Cognitive Issues

The CNS manifestations of HIV infection can be subdivided into 1) those directly attributable to HIV brain infection and 2) those indirectly related to the effects of HIV on the brain, such as CNS opportunistic infections, malignancies, and cerebro-vascular disease.

Clinical manifestations of primary CNS HIV infection identified in the mid-1980s and early 1990s include the classic triad of HIV-related encephalopathy: 1) developmental delays (particularly motor and expressive language); 2) acquired microcephaly; and 3) pyramidal tract motor deficits (Belman et al. 1985; Epstein et al. 1985, 1986). In the past, pedi-atric patients were classified with either the presence or absence of encephalopathy. However, given the broad spectrum of clinical manifestations and severity of CNS disease in infants and children and the decreased prevalence of severe encephalopathy in the HAART era, researchers developed a new classification system for pediatric HIV-related CNS disease currently used at the National Cancer Institute of the National Institutes of Health. Now patients are classified as having encephalopathy, having CNS compromise, or not being apparently affected.

In general, children younger than 3 years of age have higher rates of CNS disease than older youth (Blanche et al. 1997; England et al. 1996; Lobato et al. 1995), and patients with more advanced degrees of immune suppression have higher rates of enceph-alopathy (Brouwers et al. 1995b), a trend that remains true in the post-HAART era. Of 62 children presenting with HIV infection before the age of 3 years in London, 22% had abnormal neurological signs and 40% had significant developmental delays; children with more severe immune dysfunction had more neurological abnormalities and developmental delays (Foster et al. 2006). HIV-related CNS disease may be the presenting manifestation of HIV infection in as many as 18% of pediatric patients, an unusual occurrence in adults (Vincent et al. 1989).

Early onset of HIV infection (i.e., infection occurring in utero) increases a child's risk for poor neurodevelopmental outcome within the first 30 months of life (Smith et al. 2000). Early onset of neurological symptoms and signs in HIV-infected infants (before the age of 1 year) seems to have a different significance and pathophysiology than those occurring later on in children and adults (Tardieu et al. 2000). In addition, the infants who went on to develop early CNS symptoms had significantly smaller head sizes and weights at birth than their counterparts without neurological symptoms. These findings suggest that prenatal onset of HIV brain infection in a subgroup of infants with early-onset neurological disease has a different course and pathophysiology of CNS disease than in older children and adolescents whose course is more similar to the dementia and motor cognitive dysfunction seen in adults. This may have important therapeutic and preventive implications.

The most common computed tomography scan abnormalities in symptomatic, treatment-naive HIV-infected children are ventricular enlargement, cortical atrophy, white matter attenuation, and basal ganglia calcifications (DeCarli et al. 1993). Calcifications may indicate a selective vulnerability of the basal ganglia of the developing brain to HIV infection because they are primarily seen in vertically infected children or premature babies who were transfused in the neonatal period (Civitello et al. 1994). In addition, the severity of brain abnormalities has been correlated with lower levels of general cognitive abilities and language functioning in children with symptomatic HIV infection (Brouwers et al. 1994, 1995a; Wolters et al. 1995).

Encephalopathy can be either progressive (subtypes include plateau and the more severe subacute) or static. The subacute progressive type is often seen in infants and young children who are naive to anti-retroviral therapy (Belman et al. 1994; Mintz 1999). The hallmarks of subacute progressive en-cephalopathy are loss of previously acquired milestones, particularly motor and expressive language, with progressive nonfocal motor dysfunction (spastic quadriplegia or hypotonia in young infants and spastic diplegia or hypotonia in older infants and children) (Belman et al. 1994). The course is usually more insidious, developing over weeks to months, than the course observed with opportunistic infections, tumor, or stroke.

Children with "HIV encephalopathy" may have prominent oromotor dysfunction, facial diparesis, and abnormal eye movements (particularly nystagmus and impaired upgaze) (Civitello et al. 1993). Impaired brain growth leads to acquired microen-cephaly. Progressive cognitive deterioration occurs along with social regression and apathy. Extrapyramidal movement disorders such as bradykinesia, cerebellar signs, and seizures are less common (Mintz et al. 1996).

