Congenital X-linked retinoschisis (CXLRS) is an X-linked inherited retinal degeneration characterized by splitting of the superficial layers of the retina, most notably the nerve fiber layer. Clinically, CXLRS is a progressive disorder with predominately ocular manifestations and minimal systemic associations. The disease was first described in 2 males by Haas in 1898.1 Since then, it has been recognized by a variety of names, including neuroretinal disease in males, congenital cystic detachment of the retina, juvenile macular degeneration, and congenital vascular veils. Jager coined the term “retinoschisis” in 19532 and presently the terms X-linked retinoschisis and juvenile retinoschisis are synonymous with CXLRS. We present an updated clinical review of the epidemiology, pathophysiology, current, and future treatments of this condition in the era of small gauge vitreoretinal surgery and gene therapy.
Congenital X-linked retinoschisis is one of the most common juvenile macular degenerations. Depending on the population studied, the estimated prevalence ranges from 1 in 5000 to 1 in 20,000.3 Congenital X-linked retinoschisis occurs almost exclusively in males. Female carriers generally do not demonstrate fundus changes, although there are rare reports of heterozygotes with clinical signs.4,5 Most affected male patients present in the first decade of life, especially at school age with impaired vision and strabismus.6 However, retinal findings have also been described in infants as early as 3 months of age. Visual impairment can vary drastically, with best-corrected visual acuity ranging from 20/20 to 20/600, although typically vision is from 20/60 to 20/120.
PATHOPHYSIOLOGY AND GENETICS
Congenital X-linked retinoschisis is an X-linked recessive disorder with complete penetrance and variable expressivity. The cause of CXLRS has been associated with mutations in the retinoschisin 1 (RS1) gene on the distal short arm of the X chromosome (Xp22.1-p22.3), which encodes for the protein retinoschisin. Although over 200 disease-causing mutations have been reported, the predominant mutations are missense mutations.7,8 At this time, there is minimal consistency in visual impairment within a particular family or based on the type of mutation.
Retinoschisin is a 224 amino acid, discoid domain, secretory protein involved in cell-cell adhesion and is expressed in photoreceptors, along with other components of the inner and outer retina, including ganglion cells, amacrine cells, and bipolar cells. Thus, mutations leading to CXLRS may affect the adhesive properties of retinoschisin in these different cell types.4,5 Various cell types have been implicated as the primary cell involved in CXLRS, and to date no studies have definitively identified any single cell. Early reports attributed many of the changes seen in CXLRS to gene defects in Muller cells, although other studies also implicate other retinal cells, such as photoreceptors and/or bipolar cells, in the pathophysiology. Studies in animal models have supported a role for retinoschisin in retinal maintenance, as there is continued expression. Although the molecular role of retinoschisin within the retina has not been completely elucidated, its interaction with β2 laminin may play a part in the pathogenesis of CXLRS.6
The pathophysiology underlying the formation of the schisis cavities in CXLRS remains unknown, although various theories have been proposed. Joshi et al9 suggested that at the structural level, vitreous tractional forces in combination with the intrastructural defects in retinoschisin might lead to schisis cavity formation. Others have postulated that the interaction between retinoschisin and the intracellular Na+/K+ ATPase pumps leads to an alteration in ionic gradients and tissue balance, resulting in extracellular fluid accumulation within the schisis cavities.10 Additionally, wide-field fluorescein angiography (FA) has shown vascular leakage, a potential source of schisis fluid.11
Future Gene Therapies
As retinoschisin is expressed in the retina during early development and maintained throughout life, gene replacement has become a target for therapeutic intervention. Viral vector delivery of the RS1 gene in CXLRS mouse models shows promise, as retinoschisin was successfully expressed in all retinal layers and the b-wave amplitude was restored on electroretinography (ERG).12,13 Intravitreal injection of adeno-associated viral (AAV) vectors AAV8 and recombinant AAV2 (rAAV2) carrying functional RS1 into Rs1 knockout (KO) mouse models has demonstrated effectiveness. These targets are now currently being studied in human clinical trials. In the Rs1-KO mice, AAV8-mediated gene delivery induced reorganization of the photoreceptor-depolarizing bipolar cell synapse and was found to restore function.14
Currently, there are 2 gene therapy trials underway for the treatment of CXLRS. The National Eye Institute is conducting a phase 1/2 dose-escalation clinical trial for AAV8-scRS/IRBPhRS gene transfer in patients with CXLRS (NCT02317887). A biotechnology company, Applied Genetic Technologies Corporation, is also performing a phase 1/2 dose-escalation clinical trial for a rAAV2tYF-CB-hRS1 therapy (NCT02416622). Although both studies attempt to optimize dose, they are primarily designed to evaluate safety.
