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Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial.

ABSTRACT: BACKGROUND:Many studies have reported an association between epilepsy, nodding syndrome (NS), and onchocerciasis (river blindness). A high prevalence of epilepsy has been noted particularly in onchocerciasis hyperendemic areas where onchocerciasis is not or insufficiently controlled with mass ivermectin distribution. There is evidence that increasing the coverage of ivermectin reduces the incidence of epilepsy, and anecdotal evidence suggests a reduction in seizure frequency in onchocerciasis-associated epilepsy (OAE) patients who receive ivermectin. Finding an alternative treatment for epilepsy in these patients will have major consequences. OBJECTIVE:The goal of the study is to assess whether ivermectin treatment decreases the frequency of seizures and leads to seizure freedom in OAE patients, including patients with NS. If we are able to demonstrate such an effect, this would strengthen the argument that onchocerciasis is causing epilepsy and therefore we should increase our efforts to eliminate onchocerciasis. METHODS:We will conduct a randomized clinical trial in the Democratic Republic of Congo to compare seizure freedom in onchocerciasis-infested epilepsy patients who receive immediate ivermectin treatment with delayed (after 4 months) ivermectin treatment. All participants will simultaneously receive antiepilepsy drugs (AEDs) according to local guidelines for epilepsy treatment. The primary endpoint is seizure freedom defined as no seizures during the 4 month of follow-up. Secondary endpoint is significant (>50%) seizure reduction compared to baseline seizure frequency. Reduction of seizures will be compared between ivermectin and nonivermectin arms. RESULTS:Start of enrollment is planned for August 2017, and we expect to have enrolled all 110 participants by December 2017. Results are expected in June 2018. CONCLUSIONS:If ivermectin treatment in addition to AEDs is able to lead to seizure freedom or significantly reduces seizure frequency in OAE patients, this will have major consequences for epilepsy treatment in onchocerciasis-endemic regions. Ivermectin is donated for free and in non Loa-Loa-endemic regions has negligible side effects. Reducing the burden of epilepsy will have a major impact on quality of life and socioeconomic status of families with affected members in Africa. TRIAL REGISTRATION:ClinicalTrials.gov NCT03052998; https://clinicaltrials.gov/ct2/show/NCT03052998 (Archived by WebCite at http://www.webcitation.org/6roFVQSG0).

SUBMITTER: Colebunders R

PROVIDER: S-EPMC5597797 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial.

Colebunders Robert R Mandro Michel M Mukendi Deby D Dolo Housseini H Suykerbuyk Patrick P Van Oijen Marieke M

JMIR research protocols 20170830 8

<h4>Background</h4>Many studies have reported an association between epilepsy, nodding syndrome (NS), and onchocerciasis (river blindness). A high prevalence of epilepsy has been noted particularly in onchocerciasis hyperendemic areas where onchocerciasis is not or insufficiently controlled with mass ivermectin distribution. There is evidence that increasing the coverage of ivermectin reduces the incidence of epilepsy, and anecdotal evidence suggests a reduction in seizure frequency in onchocerc ...[more]

PMID: 28855148

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Project description:INTRODUCTION:Recent findings from onchocerciasis-endemic foci uphold that increasing ivermectin coverage reduces the epilepsy incidence, and anecdotal evidence suggests seizure frequency reduction in persons with onchocerciasis-associated epilepsy, when treated with ivermectin. We conducted a randomized clinical trial to assess whether ivermectin treatment decreases seizure frequency. METHODS:A proof-of-concept randomized clinical trial was conducted in the Logo health zone in the Ituri province, Democratic Republic of Congo, to compare seizure frequencies in onchocerciasis-infected persons with epilepsy (PWE) randomized to one of two treatment arms: the anti-epileptic drug phenobarbital supplemented with ivermectin, versus phenobarbital alone. The primary endpoint was defined as the probability of being seizure-free at month 4. A secondary endpoint was defined as >50% reduction in seizure frequency at month 4, compared to baseline. Both endpoints were analyzed using multiple logistic regression. In longitudinal analysis, the probability of seizure freedom during the follow-up period was assessed for both treatment arms by fitting a logistic regression model using generalized estimating equations (GEE). RESULTS:Ninety PWE enrolled between October and November 2017 were eligible for analysis. A multiple logistic regression analysis showed a borderline association between ivermectin treatment and being seizure-free at month 4 (OR: 1.652, 95% CI 0.975-2.799; p = 0.062). There was no significant difference in the probability of experiencing >50% reduction of the seizure frequency at month 4 between the two treatment arms. Also, treatment with ivermectin did not significantly increase the odds of being seizure-free during the individual follow-up visits. CONCLUSION:Whether ivermectin has an added value in reducing the frequency of seizures in PWE treated with AED remains to be determined. A larger study in persons with OAE on a stable AED regimen and in persons with recent epilepsy onset should be considered to further investigate the potential beneficial effect of ivermectin treatment in persons with OAE. TRIAL REGISTRATION:Registration: www.clinicaltrials.gov; NCT03052998.

