Impact of annual community-directed treatment with ivermectin on the incidence of epilepsy in Mvolo, a two-year prospective study.

OBJECTIVES: The potential impact of cumulative community-directed treatment with ivermectin (CDTI) on epilepsy epidemiology in Mvolo County, South Sudan, an onchocerciasis-endemic area with high epilepsy prevalence, was investigated. Annual CDTI was introduced in 2002 in Mvolo, with interruptions in 2016 and 2020. METHODS: Comprehensive house-to-house surveys in Mvolo (June 2020 and 2022) identified cases of epilepsy, including probable nodding syndrome (pNS). Community workers screened households in selected sites for suspected epilepsy, and medical doctors confirmed the diagnosis and determined the year of seizure onset. The incidence of epilepsy, including pNS, was analysed using 95% confidence intervals (CIs). Data on ivermectin intake and onchocerciasis-associated manifestations (itching and blindness) were collected. RESULTS: The surveys covered 15,755 (2020) and 15,092 (2022) individuals, identifying 809 (5.2%, 95% CI: 4.8-5.5%) and 672 (4.5%, 95% CI: 4.1-4.8%) epilepsy cases, respectively. Each survey reported that a third of the surveyed population experienced skin itching, and 3% were blind. Epilepsy incidence per 100,000 person-years gradually declined, from 326.5 (95% CI: 266.8-399.1) in 2013-2015 to 96.6 (95% CI: 65.5-141.7) in 2019-2021. Similarly, pNS incidence per 100,000 person-years decreased from 151.7 (95% CI: 112.7-203.4) to 27.0 (95% CI: 12.5-55.5). Coverage of CDTI was suboptimal, reaching only 64.0% of participants in 2019 and falling to 24.1% in 2021 following an interruption in 2020 due to COVID-19 restrictions. Additionally, while 99.4% of cases had active epilepsy in 2022, less than a quarter of these had access to antiseizure medication. CONCLUSIONS: The observed decrease in epilepsy incidence despite suboptimal CDTI coverage highlights the potential impact of onchocerciasis control efforts and underscores the need to strengthen these efforts in Mvolo County and across South Sudan. As a proactive measure, Mvolo and neighbouring counties are transitioning to biannual CDTI. Furthermore, the substantial epilepsy treatment gap in Mvolo should be addressed.

Review of epilepsy care in the Democratic Republic of the Congo.

Epilepsy imposes a substantial burden on the Democratic Republic of Congo (DRC). These challenges encompass the lack of comprehensive disease surveillance, an unresolved understanding of its pathophysiology, economic barriers limiting access to essential care, the absence of epilepsy surgical capabilities, and deeply ingrained societal stigmas. Notably, the national prevalence of epilepsy remains undetermined, with research primarily concentrating on infectious factors like Onchocerca volvulus, leaving other potential causes underexplored. Most patients lack insurance, incurring out-of-pocket expenses that often lead them to opt for traditional medicine rather than clinical care. Social stigma, perpetuated by common misconceptions, intensifies the social isolation experienced by individuals living with epilepsy. Additionally, surgical interventions are unavailable, and the accessibility of anti-seizure medications and healthcare infrastructure remains inadequate. Effectively tackling these interrelated challenges requires a multifaceted approach, including conducting research into region-specific factors contributing to epilepsy, increasing healthcare funding, subsidizing the costs of treatment, deploying mobile tools for extensive screening, launching awareness campaigns to dispel myths and reduce stigma, and promoting collaborations between traditional healers and medical practitioners to enhance local understanding and epilepsy management. Despite the difficulties, significant progress can be achieved through sustained and compassionate efforts to understand and eliminate the barriers faced by epilepsy patients in the region. This review outlines essential steps for alleviating the epilepsy burden in the DRC. PLAIN LANGUAGE SUMMARY: There are not enough resources to treat epilepsy in the DRC. PWEs struggle with stigma and the lack of money. Many of them still use traditional medicine for treatment and hold wrong beliefs about epilepsy. That is why there is a need for more resources to make the lives of PWEs better in the DRC.

Mapping, Associated Factors, and Pathophysiology of Nodding Syndrome in Africa: A Systematic Review.

