Topical citicoline and vitamin B12 versus placebo in the treatment of diabetes-related corneal nerve damage: a randomized double-blind controlled trial.

BACKGROUND: To evaluate the effects of topical citicoline and vitamin B12 (Cit-B12: OMK2, Omikron Italia srl, Italy) on corneal innervation of patients with diabetic neuropathy. METHODS: This prospective, randomized, double blind, placebo-controlled study included 30 patients randomised with a 2:1 ratio to Cit-B12 or placebo 3 times daily for 18 months. At baseline and at months 4, 8, 12, 18 patients underwent the Ocular Surface Disease Index questionnaire (OSDI), tear break-up time, evaluation of corneal and conjunctival staining, Schirmer I test, Cochet-Bonnet esthesiometry, and confocal biomicroscopy of corneal sub-basal plexus (SBP). Fiber lenght density (FLD) was calculated using NeuronJ and expressed in mm/mm2. Raw data and differences from baseline were analysed in the two groups. RESULTS: 29/30 patients concluded the study. The two groups had similar FLD at baseline; it progressively improved up to month 18 in both groups (Cit-B12, p < 0.0001; controls, < 0.0001-0.03); improvement at month 18 vs baseline was higher in Cit-B12 than placebo (33% vs 15%, p = 0.04). A progressive amelioration of corneal sensitivity (baseline, 28 ± 18 mm; month 18, 52 ± 10 mm, p < 0.0001), conjunctival staining (P = 0.04) and OSDI questionnaire (P = 0.05) were shown on Cit-B12 group alone. Both treatments were well tolerated and adherence during the study was high. CONCLUSIONS: Cit-B12 ameliorated both morphology and function of corneal nerves in patients with diabetes, thus suggesting a neuroregenerative effect. TRIAL REGISTRATION: Trial registration NCT03906513 , retrospectively registered on 08 April 2019.

Direct Versus Indirect Corneal Neurotization for the Treatment of Neurotrophic Keratopathy: A Multicenter Prospective Comparative Study.

PURPOSE: To analyze the comparative safety and efficacy of two techniques of corneal neurotization (CN) (direct corneal neurotization [DCN] vs indirect corneal neurotization [ICN]) for the treatment of neurotrophic keratopathy (NK). DESIGN: Multicenter interventional prospective comparative case series. METHODS: This study took place at ASST Santi Paolo e Carlo University Hospital, Milan; S.Orsola-Malpighi University Hospital, Bologna; and Santa Maria alle Scotte University Hospital, Siena, Italy. The study population consisted of consecutive patients with NK who underwent CN between November 2014 and October 2019. The intervention procedures included DCN, which was was performed by transferring contralateral supraorbital and supratrochlear nerves. ICN was performed using a sural nerve graft. The main outcome measures included NK healing, corneal sensitivity, corneal nerve fiber length (CNFL) measured by in vivo confocal microscopy (IVCM), and complication rates. RESULTS: A total of 26 eyes in 25 patients were included: 16 eyes were treated with DCN and 10 with ICN. After surgery, NK was healed in all patients after a mean period of 3.9 months without differences between DCN and ICN. Mean corneal sensitivity improved significantly 1 year after surgery (from 3.07 to 22.11 mm; P < .001) without differences between the 2 groups. The corneal sub-basal nerve plexus that was absent before surgery in all patients, except 4, become detectable in all cases (mean CNFL: 14.67 ± 7.92 mm/mm2 1 year postoperatively). No major complications were recorded in both groups. CONCLUSIONS: CN allowed the healing of NK in all patients as well as improvement of corneal sensitivity in most of them thanks to nerve regeneration documented by IVCM. One year postoperatively, DCN and ICN showed comparable outcomes.

Can Treatment With Citicoline Eyedrops Reduce Progression in Glaucoma? The Results of a Randomized Placebo-controlled Clinical Trial.

