Clinical features of acute attacks, chronic symptoms, and long-term complications among patients with acute hepatic porphyria in Japan: a real-world claims database study.

BACKGROUND: Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase-deficient porphyria. The objective of this retrospective cohort study was to provide information on the clinical features of AHP in Japan-including acute attacks, chronic symptoms, and long-term complications. METHODS: Patients with AHP between April 2008 and June 2020 were selected from Japan's Medical Data Vision claims database. Patients with AHP were matched 1:10, by sex and age, to patients without AHP. The outcomes were evaluated overall, for patients age ≥ 55 years, and for the matched population. RESULTS: A total of 391 patients with AHP were included from the Japanese Medical Data Vision database. During the observation period (April 2008-June 2020), 18.2% (71/391) of patients experienced 1 acute attack and 10.5% (41/391) experienced ≥ 2 attacks. Chronic symptoms with rates ~ 10% or higher in the AHP population compared with the matched population included neurotic, stress-related, and somatoform disorders (21.7% vs. 6.7% [15.0% difference]); sleep disorders (23.0% vs. 9.9% [13.1% difference]); other and unspecified abdominal pain (13.6% vs. 3.7% [9.9% difference]); and nausea and vomiting, excluding chemotherapy-induced emesis (17.9% vs. 8.1% [9.8% difference]). Long-term complications with higher incidence rates in the AHP population compared with the matched population included fibrosis and cirrhosis of liver (15.9% vs. 3.0% [12.9% difference]), polyneuropathies and other disorders of the peripheral nervous system (20.5% vs. 7.9% [12.6% difference]), liver cancer (16.9% vs. 4.7% [12.2% difference]), renal failure (16.4% vs. 4.3% [12.1% difference]), and hypertension (26.1% vs. 18.8% [7.3% difference]). Among AHP patients age ≥ 55 years, the most common long-term complications were hypertension, kidney failure, and liver cancer. CONCLUSIONS: In Japan, patients with AHP experience a high clinical burden in terms of acute attacks, chronic symptoms, and long-term complications. The clinical burden related to chronic symptoms and long-term complications was substantially higher in Japanese patients with AHP compared with a matched population without AHP. Recognizing these signs and symptoms of AHP may aid physicians in making an earlier diagnosis, which may help patients avoid attack triggers, implement disease management, and reduce lifetime disease burden.

Clinical features of Japanese patients with acute hepatic porphyria.

Acute hepatic porphyria (AHP) is a family of rare genetic diseases of heme biosynthesis characterized by severe neurovisceral attacks. The clinical characteristics of patients with AHP as well as the prevalence of AHP in Japan are not well understood. The objectives of this study were to describe clinical characteristics of AHP at time of diagnosis in Japanese patients and to estimate the prevalence of AHP. Patients with porphyria were selected from Japan's Medical Data Vision health care claims database between April 2008 and June 2020. Patient characteristics before and at time of AHP diagnosis were evaluated. Prevalence per 100 000 was estimated during the study period. A total of 391 cases of AHP were included. At time of AHP diagnosis, mean age was 44 years, and the most common type was acute intermittent porphyria. Median time to diagnosis was 3 months, but some patients remained undiagnosed for several years. The most common complications included metabolic disorders (54%) and diabetes mellitus (39%). In addition, the well-known complications of AHP, including hypertension (22%) and malignant neoplasms of digestive organs (22%), were observed. About 10% of patients received medications that may have aggravated porphyria attacks. The estimated prevalence of AHP in Japan during the study period was 1.18 cases per 100 000 population. At time of diagnosis, many patients with AHP in Japan are already experiencing a high burden of disease-related complications. Raising AHP awareness may aid physicians in providing an earlier diagnosis and reducing lifetime disease burden.

Effect of Simultaneous Dual-Task Training on Regional Cerebral Blood Flow in Older Adults with Amnestic Mild Cognitive Impairment.

BACKGROUND: No previous study has examined the effect of dual-task training using changes in regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) as an outcome. OBJECTIVE: This study aimed to examine the effects of simultaneous dual-task training of exercise and cognitive tasks on rCBF using SPECT in older adults with amnestic mild cognitive impairment (aMCI). METHODS: In this non-randomized control trial, 40 older adults with aMCI participated from May 2016 to April 2018. Outpatients in the intervention group (n = 22) underwent 24 sessions (12 months) of dualtask training twice a month for 60 mins per session. Participants in the control group (n = 18) continued to have regular outpatient visits. The primary outcome was rCBF at baseline and after 12 months, which was compared in each group using the two-sample t-test. The secondary outcomes were the rate of reversion and conversion from aMCI after 12 months. RESULTS: Of the 22 participants in the intervention group, six dropped out; therefore, 16 were included in the analysis. The intervention group showed more significant increases in rCBF in multiple regions, including the bilateral frontal lobes, compared with the control group. However, the rates of reversion or conversion from mild cognitive impairment (MCI) were not significantly different. CONCLUSION: Dual-task training for older adults with aMCI increased rCBF in the frontal gyrus but did not promote reversion from MCI to normal cognition. Future intervention studies, such as follow-up examinations after the intervention, are warranted to consider long-term prognosis.

