Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) 

Updated: Jul 22, 2019
Author: Lakshmana M Kooragayala, MD; Chief Editor: C Stephen Foster, MD, FACS, FACR, FAAO, FARVO 

Overview

Background

First described by Gass in 1968, acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an acquired inflammatory disorder affecting the retina, retinal pigment epithelium, and choroid of otherwise young healthy adults.[1] The disease is self-limited and is characterized by multiple yellow-white placoid subretinal lesions of the posterior pole, as shown below. The lesions are frequently bilateral and in various stages of evolution, typically resolving in weeks to months and leaving circumscribed areas of retinal pigment epithelial disturbance.

Posterior pole of right eye. Early acute posterior Posterior pole of right eye. Early acute posterior multifocal placoid pigment epitheliopathy lesion shows yellowish-white placoid lesion involving the macula and an area just inferior temporal to the macula.
Posterior pole of left eye of same patient showing Posterior pole of left eye of same patient showing acute posterior pole placoid lesion.
Inferior nasal of right eye of the same patient ap Inferior nasal of right eye of the same patient approximately 2 months later, showing scattered areas of retinal pigment epithelium atrophy and hyperplasia.

Synonyms of APMPPE include acute multifocal placoid pigment epitheliopathy (AMPPE), acute placoid pigment epitheliopathy, and multifocal placoid pigment epitheliopathy.

Pathophysiology

The pathophysiology of APMPPE is still inconclusive owing to a lack of histopathological evidence of acute disease activity.

Gass initially suggested that inflammation of the retinal pigment epithelium (RPE) and outer retina manifests as placoid lesions during the acute phase based on clinical and fluorescein angiography (FA) findings.[1]

Growing evidence supports choriocapillary perfusion abnormalities in both acute and healed phases as the underlying pathology in APMPPE, with secondary changes in the RPE and outer retina. Nonetheless, an understanding of the exact pathogenesis is still elusive owing to interpretative difficulties with new imaging technologies and lack of histopathology.[2]

Epidemiology

Frequency

United States

The incidence and prevalence of APMPPE is unknown. However, since the landmark description of Gass, APMPPE has been reported frequently and widely from ophthalmic centers, primarily in the United States and Western Europe. Most US patients reported in the literature reside in the northern and midwestern states.

International

Reports in the international literature have included patients from northwestern European countries, such as England, Scotland, France, Belgium, the Netherlands, and Denmark. Several reports have originated from Japan. Reports from other geographic areas have been sparse.

Mortality/Morbidity

APMPPE usually affects healthy adults, and, other than ocular involvement, systemic manifestations are relatively uncommon. When they do occur, many systemic manifestations are usually mild and transient in nature; however, the presence of cerebral vasculitis has been associated with permanent neurologic sequelae, such as hemiparesis and even death from intracerebral edema and brain herniation in rare instances.

Race

Almost 80% of the recorded cases include whites, with the remainder being Japanese, African American, Nepalese, and from the Indian subcontinent. Whether this racial distribution represents a predilection of APMPPE for whites or a reporting bias is unclear.

Sex

Earlier reports of APMPPE suggested a slight preponderance of women with this disease, but more recent publications suggest no sexual predilection, with equal frequency between both men and women.

Age

The mean age of onset is approximately 27 years. The documented age range of onset is 7-66 years. The most frequent age range of occurrence of APMPPE is in those patients aged 16-40 years, representing approximately 85% of cases. About 50% of patients present in the third decade of life.

Prognosis

APMPPE is a self-limiting disease, with more than 80% of affected individuals achieving a visual acuity of 20/40 or better. Visual recovery may take months. In some cases, patients with foveal involvement end up with a visual acuity of 20/50 or worse.[3]

A small number of patients have permanent visual loss due to choroidal neovascularization.

A few patients have long-term functional ocular symptoms (eg, scotomata, metamorphopsia).

An occasional death has been reported following an episode of cerebral vasculitis.

Other ocular and systemic manifestations of vasculitis usually are self-limited and non–life threatening.

Chorioretinal scarring usually is associated with few visual symptoms.[4]

Patient Education

Reassure the patient that in spite of significant vision loss, the visual decrease is usually transient and many patients regain relatively good vision.

