HIVAssociated Central Nervous System Disorders Children

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Neurological involvement was reported as a frequent complication of pediatric AIDS in the early years of the epidemic. A devastating progressive encephalopathy (PE) was described,1^] as was more stable neurological impairment.^1 It was observed that by the time HIV-1 infection had advanced to full-blown AIDS, cognitive and motor impairment of varying duration, progression, and severity were extremely common. In the majority of cases, neuropathological studies revealed no evidence of CNS opportunistic infections or neoplasms. y , [iij] [ii8] ^9 The clinical syndrome of progressive encephalopathy in children (variously termed AIDS encephalopathy, HIV-1 encephalopathy, PE, subacute PE, HIV-1-associated CNS disease, HIV-1- associated PE of childhood) is now recognized to be similar to the adult counterpart, HIV dementia (AIDS dementia complex),^ and is directly related to HIV-1 brain infection.

Pathogenesis and Pathophysiology. In adults, the pathophysiological mechanisms underlying HIV-1-asso- ciated CNS disease are not yet clearly defined. In infants and children, the study of neuropathophysiological mechanisms and their clinicopathological correlates is even more complex because developmental-maturational issues must also be considered.^ Adult HIV-1 CNS infection and disease occurs in mature, fully developed and completely myelinated nervous systems. The immune system and CNS elements of the mononuclear phagocyte system (intrinsic microglia) are also fully developed. Vertically transmitted HIV-1 infection occurs in an immature evolving organism. It is believed that HIV-1 invades the CNS early in the course of infection. Maternal-infant transmission may occur during gestation in some patients, whereas in others, the infection may occur during the perinatal period. The time of infection (gestation versus perinatal, and if gestation, in which trimester) is likely to be an important factor. The

developmental stage of the nervous and immune system when exposed to the direct and indirect effects of the virus, must be considered. Innumerable dynamic interactions occur between these two systems during development, and these undoubtedly interact in complex ways with HIV-1 variables. The maturational stage of CNS development when exposed to the effects of the virus is likely to manifest as different patterns of HIV-1 CNS disease. yd [121] W

The nervous system may also be affected secondarily by complications related to the immunodeficiency including CNS neoplasms, infections with pathogens other than HIV- 1, and strokes. The nervous system may also be affected by systemic AIDS-related conditions (neurological complications of systemic illness), nutritional deficiencies, endocrinological and metabolic derangements and by toxic/metabolic complications that arise as a consequence of therapy. These conditions are not mutually exclusive, and co-existing conditions are common. yj ^i1 [i22] h.3 [I24]

In addition, the developing nervous system in HIV-1- infected infants (as in non-HIV-1-infected infants) may be adversely affected by maternal conditions during pregnancy such as substance abuse, inadequate nutrition, deficient prenatal care, and AIDS-associated illnesses (e.g., infections with pathogens other than HIV-1).[12o1 , [1211 Premature delivery is associated with some of these high-risk maternal conditions. The prematurely born HIV-1-infected infant, like any premature infant, is, in turn, at risk for developing perinatal CNS complications--intraventricular hemorrhages, periventricular leukomalacia, hypoxic encephalopathy--that carry the risk of neurological sequelae.

Epidemiology and Risk Factors. The true incidence of pediatric HIV-1-associated CNS disease is not yet known. A review of the published literature is difficult to interpret because of differences in terminology, definitions, study populations, and study designs. An incidence of 13 to 28 percent is reported from prospective studies of children followed from birth to early childhood. y , y , y^ , y.5 , W A 23.8 percent rate was reported by Tovo and co-workers in their cohort of 433 HIV-1 perinatally infected children in Italy. ^23] Blanche and colleagues reported a 15 to 20 percent incidence of HIV-1 encephalopathy by age 3 years in their patients followed prospectively from birth and a 10 percent incidence per year thereafter. y In contrast, cohort studies of infants and children, who had already developed AIDS- related complex or AIDS, show a higher prevalence rate. A still higher rate (31 to 75 percent) is reported from cohorts of children who already developed AIDS.y , y?1 , [127] The frequency with which HIV-1-associated PE is reported as the initial AIDS-defining illness in children ranges from to 12 to 16 percent. y? This is in contrast to the much lower percentage (0.8 percent to 2.2 percent) reported for adults. y , y

