Neuropsychiatric Aspects of Pediatric HIV Infection



Neuropsychiatric Aspects of Pediatric HIV Infection


Maryland Pao

Lucy Ann Civitello



Introduction

Since the first descriptions of pediatric AIDS in the 1980s, neurodevelopmental abnormalities have been a well-known complication of human immunodeficiency virus (HIV) infection in children, causing significant morbidity and mortality (1, 2, 3). Over the last several years, significant progress has been made in the early diagnosis of HIV-infected infants and children. Treatment is being initiated earlier, with multiple drug regimens according to Centers for Disease Control (CDC) guidelines. For example, all infants younger than 12 months with documented HIV infection are being started on multidrug regimens (4). Additionally, progress has been made in the treatment of HIV infection, including the use of highly active antiretroviral therapy (HAART). As a result, infants, children, and adolescents with HIV infection are living longer, and the prevalence and natural history of neurological illnesses in these patients have changed and, in many cases, improved.

The central nervous system (CNS) manifestations of HIV infection can be subdivided into two main groups: (a) those directly attributable to HIV brain infection, and (b) those indirectly related to the effects of HIV disease on the brain, such as CNS opportunistic infections (OIs), malignancies, and cerebrovascular disease.

Peripheral nervous system (PNS) abnormalities occur relatively frequently in adult HIV-infected patients and are usually related to antiretroviral therapy, HIV disease, or OIs (5, 6, 7, 8). Although much less common in infants and children, neuropathies and myopathies do occur, with similar etiologies (9,10).


Primary HIV-Related CNS Disease

HIV-related CNS disease is a prominent feature in pediatric patients. Early in the epidemic, it was recognized that the frequent neurological abnormalities seen in these children were due to the direct effects of HIV infection on the brain and not due to OIs or malignancies (1, 2, 3). HIV was isolated from the brain and cerebrospinal fluid (CSF) in 1985 (11). Soon after, HIV antigens were detected in the brain; viral particles were visualized in brain macrophages by electron microscopy; HIV nucleic acids were detected in brain tissue by in situ hybridization; and intrathecal anti-HIV antibodies were observed (12, 13, 14, 15).



Epidemiology

The prevalence of HIV-related CNS disease in children was estimated at 50% to 90% in early studies (16, 17, 18). By the mid-1990s, the prevalence was estimated to be between 20% and 50% (19, 20, 21, 22). Since the advent of HAART, a decrease in the prevalence of CNS disease has been documented in adults in the Multicenter AIDS Cohort Study (23). In another study, the incidence of moderate or severe dementia in adults was noted to decrease from 7% in 1989 to 1% in 2000. Changes in the type of dementia in adults have also occurred; most patients with dementia now have a more-static form (24). The prevalence of encephalopathy has also decreased in children, from 40.7% in children born before 1996 to 18.2% in children born after 1996, as documented in a retrospective study of 146 vertically infected children followed up at one institution. In this study, the prevalence of progressive encephalopathy decreased from 29.6% in children born before 1996 compared with 12.1% in those born after 1996 (25). In New York, Chiriboga et al. (26) also documented a decrease in the rate of progressive encephalopathy from 31% in 1992 to 1.6% in 2000.

In general, children younger than 3 years have higher rates of CNS disease than do older children and adolescents (19, 20, 21), and patients with more advanced degrees of immune suppression have higher rates of encephalopathy (27), a trend that remains true in the post-HAART era. Of 62 children first seen 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 (28).

It also is important to note that HIV-related CNS disease may be the presenting manifestation of HIV infection in as many as 18% of pediatric patients (29). This is an unusual occurrence in adults.

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 (30). 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 (31). When pediatric patients from the French Perinatal Cohort were compared with the French SEROCO Cohort of adults, the cumulative incidence of encephalopathy was higher in children than in adults only during the first year after infection (9.9% vs. 0.3%) and during the second year (4.2% vs. 0), but was similar afterward (less than 1% per year in each group). The cumulative incidence at 7 years reached 16% in children and 5% in adults. The early encephalopathy was not prevented by zidovudine (ZDV) use during pregnancy. In addition, the infants who went on to develop early CNS symptoms had significantly smaller head sizes and weights at birth than did their counterparts without neurological symptoms. These findings suggest a prenatal onset of HIV brain infection in this subgroup of infants with early onset of neurological disease. It also suggests that the course and pathophysiology of CNS disease in older children and adolescents is more similar to the dementia and motor cognitive dysfunction seen in adults, which may have important therapeutic and preventive implications.


