Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

Some others authors have presented the use of antiangiogenic in ROP when laser treatment failed. Rychwalski and Abdala et al report 2 case series, one of 10 eyes with ROP, which in spite of thorough laser photocoagulation, had progression and were treated with antiangiogenic as a rescue therapy (closure of retinal panphotocoagulation in ridge combined with intravitreal bevacizumab). All 10 eyes treated with rescue therapy stopped evolution of the disease.19 A second case series by the same authors, Abdala and Rychwalski, in 14 eyes with severe types of ROP (threshold disease with severe plus disease, or stage 4a or 4b) received rescue therapy as primary treatment, finding involution in over half s eyes treated within four weeks, and the other half after an additional injection of bevacizumab and laser on the ridge for residual disease, concluding this combination therapy might be useful in halting ROP progression for severe cases and delivers promising results.20

Currently, a multicenter trial of intravitreal bevacizumab in ROP that does not respond to laser therapy is being conducted in the United States.

It is important to consider other mediators are also involved in the pathogenesis of ROP, such as insulin-like growth factor 1 (IGF-1). It is a non-oxygen-regulated factor, which is normally supplied by placenta and amniotic fluid in an increased manner through gestation, and drops at low levels after birth in preterm infants. Chen and Smith found that low serum levels of IGF-1 in premature babies directly correlate with the severity of clinical ROP and associated with lack of vascular growth and subsequent proliferation. The authors suggest that restoration of IGF-1 to

normal levels found in utero might prevent the disease by allowing normal vascular development. Clinical trials are actually being planned to restore IGF-1 to levels in utero in premature babies to evaluate if this supplement can prevent or reduce the severity.21

The discovery of the important role of VEGF and IGF-1 in the development of ROP is a step forward in understanding the pathophysiology and opens minds for future therapeutic medical treatment.

References

1.Good Wv et al. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics. 2005 Jul;116(1):15-23.

2.Clark D, Mandal K. Treatment of retinopathy of prematurity. Early Human Development 2008 84, 95-99.

3.Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicentre trial for cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988;106:471-9.

4.Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicentre trial for cryotherapy for retinopathy of prematurity: 15 year outcomes following threshold retinopathy of prematurity. Final results. Arch Ophthalmology 2005;123:311-8.

5.Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicentre trial for cryotherapy for retinopathy of prematurity: 5 1⁄2 year outcome structureandfunction.ArchOphthalmol1999;114:41724.

6.The Early Treatment for Retinopathy of Prematurity: better outcomes, changing strategy. Early Treatment for Retinopathy of Prematurity Cooperative Group. Pediatrics. 2004 Aug,114(2):490-1.

7.Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. Early TreatmentforRetinopathyofPrematurityCooperative Group. Trans Am Ophthalmol Soc. 2004;102:233-48.

8.The photographic screening for retinopathy of prematurity study (photo-ROP). Primary outcomes. Photographic Screening for Retinopathy of Prematurity Cooperative Group. Retina. 2008 Mar;28:S47-54.

9.Connolly BP, McNamara JA, Sharma S, Regillo CD, Tasman W .A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity Ophthalmology. 1998 Sep;105(9):1628-31

10.NagE. YJ, Connolly et al. A comparison of laser photocoagulation with cryotherapy for threshold ROP at 10 years. Ophthalmology 2002; 109:928-935

15.Tennat M, Macnamara JA. Duane ́sClinical Ophthalmology. Treatment of advanced stages of Retinopathy of Prematurity. Volume 6. Chapter 108.

16.O ́Keefe M, Burke J, et al. Diode laser photocoagulation to the vascular retina for progressively advancing retinopathy of prematurity. Br J Ophthalmol. 1995 Nov;79(11):1012-4.

17.Mintz-Hittner HA, Kuffel RR Jr. Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina. 2008 Jun;28(6):831-8.

