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The evaluation of multiple sclerosis through static chromatic perimetry Kozak, John François 1987

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THE EVALUATION OF MULTIPLE SCLEROSIS THROUGH STATIC CHROMATIC PERIMETRY by JEAN FRANCOIS KOZAK B.A., THE UNIVERSITY OF BRITISH COLUMBIA, 1975 M.A., THE UNIVERSITY OF BRITISH COLUMBIA, 1980 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES Department of Psychology We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA February, 1987 © Jean Francois Kozak, 1987 In presenting t h i s thesis in p a r t i a l fulfilment of the requirements for an advanced degree at the The University of B r i t i s h Columbia, I agree that the Library s h a l l make i t fre e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the Head of my Department or by his or her representatives. It i s understood that copying or publication of this thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of Psychology The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date: February, 1987 i i Abstract The purpose of the present study was to examine whether or not luminance thresholds through s t a t i c , chromatic perimetry could be used to distinguish v i s u a l threshold losses in multiple s c l e r o s i s from that of normal functioning. It was proposed that threshold losses would be greater at both the fovea and near foveal e c c e n t r i c i t i e s due to the assumption that the cone system, unlike the rods, would be the most effected by MS. Twenty-two MS patients and t h i r t y age matched normals were tested on an extensively modified version of the Fieldmaster F225 Automatic Perimeter. Thresholds were established for an achromatic, red, and blue stimulus along a 195 - 15 degree meridian. Testing was done using a 45 apostilb background, to which the subjects were preadapted prior to testing. Results indicated that there was extensive cone involvement (loss in chromatic thresholds) for the MS subjects. S i g n i f i c a n t differences existed at the fovea between normal and c l i n i c a l l y d e f i n i t e subjects but not between normal and probable. Correlational analyses indicated great functional changes in r e t i n a l s e n s i t i v i t y for the MS patients. Similar results were obtained between MS patients with and without optic n e u r i t i s . Discriminant analyses indicated that the red f i l t e r could c o r r e c t l y c l a s s i f y 86.27% of the normals and MS patients with few false positives or negatives. Log threshold difference values between the fovea and 30 degree nasal e c c e n t r i c i t y were used to determine a threshold value which could separate normal p r o f i l e s from MS p r o f i l e s . The t y p i c a l "swiss cheese" defects reported in the c l i n i c a l l i t e r a t u r e were found only for the achromatic and blue f i l t e r s . No irregular p r o f i l e s were found for the red f i l t e r . A possible t h e o r e t i c a l model based on the results was discussed. Limitations of the study as well as possible future research were also discussed. iv TABLE OF CONTENTS Abstract i i Table of Contents iv L i s t of Tables v i i L i s t of Figures xi Acknowledgement xiv I. Introduction 1 A. Symptomatology 3 B. Disease Onset 11 C. Mode of Onset 16 D. Motor/Brain Stem Involvement 19 1 . Nystagmus 20 2. Smooth Eye Movement 21 E. Sensory Involvement 22 1 . General 22 2. Specific 25 3. Psychophysical Assessment of MS 29 F. Visual Evoked Potentials 30 1 . Technique 30 2. Application 32 3. Modifications 36 G. Spatial Contrast S e n s i t i v i t y 43 1 . Technique 43 2. Application . 46 H. Temporal Contrast S e n s i t i v i t y 47 1 . Technique 47 2. Application 48 I. Colour Vision 55 1. Systems of C l a s s i f i c a t i o n 56 2. Assessment of Colour Vision 68 3. Application 75 J. Perimetry 83 1. Chromatic Perimetry 88 2. Threshold Estimation 89 3. Adaptation 94 4. Spatial Summation 101 5. Application 105 6. Hypothesis 114 II. Instrumentation • 118 1 . Apparatus 118 2. Physical Specifications 118 3. Control Functions 119 4. Stimulus Charac t e r i s t i c s and Presentation 126 5. Background Luminance 133 6. Threshold Estimation 137 7. Instrumental Modifications ..144 III . P i l o t Study 150 1 . Purpose 150 2. Subjects 150 3. Method 151 4. Results and Discussion 153 v i 5. Modification to Adaptation 159 IV. Study 164 1 . Subjects 1 64 2. Procedure 165 3. Results 173 V. Discussion 224 VI. Summary 250 Bibliography 253 VII. Appendix A 284 1. Power Supply .....285 2. Instrument Shell 287 VIII. Appendix B 300 IX. Appendix C 303 1 . Contents 304 X. Appendix D 305 1 . Contents 306 XI . Appendix E 307 1 . Contents 308 XII . Appendix F 309 1. Computer Interface 310 XIII . Appendix G 311 v i i L i s t of Tables Table 1. Major Symptoms Found During The Course Of MS 12 Table 2. Early Symptoms Found In MS 17 Table 3. Neuro-Ophthalmological Findings In MS And Non-MS Patients 27 Table 4. Percentage Of MS Patients With Abnormal VEP's 34 Table 5. Distinguishing Features Of The Major Colour Defects 63 Table 6. Neutral Colour Area Of Patient Groups As Determined By The Gunkel Chromograph 82 Table 7. Factors Ef f e c t i n g Perimetry 92 Table 8. Colorimetric S p e c i f i c a t i o n Of F225 F i l t e r s 127 Table 9. Scalar Values For Obtaining Thresholds 1 54 Table 10. Threshold Values (Apostilb) For MS Patients By E c c e n t r i c i t y And F i l t e r For A 5 Apostilb Background 1 56 Table 11. Foveal Threshold Values (Apostilb) For MS Patients During Adaptation 161 Table 12. Mean and Standard Deviation For Subjects Categories By Age (Years) 166 Table 13. Diagnostic Demographics Of Subjects 167 Table 14. Duration (Years) From Diagnosis 168 v i i i Table 15. Mean And Standard Deviations For Threshold Values (Apostilbs) By E c c e n t r i c i t y And Group For The Achromatic F i l t e r 174 Table 16. Mean And Standard Deviations For Threshold Values (Apostilbs) By E c c e n t r i c i t y And Group For The Red F i l t e r 175 Table 17. Mean And Standard Deviations For Threshold Values (Apostilbs) By E c c e n t r i c i t y And Group For The Blue F i l t e r 176 Table 18. Mean And Standard Deviations For Threshold Values (Apostilbs) By E c c e n t r i c i t y And Group For The Achromatic F i l t e r 1 77 Table 19. Mean And Standard Deviations For Threshold Values (Apostilbs) By E c c e n t r i c i t y And Group For The Red F i l t e r 1 78 Table 20. Mean And Standard Deviations For Threshold Values (Apostilbs) By E c c e n t r i c i t y And Group For The Blue F i l t e r 179 Table 21. Multivariate Analysis Of Variance Between Normals (n=30), C l i n i c a l l D e f i n i t e (n=14), And Probable (n=8) MS Patients 190 Table 22. Mean Thresholds (Apostilbs) For Normals (n=30), C l i n i c a l l y D e f i n i t e (n=14), And Probable (n=8) MS Patients Across F i l t e r s and E c c e n t r i c i t i e s 1 92 Table 23. Absolute Mean Threshold Difference (Apostilbs) For Normals (n=30), C l i n i c a l l y Definite (n=14), And Probable (n=8) MS Patients Across F i l t e r s and E c c e n t r i c i t i e s 1 93 Table 24. Absolute Mean Threshold Difference (Apostilbs) For Normals (n=30), C l i n i c a l l y Definite (n=14), And Probable (n=8) MS Patients Across F i l t e r s 195 ix Table 25. Mean Thresholds (Apostilbs) For A l l Groups And F i l t e r s By E c c e n t r i c i t y 196 Table 26. Absolute Mean Threshold Difference (Apostilbs) By E c c e n t r i c i t y Across Groups And F i l t e r s 197 Table 27. Absolute Mean Threshold Difference (Apostilbs) Between F i l t e r s By E c c e n t r i c i t y 199 Table 28. Absolute Mean Threshold Difference (Apostilbs) Between Groups By E c c e n t r i c i t y 201 Table 29. Absolute Mean Threshold Difference (Apostilbs) Between Groups By E c c e n t r i c i t y For The Achromatic F i l t e r 203 Table 30. Absolute Mean Threshold Difference (Apostilbs) Between Groups By E c c e n t r i c i t y For The Red F i l t e r 204 Table 31. Absolute Mean Threshold Difference (Apostilbs) Between Groups By E c c e n t r i c i t y For The Blue F i l t e r 205 Table 32. Correlations Between The Fovea And E c c e n t r i c i t i e s By Group For The Achromatic F i l t e r 208 Table 33. Correlations Between The Fovea And E c c e n t r i c i t i e s By Group For The Red F i l t e r 209 Table 34. Correlations Between The Fovea And E c c e n t r i c i t i e s By Group For The Blue F i l t e r 210 Table 35. Multivariate Analysis Of Variance Between Optic Neuritis (n=14) And Non Optic Neuritis (n=8) MS Patients 213 X T a b l e 36. A b s o l u t e Mean T h r e s h o l d D i f f e r e n c e ( A p o s t i l b s ) For O p t i c N e u r i t i s And Non O p t i c N e u r i t i s MS P a t i e n t s By F i l t e r 214 T a b l e 37. Mean T h r e s h o l d s ( A p o s t i l b s ) For O p t i c N e u r i t i s And Non O p t i c N e u r i t i s MS P a t i e n t s A c r o s s F i l t e r s By E c c e n t r i c i t y 216 T a b l e 38. A b s o l u t e Mean T h r e s h o l d D i f f e r e n c e ( A p o s t i l b s ) By E c c e n t r i c i t y A c r o s s O p t i c N e u r i t i s P a t i e n t s and Non O p t i c N e u r i t i s P a t i e n t s And F i l t e r s 217 T a b l e 39. Mean T h r e s h o l d s ( A p o s t i l b s ) For O p t i c N e u r i t i s And Non O p t i c N e u r i t i s MS P a t i e n t s By F i l t e r s And E c c e n t r i c i t y 218 T a b l e 40. A b s o l u t e Mean T h r e s h o l d ( A p o s t i l b s ) D i f f e r e n c e By Between F i l t e r s By E c c e n t r i c i t y 219 T a b l e 41. P e r c e n t C l a s s i f i c a t i o n Of S u b j e c t s By D i a g n o s i s (Normal VS. MS) And F i l t e r s 221 L i s t of Figures Figure 1. Charcot's Triad OF MS 5 Figure 2. Formation Of Myelin Sheath 7 Figure 3. VEP From Foveal Stimulation With A Red And Achromatic Source 42 Figure 4. Contrast S e n s i t i v i t y For Sine Wave 44 Figure 5. Delay Campimetry F i e l d s On A MS Patient 51 Figure 6. Impaired Temporal S e n s i t i v i t y F i e l d s In A Normal And MS Patient 53 Figure 7. Confusion Loci, Centre Of Confusion, And Neutral Axes For Dichromats 65 Figure 8. Colorimetric Information On Anomaloscope Equations Based Upon The P-N Anomaloscope 71 Figure 9. Discrimination Losses On The FM 100-Hue Of The Major Colour Vision Defects 76 Figure 10. Effect Of Fatigue On FM 100-Hue Error Scores For An MS Patient (Affected Versus Unaffected Eye). 79 Figure 11. Isopter And P r o f i l e Perimetry Plots In Relation To The Retina 86 Figure 12. Achromatic Thresholds At 0 Asb Background For 4 Monochromatic Lights 96 Figure 13. Stat i c Thresholds For Fu l l y Photopic, Mesopic, And Fully-Scotopic Conditions 98 x i i Figure 14. Standard Relative Spectral Luminous E f f i c i e n c y Functions For Photopic And Scotopic Vision 99 Figure 15. Static Thresholds (45 - 225) Of The Right Eye (asymptomatic) Of An MS Patient 107 Figure 16. Mesopic And Photopic Thresholds For An MS Patient 111 Figure 17. Thresholds Of Colours Generated On A Television Screen For Normals And MS Patients (Affected And Unaffected Eyes) 112 Figure 18. F225 Control Panel 120 Figure 19. Alignment Of Subject 123 Figure 20. C.I.E. Chromaticity Coordinates For The F225 Chromatic F i l t e r s 129 Figure 21. Transmittance Values Of F225 F i l t e r s 130 Figure 22. Bowl Position And Background Luminance 135 Figure 23. Bowl Positions Measured By The Pritchard Photometer 136 Figure 24. Threshold Testing Algorithm 141 Figure 25. Static Threshold Provided By The Fieldmaster F225 Sales Brochure 1 45 Figure 26. Replicated Fiedmaster F225 Threshold P r o f i l e 146 Figure 27. 195 - 15 Test Threshold P r o f i l e 152 x i i i Figure 28. S e n s i t i v i t y Gradients For MS Subjects At 5 Apostilb Background 157 Figure 29. S e n s i t i v i t y Gradients For A Normal Subject At 5 Apostilb Background 158 Figure 30. S e n s i t i v i t y Gradients For Normal, C l i n i c a l l y D e f i n i t e , And Probable MS Subjects For An Achromatic F i l t e r At 45 Apostilb Background 180 Figure 31. S e n s i t i v i t y Gradients For Normal, C l i n i c a l l y D e f i n i t e , And Probable Subjects For A Red F i l t e r At 45 Apostilb Background 181 Figure 32. S e n s i t i v i t y Gradients For Normal, C l i n i c a l l y D e f i n i t e , And Probable Subjects For A Blue F i l t e r At 45 Apostilb Background 182 Figure 33. S e n s i t i v i t y Gradients For Optic N e u r i t i s And Non-Optic Neuritis Subjects For An Achromatic F i l t e r At 45 Apostilb Background 183 Figure 34. S e n s i t i v i t y Gradients For Optic Neuritis And Non-Optic Neuritis Subjects For A Red F i l t e r At 45 Apostilb Background 184 Figure 35. S e n s i t i v i t y Gradients For Optic Neuritis And Non-Optic Neuritis Subjects For A Blue F i l t e r At 45 Apostilb Background 185 Figure 36. S e n s i t i v i t y Gradients For A MS Patient 186 Figure 37. S e n s i t i v i t y Gradients For A Normal Subject 187 xiv Acknowledgement This study i s dedicated to my mother Ida Kozak. I would l i k e to express my gratitude to Drs. R. Lakowski, D.J. Crockett, S. Coren and S.M. Drance for th e i r assistance and guidance. I would especially l i k e to single out Dr. R. Lakowski for his assistance and guidance throughout my academic studies and the time and insights he gave to my research. I would also l i k e to thank Dr. Crockett, for without his help t h i s study would have taken longer, i f ever, to complete. I wish to acknowledge the following external reviewers for their comments and suggestions: Dr. A. Eisen (Professor and Associate Dean of Research, Faculty of Medicine, U.B.C); Dr. D.J. MacFadyen (Professor and Head, Department of C l i n i c a l Neurological Sciences, University of Saskatchewan); Dr. D.N. Paty (Professor and Director, Department of Neurological Sciences, U.B.C); and Dr. R. Wong (Professor, Department of Psychology, U.B.C). I would also l i k e to thank Ms. K. Eisen of the MS C l i n i c , Acute Care Hospital, and Ms. Mo Gupta, Mr. D.R. Drysserinck and Mr. K. Wijsman of the Eye Care C l i n i c , Acute Care Hospital for their help in the scheduling of the patients. F i n a l l y , I would l i k e to express my appreciation of the patients who gave their time and e f f o r t throughout the various phases of t h i s study. 1 I . INTRODUCTION M u l t i p l e s c l e r o s i s h a s p r e s e n t e d b o t h r e s e a r c h e r s a n d c l i n i c i a n s w i t h e n o r m o u s p r o b l e m s i n d e t e c t i n g e a r l y o n s e t a s w e l l a s i n u n d e r s t a n d i n g t h e c o u r s e ( s ) o f t h e d i s e a s e . T r e a t m e n t a t p r e s e n t i s s y m p t o m a t i c . D e s p i t e i t s i d e n t i f i c a t i o n o v e r 100 y e a r s a g o , t h e p r o t e a n m a n n e r i n w h i c h m u l t i p l e s c l e r o s i s may p r e s e n t i t s e l f h a s m a d e i t d i f f i c u l t t o d e v e l o p a n a c c u r a t e c l i n i c a l d e s c r i p t i o n o f i t s f e a t u r e s ; a n d , t h e r e f o r e , c r e a t e d d i f f i c u l t y i n c o n d u c t i n g r e s e a r c h s u c h a s o n t h e e p i d e m i o l o g y o f t h e d i s e a s e . S y m p t o m a t i c a l l y , t h e p a t i e n t m a y e x h i b i t m o t o r i m p a i r m e n t a s w e l l a s l o s s e s i n o n e o r m o r e s e n s o r y m o d a l i t i e s . B o t h m o t o r a n d s e n s o r y i m p a i r m e n t m a y a p p e a r a l o n e o r i n s o m e c o m b i n a t i o n . I n a d d i t i o n , t h e s e v e r i t y a n d p r o g r e s s i o n o f t h e ' d i s e a s e ' i s s o v a r i a b l e t h a t o n e m a y a c t u a l l y h a v e s e v e r a l c l i n i c a l d i s e a s e s t h a t a r e t o o d i f f i c u l t t o d i f f e r e n t i a t e - a n a r g u m e n t s e e n i n s c h i z o p h r e n i a . O n e p r o m i n e n t a r e a o f i n v o l v e m e n t i n MS a p p e a r s t o b e t h a t o f t h e s e n s o r y s y s t e m , e s p e c i a l l y t h e v i s u a l . N o n - i n v a s i v e p r o c e d u r e s f o r d i a g n o s i n g t h e d i s e a s e r e l y u p o n t h e d e t e c t i o n o f a b n o r m a l i t i e s i n t h e s e n s o r y s y s t e m o f i n t e r e s t . A m a j o r a s s e s s m e n t p r o c e d u r e , a p a r t f r o m p o s t m o r t e m e x a m i n a t i o n o r c l i n i c a l p r o c e d u r e s s u c h a s e l e c t r o p h o r e s i s , 2 i s t h e v i s u a l e v o k e d p o t e n t i a l . A b n o r m a l i t i e s i n t h e v i s u a l s y s t e m d u e t o MS t e n d t o a p p e a r i n t h e e v o k e d p o t e n t i a l a s a r e d u c t i o n i n a m p l i t u d e o r g r e a t e r l a t e n c y . A l t h o u g h o t h e r m e t h o d s a r e c u r r e n t l y b e i n g s t u d i e d f o r a s s e s s i n g v i s u a l i n v o l v e m e n t , i t i s t h e w r i t e r ' s b e l i e f t h a t t h e y p r o v i d e a m b i g u o u s r e s u l t s . The p u r p o s e o f t h e f o l l o w i n g l i t e r a t u r e r e v i e w i s t o d e m o n s t r a t e t h a t t h e v i s u a l f u n c t i o n t e s t s c u r r e n t l y e m p l o y e d t e n d t o i g n o r e o r c o n f u s e t h e s p e c i f i c c o n t r i b u t i o n s o f t h e m a c u l a a n d p e r i p h e r a l r e t i n a i n r e v e a l i n g MS r e l a t e d f u n c t i o n a l l o s s e s . B o t h t h e m a c u l a a n d p e r i p h e r a l r e t i n a a r e a f f e c t e d i n M S , w i t h c o n e f u n c t i o n i n g p o s s i b l y b e i n g a f f e c t e d t h e e a r l i e s t a n d more s e v e r e l y t h a n t h e r o d s . B e c a u s e o f t h e a p p a r e n t s e n s i t i v i t y o f t h e o p t i c n e r v e t o d e m y e l i n a t i o n , i t i s p r o p o s e d t h a t by e x a m i n i n g r e t i n a l f u n c t i o n i n g t h r o u g h c h r o m a t i c p e r i m e t r y one may u n d e r s t a n d t h e e f f e c t s o f d e m y e l i n a t i o n on t h e v i s u a l s y s t e m ( r e t i n a ) a s w e l l a s p o s s i b l y p r o v i d e a m e t h o d f o r a s s e s s i n g b o t h t h e p r e s e n c e a n d s e v e r i t y o f M S . 1. M U L T I P L E S C L E R O S I S M u l t i p l e s c l e r o s i s i s a r e m i s s i v e l y p r o g r e s s i v e d i s e a s e c h a r a c t e r i z e d by t h e p r e s e n c e o f p l a q u e s i n t h e c e n t r a l n e r v o u s s y s t e m . I t i s m u l t i - f o c a l i n n a t u r e a n d a p p e a r s t o a f f e c t , o r a t l e a s t be s y m p t o m a t i c i n m a l e s a n d f e m a l e s b e t w e e n t h e a g e s o f 10 a n d 5 0 , w i t h f e m a l e s b e i n g a f f e c t e d 3 1.7:1 times more than males. Prevalence rates for multiple s c l e r o s i s are higher in the northern latitudes and comparably rare in A s i a t i c countries. The risk for contracting multiple s c l e r o s i s i s said to be four times greater for those l i v i n g in metropolitan centres than small towns, higher for professional or managerial groups than u n s k i l l e d workers, higher for Caucasians than n e g r o i d s , f i f t e e n to twenty times greater for f i r s t degree r e l a t i v e s of multiple s c l e r o s i s victims. Multiple s c l e r o s i s i s also more l i k e l y to be manifested in individuals with a history of infectious diseases. Apart from infections, some of the myriad of factors f e l t to either p r e c i p i t a t e or aggravate multiple s c l e r o s i s have been trauma, pregnancy, emotional stress, vaccination and/or innoculation, menstruation, temperature changes, and fatigue. Aetiology of the disease has, at one time or another, been ascribed to a latent virus which may or may not lead to an anti-immunal myelin response, to the presence of histocompatibility antigens (HLA) [related to four l o c i on chromosome number six] as well as diet (saturated fats) and climate. A. SYMPTOMATOLOGY The f i r s t account of multiple s c l e r o s i s (MS) appears to be that of Augustus d'Este' (1830) who prepared a di s s e r t a t i o n on the progression of the disease in himself, preceding the 4 personal insights provided by Lumsden (1970) some one hundred years. Although Carswell in 1838 and Cruveilhier (1835-1842) are attributed with demonstrating the presence of lesions in the central nervous system, i t i s Charcot (1868) who i s generally accredited with the f i r s t c l i n i c a l description of the syndrome known as MS or disseminated s c l e r o s i s ( F i e l d , 1977). Charcot f e l t that MS did not occur prior to the age of fourteen and after f i f t y - a b e l i e f s t i l l held today despite evidence to the contrary (eg. Friedman & Davison, 1945; E l i a n , 1977; F i e l d , S i n c l a i r & Swank, 1980; Bejar, Dewey & Ziegler, 1984). His description of the c y c l i c a l (remission-progression) nature of the symptoms, the presence of plaques in r e l a t i o n to either sensory and/or motor disturbances as well as the problematic presence of silent cases (asymptomatic) i s so complete that many feel that very l i t t l e has been added since. ( F i e l d , 1977). Of p a r t i c u l a r importance are those diagnostic signs t y p i c a l l y referred to as Charcot's Triad of Multiple Sclerosis (Figure 1) (Newell, 1978). According to Charcot, MS i s characterized by the presence of nystagmus, optic atrophy (optic n e u r i t i s ) and scanning speech (slow, pressured speech). The importance of t h i s t r i a d l i e s in the fact that the majority of i t s symptoms involve the v i s u a l system, indicating, as indeed is the case, that the v i s u a l system appears to be highly sensitive to the demyelinative ef f e c t s of MS. OPTIC ATROPHY NYSTAGMUS (JERK & VESTIBULAR) , SCANNING SPEECH FIGURE 1 CHARCOT'S TRIAD OF MULTIPLE SCLEROSIS 6 Multiple s c l e r o s i s i s believed to be the result of central nerve fiber demyelination (Lumsden, 1970; McAlpine, Lumsden & Acheson, 1972) as well as possible vascular changes in regions such as the retina (Lumsden, 1970; Bervoets & De Lact, 1984), loss of oligodendrogliocytes and increase in fibrous astrocytes (McDonald, 1974). 1 Through unknown mechanisms, possibly by immunal responses to viruses wherein lymphocytes and macrophages invade the brain and attack the myelin, the myelin sheath surrounding the axon of a central nerve f i b r e swells and fragments (Lumsden, 1970; McDonald, 1974). The destroyed sheath i s replaced by a s c l e r o t i c plaque, a scar r e s u l t i n g from the p r o l i f e r a t i o n of g l i a l c e l l s around the axon (Lumsden, 1970). It i s thought that symptoms c h a r a c t e r i s t i c of MS are the result of an i n a b i l i t y of such plaques to conduct impulses along the axon. 1 Myelin, f i r s t discovered by Leeuwenhoek in 1717, consists of a plasma membrane deposited by Schwann c e l l s (Figure 2). The myelin sheath i s the result of a membrane of the Schwann c e l l f i r s t forming a "flattened sheet" that envelops the axon. The Schwann c e l l then rotates around the axon u n t i l several layers of a conductive l i p i d known as sphingomyelin i s deposited. It is t h i s l i p i d that increases the resistance to ion flow almost 5,000 f o l d and decreases capacitance by 1,000 f o l d (Guyton, 1981). An unmyelinated area between the junction of two adjacent Schwann c e l l s where ions may flow e a s i l y between the e x t r a c e l l u l a r f l u i d and the axon i s known as the node of Ranvier. The function of such nodes i s to allow saltatory conduction wherein a neuronal signal jumps along a f i b e r . Although the nodes of Ranvier are unmyelinated, they are covered with a conductive membrane that surrounds the axon underneath the myelin. The function of t h i s nodal (high potassium channels) and internodal (high sodium channels) axon membrane i s presently unclear, but is f e l t to play a major role in specifying which areas of the axon w i l l become myelinated (Waxman & Foster, 1980). Schwann celt nucleus Layers of Schwann cell membranes ( Myelin sheath) FIGURE 2 FORMATION OF MYELIN SHEATH IN THE PERIPHERAL NERVOUS SYSTEM. MODIFIED FROM GUYTON ( 1 9 8 1 , p .116 ) 8 After a period of time, slow conduction within demyelinated neurons returns and the neurons begin to function on a p r i n c i p l e similar to the conduction method reported in unmyelinated axons (Smith, Blakemore & McDonald, 1981). This resumption of signal processing i s f e l t to be responsible for the remitting nature of the disease. In addition, signal conduction in damaged neurons may also result from p a r t i a l remyelination - the synthesis of myelin by undamaged oligodendroglial c e l l s (Morell & Norton, 1972). 1 This process is a limited one in that oligodendroglial c e l l s are not capable of increasing in size and are therefore unable to remyelinate plaques of any s i g n i f i c a n t s i z e . The process described above regarding demyelination i s based on neuropathological models involving the peripheral nervous system. Moreover, the normal formation of myelin discussed e a r l i e r and shown in Figure 2 represents only that which i s believed to occur in the peripheral nervous system. The involvement of the central nervous system with respect to myelin damage and neural functioning as seen in MS i s 1 It has recently been postulated that the remitting cycle of the disease may be due to an intermittent disruption in the opening of the blood/brain b a r r i e r , allowing some myelinolytic factor to enter the brain (Barrett, Drayer and Shin, 1985). Increased permeability of the endothelial c e l l s comprising the barrier has been shown to exist for various infectious diseases such as herpes simplex encephalitis as well as psychophysiologic states such as hypertension (Fishman, 1980). Although the findings regarding permeability changes in the barrier are controversial and have been conducted on lower animals such as rats, the transient transportation of macromolecules across the endothelial c e l l s have been observed in MS patients (Fishman, 1980). 9 s t i l l not completely understood* According to Hashimoto and Paty (1986) the pathological changes found in MS, both in the peripheral and central nervous systems, follow a r e l a t i v e l y consistent pattern: inflammation, oedema and swelling, demyelination, and g l i o s i s . However, the s i t e and degree of neural involvement as well as symptomatic expression may vary considerably from patient to patient. The authors state that the e a r l i e s t symptomatic lesion found " i n MS i s probably inflammatory." (Hashimoto & Paty, p.539). Whether or not v i r a l in aetiology, the inflammation leads to oedema and swelling at the neural s i t e involved. At t h i s point, i f the symptoms of oedema and swelling continue, demyelination may occur. As noted by Hashimoto and Paty, i t is s t i l l unclear whether demyelination results from the loss of either myelin or oligodendrocytes. If the pathological process i s halted, p a r t i a l and/or complete remyelination may occur - as has been demonstrated in the peripheral nervous system. If the process continues, however, the f i n a l stage of g l i o s i s i s reached. At th i s stage, inflammation and oedema tend to decrease as plaques form and age (Hashimoto & Paty, 1986). The increase of astrocytes ( g l i o s i s ) at the s i t e s involved result eventually in the formation of f i b r a l patterns (scars) along the axons. No remyelination i s believed to be possible once g l i o s i s occurs and the plaques mature. 10 It has recently been argued that demyelination does not involve destruction of Schwann c e l l s as was previously assumed ( Sumner, 1985). Instead, work with a l i p i d antigen c a l l e d galactocerebroside, which causes conduction blocks similar to MS, has led to the speculation that demyelination requires an intact Schwann c e l l . An insult of a Schwann c e l l due to some pathogen causes the c e l l to release endogenous proteases within the folds of the myelin sheath. The protease causes l y s i s of the membrane, leading to conduction block. It i s the response of an intact Schwann c e l l (creation of protease) that causes the demyelination. Destruction of the Schwann c e l l would preclude any demyelination from occurring. Despite Charcot's over-encompassing use of the term demyelination there appear to be two d i s t i n c t types of demyelination: (1) involving damage to a l l parts of the axon except the d i s t a l part of the nerve f i b r e and (2) the Wallerian type involving a l l of the fibr e (McDonald, 1974). Presumably, some a b i l i t y to conduct an impulse exists in the f i r s t type of degeneration. This in turn raises the question as to whether the conduction block experienced in MS (eg. Donny-Brown & Brenner, 1944: Morgan-Hughes, 1968; Ochoa, Fowler & G i l l i a t t , 1972; Smith, Blakemore & McDonald, 1981) results not from the i n a b i l i t y to excite demyelinated areas, but instead, as a result of an "impedance mismatch" between normal and demyelinated areas (Sears, Bostock & Sherratt, 1978; Waxman, 1978). 11 B. DISEASE ONSET Multiple s c l e r o s i s i s c l a s s i c a l l y characterized by two phases, which are (1) attack and (2) remission. The attack or relapse phase i s usually episodic in nature and may be either acute or slowly progressive (chronic) with the l a t t e r being c h a r a c t e r i s t i c of about 10% of cases (Fog, 1977). Onset tends to be rapid, usually within minutes or hours (McAlpine et a l . , 1955, 1972) as well as varied according to symptomology. Table 1 provides a summary of the types and frequency of loss generally associated with MS. As i s evident from the table, the frequency varies greatly with the most common type being v i s u a l and motor disturbances. During the acute phase, the symptoms expressed by the patient become severe. The patient tends to remain at t h i s l e v e l for a period of days or weeks u n t i l s/he enters the second stage - that of remission. In remission, the patient experiences a lessening of the symptoms with a possible return to some previous l e v e l of functioning. Although symptoms may fluctuate during t h i s period, the patient's l e v e l of functioning remains r e l a t i v e l y stable u n t i l a relapse occurs. The number of relapses per year may vary greatly (Thygesen, 1953) with no apparent decrease in the relapse rate as the individual ages (Lhermitte, Marteau, Gazengel, Dorda & Deloche, 1973). Furthermore, there does not appear to be a s i g n i f i c a n t c o r r e l a t i o n between the number of relapses and severity of the attack (Fog & Linnemann, 1970). 12 TABLE 1 Major Symptoms Found During the Course of MS Symptoms Kuroiwa e t Kuroiwa e t Poser et F i e l d a l . ( 1 9 8 2 ) 1 a l . ( 1 9 8 2 ) 2 a l . (1978) (1977) (n=488) (n=177) (n=127l) (n=527) V i s u a l 68.7% 63.8% 66.0% 23. 1% D i p l o p i a 26.0 44.6 34.0 -O p t i c A t r o p h y 58.2 57.1 - -Nystagmus 37.5 74.6 - -B a l a n c e or A t a x i a 40.8 79.7 82.0 76.7 3 P a r e s i s - - 88.0 -P a r a e s t h e s i a 60.5 77.4 87.0 -Bowel or B l a d d e r 59.9 69.5 63.0 19.4 ' A s i a n s e r i e s 2 Hungarian s e r i e s 3 C l a s s i f i e d under the g e n e r a l heading of c e r e b e l l a r d y s f u n c t i o n 13 Regarding the acute phase, Kurtzke (1970) reported that patients who experienced an attack prior to the one upon which the diagnosis was made were less affected by the disease than those patients whose onset bout was the diagnostic bout. The one distinguishing feature of the l a t t e r group was the preponderance of motor symptoms. In addition, prognosis appears to be more favourable i f the onset bout i s also characterized by the presence of optic n e u r i t i s (Newell, 1978) - a relationship which w i l l be discussed l a t e r . From the combination of acute and remission phases, there appear to be four general types of disease course (Kraft, C o r y e l l , F r e a l , Hanan & Chitnis, 1979). The f i r s t , the benign course, is found in about 20% of MS patients. It i s of an exacerbation (acute) - remission pattern, where recovery i s almost complete and subsequent exacerbations are mild and r e l a t i v e l y infrequent. Although such patients are not symptom free, they do experience r e l a t i v e l y long stable periods, with l i t t l e or no r e s t r i c t i o n s placed on their physical and/or mental functioning. The second type, the exacerbating - remitting  course, i s characterized by relapses occurring at the rate of one every six months to one every three or four years. Such patients are able to function in an occupation for about twenty years, after which 1 4 the majority develop a remitting - progressive course. The t h i r d type, the remitting - progressive  pattern, i s defined by the presence of one or more attacks followed by periods of t o t a l or p a r t i a l remission. Unlike the benign course, the remitting -progressive course is c y c l i c a l in nature u n t i l the patient reaches a stage where the disease slowly progresses without remission. The fourth type, the progressive course, occurs in a minority of MS patients (about 10%) and i s i d e n t i f i e d by the slow onset of motor weakness. There i s no remission of symptoms, re s u l t i n g in severe d i s a b i l i t y . Although relapse rate tends to be a distinguishing feature of MS, researchers (eg. Fog & Linnemann, 1970; Lhermitte, Marteau, Gazengel, Dirda & Deloch, 1973) have not confirmed Thygeson's (1953) reports that there i s a s i g n i f i c a n t c o r r e l a t i o n between number of relapses and severity of the disease. Despite the apparent a b i l i t y to define the course of MS, c l i n i c i a n s find i t impossible to predict the exact course the disease w i l l take in a patient. In addition, d i f f i c u l t i e s a r i s e with respect to diagnosing the disease at time of onset as well as i t s severity. Numerous c l i n i c a l scales exist for categorizing patients on the basis of mobility (eg. Thygesen, 1949; McAlpine and Compston, 1952; 15 Fog, 1964) or neurological signs ( d i s a b i l i t y ) (eg. Kurtzke, 1961; Alexander, Berkely & Alexander, 1958; Schumacher, Beebe, Ki b l e r , Kurland, Kurtzke, McDowell, Nagler, Sibley, T o u r t e l l o t t e & Willman, 1965; McDonald & Halliday, 1977; Bauer, 1980; Poser, Paty, Scheinberg et a l . , 1983). Although these scales c l a s s i f y patients into categories such as ' c l i n i c a l l y d e f i n i t e ' , 'probable' and 'possible', they d i f f e r on which symptoms are indicative of which category -a c l a s s i f i c a t i o n problem which makes i t d i f f i c u l t to compare results across studies using d i f f e r e n t diagnostic scales. Moreover, differences in c l a s s i f i c a t i o n c r i t e r i a are related to the time at which diagnosis is made. Thus Izquierdo, Hauw, Lyon-Caen, Marteau, Escourolle, Buge, Castaigne and Lhermitte (1985) reported that patients c l a s s i f i e d with Poser's c r i t e r i a were diagnosed s i g n i f i c a n t l y e a r l i e r than with the c l a s s i f i c a t i o n of Bauer. However, there was no difference between c l a s s i f i c a t i o n s for those patients diagnosed as "progressive". Further complicating attempts to study MS i s the presence of s i l e n t cases, those patients who are asymptomatic and are only revealed at autopsy. Georgi (1961) reported that of 66 autopsied cases, 12 unexpectedly had MS. Similar results have been reported by Alter (1962), Castaigne, Lhermitte, Escourolld, Hauw, Gray & Lyon-Caen (1981) and Gilbert & Sadler (1981), revealing the presence of widespread demyelination among asymptomatic patients. Although the death rate among MS patients i s higher than 16 that of the general public, epidemiological studies tend to indicate that over f i f t y percent of MS deaths are due to complications such as pulmonary in f e c t i o n and cardiac disease and therefore may not be detected unless an autopsy i s performed (eg. Leibowitz, Kahana, Jacobson & A l t e r ; 1972). C. MODE OF ONSET As stated e a r l i e r , onset of MS i s extremely variable with symptoms developing over a matter of minutes, hours, days, or weeks. McAlpine et a l . (1955) reported that of 219 confirmed MS patients, 68.4% had symptoms which developed within one week, 22.8% within one year and 8.8% had their symptoms develop progressively over several years. Table 2 provides the findings of several studies reporting the types of early symptoms found amoung MS patients. The majority of symptoms involve the sensory system (eg. paraethesia, optic n e u r i t i s ) with a smaller percent primarily motor in expression. Although i t i s tempting to assume that the type of symptom expressed i s related to the s i t e and extent of the demyelination, such a c o r r e l a t i o n has not been conclusively established ( F i e l d , 1977; Gi l b e r t & Sadler, 1983). Attempts made at establishing the presence of prodromal features unique to MS have been unsuccessful, generally 17 TABLE 2 Early Symptoms Found in MS Symptoms Poser et Kuroiwa et McAlpine Kurtzke et a l . (1978) a l . (1975) et a l . a l .(1968) (n=1271) (n=948) (1972) (n=293) (n=241 ) 1 Visual 36% 43% 22% 2 24% Diplopia 13 11 12 22 Balance 23 26 5 3 27 Problems Paresis 43 22 40* 40 Paraesthesia 41 26 21 42 Micturation 10s 5 8 5 Di sturbance 1 Figures are derived from a l i t e r a t u r e review 2 Optic n e u r i t i s 3 Includes vomiting due to vertigo * C l a s s i f i e d under a general category c a l l e d "motor weakness" 5 Includes defecation and sexual disturbances 18 characterizing the pre-onset period as being pseudo-rheumatic (muscle or j o i n t pains, or neuralgias without fever) or pseudo-neurasthenic (eg. fatigued, i r r i t a b l e ) (eg. Abb & Schaltenbrand, 1956). Although recent researchers such as Bervoets & Delaet (1984) have commented upon the neurasthenic feature of MS patients, psychological research has not been able to find an underlying, unitary p r o f i l e of MS patients. Psychological c h a r a c t e r i s t i c s of MS patients have ranged from that of euphoria (Sugar & Nadell, 1943; Surridge, 1969), depression and hysteria (Canter, 1951; Shontz, 1955; Whitlock & Siskind, 1980) to that of denial, anxiety and somatic concern (Peyser, Edwards & Poser, 1980). Pathological findings have revealed the multi-focal nature of the disease. In an autopsy of 70 MS patients, Ikuta and Zimmerman (1976) found plaques in 99% of the optic nerves, 97% in the cerebrum, 87% in the cerebellum, 84% in the midbrain, 98% in the pons, 88% in the medulla and 99% in the spinal cord. S i m i l a r i l y , s c l e r o t i c plaques have been reported extensively in the optic nerves, chiasm, and tracts (Walsh & Hoyt, 1969; Lumsden, 1970; Patterson & Heron, 1980). H i s t o l o g i c a l work on the eyes of MS patients have indicated the presence of optic nerve atrophy (Gartner, 1953) and abnormalities in the p e r i p a p i l l a r y nerve fiber layer (Feinsod & Hoyt, 1975). Imaging techniques such as computed tomographic (CT) scanning and magnetic resonance imaging (MRI) have indicated 19 focal decreased brain density, and abnormal enhancement with the main area of involvement being in "the per i v e n t r i c u l a r areas or within the cerebral or cerebellar white matter" (Kirshner, Tsai, Runge & Price, 1985, p.860). Despite the high rates obtained with imaging techniques in detecting the presence of demyelinative plaques (about 85%), the cor r e l a t i o n between a posit i v e scan and the duration as well as severity of the disease i s nonsignificant — although some researchers have argued that there is a strong co r r e l a t i o n with CT contrast abnormality (enhancement) and c l i n i c a l exacerbation (eg. Barrett, Drayer £< Shin, 1985). Such findings, coupled with others to be discussed, appear to indicate the s e n s i t i v i t y of the vi s u a l system to the degenerative e f f e c t s of multiple s c l e r o s i s . Because of the apparent s e n s i t i v i t y of the vi s u a l system, the following description of symptomatology w i l l deal b r i e f l y with motor signs and then focus primarily on sensory signs. D. MOTOR/BRAIN STEM INVOLVEMENT Patients whose plaques appear to center upon the cerebellum or spinal cord frequently refer to themselves as clumsy or their limbs as heavy, s t i f f , or, when a lower limb i s involved, as dragging or flapping (McAlpine et a l , 1972). Depending upon the s i t e of involvement, patients may demonstrate dip l o p i a , depression, absence of deep reflexes, focal paresis, muscular wasting, vertigo, ataxia, dysarthia 20 or,rarely, peripheral f a c i a l palsy (Lumsden, 1970; McAlpine et a l , 1972). In addition, MS patients with motor/brain stem involvement may exhibit 5th c r a n i a l nerve (Trigeminal) loss r e s u l t i n g in f a c i a l pain and loss of corneal r e f l e x . Impaired hearing due to paralysis of the tensor tympanic may also occur, but i s r e l a t i v e l y rare (Chusid & McDonald, 1978). As the thesis of t h i s study centers e n t i r e l y upon the vis u a l system, the remainder of thi s section w i l l focus on motor distubances a f f e c t i n g the visu a l system. For a more indepth discussion of motor/brain stem involvement, the reader i s referred to McAlpine et a l . , 1972). Motor involvement of the vi s u a l system centers primarily upon nystagmus and abnormalities in smooth eye movement, both of which have been used as early screening tests for MS (eg. Solingen, Baloh, Myers & E l l i s o n , 1977; Sharpe, Goldberg, Lo & Herishanu, 1980, 1981). 