Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis

A 21-year-old man experienced unilateral vision loss associated with multiple atrophic chorioretinal lesions. He was treated for a presumptive diagnosis of acute retinal necrosis, but his vision did not improve with antiviral therapy. Over the course of several weeks, his symptoms progressed to involve both eyes. The fellow eye showed characteristic yellow-white placoid lesions, prompting treatment with oral corticosteroids for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Despite high-dose therapy with prednisone 80 mg daily, the patient developed the acute onset of mental status changes within the next several days. Neuroimaging revealed multifocal large-vessel strokes associated with cerebral edema; these infarcts led to herniation and death. Postmortem histopathologic examination confirmed granulomatous inflammation in both ocular and cerebral vasculatures. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our findings support the notion that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE. This granulomatous inflammation can also affect cerebral vessels, leading to strokes.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis Robi N. Maamari, MD, Leanne Stunkel, MD, Nathan H. Kung, MD, Cole J. Ferguson, MD, PhD, Jody Tanabe, MD, Robert E. Schmidt, MD, PhD, Sonika Dahiya, MD, Amar Dhand, MD, DPhil, Gregory P. Van Stavern, MD, Rithwick Rajagopal, MD, PhD, George J. Harocopos, MD Abstract: A 21-year-old man experienced unilateral vision loss associated with multiple atrophic chorioretinal lesions. He was treated for a presumptive diagnosis of acute retinal necrosis, but his vision did not improve with antiviral therapy. Over the course of several weeks, his symptoms progressed to involve both eyes. The fellow eye showed characteristic yellow-white placoid lesions, prompting treatment with oral corticosteroids for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Despite highdose therapy with prednisone 80 mg daily, the patient developed the acute onset of mental status changes within the next several days. Neuroimaging revealed multifocal large-vessel strokes associated with cerebral edema; these infarcts led to herniation and death. Postmortem histopathologic examination confirmed granulomatous inflammation in both ocular and cerebral vasculatures. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our findings support the notion that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE. This granulomatous inflammation can also affect cerebral vessels, leading to strokes. Journal of Neuro-Ophthalmology 2019;39:260-267 doi: 10.1097/WNO.0000000000000750 © 2019 by North American Neuro-Ophthalmology Society Departments of Ophthalmology and Visual Sciences (RNM, GPVS, RR, GJH) and Neurology (LS), Washington University School of Medicine in St. Louis, St. Louis, Missouri; Blue Sky Neurology (NHK), Denver, Colorado; Department of Pathology and Immunology (CJF, RES, SD, GJH), Washington University School of Medicine, St. Louis, Missouri; Department of Radiology (JT), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Neurology (AD), Brigham and Women's Hospital, Boston, Massachusetts. The authors report no conflicts of interest. R. N. Maamari and L. Stunkel contributed equally to this work. Address correspondence to Gregory P. Van Stavern, MD, Washington University in St. Louis, St. Louis, MO; E-mail: [e-mail] 260 Drs. Maamari, Stunkel, Van Stavern, and Rajagopal: A previously healthy 21-year-old man was evaluated by a retina specialist for a 2.5-week history of sudden, progressive vision loss in his right eye. His ocular history was unremarkable and he denied any recent illness or viral prodrome, but reported daily cigarette smoking. Visual acuities were 20/200 in the right eye, and 20/20 in the left eye. The pupils reacted normally; the anterior segment was unremarkable in both eyes and intraocular pressures were normal. Ophthalmoscopy of the right eye showed several macular lesions with retinal pigment epithelium (RPE) atrophy and scattered pigmentation with associated subretinal whitening (Fig. 1A). The left fundus was normal. Fundus autofluorescence (FAF) of the right eye suggested RPE atrophy in the macular region (Fig. 1B), whereas optical coherence tomography (OCT) showed disruption of the ellipsoid zone in this area and generalized choroidal thickening (Fig. 1C). Fluorescein angiography (FA) and indocyanine green (ICG) angiography displayed well-circumscribed early and late hypofluorescent lesions in the areas of RPE atrophy with patches of late hyperfluorescence localized to the same region (Fig. 1D-F). All studies performed in the left eye were unremarkable. The initial differential diagnosis included acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), and