Although there is a broad spectrum of clinical phenotypes in patients with CXLRS, a consistent feature of CXLRS in all affected males is “foveal schisis.” Foveal schisis has a very distinct appearance of small cysts centered in the fovea and arranged in a stellate pattern or with radial striae, which on clinical examination can appear as a spoke-wheel pattern (Fig. 1). On initial examination, foveal involvement may not be clinically apparent, although with imaging foveal schisis and/or retinal pigment epithelium (RPE) atrophy may be better visualized. Peripheral retinoschisis is found in 50% of CXLRS patients, most commonly in the inferotemporal quadrant.3
Recently, CXLRS has been classified into 4 phenotypes based on examination and optical coherence tomography (OCT) characteristics: type 1, foveal; type 2, foveolamellar; type 3, complex; and type 4, foveoperipheral.15 Foveal schisis is defined as schisis that is appreciated on clinical exam. The corresponding schisis noted on OCT does not extend beyond what is observed clinically. On the other hand, lamellar schisis is recognized on OCT as macular schisis in areas that appear normal on clinical exam (Fig. 2).
The various CXLRS types are illustrated in Figures 3-6. Type 1 CXLRS refers to patients with foveal schisis and no peripheral schisis (Fig. 3). Type 2 CXLRS is both foveal and lamellar schisis without peripheral retinoschisis (Fig. 4). Type 3 CXLRS patients exhibit foveal, lamellar, and peripheral retinoschisis (Fig. 5). Lastly, type 4 CXLRS is foveal schisis and peripheral retinoschisis (Fig. 6).
One study demonstrated type 3, complex CXLRS as the predominant phenotype in 71% of patients.15 The presence of retinoschisin in the inner and outer retina may account for the presence of lamellar schisis, deep to the nerve fiber layer. Currently, no studies have evaluated the prognostic significance of the various phenotypes of CXLRS.
Retinoschisis can also be categorized as exudative and nonexudative. Eyes with exudative retinoschisis have hard exudates on examination (Fig. 7). One report described exudation in both the macula and periphery.11 It is unclear if the lipid in these patients is secondary to resolving hemorrhage, vascular incompetence, both, or neither.
The inner retina may develop retinal holes or tears, or it may fragment over time, leaving membranous remnants. Some use the term “vitreous veils” to describe these, although they are retinal or retinal and vitreal in nature and not only vitreous. In addition, the inner retina may or may not have retinal blood vessels. In some patients the inner retinal vessels may cross into the vitreous, whereas in others the retinal vessels may course in the outer leaf of the retina.
Patients may also develop optic disc and retinal neovascularization and may thus present with a vitreous hemorrhage. The retina may also be dragged nasally, possibly secondary to the dehiscence of the nerve fiber layer temporally.9 Additionally, in some patients, the peripheral retina may also have a metallic sheen, RPE changes, intraretinal blood cysts, or sheathed and occluded vessels.3 A tapetal reflex associated with the Mizuo-Nakamura phenomenon has also been described.
The natural history of CXLRS varies considerably. Often, visual acuity deteriorates during the first and second decades of life and remains stable until the fifth and sixth decades. There are reports of bullous peripheral retinoschisis resolving spontaneously with apposition of the inner and outer retinal layers, occasionally leaving a pigment line.
The classic radiating striae evident in younger patients regresses with age, resulting in a blunted foveal reflex in older patients.16 Retinal pigment epithelial changes and atrophy in the macula and periphery are common in older patients, with macular atrophy as one of the most common causes of vision loss. The intraretinal septae in the fovea can also break down and the microcysts may coalesce, forming a large posterior schisis cavity, resulting in progressive loss of vision.
Although vision loss in CXLRS is generally gradual, some patients may develop sudden vision loss secondary to retinal detachment and/or vitreous hemorrhage. Rhegmatogenous detachments develop secondary to outer retinal breaks in areas of peripheral schisis with concurrent inner retinal breaks or from full-thickness retinal breaks occurring during vitreous detachment. Others develop tractional retinal detachment from the retinoschisis cavity and/or posterior hyaloidal contraction. Although a pigment line is often associated with chronic retinal detachment, not all patients with CXLRS and chronic retinal detachment exhibit a pigment line. Similarly, chronic retinoschisis cavities without detachment can exhibit a pigmented demarcation line (Fig. 8). Therefore, a pigment line cannot solely be used to include or exclude a chronic retinal detachment in these patients. Vitreous hemorrhage is a more common complication of CXLRS with an estimated incidence of 30-40%.3 Hemorrhage can occur after bridging vessels rupture or secondary to neovascularization. Patients can also develop vascular changes with age, such as sheathing of vessels and dendritiform patterns. Additionally, rarely, neovascular glaucoma can be seen.
