acute multifocal placoid pigment epitheliopathy

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Acute Multifocal Placoid PigmentEpitheliopathy and Central NervousSystem Involvement

Nine New Cases and a Review of the Literature

Henry S. OHalloran, FRCSI,1 Joseph R. Berger, MD,2 William B. Lee, MD,1 Dennis M. Robertson, MD,3

Joseph A. Giovannini, MD,4 Gregory B. Krohel, MD,5 Roy J. Meckler, MD,6 John B. Selhorst, MD,7

Andrew G. Lee, MD,8 David A. Nicolle, MD,9 Justin ODay, MD10

Objective: The authors describe nine new cases of acute multifocal placoid pigment epitheliopathy (AMPPE)with associated central nervous system (CNS) involvement and permanent visual sequelae. The study includesa review of the literature and discussion of evaluation, management, and treatment options.

Design: Retrospective, noncomparative case series.Participants: Nine patients were identified with AMPPE and CNS involvement in addition to 22 patients

reviewed in the literature.Main Outcome Measures: A review of nine patients with AMPPE and CNS involvement was performed.

Charts were reviewed for age, gender, preceding viral prodromes, visual acuity, ophthalmologic examinationfindings, CNS findings, and treatment.

Results: Thirty-one patients (nine new patients) were diagnosed with AMPPE and various degrees of CNSinvolvement. Ages ranged from 8 to 54 years, with an average of 27 years. Twenty-one males (68%) and 10females (32%) were identified. Eleven patients (35%) had antecedent viral illnesses. Visual acuity was variableand ranged from 20/20 to count fingers. The spectrum of CNS findings ranged from headaches to sagittal sinusthrombosis.

Conclusions: Acute multifocal placoid pigment epitheliopathy can be associated with CNS abnormalitiesand permanent visual deficits. Neuroimaging, lumbar puncture, and cerebral angiography analysis provide usefuldiagnostic tools when CNS involvement is suspected. Intravenous corticosteroids and collaboration with neu-

rovascular colleagues should be considered in these situations. In cases complicated by CNS arteritis, immu-nosuppressive agents can be a beneficial adjunct to corticosteroids. Ophthalmology 2001;108:861868 2001

by the American Academy of Ophthalmology.

In Gasss1 original description of acute multifocal placoidpigment epitheliopathy (AMPPE) in 1968, he described thesalient and diagnostic features of the disorder. The lesions inthe retina were noted to be creamy white and were found atthe level of the retinal pigment epithelium. They were alsonoted to be placoid and multifocal. The fluorescein angio-gram in one patient was described as showing early hy-pofluorescence and late hyperfluorescence, the classic fea-

tures of this disorder. However, at that time, no descriptionwas made of central nervous system (CNS) involvement inthese patients. Subsequently, 17 papers have described 22cases of AMPPE with CNS involvement.218 The CNSinvolvement ranged in severity from persistent headaches todiffuse vasculitis leading to death.3,4 We identified nineadditional patients of AMPPE with various degrees of CNSinvolvement ranging from headaches to cerebral infarcts,

Originally received: November 9, 1999.Accepted: February 8, 2001. Manuscript no. 99731.1Department of Ophthalmology, University of Kentucky, Lexington, Ken-tucky.2Departments of Neurology and Internal Medicine, University of Ken-tucky, Lexington, Kentucky.3Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.4Department of Ophthalmology, Georgetown University, Washington, DC.5Private Practice, Troy, New York.6Private Practice, Louisville, Kentucky.

7Departments of Ophthalmology and Neurology, Saint Louis University,St. Louis, Missouri.8Departments of Ophthalmology and Neurology, University of Iowa, IowaCity, Iowa.9Department of Ophthalmology, London University, London, Ontario, Canada.10Department of Ophthalmology, St. Vincents Hospital, Fitzroy, Victoria,Australia.

The authors have no financial interest related to this manuscript.

Correspondence to Henry S. OHalloran, FRCSI, Department of Ophthalmology,University of Kentucky, Lexington, KY 40536. E-mail: [email protected].

