Urinary excretion of methanol in subjects with or without optic nerve head disease

The urinary excretion of methanol in 26 subjects without optic nerve head disease ranged from 0.5 to 4.4 mg/day. In 8 patients with primary open-angle or angle-closure glaucoma, the urinary excretion of methanol ranged from 1.4 to 3.9 mg/day. Of 13 patients with normal-tension glaucoma, 3 with increased serum methanol had elevated levels of urinary excretion of methanol. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacture or provider of services discussed in this article. The authors also do not discuss the use of off-label products, which includes unlabeled, unapproved, or investigative products or devices.     

Glaucoma progression associated with Leber’s hereditary optic neuropathy

The purpose of this article is to describe a case of open-angle glaucoma progression associated with Leber’s hereditary optic neuropathy. Single case analysis method is used. A 53-year-old woman with a previous diagnosis of glaucoma presented with progressive visual field loss. Complete ophthalmological examination and blood tests were negative for other concomitant diseases. Genetic counseling revealed mitochondrial DNA mutation compatible with the diagnosis of Leber’s hereditary optic neuropathy. In conclusion, the case describes the concomitant occurrence of open-angle glaucoma and Leber’s optic neuropathy. We hypothesize that the two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the consequent rapid progression of visual impairment. Screening for mitochondrial DNA mutations may be requested in patients with glaucoma who, despite pharmacologically controlled intraocular pressure, show rapid progression of the disease.     

Leber hereditary optic neuropathy associated with antiretroviral therapy for human immunodeficiency virus infection

PURPOSE: Antiretroviral therapy has reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) infection. However, side effects are increasingly recognized, including a commonly reported toxic mitochondrial myopathy. We report such a case of Leber hereditary optic neuropathy in a patient with antiretroviral therapy for HIV infection and speculate on a possible toxic etiologic role in the development of Leber hereditary optic neuropathy by a shared mitochondrial mechanism. METHODS: Case Report. Bilateral optic disk abnormalities observed in a 38-year-old HIV positive man with a family history of Leber hereditary optic neuropathy were documented with fundus photography, color vision testing, and visual field testing. Mitochondrial DNA testing was used to confirm the genetic predisposition to Leber hereditary optic neuropathy. RESULTS: Progressive bilateral optic nerve pallor temporally associated with the administration of antiretroviral medication was observed. Diagnostic testing revealed progressive visual field and color vision loss as well as a mitochondrial DNA mutation consistent with Leber hereditary optic neuropathy. CONCLUSION: Antiretroviral therapy may be associated with the onset of Leber hereditary optic neuropathy in genetically predisposed patients.     

Nuclear and mitochondrial analysis of patients with primary angle-closure glaucoma

PURPOSE: Certain types of glaucoma are linked to nuclear genetic mutations or to mitochondrial disturbances. In this study, patients with primary angle-closure glaucoma (PACG) were examined for mutations in nuclear genes reported to be associated with glaucoma and for possible mitochondrial abnormalities. METHODS: In patients with PACG, the nuclear genes MYOC, OPTN, CYP1B1, WDR36, OPA1, and OPA3 were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was measured, and mitochondrial respiratory activity (MRA) was assessed. RESULTS: No novel or previously reported mutations were present in the nuclear genes MYOC, OPTN, CYP1B1, WDR36, OPA1, and OPA3 in 29 patients with PACG. Four (13.8%) patients had potentially pathologic mtDNA nucleotide changes not found in control subjects. The patients with PACG did not differ significantly from the control subjects in relative mitochondrial content and had only a small decrease in MRA (2.4%) of indeterminate significance. CONCLUSIONS: These Middle Eastern patients with PACG had no mutations in nuclear genes associated with other types of glaucoma or inherited optic neuropathies. Mitochondrial abnormalities were minimal, and the overall pattern of those abnormalities was distinctly different from that of Leber hereditary optic neuropathy, nonarteritic ischemic optic neuropathy, primary open-angle glaucoma, and optic neuritis. These results are consistent with the hypothesis that anatomic factors may be more important determinants for PACG than the genetic and mitochondrial factors evaluated here.     

