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Epilepsy is a neurologic disorder that results in recurrent, unprovoked seizures. The biomedical burden of epilepsy can be substantial, but for many the social consequences may be just as extreme, with epilepsy victims suffering from social abandonment as well as economic and physical vulnerabilities. Since its founding in 2000, the Chikankata Epilepsy Care Team, a collaborative project between Michigan State University and the rural Zambian community of Chikankata, has worked to improve the lives of people with epilepsy. What began as a local nurse-medical student partnership in one small rural Zambian hospital has grown into a program that supports and enriches clinical services and advocacy programs throughout Zambia. Recognizing the imperative for knowledge to influence policy, this university-community partnership works tirelessly to inform key stakeholders and policy makers of its findings. The program received the 2011 Outreach Scholarship/W. K. Kellogg Foundation Engagement Award for the North Central region.

Background: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. Methods: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. Discussion: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments. [ABSTRACT FROM AUTHOR]

Background Meningitis causes significant mortality in regions with high comorbid HIV and TB. Improved outcomes are hindered by limited understanding of factors that delay adequate care. Methods In-depth interviews of patients admitted to the University Teaching Hospital with suspected meningitis, their caregivers, doctors and nurses were conducted. Patient/caregiver interviews explored meningitis understanding, treatment prior to admission and experiences since admission. Provider interviews addressed current and prior experiences with meningitis patients and hospital barriers to care. A conceptual framework based on the Three Delays Model identified factors that delayed care. Results Twenty-six patient/caregiver, eight doctor and eight nurse interviews occurred. Four delays were identified: in-home care; transportation to a health facility; clinic/first-level hospital care; and third-level hospital. Overcrowding and costly diagnostic testing delayed outpatient care; 23% of patients began with treatment inside the home due to prior negative experiences with biomedical care. Admission occurred after multiple clinic visits, where subsequent delays occurred during testing and treatment. Conclusions Delays in care from home to hospital impair quality meningitis care in Zambia. Interventions to improve outcomes must address patient, community and health systems factors. Patient/caregiver education regarding signs of meningitis and indications for care-seeking are warranted to reduce treatment delays. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Uptake of lumbar puncture (LP) remains low in regions with a high prevalence of central nervous system (CNS) infections like Zambia. Efforts to improve uptake are hindered by limited understanding of factors influencing LP uptake. Methods Semistructured qualitative interviews were conducted with patients with suspected CNS infection, caregivers, doctors and nurses at the University Teaching Hospitals in 2016. Questions focused on LP experiences, knowledge, the consent process and health system barriers to LP among patients with an LP indication. Interviews were transcribed, translated to English and analysed using a thematic approach. Results We recruited 24 adult patients, 36 caregivers of adult patients, 63 caregivers of paediatric patients, 20 doctors and 30 nurses (173 in total). LP barriers arose from both patients/caregivers and health providers and included community apprehension about LP, proxy (family) consensus consent practices, competing clinical demands, wariness of patient/caregiver responses, limitations in consumables and time to complete the LP. This could result in consent not being obtained correctly. LP enablers included patient/caregiver perceived LP utility, provider comfort with LP and in-person counselling. Conclusions LP uptake is a complex sociocultural process influenced by patient, healthcare and community-level factors. Interventions to improve uptake must address multiple barriers to be successful. [ABSTRACT FROM AUTHOR]

Background Place-based inequalities, such as exposure to violence and access to nutritious food and clean water, may contribute to human immunodeficiency virus (HIV)-associated cognitive impairment. In this study, we investigated neighborhood effects on cognition in children and adolescents with HIV in Lusaka, Zambia. Methods We conducted a prospective cohort study of 208 children with perinatally acquired HIV (ages 8–17) and 208 HIV-exposed uninfected controls. Participants underwent neuropsychological testing and interviews assessing socioeconomic status. Geographic regions with clusters of participants with HIV and cognitive impairment were identified using quantitative geographic information systems (QGIS) and SaTScan. Associations between location of residence and cognitive function were evaluated in bivariable and multivariable regression models. Mediation analysis was performed to assess direct and indirect effects of location of the residence on cognitive impairment. Results Residence in Chawama, one of the poorest neighborhoods in Lusaka, was significantly associated with cognitive impairment in participants with HIV (odds ratio 2.9; P  = .005) and remained significant in a multivariable regression model controlling for potential confounders. Mediation analysis found that 46% of the cognitive effects of residence in Chawama were explained by higher rates of malnutrition, lower school attendance, and poorer self-reported health. Conclusions Place-based socioeconomic inequality contributes to cognitive impairment in Zambian children and adolescents with HIV. Neighborhood effects may be mediated by concentrated poverty, malnutrition, limited access to education and health care, and other yet unknown environmental factors that may be potentially modifiable. [ABSTRACT FROM AUTHOR]

Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8–17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2–7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18–15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies. [ABSTRACT FROM AUTHOR]

Objective: Interactions between enzyme‐inducing anti‐seizure medications (EI‐ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co‐usage of ARVs and EI‐ASMs is associated with ARV‐resistant human immunodeficiency virus (HIV) among people living with HIV in Zambia. Methods: Eligible participants were ≥18 years of age and concurrently taking ASMs and ARVs for at least 1 month of the prior 6‐month period. Data were obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVLs), and HIV genotype and resistance profile in participants with a pVL >1000 copies/mL were obtained. Pearson's test of independence was used to determine whether treatment with EI‐ASM was associated with pVL >1000/mL copies. Results: Of 50 participants, 41 (82%) were taking carbamazepine (37 on monotherapy), and all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a tenofovir/lamivudine backbone. The majority (94%) were on a stable ARV regimen for >6 months. Median CD4 nadir was 205 cells/mm3 (interquartile range [IQR] 88‐389), and 60% of participants had commenced ARV treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm3 (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm3. Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm3. None had documented adherence concerns by providers; however, two had events concerning for clinical failure. HIV genotype testing showed mutations in three participants. Carbamazepine was not found to correlate with elevated pVL (P =.58). Significance: EI‐ASMs are commonly used in sub‐Saharan Africa. Despite concurrent use of EI‐ASMs and ARVs, the majority of participants showed CD4 counts >200 cells/mm3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV‐resistant HIV. [ABSTRACT FROM AUTHOR]

