Effect of glycerol and hyperosmolality on intracranial pressure.

Glycerol has been used in cerebral edema for hyperosmolar dehydration of brain tissue, but only empirical relationships govern this use. Since the efficacy of treatment with glycerol would likely increase with data on the relationship between drug blood levels and intracranial pressure (ICP), we examined the clinical pharmacology of the drug. Plasma samples were assayed for glycerol by a new method using gas chromatography with a flame ionization detector. Data were collected from 12 children who were in Children's Hospital of Pittsburgh (CHP) and who had cerebral edema of differing etiology that was treated with glycerol; they were monitored by intraventricular catheter. Glycerol was infused according to CHP guidelines. ICP reduction correlated with glycerol concentration and plasma concentrations of 1 to 3 mg/ml (10 to 30 mOsm/ml) were necessary to maintain an ICP below 20 torr. The relationship between osmolality and plasma glycerol level was also examined; there was good correlation between the idiogenic osmolality and drug concentration. Our studies support the clinical observations that relatively high doses of glycerol (0.2 to 1.0 gm/kg/hr), leading to plasma concentrations of 10 to 30 mOsm/l, are necessary to control ICP in patients with cerebral edema. Glycerol blood levels may be estimated from serum osmolality.

Cerebrovasculopathy following irradiation in childhood.

Symptomatic intracranial vasculopathy developed in four patients following irradiation for central nervous system tumors. All the patients presented with a stroke-like picture from 2 to 22 years after the completion of radiotherapy. Two of the patients showed abnormalities on arteriography consisting of narrowing of the supraclinoid portion of the internal carotid artery and the adjacent proximal anterior and middle cerebral arteries. Although the risks of radiotherapy for central nervous system tumors of malignant potential are outweighed by potential benefit, the risks should be carefully considered in cases of tumors with little or no malignant potential.

Biotinidase deficiency: accumulation of lactate in the brain and response to physiologic doses of biotin.

Biotinidase deficiency is the most common cause of late onset, biotin-responsive multiple carboxylase deficiency (MCD). We studied the two oldest known boys with this disorder who had high CSF content of lactate that could have contributed to the clinical disorder. The symptoms of these patients implied that near physiologic, rather than pharmacologic, doses of biotin may be sufficient for treatment.

Phenobarbital and phenytoin in neonatal seizures: metabolism and tissue distribution.

Loading doses of 15 to 20 mg per kilogram of both phenobarbital and phenytoin, administered intravenously, are necessary in the newborn to achieve rapid therapeutic plasma anticonvulsant levels. Maintenance doses of 3 to 4 mg per kilogram of both agents will maintain therapeutic levels. Phenytoin is, however, not predictably absorbed by the oral route. Brain:plasma ratios were 0.71 +/- 0.21 for phenobarbital and 1.28 +/- 0.32 for phenytoin, which are in general agreement with reported adult values. The brain:plasma ratio of phenobarbital increased with gestational age. Phenytoin was found in higher concentration in gray matter, whereas phenobarbital was equally distributed between gray and white matter.

Childhood oligodendrogliomas presenting with seizures and low-density lesions on computed tomography.

Three children with cerebral oligodendrogliomas causing partial complex or generalized seizures presented with completely normal neurologic examinations. CT showed low-density, nonenhancing surface lesions. Although these CT features are usually associated with infarcts or cysts, neoplasm was suspected because of irregularity of the margins and erosion of the adjacent inner table of the skull. Oligodendrogliomas often enlarge slowly and may cause seizures years before they produce focal neurologic signs. CT of all children with seizures not responsive to anticonvulsant medication and focal clinical or EEG abnormalities will hasten diagnosis of slowly growing intracranial mass lesions.

Basilar impression in children.

Ataxia is a common neurologic sign in childhood. Basilar impression due to bony abnormalities of the craniovertebral junction is an uncommon but readily treatable cause of ataxia in children. Two children who had neck stiffness, ataxia, nystagmus, and corticospinal tract signs are described. Basilar impression was recognized only after specific radiologic studies were performed. Both children were treated surgically with good results.

Destructive brain lesions of presumed fetal onset: antepartum causes of cerebral palsy.

