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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. [ABSTRACT FROM AUTHOR]

Objective: In Western settings, non‐convulsive status epilepticus (NCSE) and non‐convulsive seizures (NCSz) are associated with high mortality. In comatose patients, interictal epileptiform discharges (IEDs) identified on routine electroencephalogram (EEG) are predictive of NCSE/NCS. Little is known regarding the prevalence, causes, or outcomes of NCSE/NCSz in sub‐Saharan Africa (SSA). We sought to investigate the prevalence of IEDs and NCSE/NCSz at a single teaching institution in SSA. Methods: From October 3, 2017, to May 21, 2018, adult inpatients on the internal medicine service at Zambia's University Teaching Hospital (UTH) with a Glasgow Coma Score (GCS) of ≤10 were identified, excluding patients with mechanical ventilation or open head wounds. Signed consent by a proxy was required for enrollment and 30‐minute EEG. Chart abstractions provided coma duration, presence/absence of clinical seizures during/prior to admission, history of epilepsy, and presumed coma etiology. A structured neurological examination was completed. Patients were followed to discharge or death. Risk factors for IEDs were evaluated. Results: Of 392 eligible patients, 250 had EEGs. EEGs were not completed on eligible patients due to death (74), improved GCS (37), transfer within UTH (25), or lack of proxy (6). NCSE occurred in 22 of 250 (8.8%), NCSz in 3 of 250 (1.2%), and IEDs in 46 of 250 (18.4%) patients. Of the 250, 197 (78.8%) died. No specific risk factors for IEDs were identified. Significance: If the association between IEDs and NCSE among monitored populations in developed settings holds true for SSA, a projected 17%‐21% of comatose African adults have NCSE. No clinical characteristics identified those at risk. [ABSTRACT FROM AUTHOR]

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]

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]

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. 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. 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. 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. • Central nervous system IRIS in HIV causes severe morbidity and mortality. • It is likely prevalent in low- middle-income countries. • Diagnosis requires comprehensive testing, which may not be widely available. • Retrospective analysis shows limitations in diagnosis due to lack of prior HIV data. • Diagnostic criteria should be modified with attention to resource limited settings. [ABSTRACT FROM AUTHOR]