Project description:BackgroundNodding syndrome (NS) is a devastating epileptic illness of unknown aetiology mainly affecting children 5-15 years of age. Head nodding distinguishes NS from other forms of epilepsy. Other manifestations of the illness include mental and physical growth retardation. Many children die as a result of falling in fires or drowning. Recently, it was shown that NS is only one of the phenotypic presentations of onchocerciasis associated epilepsy (OAE). Despite the strong epidemiological association between epilepsy and onchocerciasis, the causal mechanism is unknown. After implementation of bi-annual community directed treatment with ivermectin (CDTi) and larviciding of rivers in northern Uganda, new cases of NS have ceased, while new cases continue to emerge in South Sudanese onchocerciasis-endemic areas with an interrupted CDTi programme. This study is designed to evaluate the potential effects of bi-annual CDTi on reducing the incidence of NS/OAE in onchocerciasis-endemic areas in South Sudan.MethodsA pre-intervention door-to-door population-based household survey will be conducted in selected onchocerciasis-endemic villages in Mundri and Maridi Counties, which have a high prevalence of epilepsy. Using a validated questionnaire, the entire village will be screened by community research assistants for suspected epilepsy cases. Suspected cases will be interviewed and examined by a trained clinical officer or medical doctor who will confirm or reject the diagnosis of epilepsy. Bi-annual CDTi will be implemented in the villages and a surveillance system for epilepsy set up. By implementing an epilepsy onchocerciasis awareness campaign we expect to obtain >?90% CDTi coverage of eligible individuals. The door-to-door survey will be repeated two years after the baseline survey. The incidence of NS/OAE will be compared before and after bi-annual CDTi.DiscussionOur study is the first population-based study to evaluate the effect of bi-annual CDTi to reduce the incidence of NS/OAE. If the study demonstrates such a reduction, these findings are expected to motivate communities in onchocerciasis-endemic regions to participate in CDTi, and will encourage policy makers, funders and other stakeholders to increase their efforts to eliminate onchocerciasis.

Project description:BackgroundThe fight against onchocerciasis in Africa has boomed thanks to the Community Directed Treatment with Ivermectin (CDTI) program. However, in Cameroon, after more than 15 years of mass treatment, onchocerciasis prevalence is still above the non-transmission threshold. This study aimed to explore a possible association between people's beliefs/perceptions of onchocerciasis and of CDTI program, and their adherence to ivermectin in three regions of Cameroon.Methodology/principal findingsA cross sectional survey was carried out in three health districts with persistent high onchocerciasis prevalence. Participants were randomly selected in 30 clusters per district. Adherence to ivermectin was comparable between Bafang and Bafia (55.0% and 48.8%, respectively, p>0.05) and lower in Yabassi (40.7%). Among all factors related to program perceptions and disease representations that were studied, perceptions of the program are the ones that were most determinant in adherence to ivermectin. People who had a "not positive" opinion of ivermectin distribution campaigns were less compliant than those who had a positive opinion about the campaigns (40% vs 55% in Bafang, and 48% vs 62% in Bafia, p<0.01), as well as those who had a negative appreciation of community drug distributors' commitment (22% vs 53% in Bafang, 33% vs 59% in Bafia, 27% vs 47% in Yabassi; p<0.01). The most common misconception about onchocerciasis transmission was the lack of hygiene, especially in Bafia and Yabassi. In Bafang, high proportions of people believed that onchocerciasis was due to high consumption of sugar (31% vs less than 5% in Bafia and Yabassi, p<0.001).Conclusion/significanceThere are still frequent misconceptions about onchocerciasis transmission in Cameroon. Perceptions of ivermectin distribution campaigns are more strongly associated to adherence. In addition to education/sensitisation on onchocerciasis during the implementation of the CDTI program, local health authorities should strive to better involve communities and more encourage community distributors' work.

