Akihiko Ueda

Cerebral amyloid angiopathy-related inflammation presenting with steroid-responsive higher brain dysfunction: case report and review of the literature

A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI) showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed β-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA)-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved.CAA-related inflammation is a rare disease, defined by the deposition of amyloid proteins within the leptomeningeal and cortical arteries associated with vasculitis or perivasculitis. Here we report a patient with CAA-related inflammation who showed higher brain dysfunction that improved with steroid therapy. In cases with atypical radiological lesions like our case, cerebral biopsy with histological confirmation remains necessary for an accurate diagnosis.

Effect of liver transplantation on transthyretin Tyr114Cys-related cerebral amyloid angiopathy

Objective: Patients with amyloidogenic transthyretin (ATTR) Tyr114Cys develop amyloid deposits in cerebral blood vessels, cerebral hemorrhage, and rapidly progressive dementia that presents with hereditary cerebral amyloid angiopathy (CAA). However, no treatment has been identified for CAA. Although liver transplantation has become an acceptable treatment of TTR-related amyloidosis, liver transplantation may not successfully treat CNS manifestations of the disorder. In this study, we examined the effect of liver transplantation on these manifestations of TTR-related CAA. Methods: We compared clinical courses of three patients with CAA associated with ATTR Tyr114Cys who underwent liver transplantation with those of five patients with the disorder who did not undergo liver transplantation. Results: The mortality and occurrence of cerebral hemorrhage and dementia in patients having transplantations were reduced compared with those in patients not having transplantations. The two groups did not differ with regard to the frequency of episodes of fluctuating consciousness and TIAs. The group undergoing transplantations had significantly smaller volumes of intracranial hemorrhage than did the no-transplantation group. Conclusion: Liver transplantation was effective for CNS manifestations of cerebral amyloid angiopathy associated with amyloidogenic transthyretin Tyr114Cys.

Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014.

This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype–phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.

Long-Term Outcome of Polymyositis Treated with High Single-Dose Alternate-Day Prednisolone Therapy

Background: We previously reported no difference in the efficacies of high-dose alternate-day (ADT) and daily-dose (DDT) prednisolone therapies in myositis patients, but that the incidence of side effects was lower in the former. The aim of the present study was to compare the long-term outcomes of both treatments in polymyositis patients. Methods: We compared clinical courses, efficacies, adverse reactions, and outcomes of 115 consecutive, biopsy-proven polymyositis patients treated between 1970 and 2008 with ADT (32 patients) or DDT (83 patients). Results: Mean onset ages, disease severity, incidences of malignancy, and response rates did not differ between the ADT and DDT groups. Adverse reactions (incidence of diabetes) were significantly higher in the DDT group. In this group, the incidences of hyperlipidemia, infection, hypertension, and psychiatric symptoms were also slightly higher, but not significantly so. The 20-year survival rate of the ADT group (68%) was significantly higher (p = 0.0112) than that of the DDT group (37%). Conclusion: ADT might be useful as an initial treatment option for polymyositis.

Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation

Abstract Background: Liver transplantation halts production of mutated transthyretin (TTR), and thus it is an accepted treatment, with improved survival, in patients with hereditary (familial) amyloidosis with polyneuropathy (FAP). However, the effects of transplantation on the clinical manifestations of FAP have not yet been adequately clarified. This study aimed to investigate whether liver transplantation would improve the long-term clinical manifestations in FAP patients who had undergone transplantations. Patients and methods: We assessed 29 non-transplant and 36 transplant FAP V30M patients using an FAP clinical scoring system. Results: The total clinical score of the non-transplant group increased and was significantly correlated with FAP duration; that of the transplant group increased slowly after transplantation. In patients 5 years or more after FAP onset, the total clinical scores of the transplant group were significantly lower than those of the non-transplant group. In the same patients, scores for sensory, motor, autonomic and organ impairments of the transplant group were significantly lower than those of the non-transplant group. Conclusions: Liver transplantation had beneficial effects on FAP clinical manifestations in patients with FAP TTR V30M. Liver transplantation should therefore be considered as an effective treatment in the clinical management of patients with FAP TTR V30M.

