Comparison of tests

DETECTION OF M-CELL DYSFUNCTION IN OCULAR HYPERTENSION AND GLAUCOMA

Comparison of two tests

M. ALTIERI,1 U. VOGT,1 M. HOFFMANN,2 A. MORLAND2 and C. MIGDAL1

1The Western Eye Hospital; 2Royal Holloway University; London,UK

Abstract

Purpose: To compare methods of detecting M-ganglion cells dysfunction by psychophysical tests of temporal response characteristics in patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG). Methods: Forty-four eyes of 44 consecutive patients were included in the study. The total group was subdivided into three sub-groups (POAG, OHT, and normal controls) according to 1998 European Glaucoma Society guidelines. Each eye was tested with stimulation software, developed at Imperial College, London, which showed that responses to the so-called ST2 stimulus have similar characteristics to neurons found in the magnocellular pathway. The ST2 measurement of temporal responses involves detection thresholds for a target that moves across a temporally modulated background (flicker). The ST2 threshold responses were measured for flicker values of 5.00, 7.50, and 10 Hz. Each eye was also tested with the frequency-doubling technology perimeter (FDT), which has the theoretical capacity to test the same retino-cortical pathway. FDT indices of FDT-MD and FDT-PSD were calculated. The temporal responses assessed with both techniques were evaluated in all three subgroups, and correlations between the two psychophysical test results were derived. The Student t test, Mann-Whitney non-parametric test, Pearson r coefficient, and Spearman correlation coefficient were used for the statistical analysis when appropriate. Results: Twelve eyes were included in the POAG group, 17 in the OHT group, and 15 in the normal-control group. Comparison of the data from the OHT to the normal-control group showed a statistically significant difference (p < 0.05) in the ST2 threshold value at 5.00 Hz and in the FDT-MD (p < 0.05) and in FDT-PSD indices (p < 0.001). Comparison of the data from the POAG to the normal-control group showed statistically significant differences in the ST2 threshold value at 5.00 and 7.5 Hz (p < 0.05) and in both FDT indices (MD and PSD p < 0.001). In addition, significant correlations were found between the FDT-PSD and the threshold value of ST2 responses at 5.00 Hz for the POAG versus the normal-control group (r = 0.67; p < 0.05) and a less strong, but nevertheless significant, correlation between the OHT and the normal-control group (r = 0.54 ; p < 0.05). Conclusions: Both the studied psychophysical tests may be used in screening for early glaucomatous damage, especially for the detection of M-ganglion cell damage in patients with OHT or POAG who remain normal on testing with standard threshold perimetry. However, some practical considerations still need to be addressed.

Introduction

Histopathological data have demonstrated loss of the largest retinal ganglion cells of the retino-cortical pathway in chronic glaucoma.1 This group of cells has been presumed

Address for correspondence: Michele Altieri MD, Via Devoto 13/10, 16131 Genova, Italy. Email: altieri.ferraris@tin.it

Perimetry Update 2002/2003, pp. 91–96

Proceedings of the XVth International Perimetric Society Meeting, Stratford-upon-Avon, England, June 26–29, 2002

edited by David B. Henson and Michael Wall

© 2004 Kugler Publications, The Hague, The Netherlands

to project to the magnocellular layers of the lateral geniculate nucleus (LGN), has fast conduction velocity, and is especially sensitive to transient change in retinal stimulation.2 Although the magnocellular pathway is thought to be damaged by the primary action of glaucoma, this fact has not been firmly established.

The aim of this study was to detect M-cell dysfunction by studying the temporal response characteristics, as assessed by frequency-doubling technology perimetry (FDT) and by the ST2 temporal responses test (a computerized version of a psychophysical test developed by Dr. A Morland3 at Imperial College, London, using a Maxwellian Optical View System4,5). We assessed response functions mediated by the magnocellular pathway in patients with primary open-angle glaucoma (POAG), ocular hypertension (OHT), and age-matched normal controls.

Material and methods

The ST2 temporal response function (ST2) test has been developed at Imperial College, London. The ST2 responses have been demonstrated to be similar to those found for neurons in the magnocellular pathway.4,5 With this test, the measurement of temporal responses relies upon the detection of a target that moves across a temporally modulated background (flicker). The present version is based on software developed with MatVis, with a Matlab Interface, which enables a stimulus presentation that is fully time-locked to the monitor. The program presents a moving dot superimposed on a stationary square wave grating, which is achieved with a combination of look up table (LUT) animation and copying of images to the video random access memory (RAM).

