Executive Function and Adherence in Children and Adolescents Living with HIV: Evidence from the HIV-associated Neurocognitive Disorders in Zambia (HANDZ) Study.

Introduction: Executive function (EF) may be impaired in people with human immunodeficiency virus (HIV) infection, and poor EF may affect medication adherence. However, there is little data on EF in children with HIV in sub-Saharan Africa. Methods: 208 children/adolescents with perinatally acquired HIV and 208 HIV-exposed uninfected controls were recruited in Zambia for this prospective cohort study. EF was measured using performance-based, self-report, and parental report measures. Adherence over one year of follow-up was assessed through questionnaires and viral load measurement. Results: Children with HIV performed significantly worse on all three measures of EF. Lower parental rating of EF was associated with poorer antiretroviral therapy adherence (OR: 1.5, 95% CI = 1.02 - 2.2, p = 0.04). Conclusion: Children with HIV have EF impairments which may lead to consequences like poor medication adherence and treatment failure. Interventions to improve EF or compensate for impaired EF may be necessary in this population.

Causes of Pediatric Deaths in Lusaka, Zambia: A Quantitative Geographic Information Systems Approach.

Background: While childhood mortality has been declining in Zambia, it remains high at 58 per 1000 live births. Importantly, many leading causes of mortality in Zambia are preventable. This study was conducted to identify clusters of childhood mortality, causes of death of recently deceased children, barriers to care, and risk factors for mortality in Lusaka, Zambia. Methods: This study was conducted as a prospective cohort study. Family members or lawfully authorized representatives (LARs) were interviewed when they came to pick up death certificates for recently deceased children from Lusaka Children's Hospital. Each interview included a verbal autopsy, determination of the child's location of residence, and collection of demographic information. Demographic data was also collected from a healthy control group. Quantitative Geographic Information Systems was used to visualize mortality and evaluate for clustering. Results: Leading primary causes of death included malnutrition (21%), complications of chronic illnesses (16%), and central nervous system infections (13%), while the leading barriers to care were cost (58%) and difficulties with travel (53%). Compared to controls, recently deceased children came from families with significantly lower incomes (1905 Kwacha vs. 2412 Kwacha, p = 0.03) and were significantly more likely to have a history of malnutrition (16.7% vs. 1.4%, p = 0.005). Mortality was clustered in two high-population density, low-income neighborhoods in Lusaka. Conclusions: Systems to reduce financial barriers to care and improve access to transportation could reduce childhood mortality in Lusaka. The aforementioned neighborhoods are ideal locations for public health interventions or improved healthcare services.

Adherence, Adverse Events and Viral Control among Children and Adolescents with HIV in Zambia Switched to an Integrase Inhibitor Regimen.

Background: Based on recent World Health Organization recommendations, there has been a large-scale transition in Sub-Saharan Africa to integrase inhibitor (II)-based antiretroviral therapy (ART) regimens. Setting: This study was conducted at an urban referral center in Lusaka, Zambia. Methods: This study included 297 children and adolescents with HIV (CAWH) on ART for one year prior to enrollment and followed for 1-4 years after enrollment. ART adherence, ART regimen, and viral load were assessed periodically. Structured interviews were conducted with a subset of 95 children to assess adherence barriers and side effects. Results: Children on protease inhibitor (PI)-based regimens were more likely to report adherence problems than children taking II- or Efavirenz-based regimens (10% vs. 28%, p=0.03) and noted more days with missed doses (median 1 vs. 0, p=0.02). In interviews, the most common reasons given for poor adherence included bad medication taste, not being home when medications were due, and perceived side effects. The PI group was more likely to report that taste was a problem affecting adherence (22% vs. 4%, p=0.05) and headache as an ART side effect (17% vs. 4%, p=0.05). Switching from a PI- to an II-based regimen was associated with improved adherence (72% vs. 92%, p=0.01) and an undetectable viral load (67% vs. 78%). Conclusions: Switching CAWH from PI-based to II-based regimens has many advantages including superior side effect profiles, adherence, and viral suppression. PI taste aversion may be a significant contributor to pediatric adherence issues. Palatability should be considered in pediatric HIV drug development.

Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.

OBJECTIVE: KCNT1-related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep-related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug-resistant seizures and global developmental delays. In addition to conventional anti-seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD-including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients. METHODS: We performed a literature review on PubMed and EMBase with the keyword "KCNT1" and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype. RESULTS: A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%-25% of patients). SIGNIFICANCE: Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug-resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1-related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors. PLAIN LANGUAGE SUMMARY: We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti-seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

Brain Imaging in New-Onset Seizure of Children Living With Human Immunodeficiency Virus in Zambia.

BACKGROUND: There are an estimated 1.5 million children living with human immunodeficiency virus (CLHIV), most residing in sub-Saharan Africa. A common hospital presentation of CLHIV is new-onset seizure, for which imaging is helpful but not routinely performed due to scarce resources. We present imaging findings and their association with clinical risk factors and outcomes in a cohort of Zambian CLHIV presenting with new-onset seizure. METHODS: In this prospective cohort study, participants were recruited at the University Teaching Hospital in Lusaka, Zambia. Various clinical and demographic characteristics were obtained. Computed tomography (CT), magnetic resonance imaging (MRI), or both were obtained during admission or shortly after discharge. If both studies were available, MRI data was used. Two neuroradiologists interpreted images using REDCap-based NeuroInterp, a tool that quantifies brain imaging findings. Age-dependent neuropsychologic assessments were administered. RESULTS: Nineteen of 39 (49%) children had a brain MRI, 16 of 39 (41%) had CT, and four of 39 (10%) had both. Mean age was 6.8 years (S.D. = 4.8). Children with advanced HIV disease had higher odds of atrophy (odds ration [OR] 7.2, 95% confidence interval [CI] 1.1 to 48.3). Focal abnormalities were less likely in children receiving antiretroviral therapy (ART) (OR 0.22, 95% CI 0.05 to 1.0). Children with neurocognitive impairment were more likely to have atrophy (OR 8.4, 95% CI 1.3 to 55.4) and less likely to have focal abnormalities (OR 0.2, 95% CI 0.03 to 0.9). CONCLUSIONS: Focal brain abnormalities on MRI were less likely in CLHIV on ART. Brain atrophy was the most common imaging abnormality, which was linked to severe neurocognitive impairment.

Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder.

BACKGROUND: ZC4H2-associated rare disorder (ZARD) is caused by pathogenic variations in the ZC4H2 gene on the X chromosome. This gene codes for a zinc finger protein involved in neural development. ZARD is characterized by highly variable symptoms, potentially influenced by the sex of the individual. METHODS: The ZC4H2-Associated Rare Disorder Natural History Study is a prospective natural history study conducted among individuals with ZARD that consists of standardized interviews, developmental assessments, and neurological examinations conducted every six months for two years. In this article, we present data from baseline visits with 40 participants, the largest ZARD cohort studied thus far, focusing on genotype-phenotype correlations and sex differences. Fisher exact, maximum likelihood χ2, and Mann-Whitney tests were utilized. RESULTS: Males tended to have maternally inherited ZC4H2 pathogenic variations, whereas females tended to have de novo variations (P < 0.001). Female participants were more likely to have contractures at birth (P < 0.01), arthrogryposis multiplex congenita (P < 0.001), spasticity on examination (P < 0.1), and lower limb muscle atrophy (P < 0.05). Male participants were more likely to have seizures (P < 0.1), intermittent pain (P < 0.01), severe vision impairment (P < 0.05), dysphagia for solids (P < 0.01), and generalized muscle atrophy (P < 0.05). CONCLUSIONS: Our study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. Further analysis is needed to better understand how pathogenic variation type affects phenotype.

Long-term outcomes after new onset seizure in children living with HIV: A cohort study.

OBJECTIVE: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure. METHODS: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality. RESULTS: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence. SIGNIFICANCE: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures. PLAIN LANGUAGE SUMMARY: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures.

Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case-Control Study.

BACKGROUND: Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS: We conducted a prospective, unmatched case-control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12-60 months or a CD4 count >350 cells/mm 3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures. RESULTS: We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm 3 (OR 3.6, P < 0.001) increased risk of seizures. CONCLUSIONS: Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV.

