Effectiveness of Microcurrent Stimulation in Preserving Retinal Function of Blind Leading Retinal Degeneration and Optic Neuropathy: A Systematic Review.

OBJECTIVES: To systematically identify and summarize the effectiveness and the parameters of electrical stimulation (ES) for the preservation of visual function in major retinal degeneration and optic neuropathy. MATERIALS AND METHODS: A systematic review of clinical studies, using ES therapy in patients with blind leading retinal degenerations, including retinitis pigmentosa (RP), age-related macular degeneration (AMD), glaucoma, retinal vein occlusion (RVO), retinal artery occlusion (RAO), and optic neuropathy was conducted. PubMed, EMBASE, Cochrane Library, and Web of Science were searched for relevant interventional studies including randomized controlled trials (RCTs) and observational studies. RESULTS: A total of 10 RCTs and 15 observational studies were included. Transcorneal ES (TcES), transpalpebral ES (TpES), transdermal ES (TdES), and repetitive transorbital alternating current stimulation (rtACS) were used for the treatment of the patients. ES using 20 Hz biphasic pulses with current strength at 150%-200% of individual electrical phosphene threshold (EPT) for RP patients showed improved retinal function detected by visual acuity (VA), visual field (VF), or electrical retinal graphs (ERG). rtACS on patients with optic neuropathy showed significant preservation of VA and VF. Clinical studies on AMD, RAO, and glaucoma indicated promising protective effects of ES on the visual function, though the amount of evidence is limited. CONCLUSIONS: ES treatment has promising therapeutic effects on RP and optic neuropathy. More large-scale RCT studies should be conducted to elucidate the potential of ES, especially on AMD, RAO, and glaucoma. A comparison of the effects by different ES methods in the same disease populations is still lacking. Parameters of the electric current and sensitive detection method should be optimized for the evaluation of ES treatment effects in future studies.

Outpatient Medication Use in Chinese Geriatric Patients Admitted for Falls: A Case-Control Study at an Acute Hospital in Hong Kong.

The study objective was to investigate the association of polypharmacy and medications with patient falls resulting in hip fractures among community-living geriatric patients. A case-control study was conducted at an acute public hospital in Hong Kong. The study population was community-living Chinese patients aged 65 years and above who were admitted for falls resulting in hip fractures during an 18-month study period. Each of these patients was matched to a control patient with the same age and sex, but without falls and fractures. Data were collected from electronic patient record. Data of 170 cases and 170 controls were eventually collected. The following variables associated with increased risk of falls resulting in hip fractures remained statistically significant after multivariate logistic regression, including benign prostatic hyperplasia [odds ratio (OR) = 2.654; 95% confidence interval (CI), 1.105-6.378; P = 0.029], first-generation antihistamines (OR = 3.176; 95% CI, 1.044-9.664; P = 0.042), antiparkinson medications (OR = 3.754; 95% CI, 1.158-12.169; P = 0.027), osteoporosis (OR = 3.159; 95% CI, 1.167-8.552; P = 0.024), and use of walking aids (OR = 2.543; 95% CI, 1.544-4.188; P < 0.001). In conclusion, this study identified various medications and comorbidities, rather than polypharmacy based on the number of medications, as predictors associated with increased risk of falls resulting in hip fractures for local geriatric patients. The findings provided insights into the potential medication-related fall prevention strategies, including clinical medication review, adverse drug event monitoring, and drug optimization.

Mechanisms of electrical stimulation in eye diseases: A narrative review.

Background: In the last two decades, electrical stimulation (ES) has been tested in patients with various eye diseases and shows great treatment potential in retinitis pigmentosa and optic neuropathy. However, the clinical application of ES in ophthalmology is currently limited. On the one hand, optimization and standardization of ES protocols is still an unmet need. On the other hand, poor understanding of the underlying mechanisms has hindered clinical exploitation. Main Text: Numerous experimental studies have been conducted to identify the treatment potential of ES in eye diseases and to explore the related cellular and molecular mechanisms. In this review, we summarized the in vitro and in vivo evidence related to cellular and tissue response to ES in eye diseases. We highlighted several pathways that may be utilized by ES to impose its effects on the diseased retina. Conclusions: Therapeutic effect of ES in retinal degenerative diseases might through preventing neuronal apoptosis, promoting neuronal regeneration, increasing neurotrophic factors production in Müller cells, inhibiting microglial activation, enhancing retinal blood flow, and modulating brain plasticity. Future studies are suggested to analyse changes in specific retinal cells for optimizing the treatment parameters and choosing the best fit ES delivery method in target diseases.

The selective vulnerability of retinal ganglion cells in rat chronic ocular hypertension model at early phase.

