Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson's disease in Black South African and Nigerian patients.

BACKGROUND: The prevalence of Parkinson's disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients. METHODS: We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2's protein structure was investigated by molecular modelling. RESULTS: We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein. CONCLUSIONS: We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.

The Nigeria Parkinson Disease Registry: Process, Profile, and Prospects of a Collaborative Project.

BACKGROUND: Clinical disease registries are useful for quality improvement in care, benchmarking standards, and facilitating research. Collaborative networks established thence can enhance national and international studies by generating more robust samples and credible data and promote knowledge sharing and capacity building. This report describes the methodology, baseline data, and prospects of the Nigeria Parkinson Disease Registry. METHODS: This national registry was established in November 2016. Ethics approval was obtained for all sites. Basic anonymized data for consecutive cases fulfilling the United Kingdom Parkinson's Disease Brain Bank criteria (except the exclusion criterion of affected family members) are registered by participating neurologists via a secure registry website (www.parkinsonnigeria.com) using a minimal common data capture format. RESULTS: The registry had captured 578 participants from 5 of 6 geopolitical zones in Nigeria by July 2019 (72.5% men). Mean age at onset was 60.3 ± 10.7 years; median disease duration (interquartile range) was 36 months (18-60.5 months). Young-onset disease (<50 years) represented 15.2%. A family history was documented in 4.5% and 7.8% with age at onset <50 and ≥ 50, respectively. The most frequent initial symptom was tremor (45.3%). At inclusion, 93.4% were on treatment (54.5% on levodopa monotherapy). Per-capita direct cost for the registry was $3.37. CONCLUSIONS: This is the first published national Parkinson's disease registry in sub-Saharan Africa. The registry will serve as a platform for development of multipronged evidence-based policies and initiatives to improve quality of care of Parkinson's disease and research engagement in Nigeria. © 2020 International Parkinson and Movement Disorder Society.

Development and Reliability of a User-Friendly Multicenter Phenotyping Application for Hemorrhagic and Ischemic Stroke.

BACKGROUND: Annotation and Image Markup on ClearCanvas Enriched Stroke-phenotyping Software (ACCESS) is a novel stand-alone computer software application that allows the creation of simple standardized annotations for reporting brain images of all stroke types. We developed the ACCESS application and determined its inter-rater and intra-rater reliability in the Stroke Investigative Research and Educational Network (SIREN) study to assess its suitability for multicenter studies. METHODS: One hundred randomly selected stroke imaging reports from 5 SIREN sites were re-evaluated by 4 trained independent raters to determine the inter-rater reliability of the ACCESS (version 12.0) software for stroke phenotyping. To determine intra-rater reliability, 6 raters reviewed the same cases previously reported by them after a month of interval. Ischemic stroke was classified using the Oxfordshire Community Stroke Project (OCSP), Trial of Org 10172 in Acute Stroke Treatment (TOAST), and Atherosclerosis, Small-vessel disease, Cardiac source, Other cause (ASCO) protocols, while hemorrhagic stroke was classified using the Structural lesion, Medication, Amyloid angiopathy, Systemic disease, Hypertensive angiopathy and Undetermined (SMASH-U) protocol in ACCESS. Agreement among raters was measured with Cohen's kappa statistics. RESULTS: For primary stroke type, inter-rater agreement was .98 (95% confidence interval [CI], .94-1.00), while intra-rater agreement was 1.00 (95% CI, 1.00). For OCSP subtypes, inter-rater agreement was .97 (95% CI, .92-1.00) for the partial anterior circulation infarcts, .92 (95% CI, .76-1.00) for the total anterior circulation infarcts, and excellent for both lacunar infarcts and posterior circulation infarcts. Intra-rater agreement was .97 (.90-1.00), while inter-rater agreement was .93 (95% CI, .84-1.00) for TOAST subtypes. Inter-rater agreement ranged between .78 (cardioembolic) and .91 (large artery atherosclerotic) for ASCO subtypes and was .80 (95% CI, .56-1.00) for SMASH-U subtypes. CONCLUSION: The ACCESS application facilitates a concordant and reproducible classification of stroke subtypes by multiple investigators, making it suitable for clinical use and multicenter research.

