Hirofumi Inoue

Serum and cerebrospinal fluid cytokine profile of patients with 2009 pandemic H1N1 influenza virus-associated encephalopathy

PURPOSEnSince April 2009, the number of patients with 2009 pandemic H1N1 influenza virus infection has been increasing in Japan just as in the rest of the world. Patients with 2009 pandemic H1N1 influenza-associated encephalopathy (pIE) have also been reported. The common clinical symptoms of this condition are seizures and progressive coma with high-grade fever. We previously reported the possible association between seasonal influenza-associated encephalopathy (sIE) and proinflammatory cytokines. However, the pathogenesis of pIE remains to be elucidated.nnnRESULTSnIn pIE patients with a poor outcome, the serum levels of interleukin (IL)-6, IL-10, and soluble tumor necrosis factor (TNF) receptor (sTNFR1) were significantly higher than those in pIE patients without neurological sequelae. Similarly, the cerebrospinal fluid (CSF) IL-6 levels in pIE patients with a poor outcome were significantly higher than those in pIE patients without neurological sequelae.nnnCONCLUSIONnOur results suggest that IL-6, TNF-α, and IL-10 play important roles in pIE, and that the serum levels of IL-6, IL-10, and sTNFR1 and the CSF levels of IL-6 are related to neurological complications.

A nationwide survey of opsoclonus–myoclonus syndrome in Japanese children

BACKGROUNDnOpsoclonus-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.nnnMETHODSnWe 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.nnnRESULTSnIn 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).nnnCONCLUSIONnThe 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.

Serum neurofilament concentrations in children with prolonged febrile seizures

OBJECTIVEnNeurofilament (NF) is a major cytoskeletal protein of neurons. Elevation of serum NF concentration suggests neuronal injury, especially damage to axons. We assessed neuronal damage in febrile seizure (FS) by using NF.nnnMETHODSnWe used enzyme-linked immunosorbent assay to measure serum levels of the phosphorylated form of NF-heavy chain (pNF-H) in 42 children with FS and 28 controls.nnnRESULTSnSerum pNF-H levels in children with prolonged febrile seizure (PFS) (n=29) were significantly higher than those in the controls (p<0.001). There were no significant differences in serum pNF-H levels between children with simple febrile seizure (n=9) and the controls. There was a significant correlation between seizure duration and serum pNF-H levels during the first week in children with FS (p=0.022, r=0.37).nnnCONCLUSIONnOur results suggest that PFS could lead to some degree of neuronal damage even in the absence of abnormal clinical neurological findings during the short-term follow up period.

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

BACKGROUNDnPatients 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.nnnMETHODSnWe 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.nnnRESULTSnSerum 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.nnnCONCLUSIONSnOur 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.

Tau protein concentrations in the cerebrospinal fluid of children with acute disseminated encephalomyelitis

BACKGROUNDnAcute disseminated encephalomyelitis (ADEM) is clinically characterized by the acute onset of neurological symptoms after a viral infection or immunization, and is thought to represent an autoimmune disease directed against myelin. Tau protein is a phosphorylated microtubule-associated protein, primarily located in neuronal axons. Increased levels of tau protein in cerebrospinal fluid (CSF) are found in various pathological conditions.nnnMETHODSnWe used tau protein as a marker of axonal damage and examined its concentration in the CSF of 27 children with ADEM.nnnRESULTSnCSF tau protein concentration in children with ADEM was significantly higher than that in the CSF of control subjects (P=0.008). There were no significant differences in CSF tau protein concentrations in the ADEM patients with and without encephalopathy. The CSF tau protein concentration in patients with partial lesion resolution in follow-up brain MRI was significantly higher than in patients with complete lesion resolution (P=0.014).nnnCONCLUSIONSnIn conclusion, we demonstrated that CSF tau protein concentration was significantly increased in ADEM patients. Our findings suggest that axonal damage may occur in addition to demyelination in children with ADEM.

