Ординатура / Офтальмология / Английские материалы / Textbook of Vitreoretinal Diseases and Surgery_Natarajan, Hussain_2008

Role of Combination Therapy in Diabetic Macular Edema

FIGURE 6-2: Showing OCT image of diffuse diabetic macular edema with central macular thickness of 660 microns and subfoveal fluid (serous macular detachment). (Courtesy: Dr. Nazimul Hussain, Al Zahra Pvt. Hospital, UAE)

•Diffuse DME is one which measures greater than 300 microns on the OpticalCoherence Tomography (OCT) is at least two disc diameters in size and a significant reduction in the reflectivity of the outer layer; subfoveal fluid collection on optical coherence tomography or both should be present

(Figure 6-2).

International Clinical Classification of Diabetic Retinopathy Severity of Diabetic Macular Edema3

Two major levels, with subcategories for diabetic macular edema

If diabetic macular edema is present, it can be categorized as follows:

Textbook of Vitreoretinal Diseases and Surgery

CSME is purely a clinical diagnosis and hence suffers from subjective variations, depending upon an individual’s experience and expertise in picking up macular thickening.

Role of Fluorescein Angiography in DME

Fluorescein angiography is useful in the treatment of diabetic macular edema. It distinguishes and localizes areas of focal versus diffuse leakage, thereby guiding the placement of laser photocoagulation. The proximity of the leakage to the foveal avascular zone (FAZ) should be noted. Also areas of macular ischaemia in the form of widening of FAZ > 1000 microns, irregularity in the margin of FAZ, capillary budding in the region of FAZ, and intercapillary distance decide whether photocoagulation will help in preventing visual loss (Figure 6-3).

FIGURE 6-3: Fundus Fluorescein Angiography showing macular ischemia (Courtesy: Dr. Nazimul Hussain, Al Zahra Pvt Hospital, UAE)

Use of Optical Coherence Tomography in DME

Fundus fluorescein angiography may give us information about excess leakiness of the macular blood vessels, focal, diffuse or cystoid, but gives no information about macular thickening. Also, a patient after receiving therapy for DME may not improve quantitatively in vision, but there may be a significant decrease in macular edema/thickening. Clinical examination may not pick up this very change, especially if it is within 50 microns.

In contrast to all the above, Optical Coherence Tomography (OCT) is the perfect tool that gives an objective assessment of macular thickening, even prognosticating a change in the same, provided it is greater than 20 microns. However, it is less frequent that changes in thickness on OCT may actually correlate with a corresponding change in visual acuity. Also, OCT suffers from the minor

60 disadvantage of not being able to document macular ischemia.

Role of Combination Therapy in Diabetic Macular Edema

FIGURE 6-4: OCT image showing diffuse retinal thickening with reduced intraretinal reflectivity and expanded areas of lower reflectivity, especially in the outer retinal layers (Courtesy: Dr Nazimul Hussain, Al Zahra Pvt Hospital, UAE)

Having said the above, it is actually the qualitative rather than the quantitative aspects of OCT that deserve highlighting. The various patterns of DME seen on OCT include:4

1.Diffuse retinal thickening (DRT) as increased retinal thickness (defined as greater than 200 microns) with reduced intraretinal reflectivity and expanded areas of lower reflectivity, especially in the outer retinal layers greater than 200 microns in width (Figure 6-4).

2.Cystoid Macular Edema was identified by the localization of intraretinal cystoid-like spaces that appeared as round or oval areas of low reflectivity with highly reflective septae separating the cystoid-like cavities (Figure 6-5).

3.Posterior Hyaloid Traction (PHT) was defined as a highly reflective signal arising from the inner retinal surface and extending towards the optic nerve or peripherally.

4.Tractional retinal detachment (TRD), defined as a peak-shaped detachment of the retina.

5.Subretinal fluid without PHT/TRD was defined as an accumulation of subretinal fluid (which appeared dark) beneath a highly reflective elevation, resembling a dome of the detached retina (see Figure 6-2). The identification of the highly reflective posterior border of detached retina

distinguished subretinal from intraretinal fluid.

