|Author:||Chu, Ho-wai Patrick|
|Title:||A new approach to early glaucomatous diagnosis by multifocal electroretinogram : luminance-modulation of the global flash stimulation paradigm|
|Subject:||Hong Kong Polytechnic University -- Dissertations.|
Glaucoma -- Diagnosis.
|Department:||School of Optometry|
|Pages:||xxv, 274 leaves : ill. (some col.) ; 30 cm.|
|Abstract:||Early recognition and accurate assessment of glaucomatous functional loss is a major goal for clinicians and researchers. Ganglion cells lost due to glaucomatous damage cannot be regenerated, but early and appropriate treatment is effective for preventing further retinal ganglion cell death. Early detection is essential to prevent the progression of glaucomatous damage, thus a more sensitive diagnostic technique is very important for early treatment. Electrophysiological tests are objective tools for measuring the functional responses of the visual system. The multifocal electroretinogram (mfERG) has been developed to study and diagnose diseases of the human retina. Using this advanced technique, localized retinal damage can be detected; however, currently unresolved problems with the mfERG are the extent to which the inner retina contributes to the response and how to create an appropriate technique for measuring this contribution. By improving the sensitivity of the mfERG measurement, the functional changes of the inner retina due to glaucomatous damage can be detected in an earlier stage, hopefully before nerve fiber loss. In an attempt to improve the efficacy of the mfERG in detecting inner retinal activity, a modification of a stimulus protocol previously employed by Fortune and his colleagues (Fortune et al., 2002a) was used in this study; the new mfERG protocol allowed early detection of glaucoma. Objectives 1. To investigate the variation of retinal functions in glaucoma by using a global flash mfERG stimulation with different stimulus contrast levels of the multifocal flashes, in an attempt to maximise inner retinal contributions. 2. To use the global flash mfERG stimulation in subjects with unilateral glaucoma to determine whether retinal function is affected in fellow eyes without glaucomatous visual field defects. 3. To investigate the association of the luminance-modulation global flash mfERG and other retinal assessments for subsets of subjects at high risk of developing glaucomatous damage. 4. To use global flash mfERG stimulation and a pharmacologic dissection method in an animal eye model to help understand the basis of damage produced in glaucoma. Methods In experiment 1, the global flash mfERG was assessed with a new stimulation paradigm in steps of four video frames, which consisted of 103 hexagonal elements followed by a dark frame, global flash, and dark frame. The localized luminance-difference was set at 96%, 65%, 49% or 29% stimulus contrast as different luminance-modulation levels. Thirty subjects with glaucoma and 30 age-matched normal subjects were recruited for visual field and mfERG measurements. In experiment 2, 40 normal subjects and 12 subjects with unilateral glaucoma were recruited for visual field and mfERG measurement. The mfERG was assessed by using a global flash stimulation paradigm with luminance-modulation as in experiment. In experiment 3, 42 subjects (75 eyes) with unilateral glaucoma, ocular hypertension (OHT), family history of glaucoma and large optic disc cupping were examined in this three-year study of visual field, optical coherence tomography (OCT) and global flash mfERG measurements with luminance-modulation. Four complete ophthalmic examinations were scheduled, one every 12 months. In experiment 4, global flash mfERG responses using the 4-frame luminance-modulation paradigm were recorded from 14 eyes of 10 six-week-old Yorkshire pigs in control conditions and after suppression of inner retinal responses with inhalation of isoflurance (ISO), and injections of tetrodotoxin (TTX) and N-methyl-D-asparatic acid (NMDA). ON- and OFF-pathway responses were isolated by injection of 2-amino-4-phosphonobutyric acid (APB) and cis-2,3-piperidinedicarboylic acid (PDA). Results The global flash stimulation paradigm induces complex local first-order responses with an early direct component (DC) and a later induced component (1C). The luminance-modulated response functions of the DC and 1C responses showed markedly different behavior. The peripheral 1C showed a linear dependence on luminance-difference, whereas the peripheral DC was saturated at higher levels of luminance-difference. This saturation became less obvious in glaucoma subjects mostly because of greater reduction of the response amplitude in the mid luminance-difference level. An "adaptive index" was calculated from the luminance-difference dependence of the peripheral DC, and it showed good sensitivity (93%) and specificity (95%) for differentiating normal from glaucomatous eyes, and also had a good correlation (r = 0.58) with the glaucomatous visual field defect. Furthermore, in better (fellow) eyes with normal visual fields of unilateral glaucoma subjects, the amplitude of the 1C was significantly reduced, and the adaptive index was also reduced by a factor of almost 10 (p < 0.0001). The adaptive index in the fellow eyes was similar to the index in the glaucoma eyes and they did not show a statistically significant difference. In the longitudinal experiment, there was significant thinning of the retinal nerve fiber layer (RNFL) thickness (p < 0.05) over the course of the study for the fellow eyes with unilateral glaucoma or the eyes with OHT which initially had an abnormal adaptive index; such eyes showed a thinning rate of -3.02 and -3.54 urn/year respectively. However, thinning was not found in eyes which initially had a normal adaptive index. The pig eye was chosen as the animal model and the porcine global flash mfERG also consisted of an early DC and a late 1C. ISO and TTX removed inner retinal contributions to the 1C; NMDA application further abolished the oscillatory wavelets in the DC and removed the residual 1C waveform. The inner retina contributed regular oscillating wavelets (Wl, W2 and W3) to the DC and shaped the 1C. After removing the inner retinal contributions, the porcine global flash mfERG waveform becomes comparable to that obtained with conventional mfERG stimulation. The remaining waveform (smoothed DC) was mainly formed by contributions of the ON- and OFF-bipolar cells, as revealed after APB or PDA injection. Photoreceptors contributed a small signal to the leading edge of Nl. The luminance-modulated response function of the DC was shown to be contributed by the inner retinal oscillation wavelets. Conclusions The peripheral DC luminance-modulated response function is altered by the adaptive mechanism that is induced by the global flash; the reduction of the adaptive index may thus relate to an abnormal adaptive mechanism, presumably due to inner retinal damage. Glaucoma appears to cause a large reduction of the adaptive index which correlates with field defects. In addition, the significant reduction of the adaptive index in the fellow eyes in subjects with unilateral glaucoma shows impaired adaptive mechanism(s) in these eyes. This implies that although eyes with high risk factors may have functionally normal visual acuity (VA) and visual fields, they are likely to have abnormal adaptive mechanisms. Furthermore, the adaptive index calculated from the measurement of luminance-modulated global flash mfERG may be useful for predicting glaucomatous progression, especially in subjects with high risk factors. The abnormal adaptive index follows from change in fast-adaptive mechanisms and may indicate the risk of developing glaucoma. The DC of the porcine global flash mfERG was shown to be composed mainly of contributions from photoreceptors, and ON- and OFF-bipolar cells, where inner retinal activity partially shapes the DC with superimposed regular oscillations. In addition, the 1C is dominated by inner retinal activity. The luminance-modulated response function of the DC consisted of both outer retinal response and oscillation wavelets of the inner retinal response. 1C and DC responses show different characteristics under various luminance-modulation levels, where the changes of W2 (second oscillating wavelet) of the inner retinal response seem independent of luminance-modulation, but the outer retinal response seems to depend on luminance-modulation. The DC luminance-modulated response feature depends mainly on the relative contribution of inner retinal activities; the impairment of inner retinal activity may alter the DC luminance-modulated response function, making it tend toward linearity. This may explain why glaucoma patients show loss of independence of the luminance-modulated response function under luminance-modulation in global flash mfERG responses.|
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