GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Healthcare utilization by children with neurological impairments and disabilities in rural Kenya: a retrospective cohort study combined with secondary analysis of audit data

Background: There is a paucity of data on healthcare utilization by children with neurological impairments (NI) in sub-Saharan Africa. We determined the rate, risk factors, causes, and outcomes of hospital admission and utilization patterns for rehabilitative care among children with NI in a defined rural area in Kenya. Methods: We designed two sub-studies to address the primary objectives. Firstly, we retrospectively observed 251 children aged 6–9 years with NI and 2162 age-matched controls to determine the rate, causes and outcomes of hospitalization in a local referral hospital. The two cohorts were identified from an epidemiological survey conducted in 2015 in a defined geographical area. Secondly, we reviewed hospital records to characterize utilization patterns for rehabilitative care. Results: Thirty-four in-patient admissions occurred in 8503 person-years of observation (PYO), yielding a crude rate of 400 admissions per 100 000 PYO (95% confidence interval (Cl): 286–560). The risk of admission was similar between cases and controls (rate ratio=0.70, 95%CI: 0.10–2.30, p = 0.31). The presence of electricity in the household was associated with reduced odds of admission (odds ratio=0.32, 95% Cl: 0.10–0.90, p < 0.01). Seizures and malaria were the main causes of admission. We confirmed six (0.3%) deaths during the follow-up period. Over 93% of outpatient paediatric visits for rehabilitative care were related to cerebral palsy and intellectual developmental delay. Health education (87%), rehabilitative exercises (79%) and assistive technology (64%) were the most common interventions. Conclusions: Surprisingly, the risk of hospitalization was not different between children with NI and those without, possibly because those with severe NI who died before this follow-up were under seclusion and restraint in the community. Evidence-based and tailored rehabilitative interventions are urgently required based on the existing secondary data

Effectiveness of participatory video in lowering stigma against people with mental, neurological and substance use disorders in Kenya

Background Globally, stigma associated with mental, neurological and substance use (MNS) disorders is rampant and a barrier to good health and overall well-being of people with these conditions. Person-centred digital approaches such as participatory video may reduce stigma, but evidence on their effectiveness in Africa is absent. Aims To evaluate the effectiveness of participatory video in reducing mental health-related stigma in a resource-limited setting. Method We evaluated the effectiveness of using participatory video and face-to-face interaction between people with MNS disorders and a target audience in lowering stigma among 420 people living in Kilifi, Kenya. Changes in knowledge, attitudes and behaviour (KAB) were measured by comparing baseline scores with scores immediately after watching the participatory videos and 4 months after the intervention. Sociodemographic correlates of stigma scores were examined using multivariable linear regression models. Results Compared with baseline, KAB scores significantly improved at both time points, suggesting reduced stigma levels. At 4 months, the changes in scores were: knowledge (β = 0.20, 95% CI 0.16–0.25; P < 0.01), liberal attitude (β = 1.08, 95% CI 0.98–1.17; P < 0.01), sympathetic attitude (β = 0.52, 95% CI 0.42–0.62; P < 0.01), tolerant attitude (β = 0.72, 95% CI 0.61–0.83; P < 0.01) and behaviour (β = 0.37, 95% CI 0.31–0.43; P < 0.01). Sociodemographic variables were significantly correlated with KAB scores; the correlations were not consistent across the domains. Conclusions Participatory video is a feasible and effective strategy in improving knowledge, attitudes and intended behaviour in a resource-limited setting. Further studies are required to understand the mechanisms through which it lowers stigma and to examine long-term sustainability and the effectiveness of multicomponent interventions

Priority mental, neurological and substance use disorders in rural Kenya: Traditional health practitioners’ and primary health care workers’ perspectives

Background: Over 75% of people with mental neurological and substance use disorders (MNSD) live in low and middle-income countries with limited access to specialized care. The World Health Organization’s Mental Health Gap Action Program (mhGAP) aims to address the human resource gap but it requires contextualization. Aim: We conducted a qualitative study in rural coastal Kenya to explore the local terms, perceived causes and management modalities of priority MNSD listed in the mhGAP, to inform implementation in this setting. Methods: We conducted 8 focus group discussions with primary health care providers and traditional health practitioners and used the framework method to conduct thematic analysis. We identified local terms, perceived causes and treatment options for MNSD. We also explored possibilities for collaboration between the traditional health practitioners and primary health care providers. Results: We found local terms for depression, psychoses, epilepsy, disorders due to substance use and self-harm/ suicide but none for dementia. Child and adolescent mental and behavioral problems were not regarded as MNSD but consequences of poor parenting. Self-harm/suicide was recognized in the context of other MNSD. Causes of MNSD were broadly either biological or supernatural. Treatment options were dependent on perceived cause of illness. Most traditional health practitioners were willing to collaborate with primary health care providers mainly through referring cases. Primary health care providers were unwilling to collaborate with traditional health practitioners because they perceived them to contribute to worsening of patients’ prognoses. Conclusions: Local terms and management modalities are available for some priority MNSD in this setting. Community level case detection and referral may be hindered by lack of collaboration between traditional health practitioners and primary health care providers. There is need for training on the recognition and management of all priority MNSD

