Effects of intravitreal injection of bevacizumab on inflammatory cytokines in the vitreous with proliferative diabetic retinopathy.

BACKGROUND: To investigate the effects of preoperative intravitreal injection of bevacizumab (IVB) on the levels of 27 inflammatory cytokines, including interleukins (ILs) and vascular endothelial growth factor. METHODS: From among 200 patients who had proliferative diabetic retinopathy and underwent vitrectomy in our department from September 2009 to October 2010, 8 study subjects met the enrollment criteria in which both eyes at nearly equivalent stages underwent vitrectomy. The first vitrectomy for each patient was performed without IVB (control group), whereas the second vitrectomy on the contralateral eye was performed with IVB treatment (1.25 mg/0.05 mL) 3 days before surgery (IVB group). Undiluted vitreous fluid was collected at the start of each vitrectomy. A multiplex assay was used to simultaneously determine the levels of 27 inflammatory cytokines and growth factors. RESULTS: Mean vascular endothelial growth factor levels were significantly lower in the IVB group (519.69 pg/mL) than in the control group (11,807.44 pg/mL) (P = 0.012, Wilcoxon signed rank test). Moreover, the mean levels (IVB/control, pg/mL) of IL-1RA (38.50/62.31, P = 0.036), IL-5 (27.75/34.00, P = 0.018), IL-10 (433.63/1,995.94, P = 0.012), IL-12 (246.69/1,033.69, P = 0.012), IL-13 (707.50/1,450.38, P = 0.012), and interferon γ (71.13/84.69, P = 0.036) were significantly lower in the IVB group. No other significant differences were observed in the levels of the other 20 cytokines and growth factors between the 2 groups. CONCLUSION: Preoperative IVB reduced not only the intravitreal vascular endothelial growth factor level but also the intravitreal levels of other inflammatory cytokines, including IL-1RA, IL-5, IL-10, IL-12, IL-13, and interferon γ. These results indicate the interaction of some cytokines in the vitreous fluid of proliferative diabetic retinopathy patients and suggest the possibility that preoperative IVB may not only reduce vascular proliferation by its direct antivascular endothelial growth factor effect but also modulate the inflammatory response through putative cytokine networks. None of the other cytokines examined were elevated after IVB.

A Novel Compound Heterozygous Mutation in the CYP4V2 Gene in a Japanese Patient with Bietti's Crystalline Corneoretinal Dystrophy.

PURPOSE: To describe the clinical and genetic characteristics of a Japanese family in which one member exhibited Bietti's crystalline corneoretinal dystrophy (BCD). METHODS: Using direct sequencing, mutation screening was performed in the CYP4V2 gene of both the patient with BCD and her daughter. Ophthalmic examinations were performed to determine the clinical features of both subjects. RESULTS: The 64-year-old female patient had a bilateral visual acuity of 0.4. Slit lamp examination revealed bilateral crystalline-like deposits at the superior limbus of the cornea. Fundus examination revealed there was chorioretinal atrophy along with numerous glistening yellowish-white crystalline deposits that were scattered throughout the posterior pole and the mid-peripheral retina. Standard flash electroretinography showed an extinguished electroretinogram and Goldmann kinetic perimetry detected a relative scotoma. Genetic analysis revealed that the patient had a heterozygous mutation in the CYP4V2 gene (IVS6-8delTCATACAGGTCATCGCG/GC), which is the most commonly found mutation in Japanese patients with BCD. Furthermore, the patient was also shown to have a novel heterozygous point mutation in exon 9 of the CYP4V2 gene (c.1168C>T). In contrast, her daughter exhibited no clinical findings for BCD even though she carried the same heterozygous mutation in the CYP4V2 gene (c.1168C>T). CONCLUSION: A novel compound heterozygous mutation was found in the CYP4V2 gene of a patient with BCD. This previously unreported c.1168C>T mutation causes a missense mutation (p.R390C) in the CYP4V2 protein.

[A case of hypertrophic pachymeningitis impeding differential diagnosis of mycosis of orbital apex syndrome].

PURPOSE: Mycosis of the orbital apex is often fatal. We report case of orbital apex syndrome, which appeared to have been caused by hypertrophic pachymeningitis with positive systemic mycosis antigens treated with systemic corticosteroid combined with antimicrobiotic therapy. CASE: A 57-year-old woman presented with disturbed ocular motility and visual disturbance of her left eye. She had rheumatoid arthritis. Magnetic resonance imaging(MRI) showed an abnormal blush in the left orbital apex and meningeal thickening in the cranial base, leading to the diagnosis of hypertrophic pachymeningitis. She also had candidemia. Systemic corticosteroids combined with antimicrobiotic therapy resulted in improved clinical ocular manifestations. She died 13 months later due to interstitial pneumonia. CONCLUSION: The diagnosis of this case was difficult because of the candidemia. But the effective steroid response indicates that the probable cause was hypertrophic pachymeningitis due to RA. To avoid complications, hypertrophic pachymeningitis associated with fungemia should be treated with corticosteroids combined with antimicrobiotic therapy.

Crystal deposits on the lens capsules in Bietti crystalline corneoretinal dystrophy associated with a mutation in the CYP4V2 gene.

