A Girl with Idiopathic Epilepsy Showing Forced Normalization after Levetiracetam Administration.

BACKGROUND: Forced normalization has been reported in association with almost all anti-epileptic drugs. PATIENT: We report on a 9-year-old girl with idiopathic epilepsy who showed forced normalization after administration of levetiracetam (LEV). She initially presented with generalized tonic-clonic seizures when she was 4 years old. Diffuse sharp and slow wave complexes (SWCs) were observed on electroencephalography (EEG). We prescribed sodium valproate (VPA) and benzodiazepines, but the seizures and EEG findings worsened gradually. Although subsequent administration of LEV stopped the seizures, the patient became subject to episodes of rage and violent behavior. Forced normalization was confirmed by the disappearance of SWCs on EEG. We reduced the dose of LEV and tried in various ways to resolve the situation, but finally we had to abandon LEV. CONCLUSIONS: To the best of our knowledge, this is the first report of a patient with idiopathic epilepsy but without disabilities in everyday life showing forced normalization associated with LEV administration.

Neglect-induced pseudo-thrombotic thrombocytopenic purpura due to vitamin B12 deficiency.

Although thrombotic thrombocytopenic purpura (TTP) is rare, early diagnosis and treatment are important for decreasing the mortality rate. Acquired vitamin B12 deficiency is frequently overlooked because of its rarity in developed countries, particularly in children and adolescents. The hematological changes in vitamin B12 deficiency present as megaloblastic anemia, increased lactate dehydrogenase, vasoconstriction, increased platelet aggregation, and abnormal activation of the coagulation followed by microangiopathy as well as neutropenia and thrombocytopenia. We report herein the case of a 15-year-old girl who had been neglected, which might have caused pseudo-TTP through malnutrition, particularly vitamin B12 deficiency. When we encounter cases of TTP in children, clinicians must be aware of the possibility of malnutrition, particularly with vitamin B12 deficiency, even in developed countries, and investigate the cause of malnutrition including neglect.

Seronegative Antiphospholipid Syndrome with Anti-phosphatidylethanolamine Antibody in a Boy.

Antiphospholipid syndrome (APS) is an autoimmune disease caused by antiphospholipid antibodies. At our institution, APS is diagnosed on the basis of the Sapporo criteria, which consist of thrombosis and recurrent pregnancy-related complications and the following laboratory findings: the presence of lupus anticoagulant, anticardiolipin antibody, or anti-ß2 glycoprotein 1 antibody. However, we sometimes treat patients we strongly suspect of having APS but who do not satisfy the laboratory criteria. To accommodate such suspected cases, a subtype of APS termed seronegative APS has been proposed. Here, we report on a man with chronic thromobocytopenic purpura since the age of 3 years and multiple cerebral infarctions since the age of 14 years who finally received a diagnosis of seronegative APS with positive antiphosphatidylethanolamine antibodies.

Visualization of different characteristics of cerebrospinal fluid with acute encephalopathy and febrile seizures using pattern recognition analysis of 1H NMR.

BACKGROUND: In acute encephalopathy, deterioration of the condition can be rapid, and early intervention is essential to prevent progression of the disease. However, in the acute period, differentiating acute encephalopathy from febrile seizures is difficult. Thus, an early diagnostic marker has been sought to enable early intervention. Proton nuclear magnetic resonance ((1)H NMR) spectroscopy is used to study the chemical characteristics of biological fluids such as cerebrospinal fluid (CSF). The purpose of this study was to ascertain if pattern recognition of (1)H NMR spectra could differentiate CSF obtained from patients with acute encephalopathy and febrile seizures. METHODS: CSF was obtained from patients with acute encephalopathy (n = 4), complex febrile seizures (n = 9), and simple febrile seizures (n = 9). RESULTS: NMR spectra of CSF did not visually differ across the three groups. Spectral data were analyzed by partial least squares discriminant analysis and visualized by plotting the partial least squares scores of each sample. The three patient groups clustered separately on the plots. CONCLUSION: In this preliminary study, we were able to visualize different characteristics of CSF obtained from patients with acute encephalopathy and simple and complex febrile seizures using pattern recognition analysis of (1)H NMR data.

