IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33^-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33^-/- and WT mice after ON injury, but not in ST2^-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.
Animals ; Interleukin-33/genetics* ; Interleukin-1 Receptor-Like 1 Protein/genetics* ; Optic Nerve Injuries/pathology* ; Retinal Ganglion Cells/pathology* ; Astrocytes/pathology* ; Mice ; Mice, Knockout ; Mice, Inbred C57BL ; Neuroprotection/physiology*

OBJECTIVE: To investigate the therapeutic effect of Epothilone D on traumatic optic neuropathy (TON) in rats. METHODS: Forty-two SD rats were randomized to receive intraperitoneal injection of 1.0 mg/kg Epothilone D or DMSO (control) every 3 days until day 28, and rat models of TON were established on the second day after the first administration. On days 3, 7, and 28, examination of flash visual evoked potentials (FVEP), immunofluorescence staining and Western blotting were performed to examine the visual pathway features, number of retinal ganglion cells (RGCs), GAP43 expression level in damaged axons, and changes of Tau and pTau-396/404 in the retina and optic nerve. RESULTS: In Epothilone D treatment group, RGC loss rate was significantly decreased by 19.12% (P=0.032) on day 3 and by 22.67% (P=0.042) on day 28 as compared with the rats in the control group, but FVEP examination failed to show physiological improvement in the visual pathway on day 28 in terms of the relative latency of N2 wave (P=0.236) and relative amplitude attenuation of P2-N2 wave (P=0.441). The total Tau content in the retina of the treatment group was significantly increased compared with that in the control group on day 3 (P < 0.001), showing a consistent change with ptau-396/404 level. In the optic nerve axons, the total Tau level in the treatment group was significantly lower than that in the control group on day 7 (P=0.002), but the changes of the total Tau and pTau-396/404 level did not show an obvious correlation. Epothilone D induced persistent expression of GAP43 in the damaged axons, detectable even on day 28 of the experiment. CONCLUSION Epothilone D treatment can protect against TON in rats by promoting the survival of injured RGCs, enhancing Tau content in the surviving RGCs, reducing Tau accumulation in injured axons, and stimulating sustained regeneration of axons.
Animals ; Disease Models, Animal ; Epothilones ; Evoked Potentials, Visual ; Nerve Regeneration/physiology* ; Optic Nerve Injuries/metabolism* ; Rats ; Rats, Sprague-Dawley ; Retinal Ganglion Cells/physiology*

PURPOSE: Though there are many reports regarding the structure-function relationship in glaucoma, they are too complicated to apply to the routine clinical setting. The aim of this study was to investigate the direct relationship between peripapillary retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) and visual field (VF) severity indices computed by standard automated perimetry. METHODS: This cross-sectional comparative study included 104 glaucomatous patients and 59 healthy subjects. Peripapillary RNFL thickness was measured by spectral domain (SD) and time domain (TD) OCTs. Four glaucoma VF severity indices, including mean deviation (MD), pattern standard deviation (PSD), Collaborative Initial Glaucoma Treatment Study (CIGTS) VF score, and Advanced Glaucoma Intervention Study (AGIS) VF score, were calculated using standard automated perimetry. The Pearson's correlation coefficients (r) between the average and quadrants of peripapillary RNFL thicknesses and the four VF severity indices were calculated. RESULTS: In glaucomatous eyes, the r value between the average RNFL thickness measured by SD OCT and each VF severity index were 0.562, -0.514, -0.577, and -0.567 for the MD, PSD, CIGTS VF score, and AGIS VF score, respectively (all p < 0.001). Among each quadrant, the inferior RNFL thickness showed the largest r value; 0.587, -0.552, -0.613, and -0.598 for the MD, PSD, CIGTS VF score, and AGIS VF score, respectively (all p < 0.001). Measurements by TD OCT showed similar strengths of association with SD OCT. CONCLUSIONS: Moderate correlation was identified between peripapillary RNFL thicknesses measured by SD/TD OCT and glaucoma VF severity indices. Among each quadrant, the inferior RNFL thickness showed the greatest association with glaucoma VF severity indices. There was no significant difference according to the type of VF severity index or the type of OCTs.
Adult ; Aged ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Nerve Fibers/*pathology ; Optic Nerve/*pathology ; Optic Nerve Diseases/*diagnostic imaging/physiopathology ; Retinal Ganglion Cells/*pathology ; Severity of Illness Index ; Tomography, Optical Coherence/*methods ; Visual Field Tests/methods ; Visual Fields/*physiology ; Young Adult