The Present Realities of

ARMD

Age-relatedmaculardegeneration(AMD)is the leading cause of permanent central visual loss in the United States in patients 60 years of age and older affecting 8 million people throughouttheUnited States.1,2 Throughoutthe world, particularly in economically developing countries, cataract remains the leading cause of legal blindness. The visual morbidity induced by cataract can be reversed with cataract extraction and intraocular lens implantation. In contrast, age-related macular degeneration leads to irreversible visual impairment with progressive diminution of central vision and frequent visits to a retinal specialist, resulting in a significant utilization of health care resources. AMD will become more prevalent in the future as a result of longer life expectancy and the increasing number of elderly people worldwide, particularly the non-exuda-

tive (dry) type, (Figures 1, 2, 4 and 5) which constitutes the majority of cases and which leads to a progressive diminution of central vision. The disease leads to an extensive decline in quality of life and increased need of daily living assistance resulting in a loss of independence in the later years of life of those affected.

Definition and Classification

Age-related macular degeneration can be defined as a progressive, degenerative disease of the retinal pigment epithelium (RPE), Bruch’smembrane andchoriocapillaris (Figure 1C, 2C, 3C) typically affecting individuals 50 years of age and older.3

Clinical diagnosis of AMD is usually made in the presence of soft or exudative drusen (Figures 4 and 8), focal hyperpigmentation of the RPE, RPE and neurosensory

Figure 1: Anatomy and Pathology of Non-Exudative, Geographic (“Dry”) Macular Degeneration. Fundus view

(A) shows an example of non-exudative, geographic atrophic “dry” macular degeneration where atrophy of the retinal pigment epithelium predominates. Notice the clinical signs of drusen (D) which can appear as discrete subretinal bodies, confluent masses or hard glinting lesions, usually yellowish in color. Darker intraretinal pigment (I) may or may not be present. Retinal pigment epithelium atrophy (E) is identified by prominence of the underlying choroidal vessels. From the oblique cross section (B), an area is magnified in (C) to show the direct relationship between clinical ophthalmoscopic fundus view above and its corresponding cellular pathology. Pathology includes subretinal drusen (D) and atrophy of the RPE (E). Compare the disorganized RPE cell layer at (E) on the right to the more normal configuration at (N) on the left. Most importantly, though not clinically visible, there is definite loss of photoreceptors (P) in the area of degeneration (compare with normal photoreceptor layer on the left). Other anatomy: inner limiting membrane (L), choriocapillaris (J) and large choroidal vessels (K). (Art from Jaypee - Highlights Medical Publishers).

Figure 2: Anatomy and Pathology of Non-Exudative, Geographic (“Dry”) Macular Degeneration with Extensive Choroidal Sclerosis. Fundus view (A) shows an example of non-exudative, geographic “dry” macular degeneration with extensive choroidal sclerosis (S). There is a clear demarcation between normal retina and the extensive atrophy of the retinal pigment epithelium, photoreceptors and choriocapillaris of the macular area. The large choroidal vessels (K) can be seen through these degenerated layers. Note surrounding drusen (D). From the oblique cross section (B), an area is magnified in

(C) to show the direct relationship between clinical ophthalmoscopic fundus view above and its corresponding cellular pathology. Pathology includes atrophy of the

of the choriocapillaris (J - note that choriocapillaris is virtually non-existent in this area). The large choroidal vessels (K) which become visible in the fundus view are noted beneath the degenerated layers. (Art from Jaypee - Highlights Medical Publishers).

detachments, RPE atrophy, choroidal neovascularization (Figures 3C, 6C, 7C and 9), geographic atrophy (Figure 5) or disciform scarring of the macula (Figure 11). The latter, however, is the unfortunate, irreversible end result of choroidal neovascularization

AMD can be broadly classified into the non-exudative (dry) and the exudative (wet, neovascular) subtypes. The non-exudative, or dry form of AMD accounts for a vast majority of patients with AMD but is responsible for a significant minority of cases with severe central visual loss (20/200 or worse). The rates of visual loss however, are different between the 2 subtypes. Changes in visual symptoms are dependent on the variety and severity of an individual eye’s involvement. Non-exudative manifestations of AMD such as drusen and RPE alterations are frequently asymptomatic (Figure 4). Larger drusen may lead to mild focal distortion or atrophy, producing central and paracentral scotomas (Figure 8) along with a gradual diminution of central acuity.