861 2001 by the American Academy of Ophthalmology ISSN 0161-6420/00/$see front matterPublished by Elsevier Science Inc. PII S0161-6420(01)00565-6


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and herein we discuss these patients in detail. We alsoreviewed the relevant literature on the subject and formu-lated a clinical plan for the evaluation, management, andtreatment of patients with complicated AMPPE.124

Patients and Methods

A MEDLINE and Grateful Med search was performed for allreferences to AMPPE and retinitis, with and without viral pro-dromes. The search terms used included acute multifocal placoidpigment epitheliopathy and retinitis. Each of these papers wasexamined for references to AMPPE and CNS involvement. A totalof 17 papers were identified. Subsequently, a letter of notice of ourpaper was sent to all members of The North American Neuro-

ophthalmology Society listed on the societys mailing list. A totalof 37 replies were received. From these replies, we identified eightother patients with AMPPE and CNS involvement. These arereported along with our own patient.

Patient 1

In April 1997, a 16-year-old white male sought treatment from hisophthalmologist after development of a scotoma in the left eye,which he related as a prodrome of his migraine, with the exceptionthat it was noted to last longer than usual. On examination, he wasnoted to have a visual acuity of 20/20 in both eyes and chorioreti-nal lesions that demonstrated early hypofluorescence and latehyperfluorescence on fluorescein angiography (Figs 1 and 2). Hewas started on prednisone 100 mg, which was tapered graduallyover 2 weeks. One year later, the patient had a seizure. Magneticresonance imaging (MRI) demonstrated meningeal enhancementand right frontal and parietal lobe encephalomalacia with areas ofenhancement (Fig 3). An electroencephalogram (EEG) was per-formed that showed right frontal slowing with intermittent sharpwaves. A diagnosis of viral meningitis was made, and the patientwas hospitalized with a presumed diagnosis of herpes simplexencephalitis and treated with intravenous acyclovir.

One month later, he sought treatment for severe headaches,confusion, and left-sided numbness. He reported no visual symp-toms. Lumbar puncture analysis revealed an opening pressure of396 mm of water, 28 white blood cells/high-power field (100%mononuclear), protein 85 mg/dl, glucose 44 mg/dl, and immuno-

globulin G 5.7 mg/dl (normal range, 2.0 5.0 mg/dl). A repeattapering dose of prednisone was administered beginning with a

daily dose of 100 mg. A repeat MRI showed biparietal hemor-rhages, and an angiogram showed a superior sagittal sinus throm-bosis. A right parietal hemorrhage was surgically evacuated, and abrain biopsy was obtained in May 1998. The brain tissue appearednormal histologically. He was treated with phenytoin 400 mg dailyand warfarin. After the prednisone taper was completed, dexa-methasone 2 mg twice daily was added to the therapeutic regimen.

A thorough hematologic evaluation revealed no evidence ofcoagulation disorder. Screenings for the presence of antinuclearantibodies, cytoplasmic and perinuclear antineutrophil cytoplas-mic antibodies, rheumatoid factor, anti-Ro, and anti-La antibodieswere all negative. The Westergren sedimentation rate was 5 mm/hour. Two weeks after surgery, the patient was alert and orientated.The CNS examination revealed mild vibratory sensory loss chiefly

in his left lower extremity. Visual acuity was 20/30 in the left eyeand 20/20 in the right eye. Dilated fundus examination revealedovoid lesions in the periphery of both retinas consistent withresolved AMPPE. The rest of the eye examination was withinnormal limits. He had continued to take prednisone and phenytoinsince the time of brain biopsy. No new neurologic or ophthalmo-

Figure 1. A fluorescein angiogram of the left eye in early arteriovenous

phase demonstrating areas of hypofluorescence.Figure 2. A fluorescein angiogram of the left eye in late arteriovenous

phase demonstrating areas of hyperfluorescence.

Figure 3. Magnetic resonance image (MRI) demonstrating a T1-weighted

sagittal image showing right frontal (black arrowhead) and parietal en-

cephalomalacia (black arrow) with enhancing borders and areas of men-

ingeal enhancement.

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logic symptoms have been noted during the follow-up interval of13 months.

