(Stroke. 1996;27:996-1001.)
© 1996 American Heart Association, Inc.
Articles |
Neurological Manifestations of Acute Posterior Multifocal Placoid Pigment Epitheliopathy
From the Division of Child Neurology (S.Ç.) and Departments of Ophthalmology (J.S.R.) and Neurology (N.A.B.), University of Pittsburgh School of Medicine, and Retina Service (T.V.), Allegheny General Hospital, Pittsburgh, Pa.
Correspondence to Sinan Çomu, MD, Children's Hospital of Pittsburgh, Division of Child Neurology, 3705 Fifth Ave, Pittsburgh, PA 15213-2583.
 |
Abstract |
|---|
 Top Abstract IntroductionCase ReportsDiscussionReferences |
|---|
Background Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a chorioretinal disease that causes acute visual symptoms with characteristic fundus findings. Although this entity has been associated with a variety of neurological complications, it has received little attention in the neurological literature. We wanted to emphasize the spectrum of neurological involvement, in particular the occurrence and management of strokes in patients with APMPPE.
Case Descriptions We report three patients with APMPPE and neurological disease. All three presented with marked visual disturbances and headaches. One patient developed recurrent strokes involving different vascular territories of the brain and required immunosuppressive treatment for presumed cerebral vasculitis. The other two patients had cerebrospinal fluid pleocytosis and persistent headaches but recovered spontaneously. The review of the literature demonstrates a particular pattern of neurological complications in a subgroup of patients with APMPPE.
Conclusions APMPPE should be considered among the causes of stroke and aseptic meningitis in young adults. The diagnosis is critically dependent on a thorough ophthalmologic examination. Severe neurological complications are difficult to predict at the onset of the ophthalmologic disease. The patients should be monitored closely. If investigations suggest cerebral vasculitis, immunosuppressive treatment may be helpful to prevent recurrences.
Key Words: cerebral infarction • meningitis • ocular disease • vasculitis • vision disorders
|
Introduction |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
Acute posterior multifocal placoid pigment epitheliopathy is a chorioretinal disease typically occurring in young adults who present with binocular visual blurring, metamorphopsia, or scotomas.1 2 Funduscopically, there are multiple circumscribed, gray-white, flat lesions at the level of the retinal pigment epithelium (Fig 1
). The clinical course is self-limited with return
of visual function over weeks to months. A third of these patients have
a flulike illness at the onset. Systemic manifestations are rare;
however, severe neurological involvement can cause strokes and sudden
death (Table 1).
|
|
We report three patients with APMPPE and neurological complications who were admitted to our neurology service since 1989. Although all three presented similarly, only one developed strokes. On the basis of the cumulative data from the reported cases, we suggest a strategy for the workup and management.
|
Case Reports |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
Patient 1
A 23-year-old woman developed severe headaches and bilaterally decreased vision in May 1993. Initial ophthalmologic evaluation revealed visual acuity of 20/400 OD, 8/200 OS, and multiple creamy yellow patches involving the retinal pigment epithelium in both posterior poles (Figs 1
and 2). Her past medical history
was significant for poor dentition with loss of all permanent teeth at
an early age. She had Native American ancestry on her paternal side.
There were no other systemic findings, and an initial MRI of the brain
was normal. The patient started treatment of 40 mg prednisone daily for
presumed Vogt Koyanagi Harada disease. Subsequently, there was some
subjective visual improvement, but her headaches persisted
intermittently. Three weeks after her initial symptoms, while still
taking steroids, she abruptly developed a severe headache followed by
unresponsiveness and right-sided weakness. On admission, she was
stuporous with dense right hemiplegia. Ophthalmologic examination at
this stage revealed early pigmentation of the subretinal lesions in
both eyes. CSF analysis showed 60x106 WBC/L
(90% lymphocytes), 20x106 RBC/L, protein of 0.45
g/L, and glucose of 3.2 mmol/L. Peripheral WBC count was
22x109/L, and erythrocyte sedimentation rate was 30
mm/h. There were a few cellular casts in the initial urinalysis. A
repeat MRI revealed bilateral parieto-occipital infarcts with gyral
enhancement, left-sided basal ganglia signal changes with an
enhancing putaminal lesion, and a nonenhancing lesion in the splenium
of the corpus callosum. The occipital lesions later underwent
hemorrhagic conversion (Fig 3A through 3E). A cerebral
angiogram was unremarkable, as was a chest radiograph and a
transthoracic echocardiogram. APMPPE with associated
cerebral vasculitis was diagnosed, and administration of
intravenous methylprednisolone, 250 mg QID, was started.
