**7. HIV associated CNS disorders: children**

#### **7.1. Introduction**

AIDS in pediatric medicine and child health has been recognized and described since the early 1980s after the identification of the virus itself. It is now a leading cause of childhood morbidity and mortality [15].

Pediatric HIV is mainly acquired through vertical mother-to-child transmission. This occurs either transplacentally during fetal development in utero; peripartum during passage of the fetus through the birth canal; or postnatally from contaminated breast milk. Other routes of infection include horizontal transmission through sexual abuse or transfusion of contaminated blood products. Adolescent HIV infection follows the same modes of transmission seen in adults, that is, sexual exposure and intravenous drug use.

The pathophysiological mechanisms in pediatric HIV-associated CNS disorders reflect the

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**Acquired microcephaly**: The diagnosis is made with stagnating or decreasing serial measurements of head circumference in children below 2 years of age. In the older child with closed skull sutures, the impaired brain growth correlates with parenchymal atrophy on

**Progressive motor dysfunction**: The motor deficit in PHE children typically results from pyramidal tract abnormalities and presents with impaired fine motor function and ultimately loss of gross motor skills. Tone is often spastic. Motor milestones are either not achieved or can be lost. Extrapyramidal dysfunction with parkinsonian features of rigidity, drooling, and hypomimic facies may occur; cerebellar involvement is unusual. Advanced disease leads to a

These motor features are symmetrical. The occurrence of focal deficits should alert to possible

**Neurodevelopmental decline**: Neurodevelopmental deterioration involves global cognitive deficit with language and visuospatial, attention, concentration, and executive function problems. Delayed language milestones especially of expressive language often herald other cognitive and motor impairments. The delay is more easily observed in school-age children, but may often be attributed to other causes like nutritional, environmental, and psychosocial factors. Other symptoms include behavioral problems such as social withdrawal, apathy,

The clinical disease pattern of PHE varies widely with respect to age of onset, rate of progression, and domain(s) of functional impairment. Onset of PHE is most common in the first year of life with incidence rates of 9.9% in the first, 4.2% in the second year and less than 1% thereafter. Rates of progression vary widely with rapid decline over few months or a gradual deterioration. Early disease onset, especially when accompanied by advanced immune sup-

A static encephalopathy with nonprogressive deficit or neurodevelopmental delay is also described. In contrast to PHE, there is no regression and there may be spontaneous

pression predicts a more rapid and aggressive course with high mortality [15].

underlying structural brain involvement by a mass lesion or infarction.

complex interactions between HIV a maturing brain.

**1.** Acquired microcephaly due to impaired brain growth.

**3.** Loss, plateau or delay of neurodevelopmental milestones.

*7.4.1. Progressive HIV encephalopathy (PHE)*

Clinically well-defined triad of:

**2.** Progressive motor dysfunction.

**7.4. Clinical features**

neuroimaging.

spastic, bedridden state.

mood disorders, and impulsiveness.

*7.4.2. Static encephalopathy*

Pediatric HIV-related CNS disease is primarily caused by the virus itself affecting all components of the neural axis, but with particular predilection for the brain. The clinical manifestations described below are thus varied with the commonest being progressive HIV encephalopathy (PHE). This selective vulnerability of the brain may in part be due to the effect of HIV on an immature brain (see below).

CNS opportunistic infections and malignancies on the other hand do not contribute significantly to HIV associated CNS disorders in childhood [15].

#### **7.2. Epidemiology**

The available data shows that approximately 2.3 million children worldwide are living with HIV/AIDS with nearly 2000 new infections and 1500 deaths occurring daily. These figures refer mainly to the developing world, and in particular Sub-Saharan Africa, dominated by the clade C strain of HIV. In these regions less than 10% of HIV positive pregnant women have access to appropriate measures to prevent mother-to-child transmission. In the developed world (clade B virus), pediatric HIV has ceased to be a significant problem as a result of effective use and delivery of antiretrovirals during pregnancy, elective cesarean section and infant formula feeding.

