Retinitis pigmentosa Retinitis pigmentosa Presenter Presenter

SAAD ALDAHMASH, MDSAAD ALDAHMASH, MD

BackgroundBackground Retinitis pigmentosa (RP) should be regarded Retinitis pigmentosa (RP) should be regarded

as a phenotypic description of several related, as a phenotypic description of several related, yet distinct, dystrophies of the photoreceptors yet distinct, dystrophies of the photoreceptors and the pigment epithelium. and the pigment epithelium.

Like many areas of medicine, new knowledge Like many areas of medicine, new knowledge of the underlying genetic mechanisms has of the underlying genetic mechanisms has revealed surprising findings; several conditions revealed surprising findings; several conditions that previously were considered identical or that previously were considered identical or closely related actually are caused by closely related actually are caused by completely different mechanisms, and completely different mechanisms, and apparently dissimilar conditions may be varying apparently dissimilar conditions may be varying expressions of a single genetic defect. expressions of a single genetic defect.

BackgroundBackgroundAs with many genetic disorders, autosomal As with many genetic disorders, autosomal

dominant (heterozygous) varieties generally dominant (heterozygous) varieties generally have a milder course than autosomal have a milder course than autosomal recessive (homozygous) varieties. recessive (homozygous) varieties.

Traditionally, disorders are grouped by their Traditionally, disorders are grouped by their clinical appearance. The increasing clinical appearance. The increasing incursion of genetic testing in the clinic may incursion of genetic testing in the clinic may completely change classification in the completely change classification in the future. future.

PathophysiologyPathophysiology With these cautionary remarks in mind, With these cautionary remarks in mind,

RP generically can be described as a RP generically can be described as a progressive cause of visual loss, which is progressive cause of visual loss, which is attributed to the loss of viable attributed to the loss of viable photoreceptors .photoreceptors .

RP usually is associated with pigmentary RP usually is associated with pigmentary changes in the retinal pigment epithelium changes in the retinal pigment epithelium (RPE), which may be primary or (RPE), which may be primary or secondary to the photoreceptor loss .secondary to the photoreceptor loss .

PathophysiologyPathophysiologyThe photoreceptors that predominantly are The photoreceptors that predominantly are

affected may be rods or cones, and the RPE affected may be rods or cones, and the RPE mostly may be affected centrally or peripherally. mostly may be affected centrally or peripherally.

Given the number and distribution of rods and Given the number and distribution of rods and cones in the retina, prognostic information about cones in the retina, prognostic information about the patient's visual loss depends on whether the the patient's visual loss depends on whether the process is primarily a rod-cone or cone-rod process is primarily a rod-cone or cone-rod dystrophy. dystrophy.

Patients with rod-cone dystrophies present with Patients with rod-cone dystrophies present with ring scotoma and night vision problems, which ring scotoma and night vision problems, which progress to a slow loss of all peripheral vision; progress to a slow loss of all peripheral vision; central vision is spared the longest.. central vision is spared the longest..

PathophysiologyPathophysiologyPatients with cone-rod or pure-cone Patients with cone-rod or pure-cone

dystrophies present with visual acuity dystrophies present with visual acuity loss, color discrimination loss, and day loss, color discrimination loss, and day vision problems.vision problems.

RP is a progressive disorder by definition; RP is a progressive disorder by definition; stationary dystrophies commonly are stationary dystrophies commonly are lumped into the category of congenital lumped into the category of congenital stationary night blindness (CSNB). stationary night blindness (CSNB).

PathophysiologyPathophysiologyThe inclusion or exclusion of different The inclusion or exclusion of different

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

PathophysiologyPathophysiologySystemic conditions associated with Systemic conditions associated with

pigmentary retinopathy are pigmentary retinopathy are numerous; e.g.Usher, Alport, numerous; e.g.Usher, Alport, Alström, Jansky-Bielschowsky, Vogt-Alström, Jansky-Bielschowsky, Vogt-Spielmeyer-Batten, Zellweger, Spielmeyer-Batten, Zellweger, Refsum, and Kearns-Sayre. Refsum, and Kearns-Sayre.