Hydrocephalus with spontaneous regression in a 14-year-old girl.

We report on a 14-year-old girl with hydrocephalus that underwent spontaneous regression without any specific treatment, such as ventriculoperitoneal shunt surgery. A 14-year-old girl was referred to our hospital with severe headache, dizziness, nausea, and vomiting. Computed tomography and FLAIR-MRI findings on admission showed markedly dilated lateral, third and fourth ventricles with periventricular hyperintensity and downward displacement of the tonsils induced by dilatation of the fourth ventricle. We diagnosed hydrocephalus of unknown etiology. Although no specific treatment for hydrocephalus was performed, the symptoms gradually improved. One year after onset, the patient was completely free of neurological symptoms, and findings of physical examination and magnetic resonance imaging of the brain had returned to normal. The etiology of the spontaneous regression is unclear, but the following mechanisms are discussed: 1) rupture of ventricular diverticulum, 2) head injury causing skull-base fracture with leakage of cerebrospinal fluid, 3) extremely radiosensitive neoplasms diminished by X-p exploration, and 4) cerebrospinal fluid leakage due to lumbar puncture.

Delayed-type hypersensitivity in response to L-asparaginase in a case of acute lymphoblastic leukemia.

L-asparaginase (L-Asp) is an important reagent for acute lymphoblastic leukemia because asparagine is required for the malignant growth of tumor cells, especially lymphoblastic leukemia cells. An allergic response to L-Asp is not unusual because L-Asp is derived from Escherichia coli and is often recognized as a foreign protein. The hypersensitivity induced by L-Asp is of the immediate type in most cases. We report on a 5-year-old girl who was hospitalized for precursor T-cell lymphoblastic leukemia. She was treated according to a Tokyo Children's Cancer Study Group protocol (TCCSG ALL L09-1603 HEX/BFM). During the intensification phase, blisters with erythema developed on the arm proximal to the catheter insertion site owing to a delayed-type hypersensitivity reaction caused by intravenous L-Asp administration. She was treated with additional methylprednisolone, tapered dexamethasone, and an antihistamine for the allergic reaction. No asparaginases other than E. coli L-Asp have been approved for use in Japan. Other asparaginases, such as polyethylene glycol L-Asp and Erwinia L-Asp should be quickly approved for use as alternative chemotherapy reagents in Japan.

Tumor necrosis factor-α-induced mononuclear cell death may contribute to polymorphonuclear cell predominance in the cerebrospinal fluid of patients with bacterial meningitis.

BACKGROUND: Bacterial meningitis is characterized by a marked predominance of polymorphonuclear leukocytes (PMNs: segmented granulocytes or neutrophils) in the cerebrospinal fluid (CSF), whereas aseptic meningitis is characterized by a predominance of mononuclear leukocytes (MNs: lymphocytes or monocytes). However, the pathophysiology of this predominance of PMNs in the CSF of patients with bacterial meningitis has never, to our knowledge, been clearly described. METHODS: To investigate the predominant cell components of CSF from pediatric patients with bacterial meningitis, we investigated cell death in association with levels of tumor necrosis factor-alpha (TNF-α) in the CSF, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay and flow cytometry. RESULTS: The MTT assay of the CSF revealed that the PMNs had survived, while the MNs rapidly had undergone cell death. Although PMNs survived in CSF with high levels of TNF-α, PMN apoptosis was demonstrated with flow cytometry. CONCLUSIONS: The present study suggests that the pathophysiology of PMN predominance in the CSF of patients in the acute phase of bacterial meningitis is related to the rapid cell death of MNs and the survival of PMNs brought about by high levels of TNF-α.

Identification of a novel biomarker candidate, a 4.8-kDa peptide fragment from a neurosecretory protein VGF precursor, by proteomic analysis of cerebrospinal fluid from children with acute encephalopathy using SELDI-TOF-MS.

