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Show Fatal Ischemic Stroke Complicating Acute Multifocal Placoid Pigment Epitheliopathy: Histopathological Findings Benjamin K.-T. Tsang, MBBS, BPharm, Devinder S. Chauhan, MBBS, MD, FRCOphth, FRANZCO, Rebecca Haward, MBBS, Ida Whiteman, MBBS, Judith Frayne, MBBS, FRACP, Catriona McLean, BSc, MBBS, FRCPA, MD Abstract: A previously healthy 29-year-old man was admitted to a tertiary referral center with acute left hemiparesis followed shortly by de novo convulsive status epilepticus. This was in the context of a 2-month history of flu-like symptoms, severe headaches, and retinopathy recently diagnosed as acute multifocal placoid pigment epitheliop-athy. Neuroimaging demonstrated bilateral, multiple territory cerebral infarction. Despite intravenous methylprednisolone and craniotomy for the management of raised intracranial pressure, the patient deteriorated and died 14 days later. At autopsy, multiple infarcts of varying ages within a 10-day period were seen in association with a segmental giant cell vasculopathy of meningeal arteries. Journal of Neuro-Ophthalmology 2014;34:10-15 doi: 10.1097/WNO.0b013e318294a4b0 © 2013 by North American Neuro-Ophthalmology Society Acute multifocal placoid pigment epitheliopathy (AMPPE) is a chorioretinal disorder characterized by creamy round exudates seen on funduscopy with bilateral involvement in approximately 75% of cases (1-3). Typical lesions are found primarily in the posterior pole at the level of the retinal pigment epithelium (RPE) and choriocapillaris (1,4,5). Symptoms include acute or subacute binocular visual blurring, metamorphopsia, and scotomas (1,6). Fluo-rescein angiography characteristically shows a pattern of early hypofluorescence and late hyperfluorescence, which is considered to indicate lobular obstruction of the chorio-capillaris caused by vascular inflammation (7). Spectral domain optical coherence tomography (SD-OCT; Cirrus, Carl Zeiss Meditec, Dublin, CA) findings in acute AMPPE lesions include elevated perifoveal retinal thickness, hyper-reflectance of the outer retinal layers with photoreceptor disorganization and, rarely, intraretinal cysts or loculations (4,8). A retrospective study at the Mayo Clinic estimated the incidence to be 0.15 cases per 100,000 persons per year (3). There is no sex predilection, but AMPPE has a striking preponderance for young adults, with a mean age of onset of 26.5 years (1). The pathophysiology of AMPPE is not well elucidated, despite being associated with a number of infectious and autoimmune conditions. The primary lesion in AMPPE appears to occur in the small choroidal arterioles whereby choriocapillaris ischemia may induce increased vascular permeability (4). Secondary ischemic changes produce dis-ruption of the RPE, resulting in placoid lesions. Alternate mechanisms include choriocapillaris occlusion, with case reports of association with anticardiolipin antibodies (9). Complaints of a "viral" prodrome with fever, malaise, upper respiratory symptoms, myalgias, or arthralgias have been reported in about 40% of cases (2,6). Associated infectious agents include adenovirus (10), measles (11), and mycobac-terium (12). Some patients have developed AMPPE in the context of recent vaccination (13) and antibiotic adminis-tration (2). In a small but significant minority of patients, evidence of a systemic vasculitis exists including erythema nodosa (2,9,14). Other systemic autoimmune or collagen vascular diseases associated with AMPPE include sarcoidosis (14,15), psoriatic arthritis (3), perinuclear antinuclear Department of Neurosciences (BK-TT, JF), Alfred Health, Victoria, Australia; Vision Retinal Institute Eastern (DSC), Box Hill, Victoria, Australia; Departments of Ophthalmology (RH) and Anatomical Pathology (CM), Alfred Health, Victoria, Australia. The authors report no conflicts of interest. Address correspondence to Benjamin K.-T. Tsang, MBBS, BPharm, Department of Neurosciences, Alfred Health, Commercial Road, Prahran 3181, Victoria, Australia; E-mail: bktsang@optusnet.com.au 10 Tsang et al: J Neuro-Ophthalmol 2014; 34: 10-15 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. cytoplasmic antibody (ANCA)-positive systemic vasculitis (16), and central nervous system (CNS) vasculitis (17). Neurological involvement associated with AMPPE includes headaches (6,9,18), strokes (6,7,17,19), cerebral venous sinus thrombosis (20), seizures (5,6), and CNS vas-culitis (6,17,21). These neurological complications tend to occur early in the clinical course and are usually self-limited (18). We report a case of AMPPE complicated by multiple territory strokes and death with autopsy correlation. CASE REPORT A healthy 29-year-old man was referred to a retinal specialist by his local optometrist with a 10-day history of right central vision loss. This was preceded by a 1-month history of flu-like symptoms including fever and night sweats. He had a history of stable asthma but no ophthalmological or neurological