References

1.Davis MD, Norton EWD, Meyers FL. The Airlie classification of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic

Retinopathy. Washington, DC: US Government Printing

Office; 1969:7–22. USPHS Publication #1890.

2.The Diabetic Retinopathy Study Research Group. A modification of the Airlie House classification of diabetic retinopathy: DRS Report 7. Invest Ophthalmol Vis Sci. 1981; 21:210–226.

3.Early Treatment Diabetic Retinopathy Study Group. Grading diabetic retinopathy from stereoscopic color fundus photographs: An extension of the modified Airlie house classification: ETDRS Report Number 10. Ophthalmology. 1991; 98: 786–806.

4.Early Treatment Diabetic Retinopathy Study Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS Report Number 12. Ophthalmology. 1991; 98: 823–833.

5.Early Treatment Diabetic Retinopathy Study Research Group. Early treatment Diabetic Retinopathy Study Design and baseline patient characteristics: ETDRS Report Number 7. Ophthalmology. 1991;98:741–756.

6.Wilkinson CP, Ferris FL III, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003;110:1677–1682.

7.Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS Report Number 9. Ophthalmology. 1991;98:766–785.

8.Patz A, Smith RE. The ETDRS and diabetes 2000. Ophthalmology. 1991;98:730–740.

9.Early Treatment Diabetic Retinopathy Study Group. Effects of aspirin treatment on diabetic retinopathy: ETDRS Report Number 8. Ophthalmology. 1991;98:758.

10.Gonzales ME, Gonzales C, Stern MP, et al. Concordance in diagnosis of diabetic retinopathy by fundus photography between retina specialists and a standardized reading center. Arch Med Res. 1995;26:127–131.

11.Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. ETDRS Report Number 4. Int Ophthalmol Clin. 1987;27:265–272.

12.Browning DJ, McOwen MD, Bowen RM Jr, et al. Comparison of the clinical diagnosis of diabetic macular edema with diagnosis by optical coherence tomography. Ophthalmology. 2004;111:712–715.

13.Browning DJ, Altaweel MM, Bressler NM, et al. Diabetic macular edema: what is focal and what is diffuse? Am J Ophthalmol. 2008;146:649–655.

14.Gangnon RE, Davis MD, Hubbard LD, et al. A severity scale for diabetic macular edema (DME) developed from ETDRS data. IOVS. 2008;49:5041–8.

15.Early Treatment Diabetic Retinopathy Study Research Group. Classification of diabetic retinopathy from fluorescein angiograms: ETDRS Report Number 11. Ophthalmology. 1991;98:807–822.

16.Early Treatment Diabetic Retinopathy Study Research Group. Fluorescein angiographic risk factors for progression of diabetic retinopathy: ETDRS Report Number 13. Ophthalmology. 1991;98:834–840.

17.Kylstra JA, Brown JC, Jaffe GJ, et al. The importance of fluorescein angiography in planning laser treatment of

diabetic macular edema. Ophthalmology. 1999;106:2068– 2073.

18.Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema: ETDRS Report Number 2. Ophthalmology. 1987;94:761–774.

19.Abu El, Asrar AM, Morse PH. Laser photocoagulation control of diabetic macular edema without fluorescein angiography. Br J Ophthalmol. 1991;75:97–99.

20.Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 2007;114:1860–1867.

21.Friberg TR, Gupta A, Yu J, et al. Ultrawide angle fluorescein angiographic imaging: a comparison to conventional digital acquisition systems. Ophthalmic Surg Lasers Imaging. 2008;39:304–311.

22.The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Study Research Group. Effects of intensive therapy on the microvascular complications of type I diabetes mellitus. JAMA 2002;287:2563–2569.

23.UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1988;352:854–865.

24.UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). Br Med J. 1998;317:703–713.

25.Lyons TJ, Jenkins AJ, Zhen D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci. 2004;45:910–918.

26.Kostraba JN, Klein R, Dorman JS, et al. The epidemiology of diabetes complications study. IV. Correlates of diabetic background and proliferative retinopathy. Am J Epidemiol. 1991;133:381–391.

27.Early Treatment Diabetic Retinopathy Study Research Group. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS Report Number 7. Ophthalmology. 1991;98:741–756.

28.Diabetes Control and Complications Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of diabetic retinopathy in the diabetes control and complications trial. Diabetes. 1995;44:968–983.

29.Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions Complications Research Group. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the diabetes control and complications trial. Arch Ophthalmol. 2008;126:1707–1715.

30.Diabetic Retinopathy Clinical Research Network. Comparison of modified-ETDRS and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469–480.

31.Ferris F. Early photocoagulation in patients with type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:505–537.