FrequencyFrequency In the US: In the US: The incidence of primary RP is The incidence of primary RP is

approximately 1 in 4000. To date, more approximately 1 in 4000. To date, more than 70 different genetic defects have been than 70 different genetic defects have been identified, including the following: X-linked identified, including the following: X-linked (9%), autosomal recessive (16%), and (9%), autosomal recessive (16%), and autosomal dominant (22%); the remaining autosomal dominant (22%); the remaining cases are primary RP or RP simplex. cases are primary RP or RP simplex.

Internationally: Internationally: Worldwide incidence is Worldwide incidence is same as in the United States. same as in the United States.

FrequencyFrequencySex: Sex: Usually, no sexual predilection Usually, no sexual predilection

exists. However, because of X-linked exists. However, because of X-linked varieties, men may be affected slightly varieties, men may be affected slightly more than women. more than women.

Age: Age: The age of onset varies depending The age of onset varies depending on the disorder. RP usually is diagnosed on the disorder. RP usually is diagnosed in young adulthood, although it can occur in young adulthood, although it can occur anywhere from infancy to mid 30s to 50s. anywhere from infancy to mid 30s to 50s.

Mortality/MorbidityMortality/MorbidityA recent multicenter population A recent multicenter population

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

Clinical featuresClinical featuresSymptoms :Symptoms :Presenting symptoms of retinal Presenting symptoms of retinal

dystrophies vary as much as the dystrophies vary as much as the spectrum of disorders. Nyctalopia (loss of spectrum of disorders. Nyctalopia (loss of night vision) and tunnel vision (loss of night vision) and tunnel vision (loss of peripheral vision) are classic complaints peripheral vision) are classic complaints of RP, principally rod-cone diseaseof RP, principally rod-cone disease

Clinical features Clinical features When obtaining historical information, When obtaining historical information,

ask about adaptation to darkness.ask about adaptation to darkness.– Patients may report difficulty driving in Patients may report difficulty driving in

low light, at dusk, or in fog.low light, at dusk, or in fog.– Dark stairwells, movie theaters, and Dark stairwells, movie theaters, and

restaurants are situations where the restaurants are situations where the transition between bright illumination and transition between bright illumination and semidarkness present difficulties to some semidarkness present difficulties to some patientspatients

Clinical featuresClinical featuresRing scotoma or loss of peripheral vision Ring scotoma or loss of peripheral vision

may be profound before the patient may be profound before the patient explicitly recognizes it.explicitly recognizes it.– Symptoms may include bumping into furniture Symptoms may include bumping into furniture

or doorframes or difficulty in playing games or doorframes or difficulty in playing games (eg, tennis, basketball, baseball).(eg, tennis, basketball, baseball).

– Pain or abnormal sensation is not reported.Pain or abnormal sensation is not reported.– The loss of vision should be reasonably The loss of vision should be reasonably

bilaterally symmetric and, once recognized, bilaterally symmetric and, once recognized, slow in onset or progression.slow in onset or progression.

Clinical featuresClinical featuresIn contrast, cone-rod dystrophies and In contrast, cone-rod dystrophies and

macular and pattern dystrophies present macular and pattern dystrophies present as bilateral, painless central visual loss.as bilateral, painless central visual loss.– Vision is often worse under bright lighting with Vision is often worse under bright lighting with

loss or color discrimination.loss or color discrimination.– Some cases of rod-cone degenerations are part Some cases of rod-cone degenerations are part

of a systemic disorder with its own signs and of a systemic disorder with its own signs and symptoms (eg, Usher syndrome, Bardet-Biedl symptoms (eg, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Batten-syndrome, Kearns-Sayre syndrome, Batten-Mayou disease, Vogt-Spielmeyer disease).Mayou disease, Vogt-Spielmeyer disease).

Clinical featuresClinical featuresPhysical: Physical: OcularOcular

The external appearance and anterior segment The external appearance and anterior segment of the eyes is generally normal in most of of the eyes is generally normal in most of these retinal dystrophies.these retinal dystrophies.

