Macular Disease Secondary to Peripheral Retinal Vasculopathy
Maximiliano Gordon
Hugo Quiroz-Mercado
Paul R.V. Chan
Peripheral retinal vascular changes are common findings associated with both local and systemic disease in the pediatric population. These changes can be helpful in differentiating between various disease states resulting from primary ocular conditions well known to the ophthalmologist or systemic disease that requires a careful clinical history and systemic workup in order to determine the etiology.
Peripheral retinal vascular changes may result in significant visual impairment, especially if the macula is involved. Patient age, extension of vascular changes, and duration of disease all contribute to the prognosis. Of major concern, however, is the presence of peripheral retinal ischemia with secondary retinal neovascularization (1). If this is to occur, appropriate management of the patient can preserve and/or improve macular function. Laser treatment is the treatment of choice and should be directed toward the peripheral retina, but at times direct intervention to the macular area may need be considered. Herein we describe the most common diseases associated with peripheral retinal vascular changes, and we focus mainly on those conditions that require laser photocoagulation, cryotherapy, or surgical intervention. Tables 48-1 and 48-2 show a classification for differential diagnosis (1, 2 and 3). Pathologies not included in this classification are the inflammatory diseases associated with vasculitis like Eales’ disease, Behcet’s disease, sarcoidosis, systemic lupus erythematosus, multiple sclerosis, pars planitis, and other less common problems that are described in other chapters.
PATHOPHYSIOLOGY
Peripheral retinal abnormalities such as retinal neovascularization, vascular tortuosity, ectasis, vascular shunts, and aneurysms may damage the inner blood-retina barrier. Damage to the retinal vascular endothelium may involve primary arteries, veins, or capillaries, or any combination of the three. Also, the endothelial alteration may be focal or widespread. Fluorescein angiography has demonstrated that the entire capillary bed may be affected in some cases, whereas in others, the changes may only be limited to capillaries in the midneuroretina, with the inner retinal vessels remaining normal.
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The extracellular space of the retina generally is considered to be relatively small compared with other tissues except for the brain. The outer plexiform layer is the primary interstitial space in the retina. If the retina becomes edematous, it is in this layer that fluid accumulates in the outer plexiform layer. The macular contains only four layers of the retina: the internal limiting membrane, the outer plexiform layer, the outer nuclear layer, and the rods and cones. The absence of Muller cells in the foveal region is also a contributing factor (4). No intermediate layers exist between the internal limiting membrane and the outer plexiform layer in the fovea, which in the macula is oblique (outer plexiform layer of Henle). This is an important factor in understanding the stellate appearance of the cystoid edema in the macula as opposed to the honeycomb appearance of cystoid edema outside the macula (3,5).
According to the severity of the damage in the bloodinner retina barrier, Gass distinguished three categories of macular edema: mild, moderate, and severe (3). If the decompensation is mild, small molecules and proteins escape into the extracellular space, and clear serous exudate may be confined to the inner retinal layers. It is not visible biomicroscopically. In fluorescein angiography, diffuse mild staining of the inner retina is observed. If capillary damage is moderate, deeper plexus of capillaries are affected. Serous fluid accumulates within the inner nuclear and outer plexiform layers. The biomicroscopic picture of cystoid macular edema then can be observed. Swelling of the retina and loss of the foveal depression is caused by the development of large central cysts. On fluorescein angiography, molecules diffuse out of the capillaries, producing a stellate pattern. If endothelial damage is severe, large proteins and lipids escape into the extracellular compartment, and the exudate may be cloudy. The
extravascular protein is transported across the pigment epithelium, choroid, and sclera. Around the outer margin of capillary leakage, the fluid is reabsorbed and small ions that are components of the blood leave behind the lipoprotein in the outer plexiform layer that tend to aggregate frequently in a circinate pattern.
extravascular protein is transported across the pigment epithelium, choroid, and sclera. Around the outer margin of capillary leakage, the fluid is reabsorbed and small ions that are components of the blood leave behind the lipoprotein in the outer plexiform layer that tend to aggregate frequently in a circinate pattern.