If one follows the assumption that management of patients with diabetic retinopathy begins with an appropriate history and clinical examination then the purpose of ancillary diagnostic testing should be to add value to evaluation of the patient. Examples of such value may be to provide patient education to gain compliance with treatment recommendations (blood sugar control); to decide when additional intervention is beneficial either at baseline (detection of diabetic macular edema) or follow-up (response of diabetic macular edema to therapy); and to help establish prognosis such that appropriate follow-up schedules can be mutually agreed upon. In a research setting, there are additional purposes for ancillary testing but the emphasis in this chapter is on clinical care of patients with diabetic retinopathy.

6.1Optical Coherence Tomography (OCT)

OCT measurements of macular structure provide both quantifiable measurements and morphologic information which are helpful in diagnosing and managing patients with diabetic macular edema.1 Time domain OCT (Stratus OCT: Carl Zeiss Meditec, Inc., Dublin, CA) was proprietary and first to market. This technique has the ability to acquire images at a rate of 400 axial scans per second with an axial resolution up to 10 mm and transverse

K. Wong (*)

University of South Florida, Sarasota, FL 34242, USA e-mail: iskeye@yahoo.com

resolution up to 6 mm. By identifying the boundaries of the internal limiting membrane and the retinal pigment epithelium Stratus OCT software algorithms allow the calculation of the thickness of the retina at up to 512 points along a linear scan thereby generating a one-dimensional thickness map (see Fig. 6.1). By acquiring thickness measurements in two dimensions a topographical thickness map can be generated with various colors being assigned to numerical measurements (see Fig. 6.2).

Multiple linear scans in two dimensions are required to generate this two-dimensional map. The most commonly utilized software strategies to acquire these multiple linear scans are the ‘‘fast macular thickness’’ acquisition protocol and the ‘‘macular thickness’’ protocol. Both protocols obtain six radial line scans separated by two clock hours and centered on the foveola (see Fig. 6.1 – ‘‘Fundus Image’’).

The fast macular thickness protocol automatically obtains these six radial line scans. Each radial line scan obtains data from 128 axial measurements. At a scan rate of 400 scans per second the fast macular thickness protocol takes 1.92 s. In contrast, in the macular thickness acquisition protocol the operator obtains each of the six radial line scans individually as separate scans. Each line scan is obtained with 512 axial measurements so the lateral resolution of each component line scan is 4 higher than with the fast macular thickness protocol. Each individual scan takes 1.28 s. The potential advantage of this higher lateral resolution is that it gives more data points with which to interpolate thickness measurements. However, the disadvantage of the macular thickness protocol is that the quality of the scan is more reliant on patient fixation. If the center point of each individual line scan is not centered precisely on

the foveal center (as in patients with poorer fixation) then the center point thickness measurement of each of the scans will vary and artifacts may be generated. This feature may lead to greater inter-operator variability and greater inter-visit variability.

Since OCT reliably2 and reproducibly3 measures the thickness of the macula it has found great clinical utility in diabetics in the management of macular edema.4 Variable terminology has been used in reporting quantitative thickness measurements.5 The quantitative measurements most commonly studied from both the fast macular thickness and the macular thickness acquisition protocols are the center point thickness and the central subfield mean thickness (CSMT) (see Fig. 6.2). The center point thickness represents the average thickness value of the center point of each of the six radial line scans. It therefore represents the average of six

measurements. The central subfield mean thickness represents the average thickness value of all of the sampling points within the central 1 mm diameter circle surrounding fixation. With the protocol acquisition scans typically taking a 6.0 mm length scan the central subfield thickness averages the thickness measurements of 512 thickness measurements if using the macular thickness protocol and 128 thickness measurements if using the fast macular thickness protocol. Although there are more data points to average using the macular thickness protocol the central subfield mean thickness does not show significant variation from the fast macular thickness protocol for patients with macular edema.6

The initial normative data were obtained from 73 eyes of 41 volunteers.7 The mean center point thickness was 152 ± 21 mm and the mean central retinal subfield thickness was 174 ± 18 mm. If one

considers 95% of normals to be within two standard deviations above the mean then the upper limit for normals for CSMT would be 174 þ 36 ¼ 210 mm. Using the Stratus OCT in diabetics with minimal or no retinopathy8 the CSMT was 201 ± 22 mm, considerably higher than that reported by Hee et al. with an older OCT version. The CSMT also varied with gender with the mean for men being 209 ± 18 mm and the mean for women being 194 ± 23 mm. Therefore 95% of normals for men would be less than 209 þ 36 ¼ 245 mm whereas 95% of normals for women would be less than 194 þ 46 ¼ 240 mm.