INTRODUCTION: Nodding syndrome (NS) remains a poorly understood disorder. For a long time, it has been thought to be restricted to East Africa; however, cases in Central Africa have been increasing over time. The objective of this systematic review (SR) was to provide a summary of the state of knowledge on NS to date. METHODS: All original articles published on NS up to November 2021 were searched in four major databases and in the gray literature. Commentaries, editorials, book chapters, books, conference paper, qualitative studies that mentioned NS cases were also included. Data retrieved included study location (with GPS coordinates searched), year of study and publication, population characteristics, definition and diagnosis of NS, associated factors, and treatment if applicable. A meta-analysis of associated factors was performed where possible, and results were presented as odds ratios (ORs) and visualized as forest plots. Geographic information systems were used for cartographic representations. The quality of the articles included was assessed. RESULTS: Of the 876 articles initially identified, 67 (corresponding to 59 studies) were included in the SR. NS is only present in Central and East Africa. Interestingly, there were reports of NS in Central Africa prior to 2010, earlier than previously thought. The way NS diagnosis was established varies according to studies, and the 2012 WHO classification was used in only 60% of the studies. Approximately 11% of the articles did not meet the quality requirements set for this review. In our meta-analysis, the main factor associated with NS was onchocerciasis (OR = 8.8 [4.8, 15.9]). However, the pathophysiology of the disease remains poorly understood. The lack of common anti-epileptic drugs is a significant barrier to the management of head nodding and associated epileptic seizures. DISCUSSION/CONCLUSION: The lack of an operational definition of NS is an obstacle to its diagnosis and, thus, to its appropriate treatment. Indeed, diagnostic difficulties might have led to false positives and false negatives which could have altered the picture of NS presented in this article. Treatment should take into account nutritional and psychological factors, as well as associated infections. Some risk factors deserve further investigation; therefore, we suggest a multicentric study with an etiological focus using a more operational definition of NS.

Treatment and prevention of epilepsy in onchocerciasis-endemic areas is urgently needed.

BACKGROUND: There is increasing epidemiological evidence supporting the association between onchocerciasis and seizures, reinforcing the concept of onchocerciasis-associated epilepsy (OAE). The aim of this paper is to provide an update on the new knowledge about OAE and to propose recommendations to the World Health Organization how to address this public health problem. MAIN TEXT: During the 2nd International Workshop on OAE held on 19-21 September, 2023, in Antwerp, Belgium, participants recognised OAE as a substantial yet neglected public health problem, particularly in areas of sub-Saharan Africa where onchocerciasis remains hyperendemic. Evidence from prospective population-based studies suggest that strengthening onchocerciasis elimination efforts leads to a significant reduction of OAE incidence. There is a need to validate an OAE case definition to estimate the burden of disease and identify onchocerciasis-endemic areas requiring intensification of onchocerciasis elimination programmes and integration of epilepsy care. It is expected that raising awareness about OAE will boost the population uptake of ivermectin. The implementation of a community-based epilepsy treatment programme offering free anti-seizure medications (ASMs) has shown high effectiveness in reducing the frequency of seizures and improving the overall quality of life of people with epilepsy. CONCLUSIONS: To reduce OAE burden, enhanced collaboration between onchocerciasis and mental health programmes at community, national, and international levels is required. Urgent efforts are needed to ensure the uninterrupted provision of free ASMs in onchocerciasis-endemic areas. Furthermore, OAE should be included in the quantification of the onchocerciasis disease burden.

Persistence of onchocerciasis and associated dermatologic and ophthalmic pathologies after 27 years of ivermectin mass drug administration in the middle belt of Ghana.