disease and a familial history of glaucoma. At presentation, the patient's visual acuity was 20/80, right eye, and 20/20, left eye. Pupillary responses and intraocular pressure measurements were normal. Slit-lamp examination of both eyes showed 1+ anterior chamber cells and fundu-scopy showed 1+ vitreous cells and widespread multiple pale subretinal lesions bilaterally (Fig. 1). On fluorescein angi-ography, there was early blockage of the lesions (Fig. 2A) with late hyperfluorescence (Fig. 2B). Indocyanine green angi-ography showed persistent hypofluorescence of the lesions (Fig. 3). Figure 4 demonstrates the findings on SD-OCT. FIG. 1. Funduscopy reveals bilateral multifocal areas of choroiditis with a large number of placoid lesions involving the fovea in the right eye and the parafoveal region in the left eye. FIG. 2. Fluorescein angiography demonstrates lesion hypofluorescence in the early phase (A) and hyperfluorescence in the late phase (B). Tsang et al: J Neuro-Ophthalmol 2014; 34: 10-15 11 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. These clinical findings were thought to be typical of bilateral AMPPE and no treatment was prescribed. One week later, the patient returned complaining of frequent severe bilateral headaches on waking associated with photophobia, phonophobia, and nausea. On fundu-scopy, the lesions were less active but a small new temporal hemorrhage was noted in the left eye. The patient saw a neurologist 2 weeks later and computed tomography (CT) brain imaging was normal. Five weeks after initial pre-sentation, the patient had visual acuity of 20/25, right eye, and 20/20, left eye, with fewer vitreous cells. Approximately 3 weeks later, the patient developed sudden onset dizziness and a left hemisensory disturbance, closely followed by acute left hemiparesis and convulsive status epilepticus. He was intubated under general anesthe-sia and transferred to our institution. On examination, pupil responses were normal, and the patient had extensor responses to peripheral pain and bilaterally sustained clonus in the lower limbs. His reflexes were symmetrically pathologically brisk with extensor plantar responses. Retinal appearance on funduscopy showed no evidence of worsen-ing ocular disease. Complete blood count showed only mild neutrophilia. Serum biochemistry, inflammatory markers, coagulation profile, and urinalysis were unremarkable. Tests for tuber-culosis and serology for HIV, syphilis, toxoplasma, and borrelia were negative. Serum antinuclear antibodies, ANCA, rheumatoid factor, angiotensin-converting enzyme, and complement levels were unremarkable. Lumbar punc-ture revealed an opening pressure greater than 30 cm H2O, and cerebrospinal fluid (CSF) revealed a lymphocyte count of 17·106/L (normal, ,5·106/L) and a mildly elevated FIG. 3. Angiography using indocyanine green shows persistent hypofluorescence of the fundus lesions in the early (A) and late (B) phase, indicative of choriocapillaris infarction. FIG. 4. Spectral domain optical coherence tomography (Cirrus, Carl Zeiss) demonstrates the loss of the photoreceptor inner segment/outer segment junction line and increased choroidal signal due to disturbance of the retinal pigment epithelium. A. Right eye. B. Left eye. 12 Tsang et al: J Neuro-Ophthalmol 2014; 34: 10-15 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. protein level of 0.53 g/L (normal, ,0.45 g/L) without evidence of oligoclonal bands. Latex agglutination studies for cryptococcus, gram stain, and polymerase chain reaction of neurotropic viruses were negative. Brain CT and magnetic resonance imaging (MRI) revealed extensive, acute bilateral infarctions in both anterior and posterior circulation (Fig. 5). Computed tomographic angiography and magnetic resonance angiography demon-strated intracranial vessels that were diffusely reduced in cal-iber without focal irregularities or stenoses. CT venography indicated no filling defects. Transesophageal echocardiogra-phy excluded the presence of a vegetation, intracardiac thrombus, or shunt. The patient underwent bilateral decom-pressive craniectomy for cerebral edema. With attempts to terminate general anesthesia, seizures occurred despite multi-ple anticonvulsant medications. Interictal electroencephalo-gram showed diffuse, bilateral, moderate amplitude theta to delta range slowing. The patient was given intravenous meth-ylprednisolone, but his condition deteriorated and died 2 weeks later. At autopsy, external examination of the circle of Willis showed a normal vascular anatomy with no evidence of atherosclerosis or thrombotic occlusion of major vessels. There was extensive softening and swelling on the external surface of the brain in both the left and right parietal and frontal regions. Focal areas of subarachnoid hemorrhage were noted. On serial cross sectioning, there was extensive softening and loss of the gray white definition in the distribution of the left and right anterior, middle, and posterior cerebral arteries with