Ying Chao Chang

Neurologic Complications in Children with Enterovirus 71 Infection

BACKGROUND Enterovirus 71 infection causes hand-foot-and-mouth disease in young children, which is characterized by several days of fever and vomiting, ulcerative lesions in the oral mucosa, and vesicles on the backs of the hands and feet. The initial illness resolves but is sometimes followed by aseptic meningitis, encephalomyelitis, or even acute flaccid paralysis similar to paralytic poliomyelitis. METHODS We describe the neurologic complications associated with the enterovirus 71 epidemic that occurred in Taiwan in 1998. At three major hospitals we identified 41 children with culture-confirmed enterovirus 71 infection and acute neurologic manifestations. Magnetic resonance imaging (MRI) was performed in 4 patients with acute flaccid paralysis and 24 with rhombencephalitis. RESULTS The mean age of the patients was 2.5 years (range, 3 months to 8.2 years). Twenty-eight patients had hand-foot-and-mouth disease (68 percent), and 6 had herpangina (15 percent). The other seven patients had no skin or mucosal lesions. Three neurologic syndromes were identified: aseptic meningitis (in 3 patients); brain-stem encephalitis, or rhombencephalitis (in 37); and acute flaccid paralysis (in 4), which followed rhombencephalitis in 3 patients. In 20 patients with rhombencephalitis, the syndrome was characterized by myoclonic jerks and tremor, ataxia, or both (grade I disease). Ten patients had myoclonus and cranial-nerve involvement (grade II disease). In seven patients the brain-stem infection produced transient myoclonus followed by the rapid onset of respiratory distress, cyanosis, poor peripheral perfusion, shock, coma, loss of the dolls eye reflex, and apnea (grade III disease); five of these patients died within 12 hours after admission. In 17 of the 24 patients with rhombencephalitis who underwent MRI, T2-weighted scans showed high-intensity lesions in the brain stem, most commonly in the pontine tegmentum. At follow-up, two of the patients with acute flaccid paralysis had residual limb weakness, and five of the patients with rhombencephalitis had persistent neurologic deficits, including myoclonus (in one child), cranial-nerve deficits (in two), and ventilator-dependent apnea (in two). CONCLUSIONS In the 1998 enterovirus 71 epidemic in Taiwan, the chief neurologic complication was rhombencephalitis, which had a fatality rate of 14 percent. The most common initial symptoms were myoclonic jerks, and MRI usually showed evidence of brainstem involvement.

MEASUREMENT OF THE URINARY LACTATE:CREATININE RATIO FOR THE EARLY IDENTIFICATION OF NEWBORN INFANTS AT RISK FOR HYPOXIC-ISCHEMIC ENCEPHALOPATHY

Background Newborn infants with perinatal asphyxia are prone to the development of hypoxic–ischemic encephalopathy. There are no reliable methods for identifying infants at risk for this disorder. Methods We measured the ratio of lactate to creatinine in urine by proton nuclear magnetic resonance spectroscopy within 6 hours and again 48 to 72 hours after birth in 58 normal infants and 40 infants with asphyxia. The results were correlated with the subsequent presence or absence of hypoxic–ischemic encephalopathy. Results Hypoxic–ischemic encephalopathy did not develop in any of the normal newborns but did develop in 16 of the 40 newborns with asphyxia. Within six hours after birth, the mean (±SD) ratio of urinary lactate to creatinine was 16.75±27.38 in the infants who subsequently had hypoxic–ischemic encephalopathy, as compared with 0.09±0.02 in the normal infants (P<0.001) and 0.19±0.12 in the infants with asphyxia in whom hypoxic–ischemic encephalopathy did not develop (P<0.001). A ratio of 0.64 or hig...

cAMP response element-binding protein activation in ligation preconditioning in neonatal brain