Figure 3: Anatomy and Pathology of Exudative, (“Wet”) Macular Degeneration with Extrafoveal Neovascularization. Fundus view (A) shows an example of exudative “wet” macular degeneration with an extrafoveal neovascular membrane (N) and limited subretinal hemorrhage (H) just at the margin of the paramacular retinal vessels surrounding the fovea (F). From the oblique cross section (B), an area is magnified in (C) to show the direct relationship between clinical ophthalmoscopic fundus view above and its corresponding cellular pathology. Pathology reveals that the retina is slightly elevated over a neovascular membrane (N). Note vessels emanating from the choriocapillaris (J), into the neovascular membrane (N) and into the sub-RPE and subretinal spaces, passing through small breaks (T) in the retinal pigment epithelial cell layer (E). There is some atrophy of photoreceptors in this area (P). Subretinal blood (H) is seen to either side of the neovascular membrane. Large choroidal vessels (K). (Art from Jaypee - Highlights Medical Publishers).

Figure 4: ARMD - Geographic, Dry, Non-Exudative Type. Geographic atrophy associated with drusen. Early stages of the disease. (Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

Figure 5: Geographic, Dry, Non-Exudative Type. Geographic atrophy with hyperpigmentation, metaplasia and scarred macula. Later stages of the disease.

(Photo courtesy of Lawrence A. Yannuzzi, M.D., selected from his extensive retinal images collection with the collaboration of Kong-Chan Tang, M.D.)

In contrast, there is rather sudden onset of visual loss in the exudative subtype with central scotomas, and metamorphopsia. Metamorphopsia may give the perception that images are smaller (i.e., micropsia) or larger (macropsia) than they really are. The changes often appear as alterations in straight lines or surfaces, which appear wavy in the involved eye.

Thehallmarkofthediseaseinbothsuptypes is the presence of drusen, metabolic waste products of the retinal pigment epithelium (RPE) which deposit between the RPE and the underlying Bruch’s membrane. Other ophthalmoscopic findings commonly observed in the non-exudative AMD are pigmentary changes, both in the form of hypo and hyperpigmentation of the RPE, degenerative changes of the RPE and geographic atrophy.

In the so-called “wet” or “exudative” form of the disease, new abnormal vessels in the form of fine capillary networks develop

from the choriocapillaris and invade the macula either in the sub-RPE space (type 1 choroidal neovascularization) or through the RPE in the sub-retinal space (type 2 choroidal neovascularization).4 There is escape of fluid from these vessels leading to accumulation of subretinal fluid, hemorrhage and secondary detachment of the RPE, Bruch’s membrane and surrounding macular tissues. Exudation from these new abnormal vessels distorts the normal foveal architecture and can lead to permanent visual loss (Figures 3, 6, 7, 9, 10, 11, 12). Although a minority of patients with age-related macular degeneration manifest the exudative form of the disease, the majority of patients with severe central visual loss (20/200 or worse) from AMD have the exudative form. Clinical manifestations include serous or hemorrhagic detachment of the retinal pigment epithelium or neurosensory retina, presence of subretinal or sub–retinal pigment epithelial hemorrhages, intraretinal edema, lipid deposition, RPE hyperplasia and subretinal fibrosis. The end result of these successive changes is disciform scarring of the macula (Figure 11). Distinguishing exudative AMD from non-exudative AMD is critical as novel therapeutic strategies with intravitreal anti-VEGF therapy have been shown to significantly improve vision in conditions complicated by CNV, especially when performed early in the course of the disease.

Risk Factors

AlthoughAMDisamultifactorialsyndrome with multiple causative factors a variety of risk factors have been well delineated. Age is clearly a significant risk factor for AMD with more than 15 percent of Caucasian women 80 years and older having advanced AMD.5

Figure 6: Anatomy and Pathology of Exudative (“Wet”) Macular Degeneration with Juxtafoveal Neovascularization. Fundus view (A) shows an example of exudative “wet” macular degeneration with a juxtafoveal neovascular membrane (N) and subretinal hemorrhage (H) extending into the foveal vascular zone but not quite to the center (F). From the oblique cross section (B), an area is magnified in (C) to show the direct relationship between clinical ophthalmoscopic fundus view above and its corresponding cellular pathology. Pathology reveals that the retina is slightly elevated over a neovascular membrane

(N). Note vessels emanating from the choriocapillaris (J), into the neovascular membrane (N) and into the sub-RPE and subretinal spaces, passing through small breaks (T) in the retinal pigment epithelial cell layer (E). There is some atrophy of photoreceptors in this area

(P). Subretinal blood (H) is seen to either side of the neovascular membrane. Large choroidal vessels (K).

