Optical Coherence Tomography Findings in Glaucoma With Coexisting Vitamin A Deficiency.

This case study reports on the presence of vitamin A deficiency in an adult with asymmetric normal tension glaucoma. The retinal OCT findings demonstrated not only expected loss of the outer retinal layers, typically seen in vitamin A deficiency, but also severe and bilateral loss of the inner retinal layers. After vitamin A supplementation, visual acuity, dark adaptation, and color vision normalized. The outer retinal layers had a restoration of thickness after vitamin A supplementation, but the inner layers did not change. This case is unique because it may give us an insight into the role of vitamin A on the inner retina and demonstrate the recovery of the outer retinal layers with vitamin A supplementation.

Familial normal tension glaucoma genetics.

Glaucoma is defined by characteristic optic nerve damage and corresponding visual field defects and is the leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is a strong risk factor for developing glaucoma. However, glaucoma can occur at any IOP. Normal tension glaucoma (NTG) arises with IOPs that are within what has been defined as a normal range, i.e., 21 mm Hg or less, which may present challenges in its diagnosis and management. Identifying inheritance patterns and genetic mutations in families with NTG has helped elucidate mechanisms of NTG, however the pathophysiology is complex and not fully understood. Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC). Herein, we review pedigree studies of NTG and autosomal dominant NTG caused by OPTN, TBK1, and MYOC mutations. We review identified mutations and resulting clinical features of OPTN-associated and TBK1-associated NTG, including long-term follow up of these patients with NTG. In addition, we report a new four-generation pedigree of NTG caused by a Glu50Lys OPTN mutation, including six family members with a mean follow up of 17 years. Common features of OPTN -associated NTG due to Glu50Lys mutation included early onset of disease with an IOP <21 mm Hg, marked optic disc cupping, and progressive visual field loss which appeared to stabilize once an IOP of less than 10 mm Hg was achieved. Lastly, we review risk factor genes which have been identified to contribute to the complex inheritance of NTG.

Population-based associations between progression of normal-tension glaucoma and Yang-deficient constitution among Chinese persons.

PURPOSE: To explore the association between constitution types as defined by traditional Chinese medicine (TCM) and risk for normal-tension glaucoma (NTG). DESIGN: Population-based cohort study. METHODS: Persons were identified in a population cohort aged ≥30 years with NTG, defined as having an untreated mean intraocular pressure measurement ≤21 mm Hg over six separate occasions, with no single reading >24 mm Hg (as in the Collaborative Normal Tension Glaucoma Study). The Body Constitution in Traditional Chinese Medicine Questionnaire was used to assess each participant's TCM constitution types. The association between various constitutions and visual field progression according to Early Manifest Glaucoma Trial criteria was assessed using Cox regression HR models. RESULTS: Among 142 participants (245 eyes), 23 persons (17.6%) and 25 eyes (10.2%) progressed, over a mean (SD) follow-up duration of 3.49 (0.99) years. Progression rates were highest in participants with Yang-deficient constitution (n=19, 13.4%), among whom 7 (36.8%) exhibited worsening fields. After adjusting for sex, age, central corneal thickness, retinal nerve fibre layer thickness and mean deviation on visual field testing, Yang-deficient constitution (HR 4.63, 95% CI 1.77 to 12.1, p=0.002) and higher mean intraocular pressure during follow-up (HR 1.25, 95% CI 1.01 to 1.56, p=0.044) were associated with field progression. CONCLUSIONS: Yang-deficient constitution and higher intraocular pressure are risk factors for visual field progression in NTG patients. Yang deficiency is characterised by abnormal vasoregulation, and these results may be consistent with prior studies linking NTG progression to Raynaud's phenomenon and migraine.

Temporal Raphe Sign in Elderly Patients With Large Optic Disc Cupping: Its Evaluation as a Predictive Factor for Glaucoma Conversion.

