Shinichiro Morichi

National survey of pandemic influenza A (H1N1) 2009-associated encephalopathy in Japanese children.

The novel pandemic (pdm) influenza A (H1N1) 2009 virus caused an epidemic of critical illness, with some patients developing severe acute respiratory distress syndrome. Pdm H1N1 2009 infection has been reported to cause fatal encephalopathy and myocarditis as well as pneumonia. To investigate the actual characteristics of the encephalopathy associated with pdm H1N1 2009 infection in Japan, questionnaires were distributed and information collected on 207 cases of encephalopathy during one season. The results of the survey showed that encephalopathy was reported predominantly in males. The outcome was recorded in 188 of the 207 cases; 16 of 188 patients (8.5%) died, while 23 (12.2%) had sequelae. Serious cases were distributed across all age groups. Febrile convulsion was noted at a higher rate in medical past‐history in cases without sequelae (40 of the 149 cases; 27%) than in serious cases. In contrast, pre‐existing epilepsy and mental retardation were observed more frequently in serious cases. Twelve cases exhibited biphasic seizures; one‐half of these had sequelae, but none was fatal. Ten cases were accompanied by high cytokine levels, and three of these children died. Among the 149 cases with good outcomes, 29 of 116 cases (25%) showed abnormalities on MRI, and 14 of these demonstrated reversible splenial lesions. Abnormal behaviors, especially delirium and visual hallucinations, were observed more frequently in cases without sequelae. In conclusion, pdm H1N1 2009 infection‐associated encephalopathy was a critical disease in children, with rapidly progressive characteristics similar to those of seasonal influenza‐associated encephalopathy. J. Med. Virol. 84: 1151–1156, 2012.

Severe form of encephalopathy associated with 2009 pandemic influenza A (H1N1) in Japan.

BACKGROUND Every year, an estimated 200-500 children in Japan develop influenza-associated encephalopathy (IAE), and 10-30% of these children die. OBJECTIVE To clarify the clinical features of a severe form of acute encephalopathy seen with 2009 pandemic influenza A (H1N1). STUDY DESIGN This retrospective survey examined 20 children with acute encephalopathy associated with the 2009 pandemic influenza A (H1N1) who died or were in a prolonged deep coma with a flat electroencephalogram tracing and loss of spontaneous respiration. We obtained demographic, clinical, laboratory, and neuroimaging data through interviews with the attending physicians and chart reviews. RESULTS Subjects were 13 boys and seven girls. Their median age was 45 (range 11-200) months. Five patients had one or more pre-existing conditions. Acute encephalopathy developed within 2 days after influenza onset in 16 patients. As the initial neurological symptom, delirious behavior was seen in six children, and brief seizures in six. Eighteen patients were comatose within 6h of the onset of encephalopathy. Marked brain edema on computed tomography (CT) was seen in all but one patient. Brainstem lesions on CT were recognized in 12 patients. Sixteen patients died 0-45 (median 2.5) days after the onset of acute encephalopathy, and the others remained in deep comas without spontaneous respiration. CONCLUSIONS The clinical course of the patients was characterized by an onset with mild neurological symptoms and rapid deterioration of consciousness into coma. Head CT revealed marked cerebral edema, often associated with brainstem lesions.

Expressions of Brain-Derived Neurotrophic Factor (BDNF) in Cerebrospinal Fluid and Plasma of Children With Meningitis and Encephalitis/Encephalopathy