1. NYSTAGMUS Nystagmus, which is found in 70% of cases (Newell, 1978) i s either of the jerk or vestibular type. Jerk  nystagmus involves a quick movement nasalward and a slow, corrective move temporalward (the opposite in the abducting eye). According to Sharpe, Goldberg, Lo & Herishanu (1981), opticokinetic nystagmus, a form of jerk nystagmus where the 21 slow phase results from f i x a t i n g on a moving object and the fast phase from mediation by higher c o r t i c a l centers, can be e l i c i t e d in MS patients in conditions where i t i s inhibited in normals (fixed target moves with the head) and i s suggestive of lesions in the temporal and o c c i p i t a l lobes (Newell, 1978). Vestibular nystagmus is a ref l e x i v e response to "asymmetric stimulation of the semi-circular canals or their central pathways" (Newell, 1978, p.537). Such patients find i t d i f f i c u l t to fixate on some target after movement i s stopped, and, i f the di r e c t i o n of the nystagmus changes with the d i r e c t i o n of the gaze, one may suspect extensive vestibular nuclei involvement (Newell, 1978). 2. SMOOTH EYE MOVEMENT With respect to saccades and smooth pursuit, MS patients are characterized by increased saccadic reaction time, saccadic inaccuracy, and impaired smooth pursuit, suggesting brain stem and/or cerebellum involvement (McAlpine et a l . , 1972; Solingen, Baloh, Myers & E l l i s o n , 1977; F i e l d et a l . , 1980). In addition, paresis of ocular muscles may occur (in at least 25% of cases according to Newell, 1978) as well as diplopia due to palsies of individual muscles or internuclear ophthalmoplegia. Reulen, Sanders and Hogenhuis (1984) reported that, in a sample of 84 MS patients, s u b c l i n i c a l eye movement disorders were 22 found in 80% of the 'd e f i n i t e ' cases, 74% of the 'probable', and 60% of the 'possible'. In a sample of 21 optic n e u r i t i s patients, only 25% showed any eye movement d e f i c i t . Assessment procedures l i k e the P u l f r i c h , which i s primarily a test of conduction loss in one optic nerve (eg. Frisen, Hoyt & Bird, 1973), require f i x a t i o n of both eyes; and, are therefore affected by the lack of eye muscle control evident in MS. Indeed, t h i s i s undoubtedly true of most vi s u a l function assessment procedures requiring f i x a t i o n - some of which w i l l be discussed l a t e r . E. SENSORY INVOLVEMENT 1. GENERAL According to McAlpine et. a l . (1972), roughly 35% of MS patients exhibit some sensory abnormality. Unfortunately, from a diagnostic standpoint, the sensory signs may be d i f f i c u l t to establish and are less severe than the expressed symptoms would seem to warrant. This incongruity between sensory sign and symptoms may be due to the poor knowledge regarding the aetiology and mechanism involved as well as the subjective nature of patients' descriptions of their sensory symptoms. Sensory involvement in MS has been recognized as early as 1876 by Layden, and subsequently in 1878 by Erb and 1887 by Oppenheim. The signs, probably associated to some degree 23 with the s i t e of demyelination, range from paraesthesiae (variously described as a tingling or pins and needles senstation to a dead f e e l i n g ) , Lhermitte's sign (an electric sensation produced by flexion of neck muscles), bowl and bladder disorders, a l t e r a t i o n in taste s e n s i t i v i t i e s , as well as a decrement in two-point discrimination, vibration sensation, and postural sensation (Kurtzke, 1970; Fogg, 1977; Catalanotto, Dore-Duffy, Donaldson, Testa, Paterson, and Ostrom 1 984). Of p a r t i c u l a r interest are the symptoms indicating involvement of the visua l system. Such patients t y p i c a l l y report their v i s i o n as misty, blurred or foggy (Kurtzke, 1970; Moore, 1983). They report transi t o r y fluctuations in acuity, depth perception impairment, the presence of phosphenes, deterioration of l i g h t perception and d i f f i c u l t y adjusting to changes in l i g h t i n t e n s i t i e s (Kurtzke, 1970; Newell, 1978; Moore, 1983). The complaint tends to be unilateral,, with the symptoms l a s t i n g anywhere from less than one day to two weeks or more. Discomfort (pressure) or pain may be present in or behind the affected eye, especially in eye movements involving traction of an inflamed optic nerve (Alpine et a l . , 1968; Lumsden, 1970; Moore, 1983). The symptoms, t y p i c a l of optic n e u r i t i s and retrobulbar n e u r i t i s , may be presented singly or in combination with other neurologic signs (Kurtzke, 1970) and may be seen in demyelinative diseases (MS, neuromyelitis optica, Schilder's 24 disease), infections ( u v e i t i s , meningitis, tuberculosis) and vascular diseases ( a r t e r i o s c l e r o s i s , giant c e l l a r t e r i t i s , pulseless disease) (Newell, 1978). It should be noted that the d i s t i n c t i o n between optic n e u r i t i s and retrobulbar n e u r i t i s appears to vary with authors. Some authors view retrobulbar n e u r i t i s as representing demyelination of the optic nerve without v i s i b l e ophthalmoscopic changes and therefore c l a s s i f y the pathology as optic n e u r i t i s (eg. Newell, 1978). Whereas others view optic n e u r i t i s and retrobulbar n e u r i t i s as c l i n i c a l l y separate - optic n e u r i t i s r e f e r r i n g to changes at the nerve head or optic disc and retrobulbar n e u r i t i s to changes in the optic nerve outside the globe (eg. Kurtze, 1970). Differences in the c l a s s i f i c a t i o n of these two c l i n i c a l conditions among authors makes i t d i f f i c u l t to assess the ophthalmological l i t e r a t u r e on MS.1 However one defines i t , the percentage of MS patients who i n i t i a l l y exhibit optic n e u r i t i s in the l i t e r a t u r e ranges from 11.5% (Kurland et a l . , 1963) to 83% (Haller, Patzld and Eckert, 1980). This high incidence has led authors such as Bradley and Whitty (1968) to speculate that 1 According to Ebers and Feasby (1983), the r e l a t i o n s h i p between optic n e u r i t i s and MS i s also confounded by the fact that central serous retinopathy (an accumulation of serous f l u i d between the retina and r e t i n a l pigment epithelium causing a lesion in the retina) and optic n e u r i t i s are similar in pattern. As optic n e u r i t i s , central serous retinopathy (CSR) tends to occur in young adults "commonly under stress, has a seasonal p r e d i l i c t i o n , i s u n i l a t e r a l , produces v i s u a l blurring and a r e l a t i v e central scotoma, improves spontaneously, but may recur" (p.79). Unlike optic n e u r i t i s however, CSR appears not to a f f e c t colour v i s i o n . 25 51% of patients with optic n e u r i t i s are manifesting the f i r s t c l i n i c a l signs of MS. Such c l i n i c a l g e n e r a l i t i e s may be misleading in that only about 35% of MS patients tend to have v i s u a l complaints ( F i e l d et a l , 1980) and reliance on the diagnosis of optic n e u r i t i s alone may increase the chance of false p o s i t i v e s . Recent attempts to index optic n e u r i t i s with other positive signs for MS by tests such as the erythrocyte unsaturated fatty acid (E-UFA) test have s t i l l only indicated that 32% of patients have MS (Cazzullo, Caputo, Bertoni and Z i b e t t i (1980). 2. SPECIFIC As early as 1870 (Albutt) i t has been shown that the optic nerves and chiasm appear to be especially vulnerable to demylinating diseases. Uhtoff (1889), in an ophthalmological examination of 100 cases, reported optic atrophy in 40% of cases and optic n e u r i t i s in 5%. Lehoczky (1954) reported optic chiasmal involvement in 11 patients and 9 with optic nerve abnormalities from a t o t a l of 20 MS patients. S i m i l a r i l y , Lumsden (1970) reported 100% involvement of the optic nerves, chiasm, or optic tract in 36 MS patients. Computer tomography of optic n e u r i t i s (Howard, Osher, & Tomsak, 1980) and MS (Wuthrich, 1980; Lodder, deWeerd, Koetsier and van der Lugt, 1984) as well as the use of nuclear magnetic resonance in MS (DeWitt, Wrag, K i s t l e r , Davis, Brady and Buomanno, 1984) have confirmed the 26 involvement of the v i s u a l system in exceptional acute stages (20-33% of cases). Examination in vivo of the r e t i n a l layer in MS has indicated diffuse and focal damage of r e t i n a l axons even among patients who have not reported any visu a l disturbances (Frisen & Hoyt, 1974). Feinsold and Hoyt (1975) reported two types of fundal abnormality in the nerve fibr e layer of 17 MS patients: s l i t - l i k e defects in the arcuate nerve fibres combined with di f f u s e thinning of the nerve fibr e layer, d i f f u s e thinning of temporal p e r i p a p i l l a r y bundles with a lesser degree of thinning in the remaining sectors surrounding the optic d i s c . In an extensive ophthalmological examination of 1,728 cases (1,180 were confirmed MS patients), Bervoets and DeLaet (1984) reported the presence of several abnormalities including r e t i n a l vein sheathing, optic atrophy, and nystagmus (see Table 3). The presence of venous sheathing (a whitish segmental structure out l i n i n g the vein) i s controversial with some authors claiming that i t s appearance is due to non-MS diseases (eg. F i e l d & Foster, 1962). Kurtzke (1970), however, reports that venous sheathing occurs in about 10% of MS patients and that 80% of patients with venous sheathing had MS. Associated with the presence of r e t i n a l venous sheathing has been the non-pathognomonic 27 TABLE 3 Neuro-ophthalmological Findings in MS and Non-MS Patients Diagnosis Typical MS Presumed Uncertain Non-MS Pat ients (n= 1 180) MS (n = 270) MS (n = 53) (n = 225) Retinal Vein 292 47 9 7 Sheathing Optic 522 91 • 21 42 Atrophy Nystagmus 392 73 18 43 Anterior 87 29 4 8 Internuclear Ophthalmoplegia Convergence 98 19 5 24 Paresis or Palsy Horner's 13 3 0 9 Syndrome Extracted from Bervoets and De Laet (1984) 28 sign of p e r i p h l e b i t i s retinae (Rucker, 1972; Engell, Jensen and Klinken, 1985). 1 Changes in v i s u a l functioning due to p e r i p h l e b i t i s retinae (PR) alone appear to be unknown. Rucker (1945) reported the presence of PR in MS, which has since been confirmed through h i s t o l o g i c a l examination of MS eyes (eg. Fog, 1965; Toussaint, 1984). Rucker also reported the presence of dot-like opacities, which has since been established as f o c i of chronic inflammation (Arnold et a l . , 1984) . More recently Engell, Jensen and Klinken (1985) reported the presence of PR in h i s t o l o g i c a l examination of two confirmed MS patients with reduced vis u a l acuity. The authors argued that p e r i p h l e b i t i c lesions in the retinae were c l i n i c a l signs of early plaque formation since disruptions in the blood-brain barrier occurred simultaneously in PR and MS - a stance supported by some (eg. Adams & Dath, 1977) and rejected by others (eg. 1 P e r i p h l e b i t i s retinae (PR), which may also be found in tuberculosis, s y p h i l i s , sarcoidosis and more frequently in c h o r i o r e t i n i t i s (Newell, 1978) i s a neovascularization of connective tissue membrane extending into the vitreous (Scheie & Albert, 1977). PR both occurs and resolves i t s e l f quickly, presenting segmental, d i l a t e d , beaded occluded veins with sheathing or exudation of lymphocytes and plasma c e l l s . In an extensive h i s t o l o g i c a l examination of the eyes of 47 MS patients, Arnold, Pepose, Hepler and Foos (1984) reported the presence of PR in four cases (8.5%). PR was found to be segmental perivenous lymphoplasmacytic i n f i l t r a t i o n . The authors reported widespread vascular changes in r e t i n a l areas among patients who had and did not have PR. Arnold et a l . f e l t that the vascular changes were more widespread (established through vessel permeability with immunoperoxidase) than could be c l i n i c a l l y detected. 29 Oppenheimer, 1976). Thus the ocular changes found in MS, i . e . PR, may represent a primary p h l e b i t i c process which in the central nervous system leads to demyelination. 3. PSYCHOPHYSICAL ASSESSMENT OF MS The following i s a discussion of the major techniques employed in assessing vis u a l function in MS. Although the f i r s t procedure to be discussed, evoked potentials, i s not a psychophysical procedure per se, i t represents the most frequently used method for a s s i s t i n g in the diagnosis of MS and therefore needs to be discussed. The argument to be developed i s that the evoked potential measures only gross functional changes (amplitude and latency). Such a procedure does not, unless modified, permit one to assess the changes occurring in the macular regions - ones which the writer feels provides a more sensitive indication of the presence and severity of MS. Following the discussion of evoked potentials, the major psychophysical methods of s p a t i a l contrast s e n s i t i v i t y , temporal contrast s e n s i t i v i t y , colour vi s i o n assessment, and perimetry w i l l be discussed. 30 F. VISUAL EVOKED POTENTIALS 1. TECHNIQUE. Since the c l a s s i c a l c l i n i c a l experiment of Halliday, McDonald and Mushin (1972), vis u a l evoked responses (VERs) have become one of the standard diagnostic methods for assessing the presence of MS, i . e . for the detection of some abnormality of the v i s u a l system which, with the presence or absence of other c l i n i c a l signs, may be indicative of MS. The VER results from changes in the potentials of an electroencephalogram (EEG) due to the presentation of some vi s u a l stimulus. As the EEG consists not only of summated e l e c t r o - c o r t i c a l a c t i v i t i e s but also b i o - e l e c t r i c a l "noise", the evoked response must be obtained by enhancing the signal-to-noise r a t i o through mathematical f i l t e r i n g techniques such as autoregressive moving averages (ARMA). As such, the v a l i d i t y and r e l i a b i l i t y of an evoked potential regardless of i t s stimulus o r i g i n (eg. v i s u a l , auditory, somatosensory) are highly dependent upon techniques sensitive to temporal s h i f t s and a c t i v i t y outside the time window of interest (Kay & Marple, 1981). An evoked potential can be characterized as being either transient or steady-state (Regan, 1982). Transient evoked potentials result from responses to abrupt stimuli such as flashes of l i g h t whereas steady-state are composed 31 of harmonics whose frequencies are precisely defined and are recognizable within the brain's background noise. In essence, the onset of a stimulus results in a transitory response that eventually becomes a steady-state p o t e n t i a l . Regardless of whether one i s examining a transient or steady-state response, v i s u a l l y evoked responses may be generated through two basic techniques. The f i r s t , flash-evoked responses, result from the presentation of multiple flashes (generally 50 to 100 t r i a l s ) of a d i f f u s e achromatic l i g h t to the entire retinae. Luminance levels of the fla s h appear to depend upon the equipment (eg. cathode ray tube) used. Flash induced VER tend to consist of complex waveforms with peaks between 50 and 150 msec., and are f e l t to result primarily from a c t i v i t y in the macula esp e c i a l l y in the case of the electroretinogram (Hirose, Wolf & Malin, 1972). Flash transient VERs are believed to be the result of processing either in the r e t i n o - g e n i c u l o - o c c i p i t a l s t r i a t e cortex or the brain stem r e t i c u l a r formation prior to i t s transmission to the o c c i p i t a l cortex (Carlow, 1980). The fla s h VER procedure i t s e l f is considered to be a r e l a t i v e l y insensitive test for assessing normal-abnormal c o r t i c a l functioning. The generated latency does not seem to be greatly affected by disease onset (unless severe), and suffers from large v a r i a b i l i t y in the latency s h i f t even among neurologically intact normals (Duwaer & Spekreijse, 1978; Neetens, Hendrata & van Rompaey, 1979; Halliday & Mushin, 1980; Bodis-Wollner and Onofrj, 1982). Additionally, 32 though equally true of a l l VER methods, fl a s h VERs are dependent upon factors such as luminance of background and target, stimulus frequency (time i n t e r v a l ) , and electrode placement and wavelength (Regan, 1977; White, White & Hintze, 1979; Carlow, 1980). The second technique for generating VERs, pattern  evoked responses, i s through the presentation of a reversing grating (sine or square wave) or checkerboard pattern. Patterns are presented at the rate of about 1 or 2 per second with the luminance being dependent upon the equipment being used, making i t d i f f i c u l t to compare results across studies. The major advantages of pattern over flash VER are that the former produces consistent waveforms with a recognizable pos i t i v e peak and a consistent latency among normal samples (eg. Halliday, McDonald & Mushin, 1972; Behrman, Halliday & McDonald, 1972). As with flash, pattern generated VERs are f e l t to result from the complex interaction between the peripheral and central fovea as well as higher and possibly lower c o r t i c a l centres. 2. APPLICATION. With respect to abnormality, the flas h and pattern VERs may be examined for changes in latency, amplitude, wave form, and d i s t r i b u t i o n of the potentials (McDonald, 1980). MS i s characterized by an increase in latency of the P100 while maintaining a well-preserved wave form unlike glaucoma 33 or Parkinson's disease (eg. Bodis-Wollner & Onofrj, 1982). Changes in the waveform and reduction in amplitude may also be seen, esp e c i a l l y during the acute stages of an attack of optic n e u r i t i s (Adachi-Usami, Kellermann & Makabe, 1972; Feinsod, Abramski & Auerbach, 1973; Feinsod & Hoyt, 1975). Abnormal VERs have been found in anywhere from 38 to 96% of MS cases (Halliday, McDonald & Mushin, 1973; Purves, Low, Galloway & Reeves, 1-981; Kupersmith, Nelson, Seiple, Carr & Weiss, 1983). As indicated in Table 4, the delay in VER occurs more often among "probable" and " d e f i n i t e " MS patients as compared with "possible" patients. Although increased latencies in evoked potentials may be seen in other modalities such as somatosensory (Purves et. a l . , 1981; Haldeman, Glick, Bhatia, Bradley & Johnson, 1982; P h i l i p s , Potuin, Syndulko, Cohen, Stanley, Tourtellote & Potuin, 1983) and auditory brain stem (Kjaer, 1980; Purves et. a l . , 1981; Green & Walcoff, 1982; Quine, Regan & Murray, 1983; Javidan, McLean & Warren, 1985), the v i s u a l system appears to be more sensitive to the ef f e c t s of multiple s c l e r o s i s (McDonald, 1980; Purves et a l . , 1981). Abnormalities in the VER have been reported also among c l i n i c a l l y d e f i n i t e MS patients who do not exhibit any v i s u a l symptoms (McDonald, 1980). Moreover, the e f f e c t s may or may not appear b i l a t e r a l l y in the affected and unaffected eye (Milner, Regan & Heron, 1974; Ketelaer, 1980). Recently Nuwer, Visscher, Packwood and Namerow (1985) demonstrated the presence of s i g n i f i c a n t l y delayed PlOO's in 34 TABLE 4 Percentage of MS Patients With Abnormal VEP's' Study Sample D e f i n i t e Probable P o s s i b l e Suspected S i z e MS MS MS MS Ghezzi et 236 84.0% 65.0% - 31.0% 2 a l . (1984) Green & 115 82.0 NC3 NC NC Walcoff (1982) Purves et 112 91.0 76.0 14.0 38.0 a l . (1981) Kjaer 99 100.0 70.0 (1980) Lowitzch 135 83.0 77.0 60.0 (1980) Franck & 74 86 89 74 Middleton (1981)• C o l l i n s et 98 78 50 23 a l . (1978) H e n n e r i c i 57 94 94 78 et a l . ( 1 977) 5 H a l l i d a y 51 97 100 91 et a l . (1973) 'Includes a b n o r m a l i t i e s i n lat e n c y and amplitude 2No o p t i c n e u r i t i s 3NC - unable to be computed from the a r t i c l e ' S t i m u l a t i o n w i t h red and black checkerboard 5 F o v e a l s t i m u l a t i o n only 35 the VEP's of neurologically normal f i r s t degree r e l a t i v e s of confirmed MS patients. The authors argued that although the findings indicate the presence of s u b c l i n i c a l demyelination or focal changes in some r e l a t i v e s , the fact that less than 2% of the r e l a t i v e s w i l l develop c l i n i c a l MS suggests that the changes are not predictive of MS onset. Despite such r e l a t i v e l y high detection rates among MS patients, delay in the f i r s t major positive wave (P100) i s not diagnostic of the presence of MS. Delays have been reported in glaucoma (Bobak, Bodis-Wollner, Harnois, Maffei, Mylin, Podos & Thornton, 1983; Regan & Neima, 1984), Parkinson's disease (Bodis-Wollner & Onofrj, 1982; Bobak et. a l . , 1983) and amblyopia (Chiappa, 1980) as well as numerous other pathologies. Depending upon the procedure and type of MS patient, the one distinguishing feature of MS may be a well preserved wave form as stated e a r l i e r . Kimura (1985) has recently argued that evoked potential procedures are used indiscriminately in c l i n i c a l settings. According to Kimura, VERs are only useful in c l a s s i f y i n g known problems such as in the case of d e f i n i t e multiple s c l e r o s i s . The major reason for t h i s i s that the "temporal c o r r e l a t i o n between c l i n i c a l and e l e c t r i c a l changes [due to the existence of some pathology] i s tenuous at best" as the i n t e r t r i a l r e l i a b i l i t y of the evoked potentials are "greater than would be expected from the changes due to the disease" (p.78). S i m i l a r i l y McDonald (1980) and Aminoff, Davis and 36 Panitch (1984), among others, have pointed out that the VER provides evidence of an abnormality as well as i t s possible general location but can not id e n t i f y the cause nor i t s course. 3. MODIFICATIONS. Attempts to remedy the lack of c l i n i c a l d i f f e r e n t i a t i o n in the VER have been numerous and f a l l within one of three general approaches. The f i r s t involves the examination of  several modalities. The procedure generally involves the auditory, somatosensory and v i s u a l systems in the assumption that their combination w i l l locate the presence of lesions in either the spinal cord, brainstem, v i s u a l system, cerebral cortex or some combination thereof. Results have indicated a higher detection rate of abnormality among MS patients than would be the case when only one modality was examined (Green and Walcoff, 1982; Purves et. a l . , 1983). This appears to be es p e c i a l l y true of d e f i n i t e MS where the detection of an abnormality may be about 80 (Ketelaer, 1980) to 97% (Purves et. a l . , 1983). Such detection rates in the presence of no other c l i n i c a l (physical) signs (eg. Hennerici, Wenzel & Freund, 1977; Small, Matthews & Small, 1978) has affirmed the often repeated b e l i e f in the presence of s u b c l i n i c a l defects, ones to which techniques l i k e the evoked potential appear to be sen s i t i v e . 37 In a study by Feinsod and Hoyt (1975), a l l 25 of their MS patients (including 10 with no v i s u a l signs or symptoms) demonstrated abnormal latencies and wave form in the VER. Seventeen of the 25 patients had an abnormality of the p e r i p a p i l l a r y nerve f i b r e layer ( s l i t - l i k e defects in the arcuate nerve f i b r e s , diffuse thinning of the nerve f i b r e layer, and diffuse thinning of temporal p e r i p a p i l l a r y nerve f i b r e bundles), six also had temporal pallor of the disc due to thinning. Because of the associated VER abnormalities, Feinsod and Hoyt speculated that d i s t o r t i o n s in the evoked potentials were due to changes in the r e t i n a l nerve fibr e layer and axons in the optic pathways. The non-uniform ef f e c t s of MS across patients with respect to the VER may be re f l e c t e d in the types of s u b c l i n i c a l changes in the nerve f i b r e layers (eg. disturbances of the wave form and latency may depend upon the width of the nerve fibres involved as well as their l o c a t i o n ) . However, possible abnormal VERs due to changes in the nerve f i b r e layer are not s p e c i f i c to MS. Glaucoma, which also has been demonstrated to be associated with nerve fibr e layer changes retina (Ariksinen, Lakowski & Drance, 1985) has yielded abnormal VERs (Schwartz & Sonty, 1981; Bobak et. a l . , 1983: Regan & Neima, 1984). According to Bobak et. a l . (1983), in comparing steady-state vis u a l evoked potentials and electroretinograms (ERGs) generated by sinusoidal gratings (2.3 cycles/degree), 38 both glaucoma and MS patients showed abnormal ERGs under mesopic illumination. The authors claimed that the MS patients showed greater abnormality in the VER latencies (7 of 10 eyes) than with the ERG, (2 of 10 eyes). However, a re-analysis by t h i s writer of their data, using a t-test for unequal sample sizes, revealed no s i g n i f i c a n t differences between the two groups on VER latency (t= 0.19, df= 11, p > 0.05), nor on VER amplitude (t= 0.84, df= 13, £ > 0.05), nor ERG latency (t= 0.06, df= 1 3, p_ > 0.05) . These unreported nonsignificant differences between the two pathologies strengthens the b e l i e f that, although the underlying processes involved in diseases such as glaucoma and MS are d i f f e r e n t , their r e s u l t i n g effects on the VER are similar in that one i s viewing the summated a c t i v i t y of the vis u a l system - be i t at the retina or o c c i p i t a l lobes at some s p e c i f i c time. Indeed, one danger with approaches where multimodalities are examined i s that the reported s h i f t in latencies may only be s h i f t s in the orientation of the dipole due to the positioning of the measuring electrodes (Wood, 1982). The second general approach to improve VER detection of MS i s the manipulation of the stimulus presentation. One of the most common involves the comparison between pattern and flas h VER (eg. Neetens, Hendrata & van Rompaey, 1980). Pattern VERs are apparently the most sensitive for reasons discussed previously. Similar attempts with pattern and 39 f l a s h stimuli have been made with ERGs, results of which have been unsatisfactory (eg. Kirkham & Coupland, 1983). Of p a r t i c u l a r interest with the pattern procedure has been the use of contrast gratings in generating VERs (eg. Maffei, 1982; Kuppersmith et. a l . , 1983). In using lower s p a t i a l frequencies (2 and 6 c y c l e s / degree) Neima and Regan (1984) reported greater VER abnormality among some MS patients for a small stimulus-check size (11 minutes of a r c ) . VER abnormalities were also found among some patients for large stimulus-checks (45 minutes of arc) regardless of s p a t i a l frequency. These results p a r a l l e l Regan's e a r l i e r work demonstrating non-selective s p a t i a l frequency loss for MS in that patients varied as to which s p a t i a l frequency demonstrated the greatest loss. VER changes due to stimulation of the fovea or periphery are interesting when taken into consideration with the results on nerve f i b r e layer l o s s . Hennerici, Wenzel and Freund (1977) reported greater delays in VERs for foveal small-size rectangle stimulation than for normal checkerboard stimulation of the entire retina among MS patients. The authors suggested that foveal stimulation was more sensitive and r e l i a b l e than the standard c l i n i c a l practice of stimulating the entire eye, and that the r e s u l t i n g abnormality was due to demyelination of foveal f ibres. From the results by Hennerici et a l . i t would appear plausible that i f the nerve f i b r e layer i s affected e a r l i e r 40 in MS, and i f one can image a stimulus to s p e c i f i c damaged areas, then stimulation of these possible pre-symptomatic st r u c t u r a l changes may afford one with a technique not only for the documentation of early onset of some disease, but also an index of severity (greater the nerve f i b r e loss, the greater the VER or ERG abnormality). The l i m i t a t i o n of such a method for charting severity may be that there i s a l i m i t to changes in an abnormal evoked response once a certain amount of area (nerve fibr e layer) has been destroyed. With respect to foveal versus peripheral stimulation in MS, others have found similar results to Hennerici et. a l . but f e e l that detection (confirmation) of an abnormality i s improved when the results from both foveal and peripheral stimulation are combined (eg. Rossini, Pirchio, Sollazzo & Caltagirone, 1979; Diener and Scheibler, 1980). Although luminance is an important factor there are no available studies on how such a variable may affe c t VERs of MS patients. With respect to colour, only one study by Franck and Middleton (1981) appears to have examined the rel a t i o n s h i p between colour and VERs. By using black and white squares as well as red (X625 nm) and black squares, the authors reported better detection with the red and black. The results, unfortunately, are d i f f i c u l t to interpret in that the two stimulus patterns were not equated for luminance; therefore one i s uncertain as to whether the improved detection was due to the colour (red) or luminance per se. 41 In a preliminary on-going study by Kozak, King and Drance (1985), r e t i n a l stimulation at the foveal region on a single individual produced similar r e s u l t s . As indicated in Figure 3, the red cinemoid f i l t e r (XD unknown) produced a well defined waveform that was s l i g h t l y more latent (average of 81.0 msec) when compared to the VER produced by a white (achromatic) stimulus (79.3 msec). In addition, the red produced a wave form with greater amplitude than the white. Although the two stimuli were of the same size (Goldmann V), the red - despite the claims by the instrument manufacturer - had less luminance than the white and therefore the two were not photometrically equated and thus may have caused the s h i f t in the latency. The s i m i l a r i t y in the results of the two studies would suggest that the differences reported by Franck and Middleton may have been due to differences in luminance equivalence rather than differences in wavelength. The t h i r d and f i n a l approach in attempting to improve VERs has been the manipulation of the physical state of the  patient. Although symptom production in MS patients has been done with methods such as the hot bath (eg. Rolak and Ashizawa, 1984), only fatigue seems to have been done with VER as the dependent variable. Persson and Sachs (1981) fatigued 15 MS patients and 5 normals on a bicycle ergometer prior to their VERs via standard pattern-reversal stimulation. When compared to pre-exercise VERs, exercise produced VERs did not d i f f e r with respect to latency. The only noticeable effect was a short l a s t i n g reduction in the 42 F i g u r e 3 VEP from f o v e a l s t i m u l a t i o n w i t h a r e d and a c h r o m a t i c s o u r c e . 43 VER amplitude and vi s u a l acuity of the MS patients. If i t i s possible to generalize from studies varying in patient c h a r a c t e r i s t i c s and procedures, i t appears that v i s u a l function i s a highly sensitive measure of pathological conditions, and that cones may be involved e a r l i e r than the rods. Moreover, i t appears that any attempt to focus upon the involvement of the visual system in MS should involve methodology outlined by visual psychophysics in order to assess changes at either the r e t i n a l (eg. rods versus cones) or central processing l e v e l . Such a paradigm would enforce s t r i c t e r methodological control (eg. stimulus c o n t r o l ) , one solely lacking in many studies. For a more detailed discussion on VERs the reader i s referred to Desmedt (1977), Nakayana (1982), and Petsche, Pockberger and Rappelsberger (1984). G. SPATIAL CONTRAST SENSITIVITY 1. TECHNIQUE Spatial contrast s e n s i t i v i t y involves assessing the a b i l i t y of the vi s u a l system to resolve sinusoidal or square wave forms varying from 0.5 to 100% contrast. The s e n s i t i v i t y of the v i s u a l system to resolve such wave forms is referred to as "contrast s e n s i t i v i t y function" (CSF). The CSF has a well defined form (see Figure 4) with "a maximum value for sp a t i a l frequencies of about 0.15 to 0.6 cycles per 1000 001 O o o o > 100 f •01 o • • 10 t . 1 <-> 0 0 1 0 I 1.0 il.O c/m r a d 0.1 1.0 10 c / d e g . F i g u r e 4 C o n t r a s t s e n s i t i v i t y f o r s i n e w a v e . F r o m L a k o w s k i ( 1 9 8 2 , p . 6 ) 45 m i l l i r a d i a n (c/m rad) or 2.5 to 10 cycles per degree (c/deg) and decreases at both higher and lower frequencies" (Lakowski, 1982, p.6). Blurring at higher frequencies results from attenuation due to o p t i c a l abnormalities (eg. refrac t i v e errors) and eye movement. As noted by Lakowski (1983), losses at lower s p a t i a l frequencies appear to be related to luminance variations in the gratings or r e t i n a l size (demonstrated by Regan, S i l v e r and Murray, 1977). The advantage of examining CSF i s based upon the be l i e f that i t permits the researcher to identif y s p e c i f i c groups of optic nerve fibres - a be l i e f central to channel theorists such as Regan (1982) who hold that the vi s u a l system i s comprised of p a r a l l e l processing information channels. Such an approach assumes that one can evaluate s p e c i f i c ganglion c e l l s in the s p a t i a l channel by stimulating receptive f i e l d s with their respective s p a t i a l frequencies, although no electrophysiological evidence exists for this in humans. 46 2. APPLICATION R e g a r d l e s s of the t h e o r e t i c a l s tance t a k e n , CSF has been found to be h i g h l y s e n s i t i v e to the presence of MS (Regan, S i l v e r and M u r r a y , 1972; B o d i s - W o l l n e r , H e n d l e y , M y l i n & T h o r n t o n , 1979; Zimmerern, Campbel l & W i l k i n s o n , 1979; Regan, W h i t l o c k , Murray & B e v e r l y , 1980; Regan, Raymond, G i n s b e r g & M u r r a y , 1981) as w e l l as a g e - r e l a t e d changes (eg . L a k o w s k i , 1981; S e k u l e r & Owsley, 1982) and glaucoma (Lakowsk i , 1981). T y p i c a l l y , CSF l o s s e s in MS occur i n both i n t e r m e d i a t e and low s p a t i a l f r e q u e n c i e s w i t h some p a t i e n t s showing a l o s s on ly in the h i g h e r f r e q u e n c i e s . These l o s s e s tend to c o r r e s p o n d to the changes i n v i s u a l a c u i t y r e p o r t e d by MS p a t i e n t s w i t h a p r i o r h i s t o r y of o p t i c n e u r i t i s - the blurring or washing out of t h e i r v i s i o n . However, v i s u a l a c u i t y in i t s e l f , as t e s t e d i n the c l i n i c a l s e t t i n g , i s not a s e n s i t i v e measure of v i s u a l l o s s i n s p a t i a l f r e q u e n c i e s (eg . Regan, 1981). R e s u l t s from c o n t r a s t s e n s i t i v i t y t e s t i n g p r o v i d e a p o s s i b l e e x p l a n a n t i o n as to why d i s t u r b a n c e s i n v i s i o n can occur wi thout be ing d e t e c t e d through a c u i t y t e s t i n g . The t y p i c a l a c u i t y t e s t , such as the S n e l l e n or L a n d o l t R ing C h a r t s are c o n s t r u c t e d w i t h 100% c o n t r a s t between the f i g u r e and background . As noted by Lakowski (1981), s p a t i a l l o s s e s are d e t e c t e d more s e n s i t i v e l y a t lower c o n t r a s t l e v e l s . Indeed, f o r v i s u a l l o s s to be d e t e c t e d at a h i g h c o n t r a s t 47 l e v e l of 100% one would probably require extensive cone and rod damage to have already occurred. Early detection of vis u a l loss would therefore necessitate testing at lower contrast l e v e l s . Unfortunately, for diagnostic purposes, losses in the intermediate and low s p a t i a l frequencies are not s p e c i f i c to MS as similar losses have been reported in other disease states such as glaucoma (Wolkstein, Atkin & Bodis-Wollner, 1980; Lakowski, 1982). More recently, Kuppersmith, Seiple, Nelson and Carr (1984) reported losses for three s p a t i a l frequencies (1, 4 and 8 c y c l e s / degree) and four orientations (0, 45, 90 and 135 degrees) among 15 MS cases with v i s u a l a c u i t i e s of 20/40 or better. The losses tended to be spotty or multifocal and involved d i f f e r e n t eyes. H. TEMPORAL CONTRAST SENSITIVITY I. TECHNIQUE Assessment of temporal s e n s i t i v i t y involves the manipulation of the rate in which a stimulus i s being presented while constantly maximizing or varying the contrast, creating the c r i t i c a l f l i c k e r frequency (CFF). The CFF is that threshold where a f l i c k e r i n g l i g h t i s perceived as becoming constant and can be obtained by one of two general procedures. One, by f l i c k e r i n g a l i g h t of constant luminance and background 48 to some part of the v i s u a l f i e l d , and secondly, in the de Lange method, by mixing a steady l i g h t to a set f l i c k e r frequency (Lakowski', 1982). Temporal s e n s i t i v i t y has been shown to be affected not only by diseases such as glaucoma (eg. Kozousek, 1968) and retrobulbar n e u r i t i s (Heron, Regan & Milner, 1974) but also by variables such as luminance, e c c e n t r i c i t y , wavelength and age (Lakowski, 1982). The lack of stimulus s p e c i f i c a t i o n in the l i t e r a t u r e makes i t extremely d i f f i c u l t to compare findings across studies. 2. APPLICATION With respect to MS, changes in temporal thresholds are seen as resulting from the effects of demyelination on the conduction rate of a neural s i g n a l . As noted by B r u s s e l l , White, M u s t i l l o & Overbury (1983), changes in temporal thresholds may result from an increase in "conduction v e l o c i t y and refractory periods, loss of synchrony between stimulation and f i r i n g rates, impulse r e f l e c t i o n , and cross-talk between f i b r e s " (p.2). Research t y p i c a l l y reports reduced CFF among MS patients (Parsons & M i l l e r , 1957; Titcombe & W i l l i s o n , 1961; Daley, Swank & E l l i s o n , 1979; Regan, 1981). In a recent a r t i c l e by Mason, Snelgar, Foster, Herron & Jones (1982), CFF losses among 20 MS patients were reported for stimuli varying in luminance and chromaticity. The 49 authors claimed that temporal losses were greater in the luminance rather than chromatic channel as has been claimed by others (eg. F a l l o w f i e l d & Krauskopf, 1984). Similar findings have been reported by Alvarez, King-smith & Bhargara (1972). On the basis of their r e s u l t s , Mason et a l . concluded that demyelination was non-selective regarding i t s ef f e c t s on nerve fibres in the v i s u a l system. In conducting the experiment the authors assumed that, on the basis of the l i t e r a t u r e , "abnormalities in temporal response [was] associated with the short wavelength sensitive mechanism" (p.247), the blue cone system. Then, inexplicably, they used a red (630 nm) and green (560 nm) light-emitting diode subtending 10 minutes of arc on a white background of 290 cd/m2. Their findings with long and middle wavelength LEDs can not be used to reject the hypothesis that chromatic channels are s e l e c t i v e l y affected. Inorder to reject the hypothesis, the authors should have used a short wavelength LED. The fact that Mason et a l . did not use a blue stimulus may be due to the present u n a v a i l a b i l i t y of r e l i a b l e short wavelength LED. What can be concluded from the Mason et a l . study i s that at high background luminances there are d e f i c i t s in CFF for both chromatic and luminance channels. Since losses are evident in the red system, which might indicate severe or quite progressed damage (eg. Pinckers, Pokorny, Smith & V e r r i e s t , 1979) the non-significant difference between chromatic and luminance CFF may be reinterpreted as 50 indicating that the cone system had already been affected to the extent that any subsequent damage would result in minimal functional losses. In examining the eff e c t s of myelin loss in retrobulbar n e u r i t i s , Alvarez (1985) reported losses in spectral f l i c k e r detection, chromatic function, and visu a l acuity. Although no information was provided on the instrumentation nor types of loss (hues) Alvarez argued that myelin loss was characterized by moderate to severe damage to the colour opponent system as well as conduction block. Other attempts to measure temporal changes in MS have centered upon perceptual delay whereby the perceived delay in the onset of two synchronously presented achromatic stimuli are assessed under photopic conditions. The task of the subject i s to adjust the onset of one of the two stimuli u n t i l they appear synchronous. MS and retrobulbar n e u r i t i s patients both demonstrate greater delay times (at least 30 msec.) necessary for perceiving the two stimuli as synchronous than normals (Heron, Regan & Milner, 1974; Regan, Milner & Heron, 1976). With the use of a 0.3 degree target, results from the technique referred to as delay campimetry can be graphed so as to create temporal delay f i e l d s of the re t i n a . The results t y p i c a l l y reveal greater i r r e g u l a r i t i e s in the temporal f i e l d s of MS patients than normals (see Figure 5). As demyelination does not appear to account e n t i r e l y for the conduction losses seen in MS patients (eg. McDonald Figure 5 Delay campimetry f i e l d s on a MS patient. The darker the area, the greater the delay. Modified from M u s t i l l o , Brussell & White (1984) 52 & Sears, 1970; Bodis-Wollner & Onofrj, 1982), Regan (1983) has argued that the results obtained in delay campimetry (temporal) demonstrate not only neural conduction problems but also d i f f e r e n t i a l response (temporal) at the r e t i n a l ganglion l e v e l (Regan, 1983). The implications of Regan's findings for the retina are d i f f i c u l t to interpret as great v a r i a b i l i t y in temporal ranges across the retina exists even among normals. What needs to be examined i s possibly not the mean temporal differences but the range of the variances under s p e c i f i c psychophysical conditions (eg. l e v e l of luminance). Modifications of delay campimetry, multi-flash and double-flash campimetry, where the subject responds to detect the presence of f l i c k e r in two stimuli presented at. the same r e t i n a l location, has yielded similar results in demonstrating greater latencies among MS, retrobulbar n e u r i t i s , glaucoma and r e t i n i t i s pigmentosa patients (eg. Galvin, Regan & Herron, 1976; White, Bross, M u s t i l l o & Borenstein, 1982; Regan, 1983; White, Brussel, Overbury & Mustillo, 1983). Both multi-flash and double-flash campimetry y i e l d temporal f i e l d s with islands of impaired temporal s e n s i t i v i t y , shown in Figure 6. Recently, in a comparison of s p a t i a l versus temporal techniques, Overbury, Brus s e l l , White, Jackson & Anderson (1983), reported that the temporal channel demonstrated greater losses than s p a t i a l for patients having amblyopia, cataract, optic n e u r i t i s or macular degeneration. Although F i g u r e 6 M o d i f i e d from Regan (1981, pp. 240-241) Y* 54 they claimed m u l t i - f l a s h campimetry was more sensitive than Goldmann perimetry in detecting losses, the conclusion i s unsupported in that the kinetic perimetry method employed was done at d i f f e r e n t luminance values than the temporal. Moreover, the two techniques are so d i f f e r e n t in methodology, subject bias (eg. greater anticipatory e f f e c t s in kinetic perimetry, for once a stimulus i s sensed i t s d i r e c t i o n and presence i s always known) and psychophysical function being assessed that i t i s d i f f i c u l t to understand why the authors f e l t the two procedures should have provided similar r e s u l t s . F i n a l l y , one other temporal technique used to assess v i s u a l delay in MS has been the P u l f r i c h Phenomenon (eg. Frisen, Hoyt, Bird & Weale, 1973; E l l & Gresty, 1982) wherein there i s a greater delay among MS patients than normals for perceiving an e l l i p t i c a l movement of a stimulus presented in a f r o n t a l plane. Rather unexpectedly, E l l and Gresty (1982) reported the phenomenon in the eye of a monocular MS patient. As the eff e c t requires binocular v i s i o n , the finding of E l l and Gresty may be either an indication of some gross r e t i n a l anomaly in their patient unrelated to the MS or a methodological problem. 