Patient 2A 25-year-old white male sought treatment from the Departmentof Ophthalmology at the Mayo Clinic in March 1993 with symp-toms of blurred vision in the right eye. Four months before thisvisit he was diagnosed with viral meningitis and posterior uveitis.At that time, he was started on systemic corticosteroids with fullresolution of his symptoms. One month later, while the cortico-steroids were tapered, generalized malaise, headaches, a righthemiparesis, and difficulty with bladder and bowel control devel-oped. His symptoms improved on reinstitution of his corticosteroidtherapy at 60 mg per day.

At presentation to the ophthalmology department, his visualacuity was 20/40 in the right eye and 20/20 in the left eye. Therewere multiple circumscribed chorioretinal lesions in each eye,

some associated with early pigment rarefaction and pigmentclumping and others with a creamy discoloration (Figs 4 and 5). Afluorescein angiogram showed patchy areas of hypofluorescenceassociated with some of the lesions in the early part of the studyand late hyperfluorescence. These findings were consistent withAMPPE. Magnetic resonance imaging studies of the head andcervical spine with and without gadolinium were negative.

A four-vessel angiogram demonstrated evidence of cerebralarteritis. The patient began a daily oral dose of 50 mg of cyclo-

phosphamide in addition to the systemic corticosteroids. The cor-ticosteroids were tapered, and the cyclophosphamide was gradu-ally increased to 200 mg daily, at which time his conditionimproved. Six months after presentation to the ophthalmologydepartment, his visual acuity was 20/20 in both eyes and hereturned to work with no restrictions. He was no longer takingcyclophosphamide at that time. At a telephone follow-up in Oc-tober 1998, the patient was stable with no new symptoms.

Patient 3

In July 1998, a 36-year-old white male sought treatment at theDepartment of Ophthalmology at Georgetown University for spotsin front of his left eye that had lasted for 4 days and of his right eyethat had lasted for 1 day. The patient described a viral-like illnessthat had developed 10 days previously. On examination, his visualacuity was 20/30 in the right eye and 20/50 in the left eye. Therewas a slight afferent pupillary defect in the left eye. The results ofthe slit-lamp examination were otherwise normal. A fundus exam-ination showed multiple elevated creamy white plaques in botheyes, and the fluorescein angiogram showed early hypofluores-cence with late hyperfluorescence consistent with AMPPE. Thepatient began taking prednisone 40 mg daily.

After 11 days, the patient was reexamined and visual acuitywas unchanged in the right eye but had deteriorated to 20/200 inthe left eye. Funduscopic examination was unchanged. Seven dayslater, the patient had an acute episode of left-sided numbness afterhe discontinued corticosteroids without medical consultation. Hisvision had deteriorated in the left eye to counting fingers. Corti-costeroids were reinstituted at 40 mg per day orally.

One week later, the patient sought treatment for persistentleft-sided numbness present over the previous 7 days. He washospitalized and started on methylprednisolone 1 g intravenouslydaily for 5 days. A lumbar puncture demonstrated an elevatedprotein of 88 mg/dl. An MRI showed multiple T2 signal abnor-malities in the thalamus and in the periventricular white matter.The patient was discharged after 5 days of being administeredprednisone with a gradual taper. At the follow-up examination 2

months after discharge, he was in good health except for somepersistent left-sided numbness. Visual acuity was 20/20 in the righteye and 20/25 in the left eye. Fundus examination showed patchyareas of retinal pigment changes but no active lesions.

