In recent years, considerable interest. Short wavelength automated perimetry. Physiological Aspects of SWAP. John M. Wild

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1 Short wavelength automated perimetry John M. Wild Department of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, UK ABSTRACT. Short Wavelength Automated Perimetry (SWAP) utilizes a blue stimulus to preferentially stimulate the blue cones and a high luminance yellow background to adapt the green and red cones and to saturate, simultaneously, the activity of the rods. This review describes the theoretical aspects of SWAP, highlights current limitations associated with the technique and discusses potential clinical applications. Compared to white-on-white (W-W) perimetry, SWAP is limited clinically by: greater variability associated with the estimation of threshold, ocular media absorption, increased examination duration and an additional learning effect. Comparative studies of SWAP and W-W perimetry have generally been undertaken on small cohorts of patients. The conclusions are frequently unconvincing due to limitations for SWAP in the delineation of abnormality and of progressive field loss. SWAP is almost certainly able to identify glaucomatous visual field loss in advance of that by W-W perimetry although the incidence of progressive field loss is similar between the two techniques. Increasing evidence suggests that functional abnormality with SWAP is preceded by structural abnormality of the optic nerve head and/or the retinal nerve fibre layer. SWAP appears to be beneficial in the detection of diabetic macular oedema and possibly in some neuro-ophthalmic disorders. Key words: perimetry visual fields short wavelength sensitive SWAP ocular hypertension glaucoma diabetes. Acta Ophthalmol. Scand. 2001: 79: Copyright c Acta Ophthalmol Scand ISSN In recent years, considerable interest has been shown in Short Wavelength Automated Perimetry (SWAP) as a potential means for detecting the presence of visual field loss prior to that identified by conventional white-on-white (W-W) perimetry and also for detecting progressive field loss in advance of W-W perimetry. SWAP has been studied in a variety of conditions including glaucoma, diabetic macular oedema and neuro-ophthalmic disorders. SWAP is currently commercially available on the Humphrey Field Analyzer (HFA) models 740 and 750 (Zeiss Humphrey Systems, Dublin, Ca), on the Octopus 101 and 311 perimeters (Interzeag AG, Schlieren, Switzerland) and as an option on the Octopus 301 perimeter. Normative databases are available with HFA Programs 30 2 and 24 2 for the Full Threshold and the FASTPAC algorithms and with Octopus Programs such as G1, G2, 32 and M2 for the Normal, Dynamic and TOP strategies. The purpose of this review is to describe the physiological aspects of SWAP, to highlight some of the confounding factors associated with the use of the technique and to provide an indication of the potential clinical application. Physiological Aspects of SWAP The utility of SWAP in glaucoma is currently based upon the likely concept that early functional damage can be most readily identified by testing visual functions which are processed by ganglion cells that exhibit sparse neural representation (Johnson 1994). The processing of the blue stimulus in SWAP is believed to be mediated by the small bistratified ganglion cells (Dacey 1993; Dacey & Lee 1994) which terminate in the interlaminar zones of the parvocellular region of the lateral geniculate nucleus (LGN) (Martin et al. 1997). Two-colour increment threshold SWAP is the clinical application of the technique developed by Stiles (Stiles 1939, 1959) to assess the blue-yellow (Short Wavelength Sensitive, SWS) chromatic channel. A blue stimulus, with a peak wavelength that approximates to that of the peak response of the blue cones (also known as S-cones), is presented on a high luminance yellow background. The high luminance yellow background helps to saturate (i.e. reduce the response of) the green, or Medium Wavelength Sensitive (MWS) cones (M-cones), and the red, or Long Wavelength Sensitive (LWS) cones (L-cones) and to suppress, simultaneously, rod activity whilst leaving the S-cones largely unaffected. As a consequence, a degree of pure SWS pathway response can be isolated which is not mediated by either the MWS or the LWS pathways. Choice of stimulus parameters The choice of stimulus parameters for SWAP is of considerable importance and represents a compromise between those 546

2 ensuring the maximum response that can be obtained from the SWS pathway (known as isolation), those ensuring the maximum available measurement range of the perimeter (known as the dynamic range) and those ensuring the minimal absorption of the blue stimulus by the ocular media. Isolation In clinical terms, the amount of isolation is important since it determines the extent of the depth of a focal defect that is mediated by the SWS pathway. If the defect depth exceeds the magnitude of isolation, the response within the defect is no longer mediated by the SWS pathway. The currently accepted clinical technique (Sample et al. 1996) incorporated into the HFA 740 and 750 and into the Octopus 101, 301 and 311 perimeters utilizes a Goldmann size V narrow band blue stimulus with a peak transmission of 440 nm (27 nm Half-Peak Width [HPW] for the HFA and 15 nm HPW for the Octopus. [The extent of the HPW indicates the purity of the wavelength in question]). The blue stimulus is presented for a duration of 200 msec on a 100 cdm ª2 yellow background that transmits wavelengths longer than approximately 530 nm. This accepted combination of stimulus size and wavelength and of background luminance and wavelength ensures that the degree of SWS pathway isolation for the HFA is approximately 1.3 log units (13dB) at fixation and approximately 0.9 log units at 20æ eccentricity (Sample et al. 1996) and for the Octopus perimeters, 18 db and 14 db, respectively. Thus, the level of SWS isolation is likely to be sufficient for the investigation of patients exhibiting mild loss (up to a defect depth of db, paracentrally, with the HFA) (Demiral & Johnson 2000). In more extensively damaged areas, the defect can still, theoretically, be monitored using the stimulus parameters of SWAP though the response will be mediated by the achromatic luminance channel (i.e. the channel which is also responsible for mediating the response from W-W perimetry) (Demiral & Johnson 2000) rather than by the SWS pathway. There is also some evidence that the response may subsequently be mediated by the M- and L-cones (Felius et al. 1995). Thus, there is no benefit to be gained from using SWAP in patients exhibiting moderate to advanced loss by W-W perimetry. Dynamic range It is desirable that any given perimeter should exhibit the maximum possible dynamic range so as to provide the widest possible range of stimulus luminance. Relative