Ophthalmology – Pattern Dystrophy

Basics

Description

Pattern dystrophies of the retinal pigment epithelium (RPE) are a heterogeneous group of inherited macular disorders characterized by abnormal deposition of lipofuscin and pigment at the level of the:

• RPE
• Photoreceptor–RPE interface

They are usually:

• Bilateral
• Slowly progressive
• Relatively symmetric

but the appearance can differ between the two eyes.

Many patients are discovered incidentally and retain useful central vision for decades.

Major Clinical Patterns

Classically described phenotypes include:

• Butterfly-shaped pattern dystrophy
• Reticular pattern dystrophy
• Adult-onset foveomacular vitelliform lesion/dystrophy
• Fundus pulverulentus
• Multifocal pattern dystrophy simulating fundus flavimaculatus

These categories overlap considerably.

A single patient may:

• Change phenotype over time
• Show different patterns between eyes
• Develop increasing RPE atrophy with age

Epidemiology

The true incidence and prevalence are uncertain because of:

• Mild symptoms
• Variable phenotype
• Overlap with age-related macular disease
• Variable penetrance

Men and women are affected approximately equally.

Presentation is often in:

• Young or middle adulthood

although clinically significant symptoms may not appear until later life.

Genetics

Most classic pattern dystrophies are inherited in an:

Autosomal dominant

fashion.

The most important gene is:

PRPH2

formerly called:

RDS/peripherin

PRPH2 is located on chromosome 6 and encodes a photoreceptor outer-segment membrane protein important for:

• Disc structure
• Photoreceptor maintenance

PRPH2 Phenotypic Variability

PRPH2 variants can produce a wide spectrum of retinal disease, including:

• Pattern dystrophy
• Adult-onset vitelliform lesions
• Central areolar choroidal dystrophy
• Cone–rod dystrophy
• Retinitis pigmentosa-like phenotypes

Therefore:

The same gene can produce markedly different retinal appearances even within the same family.

Other Genetic Associations

Not all pattern dystrophy phenotypes are caused by PRPH2.

Other implicated genes include:

• BEST1
• IMPG1
• IMPG2

depending on phenotype.

Genetic testing is most useful when:

• Diagnosis is uncertain
• Family counseling is needed
• Presentation is atypical
• There is overlap with another inherited retinal disease

Mitochondrial Association

A distinctive macular pattern dystrophy is strongly associated with:

Maternally inherited diabetes and deafness (MIDD)

usually caused by the mitochondrial DNA variant:

m.3243A>G in MT-TL1

The macular phenotype may show:

• Circumferential RPE atrophy
• Pigmentary changes surrounding the fovea
• Relative foveal sparing early

MIDD Clinical Clues

Consider MIDD when pattern dystrophy occurs with:

• Diabetes mellitus
• Sensorineural hearing loss
• Maternal inheritance pattern
• Short stature
• Other mitochondrial features

Because mitochondrial DNA is maternally inherited:

Affected fathers do not transmit the disorder, whereas affected mothers may transmit it to offspring.

Pathophysiology

Pattern dystrophies involve abnormal function of:

• Photoreceptor outer segments
• RPE

with accumulation of:

Lipofuscin and other pigmentary material

Over time this may lead to:

• RPE degeneration
• Photoreceptor loss
• Outer retinal atrophy

Complications of Progressive Disease

With age, patients may develop:

• Geographic-like RPE atrophy
• Photoreceptor loss
• Central visual decline
• Macular neovascularization (MNV/CNV)

Clinical Presentation

Many patients are initially:

Asymptomatic

When symptoms occur they may include:

• Mild reduction in central vision
• Metamorphopsia
• Difficulty reading
• Central scotoma
• Reduced contrast sensitivity

Symptoms usually progress slowly.

Fundus Appearance

Typical fundus findings include:

• Yellow
• Gray
• Orange
• Brown

pigmentary deposits at the macula.