PRECIS: Citicoline eyedrops in patients with progressing glaucoma. PURPOSE: This study aimed to test whether the additional therapy with citicoline eyedrops to intraocular pressure (IOP)-lowering treatment could slow glaucoma progression in patients with worsening of damage and IOP 18 mm Hg or less. DESIGN: This was a randomized, double-masked, placebo-controlled, multicenter 3-year study. OUTCOMES: The outcomes studied were difference in the visual field (mean deviation, MD, of 24-2; MD of 10-2) rates of progression and difference in retinal nerve fiber layer (RNFL) thickness change between the 2 study groups at 3 years. METHODS: Patients with mild to moderate open-angle glaucoma (OAG) showing damage progression of at least -0.5 dB/y in the 2 years before enrollment despite IOP ≤18 mm Hg were randomized to receive citicoline eyedrops or placebo 3 times daily for 3 years. Patients were followed every 3 months and underwent a visual field examination with 24-2 and 10-2 strategies and RNFL assessment. Analysis of variance and linear models were used to test the differences between groups. RESULTS: Eighty patients were randomized in the trial. The mean 3-year rates of progression were -1.03 (2.14) dB in the citicoline group and -1.92 (2.23) dB in the placebo group (P=0.07) for 24-2 MD and -0.41 (3.45) dB in the citicoline group and -2.22 (3.63) dB in the placebo group (P=0.02) for 10-2 MD. On average, patients receiving citicoline eyedrops lost 1.86 µm of RNFL in 3 years, versus 2.99 µm in the placebo group (P=0.02). CONCLUSIONS: Additional treatment with citicoline eyedrops to IOP-lowering treatment might reduce disease progression in patients with progressing glaucoma despite IOP ≤18 mm Hg.

Tear Film Osmolarity, Ocular Surface Disease and Glaucoma: A Review.

Glaucoma is the second leading cause of blindness in the world, affecting more than 60 million people globally. In order to reduce the progression of the disease, both medical and surgical treatments are used. Frequent side effects of both treatments include a range of modifications of the ocular surface grouped as the Ocular Surface Disease (OSD), which include Dry Eye Disease (DED). DED and other OSD negatively impact on the success of anti-glaucoma treatments and reduce the adherence to medical therapies. Tear film osmolarity (TFO) is a relatively novel test which has become a hallmark of DED. The aim of this paper was to review the association between OSD, DED and glaucoma in view of published TFO data, and to discuss future fields of research and treatments on the topic of glaucoma iatrogenic damage.

Influence of corneal biomechanical properties on intraocular pressure differences between an air-puff tonometer and the Goldmann applanation tonometer.

PURPOSE: To estimate the influence of corneal properties on intraocular pressure (IOP) differences between an air-puff tonometer (NT530P; Nidek) and the Goldmann applanation tonometer (Haag-Streit). PATIENTS AND METHODS: The influence of central corneal thickness (CCT), keratometry, and Ocular Response Analyzer (Reichert) measurements of corneal viscoelasticity [corneal hysteresis (CH) and corneal resistance factor (CRF)] on IOP differences between tonometers was evaluated. RESULTS: The CRF was calculated to be the best predictor of the differences in IOP readings between tonometers (r2=0.23; P<0.001), followed by CCT (r2=0.15; P=0.003) and CH (r2=0.14; P=0.003). Keratometry performed very poorly as lone predictor of IOP differences. In a multiple regression model, CRF, CH, and CCT together accounted for 25% (r2=0.25; P<0.01) of the variance in IOP reading differences between tonometers. CONCLUSIONS: Corneal resistance to applanation induced by either contact or noncontact tonometers was calculated to be the most determinant factor in influencing IOP differences between applanation tonometers.

Ocular surface damage by ophthalmic compounds.

