Leitthema Ophthalmologe DOI 10.1007/s00347-015-0104-9 © Springer-Verlag Berlin Heidelberg 2015

A. Sturm · W. Noske Klinik für Augenheilkunde, Städtisches Klinikum Brandenburg, Brandenburg a.d. Havel, Germany

Comparative glaucomatous diagnosis using macular optical coherence tomography and perimetry with centrally condensed stimuli English version

List of abbreviations GCC ganglion cell complex GCL ganglion cell body layer GCL+ ganglion cell body layer plus inner plexiform layer VF visual field IPL inner plexiform layer MD mean deviation LV loss variance mOCT macular optical coherence tomography MVZ macular vulnerability zone NFL nerve fiber layer OCT ocular coherence tomography PD pattern deviation pRNLF peripapillary retinal nerve fiber layer

Early diagnosis of functional and morphologic glaucoma damage still is an insufficiently solved challenge. Considerable ganglion cell damage usually has to be present in order to be revealed by visual field (VF) testing or conventional optic disc evaluation. However, on the basis of recent progress with macular ocular coherence tomography (mOCT), topographical correlation of mOCT with detailed VF results may allow detection of

glaucomatous damage and progression earlier and with more confidence. With modern spectral domain ocular coherence tomography (OCT), various parameters of the optic disc and the peripapillary retinal nerve fiber layer (pRNLF) can be analyzed. Furthermore, the three inner retinal layers comprising the ganglion cell complex (GCC) can be revealed and measured precisely (. Fig. 1). These measurements are presented in sectional images (B-scans) and color-coded volume scans (.  Fig. 2). Morphologic losses of the inner retinal layers, the retinal nerve fiber layer (NFL), the ganglion cell body layer (GCL), and the inner plexiform layer (IPL) can thus be compared to a normative databank, topographically assigned, and statistically analyzed. It has long been stated that early glaucomatous VF loss often manifests within the central macular area [1, 2]. It presents as paracentral scotomas with nasal step, isolated paracentral scotomas, or isolated nasal steps, and occurs preferentially in the upper VF [2]. In some cases early scotomas are found exclusively centrally, without peripheral scotomas [1–3]. Aulhorn and Harms [1] already described in the sixties that scotomas deepen and enlarge with advancing glaucomatous damage. As early stages of glaucoma often present with central VF defects and since the internal retinal thickness can be measured by macular OCT (mOCT), there

is increasing interest in using representative VF results in order to topographically correlate morphologic mOCT alterations with the respective VF results [4]. If morphologic and functional alterations are revealed at the same localization, it is much more likely that they represent glaucomatous damage than if the damage is only revealed by one of the methods [5]. Glaucomatous damage may thus possibly be revealed earlier and more reliably.

Examination and analysis strategies Macular OCT Examinations were performed with the Spectral Domain OCT HS100 from Canon (Canon Europa, Amstelveen, The Netherlands), with axial resolution 3 µm and transversal resolution 20 µm. The area scanned with the mOCT is relatively large (10 × 10 mm/approximately 30° × 30°); that of the papillary area OCT is 6 × 6 mm. The normative database is based on 520 normal eyes. The examinations may be displayed as shown in .  Figs.  1, 2 and 3. A high resolution B-scan is presented in .  Fig. 1. As the reflectivity from the transition from GCL to IPL is relatively low, GCL and IPL are often shown together [4]. For clinical evaluation, the thickness profile of the selected layer(s) is displayed in comparison to the normative database, with colDer Ophthalmologe

