23.1.1 Clinical Features

Affected males usually present in early childhood when reading difficulties at school are first detected. ^{6 ,​ 7 ,​ 8 ,​ 9 ,​ 10} Occasionally, the diagnosis is made earlier when there is a family history of disease and formal screening examinations are performed. Rarely, it is diagnosed in infancy when a secondary complication leads to poor fixation, white pupillary reflex, or strabismus.

The macular changes in XLJR are characteristic and account for the mild-to-moderate decrease in visual acuity that is apparent in affected children. ^{1 ,​ 2 ,​ 6 ,​ 7 ,​ 8 ,​ 9 ,​ 10} Most commonly, the macula has the so-called stellate or spoke-wheel appearance, with superficial, radiating striae of the fovea (Fig. 23-1a, b). The condition is often best appreciated under red-free viewing conditions, and although it may look like cystoid macular edema, it does not exhibit leakage of dye on fluorescein angiography.

In adult life, it is not unusual for this hallmark foveal change to disappear, leaving only a blunted foveal reflex and underlying retinal pigmentary epithelial changes that can be mistaken for age-related macular degeneration. ¹⁰ Furthermore, even in some young patients, this classic stellate appearance may not be apparent because it is obscured by a superimposed complication, such as macular dragging (Fig. 23-2a, b) or extension of the peripheral schisis cavity into the posterior pole. Once again, alterations in the pigment epithelium of the fovea may be all that is appreciated. Regardless of the appearance, some form or degree of maculopathy should be expected in nearly all affected individuals. ^{1 ,​ 10}

Peripheral retinoschisis is present in about 50 to 70% of eyes. ^{1 ,​ 2 ,​ 10} It is most common in the inferior quadrants, particularly inferotemporally, and is characterized by a gross splitting of the retina at the level of the nerve fiber layer, although occasionally inner retinal layers are included. ¹¹ The peripheral schisis is usually not present at birth but typically develops during a period of 2 to 3 years in early childhood before stabilizing. In general, it is the peripheral schisis that is the source for the major, sight-threatening complications seen in XLJR. ^{12 ,​ 13 ,​ 14 ,​ 15}

Occasionally, bullous elevation of the inner retinal layers can simulate a retinal detachment. Multiple breaks often develop in the thin inner layer, many of which become quite large. Indeed, in some instances, only small remnants of the inner layer remain, a finding referred to in the older literature as vitreous veils. With large inner wall holes, retinal blood vessels may be found coursing through this unsupported diaphanous layer. ^{13 ,​ 15} The nerve fiber layer may then develop breaks (Fig. 23-3). Breaks can also occur in the outer retinal layer or elsewhere in full-thickness retina and lead to rhegmatogenous retinal detachments. ^{12 ,​ 15} Rarely, traction or exudative retinal detachment, macular ectopia with either temporal or nasal dragging, and schisis that progresses into the macula can also be seen and lead to further loss of vision. ^{5 ,​ 14 ,​ 15} Most of these complications are likely to manifest within the first decade of life. ^{6 ,​ 10 ,​ 12 ,​ 14 ,​ 15}

Vitreous hemorrhage is the most common secondary complication and has been reported to occur, to some degree, in up to 40% of affected individuals. ^{2 ,​ 3 ,​ 8 ,​ 10 ,​ 11 ,​ 12 ,​ 13 ,​ 14 ,​ 15} In many cases, it is mild and clears spontaneously or is confined to the schisis cavity and is not of visual significance. However, in some, it can be dense and nonclearing. The source is usually an unsupported retinal blood vessel that tears, but rarely, it can come about from disc or retinal neovascularization. ⁵

Rhegmatogenous retinal detachment is the next most common problem leading to severe vision loss in XLJR, being observed in up to 22% of patients. ^{1 ,​ 2 ,​ 3 ,​ 10 ,​ 12} In some cases, the retinal detachment can be difficult to recognize, as the fluid beneath the outer layer is often shallow. As mentioned earlier, the detachment occurs either because outer wall breaks form in the presence of inner wall breaks or because full-thickness flap tears develop in the peripheral retina outside the schisis cavity. ¹⁵ Rhegmatogenous retinal detachments and their repair may be associated with a relatively high rate of proliferative vitreoretinopathy. ¹⁵

Other associated clinical findings of XLJR include hypermetropia, strabismus, tapetoretina-like sheen, and cataract formation. ⁵ In some cases, the development of cataracts may be related to recurrent vitreous hemorrhage, but cataract has also been observed in children with XLJR who have not bled or undergone any surgical procedures.

