Li-Tung Huang

Maternal Deprivation Stress Exacerbates Cognitive Deficits in Immature Rats with Recurrent Seizures

Summary: u2002Purpose: Maternal deprivation is stressful for the neonate. The aim of this study was to investigate the short‐ and long‐term effects of maternal separation on recurrent seizures in the developing brain.

Pentylenetetrazol-induced recurrent seizures in rat pups: Time course on spatial learning and long-term effects

Summary: u2002Purpose: Recurrent seizures in infants are associated with a high incidence of neurocognitive deficits. Animal models have suggested that the immature brain is less vulnerable to seizure‐induced injury than is that in adult animals. We studied the effects of recurrent neonatal seizures on cognitive tasks performed when the animals were in adolescence and adulthood.

Lithium-pilocarpine-induced status epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss

Rat pups age of 14 postnatal day (P14) were subjected to lithium-pilocarpine (Li-PC) model of status epilepticus (SE). Control rats (n=6) were given an equivalent volume of saline intraperitoneally. Behavioral testing began on P60 including the Morris water maze, the radial arm maze, and the rotarod test. Brain were then analyzed with cresyl violet stain for histological lesions and evaluated for mossy fiber sprouting with the Timm stain. We observed spatial memory deficits both in the Morris water maze and radial arm maze in Li-PC-treated rat. There was no motor impairment in Li-PC-treated rat by the rotarod test. Two of six Li-PC-treated rats showed cell loss in hippocampal CA1 subfield. The Timm staining pattern was similar in both control and Li-PC-treated rats. Result of this study suggests that Li-PC-induced SE in immature rats cause long-term cognitive deficit and permanent cell loss in hippocampal CA1, but spare motor impairment.

Effect of neonatal isolation on outcome following neonatal seizures in rats—The role of corticosterone

Emerging evidence indicates that early maternal care permanently modifies the activity of hypothalamic-pituitary-adrenal (HPA) axis and is a critical factor in determining the capacity of the brain to compensate for later encountered insults. The purpose of this study was to determine the role of corticosterone (CORT) in the detrimental effects of neonatal isolation (NI) on seizures. Rats were assigned randomly to the following five groups: (1) control (CONT) rats; (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) status epilepticus (SE) rats, induced by lithium-pilocarpine (Li-Pilo) model at P10; (4) NI plus SE (NIS) rats and (5) NISM rats, a subset of NIS rats receiving metyrapone (100 mg/kg), a CORT synthesis inhibitor, immediately after SE induction. At P10, plasma CORT levels were compared at baseline in CONT and NI rats and in response to Li-Pilo-induced SE among SE, NIS and NISM rats. We evaluated the spatial memory in the Morris water maze at P50 approximately 55, the expression of hippocampal cyclic adenosine monophosphate (cAMP)-responsive element-binding protein phosphorylation at serine-133 (pCREBSer-133) at P55, hippocampal neuronal damage at P80 and seizure threshold at P100. The isolated rats exhibited higher CORT release in response to SE than non-isolated rats, and the NIS rats had greater cognitive deficits and decreased seizure threshold compared to the CONT, NI and SE groups. By contrast, the NISM group, compared to the NIS group, showed a normal CORT response to SE and better spatial memory but no difference in seizure threshold. Compared to the CONT group, the hippocampal pCREBSer-133 level was significantly reduced in all experimental groups (NI, SE, NIS, NISM) with no differences between groups. All rats were free of spontaneous seizures later in life and had no discernible neuronal loss in the hippocampus. Results in this model demonstrate repetitive NI enhances response of plasma CORT to SE, and exacerbates the neurological consequences of neonatal SE. Amelioration of neurological sequelae following reduction of the SE-induced excessive rise in plasma CORT implicates CORT in the pathogenesis of NI increasing the vulnerability to seizures.

Bacterial meningitis in infants: the epidemiology, clinical features, and prognostic factors.

This 16-year (1986-2001) retrospective study enrolled 80 infantile patients (aged, 30-365 days old) with culture-proven bacterial meningitis. The most prevalent pathogens were Salmonellaspecies, Streptococcus (S.) agalactiae, Escherichia (E.) coli, and Haemophilus (H.) influenzae, accounting for about 59% of the episodes. Meningitis caused by Salmonella species, E. coli and H. influenzae occurs more often in the older infants, while that caused by S. agalactiae occurs more often in young infants. Our study revealed a decrease in the proportion of Salmonella meningitis from 27% in the first 8 years to 9% in the second 8 years with E. coli replacing Salmonella species as the leading pathogen of this disease during the second period. Overall mortality rate for both periods of time was 11%. However, if we take those with undesirable poor outcomes into account, 43% of patients could be considered treatment failures. The study also reveals a high prevalence of neurological complications when this disease is caused by H. influenzae, S. pneumoniae, and Salmonella species. Stepwise logistic regression analysis revealed that only initial changing levels of consciousness (P = 0.006) were independently associated with treatment failure. The most frequent neurological complications associated with this disease included subdural empyema, hydrocephalus, cerebral infarctions, and seizures. Because therapeutic regimens may require attention to the eradication of bacterial pathogen but also the neurological complications, early diagnosis and choice of appropriate antibiotics are essential to increasing the possibility of survival.