to W-W perimetry, the greater luminance of the yellow background together with the reduced transmission of the blue filter reduces the range of the perceived stimulus luminance. The maximum stimulus brightness of SWAP with the HFA is 65 apostilbs (20.6 cdm ª2 ) compared to that of 10,000 apostilbs (3183 cdm ª2 ) for W-W perimetry. The corresponding figure with the Octopus is 16 apostilbs (5 cdm ª2 ) compared to 1000 apostilbs (318.3 cdm ª2 ) for W-W perimetry. The reduced stimulus luminance renders SWAP less suitable than W-W perimetry for cases of moderate to advanced glaucoma. Rationale for the choice of stimulus parameters The pioneering and subsequent studies of SWAP by Sample and colleagues (Sample & Weinreb 1990, 1992; Sample et al. 1993, 1994) by Johnson and colleagues (Johnson et al. 1988a, 1993ab, 1995a; Johnson & Marshall 1995; Demirel & Johnson 2001) and those of others (de Jong et al. 1990; Heron et al. 1988) utilized stimulus parameters which differed between laboratories and also from the current standard (Sample et al. 1996). A narrowband blue stimulus, originally employed by Sample and colleagues (Sample & Weinreb 1990, 1992; Sample et al. 1993), ensures greater SWS pathway isolation than a broadband filter and is less susceptible to shifts in the peak retinal wavelength due to ocular media absorption (Sample et al. 1996) but reduces the dynamic range of the perimeter due to the reduced transmission of the filter (Moss et al. 1995; Hudson et al. 1993). A broadband stimulus employed by Johnson and colleagues (Johnson et al. 1993ab, 1995a; Demirel & Johnson 2001) and by others (Moss et al. 1995; Hudson et al. 1993; Wild et al. 1995; Wild & Moss 1996) increases the dynamic range of the perimeter but may, in the presence of an extensive SWS defect, stimulate the MWS pathway (Sample & Weinreb 1990). The magnitude of the background luminance used during the early studies of SWAP was also equivocal. Yeh and colleagues (Yeh et al. 1989) argued that a background luminance of 300 cdm ª2 was necessary for adequate saturation of the rod pathway. Johnson and colleagues (Johnson et al. 1988a, 1993ab) used a background luminance of 200 cdm ª2 and others of 330 cdm ª2 (Hudson et al. 1993; Moss et al. 1995; Wild et al. 1995; Wild & Moss 1996). However, Sample and Weinreb (1990) employed a background of 80.9 cdm ª2 and maintained that any greater level of background luminance merely increased the SWS threshold rather than increased the magnitude of isolation. The use of a Goldmann size V stimulus (which subtends 1.74æ in diameter) was universally advocated from the outset (Sample & Weinreb 1990, 1992; Johnson et al. 1988a, 1993ab) since little or no SWS pathway isolation is present for stimulus sizes of less than Goldmann size IV (Adams et al. 1991) and also because maximal SWS pathway isolation is obtained with a 2æ diameter stimulus (King- Smith & Carden 1976). A stimulus duration of 200 msec has also been used from the outset since temporal summation is maximal for the S- cone pathway at this duration (King- Smith & Carden 1976). For the purposes of this review, it will be assumed that, unless specified as being those which are commercially available, the stimulus parameters used in any given study refer to a prototype combination. Shape of the normal hill of vision for SWAP Age decline The magnitude of sensitivity in the normal eye across the central field declines with increasing age. The age-decline in sensitivity for W-W perimetry is approximately 0.8 db per decade (Heijl et al. 1987; Flanagan et al. 1993) and steepens as the location becomes more peripheral. The slope of the normal hill of vision with age is steeper for SWAP than that for W-W perimetry. Slopes of 1.5 db to 2.2 db per decade have been reported for prototype stimuli (Johnson et al. 1988a; Johnson & Marshall 1995) and of 1.5 db to 2.2 db per decade for the commercially available SWAP (Wild et al. 1998). The slopes become less steep by approximately 0.5 db after correction for ocular media absorption (see later). The inferior field for SWAP also exhibits higher sensitivity compared to the superior field (Sample et al. 1997a). The reason for the greater age-decline in sensitivity of SWAP is unclear but may be due to reductions in foveal cone 547

3 photopigment (Van Norren & Van Meel 1985; Kilbride et al. 1986), photoreceptor density (Gartner & Henkind 1981; Farber et al. 1985), ganglion cell density and morphology (Dolman et al. 1980; Balaszi et al. 1984) and the number and morphology of cortical cells (Scheibel et al. 1975; Devaney & Johnson 1980). S-cones may be preferentially damaged by prolonged exposure to UV radiation (Ham et al. 1982). However, such changes in the S-cone function cannot account for all of the reduction of SWS sensitivity with age (Schefrin et al. 1992). A more convincing explanation is that the SWS pathway exhibits less redundancy than other visual mechanisms (Johnson 1994). Gray scale artifacts The gray scale, used in perimetry to represent the magnitude of sensitivity at each location across the visual field, is neither age-corrected nor eccentricity compensated. The lower sensitivity of the superior field and the greater age-related decline in sensitivity for SWAP causes a darker appearance to the gray scale for SWAP in the superior field which can either resemble or mimic the presence of an arcuate defect (Fig. 1). The steeper slope of SWAP with age also leads to a darker gray particularly at the extremeties of the central field. The gray scale for SWAP is also uniformly darker across the field in cases of excessive ocular media absorption (Fig. 2). The re- Fig. 1. The visual field of the right eye for a 58-year-old with medium-risk ocular hypertension recorded, on two occasions within a three-week period, with HFA Program 24 2 and the Full Threshold algorithm for W-W perimetry (left) and SWAP (right). The darker appearance to the gray scale in the superior field for SWAP compared to that for W-W perimetry can resemble or mimic the presence of field loss not evident by Pattern Deviation probability analysis. Fig. 2. The visual field for the left eye of a 76-year-old with primary open angle glaucoma recorded, on two occasions within a two-week period, with HFA Program 24-2 and the Full Threshold algorithm for W-W perimetry (left) and SWAP (right). The darker appearance to the gray scale for SWAP compared to that for W-W perimetry is not consistent with the Total and Pattern Deviation probability analysis and is largely due to increased absorption. The probability analysis for SWAP underestimates the extent of the field loss present with W-W perimetry. 548