Trousseau's Syndrome Presenting as Multiple Cerebral Infarctions Caused by Mucin-producing Bladder Micropapillary Urothelial Cancer.

We herein report a 70-year-old man with recurrent multiple cerebral infarctions under warfarin therapy who was finally diagnosed with Trousseau's syndrome resulting from advanced bladder cancer. A histological examination of the mesenteric lymph nodes revealed metastasis of micropapillary urothelial cancer with positive mucin markers CA125 and MUC1. Blood examinations also indicated elevated tumor markers, such as CA19-9 and CA125. To our knowledge, this is the first report of Trousseau's syndrome in a patient with bladder micropapillary urothelial cancer in which mucin involvement was clearly proven by histological and serological examinations.

Characteristics of Regional Cerebral Blood Flow in Alzheimer Disease and Amnestic Mild Cognitive Impairment by Single-Photon Emission Computerized Tomography: A Cross-Sectional Study.

INTRODUCTION: The regional cerebral blood flow (rCBF) distribution can affect brain functioning, leading to amnestic mild cognitive impairment (aMCI) and mild Alzheimer disease (AD). This study aimed to clarify the detailed characteristics of rCBF distribution in patients with mild AD and aMCI. METHODS: This cross-sectional study from April 2015 to March 2018 included 103 older adults (mean age 78.9 years; 60% females), out of a total of 302 adults, and categorized them into 3 groups according to cognitive symptoms. The normal control (NC), aMCI, and mild AD groups included 20, 50, and 33 participants, respectively. The primary outcome was rCBF, which was compared among the 3 groups using a 2-sample t test without correction for multiple comparisons. RESULTS: In the aMCI group, the rCBF decreased in the bilateral parietal and left frontal association cortex and the bilateral premotor cortex (p < 0.01) but increased in the bilateral cerebellum (p < 0.01). In the mild AD group, the rCBF decreased in the bilateral parietal and occipital association cortex, the bilateral premotor cortex, the left temporal and frontal association cortex, and the left limbic lobe (p < 0.01). Conversely, the rCBF increased in some parts of the cerebellum, the bilateral frontal and temporal association cortex, the left occipital association cortex, and the right premotor cortex (p < 0.01). CONCLUSION: Based on the analysis of the values obtained, it was inferred that the rCBF undergoes reduction and elevation in aMCI and AD patients.

Homeless Patients with Lung Cancer in Metropolitan Tokyo.

Background Homeless persons are those who carry out their activities of daily living in city parks and other facilities. Little is known about homeless patients with lung cancer in Japan. Therefore, we characterized the clinical features and outcomes of homeless people in metropolitan Tokyo. Methods Between January 2014 and August 2018, 2,068 homeless patients were admitted to the homeless patient care unit at Tokyo Saiseikai Central Hospital. Of these, 13 patients were treated for primary lung cancer. We retrospectively analyzed the patients' clinical characteristics, including their age, gender, treatment, and outcome, obtained from the hospital's electronic medical records. Results A total of 13 patients were treated for lung cancer. The median age was 66.2 (range, 51-77) years old. Twelve patients (92.3%) were smokers. All of the patients were men and had advanced lung cancer. Of these, four patients had adenocarcinoma, four had squamous carcinoma, and four had other histologies. Ten patients received chemotherapy, and 3 received chemoradiotherapy (carboplatin, n=8; cisplatin, n=2, immune check point inhibitor, n=2; other, n=1). Of the patients on first-line treatment, 58% discontinued treatment, with 71% doing so willfully. The median overall survival was 7.5 (1-44) months. During the study, nine patients died in the hospital, and four were lost to follow up. Conclusion It is difficult for homeless patients to continue chemotherapy, and they often quit therapy willfully. Therefore, it is necessary to develop an education and health insurance support system to ensure treatment continuity in a good social environment.

Detection of Bartonella quintana Infection among the Homeless Population in Tokyo, Japan, from 2013-2015.

