Neurodevelopment in children infected andor affected by HIVAIDS in subSaharan Africa'

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Neurodevelopment in children infected and/or
affected by HIV/AIDS in sub-Saharan Africa.

• Annelies Van Rie, Aimee Mupuala, Anna Dow, Nadine
  Nosse, Iam Zephyrin
• Work funded by NIH/NIMH
• BRAIN DISORDERS IN THE DEVELOPING WORLD RESEARCH
  ACROSS THE LIFESPAN

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Twin girls, age 8 months
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HIV infection and CNS in children

• Neurological manifestations of HIV infection in
  vertically infected children impairs the
  development and growth of an immature CNS
• CNS involvement presents as static or progressive
  HIV encephalopathy (PHE), with microcephaly,
  delay or loss of developmental milestones (motor,
  mental and language), and pyramidal tract
  symptoms (Belman 1988)
• Prevalence in pre-HAART era in the USA 30 to 50
  (Epstein 1986, Sharer 1986)
• Treatment with antiretroviral agents can reverse
  CNS manifestations (Pizzo 1988, Brouwers 1990,
  McKinney 1991, Butler 1991, Tepper 1998, Mc Coig
  2002)
• Access to HAART has dramatically decreased the
  incidence of active PHE to 1.6 (Chiraboga, 2005)

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HIV and Neurodevelopment experience from the
US/Europe

• Early and persistent delay in motor development
  distinguishes most strongly HIV infected from HIV
  exposed children (Epstein 1986, Chase 1995,
  Drotor 1999, Knight 2000)
• Deceleration in mental development and delays in
  expressive speech occur in late infancy (Epstein
  1986, Moss 1996, McNeilly 1998, Davis-McFarland
  2000, Brouwers et al 1995)
• Correlation between presence of PHE and outcome
  increased hospitalizations, lower CD4 count and
  short survival (Epstein 1986, Duliege 1992,
  Lobato, 1995)
• Level of motor dysfunction and neuropsychological
  functioning provided predictive information
  beyond that obtainable from surrogate markers of
  HIV disease status (e.g. CD4 count, HIV RNA
  level). (Pearson et al. 2000)

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HIV and Neurodevelopment experience from the
US/Europe

• Broad variability in severity and timing, with
  the highest risk in the first year of life
  (Wachtel 1993, Epstein 1986, Lobato 1995,)
• Highest risk occurs in the first and second year
  following HIV infection incidence rate of 10,
  4.25 and 1 in first, second and subsequent years
  of life. Compared to adults 0.3 in first year
  and 1 thereafter. The cumulative 7y incidence
  postinfection reached 16 in children vs 5 in
  adults (Tardieu 2000)

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HIV and Neurodevelopment experience from Africa

• Msellati et al, 1993, Rwanda (n20-43, age 0-24
  m)
• Deliberately very simple screening tool
• HIV infected children perform more poorly
  compared to HIV exposed infants
• Boivin et al. 1995, Zaire (n11 -15 -15, age 3-18
  m)
• Portions of the Early Childhood Screening
  Profiles (cognitive, language, motor) and Kaufman
  Assessment Battery for children (cognitive)
• HIV infected children demonstrate global
  cognitive impairment that extends beyond the
  indirect effects of maternal illness
• Spatial memory and motor functions were the most
  affected
• A portion of the deficit may have been due to the
  effects of impaired health in the mother

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HIV and Neurodevelopment experience from Africa

• Drotar et al. 1997 and 1999, Uganda
  (n61-234-115, age 6-24m)
• Bayley scales of Mental and Motor development,
  first edition, and Fagan test of intelligence
• More frequent and earlier onset of deficits in
  motor than mental development
• HIV infected children demonstrate a lower mental
  and motor development and a greater deceleration
  in their rate of motor development
• Neurodevelopment is worse in children with
  abnormal neurological exam
• No difference between HIV exposed uninfected and
  control children

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Assessing neurodevelopmental outcome in African
children a challenge

• Few neurodevelopmental assessment tools have been
  evaluated and validated outside of the US and
  Europe.
• Capacity in neurodevelopmental assessment is
  extremely limited
• How to disentangle the direct biological from the
  environmental and social impact of HIV on the
  neurodevelopment of HIV infected children in the
  sub-Saharan African context?

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Neurodevelopmental concerns for orphans and other
vulnerable children

• The illness of a parent marks the beginning of
  erosion of the family and trauma in the
  emotional, psychological and material life of a
  child
• The HIV/AIDS epidemic is making millions of
  sub-Saharan African children vulnerable,
  including 12.3 million AIDS orphans (2003)
• Neurodevelopmental consequences of being
  confronted with parents suffering from AIDS can
  erode the educational opportunities which are
  considered key components of a safety net for
  vulnerable children.