Summary: Objective: Despite the heavy burden of epilepsy in Sub‐Saharan Africa, there remains a relative paucity of neurophysiology services and limited published data on electroencephalography (EEG) features among African children. The aim of this study was to describe clinical characteristics, EEG findings, and antiepileptic drug (AED) use among children referred for EEG to the University Teaching Hospital in Zambia. Methods: EEG referrals and reports from 2013–2015 were reviewed. Within the context of routine care, EEG studies were interpreted by readers with advanced training in child neurology and clinical neurophysiology. Clinical data provided in the referral including seizure semiology and EEG findings were systematically extracted and analyzed. Results: A total of 1,217 EEG reports were reviewed, with 1,187 included in the analysis. Median age was 7 years (interquartile range [IQR] 3–11) and 57% were male. Seventy‐three percent of 554 had documented seizure onset before 5 years of age. Among the 23% with seizure etiology documented, 78% were associated with perinatal injuries and central nervous system (CNS) infections. EEG abnormalities were found in 75% of the studies. Clinical semiology per referral identified focal seizures in 29%, but EEG findings increased this proportion to 63% (p = 0.004). Sixty‐two percent were taking AEDs, with 85% on monotherapy. The most commonly used AED was carbamazepine (49%).There was no association between the choice of AED and clinical semiology (all p's > 0.05). Significance: This tertiary care center study identified >60% of referred children to have localization‐related epilepsies, with at least 18% of epilepsies being from potentially preventable causes. These findings are consistent with multi‐country, population‐based data from elsewhere in Africa. Seizure semiology assessed in routine, nonspecialist care does not predict AED choice, and the presence of focality is underestimated in routine care. [ABSTRACT FROM AUTHOR]

Purpose: Epilepsy-associated stigma is an important patient-centered outcome, yet quantification remains challenging. Jacoby's 3-item Stigma Scale is commonly used to assess felt stigma among people with epilepsy (PWE) yet has ceiling effects. The Stigma Scale of Epilepsy (SSE) is a 24-item instrument that measures felt stigma among PWE and stigmatizing attitudes among others. If cross-culturally valid, the SSE may elucidate stigma determinants and provide an outcome measure for interventions. Methods: We assessed the properties of the SSE in 102 Zambian PWE using exploratory and confirmatory item response theories and compared the latent traits assessed by the SSE to those assessed by Jacoby's Stigma Scale. Differential item functioning based on forced disclosure of epilepsy was examined. Results: The SSE yielded two latent traits-the first reflected difficulties faced by PWE; the second reflected emotions associated with epilepsy. Jacoby's Stigma Scale was associated only with the first latent trait. Forced disclosure was associated with 'worry' and 'pity' that were associated with the second latent trait. Conclusions: In Zambian PWE, the SSE captured two latent traits. One trait represents feelings associated with epilepsy, which is theorized as a substantial yet unmeasured part of stigma. The SSE performs well across cultures and may more comprehensively assess felt stigma than other instruments. Further validation is required to determine whether the SSE adequately assesses stigmatizing attitudes among people without epilepsy. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Validation of the National Institute of Health Toolbox Cognition Battery (NIHTB‑CB) in Children and Adolescents with and without HIV Infection in Lusaka, Zambia" which appeared in the previous issue of the periodical.

Background: Three headache disorders - migraine, tension-type headache (TTH) and medication-overuse headache (MOH) - are major contributors to population ill-health. Policy-makers need local knowledge of these to guide priority-setting. Earlier we reported the prevalence of these disorders in Zambia; here we describe the burdens attributable to them. Methods: This was a cross-sectional population-based survey of adults aged 18-65 years, selected by cluster-randomized sampling in the mostly urban Lusaka Province and mostly rural Southern Province. Interviewers visiting households used a structured questionnaire. Diagnoses made algorithmically applied ICHD-II criteria. Burden enquiry focused on the previous 3 months and the day before interview. Disability was estimated by applying disability weights (DWs) from the Global Burden of Disease Survey 2010. Results: From 1,134 households, 1,085 unrelated adults (450 male, 635 female) were interviewed (refusal rate 4.3%). The gender- and habitation-adjusted 1-year prevalence of migraine was 22.9%, of TTH 22.8%, of headache on =15 days/month 11.5%, of probable MOH (pMOH) 7.1%. Reported mean intensity of migraine attacks was 2.7, representing severe pain. People with migraine spent 10.0% of their time in the ictal state (DW: 0.433); they were therefore 4.3% disabled overall. Disability from TTH was much lower. People with pMOH (time with headache: 37.5%; DW: 0.220) were 8.3% disabled overall. Average lost productive time in the preceding 3 months for migraine was 4.1 days from work (6.3% loss) and 4.2 days (4.7% loss) from household work. Losses for pMOH were 4.8 days (7.4% loss) from work and 4.5 days (5.0% loss) from household work. In the population aged 18-65 years (effectively the working population), estimated disability from migraine was 0.98%, with 1.4% of workdays lost, and from pMOH was 0.59%, with 0.53% of workdays lost. Headache yesterday was reported by 28.3% of participants, whose average productivity yesterday was 55.9% of expectation. Conclusions: Zambia loses 1.93% of GDP to headache, and action is required to mitigate this loss and the associated suffering. Structured headache services with their basis in primary care are the most efficient, effective, affordable and equitable solution. They could be implemented within the existing health-care infrastructure of Zambia. These matters require urgent political attention. [ABSTRACT FROM AUTHOR]

Background: Little is known of the epidemiology of primary headache disorders in sub-Saharan Africa. We performed a population-based survey in Zambia using methods previously tested in multiple other countries. Methods: This cross-sectional survey was conducted by visiting households unannounced, using cluster-randomized sampling, in the mostly urban Lusaka Province and mostly rural Southern Province. Within clusters, households were selected randomly, as was one adult member (18-65 years old) of each selected household. A structured questionnaire, translated into the local languages, was administered face-to-face by trained interviewers. Demographic enquiry was followed by diagnostic questions based on ICHD-II criteria. A random sub-sample of participants were invited for subsequent physician-interview to validate the diagnostic part of the questionnaire. Results: Of 1,134 eligible household members contacted, 1,085 (450 male, 887 urban) consented to interview (refusal rate 4.3%). Others who had been selected but remained unavailable on three visits were not counted as refusals since their reasons were unknown, but gave rise to gender biases, being mostly male in urban areas and mostly female in rural areas. Statistical correction was applied. Adjusted for gender and habitation (urban/rural), the 1-year prevalence of any headache was 61.6%, of migraine 22.9%, of tension-type headache (TTH) 22.8%, of headache on =15 days/month 11.5% and of probable medication-overuse headache (pMOH) 7.1%. The adjusted point-prevalence of any headache (headache yesterday) was 19.1%. There was a small proportion (5.3%) of unclassified headache, some of which may have been secondary. The overwhelmingly strong association was between urban dwelling and pMOH (OR: 8.6; P=0.0001), with an urban prevalence of 14.5% (gender-adjusted). Validation of the questionnaire was limited by participants' reluctance to present for physician review, substantial delays in doing so and major self-selection bias among those who did. These were unavoidable problems in resource-limited Zambia. Conclusions: Primary headache disorders, common in high-income countries, are at least as prevalent in Zambia, a sub-Saharan African country. The selectively urban problem of pMOH seems likely to reflect ready availability of non-prescription analgesics, without easy access to professional health care for headache or any focused public-health education regarding correct usage of analgesics or the dangers of their overuse. [ABSTRACT FROM AUTHOR]

