Neurological, Cognitive, and Psychological Findings Among Survivors of Ebola Virus Disease From the 1995 Ebola Outbreak in Kikwit, Democratic Republic of Congo: A Cross-sectional Study.

BACKGROUND: Clinical sequelae of Ebola virus disease (EVD) have not been described more than 3 years postoutbreak. We examined survivors and close contacts from the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo (DRC), and determined prevalence of abnormal neurological, cognitive, and psychological findings and their association with EVD survivorship. METHODS: From August to September 2017, we conducted a cross-sectional study in Kikwit, DRC. Over 2 decades after the EVD outbreak, we recruited EVD survivors and close contacts from the outbreak to undergo physical examination and culturally adapted versions of the Folstein mini-mental status exam (MMSE) and Goldberg anxiety and depression scale (GADS). We estimated the strength of relationships between EVD survivorship and health outcomes using linear regression models by comparing survivors versus close contacts, adjusting for age, sex, educational level, marital status, and healthcare worker status. RESULTS: We enrolled 20 EVD survivors and 187 close contacts. Among the 20 EVD survivors, 4 (20%) reported at least 1 abnormal neurological symptom, and 3 (15%) had an abnormal neurological examination. Among the 187 close contacts, 14 (11%) reported at least 1 abnormal neurologic symptom, and 9 (5%) had an abnormal neurological examination. EVD survivors had lower mean MMSE and higher mean GADS scores as compared to close contacts (MMSE: adjusted coefficient: -1.85; 95% confidence interval [CI]: -3.63, -0.07; GADS: adjusted coefficient: 3.91; 95% CI: 1.76, 6.04). CONCLUSIONS: EVD survivors can have lower cognitive scores and more symptoms of depression and anxiety than close contacts more than 2 decades after Ebola virus outbreaks.

Lead exposure and early child neurodevelopment among children 12-24 months in Kinshasa, the Democratic Republic of Congo.

Childhood lead exposure remains a problem in developing countries, and little is known about its effects on early child neurodevelopment and temperament in the Democratic Republic of Congo (DRC). We, therefore, conducted this study to determine the association between lead exposure and the neurodevelopment and behaviour of children aged 12-24 months in Kinshasa, DRC. A cross-sectional study was conducted between February and June 2012, and parents of 104 children were invited to participate. Blood lead levels (BLLs) of each child were tested using the flame atomic spectrophotometry method. All children were subject to a clinical examination and assessed with two selected early child neurodevelopmental tools, the Gensini-Gavito and the baby characteristics questionnaire, to measure their neurodevelopment and temperament. Detectable BLLs ranged from 1 to 30 µg/dl with a geometric mean of 6.9 (SD 4.8) µg/dl. BLLs at 5-9 and ≥10 µg/dl were significantly associated with the child temperament (p <0.05). Perinatal and maternal factors did not seem to affect early child neurodevelopment and temperament. Children exposed to lead were reported with more temperament difficulties at even blood lead levels <10 µg/dl, suggesting the need for preventive and intervention measures to reduce lead exposure among children in Kinshasa, DRC.

Bombé, an undetermined substance that caused an outbreak of illicit drug use in Kinshasa, Democratic Republic of the Congo.

BACKGROUND: Illegal drugs are becoming a public health problem in African cities. In 2021, Bombé, a new drug of unknown composition, caused an outbreak of neuro-psychiatric symptoms in Kinshasa. Bombé was rumored to be based on ground catalytic exhausts stolen from cars. METHODS: The chemical composition of six samples of Bombé obtained from different neighborhoods in Kinshasa was determined by triple quad liquid chromatography-mass spectrometry/mass spectrometry with confirmation by quadrupole time-of-flight mass spectrometry. Metals were determined by inductively coupled plasma-mass spectrometry, and polycyclic aromatic hydrocarbons were measured by gas chromatography-mass spectrometry. RESULTS: Analysis of the Bombé samples revealed that it contained heroin (2-12% of the total area under the curve of the samples) and opioid derivatives, plus paracetamol (33-72%), caffeine (17-26%), and also benzodiazepines (5/6 samples) and cyproheptadine (2/6 samples). The concentrations of neurotoxic metals were unremarkable. The median (range) concentrations of manganese and lead were 9.4 µg/g (range 3-334 µg/g) and 0.36 µg/g (range 0.1-3.12 µg/g ), respectively. All polycyclic aromatic hydrocarbons were below the level of detection (<0.10 µg/g). CONCLUSION: Thanks to international collaboration, Bombé was documented to be a heroin-based drug and its alleged origin from catalytic exhausts was not substantiated. The local human expertise and technical capacity for undertaking toxicological analyses should be increased in Africa.

