Juvenile Retinoschisis

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Practice Essentials

Retinoschisis is a condition described as the splitting of the retinal layers - which results in compromised vision in the area affected. There are 2 major causes of juvenile retinoschisis: one is Juvenile X-linked Retinoschisis and the second results from abusive head trauma (AHT).[1] X-linked retinoschisis occurs almost exclusively in males given its X-linked hereditary pattern and is associated with impaired vision, which begins at a young age. Below is an example of fundus photography in juvenile retinoschisis.



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

 

Background

In 1898, Haas first described what is now known as X-linked juvenile retinoschisis (juvenile XLRS) in a paper entitled 'Ueber das Zusammenvorkommen von Veränderungen der Retina und Choroidea.'[2]  Following Haas' initial characterization of XLRS, Pagenstecher published a pedigree in 1913 showing the X-linked inheritance pattern of the disease.[3]  Multiple different names became descriptors of the disease, based on the variable clinical presentations seen, such as "neuroretinal disease in males", "congenital vascular veils", "congenital cystic retinal detachment", and "anterior retinal dialysis", ultimately leading to the term "X-linked retinoschisis" coined by Jager in 1953.[4, 5, 6, 7]

Pathophysiology

Using positional cloning, Sauer and associates identified XLRS1, the gene responsible for X-linked juvenile retinoschisis.[8]  XLRS1 is located on band Xp22.2. XLRS1 encodes a 224 amino acid protein called retinoschisin, which is expressed in photoreceptor and bipolar cells. Retinoschisin is a secreted protein found throughout the retina and is involved in intercellular adhesion, retinal cellular organization, 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

X-Linked juvenile retinoschisis (juvenile XLRS) is a relatively rare inherited retinal disease. Prevalence of juvenile XLRS ranges from 1 case per 5,000 population to 1 case per 30,000 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.[9] Other 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 also can 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 2 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. Infants can present with nystagmus, strabismus, or amblyopia, whereas school-aged children typically present when they complain of poor vision in class or with activities, or after 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

Visual deterioration usually presents during the first decade of life, with visual acuity ranging from 20/60 to 20/120 at presentation. Often, visual acuity will deteriorate during the first 2 decades of life, but will stabilize throughout adulthood. Usually during fifth and sixth decades of life significant decline in visual acuity can transpire, which can lead to legal blindness in later decades (typically in a man's seventies or eighties). Complications may develop, including retinal detachment or vitreous hemorrhages, which can further impair visual acuity. Though there is no cure for juvenile XLRS, identification of individuals with the disease can lead to medical management, and visual acuity should be adequately preserved.

Patient Education

Any change in vision in children, including complaints of blurriness or decreased central or peripheral vision, should prompt evaluation by an eye specialist. Educating patients and family members on the symptoms of serious complications such as vitreous hemorrhage and retinal detachment in patients diagnosed with juvenile XLRS can result in prompt detection and management of these events, as without quick intervention these can lead to irreversible blindness. Patients should be educated to avoid trauma to the head and avoid high impact sports due to the increased risk of retinal detachment.

Genetic counseling is 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. Infantile patients can present with nystagmus or amblyopia, whereas school-aged children typically present when they complain of poor vision in class or with activities, or after they fail to pass a school vision screening test. Rarely, a patient may present with strabismus or severe vision loss secondary to a vitreous hemorrhage. Family history of XLRS or any childhood ocular disease with X-linked inheritance should be further evaluated.

Causes

The major causes of retinoschisis are genetic, degenerative, and secondary to traumatic brain injury. 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. 

Physical Examination

The clinical diagnosis of XLRS is made by an eye doctor, either an optometrist or ophthalmologist, based on clinical history, slit lamp examination, indirect biomicroscopy, and ancillary testing including electroretinography, optical coherence tomography, and multimodal imaging. There is variation among severity of disease, even in those with the same genetic mutation.

Presenting visual acuity ranges from 20/20 to less than 20/200, and can later progress to legal blindness. 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.[10]

Abnormalities in the anterior chamber angle have 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.[11]

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.

On funduscopic examination, 98-100% of patients have foveal schisis.[12] 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.

Complications

Most serious complications that can affect the visual acuity are vitreous hemorrhages, retinal detachments, and retinal atrophy. Neovascular glaucoma has been reported as well following vitreous hemorrhage or retinal detachment.[13, 14]

Imaging Studies

Red-free illumination fundus examination and photography can help reveal subtle foveal schisis that may be difficult to visualize with ophthalmoscopy.[11] Fundus photography may also help in childhood examinations.

