treat any residual ischemia. Despite heroic and often successful retinal reattachment, functional visual results do not always correlate with anatomic appearance. This is most likely multifactorial due to the probable disruption of the nascent neurosensory retinal and retinal pigment epithelial connections, as well as amblyopia. The goal of all treatments is to preserve and restore as much functional and ambulatory vision as possible.

15.4  Classification

While all of these diseases are proliferative retinopathies, a major distinction between them is whether the abnormal NV occurs in fully vascularized retina or immature, partially vascularized eyes. Patients with diabetes, Sickle cell, chronic retinal detachment, RP, and occasionally, IP have initially normal retinal vessels that develop ischemia and subsequent NV. In contrast, those patients with FEVR, ROP, Norrie’s Disease, and occasionally, IP have primarily immature or abnormal retinal vascular development that leads to NV. These latter four diseases typically affect infants, although FEVR can follow a benign or progressive course with its initial significant manifestation (i.e., vitreous hemorrhage or RD) occurring in late childhood or adult years. IP usually has a developmental retinal vascular abnormality associated with it. IP can initially present with normal retinal vessels and then develop capillary dropout in the fovea and/ or periphery [1], and later NV. Pathophysiologically and anatomically, IP can bridge the aforementioned classification between the two groups of peripheral retinal diseases of childhood.

vitreoretinal interface and into the vitreous gel. Activation of the hyalocytes and contraction of the vitreous gel fibrils can cause traction on the NV and its glial framework, which is connected to the retina, and thereby cause traction on the retina. This traction can cause a retinal detachment of various configurations along with vitreous hemorrhage caused by rupture of the neovascular blood vessels.

15.5.2  Natural History and Prognosis

This section will cover only diseases not extensively covered in other chapters. Therefore, in this section, only diabetes, Sickle cell, and incontentia pigmenti will be covered extensively.

15.5  Genetics (table 15.1)

15.5.1  Pathophysiology

All of these diseases develop due to a similar general mechanism. Initially, a vascular insult occurs, which leads to retinal ischemia. This ischemia then generates the production of vascular endothelial growth factor, basic fibroblast growth factor, insulin-like growth factor, and other cytokines, which then cause the development of extraretinal NV. This NV extends into the

15.5.3  Diabetes Mellitus

Significant retinopathy almost never appears in juvenile onset DM before the age 10 years or in the first 3 years of the disease [2–4]. It is from that time on that some degree of significant retinopathy may develop with nearly all juvenile onset patients developing these changes by 20 years after onset of the disease.

The pathophysiology entails the initial loss of pericytes in the retinal capillaries, followed by outpouching (microaneurysm formation) of the vessel wall with closure of the vessels and breakdown of the blood-retinal

barrier [5]. This is followed by increased vascular permeability with the formation of macular edema and proliferation of NV. Traction may then develop on these preretinal vessels that then may cause bleeding into the vitreous as well as retinal detachment.

It is well documented that good blood sugar control [6–8] in Type I DM can decrease the incidence and progression of retinopathy. By decreasing the hemoglobin A1C level by 10% to an average of 7.2%, through the use of intensive insulin therapy or an insulin pump, the incidence of significant retinopathy is decreased by 27% compared to a once-or-twice daily injection of insulin. In addition, the progression of diabetic retinopathy can be reduced by up to 76%. The earlier the implementation of intensive insulin treatment, the more substantial is the effect in reducing and preventing the diabetic retinopathy.

Diabetic retinopathy is divided into two basic categories: nonproliferative and proliferative. The major difference between these two subdivisions is the absence or presence of neovascularization and, of course, all the ramifications involved with that. Each of these two major subdivisions is divided further.

Nonproliferative diabetic retinopathy (NPDR) typically begins with microaneurysms, followed by retinal hemorrhages and hard exudates. Such whitish yellow deposits arise from solid lipid material that precipitates from plasma leakage. They are usually present in the outer and inner plexiform layers. All these changes represent mild NPDR. Disease may then progress to moderate NPDR. This occurs when cotton-wool spots and/ or intraretinal microaneurysms (IRMA) appear. Cottonwool spots represent nerve fiber layer infarcts. An old term is soft exudates, which implied the poorly demarcated margins of these lesions on ophthalmoscopy, but it is not an exudate. Severe NPDR is when one of the following findings is present: marked hemorrhages in all 4 quadrants; venous beading in 2 quadrants; or, moderately severe IRMA in 1 quadrant. Very severe NPDR is present when two of the above findings is present.

