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An Investigation of Visual Field Test Parameters in Glaucoma, Patterns Of An investigation of visual field test parameters in glaucoma, patterns of visual field loss in diabetics and multispectral imaging of the optic nerve head in glaucoma A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences 2012 Yanfang Wang School of Medicine (Human Development) 1 CONTENTS Title page……………………………………………………………1 Contents……………………………………………………….........2 List of Tables………………………………………………………..9 List of Figures……………………………………………………..10 List of Abbreviations……………………………………………...14 Abstract …………………………………………………………...16 Declaration………………………………………………………...17 Copyright statement………………………………………………17 Acknowledgment……………………………………………...…..19 1. Rationale of the study…………………………………………..20 2. Glaucoma……………………………………………………….24 2.1- Classification of glaucoma……………………………………….........24 2.2 - Clinical assessment in glaucoma……………………………………..27 2.2.1- IOP measurement………………………………………………..27 2.2.2 - Examination of structural and functional loss in glaucoma….28 2.3 - Management…………………………………………………………..32 3. Visual field testing……………………………………………..33 3.1 - Stimuli and background……………………………………………...33 3.2 - Test strategies………………………………………………………….34 3.2.1 - Frequency-of-seeing (FOS) curve and threshold………………34 3.2.2 - Supra-threshold strategy………………………………………..36 2 3.2.3 - Threshold strategy……………………………………………….38 3.2.3.1 - Full threshold, Fastpac and SITA………………………….38 3.2.3.2 - 30-2, 24-2 and 10-2 stimulus distributions…………………41 3.3 - Interpretation of results……………………………………………...42 3.3.1 - Reliable indices………………………………………………….42 3.3.2 - Global indices……………………………………………………44 3.3.3 - Glaucomatous changes and progression analysis……………..47 3.4 - Variability of visual field results………………………………………52 3.5 - Factors related with variability………………………………………..53 3.5.1 - Test parameters …………………………………………………..53 3.5.2 - Patient dependent factors………………………………………...54 4. The pupil……………………………………………………………57 4.1 - Pupillary reflexes………………………………………………………...57 4.2 –Control systems of pupil reaction ………………………………………58 4.3 - Factors affecting pupil size ………………………………………..........60 5. Vigilance……………………………………………………………62 5.1 - Definition ………………………………………………………………..62 5.2 - Measurements of vigilance………………………………………………62 5.2.1 - Subjective measurements………………………………………….62 5.2.2 - Objective measurements…………………………………………..63 5.2.2.1- Electroencephalogram (EEG)……… ……………………......63 5.2.2.1.1- EEG activities related to vigilance………………………64 5.2.2.1.2 - Sleepiness measurement…………………………………65 5.2.2.2 - Pupillography ………………………………………………….66 3 5.2.2.2.1 - Spontaneous pupillary oscillations in the dark………...66 5.2.2.2.2 - Spontaneous pupillary oscillations in the light………...68 5.2.2.2.3 - Development of pupillary parameters………………….68 5.2.2.3 - Comparison between EEG and pupillography………………71 5.3 - Vigilance and perimetric examinations………………………………...72 5.3.1 – Pupil perimetry……………………………………………………..72 5.3.2 - Pupil derived vigilance index ………………………………………75 5.3.3 - Wavelet analysis …………………………………………………….76 6. Optic nerve head …………… …………………………………….81 6.1 Anatomy of the normal optic nerve head (ONH)………………………...81 6.1.1 Structure of ONH……………………………………………………..81 6.1.2 Blood supply to ONH…………………………………………………83 6.1.3 Autoregulation of blood-flow in ONH……………………………….84 6.2 Morphological changes of ONH in glaucoma…………………………….85 6.2.1. Optic disc size………………………………………………………...86 6.2.2. Neuroretinal rim……………………………………………………..89 6.2.3. Retinal nerve fibre layer……………………………………………..91 6.2.4. Parapapillary atrophy……………………………………………….92 6.2.5. Disc haemorrhage……………………………………………………93 6.3 Mechanisms of glaucomatous damage in ONH…………………………..94 6.4 Blood flow and oxygenation measure in ONH and related changes in glaucoma …………………………………………………………………………..97 6.4.1 Measure with Doppler techniques …………………………………..97 6.4.2 Measure with Multispectral imaging ……………………………….98 4 7. Identifying the state of attention during perimetry with pupil dynamics and EEG data……………………………………………101 Contributions………………………………………………………………….101 Publication …………………………………………………………………....101 Abstract………………………………………………………………………...102 7.1 Introduction………………………………………………………………..103 7.2 Methods…………………………………………………………………….104 7.2.1 - Subjects……………………………………………………………....104 7.2.2 - Experimental apparatus……………………………………………105 7.2.3 - Experimental procedures…………………………………………..107 7.2.4 - Data analysis………………………………………………………..108 7.2.4.1 - Pupil data……………………………………………………..108 7.2.4.2 - EEG data……………………………………………………...109 7.2.4.3 - Correlation between pupil and EEG data…………………..111 7.2.4.3.1. Relationships with long term sampling………………..111 7.2.4.3.2. Relationships with short term sampling………………111 7.2.4.4 - Threshold variability………………………………………...114 7.2.4.5 - Correlation between pupil and threshold