Antepartum events have been associated with fetal brain injury and may contribute to later neurological sequelae. However, children with these injuries may be asymptomatic or exhibit few clinical signs during the neonatal period. Six neonates are presented with destructive brain lesions of fetal onset based on radiological and neurophysiological studies at birth. No intrapartum difficulties were noted in any of the cases. Two maternal histories were significant for either placental bleeding or toxemia during the second or third trimesters of pregnancy. Fetal porencephaly from presumed intraventricular hemorrhage was documented by serial abdominal sonography for these two children. No causes could be assigned for the remaining four patients with destructive brain lesions. All six children had normal results on neurological examinations at birth, although four neonates later presented with isolated seizures at 8 to 30 hours of life which resolved after administration of anti-epileptic medication. In all cases initial neonatal electroencephalographic records showed abnormalities consisting of major background asymmetries or seizures. Initial documentation of cerebral lesions was made by fetal sonography (two patients) and computed tomography scan (four patients) during the initial 30 hours of life, timing the lesions to the antepartum period. Cerebral palsy has been documented in all children; one child had resolution of her deficits by 6 months of age. Better surveillance of events during the antepartum period may help identify specific pathophysiological conditions that contribute to cerebral palsy. Neurophysiological and imaging studies should be used during the immediate new-born period for neonates believed to have cerebral lesions based on maternal sonography or isolated seizures.

Epidural abscess and vertebral osteomyelitis following serial lumbar punctures.

Lumbar epidural abscess and vertebral osteomyelitis were diagnosed in a 3-month-old infant, born prematurely, who had had repeated lumbar punctures for the treatment of posthemorrhagic hydrocephalus. Staphylococcus aureus was the causative organism. Successful treatment was achieved with 6 weeks of intravenous antibiotics without surgical drainage. Infectious complications of lumbar punctures are rare, but may occur when multiple punctures are attempted in small premature infants whose subarachnoid space contains large amounts of blood. Infection can be introduced directly by a contaminated spinal needle, or trauma to the tissues with bleeding can create a favorable site for bacterial adherence and multiplication. Posthemorrhagic ventricular dilation often resolves spontaneously and serial lumbar punctures should be used to treat this condition only when CSF flow is easy to establish and maintain.

Intracerebral hemorrhage in the full-term neonatal infant.

Supratentorial intracerebral hemorrhage was diagnosed in 18 full-term neonates, including six with primarily intraparenchymal hemorrhage and 12 with primarily intraventricular hemorrhage. Precipitating or associated factors were hypoxic-ischemic injury in five patients, polycythemia in two, and cranial birth trauma in two. Nine other infants had no identifiable medical risk events. The pathogenesis of intraparenchymal hemorrhage was probably related to hemorrhagic infarction, but the pathogenesis of intraventricular hemorrhage was often unknown. All 17 survivors returned for neurologic and developmental examinations between 1 and 7 years of age. Follow-up assessments were normal in nine children and abnormal in eight. Two had perceptual difficulties, three had moderate-to-severe cognitive deficiencies (two of the three had hemiplegia), and three had severe mental and neurologic handicaps. Eight of nine children with known or suspected hypoxic-ischemic or traumatic insults suffered moderate-to-severe disabilities whereas eight of nine children with no known precipitating cause for their hemorrhage developed normally.

Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae.

Electrographically confirmed seizures in preterm and term neonates were compared with respect to clinical correlates, incidence, associated brain lesions, and risk for neurologic sequelae. Over a 4-year period, 92 neonates from a neonatal intensive care unit population of 4020 admissions at a large obstetric hospital with 40,845 livebirths had electrographically confirmed seizures. Sixty-two neonates were preterm and 30 were full-term for gestational age. Chi-square calculations were used to compare the two groups. While the incidence of seizures for all neonates admitted to a neonatal intensive care unit was 2.3%, outborn neonates were more likely to have seizures than inborn neonates. Preterm neonates of < or = 30 weeks gestational age had a seizure frequency of 3.9%, which was significantly higher than that of older preterm neonates and full-term neonates. Clinical criteria contemporaneous with electrographic seizures were noted in only 28 (45%) of 62 preterm, and 16 (53%) of 30 full-term neonates. Subtle seizures coincident with electrographically confirmed seizures were the most predominant clinical type for both term and preterm neonates (71% and 68%, respectively). The distribution of clonic, myoclonic, and tonic seizures was also similar for both groups. Autonomic signs coincident with electrographically confirmed seizures (ie, blood pressure, heart rate, oxygenation, respiration changes) were more frequently observed in preterm than full-term neonates with subtle seizures; 7 (37%) of 19 compared with 1 (6%) of 16. Electrical seizures without clinical correlates were noted more frequently than electroclinical seizures for both populations.(ABSTRACT TRUNCATED AT 250 WORDS)

The frequency of bleeding and height of adolescent haemophiliacs.

The relation between the height of adolescent haemophiliacs and their bleeding frequency has been studied. 45 haemophiliacs aged 10--19 years were divided into 3 groups: small, medium and tall, using a Height Standard Deviation Score. The average bleeding frequency per 100 days in the group of small haemophiliacs was 8.71 +/- SD 4.47, in the medium height group 10.18 +/- SD 6.71, while the tall individuals bled in average 15.97 +/- SD 3.15 every 100 days. There was no relationship between age and bleeding frequency.

