Diagnosis of RP

The diagnosis of RP is suspected in patients with poor night vision or a family history (more than 40% of RP cases in the US have no family history). It relies upon documentation of rod dysfunction as measured by dark adaptation or electroretinogram, progressive loss in photoreceptor function, loss of peripheral vision and bilateral involvement.

The most common findings on ocular examination are usually preserved visual acuity until late-stage disease and reduced visual fields. Most adult patients have posterior subcapsular cataracts and visual acuity that varies from 20/20 to near blindness late in the disease.

1. Fundus examination is one of the most informative diagnostic methods, helping to distinguish RP from other retinal dystrophies that have similar clinical findings but distinctive retinal changes. In individuals with advanced RP, ophthalmoscopy of the retina is characterized by the presence of intraretinal clumps of black pigment (abnormal fundus with bone-spicule deposits), markedly attenuated retinal vessels, loss of RPE, pallor of the optic nerve, posterior subcapsular cataracts (Figure 3). Cells in the vitreous are commonly seen.

2. Electroretinogram (ERG) is the most critical diagnostic test for RP. It determines objectively the functional status of the photoreceptors and is sensitive to even mild photoreceptor impairment. Responses obtained under dark-adapted conditions generally reflect rod function, and responses obtained under light-adapted conditions generally reflect cone function. Thus, rod responses can be separated from cone responses, permitting definition of the type and extent of rod and/or cone involvement.

3. The full-field ERG in RP typically shows a marked reduction of both rod and cone signals. Rod loss generally predominates. Amplitudes of the a- and b-waves can be either moderately reduced or almost non-detectable, depending on the stage of the disease and the genetic defect. Time intervals from stimuli to peak rod or cone isolated responses are prolonged in typical RP. The ERG is usually abnormal by early childhood, except for some of the very mild and regional forms of RP. An observation of early and severe impairment of pure rod responses occurs is critical to the diagnosis of RP in young individuals. Individuals with advanced RP have non-detectable rod and cone responses. Patients with cone ERG amplitudes as low as 1 μV or less can still have ambulatory vision and read newspapers.

4. Fundus autofluorescence (FAF) imaging is a relatively novel quick, simple, efficient and noninvasive imaging method for topographic mapping of lipofuscin changes in the RPE (and other fluorophores in the outer retina and subneurosensory space). It gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, fluorescein angiography, and optical coherence tomography. Confocal scanning laser ophthalmoscopy (cSLO) is a useful technique for FAF imaging. It allows documentation of its spatial distribution over large retinal areas. FAF imaging became a very important diagnostic tool in a variety of retinal diseases. In RP, there is a loss of peripheral autofluorescence that corresponds to the loss of photoreceptors. Autofluorescence in the macular region is usually preserved until late stages of the disease. Rings of retinal foveal hyperautofluorescence is present in approximately 80% of patients with preserved central vision. The diameter of the ring directly correlates with the macular function (Figure 3). FAF is considered useful and sensitive non-invasive diagnostic tool to monitor retinal degeneration.

6. Optical coherence tomography (OCT) is usually not used to establish a diagnosis of RP but is especially useful for measurement of retina thickness, assessment of the status of the photoreceptor layer and determining the presence of cystoid macular edema. It is also used to evaluate the effects of therapy.

7. L'electro-oculogram (EOG) and visually evoked cortical potentials (VECPs).

8. Functional assessment of vision includes dark adaptation threshold examination of the visual field (Goldmann kinetic perimetry or a Humphrey field analyzer), color vision (assessed with Ishihara plates, the Farnsworth D15 or other tests), contrast sensitivity (measured with a contrast chart), visual acuity (using the Snellen charts for assessment of distance and central vision).

9. Genetic subtyping can be definitive test for diagnosis of RPGenetic subtyping can be definitive test for diagnosis of RP. Molecular genetic testing on a clinical basis may be available (depending on the local resources in the country) for some RP-causing genes, such as RLBP1, RP1, RP2, RHO, RDS, PRPF8, RPGR, PRPF3, CRB1, ABCA4 and RPE65. For all other genes, molecular genetic testing is available on a research basis only. Thus, it is possible now to detect disease-causing mutations in 40-50% of patients with autosomal dominant RP, roughly 30% of patients with autosomal recessive RP and nearly 90% of patients with X-linked RP. Determination of the exact inheritance pattern is critical for the genetic counseling and determining the prognosis.

Many different factors may affect the early diagnosis of RP and cause a significant delay in diagnosis. For example, reading impairment and difficulties in undertaking daily activities are typically seen later in the disease course, when the visual acuities fall below 0.5 (20/40). Electrically illuminated night-time environment permits the night-time activities to be typically done with sufficient light. As a consequence, by the time the patient recognizes the symptom of night blindness, a reduction in cone sensitivity can be significant. Thus, objective quantitative measures of retinal function are much more reliable than symptoms for diagnosis of RP and crucial to describe the degree of visual compromise and rate of its decline.

Differential diagnosis

Differential diagnosis should rule out acquired retinal degenerations (such as peripheral reticular pigmentary degeneration), infectious and inflammatory retinopathy (rubella, syphilis, cytomegalovirus infection, herpes simplex, posterior uveitis), retinopathies associated with cancer and trauma with intraocular foreign body, grouped pigmentation of the retina (bear-track), retinal detachment resolution, pigmented paravenous retinochoroidal atrophy and vitamin A deficiency should also be taken in consideration, as they manifest mainly with night blindness. Drug history is essential to rule out toxicity due to phenothiazines (chlorpromazine, thioridizine), chloroquine and deferoxamine.

Systemic evaluation should rule out conditions that present with pigmentary retinopathy and mimic RP, such as Usher syndrome, Waardenburg syndrome, Alport syndrome, Refsum disease, Leber congenital amaurosis (LCA), Senior-Loken syndrome, Bardet-Biedl syndrome, unilateral RP, abetalipoproteinemia, mucopolysaccharidoses, neuronal ceroid lipofuscinosis. Congenital stationary night blindness, dystrophies of the choroid and retina (gyrate atrophy, choroideremia).