Genetic Neuromuscular Disorders and Health Services Access, Utilization, and Needs in Zambia.

BACKGROUND: Medical and rehabilitative advances increasingly transform management of rare genetic neuromuscular diseases (GNMDs) for children in the global north. Lack of information about GNMDs and related health care needs in sub-Saharan Africa threatens to widen pre-existing health disparities. METHODS: This is a cross-sectional study of probands enrolling in a study of GNMDs at the University Teaching Hospital in Lusaka, Zambia, a member of the International Consortium for Genomic Medicine in Neuromuscular Disease. Probands/caregivers were interviewed about utilization of medical, rehabilitative, and other support services by a research assistant. A neuromuscular neurologist and/or physiotherapist examined each case and completed an independent questionnaire regarding health service utilization for each proband. Diagnoses were made on available clinical and electrophysiologic data. Molecular findings were unavailable at the time of this analysis. RESULTS: Among 50 probands, 52% were male with median age 12 (absolute range 2 months to 54 years). Motor neuron diseases (n = 16; 32%), muscle disorders (n = 20; 40%), and inherited polyneuropathies (n = 5; 10%) were most common. Six (15%) cases had insufficient clinical data to classify the GNMDs. Outside of primary care, patient/caregiver-reported access to recommended health services (n = 34; 69%) was challenging. Large disparities in current utilization of health care services versus clinician-recommended services are reported. CONCLUSIONS: Paradigms to improve access to diagnostics and therapeutic interventions are needed for GNMDs in Zambia. Multidisciplinary clinics may improve access and utilization of needed health services. Qualitative and other research focused on improving referrals, access, and quality of available health services are greatly needed.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Designing an Observing System to Study the Surface Biology and Geology (SBG) of the Earth in the 2020s.

Observations of planet Earth from space are a critical resource for science and society. Satellite measurements represent very large investments and United States (US) agencies organize their effort to maximize the return on that investment. The US National Research Council conducts a survey of Earth science and applications to prioritize observations for the coming decade. The most recent survey prioritized a visible to shortwave infrared imaging spectrometer and a multispectral thermal infrared imager to meet a range of needs for studying Surface Biology and Geology (SBG). SBG will be the premier integrated observatory for observing the emerging impacts of climate change by characterizing the diversity of plant life and resolving chemical and physiological signatures. It will address wildfire risk, behavior, and recovery as well as responses to hazards such as oil spills, toxic minerals in minelands, harmful algal blooms, landslides, and other geological hazards. The SBG team analyzed needed instrument characteristics (spatial, temporal, and spectral resolutions, measurement uncertainty) and assessed the cost, mass, power, volume, and risk of different architectures. We present an overview of the Research and Applications trade-study analysis of algorithms, calibration and validation needs, and societal applications with specifics of substudies detailed in other articles in this special collection. We provide a value framework to converge from hundreds down to three candidate architectures recommended for development. The analysis identified valuable opportunities for international collaboration to increase the revisit frequency, adding value for all partners, leading to a clear measurement strategy for an observing system architecture.

Patient, Provider, and Health Systems Factors Leading to Lumbar Puncture Nonperformance in Zambia: A Qualitative Investigation of the "Tap Gap".

Lumbar puncture (LP) and cerebrospinal fluid (CSF) diagnostics are critical for evaluating central nervous system infections but are often not conducted, resulting in the "Tap Gap." To investigate patient, provider, and health systems factors contributing to the Tap Gap in Zambia, we conducted focus group discussions with adult caregivers of hospitalized inpatients and in-depth interviews with nurses, clinicians, pharmacy workers, and laboratory staff. Transcripts were independently thematically categorized by two investigators using inductive coding. We identified seven patient-related factors: 1) alternative understandings of CSF; 2) alternative information about LPs, including misinformation; 3) mistrust of doctors; 4) consent delays; 5) fear of blame; 6) peer pressure against consent; and 7) association between LP and stigmatized conditions. Four clinician-related factors were identified: 1) limited LP knowledge and expertise, 2) time constraints, 3) delays in LP requests by clinicians, and 4) fear of blame for bad outcomes. Finally, five health systems-related factors were identified: 1) supply shortages, 2) constrained access to neuroimaging, 3) laboratory factors, 4) availability of antimicrobial medications, and 5) cost barriers. Efforts to improve LP uptake must incorporate interventions to increase patient/proxy willingness to consent and improve clinician LP competencies while addressing both upstream and downstream health system factors. Key upstream factors include inconsistently available consumables for performing LPs and lack of neuroimaging. Critical downstream factors include laboratory services that offer poor availability, reliability, and/or timeliness of CSF diagnostics and the reality that medications needed to treat diagnosed infections are often unavailable unless the family has resources to purchase privately.

