Journal of Thrombosis and Thrombolysis https://doi.org/10.1007/s11239-020-02109-4 Relapsing polychondritis coupling with cerebral amyloid deposit inducing cerebral amyloid angiopathy‑related inflammation Kosuke Matsuzono1 · Kohei Furuya1 · Takeshi Igarashi1 · Akie Horikiri1 · Takamasa Murosaki2 · Daekwan Chi3 · Yuichi Toyama4 · Kumiko Miura1 · Tadashi Ozawa1 · Takafumi Mashiko1 · Haruo Shimazaki1 · Reiji Koide1 · Ryota Tanaka1 · Shigeru Fujimoto1 © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Cerebral amyloid angiopathy-related inflammation is a syndrome of reversible encephalopathy with cerebral amyloid angiopathy, however the pathology is not well understood. We clear a part of the pathology through the first case of an 80-year-old man with cerebral amyloid angiopathy-related inflammation induced by relapsing polychondritis (RP) analysis. An 80-yearold man was diagnosed with RP by auricular cartilage biopsy. Almost no abnormality including intracranial microbleeding was detected by cranial magnetic resonance image (MRI) at diagnosis. However, he developed a headache and hallucination after five months. Seven-month cranial MRI showed novel, multiple, intracranial microbleeding, especially in the bilateral but asymmetry posterior, temporal, and parietal lobes. 123I-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography showed increased cerebral blood flow in the bilateral posterior lobes. After treatment, both of his neurological symptoms and increased cerebral blood flow improved to mild. Photon emission computed tomography using Pittsburgh compound B (PiB) for evaluation of brain amyloidosis at 12 months after onset showed an amyloid deposit in the bilateral frontal lobes, but a lack of uptake corresponded to the RP lesions. Our case suggests that inflammation coupled with an amyloid deposit, induced the multiple intracranial bleeding, and resulted in the lack of PiB uptake. Findings from our case show that inflammation including excess blood flow coupled with an amyloid deposit synergistically facilitate intracranial bleeding. Keywords CAARI · Relapsing chondritis · Vasculitis · Cerebral amyloid angiopathy · PiB-PET Highlights • The pathology in our case showed that inflammation, including excess blood flow coupling with an amyloid deposit, resulted in rapid multiple intracranial bleeding. * Kosuke Matsuzono kmatsuzono51@jichi.ac.jp 1 Division of Neurology, Department of Medicine, Jichi Medical University, Yakushiji 3311‑1, Shimotsuke, Tochigi 329‑0498, Japan 2 Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Yakushiji 3311‑1, Shimotsuke, Tochigi 329‑0498, Japan 3 Department of Plastic Surgery, Jichi Medical University, Yakushiji 3311‑1, Shimotsuke, Tochigi 329‑0498, Japan 4 Department of Dermatology, Jichi Medical University, Yakushiji 3311‑1, Shimotsuke, Tochigi 329‑0498, Japan • This is the first case reporting relapsing polychondritis coupling with an amyloid deposit inducing the cerebral amyloid angiopathy-related inflammation. • Our case has a possibility of applying the cerebral amyloid angiopathy. Introduction Relapsing polychondritis (RP), which shows swelling of the ear, destruction of the nose, fever, and arthritis, has recently attracted attention regarding neurological complications [1]. Cerebral vasculitis is involved in neurological complications of RP as shown by autopsy [2]. Cerebral amyloid angiopathy-related inflammation (CAARI) is a syndrome of reversible encephalopathy with cerebral amyloid angiopathy (CAA) [3]. However, the relationship between RP and CAARI is unknown, and the pathology of CAARI is not well understood [4]. 13 Vol.:(0123456789) K. Matsuzono et al. Clinical case A working 80-year-old man developed pain and swelling of the ears, conjunctival hyperemia, and generalized arthralgia. He had a history of percutaneous coronary intervention and had been taking dual-antiplatelet therapy (aspirin 100 mg/day, clopidogrel 75 mg/day) since 62 years old. He was admitted in our hospital. An auricular cartilage biopsy (Fig. 1(a, b)) led to the diagnosis of RP based on diagnostic criteria [5]. Initial cranial T2-star magnetic resonance imaging (T2*-MRI) showed no intracranial microbleeding (Fig. 1(c, g)). Fluid-attenuated inversion recovery (FLAIR) imaging showed only mild brain atrophy (Fig. 1(e, i)) at diagnosis. His symptoms disappeared without immunosuppression therapy and he was discharged home, but accelerated elevation of his erythrocyte sedimentation rate (ESR) to > 40 mm/h continued. Five months later, he developed a headache and hallucination. His cognitive function became disturbed, and he was unable to live by himself. Seven-month cranial T2*-MRI showed novel, multiple, intracranial microbleeding, especially in the bilateral but asymmetry posterior, temporal, and parietal lobes (Fig. 1(d, h), arrows). FLAIR imaging also showed abnormal hyperintensity (Fig. 1(f, j)). Therefore, he was admitted in our hospital again at 7 months after onset. At admission, his neurological examinations showed pure cognitive function disturbance. His mini-mental state examination (MMSE) score was 15/30 and frontal assessment battery (FAB) was 6/18. A laboratory examination showed a remarkably elevated ESR of 60 mm/h. Although there was a mild elevation of C-reactive protein (CRP) (0.39 mg/dl) and mild anemia (hemoglobin: 10.0 g/dl), any specific autoantibodies were negative. Cerebrospinal fluid analysis showed mild elevation of cell counts (8/μl), but no xanthochromia. Gadoliniumenhanced magnetic resonance imaging (Gd-MRI) showed enhancement as blood vessels that corresponded to FLAIR lesions (Fig. 2(a–c), arrows). 