Cerebrospinal fluid viral load is related to cortical atrophy and not to intracerebral calcifications in children with symptomatic HIV disease.

The relationships between viral load in plasma and cerebrospinal fluid (CSF) and computed tomography (CT) brain scan abnormalities were studied in 39 children between 0.5 and 13 years of age with symptomatic HIV-1 disease. Quantitative RNA PCR was used to determine HIV-1 RNA levels and a semiquantitative analog rating technique was used to evaluate non-contrast CT brain scans. CSF HIV-1 RNA copy number correlated significantly with CT brain scan ratings for severity of cortical atrophy (r = 0.36; P < 0.05) but not with ratings of intracerebral calcifications (r = -12; NS). The difference between these two correlations was significant (P < 0.05). Plasma HIV-1 RNA copy number did not correlate significantly with any CT brain scan ratings or with CSF viral load (r = 0.05; NS). Severity of cortical atrophy appeared to reflect the level of viral load in the CSF, supporting the notion that active HIV-1 replication in the CNS is at least in part responsible for such brain abnormalities in children. The lack of correlation of intracerebral calcifications with other CT brain scan abnormalities as well as with CSF viral load suggests that this lesion is relatively independent and may reflect a different neuropathologic process.

Pattern of neuropsychological deficit at age five years following neonatal unilateral brain injury.

The pattern of language deficit following left-hemisphere brain injury and visual/spatial deficit following right-hemisphere injury in an adult or older child is well recognized, but has been inconsistently reported following presumed neonatal brain injury. Our prospective study of 24 children at age 5 with documented neonatal unilateral brain injury lends support to the theory of hemisphere specialization at the time of birth. Twelve children who had unilateral left-hemisphere lesion were compared to 12 children with unilateral right-hemisphere lesion of similar timing and severity. Relative visual/spatial deficit following right-hemisphere lesion and receptive language deficit following left-hemisphere lesion were identified. Lateralized measures of grip strength, fine motor speed, and fine motor dexterity were not significantly different between the groups for either hand in this nonhemiparetic study sample. Only one child with a left-hemisphere lesion was left-handed, and only one child (right-lesion) had a hemiparesis.

Peripheral neuropathy in children with HIV infection.

Peripheral neuropathy is infrequently reported in children with HIV infection, but may be underrecognized. To provide a better understanding of the patterns of peripheral neuropathy in these children, we surveyed the charts of 50 children with HIV infection referred to the EMG laboratory at the National Institutes of Health for evaluation of suspected peripheral neuropathy. Twelve children had an abnormal nerve conduction study. The findings suggested a distal sensory or sensorimotor axonal neuropathy in seven children, median nerve compression at the carpal tunnel in three, a demyelinating neuropathy in one child, and a lumbosacral polyradiculopathy in one adolescent. Distal symmetric polyneuropathy occurred mostly in older-aged children.

Receptive and expressive language function of children with symptomatic HIV infection and relationship with disease parameters: a longitudinal 24-month follow-up study.

OBJECTIVES: To longitudinally assess the receptive and expressive language functioning of children with symptomatic HIV disease and to explore the relationship between immune status, computed tomography (CT) brain scan abnormalities, and language dysfunction over time. METHODS: Children with symptomatic HIV infection were administered an age-appropriate standardized comprehensive language test and general cognitive measure prior to starting antiretroviral therapy (n = 44) and again after 6 months (n = 29) and 24 months (n = 17). CD4 percentage and CT brain scans were also obtained at each evaluation. RESULTS: Expressive language was significantly more impaired than receptive language at the baseline, 6- and 24-month evaluations. No significant changes over time were found in receptive or expressive language from baseline to after 6 months of antiretroviral therapy, but despite treatment, language scores declined significantly between 6 and 24 months. Overall cognitive function, however, remained stable from baseline to 24 months. Age-adjusted CD4 percentage increased significantly over the initial 6 months, then remained stable. Overall CT brain scan severity ratings did not change significantly over 24 months. CONCLUSION: Expressive language was consistently more impaired than receptive language over 24 months, further supporting an earlier finding that expressive language was differentially affected by HIV in children with symptomatic disease. Both receptive and expressive language declined significantly after 24 months despite antiretroviral therapy, although overall cognitive function remained stable. Thus, functioning in some domains may be more vulnerable to the effects of HIV and global measures of cognitive ability may mask such differential changes in specific brain functions.

