Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome.

Impaired glucose transport across brain tissue barriers causes infantile seizures, developmental delay and acquired microcephaly. Since the first report in 1991 (De Vivo et al, NEJM, 1991) 17 patients have been identified with the glucose transporter protein syndrome (GTPS). The diagnostic feature of the syndrome is an unexplained hypoglycorrhachia in the clinical setting of an infantile epileptic encephalopathy. We review our clinical experience by highlighting one illustrative case: a 6-year old girl who presented at age 2 months with infantile seizures and hypoglycorrhachia. The CSF/blood glucose ratio was 0.33. DNA sequencing identified a missense mutation in exon 7 (C1108T). Erythrocyte GLUT1 immunoreactivity was normal. The time course of 3-O-methyl-glucose (3OMG) uptake by erythrocytes of the patient was 46% that of mother and father. The apparent Km was similar in all cases (2-4 mmol/L), but the apparent Vmax in the patient was only 28% that of the parents (500 versus 1,766 fmol/s/10(6)RBC; p < 0.004). In addition, a 3-month trial of oral thioctic acid also benefited the patient and increased the Vmax to 935 fmol/s/10(6) RBC (p < 3 x 10(-7)). Uptake of dehydroascorbic acid by erythrocytes of the patient was impaired to the same degree as that of 3OMG (Vmax was 38% of that of the mother's), which supports previous observations of GLUT1 being multifunctional. These studies confirm the molecular basis of the GTPS and the multifunctional role of GLUT1. The need for more effective treatment is compelling.

Outcome of children with cerebral edema caused by fulminant hepatic failure.

Mortality is high in patients with fulminant hepatic failure (FHF). Neurologic complications of encephalopathy and cerebral edema are major contributors to mortality. Orthotopic liver transplantation has improved survival in these patients. However, the complexity of medical and surgical problems in this patient population, coupled with a severe shortage of organs, requires careful patient selection. The aim of this study was to describe the neurologic outcome of children with FHF who developed radiologically apparent cerebral edema. The hospital and outpatient records and radiologic studies of 20 children with FHF admitted to Children's Hospital of Pittsburgh from 1981-1995 who developed encephalopathy and computed tomographic evidence of cerebral edema were reviewed. Fourteen patients died (70%), three were left with severe neurologic deficits (15%), and three were left with moderate deficits (15%). Survival was correlated with a lesser degree of coma. Histopathologic examination of eight brains demonstrated cerebral edema and widespread ischemic neuronal necrosis in all eight. The presence of radiographic cerebral edema in children with FHF is an objective measure that indicates a very poor prognosis. Termination of care is a reasonable option. Comprehensive monitoring of cerebral function and intracranial pressure is required in children with FHF. Orthotopic liver transplantation should be performed in children with severe and worsening encephalopathy before the development of radiographically apparent cerebral edema.

Regional cerebral blood flow during hypoglycaemia in children with IDDM.

Hypoglycaemia may cause transient cognitive impairment and neurological deficits that are frequently unilateral. The effect of mild hypoglycaemia (serum glucose level 3.4 +/- 0.1 mmol/l; mean +/- SEM) on regional cerebral blood flow and cerebrovascular resistance was studied in eight right-handed children with insulin-dependent diabetes mellitus (age 14.9 +/- 0.7 years; diabetes duration 7.4 +/- 1.1 years; six males) using the intravenous xenon-133 clearance method. Global mean cerebral grey and white matter blood flow, adjusted to mean pCO2 of cohort, showed a trend towards an increase from 54.7 +/- 3.5 ml.100 g-1.min-1 at baseline euglycaemia to 58.0 +/- 4.1 ml.100 g-1.min-1 during hypoglycaemia (p = 0.075). Statistically significant changes were seen in global mean cerebral grey matter blood flow, as indexed by initial slope, which increased from 88.0 +/- 6.5 min-1 before hypoglycaemia to 96.3 +/- 7.2 min-1 during hypoglycaemia (p < 0.05). Cerebral grey matter blood flow was significantly higher in the right hemisphere compared to the left during hypoglycaemia (p < 0.01) but not at baseline euglycaemia. Measurements of global cerebrovascular resistance showed a borderline decrease from 1.64 +/- 0.11 to 1.54 +/- 0.11 mm Hg.ml-1.100 g-1.min-1 (p < 0.09). In conclusion, mild hypoglycaemia is associated with increases in cerebral blood flow which are greater in grey matter flow indices and in the right hemisphere. We speculate that asymmetrical cerebral blood flow changes may explain the frequent laterality of neurological deficits during severe hypoglycaemia.

Cerebrovascular lesions in infants and children dying after extracorporeal membrane oxygenation.

The neuropathologic autopsy findings of a group of infants and children at Children's Hospital of Pittsburgh who died after treatment with extracorporeal membrane oxygenation (ECMO) were reviewed and tabulated. The study surveyed an 11-year period (February, 1980 to May, 1991); of 268 children receiving ECMO therapy for severe cardiopulmonary failure, 94 patients died, 70 of whom were autopsied and permission for brain examination was granted in only 44. The frequency of ischemic neuronal necrosis (50%), focal cerebral infarcts (50%), intracerebral hemorrhages (52%), and periventricular leukomalacia (41%) was higher in this group of ECMO-treated patients than that observed in the general autopsy population from which the study patients were selected. The frequency of ischemic and hemorrhagic brain lesions was similar among neonates and older infants and children. This documentation of cerebrovascular lesions in children dying after ECMO may provide a better understanding of potential brain damage in the larger population of infants and children who survive this invasive procedure.