Pattern dystrophies

From EyeWiki
Original article contributed by: Mahdi Rostamizadeh, MD, Musa Abdelaziz
All contributors: Mahdi Rostamizadeh, MD and Vinay A. Shah M.D.
Assigned editor: Jennifer I Lim MD
Review: Assigned status Up to Date by Mahdi Rostamizadeh, MD on September 11, 2016.



Pattern Dystrophies
Classification and external resources

Angiogram of reticular pattern dystrophy

ICD-10 H35.50
ICD-9 362.70
OMIM 169150


History

In 1950 Swedish ophthalmologist Dr. Henrik Sjögren described reticular dystrophy as Dystrophia Reticularis Laminae Pigmentosae Retinae. He is also credited for first describing Sjogren syndrome.
In 1974 Dr. Donald Gass from Vanderbelt University was the first to describe adult vitelliform dystrophy.

Different types of pattern dystrophies have been described throughout the 20th century by various ophthalmologist.

In 1950, Henrik Sjögren, Swedish discoverer of Sjögren Syndrome, described reticular dystrophy as "dystrophia reticularis laminae pigmentosa retinae".[1]

In 1970, butterfly dystrophy was described by Dutch ophthalmologist August Deutman. [2]

In 1974, world renowned American ophthalmologist Donald Gass described adult vitelliform dystrophy as a peculiar foveomacular dystrophy which he later termed 'foveomacular vitelliform dystrophy: adult type'. [3]

Originally these dystrophies were thought to be stationary. However further research has shown that they do progress at a very slow pace. [4]








Disease

Pattern dystrophies are a group of autosomal dominant macular diseases characterized by various patterns of pigment deposition within the macula. The primary layer of the retina effected is the RPE which is responsible for removing and recycling waste within the retina. In various pattern dystrophies these wastes accumulate in the form of lipofuscin.

Based on the pattern of the pigment distribution they have been classified into 5 prominent categories: [5]

  1. Adult-onset Foveomacular Vitelliform Dystrophy
  2. Butterfly-shaped Pigment Dystrophy
  3. Reticular Dystrophy
  4. Multifocal Pattern Dystrophy Simulating Stargardt's Disease
  5. Fundus Pulverulentus


Although there are distinct patterns, one pattern may turn into another in the same patient. Some patients may have a different a pattern in each eye. [5] [6] Pattern dystrophies are often associated with a relatively good visual prognosis, although slow progressive central vision loss can occur. Disease onset typically occurs in patients during their forties and fifties. However, older patients maybe misdiagnosed as age related macular degeneration due to similar macular patterns of pigment deposition.

Etiology

The PRPH2 gene (also known as RDS) provides instructions for making a protein called peripherin 2. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks [7] Within the PRPH2 gene there are many missense mutations ( Gly167Asp, Arg172Trp, Cys213Arg, Lys197Glu, Glu208Asp, Trp246Arg, Ser289Leu, Cys213Tyr,and Cys250Phe) and nonsense mutations (Gln239ter and Tyr285ter) [8] [9] [10] [11] [12][13] [2]The PRPH2 gene is located on the short (p) arm of chromosome 6 at position 21.1[2]

Prph2.jpg

Above: Transition from normal retina (right) to atrophied RPE (left). H&E stain. Below: Magnified view of RPE cell distended by lipofuscin with partially atrophied photoreceptor layer . H&E stain.
Electron microscopy: RPE cell containing lipofuscin ( Large arrowhead) Bruchs membrane with vesicular material (arrow) and intact endothelium (star)[2]

General Pathology

Pattern dystrophy is caused by lipofuscin accumulation in the RPE layer of the retina. Light and transmission electron microscopic examination shows loss of the RPE and photoreceptor cell layer, with intact choriocapillaris and lipofuscin-containing cells in the sub-retinal space in the macula. [2]

Pathophysiology

Little is known about the pathophysiology of the various pattern dystrophies. However reports have shown multiple cysteine mutations within the RDS gene. The disulfide bond within proteins is believed to be held by cysteine and any interruption of that could disrupt the integrity of the photoreceptor disc membrane. This can lead to degeneration of photoreceptor cells and ultimately resulte in an accumulation of lipofuscin in the RPE.[2] [13]