PURPOSE: We report a patient (Case 1) with Bietti crystalline corneoretinal dystrophy (BCD) associated with previously unknown findings of crystal-like deposits on the anterior and posterior lens capsules. This patient is one of four (Cases 1-4) in whom we have found BCD associated with the same mutation in the CYP4V2 gene. METHODS: We present a case report with molecular diagnosis. A 45-year-old man (Case 1) was referred to our clinic with complaints of gradual progression of visual disturbances and night blindness. His visual acuity was limited to hand movement bilaterally. Slit-lamp biomicroscopy disclosed glistening, crystal-like deposits on the anterior and posterior lens capsules, as well as on the corneal stroma near the corneoscleral limbus. No such deposit was found in the lens stroma. Fundus examination disclosed profound chorioretinal atrophy with scarce crystal deposits. Full-field electroretinography showed extinguished responses of isolated rods, isolated cones, and mixed rods and cones. RESULTS: Molecular genetic analysis revealed that the subject had a homozygous mutation in the CYP4V2 gene (IVS6-8delTCATACAGGTCATCGCG/insGC), which is most commonly found in Japanese patients with BCD. Three other cases (Cases 2-4) of BCD associated with the same mutation did not show such crystal-like deposits on the lens surface. CONCLUSIONS: Although their exact origin remains unknown, crystal-like deposits may appear on the lens capsule of patients with BCD associated with a mutation in the CYP4V2 gene.

Changes in intraocular indocyanine green concentrations during macular hole surgery.

PURPOSE: To report changes in intraocular indocyanine green (ICG) concentration which was used for visualization of the internal limiting membrane (ILM) during vitreous surgery on 3 eyes of 3 patients with full-thickness macular hole. METHODS: During intraocular surgery with ICG-assisted ILM peeling, aliquots of intraocular fluid obtained at 1 min after ICG administration (0.5 ml of 5 mg/ml ICG solution), before and after ILM peeling, and before and after fluid/gas exchange were subjected to spectrophotometric analysis. RESULTS: Intravitreous concentrations of ICG were dramatically reduced to approximately 0.4 microg/ml during the surgery for macular hole in all cases. CONCLUSION: The present study indicates that the levels of remaining intraocular ICG concentrations after macular hole surgery are much lower than the levels that induced retinal toxicity in experimental models.

Prolonged rhodopsin phosphorylation in light-induced retinal degeneration in rat models.

PURPOSE: The effects of various light-induced stresses on the retina were examined in the retinal degenerative rat model. METHODS: Retinal morphology and electroretinograms (ERGs) were analyzed after application of light-induced stress of several intensities (650, 1300, 2500, or 5000 lux). For evaluation of rhodopsin (Rho) function, the kinetics of Rho regeneration and dephosphorylation were studied by spectrophotometric analysis and immunofluorescence labeling with antibodies specifically directed toward the phosphorylated residues (334)Ser and (338)Ser in the C terminus of Rho. Retinal cGMP concentration was determined by ELISA. Expression levels of neurotrophic factors (FGF2, brain-derived neurotrophic factor [BDNF], platelet-derived growth factor [PDGF], and ciliary neurotrophic factor [CNTF]) were evaluated quantitatively by RT-PCR. RESULTS: Light intensity-dependent deterioration of ERG responses and thinning of the retinal outer nuclear layer were observed in wild-type and Royal College of Surgeons (RCS) rat retinas. Under dark adaptation after light-induced stress, the kinetics of Rho regeneration were not different between wild-type and RCS rat retinas. Rho dephosphorylation at (334)Ser and (338)Ser was extremely delayed in RCS rat retinas compared with wild-type without light-induced stress, but Rho dephosphorylation at those sites became slower in both RCS and wild-type rat retinas. In terms of expression of neurotrophic factors, almost no significant changes were observed between the animals after light-induced stress. CONCLUSIONS: The present study indicates that light-induced stress causes intensity-dependent deterioration in retinal function and morphology in wild-type and RCS rat retinas. Disruption of the phototransduction cascade resulting from slower kinetics of Rho dephosphorylation appears to be involved in retinal degeneration.

Clinical and immunologic aspects of cancer-associated retinopathy.

PURPOSE: To report clinical and immunologic aspects of cancer-associated retinopathy (CAR). DESIGN: Observational consecutive case series. METHODS: A retrospective review was made of 18 consecutive patients with cancer-associated retinopathy who had antiretinal antibody determination by Western blot testing. RESULTS: Clinically, a variety of ophthalmic observations including electroretinography impairment, retinal vessel narrowing, deterioration of visual acuity, visual field changes, and uveitis were frequently observed. As retinal autoantigens in the 18 cases, recoverin was found in all 18 cases (100%), heat shock cognate protein 70 (HSC70) was found in six cases (33%), and other proteins were found in four cases (20%). These antibodies were detected in only 60% of the patients at the initial examination, however, and then became increasingly apparent on the subsequent testing that was performed three times on serum samples obtained sequentially during the following months. CONCLUSION: For diagnosis of cancer-associated retinopathy, the presence of serum autoantibody toward recoverin is essentially required in addition to the characteristic clinical aspects noted above.