 Figure 48-1. Schematic diagram of leakage from retinal aneurysm. Small ions and water are reabsorbed. The large lipoprotein molecules are too large to enter the healthy capillary wall, and they deposit along these vessels, frequently in a circinate pattern. (Adapted from Ferris FL, Patz A. Macular edema, a complication of diabetic retinopathy. Suv Ophthalmol 1984;28(suppl):452-561, with permission.) |
After resolution of the capillary leakage or following photocoagulation, macrophages remove the lipid exudates (3,6) (Fig. 48-1).
In diseases with severe vascular abnormality involving the peripheral retina, chronic gravitation of the subretinal lipid to the macula and inferior periphery may cause widespread deposits of subretinal and outer retinal exudate remote from the vascular abnormality (3,7). Massive lipid residue may cause permanent damage to the retina and pigment epithelium, as well as choroidal neovascularization (8). Early treatment of vascular lesions may prevent permanent visual lost and resolution of lipid deposits in the macula (9).
RETINOPATHY OF PREMATURITY
Retinopathy of prematurity (ROP) is a potentially blinding eye disease (12). It has been suggested that therapeutic oxygen, although important, has been overemphasized as a cause of ROP under contemporary neonatal care practices. Other factors related to very low birth weight are probably quite important, especially in view of current nursery monitoring of oxygen. Birth weight is inversely related to risk of ROP and is at least as good an indicator as is gestational age. With current nursery practices, ROP is truly a disorder of the “smallest and sickest” infants (13).
Classification
The International Classification of ROP (ICROP) and the Cryotherapy for ROP (CRYO-ROP) trials have had a profound impact on the way in which we manage ROP (12).
The CRYO-ROP study provided a classification system for ROP which categorized the disease into zones and stages. Zone I uses the optic nerve as the center of a circle, and the radius is defined as two times the distance between the foveola and the optic nerve. Zone II uses as a radius the distance between the nasal ora serrata in the horizontal meridian and the center of the optic nerve. All of the remaining retina is zone III (14, 15 and 16).
CRYO-ROP also defined plus disease, a descriptive term for six clock hours of dilated and tortuous vessels of the posterior pole. In addition, the anterior segment in plus disease often shows dilated iris vessels (14, 15 and 16).
Preplus disease has been defined as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but shows more arterial tortuosity and more venous dilatation than normal. Over time, these vessels may dilate and become more tortuous, progressing to plus disease (13).
There are five stages of ROP. Stage 1 signifies a narrow white line present at the junction of vascular and avascular retina. Stage 2 is a ridge of activity with thickening of this line. Stage 3 involves the growth of extraretinal fibrovascular proliferation at the ridge. Stage 4 is a partial retinal detachment and is subclassified as 4-A, with the macula attached, and 4-B, with the macula detached. Stage 5 implies a total detachment of the vascularized retina (14, 15 and 16)(Fig. 48-3). Aggressive, posterior ROP is a rapidly progressive, severe form of ROP seen in very low birth weight infants. The fundus appearance is characterized by prominent plus disease and flat neovascularization. It is currently seen most commonly in zone I or posterior zone II (12,14).
Treatment
The CRYO-ROP study determined that treating threshold disease defined as five contiguous or eight cumulative clock hours of stage 3 with plus disease was beneficial over observation. The Early Treatment for ROP (ETROP) study indicated beneficial results for any eye with zone I stage 3, zone I with plus disease, zone II stage 2 or 3 ROP with plus disease. Early treatment showed better visual and structural outcomes in premature infants over a 10-year period (12).
Currently, laser photocoagulation is the treatment of choice for treatment requiring ROP. As better visualization of the retina is possible and technology has advanced, cryotherapy for ROP has fallen out of favor (17).
