Collapsin response mediator protein 5-associated optic neuropathy: clinical characteristics, radiologic clues, and outcomes.

Objective: Collapsin response mediator protein 5-associated optic neuropathy (CRMP5-ON) is a rare entity of autoimmune optic neuropathy. This study aimed to review the neuro-ophthalmic findings and outcomes in a series of patients with CRMP5-ON to further characterize its clinical phenotype, radiologic clues, and outcomes. Methods: This was a retrospective case series and a single-center medical chart review of all patients with CRPM5-seropositive ON at the Department of Neurology, Beijing Tongren Hospital, from December 1, 2020, to March 31, 2023. The main outcome measures were neuro-ophthalmic manifestations, radiologic characteristics, and clinical outcomes of CRMP5-ON; coexisting neural autoantibody, paraneoplastic associations, and the impact of immunosuppressant therapy. Results: Five patients were identified. Four (80%) were female, and the average age at onset was 59.4 years (range 53-69 years), with an average follow-up of 15.3 months (range 1.4-28.7 months). The average best-corrected visual acuity (BCVA) at nadir was 20/120 (range 20/20 to count fingers). Seven of ten affected eyes (70%) showed diffuse defects of the central field. Painless bilateral involvement and optic disk edema occurred in 100% of patients, combined with vitritis, uveitis, or retinitis in four (80%). Four patients (80%) had MRI abnormalities along the optic nerve (one patient with optic nerve enhancement and three patients had optic nerve sheath enhancement or peribulbar fat enhancement). Three patients (60%) had optic neuropathy with other neurologic symptoms. Four patients (80%) had confirmed cancer (two were small-cell lung carcinoma, one was papillary thyroid carcinoma and another was thymoma and invasive pulmonary adenocarcinoma). All cancers were identified after the presentation of the optic neuropathy. The intervention included IVIG, IVMP, surgery and chemotherapy. The average BCVA at the last follow-up was 20/50 (range 20/20 to count fingers). Three patients had surgery during the initial hospitalization, and were stable during the follow-up. Among two patients who received IVMP, both had improvement after treatment, although one patient had worsening non-ocular neurologic symptoms during the steroid taper. Conclusion: CRMP5-ON presented with optic disc edema, often bilateral involved and combined with vitreitis, retinitis, or uveitis. CRMP5-ON can present with MRI optic nerve or perineural optic nerve enhancement, especially in the optic nerve sheath. CRMP5-ON is closely related to paraneoplastic neurologic syndrome. Cancer screening and intervention are crucial to prognosis.

Comparison of Clinical and Immunological Features of Para- and Non-Paraneoplastic Autoimmune Retinopathy in Chinese - A Series of 48 Cases.

PURPOSE: To characterize and compare clinical and immunological features of para(p)-autoimmune retinopathy (AIR) and non-para(np)-AIR and to assess the clinical significance of the presence of serum anti-retinal antibodies (ARAs). METHODS: We retrospectively reviewed 48 Chinese patients with p-AIR or np-AIR who took comprehensive ophthalmic examinations and lab tests of the presence of serum ARAs. RESULTS: p-AIR patients differed from np-AIR patients in terms of disease progression, ocular inflammation, findings of OCT, FFA, and presence of ARAs. No significant difference was found in the band number of serum ARAs between AIR patients and healthy controls. The prevalence of antibodies to recoverin and ɑ-enolase in the sera of p-AIR was significantly higher than that of the healthy individuals. CONCLUSION: While having many similar clinical signs, patients with p-AIR or np-AIR nevertheless displayed unique characteristics. Detection of ARAs subtypes, rather than their quantity, may be helpful in evaluating the conditions in the verified instances.

Serum antiretinal antibodies and cytokine profiling in autoimmune retinopathy and their association with clinical outcomes.