Induction of HLA-DR expression in human lamina cribrosa astrocytes by cytokines and simulated ischemia

PURPOSE: Recent evidence strongly suggests that activated immunity occurs during the neurodegenerative process of glaucomatous optic neuropathy. Although activation of lamina cribrosa astrocytes has been identified in glaucomatous optic nerve head, their role on the activated immune responses seen in glaucoma patients is unknown. Here, the authors aimed to study the potential role of lamina cribrosa astrocytes as a component of activated immune responses seen in glaucoma patients. METHODS: Expression of HLA-DR in optic nerve head astrocytes was studied using immunohistochemistry in postmortem eyes of patients with glaucoma and normal donors. Serum cytokine levels of patients with glaucoma and control subjects were measured using enzyme-linked, immunosorbent assay. In addition, in vitro experiments were performed using astrocyte cultures derived from human optic nerve head or fetal human brain. The cultured astrocytes were incubated under selected stress conditions such as exposure to cytokines, IFN-gamma and IL-10, or simulated ischemia for up to 48 hours. The expression of HLA-DR was studied in these cells using flow cytometry and immunocytochemistry. RESULTS: Immunohistochemistry demonstrated an upregulation of the HLA-DR expression in the optic nerve head astrocytes in glaucoma. In addition, serum levels of IL-10 was higher in the patients with normal pressure glaucoma compared to age-matched control subjects (P: = 0.001). Regarding in vitro experiments, unlike brain astrocytes, the percentage of cells expressing HLA-DR was approximately 3 times higher in the cultures of optic nerve head astrocytes exposed to simulated ischemia compared to cultures incubated under normal conditions (P: = 0.09). Incubation with IFN-gamma induced HLA-DR expression in brain and lamina cribrosa astrocytes, up to 25-fold, (P < 0.001) either in the absence or presence of simulated ischemia. Induction of HLA-DR expression by IL-10 was approximately 6 times higher in lamina cribrosa astrocytes incubated under simulated ischemia compared to that incubated under normal condition (P: = 0.004) and was not prominent in brain astrocytes. CONCLUSIONS: These findings suggest that optic nerve head astrocytes function as antigen-presenting cells and that their immunogenic capacity is more sensitive to ischemia than brain astrocytes. Taken together, these findings provide novel evidence that regulation of immunogenic capacity of optic nerve head astrocytes by cytokines or ischemic stress may have a role during the neurodegeneration process in patients with glaucoma.     

Differences in parapapillary atrophy between glaucomatous and normal eyes: the Beijing Eye Study

PURPOSE: To determine in a population-based study whether parapapillary atrophy is associated with glaucoma. DESIGN: Population-based cross-sectional study. METHODS: The Beijing Eye Study included 4,439 of 5,324 subjects invited to participate (response rate, 83.4%). Mean age was 56.2 +/- 10.6 years (range, 40 to 101 years). Color optic disk photographs (30 degrees) were examined morphometrically. Parapapillary atrophy was divided into alpha and beta zones. Glaucomatous optic nerve atrophy was defined by a glaucomatous optic nerve head appearance. RESULTS: After excluding highly myopic eyes, data from 4,003 (90.2%) subjects entered the statistical analysis. Glaucomatous optic nerve damage was detected in 93 (2.3%) subjects. The beta zone of parapapillary atrophy as a whole and measured separately in four disk sectors was significantly larger and occurred significantly more frequently in the glaucomatous group than in the nonglaucomatous group (beta zone total area, 1.21 +/- 1.92 mm2 vs 0.32 +/- 0.99 mm2; P < .001). In multiple regression analysis, area of beta zone was significantly associated with age (P < .001), myopic refractive error (P < .001), and presence of glaucomatous optic nerve damage (P < .001), with no significant difference between chronic open-angle glaucoma (n = 72) and chronic angle-closure glaucoma (n = 21; beta zone area, 1.20 +/- 0.39 mm2 vs 1.19 +/- 0.46 mm2; P = .69). CONCLUSIONS: In a population-based setting, the beta zone of parapapillary atrophy is significantly larger and occurs more frequently in glaucomatous eyes than in normal eyes of Chinese adults, with no marked difference between chronic open-angle glaucoma and primary angle-closure glaucoma.     

光相干断层扫描及其血管成像在Leber遗传性视神经病变中的应用研究现状及进展

Leber遗传性视神经病变(LHON)是一种与线粒体DNA突变相关的视神经病变,主要影响青年男性,与视网膜神经节细胞变性和视神经轴突丢失有关,导致视神经萎缩。近年来,光相干断层扫描(OCT)及OCT血管成像(OCTA)在LHON中的研究有了一些进展,对临床认识该病病程、临床表现、采取干预措施有重要指导意义。但OCTA对于LHON的临床研究尚处于起步阶段。此外,LHON不同突变位点之间、相同位点不同性别之间、相同位点不同家系甚至相同家系不同分支之间的OCT、OCTA特征尚缺乏深入研究,期待在以后的工作中能够完善。     

