Risk of posterior progression
Basic approach: Observation
Barrage laser indication: Progressive enlargement, proximity to the posterior pole
Treatment goal: Prevention of further posterior progression
Retinoschisis (Congenital and Acquired)
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is retinoschisis?
Section titled “1. What is retinoschisis?”Retinoschisis is a condition in which the neurosensory retina splits at the inner or outer plexiform layer. This is fundamentally different from retinal detachment, where the photoreceptor layer detaches from the retinal pigment epithelium.
Overview of three types
Section titled “Overview of three types”| Type | Typical age and sex | Typical location | Prevalence/incidence |
|---|---|---|---|
| Age-related (acquired) retinoschisis | Age 40 and older; both sexes | Inferotemporal periphery (70%) | 7–30% of people aged 40 and older |
| X-linked (congenital) retinoschisis | School age; almost exclusively males | Fovea (nearly all cases) + periphery (about half) | 1 in 5,000 to 25,000 people2) |
| Myopic foveoschisis | Middle-aged and older; high myopia | Posterior pole, macula | A certain proportion of highly myopic eyes |
Q
Are retinoschisis and retinal detachment different diseases?
A
Retinoschisis is a condition in which splitting occurs within the layers of the neurosensory retina, and is completely different from retinal detachment (where the full-thickness retina detaches from the retinal pigment epithelium). In retinoschisis, the connection with the retinal pigment epithelium is maintained, so the visual prognosis is generally better than that of retinal detachment. However, if holes develop in both the inner and outer layers, it may progress to retinal detachment.
2. Acquired (Age-Related) Retinoschisis
Section titled “2. Acquired (Age-Related) Retinoschisis”
Wang N, et al. Case Report: A case of unexplained retinoschisis. Front Med (Lausanne). 2025. Figure 1. PMCID: PMC12518284. License: CC BY.
OCT images show retinoschisis: (A) splitting of the outer plexiform layer in the macula, (B) splitting near the superior vascular arcade, (C) splitting near the inferior vascular arcade, (D) retinoschisis temporal to the macula. This corresponds to the retinoschisis discussed in section “2. Acquired (Age-Related) Retinoschisis”.
Concept and Epidemiology
Section titled “Concept and Epidemiology”Age-related retinoschisis is a condition in which physiological cystoid degeneration (Blessig-Iwanoff cysts) of the adult peripheral retina fuses and expands, leading to splitting in the outer plexiform layer or inner nuclear layer.
The prevalence is reported to be 1.65–7%2), more common in individuals aged 40 and older, and bilateral in approximately 70% of cases. It occurs preferentially in the inferotemporal peripheral retina in 70% of cases, and the elevated surface is smooth. It is not hereditary and develops with aging.
Secondary retinoschisis can be caused by proliferative membranes, vitreous traction, cystic changes, intraretinal hemorrhage, exudation, or inflammation. Specific underlying diseases include diabetic retinopathy, old retinal detachment, age-related macular degeneration, retinopathy of prematurity (ROP), and Coats disease.
Symptoms and Clinical Findings
Section titled “Symptoms and Clinical Findings”Most cases are asymptomatic, and progression to the posterior pole is rare, with vision often normal. When the lesion extends beyond the equator, subjective symptoms such as visual field defects may occur.
| Finding | Characteristic | Significance for Differential Diagnosis |
|---|---|---|
| Dome-shaped elevation | Smooth, transparent hemispherical; fixed and immobile | Does not move with position change |
| Water silk appearance | Undulating luster of the inner layer | Characteristic of this condition |
| snowflakes (snowflake opacities) | yellow-white granular opacities on the inner surface of the separated layer | indicator of degeneration |
Even if an outer layer hole occurs and causes outer layer retinal detachment, the risk is low. If inner and outer holes develop and progress to detachment, surgical treatment for typical rhegmatogenous retinal detachment is required.
