Lucy Civitello

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.

Cognitive Functioning in School-Aged Children With Vertically Acquired HIV Infection Being Treated With Highly Active Antiretroviral Therapy (HAART)

In todays era of highly active antiretroviral therapy (HAART), few children with HIV-1 infection experience severe central nervous system (CNS) manifestations indicative of encephalopathy. However, little is known about the neurocognitive strengths and weaknesses of HIV-infected children treated with HAART. This cross-sectional study is the first to systematically investigate the relation between cognitive functioning and medical markers in HIV-infected children and adolescents treated with HAART with varying levels of computed tomography (CT) brain scan abnormalities. The Wechsler Intelligence Scale for Children–Third Edition was administered to 41 vertically infected children (mean age = 11.2 years) treated with HAART for at least 1 year. Other procedures at the time of testing included CT brain scans and collection of CD4 cell counts and plasma HIV–1 RNA PCR. Although global cognitive functioning among participants was in the Average range, children with minimal to moderate CT brain scan abnormalities scored significantly lower than children with normal scans on composite measures of cognitive functioning and five specific subtests, especially tasks involving executive functions. Furthermore, children with worse immune status (CD4+ counts ≤ 500) scored lower on subtests measuring processing speed. Viral load was unrelated to cognitive test scores. Thus, children with HIV being treated with HAART remain at risk for developing CNS disease. Findings emphasize the importance of conducting neuropsychological assessments in this population, particularly for children with cortical atrophy and absolute CD4+ cell counts ≤ 500.

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

ObjectiveTo 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. DesignConsecutive case series. SettingGovernment medical research center. PatientsEighty-six previously untreated children with symptomatic HIV-1 disease. ResultsCD4% 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). ConclusionsDegree 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.

Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue

Human immunodeficiency virus type 1 (HIV-1) central nervous system (CNS) infection in children is associated with impaired brain growth and neurodevelopmental delays. Neural progenitors are critical for neurogenesis. Human multipotential neural progenitors grown in culture are permissive for HIV-1 infection, but it is not known if infection of these cells occurs in vivo. Brain tissue from pre-highly active antiretroviral therapy (HAART) era pediatric acquired immunodeficiency syndrome (AIDS) patients was examined for evidence of HIV-1 infection of nestin-positive neural progenitors by in situ hybridization; or after laser microdissection harvest, DNA extraction, and polymerase chain reaction (PCR). HIV-1 or viral DNA was identified in nestin-positive cells in four of seven HIV-1-infected children, suggesting in vivo infection of neural progenitors.

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.

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.

CD40 Ligand Deficiency: Neurologic Sequelae With Radiographic Correlation

Patients with CD40 ligand deficiency are susceptible to central nervous system infections, but to date the neurologic progression or long-term outcome of central nervous system complications have not been reported in detail. Characterizing the central nervous system complications of immune deficiencies can lead to the identification of new pathogens. For this study, clinical data were reviewed on patients with both CD40 ligand deficiency and neurodegeneration, identified from a larger cohort of 31 patients. Five patients had progressive neurologic and cognitive decline in the absence of clinical signs of acute fulminant encephalitis, with anatomic brain abnormalities and high mortality (60%). Despite multiple evaluations, no pathogens were identified in four patients, all of whom were on standard intravenous immunoglobulin therapy at illness presentation. This clinical phenotype of progressive decline without acute fulminant encephalitis is similar to chronic enteroviral encephalitis in X-linked agammaglobulinemia, another condition with severe humoral immune defects. Whether infection secondary to subtherapeutic levels of central nervous system immunoglobulin G (IgG), inadequately protective levels of serum IgG, or impaired CD40 ligand-dependent IgG-independent antiviral responses contributed remains undetermined. Emerging gene-chip techniques applied in patients with primary immune deficiencies may identify heretofore unknown viruses. Prospective neurocognitive and evaluation of patients with CD40 ligand deficiency may identify affected patients before overt clinical signs appear.