RESUMO
Despite the increasing epidemiological evidence that the Onchocerca volvulus parasite is strongly associated with epilepsy in children, hence the name onchocerciasis-associated epilepsy (OAE), the pathophysiological mechanism of OAE remains to be elucidated. In June 2014, children with unprovoked convulsive epilepsy and healthy controls were enrolled in a case control study in Titule, Bas-Uélé Province in the Democratic Republic of the Congo (DRC) to identify risk factors for epilepsy. Using a subset of samples collected from individuals enrolled in this study (16 persons with OAE and 9 controls) plasma, buffy coat, and cerebrospinal fluid (CSF) were subjected to random-primed next-generation sequencing. The resulting sequences were analyzed using sensitive computational methods to identify viral DNA and RNA sequences. Anneloviridae, Flaviviridae, Hepadnaviridae (Hepatitis B virus), Herpesviridae, Papillomaviridae, Polyomaviridae (Human polyomavirus), and Virgaviridae were identified in cases and in controls. Not unexpectedly, a variety of bacteriophages were also detected in all cases and controls. However, none of the identified viral sequences were found enriched in OAE cases, which was our criteria for agents that might play a role in the etiology or pathogenesis of OAE.
RESUMO
Nodding syndrome has been suggested to be triggered by neurotoxic leiomodin-1 auto-antibodies cross-reacting with Onchocerca volvulus. Here, we screened serum and CSF samples of persons with nodding syndrome and other forms of onchocerciasis-associated epilepsy (OAE) and African and European controls for leiomodin-1 antibodies by a cell-based assay (CBA) and Western blot (WB). These samples were also investigated for the presence of auto-antibodies cross-reacting with rat brain tissue by immunohistochemistry (IHC). Additionally, IHC was used to detect the leiomodin-1 protein in post-mortem brain samples of persons with OAE who died. Leiomodin-1 antibodies were detected by CBA in 6/52 (12%) and by WB in 23/54 (43%) persons with OAE compared to in 14/61 (23%) (p = 0.113) and 23/54 (43%) (p = 0.479) of controls without epilepsy. Multivariable exact logistic regression did not show an association between O. volvulus infection or epilepsy status and the presence of leiomodin-1. Leiomodin-1 antibodies were not detected in 12 CSF samples from persons with OAE or in 16 CSF samples from persons with acute-onset neurological conditions, as well as not being detected in serum from European controls. Moreover, the leiomodin-1 protein was only detected in capillary walls in post-mortem brain tissues and not in brain cells. IHC on rat brain slides with serum samples from persons with OAE or controls from persons with or without O. volvulus infection revealed no specific staining pattern. In conclusion, our data do not support OAE to be an autoimmune disorder caused by leiomodin-1 antibodies.
RESUMO
A clinical trial performed in the Democratic Republic of Congo (DRC), among persons with epilepsy (PWE) infected with Onchocerca volvulus treated with anti-seizure medication suggested that ivermectin reduces the seizure frequency. We assessed the effect of ivermectin treatment on seizure frequency in PWE with and without anti-seizure medication in three onchocerciasis endemic areas (Maridi, South Sudan; Aketi, DRC; and Mahenge, Tanzania). Pre- and 3-5 months post-ivermectin microfilariae densities in skin snips and seizure frequency were assessed. After ivermectin, the median (IQR) percentage reduction in seizure frequency in the study sites ranged from 73.4% (26.0-90.0) to 100% (50.0-100.0). A negative binomial mixed model showed that ivermectin significantly reduced the seizure frequency, with a larger decrease in PWE with a high baseline seizure frequency. Mediation analysis showed that ivermectin reduced the seizure frequencies indirectly through reduction in microfilariae densities but also that ivermectin may have a direct anti-seizure effect. However, given the short half-life of ivermectin and the fact that ivermectin does not penetrate the healthy brain, such a direct anti-seizure effect is unlikely. A randomized controlled trial assessing the ivermectin effect in people infected with O. volvulus who are also PWE on a stable anti-seizure regimen may be needed to clarify the causal relationship between ivermectin and seizure frequency.