Patient 4

A 30-year-old white female sought treatment at the Albany Med-ical Center in December 1989, reporting decreased vision in botheyes over the preceding week. This was associated with a persis-tent headache that had lasted 1 week. On examination at presen-tation, her visual acuity was 20/70 in the right eye and 20/200 inthe left eye. The pupils were fixed, dilated, and unreactive to lightsecondary to pharmacologic iridoplegia. Fundus examination re-vealed placoid lesions consistent with AMPPE. The results of acomputed tomography (CT) examination of the head at that timewere normal. Over the next 3 weeks, the headache worsened andher visual acuity decreased to finger counting in both eyes. Shewas then admitted to the hospital. During hospitalization, shereported episodic ataxia and left-sided numbness. The results of arepeat CT, an MRI, and a four-vessel angiogram were normal. Alumbar puncture revealed a mild pleocytosis, elevated pressure of270 mm of water, and normal protein and glucose levels. Fundusexamination revealed papilledema in both eyes. She was admin-istered 60 mg of prednisone, which prompted swift resolution ofher headache. Her visual acuity failed to improve and the pred-nisone was increased to 80 mg daily. The visual acuity improvedto 20/70 in the right eye and 20/200 in the left eye, but the

Figure 4. Fundus photograph of the right eye demonstrating multiple

circumscribed chorioretinal lesions.

Figure 5. Fundus photograph of the left eye demonstrating multiple

circumscribed chorioretinal lesions.

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papilledema worsened significantly. The patient underwent a leftoptic nerve sheath fenestration, and her visual acuity improved to20/50 in the right eye and 20/80 in the left eye. The prednisone wastapered gradually, and 3 months later her visual acuity was stableat 20/30 in both eyes.

She remained stable over the next year, but problems withpersistent elevated intracranial pressure subsequently developedthat resolved with lumbar-peritoneal shunting. Over the following7 years, she had no further recurrences of her AMPPE and her

visual acuity is stable at 20/30 in the right eye and 20/20 in the lefteye. Fundus examination showed some pigment mottling but noactive lesions. Her headaches have fully resolved.

Patient 5

A 44-year-old white female with a history of AMPPE that hadbeen documented 6 years previously was admitted to the Depart-ment of Neurology at the Jewish Hospital in Louisville in 1996 forinvestigation of migratory paresthesias sequentially involving herright side of face, right hand, and right biceps area that hadpersisted over a 2-month period. Her visual acuity at that time was20/20 in both eyes, although she stated that her vision was sub-jectively worse in the right eye and had remained so since her

episode of AMPPE. Humphrey 30 to 2 visual fields were normal,and fundus examination revealed some mild retinal pigment epi-thelial changes consistent with inactive AMPPE.

On neurologic examination, the only abnormality elicited wassome subjective decreased sensation on the right side of the faceand the right arm. An MRI of the head revealed a small enhancinglesion at the left midbrainpontine junction and two smallerperiventricular white matter T2 lesions. Cerebrospinal fluid exam-ination was remarkable for a mildly elevated IgG index of 0.77with a mildly elevated synthesis rate of 5.2. Four weak oligoclonalbands were detected along with a normal myelin basic proteinlevel at less than 1. A multiple sclerosis-like illness was suspected,and the patient received a dose pack of methylprednisolone start-ing at 60 mg orally daily with a gradual taper. Over the following

3 years, the patient received three further courses of intravenousmethylprednisolone for progression of the T2-weighted lesionsseen on MRI scanning. Her visual acuity at all times remainedstable and there were no further episodes of AMPPE.

Patient 6

A 39-year-old white female sought treatment at the Bethesda EyeInstitute in St. Louis in 1992 for investigation of episodes ofdecreased peripheral vision in her right eye. These episodes lastedfor approximately 20 minutes and had occurred six times in theprevious 4 months. She also described an almost constant head-ache of varying severity. A CT examination performed at this timehad negative results.

On ophthalmic examination, her visual acuity was 20/20 in theright eye and 20/30 to 2 in the left eye. An afferent pupillary defectwas present on the left eye. Funduscopic examination revealedmild optic nerve swelling in the left eye and several peripheralplacoid lesions in both eyes, consistent with AMPPE. A repeatMRI showed a-right sided parasagittal contrast-enhancing lesionlocated to the right of the corpus callosum and straddling thegraywhite matter junction. The results of a lumbar puncture werenormal. The patient was given a dose pack of intravenous meth-ylprednisolone and a follow-up taper of oral corticosteroids. Herheadaches stopped shortly thereafter. Over 2 months, the discedema lessened and visual acuity improved to 20/20 in the left eye.The afferent pupillary defect persisted, however. She was then lostto follow-up.

