Long-term clinical outcome and satisfaction survey in patients with neurotrophic keratopathy after treatment with cenegermin eye drops or amniotic membrane transplantation.

PURPOSE: Neurotrophic keratopathy (NK) is a degenerative corneal disease caused by damage of trigeminal innervation. The purpose of this study is to evaluate the clinical outcomes and patient-reported satisfaction of treatment with amniotic membrane transplantation (AMT) or cenegermin eye drops in patients with NK. METHODS: Clinical charts of patients with NK treated with AMT (group A) or cenegermin eye drops (group B), with at least 12 months of follow-up, were reviewed for demographics, medical history, corneal healing, and disease recurrence. Patient satisfaction was evaluated by a newly developed questionnaire investigating patient's appreciation of treatment of NK (2 items) and satisfaction with NK treatment outcomes (5 items). RESULTS: At the end of treatment, complete corneal healing was observed in 13/15 (86%) patients in group A and in 23/24 (96%) in group B. At 12 months follow-up, 6/13 patients (46%) in group A and 3/23 patients (13%) in group B showed recurrence of NK (p = 0.037). Survival analysis showed that group B remained recurrence free for a significantly longer period of time than the group A (p = 0.028). Patients in group B showed a significantly higher satisfaction when compared with patients in group A (total score: 65.7 ± 15.7 vs 47.4 ± 12.8, p = 0.003), both in terms of patients' appreciation of treatment (78.3 ± 15.9 vs 52.2 ± 30, p = 0.020) and satisfaction with treatment outcomes (60.7 ± 21 vs 45.4 ± 13.3, p = 0.037). CONCLUSIONS: Treatment of NK with cenegermin was associated with long-term maintenance of corneal integrity and a higher degree of patient satisfaction.

Involvement of ocular surface in graft-versus-host disease: An update from immunopathogenesis to treatment.

Graft-versus-host disease is a common complication of hematopoietic stem cell transplantation and the ocular surface is a main target of inflammatory reaction.

Health-related quality of life in children at the diagnosis of Vernal Keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a bilateral, chronic, allergic condition mostly affecting children. Clinical evaluations may not necessarily reflect the impact of the disease on the patients' health-related quality of life (HRQoL). We aimed to evaluate HRQoL in children at VKC diagnosis and to analyze correlations between HRQoL and clinical and laboratory variables. METHODS: We studied 5- to 12-year-old patients with VKC. Data on clinical history, instrumental eye evaluations, blood examinations, and visual analog scale (VAS) for the subjective symptoms were collected. HRQoL was assessed through a disease-specific validated Quality of Life in Children with Vernal Keratoconjunctivitis (QUICK) questionnaire. RESULTS: Seventy subjects were included in the analysis (female/male: 10/60; tarsal/mixed VKC form: 36/34). Clinical severity of VKC according to the Bonini scale was as follows: 14, mild; 36, moderate; and 20, severe. No significant difference was found concerning the distribution of patient age, gender, and history of allergic manifestations between tarsal and mixed VKC. A significant positive correlation was found between all QUICK scores and VAS scores, including different VAS subscale, while no significant correlation was found between QUICK scores and total sign scores, Schirmer's test, and corneal thickness. The presence of active severe VKC was not associated with worse HRQoL. CONCLUSIONS: Our evidence shows that VKC patients experience impairment of HRQoL, especially in relation to the perception of symptoms independently of the ophthalmologic changes found, and that the QUICK questionnaire could be a useful tool to evaluate HRQoL in children with VKC, which may improve patients' classification and management.

Allergy screening in a schoolchildren-based population.

BACKGROUND: Schoolchildren screening for allergic diseases may improve early identification and management of atopic children. The aim of this study was to perform a schoolchildren screening program for identification of children with allergic diseases. METHODS: All parents of children attending to 13 primary schools in the city of Rome were requested to fill in a demographic data form and the ChAt questionnaire. Allergological evaluation was performed in the children with suspect of allergy (ChAt score > 2). Ocular examination was performed to identify signs of allergic conjunctivitis. The presence of allergic symptoms was related to demographic and environmental variables. RESULTS: A total of 2667 children (mean age: 7.1 ± 1 years) were included, and 2489 (93.3%) parents completed the ChAt questionnaire. Results of ChAt questionnaire showed a previous diagnosis of allergic disease in 637 (25.6%) children and the potential presence of an allergic disease (ChAt score > 2) in 35.1%. Multivariate analysis showed that older age, male gender, and having less than two siblings were associated with higher risk of allergic disease. Visual screening showed the presence of clinical signs of allergic conjunctivitis in 2% of children. Allergologic evaluation in 334 children confirmed the diagnosis of allergic disease in 324 (97%) cases. Among them, 97 (29.9%) did not refer to a previous formal diagnosis of allergic condition. CONCLUSIONS: This study confirmed that schoolchildren screening using ChAt questionnaire could represent a useful tool for early identification of yet undiagnosed atopic children.

