Publications by authors named "David R Bearden"

18 Publications

  • Page 1 of 1

Neighborhood-Based Socioeconomic Determinants of Cognitive Impairment in Zambian Children With HIV: A Quantitative Geographic Information Systems Approach.

J Pediatric Infect Dis Soc 2021 Aug 26. Epub 2021 Aug 26.

Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine, Rochester, New York, USA.

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.
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http://dx.doi.org/10.1093/jpids/piab076DOI Listing
August 2021

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.
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http://dx.doi.org/10.1093/brain/awab219DOI Listing
June 2021

Evaluating the Relationship Between Depression and Cognitive Function Among Children and Adolescents with HIV in Zambia.

AIDS Behav 2021 Sep 25;25(9):2669-2679. Epub 2021 Feb 25.

Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Ave, Box 631, Rochester, NY, 14642, USA.

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.
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http://dx.doi.org/10.1007/s10461-021-03193-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456506PMC
September 2021

Evaluating the impact of antiretroviral and antiseizure medication interactions on treatment effectiveness among outpatient clinic attendees with HIV in Zambia.

Epilepsia 2020 12 21;61(12):2705-2711. Epub 2020 Oct 21.

Department of Neurology, University of Rochester, Rochester, NY, USA.

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/mm (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/mm (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm . Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm . 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/mm and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV.
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http://dx.doi.org/10.1111/epi.16723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725895PMC
December 2020

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain 2020 10;143(10):2929-2944

Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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http://dx.doi.org/10.1093/brain/awz307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780481PMC
October 2020

Cerebrovascular Disease in Children Perinatally Infected With Human Immunodeficiency Virus in Zambia.

Pediatr Neurol 2020 11 5;112:14-21. Epub 2020 Aug 5.

Department of Educational Psychology, Sociology and Special Education, The University of Zambia, Lusaka, Zambia; Zambian Institute for Neurological Care, Research, and Education, Lusaka, Zambia; Division of Child Neurology, Department of Neurology, University of Rochester Medical Center, Rochester, New York. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554106PMC
November 2020

Stroke and HIV in Botswana: A prospective study of risk factors and outcomes.

J Neurol Sci 2020 06 26;413:116806. Epub 2020 Mar 26.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.

Objective: HIV is associated with an increased risk of stroke, but there are sparse data on risk factors for stroke in people living with HIV in Sub-Saharan African. The goal of this study was to identify HIV-specific stroke characteristics and risk factors among adults in Botswana.

Methods: We conducted a prospective cohort study in Gaborone, Botswana from June 2015 to June 2017 comparing risk factors and outcomes among adults with and without HIV admitted for acute stroke. In addition, we conducted a case-control study comparing patients with HIV and stroke to outpatients with HIV and no history of stroke.

Results: A total of 52 patients with imaging-confirmed acute stroke were enrolled. Stroke patients with HIV were younger than those without HIV (median age 40 vs 54, p = .005). Hypertension was the most common risk factor identified in both HIV+ and HIV- groups, but was more common in patients without HIV (81% vs. 55%, p = .04). Patients with HIV were significantly more likely to have a small-vessel lacunar syndrome compared to patients without HIV (67% vs. 29%, p = .02). In the case-control analysis, patients with HIV and stroke were more likely to have hypertension than stroke-free controls (53% vs. 16%; OR 7.2, 95% CI 1.5-33.8, p = .01), and were more likely to drink alcohol (53% vs. 21%, OR 3.7, 95% CI 1.1-12.1, p = .03).

Conclusions: Individuals with HIV present with strokes at younger ages than individuals without HIV. Among those with HIV, hypertension and alcohol use are significant risk factors for stroke.
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http://dx.doi.org/10.1016/j.jns.2020.116806DOI Listing
June 2020

Neuroimaging and pediatric HIV.

Neurol Clin Pract 2019 Oct;9(5):371-372

Department of Neurology, Division of Child Neurology, School of Medicine, University of Rochester, NY; and Biogen, Cambridge, MA.

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http://dx.doi.org/10.1212/CPJ.0000000000000636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814431PMC
October 2019

Brain Magnetic Resonance Imaging Findings Associated With Cognitive Impairment in Children and Adolescents With Human Immunodeficiency Virus in Zambia.

Pediatr Neurol 2020 01 9;102:28-35. Epub 2019 Sep 9.

Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, New York. Electronic address:

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 cm, 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.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924094PMC
January 2020

Neurocysticercosis Among Zambian Children and Adolescents With Human Immunodeficiency Virus: A Geographic Information Systems Approach.

Pediatr Neurol 2020 01 6;102:36-43. Epub 2019 Aug 6.

Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, New York. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864625PMC
January 2020

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.

Am J Hum Genet 2018 12 29;103(6):1030-1037. Epub 2018 Nov 29.

Human Genetics Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address:

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[H] fucose and [H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288200PMC
December 2018

Global Health: Pediatric Neurology.

Semin Neurol 2018 04 23;38(2):200-207. Epub 2018 May 23.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Neurologic disorders contribute significantly to both morbidity and mortality among children in resource-limited settings, but there are a few succinct studies summarizing the epidemiology of neurologic disorders in these settings. A review of available literature was performed to identify data on the prevalence, etiology, outcomes, and treatment of neurologic disorders in children in resource-limited settings. The burden of neurologic disorders in children is high in resource-limited settings. Barriers to optimal care include lack of trained personnel, limited access to diagnostic technology, and limited availability of drugs used to treat common conditions. Several solutions have been suggested to deal with these challenges including increased collaborations to train neurologists willing to practice in resource-limited settings and increased training of physician extenders or community health workers. Further studies are necessary to improve our understanding of the epidemiology of neurologic disorders in resource-limited settings. Future epidemiologic studies should incorporate multiple countries in resource-limited settings and utilize standardized definitions and methodologies to enable comparison across regions.
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http://dx.doi.org/10.1055/s-0038-1649336DOI Listing
April 2018

Global HIV neurology: a comprehensive review.

AIDS 2019 02;33(2):163-184

Department of Neurology, Epilepsy Division, University of Rochester, Rochester, New York, USA.

: Neurological conditions associated with HIV remain major contributors to morbidity and mortality and are increasingly recognized in the aging population on long-standing combination antiretroviral therapy (cART). Importantly, growing evidence shows that the central nervous system (CNS) may serve as a reservoir for viral replication, which has major implications for HIV eradication strategies. Although there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of neurological conditions associated with HIV infection, significant scientific gaps remain. In many resource-limited settings, antiretrovirals considered second or third line in the United States, which carry substantial neurotoxicity, remain mainstays of treatment, and patients continue to present with severe immunosuppression and CNS opportunistic infections. Despite this, increased global access to cART has coincided with an aging HIV-positive population with cognitive sequelae, cerebrovascular disease, and peripheral neuropathy. Further neurological research in low-income and middle-income countries (LMICs) is needed to address the burden of neurological complications in HIV-positive patients, particularly regarding CNS viral reservoirs and their effects on eradication.
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http://dx.doi.org/10.1097/QAD.0000000000001796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139090PMC
February 2019

Risk Factors for Cerebral Palsy in Children in Botswana.

Pediatr Neurol 2017 Dec 3;77:73-77. Epub 2017 Aug 3.

Department of Pediatrics, University of Botswana, Gaborone, Botswana; Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, New York; Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address:

Background: Although cerebral palsy is reported to have a higher prevalence in low-resource settings, there are few studies describing risk factors for cerebral palsy in these settings. A better understanding of the unique risk factors affecting children with cerebral palsy in low-resource settings could optimize both resource allocation and preventative strategies.

Methods: A case-control study comparing children with cerebral palsy at ages two to 18 years with age-matched healthy control subjects was conducted between 2013 and 2014 at a referral center in Gaborone, Botswana. Study participants were enrolled from inpatient and outpatient settings, and data were collected through caregiver interviews, review of medical records, and physical examination of subjects. Risk factors were evaluated using conditional logistic regression models.

Results: We studied 56 subjects with cerebral palsy and 56 age-matched control subjects. Significant risk factors for cerebral palsy included a history of serious neonatal infection (odds ratio 15.0, P = 0.009), complications during delivery (odds ratio 13.5, P < 0.001), and maternal human immunodeficiency virus (HIV) infection (odds ratio 3.5, P = 0.03). Maternal HIV infection remained a significant risk factor after adjusting for potential confounders and covariates (adjusted odds ratio 13.2, P = 0.05).

Conclusions: Major risk factors for cerebral palsy in Botswana differ from those described in high-resource settings. Modifiable risk factors such as maternal HIV infection should be targeted as a potential strategy to reduce the incidence of cerebral palsy in Botswana. Further studies are necessary to determine optimal preventative and treatment strategies in this population.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.07.014DOI Listing
December 2017

Risk Factors for Malnutrition Among Children With Cerebral Palsy in Botswana.

