads to late diagnosis.
В статье приведен клинический случай болезни Фабри, сопровождающийся изменениями глаз. Подробно описаны данные стандартного клинического офтальмологического обследования и результаты некоторых современных методов оценки макро- и микроструктуры ряда тканей глаза. Болезнь Фабри (болезнь Андерсона-Фабри, диффузная ангиокератома тела, наследственный дистонический липидоз) - прогрессирующее наследственное мультисистемное заболевание, которое представляет собой прогрессирующий врожденный дефект метаболизма тканей человеческого организма и входит в перечень орфанных заболеваний. Развитие дистрофических изменений в структуре роговицы является одним из локальных проявлений. Данные признаки могут иметь тенденцию к прогрессированию. Ранняя диагностика болезни Фабри крайне важна, но обширная, \'смешанная\' симптоматика часто маскирует истинные причины патологических изменений. Это приводит к позднему установлению правильного диагноза.

Diabetes mellitus (DM) is the most common endocrine disease, and therefore a pressing medical and social problem. In many cases, ocular manifestations of DM are considered the particular cause of patients\' disability. The review presents an analysis of morphological, experimental and clinical studies of the cornea in patients with diabetes mellitus - full articles, reviews and monographs of Russian and foreign authors, mostly those published in the recent years. Among the considered topics are modern methods of examining conjunctiva and cornea, clinical and morphological changes in these tissues, and the early diabetic changes in all their structural layers. The review also describes the importance of diabetes-related changes in the conjunctival vessels and corneal nerve fibers and shows the correlation between the densities of corneal nerve fibers and epidermal nerve fibers.
Сахарный диабет (СД) - самое распространенное из эндокринных заболеваний, поэтому является приоритетной медико-социальной проблемой. Часто при диабете именно глазные проявления в первую очередь приводят к инвалидизации больных. В обзоре представлен анализ морфологических, экспериментальных и клинических исследований конъюнктивы и роговицы у пациентов с СД - оригинальные статьи, обзоры и монографии отечественных и зарубежных авторов преимущественно последних лет. Рассмотрены современные методы исследований конъюнктивы и роговицы при СД. Обсуждены клинико-морфологические изменения этих тканей, описаны ранние диабетические изменения их структурных слоев. Представлена важная роль изменений сосудов конъюнктивы и нервных волокон роговицы (НВР) при диабете, показана корреляция между плотностью (НВР) и эпидермальных нервных волокон.

Diabetes mellitus (DM) has been emerging as one of the most serious health problems worldwide. Ocular complications of DM are currently one of the major causes of blindness in developed countries, among which diabetic retinopathy is relatively well studied and understood. However, although ocular surface complications of DM are common, diabetic complications of anterior segment of the eye, such as, cornea, conjunctiva, and lacrimal glands, are often overlooked. DM is associated with progressive damage to corneal nerves and epithelial cells, which increases the risk of anterior segment disorders including dry eye disease, corneal erosion, persistent epithelial defects, and even sight-threatening corneal ulcer. In this review, the authors will discuss the association of DM with disorders of anterior segment of the eye. Studies indicating the value of corneal nerve assessment as a sensitive, noninvasive, and repeatable biomarker for diabetic neuropathy will also be introduced. In addition, treatment modalities of anterior segment disorders associated with DM is discussed. The studies introduced in this review suggest that early and periodic screening of the anterior segment of the eye, as well as the retina, is important for the optimal treatment of DM.

Diabetes mellitus is a chronic disease that results from inadequate insulin production or ineffective insulin utilization. It is one of the most common systemic diseases worldwide with increasing prevalence. Diabetes mellitus is associated with premature mortality, macrovascular complications such as cardiovascular disease, and microvascular complications, including nephropathy leading to kidney failure, potentially blinding diabetic retinopathy, and diabetic neuropathy. While the retinal complications of diabetes are well recognized by eye care professionals, the effects on the ocular surface are poorly understood. Recent studies have reported on the association between peripheral neuropathy and corneal neuropathy, showing the latter to be of predictive value for the systemic disease. Corneal neuropathy can lead to loss of corneal sensation and can ultimately result in neurotrophic ulcers and significant visual morbidity. The epithelial fragility and poor wound healing that result from reduced epithelial adhesion to the underlying basement membrane in diabetes, together with corneal neuropathy, are thought to increase the susceptibility to persistent corneal erosions and infection, as well as to increase the risk of post-surgical complications. The aim of this article is to review the impact of diabetes on corneal nerve morphology and ocular surface integrity. Changes in the tear film and ocular surface microbiome are highlighted in discussion of the mechanisms that underpin ocular surface changes that increase the susceptibility to corneal erosion and infection.

OBJECTIVE: Patients suffering from corneal neuropathy may present with photoallodynia; i.e., increased light sensitivity, frequently with a normal slit-lamp examination. This study aimed to evaluate the efficacy of autologous serum tears (AST) for treatment of severe photoallodynia in corneal neuropathy and to correlate clinical findings with corneal subbasal nerve alterations by in vivo confocal microscopy (IVCM).
METHODS: Retrospective case control study with 16 patients with neuropathy-induced severe photoallodynia compared to 16 normal controls. Symptom severity, clinical examination and bilateral corneal IVCM scans were recorded.
RESULTS: All patients suffered from extreme photoallodynia (8.8±1.1) with no concurrent ocular surface disease. Subbasal nerves were significantly decreased at baseline in patients compared to controls; total nerve length (9208±1264 vs 24714±1056 μm/mm(2); P<.0001) and total nerve number (9.6±1.4 vs 28.6±2.0; P<.0001), respectively. Morphologically, significantly increased reflectivity (2.9±0.2 vs 1.8±0.1; P<.0001), beading (in 93.7%), and neuromas (in 62.5%) were seen. AST (3.6±2.1 months) resulted in significantly decreased symptom severity (1.6±1.7; P=.02). IVCM demonstrated significantly improved nerve parameters (P<.005), total nerve length (15451±1595 μm/mm(2)), number (13.9±2.1), and reflectivity (1.9±0.1). Beading and neuromas were seen in only 56.2% and 7.6% of patients.
CONCLUSIONS: Patients with corneal neuropathy-induced photoallodynia show profound alterations in corneal nerves. AST restores nerve topography through nerve regeneration, and this correlated with improvement in patient-reported photoallodynia. The data support the notion that corneal nerve damage results in alterations in afferent trigeminal pathways to produce photoallodynia.