In the United States and Europe, highly active antiretroviral therapy (HAART) has reduced the rate of PHE from 9 to 35% in the early years of the HIV epidemic to 0–2% currently. Few studies from Sub-Saharan Africa report cognitive and motor developmental delay affecting 15–40% of HIV-infected children. There is no published data on the effects of HAART in this population. PHE occurs in 32–36% of HIV positive children in Latin America. Opportunistic CNS infections were relatively frequent at 34% in a Brazilian hospital-based study and at 12% in a study from Argentina. The latter study documented a remarkable reduction of severity and frequency of PHE after the introduction of HAART [15].

#### **7.3. Pathophysiology**

The CNS is affected early during the course of HIV infection. Neuro-invasion and pathogenesis are similar to that described in adults with HIV associated cognitive impairment.

The interaction between fetal astrocytes and endothelial cells is central to the development of the blood–brain barrier (BBB). This happens in early gestation. HIV interferes with healthy BBB development by restricted or nonproductive CD4 receptor independent infection of the astrocytes. The consequently impaired or disrupted BBB has increased susceptibility to neuroinvasion. In the immature brain this leads to the encephalopathy (PHE). The restricted infection of astrocytes causes neuronal dysfunction via loss of supporting growth factors and impaired neurotransmitter re-uptake with resultant excitotoxicity. Macrophages, microglia, and multinucleated giant cells are involved in productive HIV infection with viral replication. The consequent inflammatory cascade leads to production of neurotoxic cytokines. Neuronal loss in PHE occurs from these processes as an indirect result of HIV infection. Active infection of neurons or neuronal progenitor cells remains controversial, but may occur in children at low levels [15].

The pathophysiological mechanisms in pediatric HIV-associated CNS disorders reflect the complex interactions between HIV a maturing brain.

#### **7.4. Clinical features**

infection include horizontal transmission through sexual abuse or transfusion of contaminated blood products. Adolescent HIV infection follows the same modes of transmission seen

Pediatric HIV-related CNS disease is primarily caused by the virus itself affecting all components of the neural axis, but with particular predilection for the brain. The clinical manifestations described below are thus varied with the commonest being progressive HIV encephalopathy (PHE). This selective vulnerability of the brain may in part be due to the

CNS opportunistic infections and malignancies on the other hand do not contribute signifi-

The available data shows that approximately 2.3 million children worldwide are living with HIV/AIDS with nearly 2000 new infections and 1500 deaths occurring daily. These figures refer mainly to the developing world, and in particular Sub-Saharan Africa, dominated by the clade C strain of HIV. In these regions less than 10% of HIV positive pregnant women have access to appropriate measures to prevent mother-to-child transmission. In the developed world (clade B virus), pediatric HIV has ceased to be a significant problem as a result of effective use and delivery of antiretrovirals during pregnancy, elective cesarean section and infant formula feeding.

In the United States and Europe, highly active antiretroviral therapy (HAART) has reduced the rate of PHE from 9 to 35% in the early years of the HIV epidemic to 0–2% currently. Few studies from Sub-Saharan Africa report cognitive and motor developmental delay affecting 15–40% of HIV-infected children. There is no published data on the effects of HAART in this population. PHE occurs in 32–36% of HIV positive children in Latin America. Opportunistic CNS infections were relatively frequent at 34% in a Brazilian hospital-based study and at 12% in a study from Argentina. The latter study documented a remarkable reduction of severity

The CNS is affected early during the course of HIV infection. Neuro-invasion and pathogen-

