Shan Tair Wang

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.

Epidemiologic Features of Hand-Foot-Mouth Disease and Herpangina Caused by Enterovirus 71 in Taiwan, 1998-2005

OBJECTIVE. In 1998, an epidemic of hand-foot-mouth disease/herpangina was caused by human enterovirus 71 infection in Taiwan. The underlying factors of widespread emergence of viral infection are unclear. The purpose of this study was to assess the epidemiology of hand-foot-mouth disease/herpangina in Taiwan between March 1998 and December 2005. METHODS. We analyzed data reported to surveillance systems at the Taiwan Center for Disease Control. Viral isolation was performed by 11 reference virus laboratories at medical centers as well as the Taiwan Center for Disease Control. RESULTS. During the 8-year study period, the reported incidence of mild cases of hand-foot-mouth disease/herpangina varied from 0.8 to 19.9 cases per sentinel physician per week, peaking in 1998. Seasonal variations in incidence were observed, with an incidence peak observed during the summer season. Annual incidence changed significantly from 1998 to 2005. Both age-specific incidence and fatality of severe hand-foot-mouth disease/herpangina decreased as age increased. Most (93%) cases occurred in children who were aged 4 years and younger. Inpatients had a higher rate of enterovirus 71 infection than outpatients. Among severe cases, the majority (80%) had pulmonary edema/hemorrhage and encephalitis. CONCLUSIONS. Hand-foot-mouth disease/herpangina is a common disease in Taiwan. Enterovirus 71 infection has emerged as an important public problem causing serious clinical illness and, potentially, death in young children. Vaccine development is recommended for prevention of enterovirus 71 infection in the future.

Generation of IgM anti‐platelet autoantibody in dengue patients

Dengue virus infection causes a wide range of diseases from dengue fever to life‐threatening dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). The mechanisms involved in DHF/DSS pathogenesis remain unclear. Patient sera collected from an outbreak in southern Taiwan from November 1998 to January 1999 were studied. The presence of antibodies which cross‐reacted with platelets could be detected in patient sera, and the isotype of these autoantibodies was IgM. The anti‐platelet IgM levels were higher in DHF/DSS than in dengue fever patient sera in disease acute phase. These autoantibodies were still detectable in convalescent stage (1–3 weeks after acute phase) and even eight to nine months after illness. The platelet binding activity was not observed in other virus‐infected patient sera tested. Further investigation showed that dengue patient sera caused platelet lysis in the presence of complement. The platelet cytotoxicity induced by DHF/DSS patient sera was higher than that by dengue fever sera. Dengue patient sera also inhibited platelet aggregation which, however, appeared to be not related to DHF/DSS development. J. Med. Virol. 63:143–149, 2001.

Febrile Seizures Impair Memory and cAMP Response-Element Binding Protein Activation

The long‐term effects of brief but repetitive febrile seizures (FS) on memory have not been as thoroughly investigated as the impact of single and prolonged seizure in the developing brain. Using a heated‐air FS paradigm, we subjected male rat pups to one, three, or nine episodes of brief FS on days 10 to 12 postpartum. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any FS group at adulthood. The adult rats subjected to nine episodes of early‐life FS, however, showed long‐term memory deficits as assessed by the Morris water maze. They also exhibited impaired intermediate and long‐term memory but spared short‐term memory in the inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response‐element binding (CREB) protein in the hippocampus was significantly lower in nine‐FS‐group rats than in controls. Furthermore, rolipram administration, which activated the cAMP–CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long‐term memory deficits in nine‐FS‐group rats by enhancing hippocampal CREB phosphorylation. These results raise concerns about the long‐term cognitive consequences of even brief frequently repetitive FS during early brain development. Ann Neurol 2003;54:706–718

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

Activation of coagulation and fibrinolysis during dengue virus infection

Dengue virus infection can induce mild dengue fever (DF) or severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) in human. The pathogenesis of hemorrhage in dengue virus infection is not fully understood. Since hemostasis depends on the balance between coagulation and fibrinolysis, alternation of some coagulation parameters (platelet count and activated partial thromoboplastin time, APTT) as well as fibrinolytic parameters (tissue plasminogen activator, tPA and plasminogen activator inhibitor‐1, PAI‐1) were compared in 8 DHF/DSS and 17 DF patients. Patients showed thrombocytopenia, APTT prolongation, and tPA increase in the acute stage of disease, indicating activation of coagulation and fibrinolysis. The activation of coagulation and fibrinolysis in DHF/DSS patients was much more severe than DF patients. In the convalescent stage, a rise of PAI‐1 level and platelet count with concomitant decline of tPA level and APTT returned to normal in both DHF/DSS and DF patients. Therefore, the activation of coagulation and fibrinolysis during the acute stage of dengue virus infection is offset by the increase of platelet and PAI‐1 during convalescent stage. Taken together, these results suggest that the degree of coagulation and fibrinolysis activation induced by dengue virus infection is associated with the disease severity. J. Med. Virol. 63:247–251, 2001.

Strong Association of Hepatitis C Virus (HCV) Infection and Thrombocytopenia: Implications from a Survey of a Community with Hyperendemic HCV Infection

BACKGROUND The role of hepatitis C virus (HCV) infection in thrombocytopenia (defined as a platelet count of <100,000 platelets/ mu L) is unknown. Our aim was to study the association between HCV infection and thrombocytopenia in a community where hepatitis B virus (HBV) and HCV infections are hyperendemic. METHODS A community-wide survey of subjects > or =40 years old who had undergone a preventive health examination between April 1997 and July 2000 in A-Lein Township, Kaohsiung County, Taiwan. Serum blood platelet counts and HBV surface antigen (HBsAg) and antibody to HCV (anti-HCV) levels were measured. Abdominal sonography was performed on viral hepatitis-positive participants. RESULTS Among the 1690 subjects, 70% were seronegative, 17.4% were anti-HCV positive, 9.2% were HBsAg positive, and 3.4% were coinfected with HCV and HBV. The mean platelet count in subjects with anti-HCV (180,000 platelets/microL) was lower than in those with HBsAg (201,000 platelets/microL) and in those without anti-HCV and HBsAg (234,000 platelets/microL) (P<.001). The prevalence of thrombocytopenia was 1.3% among seronegative subjects, 1.9% among HBsAg-positive subjects, 5.2% among coinfected subjects, and 10.2% among anti-HCV-positive subjects. Multiple logistic regression analysis revealed that anti-HCV positivity (odds ratio, 6.0; 95% confidence interval, 3.2-11.2), an alanine aminotransferase level of > or =40 U/L, and age of > or =65 years were significantly associated with thrombocytopenia. The prevalence of thrombocytopenia among anti-HCV-positive subjects increased as the severity of liver disease increased, but, in HBsAg-positive subjects, thrombocytopenia presented only in those with advanced liver disease. CONCLUSIONS HCV infection is strongly associated with thrombocytopenia, which is correlated with hepatocellular damage and hepatic fibrosis. It is advisable to further check the hepatic condition of the patient, especially for HCV infection, if thrombocytopenia is present.

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.