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. Through OCT, retinal layer splitting can be seen, even if not clinically observed.[11] However, with increasing age, the cysts flatten and thus may not be as evident on OCT.[15, 16]

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).



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Electroretinogram of a patient with juvenile retinoschisis.

Full-field ERG is used to assess function of the nerve tissues in the retina. After the eye is stimulated with light after dark or light adaptation, contact lenses (with an embedded electrode which is used to measure electrical imupulses created by the functioning retina) are worn. Reaction of the eye to the different light stimuli is recorded. This documents photoreceptor activity and overall function of all cell types in the inner and outer layers of the retina.[15, 17, 18]

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. A negative ERG or electronegative waveform is when the b-wave is smaller than a normal or mildly reduced a-wave. This indicates post-phototransduction dysfunction and is seen in recessive X-linked juvenile retinoschisis. With age and increasing atrophy of the retinal pigment epithelium, a-wave and b-wave amplitudes both may be reduced. However, a negative ERG is not unique to XLRS; it is seen in several acquired retinal disorders.[11, 19]

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 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.[11, 20]

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 2 proteins. They were tenascin-C, an extracellular matrix protein involved in wound healing, and cystatin C, an ubiquitous cysteine protease inhibitor implicated in inflammation. 

Approach Considerations

In most patients, XLRS has a slow deteriation, with stabilization of vision until the fifth or sixth deades of life. Given this window, future treatments should aim to target the disease in the first 3 to 4 decades of life.

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 carbonic anhydrase inhibitors, such as topical dorzolamide[21] and oral acetazolamide, have been reported to reduce cystic spaces and foveal thickness with a concomitant increase in visual acuity.[22]  Though Vitamin A may have benefits in some genetic retinal diseases, it hasn't shown improvement in retinoschisis.

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 restored b-wave function, thus a normal ERG configuration. The National Eye Institute Phase I/II Retinal AAV8-RS1 gene therapy study is evaluating the safety and tolerability of a gene transfer vector in humans.[23, 24]

Treatment of peripheral schisis cavities generally is not indicated because they typically can regress. Laser photocoagulation has been performed to flatten peripheral schisis cavities and to reduce the risk for 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.[25]  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 complications including 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.

Low vision aids and devices, as well as referral to low vision centers, may be helpful in patients with declining vision.

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.

Prevention

Given the X-linked hereditary pattern of the disease, juvenile XLRS cannot be prevented, but with early diagnosis can be closely monitored.

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. Close evaluation by a pediatric ophthalmologist or retina specialist is advised.[16]  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.

Medication Summary

No treatment is available to halt the natural progression of schisis formation in patients with X-linked juvenile retinoschisis (XLRS). However, the use of carbonic anhydrase inhibitors, such as topical dorzolamide[21] and oral acetazolamide, have been reported to reduce cystic spaces and foveal thickness with a concomitant increase in visual acuity.[22]  Though Vitamin A may have benefits in some genetic retinal diseases, it hasn't shown to help in retinoschisis.

Author

Kent W Small, MD, FASRS, Director/President, Macula and Retina Institute; President, Molecular Insight Research Foundation; Consulting Surgeon, Glendale Eye Medical Group

Disclosure: Nothing to disclose.

Coauthor(s)

Christine Garabetian, MD, Chief Resident Physician, Department of Internal Medicine, West Anaheim Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Simon K Law, MD, PharmD, Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Steve Charles, MD, Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

Chief Editor

Donny W Suh, MD, MBA, FAAP, FACS, Professor, Department of Ophthalmology, Chief of Pediatric Ophthalmology and Adult Strabismus, Medical Director of Eye-Mobile, Gavin Herbert Eye Institute, UC Irvine Health, University of California, Irvine, School of Medicine; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Chief Medical Officer, Suh Precision Syringe, LLC; Medical Staff, Children’s Hospital of Orange County

Disclosure: Nothing to disclose.

Additional Contributors

Colleen M McLellan, Mills College, Oakland, California

Disclosure: Nothing to disclose.

Leslie Small, OD, Optometrist

Disclosure: Nothing to disclose.

Russell P Jayne, MD, Vitreoretinal Surgeon, The Retina Center at Las Vegas

Disclosure: Nothing to disclose.

Acknowledgements

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

Mi-Kyoung Song, MD 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

Disclosure: Nothing to disclose.

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

Electroretinogram of a patient with juvenile retinoschisis.

Electroretinogram of a patient with juvenile retinoschisis.

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