Using Kalman Filtering to Forecast Disease Trajectory for Patients With Normal Tension Glaucoma.

PURPOSE: To determine whether a machine learning technique called Kalman filtering (KF) can accurately forecast future values of mean deviation (MD), pattern standard deviation, and intraocular pressure for patients with normal tension glaucoma (NTG). DESIGN: Development and testing of a forecasting model for glaucoma progression. METHODS: We parameterized and validated a KF (KF-NTG) to forecast MD, pattern standard deviation, and intraocular pressure at 24 months into the future using 263 eyes of 263 Japanese patients with NTG. We determined the proportion of patients with MD forecasts within 0.5, 1.0, and 2.5 dBs of the actual values and calculated the root mean squared error (RMSE) for each forecast. We compared KF-NTG with a previously published KF model calibrated using patients with high-tension open-angle glaucoma (KF-HTG) and to 3 conventional forecasting algorithms. RESULTS: The 263 patients with NTG had mean ± standard deviation age of 63.4 ± 10.5 years. KF-NTG forecasted MD values 24 months ahead within 0.5, 1.0, and 2.5 dBs of the actual value for 78 eyes (32.2%), 122 eyes (50.4%), and 211 eyes (87.2%), respectively. The proportion of eyes with MD values forecasted within 2.5 dB of the actual value for the KF-NTG (87.2%) were similar to KF-HTG (86.0%) and the null model (86.4%), and much better than the 2 linear regression-based models (72.7-74.0%; P < .001). When forecasting MD, KF-NTG (RMSE = 2.71) and KF-HTG (RMSE = 2.68) achieved lower RMSE than the other 3 forecasting models (RMSE = 2.81-3.90), indicating better performance. CONCLUSION: As observed previously for patients with HTG, KF can also effectively forecast disease trajectory for many patients with NTG.

Prevalence of Normal-Tension Glaucoma in the Chinese Population: A Systematic Review and Meta-Analysis.

PURPOSE: To investigate the prevalence of normal-tension glaucoma (NTG) in the Chinese population through systematic review and meta-analysis. DESIGN: Systematic review and meta-analysis. METHODS: All Chinese population-based studies that reported the prevalence of NTG were identified. We searched PubMed and Chinese databases including Wanfang, China National Knowledge Infrastructure, and VIP for studies published before December 31, 2017. Random effects meta-analysis was conducted to estimate the pooled prevalence of NTG. RESULTS: Twelve studies were included in this review and meta-analysis, including 9 population-based studies and 3 studies from glaucoma clinics and managed care networks. The 9 population-based studies included a total of 30,892 subjects with 498 patients with primary open-angle glaucoma (POAG) and 354 patients with NTG. The prevalence of estimated NTG ranged from 0.36% to 1.98% and the percentage of NTG among POAG ranged from 51.43% to 83.58%. In the glaucoma clinic and managed care network studies, NTG prevalence was much lower. The overall pooled proportion of NTG among POAG in the Chinese population was 70.0% (95% confidence interval [CI] 62.0-77.0%). The overall pooled prevalence of POAG and NTG was 2.0% (95% CI 1.0-2.0%) and 1.0% (95% CI 1.0-1.0%), respectively. For the meta-regression of the NTG/POAG proportion, we found that age, gender, intraocular pressure, and China versus not China were not significantly associated with NTG/POAG prevalence, although the proportional prevalence decreased with increasing age category. CONCLUSIONS: In this systematic review, we found that NTG is common among patients with POAG in the Chinese population. Our findings can help guide future glaucoma studies and public health guidelines in the Chinese population.

Translaminar pressure in Caucasian normal tension glaucoma patients.

