What's Your Diagnosis?

Glare, reduced contrast in patient with chorioretinal atrophy

Top: Chorioretinal atrophy is concentrated in the posterior pole and extends outside the arcades in the presence of moderate pigmentary changes. Bottom: A closer view of waxy disc pallor in the right eye.
Source: Bonnie-Kim Hang, OD

A 74-year-old Caucasian man presented with a chief complaint of gradually impaired contrast and progressively increased glare that was worse in the left eye compared to the right eye, as well as bilateral reduced peripheral and central vision that persisted for several months.

Posterior pole of the left eye reveals chorioretinal atrophy, pigmentary changes and waxy disc pallor obscured by dense cataract.

The patient’s ocular history was significant for nuclear sclerotic cataracts in the left eye and a posterior chamber intraocular lens in the right eye that was implanted in 2008. The patient’s medical history was positive for hyperlipidemia, depression and diabetes.

Fundus autofluorescence enhances areas of retinal pigment epithelium atrophy superior temporal to the macula of the right eye

Best-corrected visual acuity was 5/200 OD (Feinbloom chart) and light perception in the left eye. Slit lamp exam revealed a clear PC-IOL in the right eye and NO3 NC4 grade cataracts in the left eye (per Lens Opacities Classification System III). Dilated fundus exam revealed extensive chorioretinal atrophy in the posterior pole, which extended into the mid-periphery. Mild pigmentary changes were scattered throughout, and concurrent vessel attenuation and waxy disc pallor were noted in both eyes. Spectral domain optical coherence tomography (SD-OCT) revealed extensive atrophy extending from the inner to outer retinal layers with no discernable foveal pit.

Left: Radial macular OCT scan highlights the diffuse chorioretinal atrophy that can be seen extending from the macula into the posterior pole of the right eye. Right: Macular OCT scan reveals a minimally discernable foveal pit. Extensive atrophy of the outer retinal layers is also present.

What’s your diagnosis?
See answer on the next page

Differential diagnoses for retinitis pigmentosa inversa (RPI) include chorioretinal disorders that affect the macula such as Leber’s congenital amaurosis, progressive cone-rod dystrophy, Stargardt’s disease and drug toxicity from medications such as tamoxifen, chloroquine and hydroxychloroquine.

Differential diagnoses

Leber’s congenital amaurosis is an autosomal recessive retinal disease resulting in severely decreased vision, including blindness. Unlike RP inversa, this severe vision loss occurs at an early age, often by the first year of life. Initially, the fundus may appear clinically normal, but eventually retinal changes that can mimic RP are detectable. Most patients have either a salt-and-pepper appearance or atrophy localized to the macula.

Cone-rod dystrophies present as pigmentary disorders localized to the macular region. In contrast to RP (classified as rod-cone dystrophies), there is initial cone involvement, or simultaneous cone and rod loss. Decreased visual acuity is the first symptom, usually discovered within the first decade of life. Central scotomas, which may be initially discovered while reading or scanning; dyschromatopsia; and photophobia occur early during school-age years. Subsequently, night blindness ensues, and nystagmus is present. Pigmentary deposits, vessel attenuation and varying degrees of atrophy are similar to RP inversa. Electroretinography results would reveal a dominance of photopic over scotopic responses. RPI would present opposite findings.

Stargardt’s disease has one of the highest prevalences of macular dystrophies presenting during childhood. It comprises approximately 7% of all childhood macular dystrophies. Funduscopically, there are pigmentary changes in the macula. Pisciform flecks comprised of lipofuscin in the perifoveal region distinguish Stargardt’s from other maculopathies such as RPI. Stargardt’s has a male and Caucasian predilection. Age of onset varies from the first to the sixth decade, with the youngest reported case at age 5 years and a median age about 20 years. Vision gradually decreases to 20/100 after 10 years of duration and usually remains at 20/200 in the majority of patients after 20 years (Armstrong et al.).