RESUMO
Despite a long history of community-directed treatment with ivermectin (CDTI), a high ongoing Onchocerca volvulus transmission is observed in certain onchocerciasis-endemic regions in Africa with a high prevalence of epilepsy. We investigated factors associated with higher microfilarial (mf) density after ivermectin treatment. Skin snips were obtained from O. volvulus-infected persons with epilepsy before, and 3 to 5 months after ivermectin treatment. Participants were enrolled from 4 study sites: Maridi (South Sudan); Logo and Aketi (Democratic Republic of Congo); and Mahenge (Tanzania). Of the 329 participants, 105 (31.9%) had a post-treatment mf density >20% of the pre-treatment value. The percentage reduction in the geometric mean mf density ranged from 69.0% (5 months after treatment) to 89.4% (3 months after treatment). A higher pre-treatment mf density was associated with increased probability of a positive skin snip after ivermectin treatment (p = 0.016). For participants with persistent microfiladermia during follow-up, a higher number of previous CDTI rounds increased the odds of having a post-treatment mf density >20% of the pre-treatment value (p = 0.006). In conclusion, the high onchocerciasis transmission in the study sites may be due to initially high infection intensity in some individuals. Whether the decreasing effect of ivermectin with increasing years of CDTI results from sub-optimal response mechanisms warrants further research.
RESUMO
OBJECTIVES: To investigate the reasons for the high prevalence of epilepsy (>6%) discovered in 2015 in the Aketi health zone in the north of the Democratic Republic of the Congo. METHODS: Persons with epilepsy (PWE) diagnosed in a door-to-door survey in 2015 were traced and re-examined in 2017 by a neurologist. Confirmed PWE were paired with matched controls. For onchocerciasis assessment, children 7-10 years old were tested for IgG4 Onchocerca volvulus (OV16) antibodies, a rapid epidemiological mapping of onchocerciasis (REMO) study was performed, and ivermectin coverage was investigated. RESULTS: Forty-three (61.4%) previously diagnosed PWE were traced; the neurologist confirmed the epilepsy diagnosis in all of them. The overall OV16 positivity rate was 64.5%. Poor ivermectin coverage (55.9%) and a high prevalence of onchocercal nodules (>70%) were observed. The prevalence of epilepsy was 5.7% in Aketi rural town, with nine PWE (13.8%) experiencing head nodding seizures. A case-control study showed that PWE had lower body weight and higher ivermectin coverage in 2017 than healthy controls. CONCLUSIONS: The high prevalence of epilepsy in the Aketi health zone, despite 14 years of community-directed treatment with ivermectin (CDTI), was found to be associated with high onchocerciasis transmission and low ivermectin use. An awareness programme to increase ivermectin coverage and the introduction of a bi-annual CDTI programme should be considered.