The patient improved gradually over 2 weeks. At discharge, she had
residual right hemianopsia, difficulty in reading, and slight right
hemiparesis. Visual acuity had improved to 20/40 OU, and mottled
pigmentation was present in the posterior pole. Oral prednisone was
continued. Extensive laboratory investigations (Table 2)
did not reveal an etiology. Serum adenovirus antibodies at the fourth
week of her illness were positive at a titer of 1:128, but a single
measurement could not prove an acute infection. 
-Glutamyltransferase
and alanine aminotransferase were initially slightly elevated at 176
U/L and 61 U/L, respectively. Human leukocyte antigen typing was A11,
A26, B35, B44, Bw4, Bw6, Cw4, Cw5, DR14, DR15, DR52, and DQ1.
|
|
|
Two months after the initial symptoms, the patient's visual acuity was
20/25 OU with pigment stippling in both maculae, and her right
hemianopsia had slightly improved. Shortly thereafter, she experienced
brief attacks of left arm and face dysesthesia. An electroencephalogram
was unremarkable. She received phenytoin for possible focal seizures.
The attacks continued but were somewhat less pronounced. A month later,
she had a right parietal stroke when her steroid tapering was at 40
mg/d (Fig 3F). CSF revealed 32x106 WBC/L (90%
lymphocytes) and protein of 0.32 g/L. Cyclophosphamide (125 mg/d) was
added to her treatment. She again showed marked clinical improvement.
Prednisone was discontinued at 7 months because of side effects. Twelve
months after initial presentation, cyclophosphamide was
also discontinued. At 24-month follow-up, she was doing well
without medication.
Patient 2
A previously healthy 20-year-old man presented in
October 1989 complaining of 2 weeks of bilateral visual blurring, 1
week of black spots in the right eye, and 4 days of episodic right
retro-orbital headaches. His visual acuity was 20/200 OD and 1/200
OS. There were mild cellular infiltrates in the vitreous bilaterally
and multiple irregular-shaped placoid areas of pigment epithelial
graying in different stages of evolution, with the older lesions
displaying atrophic retinal pigment epithelium. Fluorescein
angiogram findings were diagnostic for APMPPE. Two weeks
later, his vision had decreased to 20/400 OU and his headaches had
intensified. Neurological examination was unremarkable. CSF
analysis showed 89x106 WBC/L (100%
mononuclear cells), 3x106 RBC/L, protein of 0.54
g/L, and glucose of 3 mmol/L. An unenhanced CT scan and a cerebral
angiogram were normal. Laboratory evaluation did not reveal an etiology
(Table 2). Angiotensin-converting enzyme level was 143
U/L (normal, 44 to 125). The visual acuity improved spontaneously over
the next 3 months to a final level of 20/25 OD and 20/20 OS. Fundus
examination demonstrated areas of atrophy and hypertrophy
of the retinal pigment epithelium at the location of the previously
active lesions. His headaches also subsided without further
intervention.
Patient 3
A previously healthy 23-year-old man presented in
April 1989 with a 1-week history of severe headaches, difficulty in
focusing, and perception of black patches and white dots. The patient
also complained of slight fever, night sweats, chills, and nausea.