The interaction between fetal astrocytes and endothelial cells is central to the development of the blood–brain barrier (BBB). This happens in early gestation. HIV interferes with healthy BBB development by restricted or nonproductive CD4 receptor independent infection of the astrocytes. The consequently impaired or disrupted BBB has increased susceptibility to neuroinvasion. In the immature brain this leads to the encephalopathy (PHE). The restricted infection of astrocytes causes neuronal dysfunction via loss of supporting growth factors and impaired neurotransmitter re-uptake with resultant excitotoxicity. Macrophages, microglia, and multinucleated giant cells are involved in productive HIV infection with viral replication. The consequent inflammatory cascade leads to production of neurotoxic cytokines. Neuronal loss in PHE occurs from these processes as an indirect result of HIV infection. Active infection of neurons or neuronal progenitor cells remains controversial, but may occur in children at low levels [15].

esis are similar to that described in adults with HIV associated cognitive impairment.

in adults, that is, sexual exposure and intravenous drug use.

cantly to HIV associated CNS disorders in childhood [15].

and frequency of PHE after the introduction of HAART [15].

effect of HIV on an immature brain (see below).

**7.2. Epidemiology**

136 Advances in HIV and AIDS Control

**7.3. Pathophysiology**

#### *7.4.1. Progressive HIV encephalopathy (PHE)*

Clinically well-defined triad of:


**Acquired microcephaly**: The diagnosis is made with stagnating or decreasing serial measurements of head circumference in children below 2 years of age. In the older child with closed skull sutures, the impaired brain growth correlates with parenchymal atrophy on neuroimaging.

**Progressive motor dysfunction**: The motor deficit in PHE children typically results from pyramidal tract abnormalities and presents with impaired fine motor function and ultimately loss of gross motor skills. Tone is often spastic. Motor milestones are either not achieved or can be lost. Extrapyramidal dysfunction with parkinsonian features of rigidity, drooling, and hypomimic facies may occur; cerebellar involvement is unusual. Advanced disease leads to a spastic, bedridden state.

These motor features are symmetrical. The occurrence of focal deficits should alert to possible underlying structural brain involvement by a mass lesion or infarction.

**Neurodevelopmental decline**: Neurodevelopmental deterioration involves global cognitive deficit with language and visuospatial, attention, concentration, and executive function problems. Delayed language milestones especially of expressive language often herald other cognitive and motor impairments. The delay is more easily observed in school-age children, but may often be attributed to other causes like nutritional, environmental, and psychosocial factors. Other symptoms include behavioral problems such as social withdrawal, apathy, mood disorders, and impulsiveness.

The clinical disease pattern of PHE varies widely with respect to age of onset, rate of progression, and domain(s) of functional impairment. Onset of PHE is most common in the first year of life with incidence rates of 9.9% in the first, 4.2% in the second year and less than 1% thereafter. Rates of progression vary widely with rapid decline over few months or a gradual deterioration. Early disease onset, especially when accompanied by advanced immune suppression predicts a more rapid and aggressive course with high mortality [15].

#### *7.4.2. Static encephalopathy*

A static encephalopathy with nonprogressive deficit or neurodevelopmental delay is also described. In contrast to PHE, there is no regression and there may be spontaneous improvement. This encephalopathy may be directly due to the HIV infection or secondary to other neurological insults, for example, premature birth, pre-natal exposure to toxins or infectious agents, genetic factors or head injury.

**7.5. Investigations**

*7.5.2. Neuroimaging*

*7.5.3. Psychometric testing*

psychosocial confounders.

*7.5.4. Treatment/management*

variety of languages and cultural settings.

can eradicate pediatric HIV altogether.