Patient 7

A 27-year-old white female sought treatment at the Department ofOphthalmology at the Cullen Institute in 1996 for decreased visionin her left eye. She had a previous episode of the same problem in1993, at which time she was told that she had a viral inflammationin her retina, which was treated with oral prednisone and resolvedwithout sequelae.

In December 1996, she experienced an upper respiratory infec-tion, and as this resolved she noted a sudden onset of painlessflashing lights in her right eye. Over 3 days, she noticed decreasedtemporal vision in her right eye and a subjective decrease in hervision in the right eye. On examination, her visual acuity was20/20 in both eyes. There was a trace afferent pupillary defect inthe right eye. Visual fields showed a normal left eye, but the righteye showed an enlarged blind spot, which extended into thetemporal periphery. Anterior segments were normal, but there wasa mild vitritis in the right eye. Fundus examination showed several

deep creamy colored lesions at the level of the retinal pigmentepithelium in the right eye (Fig 6). Examination of the optic nervesshowed minimal hyperemia of the right disc with some nasalswelling and a normal left disc. A diagnosis of AMPPE was made,but no treatment was instituted.

Two years later she sought treatment for an episode of de-creased vision in the left eye. She was treated by a neurologist witha dose pack of methylprednisolone and gradually improved. AnMRI revealed optic nerve enhancement, multiple bilateral periven-tricular T2-weighted lesions, and an enlarged pituitary gland. Ce-rebrospinal fluid examination at that time was normal, includingthe multiple sclerosis panel. The patient was then referred for anophthalmologic consultation, at which time the visual acuity was20/20 in the right eye and 20/25 in the left eye, and a mild leftafferent pupillary defect was noted. Funduscopic examination of

the left eye did not reveal any retinal lesions. There was noevidence of recurrence of AMPPE, and the patient received notreatment at this time. After 3 months, she stated that her visionhad returned to normal.

Patient 8

A 51-year-old white male was seen in the Eye Department atLondon Health Sciences Center in Ontario in 1997 for a routineeye examination. He had no new visual symptoms to report. Ofnote, the patient had a previous history of bilateral AMPPE com-plicated by cerebral vasculitis 18 months earlier and multiple oldinfarcts in the right temporal lobe consistent with strokes seen on

Figure 6. Fundus photograph of the right eye with multiple cream colored

lesions at the level of the retinal pigment epithelium (black arrow).


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MRI. Visual acuity on examination was 20/100 in both eyes.Visual fields revealed a left superior homonymous quadrantanopiasecondary to his cerebral infarcts. Fundus examination showedatrophic areas at the level of the retinal pigment epithelium,consistent with inactive AMPPE. The patient reported previoustherapy with intravenous corticosteroids during the acute illnessfollowed by a tapering dose of oral corticosteroids.

Patient 9

A 49-year-old white male sought treatment at the Eye Departmentat St. Vincents Medical Center in Victoria, Australia, in 1998. Hereported a high fever over the preceding few days, along withmyalgias and headaches. On ophthalmic examination, he hadbilateral iritis and fundus lesions consistent with AMPPE. Hisvisual acuity was 20/40 in the right eye and 20/50 in the left eye.A fluorescein angiogram demonstrated the characteristic findingsof early hypofluorescence and late hyperfluorescence. The patientsubsequently experienced a single episode of confusion and dys-phasia in association with a high fever that lasted a few hours.Neuroimaging included negative CT and MRI examinations of thehead. A presumed diagnosis of vasculitis was made, and thepatient was treated with oral prednisone, after which his symptomsand fever resolved dramatically. At follow-up, he had no docu-mented recurrences over a 10-month interval, and his vision re-

turned to 20/20 in both eyes.