 

Presentation

History

Prodromal symptoms of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) may include the following:

  • Prior viral or flulike syndrome - Occurs in approximately one third of patients; symptoms include fever, cough, swollen lymph glands, nausea, vomiting, myalgia, malaise, muscle and joint tenderness
  • Moderate-to-severe headache
  • Neurologic symptoms (rare) - Transient aphasia, numbness and weakness of extremities, feelings of clumsiness

Early-stage symptoms may include the following:

  • Acute decrease in visual acuity
  • Blotchy scotomata
  • Photopsia
  • Metamorphopsia/micropsia
  • Photophobia
  • Conjunctival injection/episcleritis (rare)

Late-stage symptoms may include the following:

  • Mild visual impairment (20/25 to 20/40), common
  • Significant visual loss (20/200), rare

Physical

Patients should have a complete eye examination, including visual acuity, pupillary reactions, slit lamp examination, and dilated indirect ophthalmoscopy.

Early stage

Visual acuity may be normal; if the macula is involved, vision can decrease to 20/200 within days after onset.

Extraocular muscle function is normal unless cerebral vasculitis develops.

No relative afferent pupillary defect is present.

Conjunctivitis or episcleritis is rarely present.

If present, anterior chamber reaction usually is mild, although fibrinous inflammation has been noted.

Vitreous cells may be found in up to 50% of eyes that are affected, but it is usually mild if present.

Retinal findings

Retinal findings are the main feature of the disease.

Multiple subretinal placoid yellow-white lesions are seen in both eyes. In some cases, the lesions are unilateral with involvement of the second eye either within a short period of time or after an extended period. New lesions may occur in the affected eye as old lesions begin their resolution.

Rarely, a well-demarcated serous retinal detachment may develop in the posterior retina and rarely located anterior to the equator.

Optic nerve involvement

Blurring of disc margins, hyperemia, edema, and superficial hemorrhages may be found.

Papillitis and optic neuritis are a less frequent occurrence.

Venous compression within the optic nerve may lead to retinal vein distension and, rarely, to central retinal vein occlusion.

Late stage

Individual placoid lesions resolve over several weeks as a natural course, along with other signs of inflammation.

Resolution of the placoid lesions is characterized by well-demarcated areas of retinal pigment epithelial loss with presence of diffuse fine foci of hyperplasia, along with similar choroidal findings.

Long-term retinal pigment epithelium (RPE) changes may continue to develop long after recovery.

In most instances, the visual acuity returns to 20/30 or better; initial visual recovery is rapid, but final recovery may take up to 6 months.

Recurrences

APMPPE tends to occur bilaterally, although both eyes may not be affected at the same time.

Long-term follow-up studies suggest that recurrences may develop in up to 50% of patients.

Systemic manifestations

Systemic manifestations, believed to result from diffuse multisystem vasculitis, may include the following:

  • Erythema nodosum

  • Thyroiditis

  • Microvascular nephropathy

  • Neurologic manifestations include cerebral vasculitis, transient ischemic attacks, fixed neurologic deficits, transient or permanent low-tone hearing loss, vertigo, labyrinthitis, and meningoencephalitis.

Rare ocular manifestations

These may include the following:

  • Perilimbal corneal stromal infiltrates

  • Serous retinal detachment

  • Retinal periphlebitis

  • Retinal venous dilation and tortuosity

  • Ciliary flush

  • Corneal edema

  • Limbal corneal neovascularization

  • Limbal corneal thinning

  • Anterior and posterior synechiae

  • Koeppe nodules

  • Relative afferent pupillary defect

Causes

APMPPE has been known to occur after different conditions or in conjunction with a broad variety of disorders, as follows:

  • Tuberculosis exposure

  • Sarcoidosis

  • Mumps

  • Lyme disease

  • Nephritis

  • Hepatitis B vaccination

  • Group A streptococcal infection

  • Swine flu vaccination

  • Tuberculin skin testing

  • Penicillin therapy

  • Thyroiditis

  • Erythromycin therapy

  • Toxoplasmosis

  • Adenovirus 5 infection

  • Use of oral contraceptives

  • Use of hormone replacements

  • Clear cell renal cell carcinoma

  • Systemic necrotizing vasculitis

  • Ulcerative colitis

  • Meningococcal C conjugate vaccine[5]

  • Adenovirus infection

  • Influenza vaccination[6]

  • Varicella vaccination[7]

The actual cause of APMPPE is not known. Approximately one third of patients in some series have a history of recent viral illness with a flulike syndrome, upper respiratory infection, or other systemic illness several days to a few weeks before appearance of the ocular lesions. Fever, headache, malaise, gastrointestinal, or upper respiratory symptoms may be preceding symptoms.

Since APMPPE seems to occur after diverse infectious diseases and other stimuli, many investigators believe that it is likely an immune disorder. A higher frequency of human leukocyte antigen B7 (HLA-B7) and human leukocyte antigen DR2 (HLA-DR2) have been reported, suggesting an inherited tendency for the disorder, and that several infectious agents and or other triggers may be the stimulus of APMPPE in susceptible individuals.[8] The general consensus is that the systemic and ocular causes of APMPPE may be a generalized vasculitis leading to choroidal lobular nonperfusion.