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Fig. 1 8 mOCT presentation using the Canon HS100 (Canon Europa, Amstelveen, The Netherlands). Vertical native B-scan crossing the foveal center. The borders of the three inner retinal layers are marked by arrows. The thicknesses of NFL, GCL, IPL, GCC, and GCL+ are represented by red bars. All three inner retinal layers taper at the foveal border and their vertical profile is quite symmetrical. The NFL thickness increases relatively evenly towards the periphery. The GCL attains its maximal thickness at 2–5° eccentricity and becomes thinner peripherally. The IPL has a relatively uniform thickness. Centrally, the thickness of the GCC is determined mainly by the GCL; and in the peripheral macular region by the NFL. The GCL+ thickness is determined within 2 mm more by the GCL and outside of 2 mm more by the IPL [8]. Please see the separate list for definitions of abbreviations

or-coded significances (.  Figs.  2 and 3). Volume scans are calculated in a similar manner (. Fig. 3). Additionally, the mean thicknesses of selected areas of the GCC layers are presented as a mirror image, so that corresponding areas of the upper and lower hemifields can easily be compared and asymmetries typical for glaucomatous damage are more easily recognizable. In color-coded volume presentations of normal retinas, paracentral clusters of ganglion cells result in a doughnut-like ring of thickening in a region of 1.5 to 8° from the foveal center with a foveal gap (.  Fig. 2). Normally, more than 30 % of all retinal ganglion cells can be found within this ring [6], whereas the fovea itself is void of ganglion cells. The ganglion cells connected to the central receptor cells are displaced eccentrically in relation to the corresponding cones by up to 0.6 mm [6–8]. This is why the parafoveal GCL (. Fig. 1) is composed of up to six to eight layers of ganglion cell bodies; whereas the GCL of the peripheral macula is reduced to a monolayer [9]. Because of the clustering of ganglion cells within the macula, this area should be suited for the detection of ganglion cell loss. The slightly elliptical form of the ring of maximal thickening of the GCL revealed by mOCT (and of the GCL plus the IPL, GCL+) has a rather good horizontal and vertical symmetry, so that asymmetric thinning of the GCL is more evident than for the GCC. Histologically

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measured thicknesses of the inner retina correspond well to values obtained with mOCT [8].

Perimetry VF testing was performed with the Twinfield perimeter (Oculus Optikgeraete GmbH, Wetzlar, Germany), applying the continuous light increment perimetry (CLIP) threshold strategy [10]. The printouts include global indices such as mean defect (MD) and loss variance (LV), and a topographical presentation of the pattern deviation (PD) with respective significances. We used a centrally condensed stimulus arrangement (area 1) of the Twinfield perimeter, which was adapted for glaucomatous field loss by the authors and has been used routinely for years. Besides a centrally condensed stimulus arrangement, peripheral thresholds are measured superiorly, inferiorly, and temporally up to 20°; and nasally up to 30° during the same examination (.   Fig. 4 upper part). The scale of the VF was not adapted to that of the OCT in the majority of figures, in order to allow interpretation of the VF results peripherally to 15°. All VF results are represented upside down in order to facilitate topographical comparison to the mOCT.

Perimetric detection of central scotomas The VF strategy with a 6°-grid pattern (. Fig. 4 lower part) is widely performed, even in scientific glaucoma studies. Using such a grid, VF defects as large as the blind spot or minor arcuate scotomas are easily underestimated or missed [3, 11]. Due to recent progress with mOCT, there is renewed interest in small central scotomas, in order to detect glaucomatous damage earlier by topographical correlation of mOCT with detailed VF results. With condensed central stimuli, scotomas were revealed within 3° eccentricity in more than 50 % of patients with slight or moderate glaucomatous damage [3]. A 10°-grid detected VF defects in 16 % of patients that had not VF damage with the 24-2 grid pattern [12]. Furthermore, detection of VF defect progression is significantly higher with the 10-2 grid compared to the 24-2 grid [13]. This is explained by the fact that with the 24-2 grid, the four most central stimuli are positioned at the external slope of the region with the most dense ganglion cells; all other stimuli are positioned external to this region, so that central defects are insufficiently revealed [3, 11]. Volume scans from mOCT are composed of a large quantity of data. It is often not easy to select the most important data, particularly in the case of slight changes. In fact, there are no satisfacto-

Abstract · Zusammenfassung ry algorithms for presenting early glaucomatous damage in the mOCT in a simple, statistically reliable way that can be easily correlated with the respective VF results. Therefore, the current work aims to present characteristic examples demonstrating the particular options of mOCT examinations and the possible topographic correlations between mOCT and VF results.