The distribution varies according to phenotype.

Butterfly Pattern Dystrophy

Characteristic finding:

Butterfly- or spoke-shaped pigmentary material centered on the fovea

The lesion consists of:

• Yellow-gray material
• Pigment clumping
• RPE alteration

Reticular Pattern Dystrophy

Shows:

• Reticular
• Net-like
• Branching pigment pattern

typically around the posterior pole.

Adult-Onset Foveomacular Vitelliform Phenotype

Usually demonstrates a:

Round or oval yellow subfoveal vitelliform lesion

It may resemble:

• Best disease
• Acquired vitelliform lesion
• Early AMD

Patients often present in:

• Middle or later adulthood

Fundus Pulverulentus

Characterized by:

• Numerous fine
• Dust-like
• Gray-white or pigmentary macular spots

The changes are usually subtle.

Multifocal Pattern Dystrophy

May produce multiple:

• Yellow-white flecks
• Pigmentary lesions

and can resemble:

Stargardt disease / fundus flavimaculatus

Visual Acuity

Visual acuity is often:

• Normal
• Mildly reduced

for many years.

Substantial loss usually occurs because of:

• Central RPE atrophy
• Photoreceptor loss
• MNV/CNV

Color Vision

Color vision is usually:

Normal early

Abnormality may occur with advanced macular or cone dysfunction.

Visual Fields

Visual fields are often normal early.

Advanced disease may produce:

• Central scotoma
• Paracentral scotoma

Dark Adaptation

Dark adaptation is usually:

Normal or minimally affected

which helps distinguish many pattern dystrophies from more diffuse retinal dystrophies.

OCT

Optical coherence tomography is one of the most useful investigations.

Findings may include:

• Hyperreflective material between RPE and photoreceptors
• Subretinal vitelliform material
• RPE irregularity
• Ellipsoid-zone disruption
• Outer retinal thinning
• RPE atrophy

OCT in Vitelliform Lesions

The yellow lesion usually corresponds to:

Hyperreflective subretinal material above the RPE

Later stages may show:

• Collapse of material
• Outer retinal disruption
• RPE atrophy

Fundus Autofluorescence

FAF is particularly useful because lipofuscin is autofluorescent.

Early lesions often demonstrate:

Increased autofluorescence

because of accumulated lipofuscin.

Areas of advanced RPE loss demonstrate:

Reduced or absent autofluorescence

Fluorescein Angiography

FA findings vary with the pattern.

Pigmented areas may cause:

• Blocked fluorescence

Areas of RPE atrophy may produce:

• Window defects
• Hyperfluorescence without leakage

FA is particularly useful when:

MNV/CNV is suspected

OCT Angiography

OCTA may detect:

• Neovascular networks
• Subclinical MNV

without dye injection.

It is particularly helpful when:

• Fluid or hemorrhage is suspicious for neovascularization
• Structural OCT findings are equivocal

Electroretinography

Full-field ERG is usually:

Normal

because the disease is predominantly macular.

An abnormal full-field ERG should raise suspicion for:

• Cone dystrophy
• Cone–rod dystrophy
• More generalized inherited retinal disease

Electrooculography

EOG may be:

• Normal
• Mildly reduced

It is not routinely needed for diagnosis.

Diagnosis

Diagnosis is based on:

• Characteristic fundus appearance
• OCT
• Fundus autofluorescence
• Family history

Additional testing is directed by phenotype.

When Genetic Testing Is Helpful

Consider testing when:

• PRPH2-associated disease is suspected
• There is a strong family history
• MIDD is suspected
• Diagnosis overlaps with Best disease or Stargardt disease
• Counseling is needed

Differential Diagnosis

Important differentials include:

• Age-related macular degeneration
• Stargardt disease
• Best vitelliform macular dystrophy
• Acquired vitelliform lesion
• Dominant drusen
• Central areolar choroidal dystrophy
• Cone dystrophy
• Benign concentric annular macular dystrophy
• Drug toxicity
• Chronic central serous chorioretinopathy

Pattern Dystrophy vs AMD

This distinction becomes particularly important in older patients.