Background Epilepsy-associated stigma contributes substantially to the social, medical, and economic burden of disease for people with epilepsy (PWE), but little is known about its impact on caregivers of PWE. Methods To better understand stigma experienced by caregivers of PWE, factors that influence caregiver stigma, and the effect of stigma on a caregiver's psychologic well being, we interviewed 100 caregivers of children with epilepsy in Zambia. Questions assessed maternal knowledge, attitudes, and practices related to epilepsy, maternal stigma, mother's proxy report of child stigma, and maternal psychiatric morbidity. Results Of 100 mothers, 39 (39%) indicated that their child was stigmatized because of his or her epilepsy. Maternal proxy report of child stigma was highly correlated with maternal stigma (OR: 5.4, p=0.04), seizure frequency (p=0.03) and seizure severity (p=0.01). One in five of 100 mothers (20%) reported feeling stigmatized because of their child's epilepsy. Higher maternal stigma was associated with lower familial and community support (ORs: 65.2 and 34.7, respectively; both p<0.0001) as well as higher psychiatric morbidity (OR: 1.2; p=0.002). Formal education and epilepsy knowledge were associated with decreased maternal stigma (ORs: 0.8 and 0.7, respectively; both p<0.001). Conclusions One in five mothers of PWE feel stigmatized because of their child's epilepsy. As maternal stigma is associated with psychiatric morbidity, educating caregivers about epilepsy and screening for anxiety and depression are warranted. [ABSTRACT FROM PUBLISHER]

Summary: Background: Among the 40 million people with epilepsy worldwide, 80% reside in low-income regions where human and technological resources for care are extremely limited. Qualitative and experiential reports indicate that people with epilepsy in Africa are also disadvantaged socially and economically, but few quantitative systematic data are available. We sought to assess the social and economic effect of living with epilepsy in sub-Saharan Africa. Methods: We did a cross-sectional study of people with epilepsy concurrently matched for age, sex, and site of care to individuals with a non-stigmatised chronic medical condition. Verbally administered questionnaires provided comparison data for demographic characteristics, education, employment status, housing and environment quality, food security, healthcare use, personal safety, and perceived stigma. Findings: People with epilepsy had higher mean perceived stigma scores (1·8 vs 0·4; p<0·0001), poorer employment status (p=0·0001), and less education (7·1 vs 9·4 years; p<0·0001) than did the comparison group. People with epilepsy also had less education than their nearest-age same sex sibling (7·1 vs 9·1 years; p<0·0001), whereas the comparison group did not (9·4 vs 9·6 years; p=0·42). Housing and environmental quality were poorer for people with epilepsy, who had little access to water, were unlikely to have electricity in their home (19%vs 51%; p<0·0001), and who had greater food insecurity than did the control group. During pregnancy, women with epilepsy were more likely to deliver at home rather than in a hospital or clinic (40%vs 15%; p=0·0007). Personal safety for people with epilepsy was also more problematic; rape rates were 20% among women with epilepsy vs 3% in the control group (p=0·004). Interpretation: People with epilepsy in Zambia have substantially poorer social and economic status than do their peers with non-stigmatised chronic medical conditions. Suboptimum housing quality differentially exposes these individuals to the risk of burns and drowning during a seizure. Vulnerability to physical violence is extreme, especially for women with epilepsy. [Copyright &y& Elsevier]

Objectives: To identify people with epilepsy (PWE) in our Zambian catchment area of 55,000 people.Methods: A nine-item, previously validated screening instrument for detecting epilepsy in developing countries was forward-and-back translated into Chitonga. Early piloting indicated poor specificity among children, so three questions were added. Local census data were used to estimate the population at risk. Community health workers conducted screening interviews with household heads. All positive screens were referred for physician assessment. A blinded neurologist assessed a randomly selected subset (100 positives, 50 negatives) to determine screening instrument characteristics.Results: We identified 799 people with possible epilepsy (unadjusted prevalence 14.5/1000). The adapted instrument exhibited 86% specificity (adjusted prevalence 12.5/1000). False positives occurred primarily among children who had experienced multiple malaria-associated seizures. Age-specific rates were highest for children aged 5-15 years (26.2/1000) and for people over 65 years (15.9/1000). Males were disproportionately represented (55.8%vs. 44.2%, P<0.05), although this trend reversed after childbearing age.Conclusion: Even using a relatively conservative definition, we identified almost 700 PWE. Use of the recommended epidemiological definitions would likely have yielded higher prevalence rates. The age-specific prevalence did not follow patterns described where neurocysticercosis is the commonest cause of epilepsy. Trends in age- and gender-specific prevalence may offer a clue to the aetiology of epilepsy in this region. [ABSTRACT FROM AUTHOR]

Those uninitiated to medicine in the tropics may consider neurology and neurologists superfluous in this environment. In actual fact, the high burden of neurologic disorders combined with a dearth of physician-level care providers brings such expertise into high demand. Clinical work in sub-Saharan Africa offers the neurologist an opportunity to care for a wide range of conditions, including disorders Westerners may only be familiar with via historical accounts. Physicians starved of academic exchange and paramedical-care providers who frequently function without physician-level support are equally enthusiastic for additional training in the diagnosis and treatment of the nervous system disorders which are encountered daily. [Copyright &y& Elsevier]

Discusses the barriers to care encountered by both patients with neurologic disease and the medical staff who care for them in Zambia. Care delivery in Zambia; Options for improving care.

