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Neuroradiologic and clinicopathologic features of oculoleptomeningeal type amyloidosis

From the Department of Clinical Medicine (Dr. Nakamura), National Institute for Minamata Disease, Minamata; Departments of Neurology (Drs. Yamashita, Ueda, Sato, Ikeda, and Uchino), Radiology (Drs. Hirai and Kuwahara), Molecular Pathology (Dr. Yamamoto), and Diagnostic Medicine (Dr. Ando), Graduate School of Medical Sciences, Kumamoto University; Department of Neurology and Neuromuscular Disorders (Dr. Obayashi), Oita University Faculty of Medicine; and Department of Neurology (Dr. Washimi), Tyubu National Hospital, Ofu, Japan.

Address correspondence and reprint requests to Dr. Yukio Ando, Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan; e-mail: yukio{at}kaiju.medic.kumamoto-u.ac.jp

Objective: To clarify the pathogenesis of leptomeningeal amyloidosis in familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C (FAP ATTR Y114C).

Methods: The authors analyzed eight FAP ATTR Y114C patients. Six patients showed CNS symptoms associated with leptomeningeal amyloidosis. To examine the function of the blood–CSF barrier and blood–brain barrier (BBB), the authors performed CSF and MRI studies. The authors also performed a histopathologic study of autopsy specimens to examine the distribution of amyloid deposition in the CNS.

Results: CSF study showed high total protein concentrations and increased albumin CSF/serum concentration quotients (Q_alb; an indication of blood–CSF barrier function). MRI with gadolinium (Gd) revealed enhancement from brainstem to spinal cord. Serial brain MRI studies with FLAIR images after Gd administration showed Gd leakage into the subarachnoid space (two patients). These findings suggested the blood–CSF barrier and BBB dysfunctions. Constructive interference in steady state (CISS) three-dimensional Fourier transformation (CISS-3DFT) sequence analysis demonstrated amyloid-induced funiculus structures joining the spinal cord and dura mater (one patient). Histopathologic study revealed intense amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. These distributions of amyloid deposition are unique compared to other TTR related leptomeningeal amyloidosis.

Conclusions: Patients with familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C had CNS disorders related to amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. The pathogenesis of CNS disorders may reflect disruption of the blood–CSF barrier and blood–brain barrier by amyloid deposition.

Supported by grants from the Amyloidosis Research Committee, the Pathogenesis, Therapy of Hereditary Neuropathy Research Committee, the Surveys and Research on Specific Disease, the Ministry of Health and Welfare of Japan, and the Charitable Trust Clinical Pathology Research Foundation of Japan; Research for the Future Program Grant; and Grants-in-Aid for Scientific Research (B) 15390275 from the Ministry of Education, Science, Sports and Culture of Japan.

Disclosure: The authors report no conflicts of interest.

Received March 10, 2005. Accepted in final form June 24, 2005.

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