Effects of seizure severity and seizure freedom on the health-related quality of life of an African population of people with epilepsy.

PURPOSE: This study aimed at determining the effects of seizure severity and seizure freedom on health-related quality of life (HRQOL) of people with epilepsy (PWE) in the presence of perceived stigma in a sub-Saharan African culture. METHODS: Health-related quality of life was assessed using QOLIE-31 in 93 consecutive adults (56 males and 37 females) with epilepsy. They were stratified into seizure-free, low-moderate seizure severity, and high seizure severity groups based on the seizure type and the number of seizures in the previous 6months. Other illness variables and sociodemographic variables were also obtained. A 3-item perceived stigma scale was administered. A modified QOLIE-31 (excluding the epilepsy-specific items) was given to 102 age- and sex-matched healthy controls. RESULTS: There was moderate negative correlation between seizure severity and mean total HRQOL score as well as scores on the Seizure Worry (p=.000), Overall Quality of Life (p=.000), and Social Function (p=.001) subscales of QOLIE-31. Overall, the healthy control subjects had a higher mean HRQOL score compared with the PWE put together (71.0+11.1 vs 64.2±13.6, p=.001). However, there was no difference in the mean HRQOL score between the seizure-free individuals and the healthy controls (p=.270). Seizure severity was associated with HRQOL independent of perceived stigma on a multiple regression analysis. CONCLUSION: This study provides evidence that seizure severity relates to health-related quality of life in an inverse, graded manner and independent of perceived stigma. Seizure-free people with epilepsy can have quality of life comparable with healthy individuals.

Outcome of Delayed Administration of Alteplase in a Resource-Poor Area: A Case Report.

An acute ischemic stroke, though carrying the risk of debilitating complications, is a preventable and treatable disease. Thrombolysis and endovascular thrombectomy are important components of its management. However, various challenges in resource-poor countries like Nigeria and other developing nations pose a great limitation in the timely intervention of ischemic stroke treatment. The challenges include late presentation, poor awareness of stroke symptoms even among health care workers, poor ambulance service/transportation network, intra-hospital delay, particularly in neuroimaging, and the unavailability of tissue plasminogen activator (alteplase/tenecteplase). We report a 32-year-old African man with an antecedent history of suspected migraine headaches with aura and a family history of hypertension and stroke, admitted 7½ hours after onset of stroke symptoms, scoring 13 on the National Institutes of Health Stroke Scale (NIHSS) with Medical Research Council (MRC) muscle power grades 1 and 3 on the right upper and lower extremities, respectively. Urgent non-contrast brain CT revealed only a hyperdense sign in the left middle cerebral artery (MCA). Intravenous tissue plasminogen activator (tPA) was administered at a lower dose of 0.6 mg/kg, 15½ hours after symptom onset, and a CT angiogram done 24 hours post-thrombolysis showed partial recanalization of the M1 segment of the MCA and intermediate collateral supply (Alberta stroke program early CT {ASPECT} score: 6). By the third day of admission, he had made a significant clinical improvement and was discharged home able to walk unsupported on the fourth day.

Secondhand smoke exposure is independently associated with stroke among non-smoking adults in West Africa.

BACKGROUND: Stroke is a leading cause of disability and mortality worldwide, but little is known about the contribution of secondhand smoke exposure (SHSE) to stroke epidemiology among indigenous Africans. OBJECTIVE: To evaluate the association of SHSE with stroke among indigenous Africans. METHODS: We analyzed the relationship of SHSE with stroke among 2990 case-control pairs of adults who had never smoked (identified in the SIREN study) using conditional logistic regression at a two-sided P < 0.05. RESULTS: Multivariable-adjusted odds ratio and 95% confidence interval; 1.25 (1.04, 1.50; P = 0.02) revealed SHSE was positively associated with stroke independent of stroke subtypes. CONCLUSION: Culturally relevant primary prevention strategies targeted at SHSE might be promising in preventing stroke among Africans.

APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson's disease.

The relationship between APOE polymorphisms and Parkinson's disease (PD) in black Africans has not been previously investigated. We evaluated the association between APOE polymorphic variability and self-declared cognition in 1100 Nigerians with PD and 1097 age-matched healthy controls. Cognition in PD was assessed using the single item cognition question (item 1.1) of the MDS-UPDRS. APOE genotype and allele frequencies did not differ between PD and controls (p > 0.05). No allelic or genotypic association was observed between APOE and age at onset of PD. In PD, APOE ε4/ε4 conferred a two-fold risk of cognitive impairment compared to one or no ε4 (HR: 2.09 (95% CI: 1.13-3.89; p = 0.02)), while APOE ε2 was associated with modest protection against cognitive impairment (HR: 0.41 (95% CI 0.19-0.99, p = 0.02)). Of 773 PD with motor phenotype and APOE characterized, tremor-dominant (TD) phenotype predominated significantly in ε2 carriers (87/135, 64.4%) compared to 22.2% in persons with postural instability/gait difficulty (PIGD) (30/135) and 13.3% in indeterminate (ID) (18/135, 13.3%) (p = 0.037). Although the frequency of the TD phenotype was highest in homozygous ε2 carriers (85.7%), the distribution of motor phenotypes across the six genotypes did not differ significantly (p = 0.18). Altogether, our findings support previous studies in other ethnicities, implying a role for APOE ε4 and ε2 as risk and protective factors, respectively, for cognitive impairment in PD.

Sleep medicine in Africa: past, present, and future.

NONE: Interest in sleep and sleep disorders in Africa dates back thousands of years, influenced by various cultural and religious beliefs. However, the practice of sleep medicine as a specialty has been inadequate compared to other regions of the world. The objective of this study was to explore the current status of sleep medicine in Africa vis-à-vis education, professional societies, and facilities, and to identify challenges of the specialty in the region. A literature search of major electronic databases (PubMed, Google Scholar) was done. This revealed that there is a high prevalence of sleep disorders in Africa and a significant association with epilepsy, human African trypanosomiasis, human immunodeficiency virus, and other diseases. There are 6 sleep societies in Africa located in 4 countries. Forty-one sleep laboratories were identified located in 4 countries. The challenges hindering development of sleep medicine in Africa include lack of awareness, poor funding, lack of facilities, and inadequate training.

Epidemiology of Epilepsy in Nigeria: A Community-Based Study From 3 Sites.

BACKGROUND: We determined the prevalence, incidence, and risk factors for epilepsy in Nigeria. METHODS: We conducted a door-to-door survey to identify cases of epilepsy in 3 regions. We estimated age-standardized prevalence adjusted for nonresponse and sensitivity and the 1-year retrospective incidence for active epilepsy. To assess potential risk factors, we conducted a case-control study by collecting sociodemographic and risk factor data. We estimated odds ratios using logistic regression analysis and corresponding population attributable fractions (PAFs). RESULTS: We screened 42,427 persons (age ≥6 years), of whom 254 had confirmed active epilepsy. The pooled prevalence of active epilepsy per 1,000 was 9.8 (95% confidence interval [CI] 8.6-11.1), 17.7 (14.2-20.6) in Gwandu, 4.8 (3.4-6.6) in Afikpo, and 3.3 (2.0-5.1) in Ijebu-Jesa. The pooled incidence per 100,000 was 101.3 (95% CI 57.9-167.6), 201.2 (105.0-358.9) in Gwandu, 27.6 (3.3-128.0) in Afikpo, and 23.9 (3.2-157.0) in Ijebu-Jesa. Children's significant risk factors included febrile seizures, meningitis, poor perinatal care, open defecation, measles, and family history in first-degree relatives. In adults, head injury, poor perinatal care, febrile seizures, family history in second-degree relatives, and consanguinity were significant. Gwandu had more significant risk factors. The PAF for the important factors in children was 74.0% (71.0%-76.0%) and in adults was 79.0% (75.0%-81.0%). CONCLUSION: This work suggests varied epidemiologic numbers, which may be explained by differences in risk factors and population structure in the different regions. These variations should differentially determine and drive prevention and health care responses.

