Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

Fig. 12.16. Macular grid scanning protocol for OCT. Unlike radial line protocols, which concentrate the sampled spots along the six radial lines, grid scanning protocols spread the spots across the macula in a pattern of concentric rings, thereby permitting a more even and dense sampling of the macula

retinal thickness map, the key quantitative output of macular OCT scans, is dependent on accurate identification of the inner and outer retinal boundaries. Hee and coworkers have described the use of standard edge-detection algorithms for identification of the retinal boundaries in the first-generation OCT devices (OCT-1, Carl Zeiss Meditec), with the two strongest edges in each tomogram believed to correspond to the vitreoretinal interface and the retinal pigment epithelium [27]. Although the algorithms for retinal boundary detection utilized by the StratusOCT have not been published, it is believed that they may also rely in part on edge-detection routines. Although these algorithms were validated in normal patients as well as in some patients with DME and found to be reproducible, it has recently been suggested that even in normal patients, the interfaces detected by these conventional algorithms do not appear to correspond to the correct anatomic boundaries of the retina [76]. The root of this problem lies in the assumption that the first inner highly reflective layer (HRL) corresponds to the RPE interface. Recent studies suggest that the inner HRL is actually part of the neurosensory retina (corresponding to photoreceptor outer segments) and that the outer HRL is likely to be the true location of the RPE [76]. Thus, Stratus OCT likely underestimates the true retinal thickness in both normal subjects and patients with retinal disease.

Even if one accounts for this “expected” misidentification of the outer retinal border, boundary detection errors are still a frequent problem with conven-

tional OCT analysis algorithms [77]. Sadda and coworkers reviewed each of the 6 radial-line scans from 200 eyes of 200 consecutive patients undergoing OCT imaging for macular disease, and graded

errors in retinal boundary detection in each line scan II 12 using a semiquantitative scale [81]. Errors in retinal boundary detection were observed in 92 % of cases,

with moderate or severe errors in 33 %. Errors were more common in scans containing subretinal fluid or pigment epithelial detachments. Errors were less frequent, however, in patients with retinal vascular disease and macular edema, which was likely related to the lower frequency of subretinal pathology and disruption of the hyperreflective RPE interface in these patients. Subretinal fluid and vitreomacular traction, as described in this chapter, are still features of retinal vascular disease which can compromise the accuracy of conventional algorithms in these cases. Current StratusOCT software allows the clinician to manually place caliper marks and measure retinal thickness at selected locations, but does not allow for global correction of errors across the entire image or image set. In addition, because the RPE interface is defined as the outer retinal boundary, subretinal fluid is frequently (but variably) included in the measurements of retinal thickness. The failure to distinguish the subretinal space from the retinal thickness represents a loss of potential clinically useful information. For example, some therapies may preferentially affect retinal edema but not subretinal fluid. Current analysis software also does not allow quantification of other OCT features of retinal vascular disease such as retinal cysts and lipid exudates.

12.5.2 Clinical Applications

Essentials

OCT definitions of macular edema may not correlate with traditional definitions of CSME

OCT grid scanning protocols and region growing software can identify zones of thickening which may correlate with prior definitions of CSME

Automated CSME-detection algorithms are more reproducible than the human gold standard

OCT parameters could be used to define a new objective definition of CSME

Retinal thickness measurements have become an integral part of clinical management of patients with retinal vascular disease. Measurements have been used to screen patients for eligibility in clinical trials

of macular edema and to monitor the response of patients to various interventions. An important area of uncertainty, however, is the relationship between OCT measurements of retinal thickness and the sub-

12 II jective standard of CSME defined in previous landmark clinical trials of diabetic retinopathy.

Brown and coworkers defined an entity of “subclinical edema” to distinguish retinal thickening apparent on OCT which was not detected by biomicroscopy or on stereoscopic fundus photographs [5]. It is uncertain, however, whether patients with subclinical edema would benefit from focal laser treatment. To more precisely identify and define CSME, Sadda et al. evaluated a concentric grid scanning protocol and region-growing software algorithm designed to automatically outline and quantify areas of CSME [80]. The performance of the algorithm for identification of CSME was compared against the clinical gold standard (biomicroscopy and/or stereoscopic photographs), and sensitivity and specificity was found to be over 85 %. Secondary analysis revealed that cases of disagreement between the automated algorithm and the clinical assessment were due to the variability and subjectivity of the clinical gold standard.

These observations suggest that OCT parameters could potentially be used to redefine a new objective standard for CSME, which could be used in future clinical trials of macular edema and retinal vascular disease. An objective OCT metric will also facilitate comparative analyses among clinical trials.