Histopathologic studies by Yanoff and associates,5 suggest that the development of macular edema is initiated by fluid accumulation within Mueller cells. In this early state, while fluid accumulates intracellularly within the Mueller cells, it can be reversed. However, if the accumulation continues, or remains chronic, then at some point death of the Mueller cells occurs and may result in the formation of large cystoid cavities, or CME. The cavities are formed following necrosis of the Mueller

cells. As suggested by Yamamoto, these histopathologic findings explain why those eyes with CME 61 may be associated with worse visual outcomes than other subgroups of DME.6

Textbook of Vitreoretinal Diseases and Surgery

FIGURE 6-5: Showing cystoid macular edema in the left eye (Courtesy: Dr Nazimul Hussain, Al Zahra Pvt Hospital, UAE)

The change in central foveal thickness (CFT), which the OCT so importantly highlights, is that of the central fovea only. This CFT may not be indicative of response to therapy if it remains unchanged even though the therapy has worked on reducing the parafoveal thickening. Hence, a change in total macular volume (i.e.macular area x average thickness) is a more sensitive indicator of response to therapy. The raster scans that Fourier domain OCTs are now taking at extremely rapid rates can actually help in performing the above volumetric analysis of the scanned area.

A further refinement while performing thickness or volume analysis is calculating the change in the same after standardizing or adjusting for baseline OCT thickness or volume of normative data where ever available or the patient’s other normal eye. A simple formula to calculate the above is

62 given as:

Role of Combination Therapy in Diabetic Macular Edema

Standardized change in foveal thickness = (Initial thickness – baseline thickness)/(Final Thickness– baseline thickness). The higher the above ratio, the better is the response to therapy.

Laser Therapy

The ETDRS showed that focal/grid photocoagulation reduced the rate of moderate visual acuity loss by 50% in patients with CSME, from 24 to 12%. This means that 12% of the patients with CSME do still undergo moderate visual loss at 3 years. This also means that focal/grid photocoagulation does not aim at improving vision. The ETDRS study showed a visual acuity improvement in only 3% of the cases. Moderate visual loss is defined as a doubling of the visual angle, e.g. from 20/40 to 20/80. Laser treatment of DME should precede panretinal photocoagulation (PRP) by at least 6 weeks because PRP before this has been known to worsen DME. PRP should not be delayed in patients with very severe nonproliferative diabetic retinopathy or high-risk proliferative diabetic retinopathy.2

TREATMENT

Area(s) of leakage can be identified by examination (areas of retinal thickening) and leakage by fluorescein angiography. Laser photocoagulation parameters:

•Burns—100 microns in diameter

•Power—100 mW, or the kind that gives a just visible burn

•Duration—100 ms

•Focal leakage—Treatment of leaking microaneurysms

•Diffuse leakage—Grid pattern photocoagulation

•Important to avoid foveal avascular zone, that is, 500 microns from the centre, 500 microns from the disk margin but can laser the papillomacular bundle

•Argon green, krypton yellow, or 532 frequency upconverted diode-laser to treat focal lesions

•Argon green, krypton red or 532 frequency upconverted diode-laser to treat diffuse lesions

•Focal leaks 300-500 mm from the foveal center causing retinal thickening and hard exudates that

persisted after a first treatment and a visual acuity of less than 20/40 provided that the perifoveal capillary network will not be destroyed can be treated

However, while laser photocoagulation reduced the rate of progression of visual loss, but once visual acuity was reduced, eyes treated with laser were unlikely to improve to 20/40 or better. Also, the degree of visual gain following laser is moderate, and may take months to occur.

Intravitreal Triamcinolone Acetonide

Role of Combination Therapy in Diabetic Macular Edema

processes, including vascular permeability, chemotaxis and inflammation, and mitogenesis.14 In addition to stimulating neovascularization, VEGF serves as a survival factor for existing vessels and for neuronal cells.15 Hypoxia and oxygen-free radicals are known inducers of VEGF expression. This would be rightly so, as VEGF is expressed constitutively at low levels by the retinal pigment epithelium, where it plays a physiologic role by providing trophic support to the neuroretina and choriocapillaris, facilitating the exchange of oxygen and nutrients.14, 16

Considering the key role of VEGF in the pathology and physiology of diabetic retinopathy, a VEGF blockade drug though appearing to be an attractive therapeutic approach in reducing DME as an anti permeability agent, may also turn out to be an anti trophic agent, in which case, caution needs to be exercised in the use of this potential double edged weapon. It is possible to block all VEGF isoforms using bevacizumab or ranibizumab. However, there is evidence to support that selective blockade of the VEGF-165 isoform (pegaptanib sodium) may reduce the VEGF mediated pathologic effect while preserving VEGF mediated normal physiologic functions.17 In contrast, nonselective VEGF blockade has been shown to impair VEGF-mediated normal physiologic functions, causing regression of normal vasculature as well as reduction of VEGF-mediated neuroprotection.14,15