PURPOSE: To evaluate the effect of pattern scan laser (PASCAL) photocoagulation on peripapillary retinal nerve fiber layer (RNFL) thickness, central macular thickness (CMT), and optic nerve morphology in patients with diabetic retinopathy. METHODS: Subjects included 35 eyes for the PASCAL group and 49 eyes for a control group. Peripapillary RNFL thickness, cup-disc area ratio and CMT were measured before PASCAL photocoagulation and at 2 and 6 months after PASCAL photocoagulation in the PASCAL or control groups. RESULTS: The average RNFL thickness had increased by 0.84 microm two months after and decreased by 0.4 microm six months after PASCAL photocoagulation compared to baseline, but these changes were not significant (p = 0.83, 0.39). The cup-disc area ratio was unchanged after PASCAL photocoagulation. CMT increased by 18.11 microm (p = 0.048) at two months compared to baseline thickness, and partially recovered to 11.82 microm (p = 0.11) at six months in the PASCAL group. CONCLUSIONS: PASCAL photocoagulation may not cause significant change in the peripapillary RNFL thickness, CMT, and optic nerve morphology in patients with diabetic retinopathy.
Adult ; Aged ; Aged, 80 and over ; Diabetic Retinopathy/physiopathology/*surgery ; Female ; Fluorescein Angiography ; Follow-Up Studies ; Humans ; Laser Coagulation/*methods ; Lasers, Solid-State/*therapeutic use ; Macula Lutea/*pathology ; Male ; Middle Aged ; Nerve Fibers/*pathology ; Optic Nerve/*pathology ; Prospective Studies ; Retinal Ganglion Cells/*pathology ; Tomography, Optical Coherence ; Visual Acuity/physiology

PURPOSE: Blind individuals who have photoreceptor loss are known to perceive phosphenes with electrical stimulation of their remaining retinal ganglion cells. We proposed that implantable lateral geniculate body (LGB) stimulus electrode arrays could be used to generate phosphene vision. We attempted to refine the basic reference of the electrical evoked potentials (EEPs) elicited by microelectrical stimulations of the optic nerve, optic tract and LGB of a domestic pig, and then compared it to visual evoked potentials (VEPs) elicited by short-flash stimuli. METHODS: For visual function measurement, VEPs in response to short-flash stimuli on the left eye of the domestic pig were assessed over the visual cortex at position Oz with the reference electrode at Fz. After anesthesia, linearly configured platinum wire electrodes were inserted into the optic nerve, optic track and LGB. To determine the optimal stimulus current, EEPs were recorded repeatedly with controlling the pulse and power. The threshold of current and charge density to elicit EEPs at 0.3 ms pulse duration was about ±10 microA. RESULTS: Our experimental results showed that visual cortex activity can be effectively evoked by stimulation of the optic nerve, optic tract and LGB using penetrating electrodes. The latency of P1 was more shortened as the electrical stimulation was closer to LGB. The EEPs of two-channel in the visual cortex demonstrated a similar pattern with stimulation of different spots of the stimulating electrodes. We found that the LGB-stimulated EEP pattern was very similar to the simultaneously generated VEP on the control side, although implicit time deferred. CONCLUSIONS: EEPs and VEPs derived from visual-system stimulation were compared. The LGB-stimulated EEP wave demonstrated a similar pattern to the VEP waveform except implicit time, indicating prosthetic-based electrical stimulation of the LGB could be utilized for the blind to perceive vision of phosphenes.
Animals ; Electric Stimulation ; Electrodes, Implanted ; Evoked Potentials, Visual/*physiology ; Geniculate Bodies/*physiology ; Male ; Optic Nerve/physiology ; Optic Tract/physiology ; Photic Stimulation ; Sus scrofa ; Visual Cortex/*physiology