55 I. COLOUR V I S I O N Of t h e p o s s i b l e s e n s o r y q u a l i t i e s o f v i s i o n t h a t one may a s s e s s , c o l o u r v i s i o n a p p e a r s t o be a f f e c t e d a t an e a r l i e r s t a g e by p a t h o l o g i e s i n v o l v i n g t h e v i s u a l s y s t e m - be t h a t i n v o l v e m e n t d i r e c t a s i n o p t i c n e u r i t i s o r i n d i r e c t a s i n t h e t r e a t m e n t o f a r t h r i t i s . T h u s , a c q u i r e d l o s s e s i n c o l o u r v i s i o n h a v e b e e n r e p o r t e d i n n u m e r o u s c l i n i c a l c o n d i t i o n s s u c h a s g l a u c o m a ( F l a m m e r & D r a n c e , 1 9 8 4 ; D r a n c e & L a k o w s k i , 1 9 8 3 ; L a k o w s k i , 1 9 8 1 ; L a k o w s k i & D r a n c e , 1 9 7 9 ) , d i a b e t e s ( R o y , M c C u l l o c h , H a n n a & M o r t i m e r , 1 9 8 4 ; B e g g & L a k o w s k i , 1 9 8 0 ; L a k o w s k i , A s p i n a l l & K i n n e a r , 1 9 7 2 ) , r h e u m a t o i d a r t h r i t i s ( L a k o w s k i , H a i n i n g & P a r t r i d g e , 1 9 6 8 ) , r e t i n i t i s p i g m e n t o s a ( W o l f , S c h e i b e r & P a s c h k e , 1 9 8 0 ; R o b e r t s o n & M o r e l a n d , 1980) a n d c e r e b r a l l e s i o n s ( D u b o i s - P o u l s o n , 1 9 8 2 ) . Due t o t h e e x t r e m e s e n s i t i v i t y o f t h e r e t i n a l c o n e s y s t e m , l o s s e s h a v e a l s o b e e n r e p o r t e d i n n o r m a l a g i n g ( L a k o w s k i , 1 9 5 8 , 1 9 6 2 , 1 9 6 4 ) , c h a n g e s i n p u p i l d i a m e t e r ( O u r g a u d , V o l a , J a y l e & D a u d , 1 9 7 2 ; L a k o w s k i & O l i v e r , 1 9 7 3 ) , l u m i n a n a c e c o n t r a s t ( V e r r i e s t , 1963 ) a n d d r u g i n t a k e ( A i k e n , 1 9 8 2 ; A i k e n & S c h n a b e l , 1 9 8 2 ; L a g e r l o f , 1 9 8 2 ) . C o l o u r v i s i o n may be c l a s s i f i e d a c c o r d i n g t o o r i g i n , m e c h a n i s m , o r p e r f o r m a n c e ( P o k o r n y , S m i t h , V e r r i e s t & P i n c k e r s , 1 9 7 9 ) . When c l a s s i f i e d a c c o r d i n g t o o r i g i n , c o l o u r v i s i o n a b n o r m a l i t i e s a r e v i e w e d a s e i t h e r c o n g e n i t a l o r a c q u i r e d . 56 1. SYSTEMS OF CLASSIFICATION a. I. C l a s s i f i c a t i o n By Origin a) Congenital: Congenital colour vision losses are due to the presence of some defect in the cone system at the time of b i r t h , the assumption being that the cone system never functioned normally throughout that individual's development. Congenital defects include the red-green and yellow-blue variety (discussed in section III on C l a s s i f i c a t i o n by Performance) as well as the achromatopsias. Achromatopsia or monochromacy refers to the condition whereby either the cone or rod system i s missing e n t i r e l y . Rod monochromats are characterized by their i n a b i l i t y to d i f f e r e n t i a t e stimuli on the basis of hue alone-resulting in the so-called "colour b l i n d " i n d i v i d u a l . In addition, rod monochromats tend to be photophobic, have poor acuity, and suffer from nystagmus. Although post mortem examination of a rod monochromat has revealed the presence of cones (Glickstein and Heath, 1975), i t is generally f e l t that the photopigments of achromatopsia subjects have spectral absorption c h a r a c t e r i s t i c s similar to that of rhodopsin (Boynton, 1979). The presence of rhodopsin-like photopigments may result in the scotopization mechanism f e l t by Verriest (1964) to 57 characterize a l l forms of achromatopsia. Cone monochromacy may be either of the red (R) cone type or the Blue (B) cone type. Although not discussed here, Weale (1953) has presented evidence for a green cone monochromat. R cone monochromats have spectral s e n s i t i v i t y curves similar to the of deuteranopes except below 500 nm where the R monochromats show higher s e n s i t i v i t y (Alpern, 1974). B cone monochromats are the most frequent type of cone monochromats. According to Boynton (1979) they have r e l a t i v e l y poor acuity, photopic spectral s e n s i t i v i t y s imilar to the blue cones in normals, and a "normal" Stiles-Crawford effect - suggesting the presence of other foveal cones. Congential colour losses tend to be expressed in a predictable manner (Lakowski, 1969). The losses are t y p i c a l l y b i l a t e r a l and r e l a t i v e l y stable over time. Discrimination losses are s p e c i f i c with well defined axes and tend not to be associated with any other v i s u a l complaints. Colour naming i s characterized by c l a s s i c a l confusions (eg. the protanope confusing red for blue-green). According to Pinckers, Pokorny, Smith and V e r r i e s t (1979), congenital colour losses are also less affected than acquired dyschromatopsias by target size and illuminance. Smith and Pokorny (1977) have demonstrated that dichromats (acquired) perform l i k e anomalous trichromats when target size i s increased. 58 b) Acquired: Acquired colour vision losses are based upon the assumption that at one time of the individual's development his/her colour v i s i o n was normal. The subsequent changes in colour v i s i o n are due to either normal (eg. ageing) or abnormal (eg. glaucoma) processes. C l a s s i f i c a t i o n of the type of acquired loss, depending upon whether one assesses colour v i s i o n on the basis of colour matching performance or wavelength and/or hue discrimination, t y p i c a l l y show red-green and yellow-blue axis loss. Losses may also be non-specific, or in the case of the Farnsworth-Munsell 100 Hue Test anarchic. Acquired losses tend not to aff e c t both eyes equally. Colour v i s i o n function i s unstable over time in that, depending upon the pathology, i t may either worsen or improve. There i s no c l e a r l y defined axis and colour naming is usually good (Lakowski, 1969). Acquired defects are occasionally accompanied with reduced v i s u a l acuity and/or v i s u a l f i e l d loss (eg. optic n e u r i t i s ) . b. I I . C l a s s i f i c a t i o n By Mechanism If c l a s s i f i e d by mechanism, colour v i s i o n defects are seen as resulting from either absorption, a l t e r a t i o n , or reduction processes. Based upon the early work of von Kries (1905), the type of mechanism responsible for the loss i s assumed from colour matches that predict the los s . 59 b) Absorption: In the f i r s t possible mechanism, the absorption system, the retina i s functionally normal and the colour defects are due to pre-receptoral changes in the lens and cornea (Verriest, 1964; Lakowski, 1962). Although most colour matches w i l l agree with the normal trichromat, some colour vi s i o n losses w i l l be evident in the yellow-blue axis. b) A l t e r a t i o n : The second mechanism, the a l t e r a t i o n system, is due to differences in one or more of the vi s u a l photopigments as compared to the normal trichromat. Abnormalities are detected through changes in photopigment absorption spectra (eg. Wald, 1966; Vos and Walraven, 1971; Ruddock and Naghshineh, 1974). c) Reduction: The reduction system, the t h i r d mechanism, i s characterized by_colour discrimination much worse than those found in the normal trichromat while at the same time accepting any matches made by normals. The reduction system may occur through the loss of one of the normal receptor mechanisms (the Konig mechanism) or by a collapse or fusion of two receptor mechanisms (the Liber-Fick or Aitken-LiberFick mechanism). For a further discussion of this topic the reader is referred to Pickford (1958), Lakowski, (1969), and Pokorny et a l . , (1979). d) C l a s s i f i c a t i o n by V e r r i e s t : Verriest (1964) has employed three other mechanisms for defining acquired colour vi s i o n loss, which are: (1) mesopization, (2) 60 s c o t o p i z a t i o n , and (3) e c c e n t r a t i o n . M e s o p i z a t i o n , o r i g i n a l l y d i s c u s s e d by Ourgaud and E t i e n n e (1961), d e s c r i b e s those c o l o u r v i s i o n l o s s e s t h a t r e s u l t from the i n c r e a s e i n p h o t o p i c t h r e s h o l d s , c a u s i n g a r e d u c t i o n i n the l e v e l of r e t i n a l i l l u m i n a n c e . Here, the change i n c o l o u r d i s c r i m i n a t i o n ( s h i f t i n VX i s e q u i v a l e n t t o t h a t seen i n normal o b s e r v e r s under mesopic a d a p t a t i o n . S c o t o p i z a t i o n o c c u r s from the i n t r u s i o n of r o d a c t i v i t y i n c o l o u r v i s i o n . The p h o t o p i c l u m i n o s i t y e f f i c i e n c y f u n c t i o n does not c h a r a c t e r i z e the r e t i n a l s e n s i t i v i t y of the o b s e r v e r . Such o b s e r v e r s , i n t h e extreme c a s e , have c o l o u r d i s c r i m i n a t i o n l o s s e s s i m i l a r t o t h a t of normals under f u l l y s c o t o p i c adapted c o n d i t i o n s . U n f o r t u n a t e l y , i t i s p r e s e n t l y u n c l e a r as t o what r o l e the rods might p l a y i n c o n t r i b u t i n g t o such c o l o u r v i s i o n matches both f o r normals as w e l l as i n d i v i d u a l s s u f f e r i n g from some form of cone degenerat i o n . V e r r i e s t ' s t h i r d mechanism, e c c e n t r a t i o n , r e f e r s t o c o l o u r v i s i o n l o s s e s r e s u l t i n g from the e x c i t a t i o n of the p a r a f o v e a l r e t i n a by p h o t o p i c s t i m u l i . Such i n d i v i d u a l s , as i n the case of s t r a b i s m i c a m b l y o p i a , a r e unable t o f i x a t e due t o eye movement problems. Because of t h e eye movement, the image i s f o c u s s e d onto t h e p a r a f o v e a l r e g i o n , r e s u l t i n g i n poorer d i s c r i m i n a t i o n . A c c o r d i n g t o V e r r i e s t (1964) and L a s z c z y k and S z u b i n s k a 61 (1973) there i s no s p e c i f i c colour defect associated with eccentration. c. I I I . C l a s s i f i c a t i o n By Performance The f i n a l method for c l a s s i f y i n g colour v i s i o n anomalies, and by far the most extensively used, i s that through performance. Performance can be categorized according to the axis of loss and severity (mild, moderate, and severe) or on chromatic discrimination tests (Lakowski, 1969). However, the c l a s s i f i c a t i o n most widely used i s that based upon colour matching performance with three primaries, from which are derived three general c l a s s i f i c a t i o n s of (a) trichromat, (b) dichromat, and (c) monochromat. a) Trichromatism: In the case of the trichromat, or normal observer, a l l three primaries (representing the short, middle, and long wavelengths of of the v i s u a l spectrum) are required to match any one spectral colour under photopic conditions. In the Wright (1946) system, the three primaries are the three spectral stimuli of 650X nm ( r ) , 530X nm (g), and 460X nm (b). Associated with the trichromatic c l a s s i f i c a t i o n is the largest group of colour v i s i o n defects known as anomalous trichromatism. Anomalous trichromatism refers to the condition where three primaries are needed to match a spectral colour except that the ratio of the mixtures are 62 d i f f e r e n t from normals Lakowski, (1969). The defect may be either protanomolous, deuteranomalous, or tritanomalous (to be discussed shortly). According to Lakowski, the incidence for the protan defect i s 1.5% (male and female) and 4.0 - 5.0% for the deutan. The protan defect i s characterized by a luminous e f f i c i e n c y involving long wavelengths (Judd & Wyszecki, 1963). Table 5 from Wyszecki and S t i l e s (1982) provides information on the salient c h a r a c t e r i s t i c s of the various defects discussed here. b) Dichromatism: Dichromats require only two primaries to match spectral colours and belong to that group t y p i c a l l y referred to as colour d e f i c i e n t (Lakowski, 1969). The defect may be c l a s s i f i e d into pairs according to the type of colour confusion mani fested. The f i r s t pair l i e s along the red-green axis and i s referred to as protanopia and deuteranopia. The terms, l i t e r a l l y meaning ' f i r s t ' and 'second' defect respectively were thus named by von Kries (1924) so as not to infer any physiological mechanisms into the terms. As can be seen in Table 5, protanopia (red defect) i s characterized by reduced luminous e f f i c i e n c y at long wavelengths (Wyszecki & S t i l e s , 1982). Best wavelength discrimination i s at about 490 nm (Vos & Walraven, 1971). Of males, about 1.0% are protanopes whereas only 0.02% of females are. Table 5 D i s t i n g u i s h i n g f e a t u r e s o f t h e m a j o r c o l o u r d e f e c t s C h j f m I c n s l i c P I K I K I H I I I I J I . U I S I r , nil miiiMn.iloiis INriitaiuirH- l )< I I I « I . I M O | K ' IriUimpv Rod- M i i i K K h r m i M l Color discrimination through the spectrum Materially reduced front red to yellowish green hin lo a vatving degree in difleient u s e s Absent front the ted lo ahoul S 'O mil At'M'iil f r o m the led lo jhoui 5 <il mn Absent in the giei nish blue lo l>lue | , i 4 X 0 nm) N o color dis-criinlnalion Neutral point (i e , wavelength of monochromatic stimulus that male h e a fined "white" stimulus)' None None 400 4S>5 nm 4<J^ Mrt nm <hK and J 7 0 nm A l l wavelength?. Shortening of the red {! c . reduced luminous efficientv of long wavelengths) Yes . N o Yes N o N o Yes Wavelength of the maximum of luminous efficiency curve Un nm MM) nm <4t>nm 5M) mn nm V»7 nm C' lh IV3I chrotnjl icily of the confusion point (uVhronuts only) >,, ^ 0 2.V. x J t ••• 1 OHO yJt = - tl IIKO «„ 0.171 Percentage frequency of occurence among males among females 1 0 0 02 4 V OJH 1 (1 <Hl2 1 1 DDI om: II lull 0 t M) 1 M o d i f i e d f r o m W y s z e c k i £, S t i l e s ( 1 9 8 2 , p . 4 6 4 ) 64 The colour confusion l o c i and neutral axis for protanopia, and other dichromats to be discussed, can be found in figure 7. The confusion l o c i defined by the isochromatic l i n e s (straight l i n e s ) characterize the defect. Provided there are no luminance differences, two chromaticities f a l l i n g along a s p e c i f i c isochromatic l i n e w i l l be confused by the colour d e f i c i e n t observer while a normal observer would see them as d i f f e r e n t as long as there is some minimum difference between the two chromaticities. A l i n e drawn perpendicular to the neutral axis indicate those colours that the dichromat is l i k e l y to discriminate. In the second defect, deuteranopia, there i s no reduced luminous e f f i c i e n c y of long wavelengths. The neutral point occurs at about X495 nm. and the peak r e l a t i v e luminous e f f i c i e n c y i s at 560 nm. Incidence rates are 1.1% for males and 0.01% for females. The second major pair of colour vi s i o n defects is determined from the confusion along the yellow-blue axis, tr i t a n o p i a and tertartanopia. Tritanopia i s characterized by an absence of discrimination between 445 to 480 nm (Wyszecki & S t i l e s , 1982). There i s no reduced luminous e f f i c i e n c y at long wavelengths and maximum luminous e f f i c i e n c y i s at about 555 nm (Wyszecki & S t i l e s , 1982). Roughly 0.002% of males and 0.001% of females have this type of defect. 65 Confusion l o c i , centre of confusion, and neutral axes for dichromats. From Lakowski (1969, p.187) 66 L i t t l e i s known about tertartanopia. Some have argued that such a condition does not exist (Boynton, 1979). However, others such as Muller (1924), Judd (1949) and Lakowski, (1969) have presented t h e o r e t i c a l evidence for tertartanopia. Loss in the yellow-blue axis involves two neutral points in the spectrum, one at 465 nm (blue) and 575 nm (yellow). As noted by Lakowski (1969), colours f a l l i n g along the confusion l i n e s shown in Figure 7 would not be discriminated by such an i n d i v i d u a l . Theoretically, there should be no reduction in luminous e f f i c i e n c y for long wavelengths. No data i s available for the incidence of tetartanopia. c) Monochromatism: The l a s t major c l a s s i f i c a t i o n by colour matching performance i s monochromatism. Monochromats, be they rod or cone, need only one primary (as well as luminance information) to match any spectral colour under photopic conditions. They are unable to discriminate any colour at a l l and are i d e n t i f i e d only by either their photopic (cone) or scotopic (rod) r e l a t i v e luminousity functions. The defect i s extremely rare. Information on rod monochromats estimates the frequency to be 0.003% amoung males and 0.002% among females. No data i s available on the frequency of cone monochromats. In a l l , i t needs to be stressed that colour v i s i o n defects should not be seen as separate categories (eg. dichromat versus trichromat) but instead as a continuum ranging from excellent colour discrimination to no discrimination at a l l . Only by doing so does one get better understanding of the process known as colour v i s i o n . 68 2. ASSESSMENT OF COLOUR VISION The assessment of colour v i s i o n may be done through colour matching and hue or wavelength discrimination (AX). Another approach, that of determining the photopic e f f i c i e n c y of the cone system to spectral energy (EX), w i l l be dealt with in the section on perimetry. a. Colour Matching Colour matching involves the mixing of spectral colours to produce a s p e c i f i c match to some reference. The procedure, t y p i c a l l y done laboriously on a colorimeter such as Wright's Colorimeter, i s used to determine what rat i o s of the three primaries (r, g, b) are required to match a given wavelength. Normal trichromats are able to match a l l hues with an appropriate mixture of the three primaries. Deviations in the type of primaries and their ratios needed provide an estimation of the type and severity of colour vision l o s s . Colour matching performance can be assessed r e l a t i v e l y easier on colorimeters c a l l e d anomaloscopes (eg. the Pickford -Nicolson Anomaloscope). Subjects view a b i p a r t i t e f i e l d and match one half of the f i e l d with the other on the basis of brightness and spectral composition. Colour v i s i o n may be examined on red-green, 69 yellow-blue, and green-blue r a t i o s . Anomaloscopes evaluate an individual on s p e c i f i c matches or equations involving the matching of two spectral colours. There are three such equations used to assess colour v i s i o n deficiences, which are: 1) the Rayleigh Equation, 2) the Pickford-Lakowski Equation, and 3) the Engelking Trendelenburg Equation. The Rayleigh and Pickford-Lakowski Equations are the most frequently used. The Rayleigh Equation discriminates between congenital red-green colour defects. Depending upon the anomalscope used (eg. the Nagel), the task involves matching a spectral l i g h t of about X589 nm to a mixture of spectral l i g h t s of X670 nm and X545 nm. The possible range of ratios between X670 nm and X545 nm a subject uses to match to X589 nm i s referred to as the matching range, providing the c l i n i c i a n with an index as to the type and extent of the severity. The median point within a range i s known as the midmatching point. The Pickford-Lakowski Equation involves determining the matching range and midmatching point of X470 nm and X585 nm f i l t e r e d l i g h t s to a white (tungsten) l i g h t . The equation was developed to test for age related changes in the yellow-blue range and has proven p a r t i c u l a r l y useful in detecting early acquired losses in various ophthomological diseases (Lakowski, 1969, Lakowski, 1972). 70 The f i n a l equation, the Engelkinq Trendelenburg  Equation, was developed to assess blue-green losses. The task for the subject i s to match a mixture of X470 nm and X517 nm to a l i g h t of X490 nm. Figure 8 from Lakowski (1981) shows the location of the various equations on the C.I.E chromaticity diagram as determined from colorimetric information form the Pickford-Nicolson Anomaloscope. Thus depending upon the equation used, the anomaloscope can, with a high degree of r e l i a b i l i t y and v a l i d i t y , assess an individual's colour v i s i o n . Indeed, many have referred to the anomaloscope as the "queen" of colour vi s i o n tests (eg. Boynton, 1979; Working Group 41, 1981). With respect to assessment using red-green matches, an individual may be c l a s s i f i e d as a normal trichromat (normal, red-green weak, colour-weak), as a simple anomalous trichromat who may be protonomalous (uses a higher r a t i o of red to green than the trichromat) or deuteranomalous (more green to red), as an extreme anomalous trichromat who may be either an extreme protonomalous (accepts a large range of red-green matches and has a reduced s e n s i t i v i t y to the red end of the spectrum) or extreme deuteranomalous (wide range for red-green r a t i o matches including the green primary), or f i n a l l y as a dichromat (protanope or deuteranope). For a more extensive discussion on colour vi s i o n F i g u r e 8 C o l o r i m e t r i c i n f o r m a t i o n on a n o m a l o s c o p e e q u a t i o n s b a s e d upon t h e P - N a n o m a l o s c o p e . M o d i f i e d f r o m L a k o w s k i (1981, p.22) 72 c l a s s i f i c a t i o n s according to anomaloscopes as well as technique, the reader i s referred to Lakowski(1969). b. Colour Confusion Although the term colour confusion can be generalized to colour matching (as on the anomaloscope) or hue or wavelength discrimination, i t i s dealt with separately here inorder to indicate colour v i s i o n assessment as done with pseudoisochromatic plates. Colour confusion occurs when an indiviudal mistakes one primary colour for that of another. It r e f l e c t s the nature of the mistake made. When one discuses the extent of t h i s mistake (how extreme i t i s ) , one refers to how poor the matching ratios of that individual i s . The concept underlying colour confusion can best be understood in r e l a t i o n to the C.I.E. chromaticity diagram previously shown in Figure 7. The dichromat w i l l confuse two chromaticities that l i e on a specifc axis with a minimal distance between them, unlike a normal who may perceive the two as d i f f e r e n t . However i f the luminosities of the two chromaticities are the same, the dichromat may not be able to discriminate the two even i f the distance between them are great. The discriminating factor here i s whether the chromaticities f a l l along the isochromatic l i n e s for a given dichromat. The isochromatic l i n e s seen in Figure 7 are the confusion l o c i for that p a r t i c u l a r dichromat. It i s 73 important to note that although the confusion l o c i and directions of the l i n e s may vary s l i g h t l y from one individual to another, the confusions for the various defects are systematic and d i r e c t i o n a l (Lakowski, 1982). Pseudoisochromatic plates such as the Dvorine, Ishihara, and Ichikawa's Standard Pseudoisochromatic Plates are constructed on the p r i n c i p l e of colour confusion. The plates contain figure and ground images made up of hues that f a l l along a p a r t i c u l a r confusion axis, ones which are confused by an individual with a s p e c i f i c defect. Thus the pseudoisochromatic plates can grossly categorize individuals on the basis of their confusions. Indeed, the v a l i d i t y of these tests can be assessed by how close the hues on the plates a l i g n themselves to the confusion axis. Colours f a l l i n g outside the axis would not be confused and thereby in v a l i d a t i n g the diagnostic d i s c r i m i n a b i l i t y of the t e s t , as has been shown for example with the Ichikawa (Lakowski, Young and Kozak, 1981). c. Hue or Wavelength Discrimination The term "colour" discrimination refers to the a b i l i t y of the observer to discriminate either small, perceptible differences in surface colurs (eg. Farnsworth-Munsell 100 Hue Test) or spectral or f i l t e r e d , l i g h t s (eg. Koning-Helmoholtz monochromator). Unlike the categorical approach in colour confusion tests 74 (excluding the anomaloscope), the i n t e r v a l - l i k e approach in colour discrimination procedures recognizes the existence of ranges of discrimination a b i l i t i e s . U t i l i z i n g the range (magnitude of error) and the axis of confusion, individuals can be quantitatively and q u a l i t a t i v e l y assessed on t h e i r a b i l i t y to discriminate colours. Colour discrimination may be assessed through wavelength discrimination (AX), matching ranges based on metameric matches on the anomaloscope, and hue discrimination involving surface colours. The most extensively used test for assessing hue discrimination i s the Farnsworth-Munsell 100 Hue test, and, as mentioned above, i t requires the observer to discriminate differences between surface colours. The FM-100 Hue consists of four boxes containing 85 moveable caps. Each cap consists of Munsell colours that are of equal saturation and brightness, with the only difference being in hue. The boxes cover hues ranging from purple to v i o l e t . The caps in each box are presented in a predetermined "randomized" order and the task of the observer i s to rearrange them according to their hues. Error scores are calculated from the misplacements, which are then plotted in either a c i r c u l a r or frequency-by-cap graph form. The degree of lack of discrimination (shown by the size of the error score) 75 and the location of the errors helps d i s t i n g u i s h the type of discrimination problems and i t s severity. Figure 9 shows the idealized discrimination losses c h a r a c t e r i s t i c of the major colour v i s i o n defects. As the discussion of colour v i s i o n testing far exceeds the rather b r i e f outline provided here, the reader is referred to the extensive reviews by Lakowski (1966, 1968, 1969, 1982), Boynton (1979), Pokorny, Smith, Verriest and Pinckers (1979), Mollon (1982), and Mollon and Sharpe (1982). 3. APPLICATION With respect to MS, colour v i s i o n losses are prominent among patients with a history of optic n e u r i t i s and tend to be of the red-green variety (Cox, 1961; Grutzner, 1972; Vola, Riss, Jayle, Gosset & Tassy, 1972; Scheibner & Thronberend, 1974; Serra, 1982; Kupersmith et. a l . , 1983). Although the defect i s of the protan variety as predicted by Kollner's Law (diseases of the optic nerve result in an acquired red-green defect), i t i s not c l a s s i c a l in that the defect tends to have a deutan component to i t (Birch-Cox, 1976). By far, the majority of research in colour v i s i o n has focused upon the use of confusion plates such as the Ishihara. This has probably led to an underestimation of the role colour discrimination may play in assessing both the ANARCHIC SCOTOPIC Figure 9 Discrimination losses on the FM 100-Hue of the major colour v i s i o n defects. From Lakowski (1969, p.274) 77 presence and severity of optic involvement in MS in that pseudo-isochromatic plates are not p a r t i c u l a r l y useful in measuring acquired colour v i s i o n losses (Lakowski, 1981). This i s especially true when one recognizes that the standard colour tests done on MS patients involved colour confusion and not colour discrimination. It has only been within the last decade that attention has focussed upon colour discrimination - mainly surface colours in the Farnsworth-Munsell 100 Hue (FM 100 Hue). Thus Serra and Mascia (1980) reported that v i r t u a l l y a l l of their MS patients (with or without optic n e u r i t i s ) showed either yellow-blue, red-green or anarchic type of losses on the FM 100 Hue. The t o t a l error score increased s i g n i f i c a n t l y i f the patient was presently in a state of acute optic n e u r i t i s . It i s unclear whether patients with a history of optic n e u r i t i s d i f f e r e d s i g n i f i c a n t l y from those who had no optic n e u r i t i s in that the tables provided by Serra and Mascia are not in agreement with th e i r reported sample sizes for the two groups. Wildberger and van L i t h (1976) reported that in the acute phase of optic n e u r i t i s (as assessed on the FM 100 Hue and Farnsworth Panel D-15), 6 of 12 eyes had a red-green defect, 2 of 12 eyes blue-yellow, and 4 of 12 eyes were u n c l a s s i f i a b l e . Four to twenty-four months after the attack, 14 of 20 eyes on the FM 100-Hue and 17 of 20 on the Panel D-15 were normal. In the case of retrobulbar n e u r i t i s (RBN), G r i f f i n and Wray (1978) found that a l l t h i r t y affected and 78 ten nonaffected (no RBN) eyes, had abnormal scores on the FM-100 Hue even though the patients had a recovery in their v i s u a l acuity. No information was made available by the authors as to the nature of the defects. According to Rigolet, Mallecourt, LeBlanc and Chain (1979) and Pokorny et. a l . (1979), the major defect in RBN is of a red-green variety and that t h i s defect i s highly correlated with other c l i n i c a l signs such as abnormal VEP's. Similar findings have been reported by Scheibner and Thranbevend (1974). The interesting feature of MS i s that, although i t i s associated with optic n e u r i t i s , MS patients tend not to show a recovery in colour v i s i o n . The persistence of the defect over time i s equal to that found with RBN. Serra (1982) reported that in a fatigue design (repeated testing of the FM 100-Hue under an illumination of one Lux) MS patients had worse error scores prior to testing than did the normals. Moreover, the colour defect was more frequently of a t r i t a n type. Fatique tended to increase the error scores in MS and non-MS patients with optic n e u r i t i s , but not normals. This was also true of affected versus unaffected (contralateral) eyes of MS patients (see Figure 10). One in t r i g u i n g finding was the presence of colour defects in co n t r a l a t e r a l eyes - a finding that had been reported with RBN (eg. Scheibner & Thranbevend, 1974). In one of the only investigations on colour discrimination of spectral colours (other studies using incremental threshold procedures w i l l be discussed in the 79 150H total score J O O H 50H Affected To 2b 30 76 50 60 MINUTES Figure 10 f ^ E f f 6 £ c ° f * a t i 9 u e °n PM 100-Hue error scores for an MS patient (affected versus una?fected eye) Modified from Serra (1982, p.447) Y 80 subsequent section), Lakowski, Harrison and S t e l l (1985) reported that 70% of MS patients (7 of 10 patients) had colour v i s i o n defects as assessed on the Pickford-Nicolson anomaloscope. A l l were characterized as yellow-blue with half having an additional green-blue loss. Red-green losses were present and showed the greatest difference between MS patients with optic n e u r i t i s versus MS patients with no optic n e u r i t i s . When compared to ocular hypertensives, the MS patients with optic n e u r i t i s had s i g n i f i c a n t l y greater red-green losses. MS patients with optic n e u r i t i s were found to be similar in their anomaloscope equations to glaucomatous patients, possibly suggesting some similar structural-functional pathology in the two c l i n i c a l e n t i t i e s . With respect to the FM 100-Hue, losses among the MS patients were found to be anarchic with no defined axis. Abnormalities in colour v i s i o n through the use of spectral colours has also been assessed with the Gunkel Chromograph (Matthews, K o l l a r i t i s , K o l l a r i t i s , Robinson, Mehelas & Calderone (1983), which involves finding the neutral points for green, magenta, turquoise, red, yellow and blue viewed on a VDT screen. In e f f e c t , the Gunkel Chromograph may be viewed as an automated yet instrumentally poorer version of an anomaloscope. MS patients with a previous history of optic n e u r i t i s were found to have enlarged neutral areas (larger regions of colours were seen as having no colour) than normals even when vi s u a l acuity was 20/20. In another study, Chu, Reingold, Cogan, Hunt and 81 Young (1983) reported the presence of enlarged neutral areas on the Gunkel for MS patients much greater than those for other patients (see Table 6). They also reported sector defects among MS patients for "orange", "cyan", and "turquoise" (no wavelengths s p e c i f i e d ) . With a rather unique method known as F l i g h t of Colours (FOC), where subjects describe the colour and brightness of a positive afterimage, differences in perceived "colour" was noted between MS and normals. After the i n i t i a l stimulation with a coloured l i g h t source (about 30 Lux), the subject is blindfolded and requested to report on the afterimage every ten seconds for a period of about ten minutes. Rolak (1984) reported that MS patients with optic n e u r i t i s had a shorter duration for the presence of the afterimage than normals and that the FOC cor r e c t l y i d e n t i f i e d 126 of 134 eyes. No information regarding the actual durations were provided by the author. Similar results have been reported by Minderhoud, Smits, Kuks, and ter Steege (1984) in MS patients with a history of retrobulbar n e u r i t i s . In addition to the shortened l i f e of the afterimages (less than 175 sec. for MS compared to 278.5 sec. for normals), Minderhoud et a l . reported that for MS patients the afterimage duration was esp e c i a l l y short for the colours red, purple, and blue. Thirty-one percent of the patients had their afterimages r e s t r i c t e d to only one colour or reported none at a l l . Unfortunately, no information was provided as to wavelengths 82 TABLE 6 Neutral Colour Area of Patient Groups As Determined by the Gunkel Chromograph Diagnosi s Mean Neutral Area Major Colour Area Increase (r e l a t i v e Involved to normals) R e t i n i t i s Pi gmentosa (n=38) 14.50 Marked yellow, moderate blue Macular Degenerat i on (n = 8l ) 6.54 Marked yellow, moderate blue Optic N e u r i t i s or Atrophy (n=20) 6.08 Mild orange, mild cyan Multiple S c l e r o s i s (n=28) Rheumatoid A r t h r i t i s (n=l9) 5.54 3.46 Moderate orange Mild yellow Systemic Lupus Erythematosis (n=68) 2.00 Mild yellow Modified from Chu et a l . (1983) 83 nor their s p e c i f i c durations. It i s apparent, therefore, that colour v i s i o n abnormalities are prevalent in MS. Red-green defects are associated in MS patients with a history of optic n e u r i t i s and retrobulbar n e u r i t i s and are possibly i n d i c a t i v e of either a longer duration or severity of the disease. Unfortunately, no study has been published either l o n g i t u d i n a l l y nor c r o s s - s e c t i o n a l l y as to how colour vi s i o n may change over time in MS - a change which may hopefully be similar to that observed in d i f f e r e n t stages of glaucoma (eg. Lakowski, 1981). J. PERIMETRY Attempts at assessing vi s u a l functioning, e s p e c i a l l y colour v i s i o n in the peripheral retina creates numerous problems. The researcher must be aware of factors such as the rapid decrease in acuity with increasing e c c e n t r i c i t y (Aulhorn, 1960), r e f r a c t i v e error causing blurred target images with reduced intensity (Aulhorn & Harms, 1972), rapid l o c a l adaption (Troxler's e f f e c t ) , changes due to aging (eg. Lakowski & A s p i n a l l , 1969; Verriest & U v i j l s , 1977a, 1977b), colour vi s i o n defects (eg. Verriest & U v i j l s , 1977b; Lakowski, Wright & Oliver, 1977), and poor f i x a t i o n as well as previous experience of the subject (Aulhorn & Harms, 1972) to name just a few. 84 Of pa r t i c u l a r importance, and possibly one of the most problematic, i s the question of the effect of stimulus area and stimulus luminance on absolute thresholds. This e f f e c t , known under the general heading of s p a t i a l summation depends upon numerous factors such as stimulus duration and chromaticity, and w i l l be discussed l a t e r . Despite these intravening variables, the assessment of " l i g h t sense" (Wentworth, 1930) through s t a t i c and kinetic (dynamic) perimetry has become one of the most valuable methods in both experimental and c l i n i c a l a p p l i c a t i o n . Perimetry has advanced over the years from a purely subjective evaluation of a patient's response to the presence or absence of coloured stimuli presented by the examiner to their s t r i c t e r evaluation of rod, cone, and rod/cone functioning under specified background and target luminances/wavelenghs (Lakowski & Dunn, 1981; Dunn & Lakowski, 1981). Indeed some researchers as Enoch (1978) fe e l that s t a t i c perimetry allows one to examine the retina layer-by-layer, providing a completely noninvasive method for l o c a l i z i n g and d i f f e r e n t i a t i n g various r e t i n a l / v i s u a l pathologies. As mentioned e a r l i e r , the two basic perimetric methods are k i n e t i c and s t a t i c . Kinetic perimetry d i f f e r s from s t a t i c in that the former involves assessing where in the v i s u a l f i e l d the subject senses a stimulus while luminance (among other variables) remains constant. This process of moving a stimulus from unseen to seen i s repeated on various 85 meridians, resulting in horizontal bearings (isopters) of what Traquair (1949) referred to as the " h i l l " of vi s i o n (see Figure 11). Stat i c perimetry involves choosing some r e t i n a l position to which a stimulus i s presented in decreasing and increasing le v e l s of luminanace u n t i l a threshold i s determined. These thresholds (Figure 11) represent the v e r i t i c a l soundings or p r o f i l e s of the three dimensional h i l l of v i s i o n (Anderson, 1982). Isopter perimetry provides information regarding the shape of vis u a l capacity as well as charting the presence of large, deep depressions (scotomas) whereas p r o f i l e perimetry enables one to determine the altimetry of a h i l l , regardless of shape as well as small shallow depressions along a s p e c i f i c meridian. Although p r o f i l e perimetry could be used to map out the v i s u a l f i e l d as in isopter perimetry, the process would be too time consuming as i t would necessitate measuring thresholds for a number of e c c e n t r i c i t i e s along a large number of meridians. Thus each method, kinetic versus s t a t i c , provides the researcher with a s p e c i f i c (isopter versus p r o f i l e ) assessment of the v i s u a l f i e l d - the method of interest being determined by the problem under investigation. For further information regarding the two techniques the reader is referred to Reed and Drance (1971), Aulhorn and Harms (1972), Tate and Lynn (1977) and Anderson (1982). 