Bonnie-Kim Hang

Retinopathy can also occur secondary to toxicity from certain types of oral medications. Damage is usually isolated to the posterior pole and macular region. Tamoxifen, an oral anti-estrogen drug, has been shown to cause retinal toxicity with doses of 100 G or more. Crystalline refractive bodies occur in a concentric ring surrounding the macula, and, in more severe cases, cystoid macular edema (CME) and retinal-pigmented epithelial abnormalities are found.

Hydroxychloroquine, historically used as an anti-malarial, is now used to treat a variety of rheumatologic conditions (rheumatoid arthritis and lupus, amongst others). Retinal toxicity has been shown to occur after 7 years of chronic use. Updated guidelines now recommend that a baseline fundus examination should be performed on all patients after 5 years of use (Marmor et al.). Visual field testing and SD-OCT have been shown to reveal functional and structural damage. Patients can manifest ring scotomas on field testing before SD-OCT with good sensitivity (Brandao et al.). High definition OCT is preferred over multifocal ERG and fundus autofluorescence (FAF), as it more clearly delineates early pathological findings. Ganglion cell and inner plexiform layers become thinned concentrically in the perifoveal region. Unlike RPI, these maculopathies are caused by long duration and high dosage of medications and do not cause progressively decreased vision over time.

Retinitis pigmentosa (RP) encompasses a wide variety of hereditary disorders that involve progressive loss of the retinal pigment epithelium and photoreceptor layer. It is one of the most common inherited retinal disorders with a prevalence of 1 out of 4,000 (Ferrucci et al). The earliest detectable ocular signs are attenuation of the vessels in the posterior pole. As the disease advances, bone spicule formation occurs, followed by optic disc pallor with a characteristic waxy appearance. Early symptoms include night blindness, followed by gradual peripheral vision loss. In later stages, patients have dramatically reduced visual acuity and fields and develop color vision defects. RP can present with ocular signs alone (non-syndromic, or classic RP), or can manifest with other systemic conditions (syndromic RP).

Retinitis pigmentosa is a heterogeneous disease that has been associated with 45 different genes. Approximately 60% of RP cases are autosomal recessive. Autosomal dominant cases comprise 30%. The remaining 10% of cases are X-linked, the most severe form of RP. X-linked cases often present in adolescence and may progress to legal blindness by the second decade of life (Fahim et al.).

Ocular findings associated with RP are optic nerve head drusen, vitreous particles and posterior subcapsular cataracts. Cystoid macular edema, RPE atrophy or epiretinal membrane formation can also manifest over time.

RP has a multitude of phenotypic expressions. Variants include sine pigmento, sector RP, unilateral RP and RPI. Sine pigmento has an absence of bone-spicules. Sector RP is characterized by regionalized areas of bone spicule pigmentation, usually in the inferior quadrants of the retina. Unilateral RP manifests signs of optic disc pallor, bone-spicule formation and arteriolar attenuation that are isolated to one eye. This type can be extremely difficult to detect at the early stages of the disease and is, accordingly, a diagnosis of exclusion.

RPI is an extremely rare form of RP with an unknown prevalence. Since its discovery in the 1800s, only a few dozen cases have been reported. The age of onset is also not known due to the low prevalence of the disease. Visual acuities can range from 20/400 to light perception only in both eyes, and patients are usually legally blind by their 40s or 50s. Signs of RPI can vary depending on the stage of the disease and are isolated to the posterior pole region. The first clinical sign that occurs is vessel attenuation, followed by pigmentary changes and ultimately atrophy of the RPE layer at later stages of the disease. Night blindness is typically the first symptom, followed by a decline in central visual acuity. At later stages, color vision defects occur.

