X-linked recessive retinoschisis is an inherited ocular disorder that occurs in males (1). It is characterized by degeneration of the vitreous and splitting of the retina at the level of the nerve fiber layer. The most common finding involves the macula and consists of a petaloid configuration. Usually there are numerous folds that radiate in a spoke-wheel configuration (Fig. 14.1). This may give the clinical appearance of cystoid macular edema, but the macula does not stain with fluorescein. When seen in a young boy, this sign should alert the observer to the possibility of the peripheral changes seen in X-linked retinoschisis. Peripheral retinoschisis, seen 50% of the time, is more common in the inferotemporal quadrant. The schisis is always bilateral but may be asymmetric. The anterior limit of the retinoschisis seldom extends to the ora serrata, and the posterior limit may extend to the optic disc. Nerve fiber layer breaks are common and appear as large round or oval holes (Fig. 14.2). In some eyes the nerve fiber layer breaks are so large that only remnants of the nerve fiber layer remain. Often, bridging retinal blood vessels are present, and there is hemorrhage into the vitreous. When vitreous hemorrhaging occurs, some patients develop dragging of the retina. Most recently, ocular coherence tomography (OCT) has demonstrated a characteristic finding of a wide hyporeflective space between the thin reflective outer layer and the thicker, more reflective inner retinal layers (Fig. 14.3) (2).

Vitreous veils and strands may also be present. The electroretinogram (ERG) often shows a subnormal b-wave in conjunction with a normal a-wave. Color vision abnormalities parallel the degree of foveal involvement. The results of electrooculogram (EOG) and dark adaptation tests are usually normal. Most commonly, patients are first seen because of decreased vision. The visual acuity on presentation is usually between 20/70 and 20/100 mmHg. This often (but not always) deteriorates up until age 20 years, reaching the 20/200 range. Other presenting symptoms are vitreous hemorrhage, retinal detachment, and strabismus.

The natural history of retinoschisis is that of a stationary or slowly progressive disease. The most important complications are vitreous hemorrhage and retinal detachment. It is important to realize that progression of X-linked retinoschisis may be followed by spontaneous partial regression, and that fluctuations in the appearance of the fundus are common during the first few years of life.

Differential diagnoses include retinal detachment, persistent fetal vasculature (PFV), Goldmann-Favre disease, retinitis pigmentosa (RP), Norrie disease, Stickler’s syndrome, and (because of occasional dragged retinas) retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR).

Retinal detachment in a child may be differentiated from X-linked retinoschisis because the latter is always bilateral. In addition, retinal detachment, unlike X-linked retinoschisis, usually extends to the ora serrata.

In some cases of PFV, extensive hyaloid remnants that are adherent to the disc and inferior retina may contract and cause an inferior retinal detachment, with or without visible retinal breaks. This condition is generally unilateral and associated with microphthalmos, and is neither familial nor hereditary.

Goldmann-Favre vitreoretinal degeneration is transmitted as an autosomal recessive trait. Although peripheral retinoschisis is often present, the disease is also characterized by night blindness and fundus changes resembling those of RP.

Stickler’s syndrome is transmitted as an autosomal dominant trait. Elevation of the retina is attributable to rhegmatogenous retinal detachment rather than retinoschisis. Additional ophthalmologic and systemic features help to distinguish this entity from X-linked retinoschisis.

Although dragging of the retina may occur in ROP and FEVR, the additional fundus features of these two entities are distinct and rarely confused with X-linked retinoschisis. In addition, ROP and FEVR can usually be identified because of a history of prematurity in the case of ROP and autosomal dominant inheritance with respect to FEVR.

As long as X-linked retinoschisis is not accompanied by rhegmatogenous retinal detachment, no treatment is indicated. Recurrent vitreous hemorrhages are usually best treated conservatively, but vitrectomy occasionally becomes necessary because of the presence of organized vitreous membranes leading to retinal detachment.

X-linked retinoschisis has a prevalence ranging from 1:5,000 to 1:25,000. Female carriers of X-linked retinoschisis generally do not show any ocular abnormalities, although peripheral retinal alterations similar to those found in affected males have been reported (3). The X-linked retinoschisis gene (XLRS1) is located on the distal short arm of the × chromosome (Xp22) (4). DNA analysis can reveal evidence of the carrier state and is of use when performing genetic counseling.