PURPOSE: To determine baseline clinical features associated with conversion to glaucoma in elderly patients with large optic-disc cupping. DESIGN: Retrospective cohort study. METHODS: Seventy-two eyes of 72 untreated elderly (≥65-year-old) patients with large vertical cup-to-disc ratio (CDR ≥0.7) and without any other glaucomatous findings were included. They had undergone a full ophthalmologic examination twice per year for at least 5 years. The optic nerve head (ONH), peripapillary retinal nerve fiber layer (RNFL), and macular ganglion cell-inner plexiform layer (GCIPL) were imaged with Cirrus high-definition optical coherence tomography (OCT). Presence of temporal raphe sign on the OCT's GCIPL thickness map was assessed as one of the morphologic factors. Conversion to normal-tension glaucoma (NTG) was defined as structural or functional deterioration on either red-free RNFL photography or standard automated perimetry, respectively. The utility of the baseline factors associated with conversion to NTG were identified. RESULTS: During the 5.5-year follow-up, 19 eyes (26.4%) converted to NTG. There were no significant differences in demographics, systemic factors, intraocular pressure factors, or OCT parameters between the nonconverters and converters. Interestingly, the temporal raphe sign was observed in the converters (18/19, 94.7%) much more frequently than in the nonconverters (3/53, 5.7%, P < .001) at baseline. A Cox proportional hazards model indicated the significant influences of temporal raphe sign positivity (hazard ratio 6.823, 95% confidence interval 2.574, 18.088, P < .001) on conversion to NTG. CONCLUSIONS: In elderly subjects with large CDR, temporal raphe sign positivity on the baseline macular GCIPL thickness map was associated with faster conversion to NTG.

Bruch's Membrane Opening Minimum Rim Width Provides Objective Differentiation between Glaucoma and Nonglaucomatous Optic Neuropathies.

PURPOSE: A challenging clinical scenario is distinguishing between normal tension glaucoma (NTG) and non-glaucomatous optic neuropathies (NGON). The key to the assessment remains identifying the presence of optic nerve head cupping. Recent optical coherence tomography (OCT) measurements now allow objective assessment of cupping by minimum rim width at Bruch's membrane opening (MRW-BMO). This study assessed the hypothesis that the MRW-BMO measurement quantifies cupping and therefore can differentiate between NTG and NGON. DESIGN: Diagnostic evaluation with area under the curve. METHODS: Setting: multicenter tertiary hospitals and outpatient clinics. PATIENT POPULATION: 81 eyes of 81 patients were enrolled, 27 with NTG and 54 with NGON, including ischemic optic neuropathy, previous optic neuritis, and compressive and inherited optic neuropathies. All NGON patients with intraocular pressure >21 mm Hg, narrow drainage angles, or a family history of glaucoma were excluded. Observational procedure: optic disc OCT images were obtained of both the retinal nerve fiber layer thickness and the MRW-BMO. MAIN OUTCOME MEASUREMENTS: the utility of the MRW-BMO in differentiating GON from NGON was assessed using the area under the curve (AUC) estimated from a logistic regression model. RESULTS: The 5-fold cross-validated AUC for glaucoma versus nonglaucoma from logistic regression models using MRW-BMO values from all sectors was 0.95 (95% confidence interval: 0.86-1.00). CONCLUSIONS: The measurement of MRW-BMO effectively differentiates between NTG and NGON with a high level of sensitivity and specificity. Incorporating this measurement into routine glaucoma assessment may provide a robust method of assisting clinicians to improve diagnosis and therefore treatment of optic nerve diseases.

Periventricular Leukomalacia in Patients With Pseudo-glaucomatous Cupping.

PURPOSE: Periventricular leukomalacia (PVL) is a structural loss of white matter pathways that carry visual information from the lateral geniculate bodies to the visual cortex. It is observed radiologically in patients with a history of prematurity and is associated with visual field (VF) defects and optic disc cupping. Advances in perinatal care have improved survival for premature babies, so many now present as adolescents and adults to comprehensive eye doctors who are unaware of the relationship of cupping, field defects, and prematurity and who may diagnose manifest or suspected normal tension glaucoma. We describe 2 such patients to raise awareness of this entity. DESIGN: Case series. METHODS: Review of clinical information of 2 patients identified during clinical practice. Charts were reviewed for gestational age, optic nerve appearance, intraocular pressure (IOP), and sequelae of prematurity. Magnetic resonance imaging (MRI), optical coherence tomography (OCT), VF, and optic disc photographs were reviewed. RESULTS: Two young patients with a history of prematurity presented with enlarged cup-to-disc ratio and normal IOP. OCT thinning was most prominent superiorly, with VF defects more notable inferior and homonymous. No progression on VF or OCT was noted in the index case over almost 4 years. CONCLUSIONS: Periventricular leukomalacia should be added to the differential diagnosis of normal tension glaucoma (NTG) when there is a history of prematurity. Careful examination of the optic nerve will assist in differentiating from NTG. Specifically, horizontal cupping with minimal or no nasal displacement of vessels, and superior optic nerve thinning with inferior VF defects, suggest PVL.