So how does quantitative OCT add value to and for

the patient? Even with the advent of pharmacother- apy9–11 the best evidence directing treatment of dia-

betic macular edema comes from the Early Treatment

Diabetic Retinopathy Study.12,13 Clinically significant macular edema is a subjective diagnosis made by slit lamp biomicroscopy but remains the only indication supported by level 1 evidence by which one should make the decision to treat with photocoagulation. In the ETDRS the presence or absence of ‘‘clinically significant macular edema’’ was determined by reading center grading of stereo fundus photographs. In the DRS and ETDRS the reading center agreed with experienced clinical investigators in the diagnosis of macular edema 55% of the time after correcting for the effects of chance agreement.14

The concordance between diabetic macular edema diagnosed by evaluation of stereo fundus photographs and by evaluation using OCT is moderate at best.15 The concordance between clinically

significant macular edema diagnosed by contact lens biomicroscopy and by evaluation using OCT is good when the edema is definitely present or definitely absent on clinical examination but is poor when the edema is clinically questionable. Brown et al.16 examined the concordance between contact lens biomicroscopy and Stratus OCT in detecting patients with a clinical diagnosis of no edema, questionable edema, and definite edema involving the fovea. The concordance was high for patients without edema or with definite edema but significant disparity occurred in the patients with questionable edema. For patients with questionable foveal edema on contact lens examination over 50% of these patients had a central foveal thickness300 mm. Browning et al.17 found a similar lack of concordance if the diagnosis of CSME was performed using noncontact lens slit lamp biomicroscopy. For this subset of patients where clinical examination and OCT data are discordant, the data regarding natural history and response to therapy are not yet available.18 Therefore, if one accepts that clinical examination with contact lens slit lamp biomicroscopy is the standard way to diagnose clinically significant macular edema then the lack of complete concordance between OCT and slit lamp biomicroscopy implies that the information obtained from OCT should remain as confirmatory.

On the contrary if one accepts that OCT measurements of diabetic macular edema are more accurate than clinical assessments then disparate information would be viewed as one’s clinical examination representing false positives and false negatives and the OCT information as true positives and true negatives. Using OCT as a surrogate measure of contact lens-determined clinically significant macular edema would subsequently imply that a significant number of patients may be undertreated or overtreated in comparison to ETDRS guidelines. Currently there are no studies to compare the relative benefit of treatment for clinically significant macular edema diagnosed by contact lens biomicroscopy vs. OCT measurement of edema.

The recent advent of spectral (Fourier) domain OCT is a new technology which operates on a similar principle to the Stratus OCT but obtains axial scan rates of at least 20,000 scans per second with an axial resolution up to 5 mm. As compared to Stratus

OCT the higher scan rate allows less fixation artifact. In addition this higher scan rate allows greater detail in generating a two-dimensional thickness map. The scans are typically acquired in a raster pattern with many more thickness measurements being acquired. Whereas the macular thickness protocol of the Stratus OCT obtains 6 512 ¼ 3,072 thickness measurements within the macula, the default setting of Topcon spectral domain OCT acquires 128 512 ¼ 65,536 thickness measurements with a central 6 6 mm square. Since the Stratus OCT samples thickness measurements only along the six radial scans at every two clock hours there are gaps of data between these radial lines. The Stratus OCT software allows interpolation of proximal thickness measurement to fill in the gaps. As compared to Stratus OCT the greater number of scans with spectral domain OCT allows for retinal thickness measurements to be calculated based on actual measurements in contrast to interpolation between actual measurements.

The algorithms for measuring retinal thickness may employ different anatomic landmarks and therefore the absolute quantitative measurement numbers may vary between Stratus OCT and spectral domain OCT systems. The Stratus time domain OCT system identifies retinal thickness as the distance between the internal limiting membrane and the junction of the photoreceptor outer segments and inner segments. In contrast the Cirrus spectral domain OCT identifies retinal thickness as the distance between the ILM and the retinal pigment epithelium. On average the quantitative measurements of retinal thickness within the various subfields of the Cirrus spectral domain OCT system are 30–55 mm greater as compared to the Stratus OCT consistent with histopathologic demonstration of the outer segments of photoreceptors measuring 50 mm in length.19 Although the absolute numbers may vary between Stratus and Cirrus OCTs, the increased resolution from these spectral domain OCT systems should not theoretically change the principles of using OCT in management of DME.

Although spectral domain OCTs offer greater resolution the software algorithms for quantifying retinal thickness have not yet reached the acceptance level of Stratus OCT. In the absence of consistent quantitative data of spectral domain OCTs the clinician will have to rely upon comparing

qualitative (morphologic) data on similarly registered scans.

To summarize the additional benefit of quantitative OCT over clinical examination, evaluation of stereo fundus photographs is the research standard by which macular thickening is classified as clinically significant or not clinically significant. Slit lamp biomicroscopy (either contact or noncontact) is an acceptable clinical surrogate for evaluation of stereo fundus photographs. The literature demonstrates a modest correlation between clinical determination of diabetic macular edema and OCT determination of diabetic macular edema with discordant results occurring primarily in cases of questionable clinical edema. Therefore in situations where subjective clinical examination and objective OCT findings are discordant one should make the decision to recommend initial treatment of diabetic macular edema based on clinical examination.