Pattern dystrophy tends to show:

• Characteristic geometric or patterned pigment
• Family history
• Relatively preserved vision for age
• Bilateral similar lesions
• Hyperautofluorescent lipofuscin

AMD more typically shows:

• Drusen
• Pigmentary changes without a characteristic pattern
• Geographic atrophy
• Age-related macular neovascularization

The two may coexist.

Pattern Dystrophy vs Stargardt Disease

Stargardt disease typically has:

• Younger onset
• More progressive central visual loss
• Flecks extending beyond the macula
• Characteristic FAF changes
• ABCA4-associated inheritance

Pattern dystrophy is more often:

• Autosomal dominant
• Later onset
• Milder

Adult-Onset Vitelliform Lesion vs Best Disease

Best disease usually:

• Begins earlier
• Has BEST1-associated inheritance
• Shows abnormal EOG in classic disease

Adult-onset vitelliform lesions:

• Present later
• Are generally smaller
• Have more limited visual effect early
• May be associated with PRPH2, BEST1, IMPG1, or IMPG2

Treatment

There is currently:

No treatment that reverses the underlying inherited RPE dystrophy

Management focuses on:

• Monitoring
• Treating complications
• Genetic counseling
• Low-vision support when necessary

Macular Neovascularization

The most important treatable complication is:

MNV/CNV

Suspect it when there is:

• Sudden visual decline
• New metamorphopsia
• New hemorrhage
• Intraretinal or subretinal fluid on OCT

Anti-VEGF Therapy

The modern first-line treatment for active MNV/CNV is:

Intravitreal anti-VEGF therapy

Agents include:

• Bevacizumab
• Ranibizumab
• Aflibercept
• Faricimab in selected settings

Treatment generally follows OCT-guided disease activity.

Photodynamic Therapy

PDT was historically used for CNV associated with pattern dystrophy.

Today it has largely been replaced by:

Anti-VEGF therapy

because anti-VEGF generally provides better anatomic and visual outcomes.

Monitoring

Patients without complications may be reviewed:

Approximately annually

depending on:

• Age
• Phenotype
• Visual symptoms
• Degree of atrophy

Home Monitoring

Patients should be advised to report:

• New distortion
• New central blur
• New scotoma

An:

Amsler grid

may be useful for home monitoring.

Low-Vision Rehabilitation

Referral is appropriate when central atrophy causes:

• Reading difficulty
• Reduced contrast sensitivity
• Loss of useful central vision

Genetic Counseling

Counseling should address:

• Autosomal dominant inheritance in many PRPH2 cases
• Variable expression
• Incomplete penetrance in some families
• Mitochondrial inheritance when MIDD is present

Prognosis

Overall visual prognosis is generally:

Good

Most patients retain useful central vision for many years.

Many maintain:

• Reading vision
• Functional independence

into late adulthood.

Poorer Prognostic Factors

More significant visual loss occurs with:

• Extensive RPE atrophy
• Foveal photoreceptor loss
• MNV/CNV
• Recurrent macular hemorrhage

Complications

Important complications include:

• Progressive central visual loss
• RPE atrophy
• Photoreceptor loss
• Central scotoma
• Macular neovascularization
• Subretinal hemorrhage