原发性急性闭角型青光眼患者外周血IL-2和IL-6水平与视神经损伤相关性分析

目的：检测原发性急性闭角型青光眼与对照组围手术期外周血IL-2和IL-6水平差异,探讨细胞因子水平与原发性急性闭角型青光眼视神经损伤的相关性。

方法：收集2013-05/2014-10我院眼科住院原发性急性闭角型青光眼患者作为病例组,按视神经损伤程度分为轻、中、重3组。同期住院白内障患者作为对照组,采用双抗体夹心酶联免疫吸附法测定研究对象外周血IL-2、IL-6浓度,分别比较病例组、对照组患者间以及不同视野损伤程度三组患者间细胞因子质量浓度的差异,分析原发性急性闭角型青光眼患者机体中细胞因子水平与视神经损伤程度的相关性。

结果：病例组血清中IL-2、IL-6浓度显著低于对照组(P<0.05)。重度视神经损伤组 IL-2、IL-6浓度显著低于轻度视神经损伤组(P<0.05)。视野损伤程度不同的三组IL-2、IL-6水平与视神经损伤严重程度进行多重线性回归分析,IL-2水平差异有统计学意义(P<0.05)。

结论：原发性急性闭角型青光眼患者机体内IL-2、IL-6水平降低。原发性急性闭角型青光眼患者IL-2水平可能与视神经损伤有关。     

Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space

PURPOSE: The lamina cribrosa, as the main structural element of the optic nerve head, forms a pressure barrier between the intraocular space and the retrobulbar space. The function as a pressure barrier may have importance for the pathogenesis of ocular diseases related to intraocular pressure and/or cerebrospinal fluid (CSF) pressure, such as the glaucomas. The purpose of the present study was to examine the anatomic relationship between the lamina cribrosa, the intraocular pressure space, and the retrobulbar cerebrospinal pressure space in eyes with glaucoma. METHODS: The study included 53 globes enucleated because of malignant choroidal melanoma (n = 42) without involvement of the optic nerve (control group) or because of painful absolute secondary angle-closure glaucoma (n = 11; glaucoma group). Anterior-posterior histologic sections through the pupil and the optic disc were morphometrically evaluated. RESULTS: In the glaucoma group compared with the control group, the lamina cribrosa was significantly (P < 0.001) thinner, the part of the outer lamina cribrosa surface directly exposed to the pia mater and indirectly exposed to the CSF space was significantly (P = 0.001) wider, and the shortest distance between the intraocular space and the CSF space was significantly (P < 0.001) shorter. The posterior lamina cribrosa surface in direct contact with the pia mater was located close to the optic disc border. CONCLUSIONS: The thickness of the lamina cribrosa and the anatomic relationships between the intraocular space and the CSF space differ significantly between normal and glaucomatous eyes. The findings may be of importance for the pathogenesis of glaucomatous optic neuropathy.     

儿童视神经炎病因分析

目的 了解临床初诊为视神经炎（ON）儿童患者的病因分布和临床特点。 方法 收集158例初诊ON的儿童患者详细的眼科和神经内科检查及实验室、影像学检查资料, 参照国际认可的标准重新诊断，并与成人ON病因进行比较 。 结果 104例初诊为ON的儿童患者最后诊断符合ON，占65.8%。其中，80例为特发性脱髓鞘性ON，占76.9%；感染性ON和炎性视神经病各3例，18例病因 未明。另54例不符合ON诊断，其中，以Leber遗传性视神经病、非器质性视力下降等较常见。 结论 初诊为ON的儿童患者病因分布与成人类似，以特发性脱髓鞘性ON最为常见。Leber遗传性视神经病和非器质性视力下降是儿童患者中最常见的与 ON混淆的疾病。 (中华眼底病杂志，2008，24：95-98)     

Hereditäre Optikusneuropathien

Hereditary optic neuropathies are caused by mutations either in the nuclear or mitochondrial genome and lead to retinal ganglion cell death mediated by reduced oxidative phosphorylation, fragmentation of the mitochondrial network, and increased sensitivity to apoptosis. Nuclear mutations result in autosomal dominant optic atrophy, autosomal recessive optic atrophy, or X-linked recessive optic atrophy, whereas mitochondrial mutations result in Leber’s hereditary optic neuropathy, which is maternally inherited. A tentative diagnosis of a hereditary optic neuropathy can usually be made on the grounds of a thorough patient and family history, visual field and color vision tests, and a detailed assessment of the optic nerve head. The rarity of hereditary optic neuropathies makes it difficult to include these disorders in the differential diagnosis. Molecular genetic testing of a blood DNA sample should be performed on every patient, with implications for future genetic counseling and prediction of the disease course.     