Several outbreaks of trench fever caused by Bartonella quintana occurred in soldiers during World Wars I and II. Although trench fever cases have been decreasing worldwide, the disease was reported among the homeless population in developing and developed countries. The current prevalence of B. quintana infection in Japan is unclear. Blood and body louse (Pediculus humanus humanus) samples were obtained from homeless inpatients with body lice during emergency hospitalization in Tokyo from January 2013 to March 2015. Patients were tested for B. quintana infections using the culture method, polymerase chain reaction, and indirect immunofluorescence assay (IFA). Among the 29 patients tested, the presence of Bartonella spp. was confirmed by genomic sequencing of DNA extracted from two samples from blood culture performed for 15 out of 29 patients and from body louse samples of 20 patients (69%). Immunoglobulin G against B. quintana was detected in 10 patients (34.5%) at a cut-off titer of 1:256 in IFA. B. quintana infection was detected in samples obtained between 2013 and 2015 in Tokyo and needs to be on the list of differential diagnoses performed for febrile homeless individuals.

Breakthrough and persistent bacteremia due to serotype K1 Klebsiella pneumoniae in an immunocompetent patient.

Herein, we report a case of breakthrough and persistent bacteremia due to serotype K1 Klebsiella pneumoniae in an immunocompetent 53- year-old man. He was diagnosed with pyogenic spondylitis owing to back pain and based on magnetic resonance imaging findings. On admission, several imaging studies were taken to search for other abscesses and infective endocarditis; however, there were no significant findings. Additionally, blood cultures were negative. Upon treatment with intravenous ampicillin/sulbactam, the patient's symptoms improved. However, eleven days after admission, the patient experienced a fever and worsening back pain. Blood cultures were taken again, and K. pneumoniae was detected, which showed sensitivity to ampicillin/sulbactam. Fourteen days after admission, K. pneumoniae was detected again, suggesting breakthrough and persistent bacteremia with K. pneumoniae. The source of the K. pneumoniae infection was unknown. The antimicrobial regimen was changed to a combination of ceftriaxone and gentamicin. Sixty days after admission, the patient was discharged without any sequelae. The isolated K. pneumoniae strains were found to carry rmpA and were confirmed as serotype K1; thus, detected hypervirulent K. pneumoniae (HvKP). HvKP is an increasingly recognized pathotype of K. pneumoniae characterized clinically by its ability to cause organ- or life-threatening infections in healthy persons. To the best of our knowledge, our case is the first report of spondylitis due to confirmed HvKP. Moreover, HvKP caused breakthrough and persistent bacteremia on an immunocompetent patient.

A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene. Patients with ALD show progressive central nervous system demyelination and primary adrenal insufficiency. In Japan, most reported ALD cases were childhood-onset, and only one case of an adult patient with Addison's disease form of ALD has ever been reported. Herein, we present a case of a 29-year-old man with Addison's disease form of ALD. The patient had anorexia, weight loss, and skin pigmentation from 18 years of age. At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old. Endocrinological examination showed low serum cortisol (1.2 µg/dL) with high plasma ACTH (4,750 pg/mL), and abdominal computed tomography showed normal adrenal glands. Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state. He had no significant neurological findings on physical examination and no white matter lesions on brain magnetic resonance imaging (MRI). He was diagnosed with ALD presenting as Addison's disease, and glucocorticoid replacement therapy was initiated. Four years after the diagnosis, he still did not show any neurological findings and any white matter lesions on brain MRI. Evaluating VLCFA levels for ALD diagnosis is important in young adult men with idiopathic primary adrenal insufficiency as well as in children. Early diagnosis enables more rational approaches including the early detection of neurological complications and might improve the prognosis of patients.

Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrhage.

OBJECTIVE: Whether intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOAC-ICH) has a better outcome compared to ICH associated with vitamin K antagonists (VKA-ICH) is uncertain. METHODS: We performed a systematic review and individual patient data meta-analysis of cohort studies comparing clinical and radiological outcomes between NOAC-ICH and VKA-ICH patients. The primary outcome measure was 30-day all-cause mortality. All outcomes were assessed in multivariate regression analyses adjusted for age, sex, ICH location, and intraventricular hemorrhage extension. RESULTS: We included 7 eligible studies comprising 219 NOAC-ICH and 831 VKA-ICH patients (mean age = 77 years, 52.5% females). The 30-day mortality was similar between NOAC-ICH and VKA-ICH (24.3% vs 26.5%; hazard ratio = 0.94, 95% confidence interval [CI] = 0.67-1.31). However, in multivariate analyses adjusting for potential confounders, NOAC-ICH was associated with lower admission National Institutes of Health Stroke Scale (NIHSS) score (linear regression coefficient = -2.83, 95% CI = -5.28 to -0.38), lower likelihood of severe stroke (NIHSS > 10 points) on admission (odds ratio [OR] = 0.50, 95% CI = 0.30-0.84), and smaller baseline hematoma volume (linear regression coefficient = -0.24, 95% CI = -0.47 to -0.16). The two groups did not differ in the likelihood of baseline hematoma volume < 30cm3 (OR = 1.14, 95% CI = 0.81-1.62), hematoma expansion (OR = 0.97, 95% CI = 0.63-1.48), in-hospital mortality (OR = 0.73, 95% CI = 0.49-1.11), functional status at discharge (common OR = 0.78, 95% CI = 0.57-1.07), or functional status at 3 months (common OR = 1.03, 95% CI = 0.75-1.43). INTERPRETATION: Although functional outcome at discharge, 1 month, or 3 months was comparable after NOAC-ICH and VKA-ICH, patients with NOAC-ICH had smaller baseline hematoma volumes and less severe acute stroke syndromes. Ann Neurol 2018;84:702-712.