12.5.3 The Future of OCT Hardware

Essentials

Improvements in the axial resolution of future OCT devices will depend principally on advances in light source technology

Continued speed optimizations will further enhance the three-dimensional depiction of tissues

Doppler OCT may be able to bridge the gap with angiography by providing dynamic OCT information

Functional imaging represents a new challenge for OCT imaging in the next decade

The hardware that enables ophthalmic OCT has undergone a tremendous evolution in the last 2 decades – even more so in the last 5 years. Significant improvements have occurred in both the axial resolution and speed of these devices.

Most of the improvement in axial resolution that has occurred in recent OCT devices has come from

changes in the light source used for the OCT instrument [17]. The superluminescent diode (SLD), a technology which could be considered the workhorse of OCT because it combines high bandwidth with low cost, has improved steadily over the last 5 years. Ongoing research into the use of multiple SLD arrays and new SLD technologies, such as those incorporating quantum dots, will likely enhance the resolution of future OCT devices. OCT instruments based on laser light sources, such as doped rareearth and titanium:sapphire (Ti:Al2O3) lasers [17], offer superb image quality but have limited commercial feasibility due to their prohibitive costs. This crucial problem could be mitigated, however, by the development of inexpensive laser systems or the use of alternative light sources. For example, several research groups are currently studying the potential of ultra-broadband halogen light sources [26]. Another exciting area of OCT hardware research involves swept source OCT [13]. In swept source OCT, the moving reference arm of time domain OCT is replaced with a sweeping frequency laser. Finally, several investigators are now attempting to integrate adaptive optics systems into OCT devices [31]. Adaptive optics systems utilize wavefront sensing technologies and deformable mirrors to remove optical aberrations from reflected light. Adaptive optics may be able to improve both the axial and transverse resolution of future OCT instruments so that specific populations of retinal cells can be evaluated.

Improvement in the scanning speed of OCT devices has been an important step forward in OCT hardware development, as it mitigates problems related to patient fixation instability and sparse sampling of the macula. Most of the speed improvements evident in the newest commercial OCT devices are due to Fourier or spectral-domain technology [1], which typically allows scan acquisition 50 times faster than with time domain devices. The faster scanning speeds possible with FD OCT instruments enable dense sampling of the fundus region being mapped. This enables pseudo-realistic three-dimen- sional reconstructions of fundus structures (3D OCT) and better rendering of invariant landmarks, such as blood vessels and the optic nerve. The latter capability facilitates alignment of OCT data between visits and with other fundus imaging modalities [110]. Full-field OCT devices have an even greater speed advantage than standard FD OCT [4]. By capturing spectral information an entire ’field’ at a time with a two-dimensional detector instead of the standard linear array, full field OCT systems remove the time penalty of conventional systems in which the scanning spot mechanism captures a single A-scan at a time.

Other promising avenues of OCT hardware research include polarization-sensitive OCT (PS OCT), Doppler OCT, and functional OCT. PS OCT [12] takes advantage of the native polarization characteristics inherent in many ocular tissues (such as the nerve fiber layer) to improve signal differentiation. Doppler OCT utilizes the motion data encoded within the OCT signal and may allow detailed mapping of retinal blood vessels and blood flow, thereby providing information previously only accessible through invasive means such as retinal angiography [118]. Although it lacks the dynamic leakage information of fluorescein angiography, it may provide a bridge that expands the capabilities of OCT towards angiography. Finally, functional imaging represents an entirely new paradigm focusing on the health and function of tissues – not just on their structural representation. Current research efforts in functional OCT are taking advantage of the spectral capabilities that are built into the new OCT systems. Coupled with adaptive optics, functional OCT could act as a powerful new tool both for research and clinical purposes.

12.5.4 The Future of OCT Software

Essentials

Current OCT software measurement techniques will be inadequate in the era of Fourier domain OCT

Future OCT software needs greater accuracy and clinical knowledge integration

Future OCT software should provide more clinically relevant measurements

Despite the giant leap toward automated quantification made by the first generation of OCT software, subsequent software advances have been slow and greatly outpaced by hardware developments. The shortcomings of currently available OCT software will become even more apparent in the era of Fou- rier-domain instrumentation where larger amounts of data are acquired in a shorter amount of time and a larger number of mathematical calculations are required to distill the data into clinically useful numbers. Clinicians who, in the past, could easily interpret findings from six B-scans during a busy clinic may not be able to review the hundreds of B- scans that are produced by 3D-OCT instruments in just a few seconds. Furthermore, in this era of quantitative medicine driven by objective measurements, subjective clinical assessments will be replaced by objective numerical data from instruments such as OCT.

