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The mechanisms by which human immunodeficiency virus (HIV) infection provokes progressive neurodegeneration and dementia in acquired immunodeficiency syndrome (AIDS) remain obscure. In HIV-infected (HIV+) individuals, we found that the brain cells preferentially infected by HIV, viz. the microglia, were abundant, activated, and intensely immunopositive for interleukin-1 alpha (IL-1 alpha), an immune response-generated cytokine that increases the synthesis and processing of beta-amyloid precursor proteins (beta-APP) and promotes proliferation and activation of astroglia. We also found an increase in the number of activated astroglia expressing elevated levels of S100 beta, a cytokine that increases intraneuronal calcium levels and promotes excessive growth of neuronal processes (neurites). These glial changes were accompanied by increased expression of beta-APP immunoreaction product in neurons and overgrown (dystrophic) neurites. In addition, some neurons contained monoclonal antibody Tau-2 immunopositive, neurofibrillary tangle-like structures. Our findings provide evidence that glial activation with increased expression of IL-1 alpha and S100 beta may be important in the neuropathogenesis of AIDS dementia. We propose that HIV infection promotes excessive microglial IL-1 alpha expression with consequent astrogliosis and increased expression of S100 beta. Overexpression of these two cytokines may then be involved in AIDS neuropathogenesis by inducing gliosis, growth of dystrophic neurites, and calcium-mediated neuronal cell loss in AIDS.

It has been proposed that hyperammonemia may be associated with valproate therapy. As astrocytes are the primary site of ammonia detoxification in brain, the effects of valproate on glutamate and glutamine metabolism in astrocytes were studied. It is well established that, because of compartmentation of glutamine synthetase, astrocytes are the site of synthesis of glutamine from glutamate and ammonia. The reverse reaction is catalyzed by the ubiquitous enzyme glutaminase, which is present in both neurons and astrocytes. In astrocytes exposed to 1.2 mM valproate, glutaminase activity increased 80% by day 2 and remained elevated at day 4; glutamine synthetase activity was decreased 30%. Direct addition of valproate to assay tubes with enzyme extracts from untreated astrocytes had significant effects only at concentrations of 10 and 20 mM. When astrocytes were exposed for 4 days to 0.3, 0.6, or 1.2 mM valproate and subsequently incubated with L-[U-14C]glutamate, label incorporation into [14C]glutamine was decreased by 11, 25, and 48%, respectively, and is consistent with a reduction in glutamine synthetase activity. Label incorporation from L-[U-14C]glutamate into [14C]aspartate also decreased with increasing concentrations of valproate. Following a 4-day exposure to 0.6 mM valproate, the glutamine levels increased 40% and the glutamate levels 100%. These effects were not directly proportional to valproate concentration, because exposure to 1.2 mM valproate resulted in a 15% decrease in glutamine levels and a 25% increase in glutamate levels compared with control cultures. Intracellular aspartate was inversely proportional to all concentrations of extracellular valproate, decreasing 60% with exposure to 1.2 mM valproate.(ABSTRACT TRUNCATED AT 250 WORDS)

We found an elevation of very long chain fatty acids in 13 of 22 plasma samples from patients on a ketogenic diet for the treatment of uncontrolled seizures. Because elevated values of very long chain fatty acids are a biochemical manifestation of peroxisomal dysfunction, this phenomenon might lead to diagnostic confusion. Thus the history and clinical status should be considered when plasma levels of very long chain fatty acids are interpreted.

An infant with neurofibromatosis developed recurrent cerebrovascular accidents beginning at 3 months of life. Cerebral arteriography demonstrated large-vessel occlusive disease and bilateral severe moyamoya. At autopsy these lesions were apparent on gross examination, and advanced intimal and medial dysplasia was seen on microscopic examination of both the anterior and posterior circulations. Although rare, neurofibromatosis cerebrovasculopathy may occur in young infants and may account for some strokes in this age group.