serpiginous choroiditis. The patient declined admission for intravenous therapy; oral valacyclovir 1 g twice a day was initiated. Two weeks later, the patient returned with temporal vision loss in his left eye. In the interim, he had developed a frontal headache. He denied any associated positive visual symptoms, floaters or ocular pain. Visual acuity was 20/300 in the right eye and 20/20-2 in the left eye. Funduscopic examination revealed enlargement of the lesions in the right Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Multimodal imaging of the right eye 2.5 weeks after onset of symptoms. A. The fundus shows deep retinal/subretinal macular lesions with circumferential whitening and central RPE atrophy with pigmentation. B. On fundus autofluorescence, there are areas of hypoautofluorescence with surrounding rims of hyperautofluorescence, corresponding to the placoid lesions in Fig. 1A. C. Optical coherence tomography demonstrates disruption of the ellipsoid zone (yellow arrows) with hyperreflectivity extending up to the outer plexiform layer in portions of the lesion, and focal RPE attenuation in the central region (blue bracket) corresponding to the fundus photograph and generalized choroidal thickening (white arrows). D. Arterial phase (13.6 seconds). Left panel, FA; right panel, ICG angiography. Both imaging modalities show well-circumscribed, early hypofluorescent patches localized to the creamy white macular lesions seen in Figure 1A. E. Venous phase (37.2 seconds). Left panel, FA; right panel, ICG angiography. Appearance of patchy hyperfluorescent areas located within the hypofluorescent macular lesions. F. Late phase (5 minutes, 42 seconds). Left panel, FA; right panel, ICG angiography. FA shows highly hyperfluorescent regions with well-demarcated borders localized to the areas of hypofluorescence seen in Figure 1B. Mildly hyperfluorescent halos surround more intensely hyperfluorescent lesions. ICG angiography shows persistent hypofluorescent lesions that are sharply delineated and continue to encompass the initial area of hypofluorescence. FA, fluorescein angiography; ICG, indocyanine green; RPE, retinal pigment epithelium. eye and a new lesion in the left eye described as a small area of whitening inferior to the fovea. Given the patient's left eye involvement, he was admitted to the hospital for treatment with intravenous acyclovir. Complete blood count, chemistry panel, erythrocyte sedimentation rate, and C-reactive protein values were normal. HIV antibody testing, rapid plasma reagin, and toxoplasma testing were all nonreactive. Due to the concern for ARN/ PORN, the patient also was given intravitreous ganciclovir in the left eye. Three days after therapy was begun, there was increased macular and peripapillary RPE atrophy in the right eye with a confluence of the previously scattered regions of subretinal Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 whitening (Fig. 2A). The left fundus had 2 deep retinal/ subretinal lesions inferior and temporal to the fovea and a third lesion nasal to the optic disc (Fig. 2B). Repeat OCT of the right eye demonstrated an irregular nerve fiber layer; conservation of the ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer; and loss of the ellipsoid and interdigitation zones with irregularity in the RPE (Fig. 2C). OCT of the left eye demonstrated increased reflectivity of the outer retinal layers at the location of the lesions, with relatively intact architecture of the inner retinal layers (Fig. 2D). This was similar to the lesions seen in the right eye 2 weeks previously. In both eyes, diffuse thickening of the choroid also was noted 261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. Multimodal imaging performed 4.5 weeks after onset of symptoms. A. The right fundus lesions have expanded to become confluent and involve the macula and peripapillary regions with increased RPE atrophy. B. The left fundus shows multiple new placoid, yellow-white lesions in the perifoveal region, as well as nasal to the optic disc. C. Optical coherence tomography of the right eye reveals an irregular temporal retinal contour, conservation of the inner retinal layers, thinning of the outer nuclear layer, loss of the ellipsoid and interdigitation zones with irregularity in the RPE, as well as diffuse thickening of the choroid (white arrows). D. Optical coherence tomography of the left eye is notable for increased reflectivity of the outer retinal layers at the location of the lesions, relatively intact architecture of the inner retinal layers, as well as diffuse thickening of the choroid (white arrows). E. Left panel of fluorescein angiogram of the right eye shows a large lesion encompassing nearly the entire macula and demonstrating early hypofluorescence (time: 1 minute, 5 seconds). Right panel shows patchy late staining in areas corresponding to a developing macular scar (time: 6 minutes, 8 seconds). F. Left panel, fluorescein angiography of the left eye shows early hypofluorescence. Right panel, late hyperfluoresence (white arrows) corresponding to the fundus lesions (time: 5 minutes, 37 seconds). RPE, retinal pigment epithelium. 