Causes and Risk Factors
Section titled “Causes and Risk Factors”The main pathology is the fusion and enlargement of cystoid degeneration of Henle fibers in the outer plexiform layer due to aging. The mechanism of absolute scotoma is that separation between layers in the outer plexiform layer causes tissue disruption at synaptic junctions, blocking signal transmission of light stimuli1).
Risk factors include aging and hyperopia2). No genetic predisposition has been identified2).
Diagnosis and Examination Methods
Section titled “Diagnosis and Examination Methods”OCT diagnosis plays a central role2). It can depict the extent, depth, and columnar structures (vertical tissue bridges) within the separation cavity, directly confirming the split at the outer plexiform layer.
Differentiation from retinal detachment is most important.
| Feature | Retinoschisis | Retinal detachment |
|---|---|---|
| Mobility of elevation | Fixed, immobile | Moves with position change |
| Transparency | High (clear) | Low (cloudy) |
| Nature of scotoma | Absolute scotoma | Relative scotoma |
| Surface appearance | Smooth (water silk) | Irregular, undulating |
Standard treatment
Section titled “Standard treatment”In principle, observation is recommended. The risk of progression to retinal detachment is low, approximately 0.05% per year, and most cases are asymptomatic and stable.
- Barrier laser photocoagulation: Performed to prevent posterior progression. Indications include progressive enlargement, posterior border close to the posterior pole, and presence of breaks in both inner and outer layers.
- Vitrectomy for macular involvement: Desjarlais et al. (2022) reported visual improvement with vitrectomy (ILM peeling and gas tamponade) 1). Surgery is an option for cases extending to the macula.
Outer layer hole formation
Basic policy: Observation
Note: Outer layer breaks increase the risk of detachment
Carefully evaluate indications: Caution is needed if an inner layer hole is also present
Schisis detachment
Basic policy: Surgery according to standard rhegmatogenous retinal detachment
Surgical indications: When holes occur in both inner and outer layers and detachment progresses
Prognosis: Generally favorable
Cases with macular involvement
Basic policy: Consider vitrectomy
Surgical technique: ILM peeling + gas tamponade
Evidence: Case report level1)
Pathophysiology
Section titled “Pathophysiology”Interlaminar separation in the outer plexiform layer causes tissue disruption at synaptic junctions, resulting in absolute scotoma 1). It is thought that Henle fibers are pulled apart by the fusion of age-related cystoid degeneration, leading to separation. Three-dimensional evaluation with SD-OCT has enabled precise assessment of the extent of the separation cavity and thinning of the inner and outer layers, advancing the identification of long-term natural history and progression predictors 2).
Q
Why does absolute scotoma occur?
A
In age-related retinoschisis, interlaminar separation occurs in the outer plexiform layer. This layer contains synaptic connections between photoreceptors and ganglion cells; when separation disrupts these synapses, light stimuli cannot be transmitted to bipolar cells and ganglion cells 1). Therefore, in the separated area, light does not conduct electrical signals, and it is perceived as an absolute scotoma.
Q
Will age-related retinoschisis always worsen in the future?
A
Most cases of age-related retinoschisis follow a stable course. The risk of progression to retinal detachment is extremely low, approximately 0.05% per year. However, if holes develop in both the inner and outer layers, the risk of detachment increases, so regular fundus examination follow-up is important 2).
3. Congenital (X-linked) retinoschisis
Section titled “3. Congenital (X-linked) retinoschisis”Concept and Genetic Background
Section titled “Concept and Genetic Background”X-linked retinoschisis (XLRS) is a congenital retinal disease with X-linked recessive inheritance caused by mutations in the RS1 gene. It is a relatively rare vitreoretinal degenerative disease, with an estimated prevalence of 1 in 5,000 to 25,000 individuals 2). Typically, only males are affected, while females are carriers.
