Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism.

BACKGROUND: Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). METHOD: PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS: ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. CONCLUSIONS: These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.

Brain imaging in neurobehavioral disorders.

Neuroimaging studies of neurobehavioral disorders are using new imaging modalities. In dyslexia, anatomic imaging studies demonstrate an abnormal symmetry of the planum temporale. Functional imaging supports the hypothesis that developmental dyslexia is frequently the result of deficits in phonologic processing and that normal reading requires a patent network organization of a number of anterior and posterior brain areas. In autism, anatomic imaging studies are conflicting. Functional imaging demonstrates temporal lobe abnormalities and abnormal interaction between frontal and parietal brain areas. In attention-deficit-hyperactivity disorder, imaging studies suggest an abnormality in the prefrontal and striatal regions. Neuroimaging studies are often contradictory, but trends, especially with functional imaging analysis, are evolving. Because neurobehavioral disorders seem to be a result of a dysfunction in brain circuits, no one region will be abnormal in all patients studied. Further studies with well-defined patient populations and appropriate activation paradigms will better elucidate the pathophysiology of these conditions.

Stroke in children: genetic and metabolic issues.

The study of genetic and metabolic etiologies of pediatric stroke, both vascular and metabolic, allows an understanding of the causes of acute focal neurologic deficits in childhood. Here, the mendelian and mitochondrial genetic causes of pediatric stroke syndromes are reviewed. This approach elucidates the etiology of childhood stroke and illustrates many of the genetic risk factors that are found in adult-onset cerebrovascular disease. Therefore, the study of childhood stroke serves as a model to elucidate the potential risk factors for all stroke. Ultimately this will serve to develop a more rational preventive and therapeutic approach for all cerebrovascular disease.

Traumatic brain injury in children and adolescents.

Traumatic brain injury is an insult to the brain caused by an external force that results in an impairment (transient or permanent) of cognitive, behavioral, emotional, or physical function. Traumatic brain injury encompasses shearing injury, which might be seen in a shaken infant, as well as penetrating injury from a foreign body, such as a bullet. This article addresses the recovery phase and functional sequelae following traumatic brain injury. Research and clinical experience over the past decade have led to a better understanding of the pathophysiology of head injury and, in turn, improved management.

Neurobehavioral manifestations and sequelae of HIV and other infections.

Central nervous system infections in children and adolescents involve a wide spectrum of illnesses, ranging from acute self-limited diseases, such as enteroviral meningitis, to severe diffuse or focal infections (i.e., arboviral encephalitis) resulting in devastating neurologic sequelae. All the clinical manifestations of CNS infections occur to some degree secondary to toxic mediators such as cytokines. These factors are neurotoxic and produce clinical manifestations such as encephalopathy, motor abnormalities, and seizures. Many of these diseases also produce radiculoneuropathies and vasculopathies (stroke). As a result, chronic neurologic conditions may result and are frequently associated with psychiatric disturbances and situational depression.

Correlation of basal ganglia magnetic resonance spectroscopy with Apgar score in perinatal asphyxia.

BACKGROUND: Brain metabolite levels are measured by proton magnetic resonance spectroscopy (1H MRS) and include N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate and the ratios NAA to Cho and Cr (NAA-ChoCr), NAA-Cr, NAA-Cho, and Cho-Cr. Brain metabolite levels may correlate with the degree of neonatal asphyxia. OBJECTIVE: To determine which brain metabolite ratios have the strongest correlation with the Apgar scores in infants with possible asphyxia; whether the correlation is stronger with basal ganglia (BG) or anterior border-zone metabolites; and whether a combined approach using routine MR imaging (MRI), diffusion-weighted MRI, and MRS can be used to evaluate the severity of neonatal asphyxia. METHODS: Twenty infants with 1-minute Apgar scores of 6 or less were studied at 2 to 28 days of age. The MRS variables were compared with routine and diffusion-weighted brain MRI. Clinical variables and MRS findings were subjected to factor analysis and stepwise multiple regressions to determine interrelationships. RESULTS: The BG region NAA-Cho and NAA-ChoCr ratios correlated with the 1-minute (P<.001) and 5-minute (P = .01 for NAA-Cho; P = .006 for NAA-ChoCr). There was no correlation between metabolite levels and the 10-minute Apgar scores. The stongest predictions exist between the 1-minute Apgar scores and the NAA-Cho and NAA-ChoCr ratios. In the anterior border zone, the only correlation was between the 1-minute Apgar score and the NAA-Cho ratio, but there was a strong age effect in these data. Lactate was found in the BG of 3 infants, all of whom had 5-minute Apgar scores of 6 or less. Three patients had focal lesions on MRI; 2 of these had elevated lactate levels in the abnormal region; and the third, who had an intrauterine stroke, had no lactate in the region. CONCLUSIONS: Correlations between NAA-Cho and NAA-ChoCr ratios and the 1- and 5-minute Apgar scores are stronger in the BG region than in the frontal border zone. The presence or absence of lactate may indicate the severity of the brain insult, and the combination of MRS, MRI, and diffusion-weighted MRI may assist in localizing and predicting a long-term brain injury.

