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.

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.

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.

Magnetic resonance spectroscopy in childhood AIDS encephalopathy.

Twenty-five children with acquired immunodeficiency syndrome (AIDS) underwent cranial magnetic resonance imaging and proton magnetic resonance spectroscopy. Patients were divided into 2 groups based on clinical parameters: encephalopathy and nonencephalopathy. N-acetyl aspartate/creatine ratios were compared between the 2 groups and to control data. Spectra were obtained for 2 volumes of interest: the basal ganglia region and the white matter. The mean basal ganglia region ratio for the AIDS encephalopathy patients (n = 8) was 1.12 and the ratio for the AIDS nonencephalopathy patients (n = 17) was 1.48. The ratio for the 9 controls was 1.57. The encephalopathy group had a significantly lower ratio than both the control (P < .001) and the AIDS nonencephalopathy group (P < .002). The mean white matter ratio for the encephalopathy group (n = 8) was 1.47 and for the AIDS nonencephalopathy group (n = 13) was 1.82 with a control (n = 6) ratio of 1.82. The encephalopathy patients had a lower white matter ratio than the nonencephalopathy (P < .05) patients but the ratio was not different than controls (P < .11). It is concluded that N-acetyl aspartate/creatine ratios are reduced in childhood AIDS encephalopathy and proton magnetic resonance spectroscopy may be helpful in defining brain human immunodeficiency virus-1 infection. However, further longitudinal studies are necessary to determine the sensitivity and specificity of this technique.

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.

Mitochondrial encephalomyopathy associated with a single nucleotide pair deletion in the mitochondrial tRNALeu(UUR) gene.

The investigation of pathogenic mitochondrial DNA (mtDNA) mutations has revealed a complex relation between patient genotype and phenotype. For unknown reasons, some mtDNA mutations produce specific clinical manifestations such as chronic progressive external ophthalmoplegia; myoclonic epilepsy and ragged-red fiber disease (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). To enhance our understanding of the association between genotype and phenotype, we investigated a patient with mitochondrial encephalomyopathy and severe cerebral calcifications for a mtDNA mutation. There was a deletion of one of three T:A nucleotide pairs in the tRNALeu(UUR) gene of the mtDNA involving positions 3271 to 3273. Pedigree analysis suggested that this mutation may have occurred spontaneously in the proband. This analysis represents the smallest mtDNA deletion observed to date and is the first deletion identified within a mitochondrial tRNA. This observation emphasizes the importance of delineating the precise mutation responsible for an oxidative phosphorylation disease for patient diagnosis as well as for genetic counseling of maternal lineage relatives.

Effects of total hemoglobin and hemoglobin S concentration on cerebral blood flow during transfusion therapy to prevent stroke in sickle cell disease.

BACKGROUND: The standard treatment of stroke in sickle cell disease is chronic transfusion to maintain the fraction of abnormal hemoglobin (hemoglobin S [HbS]) below 20%. Risks associated with such transfusion can be reduced by allowing higher HbS levels, but the physiological consequences of this modification are unknown. Cerebral blood flow is elevated in sickle cell disease proportionate to the degree of anemia and is reduced by transfusion. We tested the effects of various HbS levels on cerebral blood flow during the course of transfusion therapy. CASE DESCRIPTIONS: We monitored cerebral blood flow (by the 133Xe inhalation method) in three patients whose chronic transfusion program was changed from a traditional regimen (HbS < 20%) to a moderate one, allowing HbS to rise to 45% to 50% between treatments. As expected, cerebral blood flow was higher with lower hemoglobin and higher HbS concentration. However, the HbS fraction appeared to exert a separate influence on the hyperemia, independent of total hemoglobin concentration. Furthermore, cerebral blood flow was higher during the modified regimen, despite equivalent anemia. CONCLUSIONS: These results suggest caution in adapting the modified transfusion regimen. Although HbS concentrations of 50% did not cause any frank neurological sequelae, the possible consequences of the associated hyperemia over time are unknown. We conclude that larger clinical and physiological studies of moderate transfusion regimens (allowing higher concentration of HbS) are necessary before it can become standard therapy.

Clinical spectrum of secondary parkinsonism in childhood: a reversible disorder.

Parkinsonism is an uncommon movement disorder in childhood. Six unusual cases of acquired parkinsonism in hospitalized children are described. Clinical manifestations included an akinetic-rigid syndrome with and without tremor, the combination of parkinsonism and dystonia, and a parkinsonism-plus syndrome. Altered mental status, mutism, dysphagia, and sialorrhea were frequent associations. Etiologies included hypoxic-ischemic encephalopathy; haloperidol treatment with and without neuroleptic malignant syndrome; toxicity of cytosine arabinoside, cyclophosphamide, amphotericin B, and methotrexate; St. Louis encephalitis and other encephalitides; and a pineal tumor with hydrocephalus. Cranial magnetic resonance imaging results ranged from normal to profound cerebral and cerebellar atrophy with chemotherapeutic toxicity. The illnesses usually were severe enough to require pharmacotherapy. Incorrect diagnoses of depression or catatonia delayed treatment or aggravated the problem. Acute treatment included amantadine, levodopa/carbidopa with or without selegiline, diphenhydramine, or benztropine. The concentration of CSF homovanillic acid was normal in a neuroleptic-associated patient, but the level was low in an encephalitic patient. All patients demonstrated dramatic improvement, including two who were not treated; some had complete resolution of symptoms and none required continued antiparkinsonian drugs despite poor scores on the Unified Parkinson's Disease Rating Scale and the Modified Hoehn and Yahr Rating Scales. The causes of parkinsonism described are more common in a general pediatric hospital than the parkinsonism associated with the popularized Segawa syndrome.

Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features.

Andersen's syndrome is a clinically distinct form of potassium-sensitive periodic paralysis associated with cardiac dysrhythmias. The subtle nature of the cardiac and dysmorphic features may delay the recognition of this syndrome and its potentially lethal cardiac dysrhythmias. The genetic defect in Andersen's syndrome is not genetically linked to other forms of potassium-sensitive periodic paralysis and is probably distinct from the long QT syndrome locus.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts.

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome is one of many mitochondrially inherited multisystem diseases. The features of 110 reported mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes patients are reviewed to define the clinical spectrum of this disease. The clinical disorder, in addition to emerging concepts of genetic etiology, is promoting our understanding of mitochondrial functions. New knowledge may lead to more rational therapies. Finally, the recent revolution in the study of mitochondrial diseases may further our understanding of other degenerative disorders and even aging.