The final step in neutrophil bacterial killing is formation of a toxic halide complex. For this reason, we studied neutrophil function in children receiving bromide anticonvulsant therapy. Whole blood and serum were obtained from 7 patients with seizure disorders treated orally with triple bromide elixir to examine neutrophil function as measured by luminol enhanced chemiluminescence (CL). Serum bromide concentrations [Br-] were determined concomitantly. There was a direct correlation between [Br-] and CL activity of neutrophils (r = 0.87) with peak CL responses significantly higher than controls when [Br-] were in the therapeutic range (10-20 mM). With [Br-] above 25 mM, CL activity was reduced. Serum from patients also enhanced CL of control neutrophils with a similar relationship to measured [Br-]. To confirm that enhanced neutrophil activity was attributable to [Br-] use, [Br-] ranging from 0-50 mM were added to control neutrophils in otherwise normal physiologic conditions and the CL assay was performed. Results expressed as percent of control values were as follows: [Br-] 5 mM, 110%; 10 mM, 158%; 15 mM, 194%; 20 mM, 252%; 25 mM, 136%; 30 mM, 364%; and 50 mM, 205%. These data demonstrate that Br- enhances phagocytic and bactericidal activity of neutrophils and suggest that Br- therapy may augment host defense capabilities.

Cockayne's syndrome is associated with dementia and other physical signs of premature senescence. Death usually occurs in the first or second decade of life. Because previous neuropathologic descriptions have included neurofibrillary tangles and calcific and dystrophic cerebrovascular changes, we examined the mesial temporal lobes of three children with Cockayne's syndrome (confirmed by 254-nm ultraviolet light studies). Immunohistochemistry was used to determine if beta-amyloid immunoreactivity was present in the parenchyma or cerebral blood vessels. Tissues from the mesial temporal lobe of patients with Alzheimer's disease and Down syndrome were used as controls. None of the three temporal lobes from patients with Cockayne's syndrome contained beta-amyloid immunoreactive material in either the parenchyma or vessels; all of the Alzheimer's disease and Down syndrome controls had beta-amyloid immunoreactivity.

Bromide is not often prescribed today as antiepileptic therapy. One reason is that serum bromide concentrations are not routinely performed in hospital laboratories, making clinical decisions difficult. Because of bromide ion interference with the electrodes of commonly used automated electrolyte analyzers, factitious "hyperchloremia" (and in some cases, "hyperbicarbonatemia"), are produced. These values, and the resulting calculated anion gap, correlate well with the measured serum bromide concentration. The correlation permits results from routine automated electrolyte analyzers to be used to indirectly determine serum bromide concentration.

Migraine is a common clinical diagnosis, occurring in 4-10% of school age children. Migraine in the infant and preschool child has been infrequently described in retrospective studies. We report the prospective evaluation and therapy of six children (5-42 months) with migraine. In four of the children, Prensky's criteria were used for diagnosis, while the two youngest children presented with ophthalmoplegic migraine. All children had a strong family history of migraine and presented with headache and prominent features including facial pallor, irritability, sleep disturbance or mood changes. The oldest four children were successfully treated with either amitriptyline or imipramine in low doses. The infants with ophthalmoplegic migraine failed to completely respond to any therapy. At followup 2 to 18 months later, all children were well and without toxicity. The pediatrician should be aware that migraine may begin in infancy and can be effectively and safely treated.

