PURPOSE: Frequency Doubling Technology (FDT) perimetry is a novel perimetric test that provides rapid screening (45 to 60 seconds) and full-threshold (4 to 5 minutes) testing for detection of vision loss. The purpose of this study was to determine the specificity and sensitivity of FDT perimetry for the detection of ocular disease. METHODS: A total of 130 participants (257 eyes of 42 men and 88 women) recruited from the community completed FDT perimetry, standard achromatic automated perimetry (SAP), anterior segment biomicroscopy, tonometry, and dilated ophthalmoscopy. FDT results were considered abnormal if 1 point was abnormal (depressed below the 5% level on the screening protocol C-20-5). SAP was considered abnormal if the glaucoma hemifield test or pattern standard deviation was outside normal limits (P < .05) or a hemifield cluster of 3 depressed points on the pattern deviation probability plot (P < .05) was present. An abnormal eye examination was defined as the presence of an abnormality in the anterior segment, lens, or posterior segment that was likely to cause a visual field defect or the presence of glaucomatous or other optic neuropathy. RESULTS: The mean age (+/- SD) of participants was 55.5 years (+/- 10.3). Ethnic groups, as reported by participants, included 77 (59%) African Americans, 40 (31%) Caucasians, and 13 (10%) in other groups. On clinical examination, 116 eyes (45%) were normal, 9 eyes (3.5%) had a cataract with best corrected visual acuity worse than 20/30, 16 eyes (6%) had open-angle glaucoma, and 17 eyes (7%) had retinal findings or lesions that were likely to cause a visual field defect. For FDT perimetry, 22 (8.6%) of 257 tests were unreliable, and for SAP, 65 (25.3%) of 257 tests were unreliable. The sensitivity and specificity of FDT perimetry for detecting an abnormal clinical examination were 55% and 90% and for detecting an abnormal examination that included an abnormal SAP, 64% and 86%. CONCLUSIONS: FDP demonstrated reasonable discriminatory power for detecting eye disease.
To compare the diagnostic accuracy of the pattern electroretinogram (pattern ERG) to that of standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), and frequency-doubling technology (FDT) perimetry for discriminating between healthy and glaucomatous eyes.
83 eyes of 42 healthy recruits and 92 eyes of 54 glaucoma patients (based on optic disc appearance) from the University of California, San Diego, Diagnostic Innovations in Glaucoma Study were tested with pattern ERG for glaucoma detection (PERGLA, Lace Elettronica, Pisa, Italy), SAP, SWAP, and FDT within 9 months. Receiver operating characteristic (ROC) curves were generated and compared for pattern ERG amplitude and SAP, SWAP and FDT mean deviation and pattern standard deviation (PSD). Sensitivities and specificities were compared and agreement among tests was described.
The area under the ROC curve for pattern ERG amplitude was 0.744 (95% Confidence Interval = 0.670, 0.818). The ROC curve area was 0.786 (0.720, 0.853) for SAP PSD, 0.732 (0.659, 0.806) for SWAP PSD and 0.818 (0.758, 0.879) for FDT PSD. At 95% specificity, sensitivities of SAP and FDT PSD were significantly higher than that of pattern ERG amplitude; at 80% specificity, similar sensitivities were observed among tests. Agreement among tests was slight to moderate.
The diagnostic accuracy of the pattern ERG amplitude was similar to that of SAP and SWAP, but somewhat worse than that of FDT. Nevertheless, the pattern ERG may hold some advantage over psychophysical testing because of its largely objective nature.
To compare the diagnostic accuracy of the Matrix frequency-doubling technology (FDT) 24-2, first-generation FDT N-30 (FDT N-30), and standard automated perimetry (SAP) tests of visual function.
One eye of each of 85 glaucoma patients and 81 healthy controls from the Diagnostic Innovations in Glaucoma Study was included. Evidence of glaucomatous optic neuropathy on stereophotographs was used to classify the eyes. Matrix FDT 24-2, first-generation FDT N-30, and SAP-SITA 24-2 tests were performed on all participants within 3 months. Receiver operating characteristic (ROC) curves were generated and used to determine sensitivity levels at 80% and 90% specificity for mean deviation (MD), pattern standard deviation (PSD), number of total deviation (TD), and pattern deviation (PD) points triggered at less than 5% and 1%. The tests were compared using the best parameter for each test (that with the highest area under the ROC curve) and with the PSD.
The best parameters were MD for SAP (0.680), PSD for FDT N-30 (0.733), and number of TD less than 5% points for FDT 24-2 (0.774). Using the best parameter, the area under the ROC curve was significantly larger for FDT 24-2 than for SAP (P = 0.01). No statistically significant differences were observed between SAP and FDT N-30 (P = 0.21) and FDT N-30 and FDT 24-2 (P = 0.26). Similar results were obtained when the PSD was used to compare the tests, with the exception that the area under the ROC curve for the FDT N-30 test (0.733) was significantly larger than that of the SAP-SITA (0.641; P = 0.03).