So if one’s decision to treat is still based on clinical examination then when should an OCT be obtained? As compared to stereo photographs OCT is a more sensitive means of detecting change in retinal thickening.20 Therefore in patients with clinically significant macular edema undergoing treatment the quantitative findings from the OCT may be of value to the patient in helping to make retreatment decisions. In all therapies in which a choice of treatments is available, clinicians attempt to categorize patients into ‘‘responders’’ and ‘‘non-responders’’ or ‘‘poor responders.’’ In poor or non-responders decisions to repeat treatment or change treatment may logically improve patient outcome (although this premise has not been demonstrated by clinical trials). Obtaining an OCT at baseline and at time points where retreatment decisions are in question21 may therefore be reasonable. One should realize, however, that the ultimate clinical goal is to provide the best visual outcome and that in patients with diabetic macular edema OCT correlates modestly with vision and changes in OCT in response to therapy correlates only modestly with changes in visual acuity.22

In patients with diabetic macular edema that is not yet clinically significant, obtaining an OCT was not helpful in predicting which patients would progress to clinically significant macular edema.23 However, in those individuals with diabetic macular edema which is not yet clinically significant,

obtaining an OCT may be helpful in confirming the progression to clinically significant macular edema.24 This strategy provides added value to the patient if one believes that earlier diagnosis and treatment of clinically significant macular edema provides a better visual outcome, i.e., if chronic macular edema carries a poorer prognosis as compared to sub-acute macular edema.

Some clinicians believe that patients with proliferative diabetic retinopathy and high-risk characteristics may be at risk for worsening of macular edema in conjunction with scatter photocoagulation.25 In the DRS 14% of patients treated with argon laser and 30% of patients treated with xenon laser suffered 1 line of vision loss at 2 years.26 In the ETDRS, of the patients with baseline macular edema who underwent full-scatter photocoagulation, 4.5% suffered 3 lines of vision loss at 6 weeks and 9.7% suffered 3 lines of vision loss at 4 months.27 The beneficial effect of scatter photocoagulation as outlined in the Diabetic Retinopathy Study is to help reduce the chance of deteriorating to vision <5/200 at two consecutive 4-month visits. However, in the current era patients may not consider their scatter photocoagulation treatment a ‘‘success’’ if their vision drops in conjunction with laser-induced macular edema. OCT documentation of this edema prior to scatter photocoagulation treatment may be helpful to serve as a baseline should visual decline occur and may incline the ophthalmologist to add adjunctive therapy such as intraocular or peribulbar triamcinolone or intraocular anti-VEGF therapy.28,29 The documentation prior to therapy may be helpful in educating patients regarding their risk of suffering moderate visual loss. Should moderate visual loss occur then OCT quantification of macular edema may be helpful to follow the course of edema. Although the time course by which post-laser edema can be expected to improve is not known, if edema does not show improvement on sequential 3-month visits then additional therapy may be logical. Obtaining an OCT adds additional value to the patient by providing quantification of the improvement or lack of improvement of macular edema.

Besides quantitative information, OCT provides morphologic, qualitative information. Subclassifying diabetic macular edema by morphologic OCT patterns has been proposed:

(1)diffuse retinal thickening (see Fig. 6.3).

(2)cystoid macular edema (see Fig. 6.4)

(3)posterior hyaloidal traction (see Fig. 6.5)

(4)subretinal fluid (see Fig. 6.6)

(5)traction retinal detachment (see Fig. 6.7).30–32

Fig. 6.3 Diffuse retinal thickening

There are intuitive reasons why the qualitative information of morphology may aid in altering prognosis or therapeutic approach over and above the quantitative information of retinal thickness measurements. Chronic fluid accumulation may result

in Muller cell necrosis and accumulation of fluid in the extracellular space (presumably the ‘‘cystoid macular edema’’ OCT morphology pattern). The distinction of cystic vs. non-cystic retinal thickening may therefore imply Muller cell necrosis. On a functional basis this concept is supported by data indicating that an increased quantitative macular thickening shows a modest correlation with worse visual acuity.33 Furthermore, with moderate thickening of the macula (< 400 mm) the additional presence of cystoid changes correlates with a greater deficit in visual acuity.34 However, although cystoid morphology may correlate with

initially worse visual acuity it is unclear whether such morphology portends a poorer response to therapy. In the ETDRS the presence of cystoid changes did not eliminate the benefit of focal laser photocoagulation in reducing the risk of moderate visual loss.35

Likewise, the distinction of whether or not diabetic macular edema is caused by mechanical traction may intuitively alter the therapeutic approach. The demonstration of partially detached hyaloid which is exerting tangential traction on the macula in conjunction with subretinal fluid has been proposed as an indication to benefit from surgical