The luminance of the moving dot at detection threshold was determined with a 2- alternative forced choice (2-AFC) procedure. The subject’s task was to determine whether the stimulus moved leftor right-wards. To minimize the time for testing, an adaptive staircase, based on the BestTest algorithm, was implemented.6,7 However, the luminance steps on conventional cathode ray tube (CRT) displays were not sufficiently small to reach the detection threshold in the 2-AFC procedure and, therefore, a digital-to-analogue converter (DAC) for the three guns was combined via a passive resistor network to enhance the display range for gray levels.8 The ST2 responses were assessed for threshold values with low flickering frequencies of 5.00, 7.50, and 10.00 Hz.

Perimetry, using FDT, was assessed by standard clinical instrumentation. FDT has the theoretical capacity to test the same retino-cortical pathway.9,10 FDT presents stimuli on a black-and-white video monitor with specialized control circuity interfaced with a microprocessor. The stimulus consists of a 0.25 cycles/degree sinusoidal grating undergoing 25 Hz counterphase flicker (contrast reversal of light and dark bars). Perimetry based on FDT has a high patient preference, compared to standard automated perimetry (SAP).11-13

All patients taking part in this study were under the care of the Western Eye Hospital, London. Forty-four eyes of 44 consecutive patients were included in the study. The total group was subdivided into three subgroups, according to 1998 European Glaucoma Society guidelines,14 i.e., POAG, OHT, and normal-control groups. Each of the patients was experienced in automated perimetry. The study eyes were assessed by the Humphrey Field Analyzer (HFA) 640, central 24-2 program, full

threshold test. Perimetry with FDT was assessed by program N-30, full threshold test and FDT indices, including FDT-MD and FDT-PSD.

The temporal responses were assessed with both study techniques (ST2 and FDT) in all three subgroups, and correlations between the two psychophysical test results were calculated.

Student’s t test, Mann-Whitney non-parametric test, Pearson’s r coefficient and Spearman correlation coefficients were used for the statistical analysis, when appropriate. This study was approved by the ethics committee of the Western Eye Hospital.

Results

Twelve eyes were included in the POAG group, 17 in the OHT group, and 15 in the normal-control group. The results, comparing the temporal response functions by the two methods, are summarized in Tables 1, 2 and 3.

Table 1. Results

Normal: n = 15; mean age = 55 ± 3.2 years; OHT: n = 17; mean age = 59 ± 2.4 years; POAG: n = 12; mean age = 55 ± 4.7 years. Corrected visual acuity = 6/9 or better for all subgroups

Table 2. Results: correlations between FDT indices and ST2 responses

Comparison of the OHT with the normal-control group showed a statistically significant difference (p < 0.05) in the ST2 threshold value at 5.00 Hz, but not at the other two frequencies studied. With regard to the FDT results, a statistically significant difference was found in the FDT-MD (p <0.05) and in FDT-PSD (p <0.001) indices in these groups.

OHT versus normal patients

POAG versus normal patients

The POAG group compared with the normal-control group showed a statistically significant difference (p <0.05) in the ST2 threshold value at 5.00 and 7.5 Hz. The FDT showed marked statistically significant differences (p <0.001) in both MD and PSD.

Comparison between the two tests

When we compared the two different psychophysical tests results, highly significant correlations were found between the FDT-PSD and the threshold value of ST2 responses at 5.00 Hz in the POAG group (r = 0.67; p < 0.05) and less strong, but nevertheless significant, correlations were found in the OHT group (r = 0.54; p < 0.05).

Discussion

Previous studies of the optic nerve in glaucoma have shown evidence of preferential loss of larger fibers,15,16 and atrophy of relay neurons in the lateral geniculate nucleus, probably due to a disconnection from their major afferent pathways.2 Johnson and Samuels suggested that the contrast sensitivity with FDT targets may depend on retinal ganglion cells that are part of the magnocellular system.12 FDT perimetry has demonstrated advantages over SAP in the early detection of the glaucomatous visual field loss. The unique characteristics of the stimulus pattern make it independent of refractive errors (up to ± 7 diopters) and other kinds of interferences, theoretically reducing false positives and learning effects.12

FDT exploits contrast and, also, spatial frequency and temporal modulation. All three functions are very important in glaucoma for early diagnosis, and a test exploring them is therefore of clinical interest.14 In this respect, the ST2 computerized test also has the theoretical capability of detecting dysfunction of the magnocellular retinocortical pathway.