PURPOSE: The aim of this study was to examine the translaminar pressure difference (TLP) in Caucasian patients with normal tension glaucoma (NTG) and its possible impact onto the pathogenesis of NTG. METHODS: Retrospective analysis of medical records of patients with open-angle glaucoma (OAG) in the period from 2005 to 2015 from the Ophthalmology Department, Cantonal Hospital Aarau, Switzerland. A total of 67 eyes of 38 patients (mean age 68.6 ± 11.3 years, 21 women and 17 men) fulfilled the diagnostic criteria of progressive NTG and underwent lumbar puncture (LP) during computer-assisted cisternography (CT - cisternography). The intraocular pressure (IOP) and lumbar cerebrospinal fluid pressure (CSF-p) were analysed and the TLP calculated. The TLP was compared with the mean defect (MD) of visual fields. Statistical analysis was performed with the one and two-tailed paired and unpaired t-test and the non-parametric Spearman correlation test. RESULTS: The mean lumbar opening CSF-p measured 11.6 ± 3.7 mmHg. The mean IOP in the right eye measured 14.7 ± 2.4 mmHg, in the left eye 14.7 ± 2.5 mmHg. The calculated mean TLP was 3.0 ± 4.2 mmHg in the right and 3.3 ± 4.3 mmHg in the left eye. There was no significant correlation between TLP and the MD of visual fields in both eyes. CONCLUSIONS: This study did not confirm either a lower lumbar CSF-p or increased TLP compared to previous retrospective and prospective studies. As cerebrospinal fluid (CSF) flow is not homogenous throughout all CSF spaces and CSF-p and IOP fluctuate, the current view on TLP needs modifications to improve its validity.

Twenty-four-hour intraocular pressure and ocular perfusion pressure characteristics in newly diagnosed patients with normal tension glaucoma.

PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage.

Sensitivity and specificity for detecting early glaucoma in eyes with high myopia from normative database of macular ganglion cell complex thickness obtained from normal non-myopic or highly myopic Asian eyes.

PURPOSE: We aimed to determine the sensitivity and specificity of the normative database of non-myopic and highly myopic eyes of the macular ganglion cell complex (mGCC) thickness embedded in the NIDEK RS-3000 spectral-domain optical coherence tomography (SD-OCT) for detecting early glaucoma in highly myopic eyes. METHODS: Forty-seven highly myopic eyes (axial length ≥26.0 mm) of 47 subjects were studied. The SD-OCT images were used to determine the mGCC thickness within a 9-mm diameter circle centered on the fovea. The sensitivity and specificity of the non-myopic database were compared to that of the highly myopic database for distinguishing the early glaucomatous eyes from the non-glaucomatous eyes. The mGCC scans were classified as abnormal if at least one of the eight sectors of the significance map was < 1 % of the normative thickness. RESULTS: Twenty-one eyes were diagnosed to be non-glaucomatous and 26 eyes to have early glaucoma. . The average mGCC thickness was significantly thinner (80.9 ± 8.5 µm) in the early glaucoma group than in the non-glaucomatous group (91.2 ± 7.5 µm; p <1 × 10(-4)). The sensitivity was 96.2 % and specificity was 47.6 % when the non-myopic database was used, and the sensitivity was 92.3 % and the specificity was 90.5 % when the highly myopic database was used. The difference in the specificity was significant (p < 0.01). CONCLUSIONS: The significantly higher specificity of the myopic normative database for detecting early glaucoma in highly myopic eyes will lead to fewer false positive diagnoses. The database obtained from highly myopic eyes should be used when evaluating the mGCC thickness of highly myopic eyes.

Optimal selective laser trabeculoplasty energy for maximal intraocular pressure reduction in open-angle glaucoma.

PURPOSE: To identify the optimal energy level to be used in selective laser trabeculoplasty (SLT) for maximal intraocular pressure (IOP) reduction in open-angle glaucoma (OAG) patients. PATIENTS AND METHODS: This cohort sequentially recruited OAG subjects in Hong Kong, China during 2011 to 2012. All subjects received a single session of SLT with near confluent spots to 360 degrees of the trabecular meshwork. An initial energy of 0.8 mJ was titrated until bubble formation was just visible. The main outcomes included: change in IOP (pre-SLT to 1 mo post-SLT) and total SLT energy (SLT spots multiplied by the mean energy). For statistical analysis, only the right eye of each subject was used. Bandwidth selection by generalized cross-validation was used to determine the optimal interval and point of total SLT energy that resulted in the largest IOP reduction. RESULTS: A total of 49 Chinese OAG subjects had a mean age of 64.2±11.1 years. The pre-SLT IOP was 17.1±2.9 mm Hg while on 1.9±1.1 types of antiglaucoma eye drops. The mean total energy was 167.1±41.4 mJ (171.5±41.2 spots at 1.0±0.06 mJ). The 1 month post-SLT IOP was 13.5±2.8 mm Hg. The percentage of SLT success was 57.1% (28/49). The 95% confidence band by bootstrap method was plotted showing that a total energy between 214.6 and 234.9 mJ significantly decreased the IOP>25%, with the optimal total energy at 226.1 mJ. CONCLUSIONS: A higher SLT energy, in the range of 214.6 to 234.9 mJ, seems to be associated with an improved IOP-lowering response. Further randomized control trials with treatment stratification are needed to confirm these results.

