Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study.

OBJECTIVES: We evaluated clinical features, treatment practices and early outcome in a multicentre cohort of children with cerebral sinovenous thrombosis (CSVT). METHODS: Children with CSVT from 10 countries were enrolled from January 2003 to July 2007 in the International Paediatric Stroke Study. We analysed clinical symptoms, underlying conditions, antithrombotic treatment and neurological outcome at hospital discharge in 170 children. RESULTS: Of 170 children enrolled, 60% were male; median age 7.2 years (IQR 2.9-12.4). Headache, altered consciousness, focal deficits and seizures were common presenting clinical features. Infarction affected 37% and intracranial haemorrhage 31%. Risk factors included chronic disease in 50%; acute systemic illness or head/neck disorders 41%; prothrombotic state 20% and other haematological abnormality 19%. Discharge neurological status was normal in 48%, abnormal in 43% and unknown in 5%. Antithrombotic therapy was common, most often low molecular weight heparin was common, with significant regional variation in treatment practices. Mortality was low (4%) and was associated with no anticoagulation but not underlying chronic disease, anatomic extent of thrombosis or intracranial haemorrhage. Abnormal neurological status at discharge or death was associated with decreased level of consciousness at presentation and the presence of an identified prothrombotic state. CONCLUSIONS: Our study extends the observations of previously published smaller studies in children with CSVT that this is a morbid disease with diverse underlying causes and risk factors. Divergent treatment practices among highly specialised centres as well as limited data on treatment efficacy and safety suggest that further study of this condition is warranted.

Association of pulsatility index in the middle cerebral artery with intelligence quotient in children with sickle cell disease.

The aim of this study was to explore whether intellectual performance in children with Sickle Cell Disease and with low risk of stroke as determined with conventional transcranial Doppler ultrasonography (TCD) criteria was associated with hemodynamic parameters in imaging TCD, when controlling for hematological and socio-economical variables and presence of silent infarcts. We performed neuropsychological testing with Kaufman Brief Intelligence Test (K-BIT-IQ) and imaging TCD examinations to measure blood flow velocities and pulsatility indexes (PI) in the middle cerebral arteries (MCA) In 46 children with homozygous HbSS (mean age 108±34 months, range limits: 47-166 months; 24 females), without a history of stroke or transient ischemic attack, with no stenosis on magnetic resonance angiography and with velocities below 170 cm/s in screening conventional TCD. Mean K-BIT IQ Composite and Vocabulary scores (91±13 and 86±14 respectively) were significantly below the average scores of 100 for the age-matched population (one sample t-test=5.21, p<0.001). Using univariate and multivariate regression models, we found that lower PI in the right MCA was associated with lower K-BIT-IQ Composite and Vocabulary scores. Furthermore, we found that interhemispheric differences in PIs were even more strongly associated with neuropsychological performance, whereas flow velocities were not associated with the K-BIT-IQ score. Using a model of chronic anemia, we found that cognitive functioning was associated with cerebral hemodynamics.

Sickle cell disease in children: accuracy of imaging transcranial Doppler ultrasonography in detection of intracranial arterial stenosis.

This study aimed to determine the accuracy of imaging transcranial Doppler sonography in detection of intracranial arterial stenosis in children with sickle cell disease using three-dimensional MR angiography as a reference standard. Sixty-one children (mean age 102±39 months, 30 males), who had no history of overt stroke, and were classified as at lowest risk of stroke by mean flow velocity criterion <170 cm/s, underwent conventional and imaging transcranial Doppler ultrasonographic examinations. We employed the area under the receiver operating characteristic curve (AUC) to determine the accuracy of flow velocity measurements obtained with imaging ultrasonography with and without correction for the angle of insonation as well as with conventional ultrasonography. We also established the most efficacious velocity thresholds for detection of the stenosis. We found ten intracranial stenoses in six patients on MR angiography, but we calculated AUC only for detection of stenosis (n=6) of the left intracranial internal carotid artery. The accuracy of flow velocity with angle correction was lower than the accuracy of velocity without angle correction (AUC=0.73, 95% CI, 0.53-0.93 versus AUC=0.87, 95% CI, 0.74-1.00; p=0.017). The accuracy of flow velocity obtained with conventional ultrasonography (AUC=0.82, 95% CI, 0.67-0.97) was not different from the accuracy of flow velocities obtained with imaging ultrasonography. We found that the threshold of 165 cm/s of mean velocity without angle correction is associated with highest efficiency for imaging (92%) and conventional ultrasonography (90%). Velocity measurements without angle-correction provide good accuracy in detection of stenosis of the terminal internal carotid artery, whereas angle-corrected velocities have lower accuracy.

