Schwann cell-derived extracellular vesicles as a potential therapy for retinal ganglion cell degeneration.

Optic neuropathy is the leading cause of irreversible blindness and is characterized by progressive degeneration of retinal ganglion cells (RGCs). Several studies have demonstrated that transplantation of Schwann cells (SCs) is a promising candidate therapy for optic neuropathy and that intravitreally transplanted cells exert their effect via paracrine actions. Extracellular vesicle (EV)-based therapies are increasingly recognized as a potential strategy for cell replacement therapy. In this study, we aimed to investigate the neuroprotective and regenerative effects of SC-EVs following optic nerve injury. We found that SC-EVs were internalized by RGCs in vitro and in vivo without any transfection reagents. Intriguingly, SC-EVs significantly enhanced the survival and axonal growth of primary RGCs in a coculture system. In a rat optic nerve crush model, SC-EVs mitigated RGC degeneration, prevented RGC loss, and preserved the thickness of the ganglion cell complex, as demonstrated by the statistically significant improvement in RGC counts and thickness measurements. Mechanistically, SC-EVs activated the cAMP-response element binding protein (CREB) signaling pathway and regulated reactive gliosis in ONC rats, which is crucial for RGC protection and axonal regeneration. These findings provide novel insights into the neuroprotective and regenerative properties of SC-EVs, suggesting their potential as a cell-free therapeutic strategy and natural biomaterials for neurodegenerative diseases of the central nervous system.

Long-term Outcomes Following Endoscopic Transnasal Surgery for Optic Neuropathy Due to Craniofacial Fibrous Dysplasia.

OBJECTIVE: To investigate the feasibility of endoscopic transnasal optic canal decompression (ETOCD) guided by a navigation surgical system (NSS) for vision recovery in patients with compressive optic neuropathy (CON) caused by craniofacial fibrous dysplasia (CFD), and to explore the underlying cause of visual impairment. METHODS: All patients underwent unilateral NSS-guided ETOCD and were followed up periodically for at least six months. Paired sample t-test and Pearson correlation analyses were used to compare continuous variables of the visual outcomes at the final review. A histopathological test of abnormal bone specimens was performed postoperatively. RESULTS: Thirty-four patients were finally included, and all surgeries were uneventful. The best corrected visual acuity (BCVA) (logMAR units) decreased from 1.29 ± 0.80 preoperatively to 0.97 ± 0.78 at the last follow-up (p = 0.0012), improving in 28 patients (82.35%). The absolute value of mean defect (MD) significantly decreased (p < 0.001). Color vision was impaired in 17 patients preoperatively and improved in 6 patients. BCVA at the last follow-up was significantly correlated with preoperative BCVA, onset time, preoperative retinal nerve fibril layer thickness, and MD (all p < 0.05). Among 34 patients, 26 had a blunt bony process near the anterior foot of the optic chiasm. Of the total patients, 73.53% patients experienced bony fiber recurrence 6 months or earlier after surgery without visual loss. CONCLUSION: NSS-guided ETOCD appeared to be safe and effective for visual recovery in patients with CON due to CFD, and early surgical intervention was critical for long-term recovery. Unbalanced compression of the optic canal by the blunt bony process may be a major cause of visual impairment. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1857-1866, 2023.

Optic chiasmatic potential by endoscopically implanted skull base microinvasive biosensor: a brain-machine interface approach for anterior visual pathway assessment.