The course of the plateau type of progressive en-cephalopathy is more indolent, with either the absence of acquisition of new developmental skills or a slower rate of acquisition of skills previously mastered. The rate of cognitive development declines, as does the rate of brain growth. Motor involvement, particularly spastic diplegia, is common. Children with static encephalopathy tend to have fixed neurodevelopmental deficits with no loss of skills. Development continues at a stable but slow rate. IQs are stable but low. Motor dysfunction is common but not progressive. Whereas the etiology of progressive encephalopathy is thought to be related to the direct effects of HIV brain infection, the etiology of static encephalopathy can be varied and can include in utero exposure to drugs, alcohol, and/ or infections; prematurity; and perinatal difficulties. Other factors include genetic influences; nutritional, endocrinological, and metabolic factors; environmental and psychosocial factors; and finally HIV brain infection.

Children with "HIV-related CNS compromise" have less severe CNS dysfunction and usually function normally (e.g., attend school, interact normally) . They typically have normal overall cognitive functioning, but they may have had a significant decline in one or more neuropsychological tests (yet are still functioning above the delayed range) or they may have significant impairments in selective neurodevelopment functions. Alternatively, they may have mildly abnormal neurological examination findings (pathologically brisk deep tendon reflexes with extensor plantar responses) that do not affect their day-to-day functioning. Patients who were functioning in the average cognitive range at baseline and who have shown improvement after institution of or change in antiretroviral therapy are also classified in this category.

Children are classified as "apparently not affected" when their cognitive functioning is at least within normal limits and when there has been no evidence of a decline in functioning or of neurological deficits that affect their day-to-day functioning. In addition, there should be no therapy-related improvements in cognitive or motor functioning.

The specific domains of neuropsychological impairment seen in children with HIV disease include expressive (greater than receptive) language, attention, adaptive functioning (socialization, behavior, quality of life), and memory (Klaas et al. 2002; Wolters et al. 1995). In children treated with HAART, specific deficits in executive function and processing speed have been described (Martin et al. 2006).

Adolescents who are infected through drug use or sexual practices may display neurocognitive changes more similar to those seen in adults (Willen 2006). In adults, the features of HIV dementia consist of the new onset of progressive disabling cognitive impairment (memory loss, psychomotor slowing), usually with motor dysfunction (gait disturbance, tremor, hyperreflexia, fine motor impairments, and apraxia) and behavioral change (apathy). Neuropsychological testing usually shows impairment in frontal lobe functioning, psychomotor speed, and nonverbal memory, which has been termed a subcortical dementia.

Typically in adults, HIV dementia develops when the patient has profound immune suppression. Risk factors include low CD4 counts, anemia, increased age, female gender, and injection drug use. Prior to HAART, the course of adult HIV dementia was progressive over 3-9 months, resulting in severe neurological deficits and death, which appeared similar to the progressive encephalopathy in children. Since HAART, several subtypes of dementia have been developed including 1) a subacute progressive dementia, seen in untreated patients similar to the pre-HAART era; 2) a chronic active dementia, seen in patients on HAART with poor adherence or viral resistance; and 3) a chronic inactive dementia, seen in patients on HAART who have had some neurological recovery and are stable (McArthur 2004; McArthur et al. 2005). Minor cognitive/motor disorder is a more subtle form of HIV-related CNS disease seen in adults, which seems to be similar to CNS compromise seen in children.

Some CNS impairments are thought to be possibly due to exposure to prenatal cocaine or multiple substances (Lester et al. 2001) as well as the quality of the child's environment (Brown et al. 2004; Frank et al. 2001). Additional contextual factors such as poverty, nutrition, caregiver stability, care-giver psychiatric illness, and ongoing drug use also may play a role during child development, regardless of prenatal drug exposure and HIV disease status (Coles and Black 2006), in the etiology of CNS impairment. Finally, there are a number of secondary CNS disorders that are not directly attributable to HIV brain infection but are related to the effects of immune suppression and other unknown factors. CNS opportunistic infections such as cytomegalovirus, fungal infections (Candida and Aspergillus), and toxoplasma encephalitis can all result in cognitive impairment. Neoplasms such as primary CNS lymphoma and cerebrovascular diseases (commonly stroke) can also affect neurocognitive functioning in children and adolescents. There is a characteristic vasculopathy seen in HIV-infected children resulting in aneurysmal dilatation of vessels of the circle of Willis with or without associated ischemic infarction or hemorrhage (Husson et al. 1992; Kure et al. 1989). The etiology of this vasculopathy is unclear, but it may be related to direct viral invasion of the vessel walls (Kure et al. 1989).

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