Sickle cell disease: reference values and interhemispheric differences of nonimaging transcranial Doppler blood flow parameters.

BACKGROUND AND PURPOSE: TCD screening is widely used to identify children with SCD at high risk of stroke. Those with high mean flow velocities in major brain arteries have increased risk of stroke. Thus, our aim was to establish reference values of interhemispheric differences and ratios of blood flow Doppler parameters in the tICA, MCA, and ACA as determined by conventional TCD in children with sickle cell anemia. MATERIALS AND METHODS: Reference limits of blood flow parameters were established on the basis of a consecutive cohort of 56 children (mean age, 100 ± 40 months; range, 29-180 months; 30 females) free of neurologic deficits and intracranial stenosis detectable by MRA, with blood flow velocities <170 cm/s by conventional TCD. Reference limits were estimated by using tolerance intervals, within which are included with a probability of .90 of all possible data values from 95% of a population. RESULTS: Average peak systolic velocities were significantly higher in the right hemisphere in the MCA and ACA (185 ± 28 cm/s versus 179 ± 27 and 152 ± 30 cm/s versus 143 ± 34 cm/s respectively). Reference limits for left-to-right differences in the mean flow velocities were the following: -43 to 33 cm/s for the MCA; -49 to 38 cm/s for the ACA, and -38 to 34 cm/s for the tICA, respectively. Respective reference limits for left-to-right velocity ratios were the following: 0.72 to 1.25 cm/s for the MCA; 0.62 to 1.39 cm/s for the ACA, and 0.69 to 1.27 cm/s for the tICA. Flow velocities in major arteries were inversely related to age and Hct or Hgb. CONCLUSIONS: The study provides reference intervals of TCD flow velocities and their interhemispheric differences and ratios that may be helpful in identification of intracranial arterial stenosis in children with SCD undergoing sonographic screening for stroke prevention.

Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest.

BACKGROUND: Hypoxic ischemic brain injury secondary to pediatric cardiac arrest (CA) may result in acute symptomatic seizures. A high proportion of seizures may be nonconvulsive, so accurate diagnosis requires continuous EEG monitoring. We aimed to determine the safety and feasibility of long-term EEG monitoring, to describe electroencephalographic background and seizure characteristics, and to identify background features predictive of seizures in children undergoing therapeutic hypothermia (TH) after CA. METHODS: Nineteen children underwent TH after CA. Continuous EEG monitoring was performed during hypothermia (24 hours), rewarming (12-24 hours), and then an additional 24 hours of normothermia. The tolerability of these prolonged studies and the EEG background classification and seizure characteristics were described in a standardized manner. RESULTS: No complications of EEG monitoring were reported or observed. Electrographic seizures occurred in 47% (9/19), and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). Seizures commenced during the late hypothermic or rewarming periods (8/9). Factors predictive of electrographic seizures were burst suppression or excessively discontinuous EEG background patterns, interictal epileptiform discharges, or an absence of the expected pharmacologically induced beta activity. Background features evolved over time. Patients with slowing and attenuation tended to improve, whereas those with burst suppression tended to worsen. CONCLUSIONS: EEG monitoring in children undergoing therapeutic hypothermia after cardiac arrest is safe and feasible. Electrographic seizures and status epilepticus are common in this setting but are often not detectable by clinical observation alone. The EEG background often evolves over time, with milder abnormalities improving and more severe abnormalities worsening.

Role of diffusion MRI in diagnosis of spinal cord infarction in children.