The gut microbiome in konzo.

Konzo, a distinct upper motor neuron disease associated with a cyanogenic diet and chronic malnutrition, predominately affects children and women of childbearing age in sub-Saharan Africa. While the exact biological mechanisms that cause this disease have largely remained elusive, host-genetics and environmental components such as the gut microbiome have been implicated. Using a large study population of 180 individuals from the Democratic Republic of the Congo, where konzo is most frequent, we investigate how the structure of the gut microbiome varied across geographical contexts, as well as provide the first insight into the gut flora of children affected with this debilitating disease using shotgun metagenomic sequencing. Our findings indicate that the gut microbiome structure is highly variable depending on region of sampling, but most interestingly, we identify unique enrichments of bacterial species and functional pathways that potentially modulate the susceptibility of konzo in prone regions of the Congo.

Konzo: a distinct neurological disease associated with food (cassava) cyanogenic poisoning.

Epidemics of neurodegenerative diseases putatively caused by food toxins have been reported in the tropics with no clear understanding of their pathogenetic mechanisms. These diseases include the disease named Konzo that has been well documented in sub-Sahara Africa, mostly among children and women of childbearing age. Outbreaks of Konzo have occurred in the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroun, and most recently in Zambia. The main clinical picture consists of a symmetrical, permanent and irreversible spastic paraparesis (motor neuron disease) with no signs of sensory or genitourinary impairments. Recently, cognitive impairments and neurodevelopmental delays have been reported among school-aged and very young children. The exact pathogenetic mechanisms of the disease remain unknown. Epidemiological studies consistently show an association between outbreaks of the disease and chronic dietary reliance on insufficiently processed cyanogenic cassava (manioc or tapioca). Biochemical and toxicological studies suggest that the metabolites of linamarin (α-Hydroxyisobutyronitrile ß-D-glucopyranoside, the main cassava cyanogen), notably cyanide (mitochondrial toxin), thiocyanate (AMPA chaotropic agent), and cyanate (protein carbamoylating agent) may play an important role in the pathogenesis of Konzo. Experimental data suggest that thiol-redox and protein- folding mechanisms may also be perturbed. Factors of susceptibility including genetics, poor nutrition, poverty and dietary cyanogen exposure, or their interactions have been suggested. Serological studies have ruled out the role of retroviruses such as the human lymphotropic viruses HIV-I/II or HTLV-I/II. Because there is no cure for Konzo, prevention of the disease remains of paramount importance. Prospects for cognitive rehabilitation still need to be explored and tested.

Baseline characterization of epilepsy in an onchocerciasis endemic area of the Democratic Republic of Congo.

Increased epilepsy prevalence is reported in onchocerciasis (OC) endemic areas and is associated with the occurrence of distinct syndromes such as nodding disease and Nakalanga syndrome. To date, a causal relationship between OC and epilepsy is still a matter of controversy. We conducted a case-control study of participants with epilepsy and age- and gender-matched presumably healthy controls to elucidate the relationships between OC and epilepsy and explore the role of inflammation and growth factors in an OC endemic area in the Democratic Republic of Congo (DRC). Eighty-two participants with epilepsy (mean age ± SD: 23.2 ± 8.7 years) and 27 controls (mean age ± SD: 22.3 ± 12.0 years) underwent snip skin biopsies to determine Onchocerca volvulus infection status. Serum concentrations of cytokines, chemokines, and growth factors were measured using a Luminex Multiplex Assay kit. Children <19 years of age underwent neurocognitive assessments using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II). Overall, epilepsy was associated with OC (OR = 4.51, z = 3.11, p = 0.0019), and children with OC were more likely to be severely stunted (OR = 11.67, z = 2.62, p = 0.0087). The relationship between epilepsy and OC was no longer significant (z = 1.27, p = 0.20) when stunting was included as a correcting covariate. Epilepsy was associated with poor KABC-II test scores, high serum levels of IL-17, and low levels of IL-1RA, IL-8, and EGF. KABC-II testing scores correlated with serum levels of IL-10, MCP-1 and HGF. Familial history of epilepsy occurred frequently. Future studies should consider cytokines and/or growth factors when assessing susceptibility to epilepsy in OC endemic areas. Additional investigations, preferentially in low-prevalence OC areas, may provide further insights into the concept, risk, and burden of river epilepsy.