A Cross-Sectional Comprehensive Assessment of the Profile and Burden of Non-motor Symptoms in Relation to Motor Phenotype in the Nigeria Parkinson Disease Registry Cohort.

BACKGROUND: Data on non-motor symptoms (NMS) in black Africans with Parkinson's disease (PD) are sparse. OBJECTIVE: To describe the profile of NMS in the Nigeria PD Registry (NPDR) cohort and explore the relationship between NMS and PD motor phenotype. METHODS: We conducted a cross-sectional study of the frequency and burden of NMS, based on the non-motor symptoms scale (NMSS) and the Chaudhuri method respectively in our cohort. Baseline demographics, disease characteristics (Hoehn and Yahr stage, MDS-UPDRS total score and Part III motor score), motor phenotype (based on Stebbin et al's algorithm), and levodopa equivalent daily dose (LEDD) were documented. RESULTS: Data are presented for 825 PD whose mean age at study was 63.7 ± 10.1 years, female sex-221 [26.8%] while median PD duration was 36 months. PD phenotypes included tremor-dominant 466 (56.5%), postural instability and gait disorder (PIGD) 259 (31.4%), and indeterminate 100 (12.1%). 82.6% were on treatment (median LEDD of 500 mg/24 hours). 804 (97.5%) endorsed at least 1 NMS. The median NMSS score was 26.0 while subscores for urinary and sexual function domains were significantly higher in males (P < 0.05). PIGD-PD had more frequent NMS and higher frequency of severe/very severe NMSS burden (P = 0.000 for both). Nocturia and fatigue were the most prevalent NMS overall and across motor subtypes. PIGD phenotype and total UPDRS scores were the independent determinants of NMSS scores (P = 0.000). CONCLUSION: The profile and burden of NMS, and association with motor subtype in our black African cohort is largely similar to descriptions from other populations.

Restless legs syndrome: a rarity in the Nigerian pregnant population?

OBJECTIVES: The prevalence of RLS in pregnancy is higher when compared with the general population however it remains unknown among indigenous black Africans. Available data indicate that RLS is uncommon in sub-Saharan Africa. We embarked on this study to determine the prevalence and characteristics of RLS in an antenatal clinic sample of Nigerian pregnant women compared with a primary care sample of non-pregnant women. METHODS: A total of 310 pregnant women and non-pregnant women filled out a questionnaire which incorporated the 2014 minimal criteria of the International Restless Legs Syndrome Study Group. Demographic and clinical data, including sleep duration and samples for blood hemoglobin concentration and urinalysis were obtained. RESULTS: The mean ages of the pregnant and non-pregnant women were 24.9 ± 5.6 years and 23.6 + 5.4 years, respectively (p = 0.003). There was no case of RLS found among pregnant women while five (1.6%) of the non-pregnant women fulfilled the criteria for RLS. Overall, the prevalence report of RLS symptoms was associated with lower mean habitual nocturnal sleep duration (p < 0.05) coffee (p = 0.013) and kola nut (0.023) consumption, report of leg cramps (p < 0.001) and proteinuria (p = 0.047), Report of leg cramps and proteinuria were independently associated with RLS. CONCLUSION: The prevalence of restless legs syndrome is low among women of child-bearing age in the Nigerian population and may be lower in pregnancy. Report of leg cramps and proteinuria are independently associated with RLS.

Correlates of sleep quality and sleep duration in a sample of urban-dwelling elderly Nigerian women.