BACKGROUND: Acute encephalopathy includes rapid deterioration and has a poor prognosis. Early intervention is essential to prevent progression of the disease and subsequent neurologic complications. However, in the acute period, true encephalopathy cannot easily be differentiated from febrile seizures, especially febrile seizures of the complex type. Thus, an early diagnostic marker has been sought in order to enable early intervention. The purpose of this study was to identify a novel marker candidate protein differentially expressed in the cerebrospinal fluid (CSF) of children with encephalopathy using proteomic analysis. METHODS: For detection of biomarkers, CSF samples were obtained from 13 children with acute encephalopathy and 42 children with febrile seizure. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology, which is currently applied in many fields of biological and medical sciences. Diagnosis was made by at least two pediatric neurologists based on the clinical findings and routine examinations. All specimens were collected for diagnostic tests and the remaining portion of the specimens were used for the SELDI-TOF MS investigations. RESULTS: In experiment 1, CSF from patients with febrile seizures (n = 28), patients with encephalopathy (n = 8) (including influenza encephalopathy (n = 3), encephalopathy due to rotavirus (n = 1), human herpes virus 6 (n = 1)) were used for the SELDI analysis. In experiment 2, SELDI analysis was performed on CSF from a second set of febrile seizure patients (n = 14) and encephalopathy patients (n = 5). We found that the peak with an m/z of 4810 contributed the most to the separation of the two groups. After purification and identification of the 4.8-kDa protein, a 4.8-kDa proteolytic peptide fragment from the neurosecretory protein VGF precursor (VGF4.8) was identified as a novel biomarker for encephalopathy. CONCLUSIONS: Expression of VGF4.8 has been reported to be decreased in pathologically degenerative changes such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and encephalopathy. Thus, the VGF4.8 peptide might be a novel marker for degenerative brain conditions.

High mobility group box 1 in cerebrospinal fluid from several neurological diseases at early time points.

The present study aimed to elucidate the possible role of High Mobility Group Box 1 (HMGB1), which is a candidate prognostic marker in diseases that combine inflammation and tissue injury, in acute encephalopathy. HMGB1 in cerebrospinal fluid (CSF) obtained on admission from eight children with acute encephalopathy, and 16 children with febrile seizure, eight children with bacterial/aseptic meningitis, and eight children with fever without neurological symptoms were analyzed using enzyme-linked immunosorbent assay (ELISA). We found no increase in HMGB1 in CSF from acute encephalopathy or in CSF from febrile seizure or fever without neurological complications at early time points, while marked elevation of HMGB1 was seen in CSF from bacterial and aseptic meningitis. In conclusion, HMGB1 is a poor disease marker for acute encephalopathy.

Enhanced expression of cytokines/chemokines in cerebrospinal fluids in mumps meningitis in children.

BACKGROUND: The mumps virus is frequently the causative agent in aseptic meningitis and mumps has still prevailed in Japan. We compared data obtained from patients with mumps meningitis and patients with aseptic meningitis caused by other viruses in order to identify mumps meningitis-specific cytokine/chemokine alterations in cerebrospinal fluid (CSF). METHODS: We elucidated the cytokine/chemokine network based on the cytokine/chemokine profiles in CSF from children with mumps meningitis and meningitis due to other viral infections using multiplex cytokine measurement. Seventeen cytokines/chemokines, namely interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß), were measured simultaneously in CSF supernatants from eight children with mumps meningitis, 11 children with other types of viral meningitis and eight children with fever without neurological complications such as convulsion. RESULTS: We found that IL-8, IL-10, IL-12, IL-13 and IFN-γ showed a statistically significant increase in CSF from mumps meningitis when compared to other types of viral meningitis and fever without neurological complications. CONCLUSION: Mumps meningitis may induce a distinct immunological response when compared with other types of viral meningitis.

IL-17 is elevated in cerebrospinal fluids in bacterial meningitis in children.