DIAGNOSIS AND TESTING
Although the diagnosis of CXLRS is based on clinical examination, imaging and other diagnostic testing has greatly improved our understanding of the disease. Patients with CXLRS demonstrate abnormalities on ERG, although none of them are unique to CXLRS. On ERG, there is a reduction in the dark-adapted b-wave amplitude, even in eyes with schisis confined to the fovea. The combination of decreased b-wave amplitude and normal a-wave results in an electronegative ERG. Younger patients, in the early stages of disease, may have a normal a-wave, although with progressive involvement of the photoreceptors as patients age, there is reduction in the a-wave.17-19
On FA, there is no hyperfluorescence or leakage associated with the cystic-like spaces/retinal splitting in the fovea. This is in contrast to diabetic or classic cystoid macular edema where hyperfluorescence, secondary to leakage, is visualized on FA. Patients may occasionally have hyperfluorescence secondary to diffuse pigmentary changes or vascular leakage from retinal vessels within peripheral schisis. Additionally, some patients may demonstrate nonperfusion in both schitic and nonschitic areas.
With the advent of OCT, the evaluation of patients with CXLRS has been enhanced drastically. Optical coherence tomography can demonstrate retinal splitting in patients with an apparently normal clinical exam (lamellar schisis). Additionally, it has shown that patients with CXLRS can have splitting in layers other than the nerve fiber layer. No studies have demonstrated a correlation between foveal appearance on OCT and visual acuity. As an adjunct, red-free photography may also accentuate the presence of foveal schisis.20
Genetic testing strategies include testing the RS1 gene or use of a multigene panel that includes RS1. If genetic testing in the proband yields a mutation in the RS1 gene, some defer genetic testing in others affected within the family. Because the risk to siblings of the proband is dependent on the carrier state of the mother, genetic testing is also recommended in the mother of the proband.
The differential diagnosis of CXLRS is broad, depending on the presenting features. The exudative form may mimic Coats disease, familial exudative vitreoretinopathy, uveitis-related detachments, or retinoblastoma. The absence of inflammation in the anterior chamber and/or vitreous, lack of calcium deposits, and the specific genetic mutations are a few key distinguishing features. The nonexudative form may be similar to traumatic and nontraumatic pediatric rhegmatogenous retinal detachments. With respect to foveal schisis, conditions associated with nonleaking macular edema in the differential diagnosis include Goldman-Favre, nictonic acid, and retinitis pigmentosa. Lastly, the negative or reduced b-wave on ERG may also be found in congenital stationary night blindness, among other conditions.20
The overall management of CXLRS is complex and depends on several factors, including disease severity, retinoschisis location and configuration, visual acuity, and monocular status. Medical and surgical decisions can be divided into management of foveal retinoschisis, peripheral retinoschisis (extension into macula, overhanging macula), and/or CXLRS-related retinal detachments (combined rhegmatogenous schisis, combined tractional schisis). Because each detachment is unique, it is important to emphasize that there is no single approach or absolute rule to CXLRS-related detachment repairs.
Peripheral retinoschisis (with or without inner wall retinal breaks) that does not progress or extend into the macula is often observed given the low rates of progression. In our clinical experience, CXLRS-related retinal detachments (RD) (schisis RD) occur in less than 10% of patients. Hinds and colleagues21 report an 11% rate (2/18 eyes) of localized tractional schisis RD associated with peripheral retinoschisis, whereas the rates of rhegmatogenous schisis RDs range from 10-22%.22
Prophylactic treatment of peripheral retinoschisis is controversial, as spontaneous regression of retinoschisis cavities has been reported.23 Prophylactic laser barricade for stable peripheral retinoschisis is not recommended due to the high rates of iatrogenic retinal breaks and progression to rhegmatogenous schisis RDs.24 However, barricade laser photocoagulation—guided by OCT, if available—with low power (less than 200 mW), long duration burns (greater than 300-400 ms) for progressive peripheral retinoschisis may be an alternative option in young patients that are unable to tolerate prolonged anesthesia or refuse surgery. Prophylactic inner wall retinectomy or drainage has also been reported.25 However, in the absence of progression, the risk of a rhegmatogenous schisis RD or proliferative vitreoretinopathy (PVR) RD is a major concern.25,26 Therefore, prophylactic surgical intervention for stable peripheral retinoschisis is also not universally recommended.
