Case Report Acute Posterior Multifocal Placoid Pigment Epitheliopathy Associated with Stroke: A Case Report and Review of the Literature David Case, MD,* Joshua Seinfeld, MD,* David Kumpe, MD,† Zach Folzenlogen, MD,* William Jones, MD,‡ Jennifer Simpson, MD,‡ and Richard Hughes, MDx Background: Present a case report of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) associated with stroke along with the serologic findings, diagnostic findings, and treatment in addition to presenting a review of other case reports to date in literature. With this information, we are attempting to identify key diagnostic features and appropriate treatment options for patients with this disease. Methods: Presentation of case report, background on APMPPE, review of the literature and previous case reports, and discussion of diagnostic workup and treatment options for these patients. Results: There are 28 well-described case reports in the literature to date, not including our case report; 23 had documented radiographic findings consistent with parenchymal injury, ischemic stroke, hemorrhagic stroke, or cerebral venous thrombosis. We report a 23-year-old right-handed man with left hemiparesis, ischemic strokes, and angiographic findings characteristic of cerebral vasculitis 4 months after he was diagnosed with APMPPE. Conclusions: Based on our present case and previously documented cases to date, corticosteroid therapy with potential escalation of care to immunomodulatory treatment appears to benefit clinical outcomes. Key Words: Vasculitis—stroke—chorioretinal disease—cerebral angiography—neuroradiology—inflammatory CNS disease. Published by Elsevier Inc. on behalf of National Stroke Association Introduction From the *Department of Neurosurgery, University of Colorado, Aurora, CO; †Department of Radiology, University of Colorado, Aurora, CO; ‡Department of Neurology, University of Colorado, Aurora, CO; and xDepartment of Neurology, Denver Health, Denver, CO. Received April 9, 2015; revision received April 27, 2015; accepted June 11, 2015. Address correspondence to David Case, MD, Department of Neurosurgery, University of Colorado, 6227 S Locust St, Centennial, CO 80111. E-mail: david.case@ucdenver.edu. 1052-3057/$ - see front matter Published by Elsevier Inc. on behalf of National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.06.022 Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an uncommon chorioretinal disease characterized by multiple cream-colored lesions located in the posterior pole.1 It typically affects both eyes leading to visual blurring or scotomas.2 APMPPE predominantly occurs in young adults and is typically self-limiting.3,4 A viral prodrome can be seen in one third of patients.5 Fundus lesions are observed within days of disease onset. They typically resolve and leave alterations in the pigmented epithelium weeks after symptom onset. The visual prognosis is typically good with spontaneous recovery. Although this is a disease of the eye, extraocular manifestations can occur. Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 10 (October), 2015: pp e295-e302 e295 e296 D. CASE ET AL. Figure 1. Fundus examination at diagnosis showing yellow white placoid regions and scarring in the retinal epithelium in both the left (labeled L) and right (labeled R) eyes. Neurologic complications of APMPPE are rare and have been reported previously in the literature.6 Specifically, inflammatory and vasculitic-like changes have been described including cerebrospinal fluid (CSF) pleocytosis, headaches, transient hearing loss, optic neuritis, meningoencephalitis, transient focal deficits, and strokes. After extensive review of the literature using PubMed and Google Scholar, 28 reported cases of APMPPEassociated cerebrovascular complications have been well documented in the literature to date. We report a Figure 2. Magnetic resonance imaging brain sequence showing (A) T2 fluid-attenuated inversion recovery (FLAIR) sequence hyperintensity in the corpus callosum, (B) T2 FLAIR sequence hyperintensity in the white matter bilaterally, (C) corresponding restricted diffusion in the corpus callosum, and (D) corresponding restricted diffusion in the white matter bilaterally. APMPPE: A REVIEW OF THE LITERATURE Figure 3. Cerebral angiogram demonstrating multiple areas of anterior cerebral artery narrowing (black arrows) and a branch artery occlusion (white arrow). 