Assuntos
Epilepsia/epidemiologia , Ivermectina/uso terapêutico , Oncocercose/epidemiologia , Adolescente , Adulto , Animais , Anticorpos Anti-Helmínticos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Feminino , Grupos Focais , Humanos , Imunoglobulina G/sangue , Masculino , Onchocerca volvulus/isolamento & purificação , Oncocercose/tratamento farmacológico , Prevalência , População Rural , Convulsões/epidemiologia , Adulto JovemRESUMO
BACKGROUND: High epilepsy prevalence and incidence were observed in onchocerciasis-endemic villages in the Democratic Republic of Congo (DRC). We investigated the clinical characteristics of onchocerciasis-associated epilepsy (OAE), and the relationship between seizure severity and microfilarial density. METHODS: In October 2017, ivermectin-naive persons with epilepsy (PWE) were recruited from onchocerciasis-endemic areas in the Logo health zone in the DRC. Additional PWE were enrolled in the Aketi health zone, where ivermectin had been distributed annually for 14 years. Past medical history, clinical characteristics and skin snips for Onchocerca volvulus detection were obtained from participants. Bivariate and multivariable analyses were used to investigate associations with microfilarial density. RESULTS: Of the 420 PWE in the Logo health zone, 392 were skin snipped (36.5% positive). Generalized motor seizures were most frequent (392 PWE, 93.3%), and nodding seizures were reported in 32 (7.6%) participants. Twelve PWE (3.1%) presented Nakalanga features. Sixty-three (44.1%) skin snip-positive PWE had a family history of epilepsy, compared to only 82 (32.9%) skin snip-negative PWE (p = 0.027). Eighty-one onchocerciasis-infected PWE were recruited in the Aketi health zone. Positive correlations between seizure frequency and microfilarial density were observed in Logo (Spearman-rho = 0.175; p<0.001) and Aketi (Spearman-rho = 0.249; p = 0.029). In the multivariable model adjusted for age, gender, and previous treatment, high seizure frequency was associated with increasing microfilarial density in Aketi (p = 0.025) but not in Logo (p = 0.148). CONCLUSION: In onchocerciasis-endemic regions in the DRC, a wide spectrum of seizures was observed. The occurrence of Nodding seizures and Nakalanga features, as well as an association between seizure severity and O. volvulus microfilarial density suggest a high OAE prevalence in the study villages. TRIAL REGISTRATION: ClinicalTrials.gov NCT03052998.
Assuntos
Epilepsia/parasitologia , Microfilárias/isolamento & purificação , Oncocercose/complicações , Oncocercose/epidemiologia , Convulsões/epidemiologia , Adolescente , Adulto , Idoso , Animais , Antiparasitários/uso terapêutico , Criança , Pré-Escolar , Estudos Transversais , República Democrática do Congo/epidemiologia , Doenças Endêmicas , Feminino , Humanos , Lactente , Ivermectina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Onchocerca volvulus/efeitos dos fármacos , Oncocercose/diagnóstico , Oncocercose/tratamento farmacológico , Prevalência , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/classificação , Convulsões/diagnóstico , Convulsões/parasitologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: A high prevalence of epilepsy has been observed in onchocerciasis endemic areas in the Democratic Republic of Congo (DRC). With this study we aimed to investigate whether Onchocerca volvulus infection is a risk factor for developing epilepsy in onchocerciasis endemic regions in the DRC. METHODS: Between October and December 2015, a multi-centre case control study was performed in onchocerciasis endemic health zones (HZ) in the DRC: one study site was situated in Tshopo Province in the HZ of Wanierukula (village of Salambongo) where there had been 13 annual community distributions of treatment with ivermectin (CDTI), a second was situated in Ituri Province in the HZ of Logo (village of Draju) where ivermectin had never been distributed and in the HZ of Rethy (village of Rassia) where there had been THREE CDTI annual campaigns before the study. Individuals with unprovoked convulsive epilepsy of unknown etiology were enrolled as cases (n = 175). Randomly selected healthy members of families without epilepsy cases from the same village and age-groups and were recruited as controls (n = 170). RESULTS: Onchocerciasis associated symptoms (e.g., itching and abnormal skin) were more often present in cases compared to controls (respectively, OR = 2.63, 95% CI: 1.63-4.23, P < 0.0001 and OR = 3.23, 95% CI: 1.48-7.09, P = 0.0034). A higher number of cases was found to present with microfilariae in skin snips and with O. volvulus IgG4 antibodies in the blood compared to controls. Moreover, the microfilariae load in skin snips was 3-10 times higher in cases than controls. CONCLUSIONS: This case control study confirms that O. volvulus is a risk factor for developing epilepsy in onchocerciasis endemic regions in the DRC.