How sensitively can mOCT detect a ganglion cell defect? It is assumed that considerable ganglion cell loss has to be present before this can be detected. The maximal parafoveal thickness of the GCL of our normative databank amounts to 25 to 62 µm. The diameter of retinal ganglion cells measures more than 10  µm [7, 8]. This is above the minimal axial resolution of modern OCT machines (3–5 µm). More than 300,000 ganglion cells are located within the macular region (20 mm2; [6]). Therefore, the loss of few ganglion cells should be detectable with mOCT. On the other hand, for optic disc and peripapillary retinal NFL (pRNFL) analysis, optic sections of less than 2 mm2, which include around 100,000 axons of the whole retina (axon diameter < 1 µm), are analyzed. Therefore, theoretically, mOCT should be particularly well suited for revealing slight localized macular glaucoma damage, whereas optic disc and pRNFL analysis should be superior for detection of panretinal nerve fiber damage. .   Fig.  5 demonstrates a paracentral scotoma of a single test point of the left VF. The OCT of this patient shows relevant glaucomatous damage at the optic disc and pRNFL, and in the mOCT. This damage is less evident in the VF; however, a conspicuous paracentral scotoma is revealed in the VF. In the topographically corresponding B scan of the GCL, a step can be seen at the beginning of the GCL; and in the volume scan, a slight indentation. The step is less remarkable in the GCL+ and even less so in the GCC. We think that the reduced steepness of the ganglion cell defect of the GCL+ and the GCC compared to the GCL is due to the fact that IPL usually shows less atrophy than the GCL; therefore, nerve fiber damage would only be revealed peripheral to

Ophthalmologe  DOI 10.1007/s00347-015-0104-9 © Springer-Verlag Berlin Heidelberg 2015 A. Sturm · W. Noske

Comparative glaucomatous diagnosis using macular optical coherence tomography and perimetry with centrally condensed stimuli. English version Abstract The presentation and measurement of the internal retinal layers by current optical coherence tomography (OCT) instruments allow a precise topographic localization of macular glaucomatous damage. Ganglion cell analysis in particular can reveal slight central defects and can effectively be correlated with perimetric strategies with centrally condensed stimuli, so that small glaucomatous defects can be confirmed earlier and more confidently. Progression can also be verified in the early stages of the disease as enlargement and deepening of small localized defects. Macular OCT (mOCT) cannot sufficiently detect peripheral glaucomatous defects and may be impaired by macular pathologies; therefore,

mOCT should be combined with other morphometric examinations. In order to take advantage of the technical capabilities of current OCT devices appropriate perimetric strategies should also be applied. As the algorithms for documentation and evaluation of the results of current OCT instruments are far less advanced than the technical capabilities, OCT results still have to be visually scrutinized together with the visual field results to benefit from the technical possibilities provided by modern OCT devices. Keywords Glaucoma · Maculopathy · Progression · Ganglion cells · Sensitivity

Korrelation morphologischer und funktioneller Glaukomdiagnostik mit makulärem OCT und Perimetrie mit dichtem zentralem Prüfpunktraster. Englische Version Zusammenfassung Die Darstellung und Messung der inneren Retinaschichten mit den aktuellen OCT-Geräten erlaubt eine sehr präzise topografische Lokalisation von makulären Glaukomschäden. Vor allem mit der Ganglienzellanalyse lassen sich auch dezente zentrale Veränderungen erfassen und gut mit Perimetriebefunden entsprechend feiner Prüfpunktraster korrelieren. Dadurch lassen sich geringe Glaukomschäden früher und sicherer erfassen. Auch für die Progressionsbeurteilung eignet sich das makuläre OCT – zumindest in den Frühstadien – sehr gut, da sich die Progression auch von kleinen umschriebenen Defekten gut darstellen lässt. Makuläre OCT-Untersuchungen erfassen periphere Glaukomschäden nicht ausreichend und können durch Makulopathien