Macular edema is a special component of NPDR because it represents the primary reason for visual loss in this group. Blood-retinal barrier breakdown allows fluid leakage and collection within the retina. This can be detected clinically by ophthalmoscopy, fluorescein angiography, or optical coherence tomography. The ETDRS trial defined “clinically significant macular edema” and its treatment parameters.

Proliferative diabetic retinopathy (PDR) represents a grave prognostic development. Its hallmark is the

presence of extra retinal fibrous neovascularization. This neovascularization is not made up of normal vessels, i.e., vessels with intact blood-retinal barriers. Such vessels leak fluid, bleed, scar, produce traction, and ultimately can produce dramatic visual loss including blindness. Usually PDR is preceded by severe NPDR and PDR is subdivided into neovascularization of the optic disc (NVD) or neovascularization elsewhere (NVE). Vascular endothelial growth factor (VEGF) activity is critical to this phase of the disease. Figures 15.1a–d and 15.2a–g demonstrate the phases of this disease.

Once retinopathy, either clinically significant macular edema or proliferative diabetic retinopathy, does develop in these young patients, as is the case with adults, therapeutic options are available. As was shown in the Diabetic Retinopathy Study [9], and the Early Treatment Diabetic Retinopathy Study [10], as well as the Diabetic Retinopathy Vitrectomy Study [11], laser and vitrectomy surgery, if necessary, are beneficial in patients with severe vision-threatening disease. The various nuances defining intervention parameters are contained within these studies.

Screening for diabetic retinopathy is recommended by the American Academy of Pediatrics [12–16]. It is recommended to start with the initial dilated eye exam to check for retinopathy 3–5 years after diagnosis of the disease if the patient is 10 years old or older, with a follow-up examination at least annually. It should also be noted that with patients affected with DM in the prepubertal years, retinopathy occurs after a duration of only 11 years compared with a duration of 15 years in patients with pubertal or postpubertal onset of DM. The reason for additional risk conveyed by the prepubertal years of diabetes is unknown. Also, high blood pressure as well as elevated serum lipids is documented to be associated with a worsening of diabetic retinopathy, as is tightening control in an initially poorly controlled patient [8, 15, 17].

For type I diabetes, NV rarely occurs within 4 years of developing mild nonproliferative diabetic retinopathy (NPDR). NPDR is defined as microaneu­ rysms or retinal hemorrhages less than or equal to the level depicted in ETDRS standard photograph 1. By 10 years after onset of mild NPDR, there was a 20% cumulative probability of development of NV in one longitudinal study of 269 patients with type I diabetes [16].

15.5.4  Sickle Cell Disease

Sickle disease leads to a vasculopathy due to vessel occlusion caused by sickling of the abnormal red blood cells. This sickling is caused by any one of three changes: hypoxia; increased blood osmolarity; or, systemic acidosis. These sickled red blood cells cause retinal vascular occlusion that can produce retinal ischemia particularly in the fovea and retinal periphery. This in turn can cause macular ischemia with a resultant loss of visual function. It may also produce peripheral NV which can bleed into the vitreous and/or cause a tractional or rhegmatogenous retinal detachment potentially leading to blindness.

The types of Sickle diseases that most commonly cause these proliferative retinal changes are (in order of decreasing incidence): Sickle hemoglobin C disease (SC disease); sickle thalassemia (S Thal hemoglobinopathy); and Sickle disease (SS disease) [18–21].

Proliferative disease may develop by age 10 years, but it is more common in the 15–30-year-old age group. The extraocular (systemic) manifestations of

SS disease are the most severe of the three diseases, and they are less severe in SC and S Thal disease.

Retinal change that can be seen with sickle disease is a “salmon patch hemorrhage” which is a round preretinal hemorrhage usually in the retinal mid periphery. “Iridescent spots” represent the spots remaining after reabsorption of the “salmon patch hemorrhage.” These spots glisten and may have a faint indentation in the retina on ophthalmoscopic examination. A “black sunburst” is a pigmented round patch of hyperplastic RPE that is actually located in the neurosensory retina. These spots may evolve from previous hemorrhage or a choroidal occlusion [22–27].

