Masaya Kubota

Publications (41)68.48 Total impact

• Article: Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation.

  Mitsuhiro Kato, Takanori Yamagata, Masaya Kubota, Hiroshi Arai, Sumimasa Yamashita, Taku Nakagawa, Takanari Fujii, Kenji Sugai, Kaoru Imai, Tami Uster, [......], Mari Maeno, Kiyomi Nishiyama, Hirofumi Kodera, Mitsuko Nakashima, Yoshinori Tsurusaki, Noriko Miyake, Kayoko Saito, Kiyoshi Hayasaka, Naomichi Matsumoto, Hirotomo Saitsu
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  ABSTRACT: PURPOSE: KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation. METHODS: A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high-resolution melting (HRM) analysis or whole-exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation. KEY FINDINGS: A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression-burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate-to-profound intellectual disability was found in all except one patient who died at 3 months. SIGNIFICANCE: De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression-burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.
  Epilepsia 04/2013; · 3.96 Impact Factor
• Article: ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus.

  Mayu Shinohara, Makiko Saitoh, Daisuke Nishizawa, Kazutaka Ikeda, Shinichi Hirose, Jun-Ichi Takanashi, Junko Takita, Kenjiro Kikuchi, Masaya Kubota, Gaku Yamanaka, Takashi Shiihara, Akira Kumakura, Masahiro Kikuchi, Mitsuo Toyoshima, Tomohide Goto, Hideo Yamanouchi, Masashi Mizuguchi
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  ABSTRACT: OBJECTIVE: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures, leaving neurologic sequelae in many patients. However, its pathogenesis remains unclear. In this study, we clarified that genetic variation in the adenosine A2A receptor (ADORA2A), whose activation is involved in excitotoxicity, may be a predisposing factor of AESD. METHODS: We analyzed 4 ADORA2A single nucleotide polymorphisms in 85 patients with AESD. The mRNA expression in brain samples, mRNA and protein expression in lymphoblasts, as well as the production of cyclic adenosine monophosphate (cAMP) by lymphoblasts in response to adenosine were compared among ADORA2A diplotypes. RESULTS: Four single nucleotide polymorphisms were completely linked, which resulted in 2 haplotypes, A and B. Haplotype A (C at rs2298383, T at rs5751876, deletion at rs35320474, and C at rs4822492) frequency in patients was significantly higher than in controls (p = 0.005). Homozygous haplotype A (AA diplotype) had a higher risk of developing AESD (odds ratio 2.32, 95% confidence interval 1.32-4.08; p = 0.003) via a recessive model. mRNA expression was significantly higher in AA than AB and BB diplotypes, both in the brain (p = 0.003 and 0.002, respectively) and lymphoblasts (p = 0.035 and 0.003, respectively). In lymphoblasts, ADORA2A protein expression (p = 0.024), as well as cellular cAMP production (p = 0.0006), was significantly higher in AA than BB diplotype. CONCLUSIONS: AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients.
  Neurology 03/2013; · 8.31 Impact Factor
• Source

  Available from: Shinichi Hirose

  Article: Mutations of the SCN1A gene in acute encephalopathy.