OBJECTIVES: There is a pressing need to regularly evaluate the progress of onchocerciasis elimination programmes to timely identify and mitigate potential risks hindering the reaching of the 2030 targets proposed by the World Health Organization (WHO) in its roadmap on neglected tropical diseases (NTDs). We determined the prevalence of onchocerciasis and associated dermatological and ophthalmological manifestations in six endemic communities in the Bono Region of Ghana after 27 years of ivermectin mass treatment. METHODS: In a cross-sectional study, 564 participants aged ≥5 years were enrolled (49.1% females), with a median age of 26 (range: 5-89) years. In 54% and 47%, skin-snip microscopy and Ov16 rapid diagnostic tests were performed, respectively. Skin disease was determined using the WHO Skin NTD App. Visual function assessments included tests of visual acuity. RESULTS: The overall microfilarial prevalence was 12.5% (38/305) and Ov16 seroprevalence was 24.2% (64/265). Severe itching was recorded in 24.3%, acute papular onchodermatitis in 52.8%, chronic papular onchodermatitis in 12.5%, lichenified onchodermatitis in 0.7%, skin atrophy in 11.3%, depigmentation in 1.7% and palpable nodules in 5.3%. Of the 301 persons in which visual acuity was examined, 17% were visually impaired and 5.3% were blind and 47.3% presented with cataract. Chronic papular onchodermatitis, lichenified onchodermatitis, depigmentation and visual impairment were significantly associated with the presence of skin microfilariae and Ov16 seropositivity. CONCLUSIONS: The persistence of Onchocerca volvulus infection and onchocerciasis-associated dermatological and ophthalmological pathologies after prolonged treatment is of concern. There is a need to include morbidity management in onchocerciasis elimination programmes and understand better patterns of treatment coverage, adherence and actual intake of ivermectin.

The onchocerciasis hypothesis of nodding syndrome.

Nodding syndrome (NS) is a phenotypic presentation of onchocerciasis-associated epilepsy (OAE). OAE is an important public health problem in areas with high ongoing Onchocerca volvulus transmission. OAE, including NS, is preventable by strengthening onchocerciasis elimination programs. The presence of tau in OAE postmortem brains could be the consequence of neuroinflammation directly or indirectly induced by O. volvulus. Omics research is needed to investigate whether O. volvulus worms contain a neurotropic virus.

Disability assessment among persons with epilepsy in Mahenge, an onchocerciasis-endemic area in Tanzania: A cross-sectional study.

BACKGROUND: A high prevalence of epilepsy has been observed in the onchocerciasis-endemic focus of Mahenge, Tanzania. This study sought to assess the degree of disability experienced by persons with epilepsy (PWE) in Mahenge and identify associations with sociodemographic and clinical features. METHOD: This cross-sectional study was conducted in Mahenge, Tanzania, between February and July 2020. PWE were recruited from the Mahenge epilepsy clinic and four neighbouring rural villages (Mdindo, Mzogezi, Mzelezi and Sali). Data were collected using the 36-item version of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire for adults. For children aged 5-17 years, we used the Module on Child Functioning developed by UNICEF and the Washington Group. Questionnaires were administered by trained research assistants. Descriptive statistics were performed, and multivariable analyses (gamma and logistic regressions) were conducted. RESULTS: A total of 321 adults (45.5% males) and 48 children (55.3% males) with epilepsy participated. The overall median WHODAS 2.0 score was 4.8% (IQR: 0.9-18.9). The most affected disability domain was 'participating in the society' (median score: 12.5%, IQR: 0-29.2). Fifteen (31.3%) of the children with epilepsy had a disability in at least one domain of the child functioning module, with the 'accepting change' domain harbouring the highest proportion of disabled children (12.5%). Higher seizure frequency and longer epilepsy duration were associated with more disability. CONCLUSION: PWE in Mahenge experience variable degrees of disability. The affected domains indicate the need for societal rehabilitation of PWE in various community and/or social activities. Peer-support groups were instituted at the study sites to address these needs.

Mortality among persons with epilepsy in onchocerciasis-endemic and non-endemic areas of sub-Saharan Africa: A systematic review and meta-analysis.

PURPOSE: To document epilepsy-related mortality in sub-Saharan Africa (SSA) and investigate possible associations with onchocerciasis endemicity. METHODS: Systematic review with meta-analysis. Searches were performed in PubMed and Google Scholar (search terms: 'epilepsy'; 'mortality/death'; 'sub-Saharan Africa'). Included studies were classified as high-risk or low-risk for onchocerciasis based on documented endemicity data. Pooled mortality rates and annual case fatality rates (CFR) were calculated, and risk factors for mortality among persons with epilepsy (PWE) were investigated using meta-regression analysis. RESULTS: The 28 eligible studies reported 30 epilepsy surveys, of which 9 (30.0%) were conducted in onchocerciasis high-risk sites. The pooled epilepsy mortality rate was 20.9 (95% CI: 5.9-74.4) per 100,000 person-years, and the pooled CFR was 36.2 (95% CI: 23.9-54.4) per 1,000 PWE per year, albeit with substantial between-study heterogeneity. Compared to onchocerciasis low-risk sites, high-risk sites had higher pooled mortality (342.9 versus 10.0 per 100,000 PY; p<0.001) and CFR (57.0 versus 26.6 per 1,000 PWE per year; p = 0.001). Mortality of PWE was almost five-fold that of people without epilepsy (mortality risk ratio: 4.9; 95% CI: 3.5-6.8). Studies in onchocerciasis high-risk sites and the study which recruited only PWE with nodding syndrome were associated with higher CFR (p = 0.044 and p = 0.002, respectively). The leading causes of epilepsy-related death were status epilepticus (58.5%), drowning (15.7%), and sudden unexpected death in epilepsy (10.1%). CONCLUSION: Epilepsy mortality remains high in SSA. Most reported causes of death among PWE might be averted by improving seizure control. Better epilepsy prevention and care are urgently needed, particularly in onchocerciasis-endemic settings.