the ganglion cell defect, whereas the ganglion cell defect itself might be covered by some intact nerve fibers serving other locations. If this defect would be found only with either perimetry or mOCT, it would probably be classified as fluctuation or artifact. As there are corresponding defects in the VF and in the GCL, early glaucomatous thinning of the GCL with a corresponding scotoma is more likely [14]. This example demonstrates how sensi-

erheblich beeinträchtigt werden, sodass sie immer im Zusammenhang mit anderen morphometrischen Untersuchungen betrachtet werden sollten. Da die Algorithmen der Befunddokumentation und -auswertung der OCT-Geräte den technischen Möglichkeiten noch erheblich hinterherhinken, hat die sorgfältige visuelle Analyse der OCT- und Perimetriebefunde immer noch große Bedeutung, wenn man die technischen Möglichkeiten, die die mOCT-Untersuchung bietet, ausnutzen möchte. Schlüsselwörter Glaukom · Makulopathie · Progression · Sensitivität · Ganglienzellen

tive mOCT can be, if we succeed in highlighting slight defects by respective algorithms. Here we did not realize the mOCT alterations initially, but after reexamination of the mOCT with the VF scotomas in mind, we estimated these to be relatively evident in the paracentral B-scan. The arcuate nerve fiber defect of this eye visible in the mOCT and the pRNFL is hardly been seen in the VF, but can be seen in later VF examinations; however, the LV Der Ophthalmologe

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An overall view of the clinical findings is important

Fig. 2 8 mOCT presentation using the Canon HS100 (Canon Europa, Amstelveen, The Netherlands). For the GCC, the GCL+, and the GCL, vertical B-scan with color coding of the border of the layers (upper right panel) and thickness profile in comparison to the normal data base (lower right panel), and the respective volume and SLO scans (upper and lower left panels, respectively) crossing the foveal center. The B-scans may be scrolled across the whole area. Please see the separate list for definitions of abbreviations

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Frequently, some mOCT or VF findings are conspicuous for early glaucomatous change, but no definitive assessment concerning glaucomatous damage is possible. In the example of .  Fig. 6, only the left disc shows glaucomatous damage. The routine findings of the right eye are all within the green range when compared to the normative database. The grey scale of the VF and the disc are unremarkable. Additionally, the GCC and the pRNLF do not reach the significance level of 5 %. The LV of 8.0 and the topographic PD of the VF are conspicuous, but not “significant”, and a 6-grid VF would easily miss the relative scotomas and not reach the significance level. The GCC volume scan and the macular NFL reveal significant thinning located outside the widely used 6 × 6 mm scan area and outside the borders of the sectors analyzed by our OCT device. The circumscribed significant thinning of the pRNFL does not induce a change in the color coding. Current algorithms would classify this case as not glaucomatous. B-scans of the GCL and GCL+ show localized thinning, particularly of the GCL, which attain a significance level of 1 %. These regions are also conspicuous in the topographic PD of the VF, if one takes into account that the central ganglion cells are displaced eccentrically. In places, the B-scans of the inner retinal layers and the pRNFL nearly reach the upper limit of the normative databank and have an aboveaverage inner retinal layer thickness at the locations without glaucomatous damage. Therefore, a thorough synopsis of all findings reveals relevant glaucomatous damage that is easily overlooked with a quick glance at the optic disc and the gray scale of the visual field.