Strabismus, amblyopia, and refractive errors (usually hyperopia) heavily contribute to the visual morbidity of CXLRS patients.27,28 Therefore, the first and last steps are to maximize both strabismic management and refractive correction with a pediatric ophthalmologist. Currently, there are no clinical trials that support specific medical interventions for foveal CXLRS. Few case series have found success with topical carbonic anhydrase inhibitors (CAI) in the treatment of both foveal and peripheral retinoschisis.29-31 Verbakel and colleagues29 most recently demonstrated a reduction in foveal zone thickness in 5 of 9 patients (55.6%) with CXLRS after 6 months with oral CAI. The exact mechanism is unknown, but several authors suggest target receptors in the RPE and neurosensory retina.29 However, the duration of treatment and safety profile requires further study. The use of ocriplasmin as primary treatment for macular schisis remains equivocal. One report suggests resolution after a single injection; however, the schisis recurred.32
Vitreoretinal Surgery Indications and General Principles
The decision for surgery in foveal or peripheral retinoschisis and CXLRS-associated retinal detachments is complex, multifactorial, and physician dependent. In the absence of a retinal detachment, monocular status, progressive vision loss, and retinoschisis configuration play key roles in surgical decision-making. A monocular patient with progressive vision loss in the better eye due to advancing peripheral retinoschisis will likely undergo a surgical intervention rather than observation. On the other hand, a young patient with either stable or slowly progressive vision changes in the weaker eye may warrant more extensive discussion with the family.
Posterior hyaloid separation is critical in CXLRS vitrectomy. The posterior hyaloid in pediatric patients is intimately adherent to the retina.33 Incomplete hyaloidal separation increases the risk of PVR and posterior hyaloidal contraction-related RDs.34,35 Therefore, we first evaluate patients with rhegmatogenous schisis RDs for primary scleral buckling. Outer wall breaks are difficult to find but are often located at the posterior edge of the schisis RD cavity.
If the rhegmatogenous schisis RD involves the macula, we will tend to proceed with a vitrectomy due to the difficulty in achieving proper support of posterior outer wall breaks with an encircling buckle. We advocate the use of ocriplasmin for posterior hyaloidal separation in progressive bullous peripheral retinoschisis, rhegmatogenous schisis, and tractional schisis RDs.36,37 Alternatively, 2 international units (0.1-0.2 mL) of plasmin enzyme isolated from 20 mL autologous blood 3 days before surgery is injected intravitreally 30 minutes before the vitrectomy.37 In the absence of ocriplasmin, the use of indocyanine green (ICG), triamcinolone, and/or perfluorocarbon (PFO) are also useful adjuncts for both vitreous dissection and identification of outer wall breaks. Ideally, we try to preserve the inner leaflet as much as possible in the hopes of using future gene therapy in reapproximating the inner and outer leaflets. However, if the posterior hyaloid cannot be separated from the inner schisis leaflet due to either an intimate adherence or thin inner leaflet, a limited inner wall retinectomy may be performed with or without light laser over the retinectomy and outer wall breaks.38,39 We typically perform an 80% silicone oil exchange for primary tamponade for several reasons: to achieve long-term stabilization of the schisis RD, to avoid postoperative positioning that is difficult to perform in children, to aid in dampening the potential for recurrent PVR, and to avoid elevated intraocular pressure and long-term corneal decompensation that can occur with silicone oil.40
Foveal retinoschisis in the absence of a retinal detachment is often observed or treated medically first to avoid creating full-thickness retinal breaks associated with adherent posterior hyaloids intraoperatively. However, several reports suggest successful resolution of macular schisis with pars plana vitrectomy (PPV).41-44 The exact mechanism is unknown, but a common theme among all reports suggests that foveal retinoschisis may have a structural component related to vitreoretinal traction from the internal limiting membrane (ILM) and/or posterior vitreous. Relief of these forces promotes resolution. Ikeda et al42 demonstrated an 80% success rate (4/5 eyes) with collapse of macular retinoschisis after a PPV, posterior vitreous detachment induction, ILM peeling, and sulfur hexafluoride tamponade. Iordanous43 confirmed this finding in a separate case report with ILM peeling. Yu and colleagues44 published a prospective clinical series of 28 eyes that underwent observation (n = 11) or PPV with careful limited ILM peeling around, but not involving, the foveal schisis (n = 17). In the surgical group, all eyes exhibited resolution of macular schisis, whereas 9 eyes (82%) demonstrated progression in the nonsurgical group. Goel and Ghosh45 reported disappearance of foveal schisis after PPV and silicone oil tamponade with reappearance after oil removal. Conversely, Gupta and colleagues46 reported an improvement in foveal cysts after scleral buckling for a CXLRS-related detachment. Given the difficulty in removing all of the posterior hyaloid in pediatric patients and the risk of hyaloidal contraction, we recommend proceeding with caution when offering a PPV and including a thorough informed consent with the patient's family or legal guardian.
