Early marker of ocular neurodegeneration in children and adolescents with type 1 diabetes: the contributing role of polymorphisms in mir146a and mir128a genes.

BACKGROUND: Early ocular neurodegenerative signs of diabetic neuropathy (DN) can be found in children and adolescents with type 1 diabetes (T1D). No data are available on the potential role of polymorphisms in miRNAs genes in predisposing T1D subjects to these signs. AIMS: To determine whether MIR146A rs2910164 and MIR128A rs11888095 polymorphisms are associated with early retinal and corneal neurodegenerative changes in pediatric patients with T1D. METHODS: A total of 140 T1D children/adolescents underwent spectral domain-optical coherence tomography (SD-OCT) and in vivo confocal microscopy (IVCM) with measurement of retinal and corneal nerve fiber parameters. Risk factors for diabetes complications (diabetes duration, blood pressure, HbA1c) were recorded. Genotyping of rs2910164 and rs1188095 SNPs and genotype-phenotype association analysis were performed. RESULTS: The C allele of rs2910164 in MIR146A was associated with higher values of IVCM parameters and minimum rim width (MRW) of the peripapillary region of optic nerve head measured in the retina, whereas the T allele of rs1188095 in MIR128A was associated with a significant impairment of them. Multiple regression analysis showed that MIR146A and MIR128A polymorphisms were significantly associated with corneal nerve fiber length (beta = 0.225 and - 0.204, respectively) and other IVCM parameters, independently from age, diabetes duration, HbA1c and systolic blood pressure percentile. Similar results were found for MRW (beta = 0.213 and - 0.286, respectively). CONCLUSIONS: These results provide new insight into the genetic predisposition to DN showing that two polymorphisms in MIR146A and MIR128A genes could significantly contribute to the development of early ocular preclinical signs of DN.

Eight months follow-up of corneal nerves and sensitivity after treatment with cenegermin for neurotrophic keratopathy.

BACKGROUD: Cenegermin (Oxervate, Dompè Farmaceutici, Milan, IT), a recombinant human NGF, is a potentially healing new drug for neurotrophic keratopathy (NK), a rare but challenging disease affecting the cornea. To date, studies that evaluate its mid-term effect on corneal nerves and sensitivity are lacking. OBJECTIVE: To evaluate the recovery and morphology of subbasal corneal nerves in patients treated with Cenegermin for NK and assess their correlation with corneal sensitivity. METHODS: This prospective, observational case series study was carried out between May 2018 and August 2020 at the Ophthalmic Clinic of the University of Verona. Clinical evaluation, sensitivity, and in vivo confocal microscopy (IVCM) were performed in the central and all four corneal sectors at baseline, the end of therapy (8 weeks), and 2, 4, and 8 months after therapy. Consecutive patients with NK (stage 2-3), treated with Cenegermin (1 drop 6 times daily for 8 weeks), were enrolled. During each visit, Corneal nerve fiber length (CNFL), corneal nerve fiber total branch density (CTBD), corneal nerve fiber fractal dimension (CNFraD) and Cochet-Bonnet esthesiometry (CBE) were measured. RESULTS: We enrolled 18 patients. Complete NK healing was noted in 14/18(78%) patients after 8 weeks of treatment; then in 14(78%), 15(83%), and 13(72%) patients at 2-, 4-, and 8-months, respectively. Starting at 8 weeks through 4-month follow-up there was progressive improvement in CBE in all corneal sectors (p ≤ 0.01), which continued thereafter. There was significant corneal nerve regrowth especially in the peripheral cornea: centripetal progression starting at 8 weeks (CNFL and CNFrad) and significant branching starting at 2 months (CTBD), which continued through to the end of follow up. Sector-coupled IVCM and CBE findings correlated at all evaluations (all r ≥ 0.62 starting at 2 months, with highest values in the peripheral sectors). CONCLUSIONS: After Cenegermin we observed a subbasal corneal nerve regeneration, a recovery of sensitivity and a lasting epithelial healing, suggesting that the effect of its action persists several months after discontinuation in patients with NK.

In vivo confocal microscopy study of corneal nerve alterations in children and youths with Type 1 diabetes.