The performance of the Matrix FDT 24-2 was similar to that of the first-generation FDT N-30. The Matrix FDT 24-2 test was consistently better than SAP at discriminating between healthy and glaucomatous eyes. Further studies are needed to evaluate the ability of the Matrix FDT 24-2 to monitor glaucoma progression.
To determine the within- and between-trial repeatability of pattern electroretinogram (PERG) measurements in healthy and patient eyes, using a new clinical instrument, the PERGLA.
70 eyes of 35 healthy individuals (IOP < 22 mm Hg, healthy optic disc by stereophotograph assessment, standard visual fields within normal limits) and 90 eyes of 45 clinic patients (ocular hypertensive, glaucomatous optic neuropathy by stereophotograph assessment and/or repeatable abnormal visual fields) enrolled in the UCSD Diagnostic Innovations in Glaucoma Study (DIGS) were studied. Average mean deviation (MD) of patient eyes on standard automated perimetry was −1.81 dB (S.D. = 2.61).
The PERG was recorded using the PERGLA paradigm from both eyes simultaneously twice (i.e., 2 trials) by a single operator with electrodes being removed and re-attached between recordings. Repeatability of PERG amplitude (µV) and phase (π rad) between two runs within a single trial (within-trial condition) was compared to repeatability between two trials (i.e., after electrode replacement, between-trial condition) by calculating the coefficients of variability (CVs) and the intraclass correlation coefficients (ICCs) and displaying Bland-Altman plots.
For healthy eyes, amplitude CVs (S.D.) were 11.5% (11.5) and 9.9% (0.79) for within- and between-trial conditions, respectively. ICCs were 0.91 and 0.85. Phase CVs were 1.3% (1.5) (within-trials) and 1.5% (1.4) (between-trials) and ICCs were 0.85 and 0.88. For patient eyes, amplitude CVs (S.D.) were 12.2% (10.1) and 11.2% (7.5) for within- and between-trial conditions, respectively. ICCs were 0.92 and 0.89. Phase CVs were 2.2% (2.2) (within-trials) and 2.4% (2.2) (between-trials) and ICCs were 0.82 and 0.83. Bland-Altman plots indicated good agreement between the repeated recordings and were similar within- and between-trials for healthy and patient eyes.
Repeatability of PERGLA recordings is good and is similar within- and between-trials for both healthy and patient eyes suggesting this technique is promising for monitoring change over time.
To assess the combined diagnostic power of frequency-doubling technique (FDT)-perimetry and retinal nerve fibre layer (RNFL) thickness measurements with spectral domain optical coherence tomography (SDOCT).
The study included 330 experienced participants in five age-related groups: 77 ‘preperimetric' open-angle glaucoma (OAG) patients, 52 ‘early' OAG, 50 ‘moderate' OAG, 54 ocular hypertensivepatients, and 97 healthy subjects. For glaucoma assessment in all subjects conventional perimetry, evaluation of fundus photographs, FDT-perimetry and RNFL thickness measurement with SDOCT was done. Glaucomatous visual field defects were classified using the Glaucoma Staging System. FDT evaluation used a published method with casewise calculation of an ‘FDT-score', including all missed localized probability levels. SDOCT evaluation used mean RNFL thickness and a new individual SDOCT-score considering normal confidence limits in 32 sectors of a peripapillary circular scan. To examine the joined value of both methods a combined score was introduced. Significance of the difference between Receiver-operating-characteristic (ROC) curves was calculated for a specificity of 96%.
Sensitivity in the preperimetric glaucoma group was 44% for SDOCT-score, 25% for FDT-score, and 44% for combined score, in the early glaucoma group 83, 81, and 89%, respectively, and in the moderate glaucoma group 94, 94, and 98%, respectively, all at a specificity of 96%. ROC performance of the newly developed combined score is significantly above single ROC curves of FDT-score in preperimetric and early OAG and above RNFL thickness in moderate OAG.
Combination of function and morphology by using the FDT-score and the SDOCT-score performs equal or even better than each single method alone.
early glaucoma; frequency doubling technique; perimetry; retinal nerve fibre layer thickness; spectral domain OCT
Matrix perimetry is a new iteration of frequency doubling technology (FDT) using a smaller target size in the standard achromatic perimetry presentation pattern. This study compared Matrix and Swedish interactive thresholding algorithm (SITA) perimetry performance in detecting glaucoma diagnosed by structural assessment.
Prospective cross-sectional study.