Phenytoin (DPH) is commonly used to treat seizures associated with acute head injury. Consequent to decreases in DPH protein binding in such patients, the DPH free fraction (DPHff) may increase and thereby produce symptoms compatible with DPH toxicity despite the presence of total serum concentrations within the usually accepted therapeutic range. We examined the effect of acute traumatic injury on DPH protein binding in 13 hospitalized pediatric patients. In addition to total and free DPH serum concentrations, biochemical variables including blood pH, total and direct bilirubin, serum urea nitrogen, creatinine, albumin, gamma glutamyltransferase (GGT), and free fatty acid concentrations were measured serially over 10 days. The DPHff was compared between selected time intervals in hospitalized patients and data obtained in a control population of 27 epileptic outpatients who were maintained on DPH. Additionally, a multiple regression model was used to examine for covariance between the DPHff and the respective biochemical variables in the hospitalized patients. In the study patients, the DPHff progressively increased, attaining a maximum value (8.5 +/- 0.7%) on the fifth hospital day which was significantly greater (6.4 +/- 0.7%, p less than .05) than that on day 1 and also in the control group (6.1 +/- 0.3%; p less than .01). Blood pH, serum albumin, free fatty acids, creatinine and bilirubin concentrations did not change, but GGT did increase significantly over the 10-day sampling period. A significant (r = .51, p less than .0001) linear relationship was found between the DPHff and the serum albumin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the association of telencephalic dysgeneses (expected to occur around week 6 of gestation) with presumptive maternal carbon monoxide intoxication. This case supports the hypothesis that carbon monoxide intoxication at critical periods of human brain development may lead not only to decreased brain size and hypoxic-ischemic lesions, but also to dysgeneses.

Triple bromide elixir was used as an adjunctive antiepileptic drug in 11 children whose seizure disorders were intractable to other antiepileptic therapy. The patients' ages ranged from 2 to 17 years. The seizure disorders treated included photosensitive epilepsy (one case), acquired epileptic aphasia (one case), Lennox-Gastaut syndrome (three cases), and symptomatic localization-related epilepsies (six cases). Two patients' seizures completely stopped with bromide therapy. Four patients had a significant and sustained improvement on bromide therapy, while three more had a transient improvement. In these six patients with complete or significant control, the mean therapeutic dose was 33 mg bromide/kg daily, and the mean therapeutic serum concentration was 14.1 mmol/L (range, 4 to 30.5 mmol/L). The combination of bromide with valproate appeared to be particularly effective in these patients. Toxicity was minimal, and in only one patient was the medication stopped, because of anorexia and weight loss. Given the low cost, long half-life, and minimal toxicity when serum bromide concentrations are followed, bromide therapy should be considered as adjunctive antiepileptic drug therapy for patients whose seizures are intractable to other drugs.

Transient global amnesia has been reported to be precipitated by intense emotion in adult patients. Transient global amnesia is uncommon in the pediatric age group. We report the unusual occurrence of this syndrome, apparently precipitated on two occasions by emotion, in an adolescent who had earlier in life suffered a left temporal and occipital lobe embolic infarction from congenital heart disease. Transient global amnesia following intense emotion may be a cause of some confusional states in children and adolescents.

Cyclotrimethylenetrinitramine (RDX) is a highly explosive compound frequently used for both military and civilian purposes. Previously reported cases of human RDX intoxication were limited to wartime settings and have described no human pharmacokinetic data. We report the first human intoxication to occur in a non-wartime setting. This intoxication presented with status epilepticus in a child and permitted the description of RDX human pharmacokinetics. It also suggested a strong association between central nervous system dysfunction and RDX intoxication.

We describe the unusual association of long-standing repaired myelomeningocele, hydrocephalus, and Arnold-Chiari malformation with bilateral internuclear ophthalmoplegia in a young man. A rarely reported association, this case emphasizes the need for further neuroradiologic evaluation to determine the possibility of third-ventricle enlargement with worsening hydrocephalus.

Ophthalmoplegic migraine, headache associated with oculomotor nerve dysfunction, may present early in the pediatric age group. Two cases of ophthalmoplegic migraine in infants 5 and 7-months-old are presented and their clinical management discussed.

A 16-month-old child demonstrated cortical blindness following Hemophilus influenzae meningitis. The CT scan and flash VER findings were normal, and visual recovery was noted several weeks after hospital discharge.