Dietary cyanogen exposure and early child neurodevelopment: An observational study from the Democratic Republic of Congo.

BACKGROUND: Dietary cyanogen exposure from ingesting bitter (toxic) cassava as a main source of food in sub-Saharan Africa is related to neurological impairments in sub-Saharan Africa. We explored possible association with early child neurodevelopmental outcomes. METHODS: We undertook a cross-sectional neurodevelopmental assessment of 12-48 month-old children using the Mullen Scale of Early Learning (MSEL) and the Gensini Gavito Scale (GGS). We used the Hopkins Symptoms Checklist-10 (HSCL-10) and Goldberg Depression Anxiety Scale (GDAS) to screen for symptoms of maternal depression-anxiety. We used the cyanogen content in household cassava flour and urinary thiocyanate (SCN) as biomarkers of dietary cyanogen exposure. We employed multivariable generalized linear models (GLM) with Gamma link function to determine predictors of early child neurodevelopmental outcomes. RESULTS: The mean (SD) and median (IQR) of cyanogen content of cassava household flour were above the WHO cut-off points of 10 ppm (52.18 [32·79]) and 50 (30-50) ppm, respectively. Mean (SD) urinary levels of thiocyanate and median (IQR) were respectively 817·81 (474·59) and 688 (344-1032) µmole/l in mothers, and 617·49 (449·48) and 688 (344-688) µmole/l in children reflecting individual high levels as well as a community-wide cyanogenic exposure. The concentration of cyanide in cassava flour was significantly associated with early child neurodevelopment, motor development and cognitive ability as indicated by univariable linear regression (p < 0.05). After adjusting for biological and socioeconomic predictors at multivariable analyses, fine motor proficiency and child neurodevelopment remained the main predictors associated with the concentration of cyanide in cassava flour: coefficients of -0·08 to -.15 (p < 0·01). We also found a significant association between child linear growth, early child neurodevelopment, cognitive ability and motor development at both univariable and multivariable linear regression analyses coefficients of 1.44 to 7.31 (p < 0·01). CONCLUSION: Dietary cyanogen exposure is associated with early child neurodevelopment, cognitive abilities and motor development, even in the absence of clinically evident paralysis. There is a need for community-wide interventions for better cassava processing practices for detoxification, improved nutrition, and neuro-rehabilitation, all of which are essential for optimal development in exposed children.

Cognitive and motor performance in Congolese children with konzo during 4 years of follow-up: a longitudinal analysis.

