Experts’ opinion – Case 11

In addition to answering the questions posed to our members, our Experts were also asked the following questions :
1) What would be your work-up for intraretinal cystoid spaces?
2) What is the role of carbonic anhydrase inhibitors in JXLR?
3) What would you tell the family about the long-term prognosis?
4)Is there any ongoing research that could potentially help patients with JXLR?

Michel Michaelides

1) Which is the gene expected to be mutated in a patient with JXLR?
RS1

2) Is this patient at risk for retinal detachment?
Yes

3) Which treatment would you consider starting for this patient?
Carbonic anhydrase inhibitors

4) What would be your work-up for intraretinal cystoid spaces?
It depends on the suspected diagnosis. For presumed XLRS (symptoms, onset, XL family history, anisometropia, strabismus, etc.) I would proceed to molecular screening of RS1. Otherwise the differential diagnosis includes CRB1 and NR2E3 – for schitic appearance. If felt to be part of CMO, then the genetic differential is very broad.

5) What is the role of carbonic anhydrase inhibitors in JXLR?
I tend to consider CAIs (topical before oral) in children if there is evidence of structural or functional progression, and/or increased symptoms. I also offer CAIs to adults if they wish to explore the effects of CAI on macular structure and function. I advise patients that schisis may improve without improvement in vision.

6) What would you tell the family about the long-term prognosis?
Robust prospective natural history data is lacking. However, the condition is often relatively stable in childhood, with a reasonable prognosis, unless complicated by RD or VH. If complicated by RD and / or VH then the prognosis is poor. There is an increased likelihood of RD and VH if there is peripheral retinoschisis. In adulthood, the prognosis is variable – with some patients slowly developing macular atrophy over time.

7) Is there any ongoing research that could potentially help patients with JXLR?
There are two on-going Phase I / II intravitreal gene therapy trials in the USA –
(i) AGTC https://clinicaltrials.gov/ct2/show/NCT02416622?cond=XLRS&rank=2
(ii) NIH/NEI https://clinicaltrials.gov/ct2/show/NCT02317887?cond=retinoschisis&rank=8

 

Matteo Scaramuzzi

1) Which is the gene expected to be mutated in a patient with JXLR?
RS1. This gene is found on chromosome Xp22.2 and encodes Retinoschisin, a retina-specific protein implicated in cell-cell interactions and cell adhesion. To date, more than 190 mutations in RS1 have been identified, most of them being missense mutations leading to misfolding, misrouting, or functional loss of the protein.

2) Is this patient at risk for retinal detachment?
Yes, but low risk. JXLR presents a variety of phenotypical manifestations. Retinal detachment is one of them, but fortunately, it is not a common one. However, it is one of the most serious sight-threatening complications of the disease. Retinal detachments have been reported in 5–22% of affected individuals, while in a more recent study, this complication has been described in only 3% of patients. Detachments could be classified as rhegmatogenous, 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, or tractional – from the retinoschisis cavity and / or posterior hyaloidal contraction. Considering this patient, infero-temporal far periphery schisis is described, without any breaks or any demarcation line. Peripheral retinoschisis does not usually progress or extend, but a low rate of serious complications has to be taken in consideration.

3) Which treatment would you consider starting for this patient?
Carbonic anhydrase inhibitors. Bilateral foveal schisis is the most common clinical finding in patients with JXLR, with an overall frequency of about 90%. Recently, carbonic anhydrase inhibitor efficacy has been shown in patients with cystic-appearing macular lesions, with an average improvement in visual acuity and an improvement in the extent of cystic macular lesions in a high percentage of cases.

4) What would be your work-up for intraretinal cystoid spaces?
Considering that oral and topical carbonic anhydrase inhibitors (CAI) are effective in reducing foveal schisis in patients with JXLR, I suggest to introduce a therapy with topical Dorzolomide TID. This would, on one hand, reduce the cystoid spaces, and on the other hand, avoid the side effects associated with oral assumption. After the introduction of CAI therapy, patients should be monitored on a monthly basis, checking visual acuity evolution and changes in foveal thickness and cystoid lesions on OCT. Even in case of no visual acuity improvement, treatment should be continued in order to maintain macular architecture and decrease the occurrence of later-onset atrophic lesions and associated visual loss.

5) What is the role of carbonic anhydrase inhibitors in JXLR?
Carbonic anhydrase is an enzyme that is very diffused over our body. In the retina, the retinal pigment epithelium (RPE) contains primarily the membrane-bound form of this enzyme. Carbonic anhydrase inhibitors mainly modulate the membrane-bound carbonic anhydrase receptors present in RPE layer, enhancing fluid transportation and retinal adhesiveness.

6) What would you tell the family about the long-term prognosis?
The natural history varies considerably between patients, but visual acuity usually deteriorates between second and fifth decades, in consequence of foveal schisis and defects in outer photoreceptor layer abnormalities. On long-term photoreceptor defects evolve in macular atrophy, with severe central visual function impairment.

7) Is there any ongoing research that could potentially help patients with JXLR?
Yes. Since retinoschisin is expressed in the retina during early development and maintained throughout life, gene replacement has become a target for therapeutic intervention. Adeno-associated viral vector delivery of the RS1 gene has shown efficacy in mouse models, as retinoschisin was successfully expressed in all retinal layers, the b-wave amplitude was restored on electroretinography and reorganization of the photoreceptor-depolarizing bipolar cell synapse was induced. The vectors were injected into the vitreous, differently from recently approved Luxturna, a gene replacement subretinal injection for patients with inherited retinal dystrophy due to mutation on RPE65 gene. Nowadays there are two clinical trials in recruitment phase (NCT02317887 and NCT02416622), conducting a phase 1 / 2 dose-escalation clinical trial on human patients.

 

Sui Chien Wong

1) Which is the gene expected to be mutated in a patient with JXLR?
RS1.

2) Is this patient at risk for retinal detachment?
Yes.

3) Which treatment would you consider starting for this patient?
Carbonic anhydrase inhibitors. CAIs can reduce macular cysts. This was seen in as much as 66% of cases in 1 study (Andreuzzi et al, Retina 2017), although average visual acuity improvements were more modest.

4) What would be your work-up for intraretinal cystoid spaces?
Clinical examination to exclude uveitis-related cystoid macular oedema. If suspected, a fundus fluorescein angiogram can be useful as the macular cysts in JXLR do not hyperfluoresce. Additionally, if indicated clinically, blood tests may be considered to exclude infectious (toxocariasis, cat scratch disease, Lyme, syphilis, tuberculosis) and non-infectious (e.g. sarcoidosis) aetiologies. Other differential diagnoses include optic disc pit maculopathy, Coats disease related cystoid macular oedema and enhanced S-cone syndrome (Goldmann-Favre).

5) What is the role of carbonic anhydrase inhibitors in JXLR?
The role of CAI in reducing macular retinoschisis is not entirely clear, but it is thought to enhance retinal pigment epithelial fluid transport and enhance retinal adhesiveness.

6) What would you tell the family about the long-term prognosis?
Visual acuity may worsen slightly in the second decade of life, but is then likely to remain reasonably stable until the fifth or sixth decade of life when macular atrophy can develop with a drop of vision to less than 20/200. There is up to about a 20% chance of developing retinal detachment, and a 4-40% chance of vitreous haemorrhage, both of which may require intervention.

7) Is there any ongoing research that could potentially help patients with JXLR?
There are currently ongoing phase I / II gene therapy trials to assess the potential safety and efficacy of introducing healthy RS1 gene.

 

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