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ABSTRACT: Aim To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia. Method Eighty-six patients born at term with cerebral palsy (CP) and spastic diplegia (54 males, 32 females; median age 20y, range 7-42y) among 829 patients with CP underwent brain MRI between 1990 and 2008. The MRI and clinical findings were analysed retrospectively. Intellectual disability was classified according to the Enjoji developmental test or the Wechsler Intelligence Scale for Children (3rd edition). Results The median ages at diagnosis of CP, assignment of Gross Motor Function Classification System (GMFCS) level, cognitive assessment, and MRI were 2 years (range 5mo-8y), 6 years (2y 8mo-19y), 6 years (1y 4mo-19y), and 7 years (10mo-30y) respectively. MRI included normal findings (41.9%), periventricular leukomalacia, hypomyelination, and porencephaly/periventricular venous infarction. The frequency of patients in GMFCS levels III to V and intellectual disability did not differ between those with normal and abnormal MRI findings. Patients with normal MRI findings had significantly fewer epileptic episodes than those with abnormal ones (p=0.001). Interpretation Varied MRI findings, as well as the presence of severe motor dysfunction and intellectual disability (despite normal MRI), suggest that patients born at term with spastic diplegia had heterogeneous and unidentified pathophysiology.
Developmental Medicine & Child Neurology 11/2012; · 2.92 Impact Factor
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Shuei Watanabe,
Akitoshi Murayama,
Kazuhiro Haginoya,
Soichiro Tanaka,
Noriko Togashi,
Daiki Abukawa,
Atsushi Sato,
Masue Imaizumi,
Hideto Yoshikawa,
Rumiko Takayama,
Keisuke Wakusawa,
Satoru Kobayashi,
Ikuko Sato, Akira Onuma
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ABSTRACT: Here, we report a male child with Schinzel-Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel-Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.
Brain & development 04/2011; 34(2):151-5. · 1.74 Impact Factor
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ABSTRACT: To investigate the role of tissue inhibitors of metalloproteinases (TIMPs) in muscular dystrophy, we examined the expression of TIMP-1 using plasma and biopsied muscle from patients with various muscular dystrophies by ELISA, immunohistochemistry, and Western blot analysis. TIMP-1 immunolocalization was also studied in mouse models of muscular dystrophy. Plasma TIMP-1 was elevated and correlated with TGF-β1 in Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy (CMD), but not in Becker muscular dystrophy. In dystrophic human muscles, TIMP-1 was immunopositive in the regenerating and non-regenerating muscle fibers, and interstitial cells that consist of activated fibroblasts and macrophages. TIMP-1 immunoreactivity was also closely associated with TGF-β1. Western blot analysis showed elevated TIMP-1 protein in muscles in DMD. The semiquantitative analysis of TIMP-1 staining intensity and tissue fibrosis showed that TIMP-1 immunoreactivity is closely associated with the extent of tissue fibrosis in human and mouse dystrophic muscles. In conclusion, the present study implied that the TGF-β1-TIMP-1 pathway is activated in dystrophic muscles and the overexpression of TIMP-1 may result in increased deposition of extracellular matrix leading to tissue fibrosis.
Journal of the neurological sciences 10/2010; 297(1-2):19-28. · 2.32 Impact Factor
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Ikuko Sato, Akira Onuma,
Nobue Goto,
Fumiaki Sakai,
Ikuma Fujiwara,
Mitsugu Uematsu,
Hitoshi Osaka,
Satomi Okahashi,
Ikuya Nonaka,
Soichiro Tanaka,
Kazuhiro Haginoya
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ABSTRACT: Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease, characterized by both central and peripheral hypomyelination. We describe a 21-year-old male with mildly progressive ataxia, mental retardation, pituitary hypogonadotropic hypogonadism, delayed dentition, and cataract. Brain magnetic resonance imaging showed hypomyelinated white matter, cerebellar atrophy, and a thin corpus callosum. The literature suggests that abnormal findings upon sural nerve biopsy may indicate peripheral hypomyelination, even in the absence of clinically and physiologically evident peripheral neuropathy. A sural nerve biopsy of this patient was normal, and this finding is further discussed. Taken together with previous reports, this case suggests that 4H syndrome can be regarded as a spectrum disorder, the cardinal signs of which may be central hypomyelination, ataxia, hypogonadotropic hypogonadism, and hypodontia.
