Juvenile Retinoschisis


Background

In 1898, Haas first described X-linked juvenile retinoschisis (XLRS). This condition is also known as congenital retinoschisis, vitreous veils, congenital vascular veils in the vitreous, and congenital cystic retinal detachment; however, Jaeger introduced the term retinoschisis in 1953.

An example of juvenile retinoschisis is shown in the image below.

Fundus photograph of juvenile retinoschisis demonsFundus photograph of juvenile retinoschisis demonstrating stellate spokelike appearance with microcysts.

Pathophysiology

Using positional cloning, Sauer and associates identified XLRS1, the gene responsible for X-linked juvenile retinoschisis. [1XLRS1 is located on band Xp22.2. XLRS1 encodes a 224 amino acid protein retinoschisin that is expressed in photoreceptor and bipolar cells. Retinoschisin is a secreted protein that is involved in cellular adhesion and cell-cell interactions within the inner nuclear layer as well as synaptic connection between photoreceptors and bipolar cells. Defective or absent retinoschisin may reduce adhesion of the retinal layers, resulting in the creation of schisis cavities.

Epidemiology

Frequency

United States

Prevalence of X-linked juvenile retinoschisis ranges from 1 case per 5,000 population to 1 case per 25,000 population.

International

The highest prevalence has been reported in Finland. X-linked juvenile retinoschisis has also been reported in Indonesian, Chinese, Japanese, Indian, and Portuguese families.

Mortality/Morbidity

Early in life, the central vision usually is mildly impaired because of a cyst in the fovea. Later, the central vision can become impaired more markedly, resulting in symptoms similar to those of macular degeneration. More seriously, retinal detachments can occur when holes in the inner and outer retinal layers are present. The incidence rate is 5-22% of individuals affected. X-linked juvenile retinoschisis is the most common cause of vitreous hemorrhage in young boys. [2Other complications include neovascular glaucoma, vitreoretinal traction with secondary macular dragging, and secondary optic atrophy.

Race

This condition has been reported in whites, Cherokee Indians, and blacks.

Sex

Although this disease is primarily seen in males, a homozygous woman from a consanguineous marriage can also be affected. The daughters of males with X-linked juvenile retinoschisis are obligate carriers, whereas the sons are spared. No male-to-male transmission should be seen in families with this disease. Male offspring of two carriers have a 50% chance of being affected; female offspring have a 50% chance of being a carrier. Some cases can seem sporadic because other males in the family may be affected so mildly that they have never been diagnosed.

Age

Patients have been diagnosed as early as age 3 months; however, most patients are seen at 5 years or older. They are typically referred when they fail to pass a school vision screening test. X-linked juvenile retinoschisis often presents in a young boy with slightly decreased vision that cannot be corrected fully by refraction. Diagnosis is easily missed during early onset. 

Prognosis

With prompt identification and management of individuals with X-linked juvenile retinoschisis, the vision should be adequately preserved.

Patient Education

Educating the patient and the family members on the symptoms of vitreous hemorrhage and retinal detachment can result in prompt detection and management of these events that can threaten central vision.

Genetic counseling has become an important conversation for these patients and their family members. 


History

Typically, patients with X-linked juvenile retinoschisis (XLRS) present with mild and gradual decreasing central vision that may be unnoticeable to the patient. Occasionally, the patient presents with a peripheral visual field defect secondary to a large schisis cavity or retinal detachment. Rarely, a patient may present with strabismus or severe vision loss secondary to a vitreous hemorrhage. 

Physical

The visual acuity ranges from 20/20 to less than 20/200. The average visual acuity in young adults is around 20/70. Most patients with X-linked juvenile retinoschisis are hyperopic with astigmatic errors. Strabismus and nystagmus have been associated with X-linked juvenile retinoschisis when it significantly affects vision at a young age.

Abnormalities in the anterior chamber angle have also been described. Gonioscopy reveals a fine membrane extending from the root of the iris to the Schwalbe line. In recessive X-linked juvenile retinoschisis, foveal changes are seen in all cases and peripheral retinoschisis in one half of cases. In familial retinoschisis with autosomal inheritance (not X-linked), peripheral retinoschisis is seen in all cases and foveal changes in about one half of cases.

Maculopathy is characterized by stellate spokelike appearance with microcysts. Pigmentary changes in the retinal pigment epithelium occur, and, in the later stages, can mimic dry age-related macular degeneration. Situs inversus of the retinal vessels and optic disc dragging have been reported.