Discussion

Acute multifocal placoid pigment epitheliopathy is a well-described chorioretinal inflammatory disease of uncertainorigin. It usually occurs in both eyes simultaneously, butinvolvement can be delayed in the second eye. This condi-tion manifests as yellow-white placoid lesions at the level ofthe retinal pigment epithelium, situated mainly in the pos-terior pole and rarely anterior to the equator. The lesions

tend to fade after a few days, and after 2 weeks they arereplaced by partly depigmented pigment epithelium clumps.If the primary lesions do not involve the fovea, the visualprognosis tends to be good.1,17,25 The visual acuity can be aspoor as counting fingers or as good as 20/20 during theacute illness. The worst individual recovery in visual acuityfor males in the literature was 20/80; the worst individualrecovery in vision for females in the literature was 20/200.131 Of our nine patients, the worst visual acuity wasseen in patient 4, in whom the visual acuity was 20/200 inthe left eye and 20/70 in the right eye (Table 1).

Acute multifocal placoid pigment epitheliopathy uncom-plicated by CNS involvement appears to affect males andfemales equally and has a predilection for young adults.25

However, in published cases of AMPPE with CNS involve-ment, 16 males have been described, whereas only sixfemales have been discussed. In our case series, there werefive males and four females, which makes a total of 21males and 10 females with documented AMPPE compli-cated by CNS involvement (Table 1). This difference mayreflect selection bias. The average age (where age wasgiven) of all these cases was 27 years, with a range from 8to 54 years.

The cause is uncertain, but evidence is accumulating thatindicates that the primary lesion is in the small choroidalarterioles and that secondary ischemic changes producedisruption of the pigment epithelium, resulting in typicalplacoid lesions.12,26 Indocyanine green angiography sup-ports choroidal hypoperfusion as a likely mechanism ofinjury rather than primary pigment epitheliopathy.26,27 Thisischemia leads to retinal pigment epithelial scarring withoutpermanent retinal receptor damage, which explains why thevisual prognosis is usually, but not invariably, good.1,25,26

The frequent occurrence of an antecedent febrile illnessraises the question of an infectious agent as the trigger for

Table 1. Clinical Data of Nine New Cases with Acute Multifocal Placoid Pigment Epitheliopathy and Central NervousSystem Findings

PatientAge

(yrs) GenderVisual Acuity

before TreatmentVisual Acuity

after Treatment MRI findings TreatmentCentral Nervous System

Signs and Symptoms

1 16 M 20/20 both eyes 20/20; 20/30 FL and PL encephalomalacia,ME, PL hemorrhages

OS and BB HA, confusion, scotoma,seizure, paresthesias

2 25 M 20/40; 20/20 20/20 both eyes Normal SS and ISA HA, hemiparesis, incontinence3 36 M 20/30; 20/50 20/20; 20/25 Hyperintense signal abnormality

in thalamus and PVWM

OS and SS Paresthesias, scotoma

4 30 F 20/70; 20/200 20/30; 20/20 Normal OS, ONSF, LPS HA, ataxia, disc edema,paresthesias

5 38 F 20/40; 20/30 20/20 both eyes Hyperintense signal abnormalityin midbrain pons junctionand PVWM

OS and SS Paresthesias

6 39 F 20/20; 20/30 20/20 both eyes Hyperintense signal abnormalityof PVWM andPG enlargement

OS and SS HA, disc edema

7 27 F 20/20 both eyes 20/20; 20/25 Hyperintense signal abnormalityof right corpus callosum

OS Scotoma, disc edema

8 51 M Unknown 20/100 both eyes Right-sided TL infarcts OS and SS Quadrantanopia, paresthesias9 49 M 20/40; 20/50 20/20 both eyes Normal OS HA, confusion, dysphagia

BB brain biopsy; F female; FL frontal lobe; HA headache; ISA immunosuppressive agent; LPS lumbar peritoneal shunt; M male; ME

meningeal enhancement; MRI

magnetic resonance imaging; ONSF

optic nerve sheath fenestration; OS

oral steroids; PG

pituitary gland;PL parietal lobe; PVWM periventricular white matter; SS systemic steroids; TL temporal lobe.