Extrapolating from the experiences of many investigators, it appears that in general HIV-1-associated CNS disease in children parallels progression and severity of immunodeficiency and systemic disease. The more fulminant form of PE is more common in infancy. In a subset of infants and young children, HIV-1-associated CNS disease thus is the first AIDS-indicator disease. y , y , ^ , y?1

Clinical Features and Associated Disorders. HIV- 1-infected newborns are usually well at birth, and clinically recognizable neurological features of HIV-1-associated CNS disease are exceedingly rare. However, some HIV- 1-infected neonates do have neurological problems owing to co-morbid conditions. Observations in both clinical care settings and longitudinal research studies show the rate and pattern of disease progression to have considerable clinical diversity. y , y.01 , [121.] Neurological deterioration in some infants and young children is rapidly progressive. In some children, however, neurological deterioration occurs over a period of weeks to months, followed by a relatively stable period and then by further deterioration. Other children develop progressive and disabling motor deficits yet maintain relatively stable cognitive and socially adaptive skills. In contrast, some children have more impaired cognitive than motor function. Finally, there is a subset of children who have relatively minor and stable, motor and cognitive findings. * In an effort to delineate further the clinical characteristics of HIV-1-associated CNS disease syndromes in children, a classification scheme was adopted based on: (1) age of onset of clinically apparent disease; (2) rate and pattern of disease progression; and (3) domains of function most affected.W , [?.2Z]

The most severe, devastating, and clearly recognized syndrome is HIV-1-associated progressive encephalopathy of childhood. y Age of onset is usually in the first year of life (3 to 8 months of age) but may begin later. Neurological deterioration results in spastic quadriparesis and mental deficiency. Characteristic features are progressive corticospinal tract (CST) signs and loss of previously acquired motor milestones, acquired microcephaly, and marked delays in mental development. Opisthotonic posturing and rigidity may develop and are usually superimposed on spasticity. Pseudobulbar signs may also develop and feeding difficulties are frequent. The children develop a characteristic masklike facial appearance. They appear alert and wide eyed but have a paucity of spontaneous facial expression (manifestations of the basal ganglia and subcortical pathology). [120] Despite these features, there is little facial weakness evidenced by full movement when crying. The child is hypophonic and has decreased spontaneous and responsive vocalizations. Play deteriorates and previously acquired language skills or adaptive skills are lost. Psychometric measures document a decline in the composite cognitive score. In endstages, the child is apathetic, withdrawn, and quadriparetic with markedly impaired higher cortical function. [9 , [131]

A less severe neurological syndrome also occurs in the first 2 years of life, W , W , [128] , [131] and most of these infants are hypotonic and have marked delays in attaining motor milestones. Cognitive impairment of a variable degree and expressive language problems are common. y. , y.4 , W , [1301 Poor brain growth as determined by serial head circumference measurements may be presented , [120] [121] [122] , [128] , [131] In early childhood, some of the children develop a diparesis-type syndrome,[120] , W , [12i] whereas others fortunately remain stable and continue to acquire mental, motor, and adaptive skills. A change in gait is often the first sign of HIV-1 motor involvement in early childhood, as the child begins to toe walk. These individuals become hyperreflexic and have increased tone in the lower extremities.^ , [122] , [12.7] The rate of progression and the severity of deficits vary. Some children

* See references1J7 , 12.1 , 122 , 124 , 127 ,128 and 130 .

maintain independent ambulation for years, although they have a mildly spastic gait and are clumsy. W , [121] , [128] Impairment of fine motor ability is frequent. Progression and severity in other children may be more rapid and marked. Some require orthotics for ambulation, whereas others become wheelchair-bound within months.^ , W , W Cognitive impairment is frequent but not invariable. In a subset of children, cognitive function is not affected, and composite IQ scores remain within the normal range. For most, the degree of impairment ranges from borderline intelligence to mild or moderate retardation. [9 , ^