Representation of the VF nasal step as a temporal step in mOCT We have analyzed mOCT findings with relatively isolated nasal steps in the VF as an early sign of glaucomatous damage. In mOCT, it is common to see a temporal

Fig. 3 8 mOCT presentation using the Canon HS100 (Canon Europa, Amstelveen, The Netherlands). Displacement of the color-coded GCC volume scans; deviation from the normative databank and significances of these; and significance of RNFL deviation. In addition, mean GCC thicknesses of the presented symmetric sectors with color coding of the significances. GCC comprises NFL, GCL, and IPL. Please see the separate list for definitions of abbreviations

Fig. 4 8 Projection of perimetric stimulus pattern on a color-coded normal ganglion cell body layer (GCL) volume scan. The main thickness of the GCL is found within a symmetrical, slightly elliptical ring segment at a distance between 1.5–8° from the foveola. Upper half stimulus pattern of the Twinfield perimeter (Oculus Optikgeraete GmbH, Wetzlar, Germany) adapted by the authors. Lower half 6°-stimulus pattern: only four stimulus points fall within a radius of < 10° and measure at the tapering border of the ring of highest ganglion cell density

wedge-shaped, horizontally limited thinning in the ring of condensed ganglion cells, even in cases with peripherally located nasal steps. Even though the nasal step in . Fig. 7 is most evident at 20–30° temporally (in a region that is not recorded by mOCT), the thinning is most evident in mOCT within less than 10° eccentricity, as a step adjacent to the raphe. This nasal step is part of an arcuate scotoma that is also revealed faintly in the VF within less than 20° and as respective thinning of the pRNFL, NFL, GCC, and most evidently the GCL. Although the mean thickness of the pRNFL in some of the lower sectors is reduced by up to 30 µm in comparison to the upper pRNFL, the significance level of 5 % is only attained in a single sector (among other things, because the thickness is above average in the upper NFL).

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Fig. 5 8 Minimal paracentral defect of the GCL with corresponding isolated scotoma. Short red arrows: paracentral scotoma with corresponding paracentral defects in the mOCT. Long red arrows: arcuate defect of the lower retina/upper VF. Green arrows: regions of the NFL that are in the upper thickness region of the normative data bank. Please see the separate list for definitions of abbreviations

Macular vulnerability zone Familiar functional glaucomatous loss patterns [2, 3] may be morphologically well correlated with mOCT [4]. Upon a quick glance at the mOCT in . Fig. 8, the defect seems largely altitudinally restricted; however, only temporal to the fovea it is bordered exactly horizontal. Nasal to the fovea the thickened ring of the GCL crosses the horizontal line downwards. The mOCT thicknesses of the upper macula including parts of the lower nasal macula and the respective sectors of the pRNFL seem undamaged and upper pRNFL thickness is above average temporally. Peripheral to the macula, just inside the large temporal vessels, mOCT and pRNFL re-

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veal glaucomatous damage corresponding to the deep arcuate scotoma with nasal step. However, the lower VF, including the fovea, is inconspicuous. Hood et al. [4] have called attention to an arcuate macular vulnerability zone (MVZ) in mOCT, which has a sharp horizontal border temporal to the macula and is served by nerve fibers which enter the optic disc temporal inferiorly. The region above the MVZ often is much less vulnerable and often seems undamaged, even when advanced damage is revealed below and above the macula as in .  Fig. 8. The concept of the MVZ corresponds well to the early glaucomatous damage pattern of the VF: it occurs preferentially in the upper VF, often with a nasal step, and may,

at times, come close to the fovea nasal superiorly. The damage pattern in .  Fig. 8 also reveals that the division between upper and lower retina (raphe), similar to the representation in the VF, runs largely horizontally, is not cyclorotated, and does not cross the disc center as the algorithms of some OCT machines suggest.