OBJECTIVE: To determine whether children and youths with Type 1 diabetes (T1D) have early alterations of the corneal subbasal nerve plexus detectable with in vivo confocal microscopy (IVCM) and to investigate the role of longitudinally measured major risk factors for diabetes complications associated with these alterations. METHODS: One hundred and fifty children and youths with T1D and 51 age-matched controls were enrolled and underwent IVCM. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal fiber total branch density (CTBD), and corneal fiber fractal dimension (CNFrD) were measured. Risk factors for diabetes complications (blood pressure, BMI, HbA1c, lipoproteins, urinary albumin-creatinine ratio) were recorded at IVCM and longitudinally since T1D onset. Unpaired t-test was used to compare variables between the groups. Multiple regression models were calculated using IVCM parameters as dependent variables and risk factors as independent variables. RESULTS: All IVCM parameters, except CTBD, were significantly lower in the T1D patients. Glycometabolic control (HbA1c, visit-to-visit HbA1c variability, and mean HbA1c), and blood pressure were inversely correlated with IVCM parameters. Multiple regression showed that part of the variability in CNFL, CNFD, CTBD, and CNFraD was explained by HbA1c, blood pressure percentiles and age at IVCM examination, independent of diabetes duration, BMI percentile and LDL cholesterol. Comparable results were obtained using the mean value of risk factors measured longitudinally since T1D onset. CONCLUSIONS: Early signs of corneal nerve degeneration were found in children and youths with T1D. Glycometabolic control and blood pressure were the major risk factors for these alterations.

Effects of oral function on pupil response: a new view on bruxism pathophysiology.

BACKGROUND: There is increasing evidence of the influence of the oropharyngeal stimulations on the autonomic nervous system and an easy approach to evaluate the balance between parasympathetic and sympathetic system is the measurement of the pupil diameter. The aim of this analytic observational study is to define the effects of clenching and swallowing on pupil diameter, and how an oral appliance can affect the outcome of these tasks, to establish their influence on the sympathetic-parasympathetic balance. METHODS: We measured the pupil diameter in 30 healthy subjects during clenching and swallowing, both with and without oral appliance. We compared the results with the mandibular rest position. The respective positions with and without oral appliance were also compared. RESULTS: Pupillometry showed a mydriatic effect of swallowing (rest 6.94 mm, swallowing 7.26 mm, P=0.04) and oral appliance, more relevant in scotopic conditions. On the contrary, clenching seemed to enhance miosis, especially in intense brightness condition (rest 3.95 mm, clenching 3.83 mm, P=0.02). CONCLUSIONS: Swallowing and oral appliance facilitate the sympathetic system, while clenching activates the parasympathetic branch. We argue that probably the locus coeruleus is the main hub. These results could have practical implications in bruxism physiology, because it could be an attempt to counteract the activation of the sympathetic system.

Femtosecond laser-assisted implantation of corneal stroma lenticule for keratoconus.

PURPOSE: To review recent progress, challenges, and future perspectives of stromal keratophakia for the treatment of advanced keratoconus. METHODS: We systematically reviewed the literature in the PubMed database, last update June 30, 2020. No language restriction was applied. The authors checked the reference lists of the retrieved articles to identify any additional study of interest. RESULTS: Several techniques have been proposed for the treatment of keratoconus in order to avoid or delay keratoplasty. This was primarily due to the lack of accessibility to donor corneas in many countries. The ease and predictability of the more advanced femtosecond lasers used to correct ametropias by stromal lenticule extraction lead to hypothesize that generated refractive lenticules could be implanted into corneal stromal layers to restore volume and alter the refractive properties of the cornea in patients with corneal ectasias. At the same time, new techniques for preservation, customization, and cellular therapy of the corneal stromal have been developed, directing to the valorization of otherwise discarded byproducts such as donor corneas unsuitable for either lamellar of penetrating keratoplasty. CONCLUSIONS: Femtosecond laser-assisted stromal keratophakia could be a suitable therapeutic option for the treatment of corneal ectasias, especially in patients with advanced keratoconus, providing biomechanical support recovering the pachimetry to nearly normal value at the same time. The accuracy and predictability of the refractive outcome are yet a critical issue and the patient eligible for the procedure still has to be characterized.

In Vivo Confocal Microscopy of the Corneal-Conjunctival Transition in the Evaluation of Epithelial Renewal after SLET.

Examination of the corneal surface by in vivo confocal microscopy (IVCM) allows for objective identification of corneal and conjunctival cell phenotypes to evaluate different epithelialization patterns. Detection of a corneal-conjunctival epithelial transition could be considered as a sign of restored epithelial function following simple limbal epithelial transplantation (SLET). This is a prospective, interventional case series. We assessed patients with limbal stem cell deficiency (LSCD) by IVCM, preoperatively and at monthly intervals following SLET. Sectors in the central and peripheral cornea were scanned. Immediately upon detection of multi-layered cells with the epithelial phenotype in the central cornea and confirmation of epithelial transition in all corneal sectors, the decision for keratoplasty was taken. Ten patients were enrolled. After SLET, epithelial phenotype in the central cornea and an epithelial transition were identified within six and nine months in seven and one patients, respectively. One patient was a partial success and one failed. Five patients underwent keratoplasty, with stable results up to 12 months. Identification of the epithelial transition zone by IVCM permits assessment of the efficacy of SLET, enabling subsequent planning of keratoplasty for visual rehabilitation. The stability of the corneal surface following keratoplasty confirms that the renewal of the corneal epithelium was effectively retained.