PURPOSE OF REVIEW: To describe the changes of the ocular surface following chronic use of eye drop therapies. The possible pathogenetic mechanisms responsible for specific signs and symptoms are described and discussed. RECENT FINDINGS: Topical treatments for ocular diseases may trigger an inflammatory response in predisposed patients, with local activation of immune cells and ocular surface damage. The resulting clinical picture may vary substantially, from mild to severe, sharing a red eye as a hallmark presentation. Recent in-vitro, in-vivo, and clinical data suggest that these detrimental effects are not solely related to eye drop preservatives and may be caused by the medication itself, especially for patients with preexisting ocular diseases. However, no specific tests are currently available to make a clear cut diagnosis between what is caused by the disease and what is the effect of its therapy. Patients' history and clinical features remain essential to hypothesize the underlying pathogenetic mechanism. SUMMARY: Topical therapies may induce ocular surface allergic reactions, dry eye-like reactions, and epithelial damage. Patients in need of chronic therapies are at higher risk of facing these detrimental effects of eye drop therapies and should be treated with unpreserved compounds.

Levels of plasma homocysteine in pseudoexfoliation glaucoma.

BACKGROUND: To examine levels of serum homocysteine (Hcy), vitamin B12 and folic acid in patients with pseudoexfoliation glaucoma (PEXG), primary open-angle glaucoma (POAG), and healthy control subjects. METHODS: This study included 36 patients with PEXG, 40 with POAG, and 40 age-matched healthy subjects. Fasting plasma Hcy concentrations and levels of serum vitamin B12 and folic acid were measured using competitive chemiluminescent enzyme immunoassay; values exceeding 14 µm/l were considered elevated. RESULTS: Mean plasma Hcy was significantly higher in PEXG (16.55 ± 7.23 µm/l) compared with POAG (13.91 ± 3.61 µm/l) and controls (13.12 ± 5.13 µm/l) (p = 0.03 and p = 0.0007 respectively). There were no statistical differences in serum vitamin B12 and folic acid levels among PEXG, POAG and control subjects (p > 0.05). A moderate, although statistically significant, relationship between Hcy and folic acid levels was found in the PEXG group (R(2) = 0.23, p = 0.003). Hcy levels were found not to be related with folic acid or vitamin B12 in either POAG or control subjects. CONCLUSIONS: In this study, plasma Hcy is significantly higher in PEXG group than the POAG and control groups. Hyper-Hcy might play a role in the pathogenesis of PEXG. Hyper-Hcy may be an independent factor stressing vasculopathy in addition to pseudoexfoliation, so might be a modifiable risk factor for PEXG.

Repeatability of intra-ocular pressure and central corneal thickness measurements provided by a non-contact method of tonometry and pachymetry.

BACKGROUND: To examine the repeatability of intra-ocular pressure (IOP) and central corneal thickness (CCT) measurements provided by the Tono-Pachymeter NT530P (Nidek, Japan), and to assess agreement of the device with Goldmann applanation tonometry (GAT) and ultrasound pachymetry (UP). METHODS: Sixty-two normal eyes of 62 subjects were included in the study. Three sessions of measurements, each consisting of three sets of measurements, were completed with each device. Repeatability was determined with the coefficient of variation (CoV) and the coefficient of repeatability (CoR) values. Agreement between devices was examined by Bland-Altman analysis and intraclass correlation coefficient (ICC) analyses. RESULTS: The CoV and CoR for IOP values were 18.4% and 5.5 mmHg with the NT530P and 16.6% and 4.3 mmHg with the GAT respectively. On average, NT530P overestimated the IOP compared with GAT by 1.3 mmHg. The 95% limits of agreement between the methods ranged from -5.9 to +3.3 mmHg, and the ICC for average IOP measures between devices was 0.64 (P < 0.001). The CoV and CoR for CCT measurements were 5.5% and 59.8 µm with the NT530P and 5.5% and 60.5 µm with UP. NT530P CCT readings were on average 13 µm thinner than those obtained with UP. The 95% limits of agreement (LoA) ranged from -7.4 to +33.1 µm, and the ICC for average CCT measures between devices was 0.93 (P < 0.001). CONCLUSION: The NT530P demonstrated high IOP and CCT measurement repeatability in the normal population studied. The device tended to slightly overestimate IOP compared to GAT. CCT values provided by NT530P were interchangeable with those of UP.