Severity of brain injury following neonatal extracorporeal membrane oxygenation and outcome at age 5 years.

Neurodevelopmental evaluation in childhood provides an opportunity to study complex neurological compensation following documented neonatal brain injury, and furnishes important clinical information which may have an impact on patient care. We studied 152 term children treated with extracorporeal membrane oxygenation (ECMO) as neonates and who received routine neonatal neuroimaging and comprehensive neurodevelopmental evaluation at age 5 years. The cohort was divided into four groups based on an independent neuroimaging score: No lesion, N=88; Mild lesion, N=38; Moderate lesion, N=12; and Severe lesion, N=14. Standardized testing at age 5 included complete neuropsychological assessment, neurological evaluation, and assessment of motor function. All testing was conducted without knowledge of the neuroimaging score. The occurrence of disability by severity of neuroimaging was: No lesion=10%; Mild=13%; Moderate=33%; Severe=57%. The relative risk within the ECMO population for disability at age 5 after moderate or severe neonatal lesion was 4.3 (CI=1.0 to 17.5) and 11.7 (CI=3.3 to 41.3), respectively. The remaining non-disabled children who had moderate to severe lesions functioned within normal limits. Severity of neonatal neuroimaging was inversely associated with IQ scores, pre-academic skills, and neuromotor function. The effect size was small but the rank order was predictable. Our data identify in 5-year-old children an impact of brain lesion severity demonstrated on routine neonatal neuroimaging. The results indicate potential compensation following moderate and severe lesions, and suggest a subtle but consistent influence of even mild neonatal brain injury.

Neurobehavioral manifestations of symptomatic HIV-1 disease in children: can nutritional factors play a role?

Central nervous system (CNS) abnormalities are significant and frequent complications of human immunodeficiency virus (HIV-1) infection in infants and children. Although the predominant cause of neurological and neuropsychological abnormalities appears to be related to HIV infection of the CNS, other factors including malnutrition may also play a role. We retrospectively evaluated the association of change in body weight with changes in neurocognitive function, ventricular brain ratio, and cerebrospinal quinolinic acid levels in a small cohort of children (n=15; mean age 6.3 years) with symptomatic HIV-1 disease before and after 6 months of antiretroviral therapy with continuous intravenous infusion of zidovudine (ZVD). Significant increases in weight and neurocognitive function as well as decreases in ventricular brain ratio and cerebrospinal quinolinic acid levels were noted after therapy. Only the relation between increase in weight and decrease in ventricular brain ratio was statistically significant (P< .01); contrary to expectations, an increase in weight seemed to correlate with a decrease in neurocognitive function (NS). Another group of children treated at the same time with oral intermittent ZVD, but otherwise receiving the same care did not show the same magnitude of improvement in neurocognitive function. These results seem to suggest that general supportive and medical care as well as nutritional factors may only play a limited role in the neurocognitive improvements after antiretroviral therapy with continuous infusion ZVD. Our sample size was, however, small and the nutritional measure rather global; thus these findings have to be considered as very preliminary.

Neurodevelopmental status at age five years of neonates treated with extracorporeal membrane oxygenation.

OBJECTIVE: To determine the neurodevelopmental status at age 5 years among children who received extracorporeal membrane oxygenation (ECMO) in the newborn period as a treatment for severe cardiorespiratory failure. METHODS: We conducted a prospective cohort study of 103 five-year-old ECMO-treated children born between June 1984 and July 1988, and treated at our institution. Thirty-seven healthy control children were recruited locally. The assessment protocol included a complete neuropsychologic assessment, psychosocial assessment with parent questionnaires, a standard neurologic evaluation, assessment of gross motor and fine motor function, a medical history, and physical examination. RESULTS: Major disability was present in 17 of the ECMO cohort. Eleven ECMO-treated children (11%) were mentally retarded, one of whom was profoundly impaired. Two additional children had severe learning disabilities. Cerebral palsy was diagnosed in 5 (5%) ECMO-treated children, but all cases were mild in nature and the patients were walking unaided. One child has paraplegia. The mean Full Scale, Verbal, and Performance IQs of the EMCO-treated children were within the normal range, but as a group were significantly lower than in control children (96 vs 115, p < 0.001). Children treated with ECMO had increased risk relative to the control children for academic difficulties at school age (49% VS 22%, P < 0.01) and a higher rate of behavioral problems reported by parents (42% vs 16%, p = 0.01). CONCLUSIONS: The rate of major disability was comparable to that in other high-risk populations. The high rate of behavioral problems and increased risk of subsequent school failure among nonretarded ECMO-treated children supports the need for close follow-up of these children after hospital discharge.