23.1.2 Diagnosis

The constellation of macular and peripheral retinal findings usually allows the examiner to arrive readily at the diagnosis of XLJR. Family members should be examined, as finding other affected males will help confirm the diagnosis by demonstrating the X-linked mode of inheritance. Electroretinography (ERG) can also help establish the diagnosis by showing the characteristic decreased b-wave under both scotopic and photopic conditions. ¹⁶ This ERG finding is present in most affected individuals whether or not any peripheral schisis formation is present. Occasional cases have been reported in females, and I had the opportunity to examine two young women with clinically typical XLJS during a visit to Bogota, Colombia.

23.1.3 Differential Diagnosis

The differential diagnostic considerations in XLJR include retinopathy of prematurity (ROP), Goldmann-Favré’s disease, retinitis pigmentosa (RP), and familial exudative vitreoretinopathy (FEVR).

Patients with ROP usually have a gestational age of less than 29 weeks and a birth weight of less than 1,000 g. The disorder affects both male and female infants. Peripheral and posterior pole retinal pigmentation is common, and dragging of the retina is frequent. Peripheral retinoschisis resembling acquired or degenerative retinoschisis may occur, but dehiscences at the level of the nerve fiber layer do not develop in ROP.

Goldmann-Favré’s disease is inherited as an autosomal recessive trait. Foveal schisis is often present and, as in XLJR, fluorescein angiography does not show cystoid leakage. The vitreous is liquefied, and pigmentary changes resembling those of RP are typically apparent (Fig. 23-4). Rhegmatogenous retinal detachments are seen in both conditions. Unlike the ERG in XLJR, the ERG in Goldmann-Favré’s disease shows both a-wave and b-wave involvement and is often flat.

RP is characterized by peripheral retinal pigmentary alterations, disc pallor, attenuated retinal vessels, and an abnormal ERG. X-linked retinoschisis may have associated scattered pigmentation in the retina, but it does not show the classic bone spicule pigmentary changes of RP. The ERG findings also differ between the two conditions. In patients with RP, true cystoid macular edema may develop, and this presentation may cause some diagnostic confusion between the two conditions if the mode of RP inheritance is X-linked. The fluorescein angiogram, however, would show leakage of dye in the fovea with RP if cystoid changes are present. FEVR is discussed later.

23.1.4 Pathogenesis and Genetics

Although the pathogenesis of XLJR is unknown, histopathologic and electrophysiologic data suggest that the clinical manifestations of XLJR result from a diffuse Müller’s cell abnormality. Müller’s cells, for example, are thought to play an important role in the initiation of the b-wave, and so the early and consistent ERG finding of a reduced b-wave lends support to the theory of a primary Mueller’s cell dysfunction. ¹⁶

Recently, linkage studies have localized the retinoschisis gene to the distal short arm of the X chromosome (Xp22.1–p22.3). ^{17 ,​ 18} In contrast to the female carriers of most other X-linked hereditary eye diseases, the female carriers do not usually have any signs or symptoms of the condition. With current genetic technology, it is now possible to help confirm carriers and affected members of families suspected of having or being at risk for the disease through analysis of peripheral blood samples with DNA probes. ^{19 ,​ 20}

23.1.5 Management and Course

Observation of XLJR is the primary course of management. Most patients have mild-to-moderate visual loss that remains stable or exhibits only minimal progression until late adulthood. Beyond the sixth decade of life, some further deterioration of central vision may occur. ¹⁰