Project description:BackgroundStrongyloidiasis may cause a life-threatening disease in immunosuppressed patients. This can only be prevented by effective cure of chronic infections. Direct parasitologic exams are not sensitive enough to prove cure if negative. We used an indirect immune fluorescent antibody test (IFAT) along with direct methods for patient inclusion and efficacy assessment.Methodology/principal findingsProspective, randomized, open label, phase III trial conducted at the Centre for Tropical Diseases (Verona, Italy) to compare efficacy and safety of ivermectin (single dose, 200 µg/kg) and thiabendazole (two daily doses of 25 mg/Kg for two days) to cure strongyloidiasis. The first patient was recruited on 6(th) December, 2004. Follow-up visit of the last patient was on 11(th) January, 2007. Consenting patients responding to inclusion criteria were randomly assigned to one of the treatment arms. Primary outcome was: negative direct and indirect (IFAT) tests at follow-up (4 to 6 months after treatment) or subjects with negative direct test and drop of two or more IFAT titers. Considering 198 patients who concluded follow-up, efficacy was 56.6% for ivermectin and 52.2% for thiabendazole (p = 0.53). If the analysis is restricted to 92 patients with IFAT titer 80 or more before treatment (virtually 100% specific), efficacy would be 68.1% for ivermectin and 68.9% for thiabendazole (p = 0.93). Considering direct parasitological diagnosis only, efficacy would be 85.7% for ivermectin and 94.6% for thiabendazole (p = 0.21). In ivermectin arm, mild to moderate side effects were observed in 24/115 patients (20.9%), versus 79/108 (73.1%) in thiabendazole arm (p = 0.00).ConclusionNo significant difference in efficacy was observed, while side effects were far more frequent in thiabendazole arm. Ivermectin is the drug of choice, but efficacy of single dose is suboptimal. Different dose schedules should be assessed by future, larger studies.Trial registrationPortal of Clinical Research with Medicines in Italy 2004–004693–87

Project description:BackgroundHigh epilepsy prevalence and incidence have been reported in areas with high onchocerciasis transmission. Recent findings suggest that proper community-directed treatment with ivermectin (CDTI) is potentially able to prevent onchocerciasis-associated epilepsy (OAE). We assessed the epilepsy prevalence and onchocerciasis transmission in two Nigerian villages following more than 20 years of CDTI.MethodsA cross-sectional door-to-door survey was performed in two villages in the Imo River Basin reported to be mesoendomic for onchocerciasis (Umuoparaodu and Umuezeala). Individuals were screened for epilepsy using a validated 5-item questionnaire. Persons suspected to have epilepsy were examined by a neurologist or a physician with training in epilepsy for confirmation. Onchocerciasis was investigated via skin snip microscopy and rapid diagnostic tests for Ov16 antibodies. Results were compared with previous findings from the Imo river basin.ResultsA total of 843 individuals from 257 households in the two villages were encountered. We detected four persons with epilepsy (PWE) giving a crude epilepsy prevalence of 0.5%. This finding differs from observations reported 14 years ago which showed an epilepsy prevalence of 2.8% in the neighbouring village of Umulolo (P = 0.0001), and 1.2% from 13 villages in the Imo river basin (P = 0.07). The seroprevalence of Ov16 antibodies was found to be 0%. Only 4.6% of skin snips were positive compared to 26.8% in previous surveys (P < 0.0001). Ivermectin mass distribution coverage in the study sites in 2017 was 79.7%.ConclusionsA low epilepsy and onchocerciasis prevalence was observed following more than 20 years of CDTI in the Imo River Basin. Absence of Ov16 antibodies indicates minimal transmission of onchocerciasis. These results contrast with observations from areas of high onchocerciasis transmission, where epilepsy prevalence and incidence remain high. Findings from this study suggest that sustained efforts could eventually achieve elimination of onchocerciasis in these villages.

Project description:BackgroundA high epilepsy prevalence has been reported in several onchocerciasis-endemic villages along the Mbam and Sanaga river valleys in Cameroon, including Bilomo and Kelleng. We sought to determine the prevalence of epilepsy in these two villages following more than 13 years of community-directed treatment with ivermectin (CDTI).MethodsDoor-to-door surveys were performed on the entire resident population in the villages in August 2017 and January 2018. Epilepsy was diagnosed using a 2-step approach: administration of a standardized 5-item questionnaire followed by confirmation by a neurologist. Previously published diagnostic criteria for onchocerciasis-associated epilepsy (OAE) were used. Ov16 serology was done for children aged 7-10 years to assess onchocerciasis transmission. Findings were compared with previous data from these two villages.ResultsA total of 1525 individuals (1321 in Bilomo and 204 in Kelleng) in 233 households were surveyed in both villages. The crude prevalence of epilepsy was 4.6% in Bilomo (2017) and 7.8% in Kelleng (2018), including 12 (15.6% of cases) persons with epilepsy (PWE) with nodding seizures. The age and sex-standardized prevalence in Kelleng decreased from 13.5% in 2004 to 9.3% in 2018 (P < 0.001). The median age of PWE shifted from 17 (IQR: 12-22) years to 24 (IQR: 20-30) years in Bilomo (P < 0.001); and slightly from 24 (IQR: 14-34) years to 28 (IQR: 21.25-36.75) years in Kelleng (P = 0.112). Furthermore, 47.6% of all tested children between 7 and 10 years had Ov16 antibodies.ConclusionsThere is a decrease in epilepsy prevalence after 13 years and more of CDTI in both villages. The age-shift observed in PWE suggests that ivermectin may prevent OAE in younger residents. Ov16 seropositivity in children indicates ongoing onchocerciasis transmission possibly due to suboptimal control measures. Our findings support the existence of OAE in Cameroon and highlight the need to strengthen onchocerciasis elimination programs.