  Makiko Saitoh, Mayu Shinohara, Hideki Hoshino, Masaya Kubota, Kaoru Amemiya, Jun-Lchi Takanashi, Su-Kyeong Hwang, Shinichi Hirose, Masashi Mizuguchi
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  ABSTRACT: Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthema subitum. It occurs worldwide, but is most prevalent in East Asia. Recently, there have been sporadic case reports of epilepsy/febrile seizure and acute encephalopathy with a neuronal sodium channel alpha 1 subunit (SCN1A) mutation. To determine whether SCN1A mutations are a predisposing factor of acute encephalopathy, we sought to identify SCN1A mutations in a large case series of acute encephalopathy including various syndromes. We analyzed the SCN1A gene in 87 patients with acute encephalopathy, consisting of 20 with acute necrotizing encephalopathy (ANE), 61 with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), and six with nonspecific (unclassified) acute encephalopathy. Three patients had distinct point mutations. Two of them had epileptic seizures prior to acute encephalopathy. Clinical and neuroradiologic findings of acute encephalopathy were diverse among the three patients, although all had a prolonged and generalized seizure at its onset. The first patient with V982L had partial epilepsy and AESD. The second patient with M1977L had febrile seizures and nonspecific acute encephalopathy. The third patient with R1575C had no seizures until the onset of ANE. M1977L was a novel mutation, whereas the remaining two, V982L and R1575C, have previously been reported in cases of Dravet syndrome and acute encephalopathy, respectively. These findings provide further evidence that SCN1A mutations are a predisposing factor for the onset of various types of acute encephalopathy.
  Epilepsia 03/2012; 53(3):558-64. · 3.96 Impact Factor
• Source

  Available from: Shinichi Hirose

  Article: Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes.

  Ai Hoshino, Makiko Saitoh, Akira Oka, Akihisa Okumura, Masaya Kubota, Yoshiaki Saito, Jun-Ichi Takanashi, Shinichi Hirose, Takanori Yamagata, Hideo Yamanouchi, Masashi Mizuguchi
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  ABSTRACT: A research committee supported by the Japanese government conducted a nationwide survey on the epidemiology of acute encephalopathy in Japan using a questionnaire. A total of 983 cases reportedly had acute encephalopathy during the past 3 years, 2007-2010. Among the pathogens of the preceding infection, influenza virus was the most common, followed by human herpesvirus-6 (HHV-6) and rotavirus. Among syndromes of acute encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was the most frequent, followed by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), acute necrotizing encephalopathy (ANE) and hemorrhagic shock and encephalopathy syndrome (HSES). Influenza virus was strongly associated with ANE and MERS, HHV-6 with AESD, and rotavirus with MERS. Mortality was high in ANE and HSES, but was low in AESD, MERS and HHV-6-associated encephalopathy. Neurologic sequelae were common in AESD and ANE, but were absent in MERS.
  Brain & development 09/2011; 34(5):337-43. · 1.74 Impact Factor
• Article: Brain vascular changes in Cockayne syndrome.

  Masaharu Hayashi, Naho Miwa-Saito, Naoyuki Tanuma, Masaya Kubota
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  ABSTRACT: Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are caused by deficient nucleotide excision repair. CS is characterized by cachectic dwarfism, mental disability, microcephaly and progeria features. Neuropathological examination of CS patients reveals dysmyelination and basal ganglia calcification. In addition, arteriosclerosis in the brain and subdural hemorrhage have been reported in a few CS cases. Herein, we performed elastica van Gieson (EVG) staining and immunohistochemistry for collagen type IV, CD34 and aquaporin 4 to evaluate the brain vessels in autopsy cases of CS, XP group A (XP-A) and controls. Small arteries without arteriosclerosis in the subarachnoid space had increased in CS cases but not in either XP-A cases or controls. In addition, string vessels (twisted capillaries) in the cerebral white matter and increased density of CD34-immunoreactive vessels were observed in CS cases. Immunohistochemistry findings for aquaporin 4 indicated no pathological changes in either CS or XP-A cases. Hence, the increased subarachnoid artery space may have caused subdural hemorrhage. Since such vascular changes were not observed in XP-A cases, the increased density of vessels in CS cases was not caused by brain atrophy. Hence, brain vascular changes may be involved in neurological disturbances in CS.
  Neuropathology 07/2011; 32(2):113-7. · 2.02 Impact Factor
• Article: Oxidative stress in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS).

