Attention Deficit Hyperactivity and Oppositional Defiance Disorder in HIV-Infected South African Children

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1 JOURNAL OF TROPICAL PEDIATRICS, VOL. 56, NO. 2, 2010 Attention Deficit Hyperactivity and Oppositional Defiance Disorder in HIV-Infected South African Children by I. Zeegers, a H. Rabie, b S. Swanevelder, c C. Edson, b M. Cotton, b and R. van Toorn b a Leiden University Medical Centre, Leiden, The Netherlands b Department of Paediatrics and Child Health, Tygerberg Children s Hospital, Faculty of Health Sciences, Stellenbosch University, Western Cape, South Africa c Biostatistics Unit, Medical Research Council, Tygerberg Children s Hospital, Faculty of Health Sciences, Stellenbosch University, Western Cape, South Africa Summary Objective: To determine the prevalence of attention deficit-hyperactivity disorder (ADHD) and oppositional defiance disorder (ODD) in HIV-infected South African children. Methods: Swanson, Nolan and Pelham (SNAP-IV) questionnaires were used to determine ADHD and ODD severity and a draw-a-person (DAP) test was used to screen for developmental disorders. Associations between behavioural subtypes, psychological functioning, demographic and health variables were investigated. Results: The SNAP-IV caregiver questionnaires showed a 26% prevalence of ADHD inattentive type; 38% hyperactive type and 24% combined type. The prevalence of ODD was 12% on parent questionnaires and 9.5% on teacher s questionnaires. Conclusions: Parents/caregiver-only SNAP-IV questionnaires indicate a high prevalence of significant ADHD (all subtypes) and ODD in HIV-infected children. No significant differences were found between the severity of HIV disease and the presence of a behavioural disorder. The SNAP IV questionnaires and DAP test may prove valuable screening tools in HIV children with behavioural problems. Introduction In 2006, 5.4 million ( million) South Africans, including children aged 0 14 years, were living with human immunodeficiency virus (HIV) infection [1]. Through the reduction in mortality achieved by access to highly active antiretroviral therapy (HAART), increasing numbers of children are reaching school age [2]. There is an increased awareness on the current and future needs of these children beyond HAART. Little is known about the prevalence of behavioural disorders in African children with and without HIV infection. The few published studies documenting the rates of psychiatric and behaviour disorders in perinatally HIV-infected children are from European and North American cohorts. These studies indicate that behavioural disorders are Correspondence: R. van Toorn, Department of Pediatrics and Child Health, Tygerberg children s hospital, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa. Tel.: þ ; Fax: þ <vtoorn@sun.ac.za>. common with anxiety disorder, attention deficit hyperactivity disorder (ADHD), conduct disorder and oppositional defiance disorder (ODD) being the most prevalent [3 5]. ADHD is the most common neurobehavioral disorder of childhood occurring in 5 10% of school age children in developed countries [6]. Less is known about its prevalence among African children, but the few studies conducted report a prevalence ranging from 1 to 6% [7]. The core symptoms of ADHD are inattention, hyperactivity and impulsivity and three subtypes inattention, hyperactive-impulsive and combined have been recognized. Children with ADHD often suffer from co-morbid conditions, such as learning difficulties, conduct, oppositional defiant, mood and anxiety disorders [8]. Children with ODD have persistent or consistent patterns of disobedience and hostility towards parents, teachers or other adults. The community prevalence of ODD ranges from 1 to 10%, depending on which criteria and assessment methods are used [9]. ODD or conduct disorder coexists with ADHD in 35% of children [10]. Parent management training is recommended for families of children with ODD. ß The Author [2009]. Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 97 doi: /tropej/fmp072 Advance Access Published on 5 August 2009

2 The early diagnosis and effective management of behavioural disorders in HIV-infected children is of critical importance since it may pose substantial barriers to optimalizing health care due to a compromised adherence to care and treatment, compromised education and increased high-risk sexual behaviour. In addition, children with ODD and/or ADHD are at significant risk of developing conduct disorders [10]. The aim of this study was to explore the prevalence of ADHD and ODD in HIV-infected South African children attending the infectious disease family clinic at Tygerberg Children s hospital. Materials and Methods Study design and patients The standard assessment of patients at the Family clinic for HIV includes clinical assessment and staging as well as baseline and 6 monthly age-related CD4 values and viral load. Performing behavioural and developmental screening of all children in formal education is practiced at the clinic by general practitioners and specialist paediatricians, but not by neurologists or developmental paediatricians. Parent and teacher Swanson, Nolan and Pelham (SNAP-IV) questionnaires are used to perform behaviour assessments. Although not validated for African children, we have used the SNAP-IV 26 rating in our centre. Translations