Clinical Manifestations

The well-described classic triad of HIV-related encephalopathy identified in the mid-1980s and early 1990s included developmental delays (particularly motor and expressive language), acquired microcephaly, and pyramidal tract motor deficits (1, 2, 3). In the past, pediatric patients were classified with either the presence or absence of encephalopathy.
However, it is evident that a broad spectrum of clinical manifestations and severity of CNS disease exists in infants and children. This has become increasingly obvious with the decreased prevalence of severe encephalopathy in the HAART era. These observations have led to the development of a new classification system for pediatric HIV-related CNS disease that is currently used at the National Cancer Institute (NCI) of the National Institutes of Health (NIH). This system is used to track the CNS status of children on different treatment protocols and natural history studies. Patients are classified as having encephalopathy, as having CNS compromise, or as not apparently being affected.

Patients with encephalopathy have more severe and pervasive CNS dysfunction that affects their day-to-day functioning than do patients without encephalopathy (Table 14.1). 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 antiretroviral therapy (1, 2, 3,16,17,32,33). The hallmarks of this disorder 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) (33). The course is usually slower, developing over weeks to months, and more insidious than the course observed with OIs, tumor, or stroke. Children with HIV encephalopathy may have prominent oromotor dysfunction, facial diparesis, and abnormal eye movements (particularly nystagmus and impaired upgaze) (17). Impaired brain growth leads to acquired microcephaly. Progressive
cognitive deterioration occurs along with social regression and apathy. Extrapyramidal movement disorders (particularly bradykinesia, which can be responsive to L-dopa), cerebellar signs and symptoms, and seizures occur less commonly (34). Seizures may occur in about 16% of children with HIV-related CNS disease (17). About half of seizures seen are provoked by febrile illnesses. Recurrent unprovoked seizures (epilepsy) are rarely due to HIV CNS disease; more often they are due to other factors (e.g., complications of prematurity, CNS OIs). Rarely, infants and toddlers also exhibit generalized subcortical myoclonus that clinically resembles myoclonic seizures (infantile spasms). However, EEGs are typically normal, and myoclonus resolves with treatment of HIV CNS disease alone. In the school-aged child, the first complaints may be a decline in academic achievement, change in behavior, and psychomotor slowing. Eventually, progressive cognitive impairment and new pyramidal tract signs (hyperreflexia and gait disturbances) occur.








TABLE 14.1 CLINICAL MANIFESTATIONS OF HIV-RELATED ENCEPHALOPATHY



























































Progressive encephalopathies


Subacute progressive


Loss of milestones


Progressive motor dysfunction


Oromotor dysfunction


Acquired microcephaly


Cognitive deterioration


Apathy


Progressive long-tract signs


Movement disorders (uncommon)


Cerebellar signs (uncommon)


Seizures (uncommon)


More-rapid course (weeks to months)


Plateau


No loss of skills


No or slower acquisition of skills


Decline in rate of cognitive development


Motor dysfunction (nonprogressive)


Acquired microcephaly


More indolent course


Static encephalopathy


Fixed deficits


No loss of skills


Skills acquired at a stable but slow rate


Deficient, but stable IQ


Motor dysfunction (nonprogressive)


Static course


Many potential etiologies


The course of the plateau type of progressive encephalopathy is more indolent, with either the absence of acquisition of new developmental skills or a slower rate of acquisition of skills than previously. The rate of cognitive development declines, as does the rate of brain growth. Motor involvement is common, particularly spastic diplegia.

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, infections, or a combination of these; prematurity; and perinatal difficulties. Other factors to consider include genetic influences and nutritional, endocrinologic, and metabolic factors. Environmental and psychosocial factors may also affect development. Finally, HIV brain infection may play a role as well.

Children with HIV-related CNS compromise have less-severe CNS dysfunction and usually function normally (i.e., 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 (but are still functioning above the delayed range), or they may have significant impairments in selective neurodevelopmental functions. Alternatively, they may have a mildly abnormal neurological examination (pathologically brisk deep tendon reflexes with extensor plantar responses) that does 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.

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 (35, 36, 37, 38, 39). In children treated with HAART, specific deficits in executive function and processing speed have been described (40).