Anterior spinal artery (ASA) infarction is a rare but well-described cause of flaccid paraparesis in adults, presenting with a high thoracic spinothalamic sensory level and preservation of dorsal column function. Careful sensory examination, demonstrating loss of spinothalamic modalities with preservation of dorsal column modalities, supports a clinical diagnosis of ASA infarction. Findings on conventional MRI of the spinal cord are often non-specific, and diffusion-weighted imaging (DWI) is not routinely performed. We describe four children with ASA infarction after minor trauma. DWI was performed in all cases and confirmed the clinical diagnosis.

Angle-corrected imaging transcranial doppler sonography versus imaging and nonimaging transcranial doppler sonography in children with sickle cell disease.

BACKGROUND AND PURPOSE: Nonimaging transcranial Doppler sonography (TCD) and imaging TCD (TCDI) are used for determination of the risk of stroke in children with sickle cell disease (SCD). The purpose was to compare angle-corrected, uncorrected TCDI, and TCD blood flow velocities in children with SCD. MATERIALS AND METHODS: A total of 37 children (mean age, 7.8 +/- 3.0 years) without intracranial arterial narrowing determined with MR angiography, were studied with use of TCD and TCDI at the same session. Depth of insonation and TCDI mean velocities with and without correction for the angle of insonation in the terminal internal carotid artery (ICA) and middle (MCA), anterior (ACA), and posterior (PCA) cerebral arteries were compared with TCD velocities with use of a paired t test. RESULTS: Two arteries were not found on TCDI compared with 15 not found on TCD. Average angle of insonation in the MCA, ACA, ICA, and PCA was 31 degrees , 44 degrees , 25 degrees , and 29 degrees , respectively. TCDI and TCD mean depth of insonation for all arteries did not differ significantly; however, individual differences varied substantially. TCDI velocities were significantly lower than TCD velocities, respectively, for the right and left sides (mean +/- SD): MCA, 106 +/- 22 cm/s and 111 +/- 33 cm/s versus 130 +/- 19 cm/s and 134 +/- 26 cm/s; ICA, 90 +/- 14 cm/s and 98 +/- 27 cm/s versus 117 +/- 18 cm/s and 119 +/- 23 cm/s; ACA, 74 +/- 24 cm/s and 88 +/- 25 cm/s versus 105 +/- 23 cm/s and 105 +/- 31 cm/s; and PCA, 84 +/- 27 cm/s and 82 +/- 21 cm/s versus 95 +/- 23 cm/s and 94 +/- 20 cm/s. TCD and angle-corrected TCDI velocities were not statistically different except for higher angle-corrected TCDI values in the left ACA and right PCA. CONCLUSION: TCD velocities are significantly higher than TCDI velocities but are not different from the angle-corrected TCDI velocities. TCDI identifies the major intracranial arteries more effectively than TCD.

Recurrent hypoglycemic hemiparesis and aphasia in an adolescent patient.

A 12-year-old diabetic female with right-side hemiparesis and aphasia occurring after a hypoglycemic episode is reported. Her clinical course improved over a 24-hour period, and further investigation revealed only electroencephalographic slowing, which was more prominent on the left. Ten months later, she had a recurrence of the same symptoms, which also resolved rapidly. This potential complication of hypoglycemia is often mistaken for a cerebrovascular accident.

MK801 decreases glutamate release and oxidative metabolism during hypoglycemic coma in piglets.

Hypoglycemic coma increases extracellular excitatory amino acids, which mediate hypoglycemic neuronal degeneration. Cerebral oxygen consumption increases during hypoglycemic coma in piglets. We tested the hypothesis that the NMDA-receptor antagonist dizocilpine (MK801) attenuates the increase in cerebral oxygen consumption during hypoglycemia. We measured EEG, cerebral blood flow (CBF), cerebral oxygen consumption (CMRO(2)) and cortical microdialysate levels of glutamate, aspartate and glycine in pentobarbital-anesthetized piglets during 60 min of insulin-induced hypoglycemic coma. NMDA-receptor distribution was measured by autoradiography. MK801 (0.75 mg/kg i.v.) was given within 5 min after onset of isoelectric EEG. Saline- and MK801-treated normoglycemic control animals were also studied. Brain temperature was maintained at 38.5+/-0.5 degrees C. MK801 prevented the 5--10-fold increase in glutamate and aspartate occurring in saline-treated hypoglycemic animals, and attenuated the increase in CMRO(2). Increases in CBF of 200--400% during hypoglycemic coma were not affected by MK801. MK801 did not alter CBF, CMRO(2) or microdialysate amino acid levels in normoglycemic control animals. Parietal cortex corresponding to microdialysis sites was highly enriched in NMDA receptors, and the density and distribution overall of NMDA receptor binding sites were comparable to that reported in other species. We conclude that NMDA receptor activation plays a central role in hypoglycemia-induced glutamate release, and contributes to increased cerebral oxygen consumption. Neuroprotective effects of MK801 during hypoglycemia in piglets may involve inhibitory effects on glutamate release and oxidative metabolism.