86 Figure 11 Isopter and p r o f i l e perimetry plots in r e l a t i o n to the r e t i n a . Modified from Anderson (1982). 87 Unlike s t a t i c perimetry, kinetic perimetry i s limited in that the speed at which the stimulus is brought into the f i e l d complicates threshold interpretation. Both temporal and s p a t i a l summation factors interact in a highly complex manner, which, along with the response speed of the subject, make i t d i f f i c u l t to assess which variable or combination thereof i s a f f e c t i n g the threshold. Moreover, as kinetic perimetry uses stimuli at suprathreshold values, i t i s not possible to explore points between two isopters, i . e . , r e l a t i v e scotoma are d i f f i c u l t to assess (eg. Verriest & I s r a e l , 1956; Sloan, 1961; Aulhorn & Harms, 1972). Conversely, s t a t i c perimetry, with i t s use of invariant stimulus duration, controls confounding e f f e c t s due to temporal summation. By manipulating stimulus siz e , s p a t i a l summation effects at d i f f e r e n t e c c e n t r i c i t i e s can be evaluated (eg. Sloan & Brown, 1962; Dunn & Lakowski, 1981). Of greater importance, from a c l i n i c a l standpoint, s t a t i c perimetry enables one to examine f i e l d losses (thresholds for s p e c i f i c stimuli such as wavelength and size) under controlled conditions (eg. scotopic vs. photopic). As such, s t a t i c perimetry affords one with an excellent method for assessing r e t i n a l change. As the c l i n i c a l l i t e r a t u r e on MS appear to indicate that the functioning of the macula i s the e a r l i e s t and possibly most affected of the v i s u a l systems, i t i s the b e l i e f of the writer that the assessment of r e t i n a l s e n s i t i v i t y to chromatic stimuli under specfic l e v e l s of 8 8 preadapatation w i l l provide the most sensitive measure of the presence and severity of MS. Therefore the following sections w i l l focuss primarily upon chromatic s t a t i c perimetry. 1. CHROMATIC PERIMETRY Chromatic perimetry was f i r s t introduced by Aubert as early as 1857 wherein he and Forester studied the d i s t r i b u t i o n of space and colour perception in the v i s u a l f i e l d (Aulhorn & Harms, 1972). Aubert believed that both space and colour perception were related to " l i g h t perception", a be l i e f which became the basis for using stimuli of varying sizes and colours. Hess (1889), Engelking and Eckstein (1920), and Feree and Rand (1924) employed pigmented targets in examining colour s e n s i t i v i t y and colour defectives. Due to the d i f f i c u l t y in equating pigments, Lauber (1932) introduced the use of interference f i l t e r s in a projection pathway. These techniques, however, focussed upon kinetic perimetry and i t was not u n t i l Sloan (1939) that ' s t a t i c ' procedures were used to assess l i g h t perception at s p e c i f i c r e t i n a l posit ions. The s t a t i c method enabled Goldmann (1945a, 1945b) to develop and outline the variables important in modern experimental/clinical s t a t i c perimetry. Despite these gains, Dubois-Poulsen's (1952) c r i t i c i s m s of chromatic perimetry, 8 9 that i t did not provide any more information than using achromatic st i m u l i , e f f e c t i v e l y stopped research for almost a decade. It was the research by Verriest and his associates (eg. Verriest & I s r a e l , 1965; Francois, Verriest & I s r a e l , 1966; Verriest & U v i j l s , 1977) which began to seriously re-examine the use of coloured stimuli in studying normal and abnormal v i s u a l functioning. Since then, others such as Hansen (1974), Genio and Friedman (1981), Lakowski, Wright and Oliver (1977) and Lakowski, Drance and Carsh (1980) have extensively studied wavelength s e n s i t i v i t y in normal and abnormal eyes with other techniques such as dark adaptation. 2. THRESHOLD ESTIMATION Threshold determination in s t a t i c perimetry for chromatic stimuli can be done through one of three ways: 1) luminance, 2) hue, and 3) f l i c k e r (luminance providing 1. Of the three, only luminance and hue w i l l be discussed. F i r s t , as in achromatic perimetry, chromatic perimetry thresholds can be based upon the luminance of the stimulus. Here, where the stimulus i s of some s p e c i f i c wavelength, the subject responds when he f i r s t detects the presence of the stimulus. The detection i s based upon luminance alone and not the wavelength. In the second method, thresholds are determined from the detection of the hue of the stimulus alone. This second approach, the chromatic threshold, i s the most d i f f i c u l t due 90 to intra-subject v a r i a b i l i t y . Large v a r i a b i l i t y exists in thresholds found through the chromatic detection method due to psychological variables such as knowledge of the wavelengths during testing as well as the saturation l e v e l of which the colour must be. This alone, the problem of saturation, is a source of great intrasubject v a r i a b i l i t y . Equally important, the establishment of thresholds based upon hue are complicated by the photochromatic i n t e r v a l which depends upon wavelength, r e t i n a l area, target siz e , exposure time, and adaptation l e v e l as a stimulus s h i f t s from achromatic to chromatic (Aulhorn & Harms, 1972). 1 The time duration of the photochromatic i n t e r v a l depends upon the wavelength, with long wavelengths having the shortest interval and being nearly nonexisitent in the fovea. As noted by Aulhorn and Harms, even i f one were able to e s t a b l i s h r e l i a b l e chromatic thresholds, they could not be equated to " l i g h t perception perimetry" (luminance threshold). The reason for th i s i s that hue differences can be seen even when luminance i s constant between two hues. At most, in the case where background and target luminance i s constant, one i s detecting hue-difference s e n s i t i v i t y and not l i g h t s e n s i t i v i t y . Because of these d i f f i c u l t i e s , research in chromatic perimetry has centered primarily upon the luminance threshold method in steady state conditions (non f l i c k e r ) . 1The photochromatic in t e r v a l refers to the range from absolute rod threshold to the detection of a hue. 91 Although susceptable to numerous factors as b r i e f l y outlined in Table 7 , luminance thresholds, when done c a r e f u l l y , y i e l d r e l i a b l e results with inter-subject v a r i a b i l i t y greater than intra-subject v a r i a b i l i t y . It i s a much easier task to detect the presence (intensity) of a l i g h t than i t s presence plus hue. The remainder of the discussion w i l l focus upon achromatic perception of d i f f e r i n g wavelengths. Luminance threshold refers to the noticeable contrast between the luminance of a target and i t s background. This photometric difference between the two luminance leve l s may be expressed as; AL/L Where, AL = Difference between stimulus and background luminance L = Background Luminance The reciprocal of the AL/L provides a measure of d i f f e r e n t i a l s e n s i t i v i t y . When speaking of thresholds in terms of i n t e n s i t i e s as perceived by the observer, the equation can be rewritten into a form described by Weber's Law: AI/I Where, TABLE 7 Fa c t o r s E f f e c t i n g Parlmetry ( K i n e t i c and S t a t i c ) M e t h o d o l o g i c a l PraracaotoraI B a t i n a l Poat Receotoral P s y c h o l o g i c a l 1> F i x a t i o n C o n t r o l I) P u p i l S i z e 1 ) R e t i n a l Adaptation 1) C M S . S t a t u a -1 ea 1 one 1> Mot 1 vat Ion 2) P r e a d a p t a t i o n Luminance Laval » D u r a t i o n a) Ocular Media a) Vtaual Angle - I n f e c t lone -tumora a) Paat Experience 3) Pigmentation ( I r i s ) 3) Pigmentation ( R e t i n a l ) -chemicals ( L e a r n i n g ) 3) Background * Stimulus -inflammatlone Luminance Level 4) Ocular S t r u c t u r e (eg. tmmetropla) 4) R e t i n a l E c c e n t r i c i t y 3) At tent Ion Level 4) Background ft Stimulus Wavelength 9) Corneal A b e r r a t i o n s 9) S p a t i a l I n t e r a c t i o n s a) lechemtc Problema 4) Dec l a Ion C r i t e r i o n 6> Temporal I n t e r a c t i o n s 3) Movement S e n s i t i v i t y S) R e a c t i o n Time S ) Stimulus S i z e 6) Eye Movement ( O r b i t a l Muscle Involvement) 7) P h y s i o l o g i c a l Status 4) O l f f e r e n c e e In Informa- «) Personal 1ty 6) Stimulus D u r a t i o n (On » O f f I n t e r v a l s ) (eg. Presence of nerve F i b r e Layer O e f e c t s ) t i o n P r o c e s s i n g (eg. S p a t i a l versus Temporel 1) 7) T h r e s h o l d E s t i m a t i o n 8) Cone/Rod Status Procedure (eg. Ascending (ag. Rod Monochromat) veraua Oeacendlng) M o d i f i e d from Committee on V i s i o n (1975). p. 10. 93 AI = Difference between stimulus and background intensity I = Intensity of the background AI/I refers to the just noticeable difference required in establishing the r e l a t i v e threshold for a s p e c i f i c stimulus si z e , wavelength, and e c c e n t r i c i t y . The smaller the obtained value, the more sensitive i s that p a r t i c u l a r r e t i n a l e c c e n t r i c i t y . Prior to discussing s p e c i f i c variables relevant to establishing r e l a t i v e thresholds, i t is necessary to b r i e f l y discuss the problem of equating coloured stimulus i n t e n s i t i e s . Coloured stimuli may be matched either radiometrically or photometrically. The radiometric method involves specifying stimuli by their physical energy c h a r a c t e r i s t i c s whereas photometric e n t a i l s correcting and matching stimuli on the basis of VX (spectral s e n s i t i v i t y of the fovea). Radiometric matching views v i s u a l functioning as being equal to the physical c h a r a c t e r i s t i c s of the organ (the eye) and l i g h t . Proponents of the radiometric approach argue that the photometric method is not appropriate as VX i s not representative of the entire retina (Aulhorn & Harms, 1972). The d i f f i c u l t y with the radiometric approach, however, i s that i t i s an instrumental - physical method of specifying s t i m u l i . It removes from the researcher the only human 94 standard available to him, the invariant foveal threshold. In the photometric method where one matches spectral stimuli on the basis of VX, a psychophysical adjustment, the researcher i s able to establish differences between observers and not remove them as in the radiometric method. In perimetry involving radiometric matches, findings t y p i c a l l y result in high foveal thresholds for red and blue stimuli as compared to achromatic and green stimuli (Aulhorn and Harms, 1972). These r e l a t i v e differences, as noted by Lakowski and Dunn (1981), result e n t i r e l y from VX . By removing the effects of VX by photometrically equating the s t i m u l i , a psychophysical method, the foveal thresholds would be standardized for luminance, allowing one to assess chromatic s e n s i t i v i t y in the retina (eg. Lakowski, Wright & Oliver, 1976). Photometric equivalence also plays an important role in the periphery. If not photometrically equated, thresholds in the periphery for chromatic stimuli may vary in s e n s i t i v i t y as well as r e l a t i v e luminous e f f i c i e n c y - a problem which effected e a r l i e r researchers discussed by Aulhorn and Harms. 3. ADAPTATION The luminance l e v e l to which the eye has become adapted greatly e f f e c t s the increment thresholds for chromatic and achromatic s t i m u l i . The effect is presumably due to the complex interaction between luminance, cones and rods. 95 Unfortunately, due to early experimenter bias and instrument problems, very few studies have been done with chromatic stimuli and adaptation l e v e l s . One of the f i r s t examinations of chromatic increment thresholds and luminance background was Wentworth (1930). Using monochromatic stimuli of X672.5, X581.5, X522 and X468 nm under scotopic conditions, Wentworth reported d i f f e r e n t i a l s e n s i t i v i t i e s across the retina (0 to 180 degrees meridian) for the various s t i m u l i . As seen in Figure 12, the increment thresholds were higher for red and blue than green or yellow in the periphery. Similar results to Wentworth have been reported by Sloan (1939) and Nolte (1962). With respect to the fovea, a similar relationship was found except that there was l i t t l e difference between the green and yellow. The implications behind Wentworth's findings are d i f f i c u l t to state in that the difference in the foveal thresholds may have been due to; (1) her use of radiometric units, and (2) the p o s s i b i l i t y of poor f i x a t i o n under scotopic conditions resulting in higher s e n s i t i v i t e s in the parafovea (stimuli were 1' 16" of visu a l angle). Under photopic conditions using stimuli of equal i n t e n s i t i e s but not s i z e , Nolte (1974), Verriest and Israel (1965) and Ronchi and Galassi (1976) among others reported the presence of a central scotoma for increment thresholds with a "blue" stimulus. No such scotoma, however, was found by Lakowski and Dunn (1979) when the chromatic and Figure 12 Achromatic thresholds at 0 asb background for 4 monochromatic l i g h t s . Stimulus size = 1° 16' Modified from Aulhorn & Harms (1972, p.122) 97 achromatic stimuli were photometrically equated and size was kept constant. This finding was not due just to the method of matching but probably more so to the fact that the "blue" scotoma i s found with small targets only. In addition to the method by which stimuli were equated, the finding of a "scotoma" for short wavelengths may have been due to problems with f i x a t i o n . Under scotopic conditions, such as that used by Nolte, f i x a t i o n becomes d i f f i c u l t to maintain. Any s h i f t in f i x a t i o n w i l l result in higher s e n s i t i v i t i e s at adjacent parafoveal areas, thereby creating a r e l a t i v e scotoma. Again photometrically equating their s t i m u l i , Lakowski and Dunn (1981) reported that differences in the gradients for a blue (475 nm), green (582 nm), red (630 nm) and an achromatic stimulus in the periphery increased as the adaptation luminance decreased. As can be seen in Figure 13, the separation was greatest at the fully-scotopic (rod) level (0 cd/m2 ). When increased to the fully-photopic (cone) l e v e l of 250 cd/m2, the gradients were less separated due to the luminosities being photometric equated. The larger s h i f t for the scotopic l e v e l was probably due to the Purkinje s h i f t , a s h i f t in s e n s i t i v i t y towards the blue end of the spectrum under scotopic conditions. This difference in r e l a t i v e luminosity e f f i c i e n c y ( s e n s i t i v i t y ) for rods (510-512 nm) and cones (550-555 nm), shown in Figure 14, became the f i r s t psychophysical evidence for a dual receptor system (Duplicity Theory) in the reti n a . Photopic (VX) and 98 -3.0 -2.0 -a u o > t— m Z UJ <J~> -1.0 1.0 2.0 3.0 «i0' a A -• • • ' ' I 1 I I I I f .O -a O 11 • i 3 O • • • O o I c CNl 0' N 4 0 ' S c o t o p i c Mesopic P h o t o p i c F i g u r e 13 S t a t i c t h r e s h o l d s for f u l l y - p h o t o p i c , mesop ic , and f u l l y - s c o t o p i c c o n d i t i o n s . S t imulus s i z e = 6.8' v i s u a l a n g l e , b l u e ( • ) , green ( o ) , red ( A ) , and achromat i c (A) From Lakowski & Dunn (1981, p .196) Standard r e l a t i v e spectral luminous e f f i c i e n c y functions for photopic and scotopic v i s i o n . From Lakowski, Dahl & Rawicz (1982, p.1). 100 scotopic (VX') s e n s i t i v i t y greatly e f f e c t s increment thresholds for chromatic stimuli as seen in the question of radiometric versus photometric (VX) equivalences and the p o s s i b i l i t y of rod a c t i v i t y (VX') in Wentworth's study. Although researchers such as Wentworth (1930) Wooten and Fuld & Spillman (1975), and Verdun Lunel and Crone (1974) have reported d i f f e r e n t i a l s e n s i t i v i t y across the retina for chromatic stimuli under varying background luminance l e v e l s , the results by Lakowski and Dunn (1981) are of extreme importance with respect to the fovea. In addition to the accepted b e l i e f that there is an inverse relationship between increment s e n s i t i v i t y and background adaptation even at the fovea, Lakowski and Dunn reported no d i f f e r e n t i a l s e n s i t i v i t y for the fovea within adaptation lev e l s except at the mesopic l e v e l (blue and red having lower thresholds than the green and achromatic stimuli) as well as the photopic l e v e l . As discussed e a r l i e r , t h i s finding was opposite to that of e a r l i e r research and can be attributed to the author's use of photometric equivalence. Thus, contrary to Hedin and Verriest (1980), increment thresholds under photopic adaptation do not vary greatly with e c c e n t r i c i t y for d i f f e r e n t wavelengths whereas they do in the periphery for red under f u l l y - s c o t o p i c conditions. Despite differences in the foveal area, Nolte's (1962) results in the parafovea under mesopic and scotopic adaptation agreed with Lakowski and Dunn (see Figure 13). 101 4. SPATIAL SUMMATION In addition to adaptation luminance, the size of the stimulus effects increment thresholds. Increment thresholds, depending upon stimulus si z e , chromaticity and duration, tend to decrease with increasing stimulus s i z e . Various attempts have been made to quantify the relat i o n s h i p as an index of s p a t i a l summation would provide one with information on receptive f i e l d s i z e . Aulhorn and Harms (1972) state that luminance and stimulus area are inversely related for thresholds based upon small targets. In the fovea, summation for small targets less than 10' appears to follow Ricco's Law of Complete Spatial Summation (Luminance x Stimulus Area = summation constant). However, in the periphery of the retina, Piper's Law of P a r t i a l Summation (Luminance x Stimulus Area' 5 = summation constant) appears to be true for stimuli up to 1° (Baumgardt, 1972). Although kinetic isopter perimetry has been used to determine summation c o e f f i c i e n t s (Goldmann, 1945a, 1945b), i t should be pointed out that summation ratios should only be established by varying stimulus size at one s p e c i f i c r e t i n a l location, removing any temporal e f f e c t s , i . e . they should be established through s t a t i c perimetry. In his research on kinetic perimetry, Goldmann defined the relationship between luminance and area for thresholds as 'k', the exponent of summation. The summation exponent 102 was defined by Goldmann as: $ = (F 0/F) where where $ i s the transmitance required from a neutral density f i l t e r to maintain a f i e l d size with a stimulus of size F 0, using a stimulus with a size of F. The k exponent can vary from no summation (k=0) to complete summation (k=l). Goldmann reported that, for the kinetic perimeter, a k value of 0.84 expressed the relat i o n s h i p in his data. Since i t i s assumed that there i s an inverse r e l a t i o n s h i p between luminance and stimulus area, the c o e f f i c i e n t of s p a t i a l summation can be rewritten as: L x A To describe a change in k with a change in stimulus area, the above may be rewritten as: k = Log L 1 - Log L 2 Log A 2 _ Log a. Although the above may be used to provide a measure of s p a t i a l summation, i t applies only to absolute thresholds rather than increment thresholds for photopic and mesopic levels (Baumgardt, 1972). To estimate the increment thresholds for stimuli of d i f f e r e n t area, i t i s necessary to 103 substitute AL for L. In the si t u a t i o n where increment thresholds are obtained at d i f f e r e n t adaptation luminances, AL/L could replace L as AL i s proportional to adaptation luminance. Therefore, using either AL or AL/L, k values obtained for absolute thresholds may be estimated for increment thresholds by: 1 k = Log ALj - Log AL 2 Log A 2 - Log A, a. Relevant Literature Calculating the summation c o e f f i c i e n c t (K) on the basis of the slope and separation between s e n s i t i v i t y gradients, Fankhauser and Schmidt (1958, 1960) and Dannheim and Drance (1971) reported increased summation in the periphery of the retina when compared to the fovea, and that summation decreased with increasing stimulus s i z e . Moreover, they reported an increase in summation with increasing background luminances (0.013-12.7 cd/m 2). S i m i l a r i l y , Sloan (1961) and Sloan and Brown (1962) reported an inverse relationship for achromatic stimuli between stimulus size and increment thresholds using Goldmann sizes of I-V (1/4,1 4,16,64 mm.). Plo t t i n g 'k' 1 Note: k here expresses the relationship found under conditions of constant adaptation illumination. 104 from: LogL + kLogA Where, L = Luminance threshold A = Stimulus area Sloan and Brown found that the summation c o e f f i c i e n t varied greatly for normals and patients with central serous retinopathy. As with Fankhauser and Schmidt (1958) and Gourgnard (1961), Sloan reported increasing summation in the periphery. Dunn and Lakowski (1981) investigated s p a t i a l summation for chromatic stimuli (red and blue) with Goldmann sizes I, I I , I I I , and IV (1/4, 1, 4, and 16 mm) under fully-photopic, mesopic, and scotopic adaptation. Summation c o e f f i c i e n t 'K' was similar for the red (617 nm), blue (474 nm) and achromatic stimuli in the fully-photopic and mesopic conditions. The summation c o e f f i c i e n t s for red and blue increased with e c c e n t r i c i t y and stimulus s i z e . Spatial summation for red and blue, however, varied under scotopic adaptation in that neither changed in a consistent manner for either e c c e n t r i c i t y nor stimulus s i z e . Moreover, the red under scotopic adaptation gave larger values for 'K' than did the blue. As noted by the authors, this l a s t finding was probably due to the fact that the two 105 stimuli were photopically and not scotopically equated. As with previous studies, Dunn and Lakowski reported large variances in the summation c o e f f i c i e n t s leading them to argue that research should focus upon designs employing equivalent experimental conditions rather than seeking " s i g n i f i c a n c e " in i t s [summation c o e f f i c i e n t ] absolute value" (Dunn & Lakowski, 1981, p. 205). Thus keeping in mind that intravening variables such as age (general reduction in s e n s i t i v i t y - Lakowski & A s p i n a l l , 1969; Verriest & U v i j l s , 1977a), ref r a c t i o n (Aulhorn & Harms, 1972), colour vision abnormalities (Hedin & V e r r i e s t , 1980), and knowledge of stimulus position (Engel, 1971) can a f f e c t the increment thresholds and therefore the summation c o e f f i c i e n t , i t i s indeed d i f f i c u l t to evaluate the significance of summation as i t may only r e f l e c t variances in l i g h t s e n s i t i v i t y alone. 5. APPLICATION With respect to MS, v i r t u a l l y a l l perimetric studies (kinetic and s t a t i c ) report the presence of small r e l a t i v e scotoma both in the periphery and fovea. Serra and Mascia (1982), using an achromatic stimulus in a Goldmann perimeter (size II/2) with an unspecified background found central scotoma in a l l of their patients with MS. The majority of defects were found among those patients with a previous 106 history of optic n e u r i t i s - a finding found consistently in other research. P r o f i l e perimetry results with their patients indicated higher thresholds among recent MS patients in both the affected and unaffected eye. This i s equally true of optic n e u r i t i s alone (eg. Johnson & Keltner, 1984). Unfortunately, i t i s d i f f i c u l t to evaluate the results as no information i s provided regarding stimulus and background s p e c i f i c a t i o n s (eg.luminance l e v e l s ) . Van Dalen, Spekreyse and Greve (1981) assessed the visu a l f i e l d s of 29 MS patients by (1) Friedmann visu a l f i e l d analyzer, (2) kinetic perimetry, and (3) s t a t i c perimetry. Forty-six eyes of 58 showed abnormal v i s u a l f i e l d s as well as abnormal VERs. Although no mention was made of stimulus (presumably achromatic) nor background s p e c i f i c a t i o n s , the authors reported a central defect in six eyes, a central defect and "a defect in the intermediate visu a l f i e l d " (p.80) in 28, and a defect only in the intermediate f i e l d in 12. The defects tended to occur only between 10 degrees to 30 degrees e c c e n t r i c i t y . Static perimetry (Figure 15) shows a reduced threshold along the 45-225 degree meridian as compared to a normalized curve. Although Van Dalen et. a l . report the presence of patchy, small scotoma 10- 20 degrees temporally, the interpretations of t h i s i s limited in that no stimulus nor adaptation s p e c i f i c a t i o n s were provided nor was there any mention of correcting for r e f r a c t i v e error. As MS patients with optic n e u r i t i s have lowered acuity, one would need to 107 45° - 2 2 5 ' M e r i d i a n F i g u r e 15 S t a t i c t h r e s h o l d s ( 4 5 ° - 2 2 5 ° ) o f t h e r i g h t e y e ( a s y m p t o m a t i c ) o f an MS p a t i e n t . M o d i f i e d f r o m V a n D a l e n , S p e k r e y s e & G r e v e (19 .81 , p .81 ) 108 know i f they were accordingly corrected in the studies mentioned. Moreover, since their figure was of a patient with the right eye, the patchy scotoma in the region of 10 -20 degrees temporally may have been caused by f i x a t i o n d i f f i c u l t i e s s h i f t i n g the area of the l i g h t onto the optic nerve (blind spot). One consistent finding in t h i s study that has been reported elsewhere (Lowitzsch, 1980) i s that Friedman perimetry, involving s t a t i c thresholds, detected more defects in MS patients than kinetic perimetry. Provided there are no other methodological reasons (luminance levels of background et c . ) , t h i s difference between s t a t i c and kinetic perimetry i s undoubtedly due to the issues raised e a r l i e r . Meienberg, Flammer and Ludin (1982) examined 14 d e f i n i t e MS patients and 17 normals with the Octopus, an automatic perimeter. Using a target size of 0.43 degrees on a background luminance of 1.27 cd/m2, subjects who were corrected for acuity were examined with programs 33 and 34 (central f i e l d with a radius of 30 degrees). Eleven of the thirteen patients had abnormal f i e l d s , with the center being spared and losses in s e n s i t i v i t y occurring in the periphery. The defects tended to be patchy r e l a t i v e scotoma between 15 and 30 degrees e c c e n t r i c i t y and were shallow in depth. Similar findings with manual perimeters have been reported by Frisen and Hoyt (1974). 109 Patterson and Heron (1980), using a tangent screen with a background luminance of 2.4 cd/m2, reported v i s u a l f i e l d defects among 46 of 53 MS patients and 12 of 13 optic n e u r i t i s patients with no MS. Using an achromatic stimulus (1 mm) moved "c e n t r i p e t a l l y at r a d i a l intervals of 30° and at a speed of about 1.5°/sec (p. 205), the authors reported f i e l d defects for suprathresholds (target luminance at 172 cd/m2) among 100% of d e f i n i t e MS patients (9/9), 94% of the probable MS (15/16), 81% of the possible MS (13/16), and 75% of the MS patients with no history of vi s u a l complaints. Of the defects, 76% were arcuate scotoma, 14% l o c a l i z e d depression, 13% generalized depression, and 4% a paracentral scotoma. The high percent of v i s u a l f i e l d defects among MS patients with no history of v i s u a l complaints contradicts the results by Ellenberger and Ziegler (1977) who were unable to fin d any among 25 similar MS patients. Patterson and Heron argue that the negative findings of Ellenberger and Ziegler was due to their use of the Goldmann perimeter, which they claim can not e a s i l y detect narrow r e l a t i v e scotoma. E a r l i e r research using tangent screen have also reported small r e l a t i v e scotoma (central or paracentral) among MS patients (Paton, 1924; Scott, 1957). Beck, Savino, Schatz, Smith and Sergott (1982) reported homonymous hemianopea among MS patients, confirming the e a r l i e r results of Kurtzke, Beebe, Nagler, Auth, Kurland and Nefzger (1968). Unfortunately, neither study provided information as to the conditions nor sp e c i f i c a t i o n s under 110 which the patients were examined on the Goldmann. Only one study in the l i t e r a t u r e appears to have focussed i t s e l f upon increment thresholds for colours. Lakowski (1968) examined the thresholds of an MS patient to two chromatic s t i m u l i , one at 570 nm (cone vision) and the other at 495 nm (rod v i s i o n ) . When dark adapted on a Goldmann/Weekers adaptometer, rod functioning was normal and only during the i n i t i a l phase of dark adaptation was there any evidence of s l i g h t impairment. Examination of the patient on a Goldmann perimeter for s t a t i c p r o f i l e s along a horizontal meridian (0 - 180 degrees) under normal levels of adaptation (9.87 cd/m2) revealed extensive r e t i n a l threshold losses. As seen in Figure 16, thresholds revealed losses under mesopic and photopic conditions. Foveal s e n s i t i v i t y was reduced by two log units and v i s i o n was r e s t r i c t e d to 10 degrees e c c e n t r i c i t y for photopic adaptation. Thus of the two receptor systems, the cones (photopic) appear to be the most sensitive to the demyelination effects of MS. This i s supported by the work of F o l l o w f i e l d and Krauskopf (1984) who reported greater threshold losses for MS patients in the chromatic channel (wavelengths not specified) as compared to the achromatic (0.4 log units versus 0.2 for the l a t t e r ) . Subjects were required to respond to changes in chromaticity from white on a background of 300 cd/m2. Although no information was provided regarding their respective wavelengths, losses occurred across the four hues (see Figure 17), with the yellow possibly showing more of a loss I l l Figure 16 Mesopic and photopic thresholds for an MS patient. From Lakowski (1968, p.97) 112 Figure 17 Thresholds of colours generated on a televison screen for normals and MS patients (affected and unaffected eyes. Modified from F a l l o w f i e l d & Krauskopf (1984, p.773) 113 than the other three. Although Followfield and Krauskopf employed a di f f e r e n t method (t e l e v i s i o n monitor generating their unspecified wavelengths), their reported losses under photopic conditions as well as Lakowski's (1968) for photopic and mesopic c l e a r l y indicate the importance of assessing cone functioning in MS. Similar threshold losses for a red LED stimulus under varying luminance backgrounds having been reported by Patterson, Foster and Heron (1980). Five MS patients were preselected on the basis of having had abnormally variable visual thresholds as previously assessed on an unknown screen (no specifications provided). Wearing neutral density f i l t e r s , the patients were adapted to a background with either 0, 1.0, 2.0, or 3.0 log cd/m2 luminance. Thresholds were established for a red LED (625 nm) subtending 11 degrees and presented in the centre of four small white l i g h t s ( i n t e n s i t i e s unknown). Plotted in terms of Frequency of Seeing curves (assumes that the underlying d i s t r i b u t i o n of AI i s normal), the MS patients demonstrated greater variance in their thresholds across the 1.0, 2.0 and 3.0 log cd/m2 adaptation coditions. A l l of the MS thresholds were s i g n i f i c a n t l y higher than those for five normals across a l l of the adaptation conditions. Thus i t appears that, with respect to perimetry, MS losses appear to be greater under photopic and mesopic conditions. Less v a r i a b i l i t y from normals appear under pure 1 14 rod functioning, that is scotopic v i s i o n . Though such a statement needs to be c a r e f u l l y guarded due to the lack of precise perimetric s p e c i f i c a t i o n s in v i r t u a l l y a l l of the studies reviewed, these results along with the changes seen in colour v i s i o n discussed e a r l i e r would appear to suggest that s t a t i c perimetry on cone functioning under mesopic and photopic conditions might provide the means through which both the presence and severity of MS may be evaluated. 6. HYPOTHESIS A review of the l i t e r a t u r e has indicated that MS i s characterized by both structural and functional changes in the r e t i n a . S t r u c t u r a l l y , MS has shown the presence of optic atrophy, optic n e u r i t i s , r e t i n a l venous sheathing, and defects in the r e t i n a l nerve f i b r e layer. In addition, imaging techniques (eg CT scans) have revealed the extensive presence of plaques in the white matter. More importantly, post mortem examinations have shown a high degree of plaque involvement in the optic nerves. Functionally, MS patients have shown abnormal evoked potentials with respect to increased latencies and reduced amplitudes -- a finding which appears to be highly consistent for v i s u a l l y evoked potentials. Attempts made at d i f f e r e n t i a t i n g central versus peripheral v i s u a l stimulation with evoked potentials appears to improve detection of MS. 1 15 In addition losses have been found for s p a t i a l contrast s e n s i t i v i t y in the low and intermediate frequencies, with some MS patients showing high s p a t i a l frequency l o s s . Temporal losses have also been reported, with MS patients exhibiting greater delay than normals. Of luminance and chromatic, there i s some evidence to suggest that temporal processing of colour i s the most affected of the two. Probably the most sensitive indicants of the e f f e c t s of demyelination has been v i s u a l assessment through colour v i s i o n testing and perimetry. Extensive colour v i s i o n losses have been reported among MS patients, with red-green being the most predominant loss as assessed by the anomaloscope. Assessment on the FM-100 Hue has t y p i c a l l y shows the loss as anarchic. Perimetric (kinetic and s t a t i c ) studies with achromatic stimuli have demonstrated the presence of central and peripheral scotoma as well as an ov e r a l l loss in s e n s i t i v i t y . This appears to be espe c i a l l y true when one examines photopic and mesopic adaptation. Because of these findings, i t i s proposed that changes in v i s u a l processing due to MS be studied through establishing luminance thresholds for achromatic and chromatic s t a t i c perimetry on an automated perimeter. It i s postulated that MS patients w i l l exhibit greater losses in s e n s i t i v i t y than normals, and that the threshold losses would be dependent upon the adaptational state of the visu a l system. E a r l i e r threshold loss would be found among MS 116 p a t i e n t s under p h o t o p i c or mesopic l e v e l s than under p h o t o p i c . The t y p e s of t h r e s h o l d l o s s e x p e c t e d a r e a g e n e r a l r e d u c t i o n i n o v e r a l l s e n s i t i v i t y as w e l l as the p r e s e n c e of scotomas. From the c l i n i c a l l i t e r a t u r e , i t i s e x p e c t e d t h a t the f o v e a l t h r e s h o l d may show the most v a r i a b i l i t y i n l o s s when compared t o normals depending upon the s t a t e of a d a p t a t i o n . The importance of t h i s a s s umption, when compared to p e r i p h e r a l t h r e s h o l d s , i s t h a t the AI / I between the two f u n c t i o n a l a r e a s may e x p l a i n s u b j e c t i v e c o m p l a i n t s such as g l a r e . Thus i t i s proposed t h a t the e f f e c t s due t o d e m y e l i n a t i o n ( i t s p r e s e n c e and s e v e r i t y ) i n MS be a s s e s s e d by e x a m i n i n g luminance t h r e s h o l d s f o r c h r o m a t i c and a c h r o m a t i c s t i m u l i on an automated p e r i m e t e r . The a u t o m a t i c p e r i m e t e r i s Synemed's Fieldmaster® F225 model, which i t i s hoped w i l l p r o v i d e a f a s t and r e l i a b l e means f o r e s t a b l i s h i n g s t a t i c t h r e s h o l d s . Luminance t h r e s h o l d s w i l l be o b t a i n e d a t b oth the h i g h e s t and l o w e s t background bowl lum i n a n c e s p o s s i b l e w i t h the F225. As o p t i c n e u r i t i s appears t o be c l o s e l y a s s o c i a t e d w i t h MS, i t i s proposed t h a t the MS p a t i e n t s c o n s i s t of t h o s e w i t h and w i t h o u t a h i s t o r y of o p t i c n e u r i t i s . MS p a t i e n t s w i l l have been c l a s s i f i e d i n t o one of t h r e e c a t e g o r i e s by the MS C l i n i c , H e a l t h S c i e n c e s C e n t r e H o s p i t a l , U.B.C: 1) c l i n i c a l l y d e f i n i t e , 2) p r o b a b l e MS, and 3) p o s s i b l e MS. A t tempts w i l l be made t o d i f f e r e n t i a t e p a t i e n t s on the b a s i s of c l i n i c a l s t a b i l i t y 1 17 and frequency of episodes (acute phase). To summarize, i t i s hypothesized that: 1. Relative thresholds w i l l be s i g n i f i c a n t l y d i f f e r e n t between MS and v i s u a l l y normal subjects and that t h i s difference w i l l be highly dependent upon background preadaptation. S p e c i f i c a l l y , MS patients w i l l have elevated (higher) thresholds than normals and that the threshold differences between MS and normals w i l l be greater under brighter background adaptation l e v e l s . 2. Threshold differences between MS and normals w i l l be greater at and near the fovea than in the periphery. 3. Cone thresholds as determined by red and blue f i l t e r s w i l l show more selective loss than thresholds determined by the achromatic f i l t e r for the MS subjects when compared to normals. 1 1 8 I I . INSTRUMENTATION 1. APPARATUS The Fieldmaster® Model 225 i s an automatic perimeter i n i t i a l l y designed to provide the c l i n i c i a n w i t h the means to conduct a thorough, standardized assessment of a p a t i e n t ' s v i s u a l f i e l d s . The F 2 2 5 i s equipped with a D i g i t a l LSI-11 s i x t e e n - b i t computer with 17 f a c t o r y - i n s t a l l e d standard programs and one user-defined program. In a d d i t i o n , there i s memory cap a c i t y for an a d d i t i o n a l 81 o p t i o n a l programs that can be fact o r y programmed. 2. PHYSICAL SPECIFICATIONS The F225 c o n s i s t s of an upright hemispherical bowl, a power supply, and a motorized, height v a r i a b l e t a b l e . The bowl i s enclosed with the LSI-11 computer and c o n t r o l panel, weighing in t o t a l 58.1 kg. The dimensions of the instrument are 88.9 cm i n length, 64.8 cm i n width, and 119.4 cm i n heig h t . The power supply, d i r e c t l y under the t a b l e upon which the instrument s i t s , weighs 28.1 kg and i s 91.4 cm by 52.1 cm by 16.5 cm. The table i t s e l f weighs 6 3 . 6 kg and i s 8 8 . 9 cm by 71.1 cm by 7 4 . 9 cm. More d e t a i l e d i n f o r m a t i o n 1 19 regarding the LSI-11 may be found in Appendix A. The hemispheric bowl has a diameter of 62 cm and includes 149 locations where a stimulus may be presented. Each stimulus location consists of the polished ends of 1 mm diameter f i b r e optics (visual angle = .19°) that can be s e l e c t i v e l y illuminated with one achromatic and four chromatic stimuli of varying i n t e n s i t i e s . Stimulus positions within the bowl are not in a sequential order and therefore when presented to a subject they appear to be 'random'. Control over presentation and bowl background are controlled by the operator through the LSI-11 computer. As i s shown in figure 18, the possible positions that can be examined range 70° horizonatally and +55° to -65° v e r t i c a l l y . 