- Causative gene: RS1 gene (Xp22.2) 2)
- Encoded protein: Retinoschisin (RS)
- Function: An extracellular matrix protein expressed in photoreceptors and bipolar cells; it forms homo-oligomeric complexes and plays a crucial role in cell adhesion, synapse formation, and retinal differentiation and function 2)
- Number of mutations: Over 200 disease-causing mutations have been identified
- Phenotype: Marked phenotypic variability; severity differs even within the same mutation; non-syndromic disease (limited to the retina)
Q
Can women develop X-linked retinoschisis?
A
Usually only males are affected. Because it is an X-linked recessive inheritance, females with a mutation on only one X chromosome are carriers and are usually asymptomatic. Rarely, skewed X-inactivation or uniparental disomy has been reported to cause mild phenotypes in females2).
Symptoms and Clinical Findings
Section titled “Symptoms and Clinical Findings”Symptoms:
- Decreased vision: Often noticed during school age (around 6–10 years) with visual acuity around 0.3–0.82). In severe cases, poor vision from birth.
- Hyperopia is common; amblyopia, strabismus, and nystagmus may appear in infancy to preschool age.
- If visual acuity is around 0.6, normal university attendance is possible. With age, macular atrophy leads to a decrease in visual acuity to 0.1.
- Moderate visual acuity (0.2 to 0.7) is often maintained for a long period.
Clinical findings:
Macular findings
Foveal schisis (almost all cases): Cystoid changes with spoke-wheel folds (cysts and bridging structures on OCT).
Macular atrophy: Cystoid changes regress with age and transition to atrophy; often appears similar to simple cystoid macular edema
Fluorescein angiography: Unlike cystoid macular edema, no fluorescein leakage (fovea is normal or shows window defect)
Peripheral Findings
Peripheral retinoschisis (about half): Predilection for inferotemporal quadrant; may be associated with large inner retinal holes
Gold foil reflex: Characteristic finding in the peripheral retina; accompanied by white sheathing of retinal vessels
Vitreous veil: Seen in severe cases; vitreous is not detached and adheres strongly to the retina
Complications: Retinal detachment (5–20%), vitreous hemorrhage, intra-schisis cavity hemorrhage
Causes and Risk Factors
Section titled “Causes and Risk Factors”- Genetic background: Disruption of the homo-oligomeric complex of retinoschisin due to RS1 gene mutations leads to characteristic schisis cavities and impaired retinal signal transduction2)
- Complication risks:
- Retinal detachment (inner layer hole progressing to full-thickness hole; 5–20% of cases)
- Vitreous hemorrhage (vascular rupture due to progression of retinoschisis; vitreous hemorrhage in newborns may be a clue to suspect this disease)2)
- Amblyopia (caused by vitreous hemorrhage or postoperative form deprivation)
Diagnosis and testing methods
Section titled “Diagnosis and testing methods”Suspect this disease when bilateral cystoid macular edema is observed in male children is an important diagnostic clue.
- OCT: Evaluates foveal cysts, bridging structures (columnar Müller cell remnants), and the extent of schisis; a cohort study of 83 Korean patients found that comprehensive assessment using SD-OCT, ffERG, and fundus photography is useful2)
- ERG (electroretinogram): Characteristic electronegative pattern 2). The a-wave is preserved but the b-wave amplitude is smaller than the a-wave (negative b-wave); present from early childhood, reflecting dysfunction of the middle retinal layers throughout the fundus; some patients show normal to subnormal waveforms.
- Fluorescein angiography: Useful for differentiating from cystoid macular edema; no petaloid fluorescein leakage in XLRS.
- Genetic testing: Definitive diagnosis by mutation analysis of the RS1 gene; over 200 disease-causing mutations identified.