There are two types of RP inversa: Pericentral and central. In the pericentral form, chorioretinal atrophy and pigment migration concentrate around the macula, leaving central vision unaffected. This type tends to have a favorable prognosis with minimal progression after 3 to 5 years. On the contrary, the central form of RPI is characterized by bilateral retinal changes central to the posterior pole, affecting the macula. Pigmentary clumps and bone-spicules form along the horizontal axis. Our patient exhibits the signs and symptoms of the central form.

Treatment, management

Fundus photos highlighting typical clinical signs of RP: mid-peripheral bone spicules and vessel attenuation. No optic disc pallor is present.

Clinical observation, extensive diagnostic testing, and patient history and symptoms establish a diagnosis of RPI. A complete review of medical history and medications should be done to rule out drug toxicity.

ERG testing is a powerful clinical tool. It can reveal reduction or absence of scotopic amplitudes (rod functions) that precedes reduction of photopic amplitudes (cone functions). Performing ERG can also be helpful to identify female carriers of X-linked RP for genetic counseling, as it has been shown to be abnormal in more than 90% of female carriers. It can also differentiate RP from other mimickers. RP will show decreased b-wave amplitude, which is indicative of photoreceptor function. Other diseases will typically show normal amplitudes (Hamel).

It is recommended that RP patients have a dilated fundus exam every 6 months. Additional ancillary testing such as OCT, FAF and visual fields should be performed to document staging and prognosis of the disease. Detection and management of common, modifiable ocular side effects of RP, such as cystoid macular edema or a visually significant cataract, can improve the patient’s overall quality of life and should be pursued.

Color vision testing with Farnsworth-Munsell or H-R-R can be helpful, but abnormalities are not usually detected until the late stages. Most patients with RP tend to exhibit tritanopia; however, deuteranopia and protanopia can be present.

Mega-doses of vitamin A have been prescribed for patients 18 and older, although this practice is controversial. This recommendation is for typical forms of RP and has not been studied in atypical forms such as our patient’s. It may retard the progression of RPE atrophy, as confirmed by reduction of ERG amplitudes. One study suggested vitamin E be avoided for all RP patients, as a daily dose of 400 IU led to faster progression (Berson et al.). Systemic and topical Diamox (acetazolamide, Duramed) 500 mg or topical dorzolamide is a viable intervention if CME persists after several weeks and visual acuity has not improved.

RPI is a rare condition that slowly destroys the RPE layer and photoreceptors of the macula and posterior pole, leading to progressive loss of bilateral central vision. Patients affected by this condition usually retain their peripheral vision until very late in the disease.

The lack of larger scale studies and research due to RPI’s rarity presents a clinical challenge, as little guidance for evidence-based management exists. Although there is no direct treatment, offering supportive therapy through low vision devices, filters, night vision aids, field expanders, and orientation and mobility training can greatly improve a patient’s quality of life.

This patient’s management

Our patient did not manifest symptoms until his 20s. He noticed that his night vision was declining just before he was drafted for the Vietnam War. After a brief period, he was then discharged due to failed vision screenings. Upon returning to the U.S. when he was in his early 40s, he was involved in three consecutive car accidents, reporting that he never saw the collision despite maintaining steady central gaze while driving. Review of historical diagnostic and ancillary testing (ERG, visual fields), in addition to diagnostic testing in office, confirmed the diagnosis of RPI.

Our patient was enrolled in blind rehabilitation services and received orientation and mobility training. He had few difficulties scanning and tracking and has proven to be extremely independent. At his most recent appointment, he did not express the need for any more devices or training, but simply desired to maximize his contrast sensitivity. Because he had already undergone successful cataract surgery of the right eye, a cataract consultation was scheduled for the left eye.

In conclusion, appropriate steps should be taken to educate the patient and family members of the visual expectations and to offer any feasible treatment, surgical or rehabilitative care that could enhance remaining vision.

Disclosures: Hang reports no relevant financial interests. Semes is an advisor or on the speakers bureau for Alcon, Allergan, Bausch + Lomb, Genentech, Maculogix, OptoVue, Shire and ZeaVision. He is a stockholder with HPO.