Ophthalmologic evaluation revealed a visual acuity of 20/50 OU,
multiple paracentral scotomas on Amsler grid visual-field testing,
mild inflammation in both anterior chambers with 1+ cells and flare,
and rare cells in the central vitreous of the left eye. Fundus
examination demonstrated multiple grayish-green placoid lesions at
the level of the retinal pigment epithelium, almost confluent in the
macula, with smaller scattered nonconfluent areas in the periphery.
Fluorescein angiogram findings further supported the
diagnosis of APMPPE. Two weeks later, his visual acuity was 20/60 OD
and 20/30 OS. Fundus examination showed pigment epithelial mottling in
the evolving lesions. Despite the improvement of his visual symptoms,
the headaches persisted. Neurological examination was unremarkable. A
cerebral angiogram and unenhanced CT scan were normal. CSF revealed
61x106 WBC/L (97% mononuclear cells),
17x106 RBC/L, protein of 0.46 g/L, and glucose of 3
mmol/L. The patient improved spontaneously without further
intervention. A brain MRI at the sixth week of the illness was
normal.
|
Discussion |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
In 1968, Gass1 reported three young women with bilateral rapid loss of central visual acuity secondary to multifocal yellow-white placoid lesions at the level of the pigment epithelium and choroid of the retina. Further reports revealed that this illness affects males and females equally, with striking preponderance for young adults.2 Simultaneous onset in both eyes is the rule; however, involvement of the second eye can be delayed for a few days or even weeks. The lesions are mainly at the posterior pole and never anterior to the equator. The placoid lesions start to fade within a few days and by two weeks are replaced by areas of partly depigmented pigment epithelium with irregular pigment clumping. Fluorescein angiography demonstrates characteristic hypofluorescent lesions in the early phase of the angiogram followed by late hyperfluorescence of the same areas (Fig 2
, top and
bottom). If the primary lesions do not involve the fovea, the prognosis
is good, with nearly complete visual function returning over several
weeks. Recurrences are infrequent and usually occur in the
first 6 months.3 Occasionally, progressive disease can
lead to chorioretinal atrophy and significant visual
loss.4 Ocular histopathology of APMPPE is not available. The primary lesion was originally considered to be at the pigment epithelium; however, more recent evidence suggests that the lamina choriocapillaris is the site mainly affected.5 Indocyanine green angiography studies support choroidal hypoperfusion as a likely mechanism of injury rather than primary pigment epitheliopathy.6 7 Choroidal vasculitis has been proposed as the underlying pathological process.8
The etiology of APMPPE is unknown. The frequent history of a preceding flulike illness suggests a viral or parainfectious process. Isolated cases were associated with adenovirus,9 Lyme disease,10 11 systemic lupus erythematosus,12 juvenile rheumatoid arthritis,13 sarcoidosis,14 schistosomiasis,15 hepatitis B vaccination,16 thyroiditis,17 Crohn's disease,18 erythema nodosum,19 and nephritis.20 HLA-B7 or DR2 antigens were reported in a group of patients21 and in two familial occurrences.22 23 Despite lacking definite associations, APMPPE appears to be a manifestation of various infectious or autoimmune processes, analogous to aseptic meningitis.
The differential diagnosis of the retinal findings include serpiginous choroiditis, multiple evanescent white-dot syndrome, birdshot chorioretinitis, acute retinal pigment epitheliitis, multifocal choroiditis, and multifocal retinal metastasis.2 24 Certain systemic illnesses can involve both the brain and the eyes, leading to the so-called uveoretinal-meningoencephalitis syndromes. Specific entities include Vogt Koyanagi Harada disease, sarcoidosis, Behçet's disease, systemic lupus erythematosus, Crohn's disease, metastatic malignancies, primary intraocular lymphoma, histoplasmosis, toxoplasmosis, cytomegalovirus, and syphilis. Of these entities, Vogt Koyanagi Harada disease is a primarily ophthalmologic disease that can mimic APMPPE with initial funduscopic and angiographic findings,25 and it has been suggested that these may represent a continuum of a single disease.25
The common neurological complications of APMPPE are CSF
pleocytosis26 27 and headaches, which usually improve
spontaneously, as in two of our patients. However, some patients
develop transient hearing loss,28 optic
neuritis,3 meningoencephalitis,29 transient
focal deficits,26 and strokes30 31 32 33 due to
vasculitic changes.34 35 There are two reported cases of
death from large strokes.36 37 Of nine previously
described cases of strokes with APMPPE (Table 1), five had angiographic
findings consistent with vasculitis. In one case, brain
histopathology revealed focal granulomatous inflammation of
medium-sized arteries.36 In another case, a muscle
biopsy was suggestive of vasculitis.33 In two previous
cases, angiography was normal, as in our first patient.