are available in all three the common languages used in the region. The tool allows for rapid and consistent collection of information. Parents require only 5 10 min, while in the waiting room, to complete the questionnaire. The SNAP-IV is based on a 0 3 rating scale; symptoms are rated by teachers and parents according to intensity (0 ¼ not at all, 1 ¼ just a little, 2 ¼ pretty much and 3 ¼ very much). Subscale scores on the SNAP-IV are calculated by summing the scores on the items in the specific subset (e.g. Inattention) and dividing by the number of items in the subset. Top 5% cut-off norms (above 95th percentile) are known for both parents and teacher forms [11]. A score in top 5% is considered clinically significant for the presence of ADHD and/or ODD [12]. Usually reporting by both parents and teachers are sought. The Goodenough draw-a-person (DAP) test is used as a non-specific screening tool to assess psychological functioning [13]. Although the test was originally conceived as a measure of intelligence, it also assesses sensory defect, visual motor coordination, neurological dysfunction, personality and school readiness [14]. It was chosen because of simplicity of use and short time required for completion. In addition, persons without specific developmental paediatrics training can use it. It has been shown to be highly reliable, valid and is suitable for children from 3 to 10 years of age [4]. The DAP index of psychological functioning (IF) score is determined by the following formula: IF ¼ mental age/true age 100. Studies have shown that children with IF scores <85 are at significantly greater risk of having a developmental disorder including intellectual disability, learning problems, communication disorders and visual-perceptual and perceptualmotor problems than the general population [13]. The medical records of 100 consecutive HIVinfected children in education (5 years) attending the Family Clinic for HIV at Tygerberg Children s Hospital were retrospectively reviewed over a 3-month period from September to December Patients were excluded if a caretaker completed SNAP-IV questionnaire and Goodenough DAP test were not available and where central nervous system compromise was unrelated to HIV disease. Data was collected on parents and teacher SNAP-IV questionnaires, Good-enough-DAP test and predictor variables including demographics, clinical information, immunological status and therapeutic interventions. World Health Organization (WHO) clinical staging was used to determine disease severity and HIV encephalopathy was diagnosed based on Centre for Disease Control (CDC) Revised Criteria. The protocol was approved by the Committee of Human Research, Faculty of Health Sciences, Stellenbosch University. Statistical analysis Statistics reported were primarily descriptive. Data was summarized in frequencies and percentages for categorical variables and means SD for continuous variables. Categorical variables were compared with chi-square and Fisher s exact tests and continuous variables were analysed using the two-sample T-test when there were only two groups and the one-way ANOVA (F-test) when more than two groups were compared. Differences were reported as significant at the 5% level (p < 0.05). Results Completed caretaker SNAP-IV questionnaires and Goodenough DAP test were available for 100 cases whilst completed SNAP-IV questionnaires from teachers where available for only 42 cases. Table 1 illustrates the relevant demographic and caretaker information. There was an even distribution between African (53%) and South African coloured (47%) groups. The parents were the caregivers in 60% of cases; followed by relatives (26%) and 14% of children were in other forms of care including foster care outside the family or institutions. The majority of caregivers were HIV infected (60%) and the majority (72%) have less than high school education. Table 2 illustrates the relevant clinical data. Eighty-four percent of children assessed were on 98 Journal of Tropical Pediatrics Vol. 56, No. 2

3 TABLE 1 Demographic and caretaker information (n ¼ 100) Medium age Years 8 Gender (%) Male 51 Ethnicity (%) Indigenous African 53 South African coloured 47 Caregiver (%) Mother and/or father 60 Relative 26 Adoptive care 14 HIV status of caregiver (%) HIV infected 60 Educational level of caregiver (%) Less than high school 72 Finished high school 24 College graduate 4 Placement (%) Home 4 School 88 Daycare 8 Source of infection (%) Vertical 95 Sexual abuse 1 Unknown 4 Gestational age (%) Preterm 9 Term 91 HAART with a mean time on therapy of 36 months (range 1 48 months) and 20% were on second line regimens. Baseline age-related CD4 values were available in 100% of cases and viral load in all patients while pre-therapy viral load was done in 75% of cases (65 out of 84 children). The majority of children (71%) had clinical WHO stage 3 disease at baseline and 69% had baseline viral loads greater than copies/ml. WHO age-related CD4 values showed that the majority of children had either advanced (16.7%) or severe immune suppression (57.1%) at baseline whilst most recent CD4 values indicated immune recovery in the majority of children. Table 3 illustrates the behavioural and cognitive profile of the children that were assessed. The mean IF of the study population was 87 whilst 49% had an IF <85. Care giver