Quality of life of persons with epilepsy in Mahenge, an onchocerciasis-endemic area in Tanzania: A cross-sectional study.

OBJECTIVE: This study investigated the quality of life (QoL) of adults with epilepsy living in Mahenge, an onchocerciasis-endemic area in Tanzania with a high prevalence of onchocerciasis-associated epilepsy (OAE). METHODS: Between February and December 2020, persons with epilepsy (PWE) were recruited from four rural villages in Mahenge: Mdindo, Msogezi, Mzelezi, and Sali. For PWE who could not answer the questionnaire due to their mental or physical disability, a family member was asked to answer the questions instead. The Quality of Life in Epilepsy Inventory-31 (QOLIE-31) questionnaire used contained seven domains. The raw domain scores were transformed to 0-100% subscales, with higher scores indicating better QoL. The global QoL was calculated from the subscales using the overall QOLIE-31 score formula. RESULTS: In total, 96 PWE were enrolled in the study with a median age of 28 (range: 18-60) years, of whom 45 (47%) were male. The questionnaires were answered by PWE (54.8%) or one of their family members (45.2%). Most PWE were single (81%), and half never attended school. About two-thirds (65%) of PWE were suspected of having OAE, and a third (31%) had a history of head nodding seizures. Most PWE were treated with phenobarbital (85.4%) and had high treatment adherence (96.9%). Still, the number of seizures per week ranged from 0 to 7, with a median of one. The mean global QOLIE-31 score was 66.9 (range: 38.3-92.1) out of 100.0. Predictors of lower QoL were living in Sali Village and experiencing seizures the week before the interview. In contrast, completing primary school and switching to second-line anti-seizure medication were predictors of higher QoL. CONCLUSION: In order to improve the QoL of PWE in Mahenge, it is vital to optimize anti-seizure medication regimens to decrease the frequency of seizures and to increase the schooling of PWE.

Impact of a bi-annual community-directed treatment with ivermectin programme on the incidence of epilepsy in an onchocerciasis-endemic area of Mahenge, Tanzania: A population-based prospective study.

BACKGROUND: Community-directed treatment with ivermectin (CDTi) is used to eliminate onchocerciasis. However, despite 25 years of annual CDTi in Mahenge, Tanzania, the prevalence of onchocerciasis and onchocerciasis-associated epilepsy remained high in certain rural villages. Therefore, in 2019, bi-annual CDTi was introduced in the area. This study assessed the impact of the programme on the incidence of epilepsy in four villages. METHODOLOGY: Door-to-door epilepsy surveys were conducted prior to (2017/18) and after (2021) implementing a bi-annual CDTi program. All household members were screened for epilepsy symptoms using a validated questionnaire, and suspected cases were examined by a medical doctor to confirm/reject the diagnosis of epilepsy. The prevalence and annual incidence of epilepsy, including nodding syndrome, were calculated with 95% Wilson confidence intervals with continuity correction. The latter was also done for CDTi coverage in 2016 and 2021. RESULTS: Precisely 5,444 and 6,598 persons were screened for epilepsy before and after implementing the intervention. The CDTi coverage of the overall population was 82.3% (95%CI: 81.3-83.2%) in 2021 and sustained in both distribution rounds (81.5% and 76.8%). The coverage was particularly high in children and teenagers aged 6 to 18 years (93.2%, 95%CI: 92.1-94.2%). The epilepsy prevalence remained similar: 3.3% (95%CI: 2.9-3.9%) in 2017/18 versus 3.1% (95%CI: 2.7-3.5%) in 2021. However, the incidence of epilepsy declined from 177.6 (95%CI: 121.2-258.5) in 2015-2017 and 2016-2018 to 45.5 (95%CI: 22.2-89.7) in 2019-2021 per 100,000 persons-years. The incidence of probable nodding syndrome varied from 18.4 (95%CI: 4.7-58.5) to 5.1 (95%CI: 0.3-32.8). None of the nine incidence cases of epilepsy for which information on ivermectin intake was available took ivermectin in the year they developed their first seizures. CONCLUSION: A bi-annual CDTi programme should be implemented in areas with high prevalence of onchocerciasis and epilepsy. High CDTi coverage among children is particularly important to prevent onchocerciasis-associated epilepsy.