The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications.

In a series of previous publications we have proposed a framework for conceptualizing the optic nerve head (ONH) as a biomechanical structure. That framework proposes important roles for intraocular pressure (IOP), IOP-related stress and strain, cerebrospinal fluid pressure (CSFp), systemic and ocular determinants of blood flow, inflammation, auto-immunity, genetics, and other non-IOP related risk factors in the physiology of ONH aging and the pathophysiology of glaucomatous damage to the ONH. The present report summarizes 20 years of technique development and study results pertinent to the characterization of ONH connective tissue deformation and remodeling in the unilateral monkey experimental glaucoma (EG) model. In it we propose that the defining pathophysiology of a glaucomatous optic neuropathy involves deformation, remodeling, and mechanical failure of the ONH connective tissues. We view this as an active process, driven by astrocyte, microglial, fibroblast and oligodendrocyte mechanobiology. These cells, and the connective tissue phenomena they propagate, have primary and secondary effects on retinal ganglion cell (RGC) axon, laminar beam and retrolaminar capillary homeostasis that may initially be "protective" but eventually lead to RGC axonal injury, repair and/or cell death. The primary goal of this report is to summarize our 3D histomorphometric and optical coherence tomography (OCT)-based evidence for the early onset and progression of ONH connective tissue deformation and remodeling in monkey EG. A second goal is to explain the importance of including ONH connective tissue processes in characterizing the phenotype of a glaucomatous optic neuropathy in all species. A third goal is to summarize our current efforts to move from ONH morphology to the cell biology of connective tissue remodeling and axonal insult early in the disease. A final goal is to facilitate the translation of our findings and ideas into neuroprotective interventions that target these ONH phenomena for therapeutic effect.

Detection of Glaucoma and Its Association With Diabetic Retinopathy in a Diabetic Retinopathy Screening Program.

PURPOSE: To determine the type of glaucoma in subjects with diabetes mellitus detected during a diabetic retinopathy screening program and to determine any association between diabetic retinopathy (DR) and glaucoma. MATERIALS AND METHODS: This is a population-based prospective cross-sectional study, in which subjects with diabetes mellitus underwent screening for DR in a primary care outpatient clinic. Digital fundus photographs were taken and graded for presence/absence and severity of DR. During this grading, those fundus photographs showing increased cup-to-disc ratio (CDR) (≥0.6) were identified and these patients were referred to the specialist ophthalmology clinic for detailed examination. The presence of glaucoma was established based on CDR and abnormal visual field (VF) defects according to Hodapp-Parrish-Anderson's criteria. An elevation of intraocular pressure was not required for the diagnosis of glaucoma. The patients said to have definite glaucoma were those with vertical CDR>/=0.6, glaucomatous defects on VF examination, or retinal nerve fiber thinning if VF was unreliable. RESULTS: Of the 2182 subjects who underwent screening, 81 subjects (3.7%) had increased CDR and 40 subjects (1.8%) had confirmed glaucoma. Normal-tension variant of primary open-angle glaucoma was the most prevalent type (1.2%) We did not find any evidence that DR is a risk factor for glaucoma [odds ratio for DR vs. no DR=1.22 (95% confidence interval, 0.59-2.51)]. CONCLUSION: The overall prevalence of glaucoma in this diabetic population, based on finding increased cupping of optic disc in a teleretinal screening program was 1.8% (95% confidence interval, 1.0-3.0).