A subset of the children, who had a prolonged stable course, ultimately develop further neurological deterioration, formerly referred to as "plateau followed by further deterioration." The course then becomes similar to that of subacute PE. Wi Progressive atrophy and white matter changes are invariably seen. In contrast, other children show improvement and steadily acquire additional developmental skills. Their rate of acquisition of new skills accelerates compared with their previous plateau performance.^ , [122]

Cognitive decline, loss of interest in school performance, social withdrawal, emotional lability, decreased attention, and psychomotor slowing are reported as signs of HIV- 1-associated PE in school-age children. '9 , '117' , '122' , '127' , '132' With advancing disease, psychometric tests show a decline in the composite IQ score. Motor involvement of varying severity is common. There is usually hyperreflexia, with or without increased lower extremity extensor tone. Clumsy and poor fine-motor ability and coordination are often noted. Progressive long tract signs, movement disorders, cerebellar signs, and myelopathy may also develop. In the advanced stages of CNS disease the child has cognitive impairment and at endstage is apathetic and abulic. '128' , 'id

Children, who in infancy and early childhood had marked delays in motor and mental development and were followed from birth in prospective studies, continued to acquire milestones and skills, although the rate and quality deviated from the norm. '122' , '127' This suggests that HIV-1 may compromise the normal developmental process and result in a stable or static encephalopathy.

It is as yet unknown whether HIV-1-associated CNS disease manifestations in adolescents differs in early signs and progression from that of adults or of children, although it is anticipated that manifestations will be similar to adults.

Differential Diagnosis. The differential diagnosis includes other neurodegenerative disorders, infectious etiologies, and psychiatric conditions.

Evaluation. The evaluation of the HIV-1-infected child with neurological involvement requires the clinical skills and major diagnostic tools of the neurologist. y.' The approach to the diagnosis of HIV-1-associated CNS disease, including differential diagnosis (secondary complications co-morbid complications), involves a careful medical and developmental history, HIV-1 systemic disease history, current immunological status, neurological examination, psychological assessment, and neuroimaging studies.y.' , 'i^ The diagnosis of HIV-1-associated PE is relatively straightforward, if the patient has been followed prospectively. Longitudinal assessments of the infant or child reveal progressive involvement. The diagnosis is also fairly straightforward if the child on initial examination is found to have motor deficits (spasticity, ataxia, weakness, abnormalities of tone, change in gait, etc.), and by a careful history, either the new onset or progression of motor impairment can be documented (again, when other causes for progressive motor dysfunction have been excluded). Confirmation of progression can at times be obtained by review of family photographs of the child.

However, diagnostic difficulties arise when an HIV-1- infected youngster, who was not followed from birth or infancy by the examiner, is found at the initial neurological evaluation to have deficits or delays. Because the frequency of neurological and developmental impairment in this population is high, it is often impossible for the clinician to ascribe these findings to HIV-1-associated CNS disease rather than to possible co-morbid conditions. A careful history is paramount. If there are no other risk factors the diagnosis is likely. The child should have a formal psychological assessment and be re-evaluated by the neurologist and psychologist in 2 to 4 months.

Neuroimaging studies are extremely helpful and in fact are critical. If calcification of basal ganglia, with or without mineralization of the frontal white matter, is present, it is probable that the child has HIV-1-associated CNS disease. If cerebral atrophy is present in the absence of documented perinatal complications, steroid use, or other known causes of atrophy, the diagnosis becomes extremely likely. Follow-up neuroimaging studies should be requested in addition to the above-mentioned serial neurological and psychological evaluations.

Head circumference measurements are very helpful. It has been our experience that a careful review of medical records will document at least one or two past head circumference measurements. This allows the examiner to plot serial measurements. The pattern of downward deviation and "crossing percentiles" makes the diagnosis of HIV- 1-associated CNS disease likely. This is especially true if acquired microcephaly is documented. Thus, neuroimaging evidence of atrophy accompanied by acquired microcephaly clearly strengthens the diagnosis.

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