Predictors of success in selective laser trabeculoplasty for chinese open-angle glaucoma.

AIM: To investigate the determinants of success of selective laser trabeculoplasty (SLT) in Chinese open-angle glaucoma patients. METHODS: This prospective cohort study sequentially recruited Chinese subjects with unilateral or bilateral primary open-angle glaucoma (POAG) or normal tension glaucoma (NTG). All subjects received a single session of 360-degree SLT treatment. Success was defined as IOP reduction ≥20%. The following were analyzed in univariate and multivariate regression analyses for association with SLT success: type of glaucoma, age, sex, lens status, presenting IOP, pre-SLT IOP, day 1 IOP, 1-week IOP, number and type of anti-glaucoma medications, number of SLT shots and energy, retinal nerve fiber layer (RNFL) thickness, Visual Field Index, endothelial cell count, central corneal thickness, Snellen visual acuity, and spherical equivalent. RESULTS: In 111 eyes of 65 subjects, there were 51 POAG eyes and 60 NTG eyes. The overall success was 53.15% with a mean IOP reduction of 19.81±15.93%. In univariate analysis, a thinner RNFL [coefficient=-0.027; odds ratio (OR)=0.95; P=0.017] was associated with success. In multivariate analysis, a lower day 1 IOP (coefficient=-0.29; OR=0.75; P=0.049) and using topical carbonic anhydrase inhibitors (CAI) (coefficient=2.92; OR=18.63; P=0.0020) were associated with success. In both univariate and multivariate analyses, a higher pre-SLT IOP significantly predicted success (coefficient=0.20/0.46; OR=1.23/1.58; P=0.0017/0.0011) and using 3 anti-glaucoma medications (coefficient=-1.08/-3.74; OR=0.3/0.024; P=0.037/P=0.0081) was associated with SLT failure. CONCLUSION: The positive predictors of SLT success included: higher pre-SLT IOP, use of topical CAI, thinner RNFL, and lower day 1 IOP. Using 3 anti-glaucoma medications was associated with failure.

Open-angle glaucoma in Filipino and white Americans: a comparative study.

BACKGROUND: To compare the frequency of open-angle glaucoma (OAG) subtypes between Filipino and white Americans in a general ophthalmology clinic population. PATIENTS AND METHODS: In this retrospective cross-sectional epidemiologic study with prospective sampling, medical charts of 1113 patients aged 40 years or older (513 Filipinos, 600 whites) seen in 2008 were randomly sampled from 2 private comprehensive ophthalmology clinics. Glaucoma was diagnosed based on optic nerve appearance, visual field defects, and other ocular findings using the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) scheme. The normal-tension subtype of OAG [normal-tension glaucoma (NTG)] was defined by intraocular pressure ≤21 mm Hg as determined by review of medical records. RESULTS: NTG comprised a greater proportion of all glaucomatous disease in Filipino subjects [Filipino (F) vs. white (W): 46.7% vs. 26.8%; P=0.02]. Filipinos were more commonly diagnosed with OAG and NTG than whites (F vs. W: OAG, 11.9% vs. 8.2%; NTG, 6.8% vs. 2.5%; P=0.04, 0.001, respectively). There was no significant difference in central corneal thickness between Filipino and white subjects with NTG (P=0.66). CONCLUSIONS: Both OAG and NTG may be more common in Filipino Americans than in white Americans with the propensity for NTG being particularly high in the former relative to the latter group.

Association of HK2 and NCK2 with normal tension glaucoma in the Japanese population.