23-year-old right-handed man with left hemiparesis and imaging findings characteristic of cerebral vasculitis and ischemic stroke 4 months after he was diagnosed with APMPPE. Case Presentation A 23-year-old right-handed man presented with vision loss and multiple scotomas in his right eye followed a few weeks later by similar vision loss in his left eye. He had no medical history but described feeling malaise, headache, and flu-like symptoms 3 weeks before the onset of his visual complaints. He had returned from a trip to Southeast Asia a few months before this time but had received all required vaccinations before his travels. One month after his visual complaints began, he was found to have multiple cream-colored placoid subretinal lesions throughout the posterior poles of both eyes consistent with a diagnosis of APMPPE (Fig 1). Magnetic resonance imaging (MRI) brain was normal at the time, and he was given a 4-week course of high-dose corticosteroids and was subsequently tapered off after 2 additional weeks. His visual deficits did not improve. Four months after being diagnosed with APMPPE (5 months after onset of ocular symptoms), he presented with headache and mild left-sided weakness, leg greater than arm. His weakness progressed to near-complete paresis of his left leg along with mild left arm weakness later the same day. Brain MRI showed multiple hyperintense, nonenhancing lesions. He was placed on methylprednisolone 1 g/d intravenously but over the course of 4 days had interval increase in lesion burden on MRI brain (Fig 2). e297 A lumbar puncture was performed, which revealed normal protein, normal white blood cell count, normal red blood cell count, and no oligoclonal bands. Serologic studies including hypercoagulability studies, rheumatologic panel, and infectious panel were all negative. A cerebral angiogram demonstrated occlusion of an anterior cerebral artery branch, focal narrowing of multiple right pericallosal artery branches, and a mild left pericallosal artery narrowing (Fig 3). After completing a 5-day course of intravenous corticosteroids, he was continued on oral prednisone 80 mg/d. His left leg weakness and mild left arm weakness stabilized. He was subsequently discharged to a rehabilitation facility where he remained on high-dose steroids. By 6 weeks, he had significant improvement in his strength. His left arm weakness had resolved. His left leg was mildly weak, and he was able to ambulate without assistance. His visual deficits remained unchanged. He was continued on oral prednisone at a dose of 60 mg/d with scheduled clinic follow-up. No further diagnostic imaging or repeat cerebral angiography has been repeated to date. Discussion APMPPE is a rare multifocal, choroidal, occlusive vasculitis. Simultaneous or sequential onset in both eyes is typical. In 1968, Gass reported 3 cases with rapid loss of central visual acuity secondary to multifocal yellowwhite placoid lesions at the level of the pigment epithelium and choroid of the retina.3 Further case reports revealed a clear preponderance for young adults. Opthalmoscopic findings consist of cream-colored, flat, and discrete placoid lesions at the level of the retinal pigment epithelium, masking the fundus view of the underlying choroids.6 The lesions are mainly at the posterior pole and never anterior to the equator.5 The lesions begin to fade within days to weeks and are typically replaced by areas of depigmentation. Neurologic complications are uncommon but can include CSF pleocytosis, headaches, transient hearing loss, optic neuritis, meningoencephalitis, transient focal deficits, and strokes.5 An underlying vasculitic process is thought to account for these findings. Lunea5 provides an excellent review of previously published APMPPE cases associated with cerebrovascular complications in the French and English literature. Given the rare nature of this disease, the debilitating cerebrovascular complications, and lack of equipoise regarding treatment options, we conducted a thorough review of the literature for welldescribed case reports in all languages to better characterize APMPPE-associated cerebrovascular disease diagnostic features and treatment experience. Using PubMed and Google Scholar, we searched for cases of APMPPE-associated stroke, APMPPE-associated vasculitis, and APMPPE-associated cerebrovascular disease. e298 Table 1. Documented case reports of APMPPE associated with cerebrovascular complications to date CNS symptom onset after ocular symptoms Study Year reported Holt et al7 1976 Photophobia headache, aphasia, weakness 3d Sigelman et al8 1979 Headache, homonymous hemianopia 4d Smith et al9 1983 2 mo Weinstein et al10 1988 Wilson et al11 1988 Hammer et al12 1989 Photophobia, headache, homonymous hemianopia Bilateral vision loss, homonymous hemianopia, numbness, slurred speech Bilateral vision loss, headache, seizure Bilateral vision loss, hemiparesis Stoll et al13 1991 Bilateral vision loss, dysarthria, weakness, ataxia 4 mo Bewermeyer et al14 1993 5 mo Comu et al2 1996 Photophobia, hemiparesis, stupor, slurred speech, nystagmus Bilateral vision loss, headache, hemiparesis, CNS symptoms 2-3 mo 2 wk 3 wk 3 wk CSF findings WBC 177, protein 156 Neurologic imaging Cerebral angiogram: small-vessel vasculopathy WBC 7, Cerebral angiogram: protein 52 small-vessel vasculopathy ‘‘Lymphocytosis and Cerebral angiogram: elevated protein’’ small-vessel