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

BACKGROUND: Acute 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. METHODS: We used tau protein as a marker of axonal damage and examined its concentration in the CSF of 27 children with ADEM. RESULTS: CSF 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). CONCLUSIONS: In 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 and cerebrospinal fluid levels of visinin-like protein-1 in acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) has recently been recognized as an encephalopathy subtype. Typical clinical symptoms of AESD are biphasic seizures, and MRI findings show reduced subcortical diffusion during clustering seizures with unconsciousness after the acute phase. Visinin-like protein-1 (VILIP-1) is a recently discovered protein that is abundant in the central nervous system, and some reports have shown that VILIP-1 may be a prognostic biomarker of conditions such as Alzheimer's disease, stroke, and brain injury. METHODS: However, there have been no reports regarding serum and cerebrospinal fluid (CSF) levels of VILIP-1 in patients with AESD. We measured the serum and CSF levels of VILIP-1 in patients with AESD, and compared the levels to those in patients with prolonged febrile seizures (FS). RESULTS: Both serum and CSF levels of VILIP-1 were significantly higher in patients with AESD than in patients with prolonged FS. Serum and CSF VILIP-1 levels were normal on day 1 of AESD. CONCLUSIONS: Our results suggest that both serum and CSF levels of VILIP-1 may be one of predictive markers of AESD.

Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders.

Two novel mitochondrial DNA base changes were identified at both sides of the 3243A>G mutation, the most common mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). One was a 3244G>A transition in a girl with MELAS. The other was a 3242G>A transition in a girl with a mitochondrial disorder without a MELAS phenotype. Although the two base changes were adjacent to the 3243A>G mutation, they had different effects on the clinical phenotype, muscle pathology, and respiratory chain enzyme activity. Investigations of the different effects of the 3244G>A and 3242G>A base changes may provide a better understanding of tRNA dysfunction in mitochondrial disorders.

Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures.

Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls. Serum TIMP-1 levels in AEPFS patients were significantly lower than those in PFS, SFS, CSE and West syndrome patients and in controls. Serum MMP-9 levels and MMP-9/TIMP-1 ratios in AEPFS patients with motor paralysis were significantly higher than for those without motor paralysis. Our results suggest that prolonged seizures are related to high serum MMP-9 levels, and that an increased MMP-9/TIMP-1 ratio in AEPFS might induce dysfunction of the BBB. Furthermore, an imbalance of serum MMP-9 and TIMP-1 levels in patients with AEPFS may be associated with severe neurological sequelae.

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.

[Analysis of 11 patients with profound multiple disabilities who underwent laryngotracheal separation].

We examined the clinical usefulness of laryngotracheal separation surgery for patients with profound multiple disabilities (PMD). The subjects were 11 severely retarded children who experienced repeated incidents of aspiration pneumonia or who were enough to have aspiration pneumonia easily. A retrospective investigation of their medical records was performed regarding pre- and post-operative data, including the number of times sputum suctionings were required, the number of times pneumonia developed, respiratory conditions, and nutrition methods. The guardians were interviewed regarding musle tone, spasm, sleep quality, internal medications, and changes in mood. After surgery, improvement was confirmed in the number of times sputum suctionings were required, the incidence of pneumonia and respiratory conditions, and oral intake of food in three children. The guardians were aware of improvements in their children's sleep quality and mood. Laryngotracheal separation surgery can reduce the burden of health care for patients with PMD by improving their respiratory conditions and methods of nutrition intake.

[A case of Mondini dysplasia with bacterial meningitis].

A boy with bilateral hearing impairment developed pneumococcal meningitis at 14-month-old. Further examination revealed cerebrospinal fluid leakage due to bilateral Mondini dysplasia. He was cured by treatment with panipenem/betamiprone and dexamethasone, and then, he was performed an operation to fill the inner ear on day 30. He did not have bacterial meningitis 19 months after the operation. Children with congenital hearing impairment should be examined for malformation of the inner ear because the inner ear malformation has cerebrospinal fluid leakage and bacterial meningitis frequently.

Two Japanese families with hyperekplexia who have a Arg271Gln mutation in the glycine receptor alpha 1 subunit gene.

We report two Japanese patients from two families with hyperekplexia who have a Arg271Gln mutation in the glycine receptor alpha 1 subunit gene. The clinical course of both patients was typical for hyperekplexia, characterized by neonatal hypertonia and exaggerated startle response, and which improved gradually with age. One was associated with umbilical hernia and hip dislocation, diagnosed at 11 months, while the other was diagnosed at 1 month. Both showed positive head retraction reflex. Four Japanese families have been reported as having hyperekplexia including our cases, of which three have shown the same missense Arg271Gln mutation, most frequently found in patients from Northern Europe and the United States.

[Yersinia pseudotuberculosis type 4a infection meeting the diagnostic criteria for Kawasaki disease complicated by disseminated intravascular coagulation].