Nodding syndrome, a case-control study in Mahenge, Tanzania: Onchocerca volvulus and not Mansonella perstans as a risk factor.

BACKGROUND: Nodding syndrome (NS) has been consistently associated with onchocerciasis. Nevertheless, a positive association between NS and a Mansonella perstans infection was found in South Sudan. We aimed to determine whether the latter parasite could be a risk factor for NS in Mahenge. METHODS: Cases of epilepsy were identified in villages affected by NS in Mahenge, Tanzania, and matched with controls without epilepsy of the same sex, age and village. We examined blood films of cases and controls to identify M. perstans infections. The participants were also asked for sociodemographic and epilepsy information, examined for palpable onchocercal nodules and onchocerciasis-related skin lesions and tested for anti-Onchocerca volvulus antibodies (Ov16 IgG4) by ELISA. Clinical characteristics of cases and controls, O. volvulus exposure status and relevant sociodemographic variables were assessed by a conditional logistic regression model for NS and epilepsy status matched for age, sex and village. RESULTS: A total of 113 epilepsy cases and 132 controls were enrolled, of which, respectively, 56 (49.6%) and 64 (48.5%) were men. The median age in cases and controls was 28.0 (IQR: 22.0-35.0) and 27.0 (IQR: 21.0-33.3) years. Of the persons with epilepsy, 43 (38.1%) met the probable NS criteria and 106 (93.8%) had onchocerciasis-associated epilepsy (OAE). M. perstans infection was absent in all participants, while Ov16 seroprevalence was positively associated with probable NS (odds ratio (OR): 5.05, 95%CI: 1.79-14.27) and overall epilepsy (OR: 2.03, 95%CI: 1-07-3.86). Moreover, onchocerciasis-related skin manifestations were only found in the cases (n = 7, p = 0.0040), including persons with probable NS (n = 4, p = 0.0033). Residing longer in the village and having a family history of seizures were positively correlated with Ov16 status and made persons at higher odds for epilepsy, including probable NS. CONCLUSION: In contrast to O. volvulus, M. perstans is most likely not endemic to Mahenge and, therefore, cannot be a co-factor for NS in the area. Hence, this filaria is unlikely to be the primary and sole causal factor in the development of NS. The main risk factor for NS remains onchocerciasis.

Onchocerciasis-associated epilepsy in Maridi, South Sudan: Modelling and exploring the impact of control measures against river blindness.

BACKGROUND: Onchocerciasis, also known as "river blindness", is caused by the bite of infected female blackflies (genus Simuliidae) that transmit the parasite Onchocerca volvulus. A high onchocerciasis microfarial load increases the risk to develop epilepsy in children between the ages of 3 and 18 years. In resource-limited settings in Africa where onchocerciasis has been poorly controlled, high numbers of onchocerciasis-associated epilepsy (OAE) are reported. We use mathematical modeling to predict the impact of onchocerciasis control strategies on the incidence and prevalence of OAE. METHODOLOGY: We developed an OAE model within the well-established mathematical modelling framework ONCHOSIM. Using Latin-Hypercube Sampling (LHS), and grid search technique, we quantified transmission and disease parameters using OAE data from Maridi County, an onchocerciasis endemic area, in southern Republic of South Sudan. Using ONCHOSIM, we predicted the impact of ivermectin mass drug administration (MDA) and vector control on the epidemiology of OAE in Maridi. PRINCIPAL FINDINGS: The model estimated an OAE prevalence of 4.1% in Maridi County, close to the 3.7% OAE prevalence reported in field studies. The OAE incidence is expected to rapidly decrease by >50% within the first five years of implementing annual MDA with good coverage (≥70%). With vector control at a high efficacy level (around 80% reduction of blackfly biting rates) as the sole strategy, the reduction is slower, requiring about 10 years to halve the OAE incidence. Increasing the efficacy levels of vector control, and implementing vector control simultaneously with MDA, yielded better results in preventing new cases of OAE. CONCLUSIONS/SIGNIFICANCES: Our modeling study demonstrates that intensifying onchocerciasis eradication efforts could substantially reduce OAE incidence and prevalence in endemic foci. Our model may be useful for optimizing OAE control strategies.