Pediatr Neurol 2017 05 14;70:50-55. Epub 2017 Feb 14.

Department of Pediatrics, University of Botswana, Gaborone, Botswana; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, New York. Electronic address:

Background: Children with cerebral palsy in low-resource settings are at high risk of malnutrition, which further increases their risk of poor health outcomes. However, there are few available data on specific risk factors for malnutrition among children with cerebral palsy in the developing world.

Methods: We performed a case-control study among children with cerebral palsy receiving care at a tertiary care hospital in Gaborone, Botswana. Children with cerebral palsy and malnutrition were identified according to World Health Organization growth curves and compared with subjects with cerebral palsy without malnutrition. Risk factors for malnutrition were identified using multivariable logistic regression models. These risk factors were then used to generate a Malnutrition Risk Score, and Receiver Operating Characteristic curves were used to identify optimal cutoffs to identify subjects at high risk of malnutrition.

Results: We identified 61 children with cerebral palsy, 26 of whom (43%) met criteria for malnutrition. Nonambulatory status (odds ratio 13.8, 95% confidence interval [CI] 3.8-50.1, P < 0.001) and a composite measure of socioeconomic status (odds ratio 1.6, 95% CI 1.0-2.5, P = 0.03) were the strongest risk factors for malnutrition. A Malnutrition Risk Score was constructed based on these risk factors, and receiver operating characteristic curve analysis demonstrated excellent performance characteristics of this score (area under the curve 0.92, 95% CI 0.89-0.94).

Conclusions: Malnutrition is common among children with cerebral palsy in Botswana, and a simple risk score may help identify children with the highest risk. Further studies are needed to validate this screening tool and to determine optimal nutritional interventions in this population.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.02.003DOI Listing
May 2017

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

Am J Hum Genet 2017 Feb 26;100(2):343-351. Epub 2017 Jan 26.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.
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http://dx.doi.org/10.1016/j.ajhg.2016.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294886PMC
February 2017

Should the Frascati criteria for HIV-associated neurocognitive disorders be used in children?

Neurology 2016 07 20;87(1):17-8. Epub 2016 May 20.

From the Division of Neurology (D.R.B.), The Children's Hospital of Philadelphia; Botswana-UPenn Partnership (D.R.B.), University of Pennsylvania, Philadelphia; Department of Pediatrics (D.R.B.), University of Botswana, Gaborone; and Department of Neurology (A.-C.M.), Yale University, New Haven, CT.

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http://dx.doi.org/10.1212/WNL.0000000000002785DOI Listing
July 2016

Pediatric Cerebral Palsy in Botswana: Etiology, Outcomes, and Comorbidities.

Pediatr Neurol 2016 06 17;59:23-9. Epub 2016 Mar 17.

Botswana-UPenn Partnership, University of Pennsylvania, Philadelphia; Department of Pediatrics, University of Botswana, Gaborone, Botswana; Division of Infectious Disease, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Cerebral palsy is the most common cause of motor dysfunction in children worldwide and is often accompanied by multiple comorbidities. Although cerebral palsy has been studied extensively in high-resource settings, there are few published studies on cerebral palsy etiology, outcomes and comorbidities in low-resource settings.

Methods: Children with cerebral palsy were prospectively enrolled from inpatient and outpatient settings at a referral center in Gaborone, Botswana, in a cross-sectional study conducted from 2013 to 2014. Cerebral palsy etiology, outcomes, and comorbidities were determined through caregiver interviews, review of medical records, and direct physical examination.

Results: Sixty-eight children with cerebral palsy were enrolled. Subjects were 41% male, with a median age of 4 years (interquartile range = 2 to 7). The most common etiologies for cerebral palsy in our cohort were intrapartum hypoxic events (18%), postnatal infections (15%), prematurity (15%), focal ischemic strokes (10%), and prenatal infections (10%). Severe motor impairment was common, with the most severe category present in 41%. The predominant comorbidities were cognitive impairment (84%), epilepsy (77%), and visual impairment (46%).

Conclusions: Cerebral palsy in Botswana has different etiologies and is associated with poorer outcomes and higher prevalence of comorbidities than what has been reported in high-resource settings. Further studies are necessary to determine optimal preventative and treatment strategies in this population.
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http://dx.doi.org/10.1016/j.pediatrneurol.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912921PMC
June 2016
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