Factors influencing the development of infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion.

BACKGROUND: Infantile traumatic brain injury (TBI) with a biphasic clinical course and late reduced diffusion (TBIRD) has been reported as a type of TBI. However, it remains uncertain which pediatric patients with TBI develop TBIRD. METHODS: Patients with TBI who were admitted to our hospital and underwent magnetic resonance imaging (MRI) between December 2006 and October 2022 were included in this study. A diagnosis of TBIRD was made in patients with or suspected TBI, with initial symptoms being convulsions or disturbance of consciousness and late-onset subcortical reduced diffusion, the so-called bright tree appearance. Clinical features, neuroimaging (computed tomography (CT) and MRI) findings, laboratory data, and Tada score were retrospectively compared between TBIRD and non-TBIRD patients. Neurological prognosis was assessed using the Pediatric Cerebral Performance Category scale. RESULTS: Of 21 patients who met the inclusion criteria, a diagnosis of TBIRD was made in 7 patients (median age: 8 months). The factors contributing to TBIRD development were seizures lasting over 30 min as the initial symptom (5/7 in TBIRD vs. 0/14 in non-TBIRD), tracheal intubation during initial treatment (5/7 vs. 0/14), and brain parenchymal lesions on CT (3/7 vs. 0/14), suggesting that severe TBI may progress to TBIRD. The Tada score was more positive in patients with TBIRD (6/7) than in those without (0/14). CONCLUSIONS: It is important to monitor infant patients with severe TBI for the development of TBIRD. The Tada score can be a useful tool for TBIRD prediction.

Synthesis and structure of photodegradable 1-(4,5-dimeth-oxy-2,3-di-nitro-phen-yl)-2-methyl-propyl N-butyl-carbamate.

The reaction of 1-(4,5-dimeth-oxy-2,3-di-nitro-phen-yl)-2-methyl-propan-1-ol and butyl-iso-cyanate using di-butyl-tin dilaurate as a catalyst afforded 1-(4,5-dimeth-oxy-2,3-di-nitro-phen-yl)-2-methyl-propyl N-butyl-carbamate, C17H25N3O8, which released butyl-amine upon photoirradiation. Single crystals of the title compound were grown in a 1:1 mixed solution of hexane and ethyl acetate. Two nitro groups and one meth-oxy group are twisted out of the plane of the aromatic ring in the novel photo-protecting group. Inter-molecular hydrogen bonds are observed between N-butyl-carbamate moieties parallel to the a axis.

The impact of vitamin D on the onset and progress of Kawasaki disease.

BACKGROUND: The seasonal epidemic of Kawasaki disease (KD) in winter in Japan suggests that low vitamin D status may affect KD through the immune system. We aimed to evaluate the effect of vitamin D on the onset and clinical course of KD. METHODS: We conducted a case-control study to compare 25-hydroxyvitamin D (25(OH)D) levels in KD patients admitted to our hospital between March 2018 and June 2021, with those in healthy controls from published Japanese data. In patients with KD, we evaluated the association of 25(OH)D levels with intravenous immunoglobulin resistance and coronary artery lesions. RESULTS: We compared 290 controls and 86 age-group-adjusted patients with KD. The 25(OH)D levels in KD patients were lower than those in the controls (median: 17 vs. 29 ng/mL, P < 0.001). In winter, 25(OH)D levels in KD patients were lower than those in summer (median: 13 vs. 19 ng/mL). The adjusted odds ratios for the onset of KD were 4.9 (95% CI: 2.5-9.6) for vitamin D insufficiency (25(OH)D: 12-20 ng/mL) and 29.4 (95% CI: 12.5-78.2) for vitamin D deficiency (25(OH)D < 12 ng/mL). Among 110 KD patients, 25(OH)D levels at diagnosis of KD were not associated with intravenous immunoglobulin resistance or coronary artery lesions. CONCLUSIONS: The 25(OH)D levels in patients with KD were lower than those in the controls, especially in winter. Lower 25(OH)D levels in winter were associated with an increased risk of KD onset. It remains to be elucidated whether the observed association has a causal relationship.