Late appearance of posterior subcapsular Late appearance of posterior subcapsular cataracts is observed in RP.cataracts is observed in RP.

Depending on the stage and type of disorder, Depending on the stage and type of disorder, visual acuity may range from normal (20/20) to visual acuity may range from normal (20/20) to no light perception.no light perception.

Pupillary response may be normal or abnormal Pupillary response may be normal or abnormal with or without afferent pupillary defectwith or without afferent pupillary defect

Clinical featuresClinical featuresThe vitreous may show fine cells.The vitreous may show fine cells.The typical features of rod-cone RP may The typical features of rod-cone RP may

include RPE hyperpigmentation in the include RPE hyperpigmentation in the form of "bone spicules" that alternate form of "bone spicules" that alternate with atrophic regions, attenuation of the with atrophic regions, attenuation of the arterioles, and waxy pallor of the optic arterioles, and waxy pallor of the optic nerve head.nerve head.

Cystic macular edema may be observed Cystic macular edema may be observed in severe cases of RP.in severe cases of RP.

•Fine dust-like pigmentation•Arteriolar attenuation

Anterior and peripheral spreadUnmasking of large choroidal vessels

Perivascular ‘bone-spicule’ pigmentation

•Initially mid-peripheral

•Optic disc pallor

•Maculopathy

QuadranticQuadrantic

SectorialSectorial

PericentriPericentri

ParavenousParavenous

Ocular associations of Ocular associations of retinitis pigmentosaretinitis pigmentosa

• Cataract Cataract

Keratoconus Keratoconus

Vitreous degenerationVitreous degeneration

Optic disc drusen Optic disc drusen

Open-angle glaucomaOpen-angle glaucoma

Myopia Myopia

Clinical featuresClinical featuresCone-rod disease may present with a bull's eye Cone-rod disease may present with a bull's eye

maculopathy. By contrast, scalloped areas of maculopathy. By contrast, scalloped areas of atrophy may be seen in choroideremia, gyrate atrophy may be seen in choroideremia, gyrate atrophy, or myopic degeneration; a tapetal, atrophy, or myopic degeneration; a tapetal, transient sheen is seen in some X-linked CSNB transient sheen is seen in some X-linked CSNB (the Mizuo-Nakamura effect).(the Mizuo-Nakamura effect).

Yellow flecks or dots are seen in a wide variety Yellow flecks or dots are seen in a wide variety of disorders; most of them are not RP. Retinitis of disorders; most of them are not RP. Retinitis punctata albescens is a form of RP with punctata albescens is a form of RP with numerous flecks, whereas fundus albipunctatus numerous flecks, whereas fundus albipunctatus is a form of CSNB with a similar appearanceis a form of CSNB with a similar appearance

SystemicSystemicassociationsassociations

Systemic findings are important in diagnosing Systemic findings are important in diagnosing pigmentary retinopathies.pigmentary retinopathies.

Patients with Usher syndrome have hearing Patients with Usher syndrome have hearing loss, which may be profound or partial with a loss, which may be profound or partial with a congenital or late onset.congenital or late onset.

RP and hearing loss also are associated with RP and hearing loss also are associated with Waardenburg syndrome, Alström syndrome, Waardenburg syndrome, Alström syndrome, Alport syndrome, Refsum disease, and other Alport syndrome, Refsum disease, and other systemic conditions, which all have their own systemic conditions, which all have their own systemic manifestationssystemic manifestations

SystemicSystemicassociationsassociations

Short stature, renal dysfunction, and Short stature, renal dysfunction, and polydactyly are some signs of Bardet-Biedl polydactyly are some signs of Bardet-Biedl syndrome or Lawrence-Moon syndrome syndrome or Lawrence-Moon syndrome when associated with pigmentary when associated with pigmentary retinopathy.retinopathy.