Although family studies and genome-wide association studies have shown that genetic factors play a role in glaucoma, it has been difficult to identify the specific genetic variants involved. We tested 669 single nucleotide polymorphisms (SNPs) from the region of chromosome 2 that includes the GLC1B glaucoma locus for association with primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese population. We performed a two-stage case-control study. The first cohort consisted of 123 POAG cases, 121 NTG cases and 120 controls: the second cohort consisted of 187 POAG cases, 286 NTG cases, and 271 controls. Out of six SNPs showing significant association with POAG in the first round screening, seven SNPs were tested in the second round. Rs678350 in the HK2 gene coding sequence showed significant allelic (p=0.0027 in Stage Two, 2.7XE-4 in meta-analysis) association with POAG, and significant allelic (p=4.7XE-4 in Stage Two, 1.0XE-5 in meta-analysis) association with NTG. Although alleles in the TMEM182 gene did not show significant association with glaucoma in the second round, subjects with the A/A allele in TMEM182 rs869833 showed worse visual field mean deviation (p=0.01). Even though rs2033008 in the NCK2 gene coding sequence did not show significant association in the first round, it had previously shown association with NTG so it was tested for association with NTG in round 2 (p=0.0053 in Stage Two). Immunohistochemistry showed that both HK2 and NCK2 are expressed in the retinal ganglion cell layer. Once multi-testing was taken into account, only HK2 showed significant association with POAG and NTG in Stage Two. Our data also support previous reports of NCK2 association with NTG, and raise questions about what role TMEM182 might play in phenotypic variability. Our data suggest that HK2 may play an important role in NTG in the Japanese population.

Symptoms related to glaucomatous visual field abnormalities among male Japanese workers in a population-based setting.

PURPOSE: To identify symptoms potentially related to glaucomatous visual field abnormalities (VFAs) in a population-based setting, and to assess the applicability of using these symptoms to identify persons at risk of developing glaucoma. METHODS: In this study, 10,214 Japanese male general workers (mean age, 45.3±8.8 years) filled out a self-administered questionnaire and underwent frequency doubling technology (FDT) perimetry testing. The questionnaire inquired about whether the participant was suffering from any of nine symptoms, with scores for each response graded on a four-item Likert scale: 0 (none), 1 (rarely), 2 (sometimes), and 3 (always). Results from the questionnaire were compared among three groups: participants without any VFAs (9767), participants with VFAs as determined by the FDT test (FDT-VFA; 447), and 227 participants (of the 447 FDT-VFA participants) with glaucomatous VFAs who were newly diagnosed by ophthalmologic examinations. RESULTS: The mean summed scores for the total items were significantly (p<0.01) higher in FDT- and glaucomatous VFA groups than in normal subjects. In particular, responses citing the symptoms 'feeling of something in the front of the eye' and 'feeling of hardness to see in dark places' were significantly (p<0.05) more frequent in subjects with FDT- and glaucomatous VFAs than among normal participants. However, the respective areas under the receiver operating characteristic curve of summed scores for the nine total items and for the two items which showed significant differences for the glaucoma groups were 0.57 (95% confidence interval=0.53-0.60) and 0.58 (95% confidence interval=0.54-0.61). CONCLUSION: Although the symptoms 'feeling of hardness to see in dark places' and 'feeling of something in the front of the eye' could be associated with glaucomatous VFA in a population-based setting, inquiring about symptoms is of little aid in identifying subjects with glaucomatous VFA as a strategy for public health.

Lack of association between glaucoma and macular choroidal thickness measured with enhanced depth-imaging optical coherence tomography.

PURPOSE: To compare choroidal thickness measurements among normal eyes, eyes with normal tension glaucoma (NTG), and those with primary open-angle glaucoma (POAG), and to correlate choroidal thickness with demographic and clinical ocular parameters. METHODS: Choroidal thickness was measured with enhanced depth-imaging (EDI) optical coherence tomography (OCT) in one eye of 38 normal, 20 NTG, and 56 POAG subjects and compared among groups. The mean age was 69.3 ± 13.6 years (60.1 ± 13.4 years for normal subjects and 73.8 ± 11.3 years for glaucoma subjects; P < 0.001). Measurements were made at the fovea and in the temporal and nasal choroid every 0.5 mm up to 3 mm away from the fovea. Univariate and multivariate linear regression analyses were performed to assess the association between choroidal thickness and demographic and ocular parameters. RESULTS: There were no differences in foveal, temporal, or nasal choroidal thickness between normal, NTG, and POAG subjects (all P > 0.05) after adjusting for age, axial length, and intraocular pressure. Similarly, glaucoma severity groups did not differ from each other in all choroidal thickness measurements (all P > 0.05). Age (ß = -1.78; P < 0.001) was the most significant factor associated with subfoveal choroidal thickness in the entire group, followed by axial length (ß = -11.8; P = 0.002). CONCLUSIONS: Choroidal thickness does not differ among normal, NTG, and POAG subjects, suggesting a lack of relationship between choroidal thickness and glaucoma based on EDI OCT measurements.