Top: Chorioretinal atrophy is concentrated in the posterior pole and extends outside the arcades in the presence of moderate pigmentary changes. Bottom: A closer view of waxy disc pallor in the right eye.
Source: Bonnie-Kim Hang, OD

A 74-year-old Caucasian man presented with a chief complaint of gradually impaired contrast and progressively increased glare that was worse in the left eye compared to the right eye, as well as bilateral reduced peripheral and central vision that persisted for several months.

Posterior pole of the left eye reveals chorioretinal atrophy, pigmentary changes and waxy disc pallor obscured by dense cataract.

The patient’s ocular history was significant for nuclear sclerotic cataracts in the left eye and a posterior chamber intraocular lens in the right eye that was implanted in 2008. The patient’s medical history was positive for hyperlipidemia, depression and diabetes.

Fundus autofluorescence enhances areas of retinal pigment epithelium atrophy superior temporal to the macula of the right eye

Best-corrected visual acuity was 5/200 OD (Feinbloom chart) and light perception in the left eye. Slit lamp exam revealed a clear PC-IOL in the right eye and NO3 NC4 grade cataracts in the left eye (per Lens Opacities Classification System III). Dilated fundus exam revealed extensive chorioretinal atrophy in the posterior pole, which extended into the mid-periphery. Mild pigmentary changes were scattered throughout, and concurrent vessel attenuation and waxy disc pallor were noted in both eyes. Spectral domain optical coherence tomography (SD-OCT) revealed extensive atrophy extending from the inner to outer retinal layers with no discernable foveal pit.

Left: Radial macular OCT scan highlights the diffuse chorioretinal atrophy that can be seen extending from the macula into the posterior pole of the right eye. Right: Macular OCT scan reveals a minimally discernable foveal pit. Extensive atrophy of the outer retinal layers is also present.

What’s your diagnosis?
See answer on the next page

PAGE BREAK

Differential diagnoses for retinitis pigmentosa inversa (RPI) include chorioretinal disorders that affect the macula such as Leber’s congenital amaurosis, progressive cone-rod dystrophy, Stargardt’s disease and drug toxicity from medications such as tamoxifen, chloroquine and hydroxychloroquine.

Differential diagnoses

Leber’s congenital amaurosis is an autosomal recessive retinal disease resulting in severely decreased vision, including blindness. Unlike RP inversa, this severe vision loss occurs at an early age, often by the first year of life. Initially, the fundus may appear clinically normal, but eventually retinal changes that can mimic RP are detectable. Most patients have either a salt-and-pepper appearance or atrophy localized to the macula.

Cone-rod dystrophies present as pigmentary disorders localized to the macular region. In contrast to RP (classified as rod-cone dystrophies), there is initial cone involvement, or simultaneous cone and rod loss. Decreased visual acuity is the first symptom, usually discovered within the first decade of life. Central scotomas, which may be initially discovered while reading or scanning; dyschromatopsia; and photophobia occur early during school-age years. Subsequently, night blindness ensues, and nystagmus is present. Pigmentary deposits, vessel attenuation and varying degrees of atrophy are similar to RP inversa. Electroretinography results would reveal a dominance of photopic over scotopic responses. RPI would present opposite findings.

Stargardt’s disease has one of the highest prevalences of macular dystrophies presenting during childhood. It comprises approximately 7% of all childhood macular dystrophies. Funduscopically, there are pigmentary changes in the macula. Pisciform flecks comprised of lipofuscin in the perifoveal region distinguish Stargardt’s from other maculopathies such as RPI. Stargardt’s has a male and Caucasian predilection. Age of onset varies from the first to the sixth decade, with the youngest reported case at age 5 years and a median age about 20 years. Vision gradually decreases to 20/100 after 10 years of duration and usually remains at 20/200 in the majority of patients after 20 years (Armstrong et al.).