Neuronal death in newborn striatum after hypoxia-ischemia is necrosis and evolves with oxidative stress.

The mechanisms for neurodegeneration after hypoxia-ischemia (HI) in newborns are not understood. We tested the hypothesis that striatal neuron death is necrosis and evolves with oxidative stress and selective organelle damage. Piglets ( approximately 1 week old) were used in a model of hypoxia-asphyxia and survived for 3, 6, 12, or 24 h. Neuronal death was progressive over 3-24 h recovery, with approximately 80% of putaminal neurons dead at 24 h. Striatal DNA was digested randomly at 6-12 h. Ultrastructurally, dying neurons were necrotic. Damage to the Golgi apparatus and rough endoplasmic reticulum occurred at 3-12 h, while most mitochondria appeared intact until 12 h. Mitochondria showed early suppression of activity, then a transient burst of activity at 6 h, followed by mitochondrial failure (determined by cytochrome c oxidase assay). Cytochrome c was depleted at 6 h after HI and thereafter. Damage to lysosomes occurred within 3-6 h. By 3 h recovery, glutathione levels were reduced, and peroxynitrite-mediated oxidative damage to membrane proteins, determined by immunoblots for nitrotyrosine, occurred at 3-12 h. The Golgi apparatus and cytoskeleton were early targets for extensive tyrosine nitration. Striatal neurons also sustained hydroxyl radical damage to DNA and RNA within 6 h after HI. We conclude that early glutathione depletion and oxidative stress between 3 and 6 h reperfusion promote damage to membrane and cytoskeletal proteins, DNA and RNA, as well as damage to most organelles, thereby causing neuronal necrosis in the striatum of newborns after HI.

Hypoglycemia in the neonate.

After a brief history of the development of neonatal hypoglycemia, this review emphasizes the current approach to the anticipation, diagnosis, and management of the neonate with a low plasma glucose concentration. Current techniques for studying the neurophysiological and endocrine-metabolic effects of significant hypoglycemia provide new approaches for establishing relevant definitions of significant hypoglycemia, its prognosis, and pathogenesis. The inadequacy of glucose oxidase strips for screening, the definition of high-risk infants, new definitions for low plasma glucose concentrations, and their treatment are presented as well as the ability of the neonate to respond to significantly low glucose values. New data concerning the hereditary aspects of hyperinsulinemia (Glaser, this issue), hereditary defects in branched-chain amino acid, 3-methylglutaconic aciduria and mitochondrial betaoxidation, and degradation of fatty acids (Ozand, this issue), the role of glucose transporters (Vannucci and Vannucci, this issue), and the newer computed tomography and magnetic resonance imaging techniques (Kinnala, this issue) to study neonatal hypoglycemia are reviewed elsewhere in this issue.

Quantitative EEG during early recovery from hypoxic-ischemic injury in immature piglets: burst occurrence and duration.