Symptoms

The most common presenting symptoms are metamophospsia and a slight decrease in vision. However since the symptoms are very mild, pattern dystrophies are discovered on routine or unrelated eye exams. [14][5]

Diagnosis

Diagnosis of pattern dystrophies is based on the pattern of pigment deposition in the RPE. Fluorescein angiography can be helpful depending on the pattern and severity of disease. Results of ERG and EOG maybe normal and abnormal, with mildy reduced EOG consistent with diffuse RPE atrophy. There are multiple genetic mutations that can cause pattern dystrophy and none are diagnostic to a certain pattern. Though various modalities may help with disease identification, pattern dystrophy remains a clinical diagnosis.[15]


Adult-onset foveomacular vitelliform dystrophy

Adult Vitelliform Dystrophy. Resembles Best Disease with yolk-like lesion within the Macula [16]

This pattern dystrophy closely resembles Best disease however it occurs in adults. This is also the most common of the pattern dystrophies. It is characterized by bilateral, symmetrical, grayish-yellow, round or oval-shaped lesions within the macular area. These lesions are mildly elevated and are typically one-third to one-half disc diameter in size and contain a central pigmented spot[5] [17] The vitelliform lesions are formed mainly by photoreceptor debris, possibly as the result of faulty phagocytosis by the RPE, compounding this problem is the pigment liberated as the RPE undergoes disruption. [18]


FA typically shows hypofluorescence in the area corresponding to the vitelliform lesion, with a ring of hyperfluorescence that increases in intensity in the late phases.

Patients with many basal laminar drusen may develop vitelliform exudative macular detachment. Subretinal yellowish fluid blocks the background fluorescence early with late staining on angiogram which can be mistaken for CNV.

Patients that have been misdiagnosed with CNV and have been treated with PDT show no changes or slight improvment in VA. Subretinal vitelliform material dissapeared after 1-3months of PDT treatment.[19] Diagnosis of adult-onset vitelliform dystrophy remains clinical as FA has shown to demonstrate normal, focal, patchy, ring-like, and linear none of which correlates with visual acuity. [20][21]


OCT demonstrates the location of the yellowish material under the sensory retina and above the retinal pigment epithelium, corresponding angiographically to the late staining. The foveal thinning found by OCT in all cases probably explains the progressive visual loss and possible evolution toward a full-thickness macular hole.[22]

On EOG all mean values were within normal ranges. There is no difference between the various stages of the disease. [23]


Butterfly-shaped pattern dystrophy

Above: Butterfly-shaped pigmentary change in macula with posterior pole yellow flecks Below: FA of same eye, large hypofluorescent, butterfly-shaped macular lesion. Yellow flecks bserved funduscopically in the posterior pole block fluorescence. [2]

This dystrophy is characterized by a bilateral accumulation of yellowish or pigmented material in a butterfly-like pattern at the level of the retinal pigment epithelium. This material is yellow, white, or black, and often accumulates in an usual configuration consisting of 3 to 5 'arms' or 'wings' that resemble the wings of a butterfly. The material is present in some patients in the second decade of life but affected individuals most commonly become symptomatic in their late twenties or early thirties [4]

In butterfly pattern dystrophy the central lesion is readily shown by FA, which helps to differentiate this condition from other macular pattern dystrophies. FA generally shows a large, hypofluorescent, butterfly-shaped macular lesion. Yellow flecks observed funduscopically in the posterior pole are noted to block fluorescences. [2]

Fundus autofluorescence may show increased as well as decreased autofluorescence, corresponding with changes in RPE lipofuscin within the lesion [24] Despite the inconsistencies shown on fudus autofluoresecene, fluorescein angiography is diagnostic in cases where the butterfly-shaped lesions were not easily visible with ophthalmoscope. [25]


ERG may show some diffuse photoreceptor dysfunction with normal vision however it is generally normal. Dark adaptation and color vision is normal. EOG changes in most cases have been found to be subnormal. [4]