The mucopolysaccharidoses may be The mucopolysaccharidoses may be associated with RP (eg, Hurler syndrome, associated with RP (eg, Hurler syndrome, Scheie syndrome, Sanfilippo syndrome), as Scheie syndrome, Sanfilippo syndrome), as well as the mitochondrial disorder, Kearns-well as the mitochondrial disorder, Kearns-Sayre syndrome, which manifests as ptosis, Sayre syndrome, which manifests as ptosis, external ophthalmoplegia, and heart blockexternal ophthalmoplegia, and heart block

Differentials Differentials ARMD, nonexuditive ARMD, nonexuditive Chloroquine , hydroxychloroquine toxicity Chloroquine , hydroxychloroquine toxicity Central serious chorioretinopathyCentral serious chorioretinopathyNeuroretinitis Neuroretinitis Best diseaseBest diseaseToxoplasmosis, other infections, rubella, Toxoplasmosis, other infections, rubella,

cytomegalovirus infection, and herpes simplex cytomegalovirus infection, and herpes simplex (TORCH)(TORCH)

Cancer-associated retinopathy (CAR)Cancer-associated retinopathy (CAR)

Ocular albinism Ocular albinism

Lab Studies Lab Studies Venereal Disease Research Laboratory (VDRL) Venereal Disease Research Laboratory (VDRL)

test and fluorescent treponemal antibody test and fluorescent treponemal antibody absorption (FTA-ABS) testabsorption (FTA-ABS) test

Serum phytanic acid when other neurologic Serum phytanic acid when other neurologic abnormalities are presentabnormalities are present

Ornithine levels in patients where a diagnosis Ornithine levels in patients where a diagnosis of gyrate atrophy may be confused with RPof gyrate atrophy may be confused with RP

ECG to rule out heart block in patients with ECG to rule out heart block in patients with suspected Kearns-Sayre syndromesuspected Kearns-Sayre syndrome

Lipid profile with possible protein Lipid profile with possible protein electrophoresis in patients with suspected electrophoresis in patients with suspected abetalipoproteinemiaabetalipoproteinemia

Lab StudiesLab StudiesAntibodiesAntibodies

Antiretinal antibodies, particularly Antiretinal antibodies, particularly antirecoverin antibodies, may be antirecoverin antibodies, may be observed, especially in CAR or in severe observed, especially in CAR or in severe cases of RP. Commercial tests are cases of RP. Commercial tests are available.available.

Recoverin is part of the Recoverin is part of the phototransduction cascade in cone cells.phototransduction cascade in cone cells.

Imaging StudiesImaging Studies Although fluorescein angiography is Although fluorescein angiography is

rarely useful to the clinician in rarely useful to the clinician in diagnosing RP, cystoid macular diagnosing RP, cystoid macular edema might be appreciated more edema might be appreciated more easily than with biomicroscopy. easily than with biomicroscopy.

Other Tests Other Tests

ElectroretinogramElectroretinogramERG is the most critical diagnostic test for RP ERG is the most critical diagnostic test for RP

because it provides an objective measure of rod because it provides an objective measure of rod and cone function across the retina. and cone function across the retina. The full-field ERG in RP typically shows a marked The full-field ERG in RP typically shows a marked

reduction of both rod and cone signals, although rod loss reduction of both rod and cone signals, although rod loss generally predominates. generally predominates.

A and b waves are reduced since the primary site of A and b waves are reduced since the primary site of disease is at the photoreceptors or RPE. disease is at the photoreceptors or RPE.

The ERG is usually abnormal in infancy or early The ERG is usually abnormal in infancy or early childhood, except for some of the very mild and regional childhood, except for some of the very mild and regional forms of RP.forms of RP.

ERGERGBy contrast, the diagnosis for cone By contrast, the diagnosis for cone

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

EOGEOGElectro-oculogramElectro-oculogram

Electro-oculogram (EOG) findings are Electro-oculogram (EOG) findings are always abnormal when ERG findings are always abnormal when ERG findings are abnormal; therefore, EOG is not helpful to abnormal; therefore, EOG is not helpful to the clinician in diagnosing RP.the clinician in diagnosing RP.

Central macular changes, normal ERG Central macular changes, normal ERG findings, and abnormal EOG findings findings, and abnormal EOG findings suggest Bests vitelliform macular suggest Bests vitelliform macular dystrophy.dystrophy.