This study examined the course of EEG recovery in an animal model of hypoxic-ischemic injury. The model used periods of hypoxia, room air and asphyxia to induce cardiac arrest. One-week-old piglets (n = 16) were exposed to a period of hypoxia, room air and complete asphyxia for 7 minutes. After cardiac arrest and resuscitation, two EEG features were evaluated as prognostic indicators of behavioral outcome as assessed by a neuroscore at 24 hours after insult. A prominent EEG feature was the number and duration of bursts evident during recovery. Episodes of bursting were detected through the thresholds on sustained periods of elevated power. After the animal was resuscitated, the EEG was monitored continuously for 4 hours. To assess outcome in the recovering animal, a behavioral testing scale was used to test the animal's neurological capabilities. Trends of EEG burst counts were measured through thresholds on sustained power changes. Bursts are energy transients in the EEG record. High degrees of bursting were characteristic of animals having good neurological condition whereas piglets having low burst counts had poor 24 hr neuroscores. At 100 min the average burst rate of the good neuroscore outcome group was more than 8 per min and was significantly different from the poor outcome group's level of 2.7 (p < or = 0.05). When these counts were weighted by their total duration, differences between groups increased (p < or = 0.02). This study showed that the QEEG measure of burst counts and duration together provided a strong prognostic indication of the 24 hour outcome after asphyxic injury in a neonatal animal model. The critical determinant of the bursting character was the time when bursting occurred. Bursting occurring early in recovery was a good gauge of outcome. We conclude that quantitative EEG analysis and interpretation can be an important tool for the outcome determination during recovery from cerebral injury states.

Brain O2 consumption and glutamate release during hypoglycemic coma in piglets are temperature sensitive.

Hypoglycemic injury in the mature brain is mediated by excitotoxicity, which is worsened by disordered cellular energy metabolism. The role of excitotoxicity in relation to brain energy metabolism during hypoglycemia has not been studied in the immature brain. Brain oxygen consumption (CMRO2) increases during hypoglycemia in piglets, whereas CMRO2 decreases in adult pig models. We tested the hypothesis that increased CMRO2 during hypoglycemic coma is temperature dependent and coincides with increased excitatory amino acids (EAA). We measured cerebral blood flow (CBF), CMRO2, and cortical microdiaysate EAA in pentobarbital-anesthetized piglets during hypoglycemic coma and during 2 h of recovery and in normoglycemic controls. In warmed animals brain temperature was kept normothermic (38.5 degrees C). In unwarmed animals brain temperature was allowed to fall (37.6 degrees C). During hypoglycemia CBF increased similarly in warmed animals and unwarmed animals; CMRO2 increased in warmed animals but not unwarmed animals. Glutamate increased during coma and increased more in warmed animals than unwarmed animals but normalized quickly during recovery. EEG recovered earlier in unwarmed animals. We conclude that during a hypoglycemic coma in the immature brain, CMRO2 and glutamate are increased in a temperature-dependent manner.

Poor outcome after hypoxia-ischemia in newborns is associated with physiological abnormalities during early recovery. Possible relevance to secondary brain injury after head trauma in infants.

"Secondary hypoxia/ischemia" (i.e. regional impairment of oxygen and substrate delivery) results in secondary deterioration after traumatic brain injury in adults as well as in children and infants. However, detailed analysis regarding critical physiological abnormalities resulting from hypoxia/ischemia in the immature brain, e.g. acid-base-status, serum glucose levels and brain temperature, and their influence on outcome, are only available from non-traumatic experimental models. In recent studies on hypoxic/asphyxic cardiac arrest in neonatal piglets, we were able to predict short-term outcome using specific physiologic abnormalities immediately after the insult. Severe acidosis, low serum glucose levels and fever after resuscitation were associated with an adverse neurologic recovery one day after the insult. The occurrence of clinically apparent seizure activity during later recovery increased mortality (epileptic state), and survivors had greater neocortical and striatal brain damage. Brain damage after transient hypoxia/ischemia and "secondary brain injury" after head trauma may have some mechanistic overlap, and these findings on physiological predictors of outcome may also apply to pathologic conditions in the post-traumatic immature brain. Evaluation of data from other models of brain injury will be important to develop candidate treatment strategies for head-injured infants and children and may help to initiate specific studies about the possible role of these physiological predictors of brain damage in the traumatically injured immature brain.

Neonatal vitamin A supplementation: effect on development and growth at 3 y of age.

