Shigeaki Mitsuhashi

Progressive Wild‐Type Transthyretin Deposition after Liver Transplantation Preferentially Occurs onto Myocardium in FAP Patients

To elucidate whether progressive wild‐type transthyretin (TTR) deposition can actually occur after liver transplantation (LT), amyloid fibrils were investigated in two familial amyloid polyneuropathy patients with TTR Val30Leu variant, who died 1 year after LT. Amyloid fibrils were extracted from cardiac muscles, sciatic nerves and kidney, which were investigated by the immunoprecipitation‐mass spectrometry method and liquid chromatography‐ion trap mass spectrometry analysis. The ratio of wild‐type to variant TTR in cardiac muscle was approximately 5:5 before LT, but greatly increased to about 9:1 after transplantation. The ratios in sciatic nerves and kidney obtained at autopsy were approximately 5:5. Wild‐type TTR was undetectable in kidney amyloid obtained before LT. Our results indicate that paradoxical wild‐type TTR deposition after LT can preferentially occur in myocardium, leading to fatal cardiac dysfunction, but it is quite likely that this phenomenon can also occur in other visceral organs.

Anti-neuronal autoantibody in Hashimoto's encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients

Hashimotos encephalopathy (HE) is thought to be caused by disorders of immune mechanisms. Although immunologically mediated central nervous system vasculitis or unidentified anti-neuronal autoantibodies have been suspected of causing HE, its pathogenesis is still unclear. For the study presented here, two patients with typical clinical and laboratory/electrophysiological findings of HE were analyzed to clarify the role of anti-neuronal autoantibodies in the pathogenesis of HE. The autopsied brain of one of the patients was histopathologically examined. For Western blotting analysis and immunohistochemistry, serum and purified immunoglobulin G obtained from the other patient were used. Autopsy revealed no evidence of central nervous system vasculitis or other abnormal findings in the brain. The patients serum contained an anti-neuronal autoantibody that immunohistochemically labeled neurons of mouse and human cerebral cortices and reacted with the 36-kDa antigenic protein present in a soluble fraction obtained from human cerebral cortex. Our results indicate that anti-neuronal autoantibodies may be associated with the pathogenesis of HE.

Biochemical characteristics of variant transthyretins causing hereditary leptomeningeal amyloidosis

Transthyretin (TTR) is a tetrameric protein that can dissociate into amyloidogenic monomers and cause TTR-related amyloidosis. A rare phenotype, called hereditary leptomeningeal TTR amyloidosis, in which TTR amyloid deposition occurs mainly in leptomeninges and subarachnoid vessels, has been reported in patients with several different TTR variants. In the present study, we examined TTR variants immunoprecipitated from the serum and cerebrospinal fluid (CSF) of patients with hereditary leptomeningeal TTR amyloidosis using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (IP-Mass method). The leptomeningeal-type TTR variants were not detected in the serum but were found at low levels in the CSF. The undetectable levels of the leptomeningeal-type TTR variants in serum could explain the minute amounts of systemic deposition of these variants. The relatively high level of unstable TTR variants in CSF, probably due to increased secretion from the choroid plexus, is considered to be the pathogenesis of the leptomeningeal-type of TTR amyloidosis.

Successful treatment of fulminant pulmonary hemorrhage associated with systemic lupus erythematosus

We report a patient with systemic lupus erythematosus (SLE) who developed fulminant pulmonary hemorrhage. This patient also showed liver dysfunction, bicytopenia and hyperferritinemia, with an increase in serum levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) at the onset of pulmonary symptoms, probably indicating an associated hemophagocytic syndrome. Despite an acute progressive course temporarily requiring mechanical ventilation the patient was successfully treated with continuous drip infusion of tacrolimus, plasmapheresis and intravenous high-dose immunoglobulin and corticosteroid. In this patient increased inflammatory cytokines ascribable to activation of macrophages and/or helper T cells were considered to play an important role in the pathogenesis of the pulmonary hemorrhage. Because this complication is frequently fatal in SLE, intensive therapy, including immunosuppressants and plasmapheresis, should be actively considered as early as possible after onset.

Paraneoplastic Sensorimotor Neuropathy and Encephalopathy Associated with Anti-α-Enolase Antibody in a Case of Gastric Adenocarcinoma

Paraneoplastic Sensorimotor Neuropathy and Encephalopathy Associated with Anti-·-Enolase Antibody in a Case of Gastric Adenocarcinoma Kana Tojo a, Takahiko Tokuda a, b, Masahide Yazaki a, Takashi Oide a, Akihiro Nakamura c, Shigeaki Mitsuhashi a, Kazuma Kaneko a, Keiko Maruyamad, Fuyuki Kametani e, Keiichi Higuchi c, Shu-ichi Ikeda a aThird Department of Internal Medicine, Departments of bNeuroplasticity and c Aging Angiology, Shinshu University School of Medicine, Matsumoto, d Department of Neurology, Suwa Red Cross Hospital, and eDepartment of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo, Japan

MRI analysis on a patient with the V30M mutation is characteristic of leptomeningeal amyloid

We report a characteristic finding in gadolinium-enhanced magnetic resonance images (MRIs) of the central nervous system (CNS) in a 61-year-old man with a homozygous transthyretin (TTR) Val30Met mutation. Although he presented with polyneuropathy accompanied by autonomic dysfunction and vitreous opacities in both eyes, he has shown no overt signs or symptoms of CNS involvement. Total protein level in the cerebrospinal fluid was moderately elevated. In the gadolinium-enhanced T1-weighted MRIs of the brain and spinal cord, leptomeningeal enhancement was seen along the surfaces of the brain stem and more clearly in the spinal cord, suggesting leptomeningeal TTR-related amyloid deposition. Our result indicates that gadolinium-enhanced MRI of the CNS may be a very sensitive and useful method for detecting leptomeningeal amyloid deposition, since abnormal findings can be detected even at a presymptomatic stage of CNS involvement.