Gastrointestinal (GI) surgery in children with seizure disorders is often complicated by difficulties in administering oral anticonvulsant medications in the preoperative and postoperative periods. Because many newer anticonvulsants do not have parenteral formulations, intravenous phenobarbital, phenytoin, and benzodiazepines may appear necessary in the perioperative period. Eight children with neurologic disease with severe seizure disorders underwent gastrostomy placement and Nissen fundoplication. Perioperatively, their anticonvulsants were given successfully via the rectum. Rectal administration of anticonvulsants is a useful alternative route for drug therapy in seizure patients who are undergoing GI surgery.

Tourette's disorder is a stereotyped movement disorder that carries with it the risk of self-mutilation. Two cases are presented in which children with Tourette's disorder mutilated themselves. Possible physiologic mechanisms by which self-mutilation occurs in patients with Tourette's disorder are reviewed and treatment strategies are discussed.

The myotubular myopathies are a heterogeneous group of muscle disorders in which x-linked, autosomal recessive, and autosomal dominant inheritance have been reported. Female carriers of x-linked myotubular myopathy have been reported to have abnormal muscle biopsies. We report a woman who had a normal muscle biopsy but who had 2 sons with myotubular myopathy by different fathers, indicating that a normal muscle biopsy of the mother cannot exclude x-linked inheritance. The quantity of fetal activity correlated with the severity of the disorder in this pedigree.

Trace element deficiency in burns is an area which apparently has not been investigated. We recently encountered a severely burned patient with profound copper depletion. Neuropsychiatric symptoms and delayed healing may have been secondary to this deficiency. Further study is needed to clearly delineate the role of acquired copper deficiency in recovering burned patients.

The ketogenic diet is a well-established, but relatively infrequently used, therapy for intractable seizures in children. Currently, the standard ketogenic diet is formulated using medium chain triglyceride (MCT) oil as its major caloric source. Cost, availability, and gastrointestinal side effects limit its use in some cases. We report the successful substitution of corn oil for MCT oil in six children treated with the ketogenic diet for intractable seizures. In each case, the corn oil ketogenic diet was effective, well-tolerated by the patient and parents, and free of clinical toxicity. Corn oil also has the major advantages of being much less expensive and more available that MCT oil. Its use in the ketogenic diet appears to be effective, safe, and practical.

Delay in treatment or inadequate therapy with inappropriate antibiotics can result in a progressive cycle of inflammation, edema and infarction in children with bacterial meningitis. Early use of computed tomographic (CT) scanning and effective antibiotic therapy may significantly alter both the initial and long-term clinical courses. CT scanning also facilitates the early detection and treatment of suppurative intracranial complications.

Postinfectious encephalomyelitis and multiple sclerosis have clinical, immunologic, and neuroradiographic similarities. We studied HLA determinants in six white children consecutively diagnosed with postinfectious encephalomyelitis. Each of the children had HLA determinants which have been associated with multiple sclerosis. Relative risk (RR) calculations demonstrated that these antigens and genotypes occurred significantly more often in patients with postinfectious encephalomyelitis than in the control population (A3, RR 6.14; B7, RR 6.14; DR2, RR 4.51; A3B7, RR 9.36; A3DR2, RR 5.83; B7DR2, RR 6.13; A3B7DR2, RR 10.90). These data suggest that children with postinfectious encephalomyelitis are genetically predisposed to this demyelinating disease. Although the same HLA determinants were found in these patients as in those with multiple sclerosis, studies of a larger number of postinfectious encephalomyelitis patients will be needed before it can be concluded that the two diseases share a common genetic propensity.

In general, childhood sleep disturbances can be accurately clinically diagnosed by the primary care physician, neurologist, or psychiatrist. Careful characterization of the "spells," either by history or home videotaping, may be sufficient. Often, no laboratory studies are needed if the physician can recognize the sleep disturbance and clinically differentiate it from epilepsy or migraine. Although behavioral approaches or "tincture of time" often alleviates a great many sleep disturbances in children, psychopharmacologic therapy has a role in many and can be judiciously prescribed with safety and efficacy.