Assessment of progression The assessment of progression by VF testing is complicated by short- and longterm fluctuation, as well as by varying degrees of concentration losses and patient fatigue. Therefore, VF deterioration usually has to be confirmed by repeated VF testing in scientific studies. Further-

Fig. 6 8 Synopsis of morphologic and functional findings. A thorough synopsis of the findings reveals glaucomatous damage. Regions of reduced thickness of the inner retinal layers are encircled in red, relatively thick regions are encircled in green. The small thick and the large thick red arrows indicate the locations, to which the most central and most peripheral scotomas of the PD may be attributed to if the eccentric displacement of the retinal ganglion cells is taken into account, respectively. White frame: area corresponding to a 6 × 6-mm scan; white arrows: nasal border of the sector area. Please see the separate list for definitions of abbreviations

more, the sensitivity of perimetry in early glaucoma is relatively low [15]. The accuracy and reproducibility of modern OCT devices is excellent, particularly for GCL+ [16]; it is considerably less dependent on patient cooperation and should therefore be less time consuming and more reliable than perimetry for detecting progression. Comparative studies with mOCT and pRNFL or GCC and GCL+ for the assessment of glaucomatous damage and its progression are partly conflicting. Most consider that mOCT does not represent damage as well as pRNFL and that GCL+ is less sensitive than GCC (see [17] for review). Nearly all comparative studies have been performed with rather crude grids, which often compared the whole macula or pRNFL, or even analyzed only the

mean retinal thickness of all ten macular layers. Measuring the mean pRNFL thickness has the advantage that all nerve fibers of the retina are represented, but localized defects are better revealed if respective smaller sectors are analyzed. mOCT, particularly GCL/GCL+, has the advantage that mainly central defects may be very sensitively and topographically exactly represented. Defects of the peripheral macula and large macular defects should be better revealed with the GCC. We consider that no single OCT method can replace the other; but rather supplements the others. Dependent on the stage and location of glaucomatous changes, the most sensitive method should be considered. Therefore, we routinely perform a fovea- and disc-centered OCT, including selection of the GCL and GCL+.

Assessment of progression with mOCT

The mOCT offers interesting options for assessment of progression. In .   Figs.  9 and 10, arcuate thinning of the GCC within the MVZ can be seen, which enlarges and deepens nearly continuously within 6 months (five examinations). Only in the fifth examination was the significance level of 5 % attained in the lower hemiretina, as marked respectively. The progression rate of GCC thickness for the whole macular area is -5 µm/year and that of the lower hemiretina is well above the progression rate of the upper hemiretina. This progression rate is twenty times higher than that of published age-dependent progression rate of 0.25 µm/year for the GCC [15]. Particularly the relatively continuous enlargement and deepening of the defect Der Ophthalmologe

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Fig. 7 8 Nasal step with arcuate scotoma and corresponding loss in the pRNFL and mOCT. The VF reveals a peripheral superior nasal step (red arrow) with an arcuate scotoma (framed in red). Large red arrows: horizontal border of the nasal step and corresponding OCT alterations. Thick red arrows: Thinning in the region of the inner retinal layers correlating to the arcuate scotomas (framed in red). Despite distinct thinning in the pRNFL (encircled in red), this only attains 5 % significance level in the 30° sector; upper pRNFL thickness is above average (encircled in green). Yellow arrows: B-scan section line; blue arrows: thinning of the GCL, GCC and corresponding skotoma. Please see the separate list for definitions of abbreviations

of the inner retinal layers suggests progressive glaucomatous damage. The partner eye has a very similar progression rate (not shown), but a different damage pattern, with multiple disseminated defects preferentially near the large temporal vessels. These also progress by enlargement and deepening. This corresponds well to the progression pattern of deepening and enlarging scotomas known from perimetry [1]. The VF of this eye reveals relative scotomas within 10°; more in the upper than in the lower hemifield in the PD (VF is presented upside down). However, the pattern of the upper scotomas does not show the damage pattern one would expect from the mOCT, and the lower paracentral scotomas are within the less vul-