PURPOSE: Autoimmune retinopathy (AIR) is a group of autoimmune retinal diseases that can cause blindness. The purpose of this study is to investigate the profiles of serum antiretinal antibodies (ARAs) and cytokines and their association with disease diagnosis as well as clinical features in AIR. METHODS: The patients with presumed para (p) and non-paraneoplastic (np) AIR diagnosis, the patients with retinitis pigmentosa and bilateral uveitis as disease controls, and healthy subjects were prospectively enrolled. Western blotting and Luminex multiple cytokine assay/enzyme linked immunosorbent assay were used to determine the presence of serum ARAs and the concentration of cytokines, respectively. Kruskal-Wallis or chi square test was applied to compare the profiles of ARA and cytokines among various groups. The multilevel mixed-effect regression was used to investigate the association of ARA or cytokines with clinical features. RESULTS: No significant difference in the band number and subtypes of serum ARAs was found between AIR patients and their controls. AIR patients had higher concentration of serum IFN-ɤ, CXCL9, or CXCL10 than non-AIR controls. A positive correlation was found between increased number of ARAs and elevated TNF-α in np-AIR patients. Elevated pro-inflammatory cytokines or ARA subtypes (antibody against recoverin and α-enolase) were associated with worse retinal functions or anatomy, including visual acuity, visual field, ERG parameters, and central retinal thickness. CONCLUSIONS: The data of our study demonstrate that detection of serum ARAs has limited value in the diagnosis of AIR. Th1-type cytokines/chemokines or specific ARA subtypes are associated with pathogenesis and disease severity of the AIR.

Management of autoimmune retinopathy treated with intravitreal dexamethasone implant.

PURPOSE: The purpose of this study is to evaluate clinical outcomes of autoimmune retinopathy (AIR) in the patients treated with intravitreal dexamethasone implant (IDI). METHOD: Twenty-one eyes of 11 AIR patients treated with at least 1 injection of IDI were retrospectively reviewed. Clinical outcomes before and after treatment, including best corrected visual acuity (BCVA), optic coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ff-ERG), and visual field (VF) at last visit within 6 and/or 12 months, were recorded. RESULTS: Among all the patients, 3 had cancer-associated retinopathy (CAR) and 8 had non-paraneoplastic-AIR (npAIR) with mean followed up of 8.52 ± 3.03 months (range 4-12 months). All patients achieved improved or stable BCVA within 6 and/or 12 months after the treatment. Cystoid macular edema (CME) in 2 eyes and significant retinal inflammation in 4 eyes were markedly resolved after single injection. Central retinal thickness (CFT) in all eyes without CME, ellipsoid zone (EZ) on OCT in 71.4% of eyes, ERG response in 55% of eyes, and VF in 50% of eyes were stable or improved within 6 months after treatment. At last visit within 12 months, both BCVA and CFT remained stable in the eyes treated with either single or repeated IDI; however, progression of EZ loss and damage of ERG response occurred in some patients with single IDI. CONCLUSION: Clinical outcomes, including BCVA and parameters of OCT, ERG, and VF, were stable or improved after IDI in a majority of AIR patients. Local treatment of AIR with IDI was a good option to initiate the management or an alternative for the patients' refractory to the systemic therapy but with limited side effect.

One-year efficacy of intravitreal conbercept injection for macular oedema secondary to central retinal vein occlusion in Chinese patients.

PURPOSE: To evaluate intravitreal conbercept injection for treatment of macular oedema secondary to central retinal vein occlusion (CRVO) in Chinese patients during 1-year follow-up in the real-world setting. METHODS: Twenty-seven eyes of 27 patients with macular oedema associated with CRVO were retrospectively reviewed. The eyes received monthly intravitreal conbercept injection (0.5 mg in 50 µl) for 3 months. From then on, the patients were followed up every month and received injection pro re nata (PRN) up to 12 months. The primary outcome measurements included changes of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 3 and month 12. Other outcome measurements included proportion of patients gaining ≥15 letters in BCVA at month 3 and 12, the mean number of injections and safety concerns. RESULTS: The mean BCVA gain from baseline was 12.7 ± 7.6 letters at month 3 and 14.8 ± 9.6 letters at month 12. The mean CRT reduction from baseline was 374.5 ± 280.7 µm at month 3 and 428.2 ± 241.3 µm at month 12. The proportion of patients who gained ≥15 letters in BCVA was 45.1% at month 3 and 52.9% at month 12. The mean number of injections was 7.6 ± 1.5. No severe local and systemic complications occurred following injection. CONCLUSIONS: Intravitreal conbercept injection by three monthly loading doses followed by PRN treatment regimen was safe and efficacious for patients with macular oedema secondary to CRVO through 1-year follow-up.