OBJECTIVES: Aging, female sex, and urbanization increase the risk of sleep impairment. Sleep in urban-dwelling elderly African women has been sparsely studied. We studied the characteristics and correlates of sleep quality and habitual sleep duration in a primary care population of urban-living Nigerian women. METHODS: Sleep quality and sleep duration over the previous 1 month were estimated using the Pittsburgh Sleep Quality Index (PSQI). Excessive daytime sleepiness, risk of obstructive sleep apnea (OSA), and depressive symptoms were also assessed. RESULTS: Of the 428 subjects included, 117 (27.3%) were poor sleepers endorsing PSQI scores >5, whereas 126 (29.4%) slept <7 hours. The poor sleepers were more likely to be obese (P = .022), to have a high risk for OSA (P = .013), and to have clinically significant depressive symptoms (P = .001) compared with the good sleepers. Habitual sleep duration of <7 hours was associated with past oral contraceptive use (P = .025) and a trend toward a higher likelihood of high risk for OSA (P = .05) and coffee consumption (P = .05). On regression, the odds of high risk for OSA were higher with poor sleep quality and sleep duration <7 hours, respectively, whereas the odds of coffee consumption were higher with sleep duration <7 hours. CONCLUSIONS: Poor sleep quality and inadequate sleep are common in our population of elderly women. High risk for OSA independently predicts poor sleep quality and, along with report of coffee consumption, independently predicts habitual sleep duration of <7 hours.

Identifying patients at high risk for obstructive sleep apnoea syndrome in Nigeria: A multicentre observational study.

BACKGROUND: Obstructive sleep apnoea is associated with significant health consequences. A significant proportion of hospitalized patients at risk for obstructive sleep apnoea were never identified and referred for polysomnography for diagnosis. The objective of this study was to determine the factors associated with high risk for obstructive sleep apnoea and use it to identify patients at risk for the condition in tertiary hospitals in Nigeria. METHODS: This was a multicentre observational study of adult patients hospitalized in three selected hospitals from 15th January to 17th March 2015. Berlin questionnaire and Epworth sleepiness scale were used to assess for obstructive sleep apnoea risk and excessive daytime sleepiness respectively. Additional questions on traditional risk factors for obstructive sleep apnoea were also obtained. RESULTS: Nine hundred and twenty-six patients were recruited into the study. Respondents' mean age was 44.3 years ± 15.2years, 486 (52.5%) were females and 556 (60.0%) had one or more medical co-morbidity and none of the patients had a previous diagnosis of obstructive sleep apnoea. Factors that were independently associated with high risk for obstructive sleep apnoea include systemic hypertension(aOR-10.33;95%: CI 6.42-16.61), obesity(aOR-7.87;95% CI: 4.33-14.29); excessive daytime sleepiness (aOR-3.77;95% CI :2.28-6.22), tobacco smoking (aOR-2.99;95% CI: 1.76-5.07), snoring in a first-degree relative (aOR-1.83;95% CI: 1.19-2.81); and the use of sedative (aOR-1.82;95% CI: 1.06-3.15). CONCLUSIONS: This study shows that patients with systemic hypertension, obesity, excessive daytime sleepiness, history of smoking, snoring in a first-degree relative and use of sedatives are at high risk of obstructive sleep apnoea. None of the patients at high risk had a previous diagnosis of sleep apnoea by a physician, highlighting the diagnostic challenges of this condition. The results of this study will assist health care professionals in early identification of individuals at risk of obstructive sleep apnoea and subsequent referral for a sleep study.

Restless Legs Syndrome in a Nigerian Elderly Population.