Perinatal hypoxic‐ischemic (HI) brain injury is a major cause of permanent neurological dysfunction in children. An approach to study the treatment of neonatal HI encephalopathy that allows for neuroprotection is to investigate the states of tolerance to HI. Twenty‐four‐hour carotid‐artery ligation preconditioning established by delaying the onset of hypoxia for 24 hours after permanent unilateral carotid ligation rats markedly diminished the cerebral injury, however, the signaling mechanisms of this carotid‐artery ligation preconditioning in neonatal rats remain unknown. Ligation of the carotid artery 24 hours before hypoxia provided complete neuroprotection and produced improved performance on the Morris water maze compared with ligation performed 1 hour before hypoxia. Carotid artery ligation 6 hours before hypoxia produced intermediate benefit. The 24‐hour carotid‐artery ligation preconditioning was associated with a robust and sustained activation of a transcription factor, the cAMP response element–binding protein (CREB), on its phosphorylation site on Ser133. Intracerebroventricular infusions of antisense CREB oligodeoxynucleotides significantly reduced the 24‐hour carotid‐artery ligation–induced neuroprotection effects by decreasing CREB expressions. Pharmacological activation of the cAMP‐CREB signaling with rolipram 24 hours before hypoxia protected rat pups at behavioral and pathological levels by sustained increased CREB phosphorylation. This study suggests that 24‐hour carotid‐artery ligation preconditioning provides important mechanisms for potential pharmacological preconditioning against neonatal HI brain injury. Ann Neurol, 2004

Working memory of school-aged children with a history of febrile convulsions A population study

Objective: A prospective, population-based, case-control study was performed to ascertain whether febrile convulsion (FC) in early childhood is associated with specific working memory characteristics in school age. Methods: From a population survey of 4,340 live-birth newborns in Tainan City, Taiwan, 103 children with confirmed FC by age 3 years were followed-up until they were at least 6 years old. Three analogous searching tasks dissociating the mnemonic and executive aspects of performances were administered to 87 of these school-aged children and to 87 randomly selected age-matched control subjects to assess the learning, spatial, and sequential working memory. Results: The FC group performed significantly and consistently better than control subjects on all but one working memory measure, jumping errors. Multivariate analysis using linear regression revealed that the onset of FC before age 1 year was the only significant risk factor for deficits in mnemonic function. Prior neurodevelopmental delay was the only significant risk factor for deficits in executive function. Factors such as socioeconomic status, family predisposition for seizures, complex FC, recurrent FC, and subsequent unprovoked seizures were not risk factors for working memory deficits. Conclusion: The authors found that school-aged children with a history of FC demonstrated significantly better mnemonic capacity, more flexible mental processing, and higher impulsivity than their age-matched control subjects. The underlying mechanism for the facilitated working memory function in children with a history of FC needs further delineation.

Neurocognitive attention and behavior outcome of school-age children with a history of febrile convulsions: A population study

Summary: Purpose: A prospective population‐based case‐control study was performed to ascertain whether febrile convulsion (FC) in early childhood is associated with neurocognitive attention deficits in school age.

Altered inflammatory responses in preterm children with cerebral palsy.

Perinatal inflammatory responses contribute to periventricular leukomalacia (PVL) and cerebral palsy (CP) in preterm infants. Here, we examined whether preterm children with CP had altered inflammatory responses when school‐aged.

Risk factors for a first febrile convulsion in children: A population study in southern Taiwan

Summary: Purpose: To identify risk factors for a first febrile convulsion among 3‐year‐old children by a matched case‐control population study.

