Retinitis Pigmentosa Clinical Presentation

Presenting symptoms of RP vary, but the classic symptoms are discussed below.

Nyctalopia

The earliest symptom in RP is most commonly night blindness and is considered a hallmark of the disease.

Patients might report difficulties with tasks at night or in dark places, such as trouble walking in dim lit rooms (eg, movie theaters). Patients may report difficulties driving in low light, at dusk, or in foggy conditions.

Patients may also report a prolonged period of time needed to adapt from light to dark.

Visual loss

Peripheral vision loss is often asymptomatic; however, some patients notice this vision loss and report it as tunnel vision.

Patients may report bumping into furniture or doorframes or difficulties with sports requiring peripheral vision (eg, tennis, basketball).

The loss of vision is painless and slow to progress.

Photopsia

Many patients with RP report seeing flashes of light (photopsia) and describe them as small, shimmering, blinking lights similar to the symptoms of an ophthalmic migraine. However, in contrast to the patient with an ophthalmic migraine, the photopsia may be continuous rather than episodic.

Other history considerations

A careful family history with pedigree and possible examination of family members can be useful.

Drug history is essential to rule out phenothiazine/thioridazine toxicity.

Ocular examination

Because RP is a collection of many inherited diseases, significant variability exists in the physical findings. Interestingly, even patients with the same genetic defect can have different clinical manifestations of the disease. The most common findings are described below.

Vision

Snelling visual acuity can vary from 20/20 to light perception, but it is usually preserved until late in the disease.

Pupils

Pupil reaction can be normal with or without afferent pupillary defect.

Anterior segment

Patients can develop posterior subcapsular cataracts; up to 50% of adult patients with RP develop this type of cataract.

Fundus

The retina can appear unaffected early in the disease. Typical key findings include the following:

• Bone spicules - Midperipheral retinal hyperpigmentation in a characteristic pattern

• Optic nerve waxy pallor

• Atrophy of the RPE in the mid periphery of the retina

• Retinal arteriolar attenuation

The presence of vitreous cells is common. Patients can have a loss of the foveolar reflex or an abnormal vitreoretinal interface. A subset of patients with RP develops cystoid macular edema with an associated more rapid and potentially reversible loss of vision.

Retinitis punctata albescens, a variant of RP, presents with yellow deposits deep in the retina rather the normal increased pigmentation of the peripheral retina.

Cone-rod retinal degenerations present with central macular pigmentary changes (bull's eye maculopathy). ^[5] Choroideremia and gyrate atrophy typically present with large scalloped areas of peripheral retinal atrophy.

Systemic evaluation

A physical examination can be helpful to rule out syndromic RP, which are conditions that have pigmentary retinopathy and mimic RP. There are many syndromes; the more common and severe types are described below.

Usher syndrome is a form of RP with hearing loss. ^[1] As many as 10% of patients with RP can have hearing loss, and most of these patients have Usher syndrome. Hearing loss in this syndrome can be congenital with complete hearing loss or can occur in middle age with less profound changes in hearing. Most cases of Usher syndrome are autosomal recessive, and mutations have been found in more than 12 genetic loci and 8 identified genes.

RP and hearing loss are also associated with Waardenburg syndrome, Alport syndrome, and Refsum disease, all of which have their own systemic manifestations.

Kearns-Sayre syndrome consists of external ophthalmoplegia, lid ptosis, heart block, and pigmentary retinopathy. This syndrome is caused by a mitochondrial genetic defect, and vision loss tends to occur later in life with moderate visual field loss and night vision difficulties. The cardiac conduction block can be life-threatening; therefore, an electrocardiogram (ECG) is essential to help rule out this syndrome in patients.

Abetalipoproteinemia is a condition caused by the lack of apolipoprotein B, leading to fat malabsorption, fat-soluble vitamin deficiencies, spinocerebellar degeneration, and pigmentary retinal degeneration. High-dose therapy with vitamins A and E can prevent or limit the extent of the retinal degeneration.

The mucopolysaccharidoses (eg, Hurler syndrome, Scheie syndrome, Sanfilippo syndrome) can be affected with pigmentary retinopathy like RP.

Bardet-Biedl syndrome consists of polydactyly, truncal obesity, kidney dysfunction, short stature, and pigmentary retinopathy. In this autosomal recessive condition, intelligence is usually subnormal, and vision loss occurs in the second decade and progresses to severe vision loss by middle age. Renal dysfunction can be severe and life-threatening, requiring full evaluation with initial diagnosis.

Neuronal ceroid lipofuscinosis is characterized by dementia, seizures, and pigmentary retinopathy. Progressive vision loss occurs in early-onset cases. These disorders have been categorized clinically in relation to the age of onset and the temporal relation of vision loss to neurologic symptoms.

Onset of the infantile form is at age 8-18 months. The infantile disease is characterized by optic atrophy, macular pigmentary changes with mottling of the periphery, and low or absent electrophysiologic findings (electroretinogram [ERG] and visual-evoked response [VER]). In the infantile forms, the retinal changes can lead to confusion with Leber congenital amaurosis.