PURPOSE: To investigate patterns of subsequent progression of localized retinal nerve fiber layer (RNFL) defects and to quantify the extent of progression in normal-tension glaucoma (NTG) patients. METHODS: Thirty-three eyes of 33 consecutive NTG patients who had shown continuous progression of localized RNFL defect on serial red-free fundus photographs were selected for the study. Patterns of subsequent progression of localized RNFL defects were categorized, and extents of progression were quantified. Serial evaluations of disc stereophotographs and visual fields were also performed to detect progression. RESULTS: The most common pattern was continuous widening of the defect towards the macula (n = 11, 33.3%) followed by sharpening of the defect border after widening of the defect towards the macula (n = 5, 15.2%), continuous widening of the defect away from the macula (n = 2, 6.1%), and deepening of the defect after appearance of a new defect (n = 2, 6.1%). Four eyes (12.1%) simultaneously showed two patterns of subsequent progression. In 13 eyes that showed continuous widening of the defect, subsequent angular widening towards the macula and away from the macula were 9.2 ± 6.0degrees (range, 1.1degrees to 24.4degrees; n = 11) and 5.2 ± 4.9degrees (range, 0.3degrees to 11.3degrees; n = 2), respectively. Thirty-two eyes showed no progression of optic disc cupping. Out of the 21 eyes in which Humphrey central 30-2 threshold visual field tests were performed after progression of RNFL defects, 15 eyes showed no deterioration in the visual field. CONCLUSIONS: There were nine patterns of subsequent progression of localized RNFL defects. Among them, continuous RNFL loss proceeding temporally was the most common one. Initial progression of the defect proceeded temporally, especially in the defect located at the inferior fundus, might be at a risk of further RNFL loss temporally.
Adult ; Aged ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Intraocular Pressure/physiology ; Low Tension Glaucoma/*diagnosis/physiopathology ; Male ; Middle Aged ; Nerve Fibers/*pathology ; Optic Disk/pathology ; Photography ; Retinal Ganglion Cells/*pathology ; Tonometry, Ocular ; Visual Fields/physiology

PURPOSE: To evaluate the relationship between the structural damage as assessed by time-domain optical coherence tomography (OCT) and functional changes in glaucoma. METHODS: In total, 190 patients with normal tension glaucoma or primary open angle glaucoma were included in this study. The thickness of retinal nerve fiber layer (RNFL) around the optic disc and the area of RNFL defect were determined using OCT scans. The relationships between the RNFL thickness or area of the defect and visual field (VF) indices were assessed using the Lowess function, regression analysis and partial Spearman correlation. The differences between these associations depending on the stage of VF damage were further analyzed. Age, optic disc size, refraction, central corneal thickness and the presence of systemic disease were corrected for in order to exclude confounding factors. RESULTS: A logarithmic scale of RNFL thickness showed a negative linear relationship with VF indices. The area of the RNFL defect showed a weak correlation with the pattern of standard deviation, whereas the remnant RNFL thickness was moderately correlated with the pattern of standard deviation (partial Spearman correlation coefficient, 0.39, -0.47, respectively; p < 0.0001). Many outliers were detected in the Lowess-plotted graphs. Multiplication of the area and the inverted RNFL thickness showed a moderately correlated logarithmic relationship with the VF indices (partial Spearman correlation coefficient, 0.46; 95% confidence interval, 0.34 to 0.57; p < 0.0001). In the severe stage of VF damage, correlation between the area of the RNFL defect and mean deviation was significantly greater than in other stages (partial Spearman correlation coefficient, -0.66; p = 0.02). CONCLUSIONS: The thickness of the RNFL had a negative logarithmic correlation with the VF indices and was more relevant to the VF indices than the area of the RNFL defect, as measured by OCT.
Aged ; Female ; Glaucoma, Open-Angle/*physiopathology ; Humans ; Low Tension Glaucoma/*physiopathology ; Male ; Middle Aged ; Nerve Fibers/*pathology ; Optic Nerve Diseases/*physiopathology ; Retinal Ganglion Cells/*pathology ; Tomography, Optical Coherence ; Visual Field Tests ; Visual Fields/*physiology

OBJECTIVETo review the functions of these intracellular signals in their regulation of retinal ganglion cell (RGC) axon regeneration.

DATA SOURCESRelevant articles published in English or Chinese from 1970 to present were selected from PubMed. Searches were made using the terms "intrinsic determinants, axon regeneration, RGC, optic nerve regeneration, and central nervous system axon regeneration."

STUDY SELECTIONArticles studying the mechanisms controlling RGC and central nervous system (CNS) axon regeneration were reviewed. Articles focusing on the intrinsic determinants of axon regeneration were selected.

RESULTSLike other CNS neurons of mammals, RGCs undergo a developmental loss in their ability to grow axons as they mature, which is a critical contributing factor to the failure of nerve regeneration and repair after injury. This growth failure can be attributed, at least in part, by the induction of molecular programs preventing cellular overgrowth and termination of axonal growth upon maturation. Key intracellular signals and transcription factors, including B cell lymphoma/leukemia 2, cyclic adenine monophosphate, mammalian target of rapamycin, and Krüppel-like transcription factors, have been identified to play central roles in this process.

CONCLUSIONSIntense effort and substantial progress have been made to identify the various intrinsic growth pathways that regulate RGC axon regeneration. More work is needed to elucidate the mechanisms of and the interrelationship between the actions of these factors and to successfully achieve regeneration and repair of the severed RGC axons.