4 duced dynamic range of SWAP, particularly with a narrowband filter, can also lead to a darkening of the gray scale. Great care should thus be taken if the outcome from SWAP is to be interpreted solely in terms of the gray scale. Variability of the threshold estimate Between-individual normal variability The threshold estimate in the normal eye varies between individuals of the same age (Heijl et al. 1987). The establishment of age-corrected confidence limits for normality at each stimulus location (Heijl et al. 1987) is fundamental to the delineation of visual field loss. The calculation of such confidence limits, which are used in the height (HFA Total Deviation; Octopus Comparison) and shape (HFA Pattern Deviation; Octopus Corrected Comparison) probability analyses, is based upon the between-individual normal variability of the threshold estimate at each stimulus location. Wild and colleagues (Wild et al. 1998), using the commercially available SWAP, found that the betweenindividual variation in the normal threshold at each stimulus location was, on average, 2.7 times greater for SWAP than for W-W perimetry and 1.9 times greater after correction for ocular media absorption. Interestingly, the between-subject normal variability for SWAP is similar for the 4 2 db double crossing of threshold employed in the Full Threshold algorithm of the HFA and for the 3 db single crossing of threshold employed in the FASTPAC algorithm (Wild et al. 1998). As a consequence of the increased variability, the reduction in sensitivity required to indicate abnormality for SWAP is proportionately greater than for W-W perimetry and confounds the detection of abnormality. Short-term and Long-term fluctuation The estimate of threshold at any given stimulus location exhibits within-test variability, the short-term fluctuation (SF) (Bebié et al. 1976; Flammer et al. 1984a), and between-test variability, the long-term fluctuation (LF). The LF, as classically defined, is independent of the SF (Bebié et al. 1976; Flammer et al. 1984ab; Hutchings et al. 2000). The SF and LF for W-W perimetry increase as sensitivity declines both in the normal and in the abnormal eye (Flammer et al. 1984ab). Early studies suggested that the SF derived by SWAP was similar in magnitude to that for W-W perimetry in normal subjects (Sample & Weinreb 1993). However, it is now known that the SF for SWAP is larger than for W-W perimetry; estimates for SF using the commercially available SWAP vary between approximately 17% (Wild et al. 1998) and approximately 55% (Kwon et al. 1998). The SF is greater for patients with glaucoma than with ocular hypertension both in W- W perimetry (Flammer 1984a) and in SWAP (Sample & Weinreb 1993; Wild et al. 1995); however, the magnitudes are similar between the two techniques (Sample & Weinreb 1993; Wild et al. 1995). The LF is greater for SWAP compared to W-W perimetry in normal subjects and in patients with glaucoma. In normal subjects, a surrogate measure of the LF (which included the influence of the SF) across the central field was reported to be 107% and 41% larger, respectively, using the HFA and the Octopus (Kwon et al. 1998). In stable glaucoma, the LF at each stimulus location using a similar surrogate measure was 23% greater than that for W-W perimetry (Blumenthal et al. 2000). The two components of the classically defined LF are larger for SWAP by 79% and 43%, respectively, in glaucoma suspects and by 25% and 34% in patients with glaucoma (Hutchings et al. 2001). In clinical terms, the increased SF and, particularly the LF, for SWAP relative to W-W perimetry means that the identification of progressive visual field loss for SWAP between any two given examinations will, in general, be more difficult to recognize than that for W-W perimetry. Influence of the crystalline lens The absorption of short wavelength light resulting from yellowing of the crystalline lens gradually increases up to the age of approximately 60 years after which the increase can be much more rapid (Sample et al. 1988; Silk et al. 1991; Savage et al. 1993; Johnson et al. 1988a; Zeimer et al. 1987; Werner 1982; Cook et al. 1994; Delori & Burns 1996; Johnson et al. 1989). Ocular media absorption also exhibits large between-individual variability in the normal eye for any given age, particularly in the older age groups (Johnson et al. 1988a; Sample et al. 1988; Silk et al. 1991; Savage et al. 1993). The reduced transmission of the short wavelength stimulus arising from ocular media absorption leads to a reduction in the height of the hill of vision derived by SWAP. The reduction can vary quite markedly between individuals of the same age and, unless accounted for, can confound the measurement and interpretation of the visual field derived by SWAP. The magnitude of the Mean Sensitivity index MS (an expression of the height of the hill of vision) can be more accurately predicted for SWAP in normal subjects by an index of crystalline lens transmission, calculated from blue-green autofluorescence, than by age, alone (Teesalu et al. 1996). Similarly, the prediction of the SWAP threshold from a measure of ocular media absorption, derived from the difference in dark adapted scotopic thresholds for two wavelengths assumed to be equally sensitive to rhodopsin and scaled to a standard observer (Van Norren & Vos 1974), is not improved by the inclusion of age. The scotopic threshold technique although used extensively in the research setting (Sample et al. 1989; Johnson et al. 1989; (Lutze & Bresnick 1991; Johnson & Marshall 1995; Wild et al. 1995; Polo et al. 1998) is not clinically practical in that it requires at least 8 10 minutes of dark adaptation (Johnson et al. 1993a). A novel, video-based, method for measurement of lens density using a double-pass reflection technique based upon the intensity of the fourth Purkinje image for different wavelengths in the blue region of the visible spectrum has been used in relation to SWAP (Demirel & Johnson 2001; Johnson et al. 1993c; Keltner & Johnson 1995). This technique, described in detail by Johnson and colleagues (Johnson et al. 1993c; Johnson & Marshall 1995), takes approximately one minute per eye and shows considerable promise as a clinically feasible method. The between-subject normal variability of the threshold estimate, and hence the confidence limits for normality, is also reduced following correction for absorption measured either by autofluorescence (Teesalu et al. 1996) or by the scotopic threshold technique (Wild et al. 1998). The clinical implication of these studies is that a more accurate indication of performance during SWAP would be obtained if both the measured sensitivity and the age-corrected normal value at each location were corrected for absorption. However, such an approach is clearly impractical as it would necessitate the design and production of a commercially available device which permitted the rapid and objective assessment of ocular media absorption. It is for this reason that analysis of abnormality solely in terms of Total Deviation or Comparison probability analysis (i.e. ab- 549