VER&VF VER&VF Visually evoked cortical potentials (VECPs) Visually evoked cortical potentials (VECPs)

rarely provide additional information to the rarely provide additional information to the clinician when diagnosing RP.clinician when diagnosing RP.

Formal visual fieldFormal visual fieldThis test is the most useful measure for ongoing This test is the most useful measure for ongoing

follow-up care of patients with RP because a follow-up care of patients with RP because a progressive loss of side vision is often the major progressive loss of side vision is often the major symptom along with visual acuity changes.symptom along with visual acuity changes.

Goldmann (kinetic) perimetry is recommended Goldmann (kinetic) perimetry is recommended to reach the far periphery.to reach the far periphery.

Other tests Other tests Color testing: Mild blue-yellow axis color Color testing: Mild blue-yellow axis color

defects are common, although most defects are common, although most patients with RP do not clinically complain patients with RP do not clinically complain of major difficulty with color perception.of major difficulty with color perception.

Dark adaptationDark adaptationContrast sensitivity often is reduced out of Contrast sensitivity often is reduced out of

proportion to visual acuity in patients with RP. proportion to visual acuity in patients with RP. Patients are usually sensitive to bright light.Patients are usually sensitive to bright light.

Patients with fundus albipunctatus have poor Patients with fundus albipunctatus have poor dark adaptation but may have normal results dark adaptation but may have normal results after 3-4 hours of adaptation.after 3-4 hours of adaptation.

Treatment Treatment Vitamin A/beta-caroteneVitamin A/beta-carotene Antioxidants may be useful in treating patients with RP, Antioxidants may be useful in treating patients with RP,

but no evidence in favor of vitamin supplementation but no evidence in favor of vitamin supplementation exists; slight evidence to the contrary may even exist. exists; slight evidence to the contrary may even exist.

A recent comprehensive epidemiologic study concluded A recent comprehensive epidemiologic study concluded that very high daily doses of vitamin A palmitate that very high daily doses of vitamin A palmitate (15,000 U/d) slow the progress of RP by about 2% per (15,000 U/d) slow the progress of RP by about 2% per year. The effects are modest; therefore, this treatment year. The effects are modest; therefore, this treatment must be weighed against the uncertain risk of long-term must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A. adverse effects from large chronic doses of vitamin A.

Annually check liver enzymes and vitamin A levels. Annually check liver enzymes and vitamin A levels. Beta-carotene doses of 25,000 IU have been Beta-carotene doses of 25,000 IU have been recommendedrecommended

Acetazolamide Acetazolamide

In a small percentage of patients with RP, In a small percentage of patients with RP, cystoid edema may respond to oral carbonic cystoid edema may respond to oral carbonic anhydrase inhibitors, such as acetazolamide, anhydrase inhibitors, such as acetazolamide, with some subjective improvement in visual with some subjective improvement in visual function. function.

In these patients, the macular RPE is In these patients, the macular RPE is relatively uninvolved by disease because relatively uninvolved by disease because carbonic anhydrase inhibitors must act upon carbonic anhydrase inhibitors must act upon functional RPE to enhance water transportfunctional RPE to enhance water transport

vitamin E& ascorbic acid vitamin E& ascorbic acid High doses of vitamin E (400 U/d) High doses of vitamin E (400 U/d)

were modestly deleterious, but doses were modestly deleterious, but doses as high as 800 IU/d have been as high as 800 IU/d have been recommended.recommended.

Although doses of 1000 mg/d Although doses of 1000 mg/d ascorbic acid have been ascorbic acid have been recommended, no evidence exists recommended, no evidence exists that ascorbic acid is helpful.that ascorbic acid is helpful.

Lutein& immunosuppressive Lutein& immunosuppressive

Lutein apparently may slow retinal Lutein apparently may slow retinal degeneration, but the benefits of this degeneration, but the benefits of this substance in human diseases are uncertain. substance in human diseases are uncertain.

Doses of 20 mg/d have been recommendedDoses of 20 mg/d have been recommendedIn patients who present with antiretinal In patients who present with antiretinal

antibodies, immunosuppressive agents antibodies, immunosuppressive agents (including steroids) have been used with (including steroids) have been used with anecdotal success. anecdotal success.