questionnaires showed a high prevalence of all ADHD subtypes with a 26% prevalence of significant ADHD inattentive type; 38% hyperactive type and 24% combined ADHD. In contrast the teacher questionnaires demonstrated a much lower prevalence; 4.7% for both inattentive and hyperactive ADHD and 7.1% for the combined type. With combined assessment of the questioners fewer children were found to have all types of ADHD. The prevalence of significant ODD was 12% on parent questionnaires and 9.5% on teacher s questionnaires. The combined parent-teacher significant ODD prevalence was 2.6% (Table 3). There were no significant differences between any of the behavioural subtype categories and the immune markers (viral load, age-related CD4 values); however, marginal differences existed between ADHD inattentive categories (parent) and recent viral load (p ¼ ), also between ODD (parent) categories and recent CD4% (p ¼ ) children with higher CD4% score at baseline and also children with a recent higher CD4%, tended to have lower ODD scores (parents), however CD4% scores (baseline and recent) had no association with IF scores. The severity of inattentive- and combined- ADHD (according to parental questionnaires) increased with time spend on antiretroviral therapy. Significantly higher ADHD combined and ADHD hyperactive scores (parent questionnaire) were found in males compared with females (p ¼ and p ¼ , respectively). African children had significantly higher ADHD inattentive scores on parent questionnaires compared to coloured children (p ¼ ). Children of HIV positive caregivers had significantly lower ADHD hyperactive scores (p ¼ ) and significantly lower ADHD combined scores (p ¼ ) as well as significantly lower ODD scores (p ¼ ) on the teacher questionnaires when compared with HIV negative caregivers. No differences were found with subgroup analysis regarding type of caregiver, educational level of caregiver, placement of child, gestational age and source of infection. Significantly higher ADHD hyperactive scores (p ¼ ) on the parent questionnaires were found in children without Efavirenz, compared to children receiving Efavirenz. Discussion The aetiology of behavioural disorders in HIVinfected children is likely to be multifactorial [5]. HIV-related brain injury as well as environmental factors such as prenatal drug exposure, difficult family situations, familial genetic factors and poverty, is also important [5]. These are often comorbidities in children with chronic disease [15]. In children on HAART drugs, especially Efavirenz may also affect behaviour [16]. There is a paucity of data on the prevalence of ADHD in HIV-infected children. A review of literature of psychiatric disorders in HIV-infected children found an average prevalence of 28.6% for ADHD [3]. The prevalence of the various types of ADHD as reported by parents in this study is in concordance with reported data [3, 4]. Assessing the effect causality of this increased incidence of ADHD is complex. Heston [17] found that HIV-infected Journal of Tropical Pediatrics Vol. 56, No. 2 99

4 TABLE 2 Health variables and clinical data Antiretroviral therapy (%) On HAART 84 Mean duration of treatment 36 months (18.3 ) On second line therapy 20 On Efavirenz 57 Baseline (mean) Most recent (mean) Viral load (VL) copies/ml ( ) ( ) %(n¼65) % (n ¼ 84) VL VL VL VL > CD4 count cells/mm (343.3) (498.7) CD4 percentage (8.2) (9.7) WHO age related CD4 values % (n ¼ 84) % (n ¼ 100) None Mild Advanced Severe WHO stage of disease % (n ¼ 84) % (n ¼ 100) Stage 1 (Asymptomatic) Stage 2 (Mild) Stage 3 (Advanced) Stage 4 (Severe) TABLE 3 Behavioural and cognitive profile of the children that were assessed children have more psychiatric problems than HIVexposed uninfected children. ADHD subcategory scores were higher in HIV-infected children than uninfected controls, though only inattention severity was significantly different. Nozyce et al. [4] reported the ADHD prevalence rate in HIV infected American children (20%) four times higher compared with the general, non-hiv infected childhood population (3 5%). Contrary to criteria for other diagnoses, the criteria for ADHD require the presence of symptoms in two or more settings, such as school and home [18]. The study was hampered by the lower availability of responses from teachers. In addition, there Caregiver Teacher Combined SNAP IV questionaire scores (>95th percentile) % (n ¼ 100) % (n ¼ 42) % (n ¼ 42) Inattentive ADHD Hyperactive ADHD Combined ADHD Opposition defiance disorder DAP test % (n ¼ 100) Index of psychological functioning (IF) score IF < Medium 87.1 (17.2) were poor levels of agreement between parents/ caregivers and teachers judgements. Teacher s scores were significantly lower than the parents in all subtypes of significant ADHD and ODD. This level of disagreement is not surprising as research has also shown that the degree of agreement between parents and teachers is at best modest for any dimension of psychological development and also dependant on the behavioural dimension being rated [19]. However, given that the expected situational demands are thought to be higher at school it is surprising that the teachers reported fewer problems. This may reflect the differences in attitude, judgements and experiences between the two parties. Other 100 Journal of Tropical Pediatrics Vol. 56, No. 2