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

Adolescents who are not vertically infected with HIV, but are infected through drug use or sexual practices, may display neurocognitive changes more similar to those of adults (41). 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, hyper-reflexia, 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. Before HAART, the course of adult HIV dementia was progressive over 3 to 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 developed, including (a) a subacute progressive dementia seen in untreated patients similar to that of the pre-HAART era, (b) a chronic active dementia, seen in patients receiving HAART with poor adherence or viral resistance, and (c) a chronic inactive dementia, seen in patients receiving HAART who have had some neurological recovery and are stable (24,42). Minor cognitive/motor disorder (MCMD) is a more subtle form of HIV-related CNS disease seen in adults, which seems to be similar to CNS compromise seen in children.


Non-HIV-Related CNS Impairments

Some CNS impairments are thought possibly to be due to exposure to prenatal cocaine or multiple substances (43), as well as the quality of the child’s environment (44,45). Additional contextual factors such as poverty, nutrition, caregiver stability, caregiver psychiatric illness, and ongoing drug use on child development, regardless of prenatal drug exposure and HIV disease status (46), may play a role in the etiology of CNS impairment as well.


Neuroradiologic Findings

Neuroradiologic studies provide essential information for the evaluation and management of HIV-related CNS disease. The most common abnormalities seen on CT scans in symptomatic, treatment-naive, HIV-infected children are ventricular enlargement, cortical atrophy, white-matter attenuation, and basal ganglia calcifications (47). Calcifications are seen primarily in vertically infected children or premature babies who were given transfusions in the neonatal period. They are not typically seen in adults (48). Therefore calcifications may indicate a selective vulnerability of the basal ganglia of the developing brain to HIV infection.

In general, greater degrees of CT brain scan abnormalities are seen with more-advanced stages of HIV disease (49). In addition, the severity of CT brain abnormalities has been correlated with lower levels of general cognitive abilities and language functioning in children with symptomatic HIV infection (27,35,50).

A correlation also exists between cortical atrophy, but not calcifications and CSF RNA viral concentrations (51). This finding supports the hypothesis that active HIV replication in the CNS is at least partially responsible for the development of cortical atrophy. Intracerebral calcifications appear to have a different pathophysiologic mechanism and may not be related to active HIV replication but rather may indicate the timing and location of initial viral entry into the immature brain.

A decreased prevalence of CT-scan abnormalities has been found in children treated with combination nucleoside analogue antiretroviral therapy, even before the availability of protease inhibitors (52).

Ventricular enlargement, cortical atrophy, white-matter attenuation, and basal ganglia calcifications are seen also on magnetic resonance imaging (MRI) scans, although calcifications are not as well seen as on CT scans. White-matter abnormalities are more readily seen on MRIs. Mild white-matter MRI changes in children are not necessarily correlated with cognitive dysfunction, although extensive white-matter changes may be associated with cognitive impairments (53,54).


Proton magnetic-resonance spectroscopy (MRS) studies in adults have revealed decreased levels of N-acetyl aspartate (NAA) (indicating neuronal loss) and increased levels of choline (Cho; indicating cell membrane turnover), and myoinositol (MI) (a glial marker), particularly in the white matter (55,56). These changes have been correlated with clinical CNS disease. MRS studies in encephalopathic HIV-infected children have shown a decrease in NAA and an increase in MI, indicating neuronal loss. Decreased NAA/Cr ratios with lactate peaks (indicative of anaerobic metabolism) were reversed by ZDV in at least two children with HIV-related CNS disease (57,58). Abnormal spectra have been seen in children with normal structural imaging. The abnormalities on MRS (low NAA-to-Cho ratio) correlated with poor neuropsychological performance in these children (59). In general, MRS findings in adults and children are consistent with neuronal cell loss and inflammation, some of which can be reversed by antiretroviral treatment.


CSF Studies

Routine CSF studies may show nonspecific abnormalities, such as a mild pleocytosis or elevated protein level, but are usually normal. In adults, an aseptic meningitis is often seen at the time of seroconversion, but this has seldom been documented in the pediatric population.