*7.5.1. Cerebrospinal fluid*

The CSF findings in patients with PHE are often normal, even in florid disease. Equally common are nonspecific changes including a slightly raised protein and lymphocytic pleocytosis. Intrathecal antibody production, oligoclonal bands and other markers of immune-activation may be present in PHE children, but also in neurologically intact patients. HIV viral RNA is typically present in the CSF and may loosely correlate with PHE severity. Suppression of CSF

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CSF findings can be helpful in establishing the diagnosis of certain common or opportunistic infections (pyogenic, tuberculous and cryptococcal meningitis; toxoplasmosis; CMV encepha-

Computed tomography (CT) scans of the brain reveal varying degrees of cerebral atrophy with corresponding ventriculomegaly and white matter hypodensities. Bilateral symmetrical basal ganglia calcifications are commonly seen. Magnetic resonance imaging (MRI) is sensitive to detect white matter changes, but not the calcifications. Serial imaging studies might assist to document progression, but quantitative and volumetric studies have not yet been standardized to be useful surrogate markers for early diagnosis or disease progression in clinical practice. Emerging functional neuroimaging techniques like magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and positron emission tomography (PET) may become future tools in early disease detection and monitoring of disease progression or response to treatment.

Neuropsychological and neurobehavioral assessment tools can be useful to document the neurodevelopmental deficit and its progression, but require careful and skilled interpretation. Many factors other than HIV may influence a child's performance on testing. In addition, HIV positive children are more likely to be exposed to poor socio-economic circumstances and low levels of maternal education, and are more likely to suffer from compounding illnesses like birth asphyxia, anemia, and malnutrition leading to a multitude of biological and

Standard psychometric testing remains to children in most developing countries. Such assessment tools still need to be validated in regions outside the US and Europe and in a greater

Implementation of public health systems preventing mother to child transmission effectively

viral load is utilized as a marker of response to treatment.

litis) and neoplasm (CNS lymphoma).

#### *7.4.3. CNS infections*

HIV positive children are prone to CNS infections caused by common and opportunistic organisms. Congenital CNS infections (toxoplasmosis, CMV) have been documented albeit infrequently. The commonest reported opportunistic infections (OIs) are CMV encephalitis, *Candida albicans* meningitis and micro-abscesses secondary to septicemia. OIs and their spectrum and occurrence in developing countries are not well described in the literature. Endemic infections like tuberculosis may play a bigger role than in developed countries [4]. Malaria and HIV co-infection may contribute to neurodevelopmental delay in affected children [15].

The frequency of OIs overall is low in children compared to adults, where reactivation of previously acquired infections (toxoplasmosis, JC virus) is common.

#### *7.4.4. Cerebrovascular disease:*

Strokes, both cerebral infarction and intracranial hemorrhage have been described in HIVinfected children. The frequency is lower than that seen in adults. Hemorrhage can occur into a tumor or be due to thrombocytopenia. Cerebral infarction may result from the vasculitis accompanying meningitis, or from cardio-embolic disease secondary to cardiomyopathy. HIV aneurysmal vasculopathy has been described in pediatric AIDS cases with fusiform aneurysms affecting the arteries around the circle of Willis.

#### *7.4.5. Seizures*

HIV infected children are more prone to seizures than their HIV negative counterparts. Seizures, especially if focal/partial in onset should prompt a search for underlying localized cerebral pathology.

#### *7.4.6. Neoplasms*

Primary CNS lymphoma and metastatic lymphoma to the CNS have been described. The clinical presentation may be with seizures, focal neurological signs, or deteriorating mental function.

#### *7.4.7. Myelopathy*

Spinal cord syndromes are rare in children and due to reactivated infections, for example, CMV. Vacuolar myelopathy, a frequent manifestation in adults with HIV is rarely seen in children.