  Rie Miyata, Naoyuki Tanuma, Masaharu Hayashi, Takuji Imamura, Jun-ichi Takanashi, Rieko Nagata, Akihisa Okumura, Hirohumi Kashii, Sunao Tomita, Satoko Kumada, Masaya Kubota
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  ABSTRACT: We examined oxidative stress markers, tau protein and cytokines in the cerebrospinal fluid (CSF) in six patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). In the CSF, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct levels increased over the cutoff index in four and one out of six MERS patients, respectively. The CSF IL-6 and IL-10 levels were increased in three out of six patients, two of which had extended lesion of the cerebral white matter. The CSF value of tau protein, marker of the axonal damage, was not increased, and neuron specific enolase (NSE) in the CSF was not increased. The increased 8-OHdG levels in the CSF, DNA oxidative stress marker, in four MERS patients, suggesting involvement of oxidative stress in MERS. MERS is occasionally accompanied with hyponatremia, although our patients lacked hyponatremia. It is possible that the disequilibrium of systemic metabolism including electrolytes may lead to facilitation of oxidative stress and reversible white matter lesion in MERS. The increase of cytokine production seems to be involved in the distribution of lesions in MERS.
  Brain & development 05/2011; 34(2):124-7. · 1.74 Impact Factor
• Article: Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome.

  Yoshiaki Saito, Masaya Kubota, Kenji Kurosawa, Izumi Ichihashi, Yuu Kaneko, Ayako Hattori, Hirofumi Komaki, Eiji Nakagawa, Kenji Sugai, Masayuki Sasaki
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  ABSTRACT: A 3-months-old boy presented with partial seizures that soon evolved into infantile spasms. Magnetic resonance imaging revealed bilateral perisylvian polymicrogyria with right-sided predominance. ACTH therapy successfully controlled epilepsy and electroencephalograms were normalized. Conventional G-banded chromosomal analysis was performed due to his distinctive features and a derivative chromosome 1 derived from parental balanced translocation with a karyoptype of 46,XY,der(1)t(1;4)(p36.23;q35) was detected. Fluorescent in situ hybridization analysis confirmed the deleted region of 1p36 as large as 8.6Mb. This is the first delineation of concurrent complications of infantile spasms and polymicrogyria in patient with 1p36 deletion. 1p36 deletion syndrome should be broadly recognized as a differential diagnosis of regional polymicrogyria and/or infantile spasms.
  Brain & development 05/2011; 33(5):437-41. · 1.74 Impact Factor
• Article: Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children.

  Masaya Kubota, Junji Chida, Hideki Hoshino, Hiroshi Ozawa, Ayaka Koide, Hirohumi Kashii, Akiko Koyama, Yoko Mizuno, Ai Hoshino, Miyoko Yamaguchi, Dengbing Yao, Min Yao, Hiroshi Kido
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  ABSTRACT: Despite the decrease in Reye syndrome after the discontinuation of aspirin, acute encephalopathy (non-Reye syndrome type) has been continually reported in Japan. Recent studies suggested that the thermolabile phenotype of carnitine palmitoyltransferase II (CPT II) variation [F352C] was closely related to the pathomechanism of influenza-associated encephalopathy (IAE) in Japanese, causing mitochondrial ATP utilization failure during periods of high fever, resulting in brain edema. So, we analyzed CPT II polymorphism and peripheral blood ATP levels as a signal of "energy crisis" in 12 and 10 patients with acute encephalopathy, respectively. Out of the 12 patients with acute encephalopathy, six showed thermolabile CPT II variants [F352C], and of these six, two patients died in spite of intensive care. In contrast, the remaining six patients with no thermolabile CPT II variant [F352C] showed a relatively mild clinical course. Blood ATP levels of the 10 patients in the acute phase of encephalopathy were significantly lower than those during the convalescent phase and also those of patients with febrile seizure status. Our data suggest that the thermolabile F352C CPT II variant, found only in Japanese, might be one of the predisposing factors to trigger the pathomechanism of acute encephalopathy in the Japanese population, and that it is causally related to the severity of disease. The decreased blood ATP level seems to reflect systemic mitochondrial dysfunction including the blood brain barrier during the acute phase of encephalopathy.
  Brain & development 01/2011; 34(1):20-7. · 1.74 Impact Factor
• Article: Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases.

