Retinitis pigmentosa

Presenter SAAD ALDAHMASH, MD

Background
Retinitis pigmentosa (RP) should be regarded as a
phenotypic description of several related, yet distinct, dystrophies of the photoreceptors and the pigment epithelium. Like many areas of medicine, new knowledge of the underlying genetic mechanisms has revealed surprising findings; several conditions that previously were considered identical or closely related actually are caused by completely different mechanisms, and apparently dissimilar conditions may be varying expressions of a single genetic defect.

Background
As with many genetic disorders, autosomal
dominant (heterozygous) varieties generally have a milder course than autosomal recessive (homozygous) varieties. Traditionally, disorders are grouped by their clinical appearance. The increasing incursion of genetic testing in the clinic may completely change classification in the future.

Pathophysiology
With these cautionary remarks in mind, RP
generically can be described as a progressive cause of visual loss, which is attributed to the loss of viable photoreceptors . RP usually is associated with pigmentary changes in the retinal pigment epithelium (RPE), which may be primary or secondary to the photoreceptor loss .

Pathophysiology
The photoreceptors that predominantly are affected
may be rods or cones, and the RPE mostly may be affected centrally or peripherally. Given the number and distribution of rods and cones in the retina, prognostic information about the patient's visual loss depends on whether the process is primarily a rod-cone or cone-rod dystrophy. Patients with rod-cone dystrophies present with ring scotoma and night vision problems, which progress to a slow loss of all peripheral vision; central vision is spared the longest..

Pathophysiology
Patients with cone-rod or pure-cone
dystrophies present with visual acuity loss, color discrimination loss, and day vision problems. RP is a progressive disorder by definition; stationary dystrophies commonly are lumped into the category of congenital stationary night blindness (CSNB).

Pathophysiology
The inclusion or exclusion of different
conditions for consideration is somewhat arbitrary, given the ill-defined nature of RP. The rod-cone or cone-rod dystrophies primarily are considered, either in isolated form (primary RP) or in association with a systemic condition.

Pathophysiology
Systemic conditions associated with
pigmentary retinopathy are numerous; e.g.Usher, Alport, Alstrm, JanskyBielschowsky, Vogt-Spielmeyer-Batten, Zellweger, Refsum, and Kearns-Sayre.

Frequency
In the US: The incidence of primary RP is
approximately 1 in 4000. To date, more than 70 different genetic defects have been identified, including the following: X-linked (9%), autosomal recessive (16%), and autosomal dominant (22%); the remaining cases are primary RP or RP simplex. Internationally: Worldwide incidence is same as in the United States.

Frequency
Sex: Usually, no sexual predilection
exists. However, because of X-linked varieties, men may be affected slightly more than women. Age: The age of onset varies depending on the disorder. RP usually is diagnosed in young adulthood, although it can occur anywhere from infancy to mid 30s to 50s.

Mortality/Morbidity
A recent multicenter population study by
Grover et al of patients with RP who were at least 45 years or older found the following findings: 52% had 20/40 or better vision in at least one eye, 25% had 20/200 or worse vision, and 0.5% had no light perception.

Clinical features
Symptoms : Presenting symptoms of retinal dystrophies vary as much as the spectrum of disorders. Nyctalopia (loss of night vision) and tunnel vision (loss of peripheral vision) are classic complaints of RP, principally rod-cone disease

Clinical features
When obtaining historical information, ask
about adaptation to darkness.
Patients may report difficulty driving in low light, at dusk, or in fog. Dark stairwells, movie theaters, and restaurants are situations where the transition between bright illumination and semidarkness present difficulties to some patients

Clinical features
Ring scotoma or loss of peripheral vision may be
profound before the patient explicitly recognizes it.
Symptoms may include bumping into furniture or doorframes or difficulty in playing games (eg, tennis, basketball, baseball). Pain or abnormal sensation is not reported. The loss of vision should be reasonably bilaterally symmetric and, once recognized, slow in onset or progression.

Clinical features
In contrast, cone-rod dystrophies and macular
and pattern dystrophies present as bilateral, painless central visual loss.
Vision is often worse under bright lighting with loss or color discrimination. Some cases of rod-cone degenerations are part of a systemic disorder with its own signs and symptoms (eg, Usher syndrome, Bardet-Biedl syndrome, KearnsSayre syndrome, Batten-Mayou disease, VogtSpielmeyer disease).