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nerable zone and do not correlate well with the seemingly well-preserved lower retina. Remarkable is the fluctuation of the PD plot, as well as the MD and LV values; such that the VF does not even suggest progression. In pRNFL a thinning can be seen temporal inferiorly (. Fig. 10), but it does not confirm progression. Striking are the relatively large thickness fluctuations of some 30° sectors of the pRNFL. The example in .  Fig.  9 impressively suggests that, in appropriate cases, mOCT can reveal glaucomatous progression earlier than usual, with relatively high reliability. This may allow assessment of whether medical, surgical, or neuroprotective interventions result in a modification of the progression rate. If respective algorithms are integrated into OCT

devices, this would facilitate registration and perception of these changes, and their coupling to respective statistical values for comparison. Naghizadeh et al. [18] showed that an integrated algorithm that analyzes focal volume losses is superior to global parameters of GCC and pRNFL thickness, as well as to disc analyses in early glaucomatous damage.

Concordance of mOCT and perimetric examinations The concordance of morphologic and functional changes (VF) seems rather limited, even though histologic studies reveal a good correlation of VF defects with ganglion cell losses [19, 20]. This may be due to a rather crude segmental analysis of

Fig. 8 8 Macular vulnerability zone (MVZ): typical glaucomatous damage pattern in mOCT. The less vulnerable macular zone is bordered in green, the outer borders of the MVZ and the peripheral defects are marked in red (adapted from [4]). The extensive damage (red arrows and borders) is seen almost exclusively within the MVZ. Short green arrows: borders of the largely undamaged layers; long green arrows and border lines: areas of relatively thick layers; yellow arrows: the raphe revealed by damage pattern in the mOCT in comparison to raphe constructed by the algorithm of the OCT machine. Please see the separate list for definitions of abbreviations

morphometric examinations. Particularly with localized defects, least some correlation between mOCT and VF testing with centrally condensed stimuli is usually seen. In cases with considerable thinning of the GCL/GCL+, it is often possible to see at least conspicuities in the VF. This correlation may be very evident, as, for example, with the paracentral scotoma in .  Fig. 5 or the arcuate scotoma in .  Fig. 8. Sometimes, despite a distinct localized mOCT defect, relative scotomas are found in corresponding localizations that have only limited resemblance to the mOCT defect in terms of the outline and steepness of the defect, such as in . Figs. 9 and 10. However, in early glaucomatous damage in the GCL/GCL+, usually at least some conspicuous points can be

seen in the adapted VF test, similarly as has been described by Traynis et al. [12]. As far as we can judge from the analysis of our data, clearly evident scotomas such as those in . Fig. 9, to which no corresponding morphologic alteration can be found in the mOCT, are not frequent.

How can the sensitivity of mOCT be increased? Localized thinning of the inner retinal layers detected with mOCT usually is marked as significant if such thinning occurs in less than 5 % or 1 % of normal eyes. In several figures, we have emphasized that, quite often, localized thinning of the inner retinal layers is visible but not highlighted by the algorithm of the OCT de-

vice, because other parts of the inner retinal layers are within the upper level of the normative database. However, a similar relative thinning in an eye with average or under-average thickness of the inner retinal layer would clearly reach significance level. Because of this, circumscribed inner retinal thinning typical of early glaucoma may remain undetected. In perimetric practice it is usual to compare localized thinning not only to the normative database, but also to compare conspicuous sensitivity losses of certain topographic locations to the general layer thickness of this eye (PD plot). It can also be presented in a nontopographic manner, such as the Bebié plot; or with indices like LV, PD, or pattern standard deviation to facilitate its recognition. This is of great cliniDer Ophthalmologe

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Fig. 9 8 Progression assessment with mOCT. Progression analyses of the GCC of the right eye: 1st row: thickness of the GCC and its changes in different sectors. 2nd row: deviation of the GCC thicknesses in relation to the normative data base. 3rd row: significances of the deviations. 4th row: left: progression rate of global GCC thickness; right: mean global thicknesses. White numbers: interval between examinations in days. Enlargement and deepening of GCC defects in comparison to the previous examination are marked with red arrows; reductions of mean thickness ≥ 3 µm are encircled in red. The MVZ is bordered by red and green lines as in . Fig. 8. Please see the separate list for definitions of abbreviations

cal relevance in early glaucomatous damage [19]. Transferred to mOCT analyses, it would be important: 55to perform the thickness calculations of the individual layers not only for the whole scanned area or large areas of it, but also for many small sectors; 55to relate the calculations and significances for the individual sectors not only to the normative databank, but also to the individual layer thickness of both eyes, such as PD in the VF analysis; 55to take into account features like vertical asymmetry [21], interocular asymmetries [22], and compari-