  Mayu Shinohara, Makiko Saitoh, Jun-ichi Takanashi, Hideo Yamanouchi, Masaya Kubota, Tomohide Goto, Masahiro Kikuchi, Takashi Shiihara, Gaku Yamanaka, Masashi Mizuguchi
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  ABSTRACT: The high incidence of acute encephalopathy in East Asia suggests the role of genetic factors in its pathogenesis. It has recently been reported that variations of the CPT II (carnitine palmitoyl transferase II) gene may be associated with fatal or severe cases of influenza-associated encephalopathy. In the present study, we examined the genotype of CPT II in cases of acute encephalopathy associated with various preceding infections. Twenty-nine Japanese patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) or acute necrotizing encephalopathy (ANE) were studied. The frequency of F352C of CPT II exon 4 was significantly higher in patients than in controls. All patients who had allele C in F352C had allele I in V368I and allele M in M647V (CIM haplotype), which reportedly decreases CPT II activity to one third of that with FIM or FVM haplotype. The frequency of CIM haplotype was significantly different between patients and controls, but not between AESD and ANE. Our results revealed that having at least one CIM allele is a risk factor for the onset of acute encephalopathy, regardless of its antecedent infections.
  Brain & development 10/2010; 33(6):512-7. · 1.74 Impact Factor
• Article: STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.

  Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Kenji E Orii, Tsukasa Higuchi, Hideki Hoshino, Masaya Kubota, Hiroshi Arai, Tetsuzo Tagawa, Shigeru Kimura, [......], Yuichi Takami, Toshihide Watanabe, Akira Nishimura, Kiyomi Nishiyama, Noriko Miyake, Takahito Wada, Hitoshi Osaka, Naomi Kondo, Kiyoshi Hayasaka, Naomichi Matsumoto
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  ABSTRACT: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
  Epilepsia 09/2010; 51(12):2397-405. · 3.96 Impact Factor
• Article: High-dose lorazepam for convulsive status epilepticus in an infant with holoprosencephaly.

  Kaoru Okazaki, Masatoshi Kondo, Masaya Kubota, Ryota Kakinuma, Ai Hoshino, Hirokazu Kimura, Susumu Itoh
  Pediatrics International 08/2010; 52(4):664-7. · 0.63 Impact Factor
• Article: The axonal damage marker tau protein in the cerebrospinal fluid is increased in patients with acute encephalopathy with biphasic seizures and late reduced diffusion.

  Naoyuki Tanuma, Rie Miyata, Satoko Kumada, Masaya Kubota, Jun-ichi Takanashi, Akihisa Okumura, Shin-Ichiro Hamano, Masaharu Hayashi
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  ABSTRACT: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a recently clinicoradiologically-established encephalopathy syndrome. In the present study, we examined the levels of cerebrospinal fluid (CSF) tau protein, a marker of axonal damage, in 11 patients with AESD. CSF tau levels were normal on day 1 and increased from day 3 of the disease between the initial and the secondary seizures. Magnetic resonance imaging (MRI) reveals reduced diffusion in the subcortical white matter during days 3-7. Two patients showed elevated tau protein prior to the diffusion abnormality of subcortical white matter on MRI. Levels of CSF neuron specific enolase (NSE), a neuronal marker, were elevated in only two out of seven patients with AESD, and CSF tau levels were also increased in these patients. Our results indicated that tau protein is a more sensitive marker than NSE and axonal damage causes the conspicuous MRI findings in AESD patients. A therapeutic strategy for axonal protection should be developed to prevent severe neurological impairment of AESD patients.
  Brain & development 09/2009; 32(6):435-9. · 1.74 Impact Factor
• Article: [Long term clinical course of Canavan disease--a rare Japanese case].