BACKGROUND: Konzo is an irreversible upper-motor neuron disorder affecting children dependent on bitter cassava for food. The neurocognitive ability of children with konzo over time has yet to be fully documented. METHODS: We did a longitudinal study in a konzo outbreak zone continuously affected by konzo since 1990, in the district of Kahemba, southern Bandundu Province, Congo. We enrolled children with a record of neurological diagnosis of konzo in Kahemba town. For all study children with konzo enrolled in the final sample for the baseline assessment, a neurological exam was done by neurologists to confirm konzo diagnosis using the 1996 WHO criteria at 2 years and 4 years. In the initial baseline sample for each child with konzo, we attempted to get consent from a comparison child without konzo (1996 WHO criteria) within 2 years of age, from a neighbouring household who met inclusion criteria. The neuropsychological assessments were the Kaufman Assessment Battery for Children, second edition (KABC-II), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2). FINDINGS: Data collection occurred between Oct 12, 2011, and Aug 14, 2015, in the town of Kahemba. 123 children from the Congo with konzo and 87 presumably healthy children without konzo from neighbouring households were enrolled. The planned assessments were completed by 76 children with konzo and 82 children without konzo at 2-year follow-up, and by 55 children with konzo and 33 children without konzo at 4-year follow-up. Boys with konzo did worse than those without konzo on the KABC-II Learning (p=0·0424) and on the Mental Processing Index (MPI; p=0·0111) assessments at 2-year follow-up, but girls did not. These differences observed in boys might have been caused by stunting. At 4-year follow-up, the difference in KABC-II MPI score between boys or girls with or without konzo was not significant. Both boys and girls with konzo had lower scores on BOT-2 than children without konzo at both follow-up times (p<0·0001). These differences were not attenuated when controlling for physical growth. Boys with and without konzo declined on BOT-2 fine motor proficiency at 2-year follow-up (boys with konzo p=0·0076; boys without konzo p=0·0224) and KABC-II MPI performance at 2-year follow-up and 4-year follow-up (2 years: boys with konzo p<0·0001, boys without konzo p=0·0213; 4 years: boys with konzo p=0·0256, boys without konzo p=0·10), but that was not the case for the girls with scores remaining stable regardless of konzo status. For boys, increases in urinary thiocyanate concentration was significantly associated with reductions in BOT-2 motor proficiency (p=0·0321), but was not significantly associated in girls and urinary thiocyanate concentration was not associated with KABC-II MPI score for either boys or girls. INTERPRETATION: Motor and cognitive performance continues to be significantly impaired in boys with konzo at 2-year follow-up compared with boys without konzo. Because these impairments are associated in part with exposure to poorly processed cassava as measured by urinary thiocyanate, interventions are urgently needed to ensure improved processing of cassava to detoxify this food source. FUNDING: US National Institutes of Health.

Cyanide and the human brain: perspectives from a model of food (cassava) poisoning.

Threats by fundamentalist leaders to use chemical weapons have resulted in renewed interest in cyanide toxicity. Relevant insights may be gained from studies on cyanide mass intoxication in populations relying on cyanogenic cassava as the main source of food. In these populations, sublethal concentrations (up to 80 µmol/l) of cyanide in the blood are commonplace and lead to signs of acute toxicity. Long-term toxicity signs include a distinct and irreversible spastic paralysis, known as konzo, and cognition deficits, mainly in sequential processing (visual-spatial analysis) domains. Toxic culprits include cyanide (mitochondrial toxicant), thiocyanate (AMPA-receptor chaotropic cyanide metabolite), cyanate (protein-carbamoylating cyanide metabolite), and 2-iminothiazolidine-4-carboxylic acid (seizure inducer). Factors of susceptibility include younger age, female gender, protein-deficient diet, and, possibly, the gut functional metagenome. The existence of uniquely exposed and neurologically affected populations offers invaluable research opportunities to develop a comprehensive understanding of cyanide toxicity and test or validate point-of-care diagnostic tools and treatment options to be included in preparedness kits in response to cyanide-related threats.

Prevalence and comorbidities of autism among children referred to the outpatient clinics for neurodevelopmental disorders.

INTRODUCTION: Autism spectrum disorders (ASD) is a neurodevelopmental disorder that has been rarely diagnosed in Sub-Saharan Africa. Although a proportion of children do present features of ASD in the Democratic Republic of Congo (DRC), little is known about it prevalence. Often, the co-morbidities constitute the upfront symptoms and therefore may it recognition and management difficult, aggravating as such the prognosis. The present study therefore aimed at studying the clinical profile of autism spectrum disorder (ASD) and the associated morbidities among children and adolescents in outpatient clinics in Kinshasa, the Democratic Republic of Congo. METHODS: We conducted a cross sectional study in the three outpatients centers receiving patients referred for neurodevelopmental disorders in Kinshasa, DRC, from June 2008 to June 2010. A total of 450 subjects aged from 1-18 years old were referred and included in the study. The clinical diagnosis for ASD was made using the DSM-IV-R and the ADIR. Co-morbidities were identified using DSM-IV-R criteria together with an extensive clinical interview and observation. All patients were subject to an intellectual quotient evaluation and an electroencephalogram reporting. RESULTS: Of the 450 subjects referred, 120 (29.3%) received the diagnosis of ASD, with boys outnumbering girls (OR 3:1. The mean age was 7.9 years (SD 3.4) (p< 0.001). Intellectual disability (75.83 %) and epilepsy (72.50%) were the main co-morbidities significantly associated with autism (p< 0.001). It was also found that co-morbidities were most frequent in subjects with an IQ<70 (p=0.05). CONCLUSION: ASD is frequent among patients referred for neurodevelopmental disorders in the three outpatients' centers for neurodevelopmental disorders in Kinshasa. Males seem to be more affected than female. The main co-morbidities were epilepsy and intellectual disabilities. Our findings suggest that it is important to screen for ASD and co-morbidities among all subjects referred for neurodevelopmental disorders and to undertake survey on ASD in various structures of rejected children from the society in Kinshasa DRC. This will help to identify and manage ASD and associated co-morbidities at an early stage for a better prognosis.

