Clinical Neurology and Neurosurgery 197 (2020) 106198 Contents lists available at ScienceDirect Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro Case Report Slowly progressive cerebral amyloid angiopathy-related inflammation: Characteristic findings of sequential magnetic resonance imaging Keita Tominaga a, Tomohiro Kawaguchi a, c, *, Miki Fujimura a, Atsushi Saito a, Mika Watanabe b, Teiji Tominaga c a b c Department of Neurosurgery, Kohnan Hospital, Sendai, Miyagi, Japan Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan 1. Introduction Cerebral amyloid angiopathy (CAA) is a common small vessel dis­ ease, and is conventionally considered to be a primary cause of intra­ cerebral hemorrhage in elderly patients. Deposition of amyloid β in the vessel walls is considered to be the basic pathogenesis of CAA, but causes both vascular damage and perivascular inflammation. Recently, CAArelated inflammation (CAA-I) has been recognized in a small subset of patients who presented with seizures, cognitive decline, or headaches with hyperintensities on T2-weighted magnetic resonance (MR) imaging [1]. The diagnosis of probable CAA-I requires full concordance with the following criteria: 1) acute or subacute onset of symptoms; 2) age 40 years or older; 3) at least one of the following clinical features: head­ ache, mental status or behavioral change, focal neurologic signs, and seizures; 4) MR imaging showing patchy or confluent hyperintensity on T2-weighted or fluid-attenuated inversion recovery imaging, which is typically asymmetric, with or without mass effects and with or without leptomeningeal or parenchymal enhancement; 5) evidence of preexist­ ing CAA on susceptibility-weighted imaging, such as multiple cortical or subcortical hemorrhages or microhemorrhages, or recent or previous lobar hemorrhage; and 6) absence of neoplastic, infectious, or other causes of symptoms. Moreover, a diagnosis of definite CAA-I addition­ ally requires evidence of amyloid-associated perivascular, transmural, or intramural vascular inflammation in the brain and leptomeninges [1]. Although CAA-I is still rare, most reported cases mainly consider the radiographical characteristics, biomarkers, and treatment variation in the acute stage [1,2], because acute or subacute onset of the clinical symptoms is one of diagnostic criteria, and long-term confirmation of sequential radiographical findings and clinical course before symptom onset remain unclear. We treated a patient with CAA-I who presented with a one-year history of progressive dementia followed by sudden onset of generalized convulsion. Retrospective review of MR imaging revealed that abnormal intensity on T2-weighted images was initially evident and gradually enlarged over the years. 2. Case report A 57-year-old woman was admitted to our hospital with generalized convulsion. Her Glasgow Coma Scale on admission was 6 (E1V1M4), and recovered to 13 (E4V3M6) after anticonvulsant administration. She had been followed up in our outpatient department for unruptured right internal carotid artery aneurysm since 2008, but no significant change in size or shape was detected. Head MR imaging in 2008 showed no particular parenchymal lesions on both T2-weighted and T2 star imag­ ing (Fig. 1A, B). Follow-up T2-weighted imaging on 2009 showed a small hyperintense lesion in the left subcortical area (Fig. 1C), which had enlarged by 2015 (Fig. 1E). During this period, T2 star imaging showed no abnormal intensities (Fig. 1D, F). She was alert without cognitive impairment, but exhibited slight memory loss and disorien­ tation, which had gradually aggravated. T2-weighted MR imaging on admission showed the hyperintense area in the left parietal lobe (Fig. 1G). T2 star imaging and susceptibilityweighted imaging showed multiple low intensity spots, predominantly in the left parietal lobe (Fig. 1H). The differential diagnosis of the lesion included malignant lymphoma, viral encephalitis, encephalopathy, or CAA-I. Open biopsy of the left parietal lesion was performed to obtain the histological diagnosis and determine appropriate treatment options (Fig. 2A). Postoperative histological examination of the formalin-fixed paraffin-embedded specimens demonstrated fibrinoid degeneration of the small arteries and perivascular infiltration of lymphocytes and macrophages by hematoxylin and eosin staining (Fig. 2B). No evidence of malignancy was discovered. Immunohistochemical staining for am­ yloid β revealed positive findings on the vessel walls and several * Corresponding author at: Department of Neurosurgery, Kohnan Hospital, 4-20-1 Nagamachi Minami, Taihaku-ku, Sendai, Miyagi, 982-8523, Japan. E-mail address: kawaguchi@nsg.med.tohoku.ac.jp (T. Kawaguchi). https://doi.org/10.1016/j.clineuro.2020.106198 Received 9 July 2020; Received in revised form 28 August 2020; Accepted 29 August 2020 Available online 30 August 2020 0303-8467/© 2020 Elsevier B.V. All rights reserved. K. Tominaga et al. Clinical Neurology and Neurosurgery 197 (2020) 106198 Fig. 1. Sequential T2-weighted and T2 star magnetic resonance images. No particular abnormal findings in 2008 (A, B). A small hyperintensity lesion was detected on T2-weighted image in 2009 (C, arrow), but no abnormal intensity on T2 star image (D). She had no neurological deficit. The hyperintense lesion on T2-weighted image was enlarged in 2015 (E, arrow), but with no abnormal intensity on the T2 star image (F). She presented with slight memory loss and disorientation. On admission with convulsion, the hyperintense lesion in the left parietal lobe was enlarged on T2-weighted image (G), and the susceptibility-weighted image showed multiple low intensity spots, predominantly in the left parietal lobe (H). Two weeks after corticosteroid pulse administration, the hyperintense lesion on T2-weighted image was decreased in size (I), but no significant change in the low