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Summary Phenobarbital remains one of the most widely used antiepileptic drugs worldwide, yet there are limited data regarding side effects associated with its use in routine clinical care settings in low-income countries. Available data suggests that phenobarbital is as effective as other first-line drugs for treating tonic–clonic seizures, but side effect reports differ widely between high and low-income settings. A better understanding of phenobarbital side effect profile and severity in low-income settings is warranted given its role in efforts to decrease the epilepsy treatment gap. We used the Liverpool adverse events profile (LEAP) to assess side effects in consecutive patients with epilepsy on phenobarbital seeking care in rural Zambia. Data regarding age, gender, medication dose, and medication adherence were also collected. T -tests and Spearman's correlation coefficient were used to assess predictors of LEAP score and medication adherence. Thirty-five patients receiving a mean dose of 2.1 mg/kg/day (SD: 2.78 mg/kg/day) of phenobarbital were assessed. All participants reported at least one side effect in the previous four weeks with a median of 6 symptoms (IQR: 4–8) and a mean side effects score of 28/76 (SD: 5.38). Over half reported sleepiness and dizziness. Memory problems and depression were also common (both 46%). Total LAEP score was not associated with age ( p = 0.88), gender ( p = 0.17), or phenobarbital dose ( p = 0.13). Medication adherence was not associated with side effects total score ( p = 0.56). Rural Zambian adults taking phenobarbital at doses recommended by the World Health Organization report a significant number of side effects. The most common side effects reported were similar to those reported in high-income countries. The significant burden of phenobarbital-associated side effects in this African cohort is in contrast to data from non-randomized clinical trials in China that reported phenobarbital to be well-tolerated with few side effects. Additional investigations regarding phenobarbital side effects during routine care in low income settings is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To define the spectrum of inpatient and outpatient neurological illness in a Zambian tertiary care facility where HIV is endemic. Methods: A retrospective period prevalence study of patients seen by the consulting neurologist between 1/2/06–12/20/06 at the University of Zambia''s University Teaching Hospital (UTH). Results: 443 inpatients and 368 outpatients were seen during this period. Overall, 160 (19.7%) patients underwent HIV testing: 125 (15.4%) HIV+ and 35 (4.3%) HIV−. The other 651 (80.3%) patients were untested. The most common inpatient neurological diseases among HIV+ patients were infectious diseases 26 (38.8%), neuropathy/radiculopathy 10 (10.4%), cerebrovascular disease 6 (9.0%), and myelopathy 5 (7.5%). The most common inpatient neurological diseases in the general population were cerebrovascular disease 62 (16.5%), infectious diseases 47 (12.5%), neuropathy/radiculopathy 37 (9.8%), and seizures/epilepsy 27 (7.2%). In the outpatient population, the most common neurological illnesses in HIV+ patients were neuropathy/radiculopathy 18 (31.0%), cerebrovascular disease 8 (13.8%), dementia/neurodegenerative 8 (13.8%), and encephalopathy 7 (12.1%). Outpatients in the general population most commonly had headaches/cephalgias 60 (19.4%), movement disorders 47 (15.2%), neuropathy/radiculopathy 43 (13.8%), and seizures/epilepsy 39 (12.6%). Conclusions: HIV-infected individuals are a sizeable group among neurology patients in Zambia, and they are affected by a different disease spectrum than the general population. Infectious diseases make up the largest percentage of inpatient neurological illness. Non-infectious causes are responsible for the majority of outpatient neurological cases. Emphasis should be placed on treatment of both infectious and non-infectious neurological illnesses. The most common outpatient neurological conditions are symptomatically treatable with routinely available medications. [Copyright &y& Elsevier]

Background: High rates of cerebrovascular disease (CVD) have previously been described in pediatric human immunodeficiency virus (HIV). However, little is known about pediatric CVD in the era of antiretroviral therapy or about the contribution of CVD to HIV-associated neurocognitive disorders.Methods: We completed a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia study, a prospective cohort study of neurocognitive complications of pediatric HIV. Brain magnetic resonance imaging (1.5 T) was acquired for 34 HIV+ children on antiretroviral therapy and 17 HIV-exposed uninfected children (aged eight to 17 years). Demographics, medical history, neurological examination, and neuropsychologic testing results were collected. Two neuroradiologists, unaware of HIV status and clinical course, read the scans.Results: CVD was identified in seven of 34 children with HIV (HIV+ CVD+) and no HIV-exposed uninfected children (21% vs 0%, P = 0.05). Three participants had white matter changes suggestive of small vessel disease, four had infarcts, and two had evidence of intracranial artery stenosis. Age of antiretroviral therapy initiation and exposure to protease inhibitors or efavirenz was not significantly different between children with and without CVD. HIV+ CVD+ children had significantly worse scores on a summary measure of cognition than the HIV+ CVD- group (NPZ8 score -0.57 vs 0.33, P = 0.04).Conclusions: This study demonstrates high rates of CVD in children with HIV despite antiretroviral therapy, and worse cognitive performance in children with CVD. Longitudinal studies are necessary to determine the mechanisms and incidence of new-onset CVD in children with HIV. [ABSTRACT FROM AUTHOR]

Background: Neurocysticercosis is the most common parasitic infection of the brain and a leading cause of epilepsy in resource-limited settings. Although neurocysticercosis and human immunodeficiency virus coinfections have commonly been reported, there are few data on how they interact. As part of an observational study of human immunodeficiency virus and cognition in Lusaka, Zambia, we identified a cluster of subjects with neurocysticercosis. We hypothesized that the neighborhood of residence may be an important factor driving clustering of neurocysticercosis and used a geographic information systems approach to investigate this association.Methods: A total of 34 subjects with human immunodeficiency virus and 13 subjects without human immunodeficiency virus (aged eight to 17 years) enrolled in the HIV-Associated Neurocognitive Disorders in Zambia study, had magnetic resonance imaging of the brain performed, and were evaluated for neurocysticercosis. Quantitative geographic information systems was utilized to investigate the relationship between neighborhood of residence, HIV, and neurocysticercosis.Results: Three of 34 subjects with human immunodeficiency virus (8.82%) and one of 13 controls were found to have neurocysticercosis. Geographic cluster analysis demonstrated that all subjects with neurocysticercosis were clustered in two adjacent neighborhoods (Chawama and Kanyama) with lower rates of piped water (Chawama: 22.8%, Kanyama: 26.7%) and flush toilets (Chawama: 14.0%, Kanyama: 14.0%) than the surrounding neighborhoods.Conclusion: We describe a cluster of patients with both neurocysticercosis and human immunodeficiency virus in Lusaka. Cases of neurocysticercosis clustered in neighborhoods with low rates of piped water and limited access to flush toilets. Geographic information systems may be a useful approach for studying the relationship between human immunodeficiency virus and neurocysticercosis. Larger studies are necessary to further investigate this association. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is common in children and adolescents with human immunodeficiency virus (HIV). Brain magnetic resonance imaging (MRI) is a potentially useful tool to investigate the pathophysiology of HIV-associated cognitive impairment and may serve as a biomarker in future clinical trials. There are few published data on brain imaging in children with HIV in sub-Saharan Africa.Methods: Thirty-four perinatally infected subjects with HIV and age-matched HIV-exposed uninfected controls between the ages nine and 17 years were recruited from the Pediatric Center of Excellence in Lusaka, Zambia, as part of the HIV-associated Neurocognitive Disorders in Zambia study. Brain MRI sequences were acquired, and clinical and volumetric assessments were performed. Subjects underwent a comprehensive neuropsychologic battery, and cognitive impairment status was classified using a global deficit score approach. Regression models were used to evaluate relationships between MRI findings and cognitive function.Results: We identified cerebrovascular disease in seven of 34 subjects with HIV compared with zero of 17 controls (21% vs 0%, P = 0.04). We also identified decreased total brain volumes (1036 vs 1162 cm3, P = 0.03) and decreased cortical thickness in the right temporal lobes (3.12 vs 3.29 mm; P = 0.01) and right fusiform gyri (3.10 vs 3.25 mm; P = 0.02) of HIV-infected subjects with cognitive impairment.Conclusions: These findings support the hypothesis that brain volumes may be useful biomarkers for cognitive outcomes in children with HIV. Further studies are necessary to investigate mechanisms of cerebrovascular disease and volume loss in children with HIV. [ABSTRACT FROM AUTHOR]