5 normalities of height) cannot be relied upon. As with W-W perimetry, SWAP is also affected by forward intra-ocular light scatter arising from cataract which leads to a reduction in the height of the hill of vision i.e. a worsening of the mean deviation/defect index (Moss & Wild 1994; Moss et al. 1995). Posterior subcapsular cataract has a greater effect on the SWAP hill of vision due to the increased background luminance of SWAP and to the concomitant reduction in pupil size (Moss et al. 1995). Macular pigment absorption The peak of the SWAP hill of vision is also influenced by macular pigment absorption which causes a depression in the immediate foveal and parafoveal regions (Wild & Hudson 1995). Macular pigment absorption exhibits large between-individual variability in the normal eye. The early studies suggested that macular pigment optical density was independent of increasing age (Bone et al. 1988; Pease et al. 1987); however, more recent studies suggest an age-related decline (Hammond & Carusoo-Avery 2000; Beatty et al. 2001). Macular pigment absorption can effectively be ignored in the context of the detection and management of glaucomatous visual field loss using HFA programs 24 2 and 30 2, or equivalent, but is of importance in relation to HFA Program 10 2 or equivalent which is suit- able for the detection of conditions such as diabetic macular oedema. General height adjustment The general height adjustment developed for W-W perimetry and used in the HFA STATPAC and Octopus Three-in-One printouts, whereby the height of the field is adjusted to that of the age-corrected average, should be capable of overcoming the limitations imposed by the magnitude of, and variability associated with, ocular media absorption. However, such an approach hinders the recognition of any potential diffuse reduction in the height of the SWAP hill of vision due to neural damage. This may be of considerable importance since Sample and colleagues (Sample et al. 1994) showed that, by evaluating the asymmetry in threshold values for SWAP across the horizontal midline, with and without correction for ocular media absorption, 25% of glaucomatous eyes exhibited diffuse loss for SWAP when corrected for absorption. These results can be compared with the prevalence for diffuse loss in glaucoma of between 0.1% and 4% using W-W perimetry (Åsman & Heijl 1994; Chauhan et al. 1997). Probability analysis The increased between-subject normal variability together with the increased SF and LF for SWAP compared to W-W perimetry represents a major issue for the clinical application of SWAP both for the detection of field loss and for the delineation of progressive loss. In particular, the effect of the increased confidence limits for normality and the difficulty in determining the influence of ocular media absorption on the short wavelength stimulus are readily apparent in the HFA STATPAC analysis program for the commercially available SWAP. Unpublished work from my own group indicates that the Total and Pattern Deviation probability analysis for the commercially available SWAP frequently underestimates the depth and/or spatial extent of the field loss when compared to that of W-W perimetry (Fig. 2). Such underestimation is particularly common in the superior field and largely arises from the increased variability of SWAP in this region. Similar, or slightly greater, field loss with SWAP compared to W-W perimetry generally occurs either in the presence of a hill of vision which is elevated above that of the age-corrected average hill (Fig. 3) or when the defect is paracentral in origin and the magnitude of the confidence limits for SWAP are similar to those of W-W (Fig. 4). In the former case, the addition of the negative elevator to create the Pattern Deviation value increases the depth of the defect which then lies outside the given confidence limit. Other factors Examination duration In the normal eye with the commercially Fig. 3. The visual field of the left eye of a 72-year-old with primary open angle glaucoma recorded, on two occasions within a one-week period, with HFA Program 24-2 and the Full Threshold algorithm for W-W perimetry (left) and SWAP (right). The gray scale is darker at the extremities of the superior field for SWAP compared to W-W perimetry. The field loss for SWAP is a similar, or possibly slightly wider, compared to that of W-W perimetry and is essentially delineated as a result of the negative elevator for SWAP. 550

6 Fig. 4. The visual field for the right eye of a 51-year-old with normal tension glaucoma recorded, on two occasions within a three-week period at baseline and again at 28 months follow-up, with HFA Program 24-2 and the Full Threshold algorithm for W-W perimetry (left) and SWAP (right). The appearance for SWAP is of a similar, or possibly slightly wider, focal defect compared to that of W-W perimetry. available stimulus parameters of the HFA, SWAP takes approximately 15% longer than W-W perimetry to complete Program 30 2 using the Full Threshold strategy and approximately 17% longer with the FASTPAC strategy (Wild et al. 1998). The examination time also increases with increase in age (Wild et al. 1998). The duration of the visual field examination is thus approximately two minutes longer than for W-W perimetry. However, the extension of the SITA family of algorithms to SWAP has resulted in a dramatic reduction in the examination duration which is now in the region of four or five minutes for HFA Program 24 2 (Bengtsson & Heijl, Personal Communication). Learning effect Learning effects (whereby sensitivity improves over the initial examinations) have been known in W-W perimetry for many years (Heijl et al. 1989a; Searle et al. 1991; Wood et al. 1987; Wild et al. 1989; Werner et al. 1990; Wild et al. 1991; Kulze et al. 1990; Heijl & Bengtsson 1996). Wild & Moss (1996) examined the influence of the learning effect for SWAP. Overall, the Mean Sensitivity increased from baseline in each eye by approximately 6.5% regardless of either previous W-W perimetric experience or age; however, individuals differed widely in the extent of the improvement. Unpublished observations from the author s own group also reveal that patients with glaucomatous visual field loss and who are experienced in W-W perimetry can exhibit a quite marked improvement in SWAP with repeated examination. Clearly, a learning effect is present for SWAP and it would seem that little, if any, previous experience of W-W perimetry transfers to SWAP. Caution should thus be exercised in the interpretation of the initial visual fields for SWAP regardless of previous experience of the patient in W-W perimetry. Fatigue effect The fatigue effect in W-W perimetry, whereby sensitivity decreases during a single examination, occurs in normals, in ocular hypertension, in glaucoma and in optic neuropathies (Heijl 1977; Langerhorst et al. 1987; Johnson et al. 1988b; Wild et al. 1991; Searle et al. 1991; Hudson et al. 1994; Wildberger & Robert 1988). The fatigue effect can either mimic the presence of a defect or exacerbate the appearance of existing visual field loss (Hudson et al. 1994). The fatigue effect in SWAP has received little attention. With the Full Threshold and FASTPAC algorithms, the fatigue effect for SWAP 551