Central corneal thickness and anterior scleral thickness in Korean patients With Open-angle glaucoma: an anterior segment optical coherence tomography study.

PURPOSE: To assess the correlation between central corneal thickness (CCT) and anterior scleral thickness (AST) in Korean patients with normal tension glaucoma (NTG) and primary open angle glaucoma (POAG). PATIENTS AND METHODS: Consecutive patients with POAG, NTG, and normal individuals were recruited. Anterior segment optical coherence tomography (AS-OCT, Visante) was used to measure CCT and AST. The AST was measured 2 mm posterior to the scleral spur in the temporal meridian. Statistical analysis of the data included ANOVA and Pearson correlation analysis. RESULTS: One hundred and eight participants (36 with NTG, 35 with POAG, and 37 normal individuals) were enrolled. The CCT (NTG 514.8 1± 25.03 µm; POAG 534.43 ± 34.79 µm; controls 536.70 ± 32.11 µm) was found to be thinner in patients with NTG compared with POAG and the control eyes (P=0.023; P=0.009). The AST (NTG 738.53 ± 53.63 µm; POAG 771.86 ± 53.75 µm; controls 783.62 ± 57.03 µm) was thinner in the patients with NTG compared with POAG and the normal controls (P=0.032; P=0.002). No significant difference in AST was found among the POAG and control eyes (P=0.636). A correlation between CCT and AST was found only among the patients with NTG (r=0.469, P=0.004). However, no correlation was observed between CCT and AST in patients with POAG and controls. CONCLUSIONS: Anterior scleral thickness was correlated with CCT in the NTG group, but this correlation was not observed among the POAG or control groups.

Retinal vessel diameter, retinal nerve fiber layer thickness, and intraocular pressure in korean patients with normal-tension glaucoma.

PURPOSE: To investigate the retinal vessel diameter and evaluate the relationship of the retinal nerve fiber layer (RNFL) thickness with retinal vessel diameter and intraocular pressure (IOP) in patients with normal-tension glaucoma (NTG). DESIGN: A prospective, cross-sectional study. METHODS: This study included 60 previously untreated patients with NTG (60 eyes) and 45 age- and sex-matched healthy controls (45 eyes) that had no history of systemic vascular disease at a single institution. The diameters of the central retinal arteries and veins were measured on retinal photographs. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were calculated using the revised Parr-Hubbard formula. The RNFL thickness was measured using Stratus optical coherence tomography. RESULTS: The mean central retinal arteriolar (P = .000) and venular (P = .000) diameters were significantly smaller in the eyes with NTG than in the normal eyes. Multivariate linear regression analysis demonstrated a significant positive correlation between the RNFL thickness and CRAE (P = .014), and a negative correlation between the RNFL thickness and IOP (P = .005) in the eyes with NTG. However, there was no significant correlation between the RNFL thickness and the independent variables in the control group (P = .112). CONCLUSION: The patients with NTG had smaller diameters of the central retinal vessels than the normal subjects. Both IOP and CRAE were significantly associated with RNFL thickness in the patients with NTG. Our results suggest that narrower retinal vessels and higher IOP may be related to the thinning of the RNFL in patients with NTG.

Korean normative database for time domain optical coherence tomography to detect localized retinal nerve fiber layer defects (preliminary study).

PURPOSE: To establish a Korean normative database of retinal nerve fiber layer (RNFL) thickness. METHODS: Data was collected from 103 healthy volunteers. Total ophthalmologic examinations, including fast RNFL thickness analysis by time domain optical coherence tomography (STRATUS OCT) were performed. The RNFL thickness of 64 glaucoma patients with localized RNFL defects and 48 independent healthy subjects were collected. The RNFL thickness of both the glaucoma patients and the healthy subjects was evaluated using both normative databases. RESULTS: The average RNFL thickness of Koreans was 108.3 +/- 10.3 microm. The sensitivity rates recorded in the Korean normative database with 5% and 1% significance were 0.984 and 0.984, with specificity values of 0.938 and 1.000. By comparison, the sensitivity rates in the conventional normative database with 5% and 1% significance are 0.984 and 0.953, and the specificity values are 1.000 and 1.000. CONCLUSION: In detecting localized RNFL defects, the Korean database showed higher sensitivity than the conventional database.