Abstract Introduction Research on neuromuscular disorders in sub-Saharan Africa is scarce. We aimed to delineate referral characteristics and the neuromuscular disorders observed among electrodiagnostic (EDX) consultations in a tertiary care setting in Zambia. Methods EDX records were reviewed for all specialist-performed studies after the establishment of the laboratory. The frequency of demographic, medical characteristics, and final EDX impressions are presented. Results Among 108 referrals, 52% were male, 84% were adults (mean age 44 years). Referrals were predominantly outpatients (85%) and sent by neurologists (68%). HIV infection was common (12%). Diabetes was rare (3%). Overall, 77% of studies were abnormal. Polyneuropathy was the most common abnormal EDX finding, followed by motor neuron disease. Discussion A diverse range of neuromuscular diseases was evaluated among EDX referrals in Zambia. Though labor and expertise intensive, access to EDX consultation can enhance clinical care and facilitate research and surveillance of neuromuscular disorders in the region. [ABSTRACT FROM AUTHOR]

Abstract: Among the 50million people with epilepsy (PWE) worldwide, ~15 to 60% also likely suffer from depression and/or anxiety disorders, and 80% reside in low-income regions where these comorbidities are often underrecognized and undertreated. We developed a 10-item screening tool for the detection of depression and anxiety disorders for use in Zambian primary care clinics where the baseline detection rate of depression and/or anxiety disorders among PWE is ~1%. Consenting adults (n=595) completed the screening tool, and 53.7% screened positive. The screen was validated by a psychiatric clinical officer using DMS-IV criteria. Cronbach's alpha was 0.77 overall and 0.67 and 0.57 for the depression and anxiety components, respectively. Other test characteristics included sensitivity 56.6%, specificity 68.1%, positive predictive value 67.3%, and negative predictive value 57.5%. Interrater reliability (kappa) was 0.85. The psychometric qualities of the tool are inadequate. Development of further, better quality instruments is needed though this will likely require a longer tool which the healthcare workers delivering epilepsy care services have previously deemed nonfeasible for routine use. As we work toward development and acceptability of a more optimal instrument, use of this initial screening tool which healthcare workers are willing to use may increase the identification of comorbid depression and anxiety in the low resource setting described in the study. [Copyright &y& Elsevier]

Abstract: Epilepsy-associated stigma in Africa has been described largely in terms of enacted stigma or discrimination. We conducted a study of 169 adults with epilepsy attending epilepsy clinics in Zambia''s Lusaka or Southern province using a three-item instrument (maximum score=3). Potential determinants of felt stigma including age, gender, education, wealth, disclosure status (meaning whether or how their community members knew of their condition), seizure type (generalized vs partial), seizure frequency, the presence of visible epilepsy-associated stigmata, personal contagion beliefs, and community contagion beliefs. The median stigma score was 2.5, suggesting some ceiling effect in the instrument. People with epilepsy who believed their condition to be contagious, who thought their community believed epilepsy to be contagious, and whose condition had been revealed to their community against their wishes reported more felt stigma. Community and clinic-based educational campaigns to dispel contagion beliefs are needed. [Copyright &y& Elsevier]

Abstract: Objective: In Zambia, where emergency medical services are very limited, the police are frequently called to the scene for unaccompanied people experiencing seizures or exhibiting disturbed behaviors during a seizure. Police officers receive no formal medical training to manage such encounters. We developed and administered a police-specific survey to assess knowledge, attitudes, and practices (KAP) regarding epilepsy among police officers in Zambia. Methods: In 2004, a 28-item KAP questionnaire that included queries specific to police encounters with seizures and epilepsy was developed and delivered to a random sample of 200 police officers stationed in Lusaka. Descriptive data were reviewed and open text questions postcoded and categorized. Results: The response rate was 87.5% (n =175). Police were familiar with epilepsy, with 85% having witnessed a seizure. Although 77.1% recognized epilepsy as a brain disorder, almost 20% blamed spirit possession, 13.9% associated epilepsy with witchcraft, and more than half the respondents believed epilepsy is contagious. When asked how they would treat someone brought in for disturbing the peace during a seizure, most police provided supportive or neutral responses, but 8% reported taking harmful actions (arrest, detain, handcuff, restrain), and 14.3% indicated that people with epilepsy in police custody require quarantine. Conclusions: A significant number of police officers in Zambia lack critical knowledge regarding epilepsy and self-report detrimental actions toward people with seizures. In regions of the developing world where the police provide emergency medical services, police officers need to be a target for educational and social intervention programs. [Copyright &y& Elsevier]

Abstract: Objective: Zambia suffers from a physician shortage, leaving the provision of care for those with epilepsy to nonphysician health care workers who may not be adequately trained for this task. These individuals are also important community opinion leaders. Our goal in this study was to determine the knowledge, attitudes, beliefs, and practices of these health care workers with respect to epilepsy. Methods: Health care workers in urban and rural districts of Zambia completed a self-administered, 48-item questionnaire containing items addressing demographics, personal experience with epilepsy, social tolerance, willingness to provide care, epilepsy care knowledge, and estimates of others’ attitudes. Analyses were conducted to assess characteristics associated with more epilepsy care knowledge and social tolerance. Results: The response rate was 92% (n =276). Those who had received both didactic and bedside training (P =0.02) and more recent graduates (P =0.007) had greater knowledge. Greater knowledge was associated with more social tolerance (P =0.005), but having a family member with epilepsy was not (P =0.61). Health care workers were generally willing to provide care to this patient population, but ∼25% would not allow their child to marry someone with epilepsy and 20% thought people with epilepsy should not marry or hold employment. Respondents reported that people with epilepsy are feared and/or rejected by both their families (75%) and their community (88.8%). Conclusions: Knowledge gaps exist particularly in acute management and recognition of partial epilepsy. More recent graduates were more knowledgeable, suggesting that curriculum changes instituted in 2000 may be improving care. Health care workers expressed both personal and professional reservations about people with epilepsy marrying. In addition to improving diagnosis and treatment skills, educational programs must address underlying attitudes that may worsen existing stigmatizing trends. [Copyright &y& Elsevier]