The pattern apparent from the reported patients with strokes is that these are mostly young adults with evidence of inflammation in their CSF. Cerebral vasculitis is the presumed mechanism of injury, although angiographic evidence may be lacking. The onset of stroke is typically concurrent with the ocular disease (in one case preceding it) or within 4 to 5 months. In one instance, meningoencephalitis29 developed 5 years after the onset of ocular disease. Infarcts involve predominantly the posterior circulation and the basal ganglia. There may be a biphasic course of the neurological illness,31 and the strokes can recur during the tapering of immunosuppressives. This can be heralded by transient ischemic attacks, which may have been the case in our first patient rather than the suspected focal seizures.
APMPPE should be considered in young patients with unexplained strokes or aseptic meningitis, particularly when associated with symptoms such as scotomas or visual blurring. Although the diagnosis can be firmly established with typical fundus and fluorescein angiography findings, the lesions are difficult to identify with direct funduscopy. Therefore, a thorough ophthalmologic evaluation is necessary in suspected cases. Etiologic investigation for previously reported associations may identify medically treatable cases and help with prognostication. An initial brain MRI for patients without neurological signs is not necessary. CSF analysis, MRI, and cerebral angiogram should be undertaken if persistent headache, neck stiffness, or transient ischemic attack is present. Meningeal biopsy may be indicated if the workup is negative but the patient continues to have ischemic attacks. Once cerebral vasculitis is diagnosed, immunosuppressive treatment should be started. Although some patients with cerebral vasculitis improved spontaneously, given the risk of mortality and recurrent strokes, we advocate aggressive treatment. Combination of steroids with cyclophosphamide or azathioprine is reported to improve the outcome in primary cerebral vasculitis.38 The immunosuppressive agents can be stopped after 6 to 12 months, since there are no reported strokes after 5 months from the disease onset. It remains difficult to predict which patients with CSF pleocytosis and headaches will evolve to have strokes. We suggest that these patients be followed closely for neurological deterioration rather than treated with low-dose steroids.
|
Selected Abbreviations and Acronyms |
|---|
|
Received November 30, 1995; revision received January 17, 1996; accepted January 31, 1996.
|
References |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
1. Gass JDM. Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1968;80:177-185.
2.
Jones NP. Acute posterior multifocal placoid
pigment epitheliopathy. Br J Ophthalmol. 1995;79:384-389.
3. Gass JDM. Inflammatory diseases of the retina and choroid. In: Gass JDM, ed. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. St Louis, Mo: CV Mosby Co; 1987:504-510.
4.
Williams DF, Mieler WF. Long-term
follow-up of acute multifocal posterior placoid pigment
epitheliopathy. Br J Ophthalmol. 1989;73:985-990.
5.
Deutman AF, Oosterhuis JA, Boen-Tan TN, Aan De Kerk
AL. Acute posterior multifocal placoid pigment epitheliopathy:
pigment epitheliopathy or choriocapillaritis. Br J
Ophthalmol. 1972;56:863-874.