We reported recently that neonatal supplementation with 52 micromol vitamin A reduced infant mortality by 64%; acute side effects were limited to a 3% excess rate of a bulging fontanelle. The current study was conducted to identify developmental changes at 3 y of age associated with neonatal vitamin A supplementation or a bulging fontanelle. Children who had a bulging fontanelle (n = 91) and 432 children who had normal fontanelles after receiving vitamin A or placebo were evaluated with the Bayley Scales of Infant Development. Mean scores for the mental, psychomotor, and behavioral rating scale (BRS) plus 3 subscales of the BRS were not significantly different for treatment-fontanelle-specific groups. In regression models predicting each score, a bulging fontanelle had a small negative effect in all models; when 1 child who was injured from birth was removed from the analysis the effect of a bulging fontanelle was not significant in any model (P > or = 0.35). Vitamin A supplementation had a small beneficial effect on all developmental scores, which was significant for one of the BRS subscales (orientation-engagement) and also for a second (motor quality) when the outlier child was removed. Compared with children with normal fontanelles in the placebo group, children with a bulging fontanelle in the vitamin A group tended to grow less (-0.5 cm, P = 0.33), whereas those with normal fontanelles in the vitamin A group grew significantly more (0.68 cm, P < 0.05), over the first 3 y of life. This study provides no evidence that neonatal vitamin A supplementation is associated with biologically significant adverse growth or developmental sequelae.

Treatment with the competitive NMDA antagonist GPI 3000 does not improve outcome after cardiac arrest in dogs.

BACKGROUND AND PURPOSE: We previously showed that treatment with a competitive N-methyl-D-aspartate (NMDA) receptor antagonist GPI-3000 (GPI) improved short-term physiological recovery after incomplete global cerebral ischemia complicated by dense acidosis. We tested the hypothesis that GPI administered after resuscitation from cardiac arrest would improve a more long-term recovery as measured by neurobehavioral assessment and neuropathology 4 days after resuscitation. METHODS: Anesthetized dogs were subjected to 7 minutes of cardiac arrest followed by vest cardiopulmonary resuscitation. Neurobehavioral outcomes were scored daily on a score ranging from 0 (normal) to 500 (worst). On the fourth day, the animals were killed, and neuropathology was evaluated in a blinded manner in the hippocampus and the neocortex by hematoxylin and eosin staining and by determination of percentage of injured neurons. Three groups of animals were treated in a randomized, blinded protocol with either saline (SAL), low-dose GPI (5 mg/kg followed by 1 mg/kg per hour for 2 hours), or high-dose GPI (25 mg/kg, followed by 5 mg/kg per hour for 2 hours). RESULTS: The mortality rate was higher in animals receiving GPI than in saline-treated control animals (4 of 15 deaths in SAL, 6 of 15 in the low-dose GPI group, and 9 of 18 in the high-dose GPI group). Neurobehavioral scores were depressed in GPI-treated animals compared with saline-treated control animals in a dose-dependent manner, with 96-hour scores of essentially normal (9+/-2) in saline-treated animals compared with those animals with significant impairment (181+/-47) treated with high-dose GPI. Neuropathological damage in the neocortex was most severe in GPI-treated animals, with the percentage of injured neurons dependent on the dose: 8.3%+/-2.7% SAL, 13.2%+/-6.4% low-dose GPI, and 39.4%+/-10.1%, high-dose GPI. CA1 neuronal damage was severe regardless of treatment. CONCLUSIONS: Contrary to results seen in experimental global and focal cerebral ischemia, in which NMDA receptor antagonism may improve responses to injury, receptor antagonism with GPI does not improve brain outcome after cardiac arrest and resuscitation in the dog. Behavioral and histological outcomes both were worsened by GPI treatment at two doses, and mortality was higher relative to saline control treatment. We speculate that systemic drug effects, as well as potential neurotoxicity of the drug under ischemic conditions, may be responsible for the deleterious outcomes observed in our cardiac arrest model.

Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats.