262 Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Diffusion-weighted MRI, 41 days after onset of symptoms. There is increased signal intensity consistent with restricted diffusion in multiple vascular territories bilaterally, consistent with areas of acute ischemic infarction involving large-vessel territories. (Fig. 2C, D). FA of the right eye exhibited a large macular scar with an early blocking defect and late staining (Fig. 2E); the left eye revealed early hypofluorescence followed by late staining localized to the new fundus lesions (Fig. 2F). The new clinical data favored a diagnosis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) or ampiginous choroidopathy over an infectious etiology. Once tuberculosis and syphilis were excluded as potential causes of the patient's ocular disorder (negative interferon gamma release assay and nonreactive fluorescent treponemal antibody absorption test, respectively), the patient was started on oral prednisone 80 mg daily. However, the patient's vision loss continued to progress with development of left eye pain and expansion of the left fundus lesions. He was given an intravitreal injection of triamcinolone in the left eye. The following day, the patient noted sudden complete loss of vision in the right eye and subsequently began to hallucinate. He was intubated, noted to have abnormal movements (likely posturing), and was transferred to our medical center. FIG. 4. Noncontrast brain computed tomography reveals diffuse brain edema with uncal and central herniation. Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 5. Postmortem brain examination and pathology demonstrate vasculitis and granulomatous inflammation. A. Grossly, the left temporoparietal (left) and right occipital (right) cortices demonstrate widespread softening and hyperemia in watershed areas (arrows). Watershed zones in multiple cortical regions were affected. B. Necrotic cortical pyramidal neurons display retractions, cytoplasmic hypereosinophilia with loss of Nisl substance, and nuclear pyknosis consistent with ischemia (hematoxylin & eosin, ·1,000). C. Midline "Duret" hemorrhage, a consequence of brainstem herniation due to cerebral edema, involving the midbrain and upper pontine tegmentum. Midbrain elongation in the anterior-posterior dimension is also characteristic. D. An organizing thrombus is seen within the left middle cerebral artery (hematoxylin & eosin ·40). E. There is transmural lymphocytic inflammation of a spinal leptomeningeal vessel with giant cell formation (arrow) (hematoxylin & eosin, ·200). F. Clustered giant cells (arrows) constitute a granuloma in an inflamed spinal leptomeningeal vessel. G. Focal angionecrosis (arrow) is seen in a spinal arteriole with angiitis (hematoxylin & eosin, ·600). H. Immunohistochemical staining of chronic inflammatory cells in spinal leptomeningeal vessels shows few B cells (CD20) but abundant T cells (CD3). CD4 and CD8 stains show a predominance of helper vs. cytotoxic T cells. CD68-positive macrophages are seen surrounding and within vessels (CD20, ·100; all others, ·200). Dr. Tanabe: Computed tomography (CT) of the brain revealed bilateral hypodensities involving gray and white matter that were most compatible with acute infarcts. There was diffuse brain swelling and 6 mm of left-to-right midline shift. Diffusionweighted MRI confirmed extensive bilateral ischemic infarctions in multiple large-vessel territories (Fig. 3). Drs. Maamari, Stunkel, Van Stavern, and Rajagopal: Intravenous mannitol and hypertonic saline were used to manage the cerebral edema without effect. The rapidity of 264 the clinical decline and the lack of response to hyperosmotic therapy were greater than are typically seen in ischemic stroke and suggested breakdown of the blood-brain barrier. Bilateral decompressive hemicraniectomy was offered, but in light of the poor prognosis, the patient's family declined. Dr. Tanabe: A repeat CT scan obtained less than 24 hours after the first scan showed progression of bilateral cerebral infarcts, new left basal ganglia hypodensities, increased swelling with effacement of sulci and basal cisterns, and uncal and central herniation (Fig. 4). Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 6. Pathology of the right eye demonstrates varying degrees of granulomatous choroiditis. A. There is diffuse granulomatous choroiditis with macrophages, lymphocytes, eosinophils, occasional plasma cells, and a multinucleated giant cell (arrows). The large empty spaces at the level of the photoreceptor layer are artifactual. (hematoxylin & eosin, ·400). B. There is a higher density of inflammatory cells in the outer choroidal layers as compared to the inner layers and choriocapillaris. In addition, there is diffuse retinal pigment epithelium atrophy (arrows) and scattered areas of RPE hyperplasia (arrowheads). In the upper right portion of the frame, as the choroiditis tapers off, both RPE and outer nuclear layer atrophy are evident (hematoxylin & eosin, ·200). Drs. Maamari, Stunkel, Van Stavern, and Rajagopal: Despite continued aggressive treatment with mannitol and hypertonic saline, the patient progressed to brain death less than 48 hours after the onset of the stroke symptoms (24 days after presentation). Dr. Dahiya: As the deceased was an organ donor, autopsy was largely limited to the eyes and central nervous system (CNS) (stomach, portion of small bowel, and vertebral bone marrow also were available and showed no pathologic changes). Postmortem gross examination of the brain and spinal cord is most significant for multifocal areas of softening, gray-white matter blurring, and focal hyperemia in the brain, most prominent in the watershed areas (Fig. 5A). Marked cerebral edema and the sequelae of increased intracranial pressure leading to uncal and tonsillar herniation are also evident. Duret hemorrhages, a consequence of downward herniation, are present in the midline of the tegmentum of the upper pons (Fig. 5C). Microscopic examination shows multifocal areas of infarction corresponding to multiple vascular territories but most prominent in the watershed regions. Areas of early ischemic insult are associated with abundance of necrotic neurons that display hypereosinophilic cytoplasm, pyknotic nuclei, and loss of Nissl substance (Fig. 5B). Longer-standing lesions exhibit more extensive tissue destruction and vacuolation. Infarcts are of ischemic nature, with some having an element of superimposed reperfusion insult. Several blood vessels of all sizes show lymphocytic vasculitis (including left Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 middle cerebral artery tributaries) with a few foci harboring granulomatous inflammation that is best appreciated in the spinal cord (Fig. 5D-F). Focal angionecrosis and/or partially organized luminal thrombi also are seen in a portion of the inflamed vessels (Fig. 5G). Most foci of vasculitis are limited to the leptomeninges, with only focal involvement of the intraparenchymal vessels that is mostly confined to the brainstem. There is extensive infarction of the anterior pituitary gland as well (not shown). Immunohistochemical stains for CD3 and CD20 showed that T cells constitute the vast majority of the inflammatory cell infiltrate. CD4-positive cells (helper T cells) appear slightly more in number compared with CD8-positive (cytotoxic) T lymphocytes. A number of the inflammatory cells surrounding vessels are CD68 positive, highlighting the activated microglia in the surrounding parenchyma (Fig. 5H). Dr. Harocopos: Gross ocular pathologic findings show a few spots of chorioretinal atrophy in the posterior pole of the right eye and a creamy, yellowish lesion near the macula in the left eye. Optic disc edema is present in both eyes, right greater than left. Microscopically, both eyes exhibit similar posterior pole findings (somewhat more extensive in the right eye than in the left) with variably broad patches of granulomatous choroiditis, including macrophages with several multinucleated giant cells, lymphocytes, scattered eosinophils, and occasional plasma cells (Fig. 6A). Perivascular inflammatory infiltrates are present; however, definite vasculitis with destruction of vessel walls is not appreciated. The overlying RPE and outer nuclear layer demonstrate patchy areas of atrophy and attenuation. In these areas, the underlying choroid appears relatively less inflamed, 265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study generally adjacent to the more inflamed areas (Fig. 6B). In addition, a thin layer of subretinal fluid is occasionally observed overlying a region of inflamed choroid (not shown). HSV-1 and HSV-2 immunostains were both negative. Gram and Gomori methenamine silver (GMS) stains were negative for bacterial and fungal micro-organisms. Final Diagnosis APMPPE complicated by cerebral vasculitis leading to multifocal large-vessel strokes. Drs. Maamari, Stunkel, Van Stavern, and Rajagopal: APMPPE is a rare inflammatory chorioretinopathy of unknown etiology, first described by Gass (1) in 1968. Fundus examination is notable for flat, multifocal, creamcolored lesions, usually limited to the posterior pole, involving the retina, choroid, and RPE. APMPPE typically occurs in