Patterns of subsequent progression of localized retinal nerve fiber layer defects on red-free fundus photographs in normal-tension glaucoma.

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 ± 6.0° (range, 1.1° to 24.4°; n = 11) and 5.2 ± 4.9° (range, 0.3° to 11.3°; 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.

Vascular comorbidity in patients with low-tension glaucoma.

PURPOSE: To report vascular comorbidities, arterial hypertension (HT), ischemic heart disease (IHD), and diabetes mellitus (DM) in patients with low-tension glaucoma (LTG) with maximum intraocular pressure (IOP) of 18 mm Hg or less. Uniform criteria for glaucoma and the comorbidities were applied. METHODS: We reviewed records of 519 consecutive patients to whom the Finnish National Social Insurance Institution (FSII) had granted cost-free medication for the treatment of glaucoma. The FSII operates national health insurance, which is compulsory for all Finnish citizens. There were 344 patients with primary open-angle glaucoma (POAG) and 155 with exfoliative glaucoma (EG). Twenty cases were discarded for having other types of glaucoma. In the POAG group, there were 38 patients, with a median IOP of 16 mm Hg (range 12-18). We were masked to the systemic comorbidities when the registry provided us data on those to whom FSII had also granted cost-free medication for HT, IHD, or DM according to the uniform national criteria. RESULTS: None of the patients with LTG had exfoliation syndrome. There was a female predominance, 81%, compared to 68% in high-tension POAG. Hypertension had been diagnosed in 34%, which is the same as in high-tension POAG. A total of 24% had IHD, which is the same as in the Finnish population registry. Diabetes mellitus was present in only 5%. In all groups, patients with LTG with systemic comorbidity were markedly older than those without. CONCLUSIONS: In patients with LTG with median IOP 16 mm Hg (range 12-18), glaucomatous optic disc cupping and glaucomatous visual field defects probably developed independently of the systemic vascular comorbidity. However, the diagnostic criteria for HT, IHD, and DM used in the current study were based on the severity of stages set in the FSII system.

Patterns of Subsequent Progression of Localized Retinal Nerve Fiber Layer Defects on Red-free Fundus Photographs in Normal-tension Glaucoma

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.

Effect of Ginkgo biloba extract on visual field progression in normal tension glaucoma.

PURPOSE: To evaluate the long-term effect of Ginkgo biloba extract (GBE) on progression of visual field (VF) defects in patients with normal tension glaucoma (NTG). METHODS: Forty-two eyes of 42 patients with treated NTG who received 80 mg GBE 2 times daily and who had at least 5 VF tests using the Humphrey Visual Field Analyzer for more than a 4-year period before and after GBE treatment were evaluated in this retrospective study. We evaluated the change of progression rate using mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI) after GBE treatment. The time course of mean total deviation in 10 zones corresponding to the glaucoma hemifield test was analyzed using a linear mixed effects model with unequal random effect variances. RESULTS: The mean follow-up period was 12.3 years. The posttherapeutic intraocular pressures before and after GBE treatment were not significantly different (P=0.509 paired t test). Before GBE treatment, the regression coefficients (RCs) of MD, PSD, and VFI change were -0.619 dB/y, 0.626 dB/y, and -2.153%/y, respectively. After GBE treatment, the RCs of MD, PSD, and VFI change improved significantly to -0.379 dB/y, 0.342 dB/y, and -1.212%/y (P <0.001), respectively. In zone 1, the RC of mean total deviation change was significantly increased after GBE administration (P <0.005). CONCLUSIONS: GBE administration slowed the progression of VF damage in patients with NTG, especially in zone 1 corresponding to the superior central field.

Evaluation of optic nerve head using a newly developed stereo retinal imaging technique by glaucoma specialist and non-expert-certified orthoptist.