7 is likely, at least, to be similar in magnitude to that for W-W perimetry but may, in fact, be more pronounced due to the longer examination duration. Combined effects of learning and fatigue The learning and fatigue effects in W-W perimetry oppose each other both withinand between-eyes during any given visit and the net outcome at the initial examination changes with follow-up examination as the patient becomes more experienced in perimetry i.e. the learning effect diminishes and the influence of the fatigue effect becomes more prominent. Interestingly, Keltner & Johnson (1995) noted that the order in which W-W perimetry and SWAP was undertaken at any one visit influenced the outcome of the results between the two techniques undertaken in a variety of neuro-ophthalmological disorders. Clinical Potential of SWAP Comparative evaluation of SWAP and W-W perimetry The outcomes of many of the comparative studies of SWAP and W-W perimetry are not totally convincing for one or more of a variety of reasons including: the lack, until recently, of a standardized age-corrected normal database for SWAP thereby facilitating independent corroboration of any given finding; the absence in some studies of statistically and clinically robust criteria for the definition of abnormality, or of progressive loss, for SWAP; the absence, until very recently, of any corroboration with structural aspects of the optic nerve head in glaucoma; the inadequacy of the commercially available Total and Pattern Deviation probability analysis (referred to earlier); and methodological weaknesses which fail to account for one or more of the factors (described earlier) which can confound the visual field of SWAP. Age-corrected normal values The majority of the studies relating to SWAP have emanated from two laboratories (Sample & Weinreb 1990, 1992; Sample et al. 1993, 1994, 1997ab; Blumenthal et al. 2000; Johnson et al. 1988a, 1989, 1993ab, 1995b; Keltner & Johnson 1995; Demirel & Johnson 2001), have been undertaken with prototype stimulus parameters and, naturally, have been reported with reference to age-matched normal data which is specific to the given study and/or to the given laboratory. The advent of the commercially available SWAP for both the HFA and the Octopus perimeters should facilitate independent corroboration of the pioneering studies; however, the inadequacy of the current probability analysis for the commercially available database with the HFA will limit, for the time being at least, the extent to which SWAP can be validated. Definition of abnormality Some of the evidence concerning the utility of SWAP does not necessarily withstand rigorous scientific scrutiny particularly with regard to the statistical definition of abnormality derived by SWAP. The early studies were based upon relatively small numbers of patients and normal subjects (Sample & Weinreb 1990; Johnson et al. 1993b). Some studies defined abnormality for SWAP in terms of the deviation of the threshold from normal without taking into account the physiological variability of the threshold estimate (Sample & Weinreb 1992; Sample et al. 1993), which varies as a function of increase in eccentricity in the normal eye (Heijl et al. 1987) and with increase in defect depth (Flammer et al. 1984a), and which is now known to be greater for SWAP than for W-W perimetry (Wild et al. 1998). Other evidence for SWAP, although corrected for ocular media absorption, has been presented in terms equivalent to Total Deviation probability analysis (i.e. abnormalities of height) (Johnson et al. 1993ab; Sample & Weinreb 1990, 1992; Sample et al. 1993) rather than in terms of abnormalities of shape. In fact, with the one exception (Wild et al. 1995), the outcome of SWAP from the studies using prototype stimulus parameters has never been expressed in terms of Pattern Deviation probability analysis (i.e. abnormality of shape). Equally, other evidence (Sample et al. 1994, 2000) is apparently presented in terms of the results of the Glaucoma Hemifield Test (GHT). The GHT, which was originally developed for W-W perimetry (Åsman & Heijl 1992), compares the asymmetry of the reduction in sensitivity, designated in terms of the Pattern Deviation probability level, at each stimulus location in the superior field corresponding to the nerve fibre layer distribution with that of the mirror image zones in the inferior field. However, for SWAP the reduction in sensitivity with the GHT was inappropriately evaluated in terms of the absolute values of sensitivity (Sample et al. 1994, 2000) rather than in terms of Pattern Deviation probability values. As a consequence, the effect of the increased variability of the threshold estimate in the superior field relative to the inferior field has been overlooked. Finally, the various definitions of abnormality, with the exception of two studies (Wild et al. 1995; Sample et al. 2000) have not been applied to separate groups of normal individuals; therefore, the corresponding specificities are unknown. More recent studies utilising the commercially available stimulus parameters and the age-corrected normal database have used the Mean Sensitivity (MS) (Serra et al. 1998), Mean Deviation (MD) (Teesalu et al. 1996, 1998b) or Corrected Pattern Standard Deviation (CPSD) (Polo et al. 1999) index as a measure of field loss recorded by SWAP. This may well be due to the inadequacy of the Total and Pattern probability analysis contained within the commercially available HFA STATPAC for SWAP. However, the visual field indices, themselves, are of limited value as an indicator of abnormality in W-W perimetry, particularly for comparative studies between types of perimetry (Chauhan et al. 1989, 1990), since they do not provide an indication of the spatial location of the abnormality. The visual field indices for SWAP are additionally influenced by the extent of, relative to the average, and any correction for, ocular media absorption. Many of the studies involving SWAP have seemingly involved patients who, although experienced in W-W perimetry, have had little or no experience of SWAP; nevertheless, the results are generally presented in terms of the initial field for SWAP and fail to account for potential learning and fatigue effects. In these cases, it can reasonably be assumed that any subsequent visual field to SWAP would show a differential improvement, of unknown extent, from the initial (i.e. baseline) field due to the learning effect. On cessation of the learning effect, the SWAP field would appear less damaged than that of the baseline when compared to W-W perimetry. Similarly, the potential maximum of two W-W fields and two SWAP fields recorded at any one examination session will inevitably result in a reduction in sensitivity of one or more of the fields due to the fatigue effect leading 552