Children and adults with abnormal brain function have increased levels of HIV RNA in the CSF as compared with those patients with normal brain function (60, 61, 62, 63). As noted previously, RNA viral load in the CSF is correlated with cortical atrophy on CT scans in children (51). Therefore CSF viral load may be predictive of CNS status. In support of this notion is a study showing that elevated baseline CSF HIV RNA levels in adults significantly predicted progression to neuropsychological impairment at follow-up 1 year later (64). In addition, markers of immune activation in the CSF (and serum) such as tumornecrosis factor, [BETA]2-microglobulin, neopterin, quinolinic acid, and certain chemokines (such as MCP-1) have been correlated with CNS disease in both adults and children. These observations may be important in neuropathogenesis (65, 66, 67, 68, 69).


Diagnosis of HIV-Related CNS Disease

The diagnosis of HIV-related CNS disease remains a clinical diagnosis, based on history, physical and neurological examinations, and age-appropriate neuropsychological testing, which can be compared with prior testing, if available. Other causes of CNS disease should be ruled out, including CNS OIs, malignancies, cerebrovascular disease, and non-HIV-related conditions (static encephalopathies due to effects of prematurity; maternal drug use; other congenital infections; genetic, nutritional, and endocrinologic factors, etc.). Neuroimaging should also be part of the workup to rule out OIs, malignancies, and cerebrovascular disease, as well as to identify the characteristic features of HIV-related CNS disease. CSF studies should be done primarily to rule out OIs.


Neuropathology

The prominent neuropathologic findings in both children and adults with HIV-related CNS disease include cortical atrophy, microglial nodules, multinucleated giant cells, myelin pallor, and astrocytosis.


HIV “encephalitis” consists of perivascular inflammatory cell infiltrates (microglial nodules) composed of microglia, macrophages, and multinucleated giant cells (70,71). These infiltrates occur in the subcortical white matter, the deep gray nuclei (putamen, globus pallidus), and pons. The characteristic finding in pediatric CNS disease, not seen in adults, is a calcific basal ganglia vasculopathy, which consists of vascular and perivascular mineralization, sometimes extending into the white matter.

HIV leukoencephalopathy consists of myelin loss and reactive astrocytosis. In adults, neuronal loss is seen in the hippocampi as well as in the orbitofrontal and temporal cortex, along with loss of dendritic arborizations. These features are difficult to appreciate in pediatric patients because few standards exist for neuronal cell counts (72).


Neuropathogenesis

HIV enters the brain early during the course of infection in adults, either as free viral particles or within infected monocytes, which then set up residence in the brain as macrophages (73,74). Evidence suggests that the blood-brain barrier (BBB) is disrupted in HIV CNS disease. Matrix metalloproteinases (MMPs) (which degrade collagen type IV, a component of the BBB) and their inhibitors, both of which are produced and secreted by microglia and macrophages, may be involved in the development of CNS disease (75,76). MMP-9 has been shown to be present in the CSF of HIV-infected children with abnormal neurological findings (77).

Only two brain cell types, the microglia/macrophage and the astrocyte, have clearly been shown to be infected by HIV (78, 79, 80, 81, 82, 83). In microglia, a productive and cytopathic infection results, but in astrocytes, a latent or restricted infection results. Despite the prominent neuronal cell loss and evidence of neuronal apoptosis, neurons were previously not thought to be directly infected by HIV. However, in a recent study, HIV-infected neurons were detected in the cortical gray matter in two children with progressive CNS disease (84). In another study, HIV-1 DNA was identified in neural progenitor cells of four pre-HAART era pediatric AIDS patients, suggesting that neurons may be infected even in utero (85). The immune systems of infants and children are not as well developed as those in adults; viral loads tend to be higher in younger patients. These observations suggest that immature neurons and other brain cells in children may be more susceptible to HIV-1 infection than are those in adults, resulting in some of the differences seen between pediatric and adult neuroAIDS.

These observations lead to several important considerations. First, because glial cells outnumber neurons by 10:1 in the CNS, potentially a large number of infected cells exist in the CNS. The brain may act as an important viral reservoir and theoretically may even reseed the periphery. Second, this suggests that products released from HIV-infected glial cells may be responsible for causing neurotoxicity (78,79,83). These products may be derived from the virus or from the host and can set up a chain of events leading to a significant amount of potentially irreversible neuronal dysfunction at sites distant from infected cells.

