ARTICLE IN PRESS Case Report Case of Cerebral Amyloid Angiopathy-Related Inflammation – Is the Absence of Cerebral Microbleeds A Good Prognostic Sign? John W. Liang, MD,* Wei Zhang, MD,† Jonathan Sarlin, MD,† and Irene Boniece, MD* Objective: The aim of this study is to describe a case of pathologically proven cerebral amyloid angiopathy-related inflammation (CAA-I) without cerebral microbleeds (CMBs) and its clinical course. Background: CAA-I is an uncommon variant of cerebral amyloid angiopathy. Keys to diagnosis rely on the physician’s awareness of this entity, CMBs on magnetic resonance imaging (MRI), an often favorable response to immunosuppression, and ultimately brain biopsy. CAA-I with no CMBs is rarely reported. Results: A 76-year-old woman presented with 4 weeks of headaches and was found to have visual neglect on the left part of the visual field. MRI of the brain showed sulcal/gyriform hyperintensity with associated leptomeningeal enhancement in the right occipital lobe on fluid-attenuated inversion recovery (FLAIR) imaging. No CMBs or large parenchymal FLAIR lesions were seen on MRI. Biopsy was consistent with CAA-I. The patient’s headaches resolved spontaneously and no immunosuppression was initiated. The patient remained asymptomatic for the 18 months of follow-up. Conclusions: To the best of our knowledge, there has been only one previous case of pathology-proven CAA-I without CMBs reported and this was associated with a good prognosis. Lack of CMBs and/or large parenchymal FLAIR lesions may be a prognostic factor in this disease. Key Words: Amyloid—inflammation—microhemorrhage—CAA. © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved. Introduction From the *Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine, New York, New York; and †Department of Pathology, Mount Sinai Beth Israel, Icahn School of Medicine, New York, New York. Received April 27, 2015; revision received June 17, 2015; accepted August 2, 2015. Grant support: No grant support was provided for this study. Address correspondence to John W. Liang, Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine, 10 Union Square East, Suite 5H, New York, NY 10003. E-mail: johnliangmd@gmail.com. 1052-3057/$ - see front matter © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.08.001 Sporadic cerebral amyloid angiopathy (CAA) is a common disease associated with advanced age and is characterized by preferential β-amyloid deposition in the walls of small cortical and leptomeningeal vessels. It is associated with lobar intracerebral hemorrhage (ICH) in elderly normotensive individuals. In the 1980s, several case reports described a variant of CAA without ICH with marked inflammatory response on pathological specimens, and it was subsequently termed cerebral amyloid angiopathyrelated inflammation (CAA-I).1 Common presentations included mental status changes (59%), headaches (35%), focal deficits/seizures (24%), dementia (12%), and hallucinations (12%).2 Diagnosis relies on the physician’s Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2015: pp ■■–■■ 1 ARTICLE IN PRESS J.W. LIANG ET AL. 2 awareness of this CAA variant as well as cerebral microbleeds (CMBs) on magnetic resonance imaging (MRI). A favorable response to immunosuppression is also suggestive, and definitive diagnosis is via brain biopsy. We report an uncommon presentation of absent CMBs in a pathologically proven case of CAA-I. Case Report A 76-year-old woman with hypertension and diabetes presented to our center after 4 weeks of right frontal and periorbital headaches described as sharp and stabbing in nature and associated with visual disturbance of seeing “spots” and “spiders.” A baseline persistent pain severity of 3/10 was interspersed with frequent episodes of crescendo pain up to 10/10 in severity over a minute and remaining intense for 30 minutes with gradual resolution over another 30 minutes. The patient had no history of migraines. Her full neurological and ophthalmological exam was only significant for visual neglect on the left part of the visual field. MRI of the brain (Fig 1, A,C,D) revealed a sulcal/ gyriform hyper-intensity with associated leptomeningeal enhancement in the right occipital lobe on fluid-attenuated inversion recovery (FLAIR) sequence. No CMBs were seen on gradient-recalled echo sequence (Fig 1, B). Subsequent cerebrospinal fluid (CSF) analysis showed minimal elevation in protein (68 mg/dL, normal 12-60) with normal glucose and cell count. Bacterial, fungal and viral cultures in the CSF were negative. Testing for angiotensin converting enzyme, acid-fast bacilli, Lyme disease, cryptococcus, herpes simplex virus, and varicella zoster virus was also negative. CSF flow cytometry Figure 1. (A) Axial-FLAIR-sulcal/gyriform hyperintensity in the right occipital lobe. (B) Axial gradient-echo susceptibility-weighted absence of microhemorrhages. Coronal and axial T1 post gadolinium—local leptomeningeal enhancement in the right occipital lobe (C and D). Abbreviation: FLAIR, fluid-attenuated inversion recovery. ARTICLE IN PRESS CAA-I WITHOUT CMB and cytology showed no evidence of malignancy. Search for occult malignancy with CT imaging of the chest, abdomen, and pelvis was also negative. On hospital day 6, the patient continued to have unremitting headaches. She underwent an open brain biopsy because of the diffuse nature of the leptomeningeal enhancement pattern on MRI. Biopsies of the leptomeninges and the right posterior temporal cortex were obtained. Histopathological analysis of specimens