Journal of the neurological sciences 09/2010; 300(1-2):179-81. · 2.32 Impact Factor
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Naomi Hino-Fukuyo,
Kazuhiro Haginoya,
Mitsugu Uematsu,
Tojo Nakayama,
Atsuo Kikuchi,
Shigeo Kure,
Fumiaki Kamada,
Yu Abe,
Natsuko Arai,
Noriko Togashi, Akira Onuma,
Shigeru Tsuchiya
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ABSTRACT: Smith-Magenis syndrome is characterized by multiple congenital anomalies and mental retardation caused by the heterozygous deletion of chromosomal region 17p11.2. We present a long-term follow-up study of a girl with Smith-Magenis syndrome and West syndrome. West syndrome became apparent at 7 months of age. Since then, mental retardation, particularly in terms of language development, became increasingly more obvious. The patient's spasms and hypsarrhythmia disappeared after a course of adrenocorticotropic hormone therapy, but focal seizures reappeared at the age of 3 years and 3 months. Her craniofacial dysmorphia and mental retardation became increasingly evident compared to her condition at the onset of West syndrome. Chromosome analysis detected the characteristic 17p deletion, which was then confirmed via fluorescent in situ hybridization analysis. This is the second report of a patient with Smith-Magenis syndrome and West syndrome; taken together, these results suggest that Smith-Magenis syndrome may be a further cause of West syndrome.
Journal of child neurology 04/2009; 24(7):868-73. · 1.59 Impact Factor
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ABSTRACT: To investigate the role of the muscular renin-angiotensin system (RAS) in human muscular dystrophy, we used immunohistochemistry and Western blotting to examine the cellular localization of angiotensin-converting enzyme (ACE), the angiotensin II type 1 receptor (AT1) and the angiotensin II type 2 receptor (AT2) in muscle biopsies from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy (CMD). In normal muscle, ACE was expressed in vascular endothelial cells and neuromuscular junctions (NMJs), whereas AT1 was immunolocalized to the smooth muscle cells of blood vessels and intramuscular nerve twigs. AT2 was immunolocalized in the smooth muscle cells of blood vessels. These findings suggest that the RAS has a functional role in peripheral nerves and NMJs. ACE and AT1, but AT2 immunoreactivity were increased markedly in dystrophic muscle as compared to controls. ACE and the AT1 were strongly expressed in the cytoplasm and nuclei of regenerating muscle fibers, fibroblasts, and in macrophages infiltrating necrotic fibers. Double immunolabeling revealed that activated fibroblasts in the endomysium and perimysium of DMD and CMD muscle were positive for ACE and AT1. Triple immunolabeling demonstrated that transforming growth factor-beta1 (TGF-beta1) and ACE were colocalized on the cytoplasm of activated fibroblasts in dystrophic muscle. Furthermore, Western blotting showed increases in the expression of AT1 and TGF-beta1 protein in dystrophic muscle, which coincided with our immunohistochemical results. The overexpression of ACE and AT1 in dystrophic muscle would likely result in the increased production of Ang II, which may act on these cells in an autocrine manner via AT1. The activation of AT1 may induce fibrous tissue formation through overexpression of TGF-beta1, which potently activates fibrogenesis and suppresses regeneration. In conclusion, our results imply that the intramuscular RAS-TGF-beta1 pathway is activated in human muscular dystrophy and plays a role at least partly in the pathophysiology of this disease.