脉络膜厚度在青光眼发生发展中的作用研究进展

由于青光眼性视神经病变与供应视神经的血流异常有关,而视乳头筛板前区的血液供应主要来自视乳头周边的脉络膜血管分支,因此,青光眼和脉络膜血流之间的关系一直都备受关注。此外,在青光眼发病机制方面,脉络膜膨胀增厚也被认为是诱发急性闭角型青光眼的原因之一。随着频域OCT（SD-OCT）深度增强成像（EDI）技术应用,临床上已能在活体状态下较为准确地测量人体眼球的脉络膜厚度。笔者对SD-OCT深度增强成像技术所获得的青光眼患者脉络膜厚度方面的研究做一综述,并进一步探讨脉络膜在青光眼发生、发展中的作用。     

Pressure compliance of the optic nerve head in low tension glaucoma.

Twenty eyes of 10 healthy subjects, 11 eyes of seven patients with low tension glaucoma, and three eyes of three patients with ischaemic optic neuropathy were investigated. Visual evoked responses were recorded under stepwise artificially increased intraocular pressures. The results of the visual evoked response recording (pressure compliance test) allow a clear distinction to be made between healthy subjects, patients with low tension glaucoma, and patients with ischaemic optic neuropathy. In the groups investigated a lack of autoregulation of the optic nerve head circulation was found in patients with low tension glaucoma only. Patients with anterior ischaemic optic neuropathy showed the same pressure compliance behaviour as healthy subjects. The methods used here seem to provide a practicable clinical tool in the differential diagnosis of low tension glaucoma.     

The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse

PURPOSE: To produce a mouse model of Leber hereditary optic neuropathy. METHODS: A mutant ND4 subunit made compatible with the universal genetic code and containing an arginine-to-histidine substitution at residue 340, or a synthetic normal human ND4 gene was delivered to the mouse visual system. The expression and effects of the mutant ND4 gene on the optic nerve and cultured retinal ganglion cells was assessed by magnetic resonance imaging, immunohistochemistry, and light and transmission electron microscopy. RESULTS: The ATPc mitochondrial targeting sequence directed the allotopically expressed mutant human R340H and wild-type ND4FLAG polypeptides into mitochondria. Expression of normal human ND4 in murine mitochondria posed no ocular toxicity. In contrast, the mutant ND4 disrupted mitochondrial cytoarchitecture, elevated reactive oxygen species, induced swelling of the optic nerve head, and induced apoptosis, with a progressive demise of ganglion cells in the retina and their axons comprising the optic nerve. CONCLUSIONS: Allotopic expression of the mutant human R340H ND4 subunit of complex I replicated the hallmarks of human mitochondrial disease in the mouse. In contrast, ocular expression of the wild-type human ND4 subunit in lower mammals appears safe, suggesting that it may be useful for treatment of patients with Leber hereditary optic neuropathy.     

Bilateral nonarteritic anterior ischemic neuropathy following acute angle-closure glaucoma in a patient with iridoschisis: case report

A 55-year-old woman was referred to our clinic because of a one-week history of visual loss and raised intraocular pressure in the left eye followed 4 days later by visual loss in the right eye. Slit-lamp examination showed bilateral conjunctival hyperemia, slight diffuse corneal edema, shallow anterior chamber and fixed and dilated pupil in both eyes. Splitting of the anterior layers of the iris with fibrillar degeneration extending for approximately one quadrant inferiorly was presented in each eye. Fundus examination showed optic disc edema with no vascular tortuosity and no cup in both eyes. The condition was treated as bilateral acute angle-closure glaucoma in a patient with irisdoschisis. After medical treatment and improvement of visual acuity, perimetry revealed a significant visual field defect especially in left eye; this case represents a rare concurrence of acute angle-closure glaucoma and bilateral nonarteritic ischemic optic neuropathy. Although most cases of elevated intraocular pressure, including acute angle-closure glaucoma, do not result in optic disc edema and irreversible vision loss, variations in the vascular supply of the nerve optic head along with others ocular systemic risk factors, may predispose certain individuals to nonarteritic ischemic optic neuropathy during periods of elevated intraocular pressure.     