Serum soluble CD163 levels in patients with influenza-associated encephalopathy

BACKGROUNDnInfluenza-associated encephalopathy (IE) is a serious complication during influenza viral infection. Common clinical symptoms of IE include seizures and progressive coma with high-grade fever. We previously reported that hypercytokinemia and monocyte/macrophage activation may play an important role in the pathogenesis of IE. CD163 is a scavenger receptor for hemoglobin-haptoglobin complexes and is expressed by monocytes/macrophages. Proteolytic cleavage of monocyte-bound CD163 by matrix metalloproteinases releases soluble CD163 (sCD163). However, there have been no reports regarding serum sCD163 levels in IE patients.nnnMETHODSnWe measured serum levels of sCD163 as a marker of monocyte/macrophage activation in IE patients with poor outcomes, those without neurological sequelae, influenza patients without IE, and control subjects.nnnRESULTSnSerum sCD163 levels were significantly higher in IE patients with poor outcomes than in those without neurological sequelae. In particular, sCD163 levels in cases of death were significantly higher than those in other cases.nnnCONCLUSIONSnOur results suggest that monocyte/macrophage activation is related to the pathogenesis of severe IE.

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene

Severe protein C (PC) deficiency is a rare heritable thrombophilia leading to thromboembolic events during the neonatal period. It remains unclear how individuals with complete PC gene (PROC) defects develop or escape neonatal stroke or purpura fulminans (PF).

Successful control of radicular pain in a pediatric patient with Guillain–Barré syndrome

A 10-year-old boy was diagnosed as having the axonal form of Guillain-Barré syndrome (GBS). The patient noticed progressive weakness of the lower legs on the 1st day of illness. Intravenous immunoglobulin therapy was immediately started on the 2nd day of illness. Despite the favorable recovery of muscle weakness, he complained of severe needle-like pain in the thighs and buttocks and also painful numbness over the gastrocnemius regions. Acetaminophen and hydroxyzine therapy was ineffective for the pain control. Oral prednisolone therapy (0.7 mg/kg/day) led to drastic pain-relief with favorable improvement of the weakness. Corticosteroid therapy is not typically used in the management of GBS patients. Although GBS-associated pain frequently occurs in children, only a few reports have indicated the analgesic utility of steroids in the treatment of pediatric GBS. This observation may suggest the alternative of this therapy as for the as the limited, but potentially rapid, control of GBS-associated acute radicular pain in pediatric patients.

Elevation of tau protein levels in the cerebrospinal fluid of children with West syndrome

PURPOSEnWest syndrome is an epileptic encephalopathy with a poor developmental outcome. Tau protein levels in the cerebrospinal fluid (CSF) are reported to be markers of axonal damage and neurodegeneration. This study aimed to investigate axonal damage and the effects of adrenocorticotropic hormone (ACTH) therapy on axons in West syndrome, as measured by tau protein levels in CSF.nnnMETHODSnTau protein levels in CSF before and after ACTH therapy were determined by an enzyme-linked immunosorbent assay in 26 children with West syndrome. Of these 26 children, 18 were symptomatic, and 8 had a cryptogenic form of West syndrome. A group of 41 unaffected children was included in the study as a control group.nnnRESULTSnThe levels of tau protein in CSF were significantly higher in children with West syndrome than in the control group, and these levels remained high after ACTH therapy. ACTH therapy was effective for 20 of the 26 children with West syndrome, and their CSF tau protein levels were significantly higher after ACTH therapy than before therapy.nnnCONCLUSIONnOur results suggest that axonal damage occurs in West syndrome, as judged by tau protein levels in CSF.

Cat-scratch disease with severe pleuritis in a 6-year-old girl

We present the case of a 6‐year‐old girl with cat‐scratch disease (CSD), who developed severe pleuritis without lymphadenitis. Bartonella henselae DNA was detected on real‐time polymerase chain reaction (PCR) analysis of whole blood. This is the first report of CSD diagnosed on real‐time PCR using whole blood.