Consensus Competencies for Postgraduate Fellowship Training in Global Neurology.

BACKGROUND AND OBJECTIVES: Use a modified Delphi approach to develop competencies for neurologists completing ≥1 year of advanced global neurology training. METHODS: An expert panel of 19 United States-based neurologists involved in global health was recruited from the American Academy of Neurology Global Health Section and the American Neurological Association International Outreach Committee. An extensive list of global health competencies was generated from review of global health curricula and adapted for global neurology training. Using a modified Delphi method, United States-based neurologists participated in 3 rounds of voting on a survey with potential competencies rated on a 4-point Likert scale. A final group discussion was held to reach consensus. Proposed competencies were then subjected to a formal review from a group of 7 neurologists from low- and middle-income countries (LMICs) with experience working with neurology trainees from high-income countries (HICs) who commented on potential gaps, feasibility, and local implementation challenges of the proposed competencies. This feedback was used to modify and finalize competencies. RESULTS: Three rounds of surveys, a conference call with United States-based experts, and a semistructured questionnaire and focus group discussion with LMIC experts were used to discuss and reach consensus on the final competencies. This resulted in a competency framework consisting of 47 competencies across 8 domains: (1) cultural context, social determinants of health and access to care; (2) clinical and teaching skills and neurologic medical knowledge; (3) team-based practice; (4) developing global neurology partnerships; (5) ethics; (6) approach to clinical care; (7) community neurologic health; (8) health care systems and multinational health care organizations. DISCUSSION: These proposed competencies can serve as a foundation on which future global neurology training programs can be built and trainees evaluated. It may also serve as a model for global health training programs in other medical specialties as well as a framework to expand the number of neurologists from HICs trained in global neurology.

Longitudinal Cognitive Outcomes in Children With HIV in Zambia: 2-Year Outcomes From the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) Study.

OBJECTIVE: To describe longitudinal outcomes and predictors of cognitive outcomes in children with HIV in Zambia. BACKGROUND: Multiple studies have shown that children with HIV are at risk for impaired cognition. However, there are limited data on longitudinal cognitive outcomes in children with HIV. METHODS: We conducted a prospective cohort study of 208 perinatally infected children with HIV ages 8-17 years, all treated with antiretroviral therapy, and 208 HIV-exposed uninfected controls. Participants were followed for 2 years. Cognition was assessed with a custom NIH Toolbox Cognition Battery, and tests were combined to generate a Summary Cognition Score (SCS). The contribution of potential risk factors to outcomes was explored using regression models and group-based trajectory modeling. RESULTS: HIV was strongly associated with lower SCS at baseline [ß-14, 95% confidence interval (CI): -20 to -7, P < 0.001]. Change scores over time were similar between groups, but poorer average performance in children with HIV persisted at the 2-year follow-up visit (adjusted ß = -11, 95% CI: -22 to -0.3, P = 0.04). Other than HIV, the strongest predictors of baseline SCS included socioeconomic status index (ß =3, 95% CI: 1, 5, P = 0.004), history of growth stunting (ß=-14, 95% CI: -23 to -6, P = 0.001), history of CD4 count below 200 (ß = -19, 95% CI: -35 to -2, P = 0.02), and history of World Health Organization stage 4 disease (ß = -10, 95% CI: -19 to -0.2, P = 0.04). In the group-based trajectory model, HIV+ status predicted membership in the lowest performing trajectory group (odds ratio 2.5, 95% CI: 1.2 to 5.1, P = 0.01). CONCLUSIONS: Children with HIV are at risk of poor cognitive outcomes, despite chronic treatment with antiretroviral therapy.