Ophthalmology Pearls

• Pattern dystrophy is a group of inherited macular RPE disorders characterized by patterned lipofuscin and pigment deposition.
• Most classic cases are autosomal dominant and associated with PRPH2, formerly called RDS/peripherin.
• The phenotype can change with age and may differ between the two eyes or among members of the same family.
• Important patterns include butterfly, reticular, adult-onset vitelliform, fundus pulverulentus, and multifocal pattern dystrophy.
• OCT commonly shows subretinal or RPE-level hyperreflective material with outer retinal disruption.
• FAF is often hyperautofluorescent early from lipofuscin accumulation and becomes hypoautofluorescent where RPE atrophy develops.
• Full-field ERG is usually normal, reflecting the predominantly macular nature of the disease.
• MIDD should be considered when pattern dystrophy accompanies diabetes and sensorineural deafness, particularly with maternal inheritance.
• Pattern dystrophy can mimic AMD, Stargardt disease, and Best disease.
• Most patients retain useful vision for decades.
• The major treatable complication is macular neovascularization, for which intravitreal anti-VEGF is first-line therapy.
• New metamorphopsia, hemorrhage, or sudden visual loss should prompt urgent OCT assessment for MNV/CNV.

Major Clinical Patterns Classically described phenotypes include:  Butterfly-shaped pattern dystrophy Reticular pattern dystrophy Adult-onset foveomacular vitelliform lesion/dystrophy Fundus pulverulentus Multifocal pattern dystrophy simulating fundus flavimaculatus  These categories overlap considerably. A single patient may:  Change phenotype over time Show different patterns between eyes Develop increasing RPE atrophy with age

Epidemiology The true incidence and prevalence are uncertain because of:  Mild symptoms Variable phenotype Overlap with age-related macular disease Variable penetrance  Men and women are affected approximately equally. Presentation is often in:  Young or middle adulthood  although clinically significant symptoms may not appear until later life.

Genetics Most classic pattern dystrophies are inherited in an: Autosomal dominant fashion. The most important gene is: PRPH2 formerly called: RDS/peripherin PRPH2 is located on chromosome 6 and encodes a photoreceptor outer-segment membrane protein important for:  Disc structure Photoreceptor maintenance

PRPH2 Phenotypic Variability PRPH2 variants can produce a wide spectrum of retinal disease, including:  Pattern dystrophy Adult-onset vitelliform lesions Central areolar choroidal dystrophy Cone–rod dystrophy Retinitis pigmentosa-like phenotypes  Therefore: The same gene can produce markedly different retinal appearances even within the same family.

Other Genetic Associations Not all pattern dystrophy phenotypes are caused by PRPH2. Other implicated genes include:  BEST1 IMPG1 IMPG2  depending on phenotype. Genetic testing is most useful when:  Diagnosis is uncertain Family counseling is needed Presentation is atypical There is overlap with another inherited retinal disease

Mitochondrial Association A distinctive macular pattern dystrophy is strongly associated with: Maternally inherited diabetes and deafness (MIDD) usually caused by the mitochondrial DNA variant: m.3243A>G in MT-TL1 The macular phenotype may show:  Circumferential RPE atrophy Pigmentary changes surrounding the fovea Relative foveal sparing early

MIDD Clinical Clues Consider MIDD when pattern dystrophy occurs with:  Diabetes mellitus Sensorineural hearing loss Maternal inheritance pattern Short stature Other mitochondrial features  Because mitochondrial DNA is maternally inherited: Affected fathers do not transmit the disorder, whereas affected mothers may transmit it to offspring.

Pathophysiology Pattern dystrophies involve abnormal function of:  Photoreceptor outer segments RPE  with accumulation of: Lipofuscin and other pigmentary material Over time this may lead to:  RPE degeneration Photoreceptor loss Outer retinal atrophy

Complications of Progressive Disease With age, patients may develop:  Geographic-like RPE atrophy Photoreceptor loss Central visual decline Macular neovascularization (MNV/CNV)

Clinical Presentation Many patients are initially: Asymptomatic When symptoms occur they may include:  Mild reduction in central vision Metamorphopsia Difficulty reading Central scotoma Reduced contrast sensitivity  Symptoms usually progress slowly.

Fundus Appearance Typical fundus findings include:  Yellow Gray Orange Brown  pigmentary deposits at the macula. The distribution varies according to phenotype.