Relation between stage of disease and neurobehavioral measures in children with symptomatic HIV disease.

OBJECTIVE: To study the relationships between stage of HIV disease, reflected by CD4+ lymphocyte percentages and p24 antigen levels, and HIV-associated central nervous system (CNS) abnormalities, measured by computed tomography (CT) brain-scan ratings and neurobehavioral tests. DESIGN: Consecutive case series. SETTING: Government medical research center. PATIENTS: Eighty-six previously untreated children with symptomatic HIV-1 disease. RESULTS: CD4% measures correlated significantly with overall CT brain-scan severity ratings (r = -0.45; P < 0.001) as well as with its component parts (cortical atrophy, white matter abnormalities, and intracerebral calcifications); they were of comparable magnitude for vertically and transfusion-infected children. CD4% measures were also associated with the general level of cognitive function (r = 0.32; P < 0.005). Furthermore, patients with detectable serum p24 antigen levels (n = 39) had CT brain scans that were more abnormal than patients with undetectable p24 levels (n = 20; CT abnormality ratings of 21.3 versus 35.9; P < 0.02); similar differences were found for the cortical atrophy and calcification ratings. p24 levels also correlated with the overall CT brain-scan severity rating (r = 0.34; P < 0.01). CONCLUSIONS: Degree of CT brain-scan abnormality and level of cognitive dysfunction were significantly associated with the stage of HIV-1 disease, as reflected by either CD4 leukocyte measures or elevations of p24 antigen. The relation between the CT brain-scan lesions and markers of HIV disease (both CD4 and p24) suggest that these CNS abnormalities are most likely associated with HIV-1 infection, and further support the hypothesis that the interaction between systemic disease progression and CNS manifestations is continuous rather than discrete.

Correlation between computed tomographic brain scan abnormalities and neuropsychological function in children with symptomatic human immunodeficiency virus disease.

OBJECTIVE: To evaluate the clinical significance of computed tomographic brain scan abnormalities observed in children with symptomatic human immunodeficiency virus disease. PATIENTS: Eighty-seven previously untreated children with symptomatic human immunodeficiency virus type 1 disease. METHODS: General levels of cognitive functioning, obtained from age-appropriate intelligence tests, and social-emotional behavior were correlated with computed tomographic brain scan abnormality ratings. RESULTS: A significant relation between computed tomographic brain scan abnormalities and cognitive dysfunction as well as aberrant behavior was found, which appeared stronger in (younger) vertically infected children compared with transfusion-infected patients. Calcifications, independent from the degree of brain atrophy, were associated with significantly greater delays in neurocognitive development. CONCLUSION: Computed tomographic brain scan abnormalities, even when mild, were of clinical significance, suggesting that human immunodeficiency virus-associated central nervous system compromise is a continuous process and that scans may be helpful at baseline in defining patients at risk and for monitoring them during therapy.

Interrelations among patterns of change in neurocognitive, CT brain imaging and CD4 measures associated with anti-retroviral therapy in children with symptomatic HIV infection.

The interrelationships of patterns of change and variability between baseline and after 6 months of anti-retroviral therapy in neurocognitive, brain imaging, and immune measures were studied in 77 children with symptomatic HIV disease. Overall improvement in CNS structure/function after 6 months of anti-retroviral therapy was limited; new intracerebral calcifications tended to occur and old ones tended to progress in young children with vertically acquired HIV infection, despite treatment. Substantial inter-individual differences in change were however observed. Factors which explained part of the variance in the magnitude and direction of change were baseline structural and functional abnormalities, rating of degree of CNS penetration of the drug protocol, and concurrent changes on other variables. These preliminary data suggest that CNS specific effects of therapies as well as pretreatment status of CNS function/structure need to be taken into consideration when evaluating future trials of anti-retroviral therapy for children with symptomatic HIV infection.

