Histological reports initially suggested splitting within the neurosensory retina, predominantly the nerve fiber layer differing from senile retinoschisis in which splitting occurs in the middle layers [27–29]. A more recent study of a specimen with neovascular glaucoma reports splitting within the outer plexiform layer both in peripheral and macular schisis [15]. Focal retinal pigment epithelium degeneration and photoreceptor disruption may occur as a secondary change.

Full-field electroretinogram (ffERG) is critical for the clinical diagnosis of XLRS, especially in atypical cases: the ffERG typically shows an electronegative waveform in response to a bright flash under dark-adapted conditions (Fig. 9.6). There is a normal, or nearly normal, a-wave, reflecting normal photoreceptor function, and a severely reduced b-wave in keeping with post-photoreceptor transmission defect [30, 31]. There is also a reduced b/a ratio in response to a single flash in photopic condition as well as reduced 30 Hz flicker amplitude. These findings are consistent with inner retinal dysfunction affecting both rod and cone pathways. There is predominant dysfunction of the ON pathway, with the OFF pathway being less variably affected [23, 31–33]. Positive correlations both between mutation severity and decreased b-wave amplitude as well as age and decreased b-wave amplitude have been reported [34, 35]. ERG abnormalities are, however, variable: an a-wave amplitude reduction has been reported [36], in particular if XLRS is complicated with retinal detachment. Relative b-wave preservation has also been reported in few cases [35, 36], outlining the importance of familial history, clinical examination, and mutations screening for the proper diagnosis in atypical cases.

Differential diagnosis will include other causes of foveal cystic changes and peripheral schisis. Foveal cystic changes may be seen in rare autosomal recessive or dominant schisis [37, 38], but in these disorders there are usually normal full-field ERG responses. Other causes of foveal schisis include cystoid macular oedema in rod-cone dystrophies, the enhanced S-cone syndrome, autosomal recessive bestrophinopathy, and nicotinic acid maculopathy. These disorders can usually be easily distinguished from XLRS on the basis of family history, electrophysiological testing, imaging, and molecular diagnosis.

Other forms of peripheral schisis include senile/degenerative schisis and the retinal schisis of high myopia. Senile schisis affects both males and females after 50 years of age, is usually bilateral, and is predominantly localized in the inferotemporal quadrant. In both senile schisis and the peripheral schisis of high myopia, the full-field ERG is normal.

Differential diagnosis will also include other causes of electronegative ERG [39].

XLRS is due to mutations in RS1 located on Xp22.1 [1]. The gene spans a genomic region of 32.4 kb with six exons encoding a signal peptide, characteristic secreted proteins (exons 1 and 2), a retinoschisin domain (exon 3), and the well-conserved discoidin domain motif (exon 4–6) implicated in cell adhesion [40, 41]. The resulting protein, a 224-amino acid protein, is called retinoschisin (RS1). In the adult retina, RS1 is expressed in photoreceptors and bipolar cells and is secreted in the extracellular matrix. It plays a critical role in cell-cell adhesion and cell-matrix interaction important for retinal lamination and synaptic structure relevant for the proper retinal function, in particular at the photoreceptor presynaptic terminals and at the dendritic tips of bipolar cells [41–44].

More than 190 mutations have been reported in patients with XLRS (see the LOVD – Leiden Open Variation Database; http://​databases.​lovd.​nl/​shared/​genes/​RS1), the majority of which are missense mutations localized within the discoidin domain leading to misfolding, misrouting, or functional loss of the protein and suggesting an important function role for this domain. Other mutations include deletions, insertions, and splice site mutations leading to loss of functional protein production [45].

There is no current specific treatment for XLRS. A careful refraction, the detection of amblyopia and appropriate management, and the provision of low vision aids when needed can improve residual visual performance. In children, it is essential to provide adequate educational support at school. Patients should avoid high contact sports, and protective goggles may be advised for ball sports. Families should be offered genetic counselling.

Carbonic anhydrase inhibitors, either topically (dorzolamide three times a day) or orally, have shown to reduce intraretinal cysts with some improvement in visual acuity, although the response may take several months of treatment [46–48]. If the acuity worsens with treatment, discontinuation with retreatment has shown some benefit [49]. Although the long-term effect of such treatment is not known, it seems sensible to recommend a treatment trial for at least 3 month for patients who are keen to improve their vision and are able to tolerate the side effects.

Surgical treatment is indicated when XLRS is complicated by rhegmatogenous retinal detachment or persistent vitreous haemorrhage. Retinal detachment surgery has a higher risk of developing proliferative vitreoretinopathy and may have limited effect on visual outcome [5, 50].

Proof of principal for gene replacement therapy on mouse models has now been achieved for both for structural and functional recovery [44, 51–55] and the first gene therapy trial is now undertaken in the group of Dr Paul Sieving (ClinicalTrials.gov: NCT02317887) with other planned trials in the United States (ClinicalTrials.gov: NCT02416622).