To evaluate the odds of vitamin B12 and folate deficiencies among Zambian clinic attendees with distal symmetric polyneuropathy (DSP) and age, sex, and HIV matched controls. Cases were adults from clinics in urban/peri-urban Zambia. Controls were enrolled among persons not seeking personal medical care, such as a caregiver or person collecting antiretrovirals without a medical complaint. Participants underwent structured interviews, physician examination, and assessments of complete blood count, renal and liver profiles, serum vitamin B12 and folate, erythrocyte folate, plasma total homocysteine and methylmalonic acid. HIV testing and CD4 counts were performed when appropriate. Among 107 consenting matched case-control pairs, 65% were female, 52% HIV positive, with mean age of 47.6 (SD 13.5) years. Among HIV positive participants, mean CD4 count was 484 (SD 221) and 482 (SD 236) for cases and controls, respectively (p =.93). DSP symptoms and severity did not differ by HIV status (p's > 0.05). Height, history of tuberculosis treatment, alcohol use, education, asset index, dietary diversity, and nutritional supplement use did not differ between cases and controls (p's > 0.05). DSP cases had at least 3:1 odds of having low serum folate (p =.0001), severely low erythrocyte folate (p =.014), and elevated total homocysteine (p =.001) levels compared to controls. Markers of vitamin B12 deficiency were not associated with case status (p's > 0.05). Markers of folate deficiency are highly associated with DSP among Zambian clinic attendees. Future studies should consider a broader range of comorbid nutritional deficiencies, and strategies for interventions. • Folate deficiency is associated with neuropathy in adult clinic attendees in Zambia. • Vitamin B12 deficiency is also common, but was not associated with neuropathy. • Future studies should assess other vitamin deficiencies associated with neuropathy. • More research on nutritional neurologic morbidity in similar settings is warranted. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gretchen Birbeck and Izukanji Sikazwe report financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae., Objective: To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher., Design, Setting, and Participants: This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023., Intervention: The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher., Main Outcomes and Measures: The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance., Results: Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07)., Conclusions and Relevance: This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia., Trial Registration: ClinicalTrials.gov Identifier: NCT03399318.

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., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Background: Meningitis causes significant mortality in regions with high comorbid HIV and TB. Improved outcomes are hindered by limited understanding of factors that delay adequate care., Methods: In-depth interviews of patients admitted to the University Teaching Hospital with suspected meningitis, their caregivers, doctors and nurses were conducted. Patient/caregiver interviews explored meningitis understanding, treatment prior to admission and experiences since admission. Provider interviews addressed current and prior experiences with meningitis patients and hospital barriers to care. A conceptual framework based on the Three Delays Model identified factors that delayed care., Results: Twenty-six patient/caregiver, eight doctor and eight nurse interviews occurred. Four delays were identified: in-home care; transportation to a health facility; clinic/first-level hospital care; and third-level hospital. Overcrowding and costly diagnostic testing delayed outpatient care; 23% of patients began with treatment inside the home due to prior negative experiences with biomedical care. Admission occurred after multiple clinic visits, where subsequent delays occurred during testing and treatment., Conclusions: Delays in care from home to hospital impair quality meningitis care in Zambia. Interventions to improve outcomes must address patient, community and health systems factors. Patient/caregiver education regarding signs of meningitis and indications for care-seeking are warranted to reduce treatment delays., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neuro-disability. Evidence indicates that a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted among children with complicated malaria at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with central nervous system (CNS) malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours., Methods: In this double-blinded, placebo controlled, two-armed clinical trial, we will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation randomization either to standard of care for fever management or to prophylactic, scheduled treatment every 6 hours for 72 hours with dual antipyretic therapies using acetaminophen and ibuprofen. Assignment to treatment groups will be with 1:1 allocation using blocked randomization. The primary outcome will be maximum temperature in the 72 hours after enrolment. Secondary outcomes include parasite clearance as determined by quantitative Histidine Rich Protein II and seizures through 72 hours after enrolment., Discussion: This clinical trial seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic using two antipyretics and prophylactic administration and will elucidate the impact of antipyretics on parasite clearance and acute symptomatic seizures. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted., Competing Interests: Birbeck and Seydel receive research funding from the US National Institute of Health. Birbeck serves on the Editorial Board for Lancet Neurology and Neurology. McDermott reports support by a research grants from NIH, FDA, Cure SMA, and PTC Therapeutics; compensation for consulting from Fulcrum Therapeutics, Inc., and NeuroDerm, Ltd.; and service on Data and Safety Monitoring Boards (DSMBs) for Eli Lilly and Company, Catabasis Pharmaceuticals, Inc., Vaccinex, Inc., Neurocrine Biosciences, Inc., Voyager Therapeutics, Prilenia Therapeutics Development, Ltd., ReveraGen BioPharma, Inc., and NS Pharma, Inc. All other authors have nothing to report.