We report a case of Yersinia pseudotuberculosis (Y. ptbc) infection complicated by disseminated intravascular coagulation (DIC) that presented as Kawasaki disease (KD). A 9-year-old girl had been well until two days before, when she developed a fever, exanthem, and abdominal pain. An erythematous macular rash was observed in the perineum, and she had a strawberry tongue. The patient was admitted to Kawasaki Medical School Hospital because the macular rash spread over her entire body, and edema of her hands and conjunctivitis subsequently developed. Echo cardiography showed dilation of the left coronary artery. Thrombocytopenia and an elevated total fibrin degeneration product level were noted on the third hospital day, and the prothronmbin and partial-thromboplastin times were prolonged. Her clinical presentation was typical of KD and DIC. A stool culture and a blood culture were negative. Serologic tests were positive for antibodies to Y. ptbc. The antibody titer against Y. ptbc-derived mitogen was not elevated after her recovery. Y. ptbc infection should be considered in an older child whose clinical findings fulfill the criteria for KD complicated by DIC.

Low-dose carbamazepine therapy for benign infantile convulsions.

Benign infantile convulsions (BIC) are characterized by: (1) onset at up to 2 years of age, (2) normal development, (3) mostly brief, often clustered convulsions, and (4) normal electroencephalography during the interictal stage. BIC follow a favorable course and disappear before 2-3 years of age, although convulsions for which diazepam is ineffective frequently develop. We treated 15 children (3-16 months of age) diagnosed as having BIC, excluding convulsions associated with mild gastroenteritis, with a once-daily dose of 5mg/kg of carbamazepine until up to 2 or 3 years of age. The serum concentration of carbamazepine was as low as below the effective range in six patients, but the treatment was dramatically effective in all the BIC children. Seizures did not recur in any patients during oral administration of carbamazepine. The treatment was finished in 12 patients at age 2 years, two at age 3 years, and one at 16 months-old. Therefore, we recommend the administration of a once-daily dose of 5mg/kg of carbamazepine until up to 2 or 3 years of age as a treatment for BIC.

Analysis of cytokine levels and NF-kappaB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy.

BACKGROUND: Influenza virus-associated encephalopathy (IE) is suggested to be a proinflammatory cytokine-related disease. METHODS: We measured the concentrations of interleukin-6 (IL-6), TNF-alpha, soluble TNF receptor 1 (sTNFR1), IL-10, interferon-gamma, IL-2, IL-4, and soluble E-selectin (sE-selectin) in serum and CSF during the acute stage in 30 children with IE, 20 with influenza virus-associated febrile seizures (IFS), and 39 with influenza virus infection without complications (Flu). Moreover, the activation of transcription factor NF-kappaB in peripheral blood mononuclear cells (PBMC) of 5 children with IE was examined. RESULTS: The serum IL-6, sTNFR1, and IL-10 levels in the IE group with a poor prognosis (Group A) were significantly higher than those in the IE group without sequelae in IE (Group B), IFS, and Flu. In particular, the serum levels of IL-6, sTNFR1, and IL-10 in 5 deceased patients were markedly higher. The CSF IL-6 levels in Group A were significantly higher than those in Group B and IFS. Flow cytometric analysis revealed that NF-kappaB activation in PBMC in Group A was higher than that in Group B, IFS, and Flu. CONCLUSION: We suggest that cytokines are produced by PBMC in IE, and that the levels of serum IL-6, sTNFR1, and IL-10, CSF IL-6, and NF-kappaB activation in PBMC are useful indicators of the severity of the disease.

Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathy.

This study determined the concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1) and soluble E-selectin (sE-selectin) in cerebrospinal fluid (CSF) and serum from 15 children with influenza virus-associated encephalopathy to determine the role of cytokines in the pathogenesis. Cytokines and sTNFR1 were measured by enzyme-linked immunosorbent assay. The CSF IL-6, TNF-alpha and sTNFR1 concentrations were elevated in 9, 4 and 4 of 12 children, respectively. The serum concentrations of IL-6, TNF-alpha, sTNFR1 and sE-selectin were elevated in 10, 2, 5 and 7 of 13 children, respectively. Four children with elevated TNF-alpha and sTNFR1 levels in the CSF had neurological sequelae. The results suggested that cytokines not only in serum but also in CSF play a pivotal role in influenza virus-associated encephalopathy, and that the CSF TNF-alpha and sTNFR1 levels may be important for predicting neurological sequelae.

NF-kappaB activation in cerebrospinal fluid cells from patients with meningitis.

We examined whether or not NF-kappaB, a factor that regulates expression of the genes that code for pro-inflammatory cytokines, is activated in cerebrospinal fluid (CSF) cells to investigate the production of pro-inflammatory cytokines by CSF cells in patients with meningitis. Western blotting demonstrated that NF-kappaB was more activated in CSF cells of patients with bacterial meningitis than in those of patients with aseptic meningitis. NF-kappaB was hardly activated in carcinomatous meningitis. The NF-kappaB activation in CSF cells of patients with meningitis tended to be correlated with the CSF interleukin-6 concentration. Our data suggested that CSF cells produce pro-inflammatory cytokines through NF-kappaB activation in meningitis, and that increased NF-kappaB activation in CSF cells indicate infectious meningitis rather than carcinomatous meningitis.