young adults, with up to one third reporting a viral prodrome (2,3). Although the underlying etiology is unknown, APMPPE has been associated with autoimmune and systemic inflammatory conditions including sarcoidosis, psoriatic arthritis, and other systemic vasculitides as well as infectious agents (adenovirus, measles, and mycobacterium) (4). Ocular symptoms include acute or subacute bilateral (or sequential) vision loss, central or paracentral scotomas, photopsias, and metamorphopsia (2). The clinical course typically is self-limited with spontaneous recovery of visual function over weeks to months. APMPPE-associated cerebrovascular complications are well known, with some patients having a fatal outcome with death occurring within 2 months of the onset of ocular symptoms (3-10) Neurologic complications that are occasionally associated with APMPPE include headaches, sensorineural hearing loss, optic neuritis, peripheral vestibular disorders, meningoencephalitis, seizures, venous sinus thrombosis, intracerebral hemorrhage, and stroke/transient ischemic attack (7). High-dose corticosteroids and other immunosuppressants have been used to treat the cerebrovascular complications (5,7). Our report emphasizes the importance of recognizing headache as an early sign of neurologic involvement of APMPPE, particularly given the potential for the development of large-vessel strokes. Search of the PubMed database revealed one prior publication (6) of ocular histopathology in APMPPE and 3 prior neuropathologic descriptions of this disorder (3,4,8). de Vries et al (3) found inflammatory changes confined to the sub-RPE space. In our patient, there was granulomatous choroiditis with multinucleated giant cells, similar to the de Vries report, but also regions of granulomatous inflammation involving the full thickness of the choroid that were focally associated with subretinal fluid exudation. In addition, adjacent regions of RPE/outer retinal atrophy were seen with relative sparing of the underlying choroid. The additional findings seen in our case that were not noted by de Vries et al. may be attributable to disease duration, i.e. duration of 24 days between presentation and death in our case, as compared to only a few days in the case of de Vries et al (3). Similarly, the CNS pathology corroborated prior histologic descriptions, with leptomeningeal arteries demonstrating vasculitis with focal regions of granulomatous inflammation. A recent review of 28 cases of APMPPE found a high prevalence of multifocal segmental vascular narrowing in those patients who underwent cerebral angiography (5). Prior multimodal imaging studies suggest that the choroid, specifically the choriocapillaris, may be the initial FIG. 7. Multimodal imaging of the left eye at initial presentation 2.5 weeks after onset of symptoms. A. Optical coherence tomography shows focal hyperreflectivity at the level of the choriocapillaris (arrows) with normal retina and RPE. B. Nearinfrared reflectance show a hyperintense lesion along the inferotemporal arcade (bisected by the green scan line). C. Indocyanine green angiography of the corresponding region in (B) demonstrates focal hypofluorescence (inset). Area corresponding to (B) is normal in appearance on funduscopy (D) and autofluorescence (E). 266 Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study target of APMPPE (11,12). Our findings support this concept. At presentation, regions of the patient's retina, despite appearing normal by color fundus and FAF imaging studies, showed hyperreflectivity on near-infrared reflectance (NIR) imaging (Fig. 7B). The corresponding regions, on examination with OCT, showed focal hyperreflectivity at the level of the choriocapillaris with normal retina and RPE (Fig. 7A). The same region became hyporeflective on OCT as the placoid lesion developed. We hypothesize that initial OCT hyperreflectivity may represent alterations of inner choroidal blood flow, perivascular infiltration of inflammatory cells, or both. ICG hypofluorescence (Fig. 7C) at the equivalent region may correspond to the granulomatous reaction and edema compressing the surrounding smallcaliber choroidal vessels and resulting in focal hypoperfusion. Furthermore, retrospective scrutiny of the initial OCT revealed that a region of the left macula, initially appearing normal by ophthalmoscopy, showed a hyperreflective area of the inner choroid at the level of the choriocapillaris (Fig. 7A). In addition, the corresponding NIR image revealed a well-delineated hyperintense lesion along the inferotemporal arcade (Fig. 7B), and a hypofluorescent defect in the identical area was seen on the ICG angiogram (Fig. 7C). Importantly, both fundus photography (Fig. 7D) and FAF (Fig. 7E) were normal at this early stage, presumably because the RPE was