Two major enhancements will be necessary in the next generation of OCT software. First, the accuracy of OCT measurements must be improved. Since clinical decisions will rely more and more on the preci-

sion of OCT quantification, the standards for the II 12 next generation of OCT software should be set high-

er than currently available systems which are prone to errors. This should be an achievable goal since higher resolution image data provides the opportunity for more detailed tissue analyses including delineation and measurement of ocular tissue components such as individual retinal layers and subretinal lesions [89]. One difficult and unsolved problem, however, is how to keep pace with the evolution in our understanding of the histologic and pathologic correlates to OCT measurements. For example, it is now believed that the current StratusOCT system incorrectly detects the true outer retinal boundary. This knowledge was not available to the designers of the system nor was the system intended to learn or incorporate new data into its analysis algorithm. Ideally, future OCT software systems will be able to adapt to advances in clinical knowledge by incorporating new clinical understanding into diagnostic measurements in the field.

The other major challenge facing future OCT software systems will be to improve the relevance of clinical measurements. Although retinal thickness is an important measurement in many retinal diseases, lumping all intraretinal and subretinal findings into a single measurement does not take full advantage of the cross-sectional image data acquired by OCT. In an era of intravitreal anti-VEGF therapies, for instance, it would be useful to learn the individual volumes of the retinal tissue, cystoid spaces, subretinal fluid, subretinal tissue, and sub-RPE lesions instead of just the aggregate retinal thickness or macular volume. Furthermore, with the improved image registration capabilities of FD-OCT devices, these measurements can be compared between visits to look for clinically relevant changes in disease states. Registration will also enable integration of other diagnostic modalities such as color imaging, angiography, perimetry, and multifocal electroretinography [106, 114]. Point-to-point localization of OCT findings on fundus images or angiography will also both assist the care of the patient and advance our understanding of the pathophysiology underlying the disease.

OCT has revolutionized the practice of ophthalmology. Continued hardware and software enhancements should improve the relevance and precision of OCT measurements. These advanced capabilities will enhance the clinician’s ability to manage complex diseases, make critical treatment decisions, and potentially even diagnose diseases at an earlier stage.

References

18.Early Treatment Diabetic Retinopathy Study Research Group (1985) Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 103:1796 – 806

19.Early Treatment Diabetic Retinopathy Study Research Group (1991) Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology 98:766 – 85

20.Friedman SM (2003) Optociliary venous anastomosis after radial optic neurotomy for central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 34:315 – 7

21.Fujii GY, de Juan E, Jr, Humayun MS (2003) Improvements after sheathotomy for branch retinal vein occlusion documented by optical coherence tomography and scanning laser ophthalmoscope. Ophthalmic Surg Lasers Imaging 34:49 – 52

22.Garciia-Arumii J, Boixadera A, Martinez-Castillo V, Castillo R, Dou A, Corcostegui B (2003) Chorioretinal anastomosis after radial optic neurotomy for central retinal vein occlusion. Arch Ophthalmol 121:1385 – 91

23.Gaucher D, Tadayoni R, Erginay A, Haouchine B, Gaudric A, Massin P (2005) Optical coherence tomography assessment of the vitreoretinal relationship in diabetic macular edema. Am J Ophthalmol 139:807 – 13

24.Giovannini A, Amato GP, Mariotti C, Ripa E (1999) Diabetic maculopathy induced by vitreo-macular traction: evaluation by optical coherence tomography (OCT). Doc Ophthalmol 97:361 – 6

25.Goebel W, Kretzchmar-Gross T (2002) Retinal thickness in diabetic retinopathy: a study using optical coherence tomography (OCT). Retina 22:759 – 67

26.Grieve K, Paques M, Dubois A, Sahel J, Boccara C, Le Gargasson JF (2004) Ocular tissue imaging using ultrahigh-res- olution, full-field optical coherence tomography. Invest Ophthalmol Vis Sci 45:4126 – 31

27.Hee MR, Izatt JA, Swanson EA, Huang D, Schuman JS, Lin CP, Puliafito CA, Fujimoto JG (1995a) Optical coherence tomography of the human retina. Arch Ophthalmol 113:325 – 32

28.Hee MR, Puliafito CA, Wong C, Duker JS, Reichel E, Rutledge B, Schuman JS, Swanson EA, Fujimoto JG (1995b) Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 113:1019 – 29

29.Hee MR, Puliafito CA, Duker JS, Reichel E, Coker JG, Wilkins JR, Schuman JS, Swanson EA, Fujimoto JG (1998) Topography of diabetic macular edema with optical coherence tomography. Ophthalmology 105:360 – 70

30.Hee MR, Fujimoto JG, Ko TH, et al. (2004) Interpretation of the optical coherence tomography image. In: Schuman JS, Puliafito CA, Fujimoto JG (eds) Optical coherence tomography of ocular diseases, 2nd edn. Slack Inc., Thorofare, NJ

31.Hermann B, Fernandez EJ, Unterhuber A, Sattmann H, Fercher AF, Drexler W, Prieto PM, Artal P (2004) Adaptiveoptics ultrahigh-resolution optical coherence tomography. Opt Lett 29:2142 – 4

