Madoka Kajimoto

Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures

It is well known that an acute encephalopathy occasionally follows prolonged febrile seizures. We measured the concentrations of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and CSF during the acute stage in 13 children with acute encephalopathy following prolonged febrile seizures (AEPFS) and 23 with prolonged febrile seizures without encephalopathy (PFS) to investigate the pathogenesis of AEPFS. Serum IL-6, IL-10, sTNFR1, and CSF IL-6 levels were significantly higher in AEPFS and PFS compared with control subjects. CSF IL-6 levels in AEPFS were significantly higher than those in PFS, but not serum IL-6, IL-10, or sTNFR1. The CSF IL-6 levels were significantly higher than the serum levels in AEPFS, but not PFS. The serum levels of sTNFR1 and IL-10 were significantly higher than those in the CSF in AEPFS and PFS. The serum IL-10 and sTNFR1 levels in patients who did not experience a second seizure were significantly higher than those in patients who experienced a second seizure, which was characterized by clusters of complex partial seizures several days after the initial prolonged febrile seizure. Our results suggest that serum IL-6, IL-10, TNF-alpha, and CSF IL-6 are part of the regulatory system of cytokines in AEPFS.

Matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in influenza-associated encephalopathy.

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) play important roles in the function of the blood–brain barrier. Serum MMP-9 and TIMP-1 concentrations were determined in influenza virus infection with or without neurologic complications. Our results suggest that an imbalance between MMP-9 and TIMP-1 damages the blood–brain barrier and promotes febrile seizure or encephalopathy in influenza virus infection.

Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis

In multiple sclerosis, there have been many reports on matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). However, MMPs and TIMPs have not been reported in acute disseminated encephalomyelitis (ADEM). We determined the relationship between the serum concentrations of MMP-9 and TIMP-1 and activity of lesions on MRI in 14 patients with ADEM to investigate the roles of MMP-9 and TIMP-1 in the pathogenesis of ADEM. Serum MMP-9 and TIMP-1 levels, measured by ELISA and gadolinium-enhanced (Gd+) brain MRI, were analyzed. Serum MMP-9 and TIMP-1 levels at the acute stage were higher than controls, and the serum MMP-9 levels at the acute stage were higher than those at the convalescent stage in ADEM. In seven patients with Gd+ lesions on brain MRI, serum MMP-9 levels and the MMP-9/TIMP-1 ratio at the acute stage were higher than those at the convalescent stage, and serum TIMP1 levels at the acute stage were lower than those at the convalescent stage. In seven patients without Gd+ lesions on brain MRI, serum TIMP-1 levels at the acute stage were higher than those at the convalescent stage. We speculated that MMP-9 is related to lesion formation at the early stage in ADEM and that TIMP-1 is induced to modulate MMP-9 activity. These findings suggest that MMP-9 and TIMP-1 secondarily play some roles in the inflammatory cascade of ADEM.

Cysteinyl leukotrienes enhance tumour necrosis factor‐α‐induced matrix metalloproteinase‐9 in human monocytes/macrophages

Background Matrix metalloproteinase‐9 (MMP‐9) is an important enzyme responsible for airway remodelling. Monocytes/macrophages have a cysteinyl leukotriene 1 (cysLT1) receptor, but its function is poorly understood.

Cerebrospinal fluid levels of cytokines in non-herpetic acute limbic encephalitis: comparison with herpes simplex encephalitis.

BACKGROUND Recently, non-herpetic acute limbic encephalitis (NHALE) was identified as a new subgroup of limbic encephalitis. The immunological pathophysiology of NHALE is still unclear. METHODS We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in the cerebrospinal fluid (CSF) of 15 patients with NHALE and 13 with herpes simplex encephalitis (HSE) by cytometric bead array or ELISA. RESULTS The CSF concentrations of IL-6 in patients with NHALE and IFN-gamma, IL-6, IL-10, and sTNFR1 in HSE patients were significantly higher than those of controls (p<0.001, p=0.004, p<0.001, p=0.018, and p<0.001, respectively). There were significant correlations among CSF IL-6, IL-10, and sTNFR1 levels in HSE patients. The CSF concentrations of IFN-gamma and sTNFR1 levels of patients with HSE were significantly higher than those with NHALE (p=0.001 and p=0.002, respectively). CONCLUSIONS CSF cytokine levels in NHALE were relatively low compared with those in HSE. These results may be related to the favorable prognosis of NHALE.

Clinical Characteristics of Benign Convulsions With Rotavirus Gastroenteritis

Convulsions sometimes occur in infants and toddlers with mild gastroenteritis. We retrospectively investigated the hospital records of 106 patients admitted to our hospital who had rotavirus gastroenteritis from February 2002 to April 2008. There were 23 patients with convulsions, including 13 with benign convulsions, 9 with febrile seizures, and 1 with epilepsy. Gastroenteritis in patients with benign convulsions was mild from the viewpoint of body weights and serum creatinine concentrations on admission and the duration of admission. Serum Na+ and Cl - concentrations of patients with benign convulsions were relatively lower than those without convulsions on admission (P = .006, and P = .008, respectively). Twelve of thirteen patients had no other seizures after oral administration of 5 mg/kg of carbamazepine, while 1 patient had 1 convulsion 15 minutes after the therapy. In conclusion, carbamazepine therapy was effective for benign convulsions with rotavirus gastroenteritis.