Bonnie-Kim Hang

Retinopathy can also occur secondary to toxicity from certain types of oral medications. Damage is usually isolated to the posterior pole and macular region. Tamoxifen, an oral anti-estrogen drug, has been shown to cause retinal toxicity with doses of 100 G or more. Crystalline refractive bodies occur in a concentric ring surrounding the macula, and, in more severe cases, cystoid macular edema (CME) and retinal-pigmented epithelial abnormalities are found.

Hydroxychloroquine, historically used as an anti-malarial, is now used to treat a variety of rheumatologic conditions (rheumatoid arthritis and lupus, amongst others). Retinal toxicity has been shown to occur after 7 years of chronic use. Updated guidelines now recommend that a baseline fundus examination should be performed on all patients after 5 years of use (Marmor et al.). Visual field testing and SD-OCT have been shown to reveal functional and structural damage. Patients can manifest ring scotomas on field testing before SD-OCT with good sensitivity (Brandao et al.). High definition OCT is preferred over multifocal ERG and fundus autofluorescence (FAF), as it more clearly delineates early pathological findings. Ganglion cell and inner plexiform layers become thinned concentrically in the perifoveal region. Unlike RPI, these maculopathies are caused by long duration and high dosage of medications and do not cause progressively decreased vision over time.

Retinitis pigmentosa (RP) encompasses a wide variety of hereditary disorders that involve progressive loss of the retinal pigment epithelium and photoreceptor layer. It is one of the most common inherited retinal disorders with a prevalence of 1 out of 4,000 (Ferrucci et al). The earliest detectable ocular signs are attenuation of the vessels in the posterior pole. As the disease advances, bone spicule formation occurs, followed by optic disc pallor with a characteristic waxy appearance. Early symptoms include night blindness, followed by gradual peripheral vision loss. In later stages, patients have dramatically reduced visual acuity and fields and develop color vision defects. RP can present with ocular signs alone (non-syndromic, or classic RP), or can manifest with other systemic conditions (syndromic RP).

PAGE BREAK

Retinitis pigmentosa is a heterogeneous disease that has been associated with 45 different genes. Approximately 60% of RP cases are autosomal recessive. Autosomal dominant cases comprise 30%. The remaining 10% of cases are X-linked, the most severe form of RP. X-linked cases often present in adolescence and may progress to legal blindness by the second decade of life (Fahim et al.).

Ocular findings associated with RP are optic nerve head drusen, vitreous particles and posterior subcapsular cataracts. Cystoid macular edema, RPE atrophy or epiretinal membrane formation can also manifest over time.

RP has a multitude of phenotypic expressions. Variants include sine pigmento, sector RP, unilateral RP and RPI. Sine pigmento has an absence of bone-spicules. Sector RP is characterized by regionalized areas of bone spicule pigmentation, usually in the inferior quadrants of the retina. Unilateral RP manifests signs of optic disc pallor, bone-spicule formation and arteriolar attenuation that are isolated to one eye. This type can be extremely difficult to detect at the early stages of the disease and is, accordingly, a diagnosis of exclusion.

RPI is an extremely rare form of RP with an unknown prevalence. Since its discovery in the 1800s, only a few dozen cases have been reported. The age of onset is also not known due to the low prevalence of the disease. Visual acuities can range from 20/400 to light perception only in both eyes, and patients are usually legally blind by their 40s or 50s. Signs of RPI can vary depending on the stage of the disease and are isolated to the posterior pole region. The first clinical sign that occurs is vessel attenuation, followed by pigmentary changes and ultimately atrophy of the RPE layer at later stages of the disease. Night blindness is typically the first symptom, followed by a decline in central visual acuity. At later stages, color vision defects occur.

There are two types of RP inversa: Pericentral and central. In the pericentral form, chorioretinal atrophy and pigment migration concentrate around the macula, leaving central vision unaffected. This type tends to have a favorable prognosis with minimal progression after 3 to 5 years. On the contrary, the central form of RPI is characterized by bilateral retinal changes central to the posterior pole, affecting the macula. Pigmentary clumps and bone-spicules form along the horizontal axis. Our patient exhibits the signs and symptoms of the central form.