32.Holz FG, Jorzik J, Schutt F, Flach U, Unnebrink K (2003) Agreement among ophthalmologists in evaluating fluorescein angiograms in patients with neovascular age-related macular degeneration for photodynamic therapy eligibility (FLAP-study). Ophthalmology 110:400 – 5

33.Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, Hee MR, Flotte T, Gregory K, Puliafito CA, et al. (1991) Optical coherence tomography. Science 254:1178 – 81

34.Huang D, Kaiser PK, Lowder CY, Traboulsi E (2006) Retinal imaging, 1st edn. Elsevier, Philadelphia, p 640

35.Hussain A, Hussain N, Nutheti R (2005) Comparison of mean macular thickness using optical coherence tomography and visual acuity in diabetic retinopathy. Clin Exp Ophthalmol 33:240 – 5

36.Imai M, Iijima H, Hanada N (2001) Optical coherence tomography of tractional macular elevations in eyes with proliferative diabetic retinopathy. Am J Ophthalmol 132: 458 – 61

37.Jonas JB, Sofker A (2001) Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 132:425 – 7

38.Kaiser RS, Berger JW, Williams GA, Tolentino MJ, Maguire AM, Alexander J, Madjarov B, Margherio RM (2002) Variability in fluorescein angiography interpretation for photodynamic therapy in age-related macular degeneration. Retina 22:683 – 90

39.Kang SW, Park CY, Ham DI (2004) The correlation between fluorescein angiographic and optical coherence tomographic features in clinically significant diabetic macular edema. Am J Ophthalmol 137:313 – 22

40.Klein R, Klein BE, Moss SE (1984) Visual impairment in diabetes. Ophthalmology 91:1 – 9

41.Lai JC, Stinnett SS, Jaffe GJ (2003) B-scan ultrasonography for the detection of macular thickening. Am J Ophthalmol 136:55 – 61

42.Lam DS, Chan CK, Tang EW, Li KK, Fan DS, Chan WM (2004) Intravitreal triamcinolone for diabetic macular oedema in Chinese patients: six-month prospective longitudinal pilot study. Clin Exp Ophthalmol 32:569 – 72

43.Larsen M, Wang M, Sander B (2005) Overnight thickness variation in diabetic macular edema. Invest Ophthalmol Vis Sci 46:2313 – 6

44.Lattanzio R, Brancato R, Pierro L, Bandello F, Iaccher B, Fiore T, Maestranzi G (2002) Macular thickness measured by optical coherence tomography (OCT) in diabetic patients. Eur J Ophthalmol 12:482 – 7

45.Lerche RC, Schaudig U, Scholz F, Walter A, Richard G (2001) Structural changes of the retina in retinal vein occlusion – imaging and quantification with optical coherence tomography. Ophthalmic Surg Lasers 32:272 – 80

46.Lovestam-Adrian M, Andreasson S, Ponjavic V (2004) Macular function assessed with mfERG before and after panretinal photocoagulation in patients with proliferative diabetic retinopathy. Doc Ophthalmol 109:115 – 21

47.Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C (2002) Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 109:920 – 7

48.Martinez-Jardon CS, Meza-de Regil A, Dalma-Weiszhausz J, Leizaola-Fernandez C, Morales-Canton V, GuerreroNaranjo JL, Quiroz-Mercado H (2005) Radial optic neurotomy for ischaemic central vein occlusion. Br J Ophthalmol 89:558 – 61

49.Massin P, Vicaut E, Haouchine B, Erginay A, Paques M, Gaudric A (2001) Reproducibility of retinal mapping using optical coherence tomography. Arch Ophthalmol 119:1135 – 42

50.Massin P, Erginay A, Haouchine B, Mehidi AB, Paques M, Gaudric A (2002) Retinal thickness in healthy and diabetic subjects measured using optical coherence tomography mapping software. Eur J Ophthalmol 12:102 – 8

51.Massin P, Duguid G, Erginay A, Haouchine B, Gaudric A (2003) Optical coherence tomography for evaluating diabetic macular edema before and after vitrectomy. Am J Ophthalmol 135:169 – 77

52.Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, Caulin C, Gaudric A (2004) Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Oph-

54.Moreira RO, Trujillo FR, Meirelles RM, Ellinger VC, Zagury L (2001) Use of optical coherence tomography (OCT) and indirect ophthalmoscopy in the diagnosis of macular edema in diabetic patients. Int Ophthalmol 24:331 – 6

55.Moshfeghi AA, Mavrofrides EC, Puliafito CA (2006) Optical coherence tomography and retinal thickness assessment for diagnosis and management. In: Ryan SJ (ed) Retina, 4th edn. Vol. 2. Elsevier, Philadelphia, p 1889