Burden, causes, and outcomes of people with epilepsy admitted to a rural hospital in Kenya

Objective: People with epilepsy (PWE) develop complications and comorbidities often requiring admission to hospital, which adds to the burden on the health system, particularly in low-income countries. We determined the incidence, disability-adjusted life years (DALYs), risk factors, and causes of admissions in PWE. We also examined the predictors of prolonged hospital stay and death using data from linked clinical and demographic surveillance system. Methods: We studied children and adults admitted to a Kenyan rural hospital, between January 2003 and December 2011, with a diagnosis of epilepsy. Poisson regression was used to compute incidence and rate ratios, logistic regression to determine associated factors, and the DALY package of the R-statistical software to calculate years lived with disability (YLD) and years of life lost (YLL). Results: The overall incidence of admissions was 45.6/100,000 person-years of observation (PYO) (95% confidence interval [95% CI] 43.0–48.7) and decreased with age (p \u3c 0.001). The overall DALYs were 3.1/1,000 (95% CI, 1.8–4.7) PYO and comprised 55% of YLD. Factors associated with hospitalization were use of antiepileptic drugs (AEDs) (odds ratio [OR] 5.36, 95% CI 2.64–10.90), previous admission (OR 11.65, 95% CI 2.65–51.17), acute encephalopathy (OR 2.12, 95% CI 1.07–4.22), and adverse perinatal events (OR 2.87, 95% CI 1.06–7.74). Important causes of admission were epilepsy-related complications: convulsive status epilepticus (CSE) (38%), and postictal coma (12%). Age was independently associated with prolonged hospital stay (OR 1.02, 95% CI 1.00–1.04) and mortality (OR, 1.07, 95% CI 1.04–1.10). Significance: Epilepsy is associated with significant number of admissions to hospital, considerable duration of admission, and mortality. Improved supply of AEDs in the community, early initiation of treatment, and adherence would reduce hospitalization of PWE and thus the burden of epilepsy on the health system

The mRNA content of plasma extracellular vesicles provides a window into the brain during cerebral malaria disease progression

This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The impact of cerebral malaria on the transcriptional profiles of cerebral tissue is difficult to study using non-invasive approaches. We isolated plasma extracellular vesicles (EVs) from patients with cerebral malaria and community controls and sequenced their RNA content. Deconvolution of the tissue origins of the EV-RNA revealed that EVs from cerebral malaria patients are predominantly enriched in transcripts of brain origin. Next, we used manifold learning on the EV-RNAseq data to determine pseudotime against the community control samples as the baseline reference. We found that neuronal transcripts in plasma EVs decreased as pseudotime progressed, while transcripts of glial, endothelial, and immune cell origins increased over pseudotime. Pseudotime was associated with clinicopathological parameters of disease severity, including retinopathy, metabolic acidosis, respiratory rate, anaemia, malnutrition, depth of unconsciousness and death. Plasma EVs further provided evidence of platelet activation, TNF signalling, neurotrophin signalling, long-term potentiation and glutamatergic signalling during late disease stages of cerebral malaria. The transcriptional responses of cerebral tissue in cerebral malaria can be studied non-invasively using EVs circulating in peripheral blood.Non peer reviewe

Co-morbid mental health conditions in people with epilepsy and association with quality of life in low- and middle-income countries:a systematic review and meta-analysis