8 to an apparent differential, and apparently more severe, defect in one type of perimetry relative to the other. The lack of statistical and methodological rigor, together with the deficiency in the Pattern Deviation probability analysis with the commercially available SWAP for the HFA, raises some doubt about the claims as to the utility and effectiveness of SWAP relative to W-W perimetry. Structural corroboration The necessity for structural corroboration of any apparent superiority of SWAP relative to W-W perimetry, not only in cross-sectional studies but also in longitudinal studies, is of paramount and fundamental importance. Nevertheless, it is only in the most recent studies that the results from comparative studies of SWAP and W-W perimetry have been compared to the optic nerve head topography or to the retinal nerve fibre layer (RNFL) appearance (Mansberger et al. 1999; Polo et al. 1998,1999; Teesalu et al. 1997, 1998ab; Urgulu et al. 2000; Yamagishi et al. 1997; Girkin et al. 2000). Primary open angle glaucoma (POAG) The visual field derived by SWAP is assumed, discounting the caveats described above, to possess five characteristics relative to W-W perimetry, namely: a larger area of field loss in patients with glaucoma (Sample & Weinreb 1990; Johnson et al. 1993b); a greater rate (approximately twofold) of progressive field loss in glaucoma (Johnson et al. 1993b); more prevalent localised defects in patients with ocular hypertension (Johnson et al. 1995a); more prevalent defects in those patients with ocular hypertension at high-risk of developing glaucoma than in those patients at low-risk (Sample et al. 1993; Johnson et al. 1995a); the defects are predictive of subsequent field loss with W-W perimetry (Sample & Weinreb 1992; Johnson et al. 1993b; Demirel & Johnson 2001). Overall, SWAP is claimed to predict the development and progression of glaucomatous visual field loss 3 to 5 years earlier than W-W perimetry. Area of visual field loss with SWAP The area of visual field loss derived by SWAP is reported to be more substantial than that by W-W perimetry in patients with glaucoma. However, this conclusion is based largely upon two studies both of which used prototype stimulus parameters and both of which employed small cohorts of patients. Sample and Weinreb (1990) found that 9 of 16 glaucomatous eyes each exhibited results in two or more quadrants for SWAP which lay more than two standard deviations from the normal value based upon 10 age-matched normal subjects. Johnson and colleagues (Johnson et al. 1993b) reported that 25 of the 32 eyes exhibited a wider area of loss, relative to 95% confidence limits, for SWAP corrected for ocular media absorption, than for W-W perimetry. The definition of abnormality in these two studies was thus in terms of a reduction in the height of the field rather than an alteration in shape. Identification of progressive loss The impact of any prospective study of progressive visual field loss in glaucoma is governed by the number of individuals within the cohort who actually exhibit progressive field loss which, in turn, is largely governed by the length of the follow-up. In addition, a greater prevalence of progressive field loss would be expected in patients with glaucoma than in patients with ocular hypertension. The identification of progressive visual field loss at each stimulus location for SWAP is hindered by the lack of equivalent techniques to W-W perimetry which are based either upon the linear regression of sensitivity against time to follow-up or upon the change in sensitivity from baseline lying outside the normal random test-retest variability exhibited in stable glaucoma (Change Probability analysis) (Bengtsson et al. 1997; Heijl et al. 1989b). Kono and colleagues (Kono et al. 2000) described a method for evaluating progressive loss based upon the Cumulative Defect, or Bebié, Curve (Bebié et al. 1989). However, Åsman and Olsson (1995) have criticised the Cumulative Defect Curve on the basis that it does not deal satisfactorily with the regionaldependent variation in the physiological fluctuation associated with the threshold estimate and a similar criticism is present with the modified technique of Kono and colleagues. The concept that SWAP exhibits a greater rate of progressive field loss in glaucoma than W-W perimetry is based upon five prospective studies, four of patients with ocular hypertension and two of patients with POAG. Four of the studies (Sample & Weinreb 1992; Sample et al. 1993; Johnson et al. 1993ab) have employed small cohorts of patients whilst the fifth (Demirel & Johnson 2001) is based upon patients with ocular hypertension. Four of the studies did not utilise a formal quantitative definition of progressive loss. Because of the clinically important nature of the issue, the studies will be described in some detail. Sample and Weinreb (1992) found progressive field loss for SWAP in advance of that indicated by W-W perimetry in 21 patients with glaucoma over two visits separated by an interval varying between 6 and 26 months. Abnormality for SWAP was defined in terms of deviations in absolute values of sensitivity relative to 21 normal individuals matched to the glaucoma group. Such a definition does not consider the variability associated with the threshold estimate (Flammer et al. 1984a; Heijl et al. 1987). Nine eyes exhibited deterioration outside a betweentest variability of 3 db. Sample and colleagues (Sample et al. 1993) followed 25 patients (25 eyes) with ocular hypertension for between 13 and 37 months. Five eyes developed glaucoma over the follow-up period on the basis of a repeatable visual field defect by SWAP; of these, 4 had previously been designated as high-risk and one as mediumrisk. The criteria for progressive field loss for SWAP was not specified and the proportion of the five eyes exhibiting abnormality to W-W perimetry was also not given. Johnson and colleagues (Johnson et al. 1993ab) have suggested that SWAP is able to delineate the presence of visual field loss in advance of W-W perimetry by at least 3 to 4 years. Their conclusion was based upon a small number of patients with ocular hypertension (Johnson et al. 1993a) or with early glaucoma (Johnson et al. 1993b) exhibiting progressive loss. However, the evidence of a more severe loss in height for the SWAP field at baseline, and of a greater degree of progressive loss for SWAP, in two of three eyes in which the field plots were illustrated, is compelling. The most substantial study of SWAP, corrected for ocular media absorption, was carried out by Demirel and Johnson (2001) on 250 ocular hypertensive patients examined annually over a five-year follow-up period. The prevalence of visual field abnormality, defined without correction for abnormalities of height, at baseline was 9.4% for SWAP and 1.2% for W-W perimetry. The incidence rates of field loss were 6.2% (1.2% per year) and 5.9% (1.2% per year) for SWAP and W-W perimetry, respectively. 553