Onset of the late infantile form (Jansky-Bielschowsky disease) is age 2-4 years, and onset of the juvenile form (Vogt-Spielmeyer-Batten disease) is age 4-8 years. These forms more prominently show macular granularity or bull's eye maculopathy, and the appearance can be mistaken for a primary retinal dystrophy, such as Stargardt disease.

The adult form is known as Kufs syndrome. This form often does not have ophthalmologic manifestations, but electrophysiologic changes that are indicative of inner retinal and RPE damage have been observed.

RP is a collection of many different genetic diseases that lead to progressive photoreceptor loss and associated vision loss; therefore, the etiology is remarkably variable. As discussed in Pathophysiology, the final common pathway of all these diseases is photoreceptor cell death (predominantly rod photoreceptors). Research has shown that photoreceptor death can be induced by different pathways.

There have been so many important contributions by so many groups around the world that even cataloging them is a formidable task. Fortunately, the authors can refer the reader to the online version of McKusick's classic Mendelian Inheritance of Man (OMIM). Dr. Stephen Daiger also maintains a superb up-to-date Web site called RetNet that is dedicated to the molecular genetics of inherited retinal diseases. As shown on these websites, over 196 different genes have been found that lead to retinal disease and vision loss.

This article will not discuss all the genetic defects; however, some of the main defects, including several examples of how characteristic protein defects lead to vision loss and photoreceptor death, are discussed below.

In the United States, about 30% of autosomal dominant RP cases are caused by a mutation of the gene for rhodopsin, and approximately 15% of these cases are from a single point mutation. This single amino acid alteration in the protein rhodopsin then leads to photoreceptor cell death.

The autosomal dominant form of RP (ADRP) is usually the mildest form of RP with later age of onset. ADRP can be caused by mutations in at least 12 different genes, whereas the autosomal recessive form of RP can be triggered by changes in more than 22 different genes. X-linked RP tends to present early and is caused by mutations in only 2 known genes, with 75% of cases caused by a mutation of the retinitis pigmentosa GTPase regulator (RPGR) gene. ^[6]

Hebrard et al studied autosomal recessive RP by combining gene mapping and phenotype assessment in small, nonconsanguineous families. Comparing whole-genome scans using single nucleotide polymorphisms (SNP) microchips on 2 unrelated sibships with arRP, the study found one candidate gene for each family, thereby determining that only 2 affected individuals in each sibship were sufficient to lead to mutation identification; this can serve to avoid the long process of systematic sequencing of 506 exons. ^[7]

Photoreceptors are sensitive to light and have been placed in a high oxygen environment. As such, they are sensitive to genetic changes in multiple pathways, which can lead to their demise.

For example, some mutations in genes that control phototransduction and vitamin A delivery are expressed in the RPE (eg, RPE65, RBP, RDH5), but these RPE mutations cause the photoreceptors to die as bystanders, while the RPE initially stays healthy. Alternatively, mutations of the rhodopsin gene are expressed in the photoreceptor itself, which then leads directly to its own death.

Another interesting example is the mutation of the ABCA4 gene, which can cause both RP and Stargardt disease. This mutation affects a membrane protein called a flippase, which is found in the photoreceptor outer segments, and, as it moves, phototransduction molecules (eg, all-trans retinaldehyde) throughout the membrane. Defects in this protein cause a buildup of a toxic molecule that the RPE cells ingest when they phagocytosize the photoreceptor's outer segment. This leads to the death of the RPE. Since the photoreceptor requires the RPE for survival, it then in turn dies as well.

Another major class of mutations in RP affects the RDS/peripherin gene, which is found on chromosome arm 6p. Mutations in this gene also are found in pseudo-RP diseases, such as Gass adult foveal macular dystrophy, pattern dystrophy, and Stargardt-like disease. Therefore, classifying pigmentary retinopathies and dystrophies of the RPE by clinical appearance is problematic.

Mutations in beta-phosphodiesterase, an important protein in the phototransduction cascade, also have been linked to some cases of autosomal recessive RP. Many animal models of RP in dogs and mice demonstrate these and other defects. Underscoring the dichotomy between clinical presentation and genetic defect, a beta-phosphodiesterase mutation also has been linked to a congenital stationary night blindness.

Each syndromic form of RP has genetic defects that lead to photoreceptor death in addition to systemic complications. Over 45 genes have been found to cause these syndromic conditions, including 9 that cause Usher syndrome.

Cystoid Macular Edema (CME):

Cystoid is a common complication of RP with some studies finding up to 50% of patients experiencing edema of the macula at some point. ^[8] 126   Many treatments have been studied with some success in managing CME in RP. ^[9]  Many small case series have shown some efficacy of oral carbonic anhydrase inhibitors (CAI) such as dorzolamide and acetazolamide, ^{[10, 11]} topical or intravitreal steroids, ^{[12, 13]} and intravitreal antivascular endothelial growth factor agents. ^[14]  Nevertheless, there are no masked randomized clinical trials completed to help guide us in management of this complication.