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR-proNGF pathway.

Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.

Chronic obstructive pulmonary disease may complicate Alzheimer's disease: a comorbidity problem.

BACKGROUND AND AIM: Chronic obstructive pulmonary disease (COPD) may be associated with worsening of cognitive performance. We studied patients with Alzheimer's disease (AD) with and without COPD, and we analyzed, in a retrospective way, clinical and neuropsychological variables to verify if COPD plays a pejorative role on cognitive or functional autonomy in patients with dementia. METHODS: We enrolled 23 adult patients (AD-COPD) with probable AD and COPD and 23 with AD only (AD-only); they were matched for sex, age, educational level, and Mini Mental State Examination (MMSE) at the disease onset. Global cognitive status was estimated using MMSE at the first assessment and after 24 months. Memory, executive functions, praxia, and language were the other cognitive domains analyzed. The two groups were also compared for the presence of behavioral disorders (anxiety, depression). RESULTS: AD-COPD had worse results in executive functions screening than AD-only; no significant differences were found comparing other cognitive domains; moreover, there was no significant difference between the two groups considering the decrease in MMSE scores. AD-COPD also showed a higher presence of depression. DISCUSSION: COPD is known to be associated with the development of cognitive deficits, in particular, regarding for executive functions and attention, memory and logical reasoning. In this context, MMSE has a low diagnostic accuracy to underline effective cognitive impairment in AD-COPD. Our study shows a higher frequency of frontal deficits and behavioral disturbances in patients with AD and COPD than patients with AD-only. COPD could complicate the management of AD patients, thus necessitating a closer and multidisciplinary monitoring.

Understanding the Pathogenesis of Neurotrophic Keratitis: The Role of Corneal Nerves.

Neurotrophic keratitis (NK) is a rare degenerative disease of the cornea caused by trigeminal nerve damage, which leads to loss of corneal sensitivity, corneal epithelium breakdown, and poor healing. Though extremely uncommon, NK is increasingly recognized for its characteristics as a distinct and well-defined clinical entity rather than a rare complication of various diseases that can disrupt trigeminal innervation. Indeed, the defining feature of NK is loss of corneal sensitivity, and its clinical findings do not correlate with the wide range of systemic or ocular conditions that underlie trigeminal nerve damage. Despite increasing awareness of NK as a distinct condition, its management continues to be challenged by the lack of treatments that target nerve regeneration. This review focuses on the role of corneal nerves in maintaining ocular surface homeostasis, the consequences (such as alterations in neuromediators and corneal cell morphology/function) of impaired innervation, and advances in NK diagnosis and management. Novel therapeutic strategies should aim to improve corneal innervation in order support corneal renewal and healing. J. Cell. Physiol. 232: 717-724, 2017. © 2016 Wiley Periodicals, Inc.

Frontotemporal Dementia Presenting as Gambling Disorder: When a Psychiatric Condition Is the Clue to a Neurodegenerative Disease.

Behavioral variant frontotemporal dementia, the most common form of frontotemporal dementia, is characterized by executive dysfunction and changes in personality and behavior, sometimes with associated psychiatric disorders. We report a man who suddenly developed a gambling disorder when he was 55 years old. A year later he developed personality changes of agitation, euphoria, and disinhibition, along with binge eating and dysthymia. He did not improve on paroxetine 40 mg/day. Two years after the onset of his symptoms, he came to our clinic for evaluation. Neuropsychological testing showed deficits in cognitive control, planning, and attention. Brain magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans showed predominant frontal and temporal alterations, worse in the right hemisphere than the left. Cerebrospinal fluid analysis was not compatible with Alzheimer disease. On the basis of current criteria, we gave him a diagnosis of probable behavioral variant frontotemporal dementia presenting with a psychiatric symptom. Our findings in this unusual patient confirm the importance of close clinical monitoring in people who have a psychiatric disorder with atypical features, because the condition may mask an underlying neurodegenerative disease.

Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders.