vasculopathy WBC 9 MRI: occipital hemorrhage Cerebral angiogram: small-vessel vasculopathy WBC 0, No imaging reported protein 66 None reported CT head: anterior cerebral artery and MCA ischemic infarcts WBC 18, MRI brain: multiple protein 67 hemispheric white matter lesions Cerebral angiogram: small-vessel vasculopathy WBC 55, MRI brain: right pontine protein 36 infarct ‘‘Lymphocytosis’’ Treatment Outcome Corticosteroids Asymptomatic at 36 mo No treatment Persistent homonymous hemianopia 1 Exacerbation Corticosteroids Corticosteroids Persistent homonymous hemianopia Corticosteroids Died after 2 d of treatment Death from malignant cerebral edema from stroke Asymptomatic at 1 y Corticosteroids Corticosteroids Corticosteroids and azathioprine Right parietal infarct when steroids tapered, no relapse at 24 mo with cyclophosphamide D. CASE ET AL. Corticosteroids and MRI brain: bilateral cyclophosphamide parieto-occipital infarcts Cerebral angiogram: Normal Asymptomatic at 2 y 2001 Scotoma in left eye, seizure, HA, numbness 1y WBC 28, protein 85 O’Halloran et al4 2001 Right eye vision loss, headache, hemiparesis 3 mo WBC 28, protein 85 O’Halloran et al4 2001 Headache, hemiparesis 3 wk None reported O’Halloran et al4 2001 Bilateral vision loss, numbness 6y Protein 88 O’Halloran et al4 2001 Numbness Simultaneous Normal O’Halloran et al4 2001 Right eye vision loss 2y Normal O’Halloran et al4 2001 Homonymous hemianopia de Vries et al15 2006 Bugnone et al16 Kline et al17 Simultaneous None reported Right eye vision loss, headache, hemiparesis, numbness, seizures 3d None reported 2006 Vision loss, Right-sided weakness and paresthesia 1.5 mo None reported 2007 Bilateral vision loss, headache, left third nerve palsy Simultaneous None reported MRI brain: bilateral parietal hemorrhages Cerebral angiogram: superior sagittal sinus thrombosis MRI brain: normal Cerebral angiogram: small-vessel vasculopathy Cerebral angiogram: small-vessel vasculopathy MRI brain: multiple T2 hyperintense thalamic and white matter lesions MRI brain: right parasagittal contrastenhancing lesion MRI brain: multiple periventricular T2 lesions MRI brain: infarction in right temporal lobe Corticosteroids No relapse at 13 mo Corticosteroids, cyclophosphamide No relapse at 13 mo Corticosteroids No relapse at 5 y Corticosteroids Persistent numbness at 2 mo Corticosteroids Asymptomatic at 2 mo Corticosteroids Normal vision at 3 mo Corticosteroids MRI/MRA brain: occlusion of left MCA and narrowing of the right posterior cerebral artery with infarction MRI brain: right caudate stroke and chronic right corpus callosum stroke No treatment Persistent homonymous hemianopia, no relapse at 18 mo Death from infarction Corticosteroids CT/CT angiography head: Surgical drainage of sinuses, bilateral cavernous sinus antibiotics, thrombosis, sinusitis anticoagulation APMPPE: A REVIEW OF THE LITERATURE O’Halloran et al4 Neurologic symptoms arose after corticosteroids tapered off, spontaneous recovery 3 mo later Persistent partial left third nerve palsy (Continued ) e299 Study Year reported CNS symptoms CNS symptom onset after ocular symptoms CSF findings e300 Table 1. (Continued ) Neurologic imaging 2009 Bilateral vision loss, headache, hemiparesis 2 wk WBC 253, protein 57 MRI/MRA brain: infarction in the right MCA Cerebral angiogram: small-vessel vasculopathy Masse et al18 2009 Bilateral vision loss, headache 1 wk ‘‘Lymphocytosis’’ Bilateral parieto-occipital infarcts Pagnoux et al19 2011 Vision loss, left sided weakness 2 mo WBC 14 MRI: multiple brain stem and left parietal infarcts Volbers et al20 2012 Bilateral vision loss, aphasia, right sided hemihypesthesia 1 mo WBC 16 El Sanhouri et al21 2012 Headache, decreased responsiveness 2 wk Not reported MRI/MRA brain: left MCA stenosis and stroke Cerebral angiogram: left MCA stenosis CT head: bilateral cortical infarcts Matamala et al22 2013 Bilateral vision loss 1y WBC 16 Oleszczuk and Saeed23 2013 Headache, left eye vision loss 6 mo None reported Lunea et al MRI brain: bilateral ischemic lesions in lenticular nuclei and corona radiate Cerebral angiogram: Diffuse stenosis of mainly left posterior cerebral artery MRI brain: right basal ganglia infarct Treatment Outcome New infarction Corticosteroids, 6 mo later cyclophosphamide, while changing azathioprine cyclophosphamide to azathioprine and still receiving steroids Corticosteroids and Improvement of mitoxantrone headaches after starting mitoxantrone Corticosteroids and No residual neurologic azathioprine deficits 6 mo after treatment with addition of azathioprine Corticosteroids and Full recovery azathioprine Corticosteroids Corticosteroids Corticosteroids and azathioprine Onset of neurologic symptoms and decline in examination during corticosteroid taper at 2 wk progressing to herniation and death No recurrence at 2 y Resolution of symptoms D. CASE ET AL. 5 Abbreviations: APMPPE, acute posterior