3. CONTROL FUNCTIONS The operation of the F225 i s controlled through a panel on the side of the instrument s h e l l (see Figure 1 8 ) , which enables the researcher to control both stimulus and background conditions as well as monitor the responses of the subject. The control panel consists of touch sensitive pads and LED display windows for each controllable function. The stimulus address display window (#1 in Figure 18) presents which stimulus position in the bowl is being presented to the subject. During automatic testing (the running of a standard programme), the LED on the shutter key (#4) w i l l f l a s h . Stimuli may be presented manually by **STIMULUS ADDRESS«| p-ATTENTION MONITOR—| - MANUAL- •SENSITIVITY• •ACKGROUND |—INTENSITY—| •STIMULUS INTENSITY-3 1 5 B 3 0 | STIMULUS FILTERS 1 flB i>9 9^ TESTING KTIST ion •DISPLAY-f—CHART —|| AUTO TEST-|—PROGRAM —j -TIMING-OUIATION I N T E l V A l lRO«iajEnr.cMjF.tt&A, ® ® @ 11 13, 14) 112, FIGURE 18 F225 CONTROL PANEL MODIFIED FROM THE SYNEMED FIELDMASTER F225 MANUAL (P.8) 121 pressing numbers 1 to 149 on the input keyboard (#14) and then pressing the shutter select key (#4). When the selected position i s shown on the stimulus address window (#1), the operator may then press the shutter key to present the stimulus. The shutter w i l l remain open as long as the operator depresses the key, i . e . the stimulus w i l l be presented as long as the key i s depressed. It i s extremely important that the operator observes that the position he chooses i s actually displayed in the address window. Although the shutter l i g h t should come on when the shutter is open, at times i t w i l l not; and, therefore, the operator should not rely upon the shutter l i g h t during automatic testing. If during testing the shutter l i g h t i s not on and the subject responds, the computer w i l l automatically record the response as positive only i f a stimulus has indeed been presented. The type of response recorded (seen or missed) depends upon the choice selected by the operator (#11). The subjects response is shown as a series of dashes in the display window (#8). When operating the perimeter manually the operator should take care in that, after a period of more than f i f t e e n minutes of testing, the F225 w i l l not permit the presentation of any more stimuli and w i l l automatically print out re s u l t s . Although th i s does not occur a l l the time, i t w i l l cause the operator to lose control of the testing s i t u a t i o n and force him to begin again. Discussions with Synemed as to why the computer overrides the operator 122 during manual mode have not resolved t h i s problem. The attention monitor (#2) records the general position of the eye. The monitor operates on a corneal r e f l e c t i o n method, compensating for both the colour of the patient's i r i s and background bowl luminance. A photodetector monitors the position of the subject's eye (see Appendix A). To fix a t e the eye, the subject i s asked to adjust the chin rest u n t i l the two red horozontal and v e r t i c a l l i nes in the attention monitor are p e r f e c t l y crossed. This i s done by having the subject place his head on the chin rest, with his forehead pressed against the head rest. The subject i s then instructed to adjust (or the operator may do this) the adjust s l i d e , t i l t , and side clamps. The operator should make certa i n that the l a t e r a l canthus of the tested eye l i n e s up with the edge of the bowl. This i s done to ensure that the eye i s properly in the f i e l d of the bowl. If not, either ask the subject to press his forehead harder against the headrest or adjust the t i l t u n t i l the l a t e r a l canthus is aligned (see Figure 19). Once the subject i s properly aligned, the attention monitor i s c a l i b r a t e d by having the subject fixate d i r e c t l y at the crossed red l i n e s and then pressing the Attention Monitor Zero Key (#2) for a few seconds (a green l i g h t on the Zero key w i l l come on). Making certain that the stimulus address window shows that position one i s in place, the operator then presses the manual shutter button and requests that the subject s h i f t s his gaze to the position illuminated 123 ALIGNMENT OF SUBJECT MODIFIED FROM THE SYNEMED FIELDMASTER F225 MANUAL (P.19) 1 24 in the bowl ( 5 ° ) . Immediately press the Auto S e n s i t i v i t y Monitor Key. This causes the attention monitor to be readied for subsequent testing, permitting a 5 ° movement. Anything beyond 5 ° w i l l cause an alarm to be emitted, which remains on u n t i l the subject r e f i x a t e s . For subjects who have lost or are unable to maintain f i x a t i o n , the operator may reset the attention monitor by just pressing the attention monitor zero key. When the auto s e n s i t i v i t y monitor key i s pressed, a value i s shown in the attention display monitor. This value, which varies from subject to subject, provides the operator with a baseline from which he may either increase or decrease the s e n s i t i v i t y of the attention monitor to movement in f i x a t i o n by either pressing the "+" (increase) or "-" (decrease) s e n s i t i v i t y keys respectively. Although a 5 ° movement i s large for s t a t i c perimetry, many manufacturers of automated perimeters (eg. Octopus) have adopted the 5 ° as an acceptable deviation during testing. Despite the psychophysical dubiousness of assuming that such an allowable degree of movement w i l l enable the examiner to v a l i d l y and r e l i a b l y assess r e t i n a l s e n s i t i v i t y at some s p e c i f i c r e t i n a l e c c e n t r i c i t y , the 5 ° was probably agreed upon due to instrumental factors (eg. monitoring f i x a t i o n through gross techniques as corneal r e f l e c t i o n ) and subject c h a r a c t e r i s t i c s (eg. the strenuous demand of good fi x a t i o n and concentration in standard psychophysical paradigms). 125 The attention monitor in the F225 has several problems in that i t registers any gross head movement or blink as a loss of f i x a t i o n yet permits a 5° eye movement, one which makes i t d i f f i c u l t to e s t a b l i s h r e l i a b l e s t a t i c thresholds. Moreover, as the attention monitor r e l i e s on corneal r e f l e c t i o n , i t i s not possible to do purely scotopic adapation as the monitor requires a minimal l e v e l of l i g h t . The monitor functions better with higher background illumination (10 to 35 asb). The attention monitor presents another problem in that the red f i x a t i o n l i n e s f l a s h from time to time, which according to Synemed was done purposefully so as to keep the subject's attention trained onto the monitor. Although there is no c o r r e l a t i o n between stimulus onset and flashing of the l i n e s , subjects do however press the response chord accidently when the f i x a t i o n l i n e s f l a s h . To avoid t h i s problem, subjects must be instructed before testing that the monitor flashes and not to respond to i t . The attention monitor may be turned off by removing pin 6 (Appendix A) from i t s socket. To accomplish th i s task, the interface board with the three connectors must be removed from the backplane in the instrument. This w i l l leave the central f i x a t i o n target illuminated while power i s applied to the instrument. The attention monitor w i l l never blink after pin 6 has been removed. However, the brightness of the f i x a t i o n target w i l l s t i l l remain a function of the background intensity (as in the unmodified condition). 126 4. STIMULUS CHARACTERISTICS AND PRESENTATION Stimulus f i l t e r s are chosen by pressing the appropriate f i l t e r key (#3), which causes a f i l t e r wheel to rotate over the stimulus l i g h t source u n t i l the selected f i l t e r i s in position. The f i l t e r wheel consists of fiv e cinemoid f i l t e r s , which are: 1) a neutral density f i l t e r (NDF 1.0), 2) Kodak Wratten #29 red f i l t e r (XD 633.73), 3) Kodak Wratten # 8 yellow f i l t e r (XD 581.2), 4) Kodak Wratten #61 green f i l t e r (XD 535.86), and 5) Kodak Wratten #38A blue f i l t e r (XD 489.73). 1 The XD values are presented for illuminant 'A' as the stimulus l i g h t source i s a 16 watt tungsten bulb. The chief advantages of a tungsten source are s t a b i l i t y , continuous spectral output, a v a i l a b i l i t y , and high output at about 2854°K for illuminant 'A'. Inorder to minimize low e f f i c i e n c y due to a problem of heat d i s s i p a t i o n from high-wattage sources, the F225 u t i l i z e s a low wattage (16 watt) bulb. Thus the actual operating temperature of the tungsten bulb w i l l be well below 3000°K. The C.I.E. chromaticity coordinates for the various chromatic f i l t e r s as well as their Tristimulus values and dominant wavelengths may be found in Table 8 for both illuminants 'A' and 'C. Also presented are the sp e c i f i c a t i o n s for illuminant D65, a standard laboratory source with more u l t r a v i o l e t energy than illuminant 'C. 1 XD = Dominant Wavelength 127 COLORIMETRIC TABLE 8 SPECIFICATION OF F225 FILTERS ACHROMATIC FILTER (NDF) ILLUMINANT CHROMATICITY CO-ORDINATES x y TRISTIMULUS VALUES X Y DOMINANT WAVELENGTH A C D65 455 321 323 .414 .332 .345 22.34 19.53 18.96 20.35 20.22 20.22 6.46 21.12 19.48 581 .45 ntn, 572.22 571.79 RED FILTER (WRATTEN #29) ILLUMINANT CHROMATICITY CO-ORDINATES x y TRISTIMULUS VALUES X Y DOMINANT WAVELENGTH A C D65 709 699 699 289 289 290 27.25 15.50 14.88 11.11 6.41 6.18 0.08 0.25 0.23 633.73 nm, 632.91 632.49 BLUE FILTER (WRATTEN # 38A) CHROMATICITY TRISTIMULUS DOMINANT ILLUMINANT CO-ORDINATES VALUES WAVELENGTH x y X Y Z A .215 .339 8.19 12.93 17.04 489.73 nm. C .168 .190 15.20 17.26 58.27 479.31 D65 .168 .205 14.28 17.45 53.42 480.44 GREEN FILTER (WRATTEN #61) CHROMATICITY TRISTIMULUS DOMINANT ILLUMINANT CO-ORDINATES VALUES WAVELENGTH x y X Y Z A .262 .684 3.88 10.15 0.80 535.86 nm. C .234 .688 4.17 12.26 1.40 538.47 D65 .228 .694 4.16 12.65 1.41 537.48 128 Figure 20 provides the C.I.E. Loci of the various f i l t e r s for illuminant 'A'. The r e l a t i v e transmittance values for each of the f i l t e r s may be found in Figure 21. As can be seen from Figure 21, the red f i l t e r i s a cut off f i l t e r r e s t r i c t e d to the long wavelength region beyond 600 nm. The remaining chromatic f i l t e r s , however, are r e l a t i v e l y more broad (eg. the blue containing some of the middle frequencies). The achromatic f i l t e r (NDF) transmits and absorbs evenly across the spectrum. Attempts to photometrically measure the intensity of the presented stimuli have not been successful because of the c r i t i c a l angle at which the measurement has to be made with respect to the head of the f i b r e optic. This was of prime concern because e a r l i e r research with the Fieldmaster 101-PR by Johnson and Keltner (1980) indicated that the luminance meter readings were "lower than actual stimulus luminances by a constant factor of 4.7." (p. 732). Discussions with Synemed® about t h i s revealed that F225 was corrected for t h i s (see Appendix A). Moreover, although the F225 does equate for luminance differences between f i l t e r s (see Appendix A), t h i s has yet to be confirmed photometrically. V i s u a l , subjective comparison of the f i l t e r s does indicate the red to be less bright, i . e . transmitt less l i g h t than the other f i l t e r s . Stimulus intensity in the F225, according the the documentation provided by Synemed, varies from 8.00 asb. to 100,000 asb. in 10.00 asb. steps (or 1 decibel steps). The 129 FIGURE 20 C.I.E. CHROMATICITY COORDINATES FOR THE F225 CHROMATIC FILTERS 1 UJ o 0.9-0.8-0.7-^ 0.6-(/) < 0.5 > P 0.4-(3 0.3 H 0.2-S 0.1-,13-A - A - A - A - A - A - - A - A - A - A - A - A • / - H - ffi^ffi-ffi-'X-B-S--S--H-E/--H-a - H - H - f f i - f f i -S X / X / 0 A - A - A - A - A ^ A - X ^ O n D - D - O - M - D - O ^ X t * E = R - S = S = S = B 400 450 500 550 600 650 700 WAVELENGTH nm. Legend A YELLOW wrotton #8 X GREEN wrotton #61 • RED wrotton #29 Bl BLUE wrotton #380 ffi ACHROMATIC ncJf F I G U R E 21 T R A N S M I T T A N C E V A L U E S O F F 2 2 5 F I L T E R S CO o 131 maximum intensity that may actually be obtained i s 88,731 asb. for the achromatic f i l t e r , 70,985 asb. for the yellow, 17,746 asb. for the red, 8,873 asb. for the blue, and 6,212 asb. for the green. 1 The duration during which a stimulus may be presented ranges from 100 msec, to 9.9 sec. in .1 sec. i n t e r v a l s , and i s controlled by entering the desired time through the duration key on the control panel (#10). Interstimulus i n t e r v a l (ISI) is also variable, ranging from 100 msec, to 9.9 sec at .1 sec. i n t e r v a l s . As with the duration, ISI is con t r o l l e d by entering the desired time with the int e r v a l key on the control panel (#10). It should be noted that the ISI chosen by the operator i s not the actual one during the running of a threshold or screening programme. The ISI increases as the distance between stimulus positions increases. For example, the examiner may choose to test eight locations in the superior nasal f i e l d . Once the desired stimulus intensity, background luminance, f i l t e r , attention monitor setting, and stimulus duration and ISI has been selected, the F225 automatically begins to test the preselected locations. The ISI remains constant as long as a l l eight positions are being examined. When a threshold is determined for a given position, that position i s no longer 11 apostilb = 0.3183 cd/m2. In experimental v i s u a l psychophysics one t r a d i t i o n a l l y reports luminance values in terms of candellas (cd/m 2). However, as the majority of c l i n i c a l l i t e r a t u r e in perimetry refers to luminance in terms of apostilbs, the present study w i l l refer to apostilbs to reduce possible confusion when discussing the 1iterature. 1 3 2 tested and, therefore, the ISI between the preceeding and following stimulus locations increases. The reason for thi s i s that stimulus location i s processed sequentially. Even i f a threshold for some location has been determined, the F225 must sequentially run through that location (without presenting i t to the subject) in order to reach the subsequent location. Thus the greater the number of locations whose thresholds already are determined l i e between two locations s t i l l being tested, the greater w i l l be the ISI between the two. This can be observed by the examiner when viewing the stimulus address window on the control panel. When a f i l t e r i s selected by the operator, a neutral density f i l t e r situated above the f i l t e r wheel automatically compensates for the change in luminance due to f i l t e r density (refer to Appendix A). In addition, a correction factor for non-linearity is applied to the stimulus luminance automatically by the LSI-11. It should be noted that high stimulus i n t e n s i t i e s (above 50,000 asb) are unobtainable with certain f i l t e r s , such as the red. If thi s occurs, the stimulus intensity display (#7) w i l l show a series of dashes. 1 problem. The automatic testing l i g h t s (#5) show the operator the status of the perimeter when being run automatically. When the proceed button (#12) is pressed, the testing auto l i g h t 1 It should be noted that any error by the operator or malfunction by the F 2 2 5 w i l l result in dashes in the display in window question. 133 comes on and remains on u n t i l a l l the chosen stimulus positions have been run once, at which time the retest l i g h t (#5) becomes l i t indicating that the positions are to be retested. If the pause key i s pressed (#12), the perimeter automatically stops testing and remains inactive ( i d l e l i g h t w i l l blink) u n t i l the proceed button i s pressed again. The reset button automatically resets the perimeter to the beginning stimulus position i t began. 5. BACKGROUND LUMINANCE Background intensity in the bowl is controlled by entering the desired luminance l e v e l on the input keyboard and then pressing the enter button on the background intensity section of the control panel (#7). The desired l e v e l w i l l be registered in the background intensity display (#6). If an error has occurred, dashes w i l l appear in the display and the operator w i l l have to reenter the background value. If the dashes s t i l l appear, the background illuminant w i l l have to be replaced. The illuminant for the background i s a General E l e c t r i c 211-2 bulb. The background bowl luminantion may be set anywhere from 5 asb to 45 asb (1.59 cd/m2 to 14.32 cd/m 2). Bowl lumination i s constantly monitored and adjusted during testing by a photodiode (Appendix A). As mentioned e a r l i e r , bowl luminantion for the attention monitor i s best between 10 and 35 apostilbs. An attempt was made to disengage the 134 background illuminant so that f u l l y scotopic thresholds could be obtained. Unfortunately t h i s was unsuccessful in that the stimulus l i g h t source (a tungsten bulb) illuminates the inside back of the bowl, causing a l l of the 149 stimulus positions to appear bright in contrast with the darkened background bowl. Photometric measurements of bowl luminance was conducted with a Spectra® Pritchard® Photomter Model 1980A. Measurements were conducted 2 meters from the bowl with a 6 minute measuring f i e l d . Three measurements each were done for 20 bowl positions under 8 background luminances. The background luminances were: 1) 2 asb., 2) 5 asb., 3) 10 asb., 4) 15 asb., 5) 30 asb., 6) 45 asb., 7) 50 asb., and 8) 45 asb. Figure 22 shows the photometric results in log apostilbs units for 5 asb., 10 asb., 15 asb., 30 asb., 45 asb., and 50 asb. Results for the 2 and 55 asb. conditions were not included as they did not d i f f e r from the 5 and 50 asb. conditions respectively. The actual values for a l l eight conditions may be found in Appendix B. The 1 to 20 positions found in Figure 23 represent the points measured in the bowl, as shown in Figure 23. Positions 9 to 20 represent the 15° - 195° meridian. As can be seen in Figure 22, th i s region i s r e l a t i v e consistent with respect to background luminance. The nasal position of the bowl (13 - 15) i s s l i g h t l y darker than the temporal region. However, as the difference i s less than a log unit, the lower luminance l e v e l i s not serious. The luminance is < O Q O Z < z D 2-1.9-1.8-1.7-1.6-1.5-1.4-1.3-1.2-1.1-1-0.9-0.8-0.7-0.6-0.5 0.4 0.3 0.2 0.1-0 -0.1 - 0 . 2 - 0 . 3 - 0 . 4 - 0 . 5 - 0 . 6 - 0 . 7 - 0 . 8 - 0 . 9 -1 -1.1 -1.2 -1.3 -1.4 -1.5 -n—n t a — t a - - ia—EL -ta—si- -Ei—si- -ta—ta — t a — t a — B — t a - gj _ X — X — X — - X — X ~ X - X - - X - - X - - X - - X - - X A — A — A — A — — - A A A -T 2 - r -3 -r 5 -r-6 T 8 9 -r— 10 ~r-11 I 12 I 13 —r-14 i 15 16 17 18 I 1 19 20 Legend A 5 ASB. X 10 ASB. D 15 ASB. El 30 ASB. H 49 ASB. _ M 50 ASB. BOWL POSITION FIGURE 22 BOWL POSITION AND BACKGROUND LUMINANCE (FOR BOWL POSITION REFER TO FIGURE 23) BOWL POSITIONS FIGURE 23 MEASURED BY PHOTOMETER THE PRITCHARD 1 37 greatly reduced at the point of f i x a t i o n (position 5), indicating, contrary to the manual, the f i x a t i o n crosshairs are not co r r e c t l y adjusted for background luminance. This contrast difference in luminance may effect the determination of thresholds, but since no point i s tested with 5°s of t h i s area i t may not be of consequence. Unfortunately, there i s no way of overcoming t h i s problem given the physical configuration of the bowl. 6. THRESHOLD ESTIMATION Both suprathreshold and threshold p r o f i l e s may be obtained with the F225. Additional programmes may be stored in the computer (#13 on the display panel). Ten standard programmes are available for determining suprathresholds at various locations in the v i s u a l f i e l d . The programmes, shown in the programme display window (#9), include an examination of the f u l l v i s u a l f i e l d (149 posi t i o n s ) , a central 30°, a glaucoma screen, a cent r a l - c e c a l , as well as a test of the macula. Appendix C contains the locations for these and other programmes. The actual suprathresholds are printed in terms of isopters similar to that of the Goldmann. Results may be presented as indicating at which intensity the stimuli were seen or not seen. Suprathresholds are based upon single presentation of a stimulus at some given location ( i . e . e c c e n t r i c i t y ) . The DEC computer in the perimeter stores the subject's responses and 138 later p r i n t s out the values upon completion of the examination. As noted by Anderson (1985), this type of suprathreshold testing i s primarily adequate for rapidly detecting and establishing types of visual f i e l d defects. The procedure, however, neither permits the c l i n i c i a n to es t a b l i s h the density of the defect nor allows him to compensate for changes in r e t i n a l s e n s i t i v i t y due to e c c e n t r i c i t y ( M i l l s , 1985). Moreover, perimetric assessment may be inadequate for a given subject in that the suprathreshold value (eg. 50 asb.) chosen may not be optimal for that subject. Synemed® provides three thresholding procedures to try to overcome the above problems. The f i r s t , threshold related testing, allows the examiner to determine the i n i t i a l i ntensity by predetermining the subject's actual threshold at some given location. This intensity i s then used to determine the suprathreshold p r o f i l e . The second procedure available i s what Synemed® refers to as contour perimetry. This procedure, more correc t l y referred to by M i l l s (1985) and Anderson (1985) as " e c c e n t r i c i t y compensated" test i n g , involves the automatic adjustment of stimulus intensity for e c c e n t r i c i t y , i . e . , stimuli in the periphery are presented at a higher intensity than stimuli presented c e n t r a l l y . The F225 has four contour programmes (see Appendix D), each d i f f e r i n g as to the "multiplication factor" used to compensate the luminance l e v e l . The greater the 139 "multi p l i c a t i o n factor", the more the luminance l e v e l i s corrected for change in e c c e n t r i c i t y . The fourth contour programme (programme #4) i s the most desirable as i t i s the most sensitive to e c c e n t r i c i t y , thus reducing examination time quite appreciably. Each of the four contour programmes may be run in conjunction with any of the F225 suprathreshold or threshold programmes available (except for programme #10 on the macula). Work with the various programmes has led to the conclusion that contour programme #4 should be used whenever possible. The t h i r d suprathresholding procedure used by Synemed® is referred to by M i l l s (1985) as "defect density" t e s t i n g . The procedure involves s t a r t i n g at some predetermined suprathreshold l e v e l (eg. 50 asb.) and, when not seen by the subject, increasing the intensity u n t i l i t i s seen. Results provide the examiner with a crude record of the possible density of a detected defect. The p r o f i l e of the defect i s crude in that the e c c e n t r i c i t y one can test i s lim i t e d . This problem occurs in both f i b r e o p t i c perimeters (eg. the Fieldmaster F225) and LED perimeters (eg. the Dicon 2000 or the Fieldmaster 50). Apart from suprathreshold examination, the F225 also provides for assessment at the threshold l e v e l . Four meridonal p r o f i l e s are available, and these are: 1) 105 -285°, 2) 75 -255°, 3) 165 - 345°, and 4) 15 - 195°. The actual stimulus locations for these four p r o f i l e s may be 1 4 0 found in Appendix E. It should be noted that neither of the four threshold programmes exceeds 4 0 ° . According to Synemed®, the programmes were r e s t r i c t e d to 4 0 ° in order to shorten testing time as SYNEMED® "found that the information beyond 4 0 ° was not needed." (personal communication, July 1 9 , 1 9 8 2 ) . Whereas l i m i t i n g the examination to 4 0 ° may be appropriate for c l i n i c a l screening, i t i s of great importance to go beyond th i s e c c e n t r i c i t y in experimental research since one does not know whether an abnormality may be in the periphery or central regions of the v i s u a l f i e l d . In addition to the above four meridonal thresholds, a user defined programme (programme # 9 9 ) provided by Synemed® enables the examiner to determine a threshold for a s p e c i f i c point in the perimetric bowl. Programme # 9 9 , however, i s lim i t e d in the number of stimulus locations that may be assessed during a single testing session. Thresholds are determined through a bracketing staircase method. The algorithm, shown in Figure 2 4 , involves the i n i t i a l presentation of a stimulus at some pre-selected level of i n t e n s i t y . The subject's response, based upon pressing or not pressing a button on a response chord, i s temporarily stored by the DEC computer along with the presented stimulus l e v e l . The F 2 2 5 then proceeds to the next stimulus position, storing the intensity value along with the subject's response (button pressed or not pressed). When a l l of the stimulus locations have been tested once, the F 2 2 5 returns to the stimulus locations i t i n i t i a l l y P R E S E N T S T I M U L U S FIGURE 24 THRESHOLD TESTING ALGORITHM I — » 142 began with and commences to retest a l l the points. Depending upon the subject's response, the retest intensity w i l l either be 10.00 asb. higher or lower than the o r i g i n a l test intensity. Again, both intensity l e v e l and subject response are recorded and the entire process i s repeated u n t i l thresholds for a l l locations are computed. A threshold requires the subject to miss a stimulus at a s p e c i f i c intensity twice prior to c a l c u l a t i o n . The actual threshold value i s the average of the intensity l e v e l a s p e c i f i c stimulus was seen with the l e v e l i t was not. Thus, i f a subject saw a stimulus 15° nasally at 80 asb. and not at 76 asb., the f i n a l threshold for that' e c c e n t r i c i t y would be 78 asb. Thresholds may be found through either the ascending or descending method depending upon the intensity l e v e l at which the examiner commences tes t i n g . P i l o t work with the F225 over an i n i t i a l eight month period has revealed two major fa u l t s with such an algorithm for computing thresholds. F i r s t , the v i s u a l steps of 10.00 asb. for increasing or decreasing stimulus intensity i s too large when testing in the fovea. Secondly, and more seriously, the bracketing staircase method used by the F225 i s inappropriate because of a technical fault in the threshold algorithm. When the attention monitor temporarily halts testing because of a blink or movement in f i x a t i o n , the DEC computer incorrectly assumes that that intensity was "not seen" and therefore increases the intensity during the retest phase. Instead of 143 retesting that location with the same inte n s i t y , the increased intensity f a l s e l y raises the subject's threshold. As a threshold is calculated a f t e r not seeing a given intensity l e v e l twice, t h i s lack of retesting a f a l s e l y missed intensity i s not serious among those subjects with good or moderate f i x a t i o n . It does become problematic among subjects with poor f i x a t i o n or those who blink excessively. Presently, one can only exclude such subjects from testing as they w i l l have a r t i f i c a l l y raised thresholds. A solution to the probelm is to provide one's own algorithm based upon retesting of missed points and smaller increases and decreases in in t e n s i t y . As the DEC does not permit such f l e x i b i l i t y in programming, one w i l l have to interface the F225 with a personal computer capable of c o n t r o l l i n g the various functions of the perimeter. Appendix F b r i e f l y l i s t s how the interface should be done. 144 7. INSTRUMENTAL MODIFICATIONS As shown in Figure 25 from the Fieldmaster brochure, Synemed® claims that the F225 was capable of providing four meridian threshold p r o f i l e cuts up to 70° e c c e n t r i c i t y both nasally and temporally. Moreover the luminance threshold for the fovea (0° ec c e n t r i c i t y ) was shown to be about 3 asb. (AI/I), providing one an excellent cone p r o f i l e . When replicated, i t was discovered that the thresholds did not exceed 40° e c c e n t r i c i t y , that the i n i t i a l threshold luminance was set at 50 asb., that the AI/I value did not approach 3 asb., and that thresholds were unobtainable for any of the chromatic f i l t e r s other than in suprathreshold t e s t i n g . Figure 26 provides an example of our results when trying to r e p l i c a t e Synemed's®. Contact with the company revealed that the F225 actually did not provide threshold p r o f i l e s as they implied in Figure 25 and that the figure was only an idealized version of what they intended their perimeter to do in the future. As the above problems rendered the perimeter v i r t u a l l y useless for research, the Visual Laboratory entered a long period of interaction between Synemed® of C a l i f o r n i a , U.S.A. and their representatives in Canada, Carl Zeiss Canada Ltd. After eighteen months of repeatedly modifying the instrument, we were able to have the F225 do the following: 1. Present stimuli as low as 8 asb. (we were never able to go lower than t h i s due to a programming problem with 145 1 -j i 1 0 -70 55 40 30 25 15 5 0 5 ' 15 =25 30 40 55 70 ECCENTRICITY FIGURE 25 STATIC THRESHOLD PROFILE PROVIDED BY THE FIELDMASTER F225 SALES BROCHURE (MODIFIED FROM THE SYNEMED FIELDMASTER BROCHURE) FIGURE 26 REPLICATED FIELDMASTER F225 THRESHOLD PROFILE 147 Synemed®). 2. Conduct threshold testing up to 70° ec c e n t r i c i t y both nasally and temporally on a horizontal meridian. 3. Obtain thresholds for the various chromatic s t i m u l i , with assurances that they were photometrically equated. 4. To be able to programme any location in the bowl to be examined for threshold s e n s i t i v i t y . Despite these modifications to the perimeter, the following problems s t i l l e x i s t : 1. Maximum stimulus intensity must be set at a lower l e v e l than the perimeter i s capable of achieving. Apart from reducing testing time for determining a p r o f i l e , the major reason for doing so i s that after about f i f t e e n minutes of continuous testing the machine s t a l l s and never continues the test. Indeed, upon s t a l l i n g , the examiner loses a l l the data that has been stored up to that time. The reason for the s t a l l i n g i s that the algorithm is attempting to increase the stimulus int e n s i t y to a l e v e l i t can never reach, causing the perimeter to interrupt t e s t i n g . By setting the intensity to some l e v e l below i t s maximum prior to testing, one avoids the problem of s t a l l i n g and the eventual loss of data. 2. Threshold data i s presented in graphic form only. To obtain the actual threshold one must interpolate from the graph with appropriate adjustments (to be discussed l a t e r ) . Although the printout does provide one with an 1 48 index of r e l i a b i l i t y ( r a tio of c o r r e c t l y seen points over the number presented), individual data regarding intensity l e v e l , subject response, and eye movement for each stimulus position throughout the testing session i s not provided. To obtain the data, one w i l l be required to interface the LSI-11 to another computer which w i l l retrieve and store the relevant information. Presently, f i n a l threshold values are obtainable by connecting a terminal via a RS232-C to the perimeter and accessing the information through ODT (Octal Debugging Technique). ODT provides two sets of octal values ( l e v e l seen and not seen), which must be transformed into the decibel system prior to computation of the threshold values (see Appendix F). 3. Distraction of subject's by the flashing attention monitor and lack of repeat testing when the attention monitor temporarily stops t e s t i n g . During the modifications to the perimeter, three v i s u a l l y normal subjects (mean age of 20.3 years) with 20/20 acuity or better and no known history of r e t i n a l pathology were repeatedly tested with programmes #11 and 14 (Appendix E). Testing was done under a variety of background and stimulus conditions. Overall r e l i a b i l i t y in terms of detection (correct i d e n t i f i c a t i o n of a stimulus) was .93 for the achromatic stimulus, .91 for the red and green, .90 for the blue, and .83 for the yellow. The rates are comparable to those reported for other f i b r e optic perimeters provided 149 by Synemed® (eg. Johnson & Keltner, 1980a, 1980b; Gramer, Steinhauser & K r i e g l s t e i n , 1982). 150 I I I . PILOT STUDY 1. PURPOSE The purpose of the p i l o t study was to determine whether or not the modifications to the perimeter, discussed in the previous section, would permit one to conduct an assessement of r e t i n a l thresholds among MS patients under low (5 asb.) and high (45 asb.) background luminance for the achromatic, red, and blue f i l t e r s . 2. SUBJECTS Subjects consisted of one probable (male) and fi v e c l i n i c a l l y d e f i n i t e (females) MS patients referred by the MS C l i n i c in the Acute Care Unit of the Health Sciences Centre Hospital at the University of B r i t i s h Columbia. Seven additional patients were excluded because of either the presence of a large central scotoma 1 or spastic movements making i t impossible to position the head and respond. The mean age of the patients was 34.3 years (a = 11.4). The average disease duration from the time of diagnosed onset was 12.33 years (a = 12.53). Four of the subjects had a history of optic n e u r i t i s . 1 The Fieldmaster ® F225 cannot be used r e l i a b l y with patients whose scotoma include the fovea and exceed 5°'s temporally or nasally. 151 3. METHOD Subjects were preadapted for ten minutes under 5 asb. and 45 asb. background luminance conditions prior to te s t i n g . The order of the background preadaptation condition was randomized across subjects. Testing, in the case of optic n e u r i t i s , was done with the affected eye. Following a practice session to f a m i l i a r i z e them with the task, subjects were tested with programme #98 (dark rectangles found in Figure 27) to determine r e l a t i v e thresholds for a 15° - 195° meridian. E c c e n t r i c i t i e s examined ranged from 40° nasally to 70° temporally. This meridian was chosen because i t provided the most e c c e n t r i c i t i e s near to the t r a d i t i o n a l 0 - 180° meridian p r o f i l e done in perimetric research. Thresholds were established for the achromatic, red, and blue f i l t e r s . The order of presentation of the f i l t e r s was randomized for each background condition for every subject. Foveal thresholds for each of the three f i l t e r s , with their presentation randomized, were determined separately afte r completing the 15° - 195° meridian p r o f i l e s . The thresholds for the fovea were established by having the subject fixate at a point 5° nasally in the bowl. Fixation could be monitored by activating the attention monitor similar to normal f i x a t i o n ( f i x a t i o n set at 5° rather than at the f i x a t i o n target). Thresholds were determined by the repeated presentation of various i n t e n s i t i e s at that single FIGURE 27 153 5° point. The actual presentation was automatic and achieved by programming the LSI-11 as discussed in the Synemed® manual. There were two reasons for l i m i t i n g testing to only the achromatic, red, and blue f i l t e r s . F i r s t , research has indicated that the short ( i . e . blue) and long wavelengths ( i . e . red) are the most important regions of the v i s u a l spectrum to assess functional loss in the cone system. Secondly, the testing time for the three f i l t e r s under the two background conditions was three hours. Any additional f i l t e r s would have made the testing more d i f f i c u l t and t i r i n g even for a trained subject. The stimulus duration for the presentation of each f i l t e r was 200 msec, (nearest to the IPS recommendation of 125 msec). Interstimulus i n t e r v a l was 800 msec. (Synemed® recommended). Thresholds were printed by a thermal graph printer and the actual values were interpolated from an overlaid graph. Each threshold had to be scaled according to the region of the graph on which they were found. Table 9 provide the scalar values required. Subsequent interface of a VDT to the LSI-11 confirmed that the procedure of interpolation and scaling were correct. 4. RESULTS AND DISCUSSION Results are only presented for the low 5 asb. background condition. The 45 asb. condition w i l l be TABLE 9 SCALAR VALUES FOR OBTAINING THRESHOLDS THRESHOLD POSITION (Y CO-ORDINATE) SCALAR VALUE 5 TO 8 0.33 8 TO 14 0.67 14 TO 23 1 .00 23 TO 39 1 .78 39 TO 65 2.89 65 TO 108 4.78 108 TO 180 8.00 180 TO 300 13.33 300 TO 500 22.22 500 TO 834 37. 1 1 834 TO 1000 18.44 155 discussed l a t e r . Table 10 provides the means and a's for the achromatic, blue, and red f i l t e r s for the various e c c e n t r i c i t i e s . Figure 28 shows the log s e n s i t i v i t y gradients for each of the respective f i l t e r s . The overall r e l i a b i l i t y (correct responses) was never below .90. The results indicated that the lowest stimulus intensity that could be presented was 8 asb. It i s apparent, therefore, that the 5 asb. background does not permit one to est a b l i s h the r e l a t i v e thresholds for the central region of the f i e l d (15° nasal to 10° temporal). More importantly, the subjects reached the lower l i m i t of the stimulus intensity (8 asb.) within t h i s central region. Testing with v i s u a l l y normal subjects led to similar findings except that the lower l i m i t extended i t s e l f further from the fovea than among the MS patients. Results for a single normal subject may be found in Figure 29. The l i m i t a t i o n of the perimeter to present stimuli lower than 8 asb. greatly e f f e c t s any examination of foveal functioning. Perimetric research on foveal functioning t y p i c a l l y has found the 0° e c c e n t r i c i t y , under photopic conditions, to have a threshold less than 1 cd/m2 depending upon the stimulus (eg Lakowski & Dunn, 1980). Moreover, incremental steps for assessing foveal s e n s i t i v i t y are generally at .10 log unit steps. With respect to the F225, neither the machine l i m i t of 8 asb. nor the large incremental steps of 10 asb. permit accurate foveal assessment. TABLE 10 THRESHOLD VALUES (APOSTILB) FOR MS PATIENTS BY ECCENTRICITY AND FILTER FOR A 5 APOSTILB BACKGROUND ACHROMATIC RED BLUE ECCENTRICITY MEAN S.D MEAN S.D MEAN S.D. NASAL 40 93. 10 76, . 5 1 139. .14 44. .69 302. .03 405 .92 30 40. 55 9, .26 59. .23 0. .10 99, .50 1 13 .84 20 31 . 39 1 8 . .94 120. .10 77. .92 48. .98 57 .95 15 27. 63 20, .17 34. .75 1 . .00 8. .00 0 .00 10 12. 02 1 , .90 18. .17 14. .38 8. .84 1 .19 5 9. 07 1 , . 5 1 14. . 5 1 6. .36 8. .00 0 .00 FOVEA 0 8. 00 0, .00 8. .00 0. .00 8. .00 0 .00 TEMPORAL 5 8. 00 0, .00 8. .00 0. .00 8. .00 0 .00 10 16. 45 3, .46 19. .50 2. .12 14. ,80 9 .62 20 40. 16 31 , .06 45. .34 27. .81 37. .70 42 .00 30 23. 17 7, .31 41 . 09 39. .22 37. .70 42 .00 40 17. 88 5, .83 55. .34 40. .70 20. ,95 2 .76 55 40. 16 31 , .06 71 . 47 24. .66 38. .89 43 .69 70 59. 10 43. .50 140. ,80 46. ,39 1 54. 99 193 .73 /// A' X r~ r^ 1 i 1 1 1 1 1 1 1 1 1 1 1—-i 1 1 1 i — r < » JO 20 15 10 5 0 5 10 20 SO 4 0 5 5 ECCENTRICITY FIGURE 28 SENSITIVITY GRADIENTS FOR MS SUBJECTS AT 5 APOSTILB BACKGROUND V f ~ i r —' n i ' i i — ' — i — i — i — i — i — i 1 1 1 1 1 1 1 -40 30 20 '5 <0 9 0 5 10 20 30 40 55 70 ECCENTRICITY Legend A ACHROMATIC FIGURE 29 SENSITIVITY GRADIENTS FOR A NORMAL SUBJECT » AT 5 APOSTILB BACKGROUND , 159 5. MODIFICATION TO ADAPTATION In an attempt to approach the question of adaptation, 6 volunteer MS subjects agreed to pa r t i c i p a t e in a modification of the experimental procedure which allowed the subjects to become readapted at a lower l i g h t l e v e l (below 45 asb.). Thresholds were determined for the 0° e c c e n t r i c i t y both automatically and manually. In the automated mode, foveal thresholds were determined as outlined in the method section of the P i l o t Study. In the manual mode, subjects were instructed to f i r s t adapt to the 45 asb. background for ten minutes, after which they were presented with a stimulus below background l e v e l (40 asb.). The subjects were then asked to close their examined eye for a period of 2 minutes and not to reopen i t u n t i l asked. E a r l i e r attempts with shorter time periods had shown that adaptation was not complete. When instructed to reopen the eye, the subject fixated (him/herself) at the 0° e c c e n t r i c i t y again and was retested with either a higher or lower stimulus intensity. Testing always occurred with a 45 asb. background. The procedure was repeated u n t i l a foveal threshold was obtained. After adapting by closing the eye, thresholds were obtained through the descending method of l i m i t s . Catch t r i a l s of asking the subjects to open his/her eye and not presenting a stimulus were randomly inserted in each test session. Because of time constraints (an additional average 160 of 20 minutes to the already 3 hour period), only 1 f i l t e r could be examined for each subject—except for 1 subject who agreed to 2 testings. The results for the 2 testing conditions are presented in Table 11. A l l of the foveal thresholds, except for 1 subject, could be reduced to a lower l e v e l from that i n i t i a l l y determined in the automatic mode. A dependent «-test between the automatic and manual, 2 minute re-adaptation phase revealed that the decrease in threshold was s i g n i f i c a n t (t = 2 . 