Detection of granular osmiophilic material of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy by light microscopy in frozen sections.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-artery disease of mid-adulthood [1,2]. CADASIL is responsible for recurrent subcortical ischaemic events and leads progressively to dementia with pseudobulbar palsy [3,4]. The pathological basis of the disease is nonamyloid, nonarteriosclerotic microangiopathy with small arterial granular degeneration [5–10]. The disease is caused by mutations of the Notch3 gene, which cause an accumulation of the ectodomain of this receptor within the vascular wall [11]. Small arterial granular degeneration and granular osmiophilic material (GOM) are characteristic morphological findings of CADASIL [5–14]. At the light microscopic level, small arterial granular degeneration has been described as a band of smudgy slightly basophilic, periodic acid-Schiff (PAS)-positive granular materials in the tunica media of cerebral arteries, but not observed in skin and skeletal muscle [6,8]. In contrast, GOM deposits are found in the brain and in the extracerebral organs by electron microscopy [8]. However, GOM deposits are not easily detected in paraffin sections of extracerebral organs by light microscopy [8,13]. It remains unknown if GOM deposits are detectable in frozen sections of extracerebral organs by light microscopy. In the present study, we aimed to find evidence of GOM characterized by its size and location using PAShaematoxylin staining in frozen section of skeletal muscle and skin by light microscopy. Brain, skeletal muscle and skin autopsy samples were obtained from patient one, a 62-year-old man who was diagnosed as CADASIL with Notch3 R133C mutation. His skeletal muscle biopsy was performed at 50 years of age [15]. Skeletal muscle and skin biopsy samples were obtained from the other two patients with CADASIL. Patient two was a 53-year-old woman with Notch3 R133C mutation and patient three was a 59-year-old man with Notch3 R449C mutation. Electron microscopic examination in skin and skeletal muscle showed abnormal deposition of GOM in the three CADASIL patients. As controls, we used biceps muscle or skin obtained from 10 patients with other neuromuscular disorders, such as amyotrophic lateral sclerosis, polymyositis, dermatomyositis and three patients with cerebrovascular disease. For histochemical analysis, 10-mm frozen sections were stained with the PAS-haematoxylin stain. Ten-mm frozen sections were fixed on glass slides for 10 min in the refrigerator with Carnoy’s fixing fluid, which consists of 60% ethanol, 30% chloroform and 10% acetic anhydride. We made the following modification to the PAS-haematoxylin stain to distinguish the basophilic feature of granules from PAS-positive features of the basal laminas. The incubation times of the PAS reaction and haematoxylin stain were adjusted to reduce PAS reactivity of the basal laminas of vascular smooth muscle cells (VSMCs) and to enhance the basophilic features of the granules. For example, the incubation time for the PAS reaction was reduced to 2–5 min (usually 10–20 min) and the haematoxylin staining time (usually 30 s) was increased to a routine haematoxylin and eosin staining, which is 2 min. Harris-haematoxylin was used. Then, the sections were washed in water for less than 2 min, because the longer washing time lightened the basophilic staining of granules. We carefully scanned the arterial walls to detect GOM by light microscopy using a ¥100 objective lens using oil immersion. Electron microscopic analyses and light microscopic examinations with semithin sections were performed as routine procedures. For immunohistochemical analysis with light microscopy, 10-mm frozen sections of skeletal muscle were fixed on glass slides with 4% paraformaldehyde in phosphatebuffered saline for 30 min. Endogenous peroxidase activity was eliminated by washing with 3% H2O2 in methanol for 30 min. The sections were incubated overnight in antibodies against the extracellular domain and the intracellular domain of Notch3 at a dilution of 1 mg/ml [10,16,17]. Then, the sections were incubated for 1 h

A novel type of familial transthyretin amyloidosis, ATTR Asn124Ser, with co-localization of κ light chains