Vitreous veils are a common feature of X-linked juvenile retinoschisis. They result from a separation of the thin inner wall of a peripheral schisis cavity and the inner wall holes.

Peripheral retinoschisis often presents bilaterally and inferotemporally. In infancy, it is a large and bullous retinoschisis, which regresses, leaving behind a pigmented line in adults. [3]

In peripheral retinoschisis, holes are present in the superficial inner layer. Bridging vessels from the inner layer to the outer layer can be an associated finding. Traction on these vessels can lead to vitreous hemorrhages.

Other findings in the peripheral retina include silver-gray spots and dendritiform vascular changes.

In the female carrier state, a subtle wrinkling of the internal limiting membrane may be the only finding.

Causes

The gene responsible for X-linked juvenile retinoschisis, XLRS1, is located on band Xp22. XLRS1 encodes a 224 amino acid protein retinoschisin that is expressed in photoreceptor and bipolar cells. Retinoschisin is a secreted protein that is involved in cellular adhesion and cell-cell interactions within the inner nuclear layer as well as synaptic connection between photoreceptors and bipolar cells. 

Complications

Complications that can affect the visual acuity are vitreous hemorrhages, retinal detachments, and retinal atrophy.


Differential Diagnoses


Imaging Studies

Red-free illumination fundus examination and photography can help reveal subtle foveal schisis that may be difficult to visualize with ophthalmoscopy. [3]

Optical coherence tomography (OCT) provides high-resolution cross-sectional images of the macular region. In individuals with X-linked juvenile retinoschisis (XLRS), OCT reveals cystic spaces primarily in the inner nuclear and outer plexiform layers of the retina.

OCT can be useful in differentiating retinoschisis from retinal detachment. OCT may be limited by reflectivity from dense hemorrhage, which may interfere with the visualization of the retina. The view of the periphery using OCT is somewhat limited. However, wide-field spectral-domain OCT (SD-OCT) imaging may augment the ability to capture peripheral schisis.

Fluorescein angiography (FA) does not aid in the diagnosis of X-linked juvenile retinoschisis. However, FA can help differentiate foveal schisis cavity from cystoid macular edema. In X-linked juvenile retinoschisis, the angiographic results are normal, whereas in cystoid macular edema, late hyperfluorescence in a petaloid pattern is seen. Peripheral areas of nonperfusion can also be seen.

Indocyanine green (ICG) angiography performed on patients with X-linked juvenile retinoschisis shows a distinct hyperfluorescence in the macular region that is associated with radial lines of hypofluorescence centered on the foveola in the early phase. This feature disappears in the late phase of the ICG angiography. 

Other Tests

Electroretinogram (ERG) can be used as a diagnostic tool (see image below).

Electroretinogram of a patient with juvenile retinElectroretinogram of a patient with juvenile retinoschisis.

In recessive X-linked juvenile retinoschisis, ERG findings show negative-shaped responses (eg, normal a-wave, reduced b-wave). Normally, the b-wave has a greater amplitude than the a-wave. In recessive X-linked juvenile retinoschisis, the b-wave amplitude does not rise up to the level where the a-wave began. With age and increasing atrophy of the retinal pigment epithelium, a-wave and b-wave amplitudes may both be reduced. However, a negative ERG is not unique to XLRS; it is seen in several acquired retinal disorders. [3]

ERG dysfunction is found throughout the retina and is not limited to schitic areas. Therefore, both focal and macular ERG and full-field ERG yield similar results.

The electro-oculography findings are normal in young patients, and it is not a useful tool in the late stages as the light peak-to-dark trough ratio deteriorates. The visual-evoked response exhibits delayed peak times consistent with abnormal macular function.

DNA sequencing of the XLRS1 gene can be a useful to confirm the diagnosis.

The mutation in RS1 can be detected in 90%-95% of patients who have a clinical diagnosis. It not only helps confirm the diagnosis but also provides useful information for genetic counseling of the patient and offspring. Females who are at risk of being carriers of the mutation may also be offered genetic testing and counseling. [3 

Histologic Findings

 X-linked juvenile retinoschisis results from splitting of the inner retina, primarily within the nerve fiber layer in the fovea and in the periphery. Splitting may also occur within the ganglion cell layer or the internal limiting membrane. A filamentous, extracellular material with features consistent with a Muller cell origin has been described within the retina.