sensitivity………116 7.3. Results …………………………………………………………………….116 7.3.1 - Threshold sensitivity………………………………………………116 7.3.2 - Pupillary changes………………………………………………….117 7.3.3 - Correlation between pupil dynamics and EEG data……………118 7.3.3.1. Relationships between pupil size and EEG spectral amplitude with long term sampling (1minute)……………………………………………..118 7.3.3.2. Relationships between pupil size and EEG spectral amplitude with short term sampling (2 s)………………………..........................................119 7.3.3.3. PFW amplitude and EEG spectral amplitude with long term sampling (1minute) ……………………………………………………………...121 5 7.3.3.4. PFW amplitude and EEG spectral amplitude with short term sampling (2 s)……………………………………………………………………..122 7.3.3.5. Summary of correlation between pupil dynamics and EEG activity ……………………………………………………………………………124 7.3.4 - Correlation between pupil dynamics and threshold sensitivity...124 7.3.4.1. Pupil size parameters and threshold sensitivity variability..124 7.3.4.1.1. Mean pupil size and threshold variability……………...124 7.3.4.1.2. Slope of pupil size and threshold variability…………...125 7.3.4.1.3. Cumulative miosis and threshold variability…………..126 7.3.4.2. PFW amplitude and threshold variability…………………..127 7.3.4.3. Summary of the relationship between pupil dynamics and threshold variability……………………………………………………………...128 7.4. Discussion.…………………………………………………………………128 7.4.1 - Pupillary changes and EEG activity………………………………128 7.4.2 - Vigilance loss and test-retest threshold variability……………….131 8. Blink frequency and duration during perimetry and their relationship to test-retest threshold variability…………………...133 Contribution…………………………………………………………………..133 Publication……………………………………………………………………133 Abstract……………………………………………………………………….134 8.1 Introduction……………………………………………………………….135 8.2 Methods……………………………………………………………………136 8.2.1 Subjects………………………………………………………………136 8.2.2 Apparatus……………………………………………………………137 8.2.3 Experimental tasks…………………………………………………..137 8.2.4 Data analysis…………………………………………………………138 8.3 Results……………………………………………………………………..139 6 8.3.1 Blink characteristics………………………………………………...139 8.3.2 Blinks and stimulus presentation…………………………………..141 8.3.3 Correlation between blink parameters and threshold variability..144 8.3.4. Blinks during stimulus presentation………………………………145 8.4. Discussion…………………………………………………………………146 9. Diagnostic performance of visual field test using subsets of the 24- 2 test pattern for early glaucomatous field loss…………………...150 Contribution…………………………………………………………………..150 Publication…………………………………………………………………….150 Conferences…………………………………………………………………...150 Abstract………………………………………………………………………..151 9.1 Introduction……………………………………………………………….152 9.2 Methods……………………………………………………………………155 9.3 Results……………………………………………………………………..158 9.3.1 Visual field test performance……………………………………….158 9.3.2. Characteristics of visual field defects detected with PPV-optimized locations…………………………………………………………………………..161 9.3.3. Estimated test time for subsets of 24-2 pattern………………….162 9.4 Discussion…………………………………………………………………162 10. Spatial patterns of central visual field loss in proliferative diabetic retinopathy and related changes after Optos®-guided Pascal® laser treatment……………………………………………..167 Contribution…………………………………………………………………..167 Publication…………………………………………………………………….167 Conferences…………………………………………………………………...167 Abstract………………………………………………………………………...168 7 10.1 Introduction………………………………………………………………169 10.2 Materials and methods…………………………………………………..172 10.3 Results…………………………………………………………………….178 10.4 Discussion…………………………………………………………………184 11. Changes in the differential light absorption of optic nerve head in glaucoma with reduction of IOP………………………………...188 Contribution………………………………………………………………….188 Conferences…………………………………………………………………..188 Abstract……………………………………………………………………….189 11.1 Introduction……………………………………………………………...190 11.2 Methods…………………………………………………………………..193 11.3 Results……………………………………………………………………200 11.4 Discussion………………………………………………………………..205 12. Summary and Conclusions……………………………………..210 Appendix……………………………………………………...……..214 References…………………………………………………………...216 8 List of Tables Table 9.1 - Test duration of SITA standard visual field test ……………………..153 Table 9.2 - Areas under the ROC curve (AUROC) for the optimized and randomized patterns (R1-R5) and the p-value of the difference………………………….........160 Table 9.3 - Test time estimated for variable subsets of 24-2 test pattern…………162 Table 10.1 - Study major inclusion and exclusion criteria………………………..173 Table 10.2 - Modified Airlie House classification of proliferative diabetic retinopathy………………………………………………………………...177 Table 11.1 - Exposure time for each monochromatic image at different wavelengths………………………………………………………………..196 Table 11.2
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