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AUTHOR AND EDITOR INFORMATION

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Author: Mi-Kyoung Song, MD, Vitreoretinal Surgeon, Eye Associates of New Mexico

Mi-Kyoung Song is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Retina Specialists, and New Mexico Medical Society

Coauthor(s): Kent W Small, MD, Director/President, Macular and Retinal Disease Center; President, Molecular Insight LLC; Consulting Surgeon, Glendale Eye Medical Group

Editors: Russell P Jayne, MD, Consulting Vitreoretinal Surgeon, The Retina Center at Las Vegas; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles; Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Author and Editor Disclosure

Synonyms and related keywords: X-linked juvenile retinoschisis, XJR, congenital cystic retinal detachment, congenital vascular veils in the vitreous, vitreous veils

INTRODUCTION

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Background

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

Pathophysiology

Using positional cloning, Sauer and associates identified XLRS1, the gene responsible for XJR.1 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. Defective or absent retinoschisin may reduce adhesion of the retinal layers, resulting in the creation of schisis cavities.

Frequency

United States

Prevalence of XJR ranges from 1 in 5,000 to 1 in 25,000.

International

The highest prevalence has been reported in Finland. XJR has also been reported in Indonesian, Chinese, Japanese, Indian, and Portuguese families.

Mortality/Morbidity

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

Race

This condition has been reported in Caucasians, Cherokee Indians, and African Americans.

Sex

Although this disease is seen primarily in males, a homozygous woman from a consanguineous marriage also can be affected. Rarely, there are reports of females with juvenile retinoschisis. The daughters of males with XJR are obligate carriers, whereas the sons are spared. No male-to-male transmission should be seen in families with this disease. In a carrier, there is a 50% chance that the sons will be affected and a 50% chance that the daughters will be carriers. 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 referred when they fail to pass a school vision screening test. XJR often presents in a young boy with slightly decreased vision that cannot be corrected fully by refraction. Early on, it is very easy to miss the diagnosis.


CLINICAL

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History

Typically, the patient presents 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 XJR are hyperopic with astigmatic errors. Strabismus and nystagmus have been associated with XJR. Abnormalities in the angle have been described.
  • Gonioscopy reveals a fine membrane extending from the root of the iris to the Schwalbe line. In recessive XJR, foveal changes are seen in all cases and peripheral retinoschisis in one half of cases. In familial retinoschisis with autosomal inheritance, 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, it can mimic dry age-related macular degeneration.
  • Sinus inversus of the retinal vessels and optic disc dragging have been reported.
  • In peripheral retinoschisis, there are holes in the superficial inner layer, and 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 dendriform vascular changes.
  • In the female carrier state, a subtle wrinkling of the internal limiting membrane may be the only finding.
  • Vitreous veils are a common feature of XJR. They result from a separation of the thin inner wall of a peripheral schisis cavity and the inner wall holes.

Causes

The gene responsible for XJR, 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.


DIFFERENTIALS

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ARMD, Nonexudative
Retinitis Pigmentosa

Other Problems to be Considered

Stargardt disease
Cone dystrophy
Nicotinic acid maculopathy
Cystoid macular edema
Wagner vitreoretinal dystrophy
Norrie disease
Familial exudative vitreoretinopathy (FEV)
Goldmann-Favre dystrophy


WORKUP

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Lab Studies

  • Optical coherence tomography (OCT) provides high-resolution cross-sectional images of the macular region. In individuals with XJR, 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.

Imaging Studies

  • Fluorescein angiography (FA) does not aid in the diagnosis of XJR. However, FA can help differentiate foveal schisis cavity from cystoid macular edema. In XJR, 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 XJR 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.
    • In recessive XJR, 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 XJR, 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- and b-wave amplitudes may both be reduced.
    • 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.
  • DNA sequencing of the XLRS1 gene can be a useful adjunct to diagnosis.
  • 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.

Histologic Findings

XJR 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.

Recently, an analysis of an undiluted sample of intraschisis fluid obtained during surgical repair of a patient with XJR 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.


TREATMENT

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Medical Care

No treatment is available to halt the natural progression of schisis formation. However, the use of topical dorzolamide and oral acetazolamide in reducing cystic spaces and foveal thickness with a concomitant increase in visual acuity has been reported.  Currently, 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. 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. Retinal detachment can be caused 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 XJR should be referred to a vitreoretinal specialist for careful examination and follow-up visit.
  • Family members should be examined to rule out any members who remain undiagnosed.
  • Retinal detachments and vitreous hemorrhages associated with this disease should be managed surgically to preserve vision.
  • The gene associated with XJR has been identified. Genetic counseling should be offered to all patients with XJR as well as to potential carriers and family members.

Diet

No reports on any significance of diet with XJR exist.

Activity

No specific restrictions on activity for patients with XJR exist. However, words of caution should be given to limit activities associated with significant impact to the head.


FOLLOW-UP

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Further Outpatient Care

  • Careful funduscopic examinations should be performed initially at a frequent interval in the first decade. Thereafter, patients can be monitored on an annual basis as long as no new symptoms occur.

Complications

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

Prognosis

  • With prompt identification and management of individuals with XJR, the vision should be preserved adequately.

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.


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Patients with XJR may be unaware of their visual loss until they fail a school vision screening. Family members of individuals with XJR should be screened early with a dilated funduscopic examination to rule out any retinal pathology and to intervene with appropriate surgical management to preserve central vision. Also, it is important to educate the family members and the individual to report any decrease in vision or progressive scotoma that may represent retinal detachment.


MULTIMEDIA

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Media file 1:  Electroretinogram of a patient with juvenile retinoschisis.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Graph

Media file 2:  Fundus photograph of juvenile retinoschisis demonstrating stellate spokelike appearance with microcysts.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo


REFERENCES

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Retinoschisis, Juvenile excerpt

Article Last Updated: Nov 26, 2007