56.Muscat S, Parks S, Kemp E, Keating D (2002) Repeatability and reproducibility of macular thickness measurements with the Humphrey OCT system. Invest Ophthalmol Vis Sci 43:490 – 5

57.Nagpal M, Nagpal K, Bhatt C, Nagpal PN (2005) Role of early radial optic neurotomy in central retinal vein occlusion. Indian J Ophthalmol 53:115 – 20

58.Neubauer AS, Priglinger S, Ullrich S, Bechmann M, Thiel MJ, Ulbig MW, Kampik A (2001) Comparison of foveal thickness measured with the retinal thickness analyzer and optical coherence tomography. Retina 21:596 – 601

59.Nussenblatt RB, Kaufman SC, Palestine AG, Davis MD, Ferris FL, 3rd (1987) Macular thickening and visual acuity. Measurement in patients with cystoid macular edema. Ophthalmology 94:1134 – 9

60.Ohashi H, Oh H, Nishiwaki H, Nonaka A, Takagi H (2004) Delayed absorption of macular edema accompanying serous retinal detachment after grid laser treatment in patients with branch retinal vein occlusion. Ophthalmology 111:2050 – 6

61.Opremcak EM, Bruce RA (1999) Surgical decompression of branch retinal vein occlusion via arteriovenous crossing sheathotomy: a prospective review of 15 cases. Retina 19:1 – 5

62.Opremcak EM, Bruce RA, Lomeo MD, Ridenour CD, Letson AD, Rehmar AJ (2001) Radial optic neurotomy for central retinal vein occlusion: a retrospective pilot study of 11 consecutive cases. Retina 21:408 – 15

63.Opremcak EM, Rehmar AJ, Ridenour CD, Kurz DE (2006) Radial optic neurotomy for central retinal vein occlusion: 117 consecutive cases. Retina 26:297 – 305

64.Otani T, Kishi S (2000) Tomographic assessment of vitreous surgery for diabetic macular edema. Am J Ophthalmol 129:487 – 94

65.Otani T, Kishi S (2001) Tomographic findings of foveal hard exudates in diabetic macular edema. Am J Ophthalmol 131:50 – 4

66.Otani T, Kishi S, Maruyama Y (1999) Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol 127:688 – 93

67.Ozdek SC, Erdinc MA, Gurelik G, Aydin B, Bahceci U, Hasanreisoglu B (2005) Optical coherence tomographic assessment of diabetic macular edema: comparison with fluorescein angiographic and clinical findings. Ophthalmologica 219:86 – 92

68.Ozdemir H, Karacorlu M, Karacorlu S (2005a) Serous mac-

86.Sekiryu T, Yamauchi T, Enaida H, Hara Y, Furuta M (2000) Retina tomography after vitrectomy for macular edema of central retinal vein occlusion. Ophthalmic Surg Lasers 31:198 – 202

87.Shah GK, Sharma S, Fineman MS, Federman J, Brown MM, Brown GC (2000) Arteriovenous adventitial sheathotomy for the treatment of macular edema associated with branch retinal vein occlusion. Am J Ophthalmol 129: 104 – 6

88.Shah SP, Patel M, Thomas D, Aldington S, Laidlaw DA (2006) Factors predicting outcome of vitrectomy for diabetic macular oedema: results of a prospective study. Br J Ophthalmol 90:33 – 6

89.Shahidi M, Wang Z, Zelkha R (2005) Quantitative thickness measurement of retinal layers imaged by optical coherence tomography. Am J Ophthalmol 139:1056 – 61

90.Shimura M, Yasuda K, Nakazawa T, Kano T, Ohta S, Tamai M (2003) Quantifying alterations of macular thickness before and after panretinal photocoagulation in patients with severe diabetic retinopathy and good vision. Ophthalmology 110:2386 – 94

91.Shimura M, Saito T, Yasuda K, Tamai M (2005a) Clinical course of macular edema in two cases of interferon-asso- ciated retinopathy observed by optical coherence tomography. Jpn J Ophthalmol 49:231 – 4

92.Shimura M, Yasuda K, Nakazawa T, Tamai M (2005b) Visual dysfunction after panretinal photocoagulation in patients with severe diabetic retinopathy and good vision. Am J Ophthalmol 140:8 – 15

93.Shukla D, Rajendran A, Kim R (2006) Macular hole formation and spontaneous closure after vitrectomy for central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol

94.Spaide RF, Klancnik JM, Jr (2004) Still motion animation of the retina technique. Retina 24:315 – 7

95.Spaide RF, Lee JK, Klancnik JK, Jr, Gross NE (2003) Optical coherence tomography of branch retinal vein occlusion. Retina 23:343 – 7