  Koichi Mizuguchi, Hideki Hoshino, Hiroshi Hamaguchi, Masaya Kubota
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  ABSTRACT: Canavan disease (CD), which is a rare disease in Japan, is an autosomal-recessive neurodegenerative disorder caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain. CD affected children usually die by the age of 10 years. Here we report a long term clinical course of a 21-year-old Japanese woman who was diagnosed as CD at the age 4. This patient is the only reported case of CD in Japan that has been biochemically confirmed. Although this patient is currently bed-ridden with spastic quadriplegia and severe mental retardation, her general condition is quite stable. This patient showed a milder clinical course compared to the majority of CD patients. Because this is the only reported case of CD in Japan, we hypothesize that there might be an ethnic phenotypic polymorphism in CD.
  No to hattatsu. Brain and development 09/2009; 41(5):353-6.
• Article: Maternal uniparental disomy 14 syndrome demonstrates prader-willi syndrome-like phenotype.

  Kana Hosoki, Masayo Kagami, Touju Tanaka, Masaya Kubota, Kenji Kurosawa, Mitsuhiro Kato, Kimiaki Uetake, Jun Tohyama, Tsutomu Ogata, Shinji Saitoh
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  ABSTRACT: To delineate the significance of maternal uniparental disomy 14 (upd(14)mat) and related disorders in patients with a Prader-Willi syndrome (PWS)-like phenotype. We examined 78 patients with PWS-like phenotype who lacked molecular defects for PWS. The MEG3 methylation test followed by microsatellite polymorphism analysis of chromosome 14 was performed to detect upd(14)mat or other related abnormalities affecting the 14q32.2-imprinted region. We identified 4 patients with upd(14)mat and 1 patient with an epimutation in the 14q32.2 imprinted region. Of the 4 patients with upd(14)mat, 3 had full upd(14)mat and 1 was mosaic. Upd(14)mat and epimutation of 14q32.2 represent clinically discernible phenotypes and should be designated "upd(14)mat syndrome." This syndrome demonstrates a PWS-like phenotype particularly during infancy. The MEG3 methylation test can detect upd(14)mat syndrome defects and should therefore be performed for all undiagnosed infants with hypotonia.
  The Journal of pediatrics 09/2009; 155(6):900-903.e1. · 4.02 Impact Factor
• Article: Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications.

  Keiko Shimojima, Takehiko Inoue, Ai Hoshino, Satsuki Kakiuchi, Yoshiaki Watanabe, Masayuki Sasaki, Akira Nishimura, Akiko Takeshita-Yanagisawa, Go Tajima, Hiroshi Ozawa, Masaya Kubota, Jun Tohyama, Akira Oka, Kayoko Saito, Makiko Osawa, Toshiyuki Yamamoto
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  ABSTRACT: Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10-25% of all patients with PMD, respectively, with a wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous in patients with PMD, clarification of the genotype-phenotype correlation is the object of this study. Comprehensive genetic analyses using microarray-based comparative genomic hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities. Although the grades of dysmyelination estimated by MRI findings were well correlated to the clinical phenotypes of the patients, there is no correlation between the size of the duplications and the phenotypic severity.
  Brain & development 04/2009; 32(3):171-9. · 1.74 Impact Factor
• Article: Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection.