A 68-year-old Italian woman who had a clinical history of thyroidectomy in 2002 presented with slowly progressing renal insuffiency and non-nephrotic proteinurea in 2004. A renal biopsy showed the occurrence of amyloid; the thyroid biopsy previously taken also revealed amyloid infiltration. Other amyloid-containing tissues included bone marrow and heart. The plasma cell level in the bone marrow was found to be less than 5% and both serum and urine samples were positive for a monoclonal κ light chain band. DNA analysis unexpectedly revealed the presence of a novel transthyretin (TTR) mutation, ATTR Asn124Ser. Histologically, amyloid deposits in the thyroid had a homogeneous appearance with moderate Congophilia. In immunohistochemistry, a κ light chain antiserum showed positive immunoreactivity with amyloid deposits in the thyroid. Furthermore, a TTR antiserum, anti-TTR50-127, also recognized a number of amyloid deposits stained positive with the κ light chain antiserum. Overall, the κ light chain antiserum reacted with most of the amyloid deposits in the thyroid, whereas TTR immunoreactivity was scarcer, with a scattered appearance. In contrast, only the anti-TTR50-127 antiserum labeled amyloid in the kidney, albeit not all deposits. In this study, we report a patient having a novel TTR variant, ATTR Asn124Ser, with co-localization of κ light chains in the amyloid deposits in the thyroid tissue.

Drastic therapy for listerial brain abscess involving combined hyperbaric oxygen therapy and antimicrobial agents.

Background Listeria monocytogenes (L. monocytogenes) is a rare causative pathogen of brain abscess that is often found in immunocompromised patients. Although patients with supratentorial listerial abscesses showed a longer survival with surgical drainage, the standard therapy for patients with subtentorial lesions has not been established. Case Report We report herein a patient with supra- and subtentorial brain abscesses caused by L. monocytogenes infection. These abscesses did not respond to antibiotics, and his symptoms gradually worsened. Drainage was not indicated for subtentorial lesions, and the patient was additionally treated with hyperbaric oxygen therapy, which dramatically reduced the volume of abscesses and improved the symptoms. Conclusions This is the first report of drastic therapy for a patient with listerial brain abscesses involving combined antibiotics and hyperbaric oxygen therapy. The findings suggest that hyperbaric oxygen therapy is a good option for treating patients with deep-seated listerial abscesses and for who surgical drainage is not indicated.

Muscle biopsy findings predictive of malignancy in rare infiltrative dermatomyositis

OBJECTIVE The characteristic pathological muscular findings of polymyositis (PM) and dermatomyositis (DM) have been shown to reflect their different pathogeneses. Here, we characterized the muscle biopsy findings of PM and DM patients with or without malignancy. METHODS We evaluated the muscle biopsy findings of 215 consecutive PM and DM patients admitted to our hospital between 1970 and 2009. Pathology of the lesion biopsy sections was classified into 3 types: endomysial infiltration-type, perivascular infiltration-type, and rare-infiltrative-type. RESULTS There was no difference between the muscle pathology of PM patients with and without malignancy. However, the incidence of rare-infiltrative type muscle pathology in DM patients with malignancy was significantly higher than in those without such tumors (p=0.0345). CONCLUSION The incidence of rare-infiltrative type muscle pathology may be a predictive marker of DM with malignancy.

Therapeutic effects and prevention of recurrence of acquired idiopathic generalized anhidrosis via i.v. immunoglobulin treatment.

Dear Editor, Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis occurs in the absence of any causative skin, metabolic or neurological disease. Although the reasons that only sweat glands are disturbed in patients with AIGA and the specific mechanisms of sweat gland impairment are still unknown, autoimmune mechanisms are believed to play an important role in the development of AIGA. Thus, AIGA treatments almost always involve steroid and/or cyclosporin administration. However, these treatments have insufficient efficacy, as shown by long-term follow up of patients with the disease. Ohshima reported that 35.7% of the patients with AIGA had recurrences after steroid pulse therapy or high-dose oral steroid therapy. To prevent recurrent disease, we must thus develop novel therapies for AIGA. This study aimed to evaluate the therapeutic effects of i.v. immunoglobulin G (IVIG) and the possibility of preventing the recurrence of AIGA with IVIG treatment. Two Japanese patients (a 53-year-old woman and a 28year-old man) with AIGA who could not use steroid drugs or who did not improve after steroid therapy were chosen for evaluation. In both cases, i.d. injection of acetylcholine did not elicit any sweating, and thermoregulatory sweat testing in an artificial climate with a room temperature of 40°C revealed generalized anhidrosis. In addition, histopathological examination of an anhidrotic lesion of the left forearm skin revealed no remarkable lymphocytic infiltration around the sweat glands (Fig. 1a). They had had no specific viral illness before