Background: Visually evoked potential (VEP) is widely used to detect optic neuropathy in basic research and clinical practice. Traditionally, VEP is recorded non-invasively from the surface of the skull over the visual cortex. However, its trace amplitude is highly variable, largely due to intracranial modulation and artifacts. Therefore, a safe test with a strong and stable signal is highly desirable to assess optic nerve function, particularly in neurosurgical settings and animal experiments. Methods: Minimally invasive trans-sphenoidal endoscopic recording of optic chiasmatic potential (OCP) was carried out with a titanium screw implanted onto the sphenoid bone beneath the optic chiasm in the goat, whose sphenoidal anatomy is more human-like than non-human primates. Results: The implantation procedure was swift (within 30 min) and did not cause any detectable abnormality in fetching/moving behaviors, skull CT scans and ophthalmic tests after surgery. Compared with traditional VEP, the amplitude of OCP was 5-10 times stronger, more sensitive to weak light stimulus and its subtle changes, and was more repeatable, even under extremely low general anesthesia. Moreover, the OCP signal relied on ipsilateral light stimulation, and was abolished immediately after complete optic nerve (ON) transection. Through proof-of-concept experiments, we demonstrated several potential applications of the OCP device: (1) real-time detector of ON function, (2) detector of region-biased retinal sensitivity, and (3) therapeutic electrical stimulator for the optic nerve with low and thus safe excitation threshold. Conclusions: OCP developed in this study will be valuable for both vision research and clinical practice. This study also provides a safe endoscopic approach to implant skull base brain-machine interface, and a feasible in vivo testbed (goat) for evaluating safety and efficacy of skull base brain-machine interface.

Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy.

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. (2) Even with possible access for 'local refrigeration', cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4 °C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

Hypothermic therapy is a radical type of treatment that involves cooling a person's core body temperature several degrees below normal to protect against brain damage. Lowering body temperature slows blood flow, which reduces inflammation, and eases metabolic demands, similar to hibernation. It can also reduce lasting damage to the brain and aid recovery when used to treat people who have gone into cardiac arrest, where their heart suddenly stops beating. Recently, there has been renewed interest in using hypothermic therapy to treat people who have sustained traumatic brain injuries, which can cause brain swelling, and other nerve injuries. However, its use remains controversial because clinical trials have failed to show that inducing mild hypothermia provides any benefit for people with severe nerve injuries. This might be because cooling cells to near-freezing temperatures can damage their internal structural supports, called microtubules, thwarting any therapeutic benefit. Traumatic optical neuropathy is a type of injury in which the optic nerve ­ the nerve that connects the eyes to the brain ­ is damaged or severed, causing vision loss. There is currently no clinically proven treatment for this condition, nor is there a system that can test local treatments in large animals as a prior test to using the treatment in the clinic. Therefore, Zhang et al. wanted to establish such a animal model and test whether local hypothermic therapy could help protect the optic nerve. Zhang et al. used a surgical tool guided by an endoscope (a thin plastic tube with a light and camera attached to it) to injure the optic nerves of goats, and then deliver hypothermic therapy. To cool the surgically-injured nerves to a chilly 4C, Zhang et al. applied a deep-cooling agent, using a second reagent (a cocktail of protease inhibitors) to protect the cells' microtubules from cold-induced damage, an insight gained from a previous study of hibernating animals. This was critical, as the hypothermic therapy was only effective when the secondary protective agent was applied. The combination therapy developed by Zhang et al. relieved some aspects of nerve degeneration at the injury site and activated an anti-inflammatory response in cells, but did not restore vision. To simplify surgical techniques, Zhang et al. also developed a computer program which generates virtual surgical paths for up-the-nose endoscopic procedures based on brain scans of an animal's skull. This program was successfully applied in a range of large animals, including goats and macaque monkeys. Zhang et al.'s work establishes a method to study treatments for traumatic optical neuropathy using large animals, including hypothermic therapy. The methods developed could also be useful to study other optic nerve disorders, such as optic neuritis or ischemic optic neuropathy.

PHACOEMULSIFICATION CATARACT SURGERY WITH PROPHYLACTIC INTRAVITREAL BEVACIZUMAB FOR PATIENTS WITH COEXISTING DIABETIC RETINOPATHY: A Meta-Analysis.