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HIV/AIDS estimates for DRC and SA 2003
World Health Organization. Joint United Nations
Programme on HIV/AIDS. 2004 report on the global
HIV/AIDS epidemic 4th global report.
UNAIDS/04.16E.
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Pilot Study Design

• Prospective study
• 35 HIV infected children at baseline, 6 and 12
  months post initiation of ART - Kinshasa
• 35 HIV affected children (AIDS orphans and
  children of parents with symptomatic AIDS) -
  Kinshasa
• 90 HIV unexposed healthy children with HIV
  negative mother and healthy parents (5 boys and
  5 girls for every 6 month age class between 18
  and 71 m) - Kinshasa and Cape Town
• Data collection
• Neurodevelopmental assessment
• Maternal quality of life
• Demographic parameters and family structure
• clinical and immunological parameters

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Selection of neurodevelopmental tools

• Criteria for selection
• Age specific tools
• valid and reliable
• Cross-cultural utility
• Maximum of information in minimum of time
• 18 months 30 months
• Bayley (mental, motor and behavior)
• Rossetti (language)
• 30 months 72 months
• SON-R 2.5-7 (mental)
• Peabody (motor)
• Rossetti (language)

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Bayley Scales of Infant Development Second
Edition

• Mental Scale and Motor Scale are for assessment
  of the current level of cognitive, language,
  personal-social, fine and gross motor development
• Behavior Rating Scale assesses the childs
  behavior during testing
• Used for children from 1 month to 36-42 months

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Peabody Developmental Motor Scales

• Reflexes, Stationary, Locomotion, Object
  Manipulation, Grasping, and Visual-Motor
  Integration
• Results can be assessed as a total motor score or
  broken down to assess fine motor or gross motor
  capabilities separately
• Used for children from birth through six years of
  age

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Rossetti Infant-Toddler Language Scale

• Assesses preverbal and verbal areas of
  communication and interaction
• Uses direct observation, elicited behavior, or
  caregivers report to equally credit the childs
  performance, is therefore less dependant on the
  language itself, and is thus less problematic for
  use in different languages compared to other
  language scales
• Six areas - Interaction-Attachment, Pragmatics,
  Gesture, Play, Language Comprehension, and
  Language Expression
• Used in children from birth to 36 months
• Problems
• This measure has not been standardized, and there
  is no statistical information on it.
• Gesture and play influenced by the general status
  (weakness)

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Snijders-Oomen Nonverbal Intelligence Test
(SON-R) 2½-7

• A nonverbal, language independent tool comprised
  of six subtests.
• Two subtests (puzzles and analogies) were
  eliminated for the Africa version. The 4
  remaining tests are situations, mozaics,
  categories and patterns
• Scores provide an overall IQ as well as a
  separate score for performance (P- IQ) and
  reasoning (R-IQ) subtests
• Feedback is given after each item by telling the
  subject whether the solution was correct or
  incorrect, and an adaptive procedure is used to
  prevent the administration of too many easy or
  too many difficult questions
• Appropriate for children from 2 and a half to
  seven years of age

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Nonverbal Intelligence Test (SON-R) 2½-7
Challenges

• Mosaic poor knowledge of colors
• Categories and situations certain items are not
  recognized by the child and need modification for
  the African context
• Many chose the ice-cream to feed the rabbit. Most
  children referred to the rabbit as a mouse. I got
  the impression that the children chose the
  ice-cream because it was something they would
  like to eat themselves
• Suggestions

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Preliminary results validity of assessment
tools in the Kinshasa context

• Bayley motor scale
• Bayley mental scale
• Peabody motor scale
• SON 2½-7

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Bayley Scales of Infant Development, Psychomotor
Development Index (PDI)
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Bayley Scales of Infant Development Mental
Development Index (MDI)
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Peabody Developmental Motor Scales, Total Motor
Quotient (TMQ)
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SON-R 2.5-7, SON-IQ mental
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Conclusions validity of tools

• Distribution of the scores for the control group
  is a normal distribution.
• Mean and SD of the control group was not
  significantly different from the mean and SD of
  the normative populations.
• There is a shift to the left for the mental
  development assessment tools, especially for the
  SON 2½-7. This may be improved by adapting some
  of the pictures to the sub-Saharan African
  context.

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Preliminary results Comparison of motor and
mental development in HIV infected, HIV affected
and unaffected children

• Bayley motor scale
• Bayley mental scale
• Peabody motor scale
• SON 2½-7

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Cross sectional data motor development children
aged 18-29 months
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Cross sectional data mental development
children aged 18-29 months
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Cross sectional data behavior of children aged
18-29 months
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Cross sectional data motor development of
children aged 30-71 months
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Cross sectional data motor development of
children aged 30-71 months
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Cross sectional data language development
Language comprehension
Language expression
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Cross sectional data motor and mental
development in children aged 18-29 months
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Cross sectional data motor and mental
development in children aged 30-71 months
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Conclusions Impact of HIV on neurodevelopment

• Motor, mental and language development is delayed
  in a the overwhelming majority of HIV infected
  children.
• HIV affected children had significant delays in
  their mental development, in both age groups. The
  motor development tended to be slower but the
  difference was borderline (18 -29 m) or not (30
  71 m) statistically significant.
• The motor development of HIV infected children
  was significantly more pronounced than that of
  HIV affected children, possibly indicating both a
  biological and environmental component
• The delay in mental development of young HIV
  infected children was more pronounced compared to
  that of young HIV affected children. This
  difference became non significant in the older
  age group, possibly indicating an important
  environmental factor in the older children.
• Behavioral problems were identified in both HIV
  infected and affected children

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Conclusions Impact of HIV on neurodevelopment

• Impact seemed larger in the younger age group
• Due to use of different tools in different age
  groups?
• Younger children with neurodevelopmental problems
  are those infected in utero?
• Due to effect of survival cohort?

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Future directions CNS involvement in African
children in the era of increased access to ARV

• Prospective study to address
• incidence of CNS involvement
• Effect of ARV
• Scholastic achievement and special needs
• Correlation between neurological delay and
  progression of HIV disease in the African
  context, and its implication for timing of
  initiation of ARV treatment
• Sustainable care for neurodevelopmental
  challenged children infected and/or affected by
  HIV