96.Stitt AW, Moore JE, Sharkey JA, Murphy G, Simpson DA, Bucala R, Vlassara H, Archer DB (1998) Advanced glycation end products in vitreous: Structural and functional implications for diabetic vitreopathy. Invest Ophthalmol Vis Sci 39:2517 – 23

97.Stolba U, Binder S, Gruber D, Krebs I, Aggermann T, Neumaier B (2005) Vitrectomy for persistent diffuse diabetic macular edema. Am J Ophthalmol 140:295 – 301

98.Strom C, Sander B, Larsen N, Larsen M, Lund-Andersen H (2002) Diabetic macular edema assessed with optical coherence tomography and stereo fundus photography. Invest Ophthalmol Vis Sci 43:241 – 5

99.Tewari HK, Sony P, Chawla R, Garg SP, Venkatesh P (2005) Prospective evaluation of intravitreal triamcinolone acetonide injection in macular edema associated with retinal vascular disorders. Eur J Ophthalmol 15:619 – 26

100.Thomas D, Bunce C, Moorman C, Laidlaw DA (2005) A randomised controlled feasibility trial of vitrectomy versus laser for diabetic macular oedema. Br J Ophthalmol 89:81 – 6

101.Toth CA, Birngruber R, Boppart SA, Hee MR, Fujimoto JG, DiCarlo CD, Swanson EA, Cain CP, Narayan DG, Noojin GD, Roach WP (1997a) Argon laser retinal lesions evaluated in vivo by optical coherence tomography. Am J Ophthalmol 123:188 – 98

102.Toth CA, Narayan DG, Boppart SA, Hee MR, Fujimoto JG, Birngruber R, Cain CP, DiCarlo CD, Roach WP (1997b) A

comparison of retinal morphology viewed by optical coherence tomography and by light microscopy. Arch Ophthalmol 115:1425 – 8

103.Traynor MP, Conway BP (2004) Collateral vessel formation after radial optic neurotomy. Retina 24:616 – 7

104.Tso MO (1982) Pathology of cystoid macular edema. Ophthalmology 89:902 – 15

105.Uchino E, Uemura A, Ohba N (2001) Initial stages of posterior vitreous detachment in healthy eyes of older persons evaluated by optical coherence tomography. Arch Ophthalmol 119:1475 – 9

106.van Velthoven ME, de Vos K, Verbraak FD, Pool CW, de Smet MD (2005) Overlay of conventional angiographic and en-face OCT images enhances their interpretation. BMC Ophthalmol 5:12

107.Watanabe M, Oshima Y, Emi K (2000) Optical cross-sec- tional observation of resolved diabetic macular edema associated with vitreomacular separation. Am J Ophthalmol 129:264 – 7

108.Williamson TH, O’Donnell A (2005) Intravitreal triamcinolone acetonide for cystoid macular edema in nonischemic central retinal vein occlusion. Am J Ophthalmol 139: 860 – 6

109.Wojtkowski M, Srinivasan V, Fujimoto JG, Ko T, Schuman JS, Kowalczyk A, Duker JS (2005a) Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 112(10):1734 – 46

110.Wojtkowski M, Srinivasan V, Fujimoto JG, Ko T, Schuman JS, Kowalczyk A, Duker JS (2005b) Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 112:1734 – 46

111.Wolter JR (1981) The histopathology of cystoid macular edema. Albrecht Von Graefes Arch Klin Exp Ophthalmol 216:85 – 101

112.Wong AC, Chan CW, Hui SP (2005) Relationship of gender, body mass index, and axial length with central retinal

thickness using optical coherence tomography. Eye 19:292 – 7

114.Yamamoto S, Yamamoto T, Hayashi M, Takeuchi S (2001) Morphological and functional analyses of diabetic macular edema by optical coherence tomography and multifocal electroretinograms. Graefes Arch Clin Exp Ophthalmol 239:96 – 101

115.Yamamoto T, Hitani K, Tsukahara I, Yamamoto S, Kawasaki R, Yamashita H, Takeuchi S (2003) Early postoperative retinal thickness changes and complications after vitrectomy for diabetic macular edema. Am J Ophthalmol 135:14 – 9

116.Yang CS, Cheng CY, Lee FL, Hsu WM, Liu JH (2001) Quantitative assessment of retinal thickness in diabetic patients with and without clinically significant macular edema using optical coherence tomography. Acta Ophthalmol Scand 79:266 – 70

117.Yasukawa T, Kiryu J, Tsujikawa A, Dong J, Suzuma I, Takagi H, Ogura Y (1998) Quantitative analysis of foveal retinal thickness in diabetic retinopathy with the scanning retinal thickness analyzer. Retina 18:150 – 5

118.Yazdanfar S, Rollins AM, Izatt JA (2003) In vivo imaging of human retinal flow dynamics by color Doppler optical coherence tomography. Arch Ophthalmol 121:235 – 9