Seventy-six eyes of 76 consecutive healthy subjects, glaucoma suspects and glaucoma patients were included. All patients underwent optic nerve head (ONH) photography, SITA and Matrix perimetry and optical coherence tomography (OCT; Stratus OCT) within a six month interval. Glaucoma diagnosis was established by either glaucomatous optic neuropathy or OCT retinal nerve fiber layer (RNFL) thickness. Mean deviation (MD), pattern standard deviation (PSD), glaucoma hemifield test (GHT) and cluster of abnormal testing locations were recorded from Matrix and SITA.
Similar correlations were observed with Matrix and SITA MD and PSD with either cup-to-disc ratio or OCT mean RNFL. The area under the receiver operating characteristic (AROC) curves of MD and PSD for discriminating between healthy and glaucomatous eyes ranged from 0.69 to 0.81 for Matrix and from 0.75 to 0.77 for SITA. There were no statistically significant differences among any corresponding Matrix and SITA AROCs.
Matrix and SITA perimetry had similar capabilities for distinguishing between healthy and glaucomatous eyes regardless of whether the diagnosis was established by ONH or OCT RNFL assessment.
Visual field; glaucoma
Aim: To determine if frequency doubling technology perimetry (FDT) is more sensitive to optic nerve injury in non-arteritic ischaemic optic neuropathy (NAION) than standard automated perimetry (SAP).
Methods: Charts from 18 patients (20 eyes) with NAION with altitudinal defects who underwent a complete neuro-ophthalmic examination, SAP, and FDT were reviewed. The extent of damage as determined by SAP, FDT, and clinical estimation of the regional extent of optic disc pallor was compared. 10 subjects (20 eyes) with normal ocular examinations and full appearing optic nerve heads were included as a control group.
Results: FDT demonstrated more extensive visual field defects in the relatively intact hemifield on SAP (proportion of locations at 5% or worse in the total deviation plot was 8.7% (SD 6.2%) for SAP and 38.3% (39.5%) for FDT p<0.0027). 16 of 20 eyes with altitudinal NAION demonstrated diffuse optic disc pallor. 11 of these eyes with diffuse pallor demonstrated significant defects in both hemifields using FDT, while only two eyes demonstrated diffuse damage using SAP. Correspondence between the extent of optic disc pallor and the extent of visual scotoma was higher for FDT (85%) than with SAP (40%).
Conclusion: FDT appears more sensitive to axonal injury reflected by the extent of optic disc pallor in altitudinal NAION than SAP and in some patients reveals visual dysfunction in the hemifield that appeared relatively uninvolved when evaluated using SAP.
frequency doubling technology perimetry; non-arteritic ischaemic optic neuropathy
AIM—To determine the number of missed points on frequency doubling technology (FDT) perimetry that optimise the sensitivity and specificity of the test and to determine the topographical accuracy of the test in a clinical setting.
METHODS—In a prospective study, the perimetric data from 99 patients who underwent both FDT perimetry in the screening mode and Humphrey 24-2 (H24-2) were used to determine the sensitivity and specificity of the FDT perimetry compared with the full threshold H24-2 as the gold standard.
RESULTS—Missed points on the FDT perimetry correlated with both the mean deviation and the corrected pattern standard deviation on the Humphrey perimetry. A score assigned to abnormal points on the FDT perimetry and the Humphrey total deviation plot showed a significant correlation for both the location and the depth of the defect. In comparing the Humphrey hemifield test with the FDT perimetry results, if at least one missed point on the frequency doubling test was considered as abnormal then the overall sensitivity of the test was 78.1% and the specificity was 89.1%.
CONCLUSION—FDT perimetry in the screening mode performed in a clinical setting was highly specific, exhibited reasonable sensitivity, and accurately determined the location and depth of scotomas when compared with the full threshold Humphrey 24-2.
Matrix perimetry is a new iteration of frequency‐doubling technology (FDT) which uses a smaller target size in the standard achromatic perimetry presentation pattern.
To compare the performance of matrix and Swedish interactive thresholding algorithm (SITA) perimetry in detecting glaucoma diagnosed by structural assessment.
Prospective cross‐sectional study.
76 eyes from 15 healthy subjects and 61 consecutive glaucoma suspects and patients with glaucoma were included. All patients underwent optic nerve head (ONH) photography, SITA and matrix perimetries, and optical coherence tomography (OCT) within a 6‐month period. Glaucoma diagnosis was established by either glaucomatous optic neuropathy or OCT by assessing retinal nerve fibre layer (RNFL) thickness. Mean deviation (MD), pattern standard deviation (PSD), glaucoma hemifield test and cluster of abnormal testing locations were recorded from matrix and SITA perimetries.
Similar correlations were observed with matrix and SITA perimetry MD and PSD with either cup‐to‐disc ratio or OCT mean RNFL. The area under the receiver operating characteristic (AROC) curves of MD and PSD for discriminating between healthy and glaucomatous eyes ranged from 0.69 to 0.81 for matrix perimetry and from 0.75 to 0.77 for SITA perimetry. There were no significant differences among any corresponding matrix and SITA perimetry AROCs.