The tear film represents the interface between the eye and the environment. The alteration of the delicate balance that regulates the secretion and distribution of the tear film determines the dry eye (DE) syndrome. Despite having a multifactorial origin, the main risk factors are female gender and advanced age. Likewise, morphological changes in several glands and in the chemical composition of their secretions, such as proteins, mucins, lipidics, aqueous tears, and salinity, are highly relevant factors that maintain a steady ocular surface. Another key factor of recurrence and onset of the disease is the presence of local and/or systemic inflammation that involves the ocular surface. DE syndrome is one of the most commonly encountered diseases in clinical practice, and many other causes related to daily life and the increase in average life expectancy will contribute to its onset. This review will consider the disorders of the ocular surface that give rise to such a widespread pathology. At the end, the most recent therapeutic options for the management of DE will be briefly discussed according to the specific underlying pathology.

Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings.

Corneal dystrophies are a heterogeneous group of bilateral, inherited, rare diseases characterized by slowly progressive corneal opacities, that lead to visual impairment. Most of them have an autosomal dominant pattern of inheritance with variable expressivity, but new mutations have been described. Many corneal dystrophies have been genetically characterized and the specific gene mutations identified, such as for the epithelial-stromal TGFBI dystrophies. Current classification systems identified four main groups of corneal dystrophies based on clinical, histologic, and genetic information. Diagnosis is performed during a routine ophthalmic examination that shows typical cellular abnormalities of the corneal epithelium, stroma, or endothelium. Disease progression should be carefully monitored to decide the proper clinical management. The treatment of corneal dystrophies is variable, depending on symptoms, clinical course, severity, and type of dystrophy. Management aimed to reduce symptoms and to improve vision, includes different surgical approaches. Novel cellular and genetic therapeutic approaches are under evaluation. J. Cell. Physiol. 231: 261-269, 2016. © 2015 Wiley Periodicals, Inc.

Cocaine snorting may induce ocular surface damage through corneal sensitivity impairment.

PURPOSE: Cocaine abuse may cause severe ischemic and necrotic tissue damage in several organs, including the eye. However, the cornea is an avascular tissue relying on sensitive nerves for its trophic support, and the pathogenesis of cocaine-induced corneal lesions is unclear. In this study, we aimed to investigate if corneal sensitivity, ocular surface, and tear function are damaged by habitual cocaine snorting. METHODS: Ocular examination, corneal sensitivity, and tear function testing were carried out in 48 cocaine addicts, and in 22 heroin addicts and 30 drug-free age/sex-matched individuals who served as controls. We also performed corneal confocal microscopy, conjunctival impression cytology, and tear sample collection to evaluate corneal and conjunctival morphology, and the presence of cocaine in tears. Statistical analysis was performed to compare groups and to correlate clinical findings with anamnestic data on cocaine use. RESULTS: We observed decreased corneal sensitivity in 26 cocaine addicts, and neurotrophic keratitis in six of them, with corneal damage, absence of symptoms, reduced tear production, and prolonged interblink-time. No significant changes in ocular surface parameters including corneal sensitivity were observed in heroin addicts. The major risk factors for developing cocaine-induced neurotrophic keratitis appeared to be duration and frequency of drug abuse. CONCLUSIONS: A complete ophthalmic evaluation including corneal sensitivity testing should be planned for an optimal management of cocaine addicts, even in the absence of ocular symptoms, to reduce the risk of corneal lesions and consequent vision impairment. Sensory nerve damage should also be evaluated in cocaine-induced lesions of other organs.

The History of Nerve Growth Factor: From Molecule to Drug.

Nerve growth factor (NGF), the first neurotrophin to be discovered, has a long and eventful research journey with a series of turning points, setbacks, and achievements. Since the groundbreaking investigations led by Nobel Prize winner Rita Levi-Montalcini, advancements in the comprehension of NGF's functions have revolutionized the field of neuroscience, offering new insights and opportunities for therapeutic innovation. However, the clinical application of NGF has historically been hindered by challenges in determining appropriate dosing, administration strategies, and complications related to the production process. Recent advances in the production and scientific knowledge of recombinant NGF have enabled its clinical development, and in 2018, the United States Food and Drug Administration approved cenegermin-bkbj, a recombinant human NGF, for the treatment of all stages of neurotrophic keratitis. This review traces the evolutionary path that transformed NGF from a biological molecule into a novel therapy with potential research applications beyond the eye. Special emphasis is put on the studies that advanced NGF from discovery to the first medicinal product approved to treat a human disease.

New disposable esthesiometer (KeraSenseⓇ) to improve diagnosis and management of neurotrophic keratitis.