Detection of serum anti-retinal antibodies in the Chinese patients with presumed autoimmune retinopathy.

PURPOSE: To explore the presence of serum anti-retinal antibodies (ARAs) in the Chinese patients with presumed autoimmune retinopathy (AIR). METHODS: Twenty-three Chinese patients with presumed AIR, disease controls including 40 RP patients, 22 bilateral uveitis patients, 18 acute zonal outer occult retinopathy (AZOOR) patients, and 30 healthy donors were included. Serum samples of all the subjects were obtained and analyzed for the presence of four ARAs including recoverin, α-enolase, carbonic anhydraseII (CAII), and collapsin response-mediated protein (CRMP)-5 by Western bolt assay. RESULTS: ARAs were present in the serum of either presumed AIR patients, disease control, or healthy donors. One or more ARAs were present in the 78.2% of presumed AIR while they were indicated in the 35.0% of RP patients (p < 0.01) and 33.3% of healthy donors (p < 0.01). The prevalence of ARAs in the bilateral uveitis and AZOOR was 63.3% and 100% respectively. Positive rate of α-enolase antibody present in the presumed AIR, disease control, and healthy donors was 73.9%, 47.5%, and 33.3% respectively. Positive rate of CAII antibody present above groups was 52.1%, 50%, and 33.3% respectively. Recoverin antibody seemed to be specifically present in the serum of patients with cancer-associated retinopathy. CONCLUSION: Presence of serum ARAs including recoverin, α-enolase, CAII, or CRMP-5 in the Chinese patients with presumed AIR occurred significantly more often than RP patients and healthy donors. Seropositivity of ARAs had diagnostic value for the presumed AIR but mere presence was not sufficient for the diagnosis due to identification of them in the healthy controls and other retinal diseases.

Long-term effect of laser-induced ocular hypertension on the cone electroretinogram and central macular thickness in monkeys.

OBJECTIVE: The purpose of this study was to investigate the long-term effect of laser-induced ocular hypertension on the cone electroretinogram (ERG) and retinal thickness in monkeys. BACKGROUND DATA: Degeneration of retinal nerve fiber layer (RNFL) and loss of retinal ganglion cells in the primate glaucoma model have been confirmed by histological studies and optical coherence tomography (OCT) images. However, it remains unclear whether the outer retina distal to the RGCs (e.g., photoreceptors) is involved in histological studies and in functional test. MATERIALS AND METHODS: Subjects were five monkeys with high intraocular pressure (IOP) induced in the right eye by laser. Six years after the laser coagulation of the mid-trabecular meshwork, RNFL, ganglion cell complex (GCC), central macular thickness (CMT), and the thickness of outer retinal layer (ORL) were measured by OCT. The photopic responses of ERG were recorded in response to red flashes on a blue background. The maximum cone amplitude (Rcone) and cone sensitivity (Scone) were calculated. RESULTS: Enlarged cup-to-disc (C/D) ratio was found in the lasered eyes. RNFL and GCC were significantly thinner in the lasered eyes (p<0.05), but no significant differences were found in CMT and the thickness of ORL compared with fellow eyes (p>0.05). Mean amplitude of the photopic negative response (PhNR), Mean Rcone were significantly lower in the lasered eye (p<0.05), and no significant differences of Scone were found between the two eyes (p>0.05). CONCLUSIONS: Long-term ocular hypertension induced by laser affects the function of cone photoreceptor in monkeys.

Pharmacokinetic comparison of ketorolac after intracameral, intravitreal, and suprachoroidal administration in rabbits.