ABSTRACT Many reports in the field of childhood brain disorders have documented that brain-derived neurotrophic factor (BDNF) affects central nervous system (CNS) functions. In this clinical study, BDNF levels were evaluated in association with pediatric CNS infections. BDNF levels in the serum and cerebrospinal fluid (CSF) of 42 patients admitted during 5-year period, due to CNS infections, were measured by enzyme-linked immunosorbent assays (ELISAs). Control samples were collected from 108 patients with non-CNS infections (urinary tract infection, acute upper respiratory infection, acute gastroenteritis, etc.). Mean values of BDNF levels, at various ages, were determined and compared. BDNF levels were below the sensitivity of the ELISA in most CSF samples from the control group, but were significantly elevated in the patients with bacterial meningitis. The serum BDNF levels were elevated in all subgroups of patients with CNS infections, and the elevation was particularly notable in those with bacterial meningitis. BDNF expression in the CSF was correlated with CSF interleukin (IL)-6 levels as well as with blood platelet counts and neurological prognoses in those with bacterial meningitis. No correlation was found between BDNF levels and serum leukocyte numbers or C-reactive protein (CRP) levels. BDNF levels were found to be elevated in the serum and CSF of pediatric patients with CNS infections, particularly those with bacterial meningitis. Monitoring the changes in serum and CSF levels of BDNF may facilitate the diagnosis of acute meningitis and acute encephalopathy and allow the differential diagnosis of specific CNS infections.

Classification of acute encephalopathy in respiratory syncytial virus infection

Infection with respiratory syncytial virus (RSV) is known to be associated with central nervous system symptoms such as convulsions. We investigated cytokines, nitrogen oxide (NO)x, and the viral genome in cerebrospinal fluid (CSF) obtained from children with RSV infection-related convulsions or central nervous symptoms and compared the data with type of encephalopathy. Of nine patients enrolled (six boys and three girls; aged 10 days–3 years), one metabolic error, five excitotoxicity, one cytokine storm, and two hypoxia cases were found. The patients presented with unilateral convulsions, generalized convulsions, and convulsions following cardiopulmonary arrest, apnea, and nuchal rigidity. In all patients, a rapid check for RSV of nasal fluid was positive. The RSV genome (subgroup A) was detected in the CSF of five of the nine patients; two patients with hypoxic encephalopathy were negative for the RSV genome. The CSF interleukin (IL)-6 levels were high only in patients with the excitotoxicity and cytokine storm type of encephalopathy. NOx levels were high in all the subject cases. In the excitotoxicity type, NOx levels were significantly higher than those in the control and other groups. NOx level may become an important parameter for the diagnosis and classification of acute encephalopathy in RSV. Strategies to treat each type of encephalopathy, targeting cytokines and free radicals, should be established.

High production of interleukin‐10 and interferon‐γ in influenza‐associated MERS in the early phase

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) occurs in various diseases and pathologies, and the clinical symptoms are not consistent with the impaired region. The mechanism of the region specificity is unclear. We investigated the cytokine profiling in cerebrospinal fluid (CSF) and serum obtained from a child with MERS during influenza infection, and compared them with those of serious another serious type of influenza‐associated encephalopathy. There was no elevation of Interleukin (IL)‐1β, which induces convulsion. The inhibitory cytokines of IL‐10 and IFN‐γ were elevated in the early phase in CSF. Comparing them with other patients, the elevation of the cytokine levels were generally mild. Considering that the prognosis of this MERS case was favorable and high levels of inhibitory cytokines including IL‐10 and IFN‐γ might work to localize the lesion and to prevent sequelae.

Production of chemokines in respiratory syncytial virus infection with central nervous system manifestations

Respiratory syncytial virus (RSV) infection in children can be associated with acute encephalopathy. However, the roles of cytokines in the cerebrospinal fluid (CSF) of such patients remain unevaluated. In this study, a profile of 17 cytokines was determined for eight RSV-infected children with neurological complications. In one patient with high levels of 13 cytokines, a cytokine storm was considered to have occurred. Interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1β levels were also high in other patients. These data suggest that chemokines in CSF play roles in neurological complications in RSV-infected children.