BACKGROUND AND PURPOSE: Glutamate receptor activation can stimulate nitric oxide (NO) production and possibly play a role in long-term potentiation and excitotoxic-mediated injury. We studied the differential effect of agonist-induced activation of ion channel-linked N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtypes on NO production in vivo in rat hippocampus. We also studied whether dantrolene, a ryanodine calcium channel inhibitor previously shown to attenuate metabotropic glutamate receptor stimulation of NO production, also attenuated ionotropic glutamate receptor-mediated stimulation of NO production. METHODS: Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of pentobarbital-anesthetized adult Sprague-Dawley rats and were perfused for 5 hours with artificial cerebrospinal fluid (CSF) containing 3 mumol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 13 groups of rats, increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with no additional drugs versus combinations of NMDA, AMPA, the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the non-competitive glutamate receptor blocker MK-801, the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and dantrolene. RESULTS: Recovery of [14C]L-citrulline during perfusion with artificial CSF progressively increased to 272 +/- 73 fmol/min (+/-SEM) over 5 hours. Contralateral perfusion with 1 mmol/L L-NAME inhibited [14C]L-citrulline recovery. Perfusion with 1 mmol/L MK-801 or 1 mmol/L CNQX reduced [14C]L-citrulline recovery compared with contralateral perfusion with CSF alone. Perfusion with 1 mmol/L NMDA enhanced [14C]L-citrulline recovery, and this enhancement was attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. Perfusion with 1 mmol/L AMPA enhanced [14C]L-citrulline recovery, and this enhancement was also attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. CONCLUSIONS: Through an indirect method of assessing NO production in vivo, results with MK-801 and CNQX indicate that NMDA and AMPA receptor activation contribute to basal NO production in the rat hippocampus. Enhanced NO production with NMDA and AMPA agonists appears to involve a complex neuronal interaction because the effect of NMDA was attenuated by both MK-801 and CNQX and because the effect of AMPA was attenuated by both CNQX and MK-801. In contrast to metabotropic glutamate receptor activation, release of calcium from intracellular ryanodine calcium channels does not appear to be a prominent mediator of ionotropic glutamate receptor stimulation of NO production.

Intracranial compliance in infants: evaluation with Doppler US.

PURPOSE: To test graded fontanelle compression during Doppler ultrasound (US) scanning to identify and monitor infants with altered cranial compliance. MATERIALS AND METHODS: An ophthalmodynamometer exerted pressure on the anterior fontanelle during Doppler US scanning of the middle cerebral artery. Sixty examinations were performed in 43 infants--13 full-term and 11 premature healthy control subjects, 10 with increased intracranial volume, and nine with suspected abnormal cranial compliance but without increased intracranial volume. Resistive index (RI) and angle-corrected time-averaged mean velocities (TAV) of blood flow were compared at three different pressures. RESULTS: Baseline RI values in healthy full-term infants were significantly lower than in healthy premature infants and infants with abnormal compliance (P < .05). Values for healthy premature infants and infants with abnormal compliance were indistinguishable (P > .5). Neither RI nor TAV changed significantly in healthy infants, but both changed significantly with compression in infants with abnormal cranial compliance. CONCLUSION: This procedure may be more useful than measurement of RI of the anterior cerebral artery alone to evaluate infants with altered cranial compliance.

Nitric oxide synthase inhibition attenuates hypoglycemic cerebral hyperemia in piglets.

We tested the hypothesis that nitric oxide (NO) mediates hypoglycemia-induced cerebral vasodilation in piglets. Piglets (1-2 wk old) were made hypoglycemic with insulin (200 U/kg i.v.) with and without an NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg i.v.). Electroencephalogram (EEG), cerebral O2 consumption (CMRO2), and cerebral blood flow (CBF) were measured before L-NAME and insulin and for 180 min after insulin. Hypoglycemia led to isoelectric EEG earlier after L-NAME (87 +/- 8 min) than without L-NAME pretreatment (132 +/- 13 min). CBF increased in all brain regions during hypoglycemia at the onset of isoelectric EEG and was associated with increased CMRO2.L-NAME prevented the increase in CMRO2 and attenuated vasodilation in forebrain (154 +/- 37 vs. 400 +/- 60%), cerebellum (251 +/- 52 vs. 386 +/- 52%), and cortical gray matter (183 +/- 47 vs. 524 +/- 93%) but had no effect on CBF responses in brain stem, thalamus, caudate, or hippocampus. We conclude that NO or a NO-containing compound mediates cerebral vasodilation induced by profound insulin-hypoglycemia in piglets and that this vasodilation plays an important role in the adaptation of immature brain to hypoglycemia.