Retinal Ganglion Cells In Patients Research Articles

Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial.

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells, affecting vision. The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation. However, although the macular thickness can be normalized with each of these two therapies used alone, the vision does not improve in many patients. This might result from the incomplete recovery of retinal ganglion cell injury. Therefore, a prospective, non-randomized, controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery. In this trial, 150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods, followed by treatment with anti-vascular endothelial growth factor drugs, laser photocoagulation therapy, and their combination. All patients will be followed up for 12 months. The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment. The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1, 3, 6, and 9 months after treatment, retinal nerve fiber layer thickness, best-corrected visual acuity, macular area thickness, and choroidal thickness before and 1, 3, 6, 9, and 12 months after treatment. Safety measure is the incidence of adverse events at 1, 3, 6, 9, and 12 months after treatment. The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period. The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity. The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No. (2023)(26) on April 25, 2023, and was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2300072478, June 14, 2023, protocol version: 2.0).

Implementation of convolutional neural network for predicting glaucoma from fundus images

The contributions of this paper are two-fold. First, it uses machine learning tools to detect and monitor glaucoma. Second, it provides insight into medicine, which can assist healthcare professionals in improving disease diagnostic accuracy and help to reduce the progression and degeneration of retinal ganglion cells in patients. Glaucoma is a group of eye diseases that damage the optic nerve, which can cause vision loss and blindness at any age. The main symptom of glaucoma in the early stages is high internal eye pressure. It is still unknown what causes these diseases to develop, but if not treated, they result in optic nerve atrophy. For this reason, in this paper we propose a novel deep learning system for the automatic diagnosis of glaucoma using a convolutional neural network for classification, which demonstrates improved performance and records computation time for fundus images. The results showed an accuracy of 94 % and a loss value of only 0.27. The model we have created to investigate with Keras helped us achieve good results in our training and testing process. These study results demonstrate the ability of a deep learning model to identify glaucoma from fundus images. Increasing the filter size and training the model resulted in a higher accuracy rate. A population survey that was conducted in 2019 shows that most patients with glaucoma become aware of their disease late, after the disease causes a high level of optic nerve damage and a high percentage of vision loss. Early diagnosis and detection of glaucoma using optic nerve imaging technology have gained wide clinical interest in stopping or slowing the progression of the disease, allowing the development of new algorithms to automate the diagnosis of eye diseases

Traitements médicaux dans la neuropathie optique héréditaire de Leber

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease caused by a mutation of mitochondrial DNA. LHON targets retinal ganglion cells (RGC), whose axons form the optic nerve. The mutation that leads to LHON is silent until an unknown trigger causes dysfunction of complex I in the mitochondria of RGC. This results in discontinuation of RGC energy production and, eventually, RGC apoptosis. Patients experience bilateral sequential central scotoma over the course of a few months, with a minority recovering some vision more than 1 year after the onset of visual loss.No pharmacological treatment is recommended unless patients are symptomatic in at least one eye, as most LHON mutation carriers never experience visual loss. Research has been focused on treatments that are thought to restore the mitochondrial electron transport chain in RGC in patients with recent disease onset (<1 year). Significant advances have been made in evaluating free radical cell scavengers and gene therapy as potential treatments for LHON. Although promising, the results of clinical trials have been mixed. In patients with chronic visual loss for more than 1 year, treatment that restores vision is yet to be discovered.In this review, we summarize management strategies for patients with LHON before, during, and after the loss of vision, explain the rationale and effectiveness of previous and current treatments, and report findings about emerging treatments.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

ObjectiveTo investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS.MethodsOne hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration.ResultsThe annual rates of RNFL and GCIPL thinning were higher in patients treated with “platform” therapies (interferon-β and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = −0.22 μm/y, p = 0.02 for pRNFL; difference = −0.34 μm/y, p = 0.009 for tRNFL; and difference = −0.16 μm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-β, glatiramer acetate, fingolimod, and natalizumab), interferon-β was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab.ConclusionsProgressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-β than other DMTs. This finding may have implications for DMT selection in MS.Classification of EvidenceThis study provides Class IV evidence that for patients with MS, treatment with interferon-β compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.