Hypertensive encephalopathy, reversible occipitoparietal encephalopathy, or reversible posterior leukoencephalopathy: three names for an old syndrome.

Children with hypertension, seizures, lethargy, encephalopathy, headache, and occipital blindness are reviewed. After undergoing antihypertensive therapy, most children improve. Some patients have a similar syndrome associated with chemotherapy, transplantation, transfusion, or human immunodeficiency virus-1 (HIV-1) infection. These latter children can develop symptoms with only minimal or no discernible elevations in blood pressure and improve, in the case of cancer-associated encephalopathy, after discontinuing chemotherapy. The reported children with this distinctive clinical condition are compared to adults with reversible posterior leukoencephalopathy syndrome. Since both gray and white matter are involved, we had suggested previously that the name be changed to (reversible) occipitoparietal encephalopathy syndrome. However, reversible posterior leukoencephalopathy has been used in the adult population and probably should be employed in children for the sake of uniformity, since both children and adults have the same clinical presentation and presumably a similar pathophysiology for the encephalopathy syndrome. The diagnosis is confirmed by reversible posterior abnormalities seen on T2-weighted brain magnetic resonance imaging, and by the presence of either headache, altered mental status, seizures, or visual disturbances.

Valproate therapy: predisposition to bone fracture?

A 13-year-old girl on valproate therapy had 20 fractures over a 4-year period between the ages of 5 years and 9 years. Once valproate was withdrawn, no further fractures occurred over the ensuing 4 years. Three other children manifested at least two fractures while on valproate antiepileptic therapy. These reports suggest that valproate, along with other known causes of demineralization (e.g., lack of exercise, diet, and genetic factors), predisposes patients to fractures.

Magnetic resonance spectroscopy: use in monitoring MELAS treatment.

BACKGROUND: Sodium dichloroacetate has been used to treat patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Magnetic resonance spectroscopy (MRS) has been used to assess cerebral metabolism in MELAS, but to our knowledge, the findings of serial MRS studies performed after therapeutic intervention of strokelike episodes have not been reported. METHODS: Proton MRS was serially used to measure brain metabolites in strokelike regions and in clinically uninvolved brain regions in a patient with MELAS. PATIENT: A patient with MELAS and a strokelike episode clinically improved after treatment with sodium dichloroacetate. An elevated lactate-creatine ratio in the "stroke" region decreased on MRS studies after treatment. After a second episode, the lactate-creatine ratio increased from baseline in a region of the brain that was normal on magnetic resonance imaging scans. CONCLUSIONS: To our knowledge, this is the first study to assess the response to treatment of a MELAS strokelike episode and the first to show an increase in the lactate-creatine ratio in a brain region that was associated with a clinical abnormality, even though it appeared normal on magnetic resonance imaging. We conclude that MRS may help to monitor therapeutic efficacy in mitochondrial encephalomyopathies.

Brain lactate and N-acetylaspartate in pediatric AIDS encephalopathy.

Two children with acquired immunodeficiency syndrome (AIDS) and progressive encephalopathy underwent MR spectroscopy before and after antiretroviral therapy. Initial MR spectroscopy of the basal ganglia region showed decreased N-acetylaspartate (NAA)/creatine (Cr) and a lactate peak. After therapy, there was improvement in NAA/Cr and an absence of the abnormal lactate peak. We suggest that decreased NAA/Cr in AIDS is reversible, that brain lactate might correlate with inflammation, and that MR spectroscopy can be useful in treatment trials.

Occipital-parietal encephalopathy: a new name for an old syndrome.