Matrix and SITA perimetries had similar capabilities for distinguishing between healthy and glaucomatous eyes regardless of whether the diagnosis was established by ONH or OCT–RNFL assessment.
Frequency doubling technology (FDT) perimetry measures contrast sensitivity. The magnocellular component of ganglion cells in human retina is isolated as a whole by the FDT stimulus. The aim of this study is to investigate the role of Humphrey Matrix threshold testing in the detection of early functional retinal impairment in ocular hypertensive patients compared to standard automated perimetry (SAP).
Forty hypertensive patients were enrolled in this longitudinal observational clinical study. Functional testing included randomly Humphrey Matrix perimetry and white-on-white Humphrey visual field perimetry. Ibopamine test was performed in all forty patients. The cut-off of 3 mmHg was considered positive for this provocative test.
Out of 40 patients, we included 21 in ibopamine positive group and 19 in ibopamine negative group. These two groups are sex- and age-matched. In ibopamine positive group the mean increase in IOP is 4.6 mmHg (ranging from 3 to 10 mmHg). Statistics showed that correlation between FDT and SAP was statistically significant in ibopamine negative group and not statistically significant in ibopamine positive group. Only one patient, coming from IBO + group, converted from ocular hypertension to glaucoma. All the other subjects remained stable in both groups without any therapy and visual field abnormalities.
FDT showed to be more sensitive and specific than SAP mostly in detection of early visual field impairment in ocular hypertensive patients.
Early glaucoma; FDT; ibopamine; ocular hypertension; SAP.
Purpose. To determine the presence and type of glaucoma in a cohort of adult Chinese subjects with systemic hypertension. Methods. This prospective cohort study included 200 hypertensive Chinese adults aged >40 years old who underwent screening via frequency doubling technology (FDT) perimetry and intraocular pressure (IOP) measurement by noncontact tonometry (NCT) in a general outpatient clinic. Those with IOP > 21 mmHg and/or visual field (VF) defects on FDT were referred for complete ophthalmological examination. The diagnosis of glaucoma was based on an abnormal VF on Humphrey Field Analyzer (HFA) by Hodapp-Parrish-Anderson's criteria and an increased vertical cup-disc ratio (VCDR). Results. The mean age of the subjects was 64.66 ± 9.47 years, and the male:female ratio was 92 : 108. All patients were hypertensive with a mean blood pressure (BP) of 131.1 ± 15.1/76.6 ± 11.1 mmHg whilst on systemic antihypertensive medication. Of the 111 patients that had an abnormal initial screening, 14 (7.9%) were confirmed to have glaucoma with the highest prevalence of normal tension glaucoma (NTG) (6.2%), followed by primary angle closure glaucoma (PACG) (1.1%) and primary open angle glaucoma (POAG) (0.5%). The positive predictive value of FDT perimetry was 71%. Conclusion. Nearly 8% of the adults with systemic hypertension had glaucoma, and NTG was the most prevalent type.
Aims: To evaluate performance of frequency doubling technology (FDT) perimetry using the Humphrey Matrix 24-2 thresholding program in a hospital eye service (HES) glaucoma clinic.
Methods: A random sample of individuals referred consecutively to the HES for suspected glaucoma were examined with 24-2 threshold FDT in addition to routine clinical tests. The discriminatory power of FDT and standard automated perimetry (SAP) were assessed using glaucomatous optic nerve head appearance as the reference gold standard.
Results: 48 of 62 eligible referred individuals were recruited. Glaucoma prevalence was 31%. Median test duration per eye was 5 minutes 16 seconds for FDT and 5 minutes 9 seconds for SAP. There was no significant difference (p = 0.184) between proportions of individuals with reliable test results (FDT 75%, SAP 63%). Using a clinically appropriate binary criterion for abnormal visual field, sensitivity and specificity levels were 100% and 26% respectively for FDT and 80% and 52% for SAP. Both tests had higher negative than positive predictive values with marginal differences between tests. Criterion free receiver operator characteristic analysis revealed minimal discriminatory power differences.
Conclusions: In a HES glaucoma clinic in which new referrals are evaluated, threshold 24-2 FDT testing with the Humphrey Matrix has performance characteristics similar to SAP. These findings suggest threshold testing using the FDT Matrix and SAP is comparable when the 24-2 test pattern is used.
glaucoma; visual fields; perimetry; frequency doubling technology; screening
To describe the association between pattern electroretinogram (PERG) amplitude and spectral domain-optical coherence tomography (SD-OCT) macular thickness, retinal nerve fibre layer (RNFL) thickness and optic disc topography measurements.