Similar to all pattern dystrophies patients are asymptomatic when first diagnosed with BPD. They maintain normal vision in their twenties and thirties. However in their fifties and onward the disease can progress. When first described by Deutman et al it was not known if the disease was progressive due to only 3 years of follow up. However further research has shown that older individuals may exhibit atrophic, depigmented lesions that extend to the peripapillary region, with markedly reduced visual acuity. [26]

[27]

Fundus autofluorescence (FAF) demonstrates a butterfly-shaped pattern in the Macula OU. Hypofluorescent areas corresponded to pigment clumping seen on fundoscopy. Permission to use photo granted by Dr. Oetting from Iowa University Eyerounds.org


Reticular dystrophy

Symmetrical and reticular pattern of accumulated pigment in the fovea that radiates from the center to the periphery like a “fishnet with knots.” [28]
This dystrophy is characterized by a network of hyperpigmentation, resembling a fishing net with knots, located in the RPE and a presumed unaffected choriocapillaris. [29] The network of hyperpigmentation extends 4 to 5 disc diameters from the macula in all directions. Each net of meshes is typically 1 disc diameter or less. The midpreiphery and periphery are unaffected early in the disease process. With age most lesions fade way however some are replaced with atrophic changes in the RPE.[5] In the advance stages of the disease, the network becomes bleached and irregular and small white dots appear in the retinal pigment epithelium.[27]

Fluorescein angiography demonstrates a mosaic pattern, showing hypofluorescent bands or segments surrounded by areas of non-leaking hyperfluorescence. This corresponds to the reticular bands of pigment epithelial hyperpigmentation surrounded by halos of hypopigmentation see on ophthalmoscope. The choroidal vessels appear to be normal. Dark adaption test in patients with reticular dystrophy of retinal pigment epithelium has been reported as normal or subnormal.[27]


ERG findings are typically normal, however EOG findings could be normal or abnormal similar to butterfly dystrophy. Reticular dystrophy also has associated ocular findings outside the retina such as spherophakia with myopia and luxated lenses, partial atrophy of the iris, scleral staphyloma, onvergent strabismus and choroidal neovascularization.[4]





Multifocal pattern dystrophy simulating Stargardt disease

Multifocal Pattern dystrophy. This fundus photo displays many yellowish flecks, scattered throughout the posterior pole, with the larger flecks around a central area of chorioretinal atrophy [30]

Multifocal pattern dystrophy simulating Stargardt disease is characterized by irregular yellow-white flecks scattered throughout the posterior pole resembling those found in stargardt's disease. These flecks are variable size, shape and number and are often situated around the retinal vascular arcades, nasal and superior to the optic disc and in the macular area. Macular abnormalities may range from various patterns of yellow or grayish deposits to well-demarcated lesions of severe chorioretinal atrophy. [14] On fluorescein angiography, the flecks are hyperfluorescent in the early and late phase of the examination, sometimes with a central hypofluorescent spot. Important to note is that the characteristic dark choroid seen in Stargardts disease is absent. On fundus AF imaging, the flecks show a increased auto-fluorescence , often with small adjacent zones of decreased auto-fluorescence. [14]

On OCT, some of the Stargardt‐like flecks appear as a highly reflective focal thickening of the hyper‐reflective outer red line (ORL). Macular lesions show thickening of the ORL, with a variable increase in underlying reflectivity.[14]

Full‐field ERG results variy from normal to non‐recordable. Non‐recordable ERGs were mostly noted in patients with confluence of the yellowish flecks. Similar to other pattern dystrophies EOG can be normal or subnormal. [14]




Fundus Pulverulentus. Coarse pigment mottling of the pigment epithelium in the macular area.[31]

Fundus pulverulentus

This is the rarest of all pattern dystrophies. It is characterized by a granular appearance with coarse and punctiform mottling of the RPE within the macular region[32] Fluorescein angiography usually shows the hypofluorescent spots corresponding to the pigment mottling. [33] This dystrophy can be easily confused with AMD due to RPE mottling within the RPE. A misdiagnosis can cause unnecessary anxiety in a patient who would believe they have a progressive disease when in actuality, most pattern dystrophies are not rapidly progressive



Systemic Manifestations

Pattern dystrophies can be associated with systemic diseases. Psedudoxanthom elasticum has been seen in all pattern dystrophies with fundus pulverulentus being the most common. [34] Butterfly and reticular dystrophy has been shown to be associated with myotonic dystropy. [35] Maternally inherited diabetes and deafness (MIDD) has shown to have a high correlation, up to 85%, with pattern dystrophies. [36] Many other systemic associations may exist but it is difficult to identify them, as the visual acuity in most patients in previous studies has been normal.