Anti-vascular endothelial growth factor (anti-VEGF) agents (e.g., bevacizumab) have recently been advocated for the treatment of ROP. Quiroz-Mercado, Martinez-Castellanos et al. reported the use of bevacizumab (Avastin), injected intravitreally for ROP. Thirteen patients (18 eyes) were included in the study. Patients were separated in three different groups: group I included patients with stage IVa or IVb ROP who had no response to conventional treatment (cryotherapy or laser); group II included patients with threshold ROP who could not receive treatment secondary to poor visualization of the retina; and group III included patients with
high-risk prethreshold or threshold ROP. Regression of neovascularization occurred in 17 eyes. One patient with stage IVa ROP had spontaneous retinal reattachment after a single intravitreal injection of bevacizumab. There were no serious ocular or systemic adverse events reported (18).
high-risk prethreshold or threshold ROP. Regression of neovascularization occurred in 17 eyes. One patient with stage IVa ROP had spontaneous retinal reattachment after a single intravitreal injection of bevacizumab. There were no serious ocular or systemic adverse events reported (18).
Although retinal ablation is effective in most cases of treatment requiring ROP, a significant number of these eyes progress to retinal detachment (stages 4A, 4B, and 5) (12). The natural history arm of the CRYO-ROP study showed that a child with 8 sector 4A ROP at their due date (40 weeks PMA) has a high risk of going on to an unfavorable outcome or total retinal detachment (stage 5) (12,19 and 20).
Surgical options for ROP advancing to retinal detachment include scleral buckle (SB), vitrectomy with lensectomy, lens sparing vitrectomy (LSV), and open sky vitrectomy. Although scleral buckling for stage 4B and 5 ROP may provide an anatomic outcome superior to the natural history of the disease, this approach does not provide visual results as rewarding as one would hope because of induced anisometropia and amblyopia. Nor does scleral buckling deal directly with vitreous traction (19).
There are numerous advantages to LSV over SB for tractional stage 4A ROP retinal detachments. First, SB has an anatomic success rate on the order of only 70%. Second, placement of a SB requires an additional procedure to divide the encircling element so that the eye may continue to grow. Third, scleral buckling could produce an induced mean anisometropia of −9.5 diopters, with residual myopia on the order of −5 diopters, even after the encircling element is divided. Fourth, visual acuity results for stage 4A detachments repaired with scleral buckling surgery techniques have been very discouraging.
Although visual acuity has not yet been measured accurately in children with LSV, the potential for very good visual acuity should be high based on the central, steady, and maintained fixation behavior noted to date (19).
Capone and Trese designed a study to assess the efficacy of LSV in tractional 4A ROP retinal detachments in reducing progression to stage 4B or 5 ROP. The study included forty eyes (31 patients) with stage 4A ROP at 38 to 42 weeks postconceptional age. Pars plicata vitrectomy was performed on all patients. An infusion light pipe, vitreous cutter, and membrane peeler cutter (MPC) scissors were used in the surgical technique. At the last follow-up examination, 36 of 40 eyes showed complete retinal reattachment with central steady and maintained fixation. Four eyes progressed to 4B retinal detachments, and in three of those four eyes the retinas were reattached after repeat vitreous surgery. One eye progressed to stage 5 ROP. The 90% anatomic success rate of LSV for 4A ROP reported in the current series is far superior with regard to both anatomic outcome and visual prognosis. Also, it has been suggested that the ideal timing for vitreoretinal intervention is when the vascular activity (dilation and tortuosity) has abated and detachment has just begun (19).
In another series, Sears and Sonnie compared the anatomic outcomes of LSV with those of combined LSV and SB in surgical repair of ROP stage 4 retinal detachment. Twenty-one eyes of 15 patients with stage 4 ROP detachment were included. An SB was placed externally using either a 240 or 41 band after 360-degree conjunctival peritomy and isolation of the four rectus muscles. The SB was secured to the eye wall with 5-0 nylon sutures as close to the ridge as possible and was fastened with a Watzke sleeve. Drainage of subretinal fluid was not performed in any eye. All SBs were removed by six months of age. LSV was performed using two sclerotomies posterior to the iris root (1.5 mm from the limbus) through pars plicata at 9:30 and 2:30. An end irrigating Capone light pick was used in all cases in conjunction with a pediatric wide-angle viewing system and a 23-gauge pediatric MPC. Of the patients in whom treatment failed, two were in the LSV with SB group (2/12; 16%) and one was in the LSV alone group (1/9; 11%). Overall, the study results suggest that SB adds little to the success or failure of LSV and therefore is an unnecessary adjunct for stage 4 (A and B) (21).