Treatment, management

Fundus photos highlighting typical clinical signs of RP: mid-peripheral bone spicules and vessel attenuation. No optic disc pallor is present.

Clinical observation, extensive diagnostic testing, and patient history and symptoms establish a diagnosis of RPI. A complete review of medical history and medications should be done to rule out drug toxicity.

ERG testing is a powerful clinical tool. It can reveal reduction or absence of scotopic amplitudes (rod functions) that precedes reduction of photopic amplitudes (cone functions). Performing ERG can also be helpful to identify female carriers of X-linked RP for genetic counseling, as it has been shown to be abnormal in more than 90% of female carriers. It can also differentiate RP from other mimickers. RP will show decreased b-wave amplitude, which is indicative of photoreceptor function. Other diseases will typically show normal amplitudes (Hamel).

PAGE BREAK

It is recommended that RP patients have a dilated fundus exam every 6 months. Additional ancillary testing such as OCT, FAF and visual fields should be performed to document staging and prognosis of the disease. Detection and management of common, modifiable ocular side effects of RP, such as cystoid macular edema or a visually significant cataract, can improve the patient’s overall quality of life and should be pursued.

Color vision testing with Farnsworth-Munsell or H-R-R can be helpful, but abnormalities are not usually detected until the late stages. Most patients with RP tend to exhibit tritanopia; however, deuteranopia and protanopia can be present.

Mega-doses of vitamin A have been prescribed for patients 18 and older, although this practice is controversial. This recommendation is for typical forms of RP and has not been studied in atypical forms such as our patient’s. It may retard the progression of RPE atrophy, as confirmed by reduction of ERG amplitudes. One study suggested vitamin E be avoided for all RP patients, as a daily dose of 400 IU led to faster progression (Berson et al.). Systemic and topical Diamox (acetazolamide, Duramed) 500 mg or topical dorzolamide is a viable intervention if CME persists after several weeks and visual acuity has not improved.

RPI is a rare condition that slowly destroys the RPE layer and photoreceptors of the macula and posterior pole, leading to progressive loss of bilateral central vision. Patients affected by this condition usually retain their peripheral vision until very late in the disease.

The lack of larger scale studies and research due to RPI’s rarity presents a clinical challenge, as little guidance for evidence-based management exists. Although there is no direct treatment, offering supportive therapy through low vision devices, filters, night vision aids, field expanders, and orientation and mobility training can greatly improve a patient’s quality of life.

This patient’s management

Our patient did not manifest symptoms until his 20s. He noticed that his night vision was declining just before he was drafted for the Vietnam War. After a brief period, he was then discharged due to failed vision screenings. Upon returning to the U.S. when he was in his early 40s, he was involved in three consecutive car accidents, reporting that he never saw the collision despite maintaining steady central gaze while driving. Review of historical diagnostic and ancillary testing (ERG, visual fields), in addition to diagnostic testing in office, confirmed the diagnosis of RPI.

PAGE BREAK

Our patient was enrolled in blind rehabilitation services and received orientation and mobility training. He had few difficulties scanning and tracking and has proven to be extremely independent. At his most recent appointment, he did not express the need for any more devices or training, but simply desired to maximize his contrast sensitivity. Because he had already undergone successful cataract surgery of the right eye, a cataract consultation was scheduled for the left eye.

In conclusion, appropriate steps should be taken to educate the patient and family members of the visual expectations and to offer any feasible treatment, surgical or rehabilitative care that could enhance remaining vision.

Disclosures: Hang reports no relevant financial interests. Semes is an advisor or on the speakers bureau for Alcon, Allergan, Bausch + Lomb, Genentech, Maculogix, OptoVue, Shire and ZeaVision. He is a stockholder with HPO.