Inherited unbalanced subtelomeric translocation in a child with 8p- and Angelman syndromes.

A 10 1/2-month-old boy was found to have an unbalanced karyotype, 45,XY,der(8)t(8;15) (p23.3;q13). One of 83 analyzed cells also contained an unidentified small marker. Fluorescence in situ hybridization (FISH) using cosmid probes for SNRPN, D15S10, and GABRB3 for the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) critical region were not present on the derived chromosome. The child had some physical findings compatible with monosomy 8p. The mother also was a balanced carrier for the translocation. She also had 2/80 cells with an additional small marker chromosome, similar in size to the extra chromosome in the one cell of the propositus. FISH using an 8 paint did not show the reciprocal exchange on the der(15) but was demonstrated by using an 8p telomeric probe. At 18 months of age the child has some manifestations of AS. Earlier diagnosis may have been masked by the 8p- phenotype, or related to difficulty in diagnosing AS in infants.

Neonatal phenobarbital and phenytoin binding profiles.

Phenobarbital and phenytoin binding profiles were determined in 27 neonates. Binding of both drugs decreased compared with that in older subjects. In vitro binding of both agents correlated significantly with total protein and albumin concentrations. In vivo binding at 0.5 hours correlated significantly with birthweight and gestational age. Phenobarbital, but not phenytoin, binding decreased when three other therapeutic agents were concomitantly administered. Bilirubin concentrations, free fatty-acid concentrations, and pH values encountered in this population did not significantly influence binding. An in vitro binding profile accurately predicted in vivo free fractions (percent drug unbound) and plasma concentrations of both drugs.

Connatal brain tumors in patients with tuberous sclerosis.

Two neonates with tuberous sclerosis and giant cell astrocytomas diagnosed soon after birth are described. During attempted surgical resection of their tumors, both infants developed refractory intraoperative cardiac arrhythmias and died. At autopsy, both patients had multiple cardiac rhabdomyomas. Subependymal giant cell astrocytomas rarely present in the neonate, but genetic implications and associated cardiac hamartomas warrant special consideration of these connatal tumors. Surgical considerations suggest that an operative approach to these tumors should be delayed beyond the neonatal period.

Infusion of intrathecal baclofen for generalized dystonia in cerebral palsy.

UNLABELLED: Generalized dystonia occurs in 15 to 25% of persons with cerebral palsy (CP) and responds poorly to medical and surgical treatments. OBJECT: After the authors observed a woman whose dystonic CP was dramatically improved by continuous infusion of intrathecal baclofen, they designed this pilot study to evaluate the effect of this treatment on a group of patients with dystonic CP. METHODS: The authors assessed the short-term response to intrathecal baclofen infusion in 12 patients with dystonic CP. An intrathecal catheter was inserted percutaneously and connected to an external microinfusion pump. The infusion began at a rate of 100 microg/day and was increased by 50 microg every 12 hours until the dystonia abated, adverse effects occurred, or the dose reached 900 microg/day with no improvement. Two observers, one blinded and one not blinded to the patient's treatment status, viewed videotapes made before and after the infusions and graded the dystonia in eight body regions, using a 5-point scale. Overall and regional scores were compared by using Wilcoxon signed-rank tests. CONCLUSIONS: Dystonia diminished in 10 of 12 patients whose average daily dose of intrathecal baclofen was 575 microg. Overall dystonia scores and scores for the extremities, trunk, and cervical regions were significantly better after infusion (p = 0.003). The two observers' scores were not significantly different. Programmable infusion pumps were subsequently implanted in eight patients for long-term therapy and improvement was sustained in six (p < 0.05). Intrathecal baclofen infusion is a promising treatment option for generalized dystonia associated with CP. The effects of intrathecal baclofen infusion on dystonia can be evaluated by using short-term continuous infusions.

The epidemiology of meningococcal infections in England and Wales, 1912-1983.

The epidemiology of meningococcal infections that arose in England and Wales during the period 1912-1983 has been reviewed. The outcome of meningococcal disease was dramatically improved when treatment with sulphonamides was introduced. With the emergence of sulphonamide-resistant strains, penicillin has become the drug of choice. Despite modern treatment, however, the mortality ratio during the last 30 years has remained about the same. Prompt diagnosis as well as immediate and effective treatment are cardinal needs. Even so, when infection is overwhelming there is little chance of saving the patient. Immunisation is probably the only effective answer but as yet there is not an effective vaccine to prevent group B infections which predominate in this country.

A comparison of biotypes and serotypes of Campylobacter sp. isolated from patients with enteritis and from animal and environmental sources.