Butterfly Pattern Dystrophy Characteristic finding: Butterfly- or spoke-shaped pigmentary material centered on the fovea The lesion consists of:  Yellow-gray material Pigment clumping RPE alteration

Reticular Pattern Dystrophy Shows:  Reticular Net-like Branching pigment pattern  typically around the posterior pole.

Adult-Onset Foveomacular Vitelliform Phenotype Usually demonstrates a: Round or oval yellow subfoveal vitelliform lesion It may resemble:  Best disease Acquired vitelliform lesion Early AMD  Patients often present in:  Middle or later adulthood

Fundus Pulverulentus Characterized by:  Numerous fine Dust-like Gray-white or pigmentary macular spots  The changes are usually subtle.

Multifocal Pattern Dystrophy May produce multiple:  Yellow-white flecks Pigmentary lesions  and can resemble: Stargardt disease / fundus flavimaculatus

Visual Acuity Visual acuity is often:  Normal Mildly reduced  for many years. Substantial loss usually occurs because of:  Central RPE atrophy Photoreceptor loss MNV/CNV

Color Vision Color vision is usually: Normal early Abnormality may occur with advanced macular or cone dysfunction.

Visual Fields Visual fields are often normal early. Advanced disease may produce:  Central scotoma Paracentral scotoma

Dark Adaptation Dark adaptation is usually: Normal or minimally affected which helps distinguish many pattern dystrophies from more diffuse retinal dystrophies.

OCT Optical coherence tomography is one of the most useful investigations. Findings may include:  Hyperreflective material between RPE and photoreceptors Subretinal vitelliform material RPE irregularity Ellipsoid-zone disruption Outer retinal thinning RPE atrophy

OCT in Vitelliform Lesions The yellow lesion usually corresponds to: Hyperreflective subretinal material above the RPE Later stages may show:  Collapse of material Outer retinal disruption RPE atrophy

Fundus Autofluorescence FAF is particularly useful because lipofuscin is autofluorescent. Early lesions often demonstrate: Increased autofluorescence because of accumulated lipofuscin. Areas of advanced RPE loss demonstrate: Reduced or absent autofluorescence

Fluorescein Angiography FA findings vary with the pattern. Pigmented areas may cause:  Blocked fluorescence  Areas of RPE atrophy may produce:  Window defects Hyperfluorescence without leakage  FA is particularly useful when: MNV/CNV is suspected

OCT Angiography OCTA may detect:  Neovascular networks Subclinical MNV  without dye injection. It is particularly helpful when:  Fluid or hemorrhage is suspicious for neovascularization Structural OCT findings are equivocal

Electroretinography Full-field ERG is usually: Normal because the disease is predominantly macular. An abnormal full-field ERG should raise suspicion for:  Cone dystrophy Cone–rod dystrophy More generalized inherited retinal disease

Electrooculography EOG may be:  Normal Mildly reduced  It is not routinely needed for diagnosis.

Diagnosis Diagnosis is based on:  Characteristic fundus appearance OCT Fundus autofluorescence Family history  Additional testing is directed by phenotype.

When Genetic Testing Is Helpful Consider testing when:  PRPH2-associated disease is suspected There is a strong family history MIDD is suspected Diagnosis overlaps with Best disease or Stargardt disease Counseling is needed

Differential Diagnosis Important differentials include:  Age-related macular degeneration Stargardt disease Best vitelliform macular dystrophy Acquired vitelliform lesion Dominant drusen Central areolar choroidal dystrophy Cone dystrophy Benign concentric annular macular dystrophy Drug toxicity Chronic central serous chorioretinopathy

Pattern Dystrophy vs AMD This distinction becomes particularly important in older patients. Pattern dystrophy tends to show:  Characteristic geometric or patterned pigment Family history Relatively preserved vision for age Bilateral similar lesions Hyperautofluorescent lipofuscin  AMD more typically shows:  Drusen Pigmentary changes without a characteristic pattern Geographic atrophy Age-related macular neovascularization  The two may coexist.