Complications

Choroidal neovascularization can develop in areas of previously healed lesions associated with bleeding and/or subretinal fluid. If the lesion is close to or under the foveal system, patients can experience sudden vision decrease.

See the list below:

  • Subretinal neovascularization

  • Retinal vein occlusion

  • Death or other permanent neurologic sequelae from cerebral vasculitis; may include muscle paralysis and permanent hearing loss

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is diagnosed from its typical clinical appearance and disease course. No test is pathognomonic or diagnostic for this disease.

The following tests may be ordered to help rule out other diseases that may have somewhat similar findings:

  • Antinuclear antibody (ANA)

  • Antineutrophil cytoplasmic antibodies (ANCA)

  • Rheumatoid factor

  • Angiotensin-converting enzyme (ACE)

  • Rapid plasma reagin (RPR)

  • Purified protein derivative (PPD) skin test

  • Anergy panel

  • Chest x-ray

  • Complete blood count (CBC)

  • Sedimentation rate

  • Lyme disease titers

  • Cytomegalovirus (CMV) antibodies

  • Anticardiolipin antibodies

Imaging Studies

A CT scan or MRI is indicated in those patients with severe headache or CNS symptoms.

A cerebral arteriogram may be indicated when cerebral vasculitis is suspected.

Other Tests

Studies that may assist in the diagnosis of APMPPE include the following:

  • Lumbar puncture: Lymphocytic pleocytosis and elevated protein frequently present in spinal fluid if headache is present.

  • Urinalysis: Transient proteinuria, casts, and lymphocytes may indicate a subclinical microvascular nephropathy.

Fluorescein angiography

Early lesions: Characteristic findings of early hypofluorescence of the lesions are followed by later hyperfluorescence, as shown below, with or without central staining.

Fluorescein angiography showing peripheral hypoflu Fluorescein angiography showing peripheral hypofluorescence and central leakage of the lesion inferior temporal to the macula.

Older lesions: Such lesions may show window defects in RPE.

Fluorescein angiogram of the patient above in late Fluorescein angiogram of the patient above in late phase showing late staining of placoid areas.
Fluorescein angiography of same patient in late ph Fluorescein angiography of same patient in late phase showing areas of late staining.

Indocyanine green (ICG) angiography

Early lesions: Numerous round hypofluorescent choroidal defects frequently outnumber those seen on fluorescein angiography. Larger choroidal vessels can be visualized in the hypofluorescent areas, suggesting nonperfusion of choroidal lobules as the source of the typical APMPPE lesions.

Older lesions: Partial or complete resolution of the hypofluorescent choroidal areas occurs, and the choroidal findings observed with ICG angiography disappear or resolve earlier than fluorescein angiographic findings. In resolution, the lesions observed with ICG angiography may remain identical to those seen ophthalmoscopically and to the fluorescein angiographic changes.

Fundus autofluorescence

Fundus autofluorescence (FAF) has been used for the evaluation of the retinal pigment epithelium (RPE) in degenerative, inflammatory, and neoplastic disease conditions. The FAF signal is derived primarily from lipofuscin accumulation within the RPE and may be indicative of altered structure and function.[9, 10, 11]

FAF imaging of active placoid lesions shows hypoautofluorescence with relative hyperautofluorescence along their edge. As the disease progresses, hyperautofluorescence become more generalized over the lesions and gradually changes to hypoautofluorescence once fully healed. These lesions may be larger than the area of lesions identified by FA/ICG angiography at peak activity.

Electroencephalography

Electroencephalography may show diffuse slowing of wave patterns.

Electroretinography

Electroretinography (ERG) findings may be minimally subnormal.[12]

Electro-oculography

Electro-oculography (EOG) findings may have substantial reduction of light-to-dark ratio studies, which show diffuse functional abnormality of the RPE. Functional recovery may be slow, and, in some instances, it may take up to a year for full recovery.

Visual fields

Visual fields may show paracentral scotomata early; some visual defects may be permanent.

Dark adaptation

Dark adaptation may show delayed in the acute phase, which can return to normal with time after recovery from the acute lesions.

Optical coherence tomography

Spectral domain optical coherence tomography (SD-OCT) imaging can demonstrate structural retinal changes involving the photoreceptors and RPE layers during the APMPPE disease process.[13, 14, 15]

Serial OCT is useful in the noninvasive follow-up; it may assist in determining prognosis/staging of disease.

Stage 1 acute-phase placoid lesions appear as a prominent elevation and disruption of the inner segment/outer segment (IS/OS) junction, with an accumulation of hyperreflective material intertwined with a variable amount of subretinal fluid. This is followed by a rapid flattening of the elevation.