PURPOSE: To evaluate the clinical effectiveness of intravitreal bevacizumab (IVB) injection combined with cataract surgery in the treatment of patients with cataract and coexisting diabetic retinopathy (DR). METHODS: Pertinent comparative studies were identified through systemic searches of PubMed, EMBASE, and the Cochrane Controlled Trials Register up to March 1, 2016. Outcome measures included corrected distance vision acuity, central macular thickness, and progression of DR and maculopathy. A meta-analysis was performed using RevMan (Cochrane Collaboration, Oxford, United Kingdom). RESULTS: Six studies describing a total of 283 eyes were identified. The meta-analysis results showed that corrected distance vision acuity measured at 1 month and 3 months after cataract surgery was significantly better in the IVB groups than in the control groups (P < 0.00001 and P = 0.01), whereas the corrected distance vision acuity at 6 months did not vary significantly between the 2 groups (P = 0.24). Similarly, the central macular thickness at 1, 3, and 6 months after surgery was significantly thinner in the IVB groups than in the control groups (P = 0.01, P = 0.0004, and P = 0.01, respectively). At 6 months, the progression of postoperative DR and maculopathy occurred more frequently in the control group than in the IVB group (P = 0.0001 and P < 0.0001, respectively). CONCLUSION: Our meta-analysis indicates that cataract surgery combined with IVB seems to be an effective treatment in patients with coexisting DR in the short term (up to 6 months). More randomized, prospective, and large-sample-sized trials are needed to evaluate the long-term effects of IVB at the time of cataract surgery in patients with DR.

Expression and prognostic significance of MCM-3 and MCM-7 in salivary adenoid cystic carcinoma.

This study sought to investigate minichromosome maintenance protein 3 (MCM3) and minichromosome maintenance protein 7 (MCM7) expression in salivary adenoid cystic carcinoma (SACC) samples, and to evaluate the relationship between clinicopathological characteristics and prognosis. The expressions of MCM3 and MCM7 were evaluated using immunohistochemistry of tissue sections from SACC patients, and statistical analyses were performed to evaluate the associations between MCM expression and clinicopathological variables and to analyze the disease-free survival (DFS) and prognostic factors. The positive expression rates of MCM3 and MCM7 in SACC were 98.8% and 96.6%, respectively. MCM3 expression correlated with T-stage and nerve invasion. MCM7 expression correlated with T-stage, adjacent tissue invasion, nerve invasion, and prognosis, and was negatively associated with DFS. However, there was no significant correlation between MCM3 expression and DFS. A kappa analysis demonstrated that MCM3 was closely associated with MCM7. MCM7 may be a favorable prognosis indicator in SACC.

Repeatability, Reproducibility, and Agreement of Two Scheimpflug-Placido Anterior Corneal Analyzers for Posterior Corneal Surface Measurement.

PURPOSE: To evaluate the intraoperator repeatability and interoperator reproducibility of two Scheimpflug-Placido anterior corneal analyzers (Sirius; Costruzione Strumenti Oftalmici, Florence, Italy, and TMS-5; Tomey, Nagoya, Japan) for the measurement of posterior corneal surface in normal eyes and the agreement between the two devices. METHODS: The current prospective study investigated 55 right eyes of 55 healthy patients in a random order. The posterior steep keratometry (Ks), flat keratometry (Kf), mean keratometry (Km), and astigmatism were randomly measured by two independent experienced operators using the Sirius and TMS-5 Scheimpflug-Placido systems. Three consecutive measurements were obtained. Vector analysis was used for astigmatism. To assess intraoperator repeatability and interoperator reproducibility, within-subject standard deviation (Sw) and test-retest repeatability (TRT, 2.77 Sw) were calculated. The Bland-Altman plots and 95% limits of agreement (LoA) were used to evaluate the agreement between the two systems. RESULTS: In the Sirius Scheimpflug-Placido system, the Sw and TRT of keratometry and astigmatism were less than 0.04 and 0.12 diopters (D), respectively. The interoperator Sw and TRT were less than 0.03 and 0.07 D, respectively. In the TMS-5 Scheimpflug-Placido system, the intraoperator Sw and TRT did not exceed 0.03 and 0.08 D, respectively. The interoperator Sw and TRT were no greater than 0.02 and 0.05 D, respectively. All parameters showed minor fluctuations in the 95% LoA. CONCLUSIONS: Both Scheimpflug-Placido systems show high repeatability and reproducibility for posterior corneal surface measurement. A high concordance between the two devices suggests interchangeable use in normal eyes. [J Refract Surg. 2017;33(8):524-530.].

Postoperative Efficacy, Predictability, Safety, and Visual Quality of Laser Corneal Refractive Surgery: A Network Meta-analysis.