Case definitions for onchocerciasis-associated epilepsy and nodding syndrome: A focused review.

Onchocerciasis-associated epilepsy (OAE) is an important but neglected public health problem in onchocerciasis-endemic areas with insufficient or inadequate onchocerciasis control. Hence, there is a need for an internationally accepted, easy-to-use epidemiological case definition of OAE to identify areas of high Onchocerca volvulus transmission and disease burden requiring treatment and prevention interventions. By including OAE as a manifestation of onchocerciasis, we will considerably improve the accuracy of the overall onchocerciasis disease burden, which is currently underestimated. Hopefully, this will lead to increased interest and funding for onchocerciasis research and control interventions, notably the implementation of more effective elimination measures and treatment and support for affected individuals and their families.

Epidemiology of epilepsy and relationship with onchocerciasis prevalence in villages of the Ntui Health District of Cameroon.

BACKGROUND: A strong association between epilepsy and onchocerciasis endemicity has been reported. We sought to document the epidemiology of epilepsy in onchocerciasis-endemic villages of the Ntui Health District in Cameroon and investigate how this relates to the prevalence of onchocerciasis. METHODS: In March 2022, door-to-door epilepsy surveys were conducted in four villages (Essougli, Nachtigal, Ndjame, and Ndowe). Ivermectin intake during the 2021 session of community-directed treatment with ivermectin (CDTI) was investigated in all participating village residents. Persons with epilepsy (PWE) were identified through a two-step approach: administration of a 5-item epilepsy screening questionnaire followed by clinical confirmation by a neurologist. Epilepsy findings were analyzed together with onchocerciasis epidemiological data previously obtained in the study villages. RESULTS: We surveyed 1663 persons in the four study villages. The 2021 CDTI coverage for all study sites was 50.9%. Overall, 67 PWE were identified (prevalence of 4.0% (IQR: 3.2-5.1) with one new-onset case during the past 12 months (annual incidence of 60.1 per 100,000 persons). The median age of PWE was 32 years (IQR: 25-40), with 41 (61.2%) being females. The majority (78.3%) of PWE met the previously published criteria for onchocerciasis-associated epilepsy (OAE). Persons with a history of nodding seizures were found in all villages and represented 19.4% of the 67 PWE. Epilepsy prevalence was positively correlated with onchocerciasis prevalence (Spearman Rho = 0.949, p = 0.051). Meanwhile, an inverse relationship was observed between distance from the Sanaga river (blackfly breeding site) and the prevalence of both epilepsy and onchocerciasis. CONCLUSION: The high epilepsy prevalence in Ntui appears to be driven by onchocerciasis. It is likely that decades of CDTI have likely contributed to a gradual decrease in epilepsy incidence, as only one new case occurred in the past year. Therefore, more effective elimination measures are urgently needed in such endemic areas to curb the OAE burden.

Evaluating post-treatment Loa loa microfilarial densities to classify serious adverse events caused by ivermectin: a retrospective analysis.