Journal of the neurological sciences 03/2009; 280(1-2):40-8. · 2.32 Impact Factor
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Mitsutoshi Munakata,
Masazumi Nishikawa,
Noriko Togashi,
Eiko Nio,
Yasuko Kobayashi,
Kiyoshi Omura,
Kazuhiro Haginoya,
Soichiro Tanaka,
Takuya Abe,
Takanori Hishinuma,
Nobukazu Chida,
Shigeru Tsuchiya, Akira Onuma
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ABSTRACT: Currently, various formulas with different fatty acid compositions are used for enteral nutrition (EN). All formulas contain various concentrations of essential fatty acids: linoleic acid (LA) and alpha-linolenic acid (ALA); LA is biotransformed into arachidonic acid (AA) and ALA into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in vivo. Some formulas contain preformed EPA and DHA. However, the effects of the differences in the fatty acid composition on the fatty acid status of patients receiving long-term EN is not clear. We measured serum fatty acid concentrations in 50 patients with neurological diseases receiving long-term EN. The data were then compared retrospectively with reference to the fatty acid compositions of the formulas used. All of the patients received almost their entire nutritional intake via EN for at least 1 year. Blood samples were obtained just before injecting the EN solution. Among the formulas that did not include EPA or DHA, formulas with low ALA concentrations were associated with low serum EPA and DHA. Conversely, the ALA-enriched formulas with reduced LA concentrations significantly increased EPA and DHA levels, although the levels remained lower than the control values. With the formula containing EPA and DHA, the EPA and DHA levels reached control values. Therefore, the fatty acid composition of the EN formulas affected the fatty acid status of patients receiving long-term EN. Formulas containing preformed EPA and DHA with suitable amounts of essential fatty acids may benefit these patients.
The Tohoku Journal of Experimental Medicine 02/2009; 217(1):23-8. · 1.24 Impact Factor
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ABSTRACT: The detailed process of how dystrophic muscles are replaced by fibrotic tissues is unknown. In the present study, the immunolocalization and mRNA expression of connective tissue growth factor (CTGF) in muscles from normal and dystrophic human muscles were examined with the goal of elucidating the pathophysiological function of CTGF in muscular dystrophy. Biopsies of frozen muscle from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, congenital muscular dystrophy, spinal muscular atrophy, congenital myopathy were analyzed using anti-CTGF polyclonal antibody. Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to evaluate the expression of CTGF mRNA in dystrophic muscles. In normal muscle, neuromuscular junctions and vessels were CTGF-immunopositive, which suggests a physiological role for CTGF in these sites. In dystrophic muscle, CTGF immunoreactivity was localized to muscle fiber basal lamina, regenerating fibers, and the interstitium. Triple immunolabeling revealed that activated fibroblasts were immunopositive for CTGF and transforming growth factor-beta1 (TGF-beta1). RT-PCR analysis revealed increased levels of CTGF mRNA in the muscles of DMD patients. Co-localization of TGF-beta1 and CTGF in activated fibroblasts suggests that CTGF expression is regulated by TGF-beta1 through a paracrine/autocrine mechanism. In conclusion, TGF-beta1-CTGF pathway may play a role in the fibrosis that is commonly observed in muscular dystrophy.
Journal of the Neurological Sciences 05/2008; 267(1-2):48-56. · 2.35 Impact Factor
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ABSTRACT: Patients with severe neurological disorders often require enteral nutrition (EN). Since long-term EN can cause multiple complications, reinstating the oral intake of food is beneficial. Olfactory stimulation using black pepper oil (BPO), a strong appetite stimulant, was reported to facilitate swallowing in older people. Therefore, the effects of olfactory stimulation with BPO were investigated in pediatric patients receiving long-term EN due to neurological disorders. The effects of scenting with BPO for 1 min immediately before every meal were evaluated in ten patients: 4 boys and 6 girls, aged 19-97 months (51 +/- 26 months). The neurological disorders included periventricular leukomalacia (3 patients), hypoxic ischemic encephalopathy (3), Costello syndrome (1), Russell-Silver syndrome (1), Miller-Dieker syndrome (1), and cerebral palsy of unknown etiology (1). In eight of these patients, BPO intervention was continued for 3 months. Five of these eight patients showed increases in the amount of oral intake with desirable effects including facilitated swallowing movement, although complete elimination of the need for EN was not achieved. In the other three patients, BPO intervention was not effective; severe cerebral tissue loss, profound malformation or intractable seizures seemed to reduce the efficacy of BPO. In two cases, BPO intervention was discontinued due to cough or because the odor of BPO was unbearable to the family. In conclusion, olfactory stimulation with BPO facilitated oral intake in a subset of patients on long-term EN. BPO stimulation may be useful for facilitating oral intake when used in combination with conventional methods.