Subjects and methods
Both eyes (n=132) of 66 glaucoma patients (mean age=67.9 years) enroled in the University of California, San Diego, CA, USA, Diagnostic Innovations in Glaucoma Study (DIGS) were included. Eyes were tested with PERG (Glaid PERGLA, Lace Elettronica, Pisa, Italy), RTVue SD-OCT (Optovue Inc., Fremont, CA, USA) GCC, and NHM4 protocols on the same day. Of the 66 enroled patients, 43 had glaucoma defined by repeated abnormal standard automated perimetry (SAP) results in at least one eye and 23 were glaucoma suspects defined by a glaucomatous-appearing optic disc by physicians' examination in at least one eye and normal SAP results in both eyes. Associations (R
2) were determined between PERG amplitude (μV) and SD-OCT macular ganglion cell complex (GCC) thickness (μm), macular thickness (μm), macular outer retinal thickness (macular thickness minus GCC thickness) (μm), RNFL thickness (μm), neuroretinal rim area (mm2), and rim volume (mm3).
PERG amplitude was significantly associated with GCC thickness (R
2=0.179, P<0.001), RNFL thickness (R
2=0.174, P<0.001), and macular thickness (R
2=0.095, P<0.001). R
2 associations with other parameters were not significant (all P>0.624). Significant associations remained for GCC and average RNFL thickness when age and intraocular pressure at the time of testing were included in multivariate models (both P≤0.030).
PERG amplitude is significantly (but weakly) associated with macular GCC thickness, RNFL thickness, and macular thickness. The lack of association between PERG amplitude and macular outer retinal thickness supports previous results, possibly suggesting that that the PERG is driven primarily by retinal ganglion cell (inner retinal) responses.
glaucoma; electrophysiology; pattern electroretinogram; spectral domain; fourier domain; optical coherence tomography
We determined the time lag between loss of retinal ganglion cell function and retinal nerve fiber layer (RNFL) thickness.
Glaucoma suspects were followed for at least four years. Patients underwent pattern electroretinography (PERG), optical coherence tomography (OCT) of the RNFL, and standard automated perimetry testing at 6-month intervals. Comparisons were made between changes in all testing modalities. To compare PERG and OCT measurements on a normalized scale, we calculated the dynamic range of PERG amplitude and RNFL thickness. The time lag between function and structure was defined as the difference in time-to-criterion loss between PERG amplitude and RNFL thickness.
For PERG (P < 0.001) and RNFL (P = 0.030), there was a statistically significant difference between the slopes corresponding to the lowest baseline PERG amplitude stratum (≤50%) and the reference stratum (>90%). Post hoc comparisons demonstrated highly significant differences between RNFL thicknesses of eyes in the stratum with most severely affected PERG (≤50%) and the two strata with least affected PERG (>70%). Estimates suggested that the PERG amplitude takes 1.9 to 2.5 years to lose 10% of its initial amplitude, whereas the RNFL thickness takes 9.9 to 10.4 years to lose 10% of its initial thickness. Thus, the time lag between PERG amplitude and RNFL thickness to lose 10% of their initial values is on the order of 8 years.
In patients who are glaucoma suspects, PERG signal anticipates an equivalent loss of OCT signal by several years.
Patients suspected of glaucoma had pattern electroretinogram amplitude changes several years before equivalent optical coherence tomography changes.
A transgenic mice model of multiple sclerosis (ND4 mice) shows progressive visual loss as determined by pattern electroretinogram (PERG). Noninvasive evaluation (PERG, MRI, and OCT) of brain and optic nerve of ND4 mice has been described.
To evaluate the ND4 transgenic mouse model of multiple sclerosis using noninvasive methods.
Assessment of neurologic/behavioral abnormalities was made using pattern electroretinogram (PERG), magnetic resonance imaging (MRI), optic coherence tomography (OCT), and end point histologic analysis.
Electrophysiologic (PERG) recordings demonstrated functional deficits in vision commensurate with neurologic/behavioral abnormalities. In ND4 mice, the authors found PERG abnormalities preceded neurologic/gait abnormalities. MRI demonstrated subtle structural changes that progressed over time in correlation with behavioral abnormalities.
The ND4 mouse model has been evaluated using well-defined parameters of noninvasive methods (PERG, MRI, and OCT), enabling objective identification of functional and structural deficits and their correlation with neurologic/gait abnormality.
Aims: To investigate the agreement in results between frequency doubling technology (FDT) and the conventional automated static perimeter in eyes with normal tension glaucoma (NTG) and high tension glaucoma (HTG).
Methods: 72 eyes of 36 patients, who had two or more experiences with the Humphrey field analyser (HFA) program C30-2, were examined with the screening C-20-1 program of FDT. The result of FDT at each of the 17 stimulus points was graded as one of four categories. 58 out of 76 test points of HFA were assigned to one of the 17 clusters corresponding to FDT test points. Each cluster was represented as the lowest (scotoma of HFA) or the highest (threshold of HFA) probability symbol of total deviation (TD) of the HFA test points included in the cluster. The agreement between scotoma/threshold of HFA and FDT results was evaluated for NTG and HTG.