  Takashi Ichiyama, Yoshinori Ito, Masaya Kubota, Tsutomu Yamazaki, Kazuyuki Nakamura, Susumu Furukawa
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  ABSTRACT: Human herpesvirus-6 (HHV-6) is a causative agent of exanthema subitum. The immunological pathogenesis of acute encephalopathy associated with HHV-6 infection is still unclear. 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 serum and cerebrospinal fluid (CSF) during the acute stage in 15 infants with acute encephalopathy and 12 with febrile seizures associated with HHV-6 infection. The serum IL-6, IL-10, sTNFR1, CSF IL-6, and sTNFR1 levels of infants with encephalopathy who had neurological sequelae (n=9) were significantly higher than those with febrile seizures (p=0.011, 0.043, 0.002, 0.029, and 0.005, respectively). In acute encephalopathy, serum IL-6, sTNFR1, and CSF IL-6 levels in infants with neurological sequelae were significantly higher than those without (n=6) neurological sequelae (p=0.043, 0.026, and 0.029, respectively), and serum IFN-gamma, IL-6, IL-10, and sTNFR1 levels were significantly higher than those in the CSF (p=0.037, 0.037, 0.001, and 0.021, respectively). There were no significant differences in serum or CSF cytokine levels between infants who were positive for HHV-6 DNA in the CSF (n=6) compared to those who were negative (n=9). We suggest that cytokines mediate the pathogenesis of acute encephalopathy associated with HHV-6 infection, and that the elevated levels of serum IL-6, sTNFR1, and CSF IL-6 are important for predicting neurological sequelae.
  Brain & development 01/2009; 31(10):731-8. · 1.74 Impact Factor
• Article: [Early and serial electrodiagnostic findings in childhood Guillain-Barré syndrome].

  Koichi Mizuguchi, Hideki Hoshino, Yuichi Abe, Tetsuro Nagasawa, Akira Oka, Masaya Kubota
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  ABSTRACT: We investigated the usefulness of electrodiagnostic (EDX) studies for the early diagnosis of childhood Guillain-Barré syndrome (GBS). We retrospectively reviewed 5 patients (ages, 17-96 months) who fulfilled the diagnostic criteria of GBS. The EDX studies were performed at least twice;they included 1 or more following:motor nerve conduction study (MNCS), F-wave study, electromyography (EMG), and sensory nerve conduction study. The first and second EDX studies were performed at 8 days (range:4-13 days) and 14 days (range: 12-27 days) after the onset of motor symptoms, respectively. Although only 3 of 5 patients showed abnormal findings in the first MNCS, additional EDX studies, namely, F-wave study and EMG confirmed the presence of peripheral neuropathy in all patients. Regarding the classification of GBS subtypes, the results of the first EDX studies lead to the diagnosis of acute inflammatory demyelinating polyneuropathy (AIDP) in 3 patients and the remaining two were diagnosed with AIDP based on results of the second studies. We concluded that serial EDX studies, including F-wave studies, are essential for the early and definite diagnosis of childhood GBS.
  No to hattatsu. Brain and development 12/2008; 40(6):460-4.
• Article: Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures.

  Naoko Suenaga, Takashi Ichiyama, Masaya Kubota, Hiroshi Isumi, Jun Tohyama, Susumu Furukawa
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  ABSTRACT: 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.
  Journal of the Neurological Sciences 04/2008; 266(1-2):126-30. · 2.35 Impact Factor
• Article: Early hemispherotomy in a patient with multilobar cortical dysplasia with intractable seizure: clinical-neurophysiological study.

  Masaya Kubota, Keiji Goishi, Sachiko Takemura, Kensuke Kawai, Nobutaka Arai
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  ABSTRACT: We present a patient with multilobar cortical dysplasia who underwent hemispherotomy, a modified functional hemispherectomy, at the age of 2 months because of intractable seizures and report the clinical-neurophysiological findings including EEG and somatosensory evoked potentials (SEP). After hemispherotomy, the seizures and EEG abnormality disappeared completely and postoperative SEP showed an ipsilateral cortical response at the unaffected hemisphere, suggesting a reorganization process, which was possibly facilitated more intensively after surgery. Furthermore, developmental catch-up was observed. Our patient's clinical course and neurophysiological data suggested that very early hemispherotomy resulted in not only the control of seizures but also a better developmental outcome.
  European Journal of Paediatric Neurology 03/2008; 12(6):516-20. · 2.12 Impact Factor
• Article: Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures.

  Takashi Ichiyama, Naoko Suenaga, Madoka Kajimoto, Jun Tohyama, Hiroshi Isumi, Masaya Kubota, Masato Mori, Susumu Furukawa
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  ABSTRACT: 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.
  Brain and Development 02/2008; 30(1):47-52. · 2.12 Impact Factor