Redefining HIV encephalopathy in children living in SSA

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

2 Epidemiology of HIV in Children living SSA In M children infected Acquired infection Mother (>95%) Blood transfusions Contaminated needles Sexual

3 Maternal Transmission Cumulative 40% Breast-feeding 10-20% Accounts for >40% 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 2004:364:

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 d Ivoire USA HIV +ve (N=156) Cote d Ivoire HIV +ve (n=70) CNS pathology 96% 93% HIV encephalitis 38% 6% Lymphocytic meningitis ND 34% Inflammatory infiltrates NS 30% Other infections 10% 9% Toxoplasmosis 0 4% Basal ganglia mineralization 65% 41% CNS lymphoma 5% 0% Bell et al. J Neuropath Exp Neurol 1997; 56:

7 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:

8 Major Domains Impairment of brain growth Decline of cognitive (neurodevelopment) function Clinical motor dysfunction

9 Impairment of brain growth In the absence of other aetiologies Documented by either Infants with HC < 5 th percentile Children <3 yrs crossing 2 major percentiles from baseline HC Children HC falling below < 5 th 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 1. Child < 3 years Fall of 2 SD on a standardized non-screening developmental assessment 2. Child > 3 years Fall of at least 1SD on standardised test of intelligence 3. Any age Loss of previously attained cognitive or language milestones confirmed by standardized testing

11 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 a) diffuse and symmetric loss or deterioration of power that is not the results of systemic, nutritional or metabolic compilation b) diffuse and symmetric abnormalities of tone c) diffuse and symmetrical increases in tendon reflexes

12 In resource poor countries Impaired brain growth Infants with HC < 5 th percentile Children <3 yrs crossing 2 major percentiles from baseline HC Children HC falling below < 5 th percentile Children with serial neuroimagining studies showing loss of brain parenchyma Neurodevelopment decline Child < 3 years: Fall of 2 SD on a standardized non-screening developmental assessment Child > 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

13 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

14 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 a. Gaucher disease type II (glucosylceramide lipidosis) b. GM, gangliosidosis types I and II c. GM, gangliosidosis (Tay-Sachs, Sandhoff) d. Globoid cell leukodystrophy (Krabbe) e. Metachromatic leukodystrophy (sulfatide lipidoses) f. Multiple sulfatase deficiency g. Niemann-Pick type A (sphingomyelin lipidosis) 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 Other Genetic Disorders of White Matter 1. Galactosemia: transferase deficiency 2. Neonatal adrenoleukodystrophy 3. Pelizaeus-Merzbacher disease 4. Spongy degeneration of infancy (Canavan-Van Bogaert)

15 Opportunistic CNS infections Viral CMV Varicella Zoster Herpes simplex papovavirus Ebstein Barr Mycobacterium M. tuberculosis M. avium intracellulare Fungal Candida Cryptococcus Aspergillus sp Actinomyces Histoplasma Bacterial Pseudomonas sp Streptococcus sp. Toxoplasmosis

16 Major Domains Impairment of brain growth Decline of cognitive function Clinical motor dysfunction

17 In Kilifi Kenya Kilifi community Second poorest area in Kenya Underweight (WAZ < -2): 24% Alone 5.7% Underweight and stunted: 19.7%

18 Head circumferences in Kilifi community

19 Prevalence of Microcephaly and Macrocephaly in Community children No. Microcephaly % of children with Microcephaly malnourished or stunted Macrocephaly (9.9%) 21 (6.9%) 3 (0.9%)

20 Major Domains Impairment of brain growth Decline of neurodevelopment function Clinical motor dysfunction

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

22 Prevalence of Neurocognitive Impairment Place Age Type of Population Prevalence per 1000 (years) population Any NI Cognitive Motor Bangladesh 6-9 Rural and Urban Ghana 6-9 Rural and Urban Jamaica 2-9 Urban Kenya 6-9 Rural Pakistan 2-9 Rural and Urban South Africa 6-9 Rural *

23 Motor development in 6 centres WHO Acta Pædiatrica, 2006; Suppl 450: 66/75

24 Interobserver variation in assessment of motor signs Proportion of Kappa Agreement Sitting Crawling/kneeling Standing Walking/running/jumping Thomas et al Dev Med Child Neurol 2001; 43:

25 Major Domains Impairment of brain growth Decline of cognitive function Clinical motor dysfunction

26 Clinical motor dysfunction Loss or significant deterioration of motor skills in any two of the following criteria a) diffuse and symmetric loss or deterioration of power that is not the results of i. systemic, ii. nutritional or iii. metabolic compilation b) diffuse and symmetric abnormalities of tone c) diffuse and symmetrical increases in tendon reflexes a) Interobserver variation

27 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

28 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? < 2 years Neurodevelopmental milestones Loss of skills, particularly motor Lack of acquisition of neurodevelopment skills Diffuse symmetrical hyperreflexia Lumbar puncture to exclude CNS infections

29 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

30 Thank you

31 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

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