unaffected. Eventually, this left macular lesion became visible by both standard photography and FAF. OCT imaging studies on our patient showed early choroidal thickening (Fig. 1C), which has been reported in APMPPE (11,12). Histopathology revealed granulomatous inflammation throughout the choroid, which likely explains the increased choroidal thickness on OCT (Fig. 6A). As the disease progressed, OCT demonstrated hyperreflectivity of the outer retina extending from the RPE to the outer plexiform layer (Fig. 1C), consistent with previously published reports (4,12). These OCT changes may represent photoreceptor cell body swelling or dysfunction from hypoperfusion of the underlying choroid. Alternatively, they may represent deposition of inflammatory cells and/or photoreceptor cell injury from a migrating inflammatory process. As the placoid lesions in our patient dissipated, outer retinal hyperreflectivity resolved with normalization of outer nuclear layer appearance on OCT, but the ellipsoid zone remained absent. OCT studies in these areas demonstrated the return of the outer retinal architecture in the central portion of the lesion, whereas the outer, leading edges continued to demonstrate the hyperreflective finding. This finding possibly signified outward spread of disease (Fig. 1C). Granulomatous choroiditis may spread to adjacent regions, whereas regions that initially were inflamed leave in their wake atrophy of the overlying RPE and outer retina (corresponding to areas that appear atrophic on funduscopy, with staining on FA). Furthermore, the diffuse patches of Maamari et al: J Neuro-Ophthalmol 2019; 39: 260-267 RPE and outer retinal atrophy in the absence of adjacent inner choroidal granulomas seen in our ocular specimen may also result from progression of the granulomatous inflammation from the inner to the outer choroid. In summary, we have described a rare case of APMPPE complicated by multiple large-vessel ischemic strokes due to CNS vasculitis leading to death. This report is the second in the literature to describe ocular pathology in APMPPE and confirms the presence of granulomatous choroiditis. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our results support the likelihood that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE; they also demonstrate that this granulomatous inflammation can affect cerebral vessels, leading to strokes. In caring for patients with APMPPE, the clinician should have a low threshold for performing MRI of the brain and lumbar puncture for any suspicion of neurologic involvement. Such testing should be performed even in the setting of isolated headache to identify those individuals. who may benefit from high-dose steroids and thus prevent devastating large-vessel strokes. REFERENCES 1. Gass JD. 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. de Vries JJ, den Dunnen WF, Timmerman EA, Kruithof IG, De Keyser J. Acute posterior multifocal placoid pigment epitheliopathy with cerebral vasculitis: a multisystem granulomatous disease. Arch Ophthalmol. 2006;124:910-913. 4. Tsang BK, Chauhan DS, Haward R, Whiteman I, Frayne J, McLean C. Fatal ischemic stroke complicating acute multifocal placoid pigment epitheliopathy: histopathological findings. J Neuroophthalmol. 2014;34:10-15. 5. Case D, Seinfeld J, Kumpe D, Folzenlogen Z, Jones W, Simpson J, Hughes R. Acute posterior multifocal placoid pigment epitheliopathy associated with stroke: a case report and review of the literature. J Stroke Cerebrovasc Dis. 2015;24:e295-302. 6. Castro P, Costa A, Abreu P, Penas S, Faria O, Azevedo E. Acute posterior multifocal placoid pigment epitheliopathy presenting with multiple brain and spinal cord infarctions. J Neurol Sci. 2016;361:26-28. 7. Lunea K, Newman NJ, Srivastava S, Biousse V. A case of acute posterior multifocal placoid pigment epitheliopathy with recurrent stroke. J Neuroopthalmol. 2009;29:111-118. 8. Wilson CA, Choromokos EA, Sheppard R. Acute posterior multifocal placoid pigment epitheliopathy and cerebral vasculitis. Arch Ophthalmol. 1988;106:796-800. 9. Hammer ME, Grizzard WS, Travies D. Death associated with acute, multifocal, placoid pigment epitheliopathy. Arch Ophthalmol. 1989;107:170-171. 10. El Sanhouri AE, Sisk RA, Peterson MR. Mortality from cerebral vasculitis associated with rapid steroid taper during treatment of acute posterior multifocal placoid pigment epitheliopathy. Arch Opthalmol. 2012;130:935-937. 11. Spaide RF. Autofluorescence imaging of acute posterior multifocal placoid pigment epitheliopathy. Retina. 2006;26:479-482. 12. Mrejen S, Sarraf D, Chexal S, Wald K, Freund KB. Choroidal involvement in acute posterior multifocal placoid pigment epitheliopathy. Ophthalmic Surg Lasers Imaging Retina. 2016;47:20-26. 267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.