#### **7.5. Investigations**

improvement. This encephalopathy may be directly due to the HIV infection or secondary to other neurological insults, for example, premature birth, pre-natal exposure to toxins or

HIV positive children are prone to CNS infections caused by common and opportunistic organisms. Congenital CNS infections (toxoplasmosis, CMV) have been documented albeit infrequently. The commonest reported opportunistic infections (OIs) are CMV encephalitis, *Candida albicans* meningitis and micro-abscesses secondary to septicemia. OIs and their spectrum and occurrence in developing countries are not well described in the literature. Endemic infections like tuberculosis may play a bigger role than in developed countries [4]. Malaria and HIV co-infection may contribute to neurodevelopmental delay in affected

The frequency of OIs overall is low in children compared to adults, where reactivation of

Strokes, both cerebral infarction and intracranial hemorrhage have been described in HIVinfected children. The frequency is lower than that seen in adults. Hemorrhage can occur into a tumor or be due to thrombocytopenia. Cerebral infarction may result from the vasculitis accompanying meningitis, or from cardio-embolic disease secondary to cardiomyopathy. HIV aneurysmal vasculopathy has been described in pediatric AIDS cases with fusiform

HIV infected children are more prone to seizures than their HIV negative counterparts. Seizures, especially if focal/partial in onset should prompt a search for underlying localized

Primary CNS lymphoma and metastatic lymphoma to the CNS have been described. The clinical presentation may be with seizures, focal neurological signs, or deteriorating mental function.

Spinal cord syndromes are rare in children and due to reactivated infections, for example, CMV. Vacuolar myelopathy, a frequent manifestation in adults with HIV is rarely seen in

previously acquired infections (toxoplasmosis, JC virus) is common.

aneurysms affecting the arteries around the circle of Willis.

infectious agents, genetic factors or head injury.

*7.4.3. CNS infections*

138 Advances in HIV and AIDS Control

children [15].

*7.4.5. Seizures*

cerebral pathology.

*7.4.6. Neoplasms*

*7.4.7. Myelopathy*

children.

*7.4.4. Cerebrovascular disease:*

#### *7.5.1. Cerebrospinal fluid*

The CSF findings in patients with PHE are often normal, even in florid disease. Equally common are nonspecific changes including a slightly raised protein and lymphocytic pleocytosis. Intrathecal antibody production, oligoclonal bands and other markers of immune-activation may be present in PHE children, but also in neurologically intact patients. HIV viral RNA is typically present in the CSF and may loosely correlate with PHE severity. Suppression of CSF viral load is utilized as a marker of response to treatment.

CSF findings can be helpful in establishing the diagnosis of certain common or opportunistic infections (pyogenic, tuberculous and cryptococcal meningitis; toxoplasmosis; CMV encephalitis) and neoplasm (CNS lymphoma).

#### *7.5.2. Neuroimaging*

Computed tomography (CT) scans of the brain reveal varying degrees of cerebral atrophy with corresponding ventriculomegaly and white matter hypodensities. Bilateral symmetrical basal ganglia calcifications are commonly seen. Magnetic resonance imaging (MRI) is sensitive to detect white matter changes, but not the calcifications. Serial imaging studies might assist to document progression, but quantitative and volumetric studies have not yet been standardized to be useful surrogate markers for early diagnosis or disease progression in clinical practice. Emerging functional neuroimaging techniques like magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and positron emission tomography (PET) may become future tools in early disease detection and monitoring of disease progression or response to treatment.

#### *7.5.3. Psychometric testing*

Neuropsychological and neurobehavioral assessment tools can be useful to document the neurodevelopmental deficit and its progression, but require careful and skilled interpretation. Many factors other than HIV may influence a child's performance on testing. In addition, HIV positive children are more likely to be exposed to poor socio-economic circumstances and low levels of maternal education, and are more likely to suffer from compounding illnesses like birth asphyxia, anemia, and malnutrition leading to a multitude of biological and psychosocial confounders.

Standard psychometric testing remains to children in most developing countries. Such assessment tools still need to be validated in regions outside the US and Europe and in a greater variety of languages and cultural settings.

#### *7.5.4. Treatment/management*

Implementation of public health systems preventing mother to child transmission effectively can eradicate pediatric HIV altogether.

Once PHE has set in HAART should be initiated. The ideal timing of commencement and choice of regimen is yet to be determined. However, this is not a cure as it fails to completely eradicate the virus from the CNS reservoir.

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