Animals ; Cyclic AMP ; physiology ; Humans ; Kruppel-Like Transcription Factors ; physiology ; Nerve Regeneration ; Optic Nerve ; physiology ; PTEN Phosphohydrolase ; physiology ; Proto-Oncogene Proteins c-bcl-2 ; physiology ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; physiology ; TOR Serine-Threonine Kinases ; physiology

BACKGROUNDIndirect traumatic optic neuropathy (TON) is an acute injury of the optic nerve associated with severe visual dysfunction, which may be a result of secondary mechanical injury and vascular disorder of the optic nerve due to trauma. We analyzed the natural course of axonal loss and blood flow disturbances in patients with indirect TON to find a possible therapeutic window.

METHODSA cohort of 54 patients with indirect TON recruited between October 2008 and October 2010 at Beijing Tongren Hospital was retrospectively analyzed. The patients were divided into no light perception group (NLP) and better than NLP (btNLP) group. Specifically, the thickness of the retinal nerve fiber layer (RNFL) measured by spectral domain optical coherence tomography (SD-OCT), and hemodynamic parameters of the ophthalmic artery (OA), central retinal artery (CRA) and posterior ciliary artery (PCA) were determined.

RESULTSTwo weeks after injury, there was a statistically significant decrease in the thickness of RNFL in the btNLP group as compared with the fellow control eyes (P < 0.05). In contrast, in the NLP group, RNFL thickness slightly increased for 2 weeks following injury, then overtly reduced after 4 weeks (P < 0.05). Peak systolic velocity (PSV) of CRA was significantly decreased 4 weeks after injury (P < 0.05) in both the NLP group and btNLP group (P < 0.05). The thickness of RNFL in the NLP group was negatively correlated with PSV of CRA after 1 week of injury (P < 0.05, r = -0.962).

CONCLUSIONSSD-OCT is a useful supplement in detecting the axonal loss in TON. The dynamic change of the thickness of RNFL appears to correlate with the hemodynamic disturbances in the natural course of TON. The first 2 weeks following an injury is critical and should be considered as the therapeutic window for TON patients.

Adult ; Female ; Humans ; Male ; Middle Aged ; Nerve Fibers ; physiology ; Optic Nerve ; physiology ; Optic Nerve Injuries ; physiopathology ; Retinal Neurons ; physiology ; Retrospective Studies ; Tomography, Optical Coherence

PURPOSE: To evaluate orbital blood flow velocities and optic nerve diameter with Doppler and gray-scale sonography in patients with acute unilateral optic neuritis (ON). METHODS: Orbital Doppler and gray-scale sonography was performed in 46 eyes of 23 patients aged 19- to 47-years with acute unilateral ON. ON was diagnosed by an ophthalmologist on the basis of clinical presentation, presence of decreased visual acuity and assessment of visual evoked potentials. The peak systolic velocity (PSV) and end-diastolic velocity (EDV), as well as the resistance index (RI) and pulsatile index (PI) of the ophthalmic artery (OA), central retinal artery (CRA), posterior ciliary arteries (PCAs) and optic nerve diameter were measured in both eyes. We compared results from affected and unaffected eyes using the paired t-test. The area under the receiver operating characteristic (ROC) curves was used to assess the diagnosis of ON based on measured blood flow parameters of the OA, CRA and PCAs and optic nerve diameter. RESULTS: The mean (standard deviation) optic nerve diameter in eyes with ON was 4.1 (0.8) mm, which was significantly larger than the 3.0 (0.4) mm diameter measured in unaffected control eyes (p < 0.001). There were no differences in average PSV, EDV, RI, or PI of the OA and CRA between affected and unaffected eyes (p > 0.05). The mean RI in the PCAs was slightly lower in the eyes with ON than in the contralateral eyes (0.60 vs. 0.64, p < 0.05). The area under the ROC curves indicated that optic nerve diameter was the best parameter for the diagnosis of ON. CONCLUSIONS: Optic nerve diameter was related to ON, but orbital blood flow parameters were not.
Adult ; Humans ; Middle Aged ; Ophthalmic Artery/*physiology/*ultrasonography ; Optic Nerve/*blood supply/*ultrasonography ; Optic Neuritis/*physiopathology/*ultrasonography ; Orbit/blood supply/ultrasonography ; Pulsatile Flow/physiology ; Regional Blood Flow/physiology ; Ultrasonography, Doppler, Color ; Vascular Resistance/physiology ; Young Adult