Examination of neurological prognostic markers in patients with respiratory syncytial virus-associated encephalopathy

No biomarker has been established as a prognostic indicator of acute encephalopathy associated with various etiological factors. In this study, we examined useful prognostic biomarkers in patients with acute encephalopathy associated with respiratory syncytial virus (RSV) infection. The subjects were 11 children with RSV-associated encephalopathy admitted to our hospital. We measured the levels of interleukin (IL)-6, brain-derived neurotrophic factor (BDNF) and nitrogen oxide (NO)x in cerebrospinal fluid collected on the day of admission. Using the pediatric cerebral performance categories (PCPC) score as a prognostic indicator, we evaluated the association between the biomarkers and neurologic prognosis. Concerning neurologic prognosis, sequelae were noted in more than 50% of the subjects. There was no association between prognosis and age/sex. Increases in the levels of all biomarkers were observed in all subjects. IL-6 and BDNF levels were correlated with PCPC score, but not with NOx. Of the biomarkers investigated, the IL-6 and BDNF levels in cerebrospinal fluid were shown to be correlated with neurologic prognosis. Because many patients with this disease had severe sequelae, assessment should be conducted by early evaluation of the biomarkers examined in this study with respect to the clinical course.

Treatment of pandemic influenza A (H1N1) 2009-associated encephalopathy in children

Abstract Background: The novel pandemic influenza A (H1N1) 2009 virus (influenza A(H1N1)pdm09) caused an epidemic of critical illness, with some patients developing fatal encephalopathy as well as pneumonia. Methods: To investigate the actual efficacy of treatments, we investigated data from questionnaires regarding 207 cases that occurred between September 2009 and February 2010. Results: The outcomes were recorded in 188 of the 207 cases; 16 of 188 patients died, while 23 had sequelae. Anti-influenza drugs in patients with severe coma (Glasgow coma scale score of ≤ 8) were statistically effective. In 165 out of 199 cases, steroid pulse treatment with methylprednisolone was given at an early stage. Other intensive treatments were mostly administered in serious cases. Conclusions: Controlled studies are needed to investigate the efficacy of other treatments except for anti-influenza drugs.

Brain magnetic resonance imaging in acute phase of pandemic influenza A (H1N1) 2009--associated encephalopathy in children.

Pandemic influenza A (H1N1) 2009 has been shown to be associated more with neurological complications than the seasonal influenza virus. In this study, we focused on the clinical usefulness of magnetic resonance imaging (MRI) in the acute phase of influenza A (H1N1) 2009-associated encephalopathy. A questionnaire was distributed to pediatric and general hospitals in Japan that treat children with encephalopathy. We conducted a questionnaire-based study involving the collection of information regarding 207 patients with encephalopathy. Brain MRI was performed in 97 of these 207 patients in the age group of 9 months to 15 years (mean, 7.5 years) within 48 hours after the development of encephalopathy symptoms. Sixty-six patients (68%) showed normal imaging. Diffuse brain edema was visible in five patients and an abnormal signal in the deep gray matter in two patients which is consistent with acute necrotizing encephalopathy. Abnormal signals of the splenial lesion, subcortical white matter (bright tree appearance), and cortical area were observed in 15, 1, and 8 patients, respectively. From our findings based on the questionnaire results, we suggest that MRI is useful for determining fatal cases of pandemic influenza A (H1N1) 2009 infection when performed in the acute phase. However, MRI is not useful in predicting the development of sequelae.

Brain-Derived Neurotrophic Factor and Interleukin-6 Levels in the Serum and Cerebrospinal Fluid of Children with Viral Infection-Induced Encephalopathy

We investigated changes in the brain-derived neurotrophic factor (BDNF) and interleukin (IL)-6 levels in pediatric patients with central nervous system (CNS) infections, particularly viral infection-induced encephalopathy. Over a 5-year study period, 24 children hospitalized with encephalopathy were grouped based on their acute encephalopathy type (the excitotoxicity, cytokine storm, and metabolic error types). Children without CNS infections served as controls. In serum and cerebrospinal fluid (CSF) samples, BDNF and IL-6 levels were increased in all encephalopathy groups, and significant increases were noted in the influenza-associated and cytokine storm encephalopathy groups. Children with sequelae showed higher BDNF and IL-6 levels than those without sequelae. In pediatric patients, changes in serum and CSF BDNF and IL-6 levels may serve as a prognostic index of CNS infections, particularly for the diagnosis of encephalopathy and differentiation of encephalopathy types.