6. Dhaliwal RS, Maguire AM, Flower RW, Arribas NP. Acute posterior multifocal pigment epitheliopathy: an indocyanine green angiographic study. Retina. 1993;13:317-325. [Medline] [Order article via Infotrieve]
7. Howe LJ, Woon H, Graham EM, Fitzke F, Bhandari A, Marshall J. Choroidal hypoperfusion in acute posterior multifocal placoid pigment epitheliopathy: an indocyanine green angiography study. Ophthalmology. 1995;102:790-798. [Medline] [Order article via Infotrieve]
8.
Spaide RF, Yannuzzi LA, Slakter J. Choroidal
vasculitis in acute posterior multifocal placoid pigment
epitheliopathy. Br J Ophthalmol. 1991;75:685-687.
9. Azar P, Gohd RS, Waltman D, Gitter KA. Acute posterior multifocal placoid pigment epitheliopathy associated with an adenovirus type 5 infection. Am J Ophthalmol. 1975;80:1003-1005. [Medline] [Order article via Infotrieve]
10. Tönyes W, Mielke U, Schmidt HJ, Haass A, Holzer G. Acute multifocal placoid pigment epitheliopathy with CSF signs of inflammation: a special form of Lyme disease. Dtsch Med Wochenschr. 1989;114:793-795. [Medline] [Order article via Infotrieve]
11. Bodine SR, Marino J, Camisa TJ, Salvate AJ. Multifocal choroiditis with evidence of Lyme disease. Ann Ophthalmol. 1992;24:169-173. [Medline] [Order article via Infotrieve]
12. Kawaguchi Y, Hara M, Hirose T, Kitani A, Hirose W, Norioka K, Harigai M, Suzuki K, Kawakami M, Hidaka T. A case of SLE complicated with multifocal posterior pigment epitheliopathy. Ryumachi. 1990;30:396-402. [Medline] [Order article via Infotrieve]
13. Bridges WJ, Saadeh C, Gerald R. Acute posterior multifocal placoid pigment epitheliopathy in a patient with systemic-onset juvenile rheumatoid arthritis: treatment with cyclosporin A and prednisone. Arthritis Rheum. 1995;38:446-447. [Medline] [Order article via Infotrieve]
14.
Dick DJ, Newman PK, Richardson J, Wilkinson R, Morley
AR. Acute posterior multifocal placoid pigment epitheliopathy
and sarcoidosis. Br J Ophthalmol. 1988;72:74-77.
15.
Dickinson AJ, Rosenthal AR, Nicholson KG.
Inflammation of the retinal pigment epithelium: a unique
presentation of ocular schistosomiasis. Br J
Ophthalmol. 1990;74:440-442.
16.
Brezin AP, Massin-Korobelnik P, Boudin M, Gaudric A,
LeHoang P. Acute posterior multifocal placoid pigment
epitheliopathy after hepatitis B vaccine. Arch
Ophthalmol. 1995;113:297-300.
17.
Jacklin HN. Acute posterior multifocal placoid
pigment epitheliopathy and thyroiditis. Arch
Ophthalmol. 1977;95:995-997.
18. Gass JDM. Acute posterior multifocal placoid pigment epitheliopathy: a long-term follow up. In: Fine SL, Owens L, eds. Management of Retinal Vascular and Macular Disorder. Baltimore, Md: Williams & Wilkins Co; 1983:176-181.
19.
Van Buskirk EM, Lessell S, Friedman E.
Pigmentary epitheliopathy and erythema nodosum. Arch
Ophthalmol. 1971;85:369-372.
20.
Priluck IA, Robertson DM, Buettner H. Acute
posterior multifocal placoid pigment epitheliopathy: urinary
findings. Arch Ophthalmol. 1981;99:1560-1562.
21.
Wolf MD, Folk JC, Panknen CA, Goeken NE. HLA-B7
and HLA-DR2 antigens and acute posterior multifocal placoid pigment
epitheliopathy. Arch Ophthalmol. 1990;108:698-700.