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this illness. A viral illness is frequently suspected, and onereport documents a rising titer of adenovirus type 5 in apatient with active AMPPE.15,22,29 In fact, of the publishedcases of AMPPE with CNS findings, 6 of 16 males (37.5%)and 1 of 6 females (16%) described an antecedent illness. Ofour nine patients, four of the males (patients 1, 2, 3, and 9)and one of the females (patient 7) described a prodromalillness. In addition to viruses, tuberculosis, mycobacterium

avium, and an allergic reaction to penicillin have all beenimplicated as the causative agents.1,19,31

These external agents can produce a toxic effect in one ofthree ways: (1) by direct toxic effect or infection of vasculartissues, (2) by immune mechanisms, (3) or by a combinationof both.31 It is possible that these individuals have a geneticpredisposition to vasculitis that is precipitated by introduc-tion of an external antigen as a promoter of inflammation.Wolf et al23 described a family in which a mother and sonexperienced optic neuritis and a daughter experiencedAMPPE all within a 6-month period, suggesting a geneticpredisposition; indeed, two of our patients (patients 4 and 7)had AMPPE and optic neuritis-type symptoms. A direct

toxic effect of viruses on vascular tissue is seen in equineviral arteritis and immune factors predominate in Aleutianmink disease, in which viral specific immune complexes arefound in vessel walls. The finding that only certain strains ofmink are susceptible reinforces the theory of a geneticpredisposition.32 In 1990, Wolf et al23 described a group ofpatients with HLA-B7 and HLA-DR2 antigens who hadAMPPE. Other familial linkages have been described.33,34

Despite these associations, no definitive association hasbeen proven between AMPPE, genetic predisposition, orany causative agent.

Ocular pathologic characteristics of acute AMPPE arenot available, and yet the association between AMPPE and

various forms of vasculitis is assumed. In the previouslydocumented cases, angiographic findings consistent withvasculitis have been described.5,7,10,12,13 These findingsusually involve focal or diffuse vessel narrowing. Case 2demonstrates diffuse vessel narrowing seen with vasculitis.In the one documented autopsy of a patient with AMPPEand CNS vasculitis, granulomatous cerebral arteritis wasobserved.4 Brewmeyer et al8 in 1993 performed a musclebiopsy on a patient, and it revealed arteriolar vasculitis, butother reported biopsies have been negative.11

The association between AMPPE and CNS complica-tions has been well described. Of the 22 published cases,headaches were the most common symptom, occurring in15 of the 22 patients (six females; nine males). Hemiplegia

occurred in 5 of the 22 patients (two females; three males),and the rest had other neurologic signs. Of our nine patients,the signs included hemiparesis, dysarthria, numbness,ataxia, and incontinence. One of our patients (patient 1) hadan associated superior sagittal sinus thrombosis, a neuro-logic complication not previously observed with AMPPE.Cerebral venous thrombosis is a recognized complication ofCNS vasculitis.35,36 The seriousness of the CNS manifesta-tions is highlighted by the fact that two patients have died ofvasculitis. Therefore, it is important to have a high level ofsuspicion and a low tolerance for unusual symptoms orsigns when dealing with AMPPE cases. Where a presenting

systemic symptom was given in the published cases, it wasmost frequently headache (in 68%), followed by fever andmalaise. In our cases, three patients had headaches at pre-sentation, two with signs of meningeal irritation and twowith a flu-like illness. For these reasons, we suggest that allpatients with AMPPE who have headache, fever, or vaguemeningeal signs at presentation be investigated for systemicand CNS vasculitis.

In investigating these cases of suspected neurologic in-volvement, neuroimaging is very important. An MRI exam-ination is considered superior to a CT examination becauseof its higher resolution and ability to identify subtle lesions.In the published cases, the most commonly seen lesionswere hemorrhagic infarcts in the pons and the occipitallobes. Of our nine patients, six had positive MRI findings,which included periventricular lesions in four, subtle corpuscallosal lesions in one, and cerebral infarcts in one (Table1). These lesions were better seen on T2-weighted imaging.For this reason, we recommend an MRI scan with andwithout contrast in all suspected cases of AMPPE with CNSinvolvement, with particular attention to the T2-weighted

images. However, the results of MRI scans may be normaleven in the presence of cerebral angiitis. A definitive diag-nosis of angiitis requires cerebral angiography.