Assuntos
Epilepsia/epidemiologia , Epilepsia/etiologia , Onchocerca volvulus , Oncocercose/complicações , Oncocercose/epidemiologia , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Criança , República Democrática do Congo/epidemiologia , Geografia Médica , Humanos , Pessoa de Meia-Idade , Razão de Chances , Onchocerca volvulus/fisiologia , Oncocercose/parasitologia , Prevalência , Vigilância em Saúde Pública , Fatores de Risco , Vigilância de Evento Sentinela , Fatores Socioeconômicos , Adulto JovemRESUMO
BACKGROUND: An increased prevalence of epilepsy has been reported in many onchocerciasis endemic areas. The objective of this study was to determine the prevalence of epilepsy in onchocerciasis endemic areas in the Democratic Republic of the Congo (DRC) and investigate whether a higher annual intake of Ivermectin was associated with a lower prevalence of epilepsy. METHODOLOGY/PRINCIPLE FINDINGS: Between July 2014 and February 2016, house-to-house epilepsy prevalence surveys were carried out in areas with a high level of onchocerciasis endemicity: 3 localities in the Bas-Uele, 24 in the Tshopo and 21 in the Ituri province. Ivermectin uptake was recorded for every household member. This database allowed a matched case-control pair subset to be created that enabled putative risk factors for epilepsy to be tested using univariate logistic regression models. Risk factors relating to onchocerciasis were tested using a multivariate random effects model. To identify presence of clusters of epilepsy cases, the Kulldorff's scan statistic was used. Of 12, 408 people examined in the different health areas 407 (3.3%) were found to have a history of epilepsy. A high prevalence of epilepsy was observed in health areas in the 3 provinces: 6.8-8.5% in Bas-Uele, 0.8-7.4% in Tshopo and 3.6-6.2% in Ituri. Median age of epilepsy onset was 9 years, and the modal age 12 years. The case control analysis demonstrated that before the appearance of epilepsy, compared to the same life period in controls, persons with epilepsy were around two times less likely (OR: 0.52; 95%CI: (0.28, 0.98)) to have taken Ivermectin than controls. After the appearance of epilepsy, there was no difference of Ivermectin intake between cases and controls. Only in Ituri, a significant cluster (p-value = 0.0001) was identified located around the Draju sample site area. CONCLUSIONS: The prevalence of epilepsy in health areas in onchocerciasis endemic regions in the DRC was 2-10 times higher than in non-onchocerciasis endemic regions in Africa. Our data suggests that Ivermectin protects against epilepsy in an onchocerciasis endemic region. However, a prospective population based intervention study is needed to confirm this.
Assuntos
Doenças Endêmicas , Epilepsia/epidemiologia , Oncocercose/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Antiparasitários/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Demografia , Características da Família , Feminino , Humanos , Lactente , Recém-Nascido , Ivermectina/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Oncocercose/tratamento farmacológico , Prevalência , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The reason for the high prevalence of epilepsy in onchocerciasis endemic areas remains unknown. The aim of this study was to detect risk factors associated with epilepsy in a region endemic for onchocerciasis. METHODS: In June 2014, a case-control study was performed in Titule, Bas-Uélé Province in the Democratic Republic of the Congo. Individuals with unprovoked convulsive epilepsy of unknown aetiology were enrolled as cases (n=59). Healthy members of families without cases of epilepsy in the same village were recruited as controls (n=61). A multivariate binomial logistic regression analysis was performed to identify potential risk factors associated with epilepsy. To evaluate the potential protective effect of ivermectin