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 [β-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 β = -11, 95% CI: -22 to -0.3, P = 0.04). Other than HIV, the strongest predictors of baseline SCS included socioeconomic status index (β =3, 95% CI: 1, 5, P = 0.004), history of growth stunting (β=-14, 95% CI: -23 to -6, P = 0.001), history of CD4 count below 200 (β = -19, 95% CI: -35 to -2, P = 0.02), and history of World Health Organization stage 4 disease (β = -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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Malaria affecting the central nervous system (CM) is a major contributor to paediatric epilepsy in resource-poor settings, with 10%-16% of survivors developing epilepsy within 2 years of infection. Despite high risk for post-malaria epilepsy (PME), biomarkers indicating which CM survivors will develop epilepsy are absent. Such biomarkers are essential to identify those at highest risk who might benefit most from close surveillance and/or preventive treatments. Electroencephalography (EEG) contains signals (specifically gamma frequency activity), which are correlated with higher risk of PME and provide a biomarker for the development of epilepsy. We propose to study the sensitivity of quantitative and qualitative EEG metrics in predicting PME, and the potential increased sensitivity of this measure with additional clinical metrics. Our goal is to develop a predictive PME index composed of EEG and clinical history metrics that are highly feasible to obtain in low-resourced regions., Methods and Analyses: This prospective observational study being conducted in Eastern Zambia will recruit 250 children aged 6 months to 11 years presenting with acute CM and follow them for two years. Children with pre-existing epilepsy diagnoses will be excluded. Outcome measures will include qualitative and quantitative analysis of routine EEG recordings, as well as clinical metrics in the acute and subacute period, including histidine-rich protein 2 levels of parasite burden, depth and length of coma, presence and severity of acute seizures, presence of hypoglycaemia, maximum temperature and 1-month post-CM neurodevelopmental assessment scores. We will test the performance of these EEG and clinical metrics in predicting development of epilepsy through multivariate logistic regression analyses., Ethics and Dissemination: This study has been approved by the Boston Children's Hospital Institutional Review Board, University of Zambia Biomedical Research Ethics Committee, and National Health Research Authority of Zambia. Results will be disseminated locally in Zambia followed by publication in international, open access, peer-reviewed journals when feasible., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare the following: AAP has received a research grant from NIH/NINDS for the proposed work and serves (without compensation) on the advisory board of the ROW foundation which supplies anti-seizure medications through a donation grant to Zambia; GB has received research grants from NIH/NINDS to support the proposed work and is Ambassador to Zambia for the Royal Society of the Tropical Medicine and Hygiene; MM has stock in Pfizer; and AR is a founder and advisor for Neuromotion, Cofounder PrevEp. Past consultant for or received funding from Abbvie, CRE Medical, ENCODED, Epihunter, Gamify, Neuroelectrics, Neural Dynamics, NeuroRex, Roche, Takeda, and is listed as inventor on a patent related to integration of TMS and EEG, as well as drug delivery with focused ultrasound. The remaining authors have no conflicts of interest to disclose and declare that the research was conducted in the absence of any relevant commercial or financial relationships., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Uptake of lumbar puncture (LP) remains low in regions with a high prevalence of central nervous system (CNS) infections like Zambia. Efforts to improve uptake are hindered by limited understanding of factors influencing LP uptake., Methods: Semistructured qualitative interviews were conducted with patients with suspected CNS infection, caregivers, doctors and nurses at the University Teaching Hospitals in 2016. Questions focused on LP experiences, knowledge, the consent process and health system barriers to LP among patients with an LP indication. Interviews were transcribed, translated to English and analysed using a thematic approach., Results: We recruited 24 adult patients, 36 caregivers of adult patients, 63 caregivers of paediatric patients, 20 doctors and 30 nurses (173 in total). LP barriers arose from both patients/caregivers and health providers and included community apprehension about LP, proxy (family) consensus consent practices, competing clinical demands, wariness of patient/caregiver responses, limitations in consumables and time to complete the LP. This could result in consent not being obtained correctly. LP enablers included patient/caregiver perceived LP utility, provider comfort with LP and in-person counselling., Conclusions: LP uptake is a complex sociocultural process influenced by patient, healthcare and community-level factors. Interventions to improve uptake must address multiple barriers to be successful., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We conducted a prospective cohort study to determine the prevalence of leukotriene A4 hydrolase (LTA4H) polymorphisms in Zambian adults with tuberculous meningitis (TBM) and its association with mortality. We completed genotype testing on 101 definite cases of TBM and 119 consecutive non-TBM controls. The distribution of genotypes among TBM patients was as follows: C/C (0.83), C/T (0.14), T/T (0.03). There was no significant difference in genotype distribution between TBM and non-TBM patients. We found no relationship between LTA4H polymorphism and survival. Prospective studies are needed to determine the benefit of adjuvant steroids in TBM based upon population LTA4H genotype. ANN NEUROL 2021;90:994-998., (© 2021 American Neurological Association.)

In much of sub-Saharan Africa, lumbar punctures (LPs) are performed less frequently than indicated. This is often attributed to patient/family refusal; however, other factors have not been systematically evaluated. We investigated predictors of LP performance for a prospective cohort of people with HIV and new-onset seizures at three hospitals in Zambia. We enrolled 257 participants, including 184 (72%) adults and 144 (56%) urban participants. LPs were performed for 65% of adults and 33% of children, and for 69% of urban and 38% of rural participants. In multivariate logistic regression analyses, LP completion was significantly less likely at one rural site and among children compared to adults. The worst WHO HIV disease stage was associated with increased odds of undergoing LP. Low LP completion rates in Zambia are multifactorial and related to health system and provider factors and patient/family preferences. Further research is necessary to understand this complex problem and develop interventions to improve LP uptake.

Lumbar puncture (LP) is underused for neuroinfectious disease diagnosis in Zambia, but reasons for poor uptake remain speculative. This cross-sectional study assessed LP knowledge, attitudes, and practices among patients/caregivers and healthcare workers (HCWs) and predictors of LP completion. Patients with suspected central nervous system infection, caregivers, and HCWs at the University Teaching Hospitals in 2016 were eligible. Questions adapted from the existing literature were used for a LP knowledge score. Predictors of knowledge scores were assessed independently for patients/caregivers and HCWs. Predictors of LP completion were assessed using multivariable logistic regression. Among 123 patients/caregivers, LP knowledge was poor. Pediatric caregivers were more likely than adult patients/caregivers to report LP could be replaced by neuroimaging (90% versus 78%, P < 0.001) and cause paralysis (57% versus 39%, P = 0.01). There were no significant predictors of the knowledge score among patients/caregivers. Among HCWs, 28% said LP makes patients clinically worse, and 60% reported it could cause paralysis. The increased knowledge score was associated with greater wealth (P = 0.03) and personally knowing someone who underwent LP (P < 0.001). Lumbar puncture was completed on 67/112 (57%) patients and was associated with an increased knowledge score (OR: 1.62 [95% CI: 1.19-2.23]). Pediatric patients (OR: 0.18 [95% CI: 0.07-0.47]) and those with a fear of paralysis (OR 0.29 [95% CI: 0.11-0.77]) were less likely to undergo LP. Improving LP-related knowledge may improve uptake. Healthcare workers sense of LP risk may also play a role in encouraging/discouraging use.

Introduction: The diagnosis of IRIS is based on evidence of clinical worsening and immune reconstitution in the setting of combined antiretroviral therapy (cART) initiation. While central nervous system IRIS (CNS IRIS) is thought to be prevalent in resource limited settings (RLS), its identification is constrained by limited data on pre-treatment HIV disease and diagnostic testing. A diagnosis can be improved with neuroimaging and cerebrospinal fluid (CSF) studies, which are not universally available in RLS. This study evaluated whether diagnoses of CNS IRIS could be achieved in a resource limited setting based on established criteria., Methods: A retrospective chart review of HIV+ individuals, on ARVs at the time of presentation in two cohort studies of suspected CNS opportunistic infection or tuberculous (TB) meningitis who were admitted to a tertiary care facility in Lusaka, Zambia., Results: Using currently validated criteria, none of the 254 participants evaluated could be diagnosed with CNS IRIS, as there was no information on post-treatment trajectory of HIV viral loads or CD4 counts. Only one participant had a definitive, non-IRIS infectious diagnosis based on comprehensive testing. Of the remaining 253 patients, 68 (27%) had an identified potential CNS pathogen, 92 (36%) had inflammatory CSF in the absence of a pathogen, and 94 (37%) had normal CSF despite presenting with CNS symptoms., Conclusion: The absence of HIV disease trajectory data, and lack of comprehensive diagnostic testing, compounded by a high prevalence of infectious pathogens, substantially limits the ability to diagnose CNS IRIS in RLS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tuberculous meningitis (TBM) is a devastating infection of the central nervous system lacking an adequate point-of-care diagnostic test. We conducted a prospective cohort study of 550 Zambian adults with suspected TBM to determine the diagnostic accuracy of cerebrospinal fluid (CSF) Xpert MTB/RIF, CSF lipoarabinomannan (LAM), urine LAM, CSF total protein, and CSF glucose compared with the gold standard of CSF culture. We categorized patients with a positive CSF tuberculosis (TB) culture as definite TBM. We also assessed inpatient and 1-year mortality on definite TBM patients when CSF Xpert MTB/RIF results were available in real time to treating physicians relative to a historical comparison cohort in whom Xpert results were not available in real time. Of the 550 patients, 474 (86.2%) were HIV-infected and 105/550 (19.1%) had definite TBM based on a positive CSF culture. The sensitivity/specificity of the diagnostic tests were CSF Xpert MTB/RIF, 52.9%/94.2%; CSF LAM, 21.9%/94.2%; urine LAM, 24.1%/76.1%; and CSF glucose <40 mg/dl, and total protein, >100 mg/dl, 66.3%/90%. A model including CSF Xpert MTB/RIF, CSF LAM, CSF glucose, and CSF total protein demonstrated an area under the receiver operating curve of 0.90. The inpatient and 1-year mortality for definite TBM was 43% and 57%, respectively. There was low sensitivity for the diagnosis of TBM across all diagnostics tests. CSF Xpert MTB/RIF and CSF LAM are highly specific for the diagnosis of TBM. Despite the use of Xpert MTB/RIF for diagnostic purpose in real time, TBM was still associated with a high mortality in Zambian patients., (Copyright © 2019 American Society for Microbiology.)