Differential diagnosis:
| Disease | Key differentiating points |
|---|---|
| Rhegmatogenous retinal detachment | Usually unilateral; demarcation line formation; associated with lattice degeneration |
| Cystoid macular edema | Fluorescein angiography shows petaloid leakage; no leakage in XLRS |
| Age-related (degenerative) retinoschisis | Occurs in elderly; limited to periphery; normal b-wave |
| Goldman-Favre syndrome | With night blindness and pigmentation |
Q
What is the difference from cystoid macular edema?
A
In cystoid macular edema (CME), fluorescein angiography shows petaloid leakage and pooling of fluorescein. In XLRS, although a foveal schisis cavity exists, the blood-retinal barrier is normal, and fluorescein angiography shows no leakage, only window defects. This difference is important in differential diagnosis combining OCT and fluorescein angiography.
Standard treatment
Section titled “Standard treatment”There is no established curative treatment.
Pharmacotherapy:
- Carbonic anhydrase inhibitors (CAIs): Reported to improve schisis cavities on OCT
- Dorzolamide eye drops (topical administration): Well tolerated and often first-line
- Acetazolamide oral (systemic administration): Monitor for systemic side effects such as electrolyte abnormalities and nephrocalcinosis
- Effect varies individually; monitoring of visual acuity and cystic fluid changes on OCT is necessary
Surgical treatment:
- Vitrectomy indications:
- When peripheral retinoschisis progresses to retinal detachment (main indication)
- Flattening of large foveal cyst (visual acuity and ERG improvement unlikely)
- Induction of posterior vitreous detachment (possible prevention of future peripheral retinoschisis)
- In children, vitreous and retina are extensively adherent, making surgery risky; indications must be carefully considered
- Scleral buckling: Applied to retinal detachment cases with unclear breaks
- Laser photocoagulation: May be considered for prevention of retinal detachment, but there is debate due to the risk of iatrogenic tears.
Patient management:
- Under 10 years of age: Regular evaluation at least once a year by a pediatric ophthalmologist or retinal specialist.
- Amblyopia treatment: If amblyopia occurs due to severe schisis, hyperopia, vitreous hemorrhage, or after surgery, prescribe glasses and use occlusion therapy.
- Low vision care: Magnifiers, high-contrast materials, and special support.
- Genetic counseling: All daughters of male patients are carriers (usually asymptomatic); sons do not inherit the mutation.
Q
Does the schisis disappear with age?
A
Cystoid changes in the fovea may naturally decrease with growth 2). However, some cases progress to macular atrophy, and regression does not necessarily mean improvement in visual acuity. In some cases, peripheral schisis may decrease after the occurrence of posterior vitreous detachment.
Pathophysiology
Section titled “Pathophysiology”Retinoschisin, encoded by the RS1 gene, is a secreted protein of 224 amino acids that forms homo-oligomeric complexes via its discoidin domain 2). By binding to photoreceptors and bipolar cells, it maintains the structural and synaptic integrity of the retina. Disruption of these complexes due to RS1 mutations leads to characteristic splitting cavities and impaired retinal signal transmission 2).
Histopathologically, retinal splitting occurs mainly in the nerve fiber layer. OCT shows splitting in the outer plexiform layer and inner nuclear layer at and around the fovea. Even when morphological splitting is localized, electrophysiology reveals global retinal dysfunction, as indicated by a negative b-wave.
Genotype-phenotype correlation (Korean cohort of 83 patients, Lee et al. 2025) 2):
- Mutations that preserve RS1 protein secretion are associated with significantly better final BCVA than non-secreting mutations (P=0.021)
- Non-secreting mutations have a significantly higher frequency of ellipsoid zone (EZ) disruption (P=0.030)
- No significant differences in BCVA, OCT, or ERG parameters between truncating and missense mutations
- The secretory capacity of RS1 protein may be a more important factor than mutation type in determining phenotype
In a study analyzing the schisis cavity fluid in XLRS, interphotoreceptor retinoid-binding protein (IRBP) was identified in the fluid, suggesting possible retinal metabolic abnormalities within the schisis cavity 2). Additionally, cases of exudative maculopathy, which is not typically seen in XLRS, have been reported, indicating the presence of diverse phenotypes under the same diagnosis 2).