PURPOSE: To evaluate the reproducibility and interexaminer consistency in analyzing the optic disc parameters using a newly fundus stereoscopic camera, and their correlation with parameters of the Heidelberg Retina Tomograph II (HRT II) was also examined. METHODS: This study examined 53 eyes of 53 healthy volunteers (mean age, 21.8 y). Fifty-five eyes of 55 glaucoma patients (mean age, 59.3 y) were also involved. A Nonmyd WX retinal camera was used for stereoscopic fundus imaging. The diagnostic parameters for the optic nerve head analyses were examined under the following conditions: (1) the intraexaminer reproducibility was determined by a certified orthoptist (CO) with 1 year's experience, with the appropriate coefficient of variation in 8 healthy eyes; and (2) the interexaminer consistency of the diagnostic parameters by both glaucoma specialist and CO was examined in 45 healthy eyes and 55 glaucomatous eyes. By subgroup analysis, the healthy eyes were classified into 2 groups based on the degree of myopia, the optic disc of glaucomatous eye was classified into 4 types: focal ischemic, generalized enlargement, myopic, and senile sclerotic, and also classified into 3 stages (early, moderate, and severe) by Hodapp-Anderson-Parrish scale. (3) The correlation of parameters common to Nonmyd WX and HRT II was examined in 18 eyes of randomly selected patients. RESULTS: The results were as follows: (1) Mean coefficient of variation of 2.6% to 17.6%, with volume parameters considerably lower than the other parameters. (2) In both groups, a high or moderate degree of consistency was obtained (r=0.40 to 0.99; P=0.032 to <0.0001), except only the upper rim width in healthy subjects (r=0.28; P=0.137). In particular, good consistency was obtained in healthy eye with >-3 D of myopia, in glaucoma patients with the generalized type of optic disc and severe glaucomatous stage. (3) A strong correlation with HRT II was obtained only in the cup area and the disc area by both specialist and CO (r=0.75 to 0.90; P=0.0003 to <0.0001). CONCLUSIONS: Our studies indicated that most of the parameters were highly reproducible and consistent, and less difference was found between the results obtained by an experienced glaucoma specialist and a non-expert CO in patients with deep cupping and severe eye, but the examiner needs a clear understanding of the criteria for the rim and the cup.

[Optic neuropathies of different etiology and normal tension glaucoma: the point of differential diagnosis].

62 patients (109 eyes) with glaucoma-like optic nerve head cupping and normal IOP indices (Po not more than 21 mm Hg) were examined to find the etiology of optic nerve changes. Regarding corneal biomechanics new-onset primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) were diagnosed in 27% and 3% of examined patients respectively. In 59% of patients optic neuropathy (ON) of different etiology was found to be the cause of glaucoma-like optic nerve changes including compression ON due to lesion of intracranial portion of optic nerve and chiasma in 6% of cases. In 11% physiologic large optic nerve head cupping with normal visual functions and absence of nerve fiber structural changes was found.

Corneal thickness measurements in normal-tension glaucoma workups: is it worth the effort?

PURPOSE: To correlate central corneal thickness (CCT) and intraocular pressure (IOP) with disease severity in normal-tension glaucoma (NTG) patients. METHODS: We conducted a retrospective review of all patients diagnosed with NTG in our institution between 2002 and 2006. NTG was diagnosed according to the glaucomatous visual fields loss, glaucomatous optic disc cupping, and an IOP <22 mm Hg on diurnal curve measurements. Mean CCT and IOP values before and after treatment were also evaluated. Patients were divided into 3 groups according to advanced glaucoma intervention score (mild, moderate, and severe visual field defects). RESULTS: A total of 33 females and 35 males with bilateral NTG were enrolled. The mean follow-up was 4.6 years. CCT was inversely correlated with glaucoma severity. CCT was normal in both eyes in mild disease, thin in the right eye (RE) and normal in the left eye (LE) in moderate disease, and low in both eyes in severe disease. Initial bilateral mean maximal IOP was similar at all disease stages and became lower after treatment in parallel to disease severity: 13.44, 12.22, and 11.63 mm Hg in the RE and 13.29, 12.60, and 12.32 mm Hg in the LE, respectively. There was no statistical difference in disease severity between the RE and LE. CONCLUSIONS: CCT correlated with disease severity: the more advanced the disease, the thinner the cornea. Initial maximal IOP did not predict disease severity, but it was lower in the more severe cases after treatment, possibly representing a more aggressive treatment protocol.