Background: Recurrent seizure risks in HIV-positive people with new-onset seizure are largely unknown, making it challenging to offer optimal recommendations regarding antiepileptic drug (AED) initiation. Existing outcomes data is limited, and risk factor identification requires a diagnostic assessment, which is often unavailable in regions heavily effected by HIV, like sub-Saharan Africa., Methods: HIV-positive Zambian adults with new-onset seizure were enrolled in a prospective cohort study to determine seizure recurrence and risk factors for recurrence. Seizure etiology was evaluated, and recurrent seizures and medication usage were assessed during clinic visits. Due to unexpectedly high mortality rates, predictors of death were evaluated using proportional hazards with Gray's test to compare cumulative incidence functions for recurrent seizure across groups adjusting for the competing outcome of death., Results: 95 patients were enrolled (mean age 37 years, 43% female, 83% with Karnofsky > 50) and followed for a mean of 293 days (median 241 (IQR: 29-532)). At presentation, 50 (53%) were in status epilepticus. The majority (91, 85%) had advanced HIV disease and 65 (68%) were not on combined antiretroviral therapy (cART). After extensive workup, seizure etiology remained unknown in 16 (17%). Average time to cART initiation after enrollment was 61 days. During follow up, 37 (39%) died and 23 (24%) had recurrent seizure. Most deaths (25/37, 68%) occurred in the first 60 days post-index seizure. Individuals with advanced HIV were more likely to die (HR: 19.1 [95% CI: 1.1-333.4]) as were those whose seizure etiology remained unknown (HR: 2.2 [95% CI: 1.1-4.4]). Among participants that survived from enrolment to the end of data collection on 10 May 2013 (n = 58), 20 (34%) experienced recurrent seizures., Conclusions: New-onset seizure among HIV-positive Zambian adults is associated with high mortality despite good functional status prior to presentation. Advanced HIV infection and failure to identify an underlying seizure etiology are associated with greater mortality. Recurrent seizures occur in over a third of survivors within only 2 years of follow-up. This provides evidence to support AED initiation after first seizure in HIV-positive individuals with advanced HIV disease at the time of presentation though the risks of AED-cART interactions remain a concern and warrant further study.

Background: Non-antiretroviral (ART) drug exposures and poor nutrition may be important modifiable risk factors for distal symmetric polyneuropathies (DSP) in sub-Saharan Africa., Methods: We conducted a cross-sectional study of DSP prevalence and factors associated with DSP among clinic attendees in urban and rural Zambia. All participants underwent neurologist-performed examination. Laboratory investigations seeking comorbid risk factors for DSP were performed for DSP cases., Results: We identified 31/137 (22.6%) HIV+ and 21/177 (11.9%) HIV- DSP cases. DSP prevalence did not differ by urbanicity, although rural participants were significantly more likely to have one asymptomatic DSP sign. Low dietary diversity, history of syphilis, history of tuberculosis, and prior metronidazole and ciprofloxacin use were associated with DSP amongst HIV+ cases, while age and education were associated with DSP in HIV- participants (all p-values < 0·05). In a multivariate logistic regression model, HIV (p = 0·0001) and age (p < 0·0001), and ciprofloxacin exposure (p = 0·01) remained independently associated with DSP. While diabetes was rare, supoptimal micronutrients levels were common among DSP cases regardless of HIV status., Conclusions: While HIV infection is strongly associated with DSP in Zambia, history of non-ART drug exposures and low dietary diversity are also important determinants of DSP in HIV+ individuals. Treatable micronutrient deficiencies were common., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To describe acute EEG findings in HIV-infected adults with new-onset seizure, assess baseline clinical characteristics associated with EEG abnormalities, and evaluate the relationship between EEG abnormalities and recurrent seizure., Methods: Eighty-one HIV-infected adults with new-onset seizure had EEG recordings during their index admission. Baseline characteristics assessed included HIV stage, seizure semiology, serum and CSF studies, neuroimaging, cognitive function based on the Zambian Mini-Mental State Examination and International HIV Dementia Scale, and psychiatric symptoms using the Shona Symptom Questionnaire. We evaluated the relationship between baseline characteristics and EEG abnormalities. Patients were followed for seizure recurrence, and the association between acute EEG abnormalities and seizure recurrence was assessed. Death was a secondary outcome., Results: Fifty-five patients had abnormal EEGs (68%): 18 (22%) had interictal spikes (12) or a recorded seizure (6). Among baseline clinical characteristics, more advanced HIV disease (p = 0.039) and any imaging abnormality (p = 0.027) were associated with abnormal EEGs. Cortical (p = 0.008) and white matter (p = 0.004) abnormalities were associated with slow posterior dominant rhythm. Patients were followed for a median of 303 days (interquartile range 103-560). Twenty-four (30%) died and 23 (28%) had recurrent seizures. EEG abnormalities were not associated with recurrent seizure. There was a nonsignificant association between seizures recorded during EEG and death (67% vs 26%, p = 0.051)., Conclusions: EEG abnormalities are common in this population, particularly in patients with imaging abnormalities and advanced HIV. Acute EEG abnormalities were not associated with recurrent seizure, but high mortality rates during follow-up limited this analysis., (© 2015 American Academy of Neurology.)