Results: In a total of 65 eyes, the Spearman coefficients between the FDT and HFA (threshold/scotoma of HFA) were 0.599 and 0.515 (p<0.0001), respectively. In the HFA mean deviation matched 20 HTG eyes and 20 NTG eyes, the number of points with abnormal FDT results were 102 and 62 in eyes with HTG and NTG, respectively. The eyes with HTG had more abnormal FDT results than NTG eyes (p=0.0014, Mann-Whitney U test). The kappa coefficient between FDT and threshold of HFA in eyes with HTG and NTG was 0.288 and 0.520, respectively, and the agreement between FDT and scotoma of HFA was 0.480 and 0.439, respectively.
Conclusions: The best agreement of the results of FDT and HFA was observed in eyes with NTG using threshold of HFA. The eyes with HTG showed lower agreement with more abnormal points in FDT results, which suggests enough sensitivity of FDT in eyes with NTG, and higher sensitivity of FDT in eyes with HTG.
frequency doubling perimetry; visual field; glaucoma; normal tension glaucoma; ocular hypertension
To investigate the changes of pattern electroretinogram (PERG) after intraocular pressure lowering in glaucoma patients and normal controls.
Interventional retrospective cross-sectional study.
Twenty-five patients (49 eyes) with ocular hypertension or glaucoma undergoing topical treatment to lower IOP served as a study group; 22 patients (44 eyes) with ocular hypertension or glaucoma observed without treatment served as a control group for treated glaucoma patients; 9 normal subjects (18 eyes) receiving a 250-mg acetazolamide tablet served as a second study group; and 17 normal subjects (34 eyes) from a previous study served as a second control group for treated normal subjects.
Pattern electroretinograms were recorded simultaneously from both eyes using skin electrodes and automated analysis. Visual field (VF) analyses were performed with white-on-white standard automated perimetry (SAP). Intraocular pressure was measured with Goldmann applanation tonometry; central corneal thickness was measured with pachymetry.
Main Outcome Measures
Pattern electroretinogram amplitude (microvolts), phase (π rads), and test–retest variability (test 2–to–test 1 ratio, in decibels), SAP mean deviation (decibels), and IOP (millimeters of mercury).
In 56% of right eyes and 21% of left eyes of the treated glaucoma subgroup, the PERG amplitude and/or phase improved beyond the 95% confidence intervals of the test–retest variability of the untreated glaucoma control group. Pattern electroretinogram improvement with IOP lowering occurred in both high- and low-tension glaucoma eyes. Eyes with severely impaired VFs showed little improvement in PERG; however, eyes of normal subjects treated with acetazolamide did not show significant PERG changes relative to the test–retest variability of normal controls.
Retinal ganglion cell function can be at least partially restored after IOP reduction in glaucomatous eyes with early VF impairment.
The aim of this study was to characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4. Data from 15 patients were retrospectively reviewed and all the patients had at least one G1961E mutation. Comprehensive ophthalmic examination, full-field and pattern electroretinograms, and fundus autofluorescence (FAF) imaging were performed on all patients. Microperimetry, spectral-domain optical coherence tomography (OCT), and fluorescein angiography were performed in selected cases. Genetic screening was performed using the ABCR400 micro-array that currently detects 496 disctinct ABCA4 variants. All patients had normal full-field scotopic and photopic electroretinograms (ERGs) and abnormal pattern electroretinograms (PERGs) performed on both eyes, and all the fundi had bull’s eye maculopathy without retinal flecks on FAF. On OCT, one patient had disorganization of photoreceptor outer segment, two had outer nuclear layer (ONL) thinning likely due to photoreceptor atrophy proximal to the foveal center, and three had additional retinal pigment epithelium (RPE) atrophy. On microperimetry, six patients had eccentric superior fixation and amongst this group, five had an absolute scotoma in the foveal area. DNA analysis revealed that three patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and other ABCA4 mutations. The G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region and a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations. Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull’s eye maculopathy in either the homozygosity or heterozygosity state. In addition, genetic testing provides precise diagnosis of the underlying maculopathy, and current non-invasive imaging techniques could be used to detect photoreceptor damage at the earliest clinical onset of the disease.
Stargardt; mutation; maculopathy; retinal degeneration; dystrophy
This study examined if the delta-opioid (δ-opioid) receptor agonist, SNC-121, can improve retinal function and retinal ganglion cell (RGC) survival during glaucomatous injury in a chronic ocular hypertensive rat model.
IOP was raised in brown Norway rats by injecting hypertonic saline into the limbal venous system. Rats were treated with 1 mg/kg SNC-121 (intraperitoneally [IP]) once daily for 7 days. Pattern-electroretinograms (PERGs) were obtained in response to contrast reversal of patterned visual stimuli. RGCs were visualized by fluorogold retrograde labeling. Expression of TNF-α and p38 mitogen-activated protein (MAP) kinase was measured by immunohistochemistry and Western blotting.