Infected, activated glial cells release viral proteins (gp120, tat), as well as a number of host-derived soluble factors, which are toxic to neurons (86,87). These factors include the proinflammatory cytokines [tumor-necrosis factor (TNF-α), interleukin-1 (IL-1), IL-6, interferon (IFN)-γ and -α, arachidonic acid and its metabolites, quinolinic acid (an agonist of excitatory amino acid receptors), and nitric oxide (65, 66, 67, 68,88, 89, 90, 91). Chemokines are also released, resulting in an influx of monocytes from peripheral blood into the brain, resulting in an increase in inflammation as well as an increase in the number of target cells for the virus in the brain (92). The chemokine, monocyte chemoattractant protein-1 (MCP-1) is present in high levels in the CSF and brains of adult patients with HIV
dementia (69). In addition, in children, MCP-1 is present in the CSF and declines in parallel with CSF HIV RNA with antiretroviral treatment (77). Macrophage inflammatory protein-1α (MIP-1-α) and MIP-1-β may be important in CNS disease as well (63). The possibility also exists that some chemokines have an anti-inflammatory effect (for example, IL-10) and may be neuroprotective (93).

In addition, chemokine receptors have been identified as important co-receptors for HIV entry into target cells. Astrocytes express the CXCR4 chemokine receptor, and evidence indicates that this expression may be related to neuronal damage (94). Microglia express the CCR5 chemokine receptor (95). Individuals with defective CCR5 alleles seem to exhibit resistance to HIV-1 infection. Children with the CCR5-wt/Delta 32 genotype had significantly delayed disease progression, including less neurocognitive impairment (96). In adults, the E4 isoform for apolipoprotein E has been associated with dementia severity in some studies (24). This suggests that host factors influencing the host’s immune response may be important in the development of CNS HIV disease and that a genetic predisposition may exist to the development of neurological impairment. Alternatively, other genetic factors also may protect the host from developing CNS disease.

This entire process of HIV CNS infection is amplified by cell-to-cell interactions between HIV-infected macrophages and astrocytes, which initiate a self-perpetuating cascade of neurotoxic events in the brain. These events ultimately lead to an increase in the extracellular concentration of the excitatory amino acid glutamate, which, through activation of the N-methyl-D-aspartate (NMDA) receptor and non-NMDA excitatory amino acid receptors leads to increases in intracellular calcium concentrations and eventually disruption of mitochondrial function, generation of nitric oxide and other free radicals, and eventual activation of apoptotic and other cellular pathways (78,79,83,97, 98, 99).

Therapeutic approaches to HIV-related CNS disease will be most successful if they are based on knowledge of these mechanisms and target both active HIV replication in the brain and the associated indirect neurotoxic events.


Secondary CNS Disorders

These disorders are not directly attributable to HIV brain infection but are related to the effects of immune suppression and other unknown factors.


OPPORTUNISTIC INFECTIONS OF THE CNS

Children with HIV infection have fewer problems with CNS OIs compared with adults, probably because OIs represent reactivation of previous, relatively asymptomatic infections. Nevertheless, CNS OIs can present significant problems in children, and their incidence may increase because children with HIV disease are living longer.

Generally, OIs are seen in patients with severe immunosuppression (CD4+ lymphocyte counts less than 200 cells per microliter) and in older children and adolescents. They may also occur in infants and younger children as a result of congenital infection.

The most common CNS OI in children is cytomegalovirus (CMV) infection, which may appear as a subacute or chronic encephalitis/ventriculitis, an acute ascending radiculomyelitis, or as an acute or subacute neuritis (100, 101, 102, 103). Other viruses [herpes simplex virus (HSV), varicella-zoster virus (VZV)] may also cause an acute or subacute encephalitis (104). Progressive multifocal leukoencephalopathy (PML), caused by the JC virus (a papovavirus), has rarely been reported in the pediatric AIDS population (105).

Fungal infections (Candida and Aspergillus) are the second most common CNS OI in children. (100). Cryptococcal meningitis, although seen in 5% to 10% of adult AIDS patients,
was reported in less than 1% of pediatric AIDS patients followed up at the NCI over a period of 8 years (106).

Toxoplasma encephalitis, a protozoan CNS infection, is the most common cause of intracranial mass lesions in adults with AIDS, occurring in 10% to 50% of patients (107). However, it has been reported in only about 1% of HIV-infected children (108).

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Jul 5, 2016 | Posted by in NEUROLOGY | Comments Off on Neuropsychiatric Aspects of Pediatric HIV Infection

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