showed CAA, confirmed by positive Congo red staining and characteristic birefringence on polarized light examination of vessel walls (Fig 2). In the foci, there was also a cellular reaction to the amyloid, including multinucleated giant cells, as well as vascular thrombosis and intimal fibroplasia, all consistent with CAA-I. Initiation of immunosuppressive therapy was considered; however, the patient’s headache resolved postoperatively and a decision was made for observation. The patient remained asymptomatic for the 18 months of follow-up and headache-free without visual neglect. Figure 2. Amorphous eosinophilic extracellular materials and lymphocyte infiltration around the vessel (top). Amyloid deposition (yellowgreen) in the wall of the vessel with Congo red staining under polarized light microscopic examination (bottom). 3 Discussion We describe the uncommon presentation of a rare disease, CAA-I, which was diagnosed through biopsy. The absence of CMB in our patient is atypical and rarely reported. Additionally, our patient improved before initiation of anti-inflammatory therapy and remained asymptomatic for 18 months, highlighting the wide spectrum of presentation for this entity. Two atypical imaging findings for this case are as follows: (1) absence of typical T2 signal abnormalities and (2) absence of CMB. Kinnecom et al. 3 reported 12 pathologically confirmed CAA-I patients who all received anti-inflammatory treatment. MRI showed large confluent asymmetric T2hyperintense lesions with signal characteristics suggestive of vasogenic edema. Volumetric analysis of these T2hyperintense lesions showed a close correlation between lesion volume and clinical course, which subsequently reduced in volume with anti-inflammatory treatment. Our patient’s MRI lacked the typical steroid-responsive T2 lesions described in the case series and may explain the favorable outcome without immunosuppression. In a recent review of 69 pathologically proven cases of CAA-I, 33% died and 16 of 33 survivors (48%) were asymptomatic or mildly disabled.4 Only one patient in this group was reported to have had no CMB on imaging after presenting with cognitive decline and receiving 3 days of corticosteroids. Authors report that this patient improved but not to baseline.4,5 We add to the literature a second pathologically proven case of CAA-I without CMB. Our case is limited in that susceptibility-weighted imaging, a newer imaging technique more sensitive at detecting CMB, is not routinely performed in our center. There were, however, no CMB seen on the biopsy specimen. Imaging studies have shown an association between CAA and characteristic MRI biomarkers such as CMB and cortical superficial siderosis (CSS). Charidimou et al. reported patients with CAA with ICH are more likely to have CSS and the APOE E2 genotype, both of which predicted increased risk of future lobar ICH.6 On the contrary patients with CAA with the APOE E4 alleles were less likely to have CSS or ICH.6,7 Shoamanesh et al.7 examined 84 patients with CAA and found an association between APO E4 and lower CMB counts. Although the CMB count was high across the entire cohort (median CMB count 29), there was a decrease in CMB count with increasing severity of CSS. From prior studies, it is known that the E4 allele increases vascular amyloid burden by primarily affecting cortical capillaries while E2 promotes vessel rupture seen in ICH and often spares cortical capillaries.7,8 There is overrepresentation of the APOE E4/E4 genotype in pathologically proven CAA-I versus CAA at rates of 71%-76% and 4%-5%, respectively.3,5 Taken together these results suggest APO E2 promotes ICH and CSS via similar mechanisms, while ARTICLE IN PRESS J.W. LIANG ET AL. 4 APO E4 promotes CMB due to its preference for cortical capillaries and leads to an immune response to vascular amyloid producing the entity of CAA-I. While the mechanism is not fully understood, it is believed that amyloid infiltration leads to vessel wall weakening and subsequently extravasation of blood products resulting in CMBs.8 Greenberg et al.10 concluded that CMB is a marker of severity and predicted risk of future symptomatic ICH in survivors of initial lobar ICH.9 Pathological studies have also shown greater thickening of amyloid vessel walls in patients with CAA with higher CMB counts. Therefore, it is reasonable to consider that CMB counts as a marker of vascular amyloid load and that higher counts can lead to an immune response in susceptible individuals, likely with the APOE E4 genotype. In conclusion, we describe an atypical case of CAA-I presenting with unremitting headache, resolving spontaneously without immunosuppression, and who has been asymptomatic without relapses for 18 months. Atypical imaging findings include the absence of CMB and typical T2-hyperintense lesions, which may be associated with good prognosis in this disease. References 1. Greenberg SM, Vonsattel JP, Stakes JW, et al. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology 1993;43:2073-2079. 2. Scolding NJ, Joseph F, Kirby PA, et al. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 2005;128:500-515. 3. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related inflammation. Neurology 2007;68:1411-1416. 4. Chung KK, Anderson NE, Hutchinson D, et al. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry 2011;82:20-26. 5. Eng JA, Frosch MP, Choi K, et al. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 2004;55:250-256. 6. 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