PURPOSE: To investigate the concentrations and pharmacokinetics of ketorolac in the rabbits by three different routes of administrations: a single intracameral, intravitreal, and suprachoroidal injection. METHODS: Fifty-four New Zealand white rabbits received ketorolac (250 µg/0.05 mL) in one eye by a single intracameral injection (group A, n = 18), single intravitreal injection (group B, n = 18), and single suprachoroidal injection (group C, n = 18). Drug concentrations in the vitreous, retina-choroid (RC), and plasma were determined by the methods of high-performance liquid chromatography at 0.5, 1, 2, 4, 8, and 24 hours after injection. The concentrations in the opposite eyes were also investigated. RESULTS: The mean maximum concentrations (Cmax) of ketorolac in the vitreous and RC were 0.378 ± 0.19 µg/mL and 3.15 ± 0.49 µg/g (at 0.5 hours), respectively, in group A; 156.2 ± 20.74 µg/mL (at 0.5 hours) and 208.0 ± 21.67 µg/g (at 1 hours), respectively, in group B; and 0.873 ± 0.34 µg/mL and 56.71 ± 22.64 µg/g (at 0.5 hours), respectively, in group C. In the RC, the area under the curve (AUC0-t) in group B (866.1 ± 52.67 µg/g·h) was higher (P < 0.01) than that in group C (77.10 ± 25.90 µg/g·h). The elimination half-life (t1/2) in group B (3.09 hours) was longer (P < 0.01) than that in group C (1.19 hours). In the control eyes, a drug level below 2 µg/g was detected in the RC in group C. Plasma concentrations were below 0.4 µg/mL in all 3 groups. Ketorolac was detectable in the RC till 24 hours after the intravitreal injection and 8 hours after the suprachoroidal injection. CONCLUSION: Intravitreal injection of ketorolac produced higher intraocular drug concentrations for a longer period compared with the other two routes. Suprachoroidal injection of ketorolac could reach an effective drug level in the RC with short half-lives and low drug levels in the vitreous. The plasma drug concentrations were low by all three routes.

The role of CCR1 expression in the retinal degeneration in rd mice.

PURPOSE: Chemokine receptors are reported to be involved in neuronal cell death and CNS neurodegenerative diseases. The aim of the current study was to investigate the expression of CCR1, a major chemokine receptor for CC chemokines in retinal dystrophy in rd (retinal degeneration) mice and further explore its role in photoreceptor degeneration. MATERIALS AND METHODS: The expression levels of CCR1 mRNA in the whole control and rd retinas at postnatal days (P) 8, 10, 12, 14, 16, and 18 were determined by RT-PCR assay. Location of CCR1 in the retina of rd mice at each age group was studied by immunohistochemical analysis. Expression of CCR1 in the photoreceptor cells and apoptotic cells was determined by double labeling. RESULTS: Expression of CCR1 mRNA was noted in both control and rd retinas at each age group. CCR1-positive cells started to emerge in the outer nuclear layer (ONL) in rd retinas at P8 and reached a peak at P12 and P14. Double labeling of CCR1 with rhodopsin, CD11b, or TUNEL staining showed expression of CCR1 in the photoreceptor cells, rather than in the microglial cells. Partial CCR1 expression was observed in some of the apoptotic photoreceptor cells. CONCLUSIONS: Expression of CCR1 in the photoreceptor cells was increased with the progress of retinal degeneration in rd mice. Activation of CCR1 may play a role in the photoreceptor apoptosis.

Toxic effect of methamphetamine on the retina of CD1 mice.

PURPOSE: To investigate whether systemic administration of methamphetamine (METH) induces retinal damage in CD1 mice. MATERIALS AND METHODS: Eighteen male CD1 mice were randomly assigned to three groups, six mice per group: Group 1 receiving a single dose of 40 mg/kg METH, Group 2 receiving four doses of 10 mg/kg METH, and Group 3 (control) receiving 40 mg/kg 0.9% NaCl solution. METH and NaCl were administered by intraperitoneal injection. Immunostaining of glial fibrillary acidic protein (GFAP), S-100 for astrocytes and Muller cells, CD11b for microglia, and tyrosine hydroxylase (TH) and TUNEL labeling for apoptotic cell death were performed on the retinal sections on day 1 and day 7 post-exposure. RESULTS: GFAP and S-100 immunoreactivity was observed in Group 1 mice. CD11b+ cells in Group 1 mice showed more intensely stained shorter and thicker cellular processes than Groups 2 and 3, indicating activated microglia in the mice exposed to large-dose METH. No significant difference in TH level was seen among the three groups. TUNEL labeling did not reveal positive cells in the retinas of any of the 18 CD1 mice. CONCLUSIONS: A single large dose of METH induces an increase in short-term protein expression of GFAP and S-100 and in microglial activation. The results suggest that METH has a neurotoxic effect on CD1 mouse retina.