Reduced minimum rim width of optic nerve head: a potential early marker of retinal neurodegeneration in children and adolescents with type 1 diabetes.

AIMS: To determine whether early retinal neurodegenerative changes in pediatric patients with type 1 diabetes (T1D) can be detected by spectral domain-optical coherence tomography (SD-OCT) and whether such changes are associated with risk factors for T1D complications. METHODS: A total of 147 T1D children/adolescents and 51 healthy controls underwent SD-OCT. Spherical refractive error (SRE), macular total retinal thickness (TRT), ganglion cell layer (GCL), retinal nerve fiber layer (RNFL), minimum rim width (MRW), and Bruch's membrane opening area (BMOA) were measured. Clinical and biochemical parameters were recorded at the time of SD-OCT and starting at T1D onset. Multiple regression models were calculated using SD-OCT parameters as dependent and risk factors as independent variables. RESULTS: MRW was significantly thinner in the T1D patients (global MRW:361.58vs386.33 µm; p = 0.009), while RNFL and macular parameters were similar for both groups. MRW was inversely correlated with mean HbA1c (r ≥ -0.180, p < 0.05). Multiple regression showed that part of the variability in MRW was explained by HbA1c and BMOA (R2 = 0.21; p < 0.001), independent of other cardiometabolic risk factors. CONCLUSIONS: MRW reduction could be a potential early marker of retinal neurodegeneration detectable in pediatric patients with T1D. The association between MRW and mean HbA1c suggests that glucometabolic control may affect early retinal neurodegeneration starting in childhood.

Cenegermin in Pediatric Neurotrophic Keratopathy.

PURPOSE: We report a case of neurotrophic keratopathy (NK) arising after surgery for rhabdomyosarcoma of the jaw successfully treated with Cenegermin eye drops (Oxervate; Dompé Farmaceutici, Milan, Italy) in a 3-year-old boy. METHODS: At the age of 1 year, the boy underwent surgery for rhabdomyosarcoma of the jaw, followed by radiotherapy. Subsequent NK was initially treated with preservative-free artificial tears, topical combination of dexamethasone 0.1% and netilmicin 0.3% (Netildex; Sifi, Catania, Italy), and moxifloxacin 0.5% (Vigamox; Alcon, Fort Worth, TX), followed by 10 cycles of a topical eye biopolymer containing a poly-carboxymethyl glucose sulfate solution (Cacicol; Theà, Clermont-Ferrand, France) and 4 amniotic membrane transplantations. Keratopathy was recalcitrant to therapy and tissue transplant. Therapy was switched to Cenegermin eye drops 6 times daily for 8 weeks. RESULTS: Complete healing of the corneal epithelium was achieved at 3 weeks into treatment. CONCLUSIONS: Cenegermin was effective in restoring corneal integrity in this pediatric patient with NK.

Small-incision lenticule addition in ex vivo model of ectatic human corneas.

PURPOSE: To investigate the feasibility of intrastromal lenticule insertion to restore corneal shape in a model of ectatic human cornea. METHODS: For this experimental ex vivo study on 34 human corneas unsuitable for transplantation, 17 corneas were thinned by decentralized posterior excimer laser ablation to 200 µm thickness and 6.5 mm diameter and then inflated up to 100 mm Hg to expose the ectasias (recipient corneas). Pachimetry and topography were obtained. Stromal lenticules of the same diameter and thickness as the ectasias were shaped with a femtosecond laser from the remaining 17 donor corneas. An intrastromal pocket was created with femtosecond laser within the ectatic recipient corneas and the donor lenticule was inserted inside it. Changes in corneal architecture and profile were evaluated by means of corneal topography and anterior segment optical coherence tomography. RESULTS: All stromal lenticules were successfully implanted. Tomography confirmed regularity of the lenticule profile within the stromal pocket. Corneal thickness was significantly increased after the procedure (P < 0.0001). Maximal posterior elevation from the best-fitted toric ellipsoid was significantly reduced (P < 0.0001). Significant flattening of posterior K1 and K2 was also obtained (P = 0.041 and P = 0.004, respectively). Anterior and posterior astigmatism, anterior and posterior asphericity, and spherical aberration did not differ significantly after the procedure. CONCLUSIONS: Femtosecond laser-assisted stromal lenticule addition is feasible for restoring corneal thickness to an ectatic area and for regularizing posterior corneal elevation. The technique opens new perspectives for the treatment of corneal ectasias.