37 ,df = 6, p_=.05). Because of the small sample, no comparisons could be made of the 3 f i l t e r s and the e f f e c t changes in adaptation had on them. When the 2 minute adaptation was t r i e d on normals, there was no difference at a l l between the automated and manual mode. In both situations, the normals reached the intensity l i m i t of the perimeter (8 asb.), i . e . they reached the l i m i t of the machine. To examine whether or not the drop in foveal threshold after the 2 minute adaptation period was actually due to a change in adaptation and not rest (fatigue i s known to play a major role in psychohpysical examinations of MS patients), 3 patients were repeatedly tested at 2 temporal e c c e n t r i c i t i e s (30° and 40°) with an achromatic stimulus for a period of 30 minutes with no rest. The 2 temporal e c c e n t r i c i t i e s were chosen as there was less chance of finding a scotoma at those positions. A dependent J-test between the i n i t i a l threshold and threshold at the la s t TABLE 11 FOVEAL THRESHOLD VALUES (APOSTILB) FOR MS PATIENTS DURING ADAPATATION ACHROMATIC RED BLUE SUBJECT NORMAL ADAPTED* NORMAL ADAPTED NORMAL ADAPTED M.P. 28.34 8.00 -P.P. 8.00 8.00 - - 8.00 8.00 R.C. 14.00 8.00 -L.B. - - 36.35 8.00 T.M. - - - 70.74 8.00 S.E. 28.34 8.00 -Note: * - 2 MINUTE ADAPTATION CHANGE 162 testing revealed no s i g n i f i c a n t difference (t=-3.57, DF=2, P>.05) between the f i r s t and l a s t test at 30° as well as at 40° (t=-0.29, df = 2, 2 >.05). The mean threshold at 40° was 226.83 asb. for the f i r s t test and 250.20 for the l a s t . S i m i l a r i l y , the f i r s t mean threshold for 30° was 168.00 asb. and 249.76 asb. for the l a s t . If fatigue did play a role then one would have expected the thresholds to have become s i g n i f i c a n t l y worse, i . e . become higher over time. According to the means, there was an increase in the thresholds over repeated testing. However, the lack of a s i g n i f i c a n t difference in the repeated testing session would indicate that the improvement seen after having the subjects close their eyes for 2 minutes was primarily due to a change in adaptation l e v e l . Further elaboration on t h i s point w i l l be presented in the discussion. Although adaptation does appear to play a major role in determining thresholds in MS subjects, i t was decided to discard the investigation on the effects of lowered adaptation from the present study. The reason for t h i s decision i s that the adaptation for the "closed eye" condition would never be known and therefore introduce a methodological constraint on the data. Moreover, by manually trying to investigate the fovea, the F225 continually s t a l l s after a period of 10 minutes. This results in the LSI computer printing an empty thermal graph, after which the operator must restart t e s t i n g . P e r i o d i c a l l y the perimeter completely stops functioning, requiring the perimeter to be 163 turned off and restarted. These problems add unduly to the time required for a subject to remain motivated and prepared for t e s t i n g . a. Revised Hypothesis Based upon the results of the p i l o t study that demonstrated the i n a b i l i t y to examine foveal and peripheral s e n s i t i v i t y due to machine l i m i t a t i o n , i t was decided to remove the adaptation variable and modify the i n i t i a l hypothesis as follows: 1. Relative thresholds w i l l be s i g n i f i c a n t l y d i f f e r e n t between MS and v i s u a l l y normal subjects. 2. Threshold differences between MS and normals w i l l be greater at and near the fovea than in the periphery. 3. As a consequence of foveal involvement, cone thresholds for the MS subjects, as determined by the red and blue f i l t e r s , w i l l show more selective loss than thresholds determined by the achromatic f i l t e r . 164 IV. STUDY 1. SUBJECTS S u b j e c t s c o n s i s t e d of 22 v o l u n t e e r MS p a t i e n t s r e f e r r e d by the MS C l i n i c of the Acute Care U n i t of t h e H e a l t h S c i e n c e s H o s p i t a l a t the U n i v e r s i t y of B r i t i s h Columbia and 30 age-matched normals w i t h no h i s t o r y of m e d i c a l problems. The mean age was 32.67 y e a r s (o = 10.86) f o r the p a t i e n t s , and was 27.50 y e a r s (a = 11.30) f o r the n o r m a l s . A t - t e s t f o r independent groups w i t h unequal sample s i z e s r e v e a l s no s i g n i f i c a n t d i f f e r e n c e between the ages of t h e two groups (t=1.63, df=49, p >.05). 1 Of the n o r m a l s , 20 were male and 11 were female whereas 7 of the MS p a t i e n t s were male and 14 were f e m a l e . A c h i - s q u a r e u s i n g F i s h e r ' s Exact Test found no s i g n i f i c a n t d i f f e r e n c e s between MS and normals w i t h r e s p e c t t o gender (X 2=3.33, d f - 1 , £ >.05). 2 Ten of the MS p a t i e n t s had a h i s t o r y of o p t i c n e u r i t i s and 14 had n o t . There was no s i g n i f i c a n t d i f f e r e n c e between the ages of t h o s e w i t h or w i t h o u t o p t i c n e u r i t i s (_t = 0.90, d f = l 9 , 2 >«05) nor was t h e r e a sex d i f f e r e n c e between the two (x 2=0.02, d f = 1 . 2 >.05). 1 A l l t ^ - t e s t s r e f e r r e d t o are based upon t w o - t a i l e d t e s t s of p r o b a b i l i t y . 2 The F i s h e r ' s E x a c t T e s t s i s Computed f o r 2 x 2 c o n t i n g e n c y t a b l e s when a c e l l e n t r y has l e s s than 20 c a s e s . 165 F o u r t e e n of the MS p a t i e n t s were d iagnosed as b e i n g c l i n i c a l l y d e f i n i t e and e i g h t as p r o b a b l e . Diagnoses were based upon a n e u r o l o g i s t ' s r a t i n g of the p a t i e n t u s i n g a m o d i f i e d v e r s i o n of the Rose e t . a l . (1976) c r i t e r i a . No age d i f f e r e n c e was found between the two ( t=0.23 , df = 1, p_ >.05) nor was there a d i f f e r e n c e i n gender (x 2=.03, d f - 1 , p_ >.05) . There was no d i f f e r e n c e between the number of p a t i e n t s w i t h or wi thout o p t i c n e u r i t i s and t h e i r MS d i a g n o s t i c group (x 2=2.05, df=1, p > .05) . T a b l e 12 and 13 p r o v i d e a summary of the demographic d a t a . The mean d u r a t i o n of the d i s e a s e s i n c e d i a g n o s i s was 10.03 y e a r s (<x=8.63) f o r the e n t i r e p a t i e n t group . The average l e n g t h s i n c e d i a g n o s i s f or the c l i n i c a l l y d e f i n i t e group was 11.85 y e a r s (o=9.82) and 7.43 y e a r s (a=6.35) f o r the p r o b a b l e . T a b l e 14 p r o v i d e s the means and s t a n d a r d d e v i a t i o n s f or d u r a t i o n of i l l n e s s from d i a g n o s i s . There was no s i g n i f i c a n t d i f f e r e n c e between the two c l i n i c a l groups on d u r a t i o n ( t=1.04, df=20, p > .05) . 2. PROCEDURE S u b j e c t s were sea ted at the p e r i m e t e r and i n s t r u c t e d to p l a c e t h e i r c h i n on the c h i n - r e s t and p r e s s t h e i r forehead a g a i n s t a r e s t r a i n i n g b a r . P o s i t i o n i n g of the head i n t h i s way ensured that the l a t e r a l canthus of the eye was p r o p e r l y a l i g n e d w i t h the edge of the bowl and tha t the d i s t a n c e from the cornea to the s t i m u l u s was h e l d c o n s t a n t at 30 cm. TABLE 12 MEAN AND STANDARD DEVIATION FOR SUBJECTS CATEGORIES BY AGE (YEARS) SUBJECTS N NORMALS 30 MS 22 CLINICALLY DEFINITE 14 PROBABLE 8 OPTIC NEURITIS 8 NO OPTIC NEURITIS 14 AGE MEAN S.D. 27.50 11.30 32.67 10.86 32.15 7.60 33.50 15.37 30.25 7.34 34.15 12.59 TABLE 13 DIAGNOSTIC DEMOGRAPHICS OF SUBJECTS CLINICALLY NORMAL DEFINITE PROBABLE MALE 20 5 2 FEMALE 11 9 6 OPTIC NO OPTIC NEURITIS NEURITIS CLINICALLY DEFINITE 7 7 PROBABLE 1 7 TABLE 14 DURATION (YEARS) FROM DIAGNOSIS DURATION DIAGNOSIS N MEAN S.D. CLINICALLY DEFINITE 14 1 1 .85 9.82 PROBABLE 8 7.43 6.35 TOTAL 22 10.03 8.63 1 6 9 O n c e p o s i t i o n e d , t h e s u b j e c t ' s f i x a t i o n o n t h e c r o s s - h a i r s o f t h e f i x a t i o n m o n i t o r w a s a l i g n e d b y a d j u s t i n g e i t h e r t h e h e i g h t o f t h e p e r i m e t e r ( t h r o u g h a m o t o r i z e d t a b l e ) o r t h e l a t e r a l o r v e r t i c a l p o s i t i o n o f t h e h e a d r e s t . A n o p a q u e w h i t e o c c l u d e r w a s p l a c e d o v e r t h e n o n - t e s t e d e y e . A g a u z e p r o t e c t i v e e y e p a d w a s i n s e r t e d b e t w e e n t h e o c c l u d e r a n d e y e t o r e d u c e t h e p o s s i b i l i t y o f t h e s u b j e c t r e s p o n d i n g t o a s t i m u l u s p e r c e i v e d i n t h e p e r i p h e r y o f t h e o c c l u d e r b y t h e n o n - t e s t e d e y e . T h e F225 i s e q u i p p e d w i t h s o f t r u b b e r o c c l u d e r s t h a t m a y b e a t t a c h e d t o t h e h e a d - r e s t a n d s w u n g i n t o p o s i t i o n t o c o v e r e i t h e r t h e r i g h t o r l e f t e y e . A s t h e o c c l u d e r s d o n o t c o v e r t h e e y e p r o p e r l y a n d a r e e a s i l y d i s p l a c e d b y t h e s u b j e c t , t h e o c c l u d e r s w e r e n o t u s e d . I n t h e c a s e o f t h e MS p a t i e n t s w i t h o p t i c n e u r i t i s , t h e a f f e c t e d e y e w a s a l w a y s e x a m i n e d . O n l y o n e e y e o f e a c h s u b j e c t w a s t e s t e d , r e s u l t i n g i n a s a m p l e o f 2 2 MS e y e s a n d 3 0 n o r m a l e y e s . P r i o r t o t e s t i n g , t h e r o o m w a s c o m p l e t e l y d a r k e n e d a n d t h e s u b j e c t w a s p r e a d a p t e d t o t h e 4 5 a s b . b o w l b a c k g r o u n d f o r 10 m i n u t e s . T h e s u b j e c t w a s i n s t r u c t e d t o m o v e h i s g a z e a r o u n d t h e b o w l a n d n o t t o f i x a t e o n t h e d a r k c e n t r a l f i x a t i o n a r e a . I n t h i s w a y , a f t e r - i m a g e s w e r e a v o i d e d . W h e n p r e - a d a p t a t i o n w a s c o m p l e t e d , t h e s u b j e c t w a s i n s t r u c t e d t o f i x a t e u p o n t h e c e n t e r c r o s s - h a i r s a n d t h e a t t e n t i o n m o n i t o r w a s s e t a s d e s c r i b e d e a r l i e r i n C h a p t e r I I o n I n s t r u m e n t a t i o n . 170 Programme 98 was stored in the LSI-11 for the testing of 14 points on the 15°-195° meridian, which were: 0°, 5°, 10°, 15°, 20°, 20°, 30°, and 40° nasally; 5°, 10°, 20°, 30°, 40°, 55°, and 70° temporally. The size of each stimulus was 1mm., subtending a vi s u a l angle of 0.19'. During foveal testing, subjects were instructed to fixate at bowl position #59, which is 10° nasal on the 15°-195° meridian. The attention monitor was set for t h i s f i x a t i o n and a two log-unit neutral density f i l t e r was placed over the opening of the f i b r e optic at position #59. The LSI-11 was then programmed to test only at that one point. The purpose of the two log-unit neutral density f i l t e r was to allow for the presentation of a foveal stimulus below the machine l i m i t of 8.0 asb. With the neutral density f i l t e r , foveal stimuli could be presented as low as 0.08 asb. For foveal testing, acuity was corrected by placing t r i a l lenses into a lens holder which is connected to the head-rest. Refractions for the patients were obtained from an opthalmic technician at the Eye C l i n i c in the Acute care Unit of the Health Sciences Centre Hospital at the University of B r i t i s h Columbia. Patients with a c u i t i e s worse than 20/40 were excluded. S i m i l a r l y , normal subjects were corrected when necessary for foveal testing. Acuity was assessed with the Near Vision Acuity Test for the normals only. 171 A l t h o u g h p u p i l d i a m e t e r i s a n i m p o r t a n t v a r i a b l e i n p e r i m e t r y , t h e d i a m e t e r was n o t m o n i t o r e d d u r i n g t e s t i n g f o r two r e a s o n s . F i r s t , t o c o n t r o l p u p i l d i a m e t e r , o n e t r a d i t i o n a l l y u s e s e i t h e r a n a r t i f i c i a l p u p i l o r d i l a t e s t h e p u p i l p r i o r t o t e s t i n g . B e c a u s e o f t h e p h y s i c a l c o n f i g u r a t i o n o f t h e F225, i t w o u l d be d i f f i c u l t t o u s e an a r t i f i c i a l p u p i l w i t h o u t g r e a t l y a f f e c t i n g t h e d e t e c t i o n o f p e r i p h e r a l s t i m u l i . S e c o n d l y , p u p i l d i l a t i o n was n o t c h o s e n a s i t r e q u i r e s t h e p r e s e n c e o f a m e d i c a l l y t r a i n e d s u p e r v i s o r o r a p p r o v e d m e d i c a l t e c h n i c i a n , w h i c h w o u l d h a v e made t e s t i n g o f t h e n o r m a l s d i f f i c u l t . M o r e o v e r , r e s e a r c h h a s y e t t o r e s o l v e t h e i s s u e o f w h e t h e r t h e u s e o f a d i l a t o r a f f e c t s r e t i n a l s e n s i t i v i t y . P r i o r t o t e s t i n g , s u b j e c t s r e c e i v e d a p r a c t i c e t r i a l t o f a m i l i a r i z e t h e m s e l v e s w i t h t h e t a s k . B o t h i n t h e p r a c t i c e t r i a l a n d a c t u a l t e s t t r i a l s , s u b j e c t s w e r e i n s t r u c t e d t o p r e s s t h e r e s p o n s e c h o r d when t h e y saw a l i g h t f l a s h , r e g a r d l e s s o f i t s c o l o u r . S u b j e c t s w e r e r e q u e s t e d n o t t o r e s p o n d t o t h e f l a s h i n g o f t h e c r o s s - h a i r s on t h e a t t e n t i o n m o n i t o r a n d w e r e shown how b l i n k s a n d h e a d m o v e m e n t s w o u l d h a l t t e s t i n g . The o r d e r o f p r e s e n t a t i o n o f t h e t h r e e f i l t e r s was r a n d o m i z e d f o r e a c h s u b j e c t i n b o t h t h e 1 5 ° - 1 9 5 ° a n d f o v e a l e x a m i n a t i o n s . The f o v e a l e x a m i n a t i o n , w i t h c o r r e c t i o n f o r a c u i t y , a l w a y s f o l l o w e d c o m p l e t i o n o f t h e 1 5 ° - 1 9 5 ° e x a m . S u b j e c t s r e c e i v e d a f i v e - m i n u t e r e s t a f t e r t h e c o m p l e t i o n o f 1 72 each 15°-195° p r o f i l e and two minutes after the foveal examination. The average length of time for establishing thresholds for the 15°-195° p r o f i l e was 12 minutes and 1.5 minutes for the fovea. Total test time averaged two hours, depending upon the d i f f i c u l t y encountered in establishing the thresholds. Thresholds were established through the ascending method of l i m i t s with the LSI-11 automatically c o n t r o l l i n g stimulus duration (200 msec), interstimulus i n t e r v a l (800 msec), and luminance intensity in 10 asb. steps. Intensity was also corrected for e c c e n t r i c i t y through the use of contour programme #4. The highest intensity l e v e l presented by the F225 was set at 1,000 asb. in order to reduce testing time and the loss of data by having the perimeter s t a l l . If the threshold l e v e l was not obtained at the highest in t e n s i t y , the subject was given a value of 1,000 asb. for that e c c e n t r i c i t y . The lowest intensity obtained in the 15°-195° condition was 8.00 asb. and 0.08 asb. in the foveal condition. Thresholds were printed, upon completion of testing, in a bar chart format on the thermal printer and the actual threshold values were interpolated as described in the P i l o t Study section. 173 3. RESULTS The mean r e l i a b i l i t y of response (correct responses) for normals was 0.93 (o=0.09) for the achromatic f i l t e r , 0.91 U=0.11) for the red, and 0.90 (CT=0.11) for the blue. For the MS subjects, the mean r e l i a b i l i t y was 0.92 (a=0.l0) for the achromatic f i l t e r , 0.92 (a=0.l2) for the red, and 0.93 (ff=0.07) for the blue. Tables 15 to 17 provide the mean thresholds and standard deviations for the 3 groups by f i l t e r and e c c e n t r i c i t y . Tables 18 to 20 provide similar results for MS subjects with and without optic n e u r i t i s . Figures 30 to 32 show the log apostilb sensitivy gradients for the achromatic, red, and blue f i l t e r s respectively by subject group. Figures 33 to 35 show the log apostilb sensitivy gradients for the achromatic, red, and blue f i l t e r s respectively by diagnosis of optic n e u r i t i s . Figures 36 and 37 provide the log apostilb s e n s i t i v i t y gradients for a single MS patient and normal subject respectively. The gradients obtained from the MS patient reveal highly ir r e g u l a r fluctuations across the e c c e n t r i c i t i e s examined unlike that for the normal. These fluctuations are c h a r a c t e r i s t i c a l l y referred to in the l i t e r a t u r e as Swiss cheese f i e l d s . An interesting finding shown in Figure 36 i s the rel a t i v e y intact p r o f i l e for the red f i l t e r as compared to either the achromatic or blue. This trend is c l e a r l y evident in the mean thresholds for the TABLE 15 MEAN AND STANDARD DEVIATIONS FOR THRESHOLD VALUES (APOSTILBS) BY ECCENTRICITY AND GROUP FOR THE ACHROMATIC FILTER NORMALS CLINICALLY DEFINITE PROBABLE ECCENTRICITY MEAN S.D MEAN S.D MEAN S.D. NASAL 40 30 20 15 10 5 287.87 173.87 100.63 99.34 74.51 58.64 244.48 116.42 45.88 72.28 20.35 21 .23 527.15 477.13 375.72 302.99 354.35 291.40 302.85 274.25 295.60 329.85 372. 13 385.34 701 . 19 610.96 499.13 443.42 434. 10 432. 1 9 381.98 428.39 425.37 461 . 14 469.14 470.75 FOVEA 0 0.13 0.09 375.14 483.66 73.69 95.99 TEMPORAL 5 10 20 30 40 55 70 61 .58 91.11 135.85 162.28 135.06 179.90 421.84 22.68 34.33 82.60 134.64 67. 18 53.74 231.07 302.39 352.17 410.68 303.60 348.44 415.93 716.92 380. 11 366.09 365.44 272.23 302.85 321 .38 317.45 431.73 469.91 581.03 534.70 538.43 596.09 893.09 470.79 440.85 379.51 358.07 388.79 351.81 197.96 TABLE 16 MEAN AND STANDARD DEVIATIONS FOR THRESHOLD VALUES (APOSTILBS) BY ECCENTRICITY AND GROUP FOR THE RED FILTER NORMALS CLINICALLY DEFINITE PROBABLE ECCENTRICITY NASAL 40 30 20 15 10 5 MEAN 659.41 488.76 268.27 219.74 113.83 62.87 S.D 242.02 260.26 162.97 132.46 44. 15 29.81 MEAN 861.64 798.57 705.80 532.14 414.39 341.21 S.D 214.94 229.31 335.07 354.84 350.73 371.27 MEAN 947.71 913.04 745.75 666.56 527.13 488.63 S.D. 147.91 165.38 319.10 319.90 403.77 430.72 FOVEA 0 0. 12 0.15 304.51 457.01 58.87 73.88 TEMPORAL 5 10 20 30 40 55 70 61 .66 177.48 373.88 341.20 390.07 549.65 848.95 30.81 87.71 190.30 174.71 158.95 214.86 179.08 328.45 449.33 449.33 589.18 679.60 744.99 763.36 378.00 318.64 296.09 294.77 251.04 303.46 229.17 500.20 579.20 821.31 719.97 765.56 790.32 967.65 428.70 394.31 261.85 324. 18 323.83 298.28 91 .49 TABLE 17 MEAN AND STANDARD DEVIATIONS FOR THRESHOLD VALUES (APOSTILBS) BY ECCENTRICITY AND GROUP FOR THE BLUE FILTER NORMALS CLINICALLY DEFINITE PROBABLE ECCENTRICITY MEAN S.D MEAN S.D MEAN S.D. NASAL 40 273 .81 183. 17 623. 94 3 1 8 . 54 768. 06 359 .52 30 201 .97 174. 97 506. 88 365. 77 679. 70 442 .44 20 96 .45 46. 23 317. 03 309. 57 672. 71 451 .97 15 87 .31 54. 22 237. 4 1 273. 49 555. 75 395 . 1 4 10 64 .21 32. 38 319. 77 388. 36 424. 68 476 .86 5 33 .57 16. 14 257. 56 403. 06 406. 50 491 .87 FOVEA 0 0 .09 0. 03 370. 38 487. 30 54. 09 102 .01 TEMPORAL 5 32 .84 22. 37 254. 34 404. 76 401 . 48 495 .79 10 1 13 .57 170. 33 290. 34 385. 96 446. 49 460 .62 20 104 .55 69. 90 359. 26 385. 12 688. 75 399 .32 30 140 .85 60. 25 324. 60 271 . 46 494. 28 370 .71 40 171 .39 1 19. 82 329. 95 277. 43 649. 61 388 .37 55 234 .92 143. 35 493. 50 353. 76 634. 17 394 .91 70 520 .67 270. 62 724. 12 327. 06 91 1 . 19 193 .06 177 TABLE 18 MEAN AND STANDARD DEVIATIONS FOR THRESHOLD VALUES (APOSTILBS) BY ECCENTRICITY AND GROUP FOR THE ACHROMATIC FILTER ECCENTRICITY NASAL 40 30 20 1 5 10 5 OPTIC NEURITIS MEAN 452 410 345 300 357 315 58 47 85 47 56 16 S.D 279.94 286.07 296.20 323.49 402. 17 423.15 NO OPTIC NEURITIS MEAN 669.21 591.70 463.30 384.68 398.09 358.27 S.D 348.67 352.30 371.66 414.61 414.42 422.42 FOVEA 0 514.86 519.02 123.04 263.25 TEMPORAL 5 10 20 30 40 55 70 331.64 362.29 472.52 297.40 339.87 379.86 699.67 413.63 402.98 384.06 234.40 240.40 252.61 338.50 359.59 413.67 472.69 439.20 461.90 539.50 827.44 421.85 394.50 378.20 355 .81 387.67 371.89 256.78 178 TABLE 19 MEAN AND STANDARD DEVIATIONS FOR THRESHOLD VALUES (APOSTILBS) BY ECCENTRICITY AND GROUP FOR THE RED FILTER OPTIC NEURITIS ECCENTRICITY MEAN S.D NO OPTIC NEURITIS MEAN S.D NASAL 40 30 20 1 5 10 5 878.60 770.07 804.36 596.83 466.94 393.45 199.20 221.33 281.34 317.15 348.56 386.03 901.13 880.26 672.31 571.99 448.78 395.60 198.28 203.24 343.92 365.63 387.59 407.43 FOVEA 0 399.46 497.95 109.89 262.83 TEMPORAL 5 10 20 30 40 55 70 422.97 544. 19 682.03 664.52 723.16 743.61 878.72 388.05 332.81 319.78 362.89 318.00 303.36 226.80 372.58 469.34 668.77 711.29 769.22 790.06 924.42 413.91 360.58 300.93 268.98 253.71 299.80 178.82 179 TABLE 20 MEAN AND STANDARD DEVIATIONS FOR THRESHOLD VALUES (APOSTILBS) BY ECCENTRICITY AND GROUP FOR THE BLUE FILTER NASAL 40 30 20 15 10 5 OPTIC NEURITIS ECCENTRICITY MEAN 521.05 487.85 300.04 226.66 343.33 297.07 S.D 305.35 407.02 303.35 205.10 416.98 434.44 NO OPTIC NEURITIS MEAN 765.09 616.51 529.98 425.46 366.26 320.09 S.D 325.07 393.95 430.25 400.54 428.66 446.75 FOVEA 0 514.62 519.32 107.22 268.39 TEMPORAL 5 10 20 30 40 55 70 296.37 320.79 437.30 337.42 340.41 433.90 636.77 435.01 420.59 390.72 221.82 217.03 333. 13 318.38 314.40 362.17 502.94 414.23 506.63 607.94 880.93 450.16 420.52 439.09 360.77 402.51 381.12 250.62 THRESHOLD: LOO APOS7H.es CO w > z z CO D -3 TJ W < O Cd > >< oa f o w > a TJ i—« > tu w -3 — z >-3 *« 5C CO tn cn > CO o TJ G » O tfl CO c_, Z i—« o O •-< o G r -9 W CO CO > m C d "0 CO > O o o w o ?: O > i—t » Z z O t-t G > o z o > o X r f o •< a w n z >-i i—i -3 tr1 w w n o •— w • o 3 o o> o -TO • X > • X o z a> 0 <Q 1 cl 3 & o C81 -2 -1.5 -0.5 3 < 9 o 5 0.5 1.5-2.5 3 J Legend A NORMALS n=30 X C0n=14  • Pfln=8 ' -I 1 1 1 1 1 r-20 - 15 10 5 0 5 10 20 ECCENTRICITY FIGURE 31 SENSITIVITY GRADIENTS FOR NORMAL, CLINICALLY DEFINITE (CD), AND PROBABLE (PB) MS SUBJECTS FOR A RED FILTER AT 45 APOSTILB BACKGROUND 00 FIGURE 32 SENSITIVITY GRADIENTS FOR NORMAL, CLINICALLY DEFINITE (CD), AND PROBABLE (PB) MS SUBJECTS FOR A BLUE FILTER AT 4 5 APOSTILB BACKGROUND S -2 -1.5-2 »-o < o Q -0.5-0.5-O I u J a: i 1.5-U 2 " 2.5-A • x—•• -A" -X-A Legend A ON n=8 X N0Nn=U i i 40 -i r 30 - i 1 1 1 r~ 20 15 10 5 0 - i — 10 — i — 20 30 40 55 70 ECCENTRICITY FIGURE 33 SENSITIVITY GRADIENTS FOR OPTIC NEURITIS (ON) AND NON-OPTIC NEURITIS (NON) SUBJECTS FOR AN ACHROMATIC FILTER AT 45 APOSTILB BACKGROUND -2 -1.5 H -0.5 OH O ° , 0.5 H O or r 1.5 2.5 H 3-1 A 40 ^ y ^ A 7 — . 1 1 1 1 1 — . 30 20 15 10 5 0 5 10 20 ECCENTRICITY Legend A ON n=8 X N0Nn=U FIGURE 34 SENSITIVITY GRADIENTS FOR OPTIC NEURITIS (ON) AND NON-OPTIC NEURITIS (NON) SUBJECTS FOR A RED FILTER AT 45 APOSTILB BACKGROUND A-x-- X " * A X / \ 40- 30 20 15 10 5 0 5 10 20 30 ECCENTRICITY 40 55 70 Legend A ON n=8 X N0Nn=14 FIGURE 35 SENSITIVITY GRADIENTS FOR OPTIC NEURITIS (ON) AND NON-OPTIC NEURITIS (NON) SUBJECTS FOR A BLUE FILTER AT 45 APOSTILB BACKGROUND CLINICALLY DEFINITE MALE, AGE 20 X * 1 I I I I I I I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I 40 30 20 15 10 -5 0 5 10 20 30 40 55 70 ECCENTRICITY FIGURE 36 SENSITIVITY GRADIENTS FOR A MS PATIENT THRESHOLD: LOG APOSTILBS 188 various f i l t e r s shown in Tables 15 to 17. A l l of the f i l t e r s for the normals show a good progression of least s e n s i t i v i t y in the periphery to high s e n s i t i v i t y at the fovea. The thresholds for the probable MS patients also demonstrate a r e l a t i v e l y consistent progression from low s e n s i t i v i t y in the periphery to high s e n s i t i v i t y at the fovea. This progession i s more c h a r a c t e r i s t i c of the red than the achromatic and blue. As for the c l i n i c a l l y d e f i n i t e MS patients, the mean thresholds have an irregular progression for the achromatic and blue. Again, the red for the c l i n i c a l l y d e f i n i t e i s r e l a t i v e l y consistent in showing a regular progression of least s e n s i t i v i t y to high s e n s i t i v i t y . Examination of Tables 18 to 20 reveals a similar pattern in that the mean thresholds for the red f i l t e r show a regular pattern of least s e n s i t i v i t y in the periphery to high s e n s i t i v i t y at the fovea. A poor progression in the thresholds are found among the optic n e u r i t i s MS patients for the achromatic and blue f i l t e r s , unlike that for the non-optic n e u r i t i s patients. As can be seen from Figures 30 to 35, the greatest difference between the normals and MS groups appears to be in the fovea and less so in the periphery. Foveal depression among the MS groups appears to occur more prominently with the blue and achromatic f i l t e r s as compared to the red. The s e n s i t i v i t y gradients for the c l i n i c a l l y d e f i n i t e and probable groups t y p i c a l l y show a greater difference in the 189 foveal and adjacent regions as compared to the periphery. A similar trend i s evident in the figures for MS patients with and without optic n e u r i t i s . Patients with optic n e u r i t i s tend to demonstrate a foveal depression for the blue and achromatic f i l t e r s . L i t t l e difference between the two groups appears to be found in the periphery as compared to the center. To determine i f there was an o v e r a l l s i g n i f i c a n t difference between the three groups of normal, M S - c l i n i c a l l y d e f i n i t e , and MS-probable, a repeated measures Multivariate Analysis of Variance (MANOVA)1 with one between factor (3 groups) and two within factors (3 f i l t e r s and 14 e c c e n t r i c i t i e s ) was conducted. The 3x3x14 repeated MANOVA is a general case of the S p l i t - P l o t ANOVA design (Winer, 1971). As shown in Table 21, there were many s i g n i f i c a n t interactions and main effects in the data. Due to the lack of orthogonality (independence) between the variables, the actual interpretation of s i g n i f i c a n t main ef f e c t s becomes problemmatic. This i s especially true with the group variable as almost a l l of the other variables interact s i g n i f i c a n t l y with i t . Nevertheless, the analysis revealed a s i g n i f i c a n t main effect due to groups (F(2,49)=19.96, 2 < « 0 0 0 1 ) ' Tukey's Honestly S i g n i f i c a n t Differences (HSD) were calculated based upon the harmonic mean for subjects' of 13.06 and a c r i t i c a l difference value of 1 27 .93. 2 Using t h i s c r i t i c a l value, the 1A11 MANOVA's were performed using BMDP4V (Dixon, 1981). 2 Using a Bonferroni adjustment to correct for posssible TABLE 21 MULTIVARIATE ANALYSIS OF VARIANCE BETWEEN NORMALS (n*30) CLINICALLY DEFINITE (n=14), AND PROBABLE (n=8) MS PATIENTS SOURCE SS df MS F P-GROUP (G) 51329111 . 04 2,49 25664555. 52 19. 96 .0000 FILTER (F) 11418434. 62 2,98 5709217. 31 86. 86 .0000 ECCENTRICITY (E) 40283074. 88 13,637 3098698. 07 50. 42 .0000 G X F 296655. 38 2 .79,68. 45 74163. 85 1 . 1 3 .3417* G X E 3781798. 22 7 .15,175 .17 145453. 78 2. 37 .0237* F X E 4029295. 62 1 1 .72,574 .19 154972. 91 1 1 . 72 .0000* G X F X E 2024808. 96 23 .44,574 .19 38938. 63 2. 94 .0000* Note: * Denotes p r o b a b i l i t y after degees of freedom have been adjusted by Greenhouse-Geisser. 191 o v e r a l l mean thresholds for the normals (205.11 asb.) was found to be s i g n i f i c a n t l y d i f f e r e n t from the c l i n i c a l l y d e f i n i t e (460.71 asb.) as well as the probable (583.79 asb.) MS groups at the .0001 l e v e l of signi f i c a n c e . There was no s i g n i f i c a n t difference between the mean thresholds for the c l i n i c a l l y d e f i n i t e and probable groups. Tables 22 and 23 provide the means and absolute mean differences between the 3 groups. Thus, the Tukey's HSD indicates that the normals have s i g n i f i c a n t l y lower thresholds than the two MS groups, and that the two patient groups are similar with respect to their o v e r a l l thresholds. An o v e r a l l s i g n i f i c a n t difference was also found between f i l t e r s (F(2,98)=86.86, p<.0l), e c c e n t r i c i t y (F(13,637)=50.42, p<.01) as well as the interactions between e c c e n t r i c i t y x group (F(7.15,175.17)=2.37, £<.02)r f i l t e r x e c c e n t r i c i t y (F(11.72,574.19)=11.72, P<.01), and f i l t e r x e c c e n t r i c i t y x group (F(23.44,574.19)=2.94, p<.01).1 Tukey's HSD were calculated for each f i l t e r against one another. Using a c r i t i c a l value of 122.97, the absolute 1(cont'd) experment-wise error due to the large number of mean comparisons, a c r i t i c a l value was computed for a pro b a b i l i t y l e v e l of .01/42. The actual c r i t i c a l value associated with a ;t value of .9999 was found through the U.B.C. Computing Centre fortran subroutine programme known as UBC Probability (1981). 1 When the orthogonal polynomials were found not to be independent or to have equal variances, indicating a problem of symmetry due to o u t l i e r s or some carry over ef f e c t from one within factor l e v e l to the next, Greenhouse-Geisser adjustments were computed. The Greenhouse-Geisser i s a conservative test for rejecting the n u l l hypothesis by reducing the degrees of freedom through an epsilon (e) factor. By setting e to i t s lower bound, the Greenhouse-Geisser raises the c r i t i c a l value necessary for significance (Winer, 1962). 192 TABLE 22 MEAN THRESHOLDS (APOSTILBS) FOR NORMALS (n=30) CLINICALLY DEFINITE (n=14), AND PROBABLE (n=8) MS PATIENTS ACROSS FILTERS AND ECCENTRICITIES GROUP MEAN NORMALS 205. , 1 1 CLINICALLY DEFINITE 460, ,71 PROBABLE 583. ,79 193 TABLE 23 ABSOULTE MEAN THRESHOLD DIFFERENCE (APOSTILBS) FOR NORMALS (n=30) CLINICALLY DEFINITE (n=14), AND PROBABLE (n=8) MS PATIENTS ACROSS FILTERS AND ECCENTRICITIES COMPARISON MEAN DIFFERENCE NORMAL VS. PB 378. ,68 * NORMAL VS. CD 255. ,60 * PB VS. CD 123. .08 Note: PB CD * - PROBABLE - CLINICALLY DEFINITE - SIGNIFICANT AT THE .0001 LEVEL 194 difference (Table 24) between the mean of the achromatic f i l t e r (mean=268.06 asb.) and the red f i l t e r (453.33 asb.) was s i g n i f i c a n t l y d i f f e r e n t at the .0001 l e v e l . The absolute differences between the mean threshold value for the red and blue (275.15 asb.) f i l t e r s were also s i g n i f i c a n t l y d i f f e r e n t . There was no s i g n i f i c a n t difference between the achromatic and blue f i l t e r s . Thus, o v e r a l l , the red f i l t e r had a s i g n i f i c a n t l y higher threshold than either the achromatic or blue. The lack of a s i g n i f i c a n t difference between the achromatic and blue may have been due to the lack of blue in the red f i l t e r . The nonsignificant F for the interaction between f i l t e r and group would suggest that the pattern of red > blue, red > achromatic, and blue = achromatic i s consistent across the three groups. The main effect of e c c e n t r i c i t y (F(13,637)=50.42, 2<.01) i s a t r i v i a l one in that i t only r e f l e c t s a change in s e n s i t i v i t y across the fovea as does the s i g n i f i c a n t interaction of f i l t e r x e c c e n t r i c i t y (F(11.72,574.19)=11.72, p_<.0l). Table 25 provides the mean threshold values across the three f i l t e r s for each of the 14 e c c e n t r i c i t i e s . Tukey's HSD were calculated using a c r i t i c a l value of 118.69 for a significance level of .0001, and the resulting absolute mean differences are presented in Table 26. As can be seen from the table, the fovea (0°) i s consistently s i g n i f i c a n t l y d i f f e r e n t from e c c e n t r i c i t i e s past 10°. The 0° and the two 10° (nasal and temporal) e c c e n t i c i t i e s have the lowest mean 195 TABLE 24 ABSOLUTE MEAN THRESHOLD DIFFERENCE (APOSTILBS) FOR NORMALS (n=30) CLINICALLY DEFINITE (n=14), AND PROBABLE (n=8) MS PATIENTS BY FILTERS COMPARISON MEAN DIFFERENCE RED VS. ACHROMATIC 185.27* RED VS. BLUE 178.28* ACHROMATIC VS. BLUE 6.99 Note: * - SIGNIFICANT AT THE .0001 LEVEL 196 TABLE 25 MEAN THRESHOLDS (APOSTILBS) FOR ALL GROUPS AND FILTERS BY ECCENTRICITY ECCENTRICITY MEAN NASAL 40 539.40 30 439.25 20 313.34 15 259.83 10 217.32 5 177.77 FOVEA 0 103.87 TEMPORAL 5 177.84 10 248.17 20 347.34 30 330.96 40 361.87 55 439.22 70 694.39 TABLE 26 ABSOLUTE MEAN THRESHOLD DIFFERENCE (APOSTILBS) BY ECCENTRICITY ACROSS GROUPS AND FILTERS 40 30 20 15 5 O 5 10 20 30 40 85 70 NASAL 40 30 IOO.15 20 2 2 6 . 0 6 * 1 2 5 . 9 1 * 15 2 7 9 . 5 7 * 179 .42* 5 3 . 5 1 10 3 2 2 . 0 8 * 2 2 1 . 9 3 * 9 6 . 0 2 4 2 . 5 1 5 3 6 1 . 6 3 * 2 6 1 . 4 8 * 135 .57* 8 2 . 0 6 3 9 . 5 5 FOVEA O 4 3 5 . 5 3 * 3 3 5 . 3 8 * 2 0 9 . 4 7 * 155 .96* 113 .45 7 3 . 9 0 TEMPORAL 5 3 6 1 . 5 6 * 2 6 1 . 4 1 * 135 .50* 8 1.99 3 9 . 4 8 0 . 0 7 7 3 . 9 7 10 2 9 1 . 2 9 * 191 .08* 6 5 . 1 7 11 .66 3 0 . 8 5 7 0 . 4 0 144 .30* 7 0 . 3 3 20 192 .06* 9 1 . 9 1 34 . OO 8 7 . 5 1 130 .02* 169 57* 2 4 3 . 4 7 * 169 .50* 9 9 . 1 7 30 2 0 8 . 4 4 * 108 .29 17 .62 7 1 . 1 3 113.64 153 .19* 2 2 7 . 0 9 * 1 5 3 . 1 2 * 8 2 . 7 9 16 38 40 177 53* 7 7 . 3 8 4 8 . 5 3 102.04 144 .55* 184 .10* 258.OO* 1 8 4 . 0 3 * 1 1 3 . 7 0 1 4 . 53 SO.91 55 100 .18 0 . 0 3 125 .88* 179 .39* 22 1 90* 2 6 1 . 4 5 * 3 3 5 . 3 5 * 2 6 1 . 3 8 * 1 9 1 . 0 5 * 9 1 . 8 8 1 0 8 . 2 6 7 7 . 3 5 70 154 .99* 2 5 5 . 1 4 * 3 8 1 . 0 5 * 434 56* 4 7 7 . 0 7 * 5 1 6 . 6 2 * 5 9 0 . 5 2 * 516 55* 4 4 6 . 2 2 * 3 4 7 . 0 5 * 3 6 3 . 4 3 * 3 3 2 . 5 2 * 2 5 5 . 1 7 * NOTE: * - S IGNIFICANT AT THE .0001 LEVEL 198 threshold values compared with th e i r periphery. Adjacent peripheral e c c e n t r i c i t i e s tend not to be s i g n i f i c a n t l y d i f f e r e n t from each other except for the temporal 70° ec c e n t r i c i t y , which i s s i g n i f i c a n t l y d i f f e r e n t (higher threshold) than any other e c c e n t r i c i t y . To evaluate the s i g n i f i c a n t interaction between f i l t e r and e c c e n t r i c i t y (F(11.72,574.19)=11.72, p_<.000l), Tukey's HSD were computed between the f i l t e r s for each e c c e n t r i c i t y across the 3 f i l t e r s using the c r i t i c a l value of 118.69 (p value of .0001). The resulting absolute mean differences between the 3 f i l t e r s may be found in Table 27. As stated e a r l i e r , the s i g n i f i c a n t interaction between e c c e n t r i c i t y and f i l t e r r e f l e c t s the d i s t r i b u t i o n of the cones and rods across the retina . The largest s i g n i f i c a n t differences as calculated in Table 27 occur in the periphery (beginning from 20° temporally and 15° nasally) between the achromatic and red f i l t e r s (higher thresholds for the red), followed by the differences between the red and blue (higher thresholds for the red). There were no s i g n i f i c a n t mean differences between the blue and achromatic f i l t e r s . The pattern found in Table 27 t y p i c a l l y demonstrates the lack of s e n s i t i v i t y in the periphery for the red, i . e . the red show a higher threshold in the periphery than the other f i l t e r s . Though nonsignificant, the mean differences between the achromatic and blue r e f l e c t a similar trend as found in the red, i . e . , the blue has a higher threshold in the peripheral e c c e n t r i c i t i e s when compared to the 199 TABLE 27 ABSOLUTE MEAN THRESHOLD (APOSTILBS) DIFFERENCE BETWEEN FILTERS BY ECCENTRICITY RED VS. RED VS. BLUE VS. ECCENTRICITY ACHROMATIC BLUE ACHROMATI< NASAL 40 352.17* 342.58* 9.59 30 318.09* 288.37* 29.72 20 231.18* 221.60* 9.58 15 172.97* 184.64* 1 1 .67 10 59.42 76.24 16.75 5 29.56 57.56 28.00 FOVEA 0 19.50 15.47 4.03 TEMPORAL 5 23. 1 3 56.49 33.36 10 97.08 105.89 8.81 20 231.20* 251.68* 20.48 30 230.67* 248.99* 18.32 40 298.09* 265.18* 32.91 55 353.20* 299.64* 53.56 70 317.64* 263.02* 54.62 Note: * - SIGNIFICANT AT THE .0001 LEVEL 200 achromatic. The increase in threshold for the red and blue as one moves away from the fovea is expected as the cone population reduces d r a s t i c a l l y when moving toward the periphery ( 0 s t e r b e r g , 1935). The finding of red y i e l d i n g a s i g n i f i c a n t l y higher threshold than an achromatic or blue stimulus has been confirmed with normal subjects by Lakowski and Dunn (1981). In order to examine the s i g n i f i c a n t interaction between e c c e n t r i c i t y and group (F(7.15,175.17)=2.37, Q<.02), Tukey's HSD were computed across f i l t e r s using a c r i t i c a l value of 120.00. Table 28 provides the absolute mean differences between the 3 groups by e c c e n t r i c i t y . The largest number of s i g n i f i c a n t mean differences at the .0001 l e v e l were between the normal and probable groups. A l l e c c e n t r i c i t i e s , except the fovea (0°), were s i g n i f i c a n t l y d i f f e r e n t . A l l e c c e n t r i c i t i e s were s i g n i f i c a n t l y d i f f e r e n t between the normal and c l i n i c a l l y d e f i n i t e groups. With respect to the comparison between the two MS groups, a l l e c c e n t r i c i t i e s (excluding the 10° nasal and 55° temporal) were s i g n i f i c a n t l y d i f f e r e n t at the .0001 l e v e l . For a l l of the group comparisons, the nasal part of the f i e l d t y p i c a l l y yielded greater mean differences than the temporal region. Thus both MS groups have s i g n i f i c a n t l y higher thresholds than the normals across a l l e c c e n t r i c i t i e s , except at the fovea between the probable and normal groups. The magnitude of t h i s difference appears to be greater in the nasal f i e l d , suggesting a d i f f e r e n t i a l e f f e c t (due to TABLE 28 ABSOLUTE MEAN THRESHOLD (APOSTILBS) DIFFERENCE BETWEEN GROUPS BY ECCENTRICITY NORMAL VS. NORMAL VS. PB VS. ECCENTRICITY PB CD CD NASAL 40 398.62* 263.88* 134.74* 30 446.37* 305.99* 140.38* 20 484.08* 311.06* 173.02* 15 419.78* 222.06* 197.72* 10 377.79* 278.66* 99. 1 3 5 390.75* 245.03* 145.72* FOVEA 0 62.1 0 349.89* 287.79* TEMPORAL 5 392.42* 243.03* 149.39* 10 371.14* 236.56* 134.58* 20 492.27* 248.28* 243.99* 30 368.20* 221.15* 1 47.05* 40 419.03* 242.29* 176.74* 55 352.04* 236.1 1* 115.93 70 326.83* 174.40* 152.43* Note: PB - PROBABLE MS CD - CLINICALLY DEFINITE MS * - SIGNIFICANT AT THE .0001 LEVEL 202 the possible disease pathology) across the re t i n a . As with the normals, the probable and c l i n i c a l l y d e f i n i t e groups d i f f e r s i g n i f i c a n t l y at the fovea with the l a t t e r group having s i g n i f i c a n t l y higher thresholds. A possible factor contributing to the finding of a lack of significance at the fovea between the normal and probable groups may be found in the section e n t i t l e d Optic N e u r i t i s . To examine the s i g n i f i c a n t 3 way interaction between group x f i l t e r x e c c e n t r i c i t y (F( 23.44,574.19)=2.94 , P_<.0001 ), Tukey's HSD were calculated for each e c c e n t r i c i t y by group and f i l t e r . The c r i t i c a l value used was 118.69 (.0001 le v e l of p r o b a b i l i t y ) . Tables 29, 30, and 31 provide the absolute mean differences for the achromatic, red, and blue f i l t e r s respectively. Examination of the tables reveals that the largest mean differences tended to be between the normal and probable groups across a l l e c c e n t r i c i t i e s except at the fovea. A l l e c c e n t i c i t i e s were s i g n i f i c a n t l y d i f f e r e n t between the normal and c l i n i c a l l y d e f i n i t e groups. Although the red f i l t e r was s i g n i f i c a n t l y higher than the blue or or achromatic f i l t e r s (discussed e a r l i e r ) , the blue f i l t e r had the greater number of large mean diffrences (300 or above). Although this may not be s i g n i f i c a n t , the larger number of mean differences may indicate a greater susceptability of the blue cones over the red. It i s interesting to note that the red has sl i g h t e r larger mean differences than the achromatic. Though any interpretation TABLE 29 ABSOLUTE MEAN THRESHOLD (APOSTILBS) DIFFERENCE BETWEEN GROUPS BY ECCENTRICITY FOR THE ACHROMATIC FILTER NORMAL VS. NORMAL VS. PB VS. ECCENTRICITY PB CD CD NASAL 40 413.32* 239.28* 174.04* 30 437. 10* 303.26* 1 33.84* 20 398.51* 275.10* 123.41* 1 5 344.08* 203.66* 140.42* 10 359.59* 279.84* 79.75 5 373.55* 232.76* 140.79* FOVEA 0 73.56 375.01* 301.45* TEMPORAL 5 370.15* 240.81* 129.34* 10 378.80* 261.06* 117.74 20 445.18* 274.83* 170.35* 30 372.41* 141.32* 231.09* 40 403.37* 213.38* 189.99* 55 416.19* 236.03* 180.16* 70 472.08* 295.08* 177.00* Note: PB - PROBABLE MS CD - CLINICALLY DEFINITE MS * - SIGNIFICANT AT THE .0001 LEVEL 204 TABLE 30 ABSOLUTE MEAN THRESHOLD (APOSTILBS) DIFFERENCE BETWEEN GROUPS BY ECCENTRICITY FOR THE RED FILTER NORMAL VS. NORMAL VS. PB VS. ECCENTRICITY PB CD CD NASAL 40 288.30* 202.23* 86.07 30 424.28* 309.81* 1 14.47 20 477.48* 437.53* 39.95 15 446.82* 312.40* 134.42* 10 413.30* 300.56* 112.74 5 425.76* 278.34* 147.42* FOVEA 0 58.86 304.50* 245.64* TEMPORAL 5 438.54* 266.79* 17 1.75* 10 401.72* 271.85* 129.87* 20 447.42* 215.30* 232.14* 30 378.77* 338.40* 40.37 40 354.93* 375.48* 20.56 55 240.68* 213.71* 26.97 70 118.70* 246.50* 94.05 Note: PB -CD -* _ PROBABLE MS CLINICALLY DEFINITE MS SIGNIFICANT AT THE .0001 LEVEL 205 TABLE 31 ABSOLUTE MEAN THRESHOLD (APOSTILBS) DIFFERENCE BETWEEN GROUPS BY ECCENTRICITY FOR THE BLUE FILTER NORMAL VS. NORMAL VS. PB VS. ECCENTRICITY PB CD CD NASAL 40 494.24* 350.13* 144.12* 30 477 .74* 304.91* 172.82* 20 576.26* 220.57* 355.68* 1 5 468.44* 150.10* 318.34* 10 360.47* 255.56* 104.91 5 372.93* 223.99* 148.94* FOVEA 0 54.00 370.29* 316.29* TEMPORAL 5 368.64* 221.51 * 147.13* 10 332.92* 176.77* 156.15* 20 584.20* 254.71* 329.49* 30 354.44* 183.75* 169.69* 40 478.22* 158.56* 319.66* 55 399.25* 258.58* 140.67* 70 390.53* 203.45* 187.07* Note: PB -CD -* -PROBABLE MS CLINICALLY DEFINITE MS SIGNIFICANT AT THE .0001 LEVEL 206 of t h i s difference i s rather questionable, i t would be tempting to speculate that the finding of greater mean differences among the blue and red f i l t e r s as compared to the achromatic resulted from the s e n s i t i v i t y of the cone system over the rod to the e f f e c t s of MS. The nasal e c c e n t r i c i t i e s t y p i c a l l y revealed greater mean threshold differences than the temporal for a l l group comparisons for each f i l t e r . This trend may possibly be indic a t i v e of some selective pathological process occuring in the eyes of the MS patients. At 30° e c c e n t r i c i t y , the thresholds for v i r t u a l l y a l l of the comparisons becomes much lower than the 20° e c c e n t r i c i t y . From Tables 15 to 17, which contained the standard deviations for each group by f i l t e r and ec c e n t r i c i t y , v a r i a b i l i t y in r e t i n a l thresholds as a result of e c c e n t r i c i t y indicates the following: 1. Among the normals, threshold v a r i a b i l i t y increases with e c c e n t r i c i t y except at 20° and 30° temporally. Irregular increases may also be seen at and past 30° e c c e n t r i c i t y for the achromatic f i l t e r only. The increase in v a r i a b i l i t y among normals i s in agreement with previous investigations (eg. Aulhorn & Harms, 1972; Lakowski & Dunn, 1981). 