Core Messages

The first retinal coagulation was performed in 1949 with sunlight by Meyer-Schwickerath. It was replaced in the 1950s by xenon high pressure lamps

The development of laser technology began in 1960

The melanin in the pigment granules is the main absorbing structure in the retina. The first ruby lasers had undesirable side effects such as retinal hemorrhages and retinal tears

The first commercial argon laser systems enabled the Diabetic Retinopathy Study to be performed between 1972 and 1975

Different laser types such as krypton laser (647 nm or 530 nm), dye laser (560 – 680 nm), Nd:YAG laser (1,064 nm or 532 nm) or diode laser (810 nm) show only slight differences in histology. The relative absorption maximum of hemoglobin can be avoided with longer wavelengths. The coagulated area is replaced by unspecific scar tissue

The mechanisms of retinal laser treatment are not yet fully understood. The relation between need for oxygen and oxygen supply is opti-

mized by the retinal coagulation. But various growth factors and their time dependent course must also be taken into account in complex explanatory models

By destruction of retinal tissues the risk of severe loss of vision within 2 years can be reduced by 50 % in diabetic retinopathy

If neovascularizations of the retina or of the iris exist, the eyes benefit from full scatter panretinal laser coagulation. Treatment does not lead to improvement of visual acuity

The risk of development of neovascularization can be reduced by a modified sector laser coagulation in branch retinal vein occlusion The retinal pigment epithelium (RPE) can be selectively treated using short repetitive laser pulses with minimal heat diffuse to the adjacent retinal layers. Thus treatment of the macula is possible without damage of the overlying photoreceptors. Currently the therapeutic benefit of the procedure is being evaluated in multicenter trials in diseases such as diabetic macular edema, central serous retinopathy, and drusen in age-related macular degeneration (AMD)

13.1 History of Laser Treatment

Today light coagulation is a common treatment procedure and the basis of treatment in many retinal diseases. Its origins go back to Meyer-Schwickerath 1949 [46], who initially used sunlight as an energy source. However, sunlight was unsuitable for several reasons. A system of several mirrors and a long exposure time were necessary. The dependence on the weather forecast was an obvious problem. With the development of xenon high pressure lamps (Fig. 13.1) at the beginning of the 1950s, enough power for light coagulation of the ocular fundus became available [34]. Much scientific work was published at this time which showed the therapeutic

effect of the light coagulation and which led to a wider experience [47, 48]. The main focuses of clinically based xenon coagulation were retinopexy and the treatment of proliferative diabetic retinopathy.

13.2 Laser Sources

With the invention of laser technology in 1960 by Maiman [39], a rapid development of laser photocoagulation began. The first laser available was a ruby laser. Initially the focus on experimental examination was on interactions between pulsed ruby laser and retinal tissue [41]. It turned out that the histological effects of the laser light in the retina could be explained by absorption in different structures. The

Fig. 13.1. Xenon high pressure lamp (Mayer-Schwickerath 1959)

main absorber in the retina is represented by melanin in the pigment granules; other absorbers such as hemoglobin are of less importance. The short pulses of the ruby laser (694 nm) varied between 20 and 1,000 ns depending on the technical mode [42]. Short laser pulses initially prevented its clinical application becoming widespread, undesirable side-effects like retinal hemorrhages and tears occurred and no sufficient adhesion, e.g., in retinopexy, could be achieved [43, 44].

With the introduction of the argon laser technology at the beginning of the 1970s, there were systems available which enabled a broad clinical approach because of their continuous emission and powerful outcome. The first commercial argon laser systems in ophthalmology were used in 1971 [32]. Between 1972 and 1975 the Diabetic Retinopathy Study was performed, which was a large-scale prospective randomized multicenter clinical trial. It showed that treatment of proliferative diabetic retinopathy by coagulation brings great advantages and thus the risk of massive loss of vision can be reduced by 50 % [66, 68, 69]. For this reason the study was stopped in favor of coagulation treatment. It also turned out that there are no differences between the therapeutic effects of xenon and argon laser coagulation; however, the technical advantages of the argon laser were obvious, since the argon laser could be coupled in mirror systems more precisely and applied to the fundus more accurately. With further development of laser techniques more types of new laser systems became available. Initially all sufficiently powerful continuous wave laser systems were tested experi-

II 13

Fig. 13.2. Light absorption in the human retinal pigment epithelium

mentally and clinical trials were carried out. The various laser types like krypton laser (647 nm or 530 nm), dye laser (560 – 680), Nd:YAG laser (1,064 nm or 532 nm) or diode laser (810 nm) differ mainly in wavelengths and in technical parameters such as size of apparatus, efficacy, type of current necessary for operation and necessity for cooling. As the main difference between the various laser systems is just the wavelength, only a small difference in histology could be expected if pulse durations of 100 ms or more are used. The relative absorption maximum of hemoglobin can be avoided with longer wavelengths while the absorption rate in retinal pigment epithelium is decreasing [6, 33]. Thus, using longer wavelengths leads to increasing damage of deeper structures, e.g., the choroid. A practical advantage of longer wavelengths is the better transmission through cataract lenses [61]. None of the different types of lasers showed a significant clinical advantage in coagulation of subretinal membranes [60, 65, 80] or in treatment of vasoproliferative diseases [3, 54]. All different lasers similarly led to a considerable heat conduction out of the absorbing structures into the adjacent tissue layers as exposure times exceed 100 ms or more in clinical applications [73].