Alterations in Long-term Seizure Susceptibility and the Complex of PSD-95 with NMDA Receptor from Animals Previously Exposed to Perinatal Hypoxia

Summary:u2002 Purpose: Perinatal hypoxia is an important cause of brain injury in the newborn and has consequences that are potentially devastating and life‐long, such as an increased risk of epilepsy in later life. The postsynaptic density (PSD) is a cytoskeletal specialization involved in the anchoring of neurotransmitter receptors and in regulating the response of postsynaptic neurons to synaptic stimulation. The postsynaptic protein PSD‐95 binds to the N‐methyl‐d‐aspartate receptor (NMDAR) subunit, and hence activates cascades of NMDAR‐mediated events, such as cyclic adenosine monophosphate (cAMP)‐responsive element binding protein phosphorylation at serine‐133 (pCREBSerine‐133). Here we studied the effect of perinatal hypoxia on protein interactions involving PSD‐95 and the NMDAR, as well as pCREBSer‐133 expression at an age when the animals show increased seizure susceptibility.

Tuberculous meningitis in infancy.

The lack of specific symptoms and signs in patients with tuberculous meningitis makes early diagnosis difficult. To our knowledge, there has been no report in the literature focusing on tuberculous meningitis patients younger than 1 year of age. In this report, we reviewed the clinical features and laboratory findings of seven infants with tuberculous meningitis encountered during a 15-year period. All patients had fever, cough, and alternation of consciousness at presentation. Five patients had bulging anterior fontanel, and five had generalized tonic-clonic seizures. The purified protein derivative skin test was positive in six patients. Six patients had hyponatremia. All seven patients had abnormal cerebrospinal fluid findings, and six of them demonstrated cell counts less than 500 cells/mm(3) with lymphocytic predominance. Brain sonography examination revealed hydrocephalus in all seven patients. Therefore we conclude that antituberculosis therapy should be promptly initiated in any young infant with a clinical impression of meningitis in the context of cerebrospinal fluid white cell count of less than 500 cells/mm(3) and lymphocytic predominance, hyponatremia, and hydrocephalus.

A clinical and electrophysiologic survey of childhood Guillain-Barré syndrome

In this 16-year (1986-2001) retrospective study, 23 childhood patients were identified with Guillain-Barré syndrome. According to clinical and electrophysiologic findings, 18 patients manifested acute inflammatory demyelinating polyradiculoneuropathy, 2 had Miller Fisher syndrome, 1 had axonal forms, and 2 were unclassified. Seasonal preponderance was evident in 39% of patients with Guillain-Barré syndrome, developing the disease in the winter (November to January) with upper respiratory infection the most frequent preceding event. The most common manifestation was limb weakness, with various degrees of motor weakness in 22 patients. Bulbar involvement was the most common cranial palsy, and it was evident in 30% of the episodes. Only one of these progressed to mechanical ventilation during hospitalization. Altogether, approximately 61% of the episodes exhibited sensory symptoms. At a follow-up of 1 year or more, 20 patients recovered and 3 had residua. Furthermore, no fatality occurred in our study. Our study also demonstrates that the clinical course of childhood Guillain-Barré syndrome has a shorter recovery time as compared with an adult patient group. Therapeutic outcome is favorable for patients who receive prompt treatment.

Impaired SynGAP expression and long-term spatial learning and memory in hippocampal CA1 area from rats previously exposed to perinatal hypoxia-induced insults: beneficial effects of A68930

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological cognitive deficits. In rats at postnatal days 10-12 (P10-P12), global hypoxia induced spontaneous seizures and chronic brain injury, mimicking clinical aspects of neonatal hypoxia. Synaptic Ras-GTPase activating protein (SynGAP) has important roles in RAS/MAPK-dependent synaptic plasticity and mammalian learning. We investigated possible alterations of SynGAP expression occurring in memory-impaired animals previously exposed to perinatal hypoxia insults. We also evaluated the therapeutic efficacy of A68930, a selective agonist of dopamine D1/D5 receptors, on perinatal hypoxia insults. In the hippocampal CA1 region, perinatal hypoxia insults (P10) led to a reduction in SynGAP expression associated with impairment in long-term spatial learning and memory performance at P45. The use of A68930 (at a dose of 1, 2, 3mg/kg, P17-P23) effectively attenuated the deleterious effects as described above. Our results may indicate the involvement of SynGAP in certain forms of brain injury, leading to long-term learning and memory deficits. A68930 may have clinical potential as a therapeutic agent for alleviation of long-term cognitive deficits in rats and other animal models.

Obstructive Jaundice in Rats: Cause of Spatial Memory Deficits with Recovery after Biliary Decompression

Children with end-stage liver disease have been found to have cognitive deficits. The aim of this study was to examine whether cholestatic jaundice causes spatial deficits in rats and if these cognitive deficits are reversed by biliary drainage. Rats were randomly divided into three groups. In the first group, the bile duct was ligated for 3 weeks (BDL group); in the second group, the proximal bile duct was ligated with a Broviac CV catheter for 2 weeks followed by a tube bilioduodenostomy (TBD group); in the third group, a sham operation was performed (SHAM group). All the surviving rats were assessed for spatial learning and memory (a major cognitive function in rats) by the Morris water maze task about 3 weeks after the first operation. Blood was aspirated by cardiocentesis and assayed for total bilirubin, albumin, ammonia, and hemoglobin levels on the day following the water maze task. During the four consecutive acquisition trial days of the Morris water maze, jaundiced rats (BDL group) had a significant longer latency to escape than the SHAM group (p < 0.05). Rats that underwent biliary decompression for 1 week (TBD group) showed improved status of the spatial deficit, as they required less time to reach the escape platform, approaching the performance of the SHAM group. The BDL group had a significantly higher serum ammonia level, higher bilirubin level, and lower hemoglobin level than the other two groups. After biliary decompression for 1 week, the serum albumin concentration in the TBD group still did not return to the level of the SHAM group. The results of this study suggest that long-term cholestasis results in spatial memory deficits in rats that correlate with anemia and hyperbilirubinemia encephalopathy. Early biliary decompression of obstructive jaundice improves spatial memory deficits, possibly related to the recovery of the serum ammonia and hemoglobin levels.