PERG amplitudes in ocular hypertensive eyes were significantly reduced (14.3 ± 0.60 μvolts) when compared with healthy eyes (18.0 ± 0.62 μvolts). PERG loss in hypertensive eyes was inhibited by SNC-121 treatment (17.20 ± 0.1.3 μvolts; P < 0.05). There was a 29% loss of RGCs in the ocular hypertensive eye, which was inhibited in the presence of SNC-121. TNF-α production and activation of p38 MAP kinase in retinal sections and optic nerve samples were upregulated in ocular hypertensive eyes and inhibited in the presence of SNC-121. Furthermore, TNF-α induced increase in p38 MAP kinase activation in astrocytes was inhibited in the presence of SNC-121.
These data provide evidence that activation of δ-opioid receptors inhibited the loss of PERG amplitudes and rate of RGC loss during glaucomatous injury. Mechanistic data provided clues that TNF-α is mainly produced from glial cells and activates p38 MAP kinase, which was significantly inhibited by SNC-121 treatment. Overall, data indicate that enhancement of δ-opioidergic activity in the eye may provide retina neuroprotection against glaucoma.
Opioid receptors activation provides retina neuroprotection against glaucomatous injury. TNF-α plays critical role in retinal degeneration.
Aim: To evaluate the effect of cataract surgery on frequency doubling technology (FDT) perimetry in patients with co-existing cataract and glaucoma.
Methods: In this consecutive prospective cohort study 27 patients with open angle glaucoma scheduled for cataract extraction alone or combined with trabeculectomy were enrolled. All patients underwent FDT threshold C-20 visual fields within 3 months before and 3 months after surgery. Changes in mean deviation (MD) and pattern standard deviation (PSD) were evaluated. Additionally, changes in best corrected logMAR visual acuity (VA), intraocular pressure (IOP), and number of glaucoma medications were also studied.
Results: 22 patients completed the study. VA improved after surgery, from 0.47 (SD 0.19) to 0.12 (0.17) (p<0.001). The visual indexes changed after cataract extraction: MD improved (from −10.9 (SD 4.6) dB to −7.0 (4.6) dB; p<0.001) while PSD worsened (from 7.1 (SD 3.5) dB to 8.5 (3.8) dB; p = 0.001).
Conclusion: In patients with co-existing cataract and glaucoma, examined with FDT, MD improved and PSD worsened after cataract surgery. Global indexes of FDT should be interpreted with caution in patients with glaucoma and cataracts.
glaucoma; frequency doubling technology; visual fields; cataract
To see if scotoma detected with frequency doubling technology (FDT) is confirmed by Humphrey field analyser (HFA) 3 years later.
Subjects were first examined with the screening C‐20‐1 program of FDT. The visual field was examined annually for 4 years using HFA program C30‐2. The central 58 test points in HFA were assigned to one of the 17 clusters corresponding to FDT test points. Each cluster was represented as the lowest probability symbol of total deviation (TD) of the HFA test points included in the cluster. Clusters were graded normal, suspected scotoma, and scotoma depending on probability of TD—5% or more, 5%–1%, less than 1%, respectively. Relative risk (RR) of abnormality on FDT for future scotoma on HFA was estimated.
80 eyes of 42 patients were followed up for 4 years. While 4.0% of normal clusters of HFA with normal FDT results developed into scotoma cluster, 20.8% of normal clusters with abnormal FDT results developed into scotoma cluster with HFA at the third year. RR for future scotoma was 5.24 (95% CI, 2.75 to 10.0, p<0.05).
An abnormal result in FDT shows a high risk of future scotoma on HFA after 3 years even if the original HFA perimetry showed normal results.
glaucoma; perimetry; frequency doubling technology perimeter; visual field
A new concept for evaluating the pattern electroretinogram (PERG) in glaucoma and its clinical application are described. The PERG was elicited by two different stimulus fields, namely, the whole central retinal area with a radius of 18 degrees and the paracentral ring area between the radius of 10 degrees and 18 degrees. The amplitude of the PERG for each stimulus field and the ratio of them were analysed for 30 patients with glaucoma or ocular hypertension. Among these only a small number of eyes were detected as abnormal when we evaluated the amplitude itself either with the central stimulus or the paracentral ring stimulus, whereas the ratio of the two values was below normal in some cases of advanced glaucoma. We conclude that the ratio of the paracentral to central PERG is useful for detecting glaucoma.
To determine the existence of retinal ganglion cell dysfunction and associated risk factors in glaucoma suspects with increased optic disc cupping and normal visual field.
Cross-sectional, observational study.