The prevalence of computed tomographic abnormalities of the cerebrum in 100 consecutive children symptomatic with the human immune deficiency virus.

Qualitative analysis of 100 consecutive computed tomographic (CT) studies of the brain in children with symptomatic but untreated acquired immunodeficiency syndrome was performed. After excluding children with associated medical illnesses that might confound the diagnosis of encephalopathy or alter brain structure, an abnormality of at least one of the measures of ventricular size, cortical atrophy, white matter attenuation (leukoaraiosis), or cerebral calcification was found in 86% of the patients studied. Ventricular enlargement was the most common abnormality, followed by cortical atrophy, leukoaraiosis, and cerebral calcification. Cerebellar atrophy was an unexpected but relatively common finding in 12% of the children. Sixty-five percent of the children were encephalopathic at the time of evaluation. All 16 children with cerebral calcification were encephalopathic and had acquired human immunodeficiency virus (HIV) through vertical transmission. Encephalopathic children were significantly younger and had significantly greater abnormality ratings on each CT measure when compared with the nonencephalopathic children. Discriminant analysis using age and the qualitative CT measures was applied as a method to identify the presence of encephalopathy. CT measures proved to have a specificity and a sensitivity of only 76%. We conclude that abnormalities of cerebral structure are seen in a high percentage of children symptomatic with HIV. Although most of the children are encephalopathic, CT abnormalities are seen in children without encephalopathy, suggesting presymptomatic brain disease. The presence of cerebral calcification on CT suggests in utero infection with HIV and the presence of encephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurologic complications of HIV infection in children.

Neurologic abnormalities occur frequently in children with symptomatic HIV-1 infection (class P2) and include cognitive, language and motor deficits, as well as acquired microcephaly. Neurologic abnormalities can be seen as early as the first 3 months of age and can precede signs of immune deficiency and systemic illness. Hypotonia, delayed or poor head control and decreased vocalizations are some of the early neurologic manifestations of HIV-1 infection. In the majority of cases CNS impairment appears to be related to HIV-1 brain infection although at this time the exact timing of CNS invasion by the virus and the pathogenesis of CNS dysfunction are unknown. Treatment with antiretroviral agents can at least temporarily improve neurologic functioning in some children with HIV-1-related encephalopathy.

Leptomeningeal dissemination of low-grade gliomas in childhood.

Although leptomeningeal spread (LMS) of primary CNS tumors in children has been well documented in the literature, it has rarely been reported in children with low-grade gliomas. Between 1975 and 1985, 6 of 162 children (3.7%) with low-grade gliomas treated at Children's Hospital of Philadelphia had LMS. LMS was present at diagnosis of the original tumor in one patient, was the first sign of relapse in one patient, occurred simultaneously with local relapse in two patients, and after local relapse in two patients. Pathology of the original tumor was low-grade astrocytoma in five and low-grade oligodendroglioma in one. Primary tumor site was cervical cord in three, chiasm in one, frontal lobe in one, and cerebellum in one. All of the children with LMS had undergone surgical treatment at the time of diagnosis of the primary tumor; four had total resections at some point in their course. Three of the six patients died; three are still alive after treatment with radiation therapy and/or chemotherapy. The longest survival to date has been 3 1/2 years after diagnosis of LMS. We compared clinical characteristics of these six patients with 131 children with low-grade tumors without dissemination treated at our institution during the same time period. LMS, although relatively infrequent, does occur in children with low-grade gliomas, especially spinal cord tumors. LMS may occur at any time during illness and diagnosis may be difficult unless LMS is suspected. Treatment, at times, results in clinical improvement and considerable disease control.

High-field magnetic resonance imaging of Wilson's disease.

A single case of Wilson's hepatolenticular degeneration was imaged by computed tomography and magnetic resonance (1.5 Tesla). Findings included generalized cerebral atrophy seen both on computed tomography and magnetic resonance images. T1-weighted images revealed a slight symmetric hypointensity in the lentiform nuclei and thalamus. T2-weighted images demonstrated marked symmetric hypointensity in the lentiform nuclei. These hypointensities are ascribed to the deposition of intracellular hemosiderin (and perhaps copper), which produce heterogeneous magnetic susceptibility and preferential T2-proton relaxation. Areas of increased signal activity on T2-weighted images were also seen in areas of presumed demyelination known to occur in Wilson's disease.