A nationwide survey of opsoclonus–myoclonus syndrome in Japanese children

BACKGROUND Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease characterized by opsoclonus, myoclonus, ataxia, and behavioral changes. The aim of our study was to investigate the epidemiological characteristics of OMS in Japan and to clarify the association between therapy and prognosis. METHODS We retrospectively collected the data from 626 Japanese medical institutions from 2005 to 2010, and analyzed the clinical features of pediatric patients with OMS based on the data. RESULTS In this survey, there were 23 patients (10 males and 13 females). The median ages at the disease onset and the time of study were 16.5 months (range: 11-152 months) and 54 months (range: 24-160 months), respectively. The principal symptoms were opsoclonus (23 patients, 100%), myoclonus (21 patients, 91.3%), and ataxia (23 patients, 100%). The related factors were neuroblastoma (10, 43.5%), infection (9, 39.1%), and immunization (2, 8.7%). The treatments for OMS were included intravenous immunoglobulin (17, 73.9%), methylprednisolone pulse (13, 56.5%), oral prednisolone (12 patients, 52.2%), and chemotherapy and/or operation for the underlying tumors (6, 26.1%), and rituximab (2, 8.7%). Complete remissions were obtained in 35.3%, 23.1%, 33.3%, 66.7%, and 100% of these treatments, respectively. At the latest follow-up period, 8 (34.8%) and 17 patients (73.9%) showed neurological sequelae of motor and intellectual functions, respectively. Patients whose treatment was started more than 30 weeks after the disease onset suffered from the severest neurological sequelae (OMS severity 4) more frequently than those less than 30 weeks (p=0.022). CONCLUSION The annual incidence of OMS was estimated to be 0.27-0.40 cases per million in Japanese children. More than 70% of OMS patients had neurological sequelae, especially intellectual function. Early effective treatments within 30 weeks after the onset may be required to prevent the serious neurological outcome.

Enhancement of activated β1-integrin expression by prostaglandin E2 via EP receptors in isolated human coronary arterial endothelial cells: implication for the treatment of Kawasaki disease

Abstract.Objective:Plasma prostaglandin E2 (PGE2) levels are markedly elevated in acute Kawasaki disease (KD). We evaluated the function of the EP receptors in the expression of activated β1-integrin stimulated by PGE2 in human coronary arterial endothelial cells (HCAEC).Methods:We determined the mRNA expression of the PGE2 receptors, EP receptors (EP1-4) in HCAEC by RT-PCR and protein expression by Western blotting. We evaluated the function of the EP receptors in the expression of activated β1-integrin stimulated by PGE2 in HCAEC, using antagonists and agonists of the EP receptors, by flow cytometry.Results:RT-PCR revealed mRNAs for all four EP receptors in HCAEC. Western blotting demonstrated EP1, EP2 and EP3 expression in HCAEC. The EP2 and EP3 agonists enhanced the expression of activated β1-integrin in HCAEC. The potency of the EP2 agonist was significantly greater than that of the EP3 agonist. Pretreatment with the EP1, EP2 and EP3 antagonists inhibited the expression of activated β1-integrin induced by PGE2 in HCAEC. The potency of the EP2 antagonist was significantly greater than that of the EP1 and EP3 antagonists.Conclusions:Our results suggest that PGE2 mainly induces the activation of β1-integrins via the EP2 receptor in HCAEC. Our results further suggest that the EP2 antagonist modulates the inflammatory response during KD vasculitis.

High mobility group box 1 in patients with 2009 pandemic H1N1 influenza-associated encephalopathy.

BACKGROUND Patients with 2009 pandemic H1N1 influenza-associated encephalopathy (pIE) have been reported in Japan. The most common clinical symptoms of this condition are seizures and progressive coma with high-grade fever. We previously highlighted the cytokine profile of pIE; our results suggest that proinflammatory cytokines play an important role in the pathogenesis. High mobility group box 1 (HMGB1) protein is a late mediator of inflammation or sepsis. However, there are few reports regarding the serum and cerebrospinal fluid (CSF) levels of HMGB1 in pIE patients. METHODS We measured serum and CSF levels of HMGB1 in the following: pIE patients with poor outcomes, pIE patients without neurological sequelae, influenza patients without pIE, and control subjects. RESULTS Serum HMGB1 levels were significantly higher in pIE patients with poor outcomes compared to those without neurological sequelae. In contrast, there was no difference in CSF HMGB1 levels among all groups. Regarding pIE patients, we found a significant positive correlation between HMGB1 levels and IL-6 in the serum but not in the CSF. CONCLUSIONS Our results suggest that HMGB1 protein may be involved in the pathogenesis of pIE and that a high serum, but not CSF, level of inflammatory cytokines plays an important role in the severity of pIE.

Serial cerebrospinal fluid neurofilament concentrations in bacterial meningitis

Neurofilament (NF) is one of the major cytoskeleton proteins of neurons. We investigated the concentrations of the heavy subunit of NF (NF-H) in cerebrospinal fluid (CSF) as biomarkers of neuronal injury in bacterial meningitis. Concentrations of NF-H in CSF of 26 children with bacterial meningitis and in 16 control subjects were measured by ELISA. The CSF NF-H levels were elevated in 22 of the 26 children (85%) with bacterial meningitis. The peak CSF NF-H level occurred at a median period of 10.5 days after onset of illness (range, 1 to 35 days). The peak CSF NF-H levels of the patients with neurological sequelae (n=4) were significantly higher than those without sequelae (n=22) (7.06 vs. 2.46 ng/mL as median, p=0.048). There was no significant difference in CSF NF-H levels between patients with and without severe neurological sequelae up to day 14 of illness, but the CSF NF-H levels in patients with sequelae were significantly higher than in those without sequelae after day 14 of illness (2.04 vs. 1.19 ng/mL as median, p=0.024). We suggest that neuronal injury occurs in bacterial meningitis regardless of the presence or absence of neurological sequelae.