The Tohoku Journal of Experimental Medicine 05/2008; 214(4):327-32. · 1.24 Impact Factor
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ABSTRACT: The exposure to mercury (Hg) of various groups of people with different dietary backgrounds has been assessed because of its hazardous effects, but little is known about that in patients receiving enteral nutrition. Therefore, we studied the Hg exposure in 25 patients with severe motor disabilities, who received liquid enteral feedings for more than one year, by determining total mercury (T-Hg) in their hair samples with inductively coupled plasma-mass spectrometry. The geometric mean of the T-Hg level in hair from the patients was 88 ng/g hair (+/- 1 geometric standard deviation [GSD], 34 - 228 ng/g), whereas that for the control group on a normal diet was 1,900 ng/g (+/- 1 GSD, 1,022 - 3,531 ng/g). The T-Hg levels in the patients' hair were far lower than those in the controls (p < 0.001). The T-Hg levels in the enteral feedings used were below the detection limit of cold-vapor atomic absorption spectrophotometry (< 10 ng/g). The present study has shown that Hg exposure is low in patients receiving enteral nutrition, indicating that food is a primary source of Hg exposure.
The Tohoku Journal of Experimental Medicine 11/2006; 210(3):209-12. · 1.24 Impact Factor
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ABSTRACT: The concentrations of essential trace elements (copper, zinc, selenium, manganese, chromium, molybdenum, cobalt, and iodine) in the scalp hair of 21 patients with severe motor disabilities receiving enteral nutrition were measured using inductively coupled plasma-mass spectrometry. Preliminary results show that copper, selenium, and molybdenum concentrations in the patients' hair were significantly lower than those in an age-matched control group (p<0.01). This suggests that intake of these elements may be reduced in patients receiving restricted enteral nutrition, although the clinical significance of these results should be discussed.
Brain and Development 10/2006; 28(8):521-5. · 2.12 Impact Factor
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ABSTRACT: We examined the fiber organization of the brain in three patients with unilateral polymicrogyria (PMG) using diffusion tensor imaging (DTI) in combination with functional magnetic resonance imaging (fMRI). DTI revealed altered fiber tract architecture in patients with PMG. Long projection fibers, such as the corticospinal tract, were reduced the most, whereas long association fibers were less affected. The diminution of the fiber tracts was relevant to the loss of functionality of the PMG-affected cortex. Our preliminary study suggests that the combination of DTI and fMRI reinforces the clinical assessment of functionality in PMG.
Brain and Development 08/2006; 28(6):405-9. · 2.12 Impact Factor
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ABSTRACT: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the infantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory findings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only eight cases have been reported in the literature, and thus the natural course and treatment of this disease are not fully understood. We report a 35-month-old boy with H-ABC who had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after considering a thorough differential diagnosis, excluding other diseases involving hemidystonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cysteinate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and positron emission tomography with fluorodeoxyglucose (18)F (FDG-PET) revealed decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus, and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa) was effective at ameliorating and stopping the progression of the patient's dystonia (final effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-carbidopa may be an effective treatment for H-ABC.
The Tohoku Journal of Experimental Medicine 07/2006; 209(2):163-7. · 1.24 Impact Factor
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Mitsutoshi Munakata,
Osamu Sakamoto,
Taro Kitamura,
Mamiko Ishitobi,
Hiroyuki Yokoyama,
Kazuhiro Haginoya,
Noriko Togashi,
Hajime Tamura,
Shuichi Higano,
Shoki Takahashi,
Toshihiro Ohura,
Yasuko Kobayashi, Akira Onuma,
Kazuie Iinuma
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ABSTRACT: We report on metabolic changes in the brain of a boy with Menkes disease. He was treated with parenteral copper (Cu)-histidine supplementation, from 5 months of age, and assessed with proton magnetic resonance spectroscopy ((1)H-MRS). The single-voxel (1)H-MRS before treatment revealed an accumulation of lactate and a reduced N-acetyl aspartate (NAA)/total creatine (tCr) ratio with a z-score of -3.0. During treatment, the lactate signal faded away, whereas the NAA signal gradually increased to a z-score of -1.5 at 120 days of treatment. The choline/tCr ratio did not deviate much initially (z-score +0.5), but the ratio increased markedly during treatment (z-score +4.8). Consequently, the Cu-histidine therapy initiated after the critical period still improved the neuronal metabolism, suggesting that some Cu was delivered to neurons. Nevertheless, the brain atrophy, impaired myelination, and severe neurological symptoms were not ameliorated.
Brain and Development 07/2005; 27(4):297-300. · 2.12 Impact Factor
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ABSTRACT: To identify crucial factors that precipitate cerebral palsy by controlling confounding factors in logistic regression analyses.