123I-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (123I-IMP SPECT) showed increased cerebral blood flow in the bilateral posterior lobes (Fig. 2(d), arrowheads). However, positron emission tomography (PET) with 18 F-fluorodeoxyglucose showed hypometabolism in the same lesions (Fig. 2(f–h), arrows). Skin biopsy from erythema of the patient’s left forearm showed lymphocytes and plasma cell invasion around vessels in the dermatis (Fig. 2(i, j)). We diagnosed the patient with CAARI following RP on the basis of criteria [6]. Dual-antiplatelet therapy was decreased to clopidogrel monotherapy. Methylprednisolone pulse therapy (1000 mg/day) was performed three times and oral prednisolone (40 mg/day) was initiated. 13 Fig. 1  a Hematoxylin and eosin staining of auricular cartilage at a low magnification and b a high magnification. Lymphocytes and neutrophils are infiltrated around the cartilage tissue with bleeding. Scale bar: 100 μm. c–j T2* and FLAIR images at diagnosis of RP and 7 months after diagnosis. Multiple intracranial microbleeding (arrows) as shown by T2* and hyperintense lesions as shown by FLAIR images appeared 7 months after diagnosis. k Schema of the pathology. Bleeding occurs synergistically in CAARI compared with RP vasculitis or CAA alone On month after initiating treatment, his cognitive function recovered with an MMSE score of 20/30 and FAB of 16/18. The serum ESR was decreased to 31 mm/h and the CRP level was decreased to 0.08 mg/dl. The 123I-IMP SPECT showed increased cerebral blood flow in the bilateral posterior lobes improved to mild (Fig. 2(e), arrowheads). He was discharged home with oral prednisolone (15 mg/day). His apolipoprotein E allele analysis showed ε3/ε4. PET using Pittsburgh compound B (PiB-PET) for evaluation of brain amyloidosis [7] at 12 months after Relapsing polychondritis coupling with cerebral amyloid deposit inducing cerebral amyloid… Discussion There have only been a few reports on neurological complications, including cerebral bleeding, following RP. In addition, the clinical course of our presented case resulted in CAARI following RP although there was no previous report. The pathology in our case suggested that inflammation, including excess blood flow coupling with an amyloid deposit, resulted in rapid multiple intracranial bleeding (Fig. 1(k)). Our case PiB-PET result suggests that inflammation coupled with an amyloid deposit, induced the multiple intracranial bleeding, and resulted in the lack of PiB uptake. Although the neurological complications following RP show several kinds phenotype, the pathology is considered to be common, inflammation of the central nerves systems [8]. It is interesting that some RP cases resulted in subacute dementia [9]. Our presented case show the possibility that RP coupled with an amyloid deposit induces the subacute cognitive disturbance. CAARI is the recent disease spectrum [3]. The autoimmune inflammation link to an amyloid deposit is considered to important factor of CAARI as trial of immunization or vaccination with amyloid beta peptide developed the syndrome of meningoencephalitis in case of the immunized patients [10]. Our presented case supports this pathology hypothesis and shows the possibility that not only RP but also more other autoimmune diseases induce the CAARI. The major limitation of our case report is that there were no brain biopsy data according to CAARI because the patient survived and we were afraid of intracranial fatal bleeding following brain biopsy. We compensate the pathological date for the PiB-PET results in order to support our pathological hypothesis. In conclusion, RP coupling with an amyloid deposit synergistically facilitated intracranial bleeding, CAARI. Fig. 2  a–c Gd-MRI at 7 months after diagnosis showing enhancements a blood vessel (arrows). d 123I-IMP SPECT before and e after treatment. Increased cerebral blood flow in the bilateral posterior lobes became mild (arrowheads). f–h PET with 18F-fluorodeoxyglucose showing hypometabolism in the bilateral posterior, temporal, and parietal lobes (arrows). i Hematoxylin and eosin staining of the skin at a low magnification and j a high magnification. Severe infiltration of lymphocytes around vessels can be seen in the dermis. Scale bar: 100 μm. k, l 11C-PIB PET in the axial and sagittal views. An amyloid deposit in the bilateral frontal lobes can be seen onset showed an amyloid deposit in the bilateral frontal lobes (Fig. 2(k, l)). He lived by himself with an MMSE score of 27/30 and FAB of 15/18 without RP relapse at 15 months after onset. Acknowledgements We appreciate the cooperation of the patient and his wife. The apolipoprotein E allele analysis and the 11C-PIB PET imaging were produced at Shonan Atsugi Hospital (Kanagawa, Japan). We thank Ellen Knapp, PhD, from Edanz Group (www.edanz​ editi​ng.com/ac) for editing a draft of this manuscript. Authors’ contributions Kosuke M., K.F., T.I., A.H., T.M., and R.T. were the attending doctors of the present case. D.C. performed the auricular cartilage biopsy. Y.T. performed the skin biopsy. Kosuke M. drafted the manuscript. Kumiko M., T.D., T.M., H.S., and R.K. helped to draft the manuscript. S.F. conceived the study, participated in its coordination, and helped to draft the manuscript. All authors read and approved the final manuscript. Funding No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. 13 K. Matsuzono et al. Compliance with ethical standards Conflict of interest Drs K. Matsuzono, K. Furuya, T. Igarashi, A. Horikiri, T. Murosaki, D. Chi, Y. Toyama, K. Miura, T. Ozawa, T. Mashiko, H. Shimazaki, R. Koide, R. Tanaka, K, and S. Fujimoto report no disclosures. 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