Disinhibition of intrinsic photosensitive retinal ganglion cells in patients with X-linked congenital stationary night blindness.

To assess the pupil light response (PLR) to chromatic stimulation in patients with different types of X-linked congenital stationary night blindness (CSNB). Eight patients with CSNB due to CACNA1F and NYX mutations were exposed to blue and red light stimuli, and PLR was evaluated using infrared video pupillography. Pupil responses were compared between CSNB patients and healthy subjects (n = 34) at baseline, at maximum of constriction, for post-illumination pupil responses (PIPR) and the slope of redilation using Cohen's d. A subgroup comparison was performed descriptively between CACNA1F and NYX associated CSNB patients using the same parameters. In CSNB, smaller baseline pupil diameters compared to healthy subjects were measured both before blue and red light stimulation (d = 1.44-1.625). The maximum constriction to blue light stimuli was smaller for the CSNB group compared to healthy subjects (d = 1.251) but not for red light stimuli (d = 0.449). Pupil response latencies were prolonged in CSNB for both light stimuli (d = -1.53 for blue and d = -1.011 for red stimulation). No relevant differences were found between the CSNB group and healthy subjects for PIPR (d = 0.01), but the slope of redilation was smaller for CSNB patients (d = 2.12). Paradoxical pupil constriction at light offset was not seen in our patients. A reduced redilation and smaller baseline pupil diameters for patients with CSNB indicate a disinhibition of intrinsically photosensitive retinal ganglion cells due to affected post-photoreceptor transduction via bipolar cells and can explain the pupillary behavior in our patient group.

Normal Visual Recovery after Optic Neuritis Despite Significant Loss of Retinal Ganglion Cells in Patients with Multiple Sclerosis.

Optic neuritis (ON) is a frequent manifestation of demyelinating attack in multiple sclerosis (MS). Initial visual loss can vary from minimal to complete. Visual improvement occurs in about 95% of patients, some of them recovering to normal [visual acuity (VA), color vision, visual field (VF)]. We analyzed retinal ganglion cell layer (RGCL) thickness in MS patients who recovered their normal vision after ON to determine whether a relative preservation of RGCL existed in these patients. We conducted a retrospective study of all patients with MS and ON examined by one of us (F. X. B.) between 2013 and 2018. Inclusion criteria were strictly unilateral ON, full recovery of vision, computerized visual field, and OCT examinations. Full recovery of vision was defined as VA ≥ 10/10, Ishihara ≥ 11/13, and VF mean defect (MD) ≤ 2.6 dB. Evaluation of RGCL was obtained with spectral domain optical coherence tomography (SD-OCT). The normal fellow eye of all patients served as the control group. Relative thinning of RGCL, expressed as percentage, was calculated by comparing results from the affected eye to the fellow eye of the same patient. Twenty-one patients (21 affected eyes - Group 1, 21 normal fellow eyes - Group 2) satisfying the inclusion criteria were retrieved from our database. All patients exhibited the relapsing-remitting form of MS. There were 16 women and 5men. Mean age was 39.3 years old. There were no statistically significant differences between Group 1 and Group 2 for either VA (p = 0.3934) or Ishihara (p = 0.140), but a significant difference was found for VF MD (p = 0.0405). A markedly significant difference for RGCL thickness (p = 0.0001) was found, without any correlation with the degree of visual recovery. A subgroup of patients (n = 14) was examined at the time of initial visual loss. We correlated their results of visual function to the final RGCL thickness, and a correlation was found between either the initial VA loss or the initial VF loss and the final loss of RGCL (R2 = 0.4075 and R2 = 0.00739, respectively). In our study, all patients with ON lost a significant amount of RGCL despite a full recovery of vision, as defined by our criteria. The percentage of RGCL loss varied from 5 - 27% and could not be correlated with any final visual indices. However, a correlation was found with the degree of initial visual loss. Despite sometimes marked RGCL loss after ON, patients with MS can recover normal visual function, according to standard clinical tests.

Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling

Previous studies have demonstrated that intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury. BDNF gene therapy can improve RGC survival in experimental models of glaucoma, the leading cause of irreversible blindness worldwide. However, the therapeutic efficacy of BDNF supplementation alone is time limited at least in part due to BDNF receptor downregulation. Tropomyosin-related receptor kinase-B (TrkB) downregulation has been reported in many neurological diseases including glaucoma, potentially limiting the effect of sustained or repeated BDNF delivery.Here, we characterize a novel adeno-associated virus (AAV) gene therapy (AAV2 TrkB-2A-mBDNF) that not only increases BDNF production but also improves long-term neuroprotective signaling by increasing expression of the BDNF receptor (TrkB) within the inner retina. This approach leads to significant and sustained elevation of survival signaling pathways ERK and AKT within RGCs over 6 months and avoids the receptor downregulation which we observe with treatment with AAV2 BDNF alone. We validate the neuroprotective efficacy of AAV2 TrkB-2A-mBDNF in a mouse model of optic nerve injury, where it outperforms conventional AAV2 BDNF or AAV2 TrkB therapy, before showing powerful proof of concept neuroprotection of RGCs and axons in a rat model of chronic intraocular pressure (IOP) elevation. We also show that there are no adverse effects of the vector on retinal structure or function as assessed by histology and electroretinography in young or aged animals. Further studies are underway to explore the potential of this vector as a candidate for progression into clinical studies to protect RGCs in patients with glaucoma and progressive visual loss despite conventional IOP-lowering treatment.

Loss of Melanopsin-Expressing Retinal Ganglion Cells in Patients With Diabetic Retinopathy.

Photo-entrainment of the circadian clock is mediated by melanopsin-expressing retinal ganglion cells (mRGCs) located in the retina. Patients suffering from diabetic retinopathy (DR) show impairment of light regulated circadian activity such as sleep disorders, altered blood pressure, and abnormal melatonin secretion. The aim of this study was to assess the impact of DR on the expression of mRGCs in the human retina. The expression of mRGCs and RGCs was determined in eye sections containing retinal tissue from patients with DR (n = 6) and respective age-matched controls (n = 8) using immunohistochemistry by costaining with antibodies against RNA binding protein with multiple splicing (RBPMS), which identified RGCs and melanopsin which identified the mRGCs. The expression of RGCs in the retina from patients with severe DR was significantly reduced to a density of 146 ± 76 cells/mm2 compared with controls at 1280 ± 249 cells/mm2. The density of mRGCs was also significantly reduced from 3.12 ± 0.54 cells/mm2 in controls to 0.72 ± 0.18 cells/mm2 in patients with DR, with significant loss of 73.5% and 81.9% in mRGC density in the ganglion cell layer (GCL) and inner nuclear layer (INL), respectively. Our findings show that DR affects the expression of mRGCs in the human retina and could explain the abnormal circadian activity observed in patients with DR.

Importance of taurine in maintaining retinal function

AbstractTaurine depletion has been known to induce photoreceptor degeneration since the 70s. Recently, investigating the retinal toxicity of the antiepileptic drug, vigabatrin, we showed that taurine depletion causes retinal ganglion cell loss. Indeed, the primary site of vigabatrin‐induced injury appears to be located in retinal ganglion cells in patients. The taurine depletion was demonstrated in both vigabatrin‐treated animals and patients. In fact, an increase in intraocular pressure as in glaucoma could also induce a local retinal taurine depletion. Taurine supplementation was neuroprotective in 4 animal models with retinal ganglion cell loss. Taurine acts directly on retinal ganglion increasing their survival in pure cultures. Taurine also reduces their glutamate excitotoxicity in retinal explants. Therefore, taurine is required for the normal maintenance of photoreceptors but also for the maintenance of retinal ganglion cells. Taurine supplementation may therefore provide a novel neuroprotective strategy for retinal diseases like glaucoma.