PURPOSE: To validate the use, repeatability, and reproducibility of a new, cost-effective, disposable, sterile device (KeraSenseⓇ, Dompè farmaceutici SpA, Milan Italy) compared to Cochet-Bonnet (CB) esthesiometer. Secondly, to identify a simple, safe, rapid, and low-cost test to diagnose neurotrophic keratitis (NK). METHODS: 16 patients with diagnosis of NK stage I, 25 patients with diabetes mellitus (DM), and 26 healthy subjects were included in the study. Corneal sensitivity (CS) was assessed by CB and KeraSenseⓇ. Repeatability, accuracy, and reproducibility of the novel disposable aesthesiometer were assessed. Specificity, sensitivity, and cut-off value for NK diagnosis were calculated by ROC curve analysis. RESULTS: All NK patients showed a CS ≤ 40 mm, while none of the healthy patients showed a CS value < 50 mm. Significant agreement was found between CB measurements and the single use esthesiometer evaluations of CS (p < 0.001). Repeatability evaluations of the single use esthesiometer showed 100% agreement between different measurements (p < 0.001). Reproducibility evaluations showed 99.6% concordance between different operators (p < 0.001). A 55 mm value of the single use esthesiometer was adequate to exclude an NK diagnosis, while all NK patients showed a value ≤ 35 mm. CONCLUSIONS: Corneal hypo/anaesthesia is considered the hallmark of NK. The use of the novel single-use esthesiometer will allow for a diagnostic improvement in NK, sparing time and guaranteeing patients' safety. Diabetic patients despite normal corneal findings may show impairment of CS, suggesting a preclinical stage of NK, requiring a close follow-up.

Visuospatial Deficits Are Associated with Pisa Syndrome and not Camptocormia in Parkinson's Disease.

Background: Pisa syndrome (PS) and camptocormia (CC) are postural abnormalities frequently associated with Parkinson's disease (PD). Their pathophysiology remains unclear, but the role of cognitive deficits has been postulated. Objectives: To identify differences in the neuropsychological functioning of patients with PD with PS or CC compared with matched patients with PD without postural abnormalities. Methods: We performed a case-control study including 57 patients with PD with PS (PS+) or CC (CC+) and 57 PD controls without postural abnormalities matched for sex, age, PD duration, phenotype, and stage. Patients were divided into four groups: PS+ (n = 32), PS+ controls (PS-, n = 32), CC+ (n = 25), and CC+ controls (CC-, n = 25). We compared PS+ versus PS- and CC+ versus CC- using a neuropsychological battery assessing memory, attention, executive functions, visuospatial abilities, and language. Subjective visual vertical (SVV) perception was assessed by the Bucket test as a sign of vestibular function; the misperception of trunk position, defined as a mismatch between the objective versus subjective evaluation of the trunk bending angle >5°, was evaluated in PS+ and CC+. Results: PS+ showed significantly worse visuospatial performances (P = 0.025) and SVV perception (P = 0.038) than their controls, whereas CC+ did not show significant differences compared with their control group. Reduced awareness of postural abnormality was observed in >60% of patients with PS or CC. Conclusions: Low visuospatial performances and vestibular tone imbalance are significantly associated with PS but not with CC. These findings suggest different pathophysiology for the two main postural abnormalities associated with PD and can foster adequate therapeutic and prevention strategies.

Nerve growth factor therapy for corneal disease.

PURPOSE OF REVIEW: To review the experimental and clinical data on the effects of nerve growth factor (NGF) in corneal physiopathology and to discuss the future development of NGF therapy for corneal diseases. RECENT FINDINGS: NGF plays a key role in the modulation of immune reaction, trophic support, healing of ocular surface, corneal sensitivity and tear film function. These properties of NGF make this neurotrophin a potential therapeutic agent for several corneal diseases. In this review, experimental evidence of the mechanisms of action of NGF on the ocular surface and clinical data on topical NGF use are described and discussed. This review includes the studies performed on corneal diseases such as neurotrophic keratitis, peripheral ulcerative keratopathy, dry eye and corneal surgery. Moreover, experimental studies that extended the NGF action on herpes virus corneal infection and ocular surface stem cell differentiation and proliferation are also reviewed. SUMMARY: Since the first clinical use of topical NGF therapy in patients with neurotrophic keratitis, the ocular surface healing and immune-modulating actions of NGF have been extensively studied and demonstrated in the past two decades, opening new perspectives for its use in clinical practice in patients with infective and noninfective diseases of the ocular surface.