Glutamate neurotoxicity has been postulated to play a prominent role in glaucoma. In this study the possible roles of two subunits of glutamate receptors during the early phase of retinal ganglion cell (RGC) loss in a rat chronic ocular hypertension (COH) model were investigated. COH was induced by applying argon laser to the episcleral and limbal veins of the right eye of rats, the observation times were at 4, 14 and 28 days after the first laser. RGCs were retrogradely labeled by putting Fluoro-Gold (FG) on the surface of both side superior colliculus. Immunohistochemical staining using specific antibodies against N-methyl-D-aspartate receptor 1 (NR1) or glutamate receptor 2/3 (GluR2/3) was performed on the retinal sections of normal and COH eyes. Fluorescent images were captured using confocal laser scanning microscope and the number of NR1 and GluR2/3 labeled cells were counted and cell size was measured using Stereo Investigator. During the observation period, the numbers of NR1 and GluR2/3 positive RGCs in the RGC layer were reduced parallel to the loss of RGC. The dramatic loss of GluR2/3 immunoreactive neurons occurred starting immediately after the first laser to 4 days while the dramatic loss of NR1 immunoreactive neurons occurred from 14 to 28 days after the first laser. Size difference was detected in NR1 immunoreactive RGCs, large ones were more sensitive to the high ocular pressure. These results suggest that both NR1 and GluR2/3 are involved in the mediation of RGC death in the early stage of COH.

Enhanced survival of melanopsin-expressing retinal ganglion cells after injury is associated with the PI3 K/Akt pathway.

In the present study, we studied the factors that contribute to the injury-resistant property of melanopsin-expressing retinal ganglion cells (mRGCs). Since phosphatidylinositol-3 kinase (PI3 K)/Akt signaling pathway is one of the well-known pathways for neuronal cell survival, we investigated the survival of mRGCs by applying the PI3 K/Akt specific inhibitors after injury. Two injury models, unilateral optic nerve transection and ocular hypertension, were adopted using Sprague-Dawley rats. Inhibitors of PI3 K/Akt were injected intravitreally following injuries to inhibit the PI3 K/Akt signaling pathway. Retinas were dissected after designated survival time, immunohistochemistry was carried out to visualize the mRGCs using melanopsin antibody and the number of mRGCs was counted. Co-expression of melanopsin and phospho-Akt (pAkt) was also examined. Compared to the survival of non-melanopsin-expressing RGCs, mRGCs showed a marked resistance to injury and co-expressed pAkt. Application of PI3 K/Akt inhibitors decreased the survival of mRGCs after injury. Our previous study has shown that mRGC are less susceptible to injury following the induction of ocular hypertension. In this study, we report that mRGCs were injury-resistant to a more severe type of injury, the optic nerve transection. More importantly, the PI3 K/Akt pathway was found to play a role in maintaining the survival of mRGCs after injury.

Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension.

AIMS: Recent studies have showed that erythropoietin (EPO) is a neuroprotectant for central nerve system neurons in addition to being a hematopoietic cytokine in response to hypoxia. In this study, we investigate the role of the EPO/EPO receptor (EPOR) system in the rat retina after ocular hypertension injury that mimics glaucoma. METHODS: Elevated intraocular pressure was induced by laser coagulation of the episcleral and limbal veins. Expression of EPO and EPOR in the normal and glaucomous retinas was investigated by immunohistochemistry and Western blot. To examine the effects of endogenous EPO on the survival of retinal ganglion cells (RGCs) subjected to hypertensive injury, soluble EPOR was directly injected into the vitreous body. Recombinant human EPO was both intravitreally and systemically administrated to study the effect of exogenous EPO on the survival of RGCs after ocular hypertension injury. RESULTS: Immunohistochemistry studies identified Müller cells as the main source of EPO in the normal retina. Expression of EPO and EPOR proteins was increased significantly 2 weeks after ocular hypertension. RGCs, amacrine and bipolar cells all demonstrated an increased expression of EPOR after ocular hypertension. Neutralization of endogenous EPO with soluble EPOR exacerbated ocular hypertensive injury, suggesting a role of the EPO/EPOR system in the survival of RGCs after injury. Similarly, topical and systemic administration of recombinant human EPO rescues RGCs after chronic ocular hypertension. CONCLUSIONS: These results indicate that an endogenous EPO/EPOR system participates in intrinsic recovery mechanisms after retina injury and RGCs might be rescued by exogenous administration of EPO.

CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway.

We examined the neuroprotective effect of ciliary neurotrophic factor (CNTF) on retinal ganglion cells (RGCs) in a rat glaucoma model with increased intraocular pressure (IOP) and studied the CNTF-mediated activation of Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Elevated IOP was induced by laser photocoagulation of the episcleral and limbal veins. The survival of RGCs was studied using Fluoro-Gold labelled in ocular hypertensive eyes with or without CNTF intravitreal injection. Immunochemical staining and immunoblot analysis for CNTF and phosphorylated STAT3 (pSTAT3) were performed. There was a significant and progressive loss of RGCs in the retinas following the induction of elevated IOP. A single intravitreal injection of 2 microg in 2 microL CNTF significantly protected RGCs up to 4 weeks. pSTAT3 was only transiently expressed in ocular hypertensive eyes. However, in eyes treated with CNTF, pSTAT3 was observed up to 2 weeks after the induction of elevated IOP. In ocular hypertensive eyes, CNTF-positive cells were found in the inner nuclear layer (INL), and there was a transient increase in the pSTAT3 cells in the ganglion cell layer and INL. Immunoblots showed that STAT3 was transiently phosphorylated after IOP increase, but with an injection of CNTF, pSTAT3 protein was observed up to 2 weeks after hypertensive glaucoma induction. Laser-induced chronic ocular hypertension in rats resulted in the death of RGCs and a transient activation of STAT3 in the retina. Intravitreal injection of CNTF showed a significant protection of RGCs, and the JAK-STAT signalling could be one of the important pathways that underlie the mechanism of CNTF neuroprotection in this rat glaucoma model.