BACKGROUND: The elimination of onchocerciasis requires increasing ivermectin treatment coverage in communities hypoendemic for onchocerciasis. In areas where loiasis is co-endemic, this approach is complicated by the risk of serious adverse events following treatment with ivermectin in individuals with a high Loa loa microfilarial density (MFD). We aimed to evaluate the extent to which the pre-treatment MFD can be inferred from post-treatment MFDs. METHODS: For this retrospective analysis, we used data from seven clinical or community trials (six were used for the main analysis and one for the secondary analysis) conducted in Cameroon, in which MFDs were measured both before and after (within 14 days) receiving a single dose of ivermectin (150-200 µg/kg bodyweight). The primary objective was to establish the receiver operating characteristic curves and the corresponding area under the curve statistics of MFD measured after treatment to classify pre-treatment MFD (MFDD0) according to common risk thresholds of serious adverse events. We assessed the performance of post-treatment MFD to accurately classify MFDD0 according to commonly used thresholds using bootstrap procedures. FINDINGS: 281 individuals with MFD measurements available before and 3-10 days after ivermectin treatment were enrolled. Our results show that an MFD of more than 3500 L loa microfilariae per mL of blood (mf per mL) 3 or 4 days after treatment indicates a 68·6% chance (positive predictive value) of an MFDD0 of more than 20 000 mf per mL. An MFD of more than 3500 mf per mL at day 5-10 corresponds to a 72·2% chance of having an MFDD0 of more than 20 000 mf per mL. Conversely, an MFD of less than 2500 microfilariae per mL at day 3-4 or day 5-10 corresponds to a probability of 92·3% or 92·8% (negative predictive value) of having MFDD0 of less than 20 000 mf per mL. An MFD less than 1500 mf per mL on days 3-4 after treatment was associated with a 78·3% probability of having an MFDD0 less than 8000 mf per mL; this probability increased to 89·6% on days 5-10 after treatment. INTERPRETATION: The MFD threshold of 1000 mf per mL within 1 month of treatment, which is commonly used to attribute the occurrence of a serious adverse event to ivermectin, should be revised. In this study, we present tables that can help to assess this attributability as part of mass or individual treatments. FUNDING: None.

Comparison of Structural Changes in Nodding Syndrome and Other Epilepsies Associated With Onchocerca volvulus.

BACKGROUND AND OBJECTIVE: Nodding syndrome (NS) is a unique childhood-onset epileptic disorder that occurs predominantly in several regions of sub-Saharan Africa. The disease has been associated with Onchocerca volvulus (Ov)-induced immune responses and possible cross-reactivity with host proteins. The aim of this study was to compare structural changes in the brain on MRI between NS and other forms of onchocerciasis-associated epilepsies (OAEs) and to relate structural changes to the Ov-induced immune responses and level of disability. METHODS: Thirty-nine children with NS and 14 age-matched participants with other forms of OAE from an endemic region in Uganda underwent detailed clinical examination, serologic evaluation (including Ov-associated antibodies to Ov-16 and Hu-leiomodin-1) and quantitative volumetric analysis of brain MRIs (1.5 T scanner) using Neuroreader, a cloud-based software. RESULTS: Cerebral and cerebellar atrophy were the predominant features in both NS and OAE. On quantitative volumetric analysis, participants with NS had larger ventricular volumes compared with participants with OAE, indicative of increased global cortical atrophy (pcorr = 0.036). Among children with NS, severe disability correlated with higher degree of atrophy in the gray matter volume (pcorr = 0.009) and cerebellar volume (pcorr = 0.009). NS cases had lower anti-Ov-16 IgG signal-to-noise ratios than the OAE cases (p < 0.01), but no difference in the levels of the Hu-leiomodin-1 antibodies (p = 0.64). The levels of Ov-associated antibodies did not relate to the degree of cerebral or cerebellar atrophy in either NS or OAE cases. DISCUSSION: This is the first study to show that cerebral and cerebellar atrophy correlated with the severity of NS disability, providing an imaging marker for these endemic epileptic disorders that until now have remained poorly characterized. Both NS and OAE have cerebral and cerebellar atrophy, and the levels of Ov-associated antibodies do not seem to be related to the structural changes on MRI.

Onchocerciasis-associated epilepsy: an update and future perspectives.

Onchocerciasis-associated epilepsy (OAE) is an important neglected public health problem in areas with high ongoing onchocerciasis transmission. The risk that children in such areas develop epilepsy is related to their Onchocerca volvulus microfilarial (mf) load. Before the implementation of mass treatment with ivermectin, microfilariae were detected in cerebrospinal fluid (CSF). More recently, neither O. volvulus microfilariae nor DNA were detected in CSF or brain tissue; however, these samples were obtained years after seizure onset. It is possible that during fever-induced increased blood-brain barrier permeability, microfilariae enter the brain and, upon dying, cause an inflammatory reaction inducing seizures. Including OAE in the onchocerciasis disease burden estimation may mobilise extra resources for onchocerciasis disease elimination and treatment/care of OAE-affected persons/families.