PEGAPTANIB SODIUM

A published randomized, controlled, double-masked phase II multicentre trial evaluated the efficacy and safety of three doses of pegaptanib sodium (Macugen)17 (0.3 mg, 1 mg and 3 mg) versus sham injection in 172 subjects with centre-involving DME. Injections were given on three visits, 6 weeks apart. Additional injections or focal laser photocoagulation were given as needed for another 18 weeks. Final assessments were conducted at week 36. The 0.3 mg dose was found to be most efficacious, with median visual acuity (20/50 versus 20/63 (sham), P=0.04). A larger proportion of those receiving 0.3 mg gained visual acuities of 10 letters or more (two lines) (34% versus 10%, P=0.003). Mean central retinal thickness decreased by 68 mm with 0.3 mg, versus an increase of 4 mm with sham (P=0.02). It is unclear why the 0.3 mg dose was most efficacious. Laser photocoagulation was necessary in fewer patients in each pegaptanib arm. There was one case of endophthalmitis from 652 injections (0.15%), which was not associated with severe visual loss. 17

BEVACIZUMAB

The anti-VEGF agent bevacizumab, approved for the treatment of metastatic colon cancer, appears to show similar efficacy in the treatment of wet age-related macular degeneration to ranibizumab, and its effect on DME is being studied.

Haritoglou et al18 published a prospective, noncomparative case series of 51 patients with diffuse DME treated with 1.25 mg bevacizumab. Follow-up was short (6–12 weeks) and although injections were repeated if there was persistence of macular edema, most received just one injection. There was a significant reduction in macular thickness at 12 weeks (P=0.001) and although mean visual acuity improved significantly at 6 weeks (P=0.02), this was not sustained at 12 weeks, which may reflect the drug’s duration of effect.

Arevalo et al19 reported a multi-center uncontrolled retrospective study of 78 eyes of 63 patients with DME treated with at least one injection of intravitreal bevacizumab of dose 1.25 mg or 2.5 mg. Follow-up ranged from 6 to 9 months. Again, most eyes received just one injection (56 of 78 or 72%

of eyes). In this study, however, there was a statistically significant improvement in BCVA and 65

Role of Combination Therapy in Diabetic Macular Edema

to 257 microns at 7 months) and improved visual acuity (from 28 ETDRS or 20/80 to 40 ETDRS letters or 20/40) in 10 patients with DME. The injections were well tolerated with no reported ocular or systemic adverse events. A phase II randomized control trial (RESOLVE) is underway which should hopefully yield better information (Figure 6-7).

Combination Therapy

It was shown that macular photocoagulation (MPC) resulted in laser scars, which showed tendency to increase with time, and thus decreased the likelihood of vision improvement. For diffuse DME, MPC has even more limited results. Lee and Olk 23 demonstrated that with modified grid MPC, visual acuity was stabilized in 60.9%, decreased in 24.6%, and increased in only 14.5% of eyes with diffuse DME. Therefore, alternative or adjunct treatments for DME such as IVTA and anti–VEGF therapy have been the focus recently.

COMBINATION OF POSTERIOR SUB-TENON TRIAMCINOLONE INJECTIONS AND MACULAR GRID

Theoretically, adverse effects may be presumed to be lower than those of intra-vitreal steroids. A peribulbar corticosteroid injection is of particular interest for eyes with DME that have good visual acuity where the risks of an intravitreal injection of corticosteroid may not be justified.

Diabetic Retinopathy Clinical Research Network studied the safety and efficacy of anterior and posterior sub-tenon injections of triamcinolone either alone or in combination with focal photocoagulation in the treatment of mild diabetic macular edema and found it unlikely to be of substantial benefit.23

COMBINATION OF IVTA AND MACULAR GRID

The advantages of combining both IVTA and macular grid are:

1.Decreased foveal thickness after IVTA may enhance the effects of grid laser photocoagulation. Without IVTA, markedly increased foveal thickness, subfoveal fluid, and retinal opacity due to diffuse DME might interfere with adequate laser delivery to the retinal pigment epithelium (RPE) and photoreceptor layers. However, after IVTA, the decreased foveal thickness and restoration of retinal transparency achieved by the treatment would facilitate the delivery of the laser energy selectively to the photoreceptors and RPE.25

2.The possibility exists that steroids might act beneficially in the process of mature laser scar formation. It has been established that 2 or 3 weeks should elapse for the formation of a mature laser scar, and laser treatment itself frequently induces the aggravation of macular edema or inflammation during this period. The presence of intravitreal steroids might exert certain protective