Background: Comorbid mental health conditions are common in people with epilepsy and have a significant negative impact on important epilepsy outcomes, although the evidence is mostly from high-income countries. This systematic review aimed to synthesise evidence on the association between comorbid mental health conditions and quality of life and functioning among people with epilepsy living in low- and middle income countries (LMICs). Methods: We searched PubMed, EMBASE, CINAHL, Global Index medicus (GID) and PsycINFO databases from their dates of inception to January 2022. Only quantiative observational studies were included. Meta-analysis was conducted for studies that reported the same kind of quality of life and functioning outcome. Cohen’s d was calculated from the mean difference in quality-of-life score between people with epilepsy who did and did not have a comorbid depression or anxiety condition. The protocol was registered with PROSPERO: CRD42020161487. Results: The search strategy identified a total of 2,101 articles, from which 33 full text articles were included. Depression was the most common comorbid mental health condition (33 studies), followed by anxiety (16 studies). Meta-analysis was conducted on 19 studies reporting quality of life measured with the same instrument. A large standardized mean effect size (ES) in quality of life score was found (pooled ES = −1.16, 95% confidence interval (CI) − 1.70, − 0.63) between those participants with comorbid depression compared to non-depressed participants. There was significant heterogeneity between studies (I 2 = 97.6%, p &lt; 0.001). The median ES (IQR) was − 1.20 (− 1.40, (− 0.64)). An intermediate standard effect size for anxiety on quality of life was also observed (pooled ES = −0.64, 95% CI − 1.14, − 0.13). There was only one study reporting on functioning in relation to comorbid mental health conditions. Conclusion: Comorbid depression in people with epilepsy in LMICs is associated with poor quality of life although this evidence is based on highly heterogeneous studies. These findings support calls to integrate mental health care into services for people with epilepsy in LMICs. Future studies should use prospective designs in which the change in quality of life in relation to mental health or public health interventions across time can be measured

Association between psychosis and substance use in Kenya. Findings from the NeuroGAP-Psychosis study

Background: Substance use is prevalent among people with mental health issues, and patients with psychosis are more likely to use and misuse substances than the general population. Despite extensive research on substance abuse among the general public in Kenya, there is a scarcity of data comparing substance use among people with and without psychosis. This study investigates the association between psychosis and various substances in Kenya. Methods: This study utilized data from the Neuro-GAP Psychosis Case-Control Study between April 2018 and December 2022. The KEMRI-Wellcome Trust Research Programme recruited participants from various sites in Kenya, including Kilifi County, Malindi Sub-County, Port Reitz and Coast General Provincial Hospitals, and Moi Teaching and Referral Hospital, as well as affiliated sites in Webuye, Kapenguria, Kitale, Kapsabet, and Iten Kakamega. The collected data included sociodemographic information, substance use, and clinical diagnosis. We used the summary measures of frequency (percentages) and median (interquartile range) to describe the categorical and continuous data, respectively. We examined the association between categorical variables related to psychosis using the chi-square test. Logistic regression models were used to assess the factors associated with the odds of substance use, considering all relevant sociodemographic variables. Results: We assessed a total of 4,415 cases and 3,940 controls. Except for alcohol consumption (p-value=0.41), all forms of substance use showed statistically significant differences between the case and control groups. Cases had 16% higher odds of using any substance than controls (aOR: 1.16, 95%CI: 1.05-1.28, p=0.005). Moreover, males were 3.95 times more likely to use any substance than females (aOR:3.95; 95%CI: 3.43-4.56). All the categories of living arrangements were protective against substance use. Conclusion: The findings of this study suggest that psychotic illnesses are associated with an increased likelihood of using various substances. These findings are consistent with those of previous studies; however, it is crucial to investigate further the potential for reverse causality between psychosis and substance abuse using genetically informed methods

Perspectives on reasons for suicidal behaviour and recommendations for suicide prevention in Kenya: qualitative study

Background: Little is known about the reasons for suicidal behaviour in Africa, and communities’ perception of suicide prevention. A contextualised understanding of these reasons is important in guiding the implementation of potential suicide prevention interventions in specific settings. Aims: To understand ideas, experiences and opinions on reasons contributing to suicidal behaviour in the Coast region of Kenya, and provide recommendations for suicide prevention. Method: We conducted a qualitative study with various groups of key informants residing in the Coast region of Kenya, using in-depth interviews. Audio-recorded interviews were transcribed and translated from the local language before thematic inductive content analysis. Results: From the 25 in-depth interviews, we identified four key themes as reasons given for suicidal behaviour: interpersonal and relationship problems, financial and economic difficulties, mental health conditions and religious and cultural influences. These reasons were observed to be interrelated with each other and well-aligned to the suggested recommendations for suicide prevention. We found six key recommendations from our thematic content analysis: (a) increasing access to counselling and social support, (b) improving mental health awareness and skills training, (c) restriction of suicide means, (d) decriminalisation of suicide, (e) economic and education empowerment and (f) encouraging religion and spirituality. Conclusions: The reasons for suicidal behaviour are comparable with high-income countries, but suggested prevention strategies are more contextualised to our setting. A multifaceted approach in preventing suicide in (coastal) Kenya is warranted based on the varied reasons suggested. Community-based interventions will likely improve and increase access to suicide prevention in this study area