Latest Research (X-linked)
Section titled “Latest Research (X-linked)”RS1 gene therapy clinical trials are ongoing2)3). Animal models and early clinical trials have reported partial recovery of electroretinogram responses and improvement in retinal anatomy.
Key clinical trials:
- NEI trial (NCT02317887): Safety evaluation of intravitreal administration of AAV-RS1 vector. Closure of the schisis cavity was observed in one case in the high-dose group, but intraocular inflammation was also induced.
- AGTC trial (NCT02416622): Safety and efficacy trial of rAAV2tYF-CB-hRS1 vector. The trial was discontinued due to inflammation and lack of clinical therapeutic effect. Early post-injection intraocular inflammation was observed, particularly in the high-dose group, leaving safety concerns3).
Current challenges: In XLRS, retinal fragility is increased, making posterior vitreous detachment and subretinal injection technically very difficult3). Intravitreal administration may be preferable, but the risk of vitritis must be tolerated.
Q
Is gene therapy currently available?
A
Gene therapy for XLRS is still in clinical trials and has not been approved as a treatment in general hospitals. Some clinical trials have revealed safety issues such as intraocular inflammation, and some trials have been discontinued 3). If you wish to participate, consultation with a specialized facility is necessary.
4. Myopic Foveoschisis
Section titled “4. Myopic Foveoschisis”Concept and Pathophysiology
Section titled “Concept and Pathophysiology”Myopic foveoschisis is a separation of the inner retinal layers in the posterior pole associated with high myopia. It has long been described as a posterior pole retinal detachment associated with high myopia, and currently the concept includes cases that also have a macular hole.
The pathophysiology involves a combination of the following factors:
- Axial elongation and posterior staphyloma formation: The retina in the posterior pole is stretched, and a force pulling it inward acts.
- Traction of the vitreous, internal limiting membrane (ILM), and retinal vessels: The posterior vitreous membrane, hardened internal limiting membrane, and retinal vessels that are relatively shorter compared to the equator act to pull apart the inner retinal layers at the posterior pole.
Symptoms and Diagnosis
Section titled “Symptoms and Diagnosis”Symptoms: Decreased visual acuity, central scotoma, metamorphopsia, and blurred vision. In high myopia, symptoms may be subtle.
Diagnosis (OCT):
- Inner retinal layer separation and bridging structures (remnants of the internal limiting membrane and Müller cells) in the retinal space.
- May be accompanied by macular hole or macular detachment.
- Differential diagnosis: macular hole retinal detachment (full-thickness detachment)
Standard treatment and prognosis
Section titled “Standard treatment and prognosis”Treatment: Vitrectomy is the basic approach.
- Surgical technique: ILM peeling is basic; inverted ILM flap technique, lens-forming ILM flap method, etc.
- Postoperative retinal reattachment may take several months or more.
Prognosis:
- Cases with preoperative macular detachment have the best visual prognosis
- Preoperative macular hole or postoperative macular hole formation indicates poor visual prognosis
- Timely surgical intervention determines visual functional prognosis
5. References
Section titled “5. References”- Desjarlais EB, Barineau W, Shah CP. Surgical treatment of macula-involving degenerative retinoschisis. Retin Cases Brief Rep. 2022;16(1):73-76.
- Yang YP, Chen YP, Yang CM. Clinical manifestation and current therapeutics in X-linked juvenile retinoschisis. J Chin Med Assoc. 2022;85(3):276-278. doi:10.1097/JCMA.0000000000000666.
- van der Veen I, Stingl K, Kohl S, et al. The road towards gene therapy for X-linked retinoschisis: a systematic review of preclinical and clinical findings. Int J Mol Sci. 2024;25(2):1267. doi:10.3390/ijms25021267.