treatment on the development of epilepsy, a nested age-matched case-control study was performed including only those who were eligible for ivermectin treatment in the year before they developed epilepsy. RESULTS: Suspected onchocerciasis skin lesions were more often present in cases than in controls: 12/41 (29%) vs. 1/56 (2%), respectively (odds ratio (OR) 20.26, 95% confidence interval (CI) 2.42-170; p<0.01). Ivermectin had been taken 7 months earlier in 29/59 (49%) cases and 29/61 (48%) controls. Onchocerca volvulus (OV) DNA was detected by PCR in skin snips in 26/34 cases (76%) and 10/14 controls (71%) (p=0.7), and there was presence of OV IgG4 antibodies in 35/48 (73%) cases and 15/18 (83%) controls (p=0.5). OV DNA was not detected in the cerebrospinal fluid of cases (controls not tested). Both cases and controls reported frequent bites by blackflies (Diptera, Simuliidae). Bathing daily as opposed to less often (OR 16.7, 95% CI 2.2-125.8; p<0.01), bathing between 11 a.m. and 4 p.m. (OR 12.7, 95% CI 1.6-103.7; p=0.02), and washing clothes between 11 a.m. and 4 p.m. (OR 10.9, 95% CI 1.5-77.3; p=0.02) were all independently associated with epilepsy. Blood screening by specific PCR tests for Toxoplasma and Wuchereria bancrofti was negative in all cases and controls. A Loa loa infestation was found in only one case and one control by PCR and Giemsa smear. Antibodies to Taenia solium, Toxocara, and Trypanosoma sp were not detected in any of the participants. In an age-matched case-control analysis, 16/18 (89%) cases had not taken ivermectin the year before they developed epilepsy, compared to 7/18 (39%) controls that same year (p=0.002). CONCLUSIONS: These data suggest that frequent activities at rivers known to be blackfly breeding sites and a historical lack of ivermectin treatment were risk factors for epilepsy in this onchocerciasis endemic area.
Assuntos
Epilepsia/epidemiologia , Oncocercose/complicações , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Epilepsia/etiologia , Epilepsia/prevenção & controle , Feminino , Humanos , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Onchocerca volvulus/efeitos dos fármacos , Onchocerca volvulus/genética , Onchocerca volvulus/isolamento & purificação , Onchocerca volvulus/fisiologia , Oncocercose/epidemiologia , Oncocercose/parasitologia , Oncocercose/transmissão , Prevalência , Fatores de Risco , Simuliidae/parasitologia , Simuliidae/fisiologia , Adulto JovemRESUMO
BACKGROUND: An increased prevalence of epilepsy has been reported in many onchocerciasis endemic areas. OBJECTIVE: To determine the prevalence and distribution of epilepsy in an onchocerciasis endemic region in the Democratic Republic of the Congo (DRC). DESIGN/METHODS: An epilepsy prevalence study was carried out in 2014, in two localities of the Bas-Uélé district, an onchocerciasis endemic region in the Orientale Province of the DRC. Risk factors for epilepsy were identified using a random effects logistic regression model and the distribution of epilepsy cases was investigated using the Moran's I statistic of spatial auto-correlation. RESULTS: Among the 12,776 individuals of Dingila, 373 (2.9%) individuals with epilepsy were identified. In a house-to-house survey in Titule, 68 (2.3%) of the 2,908 people who participated in the survey were found to present episodes of epilepsy. Epilepsy showed a marked spatial pattern with clustering of cases occurring within and between adjacent households. Individual risk of epilepsy was found to be associated with living close to the nearest fast flowing river where blackflies (Diptera: Simuliidae)-the vector of Onchocerca volvulus-oviposit and breed. CONCLUSIONS: The prevalence of epilepsy in villages in the Bas-Uélé district in the DRC was higher than in non-onchocerciasis endemic regions in Africa. Living close to a blackflies infested river was found to be a risk factor for epilepsy.