Despite the fact that FDT uses a sine-wave pattern to create the frequency doubling illusion, our results show significant quantitative correlations with results obtained with the computerized ST2 responses developed by Barber and Ruddock, which show similar temporal characteristic to neurons found in the magnocellular pathway.4

A previous study with a similar test procedure that utilized a projected method of

stimulus presentation, showed statistically significant differences of the ST2 threshold values at 5.00, 7.50 and 10.00 Hz between OHT subjects and normal controls and between POAG and normal controls.17 In the present study, we have extended the utilization of ST2 methods and present the results obtained with the new computerized version of the test. Our findings show statistical differences between the ST2 responses of OHT versus control patients when assessed at 5.00 Hz. In addition, the ST2 responses between POAG and control patients assessed at 5.00 and 7.50 Hz were also statistically different.

When comparing the two types of tests, the FDT indices and threshold values assessed with the ST2 computerized tests were shown to be correlated. There were significant correlations between the FDT-PSD and the threshold value of ST2 responses at 5.00 Hz in the POAG group, and less strong, but nevertheless significant, correlations between the FDT-PSD and the threshold values assessed at 5.00 Hz (low flicker frequency) in the OHT group. The correlations of the ST2 responses with the PSD, a perimetric index that is elevated in early glaucomatous visual field loss, may be of practical use in the future. However, the normal threshold values of the ST2 responses are still not yet known and a longitudinal study on a larger number of patients is needed in order to establish these clinically normal values.

Conclusions

Both these psychophysical tests enable the detection of M-ganglion cell damage in patients with OHT and POAG, and allow differentiation from normals. However, although having the advantage of low cost and portability, the ST2 test is time-consuming and still requires refinement. Nevertheless, these results show promise for the future.

References

1.Quigley HA, Dunkelberger GR, Green WR: Chronic human glaucoma causing selectively greater loss of large optic nerve fibers. Ophthalmology 95:357-364, 1988

2.Yücel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N: Atrophy of relay neurons in magnoand parvocellular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci 43(4):3216-3221, 2002

3.Morland AB, Bronstein AM, Ruddock KH: Vision during motion in patients with absent vestibular function. Acta Otolaryngol (Stockh) (Suppl 520):338-342, 1995

4.Barber JL, Ruddock KH: Spatial characteristics of movement detection mechanism in human vision: achromatic mechanisms. Biol Cybern 37:72-92, 1980

5.Holliday IE, Ruddock KH: Two spatio-temporal filters in human vision: temporal and spatial frequency response characteristics. Biol Cybern 47:137-140, 1983

6.Lieberman HR, Pentland AP: Computer technology: microcomputer-based estimation of psychophysical thresholds. The best PEST. Behav Res Methods Instrument 14:21-25, 1992

7.Pentland A: Maximum likelihood estimation: the best PEST. Perception Psychophys 28:377-379, 1980

8.Peli DG, Zhang CL: Accurate control of contrast on microcomputer displays. Vision Res 31:13371350, 1991

9.Sponsel WE, Trigo Y, Mensah J: Frequency doubling perimetry. Am J Ophthalmol 126:155-156, 1998

10.Sponsel WE, Arango S, Trigo Y, Mensah J: Clinical classification of glaucomatous visual field loss by frequency doubling perimetry. Am J Ophthalmol 125:830-836, 1998

11.Quigley HA: Identification of glaucoma-related visual field abnormality with the screening protocol of frequency doubling technology. Am J Ophthalmol 125(6):819-828, 1998

12.Johnson CA, Samuels SJ: Screening for glaucomatous visual field loss with frequency-doubling perimetry. Invest Ophthalmol Vis Sci 38(2):413-423, 1997

13.Iester M, Mermoud A, Schnyder C: Frequency doubling technique in patients with ocular hypertension and glaucoma. Ophthalmology 107(2):288-294, 2000

14.European Glaucoma Society (EGS): Terminology and Guidelines for the Glaucoma, ch 2.2.3. Savona, Italy: Dogma 1998

15.Quigley HA, Sanchez RM, Dunkelberger GR et al: Chronic glaucoma selectively damages large optic nerve fibers. Invest Ophthalmol Vision Sci 28:913-920, 1987

16.Glovinsky Y, Quigley HA, Dunkelberger GR: Retinal ganglion cell loss is size dependent in experimental glaucoma. Invest Ophthalmol Vision Sci 32:481-492, 1991

17.Vogt U, Morland A, Migdal C, Ruddock K: Spatial and temporal visual filtering in patients with glaucoma and ocular hypertension. Eye 12:691-696, 1998