Redefining HIV encephalopathy in children living in SSA

1
Redefining HIV encephalopathy in children living
in SSA
Charles RJC Newton Kenya Medical Research
Institute/ Wellcome Trust Collaborative
Programme, Kilifi, Kenya
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Epidemiology of HIV in Children living SSA

• In 2001 2.2 M children infected
• Acquired infection
• Mother (gt95)
• Blood transfusions
• Contaminated needles
• Sexual

3
Maternal Transmission

• Cumulative 40
• Breast-feeding
• 10-20
• Accounts for gt40 of the transmission overall
• At birth
• 10-20
• In utero
• 5-10

4
Prognosis for Children

• Of those infected
• 35 die by 1 year
• 52 die by 2 years
• Mortality higher in
• East and West Africa
• Mortality likely to be greater in those not in
  the trials.

Newell et al Lancet 2004364 1236-43
5
Comparison of clinical features of NeuroAIDS in
Western countries

• Adults
• Horizontal acquisition
• Long latency
• Deterioration of mature CNS
• Motor deterioration
• Cognitive decline
• CNS OI frequent
• Brain atrophy
• Cerebrovascular disease common

• Children
• Vertical acquisition
• Short latency
• Impairment of immature CNS
• Progressive motor dysfunction
• Neurodevelopmental decline
• CNS OI infrequent
• Impaired brain growth
• Cerebrovascular disease rare

6
Comparison between CNS pathology of HIV infected
children in USA and Cote dIvoire
Bell et al. J Neuropath Exp Neurol 1997 56
686-692
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Definition of HIV encephalopathy in children

• HIV positive child who is
• neurologically normal at baseline
• Meets one of the criteria in the major domains
• Neurologically abnormal at baseline
• Meets two of the criteria in the major domains
• In the absence of another cause for these
  features
• Working group on ARV and medical management of
  infants, children and adolescents Pediatrics
  1998 102 105-66

8
Major Domains

• Impairment of brain growth
• Decline of cognitive (neurodevelopment) function
• Clinical motor dysfunction

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Impairment of brain growth

• In the absence of other aetiologies
• Documented by either
• Infants with HC lt 5th percentile
• Children lt3 yrs crossing 2 major percentiles from
  baseline HC
• Children HC falling below lt 5th percentile
• Children with serial neuroimagining studies
  showing loss of brain parenchyma

10
Decline of neurodevelopment function

• Documented by psychometric testing
• At least 2 individual, valid measurements
  separated by at least 1 month
• Child lt 3 years
• Fall of 2 SD on a standardized non-screening
  developmental assessment
• Child gt 3 years
• Fall of at least 1SD on standardised test of
  intelligence
• Any age
• Loss of previously attained cognitive or language
  milestones confirmed by standardized testing

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Clinical motor dysfunction

• Progressive on 2 individual examinations
  separated by at least 1 month
• Loss or significant deterioration of motor skills
  in any two of the following criteria
• diffuse and symmetric loss or deterioration of
  power that is not the results of systemic,
  nutritional or metabolic compilation
• diffuse and symmetric abnormalities of tone
• diffuse and symmetrical increases in tendon
  reflexes

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In resource poor countries

• Impaired brain growth
• Infants with HC lt 5th percentile
• Children lt3 yrs crossing 2 major percentiles from
  baseline HC
• Children HC falling below lt 5th percentile
• Children with serial neuroimagining studies
  showing loss of brain parenchyma
• Neurodevelopment decline
• Child lt 3 years Fall of 2 SD on a standardized
  non-screening developmental assessment
• Child gt 3 years Fall of at least 1SD on
  standardised test of intelligence
• Any age Loss of previously attained cognitive or
  language milestones confirmed by standardized
  testing
• Motor impairment
• Loss or significant deterioration of motor skills

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In the absence of another cause

• Many causes of progressive encephalopathy in
  children
• CNS infections
• Non-infectious causes
• Diagnosis needs
• Neuroimagining
• Blood tests
• extensive
• expensive

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Other causes of progressive encephalopathy

• Aminoacidurias
• 1. Homocystinuria
• 2. Maple syrup urine disease
• a. Intermediate form
• b. Thiamine-responsive form
• 3. Phenylketonuria
• Lysosomal Enzyme Disorders
• 1. Glycoprotein degradation disorders
• a. Mannosidosis type I
• b. Fucosidosis types I and II
• c. Sialidosis type II (infantile form)
• 2. Mucolipidoses
• a. Type II (1-cell)
• b. Type IV
• 3. Mucopolysaccharidoses
• a. Type I (Hurler)
• b. Type II (Sanfilippo)
• 4. Sphingolipidoses