STUDY OBJECTIVES: The prevalence of restless legs syndrome (RLS) is highest in the elderly in Caucasian populations; the prevalence of RLS in elderly Africans is not known. This study aimed at determining the frequency and associations of RLS in a Nigerian elderly population. METHODS: The study population comprised of 633 consecutive elderly individuals aged 65-105 years attending the general outpatient clinic of the State Hospital, Ilesa, for minor complaints and routine check-up. The diagnosis of RLS was made using the 2003 minimal criteria of the International Restless Legs Syndrome Study Group. Relevant sociodemographic and clinical data, including sleep duration, were also obtained. RESULTS: Restless legs syndrome was found in 3.5% of the study population with a male-female ratio of 2:1. There was no significant age (p = 0.427) or gender (p = 0.178) influence on the prevalence of RLS except in the 75- to 84-year age group where there was significant male preponderance (p = 0.044). A strong independent association between RLS and sleep duration (OR, 3.229; 95% CI, 1.283-8.486; p = 0.013) and past history of head injury (OR, 4.691; 95% CI, 1.750-12.577; p = 0.002) was found. CONCLUSIONS: Our finding support previous reports of a possible lower prevalence of RLS in Africans. Restless legs syndrome independently increases the odds of habitual sleep curtailment in elderly individuals. Head injury may be a risk factor for future RLS; this requires further investigation as indirect evidence for a possible link between RLS and traumatic brain injury exists.

Risk of obstructive sleep apnea, excessive daytime sleepiness and depressive symptoms in a Nigerian elderly population.

OBJECTIVES: To evaluate the risk of obstructive sleep apnea (OSA) in a primary care population of elderly Nigerians and to determine its correlates. METHODS: Clinical and demographic data of 414 elderly individuals in a primary care clinic were obtained. Their risk of OSA was estimated using Berlin questionnaire while Epworth sleepiness scale and the Center for Epidemiologic Studies Depression Scale (CESD-10) were also administered. RESULTS: Of the 414 subjects, 96 (23.2%) met the criteria for a high risk for OSA with a male to female ratio of 1:1. Subjects at high OSA risk (high OSA risk group) were younger than those at low OSA risk (low OSA risk group) (71.4±6.8 vs 73.6±7.7, p=0.011). Mean body mass index (BMI, kg/m(2)) (27.3±5.8 vs 24.7±5.1, p<0.001) and waist circumference (WC, cm) (90.7±13.1 vs 86.5±13.9, p=0.011) were higher in the high OSA risk group compared with the low OSA risk group. A total of 215 (51.9%) and 62 (15.0%) subjects had clinically significant depressive symptoms (CESD-10 score≥10) and excessive daytime sleepiness (EDS), respectively. On regression, the odds of EDS, depressive symptoms, increased BMI and younger age were significantly higher in the high OSA risk group compared with the low OSA risk group. CONCLUSIONS: High risk for OSA and depressive symptoms are common in our sample of elderly Nigerians. Depressive symptoms, EDS, BMI and age independently predict high OSA risk in the elderly.

Prevalence and Pattern of Chronic Kidney Disease in Antiretroviral-Naïve Patients with HIV/AIDS.

BACKGROUND: Chronic renal failure and HIV/AIDS are both prevalent in Nigeria. We performed a cross-sectional analysis of renal function in newly diagnosed, treatment-naive HIV-infected patients before initiating highly active antiretroviral therapy. METHODS: Treatment-inexperienced individuals were recruited. Patients with diabetes mellitus and hypertension were excluded. Plasma creatinine level was used to measure the estimated glomerular filtration rate ([eGFR] by Modification of Diet in Renal Disease equation). Predictors of creatinine and eGFR were determined by univariate and multivariate analyses. RESULTS: We evaluated 183 patients. In all, 44 (24%) patients had a GFR <60 mL/min/1.73 m(2), implying moderate chronic kidney disease (CKD). Considering the eGFR, 22 (12%) patients had stage 1, 117 (63.9%) stage 2, 13 (7.1%) stage 3, 27 (14.8%) stage 4, and 4 (2.2%) stage 5 CKD. Creatinine inversely correlated with CD4 (r = -.228, P = .025). CD4 predicts creatinine (odds ratio 1.6, 95% confidence interval 1.0-1.8, P = .003). CONCLUSION: In ART-naive patients, CKD is common, and low eGFR was associated with lower CD4 counts.