Activation of nuclear factor-kappaB during retinal degeneration in rd mice.

PURPOSE: Transcription factors of the nuclear factor-kappa beta (NF-kappaB) family have been demonstrated to play an important role in the regulation of gene expression in the chronic neurodegenerative disorders. The aims of the current study were to investigate the alteration of NF-kappaB activity during retinal degeneration in rd mice and further explore its role in photoreceptor apoptosis. METHODS: Activation of NF-kappaB and its nuclear translocation in the retina of rd mice at postnatal days (P) 8, 10, 12, 14, 16, 18, and 28 were studied by immunohistochemical analysis using NF-kappaB P65 antibody. The amount of NF-kappaB P65 protein and NF-kappaB DNA-binding activity in the whole retina were assessed by western blot analysis and gel shift analysis, respectively. Expression of NF-kappaB in microglial cells labeled with CD11b was determined by double labeling. RESULTS: NF-kappaB P65 nuclear translocation and its DNA binding activity started to increase in the rd retina at P10 and reached a peak at P12. Expressions of P65 remained at high levels from P12 to P18. Double labeling of P65 with CD11 at P14 showed colocalization of P65 in the microglial cells in the outer nuclear layer. CONCLUSIONS: NF-kappaB was activated in the retinal degeneration of rd mice. NF-kappaB modulation may play a role in the retinal degeneration through microglial activation.

A moephologic study of retinal toxicity induced by triamcinolone acetonide vehicles in rabbit eyes.

PURPOSE: To evaluate the toxic effects of two triamcinolone acetonide (TA) vehicles on rabbit retina at different volumes. METHODS: Vehicle A and B were prepared from two TA injections by centrifugation. Thirty-six New Zealand white rabbits were intravitreally injected with vehicle A, B, or balanced saline solution at 0.1 mL or 0.2 mL respectively. The eyes were examined by indirect ophthalmoscope, light microscope, and transmission electron microscope up to week 8 postinjection. RESULTS: Eyes with vehicle A appeared normal under the ophthalmoscope, but showed disorganization in retinal inner nuclear layer and photoreceptor layer in pathologic analyses. Eyes with vehicle B displayed more significant retinal changes including retinal hemorrhage, vascular narrowing, myelinated fiber edema, retinal necrosis and atrophy, and photoreceptor apoptosis. There was an increase in degree of the above damages as the volume of either vehicle increased. CONCLUSION: Both vehicle A and B caused volume-related toxicity in rabbit retina. The intensity of the toxic effects of different vehicles may differ. Reducing or decanting the vehicles should be considered before intravitreal use of TA injections.

Microglial activation in human diabetic retinopathy.

OBJECTIVE: To investigate microglial activation in human diabetic retinopathy. METHODS: Paraffin sections from 21 eyes of 13 patients with diabetic background, preproliferative, or proliferative retinopathies and 10 normal eyes of 9 individuals were studied with immunolabeling of microglia with antibodies against HLA-DR antigen, CD45, or CD68. RESULTS: In the healthy human eyes, ramified microglial cells were scattered in the inner retinal layers. In eyes with diabetic retinopathy, the microglia were markedly increased in number and were hypertrophic at different stages of the disease. These cells clustered around the retinal vasculature, especially the dilated veins, microaneurysms, intraretinal hemorrhages, cotton-wool spots, optic nerve, and retinal and vitreal neovascularization. In some retinas with cystoid macular edema, microglia infiltrated the outer retina and subretinal space. Cells in the epiretinal membrane were also labeled with microglial markers. CONCLUSIONS: Microglia were activated at different stages of human diabetic retinopathy and optic neuropathy. Microglial perivasculitis was a prominent feature of the disease process. CLINICAL RELEVANCE: Activated microglia and microglial perivasculitis may play a role in vasculopathy and neuropathy in diabetic retinopathy.

Activation of microglia and chemokines in light-induced retinal degeneration.