multifocal placoid pigment epitheliopathy; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; MCA, middle cerebral artery; MRI, magnetic resonance imaging; WBC, white blood cell count; RBC, red blood cell count. Corticosteroids Corticosteroids WBC ,5, RBC ,5, normal protein 5d 2015 Present case Left eye vision loss, headache, left-sided weakness WBC 17, protein 53 2 mo 2014 Tsang et al25 Left-sided weakness, seizures 2013 Del Saz-Saucedo et al24 Headaches, right-sided weakness Simultaneous Normal MRI brain: multiple vascular territory infarcts MRI brain: bilateral, anterior, and posterior circulation infarcts MRI brain: multiple white matter and corpus callosum infarct Cerebral angiogram: anterior cerebral artery branch occlusion and narrowing Corticosteroids Improved left-sided weakness at 6 mo From our review, we found 28 well-documented cases of APMPPE-associated cerebrovascular complications (Table 1). The majority of reported cases include parenchymal injury or ischemic changes (19 cases); however, hemorrhagic stroke (2 cases) and cerebral venous thrombosis (2 cases) have been reported. Of the 28 case reports to date, 12 included cerebral angiogram findings, of which only 1 was documented as normal. This supports the idea that the disease represents a ‘‘uveocerebral’’ vasculitic syndrome like Eales disease or Susac disease.6 Although APMPPE affects men and women equally, the majority of cases of cerebral vasculitis were in men.5 In addition, the majority of these patients were white.5 Ours was a young, white male patient. The mean latency from diagnosis of APMPPE to central nervous system involvement is typically 2 months, which is consistent with our reported case.4 Headache and CSF pleocytosis are common neurologic manifestations, and in our patient’s case, he did have headache but did not have abnormalities on his CSF profile. This could be explained by the delay in time of onset of symptoms to time of lumbar puncture. Previous case reports suggest an inflammatory mechanism based on lumbar puncture results; however, some of the previously documented cases reported normal lumbar puncture findings as well. In addition, multifocal segmental vessel narrowing seen on cerebral angiography is not specific for vasculitis. These findings could also suggest vasospasm or a vasculopathy. The diagnosis of cerebral ‘‘vasculitis’’ has been primarily made based on imaging findings in previous case reports. Only 2 previous case reports describe cerebral histopathologic descriptions.11,15 The small number of reported cases does not allow for definitive recommendations regarding the management and treatment of patients with APMPPE-associated cerebrovascular complications. Patients with this disease have generally been treated with corticosteroids; however, 8 patients also received immunosuppressive therapy.2,4,5,14,17,19,20,23 It has been previously suggested to limit brain imaging to patients who have focal neurologic deficits and/or headache.5 Diagnostic testing should include a brain MRI with diffusion-weighted images along with consideration for cerebral angiogram and lumbar puncture. Treatment should be guided based on the severity of the clinical presentation. Previous case reports have described ‘‘escalation of care’’ to immunomodulatory medications including azathioprine, cyclophosphamide, or mitoxantrone when patients deteriorate clinically on corticosteroids alone. To date, there have been 5 case reports documenting death due to cerebrovascular complications.11,12,15,21,25 In the majority of these cases, death occurred when corticosteroids were rapidly tapered. From a previous review of 9 patients with APMPPE-associated strokes, patients were less likely to have another stroke or die if Death from infarction at 14 d e301 Significantly improved APMPPE: A REVIEW OF THE LITERATURE e302 they received high-dose corticosteroids with prolonged taper or initiation of immunomodulatory therapy.2 In our patient’s case, corticosteroid-based treatment was the agreed on choice after the onset of neurologic symptoms. The patient demonstrated clinical improvement on continued high-dose corticosteroids with eventual stabilization of his symptoms. Steroid sparing immunosuppressant regiments are a consideration particularly in severe cases, but the risks and benefits should be weighed and discussed with the patient before initiation.5 References 1. Al Kawi A, Wang DZ, Kishore K, et al. A case of ischemic cerebral infarction associated with acute posterior multifocal placoid pigment epitheliopathy, CNS vasculitis, vitamin B(12) deficiency and homcysteinemia. 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A rare cause of ischaemic stroke. Rev Neurol 2013;56:567-572. 25. Tsang BK, Chauhan DS, Haward R, et al. Fatal ischemic stroke complicating acute multifocal placoid pigment epitheliopathy: histopathological findings. J Neuroopthalmol 2014;34:10-15.