Clinical features
Physical: Ocular
The external appearance and anterior segment of the eyes is generally normal in most of these retinal dystrophies. Late appearance of posterior subcapsular cataracts is observed in RP. Depending on the stage and type of disorder, visual acuity may range from normal (20/20) to no light perception. Pupillary response may be normal or abnormal with or without afferent pupillary defect

Clinical features
The vitreous may show fine cells. The typical features of rod-cone RP may include RPE hyperpigmentation in the form of "bone spicules" that alternate with atrophic regions, attenuation of the arterioles, and waxy pallor of the optic nerve head. Cystic macular edema may be observed in severe cases of RP.

Fine dust-like pigmentation Arteriolar attenuation

Anterior and peripheral spread Unmasking of large choroidal vessels

Perivascular bone-spicule pigmentation

Initially mid-peripheral

Optic disc pallor Maculopathy

Quadrantic

Sectorial

Pericentri

Paravenous

Ocular associations of retinitis pigmentosa

Cataract

Keratoconus

Vitreous degeneration

Optic disc drusen

Open-angle glaucoma

Myopia

Clinical features
Cone-rod disease may present with a bull's eye maculopathy. By contrast, scalloped areas of atrophy may be seen in choroideremia, gyrate atrophy, or myopic degeneration; a tapetal, transient sheen is seen in some X-linked CSNB (the Mizuo-Nakamura effect). Yellow flecks or dots are seen in a wide variety of disorders; most of them are not RP. Retinitis punctata albescens is a form of RP with numerous flecks, whereas fundus albipunctatus is a form of CSNB with a similar appearance

Systemic associations
Systemic findings are important in diagnosing pigmentary retinopathies. Patients with Usher syndrome have hearing loss, which may be profound or partial with a congenital or late onset. RP and hearing loss also are associated with Waardenburg syndrome, Alstrm syndrome, Alport syndrome, Refsum disease, and other systemic conditions, which all have their own systemic manifestations

Systemic associations
Short stature, renal dysfunction, and polydactyly are some signs of Bardet-Biedl syndrome or Lawrence-Moon syndrome when associated with pigmentary retinopathy. The mucopolysaccharidoses may be associated with RP (eg, Hurler syndrome, Scheie syndrome, Sanfilippo syndrome), as well as the mitochondrial disorder, KearnsSayre syndrome, which manifests as ptosis, external ophthalmoplegia, and heart block

Differentials
ARMD, nonexuditive Chloroquine , hydroxychloroquine toxicity Central serious chorioretinopathy Neuroretinitis Best disease Toxoplasmosis, other infections, rubella, cytomegalovirus
infection, and herpes simplex (TORCH) Cancer-associated retinopathy (CAR)

Ocular albinism

Lab Studies
Venereal Disease Research Laboratory (VDRL) test and fluorescent treponemal antibody absorption (FTA-ABS) test Serum phytanic acid when other neurologic abnormalities are present Ornithine levels in patients where a diagnosis of gyrate atrophy may be confused with RP ECG to rule out heart block in patients with suspected Kearns-Sayre syndrome Lipid profile with possible protein electrophoresis in patients with suspected abetalipoproteinemia

Lab Studies
Antibodies
Antiretinal antibodies, particularly antirecoverin antibodies, may be observed, especially in CAR or in severe cases of RP. Commercial tests are available. Recoverin is part of the phototransduction cascade in cone cells.

Imaging Studies
Although fluorescein angiography is rarely
useful to the clinician in diagnosing RP, cystoid macular edema might be appreciated more easily than with biomicroscopy.

Other Tests
Electroretinogram
ERG is the most critical diagnostic test for RP because it provides an objective measure of rod and cone function across the retina.
The full-field ERG in RP typically shows a marked reduction of both rod and cone signals, although rod loss generally predominates. A and b waves are reduced since the primary site of disease is at the photoreceptors or RPE. The ERG is usually abnormal in infancy or early childhood, except for some of the very mild and regional forms of RP.

ERG
By contrast, the diagnosis for cone dystrophies is aided in part by these clinical findings but more definitively by the ERG. Severe and selective loss of cone function occurs with varying degrees of rod abnormality.