Among the published cases, a lumbar puncture for col-lection of a sample of cerebrospinal fluid was performed in17 patients. Sixteen of these patients (94%) had an elevatedwhite cell count, and 14 patients (82%) had increased pro-tein levels. Six of the new patients whom we reportedunderwent cerebrospinal fluid examination; the results oftwo were normal, two had an elevated white cell count, andthree had an elevated protein level. Because a raised whitecell count and protein level are strongly suggestive of CNSinflammation, we recommend a lumbar puncture in all sus-

pected cases of AMPPE with CNS involvement providedthere are no contraindications.An EEG was performed only in one of our patients, and

the results were mildly abnormal. In 6 of the 22 previouslypublished cases of AMPPE with CNS involvement, an EEGwas performed; the results of two were normal, whereas theothers were read as abnormal without any specific localizingfeatures. Although the EEG may show abnormalities, thebenefit in the diagnosis of cerebral vasculitis secondary toAMPPE is uncertain, and we do not routinely obtain thistest.

No diagnostic blood test exists for AMPPE. A sedimen-tation rate is considered to be a good indicator of general-ized inflammation, but in the published literature of AMPPE

with CNS changes, only one of seven sedimentation rateswas described as abnormal. Among our patients, only onesedimentation rate was recorded, and it too was normal.Thus, a sedimentation rate is not a useful adjunctive test inthe diagnosis of CNS-complicated AMPPE. However, thepresence of cellular casts in the urine is a good indicator ofactive AMPPE in the early stage of the disease.37

When CNS complications accompany AMPPE, treat-ment should be initiated rapidly. In a review of patients withprimary angiitis of the CNS, Calabrese and Mallek31 re-ported a 95% mortality rate with no treatment, a 46%mortality rate with oral corticosteroid treatment alone, and


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an 8% mortality rate with corticosteroids and cytotoxictherapy. Although it cannot be presumed that primary an-giitis of the CNS behaves the same as AMPPE accompaniedby CNS complications, the combinations of AMPPE andCNS arteritis can lead to death. Consequently, AMPPEshould be treated aggressively, and a team effort is oftenrequired to provide optimal management of these patients.Consultation with neurology and neurovascular colleagues

can be valuable in treating these patients. We recommendtreatment with intravenous corticosteroids followed by aslow oral steroid taper. A number of documented cases haveshown that it can be difficult to taper off the steroidscompletely, and, in these cases, a switch to an immunosup-pressive agent is recommended to decrease steroid-relatedeffects.7 In patients with AMPPE complicated by CNSangiitis, we recommend treatment with intravenous cortico-steroids and an immunosuppressive agent in combination.

Our patients illustrate that AMPPE is not always a be-nign condition. It may, on occasion, represent a systemicinflammatory disease with an initial and preferential ocularmanifestation, and it can cause a generalized vasculitic

condition with cerebral complications as well. The visualoutcome, although usually good, can be poor, and the CNSeffects can cause death. We recommend a high index ofsuspicion for CNS involvement. When CNS involvement issuspected, early neuroimaging and lumbar puncture willhelp establish the presence or absence of CNS involvement.In addition, cerebral angiography can provide evidence ofarteritis. We emphasize that a team effort with neurovascu-lar colleagues is essential in providing optimal patient treat-ment in cases where CNS involvement has been established.Aggressive treatment with intravenous corticosteroidsshould be considered, with a slow and gradual oral steroidtaper thereafter. In cases of AMPPE complicated with CNS

arteritis, intravenous corticosteroids in combination with animmunosuppressive agent such as cyclophosphamide maybe necessary.

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3. Hammer ME, Grizzard WS, Travies D. Death associated withacute multifocal, placoid pigment epitheliopathy. Case report.Arch Ophthalmol 1989;107:1701.

4. Wilson CA, Choromokos EA, Sheppard R. Acute posteriormultifocal placoid pigment epitheliopathy and cerebral vascu-litis. Arch Ophthalmol 1988;106:796800.

5. Smith CH, Savino PJ, Beck RW, et al. Acute posterior mul-tifocal placoid pigment epitheliopathy and cerebral vasculitis.Arch Neurol 1983;40:4850.

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