Other changes noted in sickle diseases include the following: increased vascular tortuosity; drop out of fine macular capillaries; choroidal infarcts; central retinal artery occlusion, angioid streaks, and frank preretinal NV. The peripheral NV usually takes the shape of a “sea fan.” This neovascularization can then lead to vitreous hemorrhage and potentially traction and rhegmatogenous retinal detachments. These sea fan areas of NV can sometimes autoinfarct. However, as

Fig. 15.2  (a) Color photo of clinically significant diabetic macular edema (CSDME). (b) Mid-phase FA showing MAs and some mild capillary dropout. (c) Late phase FA with moderate ME leakage. (d) PDR with mild NVD and with multiple cotton wool spots venous beading along the inferotemporal arcade and

CSDME. (e) Early phase of FA showing focal superotemporal ME leakage. (f) Late phase of FA showing more diffuse ME leakage with NVD leakage, capillary dropout, and venous beading with staining of the inferotemporal vein. (g) Time domain optical coherence tomography (OCT) showing ME in this patient

soon as this NV is seen, peripheral laser in the avascular retina is recommended in order to induce prompt regression of this neovascular change and hopefully avert some of the vision-threatening sequelae of this disease.

A fluorescein angiogram demonstrates well the degree of peripheral NV and capillary dropout. If possible to perform this test, it should be done to help guide the treatment of the peripheral avascular retinal area (Figs. 15.3 and 15.4).

Laser is used to ablate the areas of peripheral ischemia. If vitreous hemorrhage or a traction retinal detachment develops, then vitrectomy may be necessary. Scleral buckling is also helpful in certain cases of rhegmatogenous retinal detachment, though ocular ischemia, especially anterior segment ischemia, can occur with scleral

buckling in patients with Sickle disease. This is more common however with an encircling scleral buckle than with a segmental scleral buckling element in these patients. Also in these patients, elevated intraocular pressure, either intraoperatively or postoperatively, can cause optic nerve and macular infarction at well below the threshold intraocular pressure for a nonsickle patient [28–31].

15.5.5  Incontinentia Pigmenti

IP, or Bloch-Sulzberger syndrome, is a bilateral, asymmetric disorder affecting the skin, eyes, brain, and teeth. It is inherited as an X-linked dominant disorder

(lethal in males) although sporadic cases have been reported in males, presumably due to new spontaneous mutations. The gene for the familial form of incontinentia pigmenti (IP2) maps on the distal part of Xq28 [2]. Sporadic cases involve a translocation at Xp11. This disease is not associated with premature birth.

These patients may have eye abnormalities (25–33% with proliferative retinal disorders), central nervous system abnormalities are seen in one-third (cortical blindness,mentalretardation,seizures,andcerebralinfarction),

and abnormalities of the skeleton with abnormal or missing teeth and abnormal hair (alopecia) are present in the majority of these patients [32–34]. Skin lesions include erythematous vesicles linearly arranged on the trunk and/ or extremities that evolve into hypopigmented (whorls) in infancy. Skin biopsies in these patients show dyskeratosis, acanthosis, pigment incontinence, and massive eosinophil infiltration [35] (Fig. 15.5).

The hallmarks of retinal disease in IP classically include peripheral ischemia leading to NV, vitreous

hemorrhage, and traction retinal detachment. These traction retinal detachments may develop into a “closed funnel” retinal detachment configuration with formation of a retrolental mass, which may lead to phthisis bulbi [32, 35, 36]. Other fundus lesions include the following: an irregular or enlarged foveal avascular zone with progressive capillary closure in the neonatal period and beyond; foveal hypoplasia; central retinal artery occlusions; hypopigmented macular lesions and

hypopigmented peripheral fundus lesions; persistence of fetal hyaloidal vasculature; and peripheral and posterior NV [1, 37, 38].

Peripheral retinal cryoablation or laser treatment of the avascular retinal areas is indicated in those patients with peripheral NV. With prompt treatment, blindness may be prevented [35, 39, 40]. Treatment of the avascular peripheral retina causes regression of NV and subsequent tractional retinal detachment and vitreous