Volume and Characteristics of Intracerebral Hemorrhage with Direct Oral Anticoagulants in Comparison with Warfarin
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BACKGROUND: Patients undergoing anticoagulation therapy often experience intracerebral hemorrhages (ICHs), and warfarin in particular is known to increase hematoma expansion in ICHs, which results in a poor outcome. Recent studies reported that, in comparison with warfarin, direct oral anticoagulants (DOACs) cause fewer ICHs with better functional outcome. However, since it is still unknown whether DOACs are associated with a smaller hematoma volume of ICHs, we aimed to compare the volume, hematoma expansion, and outcomes associated with ICHs treated with DOACs and warfarin. METHODS: We performed a prospective multicenter cross-sectional study. The subjects included patients with acute ICHs who received either DOACs or warfarin. We evaluated the clinical characteristics, and measured initial and follow-up ICH volumes. The volume of ICHs and hematoma expansion were compared between the DOAC and warfarin groups. Mortality and modified Rankin score at discharge were evaluated as outcomes. RESULTS: There were 18 patients in the DOAC group and 71 in the warfarin group. The baseline characteristics were similar between the 2 groups. Initial median hematoma volume of ICHs in the DOAC group was significantly lower than that in the warfarin group (6.2 vs. 24.2 mL, respectively; p = 0.04). In cases involving follow-up computed tomography scanning, the median hematoma volume of ICHs at follow-up was lower in the DOAC group than in the warfarin group (initial: DOACs 4.4 vs. warfarin 13.5 mL; follow-up: 5.0 vs. 18.4 mL, respectively; p = 0.05). Further, the hematoma in ICHs associated with DOACs did not expand. Although the mortality of ICHs associated with DOACs (11%) was lower than that associated with warfarin (24%), this difference was not statistically significant. The univariate analysis showed that the anticoagulant type (DOACs vs. warfarin) and sex (male vs. female) were associated with ICH volume. The multivariable linear regression showed that the use of DOACs (compared to warfarin; ß: -0.23, p = 0.03) and female sex (compared to male; ß: -0.25, p = 0.02) were associated with a small hematoma volume. CONCLUSIONS: Based on the results of the present study, in terms of the risks associated with ICHs, the use of DOACs appears to be safer than warfarin for anticoagulation therapy. Further studies are required to validate these findings.
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Frequency and pathogenesis of silent subcortical brain infarction in acute first-ever ischemic stroke.

OBJECTIVES: We have often observed silent subcortical brain lesions on CT or MRI in first-ever ischemic stroke, but there is little published information on the relationship of these lesions to stroke subtypes. Here, we describe the incidence of MRI-detected silent subcortical brain lesions, including infarctions and white matter lesions, in a series of patients with first-ever ischemic stroke classified according to stroke subtypes. We also discuss the pathogenesis of these silent subcortical lesions. PATIENTS: We evaluated 171 patients with acute first-ever ischemic stroke. METHODS: The subjects were divided into three groups: lacunar, atherothrombotic and cardioembolic infarction groups. We evaluated silent subcortical brain infarction (SSBI), enlargement of perivascular space (EPS), and other white-matter lesions using MRI. RESULTS: Hypertension was observed in 67.6% of lacunar infarction, 57.1% of atherosclerotic infarction, and 54.1% of cardioembolic infarction. SSBI was more frequently observed in lacunar infarction than the others (lacunar vs. atherothrombotic vs. cardiogenic infarction, 81.5% vs. 44.4% vs. 42.1%, p=0.006). High-grade EPS (grade 2 or higher) was also observed more frequently in lacunar infarction than in the others (lacunar vs. atherothrombotic vs. cardiogenic infarction, 63.3% vs. 24.2% vs. 0%, p<0.001). Scheltens' score of silent subcortical lesions was significantly higher in lacunar infarction than in the others. CONCLUSIONS: The frequency of silent subcortical ischemic brain lesions was significantly higher in lacunar infarction than in atherosclerotic or cardioembolic infarction. We suggest that the pathogenesis of silent subcortical ischemic brain lesions is common to that of lacunar infarction, that is, small-vessel vasculopathy.