PURPOSE: Microglial cells, which are activated and recruited by chemokines, have been shown to play crucial roles in neuronal degenerations of the central nervous system (CNS). This study investigated the activation and migration of retinal microglial cells and expression of chemokines in retinas in light-induced photoreceptor degeneration in mice. METHODS: Ninety-five Balb/cJ mice were kept in cyclic light for 1 week followed by dark adaptation for 48 h prior to light exposure of 3 h at 3.5 Klux. Animals were enthuanized at various times after light exposure. Terminal deoxynucleotidyl transferase-mediated dUTP nick end label (TUNEL) assay, rat-anti-mouse CD11b and 5D4 antibodies, isolectin-B4, and a chemokine-specific gene array were used to detect DNA fragmentation during retinal degeneration, to label retinal microglial cells, and to determine the expression of retinal chemokines and chemokine receptors, respectively. Reverse-transcriptase coupled polymerase chain reactions (RT-PCRs) were conducted on selected chemokine mRNAs to confirm the gene array findings. RESULTS: After intense light exposure, TUNEL-positive cells were noted in the outer nuclear layer (ONL) of the retina at 3 h, and their presence were noticeably increased at 1 day but declined at 3 days and 7 days after light exposure. In contrast, CD11b- or isolectin-B4-positive cells were seen in the ONL as early as 6 h and their presence increased significantly at 1 day and 3 days after light exposure. These cells displayed a round or ovoid morphology at 6 h and 1 day but assumed a more ameboid configuration at 3 days. By 7 day, the number of the microglial cells declined in the ONL and they became ramified, and were present mostly in the subretinal space. 5D4-positive cells with large cell bodies were only noted at 3 day and 7 day but not earlier. With chemokine-specific gene array analysis, we identified four chemokines and two chemokine receptors showing significant increases in their gene expressions. Among them, monocyte chemoattractant protein-3 (MCP-3), showed a remarkable 4.4 fold increase in its gene expression. RT-PCR confirmed a marked increase of MCP-3 expression in retinas at 3 h to 1 day, and a return to normal at 3 days following light injury. CONCLUSIONS: Retinal chemokines such as MCP-3 and their receptors are involved in the activation and migration of retinal microglia in light-induced retinal degeneration, which in turn modulate the apoptotic loss of photoreceptor cells in the outer retina.

Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice.

PURPOSE: To elucidate the role of activated microglia in the photoreceptor apoptosis of rd mice by identifying sequential events and factors associated with microglial activation, migration, and cytotoxicity during retinal degeneration. METHODS: Photoreceptor apoptosis in rd mice at postnatal days (P)8, 10, 12, 14, 16, and 18 was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglia were identified by CD11b antibody. Expression of chemokine mRNA, including monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, regulated on activation normal T-cell expressed and secreted (RANTES), interferon-gamma-inducible 10-kDa protein (IP-10), and fractalkine in the retina were examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. Production of tumor necrosis factor (TNF)-alpha in the dystrophic retina was studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis. Microglial expression of TNF-alpha was determined by double immunolabeling. RESULTS: Whereas photoreceptor apoptosis in the rd mice started at P10 and reached a peak at P16, activation and migration of microglial cells were observed at P10 and peaked at P14. The expression of MCP-1, MCP-3, MIP-1alpha, MIP-1beta, and RANTES transcripts were noted at P8 and reached a peak at P12. Production of TNF-alpha was noted in the outer nuclear layer (ONL) of the rd mice at P8 and reached a peak at P12. At the peak of microglial activity, TNF-alpha was predominantly expressed in the activated microglial cells in the ONL. CONCLUSIONS: Activation of microglia, as well as expression of their signaling molecules (chemokines) and microglia-derived toxic factor (TNF-alpha), coincides with or precedes the occurrence of photoreceptor apoptosis, suggesting activated microglia play a major role in retinal degeneration in rd mice. The chemokines MCP-1, MCP-3, MIP-1alpha, MIP-1beta, and RANTES are involved in activation and recruitment of the microglia to the degenerating photoreceptor cell layer. TNF-alpha, produced by the activated microglia, may accentuate the photoreceptor cell death.