Surgical CareSurgical CareCataract extractionCataract extraction

Cataract surgery might be beneficial.Cataract surgery might be beneficial.Late in the course of RP, when the Late in the course of RP, when the

cataracts are most likely to be significant, cataracts are most likely to be significant, the visual field is likely to be narrow. the visual field is likely to be narrow. Associated vision loss from cystoid Associated vision loss from cystoid macular edema also may exist.macular edema also may exist.

Educating patients about reasonable Educating patients about reasonable expectations of cataract surgery is expectations of cataract surgery is essentialessential

Transplantation Transplantation Small patches of retinal or RPE tissue have Small patches of retinal or RPE tissue have

been transplanted, and this technique been transplanted, and this technique could be helpful in the following RP forms: could be helpful in the following RP forms: when RP is based on an RPE defect, when when RP is based on an RPE defect, when RP with primary defects exists in the outer RP with primary defects exists in the outer segments, if the disease is driven by an segments, if the disease is driven by an overload of the phagocytic activity of the overload of the phagocytic activity of the RPE, or if the RPE cannot provide sufficient RPE, or if the RPE cannot provide sufficient nutritional support to the outer segments.nutritional support to the outer segments.

No current investigational protocols exist No current investigational protocols exist in humans for this type of interventionin humans for this type of intervention

Consultations Consultations

Clearly, RP is associated with several Clearly, RP is associated with several systemic diseases. Because of the severity of systemic diseases. Because of the severity of the systemic illness and its early presentation the systemic illness and its early presentation in most patients, the ophthalmologist may in most patients, the ophthalmologist may act as the consultant to an internist.act as the consultant to an internist.

Low-vision specialists can provide magnifying Low-vision specialists can provide magnifying devices and field-expanding lenses for devices and field-expanding lenses for patients with RP who have poor central patients with RP who have poor central vision.vision.

DietDietMany practitioners recommend a Many practitioners recommend a

well-balanced diet with adequate well-balanced diet with adequate leafy green vegetables that contain leafy green vegetables that contain the aforementioned supplements in the aforementioned supplements in nontoxic doses.nontoxic doses.

No evidence exists that particular No evidence exists that particular foods in excess are helpful or foods in excess are helpful or harmful.harmful.

ActivityActivityLight exposureLight exposure

Stressful light exposure, which generates freeradicals Stressful light exposure, which generates freeradicals and strains the regenerative capacity of the eye, and strains the regenerative capacity of the eye, might put dystrophic retinas at a disadvantage. might put dystrophic retinas at a disadvantage. However, little direct or epidemiologic evidence However, little direct or epidemiologic evidence exists that the disease is modified by light.exists that the disease is modified by light.

A specific form of RP, the Pro23His mutation in A specific form of RP, the Pro23His mutation in rhodopsin, has been shown to increase retinal rhodopsin, has been shown to increase retinal damage with increased light exposure.damage with increased light exposure.

UV-absorbing lenses are recommended, particularly UV-absorbing lenses are recommended, particularly in rhodopsin mutation varieties of RP, and patients in rhodopsin mutation varieties of RP, and patients with cone degeneration frequently benefit from with cone degeneration frequently benefit from tinted lensestinted lenses

Viagra (Sildenafil)Viagra (Sildenafil)

Although evidence suggests increased retinal Although evidence suggests increased retinal damage with the use of this new medication, the damage with the use of this new medication, the manufacturer does not recommend use in manufacturer does not recommend use in patients with RP. The medication partially inhibits patients with RP. The medication partially inhibits the retinal enzyme, phosphodiesesterase-6 (PDE-the retinal enzyme, phosphodiesesterase-6 (PDE-6). 6).

Some varieties of RP involve a genetic defect in Some varieties of RP involve a genetic defect in the gene for PDE-6. the gene for PDE-6.

Some users of sildenafil have experienced blue Some users of sildenafil have experienced blue photopsias, suggesting that the drug is active in photopsias, suggesting that the drug is active in the retina at a physiological level. the retina at a physiological level.

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