Assuntos
Doenças Endêmicas , Epilepsia/epidemiologia , Oncocercose/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Animais , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Feminino , Filaricidas/uso terapêutico , Humanos , Ivermectina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doenças Negligenciadas/epidemiologia , Onchocerca volvulus , Oncocercose/prevenção & controle , Prevalência , Fatores de Risco , Rios , Simuliidae , Adulto JovemRESUMO
BACKGROUND: Nodding syndrome (NS) is an epilepsy disorder occurring in children in South Sudan, northern Uganda and Tanzania. The etiology of NS is unknown, but epidemiological studies demonstrate an association between NS and onchocerciasis. METHODS: Between November 2013 and July 2015 we visited onchocerciasis endemic regions in South Sudan, Uganda, and the Democratic Republic of the Congo (DRC) to assess the epilepsy situation. In South Sudan we interviewed patients and affected families, health officials, colleagues and healthcare workers, and performed a small household survey to estimate the epilepsy prevalence in the village of Mvolo, Western Equatoria State. Most information from Uganda was collected through discussions with colleagues and a review of published literature and reports. In the Bas-Uélé district of the DRC, we visited the villages of Liguga, Titule and Dingila, interviewed patients with epilepsy and family members and conducted a preliminary entomological assessment. RESULTS: In South Sudan there is an ongoing NS and epilepsy epidemic in the Western Equatoria state that started around 1990. A survey of 22 households in Mvolo revealed that 28 out of 168 (16.7%) children suffered from NS or another form of epilepsy. Thirteen (59%) households had at least one child, and nine (41%) households at least two children with NS or another form of epilepsy. In northern Uganda, an NS and epilepsy epidemic started around 2000. The occurrence of new NS cases has been in decline since 2008 and no new NS cases were officially reported in 2013. The decline in NS cases coincided with the bi-annual distribution of ivermectin and the treatment of blackfly-breeding rivers with larvicides. In Bas-Uélé district in the DRC, epilepsy appears to be endemic with cases clustered in villages close to blackfly-infested, rapid-flowing rivers. The majority of epilepsy cases in Liguga, Dingila and Titule presented with generalized (tonic-clonic) seizures without nodding, but with mental retardation. In Titule, an epilepsy prevalence of 2.3% was documented. The only anthropophilic species of blackfly collected in the region belonged to the Simulium damnosum complex. CONCLUSION: Blackflies may play a key role in the transmission of an etiological agent that either directly or indirectly cause, not only NS, but also other forms of epilepsy in onchocerciasis endemic regions.
Assuntos
Doenças Endêmicas/estatística & dados numéricos , Epilepsia/complicações , Epilepsia/epidemiologia , Síndrome do Cabeceio/complicações , Síndrome do Cabeceio/epidemiologia , Oncocercose/complicações , Oncocercose/epidemiologia , República Democrática do Congo/epidemiologia , Humanos , Sudão do Sul/epidemiologia , Uganda/epidemiologiaRESUMO
BACKGROUND: A simple method called RAPLOA, to rapidly assess what proportion of people in a community are infected with L. loa and hence which communities are at high risk of severe adverse reactions following ivermectin treatment, was developed in Cameroon and Nigeria. The method needed further validation in other geographical and cultural contexts before its application in all endemic countries. The present study was designed to validate RAPLOA in two regions in the North East and South West of the Democratic Republic of Congo. METHODS: In each study region, villages were selected from different bio-ecological zones in order to cover a wide range of loiasis endemicity. In each selected community, 80 people above the age of 15 years were interviewed for a history of eye worm (migration of adult L. loa under the conjunctiva of the eye) and parasitologically examined for the presence and intensity of L. loa infection. In total, 8100 individuals from 99 villages were enrolled into the study. RESULTS: The results confirmed the findings of the original RAPLOA study: i) the eye worm phenomenon was well-known in all endemic areas, ii) there was a clear relationship between the prevalence of eye worm history and the prevalence and intensity of L. loa microfilaraemia, and iii) using a threshold of 40%, the prevalence of eye worm history was a sensitive and specific indicator of high-risk communities. CONCLUSION: Following this successful validation, RAPLOA was recommended for the assessment of loiasis endemicity in areas targeted for ivermectin treatment by lymphatic filariasis and onchocerciasis control programmes.