 An analysis of an undiluted sample of intraschisis fluid obtained during surgical repair of a patient with X-linked juvenile retinoschisis revealed the presence of two proteins. They were tenascin-C, an extracellular matrix protein involved in wound healing, and cystatin C, an ubiquitous cysteine protease inhibitor implicated in inflammation. 



Medical Care

No treatment is available to halt the natural progression of schisis formation in patients with X-linked juvenile retinoschisis (XLRS). However, the use of topical dorzolamide [4and oral acetazolamide in reducing cystic spaces and foveal thickness with a concomitant increase in visual acuity has been reported. New, nonviral vectors for ocular gene therapy have potential implications for treatment of XLRS. Current gene therapy research on an Rs1h-deficient mouse model of human retinoschisis has shown restoration of expression of retinoschisin protein in photoreceptors and normal ERG configuration. While gene therapy for XLRS has not been trialed yet, recent phase I/II clinical trials for autosomal-recessive Leber congenital amaurosis type 2 has been proven safe and restores some vision. [5Therefore, gene therapy may be a viable therapeutic option in the future.

Treatment of peripheral schisis cavities is generally not indicated because they can typically regress. Laser photocoagulation has been performed to flatten peripheral schisis cavities and to reduce the risk of retinal detachment; however, in many cases, it resulted in retinal detachment. Because of the nonprogressive nature of congenital retinoschisis, prophylactic photocoagulation may not be warranted. Surgical attempts to flatten peripheral schisis cavities in the absence of retinal detachment have not been shown to be beneficial. Therefore, a conservative approach is advocated.

Amblyopia prevention therapy is indicated in cases of hypermetropia or severe retinoschisis or following surgical intervention for vitreous hemorrhage or retinal detachment.

Surgical Care

Surgery can be performed for the management of vision threatening vitreous hemorrhage and retinal detachment.

Most patients who develop vitreous or intraschisis hemorrhage do not require treatment. Surgery is indicated if the hemorrhage is dense or if a blood-filled schisis cavity overhangs the macula. Cauterization of the bleeding vessels may be performed at the time of a vitrectomy.

Three types of retinal detachments are associated with congenital retinoschisis. Retinal detachment can be caused by a break in both the inner layer and the outer layer of the retinoschisis or by a full thickness retinal hole outside of the schisis cavity. The third type of retinal detachment involves a traction detachment via fibrovascular tissue.

Retinal detachment repair in congenital retinoschisis can be technically difficult. To repair a retinal detachment associated with a schisis cavity, care must be taken to remove as much of the vitreous attached to the schisis cavity as possible to relieve any tangential traction. Then, a retinotomy site can be made on the schisis cavity overlying the break in the outer retinal layer such that the schisis cavity and the outer retina can be flattened. An inner wall retinectomy is recommended when the cortical vitreous or preretinal fibrosis is densely adherent. Relief of vitreoretinal traction is believed to prevent the rebleeding of unsupported vessels. Internal tamponade can be achieved with a long-acting gas or with silicone oil. Silicone oil can be removed in a few weeks.

Consultations

Patients with X-linked juvenile retinoschisis should be referred to a vitreoretinal specialist for careful examination and follow-up visit. Family members should be examined to determine if any members remain undiagnosed.

Retinal detachments and vitreous hemorrhages associated with this disease should be managed surgically to preserve vision. The gene associated with X-linked juvenile retinoschisis has been identified. Genetic counseling should be offered to all patients with X-linked juvenile retinoschisis as well as to potential carriers and family members.

Diet

No reports on any significance of diet with X-linked juvenile retinoschisis have been noted.

Activity

Patients with XLRS are cautioned to avoid contact sports and activities that involve impacts.

Long-Term Monitoring

The course of the XLRS necessitates long-term monitoring of the patient. In childhood, the patient should be monitored frequently, as the disease often progresses at a young age. From the teenaged years to middle age, the disease typically stabilizes, during which time annual dilated funduscopy exams are sufficient. Older patients are once again at an increased risk of progression, vitreous hemorrhage, and retinal detachment. Closer monitoring and/or intervention is indicated in these patients. 

Further Outpatient Care

Careful funduscopic examinations should be performed initially in patients with X-linked juvenile retinoschisis (XLRS) at a frequent interval in the first decade. Thereafter, patients can be monitored on an annual basis as long as no new symptoms occur.

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