22. Kim RY, Holz FG, Gregor Z, Bird AC. Recurrent acute multifocal placoid pigment epitheliopathy in two cousins. Am J Ophthalmol. 1995;119:660-662. [Medline] [Order article via Infotrieve]
23. Wolf MD, Folk JC, Goeken NE. Acute posterior multifocal pigment epitheliopathy and optic neuritis in a family. Am J Ophthalmol. 1990;110:89-90.[Medline] [Order article via Infotrieve]
24. Jampol LM. Multifocal chorioretinopathies. In: Tsa MOM, ed. Retinal Diseases, Biomedical Foundations and Clinical Management. Philadelphia, Pa: JB Lippincott Co; 1988:318-324.
25.
Wright BE, Bird AC, Hamilton AM. Placoid pigment
epitheliopathy and Harada's disease. Br J
Ophthalmol. 1978;62:609-621.
26. Holt WS, Regan CDJ, Trempe C. Acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol. 1976;81:403-412. [Medline] [Order article via Infotrieve]
27. Bullock JD, Fletcher RL. Cerebrospinal fluid abnormalities in acute posterior multifocal placoid pigment epithelialopathy. Am J Ophthalmol. 1977;84:45-49. [Medline] [Order article via Infotrieve]
28. Clearkin LG, Hung SO. Acute posterior multifocal placoid pigment epitheliopathy with transient hearing loss. Trans Ophthalmol Soc U K. 1983;103:562-564.
29. Kersten DH, Lessell S, Carlow TJ. Acute posterior multifocal placoid epitheliopathy and late-onset meningo-encephalitis. Ophthalmology. 1987;94:393-396. [Medline] [Order article via Infotrieve]
30.
Smith CH, Savino PJ, Beck RW, Schatz NJ, Sergott
RC. Acute posterior multifocal placoid pigment epitheliopathy
and cerebral vasculitis. Arch Neurol. 1983;40:48-50.
31. Weinstein JM, Bresnick GH, Bell CL, Roschman RA, Brooks BR, Strother CM. Acute posterior multifocal placoid pigment epitheliopathy with cerebral vasculitis. J Clin Neuroophthalmol. 1988;8:195-201. [Medline] [Order article via Infotrieve]
32. Bodiguel E, Benhamou A, LeHoang P, Gautier JC. Cerebral infarction, placoid epitheliopathy and sarcoidosis. Rev Neurol. 1992;148:746-751. [Medline] [Order article via Infotrieve]
33. Bewermeyer H, Nelles G, Huber M, Althaus C, Neuen-Jacob E, Assheuer J. Pontine infarction in acute posterior multifocal placoid epitheliopathy. J Neurol. 1993;241:22-26. [Medline] [Order article via Infotrieve]
34. Sigelman J, Behrens M, Hilal S. Acute posterior multifocal placoid pigment epitheliopathy associated with cerebral vasculitis and homonymous hemianopsia. Am J Ophthalmol. 1979;88:919-924. [Medline] [Order article via Infotrieve]
35.
Stoll G, Reiners K, Schwartz A, Kaup FG, Althaus C,
Freund HJ. Acute posterior multifocal placoid pigment
epitheliopathy with cerebral involvement. J
Neurol Neurosurg Psychiatry. 1991;54:77-79.
36.
Wilson CA, Choromokos EA, Sheppard R. Acute
posterior multifocal placoid pigment epitheliopathy and cerebral
vasculitis. Arch Ophthalmol. 1988;106:796-800.
37.
Hammer ME, Grizzard WS, Travies D. Death
associated with acute, multifocal, placoid pigment
epitheliopathy. Arch Ophthalmol. 1989;107:170-171.
38. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Medicine. 1987;67:20-39.
This article has been cited by other articles:
 |
|
 |
|
  A.N. Bugnone, F. Hartker, M. Shapiro, H.S. Pineless, and G. Velez Acute and Chronic Brain Infarcts on MR Imaging in a 20-Year-Old Woman with Acute Posterior Multifocal Placoid Pigment Epitheliopathy AJNR Am. J. Neuroradiol., January 1, 2006; 27(1): 67 - 69. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||