Serum 8,12-iso-iPF2α-VI isoprostane marker of oxidative damage and cognition deficits in children with konzo.

We sought to determine whether motor and cognitive deficits associated with cassava (food) cyanogenic poisoning were associated with high concentrations of F2-isoprostanes, well-established indicators of oxidative damage. Concentrations of serum F2-isoprostanes were quantified by LC-MS/MS and anchored to measures of motor proficiency and cognitive performance, which were respectively assessed through BOT-2 (Bruininks/Oseretsky Test, 2nd Edition) and KABC-II (Kaufman Assessment Battery for Children, 2nd edition) testing of 40 Congolese children (21 with konzo and 19 presumably healthy controls, overall mean age (SD): 9.3 (3.2) years). Exposure to cyanide was ascertained by concentrations of its main metabolite thiocyanate (SCN) in plasma and urine. Overall, SCN concentrations ranged from 91 to 325 and 172 to 1032 µmol/l in plasma and urine, respectively. Serum isoprostanes ranged from 0.1 to 0.8 (Isoprostane-III), 0.8 to 8.3 (total Isoprostane-III), 0.1 to 1.5 (Isoprostane-VI), 2.0 to 9.0 (total Isoprostane-VI), or 0.2 to 1.3 ng/ml (8,12-iso-iPF2α-VI isoprostane). Children with konzo poorly performed at the BOT-2 and KABC-II testing relative to presumably healthy children (p<0.01). Within regression models adjusting for age, gender, motor proficiency, and other biochemical variables, 8,12-iso-iPF2α-VI isoprostane was significantly associated with the overall cognitive performance (ß = -32.36 (95% CI: -51.59 to -13.03; P<0.001). This model explained over 85% of variation of the KABC-II score in children with konzo, but was not significant in explaining the motor proficiency impairment. These findings suggest that cognitive deficits and, possibly, brain injury associated with cassava poisoning is mediated in part by oxidative damage in children with konzo. 8,12-iso-iPF2α-VI isoprostane appears to be a good marker of the neuropathogenic mechanisms of konzo and may be used to monitor the impact of interventional trials to prevent the neurotoxic effects of cassava cyanogenic poisoning.

Neuropsychological effects of konzo: a neuromotor disease associated with poorly processed cassava.

BACKGROUND: Konzo is an irreversible upper-motor neuron disorder affecting children dependent on bitter cassava for food. Although the neuroepidemiology of konzo is well characterized, we report the first neuropsychological findings. METHOD: Children with konzo in the Democratic Republic of Congo (mean age 8.7 years) were compared with children without konzo (mean age 9.1 years) on the Kaufman Assessment Battery for Children, second edition (KABC-II), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2). Both groups were also compared with normative KABC measures from earlier studies in a nearby nonkonzo region. RESULTS: Using a Kruskal-Wallis test, children with konzo did worse on the KABC-II simultaneous processing (visual-spatial analysis) (K [1] = 8.78, P = .003) and mental processing index (MPI) (K [1] = 4.56, P = .03) than children without konzo. Both konzo and nonkonzo groups had poorer KABC sequential processing (memory) and MPI relative to the normative group from a nonkonzo region (K [2] = 75.55, P < .001). Children with konzo were lower on BOT-2 total (K [1] = 83.26, P < .001). KABC-II MPI and BOT-2 total were predictive of konzo status in a binary logistic regression model: odds ratio = 1.41, P < .013; 95% confidence interval 1.13-1.69. CONCLUSIONS: Motor proficiency is dramatically affected, and both children with and without konzo have impaired neurocognition compared with control children from a nonoutbreak area. This may evidence a subclinical neurocognitive form of the disease, extending the human burden of konzo with dramatic public health implications.