Stargardt’s disease is most often an autosomal recessive condition that usually appears between 8 and 14 years of age. It is bilateral, slowly progressive, and sometimes associated with macular degeneration (10). Characteristically, the foveal reflex is absent or grayish in color. Pigmentary spots sometimes develop in the macular area and may accumulate irregularly. Yellowish-white pisciform flecks may be visible in the deep retina or retinal pigment epithelium (RPE) (Fig. 14.7). They are typically seen in the posterior pole but can extend out to the equator. Eventually, in some cases, a circular area of depigmentation and chorioretinal atrophy of the macula follow (Figs. 14.8 and 14.9). In the early stages of the disease, the loss of central vision may be out of proportion to the appearance of the fundus. Fluorescein angiography may reveal abnormalities, particularly a dark fundus (the so-called silent choroid) (11) before any fundus abnormalities become apparent. Fluorescein angiography of the flecks may reveal hypofluorescence, presumably because of blockage. Later, some areas may hyperfluoresce because of damage to the RPE. Sometimes, the entire choroid may show blockage on fluorescein angiography.

The evolution is slow, symmetric, and progressive, and the disease is usually well established by age 30 years, with vision in the 20/200 range. Late in life, large areas of chorioretinal atrophy may develop (12).

The disease was first described by Stargardt in 1909. Fundus flavimaculatus was described independently as a separate entity. Today, however, Stargardt’s disease and fundus flavimaculatus are thought to have a common cause and to represent different parts on the spectrum of a single disease. Stargardt’s disease is caused by a mutation of the ABCR gene located on the short arm of chromosome 1 (13). Other sites have been identified in patients with the autosomal dominant form. The mechanism of photoreceptor death has been postulated (14) with histopathology revealing the accumulation of lipofuscin within the RPE. Stargardt’s disease refers to predominantly macular involvement, and fundus flavimaculatus refers to more peripheral involvement. In fundus flavimaculatus, the vision is near normal unless macular involvement develops.

In 1905, Best reported eight members of one family with an interesting macular dystrophy, now called Best’s vitelliform degeneration (15). The transmission in this disease is autosomal dominant, but there may be variable expressivity. Vitelliform macular degeneration has a distinctive appearance characterized by a sharply defined discoid formation in, or immediately adjacent to, the macula (Fig. 14.10). The disc is usually yellow-orange or pinkish yellow and varies in size from 0.5 to 4 disc diameters. The abnormality is subretinal and resembles the yolk of a poached egg (16). It is usually diagnosed between 5 and 15 years of age and is bilateral, although unilateral cases have been reported. Multiple vitelliform lesions in the same eye have also been described. The condition is very slowly progressive. The vision is usually normal or mildly reduced at this stage. Gradually the homogeneous contents of the vitelliform disc may “scramble,” giving an irregular yellow lesion, eventually leaving abnormal pigmentation and chorioretinal atrophy (Fig. 14.11). The appearance at that point is often indistinguishable from that associated with other types of macular degeneration. Vision loss develops from these atrophic changes or, in some cases, a choroidal neovascular membrane. These macular changes can also be assessed with the OCT (17).

Best’s dystrophy of the macula is present at birth and if no change is visible postnatally, the clinical signs will not develop later.

ERG results are normal, as are the peripheral visual fields. Central scotomata cannot be elicited in eyes with normal visual acuity but are present late in the disease. Dark adaptation is normal. The EOG, however, is always
abnormal in patients with vitelliform macular degeneration, even in those who do not express the disease clinically. Thus, EOG testing is helpful diagnostically and in genetic counseling, because unaffected carriers have a 50% chance of passing the condition to their offspring. Carriers who have a normal ophthalmologic examination will have a subnormal EOG (18).

The pathogenesis of vitelliform degeneration is uncertain. The gene causing Best’s disease has been localized to 11q13 with an identified encoded protein called bestrophin, which has an unknown function (19).

The stationary forms of congenital night blindness are congenital stationary night blindness, Oguchi’s disease, and fundus albipunctatus. These diseases should be considered in the differential diagnosis of early-onset night blindness that is not progressive. All of the former differ from the progressive disorders, such as RP, Goldmann-Favre disease, and gyrate atrophy.