• Hypothyroidism
• Mitochondrial Disorders
• 1.  Mitochondrial myopathy, encephalopathy,
  lactic acidosis, stroke
• 2.  Progressive infantile poliodystophy (Alper).
• 3.  Subacute necrotizing encephalomyelopathy
• (Leigh)
• 4.  Trichopoliodystrophy (Menkes)
• Neurocutaneous Syndromes
• 1.  Chediak-Higashi syndrome
• 2.  Neurofibromatosis
• 3.  Tuberous sclerosis
• Other Genetic Disorders of Gray Matter
• 1.  Infantile ceroid lipofuscinosis (Santavuori)
• 2.  Infantile neuroaxonal dystrophy
• 3.  Lesch-Nyhan disease
•  

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Opportunistic CNS infections

• Fungal
• Candida
• Cryptococcus
• Aspergillus sp
• Actinomyces
• Histoplasma
• Bacterial
• Pseudomonas sp
• Streptococcus sp.
• Toxoplasmosis

• Viral
• CMV
• Varicella Zoster
• Herpes simplex
• papovavirus
• Ebstein Barr
• Mycobacterium
• M. tuberculosis
• M. avium intracellulare

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Major Domains

• Impairment of brain growth
• Decline of cognitive function
• Clinical motor dysfunction

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In Kilifi Kenya

• Kilifi community
• Second poorest area in Kenya
• Underweight
• (WAZ lt -2) 24
• Alone 5.7
• Underweight and stunted 19.7

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Head circumferences in Kilifi community
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Prevalence of Microcephaly and Macrocephaly in
Community children
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Major Domains

• Impairment of brain growth
• Decline of neurodevelopment function
• Clinical motor dysfunction

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Considerations.

• High prevalence of neurodevelopment impairment in
  communities
• In the age group in which most children with
  vertical HIV transmission manifest lt 3 years
• Motor function most easily assessed
• Lack of cultural appropriate tests for cognitive
  and language tests

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Prevalence of Neurocognitive Impairment
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Motor development in 6 centres
WHO Acta Pædiatrica, 2006 Suppl 450 66/75
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Interobserver variation in assessment of motor
signs
Thomas et al Dev Med Child Neurol 2001 43 97-102
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Major Domains

• Impairment of brain growth
• Decline of cognitive function
• Clinical motor dysfunction

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Clinical motor dysfunction

• Loss or significant deterioration of motor skills
  in any two of the following criteria
• diffuse and symmetric loss or deterioration of
  power that is not the results of
• systemic,
• nutritional or
• metabolic compilation
• diffuse and symmetric abnormalities of tone
• diffuse and symmetrical increases in tendon
  reflexes
• Interobserver variation

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So what do we need to do.

• Study a cohort of HIV ve children in sub-Saharan
  African with encephalopathy
• Identify CNS infections
• Obtain Neuroimagining
• Investigate possible metabolic causes
• Identify neurodevelopmental skills that can be
  applied across SSA in the age range 6 48 months
• Develop cultural and language appropriate
  assessments of neurodevelopment
• Standardised on large populations
• Improve neurological examination
• Training videos

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In the meantime.

• So can we define HIV encephalopathy in SSA?
• Child who is HIV positive
• Lack of growth in head circumference
• Serial measurements at least 3 months apart
• ? lt 2 years
• Neurodevelopmental milestones
• Loss of skills, particularly motor
• Lack of acquisition of neurodevelopment skills
• Diffuse symmetrical hyperreflexia
• Lumbar puncture to exclude CNS infections

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Acknowledgements

• Kilifi, Kenya
• Sadik Mithwani
• Penny Holding
• Amina Abubakar
• Jay Berkley

• New York University School and Family Care
  Clinic, Coast Province General Hospital, Mombasa,
  Kenya
• Shaffiq Essajee

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Thank you
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Laboratory Evaluations for Children With Acute
CNS Manifestations

• Blood
• Complete blood count
• Blood culture
• Electrolytes
• Toxicology screen
• Toxoplasmosis antibody
• Cryptococcal Ag culture

• Lumbar puncture
• Opening pressure
• Cell count, Gram stain
• Protein, Glucose
• Bacterial culture
• Cryptococcal antigen and culture
• PCR for EBV, CMV, VZV and HSV
• Viral, fungal and mycobacterial cultures
• VDRL