2. For the c l i n i c a l l y d e f i n i t e group, the v a r i a b i l i t y in thresholds i s highest at the fovea. The remaining e c c e n t r i c i t i e s also demonstrate great v a r i a b i l i t y across the 3 f i l t e r s , e s p e c i a l l y near the fovea. 207 3. For the probable group, higher v a r i a b i l i t y in the thresholds tends to occur near the periphery but not at the fovea i t s e l f . The drop in v a r i a b i l t y at 20° temporal and 30° nasal e c c e n t r i c i t y i s interesting in that one would have expected the reverse to have been true. Greater v a r i a b i l i t y should have occurred at 20° temporal e c c e n t r i c i t y resulting from i t s proximity to the blind spot. Similar findings regarding the drop in v a r i a b i l i t y in the periphery has been reported by Dunn (1981) for 40° nasal and 30° temporal e c c e n t r i c i t y under photopic conditions. a. Fovea To examine more clos e l y the involvement of the fovea with respect to the other e c c e n t r i c i t i e s , Pearson Product-Moment correlations were computed for the foveal threshold against the other e c c e n t r i c i t i e s . 1 Table 32 provides the c o r r e l a t i o n s 2 for the normal, c l i n i c a l l y d e f i n i t e , and probable groups for the achromatic f i l t e r . Tables 33 and 34 provide similar results for the red and blue f i l t e r s respectively. Correlations for the normal group tended to be nonsignificant with the fovea. The d i r e c t i o n of the co r r e l a t i o n t y p i c a l l y became negative after 5° for the red and at 5° for the blue and achromatic. This functional pattern r e f l e c t s the 1 The correlations were computed using the S t a t i s t i c a l Package for the Social Sciences, version X (1983). 2 Significance i s based upon a two-tailed test. TABLE 32 CORRELATIONS BETWEEN THE FOVEA AND ECCENTRICITIES BY GROUP FOR THE ACHROMATIC FILTER CLINICALLY ECCENTRICITY NORMALS PROBABLE DEFINITE NASAL 40 .09 .48 .30 30 .03 .47 .65* 20 -.10 .53 .65* 15 -.11 .50 .71** 10 -.11 .50 .68** 5 .04 .51 .69** TEMPORAL 5 .16 .50 .72** 10 -.06 .52 .72** 20 -.16 .49 .85** 30 -.08 -.23 .79** 40 -.12 -.07 .81** 55 .22 -.11 .83** 70 .08 .27 .58 Note: * - .05 LEVEL OF SIGNIFICANCE ** - .01 LEVEL OF SIGNIFICANCE 209 TABLE 33 CORRELATIONS BETWEEN THE FOVEA AND ECCENTRICITIES BY GROUP FOR THE RED FILTER CLINICALLY ECCENTRICITY NORMALS PROBABLE DEFINITE NASAL 40 -.09 .32 .48 30 -.13 .43 .45 20 -.07 .54 .57* 15 - . 1 9 .72* .77** 10 -.14 .74* .71** 5 -.17 .74* .76** TEMPORAL 5 .26 .72* .78** 10 -.06 .65 .73** 20 -.22 .54 .51 30 .05 -.47 .40 40 -.13 -.27 .47 55 -.37* -.35 .34 70 .25 .32 .40 Note: * - .05 LEVEL OF SIGNIFICANCE ** - .01 LEVEL OF SIGNIFICANCE 210 TABLE 34 CORRELATIONS BETWEEN THE FOVEA AND ECCENTRICITIES BY GROUP FOR THE BLUE FILTER CLINICALLY ECCENTRICITY NORMALS PROBABLE DEFINITE NASAL 40 .26 .37 .41 30 .16 .41 .76** 20 -.25 .41 .64* 15 -.20 .61 .73** 10 -.13 .64 .71** 5 -.11 .64 .72** TEMPORAL 5 -.29 .64 .73** 10 -.10 .64 .72** 20 -.15 .44 .89** 30 -.07 .54 .84** 40 .31 .36 .81** 55 .14 .37 .73** 70 .39* .26 .27 NOTE: * -** _ .05 LEVEL OF SIGNIFICANCE .01 LEVEL OF SIGNIFICANCE 21 1 d i s t r i b u t i o n of cones and rods in the re t i n a , indicating the existence of two d i f f e r e n t systems as has been demonstrated by numerous researchers. With respect to the c l i n i c a l l y d e f i n i t e and probable groups, the correlations between the foveal threshold and other e c c e n t r i c i t i e s were p o s i t i v e . The only exception to t h i s trend was between 30° and 55° temporally for the probable subjects. The majority of the correlations for the c l i n i c a l l y d e f i n i t e group were s i g n i f i c a n t . To examine more rigorously the possible differences in the correlations between the various f i l t e r s and groups, the correlations were transformed into Z'. Standard error of the differences were computed for each f i l t e r by group. The normal curve was then examined to determine i f the differences between the Z' were s t a t i s t i c a l l y s i g n i f i c a n t . Results of the analysis revealed that the blue f i l t e r for both the c l i n i c a l l y d e f i n i t e and probable MS patients had s i g n i f i c a n t l y more (>.01) large positive correlations than did either the achromatic or red. Moreover, the achromatic had s i g n i f i c a n t l y more positve correlations than the red at the .01 l e v e l of significance. For the normals, only the red demonstrated s i g n i f i c a n t l y larger negative c o r r e l a t i o n s . This confirms the descriptive observations noted e a r l i e r . 212 b. Optic Neuritis To examine the possible role that optic n e u r i t i s (ON) may have had on the threshold results from the MS patients, the data was reanalyzed. A repeated measures MANOVA for 1 between group factor (MS-ON, MS-no ON) and 2 within factors (3 f i l t e r s , 14 e c c e n t r i c i t i e s ) was done. 1 The results of the analysis are presented in Table 35. There was no s i g n i f i c a n t main ef f e c t for groups (F(1 , 20)=0.13, p >.05), nor for f i l t e r x group (F( 1 .36,27.23) = 2.69, p_ >.05), nor e c c e n t r i c i t y x group (F(3.09,61 .85) = 2. 1 9, p_ >.05). The f i l t e r x e c c e n t r i c i t y x group interaction was also nonsignificant (F(8.04,160.31)=1.21, p>.05). A s i g n i f i c a n t main ef f e c t was obtained for f i l t e r (F(2,40)=42.73, p_< . 0 1 ) . Using a c r i t i c a l value of 166.51, Tukey's HSD were computed between the mean thresholds for the achromatic (443.97 asb.), red (632.66 asb.), and blue f i l t e r s (453.83). The absolute mean differences (Table 36) between the red and the blue and achromatic f i l t e r s respectively were both s i g n i f i c a n t at the .0001 l e v e l . The mean difference between the blue and red f i l t e r s were not s i g n i f i c a n t . These findings are id e n t i c a l to that reported in the main study, indicating 1An analysis including the normal group was also done. As the r e s u l t s were similar to the one reported in the main study, i t was not discussed. The MANOVA results for t h i s analysis may be found in Appendix G. TABLE 35 MULTIVARIATE ANALYSIS OF VARIANCE BETWEEN OPTIC NEURITIS (n=14) AND NON OPTIC NEURITIS (N=8) MS PATIENTS SOURCE SS df MS F P-GROUP (G) 421653. 76 1 ,20 421653. 76 0 . 1 3 .7199 FILTER (F) 7353989. 75 2, 40 3676994. 87 42 .73 .0000 ECCENTRICITY (E) 16685914. 32 1 3 .09,61 .85 1 283531 . 87 10 .94 .0000* G X F 463532. 58 1 .36,27 .23 231766. 29 2 .69 .0799* G X E 3344496. 91 3 .09,61 .85 257268. 99 2 .19 .0960* F X E 2808966. 91 8. 04,160 .31 108037. 19 6 .42 .0000* G X F X E 530210. 39 8. 04,160 .31 20392. 71 1 .21 .2954* NOTE: * Denotes p r o b a b i l i t y a f t e r degrees of freedom were adjusted by the Greenhouse-Gei sser. 214 TABLE 36 ABSOLUTE MEAN THRESHOLD DIFFERENCE (APOSTILBS) FOR OPTIC NEURITIS AND NON OPTIC NEURITIS MS PATIENTS BY FILTER COMPARISON MEAN DIFFERENCE RED VS. ACHROMATIC 188.69* RED VS. BLUE 178.83* ACHROMATIC VS. BLUE 9.86 NOTE: * - SIGNIFICANT AT THE .0001 LEVEL 215 that the thresholds were higher for the red f i l t e r over the achromatic and blue. Although the mean threshold for the blue was s l i g h t l y higher than that of the achromatic, the difference was not s i g n i f i c a n t . The lack of significance was seen as resulting from the large contribution of blue energy in white (achromatic) l i g h t . There was a s i g n i f i c a n t main eff e c t for ec c e n t r i c i t y (F (3 . 09, 61 .85) = 1 0. 94, p_<'0l). As in the main study, the s i g n i f i c a n t e f f e c t for e c c e n t r i c i t y was seen as resulting from d i f f e r e n t i a l s e n s i t i v i t y across the r e t i n a . Threshold values were the lowest at the fovea (0°) and increased in the periphery. Table 37 provides the mean threshold values for the e c c e n t r i c i t i e s averaged across the 3 f i l t e r s . Tukey's HSD were calculated using a c r i t i c a l value of 153.43 and the absolute mean differences are shown in Table 38. Again as in the main results, the greatest s i g n i f i c a n t differences (at the .0001 level) were between the periphery and central areas of the fovea. The greatest differences tended to be found when comparing the fovea. A s i g n i f i c a n t interaction was found for f i l t e r x ec c e n t r i c i t y (F(8.04,160.31)=6.42, p_< . 0 1 ) . Table 39 provides the mean threshold values for each of the 3 f i l t e r s . Tukey's HSD, using a c r i t i c a l value of 152.34, were computed. Table 40 shows the absolute mean differences between the f i l t e r s by e c c e n t r i c i t i e s . 216 TABLE 37 MEAN THRESHOLDS (APOSTILBS) FOR OPTIC NEURITIS AND NON OPTIC NEURITIS PATIENTS ACROSS FILTERS BY ECCENTRICITY ECCENTRICITY MEAN NASAL 40 717.55 30 645.16 20 542.13 15 444.15 10 413.16 5 362.77 FOVEA 0 255.38 TEMPORAL 5 361.07 10 425.50 20 559.62 30 488.63 40 527.57 55 580.69 70 818.74 TABLE 38 ABSOLUTE MEAN THRESHOLD DIFFERENCE (APOSTILBS) BY ECCENTRICITY ACROSS OPTIC NEURITIS PATIENTS AND NON OPTIC NEURITIS PATIENTS AND FILTERS NASAL FOVEA TEMPORAL 40 30 20 15 5 1 0 5 10 20 30 40 55 70 NASAL 40 30 72 . 39 20 175 42* 102 .03 15 273 .40* 201 . 0 1 * 97 .98 10 304 39* 232 . 0 0 * 128 .97 30 99 5 354 .78* 282 . 39* 179 . 36* 81 , 38 50 . 39 FOVEA O 462 17* 389 . 78 * 286 . 7 5 * 188 . 77* 157 . 78* 107 . 39 TEMPORAL 5 356 .48* 284 0 9 * 18 1 .06* 83 . 08 52 .09 1 . 70 105 69 10 292 05 * 219 66* 1 16 63 18 . 65 12 . 34 62 . 73 170 . 12* 64 .43 20 157 9 3 * 85 .54 17 49 1 15. 47 146 . 46* 196 . 85* 304 . 24* 198 . 55* 134 12 30 228 .92* 156 53* 53 .50 44 . 48 75 .47 125 .86 233 . 2 5 * 127 .56 63 13 7 0 . 9 9 40 189 .98* 117 59 14 56 83 . 42 1 14 . 4 1 164 .80* 272 . 19* 166 50* 102 07 32 .05 38 94 55 136 86 64 47 38 56 136 . 54 167 . 5 3 * 2 17 . 92 * 325 . 3 1 * 2 19 62* 155 19* 2 1 .07 9 2 . 0 6 5 3 . 12 70 101 . 19 173 58* 276 6 1 * 374 . 59* 405 . 58 * 455 97 * 563 . 36* 457 67 * 393 24* 259 12* 3 3 0 . 1 1 * 2 9 1 . 1 7 * 238 05 NOTE: * - SIGNIFICANT AT THE .0001 LEVEL 218 TABLE 39 MEAN THRESHOLDS (APOSTILBS) FOR OPTIC NEURITIS AND NON OPTIC NEURITIS PATIENTS BY FILTERS AND ECCENTRICITY ECCENTRICITY ACHROMATIC RED BLUE NASAL 40 591.21 887.84 673.61 30 523.49 832.58 579.39 20 429.64 737.49 459.28 1 5 365.78 600. 12 366.55 10 394.86 471.85 372.77 5 353.77 410.18 324.36 FOVEA 0 275.89 224.07 266.17 TEMPORAL 5 357.49 405.40 320.31 10 408.65 509.35 358.51 20 489.99 692. 14 496.74 30 394.99 679.73 391 . 17 40 402.47 740.69 439.56 55 456.75 762.36 522.97 70 770.55 903.41 782.25 219 TABLE 40 ABSOLUTE MEAN THRESHOLD (APOSTILBS) DIFFERENCE BETWEEN FILTERS BY ECCENTRICITY RED VS . RED V S . BLUE V S . ECCENTRICITY ACHROMATIC BLUE ACHROMATIC NASAL 40 296.63* 214.23* 82.40 30 309.09* 253.19* 55.90 20 307.85* 278.21 * 29.64 1 5 234.34* 233.57* 0.77 10 76.99 99.00 22.09 5 56.41 85.82 29.41 FOVEA 0 51 .82 42. 1 0 9. 72 TEMPORAL 5 47.91 85 .09 37. 18 10 100.70 150.84 50. 1 4 20 202.15* 195.40* 6.75 30 284.74* 288.56* 3.82 40 338.22* 301 .13* 37.09 55 305.61* 239.39* 66.22 70 132.86* 121.16 1 1 .70 NOTE: * - SIGNIFICANT AT THE .0001 LEVEL 220 The largest number of s i g n i f i c a n t differences (at the .0001 level) are found between the red and achromatic f i l t e r s , followed by the red and blue. There were no s i g n i f i c a n t differences between the achromatic and blue f i l t e r s . As with the s i g n i f i c a n t e c c e n t r i c i t y x f i l t e r i nteraction found in the main study, the s i g n i f i c a n t differences tends to begin at and past 10° nasally and temporarily. This trend i s seen as res u l t i n g from the d i f f e r e n t i a l s e n s i t i v i t y of the retina to the red versus blue and achromatic f i l t e r s . Again, the lack of significance between the achromatic and blue was seen as resul t i n g from the presence of short wavelength l i g h t in white l i g h t . c. Discriminant Analysis To examine how accurately the normals and MS patients could be c l a s s i f i e d by the thresholds, a stepwise discriminant analysis was done for the three f i l t e r s . Both the thresholds for the nasal and temporal peripheries were collapsed into a mean threshold for each inorder to protect the degrees of freedom. Thus three discriminant analyses using three measures of thresholds (fovea, nasal, and periphery) were conducted separately for the achromatic, red, and blue f i l t e r s . The results of the analysis are shown in Table 41. 221 TABLE 41 PERCENT CLASSIFICATION OF SUBJECTS BY DIAGNOSIS (NORMAL VS. MS) AND FILTER ACHROMATIC PREDICTED GROUP NORMAL MS 100% 0% 52.4% 47.6% GROUP NORMAL (n=30) MS (n=22) OVERALL CORRECT CLASSIFICATION = 78.43% GROUP NORMAL (n=30) MS (n=22) RED PREDICTED GROUP NORMAL MS 96.7% 3.3% 28.6% 71.4% OVERALL CORRECT CLASSIFICATION = 86.27% GROUP NORMAL (n=30) MS (n=22) BLUE PREDICTED GROUP NORMAL MS 96.7% 3.3% 47.6% 52.4% OVERALL CORRECT CLASSIFICATION = 78.43% 222 In terms of o v e r a l l c l a s s i f i c a t i o n , the red f i l t e r c o r r e c t l y c l a s s i f i e d 86.27% of the normals and MS patients as compared to 78.43% for both the blue and achromatic. Both of these rates are far above that expected by chance. The red f i l t e r c o r r e c t l y c l a s s i f i e d 96.7% of the normals and 71.4% of the MS patients. Only 28.6% of the patients were incorrectly c l a s s i f i e d as normals whereas 3.3% of the normals were incorrectly i d e n t i f i e d as belonging to the MS group. With respect to the achromatic and blue f i l t e r s , more of the MS patients were c l a s s i f i e d as normal (52.4% and 47.6% respectively). The MS patients incorrectly i d e n t i f i e d were the probable patients. That i s , the probable patients tended to be m i s c l a s s i f i e d as normals. In terms of overa l l group prediction as well as low false positives for not having MS, the red f i l t e r appears to provide the best r e s u l t s . d. Threshold C l a s s i f i c a t i o n Inorder to provide a threshold l e v e l that would c l i n i c a l l y i d e n t i f y an abnormal threshold from a normal one, log differences between the fovea and 30° nasal e c c e n t r i c i t y were computed. Both the probable and c l i n i c a l l y d e f i n i t e patients were collapsed into one group as the question centered upon which threshold would d i f f e r e n t i a t e between MS and normals. 223 The log differences were then used to compute cummulative frequencies in an ascending manner for the normals and descending for the MS patients. The threshold at which most of the MS patients and normals could be discriminated from one another was found. This was done for each of the three f i l t e r s separately. For the achromatic f i l t e r , a log apos t i l b difference cut-off value of -2.60 c o r r e c t l y i d e n t i f i e d a l l of the MS patients and a l l but one of the normals. S i m i l a r i l y , the log apos t i l b difference value of -2.45 for the blue i d e n t i f i e d a l l but one of the MS patients as being d i f f e r e n t from the normals. No normal was i d e n t i f i e d as having an abnormal threshold using the value of -2.45. With respect to the red f i l t e r , a log apostilb threshold value of -2.25 c o r r e c t l y separated a l l of the normals from a l l but one of the MS patients. 224 V. DISCUSSION The r e s u l t s of the a n a l y s i s supported the hypothesis that there would be a d i f f e r e n c e between the MS p a t i e n t s and normals with respect to t h e i r r e l a t i v e thresholds for a red, blu e , and achromatic f i l t e r . MS p a t i e n t s have s i g n i f i c a n t l y higher t h r e s h o l d s across a l l e c c e n t r i c i t i e s when compared to age-matched normals. Although the thresholds f o r the red are s i g n i f i c a n t l y greater than e i t h e r the blue or achromatic f i l t e r s , there i s no o v e r a l l group d i f f e r e n c e by f i l t e r . T his would argue that the f u n c t i o n a l l o s s i n cone/rod f u n c t i o n i n g i s so great among the MS p a t i e n t s , at t h e i r present s t a t e i n the disease, that a l l of the f i l t e r s were a f f e c t e d . Such a conclusion needs to be guarded i n that the magnitude of the d i f f e r e n c e between the 3 f i l t e r s (across a l l groups) needs to be reassessed once the a c t u a l photometric measures for stimulus i n t e n s i t y i s achieved. U n t i l then, assuming that Synemed® i s c o r r e c t i n s t a t i n g that the F225 f i l t e r s are p h o t o m e t r i c a l l y equated, the r e l a t i v e d i f f e r e n c e between the f i l t e r s reported here are v a l i d . Support for the r e l a t i v e p o s i t i o n of the red th r e s h o l d f o r normals comes from Lakowski and Dunn (1981) who reported that the red (XD 532 nm.) y i e l d e d a "gradient from 1 and 1/2 to 2 log u n i t s below the others [ achromatic, b l u e , and green]" (p. 195). S i m i l a r r e s u l t s were reported by Aulhorn and Harms (1972). 225 However, as p o i n t e d out by Lakowski and Dunn, the r e l a t i v e t h r e s h o l d g r a d i e n t s are h i g h l y dependent upon the background bowl a d a p t a t i o n l e v e . Thus Lakowski and Dunn r e p o r t e d that under f u l l y p h o t o p i c c o n d i t i o n s (250 c d / m 2 ) the s e p a r a t i o n between the the v a r i o u s f i l t e r s become very s m a l l except at the f o v e a . The s i g n i f i c a n t i n t e r a c t i o n between group x f i l t e r x e c c e n t r i c i t y r e v e a l e d t h a t : 1. M S - p r o b a b l e p a t i e n t s had s i g n i f i c a n t l y h i g h e r t h r e s h o l d s than normals a c r o s s a l l e c c e n t r i c i t i e s except the f o v e a , 2. M S - c l i n i c a l l y d e f i n i t e p a t i e n t s had s i g n i f i c a n t l y h i g h e r t h r e s h o l d s a c r o s s a l l e c c e n t r i c i t i e s i n c l u d i n g the f o v e a , for the b l u e and achromat ic f i l t e r s o n l y . For the r e d , s i g n i f i c a n t mean t h r e s h o l d s were found o n l y i n the c e n t e r from 2 0 ° t e m p o r a l l y to 1 5 ° n a s a l l y . As wi th the normal s , the g r e a t e s t mean d i f f e r e n c e between the c l i n i c a l l y d e f i n i t e and p r o b a b l e p a t i e n t s tended to occur at the f o v e a . Thus the c l i n i c a l l y d e f i n i t e p a t i e n t s had s i g n i f i c a n t l y h i g h e r t h r e s h o l d s i n the fovea when compared to the normals or M S - p r o b a b l e pat i e n t s . 3 . Losses i n the f i e l d tended to be g r e a t e r in the n a s a l r a t h e r than tempora l r e g i o n s , wi th the b lue showing s l i g h t l y more s i g n i f i c a n t mean d i f f e r e n c e s between the v a r i o u s groups than the r e d . The d i f f e r e n c e s i n r e t i n a l s e n s i t i v i t y found i n the MS groups i s in agreement w i t h the few s t u d i e s t h a t have been 226 done using s t a t i c threshold perimetery. Serra and Mascia reported the presence of a small r e l a t i v e scotoma in the fovea of MS patients using an achromatic stimulus. The presence of a central defect and small scotoma 10 0-20° temporally through s t a t i c perimetry has also been reported by Van Dalen, Spekreyse and Greve (1981). The results from the present study are in agreement with these findings. Losses tend to be great at the fovea as well as at e c c e n t r i c i t i e s adjacent to the fovea. However, the findings d i f f e r from the others in that the loss in MS appears to occur across a l l e c c e n t r i c i t i e s except in the fovea of probable patients. A possible explanation for t h i s w i l l be discussed shortly. Suprathreshold studies t y p i c a l l y have revealed the presence of abnormal f i e l d s such as arcuate scotoma (Patterson and Heron, 1980), central and paracentral defects (Paton, 1924; Scott, 1957; Keltner, Johnson & Balestrery, 1979), and small scotoma in the periphery between 15° and 30° e c c e n t r i c i t y (Meienberg, Flammer & Hans-Peter, 1982). Again, the findings of the present study tend to agree with those from the suprathreshold studies in showing a loss in the v i s u a l f i e l d . It d i f f e r s in that the loss occurs across the f i e l d , with the fovea showing i d e n t i f i a b l e losses. Moreover, the loss found in the present study i s much more pronounced for the chromatic f i l t e r s . As perimetric studies have focused upon the standard use of achromatic stimuli (due to instrumental d i f f i c u l t i e s in 227 presenting chromatic stimuli) the involvement of the cone system in MS has not been appreciated. Thus Meienberg et. a l . (1982), in using achromatic stimuli in standard suprathreshold testing, state that abnormality in MS is better detected with VEP since the defects found through the Octopus Automated Perimeter are not in the center but periphery. By not d i f f e r e n t i a t i n g r e t i n a l receptor functioning (rod/cone), however, important information regarding basic as well as pathological functioning i s l o s t . Understanding the involvement of the 2 r e t i n a l systems has considerable t h e o r e t i c a l implications regarding symptomatology such as the fluctuation in visu a l acuity or glare reported by patients. The results from the present study do d i f f e r from those conducted by Younge (1985) on an automated perimeter: the Octopus. Younge reported that the mean thresholds for MS patients overlapped with the mean thresholds for normals despite the fact that individual threshold values were lower for the MS patients. He concluded that the reason for the overlap was due to no cases of subacute optic nerve involvement. The present study, however has shown s i g n i f i c a n t mean differences in the thresholds of MS patients from normals, both among patients with and without optic n e u r i t i s . The reason for the differences in the two studies centers upon the psychophysical conditions of the testing s i t u a t i o n . In Younge's study, patients were tested with an achromatic stimulus at mesopic l e v e l s . In the 228 p r e s e n t s t u d y , however, the s u b j e c t s were examined w i t h c h r o m a t i c f i l t e r s , one more s u i t e d f o r a s s e s s i n g cone f u n c t i o n . One s e r i o u s drawback i n the p r e s e n t study t h a t l i m i t s any comparison w i t h s t u d i e s such as Younge i s the d i f f e r e n c e i n the p s y c h o p h y s i c a l f u n c t i o n of the i n s t r u m e n t i t s e l f . The d i f f e r e n c e , d i s c u s s e d i n the s e c t i o n on M e t h o d o l o g i c a l and I n s t r u m e n t a l Problems, makes i t e x t r e m e l y d i f f i c u l t t o t r y and compare the p r e s e n t r e s u l t s w i t h any o t h e r p e r i m e t r i c f i n d i n g i n MS. T h i s , the problem of d i f f e r e n c e i n i n s t u m e n t a t i o n , i s a s e r i o u s problem i n p e r i m e t r y i n g e n e r a l . The r e s u l t s of the p r e s e n t study a l s o d i f f e r from p r e v i o u s p e r i m e t r i c s t u d i e s w i t h r e s p e c t t o the observed f l u c t u a t i o n s i n the s e n s i t i v i t y p r o g r e s s i o n from l e a s t i n the p e r i p h e r y t o the h i g h e s t i n the f o v e a . As s t a t e d e a r l i e r , p e r i m e t r i c r e s e a r c h on MS has t y p i c a l l y r e v e a l e d the p r e s e n c e of i r r e g u l a r t h r e s h o l d s a c r o s s the e c c e n t r i c i t i e s , r e s u l t i n g i n the p r o f i l e known c l i n i c a l l y as the s w i s s cheese f i e l d . R e s u l t s of the p r e s e n t study i n d i c a t e s t h a t t h i s t h r e s h o l d v a r i a b i l i t y i s o n l y found w i t h b l u e and a c h r o m a t i c f i l t e r s . The p r o f i l e f o r t h e r e d f i l t e r i s c o n s i s t e n t l y good, w i t h the s e n s i t i v i t y g r a d i e n t i n c r e a s i n g as one moves toward the f o v e a . I t would be i n c o r r e c t , t h e r e f o r e , t o s t a t e t h a t MS i s c h a r a c t e r i z e d by s w i s s cheese f i e l d s . T h i s i s o n l y t r u e f o r a c h r o m a t i c ( t y p i c a l l y used) and b l u e s t i m u l i . A r e d s t i m u l u s p r o v i d e s an e n t i r e l y d i f f e r e n t p e r i m e t r i c p r o f i l e , one p e c u l i a r t o 229 the red cone involvement in MS. The involvement of the cone system in MS can be seen in the c o r r e l a t i o n between the fovea and other e c c e n t r i c i t i e s . For the normals, the correlations between the fovea and remaining e c c e n t r i c i t i e s were nonsignificant and generally negative. Though nonsignificant, the negative d i r e c t i o n could indicate the difference in cone functioning at the fovea and cone/rod functioning in the periphery. An interesting finding with the normals i s the presence of positi v e c o r r e l a t i o n s , again nonsignificant except for 70° temporal e c c e n t r i c i t y for the blue f i l t e r , are found in the far nasal and temporal peripheries for the red and blue f i l t e r s . This would seem to argue for a functional s i m i l a r i t y between the fovea and far periphery, possibly due to the presence of cones in the periphery (eg. Curcio, 1985). The involvement of the cone system in MS reveals i t s e l f dramatically in the correlations between the fovea and remaining e c c e n t r i c i t i e s . Both in the c l i n i c a l l y d e f i n i t e and probable MS groups, the correlations with the fovea are generally s i g n i f i c a n t and p o s i t i v e . The pattern of the correlations among the two MS groups appears to result from extensive damage to the cone system, making i t functionally i n d i s t i n c t from the rod system. This i s surported by the fact that the largest p o s i t i v e correlations are found among the blue and achromatic f i l t e r s . Unfortunately, there are no published studies on 230 dark adaptation and the effects of MS. Among the normals, the correlations for the red and blue f i l t e r s tend to be higher in a negative di r e c t i o n than for the achromatic, a l b e i t nonsignificant. The dramatic change for the blue f i l t e r among the MS subjects to become highly positive with the other e c c e n t r i c i t i e s suggests that the blue cone system may have become more functionally affected. As the correlations for the red f i l t e r for the 2 patient groups show fewer s i g n i f i c a n t correlations than do the blue and achromatic, one might argue that the red cones are more resistent and tend to be the la s t of the cone system to be affected. Although in t r i g u i n g in that the results from the correlations would argue that the blue cones are more sensitive to the pathological e f f e c t s of MS, i t needs to be pointed out that t h i s interpretation i s highly dependent upon the adaptation l e v e l and f i l t e r c h a r a c t e r i s t i c s . As the adaptation l e v e l i s increased, the co r r e l a t i o n between the fovea and periphery w i l l decrease. Since i t is assumed that the normals had no pathological condition a f f e c t i n g their r e t i n a l functioning, the lack of a s i g n i f i c a n t correlation (be i t positive or negative) i s not surprising considering that the background bowl luminance was at the lower end of the photopic range (45 asb.). If the adaptation l e v e l was lowered, one would have expected to have found s i g n i f i c a n t correlations (hopefully negative) between the fovea and periphery. 231 This interpretation regarding the role of adaptation has t h e o r e t i c a l implications for the MS groups. As the c o r r e l a t i o n s between the fovea and periphery for both patients became s i g n i f i c a n t l y p o s i t i v e , one might be able to argue that the correlations were due to a functional change in the cone system re s u l t i n g from a change in the adaptational state of the MS eye, one which may fluctuate over time. This f l u c t a t i o n may result from conduction losses observed by other researchers in MS. The one problemmatic finding in the present study i s the lack of a s i g n i f i c a n t difference at the fovea between the normal and probable MS groups. This i s unexpected as one would have expected the fovea to demonstrate a difference between the two groups. Although there was a greater number of MS patients who did not have optic n e u r i t i s as compared to the c l i n i c a l l y d e f i n i t e (whose foveal thresholds were s i g n i f i c a n t l y d i f f e r e n t from both the normals and probable), optic n e u r i t i s does not appear to play a role in that there was no s i g n i f i c a n t difference in the thresholds between those patients with or without optic n e u r i t i s . A possible interpretation of the lack of a s i g n i f i c a n t difference at the fovea between the probable and normal groups i s as follows. In the i n i t i a l stages of the disease, the e f f e c t s of demyelination occurs just outside the 0° e c c e n t r i c i t y . This i s supported by the e a r l i e r perimetric r e s u l t s of acurate scotoma or losses in the near periphery. However, as the disease progresses, to the point where a 232 patient i s c l e a r l y i d e n t i f i e d as being c l i n i c a l l y d e f i n i t e , the losses have extended into the 0° e c c e n t r i c i t y . Thus although the cone system may be involved e a r l i e r in MS, the fovea i t s e l f may be r e l a t i v e l y spared u n t i l the l a t t e r stages of the disease. Theoretical support for this may come from the research on s p a t i a l frequencies and the d i s t r i b u t i o n of r e t i n a l ganglion c e l l s . MS has been reported to af f e c t the intermediate and low sp a t i a l frequencies more so than the high frequencies (eg. Regan, S i l v e r & Murrary, 1972; Bodis-Wollner, Hendley, Mylin & Thornton, 1979; Regan, Raymond, Ginsberg & Murrary, 1981). The robustness of the higher s p a t i a l frequencies may result from the d i s t r i b u t i o n of the 3 r e t i n a l ganglion c e l l s x , y, and w. According to Lennie (1980) and Stone, Dreher & Leventhal (1980), the w r e t i n a l ganglion c e l l s are maximally di s t r i b u t e d in and near the fovea and are f e l t to be responsible for sp a t i a l discrimination. As thi s would imply that input to these c e l l s may come from the cone system, the robutness may be explained by the fact that high s p a t i a l resolution would require extensive cone damage before any loss i s found at that frequency. Ideally, based upon the present c o r r e l a t i o n a l finding that the red exhibited less large mean differences than the blue, one would hope that the high s p a t i a l resolution (fine acuity) was a function of the red cone system as i t i s t y p i c a l l y the last to be affected in diseases (eg. Birch, Chisholm, Kinnear, Marre', Pinckers, Porkorny, Smith & V e r r i e s t , 1979). Thus i f the red 233 cone system was responsible for the resolution of high s p a t i a l frequencies, the higher frequencies tend to be spared because of the r e s i l i a n c e of the red cones to the pathological processes. Although t h i s entire l i n e of argument assumes that s p a t i a l frequencies are not the result of c o r t i c a l functioning, i t derives some support from the finding that the blue cone system can not mediate high s p a t i a l frequencies unlike the red (Boynton, 1979). 1 With respect to the s i g n i f i c a n t interactions between e c c e n t r i c i t y as well as between e c c e n t r i c i t y and f i l t e r indicated that the retina has a d i f f e r e n t i a l s e n s i t i v i t y across i t s receptor d i s t r i b u t i o n (rod/cone). Greater mean si g n i f i c a n t differences occurred between the periphery and the fovea. S i g n i f i c a n t differences also occurred between the central region and the periphery. Examination of the mean thresholds indicate that the fovea has the lowest threshold (highest s e n s i t i v i t y ) , followed by the central region. The thresholds increase when moving towards the periphery. In addition, there i s a selec t i v e difference between f i l t e r and e c c e n t r i c i t y , with the largest s i g n i f i c a n t mean differences found between the red and blue as well as red and achromatic. The s i g n i f i c a n t differences tended to begin 1 The importance of the cone system in s p a t i a l contrast s e n s i t i v i t y with respect to the i r d i s t r i b u t i o n across the retina may explain why the upper hemiretina i s more sensitive to s p a t i a l frequencies than the lower (Skrandies, 1985). According to a recent study by Curcio (1985), there i s a higher proportion of rods in the lower r e t i n a . In either some inh i b i t o r y role or just due to their lack of s e n s i t i v i t y , the rods may actually decrease the s e n s i t i v i t y of the lower hemiretina to s p a t i a l frequencies. 234 past 15° nasal and 20° e c c e n t i c i t y . There was no s i g n i f i c a n t mean differences between the achromatic and blue. In a l l , the s i g n i f i c a n t interactions between e c c e n t r i c i t y and e c c e n t r i c i t y and f i l t e r r e f l e c t a f u n c t i o n a l r e l a t i o n s h i p based upon cone/rod d i s t r i b u t i o n . It has generally been accepted s i n c e O s t e r b e r g (1935) that the cone population i s at i t s greatest at 0° e c c e n t r i c i t y and f a l l s rapidly into the periphery. The inverse i s f e l t to be true with the rods, none at 0° e c c e n t r i c i t y and progressively increasing as moving into the periphery. Maximum rod density is t r a d i t i o n a l l y f e l t to be at about 20° e c c e n t r i c i t y . The results obtained tend to agree functionally with t h i s d i s t r i b u t i o n . Highest s e n s i t i v i t y for the f i l t e r s i s found in the periphery. Moving into the periphery, higher thresholds are found for the red as compared to the achromatic or blue. This is f e l t as being the result of fewer c o n e s in the periphery of the retina, r e s u l t i n g in the need for greater intensity in detecting the red. The lack of a s i g n i f i c a n t mean difference between the achromatic and blue i s problemmatic in that the d i s t r i b u t i o n of cones should have resulted in a functional pattern similar to the red, as has been found by others (eg. Verriest & I s r a e l , 1965, Lakowski & Dunn, 1981). The reason for t h i s negative finding i s that the achromatic stimulus used in the F225 contains blue and that the s i m i l a r i t y in wavelengths between the 2 resulted in nonsignificant threshold differences. However, by increasing the background 235 adaptation l e v e l to f u l l y photopic (250 cd/m2) a separation between the achromatic and blue f i l t e r s should be achieved. a. Theoretical Mechanism As noted by Drance (1985a, 1985b), loss in foveal functioning tends to occur pr i o r to the c l i n i c a l detection of vi s u a l f i e l d defects. Thus Lakowski has argued and demonstrated through a variety of psychophysical techniques that colour v i s i o n losses, mediated through the cones, can occur in a wide variety of diseases before the onset of recognized v i s u a l defects (eg. Lakowski, Bryett & Drance, 1972; Lakowski & Begg, 1976; Lakowski & Drance, 1978; Lakowski, Drance & Carsh, 1980). The present study i s in agreement with the finding on cone s e n s i t i v i t y , as is evident from the correlations between the fovea and remaining e c c e n t r i c i t i e s for the 3 groups (normal, M S - c l i n i c a l l y d e f i n i t e , MS-probable). According to the correlations, the generalized loss at the fovea and adjacent e c c e n t r i c i t i e s would argue the presence of functional damage to the cone system as well as the rod. The functional loss among the cones, one which appears to be s l i g h t l y greater for the blue, makes i t d i f f i c u l t to d i f f e r e n t i a t e between the rods and cones (interpreted from the posit i v e c o r r e l a t i o n s ) . That i s , demyelination has disrupted the normal functional difference between the rod and cone systems. 236 Unfortunately, what has not been established by the present study i s which of the two receptor systems i s affected e a r l i e r . Because of the loss at the fovea, i t is assumed by the author that the cone system may have been affected e a r l i e r than the rods. 1 If t h i s i s the case then psychophysical procedures such as dark adaptation would be of great importance to use in studying MS. Throughout t h i s discussion, the loss in cone functioning has not been assumed to be structural -- at least not in the early stages of the disease. The reason for t h i s comes from the attempted p i l o t study on modifying adaptation threshold. By having MS subjects close their tested eye for a period of 2 minutes, thereby a l t e r i n g the state of r e t i n a l adaptation, foveal thresholds were dramatically lowered. As t h i s change in threshold did not appear to be due to a change in fatigue, i t i s assumed that the i n i t i a l higher threshold was not due to the presence of structural damage,i.e., at least not permanent str u c t u r a l change. If the damage was permanent, one would not have expected improvement in the threshold. Similar results regarding the effects of variable background luminances on MS has been reported by Patterson, Foster and Heron (1980). Patterson et. a l . reported that threshold v a r i a b i l i t y 'Although the mean threshold difference at the fovea between the normals and MS-probables was not s i g n i f i c a n t , i t i s f e l t that i f the fovea was analyzed separately a s i g n i f i c a n t difference would have been found. 