5 factors that may have contributed to the variability observed include overcrowded classroom behaviour, the effect of environment and tolerance level of the caretaker and child. Teachers may also be inclined to underreporting if they perceive the child s behaviour as a reflection of their own ability and performance (quality of teaching) in class. In converse, the higher rates of caretaker reporting may indicate reduced tolerance caused by disease and social strain. The present study found that children of HIV positive caregivers had significantly lower ADHD hyperactive scores (p ¼ ) and significantly lower ADHD combined scores (p ¼ ) as well as significantly lower ODD scores (p ¼ ) on the teacher questionnaires when compared with HIV negative caregivers. This may reflect that children living with biological parents where less likely to have ADHD. No significant associations were found between the severity of ADHD subgroup analyses regarding educational level of caregiver, placement of child, gestational age and source of infection and treatment regime. There was, however, a significant association between ADHD hyperactive in the parent questionnaire and Efavirenz (p ¼ ). Among the children who had ADHD hyperactive scores <95 (parent questionnaire), 71.2% were on Efavirenz compared to those children with ADHD scores >95, only 34.4% were on Efavirenz. This indicated that the introduction of Efavirenz led to less hyperactivity without affecting attention. Efavirenz was specifically investigated as it has been reported to affect the central nervous system by causing drowsiness, inattention, sleep disturbance and exacerbation of psychiatric symptoms that may persist years after initiation of therapy [16]. There was no statistically significant differences between caretaker/teacher SNAP-IV ADHD scores (all subtypes) for viral load (baseline and most recent) and age-related CD4 values. This is in concordance with Mellins et al. [20] who found that the severity of HIV disease as measured by the most recent HIV viral load and CD4 number was not related to the presence or absence of a psychiatric disorder. Nozyce et al. similarly found no significant association between CD4 counts and ADHD symptomatology, whilst Jeremy et al. found that baseline viral load not significantly related to behavioural rating by parents [5, 21]. No significant differences was found between the SNAP-IV ODD categories for CD4 percentage at baseline, however marginally significant differences (p ¼ ) was found between the SNAP-IV ODD categories for recent CD4 percentages. Children with lower CD4 percentages at base line also had lower ODD scores. This is not in concordance with a study by Nozyce et al. [5], who found that children with CD4 counts of <660 cells/mm 3 were more likely to be identified as having a conduct disorder however the baseline enrolment age in this study was higher. Misdrahi et al. [22] concluded that that the appearance of a psychiatric complication in children with very low CD4 counts, should be regarded as a factor indicating severe HIV infection. The present study found no significant differences between the index of psychological functioning scores (IF) as estimated by the DAP test and ADHD (all subtypes)/odd scores. However time spend on ARV therapy was significantly higher (p ¼ ) among the ADHD inattentive subgroup. This may be related to the improvement in general health brought about by antiretroviral therapy. ADHD symptoms may have been suppressed in the chronically ill unwell child during the early stages of therapy. Regarding cognition, the study only found marginally significant differences between IF categories in the CD4 count at baseline (p ¼ ) and also in recent CD4 percentages (p ¼ ). However, no significant differences were identified between IF categories for baseline viral load, age-related CD4 values as well as most recent VL. The relationship between plasma viral load and cognitive functioning remains unclear as unequivocal results are reported in the literature [23, 24]. Conclusion Although this study is limited by an absence of normal data for this population and the lack of a control group as well as the lack of validation of the SNAP-IV and is translations in this cohort we believe this to be the first report of the neuropsychiatric disability of HIV-infected children in sub-saharan Africa. The study results indicate a higher prevalence of both ADHD and ODD in HIV-infected children compared with general childhood populations in developing countries and children with other types of chronic illnesses. This hint to the increased needs these children will present to school systems and paediatricians. There is a need to train HIV care providers in the utilization of simplified tools to identify children as well as community programmes to assist and train care takers to improve behaviour and support learning. The fact that the majority of children are functioning within the normal range of the psychological functioning indicates the possibility of rehabilitation with the correct care. References 1. Mid-Year Population Estimates, South Africa 2006 (Statistics South Africa, August 2006). 2. Cohen J, Reddington C, Jacobs D, et al. School-related issues among HIV-infected children. Pediatrics 1997; 100:E8. 3. Scharko AM. DSM psychiatric disorders in the context of pediatric AIDS. 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