9 The superiority of SWAP over W-W perimetry in delineating progressive field loss in glaucoma is by no means clear from these studies. The similarity of the incidence rates for glaucomatous visual field loss between SWAP and W-W perimetry (Demirel & Johnson 2001) suggests that SWAP, in its current format and with its current inherent limitations described earlier, may offer little advantage over W-W perimetry for the detection of progressive loss (Caprioli 2001). Risk category of ocular hypertension If SWAP is to be used clinically, the category of patients most likely to benefit from the use of the technique will need to be identified. Sample and colleagues (Sample et al. 1993) undertook SWAP in 55 glaucoma suspects divided on the basis of intraocular pressure and vertical cup:disc ratio into low-, medium- or high-risk; all had normal W-W fields. The group mean Mean Defect and the group mean number of abnormal stimulus locations for SWAP at the initial examination (defined as a cluster of three or more locations each 6 db below the normal age and lens density corrected value) were similar for the low- and medium-risk categories but significantly higher for the high-risk category. The definition of abnormality was rather liberal and did not consider the variability associated with the threshold estimate. Johnson and colleagues (Johnson et al. 1995a) categorized the probability of developing glaucoma in both eyes of 232 patients with ocular hypertension using the risk model of Hart and colleagues (Hart et al. 1979). The prevalence of visual field abnormality for SWAP, based upon abnormality of height, increased with increase in risk category rising to one third in the high-risk group. In an almost identical study, using the commercially available SWAP, Polo and colleagues (Polo et al. 2001) found the prevalence of visual field abnormality for SWAP in patients with ocular hypertension also increased with increase in risk category rising to over 50% in the highrisk group. The increase in prevalence of visual field loss for SWAP with increase in severity of risk category for OHT is clinically sound; however, the prevalence of field loss for SWAP in the latter two studies appears to be particularly high and has not been confirmed in the author s own laboratory. Large (C/D) ratio The variation in the size and appearance of the optic nerve head in the normal eye can lead to difficulty in identifying early glaucomatous damage. Mansberger and colleagues (Mansberger et al. 1999) compared the outcome of SWAP to that of W-W perimetry in one eye of patients with a cup:disc ratio of equal to, or greater than, 0.8. The discs were classified as non-glaucomatous, suspicious, or glaucomatous. One third of the 86 patients had normal results for both W-W perimetry and SWAP. Of the 42 patients with a normal W-W field, one third exhibited an abnormal field by SWAP. Structural and functional correlation It is only recently that the outcome of SWAP, particularly in regard to progressive visual field loss, has been compared in a masked fashion to the appearance of the optic nerve head. The correlation between structural abnormality of the optic nerve head and the visual field indices derived by W-W perimetry has been the subject of numerous studies which are beyond the scope of this review. The correlation for W-W perimetry is only modest and of little clinical value. It can be hypothesised that if the field loss revealed by SWAP is in advance of that by W-W perimetry, the correlation for SWAP might be more substantial. However, the correlations between the MD index for the commercially available SWAP and each of the eight optic nerve head topographical parameters measured with the HRT are only marginally higher for SWAP than for W-W perimetry (Teesalu et al. 1997, 1998a). The MD for both W-W and the commercially available SWAP, corrected for lens transmission, is also only moderately correlated with the total diffuse loss of RNFL, derived from monochromatic RNFL photographs, in normal subjects and in patients with either ocular hypertension or glaucoma (Teesalu et al. 1998b). Polo and colleagues (Polo et al. 1999) also reported a modest correlation in patients with OHT between the MD index and the extent of overall RNFL abnormality (R 2 Ω0.38) and diffuse RNFL abnormality (R 2 Ω0.44) measured by photography. The outcome of correlational analysis, such as that used by Teesalu and colleagues (Teesalu et al. 1997, 1998a) and Polo and colleagues (Polo et al. 1999), is highly influenced by the range of structural and functional abnormality included in the cohort under study. However, it would appear that the correlation for SWAP is very similar to that of W-W perimetry. Prevalence of structural and functional abnormality Specific focal field loss for SWAP has been shown to correspond topographically with the location of the focal disc abnormality, evident from stereo-photographs and quantified with the Heidelberg Retina Tomograph, in a small number of patients with glaucoma (Yamagishi et al. 1997). However, the work of Urgulu and colleagues (Urgulu et al. 2000) suggests that structural abnormality occurs prior to that of functional abnormality identified with the commercially available SWAP. Thirty of the 72 eyes (72 patients) at risk of glaucoma which exhibited normal fields by W-W perimetry yielded structural abnormalities of the optic nerve head. Of these 30 eyes, only 13 had abnormal results for SWAP. Polo and colleagues (Polo et al. 1998) found that the prevalence of visual field loss for the commercially available SWAP, corrected for ocular media absorption, was 36% in 83 patients (160 eyes) with ocular hypertension who exhibited normal W-W fields. Forty-eight of the 57 eyes with abnormal SWAP results manifested RNFL abnormalities; however, approximately 25% with normal SWAP fields exhibited an abnormal RNFL. It would also seem that progressive changes in the optic nerve head can precede progressive visual field loss for SWAP. Girkin and colleagues (Girkin et al. 2000) found that of 22 patients deemed as progressing by disc criteria, 13 exhibited progressive field loss by W-W perimetry and 16 by SWAP. In a non-progressing group, by disc criteria, of 25 patients, the visual field was stable in 22 by W-W perimetry and in 23 by SWAP. Three inescapable clinical conclusions can be drawn from these studies. Firstly, despite the inherent limitations, described above, concerning the definition of abnormality for SWAP, functional loss derived by SWAP appears to precede that derived by W-W perimetry in one fifth to one third of cases. Secondly, structural abnormality of the optic nerve head and/ or RNFL precedes functional abnormality derived by SWAP in approximately 50% of occasions. Thirdly, SWAP is unable to detect progressive functional damage in a sizeable proportion of eyes 554