237 increased with increasing background luminance in MS but not normal control subjects., suggesting some type of fluctuating interference with the v i s u a l s i g n a l . This i s in agreement with the present study in that the standard deviations for the 2 MS groups under the 45 asb. background condition i s much greater than that of the normals. Fluctuations in cone functioning, as evidenced in the p i l o t study, may explain temporary losses seen in MS patients with respect to complaints about vis u a l acuity. More importantly, by a l t e r i n g the adaptational state, one may be able to es t a b l i s h which of the receptor systems was affected the e a r l i e s t in the disease process. Thus, by examining receptor functioning under f u l l y photopic and f u l l y scotopic l e v e l s , one should be able to iso l a t e which of the systems i s involved. As the present study used a background luminance l e v e l (45 asb.) at the lower end of the photopic range, one would have expected better cone functioning the cone system was not affected. As the reverse was true, the results argue that i t is the cone system which i s affected the most. As the course of the disease progresses, and the damage becomes more extensive, the cone system becomes indistinguishable from the rod in the former's s e n s i t i v i t y to chromatic s t i m u l i . The question that arises i s what may be responsible for the observed threshold differences. Because of the 238 r e l a t i o n s h i p of o p t i c n e u r i t i s (ON) t o MS, i t i s p o s s i b l e t h a t ON may p r o v i d e a p a r t i a l e x p l a n a t i o n . The o p t i c nerve i s e s t i m a t e d t o c o n t a i n r o u g h l y 1.1 t o 1.3 m i l l i o n nerve f i b r e s as w e l l as o t h e r s u r p o r t i v e e lements ( N e w e l l , 1978). I t may be d i v i d e d i n t o 4 a n a t o m i c a l s e c t i o n s : 1 . i n t r a o c u l a r , 2. o r b i t a l , 3. i n t r a c a n a l i c u l a r , and 4. i n t r a c r a n i a l . The i n t r a o c u l a r s e c t i o n i s u n m y e l i n a t e d (except i n p a t h o l o g i c a l c a s e s ) and c o n s i s t s of the i n n e r r e t i n a , the m i d d l e c h o r o i d a l , and the o u t e r s c l e r a l . The i n n e r r e t i n a i s viewed o p h t h a l m o s c o p i c a l l y as the o p t i c d i s k . C o n c e n t r i c t o the o p t i c d i s k i s a c e n t r a l d e p r e s s i o n known as the p h y s i o l o g i c cup. I t i s t h r o u g h the cup t h a t the c e n t r a l a r t e r y and v e i n e n t e r and l e a v e the eye. I n s i d e the cup a r e s m a l l pore l i k e s t r u c t u r e s ( l a m i n a c r i b o s a ) t h a t connect w i t h the s c l e r a l foramen. I t i s a t t h i s j u n c t u r e where the o p t i c nerve i t s e l f p a s s e s i n and out of the eye. The o p t i c nerve i t s e l f i s c o m p r i sed of a f f e r e n t axons of g a n g l i o n c e l l s c o l l e c t i v e l y c a l l e d nerve f i b r e b u n d l e s . The bundles are s e p a r a t e d by s e p t a t h a t c a r r y b l o o d v e s s e l s t o the n e rve. The axons of the r e t i n a l g a n g l i o n c e l l s a r e s p r e a d i n a r a d i a l f a s h i o n around the innermost s u r f a c e of the r e t i n a l l a y e r , c o n v e r g i n g a t 239 the optic d i s c . Normally, t h i s r e t i n a l nerve f i b r e layer (RNFL) i s s l i g h t l y opaque and appear as fine striped s t r i a t i o n s in the temporal and nasal retina (Airaksinen & Nieminen, 1985). In diseases such as glaucoma, however, diffuse and l o c a l i z e d losses in various regions can be detected prior to any measureable changes in the optic disc i t s e l f (Airaksinen & Alanko, 1983). The losses themselves are found as thining of the RNFL due to damage of the axon layer. Recently, RNFL loss has been shown to be highly correlated with colour discimination losses on the anomalscope in glaucomatous patients (Airaksinen, Lakowski & Drance, 1986). In optic neuropathies, Tagami (1979) reported central f i e l d depression on the Tiibinger perimeter correlated highly with the degree of observed atrophy in maculopapillar bundles. Although Tagami tested retrobulbar n e u r i t i s patients with an achromatic stimulus, the central loss observed i s interesting as i t , along with the findings on glaucoma, suggests that the maculopapillar region i s responsible for conveying v i s u a l information such as colour v i s i o n and acuity back to the optic d i s c . Moreover, i t i s thi s region which appears to be the most sensitive to pathological processes. In the case of MS, examination of the r e t i n a l layer has revealed the presence of diffuse and focal damage, esp e c i a l l y of the temporal p e r i p a p i l l a r y bundles 240 (Feinsold & Hoyt, 1975). In addition, there tends to be s l i t - l i k e defects in the arcuate nerve f i b r e s . As t h i s defect pattern i s similar to the ones reported by Tagami (1979) and Airaksinen et. a l . (1986), i t would seem l i k e l y that the threshold losses observed in the present study were p a r t i a l l y due to RNFL loss in the maculopapillar region. The loss within t h i s region would correspond to the large central depressions observed among the MS patients for the various f i l t e r s . If t h i s i s the case, a question then arises about the losses reported in MS as related to that disease's progression. Tagami (1979) argued that RNFL loss tended to occur outside the fovea in the temporal region of the re t i n a . The finding from the present study of increased thresholds in the nasal v i s u a l f i e l d (temporal side of the retina) would appear to indicate a similar loss in MS. If thi s is the case, the d i s t r i b u t i o n of the various cones may provide some answer to this finding. It has long been accepted, based upon kinetic perimetry, that the r e l a t i v e frequency d i s t r i b u t i o n s of the various cones d i f f e r s at the retina . It i s t y p i c a l l y f e l t that the fovea i t s e l f (1/8°) i s blue blind (Adler, 1975) and that the red sensitive cones are maximally situated there. The blue and green wavelength sensitive cones are dis t r i b u t e d away from th i s region. Trichromatic vi s i o n i t s e l f extends about 20° to 30° from f i x a t i o n (Adler, 1975). As RNFL loss appears to spare the fovea in the 241 early stages of disease, red cone functioning remains r e l a t i v e l y intact u n t i l the r e t i n a l system i s stressed as in conditions of increased background illumination. Once in such s t r e s s f u l v i s u a l situations, abnormalities in red cone functioning appear. As i t would appear that the red cone system may play a part in the resolution of high s p a t i a l frequencies, one would t h e o r e t i c a l l y expect disturbances in v i s u a l acuity under such s t r e s s f u l conditions. It i s interesting to note that a common c l i n i c a l symptom reported about MS i s early, temporary fluctuations in acuity. These fluctuations may result from abnormal processing at the cone le v e l in the fovea, and, i f Lennie (1980) is correct in his statement that w r e t i n a l ganglion c e l l s are maximally found at and around the fovea, i t is possible that the w c e l l s (carrying information mostly from the red cone system) are least susceptible to s t r u c t u r a l damage. It must be stressed that t h i s does not mean there i s no psychophysical loss for evidently losses do occur (eg. presence of red-green losses as noted by Lakowski, Harrison and S t e l l (1985). Because an area appears to be anatomically i n t a c t , i t does not follow that i t i s functionally i n t a c t . Given the correct v i s u a l conditions (eg. higher background adaptation) and the appropriate psychophysical procedure (eg. chromatic f l i c k e r perimetry), changes in s p e c i f i c types of v i s u a l functioning may become apparent. 242 If the l i n e of reasoning here i s v a l i d , one might be able to hypothsize on the progression of MS with respect to r e t i n a l functioning. The present study found that there were s l i g h t l y more s i g n i f i c a n t correlations with the blue f i l t e r than the red, keeping in mind however that such a trend depends highly upon the adaptational state. Such a pattern could be interpreted as meaning that the blue system was affected the most. 1 As the blue cones tend to be t y p i c a l l y just outside 0° e c c e n t r i c i t y , the thinning of the RNFL in the temporal part of the maculopapillar region may represent disturbance in blue cone conduction. It i s conceivable that early blue cone function loss may predict RNFL loss in t h i s region. The red cone system, though also affected by MS, tends not to show functional change early unless the system i s placed in a v i s u a l l y s t r e s s f u l s i t u a t i o n (eg. high background luminance conditions found in gla r e ) . As the disease progresses, the red cone system becomes more inmpaired u n t i l permanent dysfunctions such as loss in v i s u a l acuity i s seen. The damage continues u n t i l the cone system i s no longer functionally d i s t i n c t than the rods, both requiring large increases in intensity. As noted in the l i t e r a t u r e , disturbances in luminance perception is also observed in the progression of MS, suggesting possible higher c o r t i c a l involvement than has been suggested 1 Yellow-blue losses have been reported by Lakowski, Harrison and S t e l l (1985). 243 here. Further research involving f l i c k e r perimetry w i l l be needed to investigate the possible role of higher c o r t i c a l centres. b. Methodological and Instrumental Problems Several problems aff e c t the results and intrepretations presented here. F i r s t and foremost i s the psychophysics of the Fieldmaster® bowl. Unlike the majority of perimeters whereby a stimulus i s projected onto a bowl that has some constant l e v e l of illumination, the background luminance l e v e l in the F225 does not appear to play a s i g n i f i c a n t role. The reason for t h i s i s that the fiber optic system does not project a stimulus onto the bowl but d i r e c t l y to the eye. Thus, unlike other perimeters, the foveal threshold obtained with the F225 was much lower than normally seen. Moreover as the center of the f i b r e optic, when not being illuminated, was darker than the bowl, subjects were not only detecting changes in stimulus luminance but luminance contrast differences between the fi b r e optic position and adjacent surround. As photometrically the bowl was shown not to be equivalent in luminance, especially at the point of f i x a t i o n , the changes in the center of the v i s u a l threshold for the MS patients may have been due to an abnormal l a t e r a l i n h i b i t i o n caused by the luminance contrast. Aulhorn and Harms (1972) have reported reduced thresholds due to the presence of such 244 luminance border contrasts. This however would appear unlikely in the present study as the point used to conduct the foveal examination, as well as the other e c c e n t r i c i t i e s occurred away from the regions of d i f f e r i n g lumination. If the luminance difference between the fibre optic and surround played a s i g n i f i c a n t role, i t s e f f e c t s should have been constant across the retina (only i f , of course, i n h i b i t i o n i s the same across the r e t i n a ) . Because of the fi b r e optic system used, the background bowl l e v e l may function only to "ready" the retina at some general l e v e l of adaptation (here the lower photopic range). It does not play a role in determining threshold l e v e l s , and, as such, normal psychophysical laws as the Weber fraction which is based on background le v e l probably do not apply. Thus i t makes i t extremely d i f f i c u l t to compare the present results with those reported with other perimeters such as the Goldmann. Another problem with the results i s the manner in which thresholds are determined by the F225. If a blink occurs during testing, the computer algorithm increases the intensity l e v e l for that e c c e n t r i c i t y . Instead of retesting that e c c e n t r i c i t y with the same luminance l e v e l , the programme stores the blink as not seen at that threshold. Although not a problem e a r l i e r in the test sequence, this does become extremely important near 245 the end of testing for i t w i l l provide the operator with a f a l s e l y raised threshold. The only way of overcoming thi s problem i s to redesign the computer programme to re-test a point where f i x a t i o n has changed (eye movement, blink etc.) with the same luminance l e v e l . Problems also arose with respect to the treatment of thresholds exceeding 1 , 0 0 0 asb. Because of time constraints with the patients, the maximum intensity stimuli were presented at was 1 , 0 0 0 asb. If not seen at that l e v e l , the patient or normal was assigned that maximum value. This in effect may have biased the results by reducing the range of the actual threshold difference. In addition to a l t e r i n g how the perimeter re-tests a missed point due to a problem in f i x a t i o n , changes need to be made in the incremental steps used to change stimulus i n t e n s i t y . For the fovea the steps should be about .1 cd/m2, which is much smaller than the 1 decibel step presently used. Fixation i s another major problem. Although the r e l i a b i l i t i e s were high with the F225, the allowed 5° eye movement i s too great for research purposes. More control i s required in monitoring the eye prior to any further research. In the case of the F225 this w i l l require adaptating some external monitor to the perimeter. 246 In c o n t r o l l i n g the perimeter, i t i s recommended to bypass the LSI computer by interfacing the F225 with another, more f l e x i b l e computer. This w i l l permit the research to c o l l e c t invaluable data such as the actual apostilb l e v e l presented, one which i s only presented in graph form. The thermal graph used is both time consumming when trying to interpolate values as well as problemmatic for storage: the thermal graph fades with time or exposure to any heat. Other methodological problems may have affected the interpretation of the r e s u l t s . F i r s t , there i s no severity index for the MS patients. It would have been important to have some external severity score as to the d i s a b i l i t y of the MS i f conclusions about the progressive effects of the severity of the disease are to be made. Moreover, i t would have been desirable to have included a group of patients who were just suspected of having MS and compare these to patients who have been c l i n i c a l l y v e r i f i e d as having i t for a long period of time. In fact, what i s needed i s a longitudinal psychophysical study on MS. Another problem was the i n a b i l i t y to a l t e r rigorously the adaptational state. Without doing so, i t is impossible to draw any systematic conclusions about the role of rods and cones in MS. Unfortunately the F225 did not allow for a controlled investigation into the ef f e c t s of adaptation. 247 c. Future Research The results of the study suggest several research avenues in studying the effects of MS. F i r s t , a more intensive investigation i s needed regarding psychophysical functioning of the reti n a . Inorder to isol a t e the r e l a t i v e contributions of the two receptor systems, i t w i l l be necessary to a l t e r background i n t e n s i t i e s from the f u l l y photopic to the f u l l y scotopic. This w i l l also require the use of photometrically equated chromatic and achromatic s t i m u l i . Secondly, to understand temporal properties, the investigation should examine s p e c i f i c cone functioning (for the red, blue, and green systems) through the chromatic f l i c k e r threshold technique using low f l i c k e r rates. The procedure may be done under selective chromatic adaptation so as to understand cone functioning in greater d e t a i l than has ever been possible before. By doing so, information regarding temporal processing in the retina w i l l be obtained. S i m i l a r i l y , temporal processing in the cone system can be studied by measuring achromatic functional changes through the chromatic f l i c k e r threshold technique at high f l i c k e r rates (eg. 24 Hz). Data obtained from such a procedure w i l l provide information on the luminance channel. A l l of the research suggested 248 here, of course, w i l l need to be done on normal populations in order to determine ov e r a l l normal psychophysical functioning prior to studying MS and i t s e f f e c t s . In conjunction with the psychophysical approach, data regarding s t r u c t u r a l changes in the retina (eg. RNFL) needs to be c o l l e c t e d . It would be extremely valuable c l i n i c a l l y to correlate psychophysical changes with the anatomical, especially since the psychophysical change probably occurs prior to any str u c t u r a l change. Moreover, the noninvasive nature of psychophysical assessment makes i t a more desirable procedure to use c l i n i c a l l y . Using cut-off log apostilb threshold values such as -2.45 for the blue, -2.25 for the red, and -2.50 for the achromatic one may be able to to examine c l i n i c a l (visual) changes in the progression of MS more precisely than was previously possible. That i s , these values may be used to develop v i s u a l threshold p r o f i l e s , which in turn could be used not only for a s s i s t i n g in the diagnosis of MS but also serving as the basis of a 'visual' severity index. As the cone system appears to be the most sensitive to the presence of a pathological state, here MS, further c l i n i c a l and experimental research needs to focus upon macular functioning. Visual evoked potential procedures, for example, may be improved by using chromatic stimuli at photopic adaptation levels inorder 249 to improve the detection rate of an abnormality. In a l l , what i s need, i s an extensive prospective study whereby at r i s k patients are followed through their c l i n i c a l history with an intensive examintion of rod/cone functioning. It is strongly f e l t that the information gained through such an approach would not only t e l l us something about the nature of MS but also provide invaluable insight into v i s u a l functioning. 2 5 0 VI. SUMMARY Through the use of chromatic s t a t i c perimetery, i t was established that threshold losses occur across the retina in MS patients. The losses appear to be greater for the cone system rather than the rod, as inferred from the greater losses with the chromatic rather than achromatic f i l t e r s . S i g n i f i c a n t differences were found at the 0° e c c e n t r i c i t y between the normal and c l i n i c a l l y d e f i n i t e patients but not the probable and normal. This may have indicated the sparing of the 0° e c c e n t r i c i t y in nonestablished cases of MS. Such an interpretation needs to be guarded due to problems in monitoring eye movement as well as the lack of a severity index. Differences were found in the f i l t e r s , with the blue showing s l i g h t l y more s i g n i f i c a n t mean differences than the red or achromatic between the 3 subject groups. Both the comparison of mean differences as well as correlations between the fovea and remaining e c c e n t r i c i t i e s revealed extensive involvement of the retina among the MS patients as compared to the normals. Threshold differences between the f i l t e r s due to e c c e n t r i c i t y was also noted across groups, and was f e l t to r e f l e c t the sel e c t i v e s e n s i t i v i t y of the rod/cone system to chromatic s t i m u l i . An investigation of patients with and without optic n e u r i t i s revealed no ov e r a l l s i g n i f i c a n t differences except for the d i f f e r e n t i a l s e n s i t i v i t y across the retina to chromatic and achromatic 251 s t i m u l i . The t y p i c a l swiss cheese f i e l d resulting from irregular threshold s e n s i t i v i t y across the e c c e n t r i c i t i e s reported in the c l i n i c a l l i t e r a t u r e appears to be true only for achromatic and blue s t i m u l i . No such i r r e g u l a r i t y appears for a red stimulus. As such, the ophthalmological description of MS consisting of patchy r e l a t i v e scotoma leading to the swiss cheese f i e l d defect needs to be q u a l i f i e d . The importance of assessing MS through chromatic s t a t i c perimetry was also demonstrated by the a b i l i t y to c o r r e c t l y c l a s s i f y 86.27% of the normals and MS patients by the red f i l t e r . This high l e v e l of diagnostic accuracy along with the a b i l i t y to examine s p e c i f i c cone/rod functioning indicates the invaluable information available through chromatic perimetry. Results from a p i l o t study indicated that adaptation state plays a major role in detecting r e l a t i v e threshold losses in MS. Unfortunately, the present state of the F225 did not permit further investigation into the e f f e c t s of adaptational state. In a l l , r e t i n a l functioning as assessed with the Fieldmaster® F225 has been shown to be highly sensitive to changes due to the presence of MS (with or without optic n e u r i t i s ) . The findings suggest that a more intensive examination of cone functioning may y i e l d s i g n i f i c a n t understanding of the disease process as well as the means to both detect and chart the progression of the disease. 253 BIBLIOGRAPHY Abb, L. & Schaltenbrand, G. (1956). 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The supply (Lambda Model No. LYS-W-15) i s preset to provide the proper voltage for the individual printheads on the p r i n t e r . There are two printheads, each colour coded so as to i d e n t i f y them both on the thermal printer and power supply unit. The two printheads are: a. Blue coded -- 16.0 vol t s b. Brown coded — 17.0 vol t s b. Computer Power Supply The power supply (Lambda Model No. LYS-W-15) to the computer operates the basic functioning of the F225 including background and stimulus intensity control, 286 v i s u a l f i e l d screening, and r e l a t i v e threshold estimation. The power supply has three d i f f e r e n t outputs that are factory preset, which are: a. +5.05 vol t s b. +12.0 v o l t s c. -12.0 v o l t s . c. Analog Power Supply The analog power supply (Model No. HAA-15-0.8) provides power to the analog section of the F225. The analog board, discussed elsewhere, i s a signal processing board that buffers and amplifies analog signals. It i s factory preset to produce two voltages at: a. +15.0 v o l t s b. -15.0 v o l t s . d. Fieldmaster® Power Supply The Fieldmaster® power supply i s constructed to provide voltage to the background luminance, stimulus luminance, and stepper motor. It i s housed in a moveable section under the table of the F225. The bowl of the 287 F22f perimeter i s connected to the power supply via a 37 pin connector, which must be disconnected when removing or connecting the F225 bowl from the table. The F225 power supply i s shielded from transient fluctuations in the A.C. power l i n e by a L-C f i l t e r c i r c u i t . Examination of the power supply i t s e l f can be done by looking at the indicator LED's found in the instrument s h e l l on the Monitor card (to be discussed). When functioning normally, the LED's w i l l be a l l l i t . The power supply outputs are: a. 0 to +13.0 volts for the background bulb b. +5.8 volts for the stimulus bulb c. +12.0 volts for the stepper motor. 2. INSTRUMENT SHELL The F225 i s operated by an LSI-11/2 D i g i t a l Equipment Corporation (DEC) computer. The LSI-11/2 i s found in a card cage fixed to the lower right hand side of the instrument s h e l l when viwed from the back of the perimeter (see Figure x). The card cage i t s e l f consists of a backplane (DEC No. H9275A) that has four dual and two quad height p.c. boards. The backplane i s b a s i c a l l y a skeletal stucture that connects the various c.p. boards to one another and to sections of the perimeter. Power i s supplied through a source located in 288 the back of the c a r d cage on top of the backplane i t s e l f . F o r a d i s c u s s i o n of the terms used i n t h i s s e c t i o n the reader i s r e f e r r e d to L a b o r a t o r y computer handbook and Microcomputers and memories p u b l i s h e d by the D i g i t a l Equipment C o r p o r a t i o n . The f o l l o w i n g are the v a r i o u s boards found i n the F225 per i m e t e r . a . 1. C e n t r a l P r o c e s s i n g U n i t The c e n t r a l p r o c e s s i n g u n i t , or CPU board i s a d u a l h e i g h t p . c . board found in the lower l e f t hand c o r n e r of the c a r d cage marked "1B". I t i s used wi th the o p t i m a l f l o a t i n g p o i n t i n s t r u c t i o n (DEC No. KEV11) set and c o n t a i n s the a c t u a l computer p r o c e s s o r ( s t o r e d programmes) . The d i f f e r e n t f u n c t i o n s p o s s i b l e w i t h the CPU i s d e s c r i b e d under the s e c t i o n r e f e r r e d to as V i s u a l Tes t F u n c t i o n s . The CPU i s j u m p e r - c o n f i g u r e d to jump to address address "0" when the power i s t u r n e d on . Above the CPU c a r d , i n s l o t "1A", i s another p . c . board known as the Grant E x t e n d e r . The Grant Extender (Synemed No. 160-11519) passes backplane s i g n a l s to o ther boards and p e r m i t s the c o o l i n g of v a r i o u s p . c . boards i n the c a r d cage . 289 b . S e r i a l / M e m o r y B o a r d T h e s e r i a l / m e m o r y b o a r d i s f o u n d i n s l o t " 2 B " o f t h e c a r d c a g e . I t i s a d u a l h e i g h t p . c . b o a r d ( D E C N o . M X V 1 1 - A A ) a n d c o n s i s t s o f 8 k b y t e s o f r a n d o m a c c e s s m e m o r y ( R A M ) a n d t w o s e r i a l p o r t s . R A M i s a d d r e s s e d f r o m t h e o c t a l m e m o r y l o c a t i o n s 1 4 0 0 0 0 t o 1 5 7 7 7 6 . T h e f i r s t s e r i a l p o r t , p o r t 1 , i s a s t a n d a r d R S 2 3 2 i n t e r f a c e w i t h a b a u d r a t e o f 3 0 0 . A d d r e s s e d a t t h e m e m o r y l o c a t i o n 1 7 7 5 6 0 , i t i s c o n n e c t e d t h r o u g h a D B 2 5 ( 2 5 p i n ) c o n n e c t o r f o u n d o n t h e i n s t r u m e n t c a s e . T h e F225 d o e s n o t u s e s e r i a l p o r t 0 f o r a n y o p e r a t i o n . c . I m a g e B o a r d T h e o t h e r d u a l h e i g h t p . c . b o a r d i s t h e i m a g e b o a r d , l o c a t e d i n s l o t " 8 A " . T h e b o a r d c o n s i s t s o f r e a d - o n l y - m e m o r y ( R O M ) . T h e ROM c a r d ( D E C N o . M R V 1 1 - C ) c o n t a i n s f i x e d i n f o r m a t i o n s u c h a s b o x l i n e s , d e g r e e l i n e s , a n d h e a d e r l a b e l s u s e d i n g e n e r a t i n g p r i n t e r o u t p u t . O u t p u t i n f o r m a t i o n m a y b e e i t h e r o b t a i n e d a u t o m a t i c a l l y a t t h e e n d o f e a c h r u n o r b y r e q u e s t o f t h e o p e r a t o r . I n f o r m a t i o n i n t h i s b o a r d i s p r o c e s s e d t h r o u g h a 4 k b y t e " w i n d o w " f o u n d i n m e m o r y l o c a t i o n s 1 6 0 0 0 0 t o 1 6 7 7 6 . 290 d . P r i n t e r C o n t r o l B o a r d The p r i n t e r c o n t r o l b o a r d , f o u n d i n s l o t " 4 A " , i s a q u a d h e i g h t p . c . b o a r d . I t s f u n c t i o n i s t o t r a n s f e r d a t a t o t h e t h e r m a l p r i n t h e a d s t h r o u g h t h e p r i n t e r d r i v e b o a r d . I n a d d i t i o n , t h e p r i n t e r c o n t r o l b o a r d i n t e r f a c e s t h e p r i n t c y c l e t i m i n g (on a n d o f f t i m e f o r g e n e r a t i n g p l o t s ) a n d p r i n t c o n t r o l ( i n f o r m a t i o n f r o m t h e i m a g e b o a r d ) . N e x t t o t h i s a r e two G r a n t E x t e n d e r s ( s l o t s " 5 A " a n d " 5 B " ) , w h i c h a r e u s e d t o p a s s b u s s i g n a l s a s w e l l a s c o o l t h e v a r i o u s b o a r d s i n t h e c a r d c a g e . e . I n t e r f a c e B o a r d A n o t h e r q u a d p . c . b o a r d , t h e i n t e r f a c e b o a r d , i s f o u n d t o t h e r i g h t o f t h e G r a n t E x t e n d e r s ( s l o t s " 6 A " a n d " 6 B " ) . T h i s b o a r d c o n n e c t s t h e DEC L S I - 1 1 / 2 c o m p u t e r w i t h v a r i o u s F225 f u n c t i o n s ( e g . s t i m u l u s c o n t r o l ) a n d c o n s i s t s o f t h e f o l l o w i n g p a r t s . f . D i g i t a l - A n a l o g C o n v e r t o r The d i g i t a l t o a n a l o g c o n v e r t o r (DAC) c o n s i s t s o f v a r i o u s c i r c u i t s i n c l u d i n g a DAC1220 t w e l v e b i t c o n v e r t o r {12). The DAC e n a b l e s t h e L S I - 1 1 / 2 t o c o n t r o l t h e b a c k g r o u n d l e v e l i n t h e p e r i m e t r y b o w l t h r o u g h t h e b a c k g r o u n d d r i v e g o i n g t o t h e F i e l d m a s t e r ® P o w e r S u p p l y . T h i s i s a c c o m p l i s h e d by t h e L S I - 1 1 / 2 s e n d i n g t w e l v e b i t 291 signals to the DAC, thereby producing an analog drive signal for the Fieldmaster® Power Supply. The DAC i t s e l f i s powered by a voltage regulator (Z10) that allows the analog output to range from 0 to +10.24 v o l t s . g. Analog-Digital Convertor The analog to d i g i t a l convertor (ADC) i s comprised of an ADC1210 twelve b i t convertor (Z5), which enables the computer to record and monitor analog information from eight channels. The analog signals from the eight channels are directed into an analog multiplexer (Z7) to the DAC. Channel 1 Stimulus l e v e l Channel 2 Stimulus l e v e l X 22.11 Channel 3 Background l e v e l Channel 4 Attention monitor (x plane) Channel 5 Attention monitor (y plane) Channel 6 Attention monitor common mode Channel 7 Analog ground Channel 8 Analog ground 1 The m u l t i p l i c a t i o n value of 22.1 in the second channel i s to increase resolution at lower l i g h t l e v e l s so as to be able to accurately record stimulus intensity. Both channels 1 and 2 overlap, making i t possible to provide measures of levels continuously from high (30,000 asb) to low (x asb) stimulus i n t e n s i t i e s . 292 h. Permanent Memory Permanent memory consists of a RAM chip (1k by 4 byt). In addition, there are two batteries serving as power back-up in case of power f a i l u r e from the Fieldmaster® Power Supply. The permanent memory chip stores test information obtained from a test run. i . Attention Monitor Targets Both the attention monitor and macula target (discussed elsewhere) are monitored for i n t e n s i t i e s . The montiors are powered by signals from the background preamplifier (BGLVL) and are adjusted by the chips R70 (macula target) and R71 (attention monitor). j . Alarm Alarms are produced when either the attention monitor detects gross changes in the subject's position or when testing i s completed. An alarm i s also activated during testing when there is some problem with the perimeter i t s e l f (discussed in the section on error feedback -- Appendix x). The alarm i t s e l f i s produced by a timer and can be amplified by the Z14 chip and adjusted by the R71. 293 k. Stepper Drive There are three steper motors, the drive for which is on the interface board. The f i r s t stepper motor operates the selector arm (selects stimulus position) and the drive output for i t is found on pins 9, 10, 11, and 12 on the P8 connector. The second stepper motor controls the stimulus intensity wedge, which i s done throug pins 7, 8, 13, and 14. The f i n a l stepper motor operates the stimulus colour f i l t e r through pins 3, 4, 5, and 6. 1. Programme Board The programme board i s below the serial/memory card in s l o t "2k". It i s read-only-memory (ROM) and stores the operating programmes available on the F225. The board (DEC No. MRV11-C) has 48 bytes comprised of 12 Intel 2732 EPROM's. The EPROM's cntain the actual programmes from Synemed. When started, the programme board automatically i s configured to start at address 0. To the right of the board are two Grant Extenders used for cooling. m. Monitor Board The monitor board i s found on the l e f t of the card cage, and is recognizable by ten LED's (eight green, one 294 red, and one yellow). The red LED, when on, idicates the presence of a fau l t at which time the instrument powers down stopping a l l t e s t i n g . See Appendix D for a l i s t of possible errors. The yellow LED indicates normal functioning, and turns off when either a fa u l t i s detected or the RUN/HALT switch (discussed shortly) i s toggled. The eight green LEDs indicate the functioning of threshold comparators that monitor power voltages in the various areas of the perimeter. A green LED w i l l be turned off when i t s associated voltage comparator senses a drop in the voltage of a s p e c i f i c power supply. At the same time a drop in voltage i s sensed, the red fault LED w i l l be turned on and the cpu card begins to power down the perimeter immediately. The following i s a l i s t of what threshold voltages are associated with a s p e c i f i c green LED. a. LED #1 voltage = -15 V., threshold voltage = -12.2 V. b. LED #2 voltage = +12 V. (Fieldmaster® Power Supply), threshold voltage = +11.0 V. c. LED #3 voltage = +17 V. (Thermal Printer Power Supply), threshold voltage = +14.0 V. d. LED #4 voltage = +15 V., threshold voltage = +12.2 V. e. LED #5 voltage = +5.8 V. (Stimulus Supply), 295 threshold voltage = +4.99 V. f. LED #6 voltage = -12.0 V., voltage = -11.0 V. g. LED #7 voltage = +5.0 V. (Computer Power Supply), voltage = +4.42 V. h. LED #8 voltage = +12.0 V. (Computer Power Supply), voltage = +11.0 V. In addition to the sensing of a change in the power voltage for sections l i k e the power supply to the computer (8,9) or printer (3), wherein i f the threshold voltages l i s t e d above are reached a power down sequence commences, two buss signals (BPOK and BDCOK) monitor voltage changes from the A.C. l i n e . The monitor board also contains two toggle switches used to either power down or power up the perimeter during troubleshooting. Both switches during normal operation are in the down po s i t i o n . The f i r s t switch on the l e f t hand side, the RUN/HALT switch, i s used to power down the perimeter. This i s done by toggling the RUN/HALT switch into the up posi t i o n , causing the yellow LED to go off and, at the same time, the red to go on. The second switch on the right hand side of the monitor board is the INIT switch ( i n i t i a l i z e switch). The INIT switch i s used to i n i t i a l i z e the LSI-11/2 into running mode. To i n i t i a l i z e , the RUN/HALT switch must be in the down position and the INIT switch toggled f i r s t up and then down. If done cor r e c t l y , the yellow (running l i g h t ) 296 LED w i l l be on. When connecting any minicomputer or other peripheral to the perimeter for the purpose of debugging problems or increasing the c a p a b i l i t i e s (eg. storage) of the 225 , i t i s extremely useful to remove the back plate of the perimeter so as to have access to the switches and observe the LEDs on the monitor board. n. Analog Board The analog board i s found on the l e f t near to the monitor board. Its function i s to buffer and amplify signals coming from the attention monitor, the background preamplifier, and the stimulus preamplifier. Input to the analog board arrive on a 26 pin Berg connector (P6) and exit through a 10 pin f l a t cable to the multiplexer. A l l signals from the analog board go d i r e c t l y to the interface board through the multiplexer. o. Attention Monitor Board The monitor consists of a photodetector that doubles as an amplifier. Reflection off the cornea i s imaged onto four quadrants of a photodector housed in an o p t i c a l telescope assembly. Quadrants 1 and 3 of the photodetector create currents whose values represent changes in the ref l e c t e d l i g h t from the cornea. These changes, representing eye movements, are then summed and passed onto the analog board. S i m i l a r i l y , quadrants 2 297 and 4 pass their produced current changes whose sum is sent to the analog board. The values from the various quadrants are converted to voltages prior to transmission. p. Background Preamplifier A photodiode constantly measures the background illumination in the bowl. The photodiode creates a current that i s d i r e c t l y proportional to the luminance l e v e l in the hemisphere. Through a voltage convertor (Z1), the current i s then changed into a voltage value that i s processed to the analog board. Signals from the preamplifier are enhanced by a "background amplifier" that increases the current value by a factor of 2.2. This i s done so as to increase the " s e n s i t i v i t y " of the photodiode, i . e . small fluctuations in the current are registered. q. Stimulus Preamplifier Stimulus intensity i s monitored by sampling the f i l t e r e d l i g h t from the main projection beam. The actual i n t e n s i t y , monitored by a photodiode, is amplified through two voltage convertors (Z1, Z2) and i s corrected for non-linearity. Two other photodiodes are used to adjust the stimulus intensity c a l i b r a t i o n . The c a l i b r a t i o n adjustment occurs in conjunction with the 298 non-linear correction of luminous i n t e n s i t y . The manual on the F225 refers to the adjustment of stimulus intensity as slope correction preamplification. Output from the stimulus preamplifies goes d i r e c t l y to the Analog board wherein the various signals (attention monitor, background and stimulus intensity levels) are processed toward the the Interface board. r. Projector/Shutter/Filter Assembly This unit, situated on top of the Selector Board, converges the projected beam of l i g h t onto a selector arm l i g h t conduit. Through stepper motors controlled by the LSI-11, two (2) f i l t e r wheels rotate around an aperature from which the projected beam is passed through the f i l t e r wheels onto the f i b r e optics. One f i l t e r wheel consists of neutral density f i l t e r s used for c o n t r o l l i n g stimulus intensity whereas the other f i l t e r wheel is comprised of 4 Kodak Wratten F i l t e r s (X 632.7, 581.2, 533.8, 489.3 nm.) and one achromatic f i l t e r . The l a t t e r f i l t e r , refered to as the wedge colour, i s operated through a separate stepper motor than the neutral density f i l t e r . Both f i l t e r wheels are controlled by the Interface Board. In addition, the assembly contains photodiodes responsible for stimulus preamplifications as well as a shutter for c o n t r o l l i n g stimulus presentation. 299 s. Selector Board The board i s located c e n t r a l l y on the bottom of the instrument housing. It contains 149 fi b r e optic strands that form a c i r c u l a r pattern r a d i a l l y from a motor driven arm. A l i g h t conduit on the arm projects a l i g h t beam, o r i g i n a l l y directed to the center of the arm's rotation, to s p e c i f i c optic f i b r e s as determined by the operator defined programme. The actual position of the motor driven arm is controlled by a stepper motor operated by the Interface board. V I I I . APPENDIX B P h o t o m e t r i c B o w l M e a s u r e m e n t s PHOTOMETRIC MEASUREMENTS IN APOSTILBS (ABS.) AND CANDELLA/METER (CD/M-2) OF BACKGROUND INTENSITIES BY STIMULUS POSITION IN THE FIELDMASTER F225 PERIMETER* STIMULUS POSITION BACKGROUND INTENSITY (APOSTILBS) 1 2 3 4 5 6 7 8 9 10 2 ABS. 0 .81 0 .83 0 .88 0 .87 0 . 75 0 .05 0 .69 0 .94 0 .80 0 .85 CD/M- 2 ' 0 . 26 O .26 0 .28 0 . 28 0 . 24 O .02 O . 22 O .30 O .25 O . 27 5 ABS. 4 .75 4 .59 4 .39 4 . 56 3 . 19 0 .69 2 .56 4 .27 4 .51 4 . 53 CD/M- 2 1 .51 1 .46 1 .40 1 , .45 1 .01 0 .22 0 81 1 . 36 1 .44 1 . 44 10 ABS. 10 .58 10 43 10 . 16 10 , 39 7 29 1 . 79 5. , 75 9. 64 10 . 29 10 . 25 CO/M- 2 3 .31 3 . 32 3 23 3 .31 2 . 32 0 .57 1 . 83 3 07 3 .28 3 . 26 15 ABS. 16 .83 16 48 16 .41 16 . 39 1 1 . 39 2 98 9. 10 15. 37 16 39 16 .20 CD/M- 2 5 .08 5 .25 5 .22 5. 22 3 63 0 .95 2. 90 4 . 89 5 . 22 5 . 16 30 ABS . 35 28 34 .61 34 . 15 34 . 12 24 . . 12 6 . 16 19. 09 32 . 27 34 . 42 33 .83 CD/M- 2 1 1 . , 14 1 1 . 02 10. 87 10. 86 7. 68 1 96 6. 08 10. 37 10. 96 10 .77 45 ABS. 53 78 53. . 38 52. 69 52 . 76 36. 68 8 .73 29. 08 49. 53 52 . 76 52 . 25 CD/M- 2 16. 88 16. 99 16. 77 16. 79 1 1 . 68 2. 78 9. 26 15. 77 16. 79 16 .63 50 ABS. 59. 75 58. 95 58 . 09 58. 49 40. 74 9. 49 32 . 26 54 . 95 58 . 29 57 .42 CD/M- 2 18. 83 18. 76 18. 49 18. 62 12 . 97 3. 02 10. 27 17 . 49 18. 56 18 .28 55 ABS. 61 . 04 59. 79 58. 89 58 . 65 40. 68 9. 49 32 . 22 54 . 85 58 . 28 57 . 42 CD/M- 2 19. 18 19. 03 18 . 75 18. 67 12. 95 3. 02 10. 26 17. 46 18. 55 18 .23 Note: * - Values presented are based on the mean of 3 measurements done on each st imulus p o s i t i o n . PHOTOMETRIC MEASUREMENTS IN APOSTILBS (ABS.) AND CANDELLA/METER (CD/M-2) OF BACKGROUND INTENSITIES BY STIMULUS POSITION IN THE FIELDMASTER F225 PERIMETER* STIMULUS POSITION BACKGROUND INTENSITY (APOSTILBS) 11 12 13 14 15 16 17 18 19 20 2 ABS. 0 .81 0 .85 0 .78 0 .85 0 .85 0 .89 0 .78 0 .84 0 .93 0 .81 CD/M- 2 0 .26 0 .27 0 .25 0 .27 0 .27 0 .28 0 .25 0 .27 0 . 30 0 . 26 5 ABS. 4 .43 4 .39 4 . 34 4 .52 4 .56 4 .37 4 .04 4 .47 4 . 36 4 .24 CD/M- 2 1 .41 1 .40 1 .38 1 .44 1 .45 1 .39 1 .30 1 .42 1 .39 1 .35 10 ABS. 9 .49 9 .92 10 .09 10 .21 10 . 12 9 .99 9 .29 10 .29 10 .23 9 .82 CO/M- 2 3 . 17 3 . 16 3 .21 3 .25 3 .22 3 . 18 2 .96 3 .28 3 .26 3 . 13 15 ABS. 15 .95 15 .74 15 .89 16 . 24 16 .21 15 .93 14 .89 16 . 35 16 . 13 15 . 53 CD/M- 2 5 .08 5 .01 5 .06 5 . 17 5 . 16 5 .07 4 .74 5 .20 5 . 13 4 .94 30 ABS . 33 .69 33 .05 33 .52 34 .09 34 .21 33 . 30 31 . 30 34 . 25 34 . 1 1 32 . 15 CD/M- 2 10 .72 10 .52 10 .67 10 .85 10 .89 10 .60 9 .96 10 .90 10 .86 10 .23 45 ABS. 50 .99 50 .71 51 . 1 1 52 .06 52 .64 51 .59 47 .65 52 .84 52 .59 49 . 57 CD/M- 2 16 .23 16 . 14 16 .27 16 .57 16 .76 16 .42 15 .26 16 .82 16 .74 15 .78 50 ABS. 55 .91 55 . 10 55 .51 56 .77 56 .85 55 .66 51 .74 56 . 73 56 .63 53 . 19 CD/M- 2 17 .80 17 .54 17 .67 18 .07 18 . 10 17 .72 16 .47 18 .06 18 .03 16 .93 55 ABS. \ CD/M-2 55 17 .82 .77 Note: * - Values presented are based on the mean of 3 measurements done on each stimulus position. 303 IX. APPENDIX C F 2 2 5 Automatic Visual F i e l d Programmes 304 1. CONTENTS The v i s u a l f i e l d programmes are copywrited and are available from Synemed upon written request. X. APPENDIX D Automatic Contour Programmes 306 1 . CONTENTS The contour programmes are copywrited and are available from Synemed upon written request. XI. APPENDIX E F225 Automatic Meridian Programmes 308 1. CONTENTS The meridian programmes are copywrited and are available from Synemed upon written request. 309 XII. APPENDIX F 310 1. COMPUTER INTERFACE The Fieldmaster® F225 uses a D i g i t a l LSI 11/2 microcomputer both for programme execution and communicating with another host. The LSI can be used in a special debugging mode known as Octal Debugging Technique (ODT). The system to be connected through a s e r i a l link with the F225 must appear as a terminal to the LSI 11/2. The s e r i a l l i n k i s through a RS-232c already found in the Fieldmaster. The communications port on the host computer w i l l connect to i t s counterpart on the Fieldmaster through pins 2, 3, and 7 on the RS-232. Signals from any of the other pins w i l l be ignored. The host computer must be set on the following s p e c i f i c a t i o n s : 1. 8 b i t s , no parity 2. 1 stop b i t 3. 300 Baud rate Once connected, threshold information may be obtained in o c t a l values from two memory locations s t a r t i n g at 144650 for intensity seen and 144742 for intensity not seen. By transforming the octal values into the decimal system and averaging the seen/not seen in t e n s i t y values, one obtains the threshold for each e c c e n t r i c i t y tested. 3 1 1 -I XIII. APPENDIX G MULTIVARIATE ANALYSIS OF VARIANCE BETWEEN NORMALS (n=30) OPTIC NEURITIS (n=8), AND NON OPTIC NEURITIS (n=14) MS PATIENTS SOURCE SS df MS F P-GROUP (G) 48511962. 29 2,49 24255981. 1 4 18 .06 .0000 FILTER (F) 13381983. 78 2,98 6690991. 89 104 .52 .0000* ECCENTRICITY (E) 33959267. 43 3. 70,181 .54 2612251. 34 42 .85 .0000* G X F 464663. 53 2. 86,70. 01 116165. 88 1 .81 .1550* G X E 4099006. 93 7. 41,181 .54 1 57654. 1 1 2 . 59 .0128* F X E 4878008. 39 1 1 . 57,567 .06 187615. 71 1 4 . 1 1 .0000* G X F X E 1929719. 1 1 23. 14,567 .06 37109. 98 2 .79 .0000* NOTE: * Denotes pr o b a b i l i t y a f t e r degees of freedom have been adjusted by the Greenhouse-Geisser. 

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