A boy presented with hypertension, seizures, lethargy, headache, and occipital blindness. He improved with antihypertensive therapy. Other reported children with a similar distinctive clinical condition are compared with adults with a syndrome termed reversible posterior leukoencephalopathy. Because both gray and white matter are involved, we suggest that the name be changed to occipital-parietal encephalopathy syndrome.

Pediatric HIV infection.

Developments in the prevention and treatment of HIV infection in pregnant women and their children are encouraging. Perinatal ZDV therapy can reduce the maternal-infant transmission rate by two thirds in select populations. New therapies and the development of diagnostic assays to monitor HIV viral burden have renewed hope that, by aggressively controlling viremia, the progressive immunodeficiency can be delayed or even prevented. The general pediatric approach of preventing illnesses through aggressive vaccination and education policies must be actively incorporated into an approach to this epidemic. Success in controlling the pediatric HIV epidemic requires a concerted, coordinated effort by public policy makers, health care providers, basic science researchers, and those who are HIV-infected.

Central brain atrophy in childhood AIDS encephalopathy.

OBJECTIVE: To determine differential patterns of brain atrophy in pediatric AIDS encephalopathy. DESIGN: We measured the bicaudate, bifrontal, and ventricle-brain ratio in brain magnetic resonance imaging scans of 42 control children, nine children with progressive AIDS encephalopathy, 25 AIDS children without progressive encephalopathy, and 23 children with cerebral atrophy of other causes. RESULTS: When compared with controls, encephalopathy patients showed significantly increased bicaudate and ventricle-brain ratios, but no significant increase in bifrontal ratio, whereas children with brain atrophy from causes other than AIDS showed increases in all three ratios. CONCLUSION: Children with AIDS encephalopathy demonstrate a specific pattern of brain atrophy distinct from other etiologies: a central atrophy, primarily affecting the subcortical white matter or the basal ganglia regions.

Proton MR spectroscopy of the basal ganglia in healthy children and children with AIDS.

PURPOSE: To evaluate proton magnetic resonance (MR) spectroscopy in children with the acquired immunodeficiency syndrome (AIDS) and to establish an age-dependent spectroscopic database of the normal basal ganglia in children. MATERIALS AND METHODS: Eighteen healthy children and 45 children with AIDS underwent both brain MR imaging and single-voxel MR spectroscopy with a long-echo-time point-resolved technique. A large part of the region of interest studied at MR spectroscopy included the basal ganglia. RESULTS: Seven patients with progressive encephalopathy and eight with static encephalopathy had significantly lower mean N-acetyl aspartate (NAA)/creatine (Cr) ratios than age-matched control subjects (P<.02). In determining the presence of progressive encephalopathy in children with AIDS, MR spectroscopy appears to be more sensitive and specific than MR imaging and immunologic testing. Thirty patients without encephalopathy had normal NAA/Cr ratios but significantly lower choline/Cr ratios than age-matched control subjects (P<.02). CONCLUSION: Proton MR spectroscopy may be a more sensitive diagnostic technique than MR imaging in childhood AIDS encephalopathy.

Subacute sclerosing panencephalitis and acquired immunodeficiency syndrome: role of electroencephalography and magnetic resonance imaging.

Subacute sclerosing panencephalitis (SSPE) had largely disappeared from the United States because of nearly universal measles vaccination, but it has reemerged in children infected with human immunodeficiency virus (HIV). Two children with SSPE are described. The first was HIV positive and presented with seizures and encephalopathy at the age of 21 months. The second developed myoclonus and dementia at age 4 years; she was not infected with HIV, but her mother had acquired immunodeficiency syndrome. Magnetic resonance imaging findings were nonspecific and could have been compatible with HIV encephalopathy. Electroencephalography was characteristic of SSPE, showing high-voltage, periodic slow-wave complexes and background slowing. The diagnosis of SSPE was confirmed by brain biopsy or high measles antibody titers in the cerebrospinal fluid.

Fanconi anemia and moyamoya: evidence for an association.

We report two patients with Fanconi anemia (FA) and moyamoya disease taken from a clinical database composed of 434 FA patients. Both are compound heterozygotes for the 322delG and R185X mutations in the FA complementation group C (FACC) gene. This combination of mutations is not found in any other of the 174 FA families screened. Either the 322delG or R185X mutation alone or in combination may predispose to primary, possibly congenital, vascular anomalies.