The origin of sporadic campylobacter infections has been investigated by means of a collaborative study. From a total of 1152 cases reported in North West England in 1982, Campylobacter strains isolated during one month in each quarter of the year were biotyped and serotyped. For comparison, 875 strains of Campylobacter isolated from environmental and animal sources were similarly examined. Most strains from human beings were Campylobacter jejuni; about half of them were of three serotypes. Those serotypes commonly found in human infections were frequent among strains isolated from environmental and animal sources.

Neonatal seizures: diagnosis and treatment.

Neonatal seizures are a frequent problem encountered in neonatal nurseries, but their significance is controversial. Some investigators regard newborn seizures as simply epiphenomena and reflective of brain injury, whereas others note associated metabolic and physiologic aberrations suggesting that seizures per se are injurious to the central nervous system. The proper approach to the treatment of neonatal seizures depends on the etiology because treatment differs if seizures are of metabolic, toxic, or structural origin. Most studies reporting the efficacy of anticonvulsant agents neither define the seizure characteristics being treated nor use electroencephalographic documentation of seizure activity. The choice of anticonvulsants has been based on tradition rather than on the proven superiority of one agent over another. Although several anticonvulsants are available, phenobarbital remains the drug most frequently chosen as the initial agent in treatment. The important pharmacologic considerations of anticonvulsants include route of administration, ability to achieve therapeutically efficacious and predictable plasma levels rapidly, drug distribution, the availability and affinity of receptor sites, protein-binding characteristics, effects on brain growth, and cardiovascular toxicities. At the present time, critical questions remain regarding the effects of both seizures and anticonvulsants on the developing central nervous system.

Natural history, prognosis, and lipid abnormalities of idiopathic ischemic childhood stroke.

A study was performed to assess the natural history, prognostic factors, and lipid and apolipoprotein abnormalities of idiopathic ischemic childhood stroke. A case series of 42 children, retrospectively identified with idiopathic ischemic strokes, were reassessed an average of 7.4 years (range, 1 to 19 years) after presentation. Patients were interviewed and examined, and fasting serum was obtained for lipid and apolipoprotein analysis. Poor outcome was defined as moderate to severe hemiparesis, special educational needs, epilepsy, recurrent stroke, or stroke-related death. Eighteen (43%) of the patients had a poor outcome. Among them were moderate to severe hemiparesis in 14 (78%), recurrent strokes in seven (39%), and one death. Poor outcome was evident early in their clinical course. Independent of outcome, lipid abnormalities including an elevated triglyceride and low-density lipoprotein cholesterol, and a depressed high-density lipoprotein cholesterol were seen in one third of all patients. A depressed ratio of apolipoprotein A-1 to apolipoprotein B (using adult normative values) was seen in half of the entire cohort. Clinical features of children with unexplained ischemic strokes at presentation and their subsequent course are described. Significant risk factors for a poor outcome include (1) persistence of hemiparesis 1 month after the stroke, (2) cortical as opposed to subcortical location, and (3) bilateral occlusive disease with telangiectasia on cerebral angiography. Previously described risk factors for an unfavorable prognosis, including occurrence during infancy and presentation with seizures, were not substantiated. Lipid abnormalities occur at an increased frequency in children after unexplained ischemic strokes. Prospective assessment of lipoprotein profiles are needed to further assess clinical significance. Assessing apolipoproteins may provide further insight than lipid values alone.

Animal models of perinatal asphyxia: contributions, contradictions, clinical relevance.

Animal models have contributed immensely to our understanding of hypoxic ischemic encephalopathy in the newborn. A number of animal models have been used, including both primate and subprimate species. Although the Rhesus monkey model has a dramatically similar pathological distribution of brain injury when compared with the human, other pathologic processes secondary to asphyxia may be more appropriately assessed in other species. The maxim that because primates are closer on the phylogenetic tree to humans than are subprimates all observations in the primate are applicable to the human is simply not true. Understanding of the neurochemical consequences of asphyxia in the past decade have arisen from experiments primarily in the neonatal rat. We have come to understand that not only is the hypoxic event of major significance, but that, once reperfused, reoxygenation causes further injury. Free-radical generation following reperfusion may be massive and may further contribute to cell membrane injury. These observations have lead to rational theoretic approaches to the treatment of hypoxic ischemic brain injury. On the other hand, previously used treatments such as osmotic agents and glucocorticoids would appear to be not only inefficacious but hazardous in the treatment of hypoxic ischemic brain injury. The role of nitric oxide (NO) in the pathogenesis of brain injury is yet uncertain, but there is little doubt that it plays a significant role. Although survival of the immature animal subjected to hypoxic environment is longer than in the mature animal, the central nervous system of the immature animal is more sensitive to glutamate and N-Methyl-D-aspartate (NMDA) receptor-mediated injury.