Stage 2, the subacute phase, appears as a distinct separation between the IS/OS junction and the RPE with thinning of the outer nuclear layer.

Stage 3, the late phase, is characterized by accentuated hyperreflectivity of the RPE with partial disappearance of the IS/OS junction.

Stage 4, the last phase, demonstrates nearly complete resolution of the previous findings, with reappearance of IS/OS junction and the RPE as two separated distinguishable layers. The IS/OS junction and the RPE almost regain their normal appearance.

After disease resolution, some healed areas continue to demonstrate areas of severe photoreceptor atrophy and loss of the RPE.

Optical coherence tomography angiography

Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality that is used to visualize vasculature in fine detail in various layers of retina and choroid and allows assessment of the retinal and choroidal microvascular flow in a three-dimensional pattern. OCTA has been used to evaluate various retinochoroidal diseases for better understanding of the pathogenesis, natural course, diagnosis, and management.

OCTA has been reported to show evidence of choriocapillaris flow abnormalities in acute and healed APMPPE lesions. In acute lesions, significant loss of choriocapillaris flow was reported, whereas healed lesions showed distinct small vascular flow channels with intervening no-flow zones. These findings suggest decreased blood flow consistent with choriocapillaris changes leading to a primary ischemic insult to the RPE rather than a primary RPE inflammatory etiology.[2, 16, 17, 18, 11]

Stiles-Crawford effect

The Stiles-Crawford effect shows early profound disorientation of the photoreceptors.

Histologic Findings

No histopathology of ocular tissue has been published. Cerebral pathology of a patient with cerebral vasculitis showed granulomatous changes associated with giant cells beneath the RPE with no vasculitic changes in choroidal vessels.[19]

 

Treatment

Approach Considerations

Conservative management is recommended; treat ocular complications or systemic vasculitis as indicated.

Medical Care

The treatment of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is controversial. The fundus lesions appear to run a relatively self-limited course with no treatment. Systemic steroids or biologic agents such as tumor necrosis factor inhibitors (eg, infliximab) may be considered in cases involving significant visual problems, recurrent debilitating cases, or cases involving systemic problems.[20, 4]

Surgical Care

In cases complicated by choroidal neovascularization, laser photocoagulation and intravitreal injection of antivascular growth factors (eg, bevacizumab, ranibizumab, aflibercept [off-label use]) can be considered.[20]

Consultations

Consultations may be indicated if the diagnosis is not clear or if a systemic manifestation indicates such a need (an infrequent occurrence).

  • Neurologist/neurosurgeon - CNS symptoms

  • Urologist - Urinalysis findings

  • Dermatologist - Skin findings

  • Rheumatologist - Serum immunologic abnormalities

  • Infectious disease specialist

Diet

No dietary restrictions are indicated.

Activity

No limitations of visual or physical activities are indicated unless systemic manifestations impose limitation of physical activities.

Further Outpatient Care

Monitor the clinical course of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) every 1-2 weeks and for onset of systemic complications.

 

Medication

Medication Summary

In most cases, the lesions of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) resolve spontaneously, and no therapy is required. Some authors have used corticosteroids to treat the ocular disease and/or any severe systemic manifestations. However, there is no evidence that treatment with corticosteroids affects the visual outcome in patients with APMPPE. Various routes of administration (eg, topical, oral, pulse intravenous, sub-Tenon injection) and dosages of corticosteroids have been used. Cycloplegics may be useful for severe iritis, an infrequent finding.

Corticosteroids

Class Summary

Suppress ocular and systemic inflammation.

Prednisone (Deltasone, Rayos)

May be indicated when signs of systemic vasculitis are present, given either orally or by pulse IV therapy. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Vascular Endothelial Growth Factor Inhibitors

Class Summary

These agents slow vision loss by suppressing neovascularization.

Bevacizumab (Avastin)

Off-label indication for choroidal neovascularization.

Off-label: 1.25 mg (in 0.05 mL of solution) administered via intravitreal injection once monthly or as needed.

The need to repackage the drug from the available size vial into smaller doses increases risk for infection transmission if improper aseptic technique occurs.

Ranibizumab (Lucentis)

Off-label use for choroidal neovascularization

0.5 mg intravitreal injection monthly or as needed

Aflibercept intravitreal (Eylea)

Off-label use for choroidal neovascularization

2 mg (0.05 mL) via intravitreal injection monthly or as needed.

Immunosuppressants

Class Summary

These agents inhibit inflammatory reactions by suppressing key factors of the immune system.

Infliximab (Remicade)

Off-label use for cases with severe systemic manifestations.