13.2.1Histological Findings After Light and Laser Coagulation

Historically, the first histological examinations were done with retinal tissues coagulated by xenon light. The retinal xenon lesions showed irreversible tissue damage. Areas of mild coagulation (Fig. 13.3) as seen on ophthalmoscopy showed destruction of the choriocapillaris, the retinal pigment epithelium and the photoreceptors including the outer nuclear layer [71, 76]. Destruction of the photoreceptors meant irre-

13 II

Fig. 13.3. Mild lesion after laser coagulation with a green laser (514 nm), exposure time 100 ms. The lesion was not visible clinically

Fig. 13.4. Histology of laser lesion (514 nm), which was clinically visible (exposure time 100 ms)

versible focal loss of function in the coagulated areas. More severe lesions (Fig. 13.4) using laser power as in clinical applications showed additional damage leading to pyknotic cells in the inner nuclear layer and in the ganglion cell layer [9, 24, 71]. Using laser histology, lesions do not look different as long as laser exposures between 100 and 500 ms are used. During the 1st h, probably even during the first seconds, the effect is intensified biologically by intraor intercellular edema [35]. Besides damage of the retinal pigment epithelium (RPE), the photoreceptors were always affected. These findings are independent of the wavelength of the laser used [5, 36, 43, 76]. In stronger lesions the inner layers of the retina are also involved.

Damage of the inner retinal layers (ganglion cell layer, nerve fiber layer) is undesirable. Even if power settings for threshold lesions are used, damage of photoreceptors cannot be avoided, as there is a wide intraand interindividual range in the variety of retinal thickness and pigmentation. Retinal vessels are usually not damaged primarily by retinal coagulation, as the power is too low and the spot size is too

large, which theoretically has to be matched to the diameter of a retinal vessel of a few micrometers [8]. Temperature elevations in the RPE using common clinical coagulation parameters do not lead to coagulation effects in retinal capillaries [40]. Because of different absorption characteristics in the RPE, theoretically different effects on the tissue are expected for different wavelengths. Actually there are no differences in the damage of the RPE and the outer retinal layers using the different wavelengths of the different lasers such as krypton laser [40], Nd:YAG laser [58] and diode laser [10]. By using longer wavelengths (e.g., krypton laser) the inner retinal layers can be protected as shown in animal experiments [2]. For applications in the macula the frequency doubled Nd:YAG laser (532 nm) has a small advantage over the argon laser because of its lower absorption in macula xanthophyll [23]. On the other hand, long wavelength light increasingly penetrates into the choroid, leading to choroidal bleedings [2, 37, 72] compared with histological effects in the retina and the choroid following treatment with Nd:YAG laser (1064 nm) and argon laser coagulation. After coagulation with a 1,064 nm Nd:YAG laser there were found severe changes in the choroid, even some occlusions of major choroidal vessels, which is in accordance with the reduced absorption.

The biological response to light or laser coagulation is similarly independent of the laser light used. It seems to depend only on the amount of tissue damaged. The repair process of a laser burn is unspecific to laser lesions and similar to the repair process of retinal detachment [38, 72]. There are only minor differences between different animal species [77] After laser coagulation the coagulated area gradually regenerates by proliferating glia cells originating from the intact retina and adjacent choroid. The retinal pigment epithelium contributes to the scarring process in several ways [75]. The blood-retina barrier begins to reform after 7 days [31]. The RPE barrier is restored anatomically and functionally [75]. After 3 months microglia can be found in the coagulated area [50]. Defects in the outer nuclear layer are replaced by Müller cells. Moderate exposure leads to a differentiated regeneration without adhesions between glia tissues and RPE cell layer [74]. Stronger lesions cause retinal defects with retinal adhesion to the RPE or, if missing, with retinal adhesion to Bruch’s membrane [74]. In those adhesions proliferating cells or RPE cells layered on Bruch’s membrane are involved. The findings on repair of the choriocapillary layer are different. While recapillarization was found in cats 30 days after coagulation [55], there were persisting defects in monkeys [15]. Treatment with drugs of retinal damage, e.g., in accidental laser injuries, shows a statistical effect on the amount