EOG
Electro-oculogram
Electro-oculogram (EOG) findings are always abnormal when ERG findings are abnormal; therefore, EOG is not helpful to the clinician in diagnosing RP. Central macular changes, normal ERG findings, and abnormal EOG findings suggest Bests vitelliform macular dystrophy.

VER&VF
Visually evoked cortical potentials (VECPs) rarely provide additional information to the clinician when diagnosing RP. Formal visual field
This test is the most useful measure for ongoing follow-up care of patients with RP because a progressive loss of side vision is often the major symptom along with visual acuity changes. Goldmann (kinetic) perimetry is recommended to reach the far periphery.

Other tests
Color testing: Mild blue-yellow axis color defects are common, although most patients with RP do not clinically complain of major difficulty with color perception. Dark adaptation
Contrast sensitivity often is reduced out of proportion to visual acuity in patients with RP. Patients are usually sensitive to bright light. Patients with fundus albipunctatus have poor dark adaptation but may have normal results after 3-4 hours of adaptation.

Treatment
Vitamin A/beta-carotene
Antioxidants may be useful in treating patients with RP,
but no evidence in favor of vitamin supplementation exists; slight evidence to the contrary may even exist. A recent comprehensive epidemiologic study concluded that very high daily doses of vitamin A palmitate (15,000 U/d) slow the progress of RP by about 2% per year. The effects are modest; therefore, this treatment must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A. Annually check liver enzymes and vitamin A levels. Betacarotene doses of 25,000 IU have been recommended

Acetazolamide
In a small percentage of patients with RP,

cystoid edema may respond to oral carbonic anhydrase inhibitors, such as acetazolamide, with some subjective improvement in visual function. In these patients, the macular RPE is relatively uninvolved by disease because carbonic anhydrase inhibitors must act upon functional RPE to enhance water transport

vitamin E& ascorbic acid

High doses of vitamin E (400 U/d) were
modestly deleterious, but doses as high as 800 IU/d have been recommended. Although doses of 1000 mg/d ascorbic acid have been recommended, no evidence exists that ascorbic acid is helpful.

Lutein& immunosuppressive
Lutein apparently may slow retinal degeneration,
but the benefits of this substance in human diseases are uncertain. Doses of 20 mg/d have been recommended In patients who present with antiretinal antibodies, immunosuppressive agents (including steroids) have been used with anecdotal success.

Surgical Care
Cataract extraction
Cataract surgery might be beneficial. Late in the course of RP, when the cataracts are most likely to be significant, the visual field is likely to be narrow. Associated vision loss from cystoid macular edema also may exist. Educating patients about reasonable expectations of cataract surgery is essential

Transplantation
Small patches of retinal or RPE tissue have been transplanted, and this technique could be helpful in the following RP forms: when RP is based on an RPE defect, when RP with primary defects exists in the outer segments, if the disease is driven by an overload of the phagocytic activity of the RPE, or if the RPE cannot provide sufficient nutritional support to the outer segments. No current investigational protocols exist in humans for this type of intervention

Consultations
Clearly, RP is associated with several systemic

diseases. Because of the severity of the systemic illness and its early presentation in most patients, the ophthalmologist may act as the consultant to an internist. Low-vision specialists can provide magnifying devices and field-expanding lenses for patients with RP who have poor central vision.

Diet
Many practitioners recommend a wellbalanced diet with adequate leafy green vegetables that contain the aforementioned supplements in nontoxic doses. No evidence exists that particular foods in excess are helpful or harmful.

Activity
Light exposure
Stressful light exposure, which generates freeradicals and strains the regenerative capacity of the eye, might put dystrophic retinas at a disadvantage. However, little direct or epidemiologic evidence exists that the disease is modified by light. A specific form of RP, the Pro23His mutation in rhodopsin, has been shown to increase retinal damage with increased light exposure. UV-absorbing lenses are recommended, particularly in rhodopsin mutation varieties of RP, and patients with cone degeneration frequently benefit from tinted lenses

Viagra (Sildenafil)
Although evidence suggests increased retinal damage with the use of this new medication, the manufacturer does not recommend use in patients with RP. The medication partially inhibits the retinal enzyme, phosphodiesesterase-6 (PDE-6). Some varieties of RP involve a genetic defect in the gene for PDE-6. Some users of sildenafil have experienced blue photopsias, suggesting that the drug is active in the retina at a physiological level.

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