Pattern Dystrophy vs Stargardt Disease Stargardt disease typically has:  Younger onset More progressive central visual loss Flecks extending beyond the macula Characteristic FAF changes ABCA4-associated inheritance  Pattern dystrophy is more often:  Autosomal dominant Later onset Milder

Adult-Onset Vitelliform Lesion vs Best Disease Best disease usually:  Begins earlier Has BEST1-associated inheritance Shows abnormal EOG in classic disease  Adult-onset vitelliform lesions:  Present later Are generally smaller Have more limited visual effect early May be associated with PRPH2, BEST1, IMPG1, or IMPG2

Treatment There is currently: No treatment that reverses the underlying inherited RPE dystrophy Management focuses on:  Monitoring Treating complications Genetic counseling Low-vision support when necessary

Macular Neovascularization The most important treatable complication is: MNV/CNV Suspect it when there is:  Sudden visual decline New metamorphopsia New hemorrhage Intraretinal or subretinal fluid on OCT

Anti-VEGF Therapy The modern first-line treatment for active MNV/CNV is: Intravitreal anti-VEGF therapy Agents include:  Bevacizumab Ranibizumab Aflibercept Faricimab in selected settings  Treatment generally follows OCT-guided disease activity.

Photodynamic Therapy PDT was historically used for CNV associated with pattern dystrophy. Today it has largely been replaced by: Anti-VEGF therapy because anti-VEGF generally provides better anatomic and visual outcomes.

Monitoring Patients without complications may be reviewed: Approximately annually depending on:  Age Phenotype Visual symptoms Degree of atrophy

Home Monitoring Patients should be advised to report:  New distortion New central blur New scotoma  An: Amsler grid may be useful for home monitoring.

Low-Vision Rehabilitation Referral is appropriate when central atrophy causes:  Reading difficulty Reduced contrast sensitivity Loss of useful central vision

Genetic Counseling Counseling should address:  Autosomal dominant inheritance in many PRPH2 cases Variable expression Incomplete penetrance in some families Mitochondrial inheritance when MIDD is present

Prognosis Overall visual prognosis is generally: Good Most patients retain useful central vision for many years. Many maintain:  Reading vision Functional independence  into late adulthood.

Poorer Prognostic Factors More significant visual loss occurs with:  Extensive RPE atrophy Foveal photoreceptor loss MNV/CNV Recurrent macular hemorrhage

Complications Important complications include:  Progressive central visual loss RPE atrophy Photoreceptor loss Central scotoma Macular neovascularization Subretinal hemorrhage

Ophthalmology Pearls  Pattern dystrophy is a group of inherited macular RPE disorders characterized by patterned lipofuscin and pigment deposition. Most classic cases are autosomal dominant and associated with PRPH2, formerly called RDS/peripherin. The phenotype can change with age and may differ between the two eyes or among members of the same family. Important patterns include butterfly, reticular, adult-onset vitelliform, fundus pulverulentus, and multifocal pattern dystrophy. OCT commonly shows subretinal or RPE-level hyperreflective material with outer retinal disruption. FAF is often hyperautofluorescent early from lipofuscin accumulation and becomes hypoautofluorescent where RPE atrophy develops. Full-field ERG is usually normal, reflecting the predominantly macular nature of the disease. MIDD should be considered when pattern dystrophy accompanies diabetes and sensorineural deafness, particularly with maternal inheritance. Pattern dystrophy can mimic AMD, Stargardt disease, and Best disease. Most patients retain useful vision for decades. The major treatable complication is macular neovascularization, for which intravitreal anti-VEGF is first-line therapy. New metamorphopsia, hemorrhage, or sudden visual loss should prompt urgent OCT assessment for MNV/CNV.