Differential diagnosis

Due to its multiple presentations, the differential for pattern dystrophies is very large and include:

  • Age-related macular degeneration
  • Best disease
  • Central serous chorioretinopathy
  • Pigment epithelial detachment
  • Doyne honeycomb retinal dystrophy (malattia leventinese)
  • North Carolina macular dystrophy
  • Syphilitic retinitis
  • Blastomycosis
  • Cysticercosis
  • Acute Idiopathic Maculopathy
  • Sarcoidosis
  • Melanoma Associated Retinopathy
  • Acute exudative polymorphous vitelliform maculopathy
  • Solar Retinopathy
  • Choroidal rupture


Top left: Color photograph of a case of subfoveal CNV associated with reticular PD before anti-vegf intravitreal injections. Top right: Color photograph of the same eye after the loading phase of three anti-vegf intravitreal injections. Bottom left: FA of the same eye before the treatment, revealing diffuse leakage. Bottom right: FA of the same eye after the loading phase, showing resolution of the leakage[37]

Treatment

There is no treatment for the accumulation of the lipofucin in the various pattern dystrophies. Fortunately, vision loss is slowly progressive compared to AMD. However, vision loss progresses more rapidly in some patient than in others. As there is no treatment to reverse vision loss, patients may benefits from low vision aids and therapy.


Similar to AMD, treatment modalities are focused primarily on complications that may arise from the RPE degeneration most common yet infrequent CNV.

CNV arising from pattern dystrophies has been shown to be responsive to anti-vegf therapy. Treament with anti-vegf therapy has shown to decrease macular swelling and improve visual acuity. [38] Treatment of CNV with PDT should be considered with caution as vitilleform lesions treated with PDT without any components of CNV may have a negative impact on vision. [39][40]

Adult vitelliform dystrophy patients can develop macular holes due to degeneration of overlying outer and photoreceptor layers. Treatment with vitrectomy has mostly been ineffective. However some success has been noted with silicone oil use. [41]

Prognosis

Patients should be reassured that their condition should not significantly affect their vision and is very slow to progress. Pattern dystrophies have previously been misdiagnosed as AMD and which has led to unnecessary emotional stress in patients concerned with impending vision loss. Though these disease entities in themselves have minimal impact on vision some patients may have a small risk of CNV and macular hole due to RPE degeneration. Geographic atrophy may develop in the macula in patients over 60 and can affect central vision. However most patients retain reasonable reading vision in one eye throughout their life without the need of any treatment.


Additional Resources

References

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  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Zhang K, Garibaldi DC, Li Y, et al. Butterfly-Shaped Pattern Dystrophy: A Genetic, Clinical, and Histopathololgical report. Ophthlmic Mol Genet. 2002;120:485-490
  3. Gass JDM. A clinicopathologic study of a peculiar foveomacular dystrophy. Trans Am Ophthalmol Soc 1974; 72: 139–156.
  4. 4.0 4.1 4.2 4.3 Deutman, A. F., van Blommestein, J. D. A., Henkes, H. E., Waardenburg, P. J., Solleveld-van Driest, E. Butterfly-shaped pigment dystrophy of the fovea. Arch. Ophthal. 83: 558-569, 1970.
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  41. Heavy silicone oil effective in macular hole surgery associated with adult vitelliform macular dystrophy Clairton F de Souza MD, Philip J Polkinghorne MD FRANZCO andAndrew FC Riley FRANZCO Clinical and Experimental Optometry 06/2012; 95(6). DOI:10.1111/j.1444-0938.2012.00755.x