Configuration and location of the peripheral retinoschisis is important for the surgical approach, decision for intervention, patient counseling, and setting expectations for visual recovery. As mentioned, the presence of a demarcation line does not solely indicate the existence of a retinal detachment, as it is present in patients with long-standing retinoschisis. In our experience, peripheral retinoschisis cavities with thin inner leaflets and inner retinal holes are more stable than cavities with smooth uninterrupted inner leaflets. Although the exact reason is unknown, free communication of fluid between the intraschisis cavity and vitreous with inner wall breaks may create a more stable vitreoretinal interface by equilibrating the push-pull forces between the schisis and vitreous cavities, respectively. Progressive bullous retinoschisis overhanging, but not involving, the macula may be amenable to vitrectomy. Surgical intervention for progressive peripheral retinoschisis involving the macula may have anatomic success but visual success may be more unpredictable with a vitrectomy.
Our surgical technique for peripheral retinoschisis drainage begins with instillation of intravitreal ocriplasmin followed by a 23- or 25-gauge transconjunctival 2- or 3-port vitrectomy approach. In the 3-port technique, we use an anterior segment infusion cannula if the bullous schisis is retrolenticular. After careful core and posterior vitreous hyaloidal separation, a small gauge cannula (42-gauge) is utilized to make a partial thickness, inner wall drainage retinotomy in the schisis cavity to promote drainage under fluid-air exchange. An 80% silicone oil exchange is then performed for long-term tamponade. Garcia-Arumi and colleagues47 report a similar successful case. Armeda-Maresca and colleagues48 also published a variation of this technique by utilizing external drainage of bullous cavities abutting the lens in lieu of an internal partial-thickness drainage retinotomy.
CXLRS-Related Rhegmatogenous and Tractional Retinal Detachments
Progressive macula-involving rhegmatogenous schisis RDs and tractional schisis RDs may benefit from vitrectomy or scleral buckling as discussed above. Additional indications include vitreous hemorrhage and exudative RDs.39,49,50
Although laser barricade is generally not recommended for peripheral retinoschisis, the role of laser photocoagulation for progressive rhegmatogenous schisis RDs is also controversial. We have found success in few cases of shallow combined rhegmatogenous schisis RDs with demarcation lines by careful green indirect laser photocoagulation starting at the posterior edge of the demarcation line and extending up to the ora serrata using long duration, low power burns.
There are several reports that describe both scleral buckling and vitrectomy techniques for combined rhegmatogenous schisis RDs and tractional schisis RDs.22,39,49 Surgically, we use a 2- or 3-port technique after ocriplasmin with careful hyaloidal dissection for rhegmatogenous schisis RDs. We utilize triamcinolone, PFO, and ICG to assist in posterior hyaloid dissection as adjunctive agents and PFO to help identify small peripheral outer wall breaks. If vitreous traction remains in rhegmatogenous schisis RDs, we proceed with an inner wall retinectomy and drain through the existing outer wall break with a large bore cannula followed by silicone oil tamponade. A similar approach is utilized in PVR schisis RDs with careful peeling of the overlying proliferation in a posterior to anterior fashion using a combination of the Trese spatula and max grip forceps with or without PFO to both provide and control the degree of counter traction on the retina. In tractional schisis RDs in which a shallow macular RD is present but there is no outer wall break, vitrectomy is beneficial with careful hyaloidal dissection and internal drainage of the schisis cavity with a small gauge needle. In type 2 or 3 CXLRS (unlike type 4), we try to avoid inner wall retinectomies and dissect the anterior proliferation overlying the schisis cavity, as the lamellar cavities are more difficult to separate from the deeper layers of the retina. However, it is not an absolute contraindication.
In summary, CXLRS is a complex juvenile inherited retinal degeneration that can have evolving ocular manifestations throughout life. Gene therapy is a promising future treatment, although still in its infancy. It is important to note that there is no single surgical approach or absolute guideline for CXLRS-related detachments due to the complexity of the anatomy and disease.
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