intensity spots on the T2 star image (J). Four weeks after corticosteroid pulse administration, the hyperintense lesion on T2-weighted image was further improved (K), but still no change in the low intensity spots on the susceptibility-weighted image (L). Convulsion did not recur, but cognitive impairment remained unresolved. Fig. 2. A: Intraoperative photograph of the brain surface showing spotty hemorrhagic le­ sions (arrows). B: Photomicrograph showing fibrinoid degeneration of the arteries and peri­ vascular infiltration of lymphocytes and mac­ rophages. Hematoxylin and eosin staining, original magnification ×100. C, D: Immuno­ histochemical staining for amyloid β showing strong reactivity on the vessel walls (C, original magnification ×100) and several parenchymal plaques (D, arrows, original magnification ×40). plaques, indicating extracellular deposition of amyloid β (Fig. 2C, D). The histological diagnosis was CAA-I, and corticosteroid pulse therapy was initiated with methylprednisolone 1000 mg daily admin­ istered intravenously for 3 days and then tapered. T2-weighted MR imaging performed 2 weeks after corticosteroid administration revealed remarkable decrease in the size of the hyperintensity area (Fig. 1I). Further improvement of this abnormality was observed until 4 weeks after treatment (Fig. 1K), but no significant change was seen in the low intensity spots on T2 star imaging and susceptibility-weighted imaging (Fig. 1J, L). Her verbal consistency was resolved and Glasgow Coma Scale became 14 (E4V4M6), but delirium and cognitive impairment remained unresolved. She was transferred to another hospital for further rehabilitation. 2 K. Tominaga et al. Clinical Neurology and Neurosurgery 197 (2020) 106198 3. Discussion imaging, which confirms that the underling mechanism of inflammation is not the immune reaction to microbleeds but amyloid β deposition. Unfortunately, both T2-weighted imaging and T2 star imaging cannot directly detect amyloid β deposition. Amyloid imaging might be another option for patients with cognitive impairment. In conclusion, CAA-I is still rare and considered to be acute disorder with characteristic radiographical findings. However, abnormal findings on T2-weighted MR imaging can occur long before symptom onset and slowly aggravate. Therefore, CAA-I should be considered the differential diagnosis for atypical subcortical hyperintensity on T2-weighted MR imaging even in the absence of symptoms. To confirm the participation of amyloid β deposition, more sensitive examination, such as amyloid imaging can be helpful. Appropriate treatment and timing should be considered to avoid permanent cognitive impairment. The established diagnostic criteria for CAA-I, which consist of clin­ ical features and radiographical findings, have formed the basis for most clinical diagnoses [1]. Acute or subacute onset of symptoms is consid­ ered to be the essential clinical characteristic, together with extensive hyperintense lesion on T2-weighted MR imaging and low intensity spots on T2 star and susceptibility-weighted imaging at the onset. The diag­ nostic significance of the abnormal finding on MR imaging is well known, but the period before symptoms appear is not fully understood. In the present case, T2-weighted MR imaging detected abnormal find­ ings first, and T2 star imaging subsequently became positive years before onset of symptoms. The etiology of CAA and CAA-I is based on abnormal deposition of amyloid β on the vessel walls, and is characterized by perivascular, transmural, or intramural inflammatory changes, resulting from the autoimmune response to amyloid β [1,3]. Excessive inflammatory response induces vascular hyperpermeability and overmigration of im­ mune cells. Consequently, parenchymal edema and microbleeds are detected as hyperintense lesions on T2-weighted MR imaging and low intensity spots on T2 star imaging, respectively. Not surprisingly, our case showed abnormal findings on both T2-weighted imaging and T2 star imaging at the time of symptom onset. However, the hyperintense lesion on T2-weighted imaging was detected 10 years before onset. This finding might indicate that the pathophysiology of CAA-I is chronic slowly progressive inflammation in some cases, not fully consistent with the established clinical criteria. Steroid or immunosuppression therapy is the first line treatment for CAA-I to suppress the autoimmune response to amyloid β deposits. Our patient was treated with corticosteroid pulse therapy, and the hyperin­ tense lesion on T2-weighted MR imaging was dramatically improved. But she remained delirious and cognitive impairment was not improved, possibly due to the coexistence of Alzheimer’s disease. The histopatho­ logical findings of several plaques, indicating extracellular deposition of amyloid β, supports this possibility, and corticosteroid therapy is not effective for this entity. Functional outcome was not satisfactory in several reported cases of CAA-I with cognitive impairment [4,5]. Treatment delay might be associated with unsatisfactory outcome. The coexistence of CAA-I and Alzheimer’s disease was conceivable because amyloid β deposition is the principal factor in the pathophysi­ ology of both entities. Interestingly, our patient presented with abnormal findings on T2-weighted MR imaging first, followed by T2 star Informed consent The patient’s consent has been obtained for this publication. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors report no declarations of interest. References [1] K.K. Chung, N.E. Anderson, D. Hutchinson, B. Synek, P.A. Barber, Cerebral amyloid angiopathy related inflammation: three case reports and a review, J. Neurol. Neurosurg. Psychiatry 82 (2011) 20–26. [2] F. Crosta, B. Orlandi, F. De Santis, G. Passalacqua, J.C. DiFrancesco, F. Piazza, A. Catalucci, G. Desideri, C. 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