Transneuronal Retrograde Degeneration of the Retinal Ganglion Cells in Patients with Cerebral Infarction

The objective of this study was to determine whether transneuronal retrograde degeneration (TRD) of the retinal ganglion cells (RGCs) could be detected by optical coherence tomography (OCT) in humans with lesions other than of the occipital lobe or visual cortex. In addition, whether laterality and severity of retinal nerve fiber layer (RNFL) damage correlated with 3 other variables was determined: laterality of hemispheric damage, arterial territory of infarct, and age of infarct. Cross-sectional, case-control design. Forty-six patients with cerebral ischemic infarction diagnosed based on brain magnetic resonance imaging and 46 normal controls were enrolled. All subjects underwent a complete ophthalmic examination including OCT. Cerebral infarction was categorized by arterial territory: anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA). Eyes on the same side of the infarction were referred to as ipsilateral eyes, and eyes on the opposite side of the infarction were referred as contralateral eyes. Retinal nerve fiber layer thickness. Average, superior, temporal, inferior, and nasal RNFL thicknesses were different significantly between patients with cerebral infarction and normal controls. The RNFL thicknesses were reduced significantly at the superior, inferior, and nasal quadrants in the contralateral eyes and at the superior, inferior, and temporal quadrants in the ipsilateral eyes. The RNFL thickness reduction was greater in patients with PCA infarction, followed by MCA and ACA infarction, respectively. Factors related to the average RNFL thickness were time after stroke onset and infarction territory based on both univariate (P = 0.027 and P = 0.046, respectively) and multivariate (P = 0.036 and P = 0.047, respectively) analysis. Retinal nerve fiber layer thickness was reduced in patients with cerebral infarction, providing evidence for TRD of the RGCs. Transneuronal retrograde degeneration was more pronounced in the nasal nerve fiber layer of the contralateral side and in the temporal nerve fiber layer of the ipsilateral side of cerebral damage. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Thickness of Receptor and Post-receptor Retinal Layers in Patients with Retinitis Pigmentosa Measured with Frequency-Domain Optical Coherence Tomography

To better understand the effects of retinitis pigmentosa (RP) on post-receptor anatomy, the thicknesses of the receptor, inner nuclear, retinal ganglion cell (RGC), and retinal nerve fiber layers (RNFL) were measured with frequency-domain optical coherence tomography (fdOCT). FdOCT scans were obtained from the horizontal midline in 30 patients with RP and 23 control subjects of comparable age. Raw images were exported and the thicknesses of photoreceptor/RPE, inner nuclear, RGC plus inner plexiform, and nerve fiber layers were measured with a manual segmentation procedure aided by a computer program. The RNFL thickness was also measured in 20 controls and 25 patients using circular peripapillary fdOCT scans. Results from controls were consistent with known anatomy. In patients with RP, the pattern of photoreceptor loss with eccentricity was consistent with the field constriction characteristic of RP. INL and RGC layer measures were comparable to normal subjects, although some patients showed slightly thicker RGC layers. However, RNFL layer thickness was significantly greater than normal; a majority of patients showed a thicker RFNL on both horizontal midline scans and peripapillary scans. To make optimal use of OCT RNFL thickness as a measure of the integrity of RGCs in patients with RP, a better understanding of the causes of the thickening seen in the majority of the patients is needed. As the RGC layer thickness can be measured with fdOCT, RGC layer thickness may turn out to be a more direct and valid indicator of the presence of RGCs in patients with RP.

Anti-neuronal autoantibodies and neurological paraneoplastic syndromes.

Remote effects of cancer on the nervous system or paraneoplastic syndromes are diseases of unknown cause that occur exclusively or with increased frequency in patients with cancer. Several hypotheses have been used to explain the pathogenesis of these disorders. One hypothesis is that the tumour and the nervous system share antigens, so that an autoimmune response generated against the tumour causes the neurological disorder. The best evidence for this hypothesis is found in the Lambert-Eaton myasthenic syndrome which can be transferred to animals by injecting them with IgG from patients. The identification of autoantibodies against Purkinje cell cytoplasmic protein antigens in patients with paraneoplastic cerebellar degeneration, autoantibodies against neuronal nuclear antigens in patients with paraneoplastic syndromes associated with small cell lung cancer and autoantibodies against retinal ganglion cells in patients with small cell lung cancer and retinal degeneration supports this hypothesis. The possible role of these autoantibodies in the pathogenesis of paraneoplastic neurological disease is discussed.