swelling of the white matter and displacement of cerebral cortex superiorly within the craniectomy site with mass effect (Fig. 6). The ventricles FIG. 5. Multiple axial diffusion-weighted images of the brain show hyperintense areas involving all lobes of both cerebral hemispheres and bilateral cerebellar hemispheres consistent with acute multiterritory infarctions. Tsang et al: J Neuro-Ophthalmol 2014; 34: 10-15 13 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. appeared compressed. Sectioning through the cerebellum and brainstem were unremarkable. Microscopic examination of arteries of the meninges revealed partial or total occlusion with a segmental giant cell vasculopathy with focal intimal expansion by reactive myofibroblasts in association with histiocytes and giant cells, some of which were multinucleated (Fig. 7). The giant cells appeared to be predominantly within the intima rather than showing active destruction and association with the internal elastic lamina. The vessel wall did not show fibri-noid necrosis or was there extensive inflammation of the media and adventitia. Intracortical vessels were not involved. Cortical sections showed features of acute infarc-tion of varying ages within a 10-day period. DISCUSSION As seen in our patient with AMPPE, stroke usually occurs within months of the onset of ocular disease (6). An esti-mated 50% of AMPPE patients have headaches with or without neck stiffness (6,18). Possibly, severe headaches are the earliest indication of cerebral inflammation and can predate the onset of more severe neurologic involve-ment by several weeks to months (6,8,19,21,22). The topography of reported strokes with minimal sequelae are usually within small to medium vascular territories such as the posterior circulation (7), basal ganglia, caudate nuclei (19), and corpus callosum (19). Extensive and multiple ter-ritory strokes resulting in death, as seen in our patient, are rare (5,8,22,23). To judge if a patient is in danger of severe neu-rological complications, the severity of the ophthalmological disease has not been a reliable marker (18). In some patients, cerebral vasculitis may cause ischemic complications in the CNS. In these cases, there may be elevated erythrocyte sed-imentation rate (22) and CSF pleocytosis (6,17,21). Biopsy of the dura mater has shown lymphocytic infiltrates (18). There have been only 2 previous autopsy reports describing giant cells within the medium-sized arteries of the leptomeninges (5,23). These reports documented fragmentation of the inter-nal elastic lamina and giant cells within the intima "at the level of the internal elastic lamina," associated with prominent and focal myofibroblastic proliferation (5,23). Inflammation within the media also was noted, along with focal fibrinoid necrosis. The intimal location of the giant cells and the focal intimal myofibroblastic proliferation were seen in our case, but we found the internal elastic lamina to be intact without inflammation of the media or evidence of fibrinoid necrosis. Further cases are required to determine whether the distribu-tion of vessel involvement and pathology of giant cell vascul-opathy seen in AMPPE represents a separate type of a giant cell vasculopathy compared with that of giant cell arteritis. The differential diagnosis of systemic illnesses leading to uveoretinal meningoencephalitis includes Vogt-Koyanagi- Harada disease, sarcoidosis, Behçet disease, systemic lupus erythematosus, Crohn disease, metastatic malignancy, pri-mary intraocular lymphoma, and systemic infection (histo-plasmosis, toxoplasmosis, cytomegalovirus, syphilis). Although management of patients with stroke or cerebral vasculitis associated with AMPPE is a topic of much debate, current treatment usually includes aggressive immunosup-pression with steroids or steroid sparing agents (5-7,17,21). FIG. 7. Leptomeningeal vessel demonstrates multinucleated giant cells (arrowheads) next to the internal elastic lamina (arrow), without inflammation or necrosis in the media (dashed line). A. Hematoxylin and eosin, ·400. B. Elastic Van Gieson, ·200. FIG. 6. Infarction in the left and right frontal cortex of varying age (arrows) with mass effect through the craniec-tomy sites (arrowheads). 14 Tsang et al: J Neuro-Ophthalmol 2014; 34: 10-15 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. However, strokes (18) and even death (8,22) have been re-ported during rapid tapering of immunosuppressive therapy. REFERENCES 1. Jones NP. Acute posterior multifocal placoid pigment epitheliopathy. Br J Ophthalmol. 1995;79:384-389. 2. Roberts TV, Mitchell P. Acute posterior multifocal placoid pigment epitheliopathy: a long-term study. Aust N Z J Ophthalmol. 1997;25:277-281. 3. Abu-Yaghi NE, Hartono SP, Hodge DO, Pulido JS, Bakri SJ. White dot syndromes: a 20-year study of incidence, clinical features, and outcomes. Ocul Immunol Inflamm. 2011;19:426-430. 4. Montero JA, Ruiz-Moreno JM, Fernandez-Munoz M. 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