Validation of the National Institute of Health Toolbox Cognition Battery (NIHTB-CB) in Children and Adolescents with and without HIV Infection in Lusaka, Zambia.

The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambian children with and without HIV-infection. Children living with HIV and HIV-exposed, uninfected (HEU) children completed traditional neuropsychological and NIHTB-CB tasks. Using pairwise correlation and a linear regression model we measured associations between traditional measure composite scores and parental ratings of children's abilities, and NIHTB-CB scores. A Receiver Operating Characteristic (ROC) curve was developed to identify participants with impairment. 389 children, 8-17 years old participated. NIHTB-CB and traditional measures converged well as a whole and when comparing analogous individual tests across the two batteries. The NIHTB-CB composite score discriminated between the groups and was positively associated with external criteria for cognitive function: parental ratings of intelligence and school performance. Some English vocabulary and/or an unfamiliar cultural context presented challenges. NIHTB-CB was associated with children's everyday cognitive abilities, though future use may require linguistic and cultural adaptation.

Clinical characteristics and outcomes after new-onset seizure among Zambian children with HIV during the antiretroviral therapy era.

OBJECTIVE: This study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new-onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30-day mortality and cause of death are also reported. METHODS: Children living with HIV (CLWHIV) with new-onset seizures were prospectively evaluated at one large urban teaching hospital and two non-urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed. RESULTS: From April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2-10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presenting with multiple recurrent seizures in the 24 hours before admission or in status epilepticus. Although 36 (49%) were on ART at enrollment, only 7 of 36 (19%) were virally suppressed. Seizure etiologies were infectious in over half (54%), with HIV encephalitis, bacterial meningitis, and tuberculous meningitis being the most common. Metabolic causes (19%) included renal failure and hypoglycemia. Structural lesions identified on imaging accounted for 10% of etiologies and included stroke and non-accidental trauma. No etiology could be identified in 12 (16%) children, most of whom died before the completion of clinical investigations. Twenty-two (30%) children died within 30 days of the index seizure. SIGNIFICANCE: Despite widespread ART roll out in Zambia, new-onset seizure in CLWHIV occurs in the setting of advanced, active HIV disease. Seizure severity/burden is high as is early mortality. Enhanced programs to assure early ART initiation, improve adherence, and address ART failure are needed to reduce the burden of neurological injury and premature death in CLWHIV.

Compassionate-use pocapavir and immunoglobulin therapy for treatment of rituximab-associated enterovirus meningoencephalitis.

A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 years of progressive neurologic symptoms. She was found to have persistent hypogammaglobulinemia and B cell depletion despite rituximab discontinuation a year prior. MRI revealed diffuse meningeal enhancement along the entire neuroaxis. LP showed a CSF lymphocytic pleocytosis, elevated protein, and presence of enterovirus by PCR. The patient was hospitalized several times for progressive clinical and radiologic decline, though she had transient improvements following treatment with immunoglobulin therapy. Her CSF remained positive for enterovirus PCR for at least 12 months. Though two brain biopsies were non-diagnostic, pan-Enterovirus was ultimately identified using a high-throughput next-generation sequencing technique. She was treated with compassionate-use pocapavir with clinical stabilization at 4-month follow-up; however, she expired 8 months later from a bacterial pneumonia.

Socioeconomic Status and Cognitive Function in Children With HIV: Evidence From the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) Study.

BACKGROUND: Multiple previous studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance and may affect the relationship between HIV and cognition. METHODS: As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8-17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic regression and linear regression were used to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition. RESULTS: Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score -0.19 vs. 0.22, P < 0.001) and were more likely to have cognitive impairment (33% vs. 19%, P = 0.001). Higher SES was associated with reduced risk of cognitive impairment (odds ratio 0.8, 95% confidence interval: 0.75-0.92, P < 0.001) in both groups, with similar effects in children with HIV and HIV-exposed uninfected groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson's R 0.39 vs. 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition. CONCLUSIONS: Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.