Two hundred glaucoma suspect (GS) patients were identified based on optic disc abnormalities (vertical cup-to-disc ratios [C/D]>0.5; vertical C/D asymmetry ≥ 0.2; disc hemorrhages; notching) in association with known glaucoma risk factors (positive family history, African American descent, increased intraocular pressure [IOP]), but normal visual fields. Forty-two patients had early manifest glaucoma (EMG). Sixteen normal black subjects were added to update previous pattern electroretinogram (PERG) normative data and to establish a normal control (NC) group with a racial breakdown comparable with that of the study groups.
Pattern electroretinograms were recorded simultaneously from both eyes using skin electrodes and automated analysis; visual fields were monitored with standard white-on-white automated perimetry (SAP) central 24-2 program; vertical C/D was evaluated by an independent reader from stereo disc photographs; and univariate and multivariate statistical analysis between PERG and other outcome measures was evaluated.
Main Outcome Measures
Pattern electroretinogram amplitude (μV), phase (π rad), and interocular asymmetry in amplitude and phase (%); and SAP mean deviation (MD; decibels), vertical C/D, age (years), IOP (mmHg), and race (black vs. nonblack).
The PERG results were abnormal in at least 1 of the outcome measures in 52% of GS patients and 69% of EMG patients. The PERG amplitude was correlated weakly with both MD (P<0.01) and vertical C/D (P = 0.05). The correlation between PERG amplitude and MD and C/D was stronger (P<0.001) for interocular differences rather than absolute measures. Interocular PERG amplitude asymmetry increased with severity of disease (EMG>GS>NC; P<0.01). The PERG amplitude decline with age was steeper in patients with a more negative MD (P<0.01) and in patients with a more negative MD and a larger vertical C/D (P = 0.06). Black race (but not family history) was associated with lower PERG amplitude (P > 0.005) in GS and EMG patients, but not in normal controls (P = 0.44).
The correlation between PERG abnormality and known risk factors for glaucoma indicates that PERG has a predictive potential for the development or progression of the disease, or both.
To compare relative reduction of retinal ganglion cell (RGC) function and retinal nerve fiber layer (RNFL) thickness in early glaucoma by means of steady-state pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively.
Eighty-four persons with suspected glaucoma due to disc abnormalities (GS: mean age 56.6 ± 13.8 years, standard automated perimetry [SAP] mean deviation [MD] -0.58 ± 1.34 dB) and 34 patients with early manifest glaucoma (EMG, mean age 65.9 ± 10.7 years, SAP MD -2.7 ± 4.5 dB) were tested with PERG and OCT. Both GS and EMG patients had small refractive errors, corrected visual acuity ≥20/25, and no systemic or retinal disease other than glaucoma.
MDs from age-predicted normal values were larger for PERG amplitude (GS: -1.113 dB; EMG: -2.352 dB) compared with the PERG-matched RNFL thickness (GS: -0.217 dB; EMG: -0.725 dB). Deviations exceeding the lower 95% tolerance intervals of the normal population were more frequent for PERG amplitude (GS: 26%; EMG: 56%) than PERG-matched RNFL thickness (GS: 6%; EMG: 29%).
In early glaucoma, reduction in RGC electrical activity exceeds the proportion expected from lost RGC axons, suggesting that a population of viable RGCs in the central retina is dysfunctional. By combining PERG and OCT it is, in principle, possible to obtain unique information on reduced responsiveness of viable RGCs.
To develop a mouse model of inducible, chronic retinal ganglion cell (RGC) dysfunction not associated with cell death.
Eighteen C57BL/6J mice were longitudinally tested with pattern electroretinogram (PERG) and spectral-domain optical coherence tomography (OCT) before and after aspiration of the contralateral superior colliculus (SC), which removed terminals of optic tract axons and the superficial layers of the SC. At the 4-month end points, retinas were harvested for Brn3b immunostaining and BDNF immunoblotting.
The PERG lost approximately 60% of its baseline amplitude (P < 0.01) within the first day after lesion, and remained at a reduced level over 4 months. At the end point, the density of Brn3b-positive RGCs was normal, but their nucleus size was reduced by approximately 24% (P < 001). OCT measurements showed thinning of the inner, but not outer, retina by approximately 9% (P < 0.01) starting 10 to 20 days after lesion. Retinal nerve fiber layer thickness was unchanged. At the end point, retinal homogenates showed a substantial overexpression of BDNF protein level.
Mechanical SC lesion in adult mice results in a rapid, chronic loss of RGC electrical responsiveness that is followed by cell shrinkage but not cell death. The SC-lesion mouse represents a new, inducible model that allows investigating stages and mechanisms of RGC dysfunction without the confounding effects of cell death that are common in the existing models of optic neuropathies and optic nerve lesions.
Mechanical lesion of the superior colliculus in adult mice causes rapid, chronic loss of electrical responsiveness of retinal ganglion cells (RGCs) that is followed by cell shrinkage but not cell death. This represents a new, inducible model of chronic RGC dysfunction.