Long-term clinical efficacy of topical treatment with recombinant human nerve growth factor in neurotrophic keratopathy: a novel cure for a rare degenerative corneal disease?

BACKGROUND: Neurotrophic keratopathy (NK) is a rare, degenerative ocular disease characterized by reduction or loss of corneal sensitivity and development of non-healing corneal epithelial defects and ulcers. Cenegermin, a recombinant human nerve growth factor (rhNGF) eye drop solution, is the first drug approved for the treatment of NK. The aim of our study is to evaluate the long-term efficacy of this innovative topical treatment in patients with NK. METHODS: Retrospective, consecutive, observational case series study from a single-center setting (Department of Sense Organs, University Sapienza of Rome, Rome, Italy). 18 patients with diagnosis of stage 2 or 3 NK, treated with Cenegermin 20 mcg/ml eye drops were followed for up to 48 months. Recurrence of lesion during follow-up was evaluated at 12, 24, 36, and 48 months. In addition, corneal sensitivity, Schirmer tear test, and visual acuity (VA) were recorded at baseline, end of treatment, and at 12, 24, 36, and 48 months. RESULTS: Three patients experienced recurrence of persistent epithelial defects (PEDs) within 12 months and one patient experienced recurrence of a corneal ulcer within 36 months. Corneal sensitivity was significantly improved at all timepoints (P < 0.05). Significant improvements in visual acuity and tear production were seen at the completion of treatment as well as at 12, 24, and 36 months (P < 0.05) when compared to baseline. CONCLUSIONS: A single 8-week treatment regimen of Cenegermin eye drops has clinical efficacy that can persist for up to 48 months. The long-term clinical utility of treatment with Cenegermin for NK was demonstrated through the low rate of lesion recurrence along with improvements in corneal sensitivity and tear production.

Autophagy-lysosome pathway alteration in ocular surface manifestations in Fabry disease patients.

BACKGROUND: Fabry disease (FD) is a rare X-linked, lysosomal storage disorder caused by mutations in the alpha-galactosidase gene and characterized by neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and ocular manifestations. The aim of this study is to characterize morphological, functional and autophagy-lysosome pathway alterations of the ocular surface in FD patients. METHODS: Eleven subjects with a diagnosis of FD and fifteen healthy control subjects were examined. All patients underwent ocular surface slit lamp examination, corneal aesthesiometry and in vivo confocal laser-scanning microscopy (CCM). Conjunctival impression cytology was performed in six FD patients and six controls, to assess for expression of two markers of the autophagy-lysosome pathway: the microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein 2 (LAMP2). RESULTS: Cornea verticillata and increased conjunctival vessel tortuosity were detected respectively in 67% and 33% of patients with FD. Compared with healthy subjects, patients affected by FD showed a significant reduction in corneal nerve fiber length, density and nerve branching on CCM and a significantly increased expression of LC3 on conjunctival impression cytology (p < 0.001). No changes were observed in the conjunctival expression of LAMP2 between the two groups. CONCLUSIONS: This study shows that FD is associated with ocular surface alterations including corneal and conjunctival morphology, innervation and vascularization changes. Our data demonstrate an increased expression of LC3 protein in patients with FD, suggesting that alteration of the autophagy-lysosome pathway may play a role in the occurrence of ocular manifestations.

Diabetic retinopathy, oxidative stress, and sirtuins: an in depth look in enzymatic patterns and new therapeutic horizons.

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. DR represents the most common microvascular complication of diabetes, and its incidence is constantly rising. The complex interactions between inflammation, oxidative stress, and the production of free oxygen radicals caused by prolonged exposure to hyperglycemia determine the development of DR. Sirtuins (SIRTs) are a recently discovered class of 7 histone deacetylases involved in cellular senescence, regulation of cell cycle, metabolic pathways, and DNA repair. SIRTs participate in the progress of several pathologies such as cancer, neurodegeneration, and metabolic diseases. In DR sirtuins 1,3,5, and 6 play an important role as they regulate the activation of the inflammatory response, insulin sensibility, and both glycolysis and gluconeogenesis. A wide spectrum of direct and indirect activators of SIRTs pathways (e.g., antagomiR, resveratrol, or glycyrrhizin) is currently being developed to treat the inflammatory cascade occurring in DR. We focus on the main metabolic and inflammatory pathways involving SIRTs and DR, as well as recent evidence on SIRTs activators that may be employed as novel therapeutic approaches to DR.