Gonzales, Boshra, and Schwartz used 25 gauge pars plicata vitrectomy for stage 4 and 5 ROP. Fifteen eyes of 12 infants were included. Three-port pars plicata vitrectomy using 25-gauge instrumentation was performed. Conjunctival dissection was performed in all cases and sclerotomies were made 0.5 to 1.0 mm posterior to the limbus through the pars plicata. Several vectors of traction must be addressed including those extending from the ridge to the lens, from the ridge to the anterior vitreous base, and from the ridge to the optic nerve. Eleven of 15 (73%) eyes had documented retinal reattachment after one or more surgeries at the last follow-up. Complications included vitreous hemorrhage and postoperative cataract. But they concluded that 25-gauge vitrectomy is a safe and effective treatment approach for tractional retinal detachments in stage 4 and 5 ROP (22). Retinal photocoagulation or cryotherapy may be effective for stabilizing aggressive posterior ROP; however, it very frequently cannot stop the progression to retinal detachment (23).
In an attempt to address this issue, Azuma et al. studied the efficacy of early vitrectomy for aggressive posterior ROP to stop progression of retinal detachment. Twenty-two eyes (15 patients) with aggressive posterior ROP underwent vitrectomy with or without lens sparing, because retinal photocoagulation failed to stop progression of fibrovascular proliferation, despite being performed early, densely, and with early retreatment. Six eyes (100%) in which an LSV was performed developed a large tractional retinal detachment. In contrast, the retinas were completely reattached in 16 eyes (100%) in which vitrectomy with lensectomy was performed, nine eyes (56%) had foveal configuration, and 14 eyes (88%) had steady fixation. These results indicate the great benefit of early surgery for aggressive posterior ROP, in comparison to the poor visual outcomes after vitreous surgery for Stage 5 ROP (23).
FAMILIAL EXUDATIVE VITREORETINOPATHY
In 1969, Criswick and Schepens reported six children with peripheral retinal abnormalities resembling ROP but distinguished by their familial occurrence, and no history of prematurity or supplemental oxygen after birth. Systemic associations were absent (24). They named the disease familial exudative vitreoretinopathy (FEVR).
The clinical findings include heterotopia of the fovea with temporal traction, organized vitreous membranes, peripheral
neovascularization with abrupt termination of the temporal retinal vasculature, retinal exudates, retinal folds and tractional retinal detachment. Anterior chamber structures are uninvolved. Nonetheless, the end stages of severely affected eyes may display chronic retinal detachment with cataract, band keratopathy, and glaucoma (24).
neovascularization with abrupt termination of the temporal retinal vasculature, retinal exudates, retinal folds and tractional retinal detachment. Anterior chamber structures are uninvolved. Nonetheless, the end stages of severely affected eyes may display chronic retinal detachment with cataract, band keratopathy, and glaucoma (24).
FEVR is always bilateral and usually symmetric. Some infants have family members with similar findings, indicating that this is an autosomal dominant condition, with nearly 100% penetrance. Like other autosomal dominant conditions, expression is variable, with some members having only mild macular dragging or small areas of peripheral avascularity of the retina, demonstrable only by fluorescein angiography. X-linked recessive trait, with high penetrance, and variable expressively, and sporadic cases have also been reported (24).
The pathogenesis of FEVR appears to be a consequence of disturbed development of the retinal vasculature in the last months of gestation, with a failure of the peripheral retina to vascularize. Although the ensuing changes bear a similarity to the pathobiology of ROP, they follow a different time course and natural history. A notable difference is the tendency of ROP to progress to cicatricial stages or to abort and vascularize the periphery, whereas the avascular zone in FEVR remains a permanent feature throughout life (24).
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