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sons with typically less-involved regions [23]. For this it is important to evaluate typical defect patterns like the MVZ [4, 23], which we can reveal with mOCT and respective perimetry [4, 23]; 55to address sensitivity and specificity, which may be significantly increased if algorithms were to be developed which can integrate a suitable perimetric strategy into the OCT analysis (see 24 for discussion). This also holds true for other functional examinations, such as frequency doubling perimetry.

In order to diagnose glaucomatous damage earlier and more reliably, and to assess progression, perimetric strategies should be adapted to the options provided by the mOCT examinations. This concerns mainly the density and localization of the test points [3]; but other parameters, such as the optimal stimulus size, should also be evaluated and adapted [25]. As mOCT data collection is much faster and less exhausting for the patient, perimetric strategies should be developed that permit more specific examination, and adapted according to the extent of glaucomatous damage and to the OCT results. This might possibly be most easily achieved with microperimetry.

Fig. 10 8 Progression assessment with VF and pRNFL analyses (same patient as . Fig. 9). First row: VF PD plot (upside down; only the part of the VF covered by the OCT scan of . Fig. 9 is presented) with MD and LV values. The MVZ is bordered by red and green lines as in . Fig. 8. 2nd row: pRNFL: comparative thickness profiles of the first and last examination and the calculated progression rate of the five examinations. Red arrow scotomas corresponding with mOCT defects. 3rd row: the thicknesses of the pRNFL in 30° sectors. The measured thicknesses of the individual sectors vary considerably between the individual examinations. Please see the separate list for definitions of abbreviations

The significance of mOCT in morphologic glaucoma diagnosis As discussed in the current paper, mOCT seems well suited for detection of early macular glaucomatous damage and for revealing progression, particularly if it is combined with an adapted perimetric technique. However, the validity of mOCT is rather limited, particularly in the case of maculopathies: of 137 routine mOCT examinations, we classified 23 cases as unreliable, mostly because of maculopathies. This problem should be less frequent with OCTs of the pRNFL and disc. Macular glaucomatous damage may be revealed in the pRNFL as well. Therefore, and because mOCT examinations can provide only limited information out-

side the macular region, mOCT should always be combined with a disc-centered OCT examination. However, algorithms for such evaluations lag behind the technical possibilities. Until respective algorithms are available, it is essential to evaluate the morphologic and functional results visually with great care, and to interpret these in the context of other clinical data, if the currently existing options are to be optimally applied [26].

Conclusion 55Using mOCT macular glaucoma damage can be detected very sensitively and can be easily correlated with the corresponding sensitive findings of the central VF examinations.

55In suitable cases glaucoma progression can be detected early with mOCT so it is hoped that the influence of drugs and surgical interventions on glaucoma progression can be determined earlier than before. 55To benefit from the possibilities of mOCT the individual layer thickness level should be taken into consideration and the mOCT findings should be considered together with further functional and morphological investigations. 55The mOCT investigation cannot replace the OCT investigation centered on the optic papilla.

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Leitthema Corresponding address Prof. Dr. W. Noske Klinik für Augenheilkunde Städtisches Klinikum Brandenburg Hochstr. 29, 14770 Brandenburg a.d. Havel [email protected]

Acknowledgements.  The authors wish to thank Corinna Vogel, Heike Tretschog, Jeanette Böttger, and Elke Spielmann for their continuous engagement in VF and OCT examinations.

Compliance with ethical guidelines Conflict of interests.  A. Sturm and W. Noske state that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.

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