We retrospectively investigated a cohort of all 922 infants with gestational ages of less than 34 weeks (22-33 weeks), who were admitted to our neonatal intensive care unit between 1990 and 1998. Thirty (3.7%) were diagnosed to have cerebral palsy. We analyzed the prenatal and postnatal clinical variables of the cerebral palsy cases and compared them with 150 randomly selected controls.
Risk factors for cerebral palsy identified in univariate analysis were: twin pregnancy, long-term ritodrine tocolysis, respiratory distress syndrome, air leak, surfactant administration, intermittent mandatory ventilation, high frequency oscillation, lowest PaCO2 levels, prolonged hypocarbia during the first 72 h of life, and postnatal steroid therapy. In a conditional multiple logistic model, long-term ritodrine tocolysis, prolonged hypocarbia and postnatal steroid therapy remained associated with an increased risk of cerebral palsy after adjustment for other antenatal and postnatal variables (OR [Odds Ratio] = 8.62, 95% CI [Confidence Interval], 2.18-33.97; OR = 7.81, 95% CI, 1.42-42.92; OR = 21.37, 95% CI, 2.01-227.29, respectively).
Our results suggest that long-term ritodrine tocolysis underlines the development of cerebral palsy. Further assessments of the effect of ritodrine on fetal circulation and nervous system are required. Moreover, possible alternatives to systemic postnatal steroids are needed, and carbon dioxide levels should be more strictly controlled.
Early Human Development 07/2005; 81(6):545-53. · 2.05 Impact Factor
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ABSTRACT: This study has examined the immunological localization of platelet-derived growth factor (PDGF)-A, PDGF-B, and PDGF receptor (PDGFR) alpha and beta to clarify their role in the progression of muscular dystrophy. Biopsied frozen muscles from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy (CMD) were analysed immunohistochemically using antibodies raised against PDGF-A, PDGF-B, and PDGFR alpha and beta. Muscles from two dystrophic mouse models (dy and mdx mice) were also immunostained with antibodies raised against PDGFR alpha and beta. In normal human control muscle, neuromuscular junctions and vessels were positively stained with antibodies against PDGF-A, PDGF-B, PDGFR alpha and PDGFR beta. In human dystrophic muscles, PDGF-A, PDGF-B, PDGFR alpha and PDGFR beta were strongly immunolocalized in regenerating muscle fibres and infiltrating macrophages. PDGFR alpha was also immunolocalized to the muscle fibre sarcolemma and necrotic fibres. The most significant finding in this study was a remarkable overexpression of PDGFR beta and, to a lesser extent, PDGFR alpha in the endomysium of DMD and CMD muscles. PDGFR was also overexpressed in the interstitium of muscles from dystrophic mice, particularly dy mice. Double immunolabelling revealed that activated interstitial fibroblasts were clearly positive for PDGFR alpha and beta. However, DMD and CMD muscles with advanced fibrosis showed very poor reactivity against PDGF and PDGFR. Those findings were confirmed by immunoblotting with PDGFR beta. These findings indicate that PDGF and its receptors are significantly involved in the active stage of tissue destruction and are associated with the initiation or promotion of muscle fibrosis. They also have roles in muscle fibre regeneration and signalling at neuromuscular junctions in both normal and diseased muscle.
The Journal of Pathology 10/2003; 201(1):149-59. · 6.32 Impact Factor
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ABSTRACT: We experienced five cases of developmentally retarded children with "bottle feeding dependency", that is, refusal against entry of purees or solid foods into the mouth. All five cases had moderate to severe mental retardations (DQ: 17-37). No abnormal oral reflexes or functions were present. All had been bottle fed and rejected any purees or solid foods for a long period by turning the head, hiding the face or struggling to avoid being fed. Finally we attempted to force them to eat. Despite their initial refusal, small amounts of pureed food was forcedly pushed into their mouth. As a result, their rejecting behavior was overcome in two or three days, and food intake into the mouth markedly improved within one week. It is suspected that the rejecting behavior does not always represent aversion for solid food. We also found that termination of bottle-feeding was effective the transition to eating. Our experience indicates that forced feeding can overcome the rejecting behavior and prolonged "bottle feeding dependency" in children with developmental retardation.
No to hattatsu. Brain and development 04/2003; 35(2):153-8.