10 (possibly in the region of 30%) which exhibit progressive structural damage. Such results should be treated with caution in the absence of an optimised Pattern Deviation probability analysis for SWAP with the HFA and without any form of change probability analysis for the evaluation of progressive field loss for SWAP, but may well represent landmark findings. Comparison with other visual function tests Histological studies in primate and in human have suggested that the large diameter optic nerve fibres are selectively lost in glaucoma (Quigley et al. 1987, 1988). The original rationale for the use of SWAP in glaucoma was therefore based upon the fact that, in general, the ganglion cells mediating the SWS pathway exhibit a larger cell diameter than the midget cells projecting to the parvocellular layers of the LGN (Dacey 1993; Dacey & Lee 1994). The selective loss hypothesis of Quigley and colleagues (Quigley et al. 1987, 1988) has subsequently been questioned (Morgan et al. 2000) particularly in early glaucoma (Johnson 1994). Consequently, it has been suggested that any given ganglion cell type which exhibits less functional redundancy, such as the small bistratified ganglion cell involved in the processing of SWAP or the parasol cell involved in the processing of motion, may exhibit damage more readily even if there are greater losses for other ganglion cell types regardless of their morphology (Johnson 1994, 1995). The results of SWAP have been compared with those from psychophysical tests mediated by other ganglion cell types in an attempt to elucidate the mechanism of ganglion cell damage in glaucoma (Casson et al. 1993; Sample et al. 1997b, 2000). Casson and colleagues (Casson et al. 1993) evaluated the outcome of SWAP to that of W-W perimetry and temporal modulation perimetry (TMP) in a small cohort of patients with OHT and with early glaucomatous field loss. TMP was undertaken for 2, 8, and 16Hz sinusoidal flicker; the latter two temporal frequencies are considered to be mediated by the M, or parasol, ganglion cells which project to the magnocellular layer of the LGN. Within the limitations of the small numbers of patients with progressive loss, SWAP and TMP exhibited good sensitivity to the defect and to the progressive loss exhibited by W-W perimetry over the five year follow-up, suggesting the presence of non-selective early glaucomatous damage. Sample and colleagues (Sample et al. 1997) compared SWAP with Motion automated perimetry (MAP) measured in terms of the coherent motion threshold of a random dot motion stimulus. The MAP stimulus was assumed to be mediated by the parasol ganglion cells. The results suggested that glaucomatous damage was non-selective for either ganglion cell type or pathway but that individual differences could be present in terms of the type of ganglion cell initially damaged. In a similar study, Sample and colleagues (Sample et al. 2000) compared the results of SWAP to those of W-W perimetry, MAP, and the commercially available Frequency-doubling perimetry (FDT). The cohort comprised patients with glaucoma or with OHT defined, independently of the visual field, on the basis of stereo-photographs. FDT was assumed to be mediated either by the My ganglion cells, for the perception of doubling, or by the M cells for the perception of flicker. Using criteria for abnormality which gave a 90% specificity for each of the three tests, 46% of patients with glaucoma exhibited abnormality by W-W perimetry, 61% with SWAP, 70% with FDT and 52% with MAP. The corresponding prevalence of field loss for the OHT group were 5%, 22%, 46% and 30%, respectively. The findings and those of Casson et al. (1993) and Sample et al. (1997b) clearly suggest the presence of non-selective early glaucomatous damage. More importantly from a clinical point of view, the results of Sample et al. (1997b) and Sample et al. (2000) are compatible with those of the cross-sectional study of Urgurlu et al. (2000) and the longitudinal study of Girkin et al. (2000) and convincingly indicate that structural abnormality is likely to precede functional abnormality measured with SWAP in a sizeable proportion of patients. Diabetes The presence of selective loss of SWS pathway sensitivity in diabetes derived in laboratory studies using foveal stimuli has been known for many years (Adams et al. 1987; Greenstein et al. 1989, 1990; Zwas et al. 1980). However, it was not until 1994 that the utility of SWAP relative to W-W perimetry was investigated in diabetes. Lutze & Bresnik (1994) undertook SWAP, corrected for ocular media absorption, in a small cohort of insulin-dependent patients with Type I diabetes manifesting the complete spectrum of retinopathy across the cohort; no eyes exhibited macular oedema or vitreous haemorrhage and none had received laser treatment. After the effects of age and duration of diabetes had been excluded, the level of retinopathy significantly correlated with the results from SWAP but not with those from W-W perimetry. Nomura and colleagues (Nomura 1999) undertook a similar study of patients with non-insulin-dependent diabetes. Two thirds of the small cohort had no retinopathy and a third early background retinopathy. The group mean MS of the central field and the group mean MS of the superior field were significantly decreased in the patients with background retinopathy for the commercially available SWAP compared to W-W perimetry. The application of SWAP to the investigation of diabetic macula oedema (DMO) was pioneered by Hudson and colleagues (Hudson et al. 1998ab). In the first of their two elegant studies, Hudson and colleagues (Hudson et al. 1998a) evaluated the commercially available SWAP and W-W perimetry, using Program 10 2, in 24 patients with clinically significant DMO of whom 21 were noninsulin-dependent. A novel analysis of asymmetry between the two horizontal hemifields was utilised to overcome the effects of ocular media absorption. All 24 patients exhibited focal defects for SWAP compared to only one third for W-W perimetry. The topography of the SWAP defect corresponded to the clinical mapping of the area of DMO derived by two independent medical retina specialists masked to the outcome of the perimetry. In their companion study, Hudson and colleagues (Hudson et al. 1998b) utilized the same methodology to investigate the influence of laser photocoagulation for DMO on macular function. A significant increase in the extent of the focal defects occurred immediately following laser treatment. The increase in the extent of the field loss was greater for W-W perimetry than for SWAP. The outcome of SWAP in relation to the appearance of the perifoveal capillary network, including the perifoveal intercapillary area (PIA) and the foveal avas- 555