Follow up of focal narrowing of retinal arterioles in glaucoma

AIM: To evaluate whether focal narrowing of retinal arterioles increases with progressive glaucomatous optic neuropathy. METHODS: Focal narrowing of retinal arterioles and area of neuroretinal rim were morphometrically evaluated on colour stereo optic disc photographs of 59 patients with primary open angle glaucoma, 22 patients with normal pressure glaucoma, 11 patients with secondary open angle glaucoma, and 31 patients with ocular hypertension. Minimum follow up was 8 months. Focal arteriolar narrowing was quantified by calculating the ratio of the vessel width in the broadest to the narrowest vessel part. RESULTS: In the subgroup of patients with progressive glaucomatous optic nerve damage (n = 37), focal narrowing of retinal arterioles increased significantly (p < 0.005) with decreasing neuroretinal rim area. In the subgroup of patients with stable appearance of the optic disc (n = 86), focal narrowing of retinal arterioles did not change significantly (p = 0.79). The positive correlation between increasing focal thinning of retinal arterioles and progression of glaucomatous optic neuropathy was present, although not statistically significant, in all the glaucoma subtypes examined. The location of focal thinning of retinal arterioles did not change in the follow up. CONCLUSIONS: Focal narrowing of retinal arterioles increases significantly with progressive glaucomatous optic neuropathy, independent of the type of glaucoma. It is stable in patients with non-progressive glaucoma. The findings agree with previous reports on a higher degree of focal arteriole narrowing in eyes with pronounced optic nerve damage in comparison with those with moderate optic nerve atrophy or normal eyes. In the clinical management of patients with glaucoma, in some eyes, increasing focal arteriole narrowing may suggest progression of disease.     

Mitochondrial abnormalities in patients with primary open-angle glaucoma

PURPOSE: Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found in <5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, which causes progressive damage to axons at the optic nerve head. METHODS: In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed. RESULTS: Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21% in patients with glaucoma compared with control subjects (P<0.001). CONCLUSIONS: These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open up new experimental and therapeutic opportunities.     

Ocular and optic nerve head ischemic disorders and hearing loss

PURPOSE: To investigate in an exploratory study whether any evidence suggests that ophthalmic ischemic disorders, particularly of the optic nerve head, are associated with hearing loss. METHODS: We investigated prospectively 583 consecutive patients in eight primary ocular diagnostic groups for associated hearing loss: nonarteritic anterior ischemic optic neuropathy (n = 81), normal-tension glaucoma (n = 36), primary open-angle glaucoma (n = 138), other types of glaucoma (n = 142), ocular arterial occlusive disorders (n = 22), retinal vein occlusion (n = 89), ocular vasculitis (n = 42), and a miscellaneous group (n = 33). The patients and their relatives were questioned in detail for any evidence of hearing loss in the patients. RESULTS: In the logistic regression model, with presence or absence of hearing loss as the dependent variable and gender, age, and diagnosis as independent variables, gender (P = .003) and age (P<.0001) were found to be significantly associated with hearing loss. No significant association was found with any of the ophthalmic disease groups evaluated in this study. Whenever any significant association with any ophthalmic disease group was seen, this result could be explained by examination of the association between diagnosis and age, which showed a significant (P<.001) association. CONCLUSIONS: This study showed that there is a significant (P<.001) relationship between hearing loss and aging-the older the population, the higher the incidence of hearing loss-but the study showed that there is no association between hearing loss and ocular and optic nerve head ischemic disorders. The two represent unrelated and independent disorders.     

Leber hereditary optic neuropathy associated with use of ephedra alkaloids

PURPOSE: We report a case of Leber hereditary optic neuropathy in a patient who was using ephedra alkaloids at the time of onset of his optic neuropathy. DESIGN: Observational case report. METHODS: Bilateral, painless, progressive loss of vision developed in a 30-year-old man. He reported a one pack-per day, 10-year history of tobacco use and drinking 18 to 24 cans of beer per day as well as the use of a dietary supplement containing ephedra and caffeine before the onset of vision loss. RESULTS: We report the bilateral, progressive, painless loss of vision in a patient with bilateral cecocentral scotomas and optic nerve pallor. Mitochondrial DNA testing confirmed a Leber hereditary optic neuropathy mutation site at loci 11778. CONCLUSIONS: We propose that our patient's use of a dietary supplement containing ephedra alkaloids played an additive role to his tobacco and alcohol use in causing stress to the already abnormal mitochondrial function, and thereby contributed to the onset of his optic neuropathy. We recommend that patients and families with known Leber hereditary optic neuropathy should be asked about the use of over-the-counter drugs or supplements, and it may be prudent to advise patients against using such dietary supplements.     

Pit-like changes of the optic nerve head in open-angle glaucoma.

Six patients with open-angle glaucoma and acquired pit-like changes in the optic nerve head are presented. In 1 patient evolution of the pit-like defect is documented. In all 6 patients progression of associated visual field deficits is described. It is suggested that such pit-like changes in selected patients with glaucoma may not represent congenital lesions but rather local, progressive nerve head disease, occurring particularly in response to raised intraocular pressure. The management of patients with optic nerve head pitting and the pathogenesis of glaucomatous optic neuropathy are discussed with respect to this observation.