Kawasaki Disease Shock Syndrome in Japan and Comparison With Multisystem Inflammatory Syndrome in Children in European countries.

Multisystem inflammatory syndrome in children (MIS-C) is a severe Kawasaki-like illness that was first linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in European countries in the spring of 2020 and has been suggested to have overlap with Kawasaki disease shock syndrome (KDSS). There are few reports of MIS-C from Asia. This observational study aimed to identify the clinical features in children presenting with KDSS in Japan over a 5-year period and to summarize similarities and differences between KDSS and MIS-C. We retrospectively collected data on patient characteristics, clinical signs and symptoms, treatment, and prognosis including coronary artery abnormalities (CAAs), which were compared with data of patients with KDSS worldwide and patients with MIS-C from a review. KDSS was identified in 6 (1.1%) of 552 patients with Kawasaki disease (KD) treated at a single institution in Japan between 2015 and 2020 (1 in 2020). In patients with KDSS in Japan or worldwide vs. patients with MIS-C, KDSS was more likely to have a diagnosis of complete KD (100, 70 vs. 6.3%), a higher incidence of CAAs (50, 65 vs. 11%), and a greater requirement for vasoactive agonists (67, 67 vs. 43%) because of circulatory shock (100, 50 vs. 26%). Both KDSS and MIS-C had good prognosis (mortality 0, 6.7 vs. 1.7%). Although KDSS in Japan and MIS-C show some overlap in clinical symptoms, they are unlikely to be the same disease entity. KDSS is more likely to have a cardiovascular phenotype with CAAs and requires treatment with cardiovascular agents.

Panton-Valentine leukocidin-positive novel sequence type 5959 community-acquired methicillin-resistant Staphylococcus aureus meningitis complicated by cerebral infarction in a 1-month-old infant.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a pathogen of major importance in pediatric patients. CA-MRSA can cause skin and soft tissue infection in children and young active adults with no predisposing factors, and life-threatening infections such as meningitis or necrotizing pneumonia have been reported. We report here a case of CA-MRSA meningitis complicated by acute left middle cerebral artery (MCA) infarction and necrotizing pneumonia in a previously healthy 1-month-old Vietnamese boy. He was firstly treated with vancomycin, but changed to linezolid because of persistent fever and low vancomycin trough level. He recovered successfully with residual right-sided hemiparesis. The mode of transmission of CA-MRSA and the mechanism of cerebral infarction (thrombotic or embolic) were unknown. The isolate was genotyped as staphylococcal cassette chromosome (SCC) mec type V with a novel sequence type (ST) 5959 harboring the Panton-Valentine leukocidin (PVL) gene. ST 5959 is a double locus variant of ST 59, which is a major PVL-positive CA-MRSA strain isolated in invasive disease in Asian countries. This case report may serve as a warning about the dissemination of PVL-positive CA-MRSA in and around Japan, with the possibility of causing serious life-threatening disease. The potential of linezolid for the treatment of MRSA meningitis as one of the alternative MRSA therapeutic drugs is also discussed.

Aspirin Dose and Treatment Outcomes in Kawasaki Disease: A Historical Control Study in Japan.

Aspirin has been used as a concomitant drug in the treatment of Kawasaki disease (KD). In recent years, there has been discussion concerning whether high-dose aspirin is appropriate for treatment in the acute phase of KD. We retrospectively investigated the incidence of coronary artery abnormalities (CAAs) and the antipyretic effect of 30 to 50 mg/kg/day aspirin, the minimum and the maximum approved doses in Japan. This was a single-center, non-randomized, retrospective, historical cohort study. Patients were routinely treated with 50 mg/kg/day aspirin (50-mg Group) between 2007 and April 2014, and with 30 mg/kg/day aspirin (30-mg Group) between May 2014 and 2016. All patients were given initial and, if necessary, subsequent intravenous immunoglobulin (IVIG) 2.0 g/kg. The primary endpoint was incidence of CAAs defined as a CA diameter with a Z score ≥2.5 at treatment week 4. The secondary endpoint was incidence of further treatment. Incidences were compared using inverse probability weighting analysis adjusting for age, sex, and risk scores. In 587 patients, there was no significant difference in incidence of CAAs (odds ratio in 30-mg Group 0.769, 95% confidence interval (CI): 0.537-1.101, p = 0.151). Risk of further treatment after the first IVIG in the 30-mg Group was significantly higher than that in the 50-mg Group (odds ratio 1.379, 95% CI: 1.051-1.811, p = 0.021). Although this study has some limitations, the findings suggest that aspirin 50 mg/kg/day may have no significant effect on improving incidence of CAAs compared with 30 mg/kg/day but may have a lower rate of further treatment.