(Art from Jaypee-Highlights Medical Publishers)

Figure 7: Anatomy and Pathology of Exudative (“Wet”) Macular Degeneration with Direct Subfoveal Neovascularization. Fundus view (A) shows an example of exudative “wet” macular degeneration with direct subfoveal neovascular membrane (N) and subretinal hemorrhage

in (C) to show the direct relationship between clinical ophthalmoscopic fundus view above and its corresponding cellular pathology. Pathology reveals that the retina is moderately elevated (serous detachment) over the neovascular membrane (N). Note vessels emanating from the choriocapillaris (J), into the neovascular membrane (N) and into the sub-RPE and subretinal spaces, passing through small breaks (T) in the retinal pigment epithelial cell layer (E). There is some atrophy of photoreceptors (P) in this area. Subretinal blood (H) is seen to either side of the neovascular membrane. Large choroidal vessels (K). (Art from Jaypee-Highlights Medical Publishers.)

Other associated risk factors include drusen characteristics,visiblelight,diet,cigarettesmoking6, cardiovascular risk factors and genetic predisposition. One study conducted by the Age Related Eye Disease Study group was to describe the association of demographic, behavioral, medical, and non-retinal ocular factors with the incidence of neovascular age-related macular degeneration (AMD) and central geographic atrophy. In this clinic-based prospective cohort study individuals with early or intermediate AMD were included at baseline. After controlling for age, gender, and AREDS treatment group, smoking and BMI were found to be modifiable factors associated with progression to advanced AMD.7 A significant modifiable risk factor was dietary intake of lipid. It was determined that a higher intake of omega-3 long-chain polyunsaturated fatty acid intake was inversely associated with exudative AMD.8 Another case control study determined that patients with exudative AMD were more likely to have hypertension9 and it is prudent to have optimal hypertensive control with AMD patients.

Genetic Factors

Both genetic and environmental factors are implicated in the risk of developing AMD. Studies demonstrating familial aggregation10,11, twin studies12-16, segregation and linkage analysis17, genome-wide scans18,19, and candidate gene studies20 have affirmed the heritability of AMD. One familial aggregation study from the population-based Rotterdam Study found first-degree relatives of patients with late AMD developed AMD at an increased rate at a relatively young age.10 In another familial aggregation study, age-related

maculopathy was significantly higher among first-degree relatives of case probands (23.7%) compared with first-degree relatives of control probands (11.6%).11 In addition relatives of 78 case probands with exudative disease had a significantly higher prevalence of maculopathy (26.9%) compared with relatives of the 72 unaffected control probands (11.6%).11 One twin study compared concordance of age-related macular degeneration in monozygotic and dizygotic twin pairs. The concordance rate of AMD was 100% (25 of 25) in monozygotic and 42% (five of 12) in dizygotic twin pairs.13 In a US based study of 840 twin pairs, 331 had no signs of maculopathy, 241 had early signs, while 162 had intermediate AMD and 106 had advanced AMD.12

In early 2005, three research groups independently reported evidence of a strong association of the Tyr402His polymorphism in the complement H factor (CFH) gene and the development of AMD.21-23 In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4.23 The implication of CFH was described by Hageman and Andersen who reported the presence of complement factors within the basement membrane and drusen that are typically seen in AMD eyes.24,25 Since the identification of CFH, LOC387715/ARMS2/HTRA1, C2, C3, CFBhavebeenidentifiedasAMDsusceptibility genes.26-29 Single nucleotide polymorphisms in these genes are associated with an increased risk for progression of AMD and subsequent visual loss. Future studies will attempt to elucidate how the polymorphism affects CFH function, identify the other genes involved in AMD, and the development of promising genetic therapy which are currently in human trials.