PURPOSE: To compare the postoperative efficacy, predictability, safety, and visual quality of all major forms of laser corneal refractive surgeries for correcting myopia. DESIGN: Systematic review and network meta-analysis. METHODS: Search of MEDLINE, EMBASE, Cochrane Library, and the US trial registry was conducted up to November 2015. Randomized controlled trials (RCT) reporting in accordance with the eligibility criteria were included in this review. We performed a Bayesian random-effects network meta-analysis. RESULTS: Forty-eight RCTs were identified. For efficacy (uncorrected visual acuity [UCVA]), there were no statistically significant differences between any pair of treatments analyzed. The SUCRA (surface under the cumulative ranking curve) ranking (from best to worst) was femtosecond-based laser in situ keratomileusis (FS-LASIK), LASIK, small-incision lenticule extraction, femtosecond lenticule extraction (FLEx), photorefractive keratectomy (PRK), laser epithelial keratomileusis (LASEK), epipolis (Epi)-LASIK, transepithelial PRK (T-PRK). For predictability (refractive spherical equivalent [SE]), a statistically significant difference was found when FS-LASIK was compared with LASIK (odds ratio [OR] 2.29, 95% credible interval [CrI] 1.20-4.14), PRK (OR 2.16, 95% CrI 1.15-4.03), LASEK (OR 2.09, 95% CrI 1.08-4.55), and Epi-LASIK (OR 2.74, 95% CrI 1.11-6.20). The SUCRA ranking (from best to worst) was FS-LASIK, T-PRK, LASEK, PRK, LASIK, Epi-LASIK. There were no statistically significant differences in the safety (best spectacle-corrected visual acuity) comparisons. For both postoperative higher-order aberrations (HOAs) and contrast sensitivity (CS), there were no statistically significant differences between any pair of treatments analyzed. The SUCRA ranking results show that some corneal surface ablation techniques (PRK and LASEK) rank highest. CONCLUSIONS: This network meta-analysis shows that there were no statistically significant differences in either visual outcomes (efficacy and safety) or visual quality (HOAs and CS). FS-LASIK behaved better in predictability than any other type of surgeries.

Rasch analysis of three dry eye questionnaires and correlates with objective clinical tests.

PURPOSE: To assess the psychometric properties of Chinese versions of the Ocular Comfort Index (OCI), Ocular Surface Disease Index (OSDI) and McMonnies questionnaires. Further, to assess the correlation between questionnaire scores and objective dry eye disease (DED) clinical tests. METHODS: Translated versions of the OCI, OSDI and McMonnies questionnaires were completed in a random order by 238 participants with DED. Objective clinical tests included visual acuity (VA), fluorescein tear film break-up time (TBUT), corneal fluorescein staining, Schirmer I testing and meibomian gland grading. Rasch analysis was used to assess questionnaire psychometrics and spearman rank for correlations. RESULTS: For the OCI, the person separation was 2.31, item infit and outfit statistics ranged from 0.74-1.14 and 0.75-1.32, respectively, and targeting 1.54 logits. For the OSDI, person separation was 0.94. None of the three subscales provided valid measurements based on Rasch analysis. For the McMonnies questionnaire, person separation was 1.17, item infit and outfit statistics ranged from 0.7 to 1.21 and 0.51-3.49, respectively. There were weak correlations between questionnaire scores and clinical tests. There were weak correlations between OSDI scores and VA, fluorescein TBUT, Schirmer I testing and corneal fluorescein staining. There were weak correlations between McMonnies scores and VA, fluorescein TBUT, Schirmer I testing, and corneal fluorescein staining and meibomian gland grading. CONCLUSIONS: The OCI questionnaire was the only questionnaire that provided valid measurement on the basis of Rasch analysis, although slight multidimensionality was found. There were weak correlations between OCI scores and fluorescein TBUT, Schirmer I testing, and corneal fluorescein staining. Due to this paradoxical disconnect between symptoms and signs and the repeatability of tests, the use of both subjective and objective markers in the clinical management of patients or as endpoints in clinical trials would appear prudent.