When the disease is first diagnosed, family screening and genetic counseling are in order. Any refractive error, amblyopia, or strabismus needs to be addressed to maximize visual function. Close follow-up, particularly during the first decade of life, is needed for early detection and prompt management of secondary complications. There are no effective prophylactic techniques; attempts to flatten peripheral retinoschisis with photocoagulation resulted in a high incidence of complications. ²¹

Surgery is indicated for rhegmatogenous retinal detachment or visually significant vitreous hemorrhage. ^{12 ,​ 15 ,​ 22 ,​ 23} In some retinal detachment cases, scleral buckling alone may suffice, but because the detachments may be associated with hemorrhage or proliferative vitreoretinopathy, relatively advanced vitrectomy techniques may be necessary. ^{15 ,​ 23 ,​ 24} Intraoperatively, unsupported retinal vessels should be cauterized and divided to prevent postoperative bleeding. Furthermore, with the cortical vitreous typically firmly adherent to nerve fiber layer remnants, a so-called inner layer retinectomy may need to be performed to relieve vitreoretinal traction adequately and achieve retinal reattachment; excising the separated nerve fiber layer of the peripheral schisis cavity has not been found to have significant adverse consequences. ^{13 ,​ 23 ,​ 24}

23.2.1 Clinical Features

The clinical features of FEVR vary considerably among affected individuals, even those of the same pedigree. ^{26 ,​ 28 ,​ 29 ,​ 31 ,​ 32} Furthermore, although the condition is bilateral, it can be very asymmetric and so symptoms that do manifest can be unilateral at presentation. A majority of affected individuals are asymptomatic through most or all of their lives and, therefore, maintain good visual acuity (Fig. 23-5). ³² In these patients, the condition is diagnosed incidentally on routine examinations or through screening examinations after a family member presents with the disease. Symptoms of decreased vision, indicative of significant disease progression or secondary complications, can occur at any age, and when they come about early in life, the presenting features may be poor fixation, strabismus, or a white pupillary reflex.

The hallmark of the disease is the avascular peripheral retina (Fig. 23-6). ^{27 ,​ 32} This is an early and consistent finding. The zone of avascularity is variable in size but usually most prominent temporally and often present for 360 degrees. This finding, along with some subtle, associated nonproliferative vascular changes such as peripheral vascular sheathing, dilation, and shunt formation, represents the mildest form of disease which is typically asymptomatic. ³² It can be very subtle, and its detection is often facilitated by viewing with red-free light, or it may manifest as nonperfusion on fluorescein angiography or angioscopy. Of note is that in FEVR, but not in ROP, the peripheral zone of avascular retina is permanent; it never vascularizes with time. ²⁹

Progression is characterized by the development of varying degrees of peripheral fibrovascular proliferation or neovascularization and related complications. ^{26 ,​ 28 ,​ 29 ,​ 31 ,​ 32} The neovascularization occurs at the border of perfused and nonperfused retina. It, in turn, can lead to retinal detachment, macular dragging, and vitreous hemorrhage. The sometimes prominent intraretinal and subretinal lipid exudative response that was recognized in the earliest reports is the reason for the name used for the condition. Exudation may become so extensive as to detach the entire retina, a presentation that resembles advanced Coats’ disease. Traction retinal detachments are relatively common and vary from localized, peripheral detachments that may be asymptomatic to large detachments that involve the macula. ^{32 ,​ 33 ,​ 34} The vitreoretinal traction forces can also cause full-thickness retinal breaks and lead to combined traction-rhegmatogenous detachments. In general, nonrhegmatogenous detachments (traction or exudative) tend to be more common in younger patients, whereas rhegmatogenous detachments are seen more frequently in older patients. ³⁴ Tangentially directed traction can either drag the macula or cause a falciform fold that involves the macula.(Fig. 23-7) ^{29 ,​ 32} Vitreous hemorrhage is a surprisingly rare finding in FEVR, but does occur.

Neovascular glaucoma, cataract formation, and band keratopathy may also occur in FEVR. They are seen mainly in very severely affected eyes and probably represent the end-stage sequelae of long-standing, total retinal detachment. ²⁹ There is otherwise nothing intrinsically abnormal with the anterior segment in FEVR.