Project description:ObjectiveThis study was undertaken to examine the efficacy of a family-tailored education and problem-solving behavioral intervention, Supporting Treatment Adherence Regimens (STAR), in young children (2-12 years old) with new onset epilepsy compared to an attention control (i.e., education only [EO]) intervention. Participants randomized to the STAR intervention were hypothesized to demonstrate significantly improved adherence at postintervention and 3-, 6-, and 12-month follow-up visits compared to the EO intervention. Seizure and health-related quality of life (HRQOL) outcomes were also examined.MethodsTwo hundred children with new onset epilepsy and their caregivers were recruited during routine epilepsy clinic visits. Baseline questionnaires were completed, and electronic adherence monitors were provided. Participants with adherence less than 95% during the run-in period were randomized to either STAR or EO intervention. Active intervention was provided to both groups for 4 months. Questionnaires were completed at conclusion of the active intervention phase and three follow-up time points (3, 6, and 12 months). Group differences in adherence, seizure outcomes, and HRQOL were examined using regression-based analyses of covariance and longitudinal mixed effect linear or logistical models.ResultsAdherence at 12-month follow-up was significantly different between the STAR (mean = 82.34, SD = 21.29) and EO intervention groups (mean = 61.77, SD = 28.29), with the STAR group demonstrating 20.6% greater adherence (b = 19.11, p = .04, 95% confidence interval = 1.00-37.22, d = .83). No significant differences were found between groups in seizure and HRQOL outcomes.SignificanceA family-based behavioral adherence intervention demonstrated sustained adherence improvements 1 year following epilepsy diagnosis compared to an epilepsy-specific education intervention. STAR is an efficacious adherence intervention that can easily be implemented into routine epilepsy care.

Project description:BackgroundIn onchocerciasis-endemic areas, particularly in those with a sub-optimal onchocerciasis control programme, a high prevalence of epilepsy is observed. Both onchocerciasis and epilepsy are stigmatizing conditions. The first international workshop on onchocerciasis-associated epilepsy (OAE) was held in Antwerp, Belgium (12-14 October 2017) and during this meeting, an OAE alliance was established. In this paper, we review what is known about epilepsy-associated stigma in onchocerciasis-endemic regions, and present the recommendations of the OAE alliance working group on stigma.Main bodyFor this scoping review, literature searches were performed on the electronic databases PubMed, Scopus and Science Direct using the search terms "epilepsy AND onchocerciasis AND stigma". Hand searches were also undertaken using Google Scholar, and in total seven papers were identified that addressed epilepsy-related stigma in an onchocercisasis-endemic area. Due to the limited number of published research papers on epilepsy-associated stigma in onchocerciasis-endemic areas, other relevant literature that describes important aspects related to stigma is discussed. The thematic presentation of this scoping review follows key insights on the barriers to alleviating the social consequences of stigma in highly affected onchocerciasis-endemic areas, which were established by experts during the working group on stigma and discrimination at the first international workshop on OAE. These themes are: knowledge gaps, perceived disease aetiology, access to education, marriage restrictions, psycho-social well-being, burden on the care-giver and treatment seeking behaviour. Based on the literature and expert discussions during the OAE working group on stigma, this paper describes important issues regarding epilepsy-related stigma in onchocerciasis-endemic regions and recommends interventions that are needed to reduce stigma and discrimination for the improvement of the psycho-social well-being of persons with epilepsy.ConclusionsEducating healthcare workers and communities about OAE, strengthening onchocerciasis elimination programs, decreasing the anti-epileptic treatment gap, improving the care of epilepsy-related injuries, and prioritising epilepsy research is the way forward to decreasing the stigma associated with epilepsy in onchocerciasis-endemic regions.

Dataset Information

Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial.

Publications

Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial.

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