IgG levels in Kawasaki disease and its association with clinical outcomes.

Previous studies have suggested an association of IgG levels (before and after IVIG infusion) with clinical outcomes in Kawasaki disease. A retrospective analysis was performed that included 418 patients with KD admitted to Tokyo Women's Medical University Yachiyo Medical Center to evaluate pre- and post-IVIG IgG levels and its relation to outcomes. All patients received an initial IVIG infusion and aspirin; IgG levels were measured in 350 patients before IVIG (pre-IVIG IgG levels) and in 373 patients 48 h after starting IVIG infusion (post-IVIG IgG levels). Media and standard deviation of the pre- and post-IVIG IgG levels were reported and classified according to age. Also, IgG z-scores were calculated according to normal values of IgG by age. The number of cases and corresponding percentage of non-responders were reported by age and total patients. The association of pre-IVIG, post-IVIG IgG levels and post-IVIG IgG level/pre-IVIG IgG level ratio with no-response was evaluated by simple logistic regression model based on the IgG z-score, and regression coefficient, X2 value, p, and R2 of Nagelkerke were reported. Pre-IVIG and post-IVIG IgG levels presented an association with non-responders with statistical significance. This association was more evident between post-IVIG IgG levels and non-responders. Regarding coronary alterations, it was not possible to perform an adequate statistical analysis due the small number of patients. Pre- and post-IVIG infusion IgG levels could be an important biomarker in KD as well as in other inflammatory conditions. Higher IgG levels could be associated with a more effective immunomodulatory action and associated with better clinical outcomes.

Infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion.

Reduced diffusion in the subcortical white matter has been reported in some infants with traumatic brain injury (TBI), including abusive head trauma. However, the pathomechanisms of the lesions and clinical features are uncertain. We herein report two infants with TBI who presented with biphasic clinical courses and late reduced diffusion in the subcortical white matter, and reviewed seven clinically and radiologically similar patients with TBI. Their clinical features (secondary neurological symptoms on days 3 to 6) and radiological findings (normal diffusion on days 1 to 2, followed by reduced diffusion on days 3 to 6) are very similar to those observed in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). MR spectroscopy in one patient revealed a transient increase of glutamine, which is also observed in AESD, suggesting excitotoxicity as a possible pathomechanism.

Vital Signs as Predictor Factors of Intravenous Immunoglobulin Resistance in Patients With Kawasaki Disease.

Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) may significantly lower the frequency of coronary artery complications. However, some patients do not respond to initial therapy and are at higher risk of developing coronary artery lesion. A retrospective analysis of data from 419 KD patients was performed. The patients were divided into IVIG responders (n = 318) and IVIG nonresponders (n = 101). Multivariate logistic regression analysis revealed neutrophil percentage, albumin, aspartate aminotransferase, heart rate, and body temperature were independent predictors of IVIG resistance. We generated a predictive scoring system by assigning 1 point for the presence of these parameters (neutrophil >80%, albumin <3.4 g/dL, aspartate aminotransferase >100 IU/L, heart rate >146 bpm, and body temperature >38.8°C). This scoring system had a sensitivity of 76.2% and specificity of 64.8%, and a positive predictive value of 40.1% and a negative predictive value of 89.4%. Vital signs may be helpful to detect KD patients with IVIG resistance.

Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events.

Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

Excitotoxicity in encephalopathy associated with STEC O-157 infection.

Cytokines play an important role in the pathogenesis of the severe complications of Shiga toxin-producing Escherichia coli (STEC) infection, such as hemolytic uremic syndrome (HUS) and acute encephalopathy. A 3-year-old boy with acute encephalopathy associated with STEC O-157 HUS showed increased levels of IL-6 and IL-10, which normalized after methylprednisolone pulse therapy, and additionally exhibited a transient increase of glutamine on MR spectroscopy. This finding suggests that excitotoxicity, in addition to hypercytokinemia, may play an important role in the pathogenesis of HUS encephalopathy.

Clinically mild infantile encephalopathy associated with excitotoxicity.

Acute infectious encephalopathy is very frequently observed in children in East Asia including Japan. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype in Japan; however, more than 40% of the patients remain unclassified into specific syndromes. To investigate the underlying pathomechanism in those with unclassified acute encephalopathy, we evaluated brain metabolism by MR spectroscopy. Among 20 patients with acute encephalopathy admitted to our hospital during January 2015 to May 2016, 12 could not be classified into specific syndromes. MR spectroscopy was performed in 8 of these 12 patients with unclassified encephalopathy. MR spectroscopy showed an increase of glutamine with a normal N-acetyl aspartate level on days 3 to 8 in three of the 8 patients, which had normalized by follow-up studies. The three patients clinically recovered completely. This study suggests that excitotoxicity may be the underlying pathomechanism in some patients with unclassified mild encephalopathy.

Elevated taurine and glutamate in cerebral juvenile xanthogranuloma on MR spectroscopy.

MRI in a 2-year-old female presenting afebrile seizures and left blepharoptosis revealed multiple well-marginated round-shaped lesions, isointensity to gray matter on T1- and T2-weighted images with homogenously reduced diffusion and diffuse contrast enhancement. MRS revealed elevation of taurine, choline and glutamate, and reduction of N-acetylaspartate. A brain biopsy confirmed a diagnosis of juvenile xanthogranuloma (JXG). JXG should be considered when MR spectroscopy shows elevated taurine and glutamate, which has only previously been reported in medulloblastomas.

Variations in ORAI1 Gene Associated with Kawasaki Disease.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

WU polyomavirus detected in respiratory tract specimens from young children in Japan.

Polyomaviruses (PyV) WU and KI are reportedly associated with respiratory tract disease (RTD) worldwide but their incidence is unclear in Japan. In a 2 year prospective study, WU/KIPyV were detected in 48 (13.9%) and in five (1.4%) of 345 children hospitalized with lower RTD, respectively. The seasonal distribution was observed in spring and early summer. Other respiratory viruses were co-detected in 51% of PyV-positive patients, but eight (2.3%) of the WUPyV-positive patients were negative for other known pathogens.

Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan.

BACKGROUND: The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population. METHODS AND RESULTS: In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of ß-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high. CONCLUSIONS: Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.

Inflammatory cytokine profiles during Cyclosporin treatment for immunoglobulin-resistant Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis occurring in medium-sized arteries, especially coronary arteries. Patients with KD who fail to respond to standard therapy with intravenous immunoglobulin (IVIG) face a higher risk of developing coronary artery lesions. Cyclosporin A (CsA) is one treatment option for IVIG-resistant KD. However, the mechanism of its suppression of inflammation in patients with KD remains unknown. METHODS AND RESULTS: We analyzed time-line profiles of multiple inflammatory cytokines in sera of 19 patients treated with CsA (4 mg/kg/day, p.o., 14 days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200 ng/ml. We examined serum samples before, on day 7, and at the end (day 14) of CsA treatment. Assays were conducted using a Milliplex kit®. Fourteen patients responded to CsA and became afebrile within 5 days (Responders), although five patients were regarded as Non-responders. Serum transitional levels of IL-6 (p<0.001), sIL-2R (p<0.001), sTNFRII (p<0.001), and G-CSF (p<0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p<0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31 pg/ml, p=0.014) were significantly higher than those in Responders. CONCLUSION: CsA treatment effectively reduced the persisting serum inflammatory cytokines in most of the IVIG-resistant KD patients. Soluble IL-2R suppression implies a mechanism explaining the effects of CsA.