Unilateral pigmentary retinopathy (UPR), also called unilateral retinitis pigmentosa, is a rare sporadic disease characterized by degeneration and atrophy at the photoreceptor level in the retina of one eye.
It closely resembles retinitis pigmentosa (RP) in appearance. The fundamental difference is that RP is bilateral, whereas UPR affects only one eye while the contralateral eye remains normal.
The prevalence is estimated at about 1 in 4,000 people, but fewer than 100 cases have been reported in the literature to date. In the clinical guidelines for retinitis pigmentosa, UPR (unilateral retinitis pigmentosa) is classified as a type of atypical RP, distinct from typical RP.
Ocular toxoplasmosis is a well-known acquired disease that can mimic UPR. There have been reported cases where young men, after reactivation of toxoplasmosis, presented with bone-spicule pigmentation, cystoid macular edema, and visual field constriction, making differentiation from UPR difficult 1).
UPR and RP have different pathologies. RP is typically bilateral and a hereditary retinal degenerative disease, whereas UPR occurs in only one eye and is thought to be mainly caused by somatic mutations during embryonic development. Since the fundus findings are very similar, a sufficient observation period and detailed examination are necessary for differentiation.
The following are recognized as early symptoms of UPR:
Reported visual acuity ranges from 20/15 (equivalent to 1.2) to counting fingers.
Characteristic findings are observed in fundus examination, imaging, and electrophysiological testing.
Fundus Findings
Bone spicule pigmentation: Clumps of bone spicule-shaped pigment scattered in the mid-peripheral retina.
RPE changes: Mottling of the retinal pigment epithelium (RPE), granular pigment abnormalities, or punched-out RPE atrophic lesions.
Retinal vascular attenuation: Marked narrowing of the arterioles.
Waxy pallor of the optic disc: Seen in advanced cases.
Imaging and Electrophysiology
Fundus autofluorescence (FAF): Perifoveal hyperautofluorescent ring, loss of autofluorescence along the vascular arcades and around the optic disc. Linear hypoautofluorescence in the macula has also been reported.
OCT: Atrophy of the outer retinal layers is observed. Cystoid macular edema may be present 1).
Electroretinography: In affected eyes, the a-wave is undetectable to mildly reduced. The b-wave shows abnormal latency and amplitude. Multifocal electroretinography reflects widespread functional loss 1).
In a UPR-like case associated with ocular toxoplasmosis, the right eye showed bone-spicule pigmentation, arteriolar narrowing, cystoid macular edema, epiretinal membrane, and chorioretinal scar; multifocal electroretinography was non-recordable. Active inflammatory lesions were present only in the contralateral (left) eye, and the left eye electroretinogram showed selective loss of response only in the central 10 degrees 1).
The diagnostic criteria for UPR require an observation period of at least 5 years to exclude asymmetric hereditary RP. Regular follow-up with electroretinography and visual field testing of the contralateral eye is important (see section “Diagnosis and Testing Methods”).
The exact etiology of UPR is unknown. It is thought that a somatic mutation occurring during embryogenesis affects the cell lineage that forms the retina and retinal pigment epithelium (RPE). Because the mutation occurs early in embryogenesis, it may also affect the germline, but the risk of transmitting the mutation to the next generation is considered extremely low.
Inheritance patterns can be autosomal dominant, autosomal recessive, or X-linked recessive. The following associated mutations have been reported:
The unilaterality of UPR may be due to somatic or germline mutations, but molecular diagnosis using blood-derived specimens may not be conclusive 1).
The following acquired diseases can cause unilateral “pseudo-RP” and may need to be differentiated from UPR.
UPR is thought to be mainly caused by somatic mutations during embryonic development, and the genetic risk to the next generation is considered extremely low. However, cases with germline mutations in RP1, USH2A, etc. have also been reported, so genetic counseling is recommended if a genetic predisposition is suspected.
The diagnostic criteria for unilateral pigmentary retinopathy (idiopathic) by Francois and Verriest consist of the following four items.
Among these criteria, condition (3) “exclusion of inflammatory causes” may not be met in cases associated with ocular toxoplasmosis1).
The following tests are combined to proceed with diagnosis.
| Examination | Main Findings/Role |
|---|---|
| Electroretinogram (ERG) | a-wave absent to mildly reduced; b-wave latency and amplitude abnormalities; also useful for differentiation from syphilis |
| Fundus autofluorescence (FAF) | Perifoveal hyperautofluorescent ring; loss of autofluorescence along vascular arcades and around optic disc |
| Optical coherence tomography (OCT) | Outer retinal layer atrophy; evaluation of CME and epiretinal membrane |
Electroretinography is the most important confirmatory test, and the diagnostic criteria include evidence of extensive dysfunction in the affected eye and a normal ERG in the contralateral eye. This is combined with FAF, OCT, genetic testing, and serological testing to systematically rule out acquired causes (infection, inflammation, drug toxicity, trauma). Follow-up of at least 5 years is also required.
There is currently no gold standard or definitive treatment for UPR. Supportive care is the standard of care.
If cystoid macular edema (CME) is present, drug therapy according to the cause is necessary.
If the cause of cystoid macular edema is retinal degeneration itself, carbonic anhydrase inhibitors (CAIs) may be effective. On the other hand, cystoid macular edema due to intraocular inflammation is less responsive to CAIs, and intravitreal injections, periocular injections, or oral steroids may be considered.
The formation of bone spicule-like pigmentation in UPR is thought to occur through the following sequence of events (based on mouse model studies).
The nature of pigment changes alone cannot reliably predict diagnosis or functional phenotype. Intraretinal pigmentation, RPE depigmentation, optic disc pallor, and vascular attenuation can occur in UPR, but these are not pathognomonic findings.
Similar to the pathology of RP, primary degeneration of rods, which are abundant in the peripheral retina, occurs first.
Rod degeneration causes peripheral visual field restriction (tunnel vision), decreased scotopic sensitivity, and night blindness. Patients may adapt well in well-lit environments. As the disease progresses, cones also degenerate, leading to decreased visual acuity, contrast sensitivity, and color vision. Eventually, the fovea is affected, resulting in significant impairment of daily living functions.
The rate of disease progression varies greatly among individuals, and younger-onset cases tend to have a poorer visual prognosis.
For retinitis pigmentosa as a whole, due to the diversity of abnormal genes, genetic diagnosis itself is not easy, and it is difficult to narrow down therapeutic targets. At present, gene therapy is performed only in special cases. Since 2006, gene transfer therapy using viral vectors has been implemented for Leber congenital amaurosis with RPE65 gene mutations. Application of gene therapy to UPR first requires identification of the causative gene.
Due to the somatic mutation nature of UPR, molecular diagnosis based on blood samples has limitations 1). Advanced genetic testing including whole exome sequencing may be necessary to confirm the diagnosis. Since RP is caused by mutations in about 40 or more genes (such as those encoding rhodopsin and peripherin), the importance of comprehensive gene panel testing is increasing 1).