Perinatal brain injury and regulation of transcription

Purpose of reviewPerinatal hypoxic–ischemic brain injury is a major cause of mortality and morbidity in infants. The understanding of transcription factor activation leading to prosurvival gene expression is important as it pertains to the development of new therapy. Here, we highlight the regulation of transcription factors that potentially could promote neuro-survival in the immature brain. Recent findingscAMP response element binding protein (CREB), nuclear factor-κB (NF-κB) and hypoxia-inducible factor 1 (HIF-1) are developmentally regulated in the neural system, and are necessary for the induction of preconditioning against hypoxic–ischemia. CREB and NF-κB are also involved in the regulation of synaptic plasticity, and learning and memory. CREB phosphorylation is sufficient and necessary for survival in adult and immature neurons, and NF-κB activation in neurons could promote survival, whereas activation in glial cells enhances neuronal death. Although HIF-1 is necessary for hypoxic preconditioning, paradoxically, in the absence of preconditioning, this factor promotes ischemia-induced neuronal death. Erythropoietin, one of the HIF-1 targeted genes, is potently neuroprotective and may be beneficial in treating newborns with hypoxic–ischemic brain damage. SummaryDrugs that activate the specific signaling leading to the transcriptional activation of prosurvival genes may provide therapy for the treatment of perinatal hypoxic–ischemic brain injury. Investigation of the transcriptional mechanisms of neuro-survival is likely to reveal other novel transcription factors whose activation by small molecules or drugs will complement current medication in activating the salutary gene program.

Low-dose lipopolysaccharide selectively sensitizes hypoxic ischemia-induced white matter injury in the immature brain

Little is known about roles of inflammation and hypoxic ischemia (HI) in the generation of neuroinflammation and damage of blood-brain barrier (BBB) in the white matter (WM) that displays regional vulnerability in preterm infants. We investigated whether low-dose lipopolysaccharide (LPS) sensitizes HI-induced WM injury in postpartum (P) day 2 rat pups by selectively increasing neuroinflammation and BBB damage in the WM. Pups received LPS (0.05 mg/kg) (LPS + HI) or normal saline (NS + HI) followed by 90-min HI. LPS and NS group were the pups that had LPS or NS only. Myelin basic protein immunohistochemistry on P11 showed WM injury in LPS + HI group, but not in NS + HI, LPS, and NS groups. In contrast, no gray matter injury was found in the four groups. LPS + HI group also showed decreased number of oligodendrocytes in the WM 72-h postinsult. In the same brain region, increases of activated microglia, TNF-α expression, BBB leakage, and cleaved caspase-3 positive cells were much more prominent in LPS + HI group than in the other three groups 24-h postinsult. The oligodendrocytes were the major cells with cleaved caspase-3 expression. We concluded that low-dose LPS sensitized HI-induced WM injury in the immature brain by selectively up-regulating neuroinflammation and BBB damage in the WM.

CREB activation in the rapid, intermediate, and delayed ischemic preconditioning against hypoxic–ischemia in neonatal rat

Ischemic preconditioning (IP) is a defense program in which exposure to sublethal ischemia followed by a period of reperfusion results in subsequent resistance to severe ischemic insults. Very few in vivo IP models have been established for neonatal brain. We examined whether rapid, intermediate, and delayed IP against hypoxic–ischemia (HI) could be induced in neonatal brain, and if so, whether the IP involved phosphorylation of cAMP response element‐binding protein (pCREB) after HI. Postnatal day 7 rat pups were subjected to HI at 2 h (2‐h IP), 6 h (6‐h IP), or 22 h (22‐h IP) after IP. We found all three IP groups had significantly reduced neuronal damage and TUNEL‐(+) cells 24 h post‐HI than no‐IP group. Compared with control, the no‐IP group had significant decreases of pCREB and mitochondria Bcl‐2 levels in the ipsilateral cortex 24 h post‐HI. In contrast, the three IP groups had increased pCREB and mitochondria Bcl‐2 levels, and significant differences were found between three IP and no‐IP groups. The increases of cleavage of caspase‐3 and poly (ADP‐ribose) polymerase and of cells with nuclear apoptosis inducing factor post‐HI in no‐IP group were all significantly reduced in three IP groups. The increases of caspase‐3 and calpain‐mediated proteolysis of α‐spectrin post‐HI were significantly reduced only in 22‐h IP group. Furthermore, all three IP groups had long‐term neuroprotection at behavioral and pathological levels compared with no‐IP group. In conclusion, IP, rapid, intermediate, or delayed, in neonatal rat brain activates CREB, up‐regulates Bcl‐2, induces extensive brakes on caspase‐dependent and ‐independent apoptosis after HI, and provides long‐term neuroprotection.