Bacterial meningitis has a poor prognosis and neurologic complications. The present study aimed to investigate the cytokine/chemokine network in cerebrospinal fluid (CSF) from children with bacterial meningitis and aseptic meningitis. Interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta, were measured simultaneously in CSF supernatants. We found that, IL-17 was significantly elevated in CSF with bacterial meningitis. We believe that IL-17 plays a key role in neutrophil infiltration into CSF and neuronal protection in bacterial meningitis.

High prevalence of antibodies against Bartonella henselae with cervical lymphadenopathy in children.

BACKGROUND: Cat-scratch disease is the most common form of Bartonella henselae infection. Although reports have shown that CSD is relatively common, they have not shown the prevalence of seropositivity for Bartonella henselae in cases of cervical lymphadenitis and Kawasaki disease, which are relatively common diseases in children. METHODS: We evaluated the presence of immunoglobulin (Ig) G- and IgM-class antibodies against Bartonella henselae in children with cervical lymphadenitis, Kawasaki disease, and infectious diseases without lymphadenopathy in a semi-rural area in Japan. RESULTS: We found that the positivity rate for the IgG antibody against Bartonella henselae in patients with cervical lymphadenitis who owned cats or dogs was significantly higher than that in patients with Kawasaki disease and infectious diseases without lymphadenopathy. However, the average age of children with cervical lymphadenitis did not significantly differ when compared to those with other infectious diseases. CONCLUSION: Our serological study showed that Bartonella henselae infection may contribute to the etiology of cervical lymphadenitis in children.

Fungal thoracic Spondylodiskitis in an immunocompetent 14-year-old girl.

Fungal spondylodiskitis (inflammation of intervertebral disk tissue and adjacent vertebrae) is rare, particularly in immunocompetent patients. Here, we report a case of fungal and bacterial thoracic spondylodiskitis in a 14-year-old girl with abdominal and back pain. The spondylodiskitis was diagnosed on the basis of the presence of beta-D glucan and the unusual clinical course, although cultures for fungus were negative. We conclude spondylodiskitis must be considered in cases of abdominal pain without clear etiology and in cases of fungal infection with unexplainable findings after standard treatment for bacterial infection, even when fungal cultures are negative.

Concomitant severe normocytic and normochromic anemia in poststreptococcal acute glomerulonephritis.

Although anemia frequently occurs in poststreptococcal acute glomerulonephritis (PSAGN), severe anemia is rare. We report severe normocytic, normochromic anemia (hematocrit, 19.8%) in PSAGN in a 6-year-old girl with edema, macrohematuria, and proteinuria for 1 month. The potential causes of severe anemia found in this case were: 1) longer duration of massive hematuria from onset of macrohemauria to treatment, 2) a level of erythropoietin much lower than that in cases of iron deficiency anemia, and 3) hemodilution. We speculate that these factors combined to cause an unusual case of severe anemia in PSAGN.

An 8-year-old boy with vertebral artery dissection with cerebellar ataxia featuring suspected vertebral artery hypoplasia.

We report an 8-year-old boy with left vertebral artery dissection featuring cerebellar ataxia in which congenital vertebral artery hypoplasia was suspected as a predisposing factor in the dissection. The patient suddenly suffered from vertigo and vomiting while swimming, and he was brought to our department. The initial brain Computed Tomography (CT) demonstrated no abnormalities, and his symptoms disappeared the next morning. However, one month after onset, brain Magnetic Resonance Imaging (MRI) revealed ischemic changes (infarction) in the left cerebellum. Transfemoral angiography showed complete occlusion at the C2 portion of the left vertebral artery, suggesting dissection and diffuse narrowing of the proximal segment of the occlusion site. Three-dimensional CT angiography also revealed diffuse narrowing of the left vertebral artery from the bifurcation of the subclavian artery. He has since been living daily life without any difficulties. The detailed etiology of cerebral artery dissection remains unknown, but arterial anomalies should be considered as a predisposing factor.

Acute pancreatitis complicating typhoid fever in a 4-year-old girl.

Pancreatitis represents